Pd(II)-Catalyzed, Picolinamide-Aided γ-(sp²)-C–H Functionalization of Racemic and Enantiopure α-Methylbenzylamine and Phenylglycinol Scaffolds

Abstract

In this paper, we report the Pd(II)-catalyzed, picolinamide DG-aided sp² γ-C–H functionalization and expansion of the library of enantiopure α-methylbenzylamine and phenylglycinol scaffolds. We have shown the synthesis of a wide range of racemic and enantiopure ortho-C–H arylated, alkylated, brominated, and iodinated α-methylbenzylamine and phenylglycinol scaffolds. Various racemic and R and S (chiral) sp² γ-C–H functionalized α-methylbenzylamine and phenylglycinol scaffolds were synthesized with good enantiopurities. Racemic and enantiopure α-methylbenzylamine and phenylglycinol derivatives are important building blocks in organic synthesis and medicinal chemistry. Accordingly, this work contributes to the expansion of the libraries of α-methylbenzylamine and phenylglycinol motifs and substrate scope development through the Pd(II)-catalyzed bidentate directing group picolinamide-aided site-selective C–H activation and functionalization method.

From the last decade of the 20th century, we have witnessed rapid developments in the transition-metal-catalyzed C–H activation and functionalization of organic compounds.[1] [2] [3] [4] The regio- or site-selective functionalization of organic molecules has been achieved by using the directing group-aided (chelation-assisted) C–H activation/functionalization protocol.[1–4] In particular, the Pd(II)-catalyzed bidentate directing group-aided functionalization (e.g., arylation, alkylation, halogenation, amidation, oxygenation, etc) is emerging as a valuable method in organic synthesis.[4] Elaboration of the substrate scope in the bidentate directing group-aided site-selective C–H functionalization has been a persistent objective.[4] [5] [6] [7] [8] [9] [10] [11] [12]

In a continuation to our interest in expanding substrate scope in the directing group-aided C–H functionalization,[8] we became interested in expanding the library of enantiopure α-methylbenzylamine and phenylglycinol scaffolds via the DG-aided sp² γ-C–H functionalization. A literature survey revealed that there exist a limited number of reports dealing with the Pd(II)-catalyzed directing group-aided functionalization of α-methylbenzylamine and aromatic amino alcohol such as phenylglycinol (Figure [1]).

Ilies/Nakamura[9a] and Ackermann[9b] reported the preparation of a few examples of sp² γ-C–H alkylated/arylated racemic α-methylbenzylamines (1a) by using organometallic reagents. Next, a few examples of sulfenylation[9c] and alkylation[9e] (Daugulis), benzoylation[9d] (Zeng), silylation/germanylation[9f] (Wen/Zhao), fluorination[9g] (Zhao) affording the corresponding racemic α-methylbenzylamines (1a) were reported. A few examples of carbonylation[9i] (Zhao/Shi) and alkenylation[9h] [j] (Daugulis and Grigorjeva), affording the corresponding racemic α-methylbenzylamine derivatives (1b and 1c), were also reported. On similar lines, a few instances of germanylation[9f] (Wen/Zhao), fluorination[9g] (Zhao), affording the corresponding racemic phenylglycinol (1d), and carbonylation[9i] [10] (Zhao/Shi, Li/Wang and Grigorjeva), affording the corresponding racemic phenylglycinol derivatives (1c, 1e and 1f), were reported (Figure [1]).

There exist rare reports that describe dispersed examples of Pd(II)-catalyzed, DG-aided sp² γ-C–H functionalization of enantiopure α-methylbenzylamine and phenylglycinol scaffolds. Examples of alkynylation[11a] (Balaraman) alkylation[11b] (Chen) and sulfonylation[11c] (Samanta), affording the corresponding enantiopure α-methylbenzylamine derivatives (1g), were reported. Ilies/Nakamura disclosed[9a] [d] sp² γ-C–H methylation, affording enantiopure α-methylbenzylamine (1h), using AlMe₃. A few examples of carbonylation[11e] (Zhong) and alkenylation[11f] (Carretero), affording the corresponding enantiopure α-methylbenzylamine derivatives (1i and 1j), were reported. Furthermore, instances of carbonylation[10b] (Grigorjeva) and alkenylation[9j] (Grigorjeva), affording the corresponding enantiopure phenylglycinol products (1i and 1k), were reported.

The available reports reveal that the investigations on the sp² γ-C–H functionalization of enantiopure α-methylbenzylamine and phenylglycinol scaffolds are limited (Figure [1]). Nevertheless, the arylation and methylation of racemic α-methylbenzylamine have been performed with organometallic reagents. Apart from the attempts and examples that have been shown in Figure [1], to our knowledge, there exists no literature precedent for the Pd(II)-catalyzed picolinamide DG-aided arylation, benzylation and halogenation of ortho C–H bonds of enantiopure α-methylbenzylamine and phenylglycinol scaffolds.[4] [5] [6] [7] [8] [9] [10] [11] [12] Accordingly, we started our investigation to expand the library of enantiopure α-methylbenzylamine and phenylglycinol scaffolds via the picolinamide DG-aided sp² γ-C–H functionalization. During our involvement in the picolinamide DG-aided ortho C–H functionalization of enantiopure α-methylbenzylamine and phenylglycinol scaffolds, Grigorjeva revealed[9j] [10b] examples of cobalt-catalyzed carbonylation and alkenylation affording the corresponding enantiopure phenylglycinol derivatives 1i and 1k. Consequently, we disclosed[12] our preliminary works on the palladium(II)-catalyzed picolinamide-aided sp² γ-C–H functionalization of phenylglycinols. In this full paper, we now report our efforts toward expanding the library of both racemic and enantiopure α-methylbenzylamine and phenylglycinol scaffolds via the DG-aided sp² γ-C–H functionalization.

The α-methylbenzylamine and phenylglycinol scaffolds are important molecules in organic synthesis and medicinal chemistry.[13] [14] [15] Various α-methylbenzylamines and phenylglycinols are being used as versatile ligands, chiral auxiliaries, and building blocks in the synthesis of natural products and bioactive/drug molecules (Figure [2]).[13–15]

To begin our investigations on the Pd(II)-catalyzed, directing group-aided sp² γ-C–H functionalization of α-methylbenzylamine and phenylglycinol scaffolds, initially we prepared suitable DG-linked α-methylbenzylamine- and phenylglycinol-based substrates (Figure [3]). Accordingly, various racemic α-methylbenzylamines and phenylglycinols were linked with 2-picolinic acid (PA) to afford the racemic α-methylbenzylamine and phenylglycinol substrates 3a–d-(RS) and 4a–c-(RS) possessing picolinamide DG. Next, α-methylbenzylamine and phenylglycinol were linked with 5-methylisoxazole-3-carboxylic acid (MICA), pyrazine-2-carboxylic acid, quinoline-2-carboxylic acid, cyclopentanecarboxylic acid, and benzoic acid to afford the corresponding substrates 3e–h-(RS) and 4d–g-(RS). Subsequently, enantiopure (R) and (S) α-methylbenzylamines were linked with 2-picolinic acid and 5-methylisoxazole-3-carboxylic acid to afford the corresponding enantiopure α-methylbenzylamine substrates 3a–c-(R), 3e-(R), 3a–c-(S) and 3e-(S). Furthermore, (R) and (S) phenylglycinols were linked with 2-picolinic acid to afford the corresponding enantiopure phenylglycinol substrates 4a-(R) and 4a-(S).

Optimization reactions comprising the picolinamide-aided γ-C(sp²)–H arylation of racemic α-methylbenzylamine substrate 3a-(RS) with an aryl iodide 5a in the presence of various Pd(II) catalysts, silver salt additives, and solvents are summarized in Table [1]. Generally, it is required to use a halide ion scavenger in the Pd(II)-catalyzed bidentate directing group-aided C–H arylation reactions. Thus, reactions were carried out by using silver salts such as AgOAc, Ag₂CO₃ or the alkali metal-based salts such as K₂CO₃, KOAc, etc.[4] [5b] [g] These salt additives function as the I^– (iodide anion) scavenger and this process helps to regenerate the Pd(II) catalyst in the proposed Pd^II–Pd^IV catalytic cycle.[4] [5b] [g] Generally, the use of silver salts is found to afford the C–H arylated products in good yields.[4] [5b] [g] The arylation of 3a-(RS) with 5a (4 equiv) in the presence of only the AgOAc additive or Pd(OAc)₂ catalyst did not yield the expected mono or bis C–H arylated product 6a-(RS) or 7a-(RS) (entries 1 and 2). Heating the substrate 3a-(RS) in the presence of the Pd(OAc)₂ catalyst (5 mol%) and AgOAc additive (1 equiv) in toluene at 110 °C was found to afford the bis C–H arylated product 7a-(RS) in 40% yield (entry 3). The same reaction with using other additives such as Ag₂CO₃ or K₂CO₃ or KOAc or PhI(OAc)₂ did not afford the product 7a-(RS) in good yield (entries 4–7).

Table 1 Optimization of Reaction Conditions: Pd(II)-Catalyzed γ-C(sp²)–H Arylation of α-Methylbenzylamine Substrate 3a-(RS)

Entry	PdL2	Additive	Solvent	T (°C)	Yield of 7a-(RS) (%)a,l
1	–	AgOAc	toluene	110	0
2	Pd(OAc)2	nil	toluene	110	0
3b	Pd(OAc)2	AgOAc	toluene	110	40
4	Pd(OAc)2	Ag2CO3	toluene	110	0
5	Pd(OAc)2	K2CO3	toluene	110	<5
6	Pd(OAc)2	KOAc	toluene	110	20
7	Pd(OAc)2	PhI(OAc)2	toluene	110	0
8	PdCl2	AgOAc	toluene	110	33
9	Pd(TFA)2	AgOAc	toluene	110	21
10	Pd(MeCN)2Cl2	AgOAc	toluene	110	20
11	Pd(OAc)2	AgOAc	1,2-DCE	80	20
12	Pd(OAc)2	AgOAc	1,4-dioxane	100	0
13	Pd(OAc)2	AgOAc	t-BuOH	85	10
14	Pd(OAc)2	AgOAc	t-AmylOH	110	35
15c,d	Pd(OAc)2	AgOAc	toluene	110	<5
16e	Pd(OAc)2	AgOAc	toluene	110	10
17f	Pd(OAc)2	AgOAc	toluene	110	15
18g	Pd(OAc)2	AgOAc	toluene	110	36
19h	Pd(OAc)2	AgOAc	toluene	110	60
20	Pd(OAc)2	AgOAc	toluene	110	83
21i	Pd(OAc)2	AgOAc	toluene	110	0
22j	Pd(OAc)2	AgOAc	toluene	110	0
23k	Ni(OTf)2	Na2CO3	toluene	160	0

^a Reactions were performed using 3a-(RS) (0.25 mmol) and 5a (1 mmol) unless otherwise noted.

^b 0.25 mmol AgOAc.

^c 0.2 mmol of 3a-(RS) and 0.05 mmol of 5a.

^d 0.2 mmol of 3a-(RS) and 0.1 mmol of 5a.

^e 0.2 mmol of 3a-(RS) and 0.15 mmol of 5a.

^f 0.25 mmol of 3a-(RS) and 0.25 mmol of 5a.

^g 0.25 mmol of 3a-(RS) and 0.5 mmol of 5a.

^h 0.25 mmol of 3a-(RS) and 0.75 mmol of 5a.

ⁱ p-Anisyl bromide was used.

^j p-Anisyl chloride was used.

^k In a sealed tube.

^l 6a-(RS) was not obtained in sufficient amounts for characterization.

Heating a mixture of substrate 3a-(RS) in the presence of 5 mol% of PdCl₂ or Pd(TFA)₂ or Pd(MeCN)₂Cl₂ and AgOAc (2.2 equiv) yielded the bis C–H arylated product 7a-(RS) in 20–33% yields (Table [1], entries 8–10). The arylation of 3a-(RS) in the presence of 5 mol% of Pd(OAc)₂ and AgOAc was tried in solvents such as 1,2-DCE or 1,4-dioxane or t-BuOH or t-AmylOH and these trials afforded the bis C–H arylated product 7a-(RS) in 0–35% yields (entries 11–14). To find out whether the mono arylated product 6a-(RS) can be obtained, we performed the arylation of 3a-(RS) by using 0.25 or 0.5 or 0.75 equiv of 5a (entries 15 and 16). The trials were not fruitful and did not give the mono arylated product 6a-(RS) in amounts that were sufficient for characterization, and afforded only the product 7a-(RS) in <5–10% yields. Next, the arylation of 3a-(RS) with 1 or 2 or 3 equiv of aryl iodide (5a) in the presence of 5 mol% of Pd(OAc)₂ and AgOAc in toluene at 110 °C afforded the bis C–H arylated product 7a-(RS) in 15–60% yields (entries 17–19). The arylation of 3a-(RS) with 4 equiv of aryl iodide (5a) in the presence of Pd(OAc)₂ (5 mol%) and AgOAc (2.2 equiv) in toluene at 110 °C was found to afford the bis C–H arylated product 7a-(RS) in a maximum of 83% yield (entry 20). The arylation of 3a-(RS) with p-anisyl bromide or p-anisyl chloride instead of 5a did not yield the product 7a-(RS). Further, the arylation of 3a-(RS) with 5a in the presence of Ni(OTf)₂ instead of Pd(OAc)₂ did not yield the product 7a-(RS) (entries 21–23). Column chromatography purification of the corresponding crude reaction mixtures did not yield the expected mono C–H arylated product 6a-(RS) in amounts sufficient for characterization in any of the reactions.

Having established optimized conditions, we then wished to investigate the substrate scope and generality of this protocol comprising the Pd(II)-catalyzed, picolinamide-aided γ-C(sp²)–H functionalization of racemic and enantiopure α-methylbenzylamines and phenylglycinols. Before performing the arylation of enantiopure α-methylbenzylamine and phenylglycinol substrates, we performed the arylation of the corresponding racemic α-methylbenzylamine and phenylglycinol substrates. In this regard, Scheme [1] shows the Pd(OAc)₂-catalyzed, AgOAc-promoted picolinamide directing group-aided γ-C(sp²)–H arylation of various racemic α-methylbenzylamine and phenylglycinol derivatives with a variety of aryl iodides.

At first, we performed the arylation of substate 3a-(RS) with aryl iodides containing different substituents at the para position in the presence of Pd(OAc)₂ (5 mol%) and AgOAc (2.2 equiv) in toluene at 110 °C. These reactions afforded the corresponding bis ortho C–H arylated α-methylbenzylamine derivatives 7a–g-(RS) in 53–92% yields (Scheme [1]). The Pd(II)-catalyzed picolinamide-aided arylation of 3a-(RS) with disubstituted aryl iodides afforded the corresponding bis ortho-C–H arylated α-methylbenzylamine derivatives 7h–j-(RS) in 68–92% yields. Subsequently, we performed the Pd(OAc)₂-catalyzed AgOAc-promoted γ-C(sp²)-H arylation of racemic phenylglycinol substrate 4a-(RS) with aryl iodides possessing different substituents at the m/p positions. These reactions gave the corresponding bis ortho-C–H arylated phenylglycinol derivatives 8a–o-(RS) in 60–95% yields. Next, the arylation of substrate 4a-(RS) with different disubstituted aryl iodides and 5-iodoindole afforded the corresponding bis ortho-C–H arylated phenylglycinol derivatives 8p–s-(RS) and 8za-(RS) in 42–88% yields.

We then performed the Pd(OAc)₂-catalyzed, AgOAc-promoted, picolinamide-aided γ-C(sp²)–H arylation α-methylbenzylamine substrates 3b-(RS) and 3c-(RS) containing a substituent at the para position with phenyl iodide and 5a. These reactions afforded the corresponding bis ortho-C–H arylated α-methylbenzylamine derivatives 7k-(RS) and 7l-(RS) in 58–62% yields (Scheme [2]). The Pd(II)-catalyzed picolinamide-aided γ-C(sp²)–H arylation α-ethylbenzylamine substrate 3d-(RS) with 5a afforded the bis ortho-C–H arylated α-ethylbenzylamine derivative 7m-(RS) in a poor yield (30%). The Pd(II)-catalyzed, picolinamide-aided arylation of o-/p-chlorophenylglycinol substrates 4b-(RS) and 4c-(RS), with different aryl iodides, was found to afford the corresponding ortho-C–H arylated phenylglycinol derivatives 8t–w-(RS) in 43–90% yields.

Having performed the Pd(II)-catalyzed arylation reactions by using the picolinamide directing group, next we wished to test the γ-C(sp²)–H arylation of α-methylbenzylamine and phenylglycinol substrates by using different directing groups. We performed the Pd(II)-catalyzed arylation of α-methylbenzylamine and phenylglycinol substrates 3e-(RS) and 4d-(RS), containing the 5-methylisoxazole-3-carboxamide (MICA) directing group. Accordingly, the Pd(II)-catalyzed MICA DG-aided arylations of 3e-(RS) and 4d-(RS) afforded the corresponding ortho-C–H arylated α-methylbenzylamine and phenylglycinol derivatives 7n-(RS) and 8x-(RS) in 59–67% yields (Scheme [2]).

Table 2 Optimization of Reaction Conditions: Pd(II)-Catalyzed γ-C(sp²)–H Arylation of Enantiopure Phenylglycinol Substrate 4a-(R)

Entry	PdL2	5e (mmol)	Additive	T (°C)	Yield 8aa-(R) (%)	Yield 8a-(R) (%)
1	Pd(OAc)2	0.3	AgOAc	110	7	60
2a	Pd(OAc)2	0.3	AgOAc	110	0	16
3b	Pd(OAc)2	0.3	AgOAc	110	8	42
4c	Pd(OAc)2	0.3	AgOAc	110	10	56
5	PdCl2	0.3	AgOAc	110	traces	26
6	Pd(TFA)2	0.3	AgOAc	110	23	25
7	Pd(AcAc)2	0.3	AgOAc	110	0	0
8	PdCl2(Ph3P)2	0.3	AgOAc	110	0	0
9	PdCl2(MeCN)2	0.3	AgOAc	110	7	31
10	PdCl2(PhCN)2	0.3	AgOAc	110	traces	30
11	Pd(dba)2	0.3	AgOAc	110	traces	22
12	Pd(OAc)2	0.3	Ag2CO3	110	<5	30
13	Pd(OAc)2	0.3	Ag2O	110	0	8
14	Pd(OAc)2	0.3	PhI(OAc)2	110	0	0
15	Pd(OAc)2	0.3	K2CO3	110	18	13
16d	Pd(OAc)2	0.3	KOAc	110	41	20
17e	Pd(OAc)2	0.3	AgOAc	100	8	25
18f	Pd(OAc)2	0.3	AgOAc	100	7	28
19	Pd(OAc)2	0.3	AgOAc	130	10	50
20g	Pd(OAc)2	0.3	AgOAc	130	10	65
21	Pd(OAc)2	0.8	AgOAc	110	traces	70
22h	Pd(OAc)2	0.8	AgOAc	130	traces	96

^a Pd(OAc)₂ (5 mol%).

^b PivOH (0.04 mmol).

^c (BnO)₂PO₂H (0.04 mmol).

^d 8aa-(R) (ee 96%) was obtained from 4a-(R) (ee 98%). Furthermore, we also prepared the corresponding mono-arylated product 8aa-(S) (37%, ee 95%) from 4a-(S) (ee 98%) using the conditions given in entry 16. Additionally, we prepared the corresponding racemic mono-arylated product 8aa-(RS) (35%) from 4a-(RS) using the conditions in entry 16.

^e t-AmylOH.

^f 1,4-Dioxane.

^g p-Xylene.

^h 8a-(R) (ee >97%) was obtained from 4a-(R) (ee 98%).

Next, the Pd(II)-catalyzed arylation of α-methylbenzylamine and phenylglycinol substrates 3f-(RS) and 4f-(RS), containing the pyrazine-2-carboxamide directing group, were performed. These reactions afforded the corresponding mono ortho-C–H arylated α-methylbenzylamine derivative 7o-(RS) and bis ortho-C–H arylated phenylglycinol derivative 8y-(RS) in low yields (<10–26%). The Pd(II)-catalyzed arylation of α-methylbenzylamine and phenylglycinol substrates 3g-(RS) and 4e-(RS), containing the quinoline-2-carboxamide directing group, did not yield the corresponding products 7p-(RS) and 8z-(RS). Similarly, the Pd(II)-catalyzed arylation of α-methylbenzylamine and phenylglycinol substrates 3h-(RS) and 4g-(RS), containing the simple amide directing groups, did not yield the corresponding products 7q-(RS) and 8zb-(RS). Overall, the reactions shown in Table [1], Scheme [1] and the screening of various directing groups (Scheme [2]), indicated that picolinamide is a better directing group for the γ-C(sp²)–H arylation of α-methylbenzylamine and phenylglycinol substrates.

We then paid attention to establishing the arylation of enantiopure α-methylbenzylamine and phenylglycinol substrates and synthesis of libraries of enantiopure γ-C(sp²)–H functionalized α-methylbenzylamine and phenylglycinol derivatives. Initially, we optimized reaction conditions to find suitable conditions that will afford enantiopure γ-C(sp²)–H arylated phenylglycinol derivative. In this regard, we carried out the picolinamide-aided arylation of enantiopure phenylglycinol substrate 4a-(R) (0.2 mmol) with aryl iodide 5e (1.5 equiv) in the presence of the Pd(OAc)₂ catalyst (10 mol%) and AgOAc as an additive (iodide ion scavenger)[4] [5b] [g] in toluene at 110 °C for 24 h. This reaction was found to yield the bis γ-C(sp²)–H arylated phenylglycinol derivative 8a-(R) in 60% yield and the mono γ-C(sp²)–H arylated phenylglycinol derivative 8aa-(R) in 7% yield. Then, we performed the same reaction by using 5 mol% of the Pd(OAc)₂ catalyst, which afforded the bis γ-C(sp²)–H arylated phenylglycinol derivative 8a-(R) in 16% yield (Table [2], entries 1 and 2).

Next, we performed the Pd(II)-catalyzed ortho C–H arylation of enantiopure substrate 4a-(R) by using some additional additives or different iodide ion scavenging additives instead of AgOAc and various Pd catalysts. Accordingly, as shown in Table [2] (entries 3–16) the attempts yielded the bis γ-C(sp²)–H arylated phenylglycinol derivative 8a-(R) in 0–56% yields and the mono γ-C(sp²)–H arylated phenylglycinol derivative 8aa-(R) in 0–41% yields, respectively. Notably, the reaction involving KOAc as an additive yielded the mono γ-C(sp²)–H arylated phenylglycinol derivative 8aa-(R) in a maximum of 41% yield (entry 16). The Pd(II)-catalyzed ortho C–H arylation of enantiopure substrate 4a-(R) in t-AmylOH or 1,4-dioxane solvent afforded the products 8aa-(R)/8a-(R) in low yields (entries 17 and 18).

Next, we performed the Pd(II)-catalyzed, AgOAc-promoted ortho C–H arylation of enantiopure substrate 4a-(R) with 5e in toluene or p-xylene solvent at 130 °C. These reactions yielded the bis γ-C(sp²)–H arylated phenylglycinol derivative 8a-(R) in 50–65% yields and the mono γ-C(sp²)–H arylated phenylglycinol derivative 8aa-(R) in 10% yield (Table [2], entries 19 and 20). Finally, we performed the Pd(II)-catalyzed AgOAc-promoted C–H arylation of enantiopure substrate 4a-(R) by using 4 equiv of 5e in toluene (at 110 °C) or p-xylene (at 130 °C). These reactions selectively yielded the enantiopure bis γ-C(sp²)–H arylated phenylglycinol derivative 8a-(R) in 70–96% yields with only traces of the mono γ-C(sp²)–H arylated phenylglycinol derivative 8aa-(R) (entries 21 and 22).

After the optimization reactions, we then wished to expand the substrate scope in synthesizing various enantiopure γ-C(sp²)–H arylated α-methylbenzylamine and phenylglycinol products. At first, the Pd(OAc)₂-catalyzed, AgOAc-promoted γ-C(sp²)–H arylation of the enantiopure α-methylbenzylamine substrates 3a-(R), 3b-(R), and 3c-(R), phenylglycinol substrate 4a-(R), possessing the picolinamide (PA) directing group, and 3e-(R), having the MICA directing group, were carried out. The arylation of enantiopure 3a-(R) with aryl iodides containing different substituents at the para position and disubstituted aryl iodides, afforded the corresponding enantiopure bis C–H arylated α-methylbenzylamine derivatives 7a,b,d–j-(R) in 56–91% yields with good enantiopurities (ee 89–98%, Scheme [3]). Similarly, the enantiopure bis C–H arylated α-methylbenzylamine derivatives 7k-(R) and 7l-(R) were obtained in 58–59% yields (ee 94–95%) from their corresponding α-methylbenzylamine substrates 3b-(R) and 3c-(R), containing a substituent at the para position. The arylation of enantiopure α-methylbenzylamine substrate 3e-(R) possessing the MICA directing group yielded the enantiopure bis C–H arylated α-methylbenzylamine derivative 7n-(R) in 51% yield (ee 95%, Scheme [3]).

Subsequently, the Pd(II)-catalyzed picolinamide-aided arylation of enantiopure phenylglycinol substrate 4a-(R) was carried out using various aryl iodides containing different substituents at the meta/para positions and disubstituted aryl iodides. These reactions yielded the corresponding enantiopure bis C–H arylated phenylglycinol derivatives 8a,c,j,k,l,p,s-(R) in 72–96% yields with good enantiopurities (ee 91–98%, Scheme [3]).

Next, we performed the Pd(II)-catalyzed, picolinamide-aided arylation reactions using the substrates prepared from (S)-α-methylbenzylamine and (S)-phenylglycinol substrates (Scheme [4]). Accordingly, the corresponding enantiopure bis C–H arylated α-methylbenzylamine derivatives 7a,b,d–j-(S) were obtained in 52–89% yields with good enantiopurities (ee 92–98%) from the γ-C(sp²)–H arylation of enantiopure α-methylbenzylamine substrate 3a-(S) (Scheme [4]). The enantiopure bis C–H arylated α-methylbenzylamine derivatives 7k-(S) and 7l-(S) were obtained in 60–63% yields (ee 97 to >98%) from their corresponding substrates 3b-(S) and 3c-(S), containing a substituent at the para position. The arylation of enantiopure substrate 3e-(S), possessing the MICA directing group, yielded the enantiopure bis C–H arylated α-methylbenzylamine derivative 7n-(S) in 54% yield (ee 95%, Scheme [4]). Furthermore, the corresponding bis C–H arylated phenylglycinol derivatives 8a,e,j,p,s-(S) were obtained in 76–95% yields with good enantiopurities (ee 90 to >98%) from the arylation of enantiopure phenylglycinol substrate 4a-(S) (Scheme [4]).

We extended the scope of this protocol concerning the γ-C(sp²)–H functionalization of enantiopure α-methylbenzylamine and phenylglycinol substrates by attempting the alkylation/benzylation, bromination and iodination reactions. An initial attempt involving the Pd(II)-catalyzed alkylation of phenylglycinol substrate 4a-(RS) with alkyl iodide 9a afforded the mono γ-C(sp²)–H alkylated product 10a-(RS) in 42% yield (Scheme [5]). This observation is in concurrence with the previous report by Jiang. Jiang reported[6d] a few examples of picolinamide-aided ortho-C–H alkylation of phenylglycine substrate, which selectively yielded the mono C–H alkylated phenylglycines in 42–50% yields. On the other hand, the Pd(II)-catalyzed benzylation of phenylglycinol substrate 4a-(RS) with benzyl bromide 9b afforded the bis γ-C(sp²)–H benzylated product 10b-(RS) in 71% yield.

Subsequently, we performed the Pd(II)-catalyzed alkylation of enantiopure phenylglycinol substrates 4a-(R) and 4a-(S) with alkyl iodide 9a. These attempts afforded the corresponding mono γ-C(sp²)–H alkylated phenylglycinols 10a-(R) and 10a-(S) in 45–46% yields with good enantiopurities (ee 97–98%, Scheme [5]). The Pd(II)-catalyzed benzylation of enantiopure phenylglycinol substrate 4a-(R) with benzyl bromide 9b yielded bis γ-C(sp²)–H benzylated phenylglycinol 10b-(R) in 46% yield with good enantiopurity (ee 94%, Scheme [5]). Similarly, the Pd(II)-catalyzed benzylation of enantiopure α-methylbenzylamine substrate 3a-(R) with benzyl bromides 9c,d yielded the corresponding enantiopure bis γ-C(sp²)–H benzylated α-methylbenzylamines 11a-(R) and 11b-(R) in 47–58% yields with good enantiopurities (ee 92–98%, Scheme [5]). To establish the HPLC profile of 11a-(R) and 11b-(R), the corresponding racemic bis γ-C(sp²)–H benzylated α-methylbenzylamines 11a-(RS) and 11b-(RS) were also obtained in 55–56% yields via the Pd(OAc)₂-catalyzed, AgOAc-promoted γ-C(sp²)–H benzylation of 3a-(RS). Earlier, Daugulis reported[9e] the picolinamide-aided alkylation and benzylation of racemic α-methylbenzylamine by using the combination of Pd(OAc)₂ (10 mol%) and CuBr₂ (20 mol%) in the presence of K₂CO₃.

We then attempted the Pd(II)-catalyzed, picolinamide-aided ortho C–H bromination and iodination of racemic and enantiopure α-methylbenzylamine and phenylglycinol substrates (Scheme [6]). The Pd(II)-catalyzed bromination and iodination of racemic α-methylbenzylamine substrates 3a-(RS), 3b-(RS) and 3c-(RS) with NBS or NIS yielded the corresponding racemic bis γ-C(sp²)–H brominated and iodinated α-methylbenzylamine derivatives 12a,c,d-(RS) and 12b,e,f-(RS) in 51–88% yields (Scheme [6]). The X-ray structure analysis unambiguously confirmed the structure of a representative γ-C(sp²)–H iodinated α-methylbenzylamine derivative 12e-(RS).[16] Subsequently, the Pd(II)-catalyzed ortho C–H bromination and iodination of enantiopure α-methylbenzylamine substrates 3a-(R) and 3a-(S) with NBS or NIS yielded the corresponding bis γ-C(sp²)–H brominated and iodinated α-methylbenzylamine derivatives 12a-(R), 12b-(R), 12a-(S) and 12b-(S) in 56–89% yields with good enantiopurities (ee 94–99%, Scheme [6]). Similarly, the Pd(II)-catalyzed, picolinamide-aided ortho C–H bromination and iodination of racemic phenylglycinol substrate 4a-(RS) with NBS or NIS yielded the corresponding racemic bis γ-C(sp²)–H brominated and iodinated phenylglycinol derivatives 13a,b-(RS) in 63–84% yields (Scheme [6]). The Pd(II)-catalyzed ortho C–H bromination and iodination of enantiopure phenylglycinol substrates 4a-(R) and 4a-(S) with NBS or NIS also yielded the corresponding bis γ-C(sp²)–H brominated and iodinated phenylglycinol derivatives 13a-(R), 13b-(R), 13a-(S) and 13b-(S) in 64–89% yields with good enantiopurity (ee >98%, Scheme [6]).

The Pd(II)-catalyzed, picolinamide-aided γ-C(sp²)–H arylation of phenylglycinol derivative 4a-(RS) with p-tolyl iodide was performed on a slightly larger scale (0.5 g scale), which yielded the bis γ-C(sp²)–H arylated phenylglycinol derivative 8f-(RS) in 74% yield (0.6 g, Scheme [7]). We also attempted the removal of the picolinamide directing group after performing the Pd(II)-catalyzed γ-C(sp²)–H arylation of α-methylbenzylamine and phenylglycinol substrates. Various attempts were made to establish better reaction conditions for removing the picolinamide directing group, and it was found that treatment of the γ-C(sp²)–H arylated phenylglycinol derivative 8p-(RS) with TfOH in toluene/H₂O mixture at 110 °C for 48 h, yielded the picolinamide DG-free racemic phenylglycinol 14-(RS) in 61% yield (Scheme [7]). Another trial involving a sequential process comprising the removal of picolinamide moiety from the γ-C(sp²)–H arylated phenylglycinol derivative 8j-(RS) followed by protection of the OH group yielded the picolinamide DG-free TBS-protected phenylglycinol (OTBS derivative) 15a-(RS) in 63% yield. Subsequently, we prepared the corresponding enantiopure phenylglycinol 14-(R) and TBS-protected phenylglycinol 15a-(R). However, due to poor peak separation with a range of chiral columns, we could not establish the HPLC profiles of both the racemic/enantiopure phenylglycinol derivatives 14-(RS) or 14-(R) and TBS-protected phenylglycinol derivatives 15a-(RS) or 15a-(R).

Thus, we tried another method to remove the picolinamide to establish the HPLC profiles by using the racemic/enantiopure phenylglycinol derivatives 8s-(RS) and 8s-(S). Deprotection of the acetyl group of 8s-(RS) with K₃CO₃ gave the crude compound 8sA-(RS). Then, Zn dust-mediated removal of the picolinamide group from 8sA-(RS) gave the crude phenylglycinol derivative 8sB-(RS). Then, Boc protection of the NH₂ group gave the N-Boc compound 15b-(RS). We could obtain the HPLC profile for compound 15b-(RS). Accordingly, we prepared the enantiopure N-Boc-protected phenylglycinol derivative 15b-(S) (Scheme [7]).

Subsequently, we treated the γ-C(sp²)–H arylated α-methylbenzylamine derivative 7i-(RS) with Zn dust and 12 N HCl in THF/H₂O mixture at room temperature for 24 h in air. This reaction yielded the racemic picolinamide DG-free α-methylbenzylamine 16-(RS) in 66% yield (Scheme [8]). Similarly, treatment of the enantiopure γ-C(sp²)–H arylated α-methylbenzylamine derivatives 7i-(R) and 7i-(S) with Zn dust and 12 N HCl in THF/H₂O mixture at room temperature for 24 h in air, yielded the corresponding picolinamide DG-free α-methylbenzylamines 16-(R) and 16-(S) in 57–63% yields. Another trial involving a sequential process comprising the removal of picolinamide moiety from 7i-(RS) followed by Boc protection of the NH₂ group of 16-(RS) yielded the N-Boc α-methylbenzylamine derivative 17-(RS) in 58% yield (Scheme [8]). However, due to poor peak separation on a range of chiral columns, we could not establish the HPLC profiles of the racemic compounds 16-(RS) or 17-(RS) and enantiopure compounds 16-(R) and 16-(S).

Thus, to confirm the enantiopurity of compounds 16-(R) and 16-(S), we again prepared the corresponding parent picolinamide-linked α-methylbenzylamine derivatives 7i-(RS), 7i-(R) and 7i-(S). We then compared the HPLC profiles of these compounds with those of the corresponding products 7i-(RS), 7i-(R) and 7i-(S) obtained from the γ-C(sp²)–H arylation of 3a-(RS), 3a-(R) and 3a-(S). This process indirectly confirmed that the α-methylbenzylamines 16-(R) and 16-(S) obtained from the Zn-mediated picolinamide removal process are enantiopure (Scheme [8]).

In summary, we have reported our efforts toward expanding the library of both racemic and enantiopure α-methylbenzylamine and phenylglycinol scaffolds via Pd(II)-catalyzed, picolinamide DG-aided sp² γ-C–H functionalization. Primarily, we were interested in expanding the library of enantiopure α-methylbenzylamine and phenylglycinol scaffolds via the sp² γ-C–H arylation-, alkylation-, halogenation (bromination and iodination) of α-methylbenzylamine and phenylglycinol substrates. We have shown the synthesis of a wide range of racemic and enantiopure sp² γ-C–H arylated, alkylated, brominated, and iodinated α-methylbenzylamine and phenylglycinol scaffolds. In general, we obtained both the R and S chiral sp² γ-C–H functionalized α-methylbenzylamine and phenylglycinol scaffolds with good enantiopurities. To our knowledge, there is no literature report dealing with the Pd(II)-catalyzed picolinamide-aided DG-aided arylation and halogenation of sp² γ-C–H bonds of enantiopure α-methylbenzylamine and phenylglycinol substrates. Considering the importance of racemic and enantiopure α-methylbenzylamine and phenylglycinol derivatives in organic synthesis and medicinal chemistry, this work on assembling racemic and enantiopure ortho-C–H functionalized α-methylbenzylamine and phenylglycinol scaffolds via the C–H functionalization route might be a valuable contribution.

Reactions were performed in oven-dried, round-bottom flasks/sealed tubes in anhydrous solvents under a nitrogen atmosphere. TLC analyses were performed on silica gel or silica gel 60 F₂₅₄ pre-coated plates and components were visualized with exposure to iodine vapor or by irradiation under a UV lamp. The column chromatography purification was performed using silica gel (100–200 mesh) or neutral alumina (eluent = ethyl acetate/hexane). ¹H and ¹³C{¹H} NMR spectra of samples were recorded with 400 and ~101 MHz (or 500 and ca. 126 MHz) spectrometers, respectively (using TMS as an internal standard), and ¹⁹F{¹H} NMR was recorded with a ca. 376 MHz spectrometer. In some of the ¹H and ¹³C{¹H} NMR spectra of a few samples, we observed broadening of a few signals. The HRMS data were obtained with a QTOF mass analyzer using the electrospray ionization (ESI) method. The IR spectra of samples were recorded either as neat samples or using KBr pellets or in an appropriate solvent. For finding the specific rotations of enantiopure samples, the solutions were prepared in DCM or CHCl₃. Polarimeter analysis data were recorded at 589 nm wavelength using 100 mm cell length, concentration (c) taken as g/100 mL. HPLC analysis was carried out on isolated samples. In Table [2], in almost all the entries the product 8a-(R) was isolated. However, the HPLC analysis was carried out for 8a-(R) obtained in entry 22 only (though we used 4a-(R) (ee 98%) for all entries). Similarly, the product 8aa-(R) (ee 96%) was obtained from 4a-(R) (ee 98%) in entry 16. We also prepared the corresponding mono-arylated product 8aa-(S) (37%, ee 95%) from 4a-(S) (ee 98%) using the conditions of entry 16. Additionally, we prepared the corresponding racemic mono-arylated product 8aa-(RS) (35%) from 4a-(RS) using the conditions of entry 16. All the yields reported are isolated yields and the yields are not optimized. Sometimes there are marginal variations in yields for the racemic/enantiopure pairs. This is perhaps due to inadvertent handling/processing errors and manual gathering of all possible pure fractions (during column chromatographic purification). While there seems to be partial racemization under the experimental conditions, the observed best ee values in HPLC analysis are reported. The observed ee was checked for some typical pairs by repeating the reaction another time. For example, the arylation reactions affording the corresponding pairs 8p-(R), 8p-(S) and 8a-(R), 8a-(S) were run two times. In a typical case, for the pairs, 8p-(R), 8p-(S) independent HPLC analysis showed comparable results with marginal changes.

Preparation of the OAc-Protected Picolinamide-Installed Phenylglycinol Carboxamides 4 (Procedures A and B)

Procedure A: An appropriate amount of aromatic or heteroaromatic carboxylic acid (5 mmol, ligand), N,N′-dicyclohexylcarbodiimide (1.1 equiv), 1-hydroxybenzotriazole hydrate (1.1 equiv) in DCM (20 mL) were stirred at 0 °C for 1 h under a nitrogen atmosphere. Then an appropriate amount of phenylglycinol (1 equiv) was added to the above mixture and stirred at r.t. for 24 h. The resulting solution was subjected to an aq. workup and washed with aq. sodium bicarbonate solution (two times). The resultant crude reaction mixture was purified on silica gel column chromatography to obtain the corresponding (OH group free) phenylglycinol carboxamide, which was then used in the next step.

Procedure B: An appropriate amount of (OH group free) phenylglycinol carboxamide prepared in the above step, was dissolved in anhydrous DMF followed by the addition of 4-(dimethylamino)pyridine (0.1 equiv) and acetic anhydride (1.1 equiv), and the resulting reaction mixture was stirred overnight at r.t. under a nitrogen atmosphere. The resulting solution was diluted with water and was extracted with ethyl acetate, and the combined organic phase was washed with brine solution. The resulting solution was then concentrated and purified on silica gel column chromatography (eluent = EtOAc/hexane) to give the corresponding alcohol group acetylated phenylglycinol carboxamide.

Preparation of α-Methyl Benzylamine Carboxamides (3a, 3c, 3e); General Procedure

An appropriate amount of carboxylic acid (1–5 mmol), N,N′-dicyclohexylcarbodiimide (1.1 equiv), 1-hydroxybenzotriazole hydrate (1.1 equiv) in DCM (10–20 mL) were stirred at 0 °C for 1 h under a nitrogen atmosphere. An appropriate amount of α-methyl benzylamine (1 equiv) was added and stirred at r.t. for 24 h. The resulting solution was subjected to an aq. workup and washed with aq. sodium bicarbonate solution (two times). The resulting crude reaction mixture was purified by using silica gel column chromatography to obtain the corresponding carboxamides.

Preparation of α-Methylbenzylamine Carboxamides (3b, 3d, 3f, 3g, 3h); General Procedure

An oven-dried RB flask was charged with an appropriate carboxylic acid (3 mmol) and anhydrous DCM (7–8 mL) and DMF (catalytic amount). To this solution, oxalyl chloride (3.6 mmol) was added dropwise at 0 °C. After this, the reaction mixture was stirred at r.t. for 12 h. The solvent was removed under vacuum and diluted with DCM (5 mL), and the resulting acid chloride solution was used immediately in the next step without purification. Another oven-dried RB flask was charged with an appropriate benzylamine derivative (3 mmol), Et₃N (3.6 mmol), and DMAP (0.1 mmol). To this solution, the acid chloride solution (obtained in the previous step) was added dropwise at 0 °C. After the addition, the reaction mixture was warmed to r.t., and stirring was continued overnight. The crude reaction mixture was then quenched with saturated aq. NaHCO₃ solution (10–15 mL) and the organic layers were dried over anhydrous Na₂SO₄, and evaporated in a vacuum. Purification of the resulting reaction mixture by column chromatography on silica gel (eluant: EtOAc/hexane = 20:80) afforded the corresponding carboxamides.

Pd(II)-Catalyzed ortho C–H Arylation of Picolinamide Derived from Phenylglycinol or α-Methyl Benzylamine; General Procedure C

A mixture of an appropriate carboxamide derived from phenylglycinol or α-methyl benzylamine (1 equiv), an appropriate aryl iodide (4 equiv), Pd(OAc)₂ (5–10 mol%) and AgOAc (2.2 equiv) in anhydrous toluene (2–3 mL) was heated at 110–130 °C for 24 h under a nitrogen atmosphere. After the reaction period, the reaction mixture was concentrated in vacuum. Purification of the resulting reaction mixture by column chromatography on silica gel (eluent = EtOAc/hexane) gave the corresponding ortho C–H arylated phenylglycinol or α-methyl benzylamine derivative.

Pd(II)-Catalyzed ortho C–H Benzylation of Carboxamide Derived from Phenylglycinol or α-Methyl Benzylamine; General Procedure D

A mixture of an appropriate carboxamide derived from phenylglycinol or α-methyl benzylamine (1 equiv), an appropriate benzyl bromide (4 equiv), Pd(OAc)₂ (10 mol%), K₂CO₃ (2 equiv) and PivOH (0.2–0.4 equiv) in anhydrous t-amylOH (2 mL) was heated at 100 °C for 36–48 h under a nitrogen atmosphere. Workup and purification were carried out as described in procedure C.

Pd(II)-Catalyzed ortho C–H Bromination of Carboxamide Derived from Phenylglycinol or α-Methyl Benzylamine; General Procedure E

A mixture of an appropriate carboxamide derived from phenylglycinol or α-methyl benzylamine (1 equiv), N-bromosuccinimide (4 equiv), and Pd(OAc)₂ (10 mol%) in anhydrous 1,2-DCE (2 mL) was heated at 110 °C for 48 h in air. Workup and purification were carried out as described in procedure C.

Pd(II)-Catalyzed ortho C–H Iodination of Carboxamide Derived from Phenylglycinol or α-Methyl Benzylamine; General Procedure F

A mixture of an appropriate carboxamide derived from phenylglycinol or α-methyl benzylamine (1 equiv), N-iodosuccinimide (4 equiv), and Pd(OAc)₂ (10 mol%) in anhydrous toluene (2 mL) was heated at 110 °C for 48 h in air. Workup and purification were carried out as described in procedure C.

Pd(II)-Catalyzed ortho C–H Alkylation of Phenylglycinol Carboxamide; General Procedure G

A mixture of an appropriate phenylglycinol carboxamide (1 equiv), 1-iodobutane (4 equiv), Pd(OAc)₂ (10 mol%), KHCO₃ (2 equiv) and o-toluic acid (0.2 equiv) in anhydrous 1,2-DCE (2 mL) was heated at 100 °C for 48 h in air. Workup and purification were carried out as described in procedure C.

Removal of Picolinamide Directing Group after C–H Arylation of Phenylglycinol Derivative; General Procedure H

An appropriate amount of ortho C–H arylated phenylglycinol carboxamide (1 equiv) was taken in a reaction flask/tube, in which trifluoromethanesulfonic acid (1 mL), and toluene/H₂O (5 mL: 0.5 mL) were added under air. The reaction mixture was stirred at 110 °C for 48 h. After the reaction period, the reaction mixture was cooled to r.t. and quenched by slowly adding a saturated solution of Na₂CO₃ (10 mL). The aqueous phase was extracted with EtOAc (3 times), evaporation of the solvent, and purification of the resulting reaction mixture by column chromatography on silica gel (eluent = EtOAc/hexane) gave the corresponding directing group-free C–H arylated phenylglycinol [e.g., 14-(RS)].

Sequential Removal of Picolinamide Directing Group after C–H Arylation of Phenylglycinol Derivative and TBS Protection of the OH Group; General Procedure I

The resulting crude mixture obtained in procedure H was directly dissolved in anhydrous DCM (5 mL) and cooled to 0 °C. Then, imidazole (2 equiv), DMAP (0.1 equiv) and TBSCl (1.3 equiv) were added, and the resulting solution was stirred at r.t. for 24 h under a nitrogen atmosphere. After this period, the reaction mixture was quenched with saturated NaHCO₃ solution. The organic layers were washed with NaHCO₃ solution and brine solution. Evaporation of solvent and purification of the resulting crude material on silica gel column to (eluent = EtOAc/hexane) afforded the corresponding O-TBS protected, free amine-based phenylglycinol derivative [e.g., 15a-(RS)].

Deacetylation of the OAc Group after C–H Arylation of Phenylglycinol Derivative; General Procedure J

An appropriate amount of ortho C–H arylated phenylglycinol carboxamide (1 equiv) was dissolved in MeOH (2–4 mL). To this solution, K₂CO₃ (3 equiv) was added and the reaction mixture was stirred at r.t. for 24 h in air. The reaction mixture was then diluted with water and extracted with EtOAc (three times) and the organic layers were dried over anhydrous Na₂SO₄. The resulting solution was then concentrated and used for the next step without further purification.

Removal of the Picolinamide Directing Group from C–H Arylated Phenylglycinol or α-Methyl Benzylamine and Boc Protection of the NH₂ Group; General Procedure K

To an appropriate picolinamide of phenylglycinol or α-methyl benzylamine (1 equiv) dissolved in H₂O/THF (1:1, 4–6 mL), 12 M HCl (0.4–0.95 mL) was added. The mixture was stirred at r.t. for 15 min. Zinc dust (15 equiv) was then added in three portions and the mixture was stirred at r.t. for 24 h. The reaction was filtered through a Celite plug. The filtrate was transferred to a separating funnel with 2 M NaOH (50 mL) and extracted with DCM. The reaction mixture was concentrated in a vacuum and used for the next step. An appropriate amount of picolinamide directing group removed phenylglycinol or α-methyl benzylamine carboxamide obtained in the above procedure (1 equiv), Et₃N (2 equiv), Boc₂O (1.2–2.0 equiv) were dissolved DCM (5 mL) and the reaction mixture was stirred at r.t. for 24 h under a nitrogen atmosphere. Work-up using brine solution and evaporation of solvent gave a crude mixture, which was purified on silica gel column chromatography to afford the corresponding N-Boc phenylglycinol or α-methyl benzylamine derivative.

N-(1-Phenylethyl)picolinamide (3a-(RS))[9e]

The compound 3a-(RS) was obtained as a colorless solid (650 mg, 96%, 3.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 134–136 °C.

IR (DCM): 3379, 1670, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.54–8.52 (m, 1 H), 8.34 (d, J = 6.8 Hz, 1 H), 8.19 (dt, ¹ J = 7.8, ² J = 0.9 Hz, 1 H), 7.82 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.42–7.38 (m, 3 H), 7.36–7.33 (m, 2 H), 7.28–7.24 (m, 1 H), 5.36–5.29 (m, 1 H), 1.62 (d, 3 H, J = 7.0 Hz).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.4, 149.9, 148.0, 143.3, 137.4, 128.7, 127.3, 126.2, 126.2, 122.3, 48.8, 22.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₄N₂NaO: 249.1004; found: 249.1015.

The HPLC of compound 3a-(RS) was determined by using the Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 19.27 min, t_S = 29.83 min.

(R)-N-(1-Phenylethyl)picolinamide (3a-(R))[11b]

Compound 3a-(R) was obtained as a colorless solid (600 mg, 88%, 3.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 134–136 °C; [α] _d ²⁵ –7.23 (c = 0.10, DCM).

IR (DCM): 3382, 1670, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.54–8.52 (m, 1 H), 8.34 (d, 1 H, J = 6.9 Hz), 8.19 (dt, 1 H, ¹ J = 7.8, ² J = 1.0 Hz), 7.82 (td, ¹ J = 7.7, ³ J = 1.7 Hz, 1 H), 7.42–7.38 (m, 3 H), 7.36–7.33 (m, 2 H), 7.28–7.24 (m, 1 H), 5.36–5.29 (m, 1 H), 1.62 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.3, 149.8, 147.9, 143.2, 137.3, 128.6, 127.2, 126.1, 126.1, 122.2, 48.7, 22.0.

The enantiomeric excess (ee 97%) of compound 3a-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 17.94 min, t_S = 28.66 min.

(S)-N-(1-Phenylethyl)picolinamide (3a-(S))[11f]

Compound 3a-(S) was obtained as a colorless solid (540 mg, 80%, 3.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 134–136 °C; [α] _d ²⁵ 8.20 (c = 0.10, DCM).

IR (DCM): 3381, 1670, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52–8.51 (m, 1 H), 8.33 (d, J = 6.9 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.80 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.42–7.32 (m, 5 H), 7.27–7.23 (m, 1 H), 5.36–5.29 (m, 1 H), 1.62 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.3, 149.8, 147.9, 143.2, 137.3, 128.6, 127.2, 126.1, 126.1, 122.2, 48.7, 22.0.

The enantiomeric excess (ee 99%) of compound 3a-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 19.62 min, t_S = 30.11 min.

N-(1-(p-Tolyl)ethyl)picolinamide (3b-(RS))[11a]

Compound 3b-(RS) was obtained as a colorless solid (311 mg, 65%, 2.0 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 90–92 °C.

IR (DCM): 3384, 1673, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52–8.51 (m, 1 H), 8.30 (d, J = 7.2 Hz, 1 H), 8.19 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.82 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.41–7.38 (m, 1 H), 7.30 (d, J = 8.1 Hz, 2 H), 7.15 (d, J = 7.9 Hz, 2 H), 5.32–5.25 (m, 1 H), 2.32 (s, 3 H), 1.61 (d, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.3, 149.9, 147.9, 140.3, 137.3, 136.9, 129.3, 126.1, 126.1, 122.2, 48.5, 22.0, 21.0.

The HPLC of compound 3b-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 60:40, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 8.12 min, t_S = 12.50 min.

(R)-N-(1-(p-Tolyl)ethyl)picolinamide (3b-(R))[17]

Compound 3b-(R) was obtained as a colorless solid (304 mg, 63%, 2.0 mmol scale).

R _f = 0.6 (EtOAc/hexane = 20:80); mp 90–92 °C; [α] _d ²⁵ –6.31 (c = 0.10, DCM).

IR (DCM): 3388, 1673, 1514 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.51 (d, J = 4.2 Hz, 1 H), 8.31 (d, J = 7.3 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.81 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.40–7.37 (m, 1 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 5.33–5.25 (m, 1 H), 2.32 (s, 3 H), 1.61 (d, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.2, 149.9, 147.9, 140.2, 137.2, 136.8, 129.2, 126.1, 126.0, 122.2, 48.5, 22.0, 21.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₇N₂O: 241.1341; found 241.1340.

The enantiomeric excess (ee 97%) of compound 3b-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 60:40, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 8.10 min, t_S  = 12.48 min.

(S)-N-(1-(p-Tolyl)ethyl)picolinamide (3b-(S))

Compound 3b-(S) was obtained as a colorless solid (311 mg, 65%, 2.0 mmol scale).

R _f = 0.6 (EtOAc/hexane = 20:80); mp 90–92 °C; [α] _d ²⁵ 9.22 (c = 0.10, DCM).

IR (DCM): 3376, 1672, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.51 (d, J = 4.6 Hz, 1 H), 8.30 (d, J = 7.0 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.82 (td, ¹ J = 7.7, ² J = 1.6 Hz, 1 H), 7.42–7.38 (m, 1 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 7.9 Hz, 2 H), 5.32–5.25 (m, 1 H), 2.33 (s, 3 H), 1.61 (d, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.3, 150.0, 148.0, 140.3, 137.3, 137.0, 129.3, 126.2, 126.1, 122.3, 48.6, 22.1, 21.1.

The enantiomeric excess (ee 99%) of compound 3b-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 60:40, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 8.08 min, t_S = 12.46 min.

N-(1-(4-Chlorophenyl)ethyl)picolinamide (3c-(RS))

Compound 3c-(RS) was obtained as a colorless solid (215 mg, 83%, 1.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 118–120 °C.

IR (DCM): 3353, 1654, 1514 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.46 (d, J = 4.2 Hz, 1 H), 8.21 (d, J = 5.5 Hz, 1 H), 8.10 (d, J = 7.7 Hz, 1 H), 7.76 (t, J = 7.6 Hz, 1 H), 7.34 (t, J = 6.2 Hz, 1 H), 7.27–7.19 (m, 4 H), 5.23–5.17 (m, 1 H), 1.52 (d, J = 6.8 Hz, 3 H).

¹³C{¹H} NMR (~75 MHz, CDCl₃): δ = 163.4, 149.7, 148.0, 141.9, 137.3, 132.9, 128.7, 127.6, 126.2, 122.3, 48.2, 22.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₄ClN₂O: 261.0795; found: 261.0786.

The HPLC of compound 3c-(RS) was determined using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 10.90 min, t_S = 15.28 min.

(R)-N-(1-(4-Chlorophenyl)ethyl)picolinamide (3c-(R))[11a]

Compound 3c-(R) was obtained as a colorless solid (445 mg, 85%, 2.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 118–120 °C; [α] _d ²⁵ –10.18 (c = 0.10, DCM).

IR (DCM): 3374, 1654, 1514 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (d, J = 4.7 Hz, 1 H), 8.32 (d, J = 7.3 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.83 (td, ¹ J= 7.7 Hz, ² J₌ 1.5 Hz, 1 H), 7.44–7.41 (m, 1 H), 7.35–7.29 (m, 4 H), 5.32–5.24 (m, 1 H), 1.60 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.5, 149.7, 148.1, 141.9, 137.4, 133.0, 128.8, 127.6, 126.3, 122.3, 48.3, 22.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₃ClN₂NaO: 283.0614; found: 283.0623.

The enantiomeric excess (ee 95%) of compound 3c-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 10.99 min, t_S = 15.39 min.

(S)-N-(1-(4-Chlorophenyl)ethyl)picolinamide (3c-(S))

The compound 3c-(S) was obtained as a colorless solid (430 mg, 83%, 2.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 117–119 °C; [α]_D ²⁵ 15.23 (c = 0.10, DCM).

IR (DCM): 3354, 1654, 1514 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (d, J = 4.7 Hz, 1 H), 8.32 (d, J = 7.2 Hz, 1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.83 (td, ¹ J= 7.7 Hz, ² J₌ 1.6 Hz, 1 H), 7.44–7.40 (m, 1 H), 7.35–7.29 (m, 4 H), 5.32–5.24 (m, 1 H), 1.60 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.5, 149.7, 148.1, 141.9, 137.4, 133.0, 128.8, 127.6, 126.3, 122.3, 48.3, 22.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₄ClN₂O: 261.0795; found: 261.0782.

The enantiomeric excess (ee 95%) of compound 3c-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 10.83 min, t_S = 15.10 min.

N-(1-Phenylpropyl)picolinamide (3d-(RS))

Compound 3d-(RS) was obtained as a colorless solid (688 mg, 95%, 3.0 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 119–121 °C.

IR (KBr): 3055, 2987, 1710, 1265 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.56 (d, J = 4.7 Hz, 1 H), 8.39 (d, J = 7.8 Hz, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 7.84 (t, J = 7.7 Hz, 1 H), 7.44–7.40 (m, 3 H), 7.38–7.34 (m, 2 H), 7.29–7.26 (m, 1 H), 5.11 (q, J = 7.6 Hz, 1 H), 2.04–1.96 (m, 2 H), 0.99 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 163.6, 150.0, 148.0, 142.3, 137.4, 128.6, 127.3, 126.7, 126.1, 122.3, 55.0, 29.5, 10.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₆N₂NaO: 263.1160; found: 263.1149.

N-5-Methyl-N-(1-phenylethyl)isoxazole-3-carboxamide (3e-(RS))

Compound 3e-(RS) was obtained as a colorless solid (1.01 gm, 88%, 5.0 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); mp 118–120 °C.

IR (DCM): 3342, 1654, 1215 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.31 (m, 4 H), 7.28–7.24 (m, 1 H), 7.13 (br. s, 1 H), 6.41 (s, 1 H), 5.31–5.23 (m, 1 H), 2.44 (s, 3 H), 1.58 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.1, 158.7, 158.1, 142.5, 128.6, 127.4, 126.1, 101.4, 48.9, 21.7, 12.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄N₂NaO₂: 253.0953; found: 253.0943.

The HPLC compound 3e-(RS) was determined by using a Daicel Chiralpak IA column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 4.81 min, t_S = 5.40 min.

(R)-N-5-Methyl-N-(1-phenylethyl)isoxazole-3-carboxamide (3e-(R))

Compound 3e-(R) was obtained as a colorless solid (586 mg, 85%, 3.0 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); mp 118–120 °C; [α] _d ²⁵ 23.3 (c = 0.03, CHCl₃).

IR (DCM): 3342, 1648, 1214 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.31 (m, 4 H), 7.28–7.24 (m, 1 H), 7.16 (d, J = 7.2 Hz, 1 H), 6.41 (s, 1 H), 5.31–5.24 (m, 1 H), 2.43 (s, 3 H), 1.57 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.1, 158.7, 158.1, 142.5, 128.6, 127.4, 126.1, 101.4, 48.9, 21.7, 12.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄N₂NaO₂: 253.0953; found: 253.0942.

The enantiomeric excess (ee 98%) of compound 3e-(R) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 5.13 min, t_S  = 5.84 min.

(S)-N-5-Methyl-N-(1-phenylethyl)isoxazole-3-carboxamide (3e-(S))

Compound 3e-(S) was obtained as a colorless solid (580 mg, 84%, 3.0 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); mp 118–120 °C; [α] _d ²⁵ –23.3 (c = 0.03, CHCl₃).

IR (DCM): 3341, 1669, 1214 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.31 (m, 4 H), 7.28–7.24 (m, 1 H), 7.12 (d, J = 6.6 Hz, 1 H), 6.41 (s, 1 H), 5.31–5.23 (m, 1 H), 2.44 (s, 3 H), 1.58 (d, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.1, 158.7, 158.1, 142.5, 128.6, 127.4, 126.1, 101.4, 48.9, 21.7, 12.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄N₂NaO₂: 253.0953; found: 253.0943.

The enantiomeric excess (ee 95%) of compound 3e-(S) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t _R = 5.16 min, t _S  = 5.81 min.

N-(1-Phenylethyl)pyrazine-2-carboxamide (3f-(RS))

Compound 3f-(RS) was obtained as a colorless solid (375 mg, 55%, 3.0 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); mp 145–147 °C.

IR (KBr): 3055, 2936, 1721, 1265, cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.43 (d, J = 1.4 Hz, 1 H), 8.76 (d, J = 2.5 Hz, 1 H), 8.53 (dd, ¹ J = 2.4, ² J = 1.5 Hz, 1 H), 8.08 (d, J = 10.0 Hz, 1 H), 7.44–7.40 (m, 4 H), 7.38–7.30 (m, 1 H), 5.39–5.32 (m, 1 H), 1.66 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 162.1, 147.3, 144.5, 144.5, 142.8, 142.5, 128.8, 127.6, 126.2, 49.0, 22.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₄N₃O: 228.1137; found 228.1132.

N-(1-Phenylethyl)quinoline-2-carboxamide (3g-(RS))[6g]

Compound 3g-(RS) was obtained as a faint orange colored solid (500 mg, 60%, 3.0 mmol scale).

R_f = 0.5 (EtOAc/hexane = 20:80); mp 104–106 °C.

IR (KBr): 3055, 1709, 1424, 1265 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.56 (d, J = 8.1 Hz, 1 H), 8.32–8.25 (m, 2 H), 8.10 (d, J = 8.5 Hz, 1 H), 7.83 (d, J = 8.1 Hz, 1 H), 7.75–7.71 (m, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.45 (d, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.28–7.24 (m, 1 H), 5.43–5.36 (m, 1 H), 1.67 (d, J = 7.0 Hz, 3 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 163.5, 149.7, 146.4, 143.2, 137.4, 130.0, 129.6, 129.2, 128.6, 127.8, 127.7, 127.3, 126.2, 118.8, 48.9, 22.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₆N₂NaO: 299.1160; found: 299.1157.

N-(1-Phenylethyl)cyclopentanecarboxamide (3h-(RS))

Compound 3h-(RS) was obtained as a colorless solid (450 mg, 69%, 3.0 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 102–104 °C.

IR (KBr): 3055, 2986, 1709, 1265 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.32 (m, 4 H), 7.30–7.25 (m, 1 H), 5.79 (d, J = 6.6 Hz, 1 H), 5.18–5.11 (m, 1 H), 2.57–2.49 (m, 1 H), 1.91–1.81 (m, 3 H), 1.79–1.70 (m, 3 H), 1.61–1.54 (m, 2 H), 1.50 (d, J = 6.9 Hz, 3 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 175.3, 143.5, 128.6, 127.2, 126.1, 48.5, 45.9, 30.4, 26.0, 21.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₂₀NO: 218.1545; found: 218.1553.

2-Phenyl-2-(picolinamido)ethyl Acetate (4a-(RS))

Compound 4a-(RS) was obtained (from procedures A and B) as a colorless solid (1.19 g, 84%, 5 mmol scale).

R_f = 0.50 (EtOAc/hexane = 50:50); mp 88–90 °C.

IR (DCM): 3374, 1740, 1518 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.65 (d, J = 8.1 Hz, 1 H), 8.59 (d, J = 4.3 Hz, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 7.85 (t, J = 7.6 Hz, 1 H), 7.46–7.29 (m, 6 H), 5.55–5.50 (m, 1 H), 4.54–4.43 (m, 2 H), 2.06 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.9, 164.0, 149.5, 148.2, 138.4, 137.4, 128.8, 128.0, 126.8, 126.4, 122.4, 66.3, 52.3, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₃: 285.1239; found: 285.1230.

The HPLC of compound 4a-(RS) was determined using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_s = 25.88 min, t_R = 29.39 min.

(R)-2-Phenyl-2-(picolinamido)ethyl Acetate (4a-(R))

Compound 4a-(R) was obtained (from procedures A and B) as a colorless solid (1.15 g, 81%, 5 mmol scale).

R_f = 0.50 (EtOAc/hexane = 50:50); mp 88–90 °C; [α] _d ²⁵ 19.6 (c = 0.1, CHCl₃).

IR (DCM): 3369, 1740, 1517 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.65 (d, J = 8.3 Hz, 1 H), 8.59 (d, J = 4.6 Hz, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 7.85 (td, ¹ J = 7.7 Hz, ² J = 1.2 Hz, 1 H), 7.46–7.29 (m, 6 H), 5.55–5.50 (m, 1 H), 4.54–4.43 (m, 2 H), 2.05 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.9, 163.9, 149.5, 148.2, 138.4, 137.4, 128.8, 128.0, 126.8, 126.4, 122.4, 66.3, 52.3, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₃: 285.1239; found: 285.1225.

The enantiomeric excess (ee 98%) of compound 4a-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_s = 24.78 min, t_R = 29.64 min.

(S)-2-Phenyl-2-(picolinamido)ethyl Acetate (4a-(S))

Compound 4a-(S) was obtained (from procedures A and B) as a colorless solid (1.16 g, 82%, 5 mmol scale).

R_f = 0.50 (EtOAc/hexane = 50:50); mp 88–90 °C; [α] _d ²⁵ –11.2 (c = 0.1, CHCl₃).

IR (DCM): 3370, 1739 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.65 (d, J = 8.1 Hz, 1 H), 8.59 (d, J = 4.3 Hz, 1 H), 8.20 (d, J = 7.8 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.47–7.28 (m, 6 H), 5.55–5.50 (m, 1 H), 4.54–4.43 (m, 2 H), 2.06 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.0, 164.0, 149.5, 148.2, 138.4, 137.4, 128.8, 128.0, 126.8, 126.4, 122.4, 66.3, 52.3, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₇N₂O₃: 285.1239; found: 285.1233.

The enantiomeric excess (ee 98%) of compound 4a-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_s = 25.03, min t_R = 28.94 min.

2-(2-Chlorophenyl)-2-(picolinamido)ethyl Acetate (4b-(RS))

Compound 4b-(RS) was obtained (from procedures A and B) as a yellow colored semi-solid (527 mg, 83%, 2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50).

IR (DCM): 3370, 1741, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 8.0 Hz, 1 H), 8.63 (d, J = 4.6 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.87 (t, J = 7.7 Hz, 1 H), 7.49–7.40 (m, 3 H), 7.27–7.25 (m, 2 H), 5.89–5.85 (m, 1 H), 4.59 (dd, ¹ J = 11.5 Hz, ² J = 7.0 Hz, 1 H), 4.44 (dd, ¹ J = 11.5 Hz, ² J ₌ 4.4 Hz, 1 H), 2.07 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.9, 163.9, 149.4, 148.3, 137.4, 135.8, 133.1, 130.0, 129.2, 128.1, 127.1, 126.5, 122.3, 64.9, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆ClN₂O₃: 319.0849; found: 319.0838.

2-(4-Chlorophenyl)-2-(picolinamido)ethyl Acetate (4c-(RS))

The compound 4c-(RS) was obtained (from procedures A and B) as a yellow colored semi-solid (540 mg, 85%, 2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50).

IR (DCM): 3364, 1738, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.68 (d, J = 8.2 Hz, 1 H), 8.49 (d, J = 4.0 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.76 (t, J = 7.7 Hz, 1 H), 7.38–7.24 (m, 5 H), 5.46–5.41 (m, 1 H), 4.46–4.35 (m, 2 H), 1.98 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.8, 164.0, 149.3, 148.2, 137.4, 137.1, 133.6, 128.8, 128.2, 126.5, 122.3, 66.0, 51.9, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₆ClN₂O₃: 319.0849; found: 319.0838.

2-(5-Methylisoxazole-3-carboxamido)-2-phenylethyl Acetate (4d-(RS))

Compound 4d-(RS) was obtained (from procedures A and B) as a colorless solid (328 mg, 57%, 2 mmol scale).

R_f = 0.50 (EtOAc/hexane = 50:50); mp 124–126 °C.

IR (DCM): 3379, 1741, 1544 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.45 (d, J = 8.1 Hz, 1 H), 7.38–7.35 (m, 4 H), 7.34–7.30 (m, 1 H), 6.44 (s, 1 H), 5.49–5.44 (m, 1 H), 4.48–4.39 (m, 2 H), 2.48 (s, 3 H), 2.06 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.4, 171.0, 158.8, 158.5, 137.7, 128.9, 128.2, 126.7, 101.5, 66.0, 52.4, 20.8, 12.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₆N₂NaO₄: 311.1008; found: 311.0995.

2-Phenyl-2-(quinoline-2-carboxamido)ethyl Acetate (4e-(RS))

Compound 4e-(RS) was obtained (from procedures A and B) as a colorless solid (541 mg, 81%, 2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 104–106 °C.

IR (DCM): 3372, 1738, 1372 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.87 (d, J = 8.4 Hz, 1 H), 8.33 (s, 2 H), 8.18 (d, J = 8.5 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 1 H), 7.80 (t, J = 7.2 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.49 (d, J = 7.7 Hz, 2 H), 7.43–7.39 (m, 2 H), 7.35–7.32 (m, 1 H), 5.62–5.57 (m, 1 H), 4.62–4.50 (m, 2 H), 2.10 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.1, 164.2, 149.4, 146.5, 138.4, 137.6, 130.2, 129.9, 129.4, 128.9, 128.1, 128.0, 127.8, 126.9, 118.9, 66.3, 52.5, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₉N₂O₃: 335.1396; found: 335.1390.

2-Phenyl-2-(pyrazine-2-carboxamido)ethyl Acetate (4f-(RS))

Compound 4f-(RS) was obtained (from procedures A and B) as a colorless solid (467 mg, 82%, 2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 150–152 °C.

IR (DCM): 3373, 1741, 1518 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.40 (s, 1 H), 8.76 (s, 1 H), 8.56 (s, 1 H), 8.42 (d, J = 8.2 Hz, 1 H), 7.41–7.29 (m, 5 H), 5.54–5.49 (m, 1 H), 4.52 (dd, ¹ J = 11.5 Hz, ² J = 7.5 Hz, 1 H), 4.43 (dd, ¹ J = 11.6 Hz, ² J = 4.6 Hz, 1 H), 2.05 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.0, 162.7, 147.5, 144.5, 144.1, 142.7, 137.9, 128.9, 128.2, 126.8, 66.1, 52.5, 20.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₅N₃NaO₃: 308.1011; found: 308.1019.

2-Benzamido-2-phenylethyl Acetate (4g-(RS))

Compound 4g-(RS) was obtained (from procedures A and B) as a colorless solid (240 mg, 85%, 1 mmol scale).

R_f = 0.50 (EtOAc/hexane = 50:50); mp 126–128 °C.

IR (DCM): 1741, 1638 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.82 (d, J = 7.6 Hz, 2 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.47–7.43 (m, 2 H), 7.39–7.32 (m, 5 H), 7.04 (d, J = 7.0 Hz, 1 H), 5.52–5.47 (m, 1 H), 4.62 (dd, ¹ J = 11.4 Hz, ² J = 8.3 Hz, 1 H), 4.34 (dd, ¹ J = 11.6 Hz, ² J = 4.1 Hz, 1 H), 2.08 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.8, 167.0, 138.3, 134.0, 131.7, 128.9, 128.6, 128.0, 127.1, 126.7, 66.2, 53.5, 20.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₇NNaO₃: 306.1106; found: 306.1111.

N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7a-(RS))

The compound 7a-(RS) was obtained as a colorless solid (91 mg, 83%, 0.25 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); mp 107–109 °C.

IR (KBr): 3056, 1674, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42–8.40 (m, 1 H), 8.08–8.06 (m, 1 H), 7.80–7.76 (m, 2 H), 7.39–7.36 (m, 4 H), 7.28–7.23 (m, 2 H), 7.14 (d, J = 7.3 Hz, 2 H), 6.94 (br. s, 4 H), 5.58–5.51 (m, 1 H), 3.88 (s, 6 H), 1.38 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 158.6, 149.9, 147.5, 141.6, 139.2, 137.0, 134.7, 130.8, 130.6, 125.8, 121.9, 113.4, 55.3, 46.6, 23.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₂₆N₂NaO₃: 461.1841; found: 461.1849.

The HPLC of compound 7a-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 22.81 min, t_R = 26.31 min.

(R)-N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7a-(R))

Compound 7a-(R) was obtained as a colorless solid (70 mg, 80%, 0.20 mmol scale).

R_f =0.4 (EtOAc/hexane = 20:80); mp 107–109 °C; [α] _d ²⁵ –73.0 (c = 0.05, CHCl₃).

IR (DCM): 3380, 1674, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.39–8.37 (m, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.77–7.73 (m, 2 H), 7.36–7.20 (m, 6 H), 7.11 (d, J = 7.4 Hz, 2 H), 6.90 (br. s, 4 H), 5.55–5.50 (m, 1 H), 3.85 (s, 6 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 158.6, 149.9, 147.5, 141.5, 139.2, 137.0, 134.6, 130.8, 130.6, 125.7, 125.7, 121.9, 113.4, 55.3, 46.6, 23.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O₃: 439.2022; found 439.2021.

The enantiomeric excess (ee 98%) of compound 7a-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 22.98 min, t_R = 26.30 min.

(S)-N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7a-(S))

Compound 7a-(S) was obtained as a colorless solid (68 mg, 78%, 0.20 mmol scale).

R_f =0.4 (EtOAc/hexane = 20:80); mp 107–109 °C; [α] _d ²⁵ 75.2 (c = 0.05, CHCl₃).

IR (DCM): 3377, 1672, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.39–8.37 (m, 1 H), 8.05 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.77–7.73 (m, 2 H), 7.36–7.21 (m, 6 H), 7.11 (d, J = 7.3 Hz, 2 H), 6.90 (br. s, 4 H), 5.54–5.50 (m, 1 H), 3.85 (s, 6 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 158.6, 149.9, 147.5, 141.5, 139.2, 137.0, 134.6, 130.8, 130.6, 125.7, 125.7, 121.9, 113.4, 55.3, 46.6, 23.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O₃: 439.2022; found 439.2022.

The enantiomeric excess (ee 98%) of compound 7a-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 22.69 min, t_R = 26.00 min.

N-(1-(4,4′′-Dimethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7b-(RS))

Compound 7b-(RS) was obtained as a light-yellow solid (93 mg, 92%, 0.25 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 170–172 °C.

IR (DCM): 3383, 1670, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36 (d, J = 4.2 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.77–7.71 (m, 2 H), 7.35–7.10 (m, 12 H), 5.53–5.46 (m, 1 H), 2.40 (s, 6 H), 1.35 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 149.9, 147.5, 141.9, 139.4, 138.8, 137.0, 136.5, 130.6, 129.4, 128.7, 125.8, 125.7, 121.9, 46.6, 23.5, 21.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O: 407.2123; found: 407.2135.

The HPLC of compound 7b-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 16.74 min, t_R = 26.69 min.

(R)-N-(1-(4,4′′-Dimethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7b-(R))

Compound 7b-(R) was obtained as a light-yellow solid (127 mg, 89%, 0.35 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 170–172 °C; [α] _d ²⁵ –91.9 (c = 0.06, CHCl₃).

IR (DCM): 3383, 1671, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36 (d, J = 4.7 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.77–7.71 (m, 2 H), 7.35–7.10 (m, 12 H), 5.53–5.46 (m, 1 H), 2.40 (s, 6 H), 1.35 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.5, 149.8, 147.4, 141.8, 139.3, 138.7, 136.9, 136.4, 130.5, 129.3, 128.6, 125.7, 125.6, 121.8, 46.5, 23.4, 21.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O: 407.2123; found: 407.2116.

The enantiomeric excess (ee 98%) of compound 7b-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 16.91 min, t_R = 26.77 min.

(S)-N-(1-(4,4′′-Dimethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7b-(S))

Compound 7b-(S) was obtained as a light-yellow colored solid (127 mg, 89%, 0.35 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 171–173 °C; [α] _d ²⁵ 71.9 (c = 0.06, CHCl₃).

IR (DCM): 3377, 1670, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36 (d, J = 4.6 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.75–7.71 (m, 2 H), 7.33–7.10 (m, 12 H), 5.54–5.47 (m, 1 H), 2.40 (s, 6 H), 1.35 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.5, 149.8, 147.3, 141.7, 139.3, 138.7, 136.8, 136.4, 130.5, 129.3, 128.6, 125.6, 125.6, 121.8, 46.5, 23.3, 21.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₇N₂O: 407.2123; found: 407.2117.

The enantiomeric excess (ee 96%) of compound 7b-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 16.88 min, t_R = 27.01 min.

N-(1-(4,4′′-Diethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7c-(RS))

The compound 7c-(RS) was obtained as a yellow colored semi-solid (72 mg, 67%, 0.25 mmol scale).

R_f =0.7 (EtOAc/hexane = 20:80).

IR (KBr): 2967, 1675, 1513, 1265 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.39–8.37 (m, 1 H), 8.08 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.78 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.73 (d, J = 8.8 Hz, 1 H), 7.44–7.31 (m, 4 H), 7.28–7.18 (m, 5 H), 7.16 (d, J = 7.3 Hz, 2 H), 7.14–7.01 (m, 1 H), 5.57–5.49 (m, 1 H), 2.74 (q, J = 7.6 Hz, 4 H), 1.40 (d, J = 7.2 Hz, 3 H), 1.33 (t, J = 7.6 Hz, 6 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 162.7, 150.0, 147.5, 142.8, 141.9, 139.6, 138.9, 137.0, 130.6, 129.5, 127.5, 125.7, 125.7, 121.9, 46.7, 28.6, 23.5, 15.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁N₂O: 435.2436; found: 435.2439.

N-(1-([1,1′:3′,1′′-Terphenyl]-2′-yl)ethyl)picolinamide (7d-(RS))

Compound 7d-(RS) was obtained as a colorless solid (76 mg, 81%, 0.25 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 98–100 °C.

IR (DCM): 3375, 1671, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36–8.34 (m, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.74 (td, ¹ J= 7.7 Hz, ² J₌ 1.7 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.35–7.13 (m, 14 H), 5.51–5.44 (m, 1 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~75 MHz, CDCl₃): δ = 162.7, 149.9, 147.6, 142.3, 141.9, 138.6, 136.9, 130.6, 129.6, 128.0, 127.0, 125.7, 125.7, 121.9, 46.6, 23.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₃N₂O: 379.1810; found: 379.1819.

The HPLC of compound 7d-(RS) was determined by using a Daicel Chiralcel OD column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 8.95 min, t_S = 14.21 min.

(R)-N-(1-([1,1′:3′,1′′-Terphenyl]-2′-yl)ethyl)picolinamide (7d-(R))

Compound 7d-(R) was obtained as a colorless solid (95 mg, 72%, 0.35 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 98–100 °C; [α] _d ²⁵ –65.5 (c = 0.06, CHCl₃).

IR (DCM): 3382, 1672, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36–8.34 (m, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.74 (td, ¹ J= 7.7 Hz, ² J₌ 1.7 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.35–7.13 (m, 14 H), 5.51–5.44 (m, 1 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 162.7, 149.8, 147.6, 142.3, 141.9, 138.6, 137.0, 130.6, 129.6, 128.0, 127.0, 125.7, 125.7, 121.9, 46.6, 23.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₃N₂O: 379.1810; found: 379.1819.

The enantiomeric excess (ee 91%) of compound 7d-(R) was determined by HPLC using a Daicel Chiralcel OD column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 8.98 min, t_S = 14.34 min.

(S)-N-(1-([1,1′:3′,1′′-Terphenyl]-2′-yl)ethyl)picolinamide (7d-(S))

Compound 7d-(S) was obtained as a colorless solid (96 mg, 73%, 0.35 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 98–100 °C; [α] _d ²⁵ 47.2 (c = 0.06, CHCl₃).

IR (DCM): 3383, 1670, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36–8.34 (m, 1 H), 8.04 (dt, ¹ J = 6.8 Hz, ² J = 1.0 Hz, 1 H), 7.75 (td, ¹ J = 7.7 Hz, ² J = 1.8 Hz, 1 H), 7.69 (d, J = 8.2 Hz, 1 H), 7.45–7.24 (m, 12 H), 7.15–7.13 (m, 2 H), 5.51–5.43 (m, 1 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~75 MHz, CDCl₃): δ = 162.6, 149.9, 147.5, 142.3, 141.9, 138.6, 136.9, 130.6, 129.6, 128.0, 127.0, 125.7, 125.7, 121.9, 46.6, 23.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₃N₂O: 379.1810; found: 379.1802.

The enantiomeric excess (ee 92%) of compound 7d-(S) was determined by HPLC using a Daicel Chiralcel OD column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 9.04 min, t_S = 14.36 min.

N-(1-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide 7e-((RS))

Compound 7e-(RS) was obtained as a yellow viscous liquid (71 mg, 62%, 0.25 mmol scale).

R_f = 0.35 (EtOAc/hexane = 20:80).

IR (KBr): 3055, 1679, 1514, 1266 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.27–8.25 (m, 1 H), 8.05–8.03 (m, 2 H), 8.00–7.82 (m, 3 H), 7.79 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.71–7.40 (m, 4 H), 7.38–7.35 (m, 1 H), 7.33–7.26 (m, 2 H), 7.14 (d, J = 7.6 Hz, 2 H), 5.42–5.34 (m, 1 H), 2.65 (s, 6 H), 1.37 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.8, 162.7, 149.3, 147.6, 147.3, 140.8, 138.3, 137.2, 135.8, 130.6, 129.8, 128.2, 126.1, 126.1, 121.8, 46.7, 26.7, 23.4.

HRMS (ESI): m/z [M + Na]⁺ C₃₀H₂₆N₂NaO₃: 485.1841; found: 485.1834.

The HPLC of compound 7e-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 50:50, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 22.09 min, t_R = 29.94 min.

(R)-N-(1-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7e-(R))

Compound 7e-(R) was obtained as a yellow colored semi-solid (60 mg, 65%, 0.20 mmol scale).

R_f = 0.35 (EtOAc/hexane = 20:80); [α] _d ²⁵ –145.6 (c = 0.16, CHCl₃).

IR (DCM): 3381, 1676, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.26–8.25 (m, 1 H), 8.05–7.76 (m, 6 H), 7.54–7.27 (m, 7 H), 7.14 (d, J = 7.6 Hz, 2 H), 5.41–5.34 (m, 1 H), 2.65 (s, 6 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.8, 162.7, 149.3, 147.6, 147.3, 140.8, 138.3, 137.2, 135.8, 130.6, 129.8, 128.2, 126.1, 126.1, 121.8, 46.7, 26.7, 23.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₃: 463.2022; found 463.2023.

The enantiomeric excess (ee 93%) of compound 7e-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 50:50, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 24.69 min, t_R = 32.42 min.

(S)-N-(1-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7e-(S))

Compound 7e-(S) was obtained as a yellow colored semi-solid (58 mg, 63%, 0.20 mmol scale).

R_f = 0.35 (EtOAc/hexane = 20:80).

[α] _d ²⁵ 138.8 (c = 0.16, CHCl₃).

IR (DCM): 3383, 1676, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.26–8.25 (m, 1 H), 8.05–7.76 (m, 6 H), 7.54–7.27 (m, 7 H), 7.14 (d, J = 7.6 Hz, 2 H), 5.41–5.34 (m, 1 H), 2.65 (s, 6 H), 1.36 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.8, 162.7, 149.3, 147.6, 147.3, 140.8, 138.3, 137.2, 135.8, 130.5, 129.7, 128.2, 126.1, 126.1, 121.8, 46.7, 26.7, 23.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₃: 463.2022; found 463.2023.

The enantiomeric excess (ee 93%) of compound 7e-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 50:50, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 22.30 min, t_R = 30.48 min.

N-(1-(4,4′′-Difluoro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7f-(RS))

Compound 7f-(RS) was obtained as a yellow colored semi-solid (67 mg, 65%, 0.25 mmol scale).

R_f =0.7 (EtOAc/hexane = 20:80).

IR (DCM): 3055, 1673, 1511, cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.44–8.42 (m, 1 H), 8.08–8.06 (m, 1 H), 7.79 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.41–7.38 (m, 3 H), 7.29–7.25 (m, 4 H), 7.14 (d, J = 7.5 Hz, 2 H), 7.11–6.88 (m, 3 H), 5.49–5.42 (m, 1 H), 1.37 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 162.0 (d, J _C–F = 244.0 Hz), 149.5, 147.7, 140.9, 139.0, 138.1 (d, J _C–F = 3.5 Hz), 137.1, 131.1, 131.1, 131.0, 126.0 (d, J _C–F = 7.6 Hz), 121.9, 114.9 (d, J _C–F = 21.2 Hz), 46.6, 23.3.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –115.71.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₁F₂N₂O: 415.1622; found: 415.1630.

The HPLC of compound 7f-(RS) was determined by HPLC using a Daicel Chiralpak IB column, hexane/i-PrOH 98:02, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 11.35 min, t_S = 18.51 min.

(R)-N-(1-(4,4′′-Difluoro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7f-(R))

Compound 7f-(R) was obtained as a colorless semi-solid (60 mg, 72%, 0.20 mmol scale).

R_f =0.7 (EtOAc/hexane = 20:80); [α] _d ²⁵ –104.4 (c = 0.12, CHCl₃).

IR (DCM): 3386, 1676, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.41–8.39 (m, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.77 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.66–7.10 (m, 13 H), 5.46–5.39 (m, 1 H), 1.34 (d, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 162.1 (d, J _C–F = 250.0 Hz), 149.5, 147.7, 140.8, 139.0, 138.1 (d, J _C–F = 3.5 Hz), 137.1, 131.1, 131.0, 131.0, 126.0 (d, J _C–F = 6.2 Hz), 121.8, 114.9 (d, J _C–F = 21.1 Hz), 46.5, 23.3.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –115.74.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₁F₂N₂O: 415.1622; found 415.1620.

The enantiomeric excess (ee 89%) of compound 7f-(R) was determined by HPLC using a Daicel Chiralpak IB column, hexane/i-PrOH 98:02, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 11.23 min, t_S = 18.21 min.

(S)-N-(1-(4,4′′-Difluoro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7f-(S))

Compound 7f-(S) was obtained as a colorless semi-solid (56 mg, 68%, 0.20 mmol scale).

R_f =0.7 (EtOAc/hexane = 20:80); [α] _d ²⁵ 103.8 (c = 0.12, CHCl₃).

IR (DCM): 3389, 1674, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.41–8.39 (m, 1 H), 8.04 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.77 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.38–7.10 (m, 12 H), 5.46–5.39 (m, 1 H), 1.34 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 162.1 (d, J _C–F = 244.2 Hz), 149.5, 147.7, 140.8, 139.0, 138.1 (d, J _C–F = 3.6 Hz), 137.1, 131.1, 131.0, 131.0, 126.0 (d, J _C–F = 5.6 Hz), 121.8, 114.9 (d, J _C–F = 21.2 Hz), 46.5, 23.3.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –115.72.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₁F₂N₂O: 415.1622; found 415.1623.

The enantiomeric excess (ee 98%) of compound 7f-(S) was determined by HPLC using a Daicel Chiralpak IB column, hexane/i-PrOH 98:02, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 10.71 min, t_S = 17.45 min.

N-(1-(4,4′′-Dichloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7g-(RS))

Compound 7g-(RS) was obtained as a colorless solid (59 mg, 53%, 0.25 mmol scale).

R_f = 0.7 (EtOAc/hexane = 20:80); mp 165–167 °C.

IR (KBr): 3055, 1675, 1513, cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46–8.44 (m, 1 H), 8.05 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.80 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 1 H), 7.42–7.39 (m, 4 H), 7.37–7.26 (m, 6 H), 7.13 (d, J = 7.5 Hz, 2 H), 5.47–5.39 (m, 1 H), 1.37 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 149.4, 147.8, 140.6, 140.6, 138.8, 137.1, 133.1, 130.8, 130.8, 128.3, 126.0, 121.7, 46.6, 23.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₁Cl₂N₂O: 447.1031; found 447.1030.

The HPLC of compound 7g-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 10.89 min, t_R = 12.29 min.

(R)-N-(1-(4,4′′-Dichloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7g-(R))

Compound 7g-(R) was obtained as a colorless solid (50 mg, 56%, 0.20 mmol scale).

R_f = 0.7 (EtOAc/hexane = 20:80); mp 165–167 °C; [α] _d ²⁵ –92.2 (c = 0.10, CHCl₃).

IR (DCM): 3386, 1674, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.43–8.41 (m, 1 H), 8.03 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.77 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.62–7.09 (m, 13 H), 5.44–5.37 (m, 1 H), 1.35 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 149.4, 147.8, 140.6, 140.6, 138.8, 137.1, 133.1, 130.8, 130.8, 128.3, 126.0, 121.7, 46.6, 23.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₁Cl₂N₂O: 447.1031; found 447.1031.

The enantiomeric excess (ee 95%) of compound 7g-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 10.57 min, t_R = 12.10 min.

(S)-N-(1-(4,4′′-Dichloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7g-(S))

Compound 7g-(S) was obtained as a colorless solid (46 mg, 52%, 0.20 mmol scale).

R _f = 0.7 (EtOAc/hexane = 20:80); mp 165–167 °C; [α] _d ²⁵ 83.6 (c = 0.10, CHCl₃).

IR (DCM): 3382, 1675, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.43–8.41 (m, 1 H), 8.03 (dt, ¹ J = 7.8, ² J = 0.9 Hz, 1 H), 7.77 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.62–7.09 (m, 13 H), 5.44–5.37 (m, 1 H), 1.35 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 149.4, 147.8, 140.6, 140.6, 138.8, 137.1, 133.1, 130.8, 130.8, 128.3, 126.0, 121.7, 46.6, 23.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₁Cl₂N₂O: 447.1031; found 447.1032.

The enantiomeric excess (ee 97%) of compound 7g-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 11.67 min, t_R = 13.39 min.

N-(1-(3,3′′,5,5′′-Tetrachloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7h-(RS))

Compound 7h-(RS) was obtained as a colorless semi-solid (88 mg, 68%, 0.25 mmol scale).

R_f = 0.75 (EtOAc/hexane = 20:80).

IR (KBr): 3056, 1675, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.48–8.46 (m, 1 H), 8.10 (dt, ¹ J = 7.8, ² J = 1.0 Hz, 1 H), 7.77 (td, ¹ J = 7.6, ² J = 1.7 Hz, 1 H), 7.71 (d, J = 7.8 Hz, 1 H), 7.61–7.47 (m, 2 H), 7.42–7.40 (m, 1 H), 7.38–7.37 (m, 2 H), 7.30–7.26 (m, 1 H,), 7.12 (d, J = 7.6 Hz, 4 H), 5.39–5.32 (m, 1 H), 1.43 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.9, 149.2, 148.2, 144.8, 139.2, 138.6, 137.2, 134.7, 131.0, 128.1, 127.4, 126.3, 126.1, 122.0, 46.6, 23.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₁₉Cl₄N₂O: 515.0251; found: 515.0259.

The HPLC of compound 7h-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.73 min, t_R = 8.31 min.

(R)-N-(1-(3,3′′,5,5′′-Tetrachloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7h-(R))

Compound 7h-(R) was obtained as a colorless semi-solid (62 mg, 60%, 0.20 mmol scale).

R _f = 0.75 (EtOAc/hexane = 20:80); [α] _d ²⁵ –138.3 (c = 0.05, CHCl₃).

IR (DCM): 3385, 1673, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.45–8.44 (m, 1 H), 8.08–8.06 (m, 1 H), 7.78 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.50–7.08 (m, 10 H), 5.36–5.29 (m, 1 H), 1.40 (d, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.9, 149.2, 148.2, 144.8, 139.2, 138.6, 137.2, 134.7, 131.0, 128.1, 127.4, 126.3, 126.1, 122.0, 46.6, 23.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₁₉Cl₄N₂O: 515.0251; found 515.0253.

The enantiomeric excess (ee 98%) of compound 7h-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.26 min, t_R = 8.34 min.

(S)-N-(1-(3,3′′,5,5′′-Tetrachloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7h-(S))

Compound 7h-(S) was obtained as a colorless semi-solid (60 mg, 59%, 0.20 mmol scale).

R _f = 0.75 (EtOAc/hexane = 20:80); [α] _d ²⁵ 120.7 (c = 0.05, CHCl₃).

IR (DCM): 3383, 1673, 1506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.45–8.44 (m, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.78 (td, ¹ J = 7.7, ² J = 1.7 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.40–7.09 (m, 10 H), 5.36–5.28 (m, 1 H), 1.40 (d, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.9, 149.2, 148.2, 144.8, 139.2, 138.5, 137.2, 134.6, 131.0, 128.0, 127.4, 126.2, 126.1, 122.0, 46.6, 23.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₁₉Cl₄N₂O: 515.0251; found 515.0250.

The enantiomeric excess (ee 98%) of compound 7h-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.87 min, t_R = 8.62 min.

N-(1-(3,3′′,4,4′′-Tetramethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7i-(RS))

Compound 7i-(RS) was obtained as a colorless solid (100 mg, 92%, 0.25 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80); mp 135–137 °C.

IR (DCM): 3388, 1675, 1508 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.29 (d, J = 4.5 Hz, 1 H), 7.99 (d, J = 7.7 Hz, 1 H), 7.70–7.65 (m, 2 H), 7.28–7.25 (m, 1 H), 7.18–7.02 (m, 9 H), 5.46–5.40 (m, 1 H), 2.23 (m, 6 H), 2.10 (m, 6 H), 1.29 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.4, 150.0, 147.4, 141.8, 139.9, 138.5, 136.8, 136.0, 135.0, 130.7, 130.4, 129.1, 126.8, 125.6, 125.5, 121.9, 46.6, 23.4, 19.7, 19.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁N₂O: 435.2436; found: 435.2446.

The HPLC of compound 7i-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.53 min, t_R = 7.96 min.

(R)-N-(1-(3,3′′,4,4′′-Tetramethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7i-(R))

Compound 7i-(R) was obtained as a colorless solid (138 mg, 91%, 0.35 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80); mp 135–137 °C; [α] _d ²⁵ –123.7 (c = 0.02, CHCl₃).

IR (DCM): 3383, 1671, 1511 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.29 (d, J = 4.3 Hz, 1 H), 7.99 (d, J = 7.7 Hz, 1 H), 7.70–7.65 (m, 2 H), 7.27–7.25 (m, 1 H), 7.18–7.02 (m, 9 H), 5.47–5.41 (m, 1 H), 2.23 (m, 6 H), 2.10 (m, 6 H), 1.29 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.5, 150.1, 147.5, 141.9, 139.9, 138.6, 136.9, 136.1, 135.1, 130.8, 130.5, 129.2, 126.9, 125.6, 125.5, 121.9, 46.7, 23.5, 19.7, 19.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁N₂O: 435.2436; found: 435.2449.

The enantiomeric excess (ee 92%) of compound 7i-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.53 min, t_R  = 7.97 min.

(S)-N-(1-(3,3′′,4,4′′-Tetramethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7i-(S))

Compound 7i-(S) was obtained as a colorless solid (135 mg, 89%, 0.35 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80); mp 135–137 °C; [α] _d ²⁵ 139.7 (c = 0.02, CHCl₃).

IR (DCM): 3378, 1675, 1508 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.30 (d, J = 4.3 Hz, 1 H), 8.02 (d, J = 7.7 Hz, 1 H), 7.76–7.73 (m, 2 H), 7.33–7.31 (m, 1 H), 7.19–7.02 (m, 9 H), 5.45–5.39 (m, 1 H), 2.22 (m, 6 H), 2.10 (m, 6 H), 1.30 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.4, 150.0, 147.4, 141.8, 139.9, 138.5, 136.8, 136.0, 135.0, 130.7, 130.4, 129.1, 126.8, 125.6, 125.5, 121.9, 46.6, 23.4, 19.7, 19.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁N₂O: 435.2436; found: 435.2447.

The enantiomeric excess (ee 95%) of compound 7i-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.52 min, t_R = 7.95 min.

N-(1-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)ethyl)picolinamide (7j-(RS))

Compound 7j-(RS) was obtained as an orange colored solid (91 mg, 74%, 0.25 mmol scale).

R_f = 0.2 (EtOAc/hexane = 20:80); mp 96–98 °C.

IR (DCM): 3374, 1670, 1503 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 4.6 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.75 (td, ¹ J = 7.7 Hz, ² J = 1.4 Hz, 1 H), 7.35–7.32 (m, 1 H), 7.22–7.18 (m, 1 H), 7.10 (d, J = 7.6 Hz, 2 H), 7.00–6.20 (m, 6 H), 5.59–5.52 (m, 1 H), 4.29 (s, 8 H), 1.41 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 150.0, 147.6, 142.9, 142.7, 141.2, 138.9, 137.0, 135.6, 130.8, 125.7, 125.6, 122.8, 122.0, 118.5, 116.8, 64.4, 46.6, 23.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₅: 495.1920; found: 495.1914.

The HPLC of compound 7j-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 12.50 min, t_R = 19.48 min.

(R)-N-(1-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)ethyl)picolinamide (7j-(R))

Compound 7j-(R) was obtained as an orange colored solid (101 mg, 82%, 0.25 mmol scale).

R_f = 0.2 (EtOAc/hexane = 20:80); mp 96–98 °C; [α] _d ²⁵ –46.8 (c = 0.06, CHCl₃).

IR (DCM): 3382, 1670, 1504 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 4.5 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.75 (td, ¹ J = 7.7 Hz, ² J = 1.5 Hz, 1 H), 7.35–7.32 (m, 1 H), 7.22–7.18 (m, 1 H), 7.10 (d, J = 7.5 Hz, 2 H), 7.00–6.20 (m, 6 H), 5.59–5.52 (m, 1 H), 4.29 (s, 8 H), 1.41 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 150.0, 147.6, 142.9, 142.7, 141.2, 138.9, 137.0, 135.6, 130.8, 125.7, 125.6, 122.8, 122.0, 118.5, 116.8, 64.4, 46.6, 23.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₅: 495.1920; found: 495.1916.

The enantiomeric excess (ee 98%) of compound 7j-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 11.96 min, t_R = 18.56 min.

(S)-N-(1-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)ethyl)picolinamide (7j-(S))

Compound 7j-(S) was obtained as an orange colored solid (92 mg, 75%, 0.25 mmol scale).

R_f = 0.2 (EtOAc/hexane = 20:80); mp 96–98 °C; [α] _d ²⁵ 44.9 (c = 0.06, CHCl₃).

IR (DCM): 3370, 1670, 1504 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 4.5 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.75 (td, ¹ J = 7.7 Hz, ² J = 1.6 Hz, 1 H), 7.35–7.32 (m, 1 H), 7.22–7.18 (m, 1 H), 7.10 (d, J = 7.5 Hz, 2 H), 7.00–6.20 (m, 6 H), 5.59–5.52 (m, 1 H), 4.29 (s, 8 H), 1.41 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 150.0, 147.6, 142.9, 142.7, 141.2, 138.9, 137.0, 135.6, 130.8, 125.7, 125.6, 122.8, 122.0, 118.5, 116.8, 64.4, 46.6, 23.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₇N₂O₅: 495.1920; found: 495.1904.

The enantiomeric excess (ee >98%) of compound 7j-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 70:30, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 11.82 min, t_R = 18.38 min.

N-(1-(5′-Methyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7k-(RS))

Compound 7k-(RS) was obtained as a colorless semi-solid (48 mg, 62%, 0.20 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80).

IR (DCM): 3384, 1670, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.35 (d, J = 4.6 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.75–7.69 (m, 2 H), 7.61–7.16 (m, 11 H), 7.00 (s, 2 H), 5.48–5.40 (m, 1 H), 2.31 (s, 3 H), 1.34 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 149.8, 147.5, 142.4, 141.7, 136.9, 135.6, 135.2, 131.3, 129.5, 127.9, 126.9, 125.6, 121.8, 46.3, 23.4, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₅N₂O: 393.1967; found: 393.1970.

The HPLC of compound 7k-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 12.20 min, t_S = 13.37 min.

(R)-N-(1-(5′-Methyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7k-(R))

Compound 7k-(R) was obtained as a colorless semi-solid (46 mg, 59%, 0.20 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80); [α] _d ²⁵ –59.2 (c = 0.03, CHCl₃).

IR (DCM): 3383, 1670, 1492 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.36–8.34 (m, 1 H), 8.05–8.02 (m, 1 H), 7.76–7.68 (m, 2 H), 7.48–7.25 (m, 11 H), 7.00 (s, 2 H), 5.47–5.41 (m, 1 H), 2.32 (s, 3 H), 1.34 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 149.8, 147.5, 142.3, 141.7, 136.9, 135.6, 135.2, 131.3, 129.5, 127.9, 126.8, 125.6, 121.8, 46.3, 23.3, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₅N₂O: 393.1967; found: 393.1954.

The enantiomeric excess (ee 95%) of compound 7k-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 12.18 min, t_S = 13.40 min.

(S)-N-(1-(5′-Methyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7k-(S))

Compound 7k-(S) was obtained as a colorless semi-solid (49 mg, 63%, 0.20 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80); [α] _d ²⁵ = +57.8 (c = 0.03, CHCl₃).

IR (DCM): 3383, 1670, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.35 (d, J = 4.4 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.75–7.68 (m, 2 H), 7.34–7.24 (m, 11 H), 7.00 (s, 2 H), 5.48–5.40 (m, 1 H), 2.31 (s, 3 H), 1.34 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 149.8, 147.5, 142.3, 141.7, 136.9, 135.6, 135.2, 131.3, 129.5, 127.9, 126.8, 125.6, 121.8, 46.3, 23.3, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₅N₂O: 393.1967; found: 393.1971.

The enantiomeric excess (ee 97%) of compound 7k-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 12.25 min, t_S = 13.38 min.

N-(1-(5′-Chloro-4,4′′-dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7l-(RS))

Compound 7l-(RS) was obtained as a yellow colored semi-solid (68 mg, 58%, 0.25 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80).

IR (DCM): 3380, 1673, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.37 (d, J = 4.3 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.76 (t, J = 7.7 Hz, 1 H), 7.69 (d, J = 7.8 Hz, 1 H), 7.36–7.26 (m, 5 H), 7.12 (s, 2 H), 7.00–6.80 (m, 4 H), 5.48–5.40 (m, 1 H), 3.84 (s, 6 H), 1.33 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.6, 158.8, 149.6, 147.5, 143.2, 138.0, 137.0, 133.2, 131.0, 130.4, 130.3, 125.8, 121.8, 113.5, 55.2, 46.1, 23.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₆ClN₂O₃: 473.1632; found: 473.1624.

The HPLC of compound 7l-(RS) was determined by using a Daicel Chiralpak IA column, hexane/i-PrOH 50:50, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 6.07 min, t_S = 7.40 min.

(R)-N-(1-(5′-Chloro-4,4′′-dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7l-(R))

Compound 7l-(R) was obtained as a yellow colored semi-solid (68 mg, 58%, 0.25 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); [α] _d ²⁵ –33.9 (c = 0.04, CHCl₃).

IR (DCM): 3375, 1675, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.38 (d, J = 4.1 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.76 (td, ¹ J = 7.7 Hz, ² J = 1.6 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.37–7.26 (m, 5 H), 7.12 (s, 2 H), 7.00–6.80 (m, 4 H), 5.48–5.40 (m, 1 H), 3.84 (s, 6 H), 1.33 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 158.9, 149.7, 147.6, 143.3, 138.1, 137.1, 133.3, 131.1, 130.5, 130.4, 125.8, 121.9, 113.5, 55.3, 46.2, 23.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₆ClN₂O₃: 473.1632; found: 473.1642.

The enantiomeric excess (ee 94%) of compound 7l-(R) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 50:50, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 5.85 min, t_S = 7.16 min.

(S)-N-(1-(5′-Chloro-4,4′′-dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)picolinamide (7l-(S))

Compound 7l-(S) was obtained as a yellow colored semi-solid (70 mg, 60%, 0.25 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); [α] _d ²⁵ 49.9 (c = 0.04, CHCl₃).

IR (DCM): 3380, 1675, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.38 (d, J = 4.3 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.76 (td, ¹ J = 7.7 Hz, ² J = 1.5 Hz, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.37–7.26 (m, 5 H), 7.12 (s, 2 H), 7.00–6.80 (m, 4 H), 5.47–5.40 (m, 1 H), 3.85 (s, 6 H), 1.33 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.7, 158.9, 149.7, 147.6, 143.3, 138.1, 137.0, 133.3, 131.1, 130.5, 130.4, 125.8, 121.9, 113.5, 55.3, 46.2, 23.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₆ClN₂O₃: 473.1632; found: 473.1644.

The enantiomeric excess (ee 98%) of compound 7l-(S) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 50:50, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 6.06 min, t_S = 7.42 min.

N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)propyl)picolinamide (7m-(RS))

Compound 7m-(RS) was obtained as a black colored liquid (35 mg, 30%, 0.25 mmol scale).

R _f = 0.4 (EtOAc/hexane = 20:80).

IR (KBr): 3346, 2937, 1394, 1265 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.43 (d, J = 4.6 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.81–7.75 (m, 2 H), 7.39–7.36 (m, 4 H), 7.27 (d, J = 7.0 Hz, 1 H), 7.24 (d, J = 7.5 Hz, 1 H), 7.14 (d, J = 7.5 Hz, 2 H), 7.00–6.90 (m, 4 H), 5.37–5.31 (m, 1 H), 3.89 (s, 6 H), 1.77–1.69 (m, 2 H), 0.66 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 163.1, 158.6, 149.9, 147.5, 141.8, 138.5, 137.0, 134.7, 130.8, 130.7, 125.7, 125.7, 122.0, 113.3, 55.3, 52.7, 30.8, 11.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₉N₂O₃: 453.2178; found: 453.2158.

N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)-5-methylisoxazole-3-carboxamide (7n-(RS))

Compound 7n-(RS) was obtained as a yellow colored semi-solid (52 mg, 59%, 0.20 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80).

IR (DCM): 3410, 1678, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.22 (m, 5 H), 7.12 (d, J = 7.5 Hz, 2 H), 6.96–6.94 (m, 4 H), 6.53 (d, J = 8.6 Hz, 1 H), 6.29 (s, 1 H), 5.49–5.41 (m, 1 H), 3.85 (s, 6 H), 2.42 (s, 3 H), 1.29 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.5, 158.7, 158.4, 157.5, 141.5, 138.5, 134.2, 130.7, 130.5, 125.9, 113.5, 101.1, 55.2, 46.6, 23.0, 12.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₇H₂₆N₂NaO₄: 465.1790; found: 465.1779.

The HPLC of compound 7n-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 19.22 min, t_R = 22.34 min.

(R)-N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)-5-methylisoxazole-3-carboxamide (7n-(R))

Compound 7n-(R) was obtained as a yellow colored semi-solid (45 mg, 51%, 0.20 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); [α] _d ²⁵ –8.9 (c = 0.06, CHCl₃).

IR (DCM): 3415, 1678, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.22 (m, 5 H), 7.12 (d, 2 H, J = 7.6 Hz), 6.96–6.94 (m, 4 H), 6.53 (d, 1 H, J = 8.5 Hz), 6.29 (s, 1 H), 5.48–5.40 (m, 1 H), 3.86 (s, 6 H), 2.43 (s, 3 H), 1.29 (d, 3 H, J = 7.2 Hz).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.6, 158.8, 158.5, 157.6, 141.6, 138.6, 134.3, 130.8, 130.6, 126.0, 113.5, 101.2, 55.3, 46.7, 23.0, 12.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₇N₂O₄: 443.1971; found: 443.1948.

The enantiomeric excess (ee 95%) of compound 7n-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 18.38 min, t_R = 21.35 min.

(S)-N-(1-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl)-5-methylisoxazole-3-carboxamide (7n-(S))

Compound 7n-(S) was obtained as a yellow colored semi-solid (48 mg, 54%, 0.20 mmol scale).

R_f = 0.4 (EtOAc/hexane = 20:80); [α] _d ²⁵ = +8.32 (c = 0.06, CHCl₃).

IR (DCM): 3402, 1678, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.22 (m, 5 H), 7.12 (d, J = 7.6 Hz, 2 H), 6.96–6.94 (m, 4 H), 6.53 (d, J = 8.5 Hz, 1 H), 6.29 (s, 1 H), 5.48–5.40 (m, 1 H), 3.86 (s, 6 H), 2.43 (s, 3 H), 1.29 (d, J = 7.2 Hz, 3 H).

¹³C NMR (~101 MHz, CDCl₃): δ = 170.6, 158.8, 158.5, 157.6, 141.6, 138.6, 134.3, 130.8, 130.6, 126.0, 113.5, 101.2, 55.3, 46.7, 23.0, 12.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₇H₂₇N₂O₄: 443.1971; found: 443.1991.

The enantiomeric excess (ee 95%) of compound 7n-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 17.89 min, t_R = 21.10 min.

N-(1-(4′-Bromo-[1,1′-biphenyl]-2-yl)ethyl)pyrazine-2-carboxamide (7o-(RS))

Compound 7o-(RS) was obtained as a colorless solid (25 mg, 26%, 0.25 mmol scale).

R_f = 0.7 (EtOAc/hexane = 20:80); mp 131–133 °C.

IR (KBr): 3055, 1721, 1428, 1265 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.30 (d, J = 1.4 Hz, 1 H), 8.71 (d, J = 2.4 Hz, 1 H), 8.45 (br. s, 1 H), 7.53–7.50 (m, 3 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.31–7.27 (m, 2 H), 7.14 (d, J = 7.6 Hz, 2 H), 5.46–5.38 (m, 1 H), 1.41 (d, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (CDCl₃, ~101 MHz): δ = 161.4, 147.1, 144.1, 144.1, 144.0, 142.6, 140.2, 138.0, 132.4, 130.9, 130.3, 129.7, 128.1, 126.2, 122.4, 46.7, 23.4

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₇BrN₃O: 382.0555; found: 382.0567.

2-(4′-Acetyl-[1,1′-biphenyl]-2-yl)-2-(picolinamido)ethyl Acetate (8aa-(RS))

The racemic compound 8aa-(RS) (from 4a-(RS) under the optimized condition using Pd(OAc)₂, KOAc condition) was obtained as a colorless semi-solid (28 mg, 35%, 0.2 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50).

IR (DCM): 3367, 1751, 1505 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J = 7.7 Hz, 1 H), 8.60 (d, J = 4.2 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.08 (d, J = 7.9 Hz, 2 H), 7.85 (t, J = 7.7 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 2 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.48–7.36 (m, 3 H), 7.25 (d, J = 7.4 Hz, 1 H), 5.61–5.56 (m, 1 H), 4.33 (dd, ¹ J = 11.5 Hz, ² J = 7.4 Hz, 1 H), 4.12 (dd, ¹ J = 11.5 Hz, ² J = 4.5 Hz, 1 H), 2.67 (s, 3 H), 2.00 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.9, 170.9, 163.9, 149.4, 148.2, 145.5, 140.7, 137.4, 136.1, 136.0, 130.2, 129.7, 128.6, 128.4, 127.9, 126.4, 126.4, 122.2, 65.9, 49.7, 26.7, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₃N₂O₄: 403.1658; found: 403.1646.

The HPLC of compound 8aa-(RS) was determined by using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 11.01 min, t_R = 11.95 min.

(R)-2-(4′-Acetyl-[1,1′-biphenyl]-2-yl)-2-(picolinamido)ethyl Acetate (8aa-(R))

Compound 8aa-(R) (from 4a-(R) under the optimized condition using Pd(OAc)₂, KOAc condition) was obtained as a colorless semi-solid (33 mg, 41%, 0.2 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50); [α] _d ²⁵ 175.9 (c = 0.06, CHCl₃).

IR (DCM): 3367, 1738, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J = 7.8 Hz, 1 H), 8.60 (d, J = 4.5 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 2 H), 7.85 (td, ¹ J = 7.7 Hz, ² J = 1.2 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.47–7.35 (m, 3 H), 7.25 (d, J = 7.3 Hz, 1 H), 5.61–5.56 (m, 1 H), 4.36–4.31 (m, 1 H), 4.13 (dd, ¹ J = 11.5 Hz, ² J = 4.6 Hz, 1 H), 2.67 (s, 3 H), 2.00 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.9, 170.9, 163.9, 149.4, 148.2, 145.5, 140.7, 137.4, 136.1, 136.0, 130.2, 129.7, 128.6, 128.4, 127.9, 126.4, 126.4, 122.2, 65.9, 49.7, 26.8, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₃N₂O₄: 403.1658; found: 403.1642.

The enantiomeric excess (ee 96%) of compound 8aa-(R) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 11.48 min, t_R = 12.14 min.

(S)-2-(4′-Acetyl-[1,1′-biphenyl]-2-yl)-2-(picolinamido)ethyl Acetate (8aa-(S))

Compound 8aa-(S) (from 4a-(S) under the optimized condition using Pd(OAc)₂, KOAc condition) was obtained as a colorless semi-solid (30 mg, 37%, 0.2 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50); [α] _d ²⁵ –170.5 (c = 0.06, CHCl₃).

IR (DCM): 3367, 1751, 1505 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J = 7.6 Hz, 1 H), 8.60 (d, J = 4.6 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 2 H), 7.85 (t, J = 7.7 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 2 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.48–7.35 (m, 3 H), 7.25 (d, J = 7.4 Hz, 1 H), 5.61–5.56 (m, 1 H), 4.33 (dd, ¹ J = 11.3 Hz, ² J = 7.4 Hz, 1 H), 4.12 (dd, ¹ J = 11.4 Hz, ² J = 4.5 Hz, 1 H), 2.67 (s, 3 H), 2.00 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.9, 170.9, 163.9, 149.4, 148.2, 145.5, 140.7, 137.4, 136.1, 136.0, 130.2, 129.7, 128.6, 128.4, 127.9, 126.4, 126.4, 122.2, 65.9, 49.7, 26.7, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₃N₂O₄: 403.1658; found: 403.1648.

The enantiomeric excess (ee 95%) of compound 8aa-(S) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 10.20 min, t_R = 10.92 min.

2-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8a-(RS))

Compound 8a-(RS) was obtained as a colorless solid (89 mg, 86%, 0.2 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50); mp 104–106 °C.

IR (DCM): 3371, 1740, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.31 (d, J = 4.6 Hz, 1 H), 8.05–7.34 (m, 13 H), 7.18 (d, J = 7.6 Hz, 2 H), 5.68–5.62 (m, 1 H), 4.27–4.22 (m, 1 H), 4.14 (dd, ¹ J = 11.5 Hz, ² J = 4.9 Hz, 1 H), 2.67 (s, 6 H), 1.88 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.8, 170.6, 163.4, 149.0, 147.8, 146.6, 141.8, 137.2, 136.1, 132.9, 130.8, 130.0, 128.4, 127.1, 126.3, 121.9, 65.8, 50.5, 26.8, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₉N₂O₅: 521.2076; found: 521.2058.

The HPLC of compound 8a-(RS) was determined by using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t _S = 13.44 min, t _R = 15.05 min.

(R)-2-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8a-(R))

Compound 8a-(R) was obtained as a colorless solid (100 mg, 96%, 0.2 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50); mp 104–106 °C; [α] _d ²⁵ 119.5 (c = 0.04, CHCl₃).

IR (DCM): 3371, 1742, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.31–8.30 (m, 1 H), 8.04–7.33 (m, 13 H), 7.17 (d, J = 7.6 Hz, 2 H), 5.67–5.62 (m, 1 H), 4.26–4.21 (m, 1 H), 4.13 (dd, ¹ J = 11.5 Hz, ² J = 5.0 Hz, 1 H), 2.65 (s, 6 H), 1.86 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.7, 170.6, 163.4, 149.0, 147.8, 146.5, 141.8, 137.2, 136.1, 132.9, 130.7, 129.8, 128.3, 127.0, 126.2, 121.9, 65.8, 50.5, 26.7, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₉N₂O₅: 521.2076; found: 521.2056.

The enantiomeric excess (ee >97%) of compound 8a-(R) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t _S = 13.03 min, t_R = 14.30.

(S)-2-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8a-(S))

Compound 8a-(S) was obtained as a colorless solid (79 mg, 76%, 0.2 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50); mp 104–106 °C; [α] _d ²⁵ –127.0 (c = 0.04, CHCl₃).

IR (DCM): 3367, 1738, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.32 (d, J = 4.6 Hz, 1 H), 8.06–7.34 (m, 13 H), 7.17 (d, J = 7.6 Hz, 2 H), 5.67–5.64 (m, 1 H), 4.27–4.12 (m, 2 H), 2.67 (s, 6 H), 1.88 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.8, 170.6, 163.4, 149.0, 147.8, 146.6, 141.8, 137.2, 136.1, 132.9, 130.7, 129.8, 128.4, 127.0, 126.3, 121.9, 65.8, 50.5, 26.7, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₉N₂O₅: 521.2076; found: 521.2064.

The enantiomeric excess (ee >98%) of compound 8a-(S) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t _S = 12.76 min, t_R = 14.44.

2-(4,4′′-Dibromo-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8b-(RS))

Compound 8b-(RS) was obtained as a yellow colored solid (107 mg, 90%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 185–187 °C.

IR (DCM): 3298, 1672, 1351 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (d, J = 4.5 Hz, 1 H), 8.05 (d, J = 7.8 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.63–7.15 (m, 12 H), 5.72–5.66 (m, 1 H), 4.28–4.23 (m, 1 H), 4.17–4.13 (m, 1 H), 1.93 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.0, 148.0, 141.6, 140.5, 137.2, 133.2, 131.4, 131.1, 130.9, 127.0, 126.2, 121.8, 121.7, 66.0, 50.5, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃Br₂N₂O₃: 593.0075; found: 593.0099.

2-(4,4′′-Dinitro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8c-(RS))

Compound 8c-(RS) was obtained as a yellow colored semi-solid (84 mg, 80%, 0.2 mmol scale).

R_f = 0.40 (EtOAc/hexane = 50:50).

IR (DCM): 3370, 1739, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.33–7.21 (m, 16 H), 5.58–5.53 (m, 1 H), 4.28–4.12 (m, 2 H), 1.90 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.5, 163.5, 148.6, 148.2, 147.9, 147.3, 140.8, 137.4, 132.9, 131.0, 130.5, 127.4, 126.6, 123.5, 121.9, 65.3, 50.8, 20.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃N₄O₇: 527.1567; found: 527.1589.

The HPLC of compound 8c-(RS) was determined by using a Daicel Chiralpak AD-H column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 19.85 min, t_R = 26.06 min.

(R)-2-(4,4′′-Dinitro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8c-(R))

Compound 8c-(R) was obtained as a yellow colored semi-solid (82 mg, 78%, 0.2 mmol scale).

R_f = 0.40 (EtOAc/hexane = 50:50); [α] _d ²⁵ 135.3 (c = 0.06, CHCl₃).

IR (DCM): 3374, 1742, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.33–7.21 (m, 16 H), 5.58–5.52 (m, 1 H), 4.28–4.12 (m, 2 H), 1.89 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.6, 163.5, 148.6, 148.2, 147.9, 147.3, 140.8, 137.4, 132.9, 131.0, 130.5, 127.4, 126.6, 123.6, 121.9, 65.3, 50.8, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃N₄O₇: 527.1567; found: 527.1585.

The enantiomeric excess (ee 98%) of compound 8c-(R) was determined by HPLC using a Daicel Chiralpak AD-H column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 22.43 min, t_R = 27.45 min.

2-(4,4′′-Dichloro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8d-(RS))

Compound 8d-(RS) was obtained as a colorless solid (75 mg, 75%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50); mp 127–129 °C.

IR (DCM): 3374, 1741, 1505 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.48 (d, J = 4.0 Hz, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.82–7.79 (m, 2 H), 7.57–7.15 (m, 12 H), 5.72–5.66 (m, 1 H), 4.28–4.13 (m, 2 H), 1.91 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.1, 147.9, 141.6, 140.0, 137.1, 133.5, 133.4, 131.0, 130.8, 128.5, 127.0, 126.2, 121.8, 66.0, 50.5, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃Cl₂N₂O₃: 505.1086; found: 505.1093.

2-([1,1′:3′,1′′-Terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8e-(RS))

Compound 8e-(RS) was obtained as a yellow colored semi-solid (82 mg, 94%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50).

IR (DCM): 3373, 1742, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.43 (d, J = 4.4 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 8.9 Hz, 1 H), 7.79 (t, J = 7.7 Hz, 1 H), 7.58–7.18 (m, 14 H), 5.79–5.74 (m, 1 H), 4.30–4.16 (m, 2 H), 1.88 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.5, 147.7, 142.9, 141.7, 137.0, 133.4, 130.7, 129.6, 128.2, 127.4, 126.7, 126.0, 121.8, 66.2, 50.4, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₅N₂O₃: 437.1865; found: 437.1854.

The HPLC of compound 8e-(RS) was determined by using a Daicel Chiralcel OD column, hexane/i-PrOH 96:04, flow rate 0.5 mL/min, UV detection at 254 nm, t_S = 25.90 min, t_R = 29.35 min.

(S)-2-([1,1′:3′,1′′-Terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8e-(S))

Compound 8e-(S) was obtained as a yellow colored semi-solid (76 mg, 87%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50); [α] _d ²⁵ –47.2 (c = 0.05, CHCl₃).

IR (DCM): 3370, 1738, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.43 (d, J = 4.6 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.91 (d, J = 9.0 Hz, 1 H), 7.79 (t, J = 7.7 Hz, 1 H), 7.49–7.18 (m, 14 H), 5.80–5.74 (m, 1 H), 4.28 (t, J = 10.8 Hz, 1 H), 4.28 (t, ¹ J = 11.5, ² J = 4.88 Hz, 1 H), 1.88 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.5, 147.7, 142.9, 141.7, 137.0, 133.4, 130.7, 129.6, 128.2, 127.4, 126.7, 126.0, 122.0, 66.2, 50.4, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₅N₂O₃: 437.1865; found: 437.1846.

The enantiomeric excess (ee 90%) of compound 8e-(S) was determined by HPLC using a Daicel Chiralcel OD column, hexane/i-PrOH 96:04, flow rate 0.5 mL/min, UV detection at 254 nm, t_S = 25.55 min, t_R = 28.91 min.

2-(4,4′′-Dimethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8f-(RS))

Compound 8f-(RS) was obtained as a yellow colored solid (73 mg, 79%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 80–82 °C.

IR (DCM): 3372, 1741, 1512 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.44 (d, J = 4.7 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 9.1 Hz, 1 H), 7.80 (td, ¹ J = 7.7 Hz, ² J = 1.0 Hz, 1 H), 7.40–7.17 (m, 12 H), 5.82–5.76 (m, 1 H), 4.28–4.16 (m, 2 H), 2.45 (s, 6 H), 1.89 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.8, 163.3, 149.6, 147.6, 142.9, 138.8, 137.0, 136.9, 133.6, 130.7, 129.4, 128.9, 126.6, 125.9, 122.0, 66.4, 50.3, 21.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃: 465.2178; found: 465.2174.

2-(4,4′′-Diisopropyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8g-(RS))

Compound 8g-(RS) was obtained as a yellow colored semi-solid (65 mg, 63%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50).

IR (DCM): 3371, 1740, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.41 (d, J = 4.4 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 8.6 Hz, 1 H), 7.79 (t, J = 7.7 Hz, 1 H), 7.39–7.26 (m, 10 H), 7.19 (d, J = 7.4 Hz, 1 H), 5.83–5.77 (m, 1 H), 4.28–4.25 (m, 2 H), 3.04–3.0 (m, 2 H), 1.90 (s, 3 H), 1.35 (d, J = 6.8 Hz, 12 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.6, 147.7, 142.9, 139.1, 137.2, 137.0, 133.7, 130.8, 129.4, 126.6, 126.2, 125.9, 122.0, 66.6, 50.5, 30.8, 24.2, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₃₇N₂O₃: 521.2804; found: 521.2820.

2-(4,4′′-Bis(tosyloxy)-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8h-(RS))

Compound 8h-(RS) was obtained as a colorless solid (105 mg, 68%, 0.2 mmol scale).

R_f = 0.45 (EtOAc/hexane = 50:50); mp 174–176 °C.

IR (DCM): 3374, 1743, 1506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.54 (d, J = 4.3 Hz, 1 H), 8.04 (d, J = 7.8 Hz, 1 H), 7.83–7.78 (m, 6 H), 7.44–7.13 (m, 12 H), 7.05 (br. s, 4 H), 5.61–5.56 (m, 1 H), 4.13–4.03 (m, 2 H), 2.45 (s, 6 H), 1.90 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.4, 163.5, 149.0, 148.3, 145.4, 141.6, 140.4, 137.1, 133.5, 132.3, 131.0, 130.9, 130.8, 129.8, 126.9, 126.3, 122.2, 121.8, 65.9, 50.3, 21.7, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₄₂H₃₇N₂O₉S₂: 777.1940; found: 777.1978.

2-(4,4′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8i-(RS))

Compound 8i-(RS) was obtained as a yellow colored semi-solid (79 mg, 80%, 0.2 mmol scale).

R_f = 0.40 (EtOAc/hexane = 50:50).

IR (DCM): 3363, 1743, 1505 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.45 (d, J = 4.4 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.97 (d, J = 9.1 Hz, 1 H), 7.79 (td, ¹ J = 7.7 Hz, ² J = 1.4 Hz, 1 H), 7.47–7.17 (m, 8 H), 6.98 (br. s, 4 H), 5.84–5.78 (m, 1 H), 4.28–4.17 (m, 2 H), 3.89 (s, 6 H), 1.90 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.8, 163.3, 158.9, 149.6, 147.7, 142.6, 137.0, 134.0, 134.0, 131.0, 130.6, 126.7, 126.0, 122.0, 113.6, 66.4, 55.3, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₅: 497.2076; found: 497.2064.

2-(3,3′′-Dibromo-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8j-(RS))

Compound 8j-(RS) was obtained as a yellow colored semi-solid (98 mg, 83%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50).

IR (DCM): 3376, 1743, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (d, J = 0.5 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.89 (d, J = 8.6 Hz, 1 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.56–7.17 (m, 12 H), 5.70–5.65 (m, 1 H), 4.29–4.16 (m, 2 H), 1.95 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.1, 148.4, 143.5, 141.4, 137.1, 133.4, 132.5, 131.0, 130.6, 129.7, 128.2, 126.9, 126.1, 122.5, 122.0, 66.0, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃Br₂N₂O₃: 593.0075; found: 593.0104.

The HPLC of compound 8j-(RS) was determined by using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t _S = 8.58 min, t_R = 7.85 min.

(R)-2-(3,3′′-Dibromo-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8j-(R))

Compound 8j-(R) was obtained as a yellow colored semi-solid (98 mg, 84%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); [α] _d ²⁵ 105.3 (c = 0.06, CHCl₃).

IR (DCM): 3375, 1742, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.56–7.17 (m, 12 H), 5.70–5.65 (m, 1 H), 4.29–4.16 (m, 2 H), 1.94 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.1, 148.4, 143.5, 141.4, 137.1, 133.4, 132.5, 131.0, 130.6, 129.7, 128.2, 126.9, 126.1, 122.5, 122.0, 66.0, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃Br₂N₂O₃: 593.0075; found: 593.0046.

The enantiomeric excess (ee 92%) of compound 8j-(R) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 8.61 min, t_R  = 7.88 min.

(S)-2-(3,3′′-Dibromo-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8j-(S))

Compound 8j-(S) was obtained as a yellow colored semi-solid (109 mg, 92%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); [α] _d ²⁵ –120.7 (c = 0.06, CHCl₃).

IR (DCM): 3375, 1740, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.52 (s, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 8.5 Hz, 1 H), 7.80 (t, J = 7.7 Hz, 1 H), 7.56–7.17 (m, 12 H), 5.71–5.66 (m, 1 H), 4.29–4.16 (m, 2 H), 1.94 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.1, 148.3, 143.5, 141.4, 137.1, 133.4, 132.5, 131.0, 130.6, 129.7, 128.2, 127.0, 126.1, 122.5, 122.0, 66.0, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃Br₂N₂O₃: 593.0075; found: 593.0046.

The enantiomeric excess (ee 92%) of compound 8j-(S) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 8.42 min, t_R = 7.72 min.

2-(3,3′′-Bis(trifluoromethyl)-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8k-(RS))

Compound 8k-(RS) was obtained as a colorless solid (91 mg, 80%, 0.2 mmol scale).

R_f = 0.50 (EtOAc/hexane = 50:50); mp 135–137 °C.

IR (DCM): 3379, 1745, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.38 (d, J = 0.24 Hz, 1 H), 8.06 (d, J = 7.7 Hz, 1 H), 7.81–7.37 (m, 12 H), 7.22 (d, J = 7.5 Hz, 2 H), 5.64–5.59 (m, 1 H), 4.26–4.17 (m, 2 H), 1.91 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.5, 163.5, 148.9, 148.0, 142.3, 141.5, 137.1, 133.6, 132.9, 131.3, 130.6 (q, J _C–F = 25.9 Hz), 128.8, 127.1, 126.3 (d, J _C–F = 2.4 Hz), 126.2, 124.4 (d, J _C–F = 2.1 Hz), 124.0 (q, J _C–F = 216.7 Hz), 121.9, 65.6, 50.5, 20.6.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –62.59.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₃F₆N₂O₃: 573.1613; found: 573.1635.

The HPLC of compound 8k-(RS) was determined by using a Daicel Chiralcel OD-H column, hexane/i-PrOH 98:02, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 9.38 min, t_R = 14.40 min.

(R)-2-(3,3′′-Bis(trifluoromethyl)-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8k-(R))

Compound 8k-(R) was obtained as a colorless solid (95 mg, 83%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 135–137 °C; [α] _d ²⁵ 60.0 (c = 0.08, CHCl₃).

IR (DCM): 3379, 1745, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.38 (d, J = 3.4 Hz, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.81–7.68 (m, 10 H), 7.40–7.36 (m, 2 H), 7.22 (d, J = 7.6 Hz, 2 H), 5.63–5.57 (m, 1 H), 4.27–4.16 (m, 2 H), 1.91 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.6, 163.5, 148.9, 148.0, 142.3, 141.5, 137.1, 133.6, 132.9, 131.3, 130.6 (q, J _C–F = 32.1 Hz), 128.8, 127.1, 126.3 (q, J _C–F = 3.6 Hz), 126.2, 124.4 (q, J _C–F = 3.6 Hz), 124.0 (q, J _C–F = 271 Hz), 121.9, 65.8, 50.5, 20.5.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –62.59.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₃F₆N₂O₃: 573.1613; found: 573.1639.

The enantiomeric excess (ee 91%) of compound 8k-(R) was determined by HPLC using a Daicel Chiralcel OD-H column, hexane/i-PrOH 98:02, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 9.99 min, t_R  = 14.28 min.

2-(3,3′′-Difluoro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8l-(RS))

Compound 8l-(RS) was obtained as a colorless solid (84 mg, 90%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 128–130 °C.

IR (DCM): 3374, 1741, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 3.9 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.93 (d, J = 8.7 Hz, 1 H), 7.80 (t, J = 7.7 Hz, 1 H), 7.41–7.11 (m, 12 H), 5.76–5.70 (m, 1 H), 4.29 (t, J = 10.6 Hz, 1 H), 4.17 (dd, ¹ J = 11.3 Hz, ² J = 4.9 Hz, 1 H), 1.91 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 162.4 (d, J _C–F = 245.8 Hz), 149.2, 148.0, 143.5 (d, J _C–F = 7.5 Hz), 141.6, 137.1, 133.3, 130.9, 129.8 (d, J _C–F = 8.5 Hz), 126.9, 126.1, 125.4 (d, J _C–F = 2.4 Hz), 121.9, 116.9 (d, J _C–F = 21.4 Hz), 114.5 (d, J _C–F = 20.8 Hz), 65.9, 50.3, 20.7.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –112.40, –112.96.[18]

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃F₂N₂O₃: 473.1677; found: 473.1661.

The HPLC of compound 8l-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 97:03, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 26.90 min, t_R = 30.67 min.

(R)-2-(3,3′′-Difluoro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8l-(R))

The compound 8l-(R) was obtained as a colorless solid (90 mg, 95%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 128–130 °C; [α] _d ²⁵ 65.2 (c = 0.05, CHCl₃).

IR (DCM): 3374, 1741, 1579 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 4.4 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 1 H), 7.80 (t, J = 7.7 Hz, 1 H), 7.41–7.11 (m, 12 H), 5.76–5.70 (m, 1 H), 4.31–4.13 (m, 2 H), 1.90 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 162.4 (d, J _C–F = 245.0 Hz), 149.2, 148.0, 143.5 (d, J _C–F = 7.6 Hz), 141.6, 137.1, 133.3, 130.9, 129.8 (d, J _C–F = 8.5 Hz), 126.9, 126.1, 125.4 (d, J _C–F = 2.5 Hz), 121.9, 116.9 (d, J _C–F = 21.6 Hz), 114.5 (d, J _C–F = 20.8 Hz), 65.9, 50.3, 20.7.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –112.46, –113.05.[18]

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃F₂N₂O₃: 473.1677; found: 473.1656.

The enantiomeric excess (ee >98%) of compound 8l-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 97:03, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = not detected min, t_R = 30.26 min.

2-(3,3′′-Dichloro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8m-(RS))

Compound 8m-(RS) was obtained as a yellow colored semi-solid (60 mg, 60%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50).

IR (DCM): 3375, 1742, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.50 (s, 1 H), 8.08 (d, J = 7.7 Hz, 1 H), 7.91 (d, J = 8.5 Hz, 1 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.40–7.17 (m, 12 H), 5.69–5.66 (m, 1 H), 4.29–4.16 (m, 2 H), 1.93 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.4, 149.1, 148.3, 143.2, 141.5, 137.1, 134.2, 133.4, 131.0, 129.7, 129.5, 127.7, 127.7, 126.9, 126.1, 122.0, 66.9, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₃Cl₂N₂O₃: 505.1086; found: 505.1096.

2-(3,3′′-Dimethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8n-(RS))

Compound 8n-(RS) was obtained as a yellow colored semi-solid (88 mg, 95%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50).

IR (DCM): 3375, 1740, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.46 (d, J = 4.4 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 8.01 (d, J = 9.1 Hz, 1 H), 7.77 (t, J = 7.7 Hz, 1 H), 7.39–7.20 (m, 12 H), 5.90–5.84 (m, 1 H), 4.36–4.30 (m, 1 H), 4.24 (dd, ¹ J = 11.3 Hz, ² J = 5.0 Hz, 1 H), 2.47 (s, 6 H), 1.90 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.3, 149.8, 149.7, 147.8, 143.0, 141.7, 137.8, 137.0, 133.3, 130.6, 130.3, 128.1, 126.6, 126.6, 125.9, 122.1, 66.3, 50.4, 21.5, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃: 465.2178; found: 465.2196.

2-(3,3′′-Dimethoxy-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8o-(RS))

Compound 8o-(RS) was obtained as a yellow colored semi-solid (83 mg, 84%, 0.2 mmol scale).

R_f = 0.40 (EtOAc/hexane = 50:50).

IR (DCM): 3367, 1740, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.43 (d, J = 4.4 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.93–7.91 (m, 1 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.47–6.93 (m, 12 H), 5.86–5.80 (m, 1 H), 4.40–4.34 (m, 1 H), 4.20 (dd, ¹ J = 11.3 Hz, ² J = 4.8 Hz, 1 H), 3.95–3.62 (m, 6 H), 1.89 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.8, 163.5, 159.3, 149.5, 147.9, 142.9, 142.7, 137.0, 133.2, 130.6, 129.3, 126.7, 125.9, 121.9, 121.8, 114.6, 113.6, 66.4, 55.0, 50.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₅: 497.2076; found: 497.2058.

2-(Picolinamido)-2-(3,3′′,5,5′′-tetramethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl Acetate (8p-(RS))

Compound 8p-(RS) was obtained as a colorless solid (80 mg, 82%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 113–115 °C.

IR (DCM): 3376, 1742, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.48 (dd, ¹ J = 4.7 Hz, ² J = 0.6 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 9.1 Hz, 1 H), 7.80 (td, ¹ J = 7.7 Hz, ² J = 1.7 Hz, 1 H), 7.41–7.37 (m, 1 H), 7.32–7.06 (m, 9 H), 5.80–5.78 (m, 1 H), 4.26–4.24 (m, 2 H), 2.38 (br. s, 12 H), 1.92 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.2, 149.8, 147.9, 143.2, 141.6, 137.6, 137.0, 133.2, 130.4, 129.0, 127.4, 126.5, 125.9, 122.2, 66.4, 50.4, 21.4, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₃N₂O₃: 493.2491; found: 493.2501.

The HPLC of compound 8p-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 9.44 min, t_R = 13.80 min.

(R)-2-(Picolinamido)-2-(3,3′′,5,5′′-tetramethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl Acetate (8p-(R))

Compound 8p-(R) was obtained as a colorless solid (90 mg, 92%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 114–116 °C; [α] _d ²⁵ 7.7 (c = 0.09, CHCl₃).

IR (DCM): 3378, 1741, 1510 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.43 (d, J = 4.7 Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.98 (d, J = 9.1 Hz, 1 H), 7.75 (td, ¹ J = 7.6 Hz, ² J = 1.7 Hz, 1 H), 7.35–7.33 (m, 1 H), 7.26–7.23 (m, 1 H), 7.15–7.01 (m, 6 H), 7.01 (s, 2 H), 5.76–5.72 (m, 1 H), 4.21–4.19 (m, 2 H), 2.32 (br. s, 12 H), 1.87 (s, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 170.6, 163.2, 149.9, 147.9, 143.2, 141.7, 137.6, 137.0, 133.3, 130.4, 129.0, 127.4, 126.5, 125.8, 122.2, 66.4, 50.4, 21.4, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₃N₂O₃: 493.2491; found: 493.2511.

The enantiomeric excess (ee 98%) of compound 8p-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 10.70 min, t_R = 14.66 min.

(S)-2-(Picolinamido)-2-(3,3′′,5,5′′-tetramethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl Acetate (8p-(S))

Compound 8p-(S) was obtained as a colorless solid (92 mg, 95%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 114–116 °C; [α] _d ²⁵ –4.7 (c = 0.09, CHCl₃).

IR (DCM): 3378, 1741, 1510 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.49–8.48 (m, 1 H), 8.12 (dd, ¹ J = 7.8 Hz, ² J = 0.9 Hz, 1 H), 8.03 (d, J = 9.1 Hz, 1 H), 7.81–7.78 (m, 1 H), 7.40–7.37 (m, 1 H), 7.32–7.29 (m, 1 H), 7.20–7.02 (m, 8 H), 5.82–5.77 (m, 1 H), 4.26–4.24 (m, 2 H), 2.37 (br. s, 12 H), 1.92 (s, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 170.6, 163.2, 149.9, 147.9, 143.2, 141.7, 137.6, 137.0, 133.3, 130.4, 129.0, 127.4, 126.5, 125.8, 122.2, 66.4, 50.4, 21.4, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₃N₂O₃: 493.2491; found: 493.2511.

The enantiomeric excess (ee 95%) of compound 8p-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 95:05, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 10.43 min, t_R = 15.02 min.

2-(Picolinamido)-2-(3,3′′,4,4′′-tetrachloro-[1,1′:3′,1′′-terphenyl]-2′-yl)ethyl Acetate (8q-(RS))

Compound 8q-(RS) was obtained as a colorless solid (101 mg, 88%, 0.2 mmol scale).

R_f = 0.70 (EtOAc/hexane = 50:50); mp 172–174 °C.

IR (DCM): 3379, 1745, 1513 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 4.0 Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.87–7.79 (m, 2 H), 7.56–7.16 (m, 10 H), 5.67–5.62 (m, 1 H), 4.28–4.14 (m, 2 H), 1.96 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.6, 163.4, 148.8, 148.3, 141.4, 140.4, 137.2, 133.4, 132.5, 131.8, 131.4, 131.2, 130.2, 128.8, 127.2, 126.3, 121.9, 65.8, 50.4, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₁Cl₄N₂O₃: 573.0306; found: 573.0311.

2-(4,4′′-Dibromo-3,3′′-difluoro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8r-(RS))

Compound 8r-(RS) was obtained as a colorless solid (94 mg, 75%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 152–154 °C.

IR (DCM): 3377, 1743, 1514 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 4.4 Hz, 1 H), 8.06 (d, J = 7.8 Hz, 1 H), 7.86–7.80 (m, 2 H), 7.65–7.17 (m, 10 H), 5.70–5.64 (m, 1 H), 4.26 (t, J = 10.6 Hz, 1 H), 4.15 (dd, ¹ J = 11.5 Hz, ² J = 5.0 Hz, 1 H), 1.94 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.6, 163.4, 158.7 (d, J _C–F = 247.5 Hz), 148.8, 148.2, 142.6 (d, J _C–F = 6.9 Hz), 140.6, 137.3, 133.3, 133.2, 131.1, 127.2, 126.4 (d, J _C–F = 2.1 Hz), 126.3, 121.8, 117.9 (d, J _C–F = 22.4 Hz), 108.4 (d, J _C–F = 20.7 Hz), 65.7, 50.4, 20.8.

¹⁹F{¹H} NMR (~376 MHz, CDCl₃): δ = –106.35, –106.92.[18]

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₁Br₂F₂N₂O₃: 628.9887; found: 628.9913.

2-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-2-(picolinamido)ethyl Acetate (8s-(RS))

Compound 8s-(RS) was obtained as a yellow colored solid (87 mg, 79%, 0.2 mmol scale).

R_f = 0.45 (EtOAc/hexane = 50:50); mp 190–192 °C.

IR (DCM): 3367, 1740, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 4.4 Hz, 1 H), 8.11–8.07 (m, 2 H), 7.78 (t, J = 7.6 Hz, 1 H), 7.40–7.37 (m, 1 H), 7.28–7.25 (m, 1 H), 7.16 (d, J = 7.5 Hz, 2 H), 6.91 (br. s, 6 H), 5.87–5.81 (m, 1 H), 4.33–4.28 (m, 9 H), 4.21–4.17 (m, 1 H), 1.93 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.3, 149.7, 147.8, 143.1, 142.9, 142.3, 137.0, 134.9, 133.8, 130.9, 126.6, 125.8, 122.8, 122.0, 118.6, 116.9, 66.4, 64.4, 50.2, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₉N₂O₇: 553.1975; found: 553.1949.

The HPLC of compound 8s-(RS) was determined by using a Daicel Chiralpak AD column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 23.78 min, t_R = 21.59 min.

(R)-2-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-2-(picolinamido)ethyl Acetate (8s-(R))

Compound 8s-(R) was obtained as a yellow colored solid (79 mg, 72%, 0.2 mmol scale).

R_f = 0.45 (EtOAc/hexane = 50:50); mp 190–192 °C; [α] _d ²⁵ 38.1 (c = 0.04, CHCl₃).

IR (DCM): 3368, 1740, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 4.3 Hz, 1 H), 8.11–8.08 (m, 2 H), 7.79 (t, J = 7.6 Hz, 1 H), 7.40–7.37 (m, 1 H), 7.29–7.25 (m, 1 H), 7.16 (d, J = 7.6 Hz, 2 H), 6.92 (br. s, 6 H), 5.87–5.81 (m, 1 H), 4.33–4.28 (m, 9 H), 4.19 (dd, ¹ J = 11.3 Hz, ² J ₌ 5.2 Hz, 1 H), 1.93 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.3, 149.6, 147.8, 143.1, 142.9, 142.3, 137.0, 134.9, 133.7, 130.9, 126.6, 125.9, 122.8, 122.1, 118.6, 116.9, 66.4, 64.4, 50.2, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₉N₂O₇: 553.1975; found: 553.1956.

The enantiomeric excess (ee 98%) of compound 8s-(R) was determined by HPLC using a Daicel Chiralpak AD column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 23.93 min, t_R = 21.43 min.

(S)-2-(2,6-Bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-2-(picolinamido)ethyl Acetate (8s-(S))

Compound 8s-(S) was obtained as a yellow colored solid (88 mg, 80%, 0.2 mmol scale).

R_f = 0.45 (EtOAc/hexane = 50:50); mp 190–192 °C; [α] _d ²⁵ –27.6 (c = 0.04, CHCl₃).

IR (DCM): 3367, 1739, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.49 (d, J = 4.4 Hz, 1 H), 8.11–8.07 (m, 2 H), 7.78 (t, J = 7.7 Hz, 1 H), 7.40–7.36 (m, 1 H), 7.28–7.25 (m, 1 H), 7.16 (d, J = 7.5 Hz, 2 H), 6.91 (br. s, 6 H), 5.87–5.81 (m, 1 H), 4.33–4.28 (m, 9 H), 4.22–4.17 (m, 1 H), 1.93 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.3, 149.6, 147.8, 143.1, 142.9, 142.3, 137.0, 134.9, 133.7, 130.9, 126.6, 125.8, 122.8, 122.1, 118.6, 116.9, 66.4, 64.4, 50.2, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₂₉N₂O₇: 553.1975; found: 553.1957.

The enantiomeric excess (ee 98%) of compound 8s-(S) was determined by HPLC using a Daicel Chiralpak AD column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 23.69 min, t_R = 21.96 min.

2-(2,6-Bis(1-methyl-1H-indol-5-yl)phenyl)-2-(picolinamido)ethyl Acetate (8za-(RS))

The compound 8za-(RS) was obtained as a red colored semi-solid (46 mg, 42%, 0.20 mmol scale).

R_f = 0.35 (EtOAc/hexane = 50:50).

IR (DCM): 3369, 1740, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.17 (br. s, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.72–7.09 (m, 14 H), 6.46 (br. s, 2 H), 5.93–5.87 (m, 1 H), 4.26–4.18 (m, 2 H), 3.83 (s, 6 H), 1.79 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.1, 149.8, 147.5, 143.9, 136.7, 135.9, 134.1, 132.9, 131.0, 129.3, 128.2, 126.1, 125.5, 123.5, 121.9, 121.8, 108.7, 101.1, 66.7, 50.2, 32.9, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₄H₃₁N₄O₃: 543.2396; found: 543.2398.

2-(3-Chloro-[1,1′-biphenyl]-2-yl)-2-(picolinamido)ethyl acetate (8t-(RS))

Compound 8t-(RS) was obtained as a yellow colored semi-solid (31 mg, 43%, 0.18 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50).

IR (DCM): 3382, 1743, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.09 (br. s, 1 H), 8.58 (d, J = 4.3 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.82 (t, J = 7.6 Hz, 1 H), 7.51–7.16 (m, 9 H), 5.89–5.83 (m, 1 H), 4.71–4.65 (m, 1 H), 4.44 (dd, ¹ J = 11.2 Hz, ² J = 5.8 Hz, 1 H), 1.96 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.6, 149.6, 148.2, 145.4, 140.2, 137.2, 133.9, 132.9, 130.2, 129.7, 129.4, 128.6, 128.3, 127.9, 126.2, 122.2, 64.2, 49.7, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₀ClN₂O₃: 395.1162; found: 395.1172.

2-(3-Chloro-4′-methyl-[1,1′-biphenyl]-2-yl)-2-(picolinamido)ethyl Acetate (8u-(RS))

Compound 8u-(RS) was obtained as a yellow colored semi-solid (46 mg, 51%, 0.22 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50).

IR (DCM): 3375, 1751, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.10 (br. s, 1 H), 8.58 (d, J = 4.5 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.82 (t, J = 7.7 Hz, 1 H), 7.44–7.15 (m, 8 H), 5.91–5.85 (m, 1 H), 4.66 (t, J = 10.7 Hz, 1 H), 4.44 (dd, ¹ J = 11.2 Hz, ² J = 5.8 Hz, 1 H), 2.45 (s, 3 H), 1.97 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.8, 163.6, 149.7, 148.2, 145.4, 137.5, 137.3, 137.2, 133.9, 132.9, 130.1, 129.8, 129.2, 129.0, 128.5, 126.1, 122.2, 64.2, 49.7, 21.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₂ClN₂O₃: 409.1319; found: 409.1337.

2-(5′-Chloro-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl ­acetate (8v-(RS))

Compound 8v-(RS) was obtained as a yellow colored semi-solid (76 mg, 90%, 0.18 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50).

IR (DCM): 3372, 1741, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.42 (d, J = 4.3 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.88–7.77 (m, 2 H), 7.44–7.27 (m, 11 H), 7.22 (s, 2 H), 5.72–5.66 (m, 1 H), 4.25 (t, J = 10.5 Hz, 1 H), 4.15 (dd, ¹ J = 11.4 Hz, ² J = 4.9 Hz, 1 H), 1.88 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.6, 163.4, 149.3, 147.8, 144.6, 140.4, 137.1, 132.2, 132.2, 130.5, 129.4, 128.3, 127.8, 126.0, 122.0, 65.8, 50.0, 20.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₄ClN₂O₃: 471.1475; found: 471.1463.

2-(5′-Chloro-4,4′′-dimethyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(picolinamido)ethyl Acetate (8w-(RS))

Compound 8w-(RS) was obtained as a yellow colored semi-solid (87 mg, 80%, 0.22 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50).

IR (DCM): 3372, 1741, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.44 (d, J = 4.4 Hz, 1 H), 8.08 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 8.9 Hz, 1 H), 7.80 (t, J = 7.6 Hz, 1 H), 7.46–7.02 (m, 11 H), 5.75–5.72 (m, 1 H), 4.23 (t, J = 10.6 Hz, 1 H), 4.15 (dd, ¹ J = 11.4 Hz, ² J = 5.2 Hz, 1 H), 2.45 (s, 6 H), 1.90 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.7, 163.3, 149.4, 147.7, 144.6, 137.5, 137.5, 137.1, 132.4, 132.1, 130.5, 129.2, 129.0, 126.0, 122.0, 66.0, 49.9, 20.3, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₈ClN₂O₃: 499.1788; found: 499.1773.

2-(4,4′′-Diacetyl-[1,1′:3′,1′′-terphenyl]-2′-yl)-2-(5-methylisoxazole-3-carboxamido)ethyl Acetate (8x-(RS))

Compound 8x-(RS) was obtained as a yellow colored semi-solid (70 mg, 67%, 0.2 mmol scale).

R_f = 0.30 (EtOAc/hexane = 50:50).

IR (DCM): 3401, 1740, 1599 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.04 (br. s, 4 H), 7.53–7.36 (m, 5 H), 7.19 (d, J = 7.6 Hz, 2 H), 6.52 (d, J = 8.1 Hz, 1 H), 6.30 (s, 1 H), 5.58–5.52 (m, 1 H), 4.17 (d, J = 11.2 Hz, 1 H), 4.08 (dd, ¹ J = 11.6 Hz, ² J ₌ 4.8 Hz, 1 H), 2.67 (s, 6 H), 2.45 (s, 3 H), 1.89 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 197.7, 171.2, 170.6, 158.3, 157.9, 146.2, 141.8, 136.3, 132.3, 130.8, 129.7, 128.4, 127.3, 101.0, 65.3, 50.8, 26.7, 20.7, 12.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₁H₂₉N₂O₆: 525.2026; found: 525.2007.

2-(2-Butylphenyl)-2-(picolinamido)ethyl Acetate (10a-(RS))

Compound 10a-(RS) was obtained as a colorless semi-solid (28 mg, 42%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50).

IR (DCM): 3375, 1738, 1220 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60–8.57 (m, 2 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.89–7.84 (m, 1 H), 7.47–7.39 (m, 2 H), 7.26–7.23 (m, 3 H), 5.78–5.73 (m, 1 H), 4.45–4.42 (m, 2 H), 2.85–2.80 (m, 2 H), 2.07 (s, 3 H), 1.72–1.63 (m, 2 H), 1.49–1.44 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.0, 163.8, 149.6, 148.2, 141.1, 137.4, 136.1, 130.0, 128.0, 126.3, 126.0, 125.8, 122.4, 66.1, 48.4, 33.6, 32.5, 22.8, 20.9, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₅N₂O₃: 341.1865; found: 341.1878.

The HPLC of compound 10a-(RS) was determined by using a Daicel Chiralpak IA column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 5.67 min, t_R = 9.29 min.

(R)-2-(2-Butylphenyl)-2-(picolinamido)ethyl Acetate (10a-(R))

Compound 10a-(R) was obtained as a colorless semi-solid (30 mg, 45%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50); [α] _d ²⁵ 14.7 (c = 0.08, CHCl₃).

IR (DCM): 3377, 1738, 1225 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 8.57–8.56 (m, 2 H), 8.18–8.16 (m, 1 H), 7.83 (td, ¹ J = 7.7 Hz, ² J = 1.6 Hz, 1 H), 7.43–7.38 (m, 2 H), 7.23–7.20 (m, 3 H), 5.78–5.74 (m, 1 H), 4.45–4.39 (m, 2 H), 2.83–2.78 (m, 2 H), 2.04 (s, 3 H), 1.70–1.63 (m, 2 H), 1.47–1.42 (m, 2 H), 0.95 (t, J = 7.4 Hz, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 171.0, 163.8, 149.6, 148.2, 141.1, 137.4, 136.1, 130.0, 127.9, 126.3, 126.3, 126.0, 122.3, 66.1, 48.4, 33.6, 32.5, 22.8, 20.9, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₅N₂O₃: 341.1865; found: 341.1855.

The enantiomeric excess (ee 97%) of compound 10a-(R) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.70 min, t_R  = 10.78 min.

(S)-2-(2-Butylphenyl)-2-(picolinamido)ethyl Acetate (10a-(S))

Compound 10a-(S) was obtained as a colorless semi-solid (30 mg, 46%, 0.2 mmol scale).

R_f = 0.65 (EtOAc/hexane = 50:50); [α] _d ²⁵ –8.8 (c = 0.08, CHCl₃).

IR (DCM): 3377, 1740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.60–8.58 (m, 2 H), 8.19 (d, J = 7.8 Hz, 1 H), 7.86 (t, J = 7.7 Hz, 1 H), 7.46–7.40 (m, 2 H), 7.30–7.24 (m, 3 H), 5.81–5.75 (m, 1 H), 4.48–4.41 (m, 2 H), 2.85–2.80 (m, 2 H), 2.06 (s, 3 H), 1.74–1.63 (m, 2 H), 1.51–1.42 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.0, 163.8, 149.6, 148.2, 141.1, 137.4, 136.1, 130.0, 128.0, 126.3, 126.0, 125.8, 122.4, 66.1, 48.4, 33.6, 32.5, 22.8, 20.9, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₅N₂O₃: 341.1865; found: 341.1880.

The enantiomeric excess (ee 98%) of compound 10a-(S) was determined by HPLC using a Daicel Chiralpak IA column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 6.53 min, t_R = 10.42 min.

2-(2,6-Bis(2-methylbenzyl)phenyl)-2-(picolinamido)ethyl Acetate (10b-(RS))

Compound 10b-(RS) was obtained (from procedure D) as a colorless solid (69 mg, 71%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 142–144 °C.

IR (DCM): 3380, 1739, 1509 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.62 (d, J = 7.7 Hz, 1 H), 8.35 (d, J = 4.6 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.75 (t, J = 7.7 Hz, 1 H), 7.35–7.32 (m, 1 H), 7.17–6.91 (m, 11 H), 5.91–5.58 (m, 1 H), 4.74 (t, J = 10.8 Hz, 1 H), 4.48 (br. s, 2 H), 4.24–4.15 (m, 2 H), 3.94 (dd, ¹ J = 11.7 Hz, ² J = 4.4 Hz, 1 H), 2.39 (s, 6 H), 2.00 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.3, 164.1, 149.3, 147.9, 138.7, 136.9, 136.5, 134.8, 130.0, 129.4, 129.4, 129.3, 128.0, 126.2, 126.0, 125.8, 121.8, 64.7, 49.8, 37.6, 20.8, 19.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₃N₂O₃: 493.2491; found: 493.2477.

The HPLC of compound 10b-(RS) was determined by using a Daicel Chiralpak ADH column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 8.28 min, t_R = 11.37 min.

(R)-2-(2,6-Bis(2-methylbenzyl)phenyl)-2-(picolinamido)ethyl Acetate (10b-(R))

Compound 10b-(R) was obtained (from procedure D) as a colorless solid (45 mg, 46%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 142–144 °C; [α] _d ²⁵ 95.6 (c = 0.05, CHCl₃).

IR (DCM): 3380, 1739, 1450 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.62 (d, J = 7.7 Hz, 1 H), 8.35 (d, J = 4.6 Hz, 1 H), 8.02 (d, J = 7.8 Hz, 1 H), 7.75 (t, J = 7.7 Hz, 1 H), 7.35–6.90 (m, 12 H), 5.90–5.58 (m, 1 H), 4.74 (t, J = 10.8 Hz, 1 H), 4.51–4.45 (m, 2 H), 4.21 (d, J = 16.2 Hz, 1 H), 3.94 (dd, ¹ J = 11.7 Hz, ² J = 4.4 Hz, 1 H), 2.38 (s, 6 H), 2.00 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 171.3, 164.1, 149.3, 147.9, 138.7, 136.9, 136.4, 134.8, 130.0, 129.4, 129.4, 129.4, 128.0, 126.2, 126.0, 125.8, 121.8, 64.7, 49.8, 37.6, 20.8, 19.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₃N₂O₃: 493.2491; found: 493.2509.

The enantiomeric excess (ee 94%) of compound 10b-(R) was determined by HPLC using a Daicel Chiralpak ADH column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 8.39 min, t_R = 11.67 min.

N-(1-(2,6-Bis(3-methylbenzyl)phenyl)ethyl)picolinamide (11a-(RS))

Compound 11a-(RS) was obtained (from procedure D) as a colorless semi-solid (47 mg, 55%, 0.20 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80).

IR (DCM): 3392, 1673, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.33 (d, J = 7.2 Hz, 1 H), 8.28 (d, J = 4.7 Hz, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.72 (td, ¹ J = 7.7 Hz, ² J = 1.7 Hz, 1 H), 7.30–7.27 (m, 1 H), 7.16–6.88 (m, 11 H), 5.72–5.65 (m, 1 H), 4.41 (br. s, 2 H), 4.17 (d, J = 16.0 Hz, 2 H), 2.20 (s, 6 H), 1.24 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.4, 149.6, 147.7, 141.0, 139.7, 138.8, 137.7, 136.9, 130.4, 129.5, 128.1, 127.1, 126.5, 125.9, 125.6, 121.7, 45.5, 39.8, 21.3, 20.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁N₂O: 435.2436; found: 435.2434.

The HPLC of compound 11a-(RS) was determined by using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 7.84 min, t_S = 10.68 min.

(R)-N-(1-(2,6-Bis(3-methylbenzyl)phenyl)ethyl)picolinamide (11a-(R))

Compound 11a-(R) was obtained (from procedure D) as a colorless semi-solid (40 mg, 47%, 0.20 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); [α] _d ²⁵ –65.1 (c = 0.04, CHCl₃).

IR (DCM): 391, 1673, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.33 (d, J = 7.2 Hz, 1 H), 8.28 (d, J = 4.7 Hz, 1 H), 8.03 (d, J = 7.8 Hz, 1 H), 7.72 (td, ¹ J = 7.7 Hz, ² J = 1.7 Hz, 1 H), 7.30–7.27 (m, 1 H), 7.16–6.88 (m, 11 H), 5.72–5.65 (m, 1 H), 4.41 (br. s, 2 H), 4.17 (d, J = 16.0 Hz, 2 H), 2.20 (s, 6 H), 1.24 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.4, 149.6, 147.7, 141.0, 139.7, 138.7, 137.7, 136.9, 130.4, 129.5, 128.1, 127.1, 126.5, 125.9, 125.6, 121.7, 45.5, 39.8, 21.3, 20.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₁N₂O: 435.2436; found: 435.2435.

The enantiomeric excess (ee 92%) of compound 11a-(R) was determined by HPLC using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 7.82 min, t_S = 10.75 min.

N-(1-(2,6-Bis(3-chlorobenzyl)phenyl)ethyl)picolinamide (11b-(RS))

Compound 11b-(RS) was obtained (from procedure D) as a colorless semi-solid (53 mg, 56%, 0.20 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80).

IR (DCM): 3389, 1673, 1510 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.29 (d, J = 4.6 Hz, 1 H), 8.22 (d, J = 7.0 Hz, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.71 (td, ¹ J = 7.7 Hz, ² J = 1.6 Hz, 1 H), 7.31–7.28 (m, 1 H), 7.23–7.00 (m, 11 H), 5.59–5.52 (m, 11 H), 4.46 (br. s, 2 H), 4.16 (d, J = 16.2 Hz, 2 H), 1.23 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.5, 149.2, 147.7, 143.1, 139.9, 137.8, 136.9, 134.0, 130.9, 129.4, 128.7, 127.4, 126.8, 125.9, 125.7, 121.7, 45.5, 39.5, 20.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₅Cl₂N₂O: 475.1344; found: 475.1342.

The HPLC of compound 11b-(RS) was determined by using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 9.82 min, t_S = 12.23 min.

(R)-N-(1-(2,6-Bis(3-chlorobenzyl)phenyl)ethyl)picolinamide (11b-(R))

Compound 11b-(R) was obtained as a colorless semi-solid (55 mg, 58%, 0.20 mmol scale).

R_f = 0.65 (EtOAc/hexane = 20:80); [α] _d ²⁵ –47.1 (c = 0.04, CHCl₃).

IR (DCM): 3388, 1672, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.28 (d, J = 4.6 Hz, 1 H), 8.22 (d, J = 7.0 Hz, 1 H), 7.99 (d, J = 7.8 Hz, 1 H), 7.71 (td, ¹ J = 7.7 Hz, ² J = 1.6 Hz, 1 H), 7.32–7.00 (m, 11 H), 5.59–5.52 (m, 1 H), 4.46 (br. s, 2 H), 4.16 (d, 2 H, J = 16.2 Hz), 1.23 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.6, 149.3, 147.8, 143.2, 140.0, 137.9, 137.0, 134.1, 131.0, 129.5, 128.8, 127.5, 126.9, 126.0, 125.8, 121.8, 45.6, 39.6, 20.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₈H₂₅Cl₂N₂O: 475.1344; found: 475.1342.

The enantiomeric excess (ee 98%) of compound 11b-(R) was determined by HPLC using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 9.74 min, t_S = 11.98 min.

N-(1-(2,6-Dibromophenyl)ethyl)picolinamide (12a-(RS))

Compound 12a-(RS) was obtained as a colorless solid (55 mg, 57%, 0.25 mmol scale).

R_f = 0.55 (EtOAc/hexane = 20:80); mp 100–102 °C.

IR (DCM): 3391, 1676, 1506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 7.9 Hz, 1 H), 8.58 (d, J = 4.5 Hz, 1 H), 8.16 (d, J = 7.7 Hz, 1 H), 7.81 (t, J = 7.6 Hz, 1 H), 7.55–7.45 (m, 2 H), 7.43–7.40 (m, 1 H), 6.93 (t, J = 8.0 Hz, 1 H), 6.20–6.12 (m, 1 H), 1.70 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 163.1, 149.6, 148.1, 139.5, 137.2, 133.9, 132.8, 129.3, 126.1, 122.3, 50.1, 18.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃Br₂N₂O: 382.9395; found: 382.9386.

The HPLC of compound 12a-(RS) was determined by using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 14.11 min, t_R = 15.93 min.

(R)-N-(1-(2,6-Dibromophenyl)ethyl)picolinamide (12a-(R))

Compound 12a-(R) was obtained as a colorless solid (54 mg, 56%, 0.25 mmol scale).

R_f = 0.55 (EtOAc/hexane = 20:80); mp 101–103 °C; [α] _d ²⁵ –148.0 (c = 0.07, CHCl₃).

IR (DCM): 3390, 1676, 1506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 8.1 Hz, 1 H), 8.59 (dd, ¹ J = 4.7 Hz, ² J = 0.7 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.82 (td, ¹ J = 7.7 Hz, ² J = 1.7 Hz, 1 H), 7.55–7.45 (m, 2 H), 7.44–7.40 (m, 1 H), 6.93 (t, J = 8.0 Hz, 1 H), 6.20–6.12 (m, 1 H), 1.71 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 163.2, 149.8, 148.2, 139.7, 137.3, 134.0, 132.9, 129.4, 126.1, 122.4, 50.2, 18.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃Br₂N₂O: 382.9395; found: 382.9402.

The enantiomeric excess (ee 94%) of compound 12a-(R) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 14.11 min, t_R = 15.93 min.

(S)-N-(1-(2,6-Dibromophenyl)ethyl)picolinamide (12a-(S))

Compound 12a-(S) was obtained as a colorless solid (55 mg, 57%, 0.25 mmol scale).

R_f = 0.55 (EtOAc/hexane = 20:80); mp 101–103 °C; [α] _d ²⁵ 137.2 (c = 0.07, CHCl₃).

IR (DCM): 3385, 1676, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 8.2 Hz, 1 H), 8.60–8.58 (m, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.82 (td, ¹ J = 7.7 Hz, ² J = 1.7 Hz, 1 H), 7.55–7.45 (m, 2 H), 7.43–7.40 (m, 1 H), 6.93 (t, J = 8.0 Hz, 1 H), 6.20–6.12 (m, 1 H), 1.70 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~126 MHz, CDCl₃): δ = 163.2, 149.7, 148.2, 139.7, 137.4, 134.0, 133.0, 129.4, 126.1, 122.4, 50.2, 18.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃Br₂N₂O: 382.9395; found: 382.9403.

The enantiomeric excess (ee 99%) of compound 12a-(S) was determined by HPLC using a Daicel Chiralpak IC column, hexane/i-PrOH 80:20, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 14.05 min, t_R = 15.97 min.

N-(1-(2,6-Diiodophenyl)ethyl)picolinamide (12b-(RS))

Compound 12b-(RS) was obtained as a colorless solid (105 mg, 88%, 0.25 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 112–114 °C.

IR (DCM): 3383, 1671, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.19 (d, J = 7.2 Hz, 1 H), 8.60 (d, J = 4.4 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.89–7.79 (m, 3 H), 7.44–7.41 (m, 1 H), 6.54 (t, J = 7.8 Hz, 1 H), 5.86–5.79 (m, 1 H), 1.66 (d, J = 7.3 Hz, 3 H).

¹³C NMR (~101 MHz, CDCl₃): δ = 162.9, 149.5, 148.1, 143.1, 142.3, 140.4, 137.2, 130.1, 126.1, 122.2, 57.2, 18.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃I₂N₂O: 478.9117; found: 478.9106.

The HPLC of compound 12b-(RS) was determined by using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 16.27 min, t_S = 18.89 min.

(R)-N-(1-(2,6-Diiodophenyl)ethyl)picolinamide (12b-(R))

Compound 12b-(R) was obtained as a colorless solid (104 mg, 87%, 0.25 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 112–114 °C; [α] _d ²⁵ –274.6 (c = 0.05, CHCl₃).

IR (DCM): 3382, 1671, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.20 (d, J = 7.3 Hz, 1 H), 8.60 (d, J = 4.7 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.88–7.79 (m, 3 H), 7.43–7.40 (m, 1 H), 6.53 (t, J = 7.8 Hz, 1 H), 5.86–5.79 (m, 1 H), 1.66 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.9, 149.5, 148.1, 143.1, 142.3, 140.4, 137.2, 130.1, 126.1, 122.2, 57.2, 18.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃I₂N₂O: 478.9117; found: 478.9114.

The enantiomeric excess (ee 95%) of compound 12b-(R) was determined by HPLC using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 16.90 min, t_S = 19.64 min.

(S)-N-(1-(2,6-Diiodophenyl)ethyl)picolinamide (12b-(S))

Compound 12b-(S) was obtained as a colorless solid (106 mg, 89%, 0.25 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 112–114 °C; [α] _d ²⁵ 274.2 (c = 0.05, CHCl₃).

IR (DCM): 3384, 1673, 1505 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.20 (d, J = 7.3 Hz, 1 H), 8.60 (d, J = 4.8 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.88–7.79 (m, 3 H), 7.44–7.40 (m, 1 H), 6.54 (t, J = 7.8 Hz, 1 H), 5.86–5.79 (m, 1 H), 1.66 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 162.9, 149.5, 148.1, 143.1, 142.3, 140.4, 137.2, 130.1, 126.1, 122.2, 57.2, 18.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₃I₂N₂O: 478.9117; found: 478.9128.

The enantiomeric excess (ee 96%) of compound 12b-(S) was determined by HPLC using a Daicel Chiralcel OD-H column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_R = 16.89 min, t_S = 19.53 min.

N-(1-(2,6-Dibromo-4-methylphenyl)ethyl)picolinamide (12c-(RS))

Compound 12c-(RS) was obtained as a yellow colored semi-solid (61 mg, 51%, 0.30 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80).

IR (DCM): 3383, 1675, 1506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.15 (d, J = 8.2 Hz, 1 H), 8.59 (d, J = 4.7 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.81 (td, ¹ J = 7.7 Hz, ² J = 1.0 Hz, 1 H), 7.43–7.35 (m, 3 H), 6.14–6.07 (m, 1 H), 2.24 (s, 3 H), 1.68 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, DMSO-d ₆): δ = 162.7, 149.5, 149.1, 140.9, 138.5, 136.6, 134.3, 134.0, 127.3, 122.3, 49.9, 19.9, 18.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₅Br₂N₂O: 396.9551; found: 396.9565.

N-(1-(2,6-Dibromo-4-chlorophenyl)ethyl)picolinamide (12d-(RS))

Compound 12d-(RS) was obtained as a yellow colored semi-solid (84 mg, 67%, 0.30 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80).

IR (DCM): 3391, 1672, 1508 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.10 (d, J = 8.0 Hz, 1 H), 8.59 (dd, ¹ J = 4.7 Hz, ² J = 0.6 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.83 (td, ¹ J = 7.7 Hz, ² J = 1.7 Hz, 1 H), 7.60–7.50 (m, 2 H), 7.45–7.41 (m, 1 H), 6.10–6.02 (m, 1 H), 1.68 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.2, 149.5, 148.2, 138.3, 137.4, 133.8, 133.4, 132.3, 126.3, 122.4, 49.9, 18.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₂Br₂ClN₂O: 416.9005; found: 416.9021.

N-(1-(2,6-Diiodo-4-methylphenyl)ethyl)picolinamide (12e-(RS))

Compound 12e-(RS) was obtained as a colorless solid (139 mg, 81%, 0.35 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 139–141 °C.

IR (DCM): 3381, 1671, 1506 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.15 (d, J = 7.4 Hz, 1 H), 8.60 (d, J = 4.7 Hz, 1 H), 8.15 (d, J = 7.8 Hz, 1 H), 7.83–7.73 (m, 3 H), 7.43–7.40 (m, 1 H), 5.82–5.75 (m, 1 H), 2.18 (s, 3 H), 1.65 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.0, 149.7, 148.2, 143.0, 141.0, 140.3, 140.2, 137.3, 126.1, 122.3, 56.9, 19.5, 18.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₁₅I₂N₂O: 492.9274; found: 492.9283.

N-(1-(4-Chloro-2,6-diiodophenyl)ethyl)picolinamide (12f-(RS))

Compound 12f-(RS) was obtained as a colorless solid (119 mg, 78%, 0.30 mmol scale).

R_f = 0.6 (EtOAc/hexane = 20:80); mp 110–112 °C.

IR (DCM): 3388, 1671, 1502 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.11 (d, J = 6.7 Hz, 1 H), 8.60 (d, J = 4.6 Hz, 1 H), 8.14 (d, J = 7.8 Hz, 1 H), 7.90–7.80 (m, 3 H), 7.45–7.41 (m, 1 H), 5.78–5.70 (m, 1 H), 1.64 (d, J = 7.2 Hz, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 163.0, 149.3, 148.2, 141.7, 141.5, 139.5, 137.3, 133.6, 126.2, 122.2, 56.8, 18.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₂ClI₂N₂O: 512.8728; found: 512.8738.

2-(2,6-Dibromophenyl)-2-(picolinamido)ethyl Acetate (13a-(RS))

Compound 13a-(RS) was obtained as a colorless solid (56 mg, 63%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 80–82 °C.

IR (DCM): 3379, 1745, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.38 (d, J = 9.0 Hz, 1 H), 8.62 (d, J = 4.7 Hz, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.84 (td, ¹ J = 7.7 Hz, ² J = 1.6 Hz, 1 H), 7.59 (br. s, 2 H), 7.46–7.43 (m, 1 H), 7.00 (t, J = 8.0 Hz, 1 H), 6.46–6.40 (m, 1 H), 4.83 (dd, ¹ J = 11.2 Hz, ² J = 8.8 Hz, 1 H), 4.51 (dd, ¹ J = 11.3 Hz, ² J = 6.0 Hz, 1 H), 2.06 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.8, 163.9, 149.4, 148.4, 137.3, 135.6, 134.1, 133.1, 130.3, 126.3, 122.4, 63.0, 53.5, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅Br₂N₂O₃: 440.9449; found: 440.9429.

The HPLC of compound 13a-(RS) was determined by using a Daicel Chiralcel OJ column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 31.20 min, t_R = 26.99 min.

(R)-2-(2,6-Dibromophenyl)-2-(picolinamido)ethyl Acetate (13a-(R))

Compound 13a-(R) was obtained as a colorless solid (58 mg, 66%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 82–84 °C; [α] _d ²⁵ 170.0 (c = 0.02, CHCl₃).

IR (DCM): 3379, 1745, 1511 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.38 (d, J = 9.0 Hz, 1 H), 8.62 (d, J = 4.6 Hz, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.84 (t, J = 7.7 Hz, 1 H), 7.57 (br. s, 2 H), 7.46–7.43 (m, 1 H), 7.00 (t, J = 8.0 Hz, 1 H), 6.45–6.39 (m, 1 H), 4.83 (dd, ¹ J = 11.2 Hz, ² J = 8.9 Hz, 1 H), 4.50 (dd, ¹ J = 11.3 Hz, ² J = 6.0 Hz, 1 H), 2.06 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.9, 163.9, 149.4, 148.4, 137.3, 135.6, 134.1, 133.0, 130.3, 126.4, 122.4, 63.0, 53.4, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅Br₂N₂O₃: 440.9449; found: 440.9429.

The enantiomeric excess (ee >98%) of compound 13a-(R) was determined by HPLC using a Daicel Chiralcel OJ column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = not detected min, t_R = 27.36 min.

(S)-2-(2,6-Dibromophenyl)-2-(picolinamido)ethyl Acetate (13a-(S))

Compound 13a-(S) was obtained as a colorless solid (56 mg, 64%, 0.2 mmol scale).

R_f = 0.55 (EtOAc/hexane = 50:50); mp 82–84 °C; [α] _d ²⁵ –102.0 (c = 0.02, CHCl₃).

IR (DCM): 3376, 1742, 1507 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.38 (d, J = 8.9 Hz, 1 H), 8.62 (d, J = 4.6 Hz, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.84 (t, J = 7.6 Hz, 1 H), 7.58 (br. s, 2 H), 7.46–7.43 (m, 1 H), 7.00 (t, J = 8.0 Hz, 1 H), 6.46–6.40 (m, 1 H), 4.83 (dd, ¹ J = 11.1 Hz, ² J = 9.0 Hz, 1 H), 4.51 (dd, ¹ J = 11.3 Hz, ² J = 6.0 Hz, 1 H), 2.06 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.9, 163.9, 149.4, 148.4, 137.3, 135.6, 134.1, 133.0, 130.3, 126.4, 122.4, 63.0, 53.5, 20.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅Br₂N₂O₃: 440.9449; found: 440.9434.

The enantiomeric excess (ee >98%) of compound 13a-(S) was determined by HPLC using a Daicel Chiralcel OJ column, hexane/i-PrOH 90:10, flow rate 1.0 mL/min, UV detection at 254 nm, t_S = 32.54 min, t_R = 28.89 min.

2-(2,6-Diiodophenyl)-2-(picolinamido)ethyl Acetate (13b-(RS))

Compound 13b-(RS) was obtained as a yellow colored solid (90 mg, 84%, 0.2 mmol scale).

R_f = 0.60 (EtOAc/hexane = 50:50); mp 120–122 °C.

IR (DCM): 3367, 1739, 1504 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 9.43 (d, J = 8.0 Hz, 1 H), 8.64 (d, J = 4.6 Hz, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 7.96–7.82 (m, 3 H), 7.47–7.44 (m, 1 H), 6.61 (t, J = 7.8 Hz, 1 H), 6.16–6.10 (m, 1 H), 4.85 (t, J = 10.7 Hz, 1 H), 4.46 (dd, ¹ J = 11.4 Hz, ² J = 5.8 Hz, 1 H), 2.09 (s, 3 H).

¹³C{¹H} NMR (~101 MHz, CDCl₃): δ = 170.9, 163.7, 149.3, 148.4, 142.5, 140.7, 139.5, 137.3, 130.9, 126.3, 122.4, 62.9, 60.4, 20.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₁₅I₂N₂O₃: 536.9172; found: 536.9191.