'Click'-BINOLs: A New Class of Tunable Ligands for Asymmetric Catalysis

Abstract

A new class of easily tunable 1,2,3-triazole-BINOL ligands, 'click'-BINOLs, have been synthesized from readily available alkynes and several azido-BINOL derivatives using the powerful Huisgen [3+2] cycloaddition 'click' approach. The activity of these ligands in asymmetric Lewis acid catalysis has been explored for the first time in the diethylzinc addition to aldehydes. The C ₂-symmetric ligand 1d showed an interesting catalytic behavior, which suggests the non-innocent participation of the triazole units. Thus, good enantioselectivities (up to 86% ee) were obtained by both the right selection of the substitution pattern at the triazole ring and the fine tuning of the reaction conditions.

Chiral axial 1,1′-bi-2-naphthol (BINOL) represents a privileged ligand structure in asymmetric catalysis and therefore its derivatives have been extensively used.[ ¹ ] The hydroxy basic sites of the BINOL moiety allow the incorporation of hard metal Lewis acids such as Ti(IV) or Al(III), providing with chiral complexes for catalysis. On the other hand, the substituents at the 3 and 3′ positions can modulate the electronic and steric properties of the generated Lewis acid complex, leading in many cases to more active and selective catalysts. Although the chemistry of BINOL is well studied, permitting the easy functionalization of its skeleton, often many linear synthetic steps are required to produce a desired derivative.[ ¹ ] It would be then very desirable to be able to generate in a very efficient manner a library of such ligands from simple common precursors. In this regard, a very powerful synthetic method is the copper-catalyzed Huisgen [3+2] cycloaddition[2] [3] between an azide and an alkyne to link the two units via a triazole moiety. Surprisingly, the combination of the high performance of BINOL ligands with this extremely efficient transformation and the ready availability of alkynes has not yet been exploited. To easily tune the properties of the catalysts for their application in asymmetric catalysis, we herein propose a modular and flexible strategy by using such 'click' chemistry[ ⁴ ] to introduce into BINOL derivatives a 1,2,3-triazole group as a possible second coordination site.[ ⁵ ] Thus, a small set of ­BINOL azides will be used in combination with commercially available or easy to prepare substituted terminal alkynes to generate a new family of 'click'-BINOL ligands 1 (Figure [1]).

The introduction of azido groups into the 3 and 3′ positions of BINOL was carried out first (Scheme [1]). The preparation in multigram scale of the BINOL azides building blocks 2a–d was easily accomplished by a first ortho-lithiation of MOM-protected (S)-BINOL and treatment with an appropriate electrophile. Thus, methylene azide derivatives 2a and 2b were obtained by reaction with paraformaldehyde or DMF followed by reduction, affording the mono- or dimethyl alcohols, respectively. After mesylation and treatment of the crude reaction mixture with NaN₃, 2a and 2b were obtained in good overall yields (3–4 steps, 47–60%; Scheme [1], left). On the other hand, precursors 2c and 2d, having the azide group directly linked at the BINOL backbone, were prepared in a single step by reaction of the corresponding lithiated species with TosN₃ (51–68% yields; Scheme [1], right).

The new family of 'click'-BINOL ligands 1a–l were then synthesized in a divergent manner from these BINOL azides 2 using various substituted alkynes under standard conditions for the Huisgen [3+2] cycloaddition: combination of CuSO₄ (4–8 mol%) and Na ascorbate (12–24 mol%) in a 1:1:1 mixture of t-BuOH–H₂O–CH₂Cl₂ at 50 °C. A number of terminal alkynes, containing sterically and electronically different aryl and alkyl groups, were employed. Finally, the obtained MOM-intermediates 3 were directly deprotected under acidic conditions (aq 12 M HCl) to give the desired OH-free ligands 1 (Scheme [2]).

With these 'click'-BINOL ligands 1 in hand, we decided to explore their performance in Lewis acid catalyzed asymmetric reactions. Among important classes of such transformations, the asymmetric addition of diethylzinc to aldehydes is considered as one of the benchmark reactions for investigating the catalytic activity and potential of new ligands.[ ⁶ ] Moreover, this reaction leads to pharmaceutically important carbinol derivatives. Therefore, the addition of Et₂Zn to benzaldehyde 4a was chosen as the model reaction.

Initially, the performance of the first generation of 'click'-(S)-BINOLs (R² = Ph) was tested and compared with simple (S)-BINOL (Scheme [3]). The reactions were performed using the combination of 10 mol% of the ligand, 10 mol% Ti(Oi-Pr)₄ as Lewis acid, and 2 equivalents of Et₂Zn (1 M in hexanes) in toluene (0.25 M) at room temperature (23–25 °C). Under these conditions, ligands 1a and 1b with mono- and bis-methylene-bridged triazoles led to results similar to the parent BINOL [85%, 54–58% ee (S) vs 84%, 53% ee (S)] (Scheme [3]). Conversely, the ligands having the triazole units directly linked to the binaphthol backbone 1c,d showed more interesting and promising results. Whereas unsymmetrical 'click'-BINOL 1c provided carbinol 5a in a modest 38% ee, the C ₂-symmetric ligand 1d built the new stereocenter in a significantly improved 72% ee. Interestingly, now the opposite enantiomer R was formed. For this ligand, we also observed a strong influence of the incubation time to form the chiral Lewis acid catalyst on the final enantioselectivity. Thus, the stirring of 1d with Ti(Oi-Pr)₄ for 15–30 minutes prior to the addition of benzaldehyde was critical to obtain good selectivities (66–74% ee). Moreover, shorter or longer incubation times, such as overnight, led to considerable lower or even inverse enantioselectivity. This indicates the different participation of kinetic and thermodynamic active catalytic species. Therefore, a study on the variation of the enantiomeric excess with the reaction time was carried out (Scheme [3], below). In this case, after 15 minutes catalyst incubation, benzaldehyde was added and stirred for another 15 minutes before the treatment with Et₂Zn. We were pleased to observe that the enantiomeric excess did not fluctuate significantly during the course of the reaction under these conditions [final ee = 66% (R)].

Next, the optimization of the reaction conditions with the best first generation ligand 1d and an incubation time of 30 minutes was carried out (Table [1]). We found out that the use of Ti(Oi-Pr)₄ and the ratio of Lewis acid/ligand were also crucial (Table [1], entries 1–5). Thus, the reaction in the absence of Lewis acid delivered the product in only 18% ee (entry 2) and the use of other metal species such as Al(Oi-Pr)₃ gave 5a in a 27% ee (entry 6). On the other hand, by decreasing (entry 3) or increasing (entries 4, 5) the amount of Ti(Oi-Pr)₄ with respect to 1d, 5a was obtained in remarkably lower enantiomeric excesses. Moreover, in the case of utilizing a large excess of Ti (4:1 Ti/ligand, entry 5), the reverse S-enantiomer started to build, although in a modest 22% ee.

Table 1 Optimization of the Reaction of 4a with 1d ^a

Entry	Ti/1d	Et2Zn (equiv)	Solvent (M)	Yield (%)b	ee (%)c (config)
1	1:1	2.0	toluene (0.25)	74d	72 (R)
2	–/1	2.0	toluene (0.25)	86	18 (R)
3	1:4	2.0	toluene (0.25)	75	58 (R)
4	2:1	2.0	toluene (0.25)	87	0
5	4:1	2.0	toluene (0.25)	86	22 (S)
6	1:1e	2.0	toluene (0.25)	96	27 (R)
7	1:1	2.0	toluene (0.4)	85	28 (R)
8	1:1	2.0	toluene (0.17)	73	52 (R)
9	1:1	2.0	hexane (0.25)	86	26 (S)
10	1:1	2.0	CH2Cl2 (0.25)	62	36 (R)
11	1:1	2.0	Et2O (0.25)	78	18 (R)
12	1:1	2.0f	toluene (0.25)	79d	86 (R)
13	1:1	1.5f	toluene (0.25)	80	83 (R)
14	1:1	1.1f	toluene (0.25)	68	81 (R)
15	1:1	1.0f	toluene (0.25)	65	63 (R)
16	1:1	2.0f	toluene (0.25)	40	80 (R)g

^a Reaction conditions: 1d (10 mol%) and Ti(Oi-Pr)₄ (10 mol%) in toluene (30 min); next addition of 4a (0.25 mmol), and after 30 min addition of Et₂Zn (0.50 mmol, 2 equiv, 1 M in hexanes). The reaction was then stirred at r.t. for 24 h.

^b GC yield.

^c The ee was determined by chiral HPLC.

^d Isolated yield.

^e Al(Oi-Pr)₃ was used as Lewis acid.

^f A 1.1 M solution of Et₂Zn in toluene was used.

^g Reaction at 0 °C for 96 h.

The concentration of the reaction (entries 7, 8 vs 1) and the solvent used (entries 9–11) were also essential to obtain a high enantioselectivity. Hence, the initial concentration of 0.25 M and toluene turned out to be the optimal concentration and solvent. Importantly, we observed that the reaction in hexane gave a poor enantiomeric excess (26% ee, entry 9). Considering that the Et₂Zn that we were employing was a 1 M solution in hexanes, in order to improve the enantioselectivity we decided to use a solution in toluene (1.1 M). As expected, the enantiomeric excess increased substantially to 86% ee (entry 12). The effect of the amount of Et₂Zn on the asymmetric induction of the reaction was next explored (entries 12–15). The amount of Et₂Zn could be reduced from 2 to 1.1 equivalents without significant loss of enantioselectivity. However, when only 1 equivalent was used both the reactivity and the enantiomeric excess sank (entry 15). Lastly, the reaction was carried out at 0 °C. Unfortunately, the reaction was considerably slower and no improvement in the ee was achieved (entry 16).

With these initial optimized conditions for ligand 1d [10 mol% Ti(Oi-Pr)₄/1 and Et₂Zn (2 equiv, 1.1 M in toluene) in toluene (0.25 M) at r.t.], the effect of the substituents at the triazole ring was next explored (Figure [2]).

We were surprised to observe a strong decrease of enantio­selectivity by the increase of the steric hindrance of the ­aromatic substituent at the triazole ring. Thus, the 9-anthracenyl derivative 1e led to a poor 5% ee, whereas mesityl 1f or even a fluorinated aryl-substituted triazole ligand 1g provided now the opposite S-enantiomer in low or moderate enantioselectivities (30% or 59% ee, respectively). Conversely, the unsubstituted triazole ligand 1h resulted highly ineffective (racemic 5a was formed in 50% yield). On the other hand, bulky aliphatic substituents such as tert-butyl (1i) or 1-adamantyl (1j) worked relatively well, providing carbinol 5a in good yields and 62% ee. Finally, the introduction of a further coordination group in the 'click'-BINOL ligand such as a dimethylamine (1k) or a 2-pyridine (1l), led to a very low asymmetric induction or again the reverse enantioselectivity. This can be explained by a competitive formation of different Lewis acid complexes in which the triazole and this new coordination unit, further from the chirality source, are the principal players. All these results indicate that the triazole unit is not an innocent group and participates in the coordination and modulates the activity of the active Lewis acid catalyst.[ ⁷ ] In this sense, although complex cluster metallic species can be formed,[ ¹ ] three simplified scenarios in which a different coordination with the nitrogens or the acidic C-5 position of the triazoles can be envisioned: A) the triazole also coordinates with the N-atoms to the organometallic species; B) the C-5 position of the triazole is metallated and participates in the formation of a multi-metallic active catalyst;[ ⁸ ] and C) a mixture of both coordination modus A and B occur. In the scenario A, a little effect on the enantioselectivity of the substituent, which is pointing out of the coordination sphere, could be expected. However, we observed a clear influence of this substitution. Therefore, scenarios B or C are more likely to generate the enantioselective active catalyst. Moreover, in order to avoid strong steric interactions between the substituents at the C-4 position, a dynamic interconversion might take place. Thus, the rotation of the triazoles and the different interaction can justify the lower performance, and even the favored generation of the opposite S-enantiomer. Therefore, after this short substitution screening, the phenyl group in 1d was taken as optimal compromise.

Additionally, the regioisomeric 1,5-triazole ligand 1d′,[9] [10] in which the C-5 position is blocked, showed a lower reactivity (56% yield after 16 h) and enantioselectivity in favor to the S-alcohol [20% ee (S) 1d′ vs 86% ee (R) 1d; Figure [2], bottom]. Again, this result indicates the active participation and influence of the triazole group in the formation and asymmetric induction activity of the active Lewis acid catalyst.

Table 2 Asymmetric Addition of Et₂Zn to Aldehydes: Substrate Scope^a

Entry	R	Product 5	Yield (%)b	ee (%)c
1	2-naphthyl	5b	99	86
2	1-naphthyl	5c	86	86
3	4-MeOC6H4	5d	96	77
4	4-FC6H4	5e	75	78
5	4-ClC6H4	5f	94	81
6	3-ClC6H4	5g	66	46
7	2-ClC6H4	5h	86	54
8	cyclohexyl	5i	39	50
9	2-pyridyl	5j	29	0

^a Reaction conditions: 1d (10 mol%) and Ti(Oi-Pr)₄ (10 mol%) in toluene (30 min); next addition of 4a (0.25 mmol), and after 30 min addition of Et₂Zn (0.50 mmol, 2 equiv, 1.1 M in toluene). The reaction was then stirred at r.t. for 15–48 h.

^b Isolated yield.

^c The ee was determined by chiral HPLC or GC.

Lastly, the performance of 1d for the addition of Et₂Zn to diverse aldehydes was studied (Table [2]). All reactions lead to the formation of the R-configured carbinols 5, with the exception of the N-coordinating 2-pyridylcarboxaldehyde, which provided a racemic product (entry 9). The 2- and 1-naphthaldehydes, as well as both electron-withdrawing and -donating para-substituted benzaldehydes reacted well, giving alcohols 5b–f in similar good enantio­selectivities (entries 1–5). On the other hand, meta- and ortho-substituted benzaldehydes, as well as aliphatic cyclohexyl carboxaldehyde, afforded 5g–j in significantly lower ee values (entries 6–8). These results indicate a strong substrate-recognition dependence and face discrimination by the catalysts, in which steric issues might play again an important role.

In conclusion, an easy and modular synthetic approach to a new family of 'click'-BINOL ligands from simple alkynes and azido-BINOL derivatives has been developed. Among all synthesized ligands, the C ₂-symmetric 1,4-disubstituted bis-triazole (S)-1d, in combination with Ti(Oi-Pr)₄ as Lewis acid, behaved as interesting chiral catalyst in the asymmetric addition of diethylzinc to aldehydes. Its performance suggested a non-innocent participation of the triazole units in both the formation and reactivity of the active Lewis acid metal catalyst.

All reactions were carried out in heat-gun-dried glassware under argon atmosphere. CH₂Cl₂ was distilled over CaH₂; and THF, Et₂O, and toluene were distilled and dried over Na. ¹H, ¹³C and ¹⁹F NMR spectra were recorded in CDCl₃ and DMSO-d ₆ (reference signals: ¹H = 7.26 ppm, ¹³C = 77.16 ppm, CDCl₃; ¹H = 2.50 ppm, ¹³C = 39.52 ppm, DMSO-d ₆) on a Bruker ARX-300 and a Varian AV-300, 400 or 600 MHz spectrometers. Chemical shifts (δ) are given in ppm and spin-spin coupling constants (J) are given in Hz. Analytical TLC was performed using silica gel 60 F₂₅₄ and a solution of KMnO₄ served as staining agent. Column chromatography was performed on silica gel 60 (0.040–0.063 mm). Exact masses (HRMS) were recorded on a Bruker Daltonics MicroTof spectrometer (samples in MeOH as solvent). Melting points were measured by differential scanning calorimetry with a Ta Instruments Q20 calorimeter. HPLC and GC analysis were performed with Agilent Technologies 1200 Series and 6890 Series spectrometers, respectively. Aldehydes were freshly distilled for the catalytic reaction. Analytical grade solvents and other commercially available reagents were used without further purification. The structures of intermediates 6–8 are shown in the Supporting Information.

MOM-BINOL[ ¹¹ ]

NaH (1.35 g, 60% in mineral oil, 33.8 mmol, 2.24 equiv) was suspended in THF–DMF (90 mL, 2:1) and cooled to 0 °C. Then, a solution of (S)- or (R)-1,1′-binaphthol (4.32 g, 15.1 mmol, 1.00 equiv) in THF (18 mL) was added dropwise and the resulting mixture was stirred 1 h at r.t. Chloro(methoxy)methane (3.62 mL, 47.7 mmol, 3.16 equiv) was added and the reaction mixture was stirred at r.t. for 4 h. The mixture was quenched with H₂O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. After recrystallization from MeOH, the desired product (5.45 g, 14.6 mmol, 97%) was obtained as a white solid; mp 104–105 °C.

(S)-MOM-BINOL: [α]_D ²⁰ –93 (c 1.0, THF); (R)-MOM-BINOL: [α]_D ²⁰ +96 (c 1.0, THF).

¹H NMR (400 MHz, CDCl₃): δ = 7.96 (d, J = 9.0 Hz, 2 H), 7.88 (d, J = 8.2 Hz, 2 H), 7.59 (d, J = 9.0 Hz, 2 H,), 7.35 (ddd, J = 8.0 Hz, 6.7 Hz, 1.3 Hz, 2 H), 7.23 (ddd, J = 8.0 Hz, 6.7 Hz, 1.3 Hz, 2 H), 7.17 (br d, J = 8.5 Hz, 2 H), 5.10 (d, J = 6.8 Hz, 2 H), 4.99 (d, J = 6.8 Hz, 2 H), 3.15 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.8, 134.1, 130.0, 129.5, 128.0, 126.4, 125.7, 124.2, 121.4, 117.4, 95.3, 56.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₂O₄ + Na: 397.1410; found: 397.1412.

(S)-3-(Azidomethyl)-MOM-BINOL (2a)

(S)-3-Hydroxymethyl-MOM-BINOL (6):[ ¹² ] (S)-MOM-BINOL (6.37 g, 17.0 mmol, 1.0 equiv) was dissolved in THF (100 mL) and the solution was cooled to –78 °C. Then, t-BuLi (11.3 mL, 1.5 M in hexane, 17.0 mmol, 1.0 equiv) was added dropwise and the mixture was stirred at –78 °C for 2 h. Paraformaldehyde (782 mg, 25.5 mmol, 1.5 equiv) was then added and the reaction mixture was stirred at r.t. for 12 h. The mixture was quenched with H₂O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. After flash column chromatography (pentane–EtOAc, 2:1), the desired product (3.94 g, 9.74 mmol, 57%) was obtained as a colorless resin; [α]_D ²⁰ –200 (c 1.1, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 8.01–7.96 (m, 2 H), 7.92–7.85 (m, 2 H), 7.60 (d, J = 9.1 Hz, 1 H), 7.43–7.33 (m, 2 H), 7.30–7.21 (m, 2 H), 7.19–7.12 (m, 2 H), 5.12 (d J = 7.0 Hz, 1 H), 5.04 (d, J = 7.0 Hz, 2 H), 4.95 (dd, J = 12.4 Hz, 6.5 Hz, 1 H), 4.90 (dd, J = 12.4 Hz, 6.5 Hz, 1 H), 4.69 (d, J = 6.1 Hz, 1 H), 4.48 (d, J = 6.1 Hz, 1 H), 3.52 (t J = 6.5 Hz, 1 H), 3.25 (s, 3 H), 3.16 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.3, 152.9, 134.4, 133.9, 133.9, 131.2, 130.2, 129.8, 129.3, 128.1, 128.1, 127.0, 126.4, 125.8, 125.6, 125.5, 125.3, 124.4, 120.6, 116.6, 99.5, 95.0, 62.3, 57.2, 56.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₂₄O₅ + Na: 427.1516; found: 427.1520.

BINOL-azide 2a : Compound 6 (3.52 g, 8.70 mmol, 1.0 equiv) and Et₃N (4.80 mL, 34.8 mmol, 4.0 equiv) were dissolved in toluene–EtOAc (100 mL, 1:1) and the solution was cooled to 0 °C. Then, MsCl (1.4 mL, 17.4 mmol, 2.0 equiv) was added and the mixture was stirred 1 h at 0 °C. After filtration through Celite, the obtained filtrate was treated with NaN₃ (5.65 g, 87.0 mmol, 10.0 equiv), previously dissolved in DMF (100 mL), and stirred at r.t. for 4 h. The reaction mixture was then diluted with H₂O (100 mL) and extracted with Et₂O (3 × 100 mL). The combined organic layers were washed with H₂O (2 × 100 mL), 1 M aq HCl (100 mL) and brine (100 mL), dried (Na₂SO₄), and filtered. After removal of the solvent under reduced pressure, the desired product (3.30 g, 7.70 mmol, 89%) was obtained as a white solid; mp 129–133 °C; [α]_D ²⁰ –52 (c 1.4, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 8.01–7.97 (m, 2 H), 7.94–7.85 (m, 2 H), 7.61 (d, J = 9.1 Hz, 1 H), 7.46–7.34 (m, 2 H), 7.32–7.23 (m, 2 H), 7.18 (br t, J = 7.3 Hz, 2 H), 5.14 (d, J = 7.0 Hz, 1 H), 5.06 (d, J = 7.0 Hz, 1 H), 4.74 (s, 2 H), 4.64 (d, J = 5.6 Hz, 1 H), 4.52 (d, J = 5.7 Hz, 1 H), 3.18 (s, 3 H), 3.06 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.0, 152.4, 134.0, 133.9, 130.8, 130.2, 129.8, 129.4, 129.1, 128.1, 128.1, 127.0, 126.7, 125.9, 125.8, 125.5, 125.4, 124.4, 120.3, 116.5, 99.5, 94.9, 57.0, 56.1, 51.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₅H₂₃N₃O₄ + Na: 452.1581; found: 452.1582.

(S)-3,3′-Bis(azidomethyl)-MOM-BINOL (2b)

(S)-3,3′-Dicarboxyaldehyde-MOM-BINOL (7):[ ¹³ ] (S)-MOM-BINOL (6.00 g, 16.0 mmol, 1.0 equiv) and TMEDA (9.5 mL, 64.0 mmol, 4.0 equiv) were dissolved in THF (100 mL) and the solution was cooled to 0 °C. n-BuLi (1.6 M solution in pentane) (25.0 mL, 40.0 mmol, 2.5 equiv) was added dropwise and the mixture was stirred 1 h at 0 °C. DMF (6.20 mL, 80.0 mmol, 5.0 equiv) was added and the reaction mixture was stirred at r.t. for 12 h. The reaction was quenched with H₂O (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. After flash column chromatography (pentane–EtOAc, 3:1), the desired product (5.99 g, 13.9 mmol, 87%) was obtained as a yellow solid; mp 118–119 °C.

¹H NMR (300 MHz, CDCl₃): δ = 10.55 (s, 2 H), 8.61 (s, 2 H) 8.07 (dd, J = 8.1 Hz, 2 H), 7.61–7.47 (m, 2 H), 7.47–7.34 (m, 2 H), 7.24–7.19 (m, 2 H), 4.73 (d, J = 6.2 Hz, 2 H), 4.68 (d, J = 6.2 Hz, 2 H), 2.87 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 190.8, 154.2, 136.8, 132.4, 130.4, 130.2, 129.8, 129.0, 126.4, 126.2, 126.0, 100.7, 57.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₂O₆ + Na: 453.1309; found: 453.1319.

(S)-3,3′-Dihydroxymethyl-MOM-BINOL (8):[ ¹⁴ ] Compound 7 (4.30 g, 10.0 mmol, 1.0 equiv) was dissolved in MeOH (50 mL) and the solution was cooled to 0 °C. Then, NaBH₄ (907 mg, 24.0 mmol, 2.4 equiv) was added and the resulting mixture was stirred 1 h at r.t. The reaction was quenched with H₂O (50 mL) and extracted with CH₂Cl₂ (3 × 75 mL). The combined organic layers were dried (Na₂SO₄) and filtered. After removal of the solvent under reduced pressure, the desired product (4.15 g, 9.60 mmol, 96%) was obtained as a white solid; mp >268 °C (dec.); [α]_D ²⁰ +224 (c 0.3, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 8.03 (s, 2 H), 7.90 (d, J = 8.1 Hz, 2 H), 7.46–7.38 (m, 2 H), 7.30–7.22 (m, 2 H), 7.19–7.12 (m, 2 H), 4.99 (d, J = 12.6 Hz, 2 H), 4.85 (d, J = 12.6 Hz, 2 H), 4.48 (d, J = 6.2, 2 H), 4.45 (d, J = 6.2 Hz, 2 H), 3.18 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.2, 134.6, 133.8, 131.0, 129.8, 128.2, 126.9, 125.8, 125.5, 125.2, 99.4, 61.9, 57.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₆O₆ + Na: 457.1622; found: 457.1626.

BINOL-azide 2b : Compound 8 (4.15 g, 9.50 mmol, 1.0 equiv) and Et₃N (10.6 mL, 76.0 mmol, 8.0 equiv) were dissolved in toluene–EtOAc (100 mL, 1:1) and the solution was cooled to 0 °C. MeSO₂Cl (3.0 mL, 38.0 mmol, 4.0 equiv) was added and the mixture was stirred at 0 °C for 2 h. After filtration of the mixture through Celite, the obtained filtrate was treated with NaN₃ (6.18 g, 95.0 mmol, 10.0 equiv), previously dissolved in DMF (100 mL), and stirred for 4 h at r.t. The mixture was diluted with H₂O (100 mL) and extracted with Et₂O (3 × 100 mL). The combined organic layers were washed with H₂O (2 × 100 mL), 1 M aq HCl (100 mL), and brine (100 mL), dried (Na₂SO₄), and filtered. After removal of the solvent under reduced pressure, the desired product (3.12 g, 7.70 mmol, 81%) was obtained as a colorless oil; [α]_D ²⁰ +166 (c 0.5, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 8.03 (s, 2 H) 7.93 (d, J = 8.1 Hz, 2 H), 7.49–7.41 (m, 2 H), 7.35 –7.27 (m, 2 H), 7.22–7.15 (m, 2 H), 4.81 (d, J = 14.1 Hz, 2 H), 4.69 (d, J = 14.1 Hz, 2 H), 4.54 (d, J = 5.9 Hz, 2 H), 4.49 (d, J = 5.9 Hz, 2 H), 3.02 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.6, 134.1, 130.7, 130.0, 129.4, 128.3, 127.3, 126.1, 125.7, 125.5, 99.6, 57.0, 51.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₆H₂₄N₆O₄ + Na: 507.1751; found: 507.1749.

(S)-3-Azido-MOM-BINOL (2c)

(S)-MOM-BINOL (11.23 g, 30.0 mmol, 1.0 equiv) was dissolved in THF (200 mL) and the solution was cooled to –78 °C. Then, t-BuLi (20.0 mL, 1.5 M in pentane, 30.0 mmol, 1.0 equiv) was added dropwise and the resulting mixture was stirred for 2 h at –78 °C. After the addition of TosN₃ (7.11 g, 36 mmol, 1.2 equiv), the reaction mixture was warmed up to r.t. and stirred further for 6 h. The reaction was quenched with H₂O (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. After removal of the excess of TosN₃ by flash column chromatography (pentane–EtOAc, 12:1), the obtained crude product (yellow oil) was crystallized from a EtOAc solution (30 mL) overlayed with pentane (400 mL) and kept for 2 days at –20 °C. After filtration, the desired product (7.3 g, 17.6 mmol, 59%) was obtained as a white solid; mp 85–89 °C; [α]_D ²⁰ –45 (c 1.5, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 7.82 (d, J = 8.5 Hz, 1 H), 7.72 (d, J = 8.1 Hz, 1 H), 7.67 (d, J = 8.3 Hz, 1 H), 7.54 (s, 1 H), 7.46 (d, J = 9.1 Hz, 1H), 7.30–7.07 (m, 3 H), 7.07–7.00 (m, 3 H), 5.01 (d, J = 7.0 Hz, 1 H), 4.91 (d, J = 7.0 Hz, 1 H), 4.66 (d, J = 5.7 Hz, 1 H), 4.59 (d, J = 5.7 Hz, 1 H), 3.06 (s, 3 H), 2.59 (s, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 152.9, 145.7, 133.9, 133.3, 131.5, 131.1, 130.1, 129.6, 128.0, 127.9, 126.8, 126.8, 126.1, 125.9, 125.8, 125.6, 124.2, 119.9, 117.4, 116.4, 99.0, 94.9, 56.6, 56.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₁N₃O₄ + Na: 438.1424; found: 438.1424.

3,3′-Diazido-MOM-BINOL (2d)

(S)-MOM-BINOL (5.00 g, 13.4 mmol, 1.0 equiv) and TMEDA (8.00 mL, 53.4 mmol, 4.0 equiv) were dissolved in Et₂O (300 mL) and the solution was cooled to 0 °C. n-BuLi (23.0 mL, 1.6 M in pentane, 36.7 mmol, 2.75 equiv) was added dropwise and the resulting mixture was stirred for 1 h at r.t. The reaction mixture was cooled to 0 °C and TosN₃ (7.90 g, 40.1 mmol, 3.0 equiv) was added dropwise. The resulting mixture was stirred for 1 h at 0 °C and for further 3 h at r.t. The reaction was quenched with H₂O (50 mL) and extracted with CH₂Cl₂ (3 × 100 mL). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. After flash column chromatography (gradient of pentane–EtOAc–CH₂Cl₂, 30:2:1 → 20:2:1), the desired product (3.84 g, 8.41 mmol, 63%) was obtained as a slightly brown solid; mp 81–84 °C.

(S)-2d: [α]_D ²⁰ +24 (c 0.50, CHCl₃); (R)-2d: [α]_D ²⁰ –23 (c 0.25, CHCl₃).

¹H NMR (300 MHz, CDCl₃): δ = 7.64 (d, J = 8.2 Hz, 2 H), 7.52 (s, 2 H), 7.26 (ddd, J = 8.2, 6.7, 1.3 Hz, 2 H), 7.10–7.04 (m, 2 H), 6.98 (d, J = 8.6 Hz, 2 H), 4.71 (d, J = 5.9 Hz, 2 H), 4.59 (d, J = 5.9 Hz, 2 H), 2.47 (s, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 145.8, 133.2, 131.4, 130.9, 127.3, 126.8, 126.5, 126.2, 126.1, 117.8, 99.0, 56.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₂₀N₆O₄ + Na: 479.1444; found: 479.1440.

Copper-Catalyzed Cycloaddition of Azides 2 with Alkynes ­(CuAAC);[ ³ ] General Procedure

A mixture of azide 2 (7.70 mmol, 1.0 equiv), the corresponding alkyne [1.5 equiv for mono-N₃ (2a and 2d) or 3.0 equiv for di-N₃ (2b and 2d), respectively], 0.04 M aq CuSO₄ (4–8 mol%), and 0.12 M aq sodium ascorbate (12–24 mol%) in 1:1:1 mixture of CH₂Cl₂–t-BuOH–H₂O (15–30 mL, H₂O solvent from the CuSO₄ and Na ascorbate stock solutions) was stirred vigorously at 50 °C under argon in a pressure Schlenk flask. After completion of the reaction (followed by TLC), the mixture was diluted with H₂O (8 mL) and extracted with CH₂Cl₂ (3 × 8 mL). The combined organic layers were washed with 25% aq ammonia (3 × 8 mL) and brine (8 mL), dried (Na₂SO₄) and concentrated under reduced pressure. The desired products were obtained by crystallization, precipitation, or flash column chromatography of the crude product.

(S)-3-{[1H-(4-Phenyl)-1,2,3-triazol-1-yl]methyl}-MOM-­BINOL (3a)

Following the general CuAAC procedure, azide 2a (3.30 g, 7.70 mmol, 1.0 equiv) was reacted with phenylacetylene (1.30 mL, 11.6 mmol, 1.5 equiv) for 18 h using 4 mol% CuSO₄. The desired product (3.67 g, 6.90 mmol, 90%) was obtained as a white solid by precipitation (Et₂O–pentane) of the crude product; mp >152 °C (dec.); [α]_D ²⁰ –44 (c 0.1, CH₂Cl₂).

¹H NMR (300 MHz, CDCl₃): δ = 8.02 (s, 1 H), 7.99 (s, 1 H) 7.93–7.79 (m, 5 H), 7.62 (d, J = 9.1 Hz, 1 H), 7.47–7.10 (m, 9 H), 6.01 (d, J = 15.0 Hz, 1 H), 5.93 (d, J = 15.0 Hz, 1 H), 5.10 (d, J = 7.0 Hz, 1 H), 5.05 (d, J = 7.0 Hz, 1 H), 4.66 (d, J = 5.9 Hz, 1 H), 4.51 (d, J = 5.9 Hz, 1 H), 3.18 (s, 3 H), 3.13 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.9, 152.2, 134.2, 133.8, 130.9, 130.8, 130.4, 129.7, 129.5, 128.9, 128.5, 128.2, 128.2, 127.1, 127.0, 125.9, 125.8, 125.7, 125.6, 125.2, 124.4, 119.8, 116.3, 99.8, 94.9, 57.3, 56.1, 50.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₃H₂₉N₃O₄ + Na: 554.2050; found: 554.2058.

(S)-3,3′-Bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-MOM-­BINOL (3b)

Following the general CuAAC procedure, azide 2b (3.12 g, 6.50 mmol, 1.0 equiv) was reacted with phenylacetylene (2.10 mL, 20.0 mmol, 3.0 equiv) for 48 h using 5 mol% CuSO₄. The desired product (4.01 g, 5.80 mmol, 90%) was obtained as a white solid by precipitation (Et₂O–pentane) of the crude product; mp 114–116 °C; [α]_D ²⁰ –44 (c 0.1, CH₂Cl₂).

¹H NMR (300 MHz, CDCl₃): δ = 7.99 (s, 2 H), 7.89–7.85 (m, 2 H) 7.85–7.82 (m, 4 H), 7.45–7.37 (m, 7 H), 7.36–7.27 (m, 5 H), 7.18 (d, J = 8.5 Hz, 2 H), 6.02 (d, J = 15.1 Hz, 2 H), 5.90 (d, J = 15.1 Hz, 2 H), 4.45 (d, J = 6.0 Hz, 2 H), 4.40 (d, J = 6.0 Hz, 2 H), 3.07 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 152.4, 148.3, 134.1, 132.2, 130.8, 130.7, 130.2, 129.0, 129.0, 128.9, 128.5 128.4, 128.3, 127.7, 126.0, 125.7 125.3, 120.1, 99.9, 57.3, 50.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₂H₃₆N₆O₄ + Na: 711.2690; found: 711.2688.

(S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-MOM-BINOL (3c)

Following the general CuAAC procedure, azide 2c (11.31 g, 27.0 mmol, 1.0 equiv) was reacted with phenylacetylene (4.50 mL, 41.0 mmol, 1.5 equiv) for 18 h using 4 mol% CuSO₄. The desired product (10.7 g, 22.7 mmol, 84%) was obtained as a white solid by precipitation (Et₂O–pentane) of the crude product; mp 82–86 °C; [α]_D ²⁰ –103 (c 0.1, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 8.53 (s, 1 H), 8.41 (s, 1 H), 8.04–7.93 (m, 4 H), 7.90 (d, J = 8.1 Hz, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 7.54–7.22 (m, 9 H), 5.19 (d, J = 7.0 Hz, 1 H), 5.08 (d, J = 7.0 Hz, 1 H), 4.47 (d, J = 5.5 Hz, 1 H), 4.40 (d, J = 5.6 Hz, 1 H), 3.20 (s, 3 H), 2.58 (s, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 153.0, 147.9, 145.9, 133.8, 133.8, 130.6, 130.6, 130.5, 130.5, 129.7, 129.0, 128.6, 128.3, 128.2, 127.9, 127.7, 127.2, 126.4, 126.0, 125.9, 125.4, 125.2, 124.5, 122.4, 119.4, 116.4, 99.6, 94.9, 56.7, 56.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₂₇N₃O₄ + Na: 540.1899; found: 540.1886.

3,3′-Bis(4-phenyl-1H-1,2,3-triazol-1-yl)-MOM-BINOL (3d)

Following the general CuAAC procedure, azide 2d (0.50 g, 1.10 mmol, 1.0 equiv) was reacted with phenylacetylene (370 μL, 3.30 mmol, 3.0 equiv) for 60 h using 8 mol% CuSO₄. The desired product (636 mg, 0.96 mmol, 87%) was obtained as a white solid by flash column chromatography (CH₂Cl₂–EtOAc, 20:1) followed by precipitation (CH₂Cl₂–pentane); mp >153 °C (dec.).

(S)-3d: [α]_D ²⁰ –53 (c 0.1, CH₂Cl₂); (R)-3d: [α]_D ²⁰ –159.6 (c 0.8, CH₂Cl₂).

H NMR (300 MHz, CDCl₃): δ = 8.54 (s, 2 H), 8.45 (s, 2 H), 8.03 (d, J = 8.1 Hz, 2 H), 7.99– 7.93 (m, 4 H), 7.61–7.51 (m, 2 H), 7.52–7.29 (m, 10 H), 4.51 (d, J = 5.8 Hz, 2 H), 4.41 (d, J = 5.8 Hz, 2 H), 2.57 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.2, 146.5, 133.7, 130.5, 130.4, 130.3, 129.1, 128.8, 128.5, 128.4, 126.9, 126.8, 126.4, 126.2, 125.9, 122.1, 99.7, 56.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₀H₃₂N₆O₄ + Na: 683.2377; found: 683.2367.

(S)-3,3′-Bis(5-phenyl-1H-1,2,3-triazol-1-yl)-MOM-BINOL (3d′)[ ⁹ ]

Azide 2d (114 mg, 0.25 mmol, 1.0 equiv) and phenylacetylene (84 μL, 0.75 mmol, 3.0 equiv) were dissolved in DMSO (1 mL). Then, a 0.45 M solution of KOH in DMSO–H₂O (3:1, 111 μL, 0.05 mmol, 20 mol%) was added and the resulting mixture was stirred for 16 h at r.t. The desired product (135 mg, 0.20 mmol, 82%) was obtained after flash column chromatography (gradient CH₂Cl₂–EtOAc, 1:0 → 3:1) as a slightly yellow solid; mp >88 °C (dec.); [α]_D ²⁰ –143.7 (c 0.19, CH₂Cl₂).

¹H NMR (400 MHz, CDCl₃): δ = 8.18 (s, 2 H), 7.92 (s, 2 H), 7.91 (d, J = 8.9 Hz, 2 H), 7.49 (ddd, J = 8.1, 6.8, 1.2 Hz, 2 H), 7.37–7.26 (m, 12 H), 7.03 (br s, 2 H), 4.19 (d, J = 5.7 Hz, 2 H), 4.11 (br d, J = 5.7 Hz, 2 H), 2.35 (s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.2, 140.4, 134.1, 132.7, 130.2, 130.1, 129.4, 129.3, 129.0, 128.5, 128.2, 128.2, 127.1, 126.7, 126.5, 126.3, 99.0, 56.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₀H₃₂N₆O₄ + Na: 683.2377; found: 683.2371.

MOM-Deprotection (MOM-D) of BINOL Derivatives 3; General Procedure

MOM-protected BINOL derivative 3 (1.00 mmol, 1 equiv) was dissolved in CH₂Cl₂–MeOH (1:2, 33.0 mL) in a pressure tube. Then, 12 M aq HCl (38 equiv) was added and the reaction mixture was stirred for 12 h at 50 °C. The mixture was neutralized with sat. aq NaHCO₃ and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic layers were concentrated under reduced pressure followed by precipitation (CH₂Cl₂–pentane) and filtration to obtain the desired product 1.

(S)-3-[(4-Phenyl-1H-1,2,3-triazol-1-yl)methyl]-BINOL (1a)

Following the MOM-D procedure, the deprotection of 3a (1.45 g, 2.72 mmol) gave compound 1a (992 mg, 2.23 mmol, 82%) as a white solid; mp 269–273 °C; [α]_D ²⁰ –79 (c 0.5, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.41 (s, 1 H), 8.64 (s, 1 H), 8.59 (s, 1 H), 7.94–7.82 (m, 5 H), 7.73 (s, 1 H), 7.48–7.40 (m, 2 H), 7.37–7.14 (m, 6 H), 6.91 (d, J = 13.7 Hz, 1 H), 6.89 (d, J = 13.8 Hz, 1 H), 5.84 (s, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 154.0, 150.8, 146.3, 134.3, 133.9, 130.9, 129.6, 128.9, 128.5, 128.4, 128.1, 128.0, 128.0, 127.8, 126.3, 126.1, 125.2, 125.2, 124.4, 124.0, 123.1, 122.4, 121.8, 118.8, 116.3, 113.1, 49.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₉H₂₁N₃O₂ + Na: 466.1526; found: 466.1530.

(S)-3,3′-Bis[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-BINOL (1b)

Following the MOM-D procedure, the deprotection of 3b (1.42 g, 2.06 mmol) gave compound 1b (1.05 g, 1.74 mmol, 93%) as a white solid; mp 253–256 °C; [α]_D ²⁰ –96 (c 0.2, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 8.88 (s, 2 H), 8.53 (s, 2 H), 7.94–7.80 (m, 8 H), 7.46–7.39 (m, 4 H), 7.36–7.26 (m, 4 H), 7.26–7.18 (m, 2 H), 6.90 (d, J = 8.3 Hz, 2 H), 5.86 (d, J = 17.4 Hz, 2 H), 5.81 (d, J = 17.4 Hz, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 152.1, 146.1, 134.2, 130.9, 130.2, 128.9, 128.3, 128.2, 127.8, 126.7, 125.1, 124.9, 124.0, 123.3, 121.7, 114.2, 49.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₈H₂₈N₆O₂ + Na: 623.2166; found: 623.2157.

(S)-3-(4-Phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1c)

Following the MOM-D procedure, the deprotection of 3c (4.44 mmol, 2.30 g) gave compound 1c (1.64 g, 3.82 mmol, 86%) as a white solid; mp 254–256 °C; [α]_D ²⁰ –147 (c 0.2, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.60 (br s, 1 H), 9.18 (br s, 1 H), 9.08 (s, 1 H), 8.38 (s, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 8.04–7.99 (m, 2 H), 7.96 (d, J = 8.9 Hz, 1 H), 7.94–7.89 (m, 1 H), 7.54–7.46 (m, 2 H), 7.44–7.22 (m, 6 H), 7.07–6.94 (m, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 154.0, 146.3, 146.2, 134.2, 133.8, 130.6, 129.9, 129.0, 128.5, 128.3, 128.2, 128.1, 127.5, 127.3, 127.0, 126.4, 125.4, 124.7, 124.6, 124.1, 124.0, 123.6, 122.6, 118.9, 118.8, 113.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₈H₁₉N₃O₂ + Na: 452.1369; found: 452.1362.

3,3′-Bis(4-phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1d)

Following the MOM-D procedure, the deprotection of 3d (315 mg, 0.48 mmol) gave compound 1d (275 g, 0.48 mmol, quant) as a white solid; mp 174–177 °C.

(S)-1d: [α]_D ²⁰ +18 (c 0.6, DMSO); (R)-1d: [α]_D ²⁰ –16 (c 0.25, ­DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.57 (s, 2 H), 9.04 (s, 2 H), 8.46 (s, 2 H), 8.11 (br d, J = 8.5 Hz, 2H), 8.03–7.97 (m, 4 H), 7.54–7.43 (m, 5 H), 7.43–7.34 (m, 5 H), 7.09–7.03 (m, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 147.2, 146.3, 133.8, 130.5, 129.1, 128.7, 128.1, 127.8, 127.7, 127.3, 125.5, 125.4, 124.2, 124.2, 123.4, 116.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₂₄N₆O₂ + Na: 595.1853; found: 595.1852.

(S)-3,3′-Bis(5-phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1d′)

Following the MOM-D procedure, the reaction of 3d′ (86 mg, 0.13 mmol) gave compound 1d′ (70 mg, 0.12 mmol, 92%) as a purple solid; mp 175 °C; [α]_D ²⁰ –213 (c 0.19, DMSO).

¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 2 H), 7.73 (d, J = 8.1 Hz, 2 H), 7.64 (s, 2 H), 7.39–7.23 (m, 16 H), 6.99 (d, J = 8.4 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 147.5, 139.6, 133.9, 132.5, 129.5, 129.0, 128.8, 128.6, 128.3, 128.2, 128.2, 127.0, 125.8, 125.1, 124.5, 115.8.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₆H₂₄N₆O₂ + Na: 595.1853; found: 595.1847.

(S)-3,3′-Bis[4-(anthracen-9-yl)-1H-1,2,3-triazol-1-yl]-BINOL (1e)

Following the general CuAAC procedure, azide 2d (150 mg, 0.33 mmol, 1.0 equiv) was reacted with 9-ethynylanthracene (169 mg, 0.83 mmol, 2.5 equiv) for 72 h using 8 mol% CuSO₄. Due to the low reactivity, additional CuSO₄ (8 mol%) and sodium ascorbate (24 mol%) were added and the reaction mixture was stirred for further 48 h at 55 °C. The MOM-'click' product was obtained by flash column chromatography (gradient CH₂Cl₂–EtOAc, 30:1 → 5:1). Subsequent deprotection by using the MOM-D procedure (48 h) afforded the desired product 1e (93 mg, 0.12 mmol, 37% over two steps) as a slightly brown solid; mp >106 °C (dec.); [α]_D ²⁰ –458 (c 0.1, DMSO).

¹H NMR (600 MHz, CDCl₃): δ = 8.53 (s, 2 H), 8.05–8.02 (m, 4 H), 8.00 (s, 2 H), 7.96 (d, J = 8.5 Hz, 2 H), 7.72–7.68 (m, 2 H), 7.56 (d, J = 8.6 Hz, 2 H), 7.52–7.48 (m, 4 H), 7.40 (ddd, J = 8.2, 6.6, 1.1 Hz, 2 H), 7.34–7.29 (m, 4 H), 7.15 (d, J = 7.4 Hz, 2 H), 7.11–7.05 (m, 2 H), 7.00–6.97 (m, 2 H), 6.40 (d, J = 8.4 Hz, 2 H).

¹³C NMR (150 MHz, CDCl₃): δ = 145.7, 135.3, 134.9, 132.3, 130.5, 130.3, 130.1, 130.1, 129.0, 128.0, 127.9, 127.4, 127.1, 126.5, 126.4, 126.2, 124.8, 124.6, 124.3, 124.1, 124.0, 124.0, 123.5, 123.2, 118.8, 115.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₅₂H₃₂N₆O₂ + Na: 795.2479; found: 795.2476.

(S)-3-(4-Mesityl-1H-1,2,3-triazol-1-yl)-BINOL (1f)

Following the general CuAAC procedure, azide 2d (201 mg, 0.44 mmol, 1.0 equiv) was reacted with 2-ethynyl-1,3,5-trimethylbenzene (190 mg, 1.32 mmol, 3.0 equiv) for 4 days using 8 mol% CuSO₄. Due to the low reactivity, additional CuSO₄ (8 mol%) and sodium ascorbate (24 mol%) were added and the reaction mixture was stirred for further 6 days at 70 °C. The MOM-'click' product was obtained by flash column chromatography (CH₂Cl₂–EtOAc 20:1). Subsequent deprotection by using the MOM-D procedure (16 h) afforded the desired product 1f (118 mg, 0.18 mmol, 41% over two steps) as a white solid; mp >268 °C (dec.); [α]_D ²⁰ +16 (c 0.3, DMSO).

¹H NMR (300 MHz, CDCl₃): δ = 9.59 (br s, 2 H), 8.25 (br s, 4 H), 7.95 (d, J = 7.7 Hz, 2 H), 7.48–7.33 (m, 4 H), 7.28 (d, J = 8.7 Hz, 2 H), 6.99 (s, 4 H), 2.35 (s, 6 H), 2.19 (s, 12 H).

¹³C NMR (75 MHz, CDCl₃): δ = 145.3, 138.8, 137.9, 137.9, 133.3, 128.7, 128.7, 128.6, 128.1, 128.0, 126.1, 125.2, 124.9, 122.1, 120.1, 118.6, 21.3, 20.9.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₂H₃₆N₆O₂ + Na: 679.2792; found: 679.2799.

(S)-3,3′-Bis[4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]-BINOL (1g)

Following the general CuAAC procedure, azide 2d (201 mg, 0.44 mmol, 1.0 equiv) was reacted with 1-ethynyl-2,3,5,6-tetrafluo­ro-4-methoxybenzene (269 mg, 1.32 mmol, 3.0 equiv) for 4 days using 8 mol% CuSO₄. Due to the low reactivity, additional CuSO₄ (8 mol%) and sodium ascorbate (24 mol%) were added and the reaction mixture was stirred for further 4 days at 60 °C. The MOM-'click' product was obtained by flash column chromatography (CH₂Cl₂–EtOAc, 30:1). Subsequent deprotection by using the MOM-D protocol afforded the desired product 1g (130 mg, 0.17 mmol, 39% (over two steps)) as a white solid; mp >90 °C (dec.); [α]_D ²⁰ +56 (c 0.2, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.66 (s, 2 H), 8.92 (s, 2 H), 8.53 (s, 2 H), 8.12 (d, J = 8.0 Hz, 2 H), 7.49–7.34 (m, 4 H), 7.06 (d, J = 8.0 Hz, 2 H), 4.12 (t, J = 1.4 Hz, 6 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 147.1, 145.8–145.3 (m), 142.6–142.1 (m), 139.4–139.0 (m), 137.8–137.3 (m), 133.9, 133.8–133.5 (m), 128.8, 127.9, 127.7, 127.3 (t, J = 3.9 Hz), 126.9, 125.7, 124.3 (d, J = 8.2 Hz), 116.1, 104.1 (t, J = 16.0 Hz), 62.4 (t, J = 3.6 Hz).

¹⁹F NMR (282 MHz, DMSO-d ₆): δ = –142.16 to –142.31 (m), –157.79 to –158.09 (m).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₈H₂₀F₈N₆O₄ + Na: 799.1310; found: 799.1307.

(S)-3,3′-Bis(1H-1,2,3-triazol-1-yl)-BINOL (1h)

Following the general CuAAC procedure, azide 2d (201 mg, 0.44 mmol, 1.0 equiv) was reacted with ethynyltrimethylsilane (0.5 mL, 3.5 mmol, 8.0 equiv) for 6 days using 8 mol% CuSO₄. The corresponding MOM-'click' product was obtained by flash column chromatography (gradient pentane–EtOAc, 6:1 → 3:1). Subsequent deprotection by using the MOM-D protocol gave a complex mixture due to the partial cleavage of the trimethylsilyl group. Finally, the crude reaction mixture was treated with 1 M aq KOH (2 mL) for 12 h at r.t. to afford 1j (56 mg, 0.11 mmol, 25% over two steps) as a white solid; mp >144 °C (dec.); [α]_D ²⁰ –56 (c 0.3, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.50 (s, 2 H), 8.57 (d, J = 1.1 Hz, 2 H), 8.42 (s, 2 H), 8.09 (d, J = 7.6 Hz, 2 H), 7.99 (d, J = 1.1 Hz, 2 H), 7.47–7.31 (m, 4 H), 7.01 (d, J = 8.3 Hz, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 147.0, 133.6, 133.4, 128.7, 127.7, 127.6, 127.3, 126.9, 125.2, 124.2, 124.1, 116.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₂₄H₁₆N₆O₂ + Na: 443.1227; found: 443.1232.

(S)-3,3′-Bis[4-(tert-butyl)-1H-1,2,3-triazol-1-yl]-BINOL (1i)

Following the general CuAAC procedure, azide 2d (201 mg, 0.44 mmol, 1.0 equiv) was reacted with 3,3-dimethylbut-1-yne (324 μL, 2.64 mmol, 6.0 equiv) for 2.5 days using 8 mol% CuSO₄. The MOM-'click' product was obtained by flash column chromatography (CH₂Cl₂–EtOAc, 20:1). Subsequent deprotection by using the MOM-D procedure afforded the desired product 1i (223 mg, 0.42 mmol, 95% over two steps) as a white solid; mp >163 °C (dec.); [α]_D ²⁰ –29 (c 0.6, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.49 (s, 2 H), 8.41 (s, 2 H), 8.35 (s, 2 H), 8.06 (d, J = 8.1 Hz, 2 H), 7.45–7.30 (m, 4 H), 7.00 (d, J = 8.4 Hz, 2 H), 1.37 (s, 18 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 156.2, 146.8, 133.4, 128.6, 127.8, 127.5, 127.3, 124.5, 124.1, 121.6, 121.6, 116.4, 30.6, 30.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₂H₃₂N₆O₂ + Na: 555.2488; found: 555.2488.

(S)-3,3′-Bis[4-(adamantan-1-yl)-1H-1,2,3-triazol-1-yl]-BINOL (1j)

Following the general CuAAC procedure, azide 2d (60 mg, 0.13 mmol, 1.0 equiv) was reacted with 1-ethynyladamantane (45 mg, 0.28 mmol, 2.1 equiv) for 2.5 days using 8 mol% CuSO₄. The MOM-'click' product was obtained by flash column chromatography (CH₂Cl₂–EtOAc, 15:1). Subsequent deprotection by using the MOM-D protocol afforded the desired product 1j (35 mg, 0.05 mmol, 38% over two steps) as a white solid; mp >273 °C (dec.); [α]_D ²⁰ –9 (c 0.2, DMSO).

¹H NMR (300 MHz, CDCl₃): δ = 9.92 (s, 2 H), 8.08 (s, 2 H), 8.03 (s, 2 H), 7.86 (d, J = 8.1 Hz, 2 H), 7.41–7.27 (m, 4 H), 7.21 (dd, J = 8.4, 1.3 Hz, 2 H), 2.09 (s, 6 H), 2.03 (s, 12 H), 1.80 (s, 12 H).

¹³C NMR (75 MHz, CDCl₃): δ = 158.1, 145.5, 133.2, 128.4, 127.9, 127.8, 124.9, 124.9, 124.8, 119.3, 118.8, 118.1, 42.5, 36.7, 32.9, 28.5.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄₄H₄₄N₆O₂ + Na: 711.3418; found: 711.3409.

(S)-3,3′-Bis{4-[(dimethylamino)methyl]-1H-1,2,3-triazol-1-yl}-BINOL (1k)

Following the general CuAAC procedure, azide 2d (201 mg, 0.44 mmol, 1.0 equiv) was reacted with N,N-dimethylprop-2-yn-1-amine (142 μL, 1.32 mmol, 3.0 equiv) for 12 h using 8 mol% CuSO₄. The MOM-'click' product was obtained by flash column chromatography (CH₂Cl₂–MeOH, 2:1). Subsequent deprotection by using the MOM-D procedure afforded the desired product 1k (111 mg, 0.21 mmol, 47% over two steps) as an olive colored solid; mp >223 °C (dec.); [α]_D ²⁰ +942 (c 0.1, DMSO).

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.75 (s, 2 H), 8.36 (s, 2 H), 7.96 (d, J = 7.8 Hz, 2 H), 7.23 (ddd, J = 8.0, 6.7, 1.3 Hz, 2 H), 7.16 (ddd, J = 8.3, 6.7, 1.5 Hz, 2 H), 7.01 (d, J = 1.2 Hz, 2 H), 3.82 (s, 4 H), 2.34 (s, 12 H).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 151.9, 141.7, 133.6, 129.0, 128.6, 126.1, 126.0, 126.0, 125.16, 122.3, 122.2, 119.2, 53.0, 44.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₃₀N₈O₂: 535.2564; found: 535.2555.

(S)-3,3′-Bis[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]-BINOL (1l)

Following the general CuAAC procedure, azide 2d (730 mg, 1.60 mmol, 1.0 equiv) was reacted with 2-ethynylpyridine (363 mg, 3.52 mmol, 2.2 equiv) for 16 h using 4 mol% CuSO₄. The MOM-'click' product was obtained by flash column chromatography (CH₂Cl₂–MeOH, 40:1). Subsequent deprotection, by using the MOM-D procedure and direct filtration of the neutralized reaction mixture, afforded the desired product 1l (829 mg, 1.44 mmol, 90% over two steps) as a slightly olive colored solid; mp >113 °C (dec.); [α]_D ²⁰ +39 (c 0.2, DMSO).

¹H NMR (300 MHz, DMSO-d ₆): δ = 9.61 (s, 2 H), 8.99 (s, 2 H), 8.64 (s, 2 H), 8.52 (s, 2 H), 8.17 (d, J = 8.1 Hz, 2 H), 8.12 (d, J = 7.7 Hz, 2 H), 7.96 (t, J = 7.5 Hz, 2 H), 7.51–7.32 (m, 6 H), 7.09 (d, J = 8.3 Hz, 2 H).

¹³C NMR (75 MHz, DMSO-d ₆): δ = 149.8, 149.7, 147.2, 147.0, 137.4, 133.7, 128.8, 127.8, 127.7, 127.2, 125.4, 125.0, 124.3, 124.2, 123.3, 119.7, 116.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₃₄H₂₂N₈O₂ + Na: 597.1758; found: 597.1745.

Addition of Et₂Zn to Aldehydes 4: General Procedure

3,3′-Bis(4-phenyl-1H-1,2,3-triazol-1-yl)-BINOL (1d; 14.3 mg, 0.025 mmol, 10 mol%) and a 0.05 M Ti(Oi-Pr)₄ solution in toluene (0.5 mL, 0.025 mmol, 10 mol%) were combined in a heat-gun-dried Schlenk tube (5 mL) under argon atmosphere and stirred for 30 min at r.t. (20–25 °C). The corresponding aldehyde 4 (0.25 mmol, 1.0 equiv) was added and the resulting mixture was stirred for further 30 min. Then, Et₂Zn (0.46 mL, 1.1 M in toluene, 0.5 mmol, 2.0 equiv) was added. The reaction was monitored by GC-MS and quenched with H₂O (1 mL) after consumption of the corresponding aldehyde 4 (15–48 h). The mixture was extracted with EtOAc (3 × 3 mL) and the combined organic layers were dried (MgSO₄) and filtered. The crude product was adsorbed on silica gel and alcohols 5 were obtained after purification by flash column chromatography.

1-Phenylpropan-1-ol (5a)

Following the general procedure (15 h), after flash column chromatography (pentane–EtOAc, 3:1), 5a was obtained as an oil (28 mg, 0.206 mmol, 82%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (97.5:2.5), flow rate 1.0 mL/min, 210 nm; t _R = 13.8 min (R-isomer) and 15.2 min (S-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.31–7.16 (m, 5 H), 4.51 (dd, J = 7.2, 6.0 Hz, 1 H), 1.88 (s, 1 H), 1.85–1.57 (m, 2 H), 0.84 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 144.7, 128.5, 127.6, 126.1, 76.1, 32.0, 10.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₂O + Na: 159.0780; found: 159.0780.

1-(Naphthalen-2-yl)propan-1-ol (5b)

Following the general procedure (19 h), after flash column chromatography (pentane–EtOAc, 10:1), 5b was obtained as a white solid (46 mg, 0.247 mmol, 99%); mp 37–38 °C.

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (90:10), flow rate 0.8 mL/min, 210 nm; t _R = 12.1 min (S-isomer) and 13.1 min (R-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.89–7.80 (m, 3 H), 7.79–7.77 (m, 1 H), 7.54–7.43 (m, 3 H), 4.77 (t, J = 6.6 Hz, 1 H), 2.01–1.77 (m, 2 H), 1.98 (br s, 1 H) 0.95 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.0, 133.4, 133.1, 128.4, 128.1, 127.8, 126.2, 125.9, 124.9, 124.3, 76.3, 31.9, 10.3.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄O + Na: 209.0937; found: 209.0942.

1-(Naphthalen-1-yl)propan-1-ol (5c)

Following the general procedure (18 h), after flash column chromatography (pentane–EtOAc, 11:1), 5c was obtained as an oil (40 mg, 0.215 mmol, 86%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (90:10), flow rate 0.8 mL/min, 210 nm; t _R = 10.4 min (S-isomer) and 17.7 min (R-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 8.16–8.07 (m, 1 H), 7.94–7.85 (m, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.63 (d, J = 7.2 Hz, 1 H), 7.57–7.44 (m, 3 H), 5.38 (dd, J = 7.4, 5.0 Hz, 1 H), 2.11 (s, 1 H), 2.08–1.84 (m, 2 H), 1.04 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 140.3, 133.9, 130.6, 129.0, 128.0, 126.0, 125.6, 125.5, 123.4, 123.02, 72.7, 31.2, 10.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₄O + Na: 209.0937; found: 209.0942.

1-(4-Methoxyphenyl)propan-1-ol (5d)

Following the general procedure (15 h), after flash column chromatography (pentane–EtOAc, 8:1), 5d was obtained as an oil (40 mg, 0.241 mmol, 96%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (97.5:2.5), flow rate 1.0 mL/min, 210 nm; t _R = 20.0 min (R-isomer) and 23.6 min (S-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.30–7.23 (m, 2 H), 6.92–6.84 (m, 2 H), 4.53 (t, J = 6.7 Hz, 1 H), 3.80 (s, 3 H), 1.88 (br s, 1 H), 1.87–1.64 (m, 2 H), 0.89 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 159.1, 136.9, 127.3, 113.9, 75.8, 55.4, 31.9, 10.4.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₄O₂ + Na: 189.0881; found: 189.0886.

1-(4-Fluorophenyl)propan-1-ol (5e)

Following the general procedure (15 h), after flash column chromatography (pentane–EtOAc, 9:1), 5e was obtained as an oil (29 mg, 0.188 mmol, 75%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (99.5:0.5), flow rate 0.4 mL/min, 210 nm; t _R = 84.1 min (S-isomer) and 89.5 min (R-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.27–7.18 (m, 2 H), 7.00–6.90 (m, 2 H), 4.50 (t, J = 6.6 Hz, 1 H), 1.88 (br s, 1 H), 1.82–1.54 (m, 2 H), 0.82 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.3 (d, J = 245.0 Hz), 140.4 (d, J = 3.1 Hz), 127.7 (d, J = 8.0 Hz), 115.3 (d, J = 21.3 Hz), 75.5, 32.1, 10.2.

¹⁹F NMR (282 MHz, CDCl₃): δ = –115.32.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₁FO + Na: 177.0686; found: 177.0687.

1-(4-Chlorophenyl)propan-1-ol (5f)

Following the general procedure (15 h), after flash column chromatography (pentane–EtOAc, 10:1), 5f was obtained as an oil (40 mg, 0.234 mmol, 94%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH, 97.5/2.5, flow rate 1.0 mL/min, 210 nm; t _R = 12.8 min (S-isomer) and 13.9 min (R-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.27–7.17 (m, 4 H), 4.51 (t, J = 6.5 Hz, 1 H), 1.82 (br s, 1 H), 1.80–1.56 (m, 2 H), 0.83 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 143.1, 133.2, 128.6, 127.5, 75.4, 32.1, 10.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₁ClO + Na: 193.0391; found: 193.0392.

1-(3-Chlorophenyl)propan-1-ol (5g)

Following the general procedure (18 h), after flash column chromatography (pentane–EtOAc, 10:1), 5g was obtained as an oil (28 mg, 0.164 mmol, 66%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (96:4), flow rate 0.5 mL/min, 210 nm; t _R = 17.0 min (S-isomer) and 18.7 min (R-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.29–7.25 (m, 1 H), 7.23–7.16 (m, 2 H), 7.16–7.11 (m, 1 H), 4.50 (t, J = 6.5 Hz, 1 H), 1.87 (br s, 1 H), 1.80–1.58 (m, 2 H), 0.84 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 146.8, 134.4, 129.8, 127.7, 126.3, 124.3, 75.5, 32.1, 10.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₁ClO + Na: 193.0391; found: 193.8396.

1-(2-Chlorophenyl)propan-1-ol (5h)

Following the general procedure (20 h), after flash column chromatography (pentane–EtOAc, 20:1), 5h was obtained as an oil (37 mg, 0.217 mmol, 87%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH (99:1), flow rate 0.5 mL/min, 210 nm; t _R = 35.2 min (S-isomer) and 36.8 min (R-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 7.47 (dd, J = 7.7, 1.8 Hz, 1 H), 7.25 (dd, J = 7.7, 1.4 Hz, 1 H), 7.22–7.18 (m, 1 H), 7.12 (td, J = 7.6, 1.8 Hz, 1 H), 4.99 (dd, J = 7.6, 4.9 Hz, 1 H), 1.94 (s, 1 H), 1.85–1.57 (m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.1, 132.1, 129.5, 128.5, 127.3, 127.1, 72.1, 30.6, 10.2.

HR-MS (ESI): m/z [M + Na]⁺ calcd for C₉₉H₁₁ClO + Na: 193.0391; found: 193.0391.

1-Cyclohexylpropan-1-ol (5i)

Following the general procedure (48 h), after flash column chromatography (pentane–EtOAc, 20:1), 5i was obtained as an oil (14 mg, 0.098 mmol, 39%).

Chiral GC: β-dex 225, (30 m × 0.25 mm × 0.25 μm), isotherm 90 °C; t _R = 28.9 min (R-isomer) and 30.6 min (S-isomer).

¹H NMR (400 MHz, CDCl₃): δ = 3.27 (ddd, J = 8.5, 5.4, 3.8 Hz, 1 H), 1.86–1.70 (m, 3 H), 1.70–1.60 (m, 2 H), 1.60–1.49 (m, 1 H), 1.46–0.97 (m, 8 H), 0.95 (t, J = 7.4 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 77.8, 43.3, 29.5, 27.9, 27.0, 26.7, 26.5, 26.4, 10.4.

HR-MS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₈O + Na: 165.1250; found: 165.1252.

1-(Pyridin-2-yl)propan-1-ol (5j)

Following the general procedure (19 h), after flash column chromatography (pentane–EtOAc, 2:1) 5j was obtained as an oil (10 mg, 0.073 mmol, 29%).

HPLC: Daicel Chiralpak OD-H, hexane–i-PrOH, 95:5, flow rate 1.0 mL/min, 210 nm; t _R = 8.5 min (R-isomer) and 9.1 min (S-isomer).

¹H NMR (300 MHz, CDCl₃): δ = 8.55 (d, J = 4.7 Hz, 1 H), 7.70 (td, J = 7.8, 1.7 Hz, 1 H), 7.27 (d, J = 7.8 Hz, 1 H), 7.22 (ddd, J = 7.3, 4.7, 0.9 Hz, 1 H), 4.71 (dd, J = 7.2, 4.6 Hz, 1 H), 1.98–1.82 (m, 1 H), 1.81–1.64 (m, 1 H), 0.95 (t, J = 7.4 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 162.0, 148.0, 137.0, 122.4, 120.6, 73.8, 31.5, 9.5.

HR-MS (ESI): m/z [M + H]⁺ calcd for C₈H₁₁NO: 138.0913; found: 138.0910.

Acknowledgment

The Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie are gratefully acknowledged for financial support. S. B. thanks the Deutsche Forschungsgemeinschaft within the SFB 858 for a predoctoral contract.

• References


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• Supplementary Material