One-Pot Synthesis of α-Halo β-Amino Acid Derivatives via the Difunctional Coupling of Ethyl α-Diazoacetate with Silyl Halides and N,O-Acetals or Aromatic Tertiary Amines

Abstract

The difunctionalization of ethyl α-diazoacetate (EDA) using silyl halides as a nucleophile and N,O-acetals as an electrophile under metal-free conditions is described. This process undergoes a novel three-component coupling (3-CC) reaction using EDA, which leads to a one-pot preparation of α-halo β-amino acid esters. Also, this protocol could be adapted to accept an electrophile composed of aromatic tertiary amines. In both 3-CC reactions, the key reaction intermediate is an iminium intermediate that can be easily and effectively generated either from N,O-acetals or from aromatic tertiary amines.

α-Diazocarbonyl compounds continue to attract much attention in synthetic organic chemistry using various active carbon species, since the reactive intermediates, carbenes or carbenoids, which are generated via the photochemical, thermodynamic and catalytic elimination of nitrogen from α-diazocarbonyl compounds, have been effectively utilized in the preparations of a variety of naturally occurring compounds and highly valuable compounds as well as functional materials.[1] The central reaction manner of α-diazocarbonyl compounds is α,α-insertion, namely, difunctionalization through the formal insertion of carbenes (or carbenoids) between the X–Y bonds (Scheme [1], eq 1). For this type of reaction, several reaction substrates, such as halogens, hydrogen halides, alcohols, amines, and organo­boron, organosilicon, organophosphorus, organosulfur and organoselenium compounds have been employed.[1a] [d] Also, in another significant application using difunctionalization, an intermolecular or intramolecular C–H insertion of the in situ generated carbene (or carbenoid) intermediate has been developed. The intramolecular process has been widely applied particularly in the practical preparation of a variety of complicated natural compounds.[2] However, these useful methods are naturally limited to the two-component coupling (2-CC) of α-diazocarbonyl compounds and their counterparts.[3]

Also, three-component coupling (3-CC) reactions via difunctionalization of α-diazocarbonyl compounds with two electronically and structurally different reactants, electrophiles and nucleophiles in the presence of a transition metal catalyst, in which an ylide intermediate derives from a metal carbenoid and a nucleophile, such as an amine, an alcohol and a carboxylic acid, plays a central role, have recently gained attention (Scheme [1], eq 2).[4] Compared with eq 1 in Scheme [1], this type of difunctionalization simultaneously undergoes two sorts of bond formation on the carbon of carbenoid species, which would enable the practical construction of more complicated organic molecules. Recently, under transition-metal-free conditions, the same type of 3-CC reactions of α-diazocarbonyl compounds, nucleophiles, and electrophiles have been developed, but these types of coupling are not investigated extensively (Scheme [1], eq 3).[5] [6] In this context, it has been disclosed that transition-metal-free 3-CC reactions of α-diazocarbonyl compounds with aromatic tertiary amines and nucleophiles in the presence of an appropriate oxidizing agent proceed via a radical process.[7]

On the other hand, we previously reported that a catalytic system composed of a Lewis acid, Hf(OTf)₄ and a promoter, chlorotrimethylsilane (Me₃SiCl) effectively promotes aminomethylation of various carbon nucleophiles with an iminium intermediate generated in situ from an N,O-acetal.[8] During ongoing study on the utility of an iminium ion from an N,O-acetal and a common Lewis acid, we anticipated that an introduction of an α-diazocarbonyl compound, ethyl α-diazoacetate (EDA), into our reaction system involving carbon nucleophiles and iminium electrophiles would undertake a unique 3-CC reaction.

After several preliminary examinations, we found that a combination of EDA, silyl halides, and iminium intermediates derived from N,O-acetals could accomplish the novel type of 3-CC reaction, producing α-halo β-amino acid ester derivatives (Scheme [2], path a). Unlike related studies, a remarkable finding in this examination involves that a counter anion of silyl halides, which effectively activate an N,O-acetal, simultaneously functions as a novel nucleophile. Herein, we report the details on a novel type of 3-CC reaction using an α-diazocarbonyl compound. Also, in another application, we disclose a similar difunctionalization of EDA with silyl halides and tertiary aromatic amines under oxidizing conditions composed of a Cu(II)/TBHP (tert-butyl hydroperoxide) system (Scheme [2], path b).

Initially, to establish the optimal conditions, a model 3-CC reaction was conducted. An N,O-acetal (1 mmol) – which was prepared from N-methylaniline, formaldehyde, and methanol – ethyl diazoacetate (EDA: 1.1 equiv), and Me₃SiCl (1.5 equiv) were treated with CuCl (10 mol %) in a 1,2-dichloroethane (DCE) solution at 40 °C for 24 hours (Table [1]). Consequently, the expected α-chloro β-amino acid ester, ethyl 2-chloro-3-(N-methyl-N-phenylamino)propanoate (1), was obtained in a 50% yield (Table [1], entry 1). The Me₃SiCl performed dual roles as the Lewis acidic activator of an N,O-acetal that would lead to an iminium intermediate and as a nucleophilic source of the coupling product. Also, a common C–H insertion into an N-methyl group by EDA was not observed during the coupling reaction. Among several copper catalysts, CuSO₄ demonstrated the most effective activity for the present reaction to give 1 in an 80% yield (entries 2, 3, and 5) and a strong Lewis acid, Cu(OTf)₂, resulted in a complicated mixture (entry 4). Moreover, a series of three-component couplings was completed within 1 hour and an equivalent of the copper catalyst was reduced to 5 mol% (entries 6 and 7). Surprisingly, the present coupling proceeded equally well without the copper catalyst (entry 8). Although the polarity of solvents is not critical to the improvement of the yield (entries 9–11), acetonitrile finally showed the best coupling effect, and 1 was isolated in a good yield (entry 12).

Table 1 Examination of Reaction Conditions^a

Entry	Catalyst	mol%	Solvent	Time (h)	Yield (%)b
1	CuCl	10	DCE	24	50
2	Cu(OAc)2	10	DCE	24	32
3	CuCl2	10	DCE	24	32
4	Cu(OTf)2	10	DCE	24	–c
5	CuSO4	10	DCE	24	80
6	CuSO4	10	DCE	1	75
7	CuSO4	5	DCE	1	85
8	–	–	DCE	1	72
9	–	–	CHCl3	1	82
10	–	–	toluene	1	77
11	–	–	THF	1	86
12	–	–	MeCN	1	93 (89)

^a Standard conditions: an N,O-acetal (0.5 mmol), EDA in 15 wt% toluene solution (1.1 equiv), Me₃SiCl (1.5 equiv), MeCN (1 mL), 40 °C, 24 h.

^b NMR (isolated) yield.

^c A complex mixture.

Then, to expand the substrate scope of the present coupling, N,O-acetals with various substituents were subjected to the optimal conditions involving EDA and Me₃SiCl, and the results are summarized in Table [2]. Most N,O-acetals bonded to either an electron-donating group, such as a methyl and a methoxy group, or to an electron-withdrawing group, such as a fluoro group, on an aryl amine moiety gave the corresponding α-chloro β-amino acid esters 2–8 in good to excellent yields. The exception was product 6, which had a m-methoxy group (Table [2], entries 1–7). In cases involving extensions of an N-alkyl chain to an ethyl group, the desired α-chloro β-amino acid esters 9 and 10 were obtained in good yields (entries 8 and 9). Also, the ­extension to an N,O-acetal with a benzyl group afforded the expected α-chloro β-amino acid ester 11 in a low 31% yield (entry 10).

Table 2 Substrate Scope of N,O-Acetals

Entry	Ar	R	Product	Yield (%)a
1	o-MeC6H4	Me	2	63
2	m-MeC6H4	Me	3	87
3	p-MeC6H4	Me	4	91
4	o-MeOC6H4	Me	5	61
5	m-MeOC6H4	Me	6	13
6	p-MeOC6H4	Me	7	63
7	p-FC6H4	Me	8	88
8	Ph	Et	9	77
9	m-MeC6H4	Et	10	93
10	PhCH2	Me	11	31

^a Isolated yield.

Table 3 Substrate Scope of Silyl Halides

Entry	Ar	Silane X	Product	Yield (%)a
1	Ph	Br	12	83
2	p-MeC6H4	Br	13	60
3	p-FC6H4	Br	14	81
4	Ph	I	15	25 (61)b

^a Isolated yield.

^b Use of Me₃SiI generated in situ from (Me₃Si)₂ and I₂.

The adaptation to other silyl halides, such as trimethylbromosilane (Me₃SiBr) and trimethyliodosilane (Me₃SiI), also was investigated under the optimal conditions, and the results are lined in Table [3]. Consequently, the 3-CC reaction with Me₃SiBr gave the desired α-bromo β-amino acid derivatives 12–14 in relatively good yields, regardless of an electronic effect on the aryl group of N,O-acetals (Table [3], entries 1–3). In a similar manner, the 3-CC reaction involving an N,O-acetal, EDA and Me₃SiI, the latter of which was prepared from hexamethyldisilane and molecular iodine,[9] led to the preparation of α-iodo β-amino acid 15 in a 61% yield (entry 4). Although both silyl halides generally show stronger Lewis acidity and a high nucleophilicity of the counter anion than those of Me₃SiCl, neither the reactivity nor the yield showed remarkable improvement. On the other hand, the use of silyl halide analogues, such as Me₃SiN₃ and Me₃SiCN, resulted in the formation of a complicated mixture.

At this stage, we expect an iminium intermediate to be a key electrophilic counterpart that would be generated in situ from an N,O-acetal and Me₃SiCl in a series of 3-CC reaction. In this context, we previously reported the cobalt(II)-catalyzed oxidative cyanation of aromatic tertiary amines with tert-butyl hydroperoxide (TBHP), in which an iminium species functions as a reaction intermediate.[5b] Based on that outcome, we recalled that an aromatic tertiary amine, instead of an N,O-acetal, would be adaptable as a new electrophilic partner.

As a preliminary examination, when the reaction mixture involving N,N-dimethylaniline (0.45 mmol), EDA (0.5 mmol), and Me₃SiCl (0.75 mmol) was treated with an acetonitrile solution (1 mL) containing CuCl₂ (10 mol%) and TBHP (1.5 equiv) at 40 °C for 12 hours, in contrast to our expectation, the expected α-chloro β-amino acid 1 was not obtained (Table [4], entry 1). Therefore, we started to explore the optimal conditions using several copper catalysts and solvents. Consequently, the most effective catalytic system for the coupling proved to be Cu(acac)₂ in a CH₂Cl₂ solution (entries 2–5). Strangely, unlike the previous work,[4c] Cu(OTf)₂ led to a complicated mixture. Typical solvents, such as toluene, THF, and chloroform, were ineffective for the 3-CC reaction. By contrast, an increase in the equivalent of dimethylaniline to 3.5 equivalents for EDA enhanced the yield of 1 to a practical level (entry 6). Moreover, running the same reaction under an ambient atmosphere resulted in equivalent behavior and 1 was isolated in a 62% yield after purification (entry 7). On the other hand, other metal catalysts, such as Fe(acac)₃ and Co(acac)₂, led to a decrease in the yield of 1 (entries 8 and 9). Throughout the examination with a copper catalyst, the formation of a small amount of by-product, such as a hydrolysate of the iminium intermediate, N-methylaniline, and a homo-coupling product of N,N-dimethylaniline was observed, but a dimerization product of EDA, which is derived from a carbene (a copper carbenoid) species, was not detected.

Table 4 Examination of Reaction Conditions for Dimethylaniline^a

Entry	Catalyst (10 mol%)	Amine (ratio)	Solvent	Yield (%)b
1	CuCl2	0.9	MeCN	trace
2	CuBr2	0.9	MeCN	29
3	Cu(OTf)2	0.9	MeCN	–c
4	Cu(acac)2	0.9	MeCN	35
5	Cu(acac)2	0.9	CH2Cl2	36
6d	Cu(acac)2	3.5	CH2Cl2	71
7d,e	Cu(acac)2	3.5	CH2Cl2	73 (62)
8d	Fe(acac)3	2	CH2Cl2	32
9d	Co(acac)2	2	CH2Cl2	13

^a Standard conditions: N,N-dimethylaniline (0.9–3.5 equiv for EDA), EDA in 15 wt% toluene solution (0.5 mmol), Me₃SiCl (1.5 equiv), solvent (1 mL), 40 °C, 12 h.

^b NMR yield in entries 1–7 and GC (isolated) yield in entries 8–13.

^c A complex mixture.

^d EDA (neat).

^e Under ambient atmosphere.

The 3-CC reactions were then conducted with a variety of tertiary aromatic amines under the optimal conditions (Table [5]). Most dimethylanilines with an electron-donating and -withdrawing group gave the corresponding α-chloro β-amino acid derivatives in moderate to good yields equal to the above N,O-acetals (entries 1–7). However, the cases of an aromatic amine with a relatively strong electron-withdrawing group, such as a CF₃ group showed low reactivity, and afforded α-chloro β-amino acid 18 in a low yield (entry 8). Also, the introduction of a bromo group into the β-amino acid, via Me₃SiBr instead of Me₃SiCl, produced the desired α-bromo β-amino acid derivative 12 in a rather low yield (entry 9). Moreover, during the experimental workup, unlike the above study using N,O-acetals, we encountered both the problematic isolation of α-halo β-amino acids from the residue containing the remaining aromatic tertiary amines and TBHP, and the decomposition of these β-amino acids, which, unfortunately, led to a remarkable decrease in the product yield. Although there are no clear reasons for the latter situation, presumably a remaining copper(II) catalyst would cause some kind of side reaction toward the obtained α-halo β-amino acid derivatives. Surprisingly, unlike the above case using an N,O-acetal under metal-free conditions, when the same coupling was carried out with Me₃SiN₃, the desired α-azido β-amino acid 19 was obtained in a relatively good yield (entry 10). On the other hand, instead of EDA, when the same coupling (Table [4], entry 7) was performed with a disubstituted α-diazoacetate, methyl α-diazo-α-phenylacetate, under the optimal conditions, the reaction led to a complicated mixture (entry 11).

Table 5 Substrate Scope of Tertiary Aromatic Amines and α-Diazo­acetates^a

Entry	R	Silane X	Product Ar		Yield (%)b
1	H	Cl	o-MeC6H4	2	24 (68)
2	H	Cl	m-MeC6H4	3	36 (65)
3	H	Cl	p-MeC6H4	4	42 (63)
4	H	Cl	p-MeOC6H4	7	38 (58)
5	H	Cl	p-FC6H4	8	56 (79)
6	H	Cl	p-ClC6H4	16	44 (83)
7	H	Cl	p-BrC6H4	17	24 (61)
8	H	Cl	p-CF3C6H4	18	18 (34)
9	H	Br	Ph	12	25
10c	H	N3	Ph	19	60 (70)
11	Ph	Cl	Ph	20	–d

^a Standard conditions: N,N-dimethylaniline (3.5 equiv for EDA), EDA (0.5 mmol), Me₃SiCl (1.5 equiv), CH₂Cl₂ (1 mL), 40 °C, 12 h.

^b Isolated (NMR) yield.

^c MeCN as a solvent.

^d A complex mixture.

To demonstrate the utility of the prepared α-chloro β-amino acid derivative, the halogen moiety was then subjected to transformations of other usefully functional groups (Scheme [3]). For instance, α-chloro β-amino acid ester 1 was initially treated with NaN₃, followed by a Staudinger reduction of formed azide 19 with a mixture of PPh₃ and H₂O to produce α-amino β-amino acid derivative 21 in a 54% yield.[10] When 1 was then treated with a benzenethiol derivative with a para-isopropyl group in the presence of a typical base, such as sodium methoxide, the expected α-mercapto-β-amino acid derivative 22 was obtained in a 73% yield. Also, when a similar reaction of 1 with potassium thioacetate was performed, the corresponding thioacetate derivative 23 was obtained, but the yield was lower than we expected, which was likely due to the low nucleophilicity of potassium thioacetate.[11]

We assumed that an in situ generated iminium inter­mediate through both activation of an N,O-acetal or an aromatic tertiary amine would be a central and key compound of the 3-CC reaction. Thus, to enhance our outlook for the former reaction system using an N,O-acetal, a control experiment was examined (Scheme [4]). When attempting difunctionalization of an N,N-aminal as another iminium precursor,[12] with EDA and acetyl chloride both as a promoter and a nucleophile, the formation of the expected α-chloro β-amino acid ester 1 was confirmed in a good yield.

On the basis of these results, two plausible reaction paths are shown in Scheme [5]. As a main route (upper path in Scheme [5]), initially, the reaction of either the starting N,O-acetal A (R= Me) or the N,O-acetal analogue A (R = t-BuO), which is generated from tertiary aromatic amine B using a Cu(II)/TBHP oxidizing system with a silyl halide occurs to form iminium intermediate C.[12] [13] [14] Then, intermediate C underwent nucleophilic attack from EDA (D) to form diazonium salt E.[15] Finally, as a nucleophile, the releasing halide ion reacted with E to produce α-halo β-amino acid ester F along with the liberation of N₂. It seems that because the liberated alkoxide ion from the acetal is smoothly trapped with the silyl halide, a releasing halide ion (X^–) is relatively free to behave as a nucleophilic source. On the other hand, as another route proposed by Li, Tu and Jiang’s group (bottom path in Scheme [5]),[4c] it is anticipated that the reaction of copper carbenoid G with a silyl halide (or a silyl azide) generates ylide intermediates H or I, followed by nucleophilic addition to iminium C to produce final product F.

In conclusion, we have described a 3-CC reaction of N,O-acetals, ethyl α-diazoacetate (EDA), and silyl halides under metal-free and neutral conditions along with a copper-catalyzed oxidative coupling reaction of aromatic tertiary amines, ethyl diazoacetate (EDA), and silyl halides. This reaction is a novel approach to the preparation of a variety of α-halo β-amino acid esters with a framework that is easily converted to useful compounds. One of the key step in a series of the 3-CC coupling involves a nucleophilic addition of EDA to an iminium intermediate, which is derived from an N,O-acetal activated by a silyl halide. Another key is the subsequent S_N2 reaction of the diazonium compound with a liberated halide anion. Our group is currently developing a new combination of electrophiles and nucleophiles that could be applied to the 3-CC reaction.

MeOH was dried over Mg and I₂ and then distilled. THF was fleshly distilled over Na-benzophenone prior to use. MeCN, DMF, and Me₃SiCl were dried over CaH₂ and distilled. CH₂Cl₂ was dried over P₂O₅ and distilled. Chemicals, such as Cu(acac)₂, Na₂SO₄, K₂CO₃, NaN₃, NaOMe, KSAc, PPh₃, tert-butyl hydroperoxide (TBHP), ethyl diazoacetate (EDA), 4-bromo-N,N-dimethylaniline, Me₃SiBr, and Me₃SiN₃ were commercially available and used without further purification, unless otherwise noted. N,N-Dimethylaniline, 4-methyl-N,N-dimethylaniline, and 4-isopropylbenzenethiol were commercially available, and purified by distillation under reduced pressure prior to use. Column chromatography was performed using silica gel. ¹H NMR spectra were recorded at 500 MHz using TMS as an internal standard (0.00 ppm). The ¹³C NMR spectra were recorded at 125 MHz using the center peak of CHCl₃ (77.0 ppm) as standard. High-resolution mass spectra (HRMS) were recorded using NBA (3-nitrobenzyl alcohol) as a matrix. The starting N,O-acetals are known compounds, and were prepared according to the literature procedure,[16] and each structure was characterized by ¹H and ¹³C NMR spectra. Also, Me₃SiI and methyl α-diazo-α-phenylacetate were prepared via the procedure described in the literature, respectively.[9] [17]

Difunctionalization of EDA with an N,O-Acetal and a Silyl Halide Leading to an α-Halo β-Amino Acid Ester Derivative; General Procedure A

An N,O-acetal (1 mmol) and ethyl α-diazoacetate (1.1 mmol in 15 wt% toluene solution) were added to freshly distilled MeCN (1 mL) in a screw-capped test tube at rt. The tube was sealed with a cap that contained a PTFE septum, followed by replacement with N₂. The tube was cooled to 0 °C with an ice bath, and the distilled or in situ prepared silyl halide (1.5 mmol) was added via a syringe. The reaction mixture was stirred at 40 °C for 1 h. After cooling, to remove volatile ­compounds, the resultant mixture was passed through a silica gel pad (3 cm) with an eluent (EtOAc containing 1 wt% of Et₃N). The filtrate was evaporated, and the crude residue was purified by silica gel column chromatography (eluent: hexane/EtOAc (9:1 to 19:1) containing 1 wt% of Et₃N) to obtain the corresponding α-halo β-amino acid ester.

Difunctionalization of EDA with a Tertiary Aromatic Amine and a Silyl Halide Leading to an α-Halo β-Amino Acid Ester Derivative; General Procedure B

To a screw-capped test tube in a glovebox was added Cu(acac)₂ (0.05 mmol). The test tube was sealed with a cap that contained a PTFE septum, and then removed from the glovebox. CH₂Cl₂ (1 mL), a tertiary amine (1.75 mmol), and ethyl diazoacetate (0.5 mmol) were added to the test tube in that order. Then, the tube was cooled to 0 °C, and a silyl halide (0.75 mmol) and TBHP (0.750 mmol, 0.136 mL, 5.5 M solution in decane) were successively added. The mixture was heated at 40 °C for 1 h. To quench the reaction, the resultant mixture was directly subjected to a short pad filled with wet silica gel (eluent: EtOAc containing 1 wt% of Et₃N), and the collected filtrate was evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (eluent: hexane/EtOAc (20:1 to 5:1) containing 1 wt% of Et₃N) to give the corresponding α-halo β-amino acid ester.

Ethyl 2-Chloro-3-[methyl(phenyl)amino]propanoate (1)[18]

General procedure A was followed with N-(methoxymethyl)-N-methylaniline (150 mg, 0.992 mmol) and Me₃SiCl (158 mg, 1.45 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing 1 wt% of Et₃N) afforded 1; yield: 214 g (89%); pale yellow oil.

General procedure B was followed with N,N-dimethylaniline (213 mg, 1.75 mmol), Me₃SiCl (80.5 mg, 0.741 mmol), and ethyl diazoacetate (58.8 mg, 0.515 mmol) for 12 h. Column chromatography ­(hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 1; yield: 77.2 mg (62%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.26 (dt, J = 7.5, 2.0 Hz, 2 H, ArH), 6.78–6.72 (m, 3 H, ArH), 4.49 (dd, J = 8.0, 6.5 Hz, 1 H, CH), 4.24–4.13 (m, 2 H, CH₂), 4.02 (dd, J = 15.0, 8.0 Hz, 1 H, CH), 3.74 (dd, J = 15.0, 6.0 Hz, 1 H, CH), 3.02 (s, 3 H, CH₃), 1.26 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.0, 148.0, 129.4, 117.4, 112.2, 62.3, 56.7, 53.3, 39.4, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₆ClNO₂: 241.0870; found: 241.0872.

Ethyl 2-Chloro-3-[(2-methylphenyl)(methyl)amino]propanoate (2)

General procedure A was followed with 2-methyl-N-(methoxymethyl)-N-methylaniline (159 mg, 0.963 mmol) and Me₃SiCl (178 mg, 1.64 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing 1 wt% of Et₃N) afforded 2; yield: 154 mg (63%); colorless oil.

General procedure B was followed with Cu(acac)₂ (19.8 mg, 0.0756 mmol), N,N-dimethyl-o-toluidine (179 mg, 1.32 mmol), Me₃SiCl (61.0 mg, 0.561 mmol), ethyl diazoacetate (47.9 mg, 0.420 mmol), and TBHP (1.26 mmol, 0.228 mL, 5.5 M solution in decane) for 14 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 2; yield: 25.7 mg (24%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.16 (t, J = 7.5 Hz, 2 H, ArH), 7.10 (d, J = 8.0 Hz, 1 H, ArH), 7.01 (t, J = 7.5 Hz, 1 H, ArH), 4.25 (dd, J = 9.0, 6.0 Hz, 1 H, CH), 4.18–4.14 (m, 2 H, CH₂), 3.62 (dd, J = 13.5, 9.0 Hz, 1 H, CH), 3.44 (dd, J = 13.5, 6.0 Hz, 1 H, CH), 2.72 (s, 3 H, CH₃), 2.26 (s, 3 H, CH₃), 1.24 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.2, 150.4, 134.1, 131.2, 126.6, 124.2 121.2, 61.9, 59.2, 53.8, 43.5, 17.9, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₈ClNO₂: 255.1026; found: 255.1026.

Ethyl 2-Chloro-3-[(3-methylphenyl)(methyl)amino]propanoate (3)

General procedure A was followed with 3-methyl-N-(methoxymethyl)-N-methylaniline (171 mg, 1.03 mmol) and Me₃SiCl (189 mg, 1.74 mmol) for 1 h. Column chromatography (hexane/EtOAc 29:1 containing 1 wt% of Et₃N) afforded 3; yield: 231 mg (87%); colorless oil.

General procedure B was followed with N,N-dimethyl-m-toluidine (239 mg, 1.76 mmol), Me₃SiCl (87.4 mg, 0.804 mmol), and ethyl di­hazoacetate (61.3 mg, 0.537 mmol) for 12 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 3; yield: 49.4 mg (36%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.15 (dt, J = 7.5, 3.0 Hz, 1 H, ArH), 6.60 (d, J = 7.0 Hz, 1 H, ArH), 6.53 (d, J = 6.5 Hz, 1 H, ArH), 4.49 (dd, J = 8.0, 6.5 Hz, 1 H, CH), 4.25–4.14 (m, 2 H, CH₂), 4.01 (dd, J = 15.0, 8.0 Hz, 1 H, CH), 3.72 (dd, J = 15.0, 6.5 Hz, 1 H, CH), 3.00 (s, 3 H, CH₃), 2.33 (s, 3 H, CH₃), 1.27 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.1, 148.0, 139.1, 129.2, 118.3, 112.9, 109.4, 62.3, 56.8, 53.3, 39.5, 21.9, 13.9.

HRMS (FAB): m/z [M]⁺ Calcd for C₁₃H₁₈ClNO₂: 255.1026; found: 255.1033.

Ethyl 2-Chloro-3-[(4-methylphenyl)(methyl)amino]propanoate (4)

General procedure A was followed with 4-methyl-N-(methoxymethyl)-N-methylaniline (167 mg, 1.01 mmol) and Me₃SiCl (176 mg, 1.62 mmol) for 1 h. Column chromatography (hexane/EtOAc 29:1 containing Et₃N) afforded 4; yield: 236 mg (91%); colorless oil.

General procedure B was followed with N,N-dimethyl-p-toluidine (239 mg, 1.77 mmol), Me₃SiCl (83.5 mg, 0.769 mmol), and ethyl di­azoacetate (61.7 mg, 0.541 mmol) for 14 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 4; yield: 58.1 mg (42%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ =7.07 (d, J = 8.0 Hz, 2 H, ArH), 6.66 (d, J = 8.5 Hz, 2 H, ArH), 4.47 (dd, J = 8.0, 6.0 Hz, 1 H, CH), 4.24–4.13 (m, 2 H, CH₂), 3.98 (dd, J = 14.5, 8.0 Hz, 1 H, CH), 3.70 (dd, J = 15.0, 6.0 Hz, 1 H, CH), 2.98 (s, 3 H, CH₃), 2.26 (s, 3 H, CH₃), 1.26 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.1, 145.9, 129.9, 126.7, 112.5, 62.3, 57.0, 53.3, 39.5, 20.2, 13.9.

HRMS (FAB): m/z [M + H]⁺ calcd for C₁₃H₁₈ClNO₂: 256.1104; found: 256.1108.

Ethyl 2-Chloro-3-[(2-methoxyphenyl)(methyl)amino]propanoate (5)

General procedure A was followed with 2-methoxy-N-(methoxymethyl)-N-methylaniline (137 mg, 0.772 mmol) and Me₃SiCl (175 mg, 1.61 mmol) for 1 h. Column chromatography (hexane/EtOAc 9:1 containing 1 wt% of Et₃N) afforded 5; yield: 129 mg (61%); yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 6.99–6.94 (m, 2 H, ArH), 6.90 (dd, J = 8.0, 1.5 Hz, 1 H, ArH), 6.87 (dd, J = 8.0, 1.0 Hz, 1 H, ArH), 4.45 (dd, J = 7.5, 6.0 Hz, 1 H, CH), 4.10 (q, J = 7.0 Hz, 2 H, CH₂), 3.91 (dd, J = 14.0, 8.0 Hz, 1 H, CH), 3.86 (s, 3 H, CH₃), 3.54 (dd, J = 14.0, 6.0 Hz, 1 H, CH), 2.93 (s, 3 H, CH₃), 1.23 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.5, 152.4, 139.5, 122.9, 120.8, 120.2, 111.5, 61.9, 58.4, 55.3, 54.5, 41.1, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₈ClNO₃: 271.0975; found: 271.0975.

Ethyl 2-Chloro-3-[(3-methoxyphenyl)(methyl)amino]propanoate (6)

General procedure A was followed with 3-methoxy-N-(methoxymethyl)-N-methylaniline (139 mg, 0.767 mmol) and Me₃SiCl (174 mg, 1.60 mmol) for 1 h. Column chromatography (hexane/EtOAc 9:1 containing 1 wt% of Et₃N) afforded 6; yield: 26.1 mg (13%); yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.17 (t, J = 8.0 Hz, 1 H, ArH), 6.35–6.33 (m, 2 H, ArH), 6.27 (t, J = 2.5 Hz, 1 H, ArH), 4.50 (dd, J = 8.0, 6.0 Hz, 1 H, CH), 4.25–4.14 (m, 2 H, CH₂), 4.01 (dd, J = 15.0, 8.5 Hz, 1 H, CH), 3.80 (s, 3 H, CH₃), 3.72 (dd, J = 15.5, 6.0 Hz, 1 H, CH), 3.01 (s, 3 H, CH₃), 1.27 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.0, 160.8, 149.3, 130.1, 105.1, 102.0, 98.9, 62.3, 56.7, 55.1, 53.2, 39.6, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₈ClNO₃: 271.0975; found: 271.0969.

Ethyl 2-Chloro-3-[(4-methoxyphenyl)(methyl)amino]propanoate (7)

General procedure A was followed with 4-methoxy-N-(methoxymethyl)-N-methylaniline (185 mg, 1.02 mmol) and Me₃SiCl (167 mg, 1.54 mmol) for 1 h. Column chromatography (hexane/EtOAc 9:1 containing 1 wt% of Et₃N) afforded 7; yield: 186 mg (63%); yellow oil.

General procedure B was followed with Cu(acac)₂ (25.3 mg, 0.0967 mmol), 4-methoxy-N,N-dimethylaniline (264 mg, 1.75 mmol), Me₃SiCl (83.2 mg, 0.766 mmol), ethyl diazoacetate (58.4 mg, 0.512 mmol), and TBHP (1.54 mmol, 0.279 mL, 5.5 M solution in decane) for 14 h. Column chromatography (hexane/EtOAc 5:1 containing 1 wt% of Et₃N) afforded 7; yield: 52.9 mg (38%); yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 6.84 (d, J = 9.0 Hz, 2 H, ArH), 6.71 (d, J = 9.0 Hz, 2 H, ArH), 4.45 (dd, J = 8.5, 6.5 Hz, 1 H, CH), 4.24–4.13 (m, 2 H, CH₂), 3.94 (dd, J = 15.0, 8.5 Hz, 1 H, CH), 3.76 (s, 3 H, CH₃), 3.64 (dd, J = 15.0, 6.0 Hz, 1 H, CH), 2.95 (s, 3 H, CH₃), 1.26 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.1, 152.3, 142.9, 114.9, 114.4, 62.2, 57.9, 55.8, 53.4, 39.8, 14.0.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₈ClNO₃: 271.0975; found: 271.0970.

Ethyl 2-Chloro-3-[(4-fluorophenyl)(methyl)amino]propanoate (8)

General procedure A was followed with 4-fluoro-N-(methoxymethyl)-N-methylaniline (173 mg, 1.02 mmol) and Me₃SiCl (170 mg, 1.56 mmol) for 1 h. Column chromatography (hexane/EtOAc 9:1 containing Et₃N) afforded 8; yield: 233 mg (88%); pale yellow oil.

General procedure B was followed with Cu(acac)₂ (25.7 mg, 0.0981 mmol), 4-fluoro-N,N-dimethylaniline (246 mg, 1.77 mmol), Me₃SiCl (88.0 mg, 0.810 mmol), ethyl diazoacetate (58.2 mg, 0.510 mmol), and TBHP (1.53 mmol, 0.277 mL, 5.5 M solution in decane) for 14 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 8; yield: 74.2 mg (56%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 6.96 (t, J = 9.0 Hz, 2 H, ArH), 6.69–6.66 (m, 2 H, ArH), 4.45 (dd, J = 8.0, 6.0 Hz, 1 H, CH), 4.24–4.13 (m, 2 H, CH₂), 3.97 (dd, J = 15.0, 8.5 Hz, 1 H, CH), 3.67 (dd, J = 15.0, 6.5 Hz, 1 H, CH), 2.97 (s, 3 H, CH₃), 1.26 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.0, 156.8 (d, J = 236.4 Hz), 144.7, 115.8 (d, J = 21.4 Hz), 113.5 (d, J = 7.5 Hz), 62.3, 57.4, 53.2, 39.7, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₅ClFNO₂: 259.0775; found: 259.0778.

Ethyl 2-Chloro-3-[ethyl(phenyl)amino]propanoate (9)

General procedure A was followed with N-(methoxymethyl)-N-ethylaniline (175 mg, 1.06 mmol) and Me₃SiCl (173 mg, 1.59 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing 1 wt% of Et₃N) afforded 9; yield: 211 mg (77%); yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.27–7.23 (m, 2 H, ArH), 6.76–6.71 (m, 3 H, ArH), 4.45 (dd, J = 8.0, 5.5 Hz, 1 H, CH), 4.24–4.16 (m, 2 H, CH₂), 3.96 (dd, J = 15.0, 8.0 Hz, 1 H, CH), 3.69 (dd, J = 15.5, 6.0 Hz, 1 H, CH), 3.51–3.38 (m, 2 H, CH₂), 1.27 (t, J = 7.0 Hz, 3 H, CH₃), 1.13 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.2, 146.7, 129.4, 117.2, 112.6, 62.2, 54.8, 53.2, 45.9, 13.9, 11.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₈ClNO₂: 255.1026; found: 255.1032.

Ethyl 2-Chloro-3-[ethyl(3-methylphenyl)amino]propionate (10)

General procedure A was followed with 3-methyl-N-(methoxymethyl)-N-ethylaniline (177 mg, 0.987 mmol) and Me₃SiCl (177 mg, 1.63 mmol) for 1 h. Column chromatography (hexane/EtOAc 9:1 containing 1 wt% of Et₃N) afforded 10; yield: 248.1 mg (93%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.14 (dd, J = 9.0, 7.5 Hz, 1 H, ArH), 6.59–6.52 (m, 3 H, ArH), 4.45 (dd, J = 8.5, 6.0 Hz, 1 H, CH), 4.24–4.16 (m, 2 H, CH₂), 3.94 (dd, J = 15.0, 8.0 Hz, 1 H, CH), 3.67 (dd, J = 14.5, 5.5 Hz, 1 H, CH), 3.50–3.36 (m, 2 H, CH₂), 2.32 (s, 3 H, CH₃), 1.27 (t, J = 7.0 Hz, 3 H, CH₃), 1.12 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.2, 146.8, 139.1, 129.3, 118.1, 113.3, 109.7, 62.2, 54.8, 53.3, 45.9, 22.0, 13.9, 12.0.

HRMS (FAB): m/z [M]⁺ calcd for C₁₄H₂₀ClNO₂: 269.1183; found: 269.1183.

Ethyl 3-[Benzyl(methyl)amino]-2-chloropropanoate (11)

General procedure A was followed with N-(methoxymethyl)-N-methylbenzylamine (165 mg, 0.999 mmol) and Me₃SiCl (161 mg, 1.48 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing 1 wt% of Et₃N) afforded 11; yield: 80.0 mg (31%); colorless oil.

¹H NMR (CDCl₃, 500 MHz) δ = 7.32–7.23 (m, 5 H, ArH), 4.43–4.21 (m, 3 H, CH₂, CH), 3.63–3.56 (m, 2 H, CH₂), 3.12 (dd, J = 13.0, 9.0 Hz, 1 H, CH), 2.83 (dd, J = 13.0, 6.0 Hz, 1 H, CH), 2.26 (s, 3 H, CH₃), 1.30 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.3, 138.4, 128.8, 128.2, 127.2, 62.4, 61.9, 60.9, 53.9, 42.4, 14.0.

HRMS (FAB): m/z [M + H]⁺ calcd for C₁₃H₁₉ClNO₂: 256.1104; found: 256.1105.

Ethyl 2-Bromo-3-[methyl(phenyl)amino]propanoate (12)[19]

General procedure A was followed with N-(methoxymethyl)-N-methylaniline (150 mg, 0.992 mmol) and Me₃SiBr (277 mg, 1.81 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing Et₃N) afforded 12; yield: 235 mg (83%); pale yellow oil.

General procedure B was followed with N,N-dimethylaniline (214 mg, 1.77 mmol), Me₃SiBr (114 mg, 0.754 mmol), and ethyl diazoacetate (61.3 mg, 0.537 mmol) for 12 h. Column chromatography ­(hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 12; yield: 38.3 mg (25%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.26 (t, J = 7.5 Hz, 2 H, ArH), 6.77 (t, J = 7.0 Hz, 1 H, ArH), 6.71 (d, J = 8.0 Hz, 2 H, ArH), 4.41 (dd, J = 9.5, 5.0 Hz, 1 H, CH), 4.24–4.14 (m, 2 H, CH₂), 4.03 (dd, J = 15.0, 9.5 Hz, 1 H, CH), 3.81 (dd, J = 15.0, 5.0 Hz, 1 H, CH), 3.00 (s, 3 H, CH₃), 1.26 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.3, 147.9, 129.4, 117.5, 112.2, 62.2, 56.5, 41.3, 39.3, 13.9.

MS (FAB): m/z = 286 (M + H)⁺.

Ethyl 2-Bromo-3-[(4-methylphenyl)(methyl)amino]propanoate (13)

General procedure A was followed with 4-methyl-N-(methoxymethyl)-N-methylaniline (160 mg, 0.969 mmol) and Me₃SiBr (236 mg, 1.54 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing 1 wt% of Et₃N) afforded 13; yield: 175 mg (60%); yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.08 (d, J = 9.0 Hz, 2 H, ArH), 6.65 (d, J = 8.5 Hz, 2 H, ArH), 4.39 (dd, J = 10.0, 5.5 Hz, 1 H, CH), 4.24–4.14 (m, 2 H, CH₂), 3.99 (dd, J = 14.5, 5.0 Hz, 1 H, CH), 3.77 (dd, J = 15.0, 5.0 Hz, 1 H, CH), 2.96 (s, 3 H, CH₃), 2.26 (s, 3 H, CH₃), 1.26 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.4, 145.9, 129.9, 126.8, 112.4, 62.2, 56.8, 41.4, 39.4, 20.2, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₈BrNO₂: 299.0521; found: 299.0525.

Ethyl 2-Bromo-3-[(4-fluorophenyl)(methyl)amino]propanoate (14)

General procedure A was followed with 4-fluoro-N-(methoxymethyl)-N-methylaniline (151 mg, 0.892 mmol) and Me₃SiBr (230 mg, 1.50 mmol) for 1 h. Column chromatography (hexane/EtOAc 19:1 containing 1 wt% of Et₃N) afforded 14; yield: 219 mg (81%); yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 6.96 (t, J = 9.0 Hz, 2 H, ArH), 6.68–6.65 (m, 2 H, ArH), 4.37 (dd, J = 9.5, 5.0 Hz, 1 H, CH), 4.24–4.14 (m, 2 H, CH₂), 3.99 (dd, J = 15.0, 9.5 Hz, 1 H, CH), 3.73 (dd, J = 15.0, 5.0 Hz, 1 H, CH), 2.95 (s, 3 H, CH₃), 1.26 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.3, 155.0 (d, J _C,F = 236.5 Hz), 144.7, 115.6 (d, J _C,F = 22.6 Hz), 113.6 (d, J _C,F = 7.5 Hz), 62.3, 57.2, 41.2, 39.6, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₅BrFNO₂: 303.0270; found: 303.0268.

Ethyl 2-Iodo-3-[methyl(phenyl)amino]propanoate (15)

General procedure A was followed with N-(methoxymethyl)-N-methylaniline (159 mg, 1.05 mmol) and Me₃SiI (320 mg, 1.60 mmol) for 1 h. Column chromatography (hexane containing 1 wt% of Et₃N) afforded 15; yield: 83.3 mg (25%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.26 (t, J = 8.0 Hz, 2 H, ArH), 6.77 (t, J = 9.0 Hz, 1 H, ArH), 6.68 (d, J = 8.0 Hz, 2 H, ArH), 4.50 (dd, J = 10.5, 4.0 Hz, 1 H, CH), 4.22–4.12 (m, 2 H, CH₂), 3.99 (dd, J = 15.0, 10.5 Hz, 1 H, CH), 3.85 (dd, J = 15.0, 4.0 Hz, 1 H, CH), 2.99 (s, 3 H, CH₃), 1.24 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 171.0, 147.8, 129.4, 117.4, 112.1, 62.0, 57.8, 39.3, 18.1, 13.7.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₆INO₂: 333.0226; found: 333.0221.

Ethyl 2-Chloro-3-[(4-chlorophenyl)(methyl)amino]propanoate (16)

General procedure B was followed with Cu(acac)₂ (25.7 mg, 0.0981 mmol), 4-chloro-N,N-dimethylaniline (273 mg, 1.75 mmol), Me₃SiCl (83.6 mg, 0.770 mmol), ethyl diazoacetate (60.4 mg, 0.529 mmol), and TBHP (1.59 mmol, 0.288 mL, 5.5 M solution in decane) for 12 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 16; yield: 64.3 mg (44%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.18 (d, J = 9.0 Hz, 2 H, ArH), 6.63 (d, J = 9.0 Hz, 2 H, ArH), 4.46 (dd, J = 8.0, 6.0 Hz, 1 H, CH), 4.25–4.14 (m, 2 H, CH₂), 3.99 (dd, J = 15.5, 8.0 Hz, 1 H, CH), 3.71 (dd, J = 15.5, 6.5 Hz, 1 H, CH), 2.99 (s, 3 H, CH₃), 1.27 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 168.8, 146.6, 129.1, 122.4, 113.4, 62.4, 56.7, 53.1, 39.5, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₅Cl₂NO₂: 275.0480; found: 275.0480.

Ethyl 2-Chloro-3-[(4-bromophenyl)(methyl)amino]propanoate (17)

General procedure B was followed with Cu(acac)₂ (26.7 mg, 0.102 mmol), 4-bromo-N,N-dimethylaniline (350 mg, 1.75 mmol), Me₃SiCl (82.4 mg, 0.758 mmol), ethyl diazoacetate (56.5 mg, 0.495 mmol), and TBHP (1.49 mmol, 0.269 mL, 5.5 M solution in decane) for 12 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 17; yield: 38.1 mg (24%); brown oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.32 (d, J = 9.0 Hz, 2 H, ArH), 6.59 (d, J = 9.0 Hz, 2 H, ArH), 4.45 (dd, J = 8.0, 6.5 Hz, 1 H, CH), 4.25–4.14 (m, 2 H, CH₂), 3.98 (dd, J = 15.5, 8.0 Hz, 1 H, CH), 3.71 (dd, J = 15.5, 6.0 Hz, 1 H, CH), 2.99 (s, 3 H, CH₃), 1.27 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 168.8, 147.0, 132.0, 113.8, 109.5, 62.4, 56.6, 53.1, 39.5, 14.0.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₅BrChlNO₂: 318.9975; found: 318.9978.

Ethyl 2-Chloro-3-{4-[(trifluoromethyl)phenyl](methyl)amino}propanoate (18)

General procedure B was followed with Cu(acac)₂ (26.2 mg, 0.100 mmol), 4-trifluoromethyl-N,N-dimethylaniline (325 mg, 1.72 mmol), Me₃SiCl (85.4 mg, 0.786 mmol), ethyl diazoacetate (56.0 mg, 0.491 mmol), and TBHP (1.47 mmol, 0.267 mL, 5.5 M solution in decane) for 14 h. Column chromatography (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) afforded 18; yield: 27.3 mg (18%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.48 (d, J = 8.5 Hz, 2 H, ArH), 6.73 (d, J = 9.0 Hz, 2 H, ArH), 4.48 (dd, J = 7.5, 6.5 Hz, 1 H, CH), 4.26–4.15 (m, 2 H, CH₂), 4.08 (dd, J = 15.5, 8.0 Hz, 1 H, CH), 3.79 (dd, J = 15.5, 6.5 Hz, 1 H, CH), 3.07 (s, 3 H, CH₃), 1.27 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 168.7, 150.1, 126.6 (q, J _C,F = 3.8 Hz), 125.9 (t, J _C,F = 270.4 Hz), 119.0 (q, J _C,F = 32.7 Hz), 62.5, 56.2, 53.0, 39.5, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₁₃H₁₅ClF₃NO₂: 309.0743; found: 309.0733.

Ethyl 2-Azido-3-[methyl(phenyl)amino]propanoate (19)[20]

General procedure B was followed with Cu(acac)₂ (26.2 mg, 0.100 mmol), N,N-dimethylaniline (214 mg, 1.77 mmol), trimethylsilyl azide (88.7 mg, 0.770 mmol), ethyl diazoacetate (67.0 mg, 0.586 mmol), TBHP (1.54 mmol, 0.279 mL, 5.5 M solution in decane), and MeCN (1 mL) instead of CH₂Cl₂ for 14 h. Column chromatography (hexane/EtOAc 10:1 containing 1 wt% of Et₃N) afforded 19; yield: 87.4 mg (60%); colorless oil.

According to another approach shown in Scheme [3], to a screw-capped vial were added NaN₃ (65.0 mg, 1.00 mmol), DMF (2 mL), and 1 (120.9 mg, 0.500 mmol) in that order. The tube was sealed with a cap that contained a PTFE septum, following replacement of the atmosphere with N₂. The mixture was stirred at rt for 40 h. After completion of the reaction, the mixture was poured into H₂O (2 mL) and extracted with hexane/EtOAc (10: 1; 3 × 5 mL). The combined organic layers were dried (Na₂SO₄) and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/EtOAc 10:1 containing 1 wt% of Et₃N) to give the desired product 19; yield: 84.4 mg (68%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.28–7.25 (m, 2 H, ArH), 6.78–6.76 (m, 3 H, ArH), 4.29–4.19 (m, 3 H, CH₂, CH), 3.95 (dd, J = 15.0, 4.5 Hz, 1 H, CH), 3.54 (dd, J = 15.0, 8.0 Hz, 1 H, CH), 3.04 (s, 3 H, CH₃), 1.31 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 169.3, 148.0, 129.4, 117.4, 112.3, 62.1, 60.4, 54.4, 39.4, 14.1.

HRMS (FAB): m/z [M]⁺ calcd for C₁₂H₁₆N₄O₂: 248.1273; found: 248.1273.

Ethyl 2-Amino-3-[methyl(phenyl)amino]propanoate (21)

To a screw-capped vial were added NaN₃ (65.0 mg, 1.00 mmol), DMF (2 mL), and 1 (120.9 mg, 0.5000 mmol) in that order. The tube was sealed with a cap that contained a PTFE septum, followed by replacement of the atmosphere with N₂. The mixture was stirred at rt for 40 h. After completion of the reaction, the mixture was poured into H₂O (2 mL) and extracted with hexane/EtOAc (10: 1; 3 × 5 mL). The combined organic layers were dried (Na₂SO₄) and filtered. The solvent was removed under reduced pressure and the residue was dissolved in THF (2 mL), to which was added PPh₃ (196.7 mg, 0.750 mmol) and H₂O (90.1 mg, 5.00 mmol) for 2 h at rt under N₂. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (CH₂Cl₂/MeOH 70:1 to 9:1) to give the desired product 21; yield: 60.0 mg (54%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.24 (t, J = 7.5 Hz, 2 H, ArH), 6.79 (d, J = 9.0, 2 H, ArH), 6.73 (t, J = 7.5 Hz, 1 H, ArH), 4.20–4.08 (m, 2 H, CH₂), 3.81 (t, J = 6.5 Hz, 1 H, CH), 3.75–3.69 (m, 1 H, CH), 3.45 (dd, J = 15.0, 7.5 Hz, 1 H, CH), 2.99 (s, 3 H, CH₃), 1.63 (s, 2 H, NH₂), 1.25 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 174.7, 149.1, 129.2, 116.9, 112.4, 61.2, 57.5, 53.4, 39.3, 14.1.

HRMS (FAB): m/z [M + H]⁺ calcd for C₁₂H₁₉N₂O₂: 223.1447; found: 223.1451.

Ethyl 2-[(4-Isopropylphenyl)thio]-3-[methyl(phenyl)amino]propanoate (22)[21]

To a screw-capped vial, NaOMe (27.0 mg, 0.500 mmol), MeOH (1 mL), and 4-isopropylbenzenethiol (76.1 mg, 0.500 mmol) were added in that order. The tube was sealed with a cap that contained a PTFE septum, following replacement of the atmosphere with N₂. Then, the reaction mixture was heated at 60 °C for 1 h. After cooling to rt, 1 (120.9 mg, 0.500 mmol) was added. Then the mixture was heated at 60 °C for another 24 h under N₂ atmosphere. After cooling to rt, the mixture was poured into H₂O (2 mL) and extracted with Et₂O (3 × 5 mL). The combined organic layers were dried (Na₂SO₄) and filtered. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (hexane/EtOAc 20:1 containing 1 wt% of Et₃N) to give the desired product 22; yield: 130 mg (73%); colorless oil.

¹H NMR (CDCl₃, 500 MHz): δ = 7.42 (d, J = 8.0 Hz, 2 H, ArH), 7.20–7.17 (m, 4 H, ArH), 6.71 (t, J = 7.0 Hz, 1 H, ArH), 6.58 (d, J = 8.0 Hz, 2 H, ArH), 4.12–4.02 (m, 2 H, CH₂), 3.89 (dd, J = 9.5, 4.5 Hz, 1 H, CH), 3.82 (dd, J = 14.5, 9.5 Hz, 1 H, CH), 3.71 (dd, J = 15.0, 4.5 Hz, 1 H, CH), 2.94–2.88 (m, 4 H, CH₃, CH), 1.23 (d, J = 7.0 Hz, 6 H, 2 × CH₃), 1.14 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 171.5, 149.6, 148.2, 134.1, 129.2, 129.1, 127.2, 116.8, 112.2, 61.4, 54.8, 48.7, 39.1, 33.8, 23.88, 23.85, 13.9.

HRMS (FAB): m/z [M]⁺ calcd for C₂₁H₂₇NO₂S: 357.1762; found: 357.1761.

Ethyl 2-(Acetylthio)-3-[methyl(phenyl)amino]propanoate (23)

To a screw-capped vial were added KSAc (114.2 mg, 1.000 mmol), MeCN (2 mL), and 1 (120.9 mg, 0.500 mmol) in that order. The tube was sealed with a cap that contained a PTFE septum, followed by replacement of the atmosphere with N₂. Then, the reaction mixture was heated at 80 °C for 3 h. After cooling to rt, the mixture was poured into H₂O (2 mL) and extracted with Et₂O (3 × 5 mL). The combined organic layers were dried (Na₂SO₄) and filtered. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane/EtOAc 10:1 to 2:1 containing 1 wt% of Et₃N) to give the desired product 23; yield: 53.4 mg (38%); pale yellow oil.

¹H NMR (CDCl₃, 500 MHz): δ =7.25 (t, J = 8.0 Hz, 2 H, ArH), 6.80 (d, J = 8.5 Hz, 2 H, ArH), 6.75 (t, J = 7.5 Hz, 1 H, ArH), 4.51 (dd, J = 9.0, 5.5 Hz, 1 H, CH), 4.15–4.05 (m, 2 H, CH₂), 3.88 (dd, J = 15.0, 9.5 Hz, 1 H, CH), 3.60 (dd, J = 15.0, 5.5 Hz, 1 H, CH), 2.97 (s, 3 H, CH₃), 2.37 (s, 3 H, CH₃), 1.20 (t, J = 7.0 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 125 MHz): δ = 193.6, 170.6, 148.5, 129.2, 117.2, 112.5, 61.9, 54.9, 44.3, 38.8, 30.3, 13.9.

HRMS (FAB): m/z [M + H]⁺ calcd for C₁₄H₂₀NO₃S: 282.1164; found: 282.1169.

Acknowledgment

We gratefully acknowledge Shin-Etsu Chemical Co. Ltd. for the generous donation of a chlorosilane and a disilane.

• References


For example:
• 1a Ford A, Miel H, Ring A, Slattery CN, Maguire AR, McKervey MA. Chem. Rev. 2015; 115: 9981
  CrossrefPubMedSearch in Google Scholar
• 1b Zhang Y, Wang J. Chem. Commun. 2009; 5350
  PubMed
• 1c Zhang Z, Wang J. Tetrahedron 2008; 64: 6577
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• 1d Ye T, McKervey MA. Chem. Rev. 1994; 94: 1091
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• 2a Doyle MP, Duffy R, Ratnikov M, Zhou L. Chem. Rev. 2010; 110: 704
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• 2b Davies HM. L, Manning JR. Nature 2008; 451: 417
  Search in Google Scholar
• 3 For the 2-CC reaction through the transition-metal-free coupling of α-diazocarbonyl compounds with aryl boronic acids, see: Li H, Zhang Y, Wang J. Synthesis 2013; 45: 3090
  Thieme ConnectSearch in Google Scholar

For selected review and papers, see:
• 4a Guo X, Hu W. Acc. Chem. Res. 2013; 46: 2427
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• 4b Kang Z, Zhang D, Shou J, Hu W. Org. Lett. 2018; 20: 983
  CrossrefPubMedSearch in Google Scholar
• 4c Zhang T.-S, Hao W.-J, Wang N.-N, Li G, Jiang D.-F, Tu S.-J, Jiang B. Org. Lett. 2016; 18: 3078
  CrossrefPubMedSearch in Google Scholar
• 4d Jia S, Xing D, Zhang D, Hu W. Angew. Chem. Int. Ed. 2014; 53: 13098
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• 4e Zhai C, Xing D, Qian Y, Ji J, Ma C, Hu W. Synlett 2014; 25: 1745
  Thieme ConnectSearch in Google Scholar
• 4f Guo Z, Shi T, Jiang J, Yang L, Hu W. Org. Biomol. Chem. 2009; 7: 5028
  CrossrefPubMedSearch in Google Scholar
• 4g Wang Y, Chen Z, Mi A, Hu W. Chem. Commun. 2004; 2486
  PubMed

For selected recent papers, see:
• 5a Döben N, Yan H, Kischkewitz M, Mao J, Studer A. Org. Lett. 2018; 20: 7933
  CrossrefPubMedSearch in Google Scholar
• 5b Luan Y, Yu J, Zhang X, Schaus SE, Wang G. J. Org. Chem. 2014; 79: 4694
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• 5c See also refs 3 and 14a.
• 6 For a copper-catalyzed 3-CC reaction of diazo esters, arylboranes, and carbamoyl imines, see: Luan Y, Schaus SE. Org. Lett. 2011; 13: 2510
  CrossrefPubMedSearch in Google Scholar

For example:
• 7a Zhu D, Yao Y, Zhao R, Liu Y, Shi L. Chem. Eur. J. 2018; 24: 4805
  CrossrefPubMedSearch in Google Scholar
• 7b Wang N.-N, Hao W.-J, Zhang T.-S, Li G, Wu Y.-N, Tu S.-J, Jiang B. Chem. Commun. 2016; 52: 5144
  CrossrefPubMedSearch in Google Scholar
• 8a Sakai N, Sato A, Konakahara T. Synlett 2009; 1449
  Thieme Connect
• 8b Sakai N, Asano J, Shimano Y, Konakahara T. Tetrahedron 2008; 64: 9208
  CrossrefSearch in Google Scholar
• 8c Sakai N, Asano J, Shimano Y, Konakahara T. Synlett 2007; 2675
  Thieme Connect
• 8d Sakai N, Hirasawa M, Hamajima T, Konakahara T. J. Org. Chem. 2003; 68: 483
  CrossrefPubMedSearch in Google Scholar
• 9 For example: Sakurai H, Shirahata A, Sasaki K, Hosomi A. Synthesis 1979; 740
  Thieme Connect
• 10 For example: Lin FL, Hoyt HM, van Halbeek H, Bergman RG, Bertozzi CR. J. Am. Chem. Soc. 2005; 127: 2686
  CrossrefPubMedSearch in Google Scholar
• 11 To expand transformation of 1 shown in Scheme 3, one reviewer suggested a conventional cyanation of compound 1. Thus, when cyanation of 1 was conducted with KCN, the desired cyanated product was not obtained; instead, a smooth decomposition of 1 was observed.

For selected papers of an in situ formation of an iminium intermediate from an N,N-aminal and silyl halides, see:
• 12a Heaney H, Papageorgiou G, Wilkins RF. Tetrahedron 1997; 53: 2941
  CrossrefSearch in Google Scholar
• 12b Heaney H, Papageorgiou G, Wilkins RF. J. Chem. Soc., Chem. Commun. 1988; 1161

For selected papers on the in situ formation of an iminium intermediate from an N,O-acetal and silyl halides, see:
• 13a Sakai N, Okano H, Shimamura K, Konakahara T. Chem. Lett. 2014; 43: 501
  CrossrefSearch in Google Scholar
• 13b Sakai N, Watanabe A, Ikeda R, Nakaike Y, Konakahara T. Tetrahedron 2010; 66: 8837
  CrossrefSearch in Google Scholar

For selected papers on the oxidative formation of an iminium intermediate from an aromatic tertiary amine using a metal catalyst and TBHP as an oxidant, see:
• 14a Ratnikov MO, Doyle MP. J. Am. Chem. Soc. 2013; 135: 1549
  CrossrefPubMedSearch in Google Scholar
• 14b Boess E, Schmitz C, Klussmann M. J. Am. Chem. Soc. 2012; 134: 5317
  CrossrefPubMedSearch in Google Scholar

For a selected review and paper of the reactions with α-diazocarbonyl compounds as a nucleophile, see:
• 15a Zhao Y, Wang J. Synlett 2005; 2886
  Thieme Connect
• 15b Gulevich AV, Helan V, Wink DJ, Gevorgyan V. Org. Lett. 2013; 15: 956
  CrossrefPubMedSearch in Google Scholar
• 16a Giumanini AG, Chiavari G, Musiani MM, Rossi P. Synthesis 1980; 743
  Thieme Connect
• 16b Sakai N, Shimamura K, Ikeda R, Konakahara T. J. Org. Chem. 2010; 75: 3923
  CrossrefPubMedSearch in Google Scholar
• 17 Keipour H, Ollevier T. Org. Lett. 2017; 19: 5736
  CrossrefPubMedSearch in Google Scholar
• 18 Xing L, Li C. J. Org. Chem. 2015; 80: 10000
  CrossrefPubMedSearch in Google Scholar
• 19 Bonge HT, Hansen T. Synthesis 2009; 91
  Thieme Connect
• 20 Zhu D, Yao Y, Zhao R, Liu Y, Shi L. Chem. Eur. J. 2018; 24: 4805
  CrossrefPubMedSearch in Google Scholar
• 21 Katritzky AR, Fan W.-Q, Long Q.-H. Synthesis 1993; 229
  Thieme Connect

• References


For example:
• 1a Ford A, Miel H, Ring A, Slattery CN, Maguire AR, McKervey MA. Chem. Rev. 2015; 115: 9981
  CrossrefPubMedSearch in Google Scholar
• 1b Zhang Y, Wang J. Chem. Commun. 2009; 5350
  PubMed
• 1c Zhang Z, Wang J. Tetrahedron 2008; 64: 6577
  CrossrefSearch in Google Scholar
• 1d Ye T, McKervey MA. Chem. Rev. 1994; 94: 1091
  CrossrefSearch in Google Scholar
• 2a Doyle MP, Duffy R, Ratnikov M, Zhou L. Chem. Rev. 2010; 110: 704
  CrossrefPubMedSearch in Google Scholar
• 2b Davies HM. L, Manning JR. Nature 2008; 451: 417
  Search in Google Scholar
• 3 For the 2-CC reaction through the transition-metal-free coupling of α-diazocarbonyl compounds with aryl boronic acids, see: Li H, Zhang Y, Wang J. Synthesis 2013; 45: 3090
  Thieme ConnectSearch in Google Scholar

For selected review and papers, see:
• 4a Guo X, Hu W. Acc. Chem. Res. 2013; 46: 2427
  CrossrefPubMedSearch in Google Scholar
• 4b Kang Z, Zhang D, Shou J, Hu W. Org. Lett. 2018; 20: 983
  CrossrefPubMedSearch in Google Scholar
• 4c Zhang T.-S, Hao W.-J, Wang N.-N, Li G, Jiang D.-F, Tu S.-J, Jiang B. Org. Lett. 2016; 18: 3078
  CrossrefPubMedSearch in Google Scholar
• 4d Jia S, Xing D, Zhang D, Hu W. Angew. Chem. Int. Ed. 2014; 53: 13098
  CrossrefPubMedSearch in Google Scholar
• 4e Zhai C, Xing D, Qian Y, Ji J, Ma C, Hu W. Synlett 2014; 25: 1745
  Thieme ConnectSearch in Google Scholar
• 4f Guo Z, Shi T, Jiang J, Yang L, Hu W. Org. Biomol. Chem. 2009; 7: 5028
  CrossrefPubMedSearch in Google Scholar
• 4g Wang Y, Chen Z, Mi A, Hu W. Chem. Commun. 2004; 2486
  PubMed

For selected recent papers, see:
• 5a Döben N, Yan H, Kischkewitz M, Mao J, Studer A. Org. Lett. 2018; 20: 7933
  CrossrefPubMedSearch in Google Scholar
• 5b Luan Y, Yu J, Zhang X, Schaus SE, Wang G. J. Org. Chem. 2014; 79: 4694
  CrossrefPubMedSearch in Google Scholar
• 5c See also refs 3 and 14a.
• 6 For a copper-catalyzed 3-CC reaction of diazo esters, arylboranes, and carbamoyl imines, see: Luan Y, Schaus SE. Org. Lett. 2011; 13: 2510
  CrossrefPubMedSearch in Google Scholar

For example:
• 7a Zhu D, Yao Y, Zhao R, Liu Y, Shi L. Chem. Eur. J. 2018; 24: 4805
  CrossrefPubMedSearch in Google Scholar
• 7b Wang N.-N, Hao W.-J, Zhang T.-S, Li G, Wu Y.-N, Tu S.-J, Jiang B. Chem. Commun. 2016; 52: 5144
  CrossrefPubMedSearch in Google Scholar
• 8a Sakai N, Sato A, Konakahara T. Synlett 2009; 1449
  Thieme Connect
• 8b Sakai N, Asano J, Shimano Y, Konakahara T. Tetrahedron 2008; 64: 9208
  CrossrefSearch in Google Scholar
• 8c Sakai N, Asano J, Shimano Y, Konakahara T. Synlett 2007; 2675
  Thieme Connect
• 8d Sakai N, Hirasawa M, Hamajima T, Konakahara T. J. Org. Chem. 2003; 68: 483
  CrossrefPubMedSearch in Google Scholar
• 9 For example: Sakurai H, Shirahata A, Sasaki K, Hosomi A. Synthesis 1979; 740
  Thieme Connect
• 10 For example: Lin FL, Hoyt HM, van Halbeek H, Bergman RG, Bertozzi CR. J. Am. Chem. Soc. 2005; 127: 2686
  CrossrefPubMedSearch in Google Scholar
• 11 To expand transformation of 1 shown in Scheme 3, one reviewer suggested a conventional cyanation of compound 1. Thus, when cyanation of 1 was conducted with KCN, the desired cyanated product was not obtained; instead, a smooth decomposition of 1 was observed.

For selected papers of an in situ formation of an iminium intermediate from an N,N-aminal and silyl halides, see:
• 12a Heaney H, Papageorgiou G, Wilkins RF. Tetrahedron 1997; 53: 2941
  CrossrefSearch in Google Scholar
• 12b Heaney H, Papageorgiou G, Wilkins RF. J. Chem. Soc., Chem. Commun. 1988; 1161

For selected papers on the in situ formation of an iminium intermediate from an N,O-acetal and silyl halides, see:
• 13a Sakai N, Okano H, Shimamura K, Konakahara T. Chem. Lett. 2014; 43: 501
  CrossrefSearch in Google Scholar
• 13b Sakai N, Watanabe A, Ikeda R, Nakaike Y, Konakahara T. Tetrahedron 2010; 66: 8837
  CrossrefSearch in Google Scholar

For selected papers on the oxidative formation of an iminium intermediate from an aromatic tertiary amine using a metal catalyst and TBHP as an oxidant, see:
• 14a Ratnikov MO, Doyle MP. J. Am. Chem. Soc. 2013; 135: 1549
  CrossrefPubMedSearch in Google Scholar
• 14b Boess E, Schmitz C, Klussmann M. J. Am. Chem. Soc. 2012; 134: 5317
  CrossrefPubMedSearch in Google Scholar

For a selected review and paper of the reactions with α-diazocarbonyl compounds as a nucleophile, see:
• 15a Zhao Y, Wang J. Synlett 2005; 2886
  Thieme Connect
• 15b Gulevich AV, Helan V, Wink DJ, Gevorgyan V. Org. Lett. 2013; 15: 956
  CrossrefPubMedSearch in Google Scholar
• 16a Giumanini AG, Chiavari G, Musiani MM, Rossi P. Synthesis 1980; 743
  Thieme Connect
• 16b Sakai N, Shimamura K, Ikeda R, Konakahara T. J. Org. Chem. 2010; 75: 3923
  CrossrefPubMedSearch in Google Scholar
• 17 Keipour H, Ollevier T. Org. Lett. 2017; 19: 5736
  CrossrefPubMedSearch in Google Scholar
• 18 Xing L, Li C. J. Org. Chem. 2015; 80: 10000
  CrossrefPubMedSearch in Google Scholar
• 19 Bonge HT, Hansen T. Synthesis 2009; 91
  Thieme Connect
• 20 Zhu D, Yao Y, Zhao R, Liu Y, Shi L. Chem. Eur. J. 2018; 24: 4805
  CrossrefPubMedSearch in Google Scholar
• 21 Katritzky AR, Fan W.-Q, Long Q.-H. Synthesis 1993; 229
  Thieme Connect

• Supplementary Material