Hydrogenation of β-N-Substituted and β-N,N-Disubstituted Enamino Esters in the Presence of Iridium(I) Catalyst

Abstract

Several new β-amino esters were prepared in two simple steps from β-keto ester derivatives and primary and secondary amines under mild conditions. The hydrogenation of various enamino esters was performed at 50 ˚C in the presence of iridium catalysts. The new β-N-substituted amino esters were isolated in high yields.

β-Amino acid derivatives are building blocks of choice for the preparation of β-peptides. These types of peptides usually present high enzymatic stability and three-dimensional structures of interest. [¹] Some β-amino acids themselves are biologically active products, for instance cis-pentacine shows high antibiotic and antifungal activities, [²] and emeriamine exhibits hypoglycemic and anticetogenic properties (Figure  [¹] ). [³] A variety of polyfunctional linear products, [4] as well as macrocycles [5] incorporating β-amino acid substructures have revealed interesting biological activities (Figure  [¹] ).

The preparation of such β-amino acid derivatives in optically pure form has become a challenge for organic chemists in recent years. [6] The main approaches for stereoselective synthesis of β-amino acids are based on homologation of α-amino acids, [7] enzymatic resolution, [8] enolate addition to imines, [9] Curtius rearrangement, [¹0] conjugate addition of nitrogen nucleophile to α,β-unsaturated derivatives, [¹¹] aminohydroxylation, [¹²] and β-lactam synthesis. [¹³] However, the most promising method for a large scale preparation of optically pure β-amino acids appears to be the catalytic asymmetric hydrogenation of β-acet­amidoacrylates, which involves clean atom economical reactions and offers the preparation of both R- and S-enantiomers. [¹4] Most of the current approaches required an N-acyl or N-carbamoyl protecting groups on the β-dehydroamino acids to achieve high enantioselectivities, via a chelation between the substrate and the metal. But the major drawback of this strategy was the difficulty to protect and remove this protecting-chelating group. To avoid these extra steps, one solution might be either the enan­tioselective hydrogenation of β-N-alkyl- or β-N-aryl­enamino esters or a direct reductive amination. After the evidence that enamines could be hydrogenated by transition metal complexes, [¹5] the first enantioselective hydrogenation of unprotected enamino esters was reported by the Merck group in 2004. [¹6] In 2005, Zhang reported the hydrogenation of β-N-arylenamino esters in the presence of a catalytic amount of Rh-Tangphos in TFE at 50 ˚C. [¹7] The first and up to date only, direct reductive amination was reported by the Lanxess and the Takasago groups. [¹8] The chiral β-amino esters were obtained in a one-pot synthesis from β-keto esters and ammonium acetate under a pressure of hydrogen in the presence of a ruthenium catalyst bearing a Josiphos type optically active ligand. From acyclic β-keto esters, the chemoselectivity in favor of the amino ester and the enantioselectivity were excellent, from acyclic β-keto ester the chemoselectivity in favor of the amino ester was still high, but the diastereo- and the enantioselectivity were moderate.

Finally, in the literature, no general report on hydrogenation of β-N-substituted enamino esters was described. We report here a general procedure for the synthesis of a wide range of β-N-substituted amino esters via a catalytic hydrogenation of β-N-substituted enamino esters under mild conditions.

We recently described the synthesis of various β-N-substituted enamino esters [¹8] and β-N,N-disubstituted enamino esters [¹9] based on a simple condensation of a primary or a secondary amine with β-keto esters in the presence of a Lewis acid. We have extended this study to several substituted anilines 2e-h leading to the formation of the enamino esters 3o-s. Whatever the substituents on the aromatic ring and the β-keto esters used, the yields are good (73-97%, see experimental section). It is worth to mention that using this procedure, only the Z-β-N-substituted enamino esters were isolated from the condensation of a primary amine with a β-keto ester, and only the E-β-N,N-disubstituted enamino esters resulted from the condensation of a secondary amine (Scheme  [¹] ).

The direct hydrogenation of these substrates was investigated with transition-metal catalysts. As they demonstrated good efficiency in the hydrogenation of β-acet-amidoacrylates, [¹4] [Rh(diphosphine)(cod)]BF₄ rhodium complexes were used as precatalyst in our first attempts. No reaction was observed in methanol or in the more acidic trifluoroethanol [²0] at 50 ˚C under 10 bar of hydrogen starting from methyl 3-N-benzylaminobut-2-enoate (3a) and methyl 3-pyrrolidinobut-2-enoate (3t). Even an increase of the catalyst loading (from 1 to 5 mol%) did not improve the reactivity. Under the same reaction conditions, ruthenium complexes, such as [Ru(p-cymene)(diphosphine)Cl]Cl and RuClCp(diphosphine), did not provide any hydrogenated products either.

However, in the presence of the iridium complex [Ir(P(OPh)₃)₂(cod)]PF₆, either in trifluoroethanol or in methanol as solvent, at 50 ˚C for 20 hours under 15 bar of hydrogen, 3a was hydrogenated to methyl 3-N-benzyl­aminobutan-2-oate (4a) in moderate yield (50%). A rapid screening of iridium catalysts demonstrated that the simple [IrCl(cod)]₂ iridium precursor at 50 ˚C under 15 bar of hydrogen led to the saturated amino ester in good yield (Scheme 2). The nature of the solvent had a strong influence on the reactivity; alcohols (such as methanol or tri­fluoroethanol), and THF did not lead to complete hydrogenation, whereas in CH₂Cl₂ full conversion was reached. The hydrogen pressure is also crucial for this ­hydrogenation; below 10 bar of hydrogen in dichloro-methane, the reaction did not go to completion. Thus, hydrogenation in the presence of 1 mol% of [IrCl(cod)]₂ at 50 ˚C in CH₂Cl₂ under 10 bar of hydrogen was selected as our standard conditions for this study.

With these conditions, the scope of the hydrogenation reaction was evaluated for a variety of β-N-substituted enamino esters (Table  [¹] ). In all reactions, whatever the N-alkyl substituent, the conversions were complete and isolated yields of products were almost quantitative. Except for enamino ester 3j, the hydrogenation occurred rapidly (<3 h). The lower reactivity of 3j might be due to the conjugation of the enamine double bond with the aromatic substituent at C-3.

Table 1 Hydrogenation of 3-N-Alkylenamino Esters 3a-j ^a

Entry	Alkyl	Product	Time (h)	R¹	R²
1	Bn	4a	2	Me	Me
2	Bn	4b	2	Me	Et
3	Bn	4c	1	Me	t-Bu
4	Bu	4d	3	Me	Me
5	Bu	4e	3	Me	Et
6	Bu	4f	3	Me	t-Bu
7	i-Pr	4g	3	Me	Me
8	i-Pr	4h	3	Me	Et
9	i-Pr	4i	2	Me	t-Bu
10b	Bn	4j	20	Ph	Et
a The hydrogenation reactions were carried out with 0.5 mmol of enamino ester 3a-j and 1% of [IrCl(cod)]2 precatalyst in 5 mL of CH2Cl2. b Amount of catalyst used: 2 mol%.

Starting from N-aryl-substituted enamino esters, conversions were complete and isolated yields were almost quantitative (superior to 95% after purification on silica gel chromatography in all the following examples). As compared to the alkyl series, the enamino esters 3k-s were less reactive and hydrogenations took usually longer reaction times. The nature and the position of the substituent on the aromatic ring had no noticeable influence on the reactivity (Table  [²] , entries 5-9).

Table 2 Hydrogenation of 3-N-Arylenamino Esters 3k-s ^a

Entry	Aryl	Product	Time (h)	R¹	R²
1	Ph	4k	18	Me	Me
2	Ph	4l	16	Me	Et
3	Ph	4m	16	Me	t-Bu
4b	Ph	4n	48	Ph	Et
5	4-MeC6H4	4o	4	Me	Me
6	2-MeC6H4	4p	4	Me	Me
7	2-BrC6H4	4q	2	Me	Me
8	3,4-Me2C6H3	4r	2	Me	Me
9b	2-BrC6H4	4s	2	Ph	Me
a The hydrogenation reactions were carried out with 0.5 mmol of enamino ester 3a-j and 1% of iridium precatalyst in 5 mL of CH2Cl2. b Amount of catalyst used: 2 mol%.

With secondary enamino esters 3t,u, the hydrogenation proceeded also efficiently. As observed with the previous enamino esters 3a-s, in methanol or mixture of MeOH-CH₂Cl₂ the reaction was slower than in CH₂Cl₂. Then, in methanol after 6 or 16 hours, the reaction was not completed, whereas in CH₂Cl₂, the amino esters 4t,u were isolated in 98 and 99% yield, respectively, within 4 hours under 10 bar of hydrogen (Scheme  [³] ).

We then investigated two phosphoramidites L₁ and L₂ (Figure  [²] ), which were recently introduced as efficient chiral ligands for a number of reactions, in the hydrogenation of the enamino ester 3a. After a screening of solvent (MeOH, THF, CH₂Cl₂, i-PrOH, toluene, EtOAc), pressure (10, 20, 30 bar) and temperature (40, 50, 60, 70 ˚C), we found that using 1 mol% of previously prepared catalyst [Ir(cod)L₁Cl] or [Ir(cod)L₂Cl] the amino ester 4a was obtained quantitatively at 70 ˚C in THF under 10 bar of hydrogen, but as a racemic mixture.

In conclusion, we have found a general procedure for the synthesis of a wide range of new β-N-substituted and β-N,N-disubstituted amino esters via catalytic hydrogenation of β-N-substituted and β-N,N-disubstituted enamino esters under mild conditions in the presence of [IrCl(cod)]₂ as catalyst. Further efforts are now devoted to the asymmetric version of this transformation.

^¹H NMR and ^¹³C NMR spectra were recorded on 300 MHz Bruker AC 200 spectrometers. Chemical shifts are reported in ppm referenced to the residual proton resonances of the solvents. Mass spectra (MS) were obtained on GC-MS Hewlett-Packard HP 5971 apparatus. TLC was performed on Merck silica gel 60 F 254. Silica gel Merck Geduran SI (40-63 µm) was used for column chromatography.

N -Arylaminoacrylates 3a-s; General Procedure

To CH₂Cl₂ (5 mL/mmol), were successively added under argon FeCl₃˙6H₂O (5 mol%), the dicarbonyl derivative 1 (1 equiv), and finally the amine 2 (1.5 equiv). The reaction mixture was stirred at r.t. or under reflux until complete conversion of the keto ester 1 was detected by TLC analysis. The solution was then directly poured at the top of a silica gel column and eluted with a heptane-EtOAc (7:3) mixture. All the N-substituted aminoacrylates were fully characterized with ^¹H and ^¹³C NMR spectra. Spectroscopic data of 3a-n have been reported previously. [¹9] [²¹]

Methyl 3-( p -Tolylamino)but-2-enoate (3o)

Yield: 97%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.98 (s, 3 H), 2.36 (s, 3 H), 3.71 (s, 3 H), 4.70 (s, 1 H), 7.00 (d, J = 10 Hz, 2 H), 7.16 (d, J = 8 Hz, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.3, 20.9, 50.2, 84.9, 124.8, 129.6, 135.0, 136.6, 159.6, 170.8.

Methyl 3-( o -Tolylamino)but-2-enoate (3p)

Yield: 98%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.88 (s, 3 H), 2.31 (s, 3 H), 3.72 (s, 3 H), 4.73 (s, 1 H), 7.05-7.27 (m, 4 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 18.0, 20.1, 50.2, 84.7, 126.1, 126.4, 126.5, 130.7, 133.9, 137.9, 160.0, 170.9.

Methyl 3-(4-Bromophenylamino)but-2-enoate (3q)

Yield: 84%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 2.00 (s, 3 H), 3.70 (s, 3 H), 4.74 (s, 1 H), 6.97 (d, J = 8 Hz, 2 H), 7.45 (d, J = 8 Hz, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.7, 50.8, 87.0, 118.5, 126.2, 132.6, 138.8, 158.8, 171.1.

Methyl 3-(3,4-Dimethylphenylamino)but-2-enoate (3r)

Yield: 82%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.98 (s, 3 H), 2.27 (s, 6 H), 3.71 (s, 3 H), 4.68 (s, 1 H), 6.83-7.12 (m, 3 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 19.6, 20.3, 20.7, 50.7, 85.1, 122.6, 126.5, 130.5, 134.1, 137.3, 137.8, 160.1, 171.2.

Ethyl 3-(4-Bromophenylamino)-3-phenylacrylate (3s)

Yield: 73%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.43 (t, J = 7 Hz, 3 H), 4.23 (q, J = 7.3 Hz, 2 H), 5.06 (s, 1 H), 6.54 (d, J = 10 Hz, 2 H), 7.20 (d, J = 8 Hz, 2 H), 7.29-7.40 (m, 5 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 15.0, 59.9, 92.5, 116.1, 124.0, 128.6, 129.1, 130.1, 132.0, 136.0, 140.0, 158.9, 170.5.

N , N -Dialkylaminoacrylates 3t,u; General Procedure

In a Schlenk tube, methyl acetylacetate or tert-butyl acetylacetate (1 equiv), and pyrrolidine (1.5 equiv) were successively added under argon. The neat reaction mixture was stirred at 25 ˚C. The reaction was monitored by TLC analysis. The crude mixture was recrystallized from a mixture of Et₂O-pentane.

Methyl 3-(Pyrrolidino)but-2-enoate (3t)

Yield: 88%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 4.89 (m, 4 H), 2.41 (s, 3 H), 3.25 (m, 4 H), 3.56 (s, 1 H), 4.41 (s, 1 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 16.6, 25.1, 47.9, 49.8, 82.7, 159.6, 169.5.

tert -Butyl 3-(Pyrrolidino)but-2-enoate (3u)

Yield: 89%.

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.47 (s, 9 H), 1.91 (m, 4 H), 2.43 (s, 3 H), 3.28 (m, 4 H), 4.41 (s, 1 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 16.5, 25.2, 28.8, 47.8, 77.2, 85.1, 158.8, 169.2.

β-Amino Esters 4a-u; General Procedure

In a 25 mL stainless steel autoclave were placed under argon, the N-substituted β-amino acrylate (0.5 mmol, 1 equiv) and the iridium precatalyst (0.005 mmol, 1% mol). The mixture was degassed by three vacuum-filling with argon cycles before adding degassed and distilled CH₂Cl₂ (5 mL). Then, the autoclave was purged three times with H₂ and the vessel was pressurized to 10 or 20 bar. After 1-48 h (see text) at 50 ˚C, the autoclave was carefully opened, and the solvent was removed under reduced pressure. Conversion was determined by ^¹H NMR analysis of the crude mixture. Subsequently, the residue was purified by purification on silica gel by eluting with a 1:1 mixture of heptane and EtOAc.

Methyl 3-(Benzylamino)butanoate (4a)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.15 (d, J = 6 Hz, 3 H), 2.44 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 3.16 (m, 1 H), 3.66 (s, 3 H), 3.79 (AB, J _AB = 12 Hz, 2 H), 7.20-7.34 (m, 5 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.5, 41.4, 49.7, 51.2, 51.5, 126.9, 128.1, 128.4, 140.4, 172.8.

HRMS: m/z calcd for C₁₁H₁₄NO₂ [M - CH₃]⁺: 192.1024; found: 192.1013.

Ethyl 3-(Benzylamino)butanoate (4b)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.15 (d, J = 6 Hz, 3 H), 1.24 (t, J = 7.5 Hz, 3 H), 2.42 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 3.16 (m, 1 H), 3.79 (AB, J _AB = 12 Hz, 2 H), 4.12 (q, J = 7 Hz, 2 H), 7.20-7.35 (m, 5 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.2, 20.5, 41.7, 49.7, 51.2, 60.3, 126.9, 128.1, 128.4, 140.4, 172.3.

HRMS: m/z calcd for C₁₂H₁₆NO₂ [M - CH₃]⁺: 206.1181; found: 206.1196.

tert -Butyl 3-(Benzylamino)butanoate (4c)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.15 (d, J = 6 Hz, 3 H), 1.44 (s, 9 H), 2.34 (ABX, J _AB = 15 Hz, J _AX = 9 Hz, J _BX = 6 Hz, 2 H), 3.12 (m, 1 H), 3.78 (AB, J _AB = 13.5 Hz, 2 H), 7.20-7.35 (m, 5 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.4, 28.1, 42.9, 49.9, 51.2, 80.4, 126.9, 128.1, 128.4, 140.5, 171.7.

HRMS: m/z calcd for C₁₁H₁₄NO₂ [M - t-Bu]⁺: 192.1024; found: 192.1015.

Methyl 3-(Isopropylamino)butanoate (4d)

^¹H NMR (300.13 MHz, CDCl₃): δ = 0.98 (dd, J = 6, 12 Hz, 6 H), 1.04 (d, J = 6 Hz, 3 H), 2.32 (ABX, J _AB = 15 Hz, J _AX = 7.5 Hz, J _BX = 9 Hz, 2 H), 2.83 (m, 1 H), 3.12 (m, 1 H), 3.61 (s, 3 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.9, 22.9, 23.5, 41.7, 45.2, 47.1, 51.3, 172.7.

HRMS: m/z calcd for C₈H₁₇NO₂: 159.1259; found: 159.1271.

Ethyl 3-(Isopropylamino)butanoate (4e)

^¹H NMR (300.13 MHz, CDCl₃) : δ = 1.03 (dd, J = 3, 9 Hz, 6 H), 1.09 (d, J = 6 Hz, 3 H), 1.25 (t, J = 6 Hz, 3 H), 2.36 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 2.89 (m, 1 H), 3.18 (m, 1 H), 4.12 (q, J = 7 Hz, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.2, 21.0, 23.0, 23.5, 41.9, 45.3, 47.2, 60.2, 172.4.

HRMS: m/z calcd for C₈H₁₆NO₂ [M - CH₃]⁺: 158.1181; found: 158.1197.

tert -Butyl 3-(Isopropylamino)butanoate (4f)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.03 (dd, J = 3 Hz, 9 Hz, 6 H), 1.08 (d, J = 6 Hz, 3 H), 1.44 (s, 9 H), 2.27 (ABX, J _AB = 15 Hz, J _AX = 9 Hz, J _BX = 6 Hz, 2 H), 2.89 (m, 1 H), 3.13 (m, 1 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.9, 23.0, 23.6, 28.1, 43.1, 45.2, 47.3, 80.3, 171.8.

HRMS: m/z calcd for C₈H₁₆NO₂ [M - C₃H₇]⁺: 158.1181; found: 158.1197.

Methyl 3-(Butylamino)butanoate (4g)

^¹H NMR (300.13 MHz, CDCl₃): δ = 0.89 (t, J = 7,5 Hz, 3 H), 1.09 (d, J = 6 Hz, 3 H), 1.32 (m, 2 H), 1.42 (m, 2 H), 2.38 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 2.57 (m, 2 H), 3.07 (m, 1 H), 3.66 (s, 3 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.0, 20.5, 20.6, 32.4, 41.3, 46.8, 50.2, 51.4, 172.9.

HRMS: m/z calcd for C₉H₁₉NO₂: 173.1416; found: 173.1423.

Ethyl 3-(Butylamino)butanoate (4h)

^¹H NMR (300.13 MHz, CDCl₃): δ = 0.88 (t, J = 7.5 Hz, 3 H), 1.08 (d, J = 6 Hz, 3 H), 1.23 (t, J = 6 Hz, 3 H), 1.31 (m, 2 H), 1.41 (m, 2 H), 2.35 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 2.57 (m, 2 H), 3.06 (m, 1 H), 4.11 (q, J = 7 Hz, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 13.9, 14.2, 20.5, 20.5, 32.4, 41.6, 46.8, 50.2, 60.2, 172.4.

HRMS: m/z calcd for C₁₀H₂₁NO₂: 187.1572; found: 187.1581.

tert -Butyl 3-(Butylamino)butanoate (4i)

^¹H NMR (300.13 MHz, CDCl₃): δ = 0.89 (t, J = 7.5 Hz, 3 H), 1.07 (d, J = 6 Hz, 3 H), 1.23 (m, 2 H), 1.33 (m, 2 H), 1.42 (s, 9 H), 2.27 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 2.56 (m, 2 H), 3.02 (m, 1 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.0, 20.5, 28.1, 32.5, 42.8, 46.8, 50.4, 80.3, 171.8.

HRMS: m/z calcd for C₈H₁₆NO₂ [M - t-Bu]⁺: 158.1181; found: 158.1197.

Ethyl 3-(Benzylamino)-3-phenylpropanoate (4j)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.22 (t, J = 7.5 Hz, 3 H), 2.70 (ABX, J _AB = 15 Hz, J _AX = 9 Hz, J _BX = 6 Hz, 2 H), 3.64 (AB, J _AB = 12 Hz, 2 H), 4.09-4.18 (m, 3 H), 7.24-7.40 (m, 10 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.2, 43.2, 51.4, 58.9, 60.5, 126.9, 127.2, 127.5, 128.2, 128.4, 128.6, 140.3, 142.6, 171.8.

HRMS: m/z calcd for C₁₈H₂₂NO₂ [M + H]⁺: 284.1650; found: 284.1649.

Methyl 3-(Phenylamino)butanoate (4k)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.30 (d, J = 6 Hz, 3 H), 2.56 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 3.70 (s, 3 H), 3.97 (m, 1 H), 6.64-6.76 (m, 3 H), 7.09-7.37 (m, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.7, 40.8, 46.0, 51.6, 113.6, 117.7, 129.4, 146.8, 172.3.

HRMS: m/z calcd for C₁₁H₁₅NO₂: 193.1103; found: 193.1096.

Methyl 3-( p -Tolylamino)butanoate (4l)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.29 (d, J = 6 Hz, 3 H), 2.27 (s, 3 H), 2.56 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 9 Hz, 2 H), 3.71 (s, 3 H), 3.94 (m, 1 H), 6.59 (d, J = 9 Hz, 2 H), 7.02 (d, J = 9 Hz, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.4, 20.7, 40.8, 46.4, 51.6, 114.0, 127.0, 129.9, 114.5, 172.4.

HRMS: m/z calcd for C₁₂H₁₇NO₂: 207.1259; found: 207.1256.

Methyl 3-( o -Tolylamino)butanoate (4m)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.21 (d, J = 6 Hz, 3 H), 2.03 (s, 3 H), 2.47 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 9 Hz, 2 H), 3.58 (s, 3 H), 3.89 (m, 1 H), 6.53-6.58 (m, 2 H), 6.94-7.05 (m, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 17.6, 20.8, 40.7, 45.7, 51.6, 110.5, 117.1, 122.4, 127.2, 130.4, 144.8, 172.3.

HRMS: m/z calcd for C₁₂H₁₇NO₂: 207.1259; found: 207.1276.

Methyl 3-(4-Bromophenylamino)butanoate (4n)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.27 (d, J = 6 Hz, 3 H), 2.53 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 3.69 (s, 3 H), 3.88 (m, 1 H), 6.50 (d, J = 9 Hz, 2 H), 7.25 (d, J = 9 Hz, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.5, 40.6, 46.1, 51.7, 109.1, 115.1, 132.0, 145.9, 172.1.

HRMS: m/z calcd for C₁₁H₁₄BrNO₂: 271.0208; found: 271.0223.

Methyl 3-(3′,4′-Dimethylphenylamino)butanoate (4o)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.32 (d, J = 6 Hz, 3 H), 2.22 (s, 3 H), 2.26 (s, 3 H), 2.58 (ABX, J _AB = 15 Hz, J _AX = 3 Hz, J _BX = 6 Hz, 2 H), 3.74 (s, 3 H), 3.97 (m, 1 H), 6.45-6.53 (m, 2 H), 6.71 (d, J = 9 Hz, 1 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 18.7, 20.1, 20.7, 40.9, 46.4, 51.6, 111.2, 115.7, 125.8, 130.4, 137.4, 145.0, 172.4.

HRMS: m/z calcd for C₁₃H₁₉NO₂: 221.1416; found: 221.1426.

Ethyl 3-(Phenylamino)butanoate (4p)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.26 (d, J = 6 Hz, 3 H), 1.30 (t, J = 4.5 Hz, 3 H), 2.54 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 3.96 (m, 1 H), 4.16 (q, J = 7 Hz, 2 H), 6.62-6.75 (m, 3 H), 7.15-7.23 (m, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.3, 20.6, 41.1, 46.0, 60.5, 113.6, 117.6, 129.4, 146.9, 171.8.

HRMS: m/z calcd for C₁₂H₁₇NO₂: 207.1259; found: 207.1276.

tert -Butyl 3-(Phenylamino)butanoate (4q)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.29 (d, J = 6 Hz, 3 H), 1.47 (s, 9 H), 2.46 (ABX, J _AB = 15 Hz, J _AX = 6 Hz, J _BX = 6 Hz, 2 H), 3.92 (m, 1 H), 6.61-6.75 (m, 3 H), 7.16-7.23 (m, 2 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 20.5, 28.1, 42.3, 46.2, 80.7, 113.5, 117.5, 129.3, 147.0, 171.2.

HRMS: m/z calcd for C₁₀H₁₃NO₂ [M - C₄H₈]⁺: 179.0946; found: 179.0958.

Ethyl 3-Phenyl-3-(phenylamino)propanoate (4r)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.24 (t, J = 7.5 Hz, 3 H), 2.86 (d, J = 6 Hz, 2 H), 4.16 (q, J = 6 Hz, 2 H), 4.90 (t, J = 6 Hz, 1 H), 6.62 (d, J = 9 Hz, 2 H), 6.73 (t, J = 7.5 Hz, 1 H), 7.16 (t, J = 7.5 Hz, 2 H), 7.27-7.46 (m, 5 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.2, 43.0, 55.1, 60.8, 113.7, 117.8, 126.3, 127.5, 128.8, 129.2, 142.3, 146.9, 171.2.

HRMS: m/z calcd for C₁₇H₁₉NO₂: 269.1416; found: 269.1428.

Ethyl 3-(4-Bromophenylamino)-3-phenylpropanoate (4s)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.22 (t, J = 7.5 Hz, 3 H), 2.83 (ABX, J _AB = 15 Hz, J _AX = 4.5 Hz, J _BX = 7.5 Hz, 2 H), 4.15 (q, J = 7 Hz, 2 H), 4.82 (t, J = 7.5 Hz, 1 H), 6.47 (d, J = 9 Hz, 2 H), 7.20 (d, J = 9 Hz, 2 H), 7.26-7.41 (m, 5 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 14.2, 42.8, 55.0, 60.9, 109.5, 115.3, 126.3, 127.7, 128.9, 131.9, 141.7, 145.9, 171.1.

HRMS: m/z calcd for C₁₇H₁₈BrNO_2: 347.0521; found: 347.0525.

Methyl 3-(Pyrrolidin-1-yl)butanoate (4t)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.11 (d, J = 6 Hz, 3 H), 1.73 (m, 4 H), 2.22-2.67 (m, 1 H + 4 H + 1 H), 2.84 (m, 1 H), 3.64 (s, 3 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 18.7, 23.4, 40.1, 50.7, 51.5, 55.5, 172.9.

HRMS: m/z calcd for C₉H₁₇NO₂: 171.1259; found: 171.1268.

tert -Butyl 3-(Pyrrolidin-1-yl)butanoate (4u)

^¹H NMR (300.13 MHz, CDCl₃): δ = 1.12 (d, J = 6 Hz, 3 H), 1.42 (s, 9 H), 1.74 (m, 4 H), 2.11-2.59 (m, 1 H + 5 H), 2.82 (m, 1 H).

^¹³C NMR (75.03 MHz, CDCl₃): δ = 18.6, 23.4, 28.1, 41.6, 50.6, 55.6, 80.2, 171.9.

HRMS: m/z calcd for C₈H₁₄O₂ [M - C₄H₉N ]⁺: 142.0994; found: 142.0982.

References

• 1a Gademann K. Hintermann T. Schreiber JV. Curr. Med. Chem.  1999,  6:  905 
  Search in Google Scholar
• 1b Gellman SH. Acc. Chem. Res.  1998,  31:  173 
  Search in Google Scholar
• 1c Hoekstra WJ. Curr. Med. Chem.  1999,  6:  7940 
  Search in Google Scholar
• 1d Juaristi E. Enantioselective Synthesis of β-Amino Acids   Wiley-VCH; New York: 1997. 
• 1e Guenard D. Guéritte-Voegelein R. Potier P. Acc. Chem. Res.  1993,  26:  160 
  Search in Google Scholar
• 1f Seebach D. Matthews JL. Chem. Commun.  1997,  2015 
• 2a Konichi M. Nishio M. Saitoh T. Miyaki T. Oki T. Kawaguchi H. J. Antibiot.  1989,  42:  1749 
  Search in Google Scholar
• 2b Oki T. Hirano M. Tomatsu K. Numata K. Kamei H. J. Antibiot.  1989,  42:  1756 
  Search in Google Scholar
• 3 Shinagawa S. Kanamaru T. Harada S. Asai M. Okazaki H. J. Med. Chem.  1987,  30:  1458 
  CrossrefPubMedSearch in Google Scholar
• 4a Namikoshi M. Rinehart KL. Dahlem AM. Beasley VR. Carmichael WW. Tetrahedron Lett.  1989,  30:  4349 
  Search in Google Scholar
• 4b Roers R. Verdine GL. Tetrahedron Lett.  2001,  42:  3563 
  Search in Google Scholar
• 4c Wehner V. Blum H. Kurz M. Stilz HU. Synthesis  2002,  2023 
• 4d Bull SD. Davies SG. Fox DJ. Gianotti M. Kelly PM. Pierres C. Savory ED. Smith AD. J. Chem. Soc., Perkin Trans. 1  2002,  1858 
• 5a Crews P. Manes L. Boehler M. Tetrahedron Lett.  1986,  27:  2797 
  Search in Google Scholar
• 5b Shih C. Gossett LS. Gruber JM. Grossman CS. Andis SL. Schultz RM. Worzalla JF. Corbett TH. Metz JT. Bioorg. Med. Chem. Lett.  1999,  9:  69 
  Search in Google Scholar
• 6a Lui M. Sibi MP. Tetrahedron  2002,  58:  7991 
  Search in Google Scholar
• 6b Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1 
• See for example:
• 7a Yuan C. Williams RM. J. Am. Chem. Soc.  1997,  119:  11777 
  Search in Google Scholar
• 7b Yang H. Foster K. Stephenson CRJ. Brown W. Roberts E. Org. Lett.  2000,  2:  2177 
  Search in Google Scholar
• 8 Gedey S. Liljeblad A. Lázár L. Fülöp F. Kanerva LT. Tetrahedron: Asymmetry  2001,  12:  105 ; and references cited therein
  CrossrefSearch in Google Scholar
• See for example:
• 9a Tang TP. Ellman JA. J. Org. Chem.  2002,  67:  7819 
  Search in Google Scholar
• 9b Wenzel AG. Jacobsen EN. J. Am. Chem. Soc.  2002,  124:  12964 
  Search in Google Scholar
• 9c Murahashi S.-i. Imada Y. Kawakami T. Harada K. Yonemushi Y. Tomita N. J. Am. Chem. Soc.  2002,  124:  2888 
  Search in Google Scholar
• 9d Miaybe H. Fujii K. Goto T. Naito T. Org. Lett.  2000,  2:  4071 
  Search in Google Scholar
• See for example:
• 10a Sibi MP. Deshpande PK. J. Chem. Soc., Perkin Trans. 1  2000,  1461 
• 10b Evans DA. Wu LD. Wiener JJM. Johnson JS. Ripin DHB. Tedrow JS. J. Org. Chem.  1999,  64:  6411 
  Search in Google Scholar
• See for example:
• 11a Sibi MP. Shay JJ. Liu M. Jasperse CP. J. Am. Chem. Soc.  1998,  120:  6615 
  Search in Google Scholar
• 11b Sibi MP. Asano Y. J. Am. Chem. Soc.  2001,  123:  9708 
  Search in Google Scholar
• 11c Doi H. Sakai T. Iguchi M. Yamada K.-i. Tomioka K. J. Am. Chem. Soc.  2003,  125:  2886 
  Search in Google Scholar
• 11d Myers JK. Jacobsen EN. J. Am. Chem. Soc.  1999,  121:  8959 
  Search in Google Scholar
• 11e Guerin DJ. Miller SJ. J. Am. Chem. Soc.  2002,  124:  2134 
  Search in Google Scholar
• See for example:
• 12a Bruncko M. Schlingoff G. Sharpless KB. Angew. Chem,. Int. Ed. Eng.  1997,  36:  1483 
  Search in Google Scholar
• 12b O’Brien P. Angew. Chem. Int. Ed.  1999,  38:  326 
  Search in Google Scholar
• 13a For recent examples, see: For a review, see: Palomo C. Aizpurua JM. Ganboa I. Oiarbide M. Eur. J. Org. Chem.  1999,  3223 
• 13b Hodous BL. Fu GC. J. Am. Chem. Soc.  2002,  124:  1578 
  Search in Google Scholar
• 13c Lo MM.-C. Fu GC. J. Am. Chem. Soc.  2002,  124:  4572 
  Search in Google Scholar
• 14 Bruneau C. Renaud J.-L. Jerphagnon T. Coord. Chem. Rev.  2008,  252:  532 
  CrossrefSearch in Google Scholar
• 15a Spindler F. Blaser H.-U. In Handbook of Homogeneous Hydrogenation   de Vries JG. Elsevier CJ. Wiley-VCH; Weinheim: 2007.  p.1193-1214  
• 15b Tararov VI. Kadyrov R. Riermeier TH. Holz J. Börner A. Tetrahedron Lett.  2000,  41:  2351 
  Search in Google Scholar
• 15c Tavarov VI. Börner A. Synlett  2005,  203 
• 16a Hsiao Y. Rivera NR. Rosner T. Krska SW. Njolito E. Wang F. Sun Y. Armstrong JD. Grabowski EJJ. Tillyer RD. Spindler F. Malan C. J. Am. Chem. Soc.  2004,  126:  9918 
  Search in Google Scholar
• 16b Xiao Y, Armstrong JD, Krska SW, Njolito E, Rivera NR, Sun Y, Rosner T, and Clausen AM. inventors; Patent WO  2006/082251 A1. 
• 16c Hansen KB. Rosner T. Kubryk M. Dormer PG. Armstrong JD. Org. Lett.  2005,  7:  4935 
  Search in Google Scholar
• 16d Clausen AM. Dziadul B. Cappuccio KL. Kaba M. Starbuck C. Hsiao Y. Dowling TM. Org. Process Res. Dev.  2006,  10:  723 
  Search in Google Scholar
• 16e Kubryk M. Hansen KB. Tetrahedron: Asymmetry  2006,  17:  205 
  Search in Google Scholar
• 17 Dai Q. Yang W. Zhang X. Org. Lett.  2005,  7:  5343 
  CrossrefPubMedSearch in Google Scholar
• 18a Bunlaksananusorn T. Rampf F. Synlett  2005,  2682 
• 18b Matsumara K, and Saito K. inventors; World Patent WO  2005/028419. 
• 19a Vohra RK. Renaud J.-L. Bruneau C. Collect. Czech. Chem. Commun.  2005,  70:  1943 
  Search in Google Scholar
• 19b Hebbache H. Hank Z. Boutamine S. Meklati M. Bruneau C. Renaud J.-L. C. R. Chim.  2008,  612 
• 21 Vohra RK. Renaud J.-L. Bruneau C. Synthesis  2007,  731 
  Thieme Connect

It was reported that trifluoroethanol was the best solvent for the hydrogenation of enamino esters and β-N-arylenamino esters in the presence of rhodium catalysts; see references 15 and 16.

References

• 1a Gademann K. Hintermann T. Schreiber JV. Curr. Med. Chem.  1999,  6:  905 
  Search in Google Scholar
• 1b Gellman SH. Acc. Chem. Res.  1998,  31:  173 
  Search in Google Scholar
• 1c Hoekstra WJ. Curr. Med. Chem.  1999,  6:  7940 
  Search in Google Scholar
• 1d Juaristi E. Enantioselective Synthesis of β-Amino Acids   Wiley-VCH; New York: 1997. 
• 1e Guenard D. Guéritte-Voegelein R. Potier P. Acc. Chem. Res.  1993,  26:  160 
  Search in Google Scholar
• 1f Seebach D. Matthews JL. Chem. Commun.  1997,  2015 
• 2a Konichi M. Nishio M. Saitoh T. Miyaki T. Oki T. Kawaguchi H. J. Antibiot.  1989,  42:  1749 
  Search in Google Scholar
• 2b Oki T. Hirano M. Tomatsu K. Numata K. Kamei H. J. Antibiot.  1989,  42:  1756 
  Search in Google Scholar
• 3 Shinagawa S. Kanamaru T. Harada S. Asai M. Okazaki H. J. Med. Chem.  1987,  30:  1458 
  CrossrefPubMedSearch in Google Scholar
• 4a Namikoshi M. Rinehart KL. Dahlem AM. Beasley VR. Carmichael WW. Tetrahedron Lett.  1989,  30:  4349 
  Search in Google Scholar
• 4b Roers R. Verdine GL. Tetrahedron Lett.  2001,  42:  3563 
  Search in Google Scholar
• 4c Wehner V. Blum H. Kurz M. Stilz HU. Synthesis  2002,  2023 
• 4d Bull SD. Davies SG. Fox DJ. Gianotti M. Kelly PM. Pierres C. Savory ED. Smith AD. J. Chem. Soc., Perkin Trans. 1  2002,  1858 
• 5a Crews P. Manes L. Boehler M. Tetrahedron Lett.  1986,  27:  2797 
  Search in Google Scholar
• 5b Shih C. Gossett LS. Gruber JM. Grossman CS. Andis SL. Schultz RM. Worzalla JF. Corbett TH. Metz JT. Bioorg. Med. Chem. Lett.  1999,  9:  69 
  Search in Google Scholar
• 6a Lui M. Sibi MP. Tetrahedron  2002,  58:  7991 
  Search in Google Scholar
• 6b Abele S. Seebach D. Eur. J. Org. Chem.  2000,  1 
• See for example:
• 7a Yuan C. Williams RM. J. Am. Chem. Soc.  1997,  119:  11777 
  Search in Google Scholar
• 7b Yang H. Foster K. Stephenson CRJ. Brown W. Roberts E. Org. Lett.  2000,  2:  2177 
  Search in Google Scholar
• 8 Gedey S. Liljeblad A. Lázár L. Fülöp F. Kanerva LT. Tetrahedron: Asymmetry  2001,  12:  105 ; and references cited therein
  CrossrefSearch in Google Scholar
• See for example:
• 9a Tang TP. Ellman JA. J. Org. Chem.  2002,  67:  7819 
  Search in Google Scholar
• 9b Wenzel AG. Jacobsen EN. J. Am. Chem. Soc.  2002,  124:  12964 
  Search in Google Scholar
• 9c Murahashi S.-i. Imada Y. Kawakami T. Harada K. Yonemushi Y. Tomita N. J. Am. Chem. Soc.  2002,  124:  2888 
  Search in Google Scholar
• 9d Miaybe H. Fujii K. Goto T. Naito T. Org. Lett.  2000,  2:  4071 
  Search in Google Scholar
• See for example:
• 10a Sibi MP. Deshpande PK. J. Chem. Soc., Perkin Trans. 1  2000,  1461 
• 10b Evans DA. Wu LD. Wiener JJM. Johnson JS. Ripin DHB. Tedrow JS. J. Org. Chem.  1999,  64:  6411 
  Search in Google Scholar
• See for example:
• 11a Sibi MP. Shay JJ. Liu M. Jasperse CP. J. Am. Chem. Soc.  1998,  120:  6615 
  Search in Google Scholar
• 11b Sibi MP. Asano Y. J. Am. Chem. Soc.  2001,  123:  9708 
  Search in Google Scholar
• 11c Doi H. Sakai T. Iguchi M. Yamada K.-i. Tomioka K. J. Am. Chem. Soc.  2003,  125:  2886 
  Search in Google Scholar
• 11d Myers JK. Jacobsen EN. J. Am. Chem. Soc.  1999,  121:  8959 
  Search in Google Scholar
• 11e Guerin DJ. Miller SJ. J. Am. Chem. Soc.  2002,  124:  2134 
  Search in Google Scholar
• See for example:
• 12a Bruncko M. Schlingoff G. Sharpless KB. Angew. Chem,. Int. Ed. Eng.  1997,  36:  1483 
  Search in Google Scholar
• 12b O’Brien P. Angew. Chem. Int. Ed.  1999,  38:  326 
  Search in Google Scholar
• 13a For recent examples, see: For a review, see: Palomo C. Aizpurua JM. Ganboa I. Oiarbide M. Eur. J. Org. Chem.  1999,  3223 
• 13b Hodous BL. Fu GC. J. Am. Chem. Soc.  2002,  124:  1578 
  Search in Google Scholar
• 13c Lo MM.-C. Fu GC. J. Am. Chem. Soc.  2002,  124:  4572 
  Search in Google Scholar
• 14 Bruneau C. Renaud J.-L. Jerphagnon T. Coord. Chem. Rev.  2008,  252:  532 
  CrossrefSearch in Google Scholar
• 15a Spindler F. Blaser H.-U. In Handbook of Homogeneous Hydrogenation   de Vries JG. Elsevier CJ. Wiley-VCH; Weinheim: 2007.  p.1193-1214  
• 15b Tararov VI. Kadyrov R. Riermeier TH. Holz J. Börner A. Tetrahedron Lett.  2000,  41:  2351 
  Search in Google Scholar
• 15c Tavarov VI. Börner A. Synlett  2005,  203 
• 16a Hsiao Y. Rivera NR. Rosner T. Krska SW. Njolito E. Wang F. Sun Y. Armstrong JD. Grabowski EJJ. Tillyer RD. Spindler F. Malan C. J. Am. Chem. Soc.  2004,  126:  9918 
  Search in Google Scholar
• 16b Xiao Y, Armstrong JD, Krska SW, Njolito E, Rivera NR, Sun Y, Rosner T, and Clausen AM. inventors; Patent WO  2006/082251 A1. 
• 16c Hansen KB. Rosner T. Kubryk M. Dormer PG. Armstrong JD. Org. Lett.  2005,  7:  4935 
  Search in Google Scholar
• 16d Clausen AM. Dziadul B. Cappuccio KL. Kaba M. Starbuck C. Hsiao Y. Dowling TM. Org. Process Res. Dev.  2006,  10:  723 
  Search in Google Scholar
• 16e Kubryk M. Hansen KB. Tetrahedron: Asymmetry  2006,  17:  205 
  Search in Google Scholar
• 17 Dai Q. Yang W. Zhang X. Org. Lett.  2005,  7:  5343 
  CrossrefPubMedSearch in Google Scholar
• 18a Bunlaksananusorn T. Rampf F. Synlett  2005,  2682 
• 18b Matsumara K, and Saito K. inventors; World Patent WO  2005/028419. 
• 19a Vohra RK. Renaud J.-L. Bruneau C. Collect. Czech. Chem. Commun.  2005,  70:  1943 
  Search in Google Scholar
• 19b Hebbache H. Hank Z. Boutamine S. Meklati M. Bruneau C. Renaud J.-L. C. R. Chim.  2008,  612 
• 21 Vohra RK. Renaud J.-L. Bruneau C. Synthesis  2007,  731 
  Thieme Connect

It was reported that trifluoroethanol was the best solvent for the hydrogenation of enamino esters and β-N-arylenamino esters in the presence of rhodium catalysts; see references 15 and 16.