2-Aryl-2-nitroacetates as Central Precursors to Aryl Nitromethanes, α-Ketoesters, and α-Amino Acids

Abstract

Nitroarylacetates are useful small molecular building blocks that act as precursors to α-ketoesters and aryl nitromethanes as well as α-amino acids. Methods were developed that produce each of these compound types in good yields. Two different conditions for decarboxylation are discussed for substrates with neutral and electron-poor aryl groups versus electron-rich aryl groups. For formation of the α-ketoesters, new mild conditions for the Nef disproportionation were identified.

2-Aryl-2-nitroacetates are central precursors (Scheme 1) making them valuable building blocks in synthesis.¹ Access to 2-aryl-2-nitroacetates^2,3 is best accomplished by our previously reported cross-coupling between nitroacetates and aryl bromides (eq 1).⁴ In this note, we describe efficient methods for the conversion of 2-aryl-2-nitroacetates to several product classes that are surprisingly difficult to make: aryl nitromethanes, α-ketoesters, and α-aryl α-amino acids (Scheme 1).

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Scheme 1.

2-Aryl-2-nitroacetates as central precursors.

For aryl nitromethanes, current approaches (Scheme 2), with yields from 30–60%, produce multiple by-products, and require arduous purification.^5–7 Low yields are a result of competing benzyl nitrite formation or disproportionation of the phenyl nitromethane product to generate aldehyde. Purification is also difficult as these byproducts co-elute with the desired product. Typically excess nitrite reagent is needed, which is also not cost effective if silver reagents are used. We have recently described another route to aryl nitromethanes, which enables the direct coupling of nitromethane with arylbromides.⁸

Scheme 2.

Reported syntheses of arylnitromethanes.

Hydrolysis and decarboxylation conditions were initially optimized for the formation of phenyl nitromethane and were comprised of initial treatment with NaOH in EtOH at 80 °C followed by exposure to 1 M HCl in THF after solvent removal (Table 1, entry 1).^9–11 This protocol worked well for substrates with neutral or electron-withdrawing substituents (entries 1–5).

Table 1.

Decarboxylation to form aryl nitromethanes (eq 2).^a

Entry	Product	Method	Yield (%)
1		A	79
2		A	98
3		A	79
4		A	98
5		A	76
6		B	77
7		B	76
8		B	80
9		B	88

^aReaction conditions Method A: 1) 1 M NaOH, EtOH (0.14 M), 85 °C, 1 h; 2) 1 M HCl, THF (0.17 M), 85 °C, 1 h. Method B: 1) 1 M NaOH, EtOH:toluene (1:1, 0.14 M), 85 °C, 1 h; 2) urea (17 equiv as a 2.8 M solution in 20% aq AcOH), THF (0.17 M), 0 °C to rt, 1 h.

On the other hand, electron-rich substrates were more prone to the Nef reaction (Scheme 3)^12,13 forming an aldehyde by-product. This observation contradicts Kornblum’s report that stabilization of the nitronate anion by an aryl group decelerates the Nef reaction.¹⁴ Apparently, this stabilization is offset by the presence of electron donating groups on the aromatic ring. To circumvent this problem, less acidic conditions that do not facilitate protonation of the corresponding nitronic acid and that stabilize the nitro group by hydrogen bonding (acetic acid/urea)¹⁴ were employed in the second step for this class of substrates. This procedure slowed the competing elimination of dihydroxyamine [HN(OH)₂] and generated aryl nitromethanes in 77–80% yield (Table 1, entries 6–8).

Scheme 3.

Formation of aryl nitromethanes instead of aldehyde.

α-Ketoesters are highly-valued substrates utilized in a variety of synthetic endeavors.^15–18 Unfortunately, we have found there is no uniform method to generate a broad range of α-ketoesters.^19,20 The reported protocols either utilize harsh acidic conditions or strong oxidizing agents, either of which is incompatible with many desirable functional groups. For example, aroylformates are generated by Friedel-Crafts acylation of benzene derivatives using ethyl chlorooxoacetate²¹ or by oxidation of the corresponding α-hydroxy-α-arylacetate²² (Jones reagent) or aryl alkynes (KMnO₄).²³ In addition, the Friedel-Crafts protocol is restricted to arenes with electron-donating substituents. Alkyl α-ketoesters have been generated by a harsher version of the Nef reaction proceeding via formation of the nitronate salt and subsequent ozonolysis.²⁴

Notably, application of conventional Nef conditions^25–28 to the 2-aryl-2-nitroacetates did not provide the expected α-ketoesters. Specifically, deprotonation with aqueous NaOH in THF at rt followed by acidification with 5 M HCl yielded only starting material and some decarboxylated byproduct as a result of ester hydrolysis.²⁵ An amidine base was also ineffective.²⁷ Futhermore, exposure of the aryl nitroaceates to 30% H₂O₂ in the presence of aqueous K₂CO₃ in MeOH at rt gave only a 20% conversion by ¹H NMR to the α-ketoester after 24 h.²⁸

Significantly, we had observed formation of the α-ketoesters during efforts to α-alkylate the 2-aryl-2-nitroacetates using phase transfer catalysis (PTC) conditions.^29.30 Ultimately, TBAF, MeI, and KF in THF proved quite efficient in generating α-ketoesters. Both electron-poor and electron-rich substrates afforded the α-ketoesters in good yields (Table 2). In many cases, less than 100% isolated yield resulted from a variable amount of an undesired O-methylated byproduct.

Table 2.

Disproportionation of 2-aryl-2-nitroacetates (eq 3).^a

Entry	Product	Yield (%)
1		72
2		86
3		67
4		74
5		51
6		66
7		80
8		70
9		59

^aReaction conditions: TBAF (5 mol %, 1M solution in THF), MeI (2.5 equiv), KF (12.5 equiv), THF (0.3 M).

The success of this combination of reagents was unexpected and experiments indicated that all the reagents are important for the transformation (Table 3). The fact that the reactions including MeI were slightly faster than ones that did not (entries 2 vs. 3) suggests the involvement of a nitronic ester. Similar compounds have been reported to undergo the Nef reaction.³¹ However, the reaction still progresses well without MeI indicating a classical Nef mechanism is concurrently in operation (entry 4). Evidence of a thick precipitate during reaction progression suggests TBAF is necessary to increase anion solubility (entry 9). Without KF (entry 6) the reaction rate is slower, but significant product was observed after 3 h (entry 7). The reaction is sensitive to the amount of water present. Addition of 1 equiv of water aided reaction progress, while 5 equiv inhibited product formation dramatically. Concentrations lower than 0.3 M lead to a slower rate while higher concentrations give an O-methylated product with less than 10% of the desired product observed. Tetrabutylammonium hydroxide (TBAH) is also sufficient for the transformation (entry 10). However excess water needs to be removed from its solution in water, and it needs to be added as a solution in THF (similar to TBAF). The fluoride anion is suspected to act as a mild base for initial deprotonation of nitroarylacetate (pKa = 5.8). Notably, these conditions produced the nitronic ester rather than the aldehyde or ketone for phenylnitromethane or nitrodiphenyl methane.

Table 3.

Exploring Nef reaction conditions (eq 4).^a

entry	reagents	time (h)	conversionb (%)
1	TBAF, Mel, KF	1	31
2		2.25	>95
3	TBAF, KF	2	6
4		4	50
5	TBAF	2	6
6	TBAF, Mel	1	1
7		3	>74
8	KF	2	0
9	KF, Mel	2	0
10	TBAH, KF, Mel	2	>95

^aReaction conditions: 5 mol % TBAF (1M solution in THF), MeI (2.5 equiv), KF (12.5 equiv), THF (0.3M)

^bDetermined by ¹H NMR with respect an internal standard (mesitylene).

2-Aryl-2-nitroacetates are also precursors for α-amino acids³² and aryl acetic acids.³³ The generation of unnatural amino acids enables modification of molecular structures in medicinal chemistry.^34,35 For this reason, the synthesis of α-aryl-α-amino acids has been extensively studied.^36–40 2-Aryl-2-nitroacetates are sensitive to catalytic hydrogenation and usually give poor results.³ However, reduction of 2-aryl-2-nitroacetates using Zn⁰/AcOH (Table 4) proceeds well for electron-rich (entry 2), electron-poor (entry 6), and heteroaromatic (entry 4) substrates.

Table 4.

Reduction of 2-aryl-2-nitroacetates to α-amino esters (eq 5).^a

Entry	Product	Yield (%)
1		85
2		73
3		71
4		63
5		68
6		65

^aReaction conditions: Zinc dust (4 × 6 equiv added in 30 min intervals), AcOH (glacial, 0.2 M)

Reducing catalysts (Table 5), such as Raney nickel in the presence hydrogen (entry 8) also afforded good amounts of the amino ester 3, but isolated yields were lower than those in Table 4 due to competing cleavage of the benzylic nitro bond to form phenyl acetate 2.³³ With hydrogen (1 atm), a range of metal catalysts (palladium on carbon, rhodium on alumina, and platinum dioxide) provided mainly the phenyl acetate. Under certain conditions, the phenyl acetate could be produced quantitatively (eq 7). This method serves as an alternative entry to aryl acetates relative to the Arndt-Eistert rearrangement⁴¹ of the acid chloride formed from the corresponding benzoic acid, which is not viable on scale due to nitromethane, or a three-step sequence from the benzyl halide involving displacement with cyanide, cyanide hydrolysis, and esterification.⁴²

Table 5.

Identifying conditions for nitro group reduction (eq 6).

Entry	Reaction Conditions
1	NiCl2 • 6H2O, NaBH4, MeOH
2	Pt2O hydrate, H2 (1 atm), THF
3	Zn0, HCl, EtOH
4	Zn0, AcOH,EtOH
5	Rh/Al2O3, H2 (1 atm), EtOAc
6	Rh/Al2O3, H2 (1 atm), EtOH
7	Raney Nickel, H2 (1 atm), EtOH
8	Raney Nickel, H2 (10 atm), EtOH
9	Pd, H2 (1 atm), EtOH
10	Pd, H2 (1 atm), EtOAc
11	Lindlar's catalyst, H2 (1 atm), EtOAc
12	Fe0, AcOH, MeOH

^a

Determined by ¹H NMR.

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Conclusion

In summary, we have developed conditions for selective transformation of 2-aryl-2-nitroacetates to valuable precursors. Decarboxylation afforded aryl nitromethanes, disproportionation produced α-ketoesters, and reduction generated α-amino esters in good isolated yields.

Experimental Section

Formation of Aryl Nitromethanes

Method A

To a flask was added nitroarylacetate as a solution in EtOH (0.14 M) followed by an equal volume of 1 M aq NaOH. The mixture was stirred at 85 °C for 1 h at which point the reaction was cooled to rt and the solvents were removed in vacuo. To the remaining salts were added THF (0.17 M with respect to the nitroarylacetate) and an equal volume of aq HCl (1 M). The mixture was heated at 85 °C for 1 h. The reaction mixture was diluted with EtOAc (1 mL). The layers were separated and the water layer was extracted with EtOAc (3 × 1 mL), dried with NaSO₄, and concentrated in vacuo to yield a crude residue. The residue was chromatographed (2:98 to 5:95 EtOAc:hexanes) to afford the desired product.

Method B

To a flask was added nitroarylacetate as a solution in EtOH:toluene (1:1, 0.14 M) followed by an equal volume of 1 M aq NaOH. The mixture was stirred at 85 °C for 1 h at which point the reaction was cooled to rt and the solvents were removed in vacuo. To the remaining salts was added THF (0.17 M with respect to the nitroarylacetate) and urea (17 equiv as a 2.8 M solution in 20% aq AcOH) at 0 °C. The mixture was warmed to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc (1 mL). The layers were separated and the water layer was extracted with EtOAc (3 × 1 mL), dried with NaSO₄, and concentrated in vacuo to yield a crude residue. The residue was chromatographed (2:98 to 5:95 EtOAc:hexanes) to afford the desired product.

(Nitromethyl)benzene. (Table 1, entry 1) Method A of the general procedure was carried out on ethyl 2-nitro-2-phenylacetate (25.0 mg, 0.120 mmol). The title compound was obtained as a yellow oil (13.0 mg, 79%). The spectral data were in agreement with reported literature values.^{43 1}H NMR (500 MHz, CDCl₃) δ 7.47-7.45 (m, 5H), 5.46 (s, 2H).

1-(Nitromethyl)-4-(trifluoromethyl)benzene. (Table 1, entry 2) Method A of the general procedure was carried out on ethyl 2-nitro-2-(4-(trifluoromethyl)phenyl)acetate (30.0 mg, 0.108 mmol). The title compound was obtained as a yellow oil (21.7 mg, 98%). The spectral data were in agreement with reported literature values.^{8 1}H NMR (500 MHz, CDCl₃) δ 7.72 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 5.51 (s, 2H).

1-Methyl-4-(nitromethyl)benzene. (Table 1, entry 3) Method A of the general procedure was carried out on ethyl 2-nitro-2-(p-tolyl)acetate (43.7 mg, 0.200 mmol). The title compound was obtained as a yellow oil (24.2 mg, 79%). The spectral data were in agreement with reported literature values.^{44 1}H NMR (500 MHz, CDCl₃) δ 7.35 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.41 (s, 2H), 2.39 (s, 3H).

2-(Nitromethyl)naphthalene. (Table 1, entry 4) Method A of the general procedure was carried out on ethyl 2-(naphthalen-2-yl)-2-nitroacetate (21.8 mg, 0.080 mmol). The title compound was obtained as a white solid (15.4 mg, 98%). mp 83–84 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.94-7.88 (m, 4H), 7.58-7.55 (m, 3H), 5.62 (s, 2H);¹³C NMR (125 MHz, CDCl₃) δ133.9, 133.3, 130.3, 129.3, 128.5, 128.0, 127.5, 127.2, 127.1, 126.7, 80.5; IR (film) 3066, 2927, 2858, 1552, 1367 cm⁻¹; HRMS-CI (m/z): [M + H]⁺ calcd for C₁₁H₁₀NO₂, 188.0712; found, 188.0719.

1-(4-(Nitromethyl)phenyl)ethanone. (Table 1, entry 5) Method A of the general procedure was carried out on ethyl 2-(4-acetylphenyl)-2-nitroacetate (28.0 mg, 0.110 mmol). The title compound was obtained as a yellow oil (14.9 mg, 76%). ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 5.52 (s, 2H), 2.64 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 197.3, 138.3, 134.1, 130.4, 129.1, 79.5, 26.8; IR (film) 3059, 2966, 2927, 2858, 1684, 1552, 1367 cm⁻¹; HRMS-ESI (m/z): [M – H]⁻ calcd for C₉H₈NO₃,178.0504; found, 178.0503.

1-Methyl-5-(nitromethyl)-1H-indole. (Table 1, entry 6) Method B of the general procedure was carried out on ethyl 2-(1-methyl-1H-indol-5-yl)-2-nitroacetate (28.5 mg, 0.108 mmol). The title compound was obtained as white solid (15.4 mg, 77%). mp 64–66 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.73 (s, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 3.1, 1H), 6.53 (d, J = 3.1, 1H), 5.55 (s, 2H), 3.83 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 137.3, 130.3, 128.8, 123.4, 123.3, 121.0, 109.9, 101.7, 81.1, 33.1; IR (film) 2920, 1552, 1375 cm¹; HRMS-CI (m/z): [M – H]⁻ calcd for C₁₀H₉N₂O₂, 189.0664; found, 189.0661.

1-Methoxy-4-(nitromethyl)benzene. (Table 1, entry 7) Method B of the general procedure was carried out on ethyl 2-(4-methoxyphenyl)-2-nitroacetate (30.0 mg, 0.126 mmol). The title compound was obtained as a yellow oil (16.0 mg, 76%). The spectral data were in agreement with reported literature values.^{45 1}H NMR (500 MHz, CDCl₃) δ 7.39 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 5.38 (s, 2H), 3.84 (s, 3H).

2-Methoxy-6-(nitromethyl)naphthalene. (Table 1, entry 8) Method B of the general procedure was carried out on ethyl 2-(6-methoxynaphthalen-2-yl)-2-nitroacetate (30.0 mg, 0.100 mmol). The title compound was obtained as a white solid (19.5 mg, 90%). mp 66–71 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.86 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 8.7 Hz, 1H), 7.21 (dd, J = 2.1, 8.7 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 5.58 (s, 2H), 3.95 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 158.9, 135.3, 130.0, 129.8, 128.6, 127.9, 127.2, 124.9, 119.9, 105.8, 80.4, 55.5; IR (film) 2920, 1552, 1375, 1267 cm¹; HRMS-CI (m/z): [M – H]⁻ calcd for C₁₂H₁₀NO₃, 216.0661; found, 216.0675.

1-Methoxy-2-(nitromethyl)benzene. (Table 1, entry 9) Method B of the general procedure was carried out on ethyl 2-(2-methoxyphenyl)-2-nitroacetate (46.5 mg, 0.190 mmol). The title compound was obtained as a brown oil (27.9 mg, 88%). The spectral data were in agreement with reported literature values.^{46 1}H NMR (500 MHz, CDCl₃) δ 7.44 (ddd, J = 1.6, 7.5, 7.5 Hz, 1H), 7.31 (dd, J = 1.6, 7.5 Hz, 1H), 7.01 (dd, J = 7.5, 7.5 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 5.49 (s, 2H), 3.86 (s, 3H).

Formation of α-Keto Esters

To a flask under Ar was added nitroarylacetate as a solution in THF (0.3 M) followed by tetrabutylammonium fluoride (5 mol %, 1 M solution in THF at 0 °C) and KF (12.5 equiv). The reaction mixture was cooled to 0 °C and MeI (2.5 equiv) was added. The mixture was warmed to rt and stirred for 16 h at which point aq HCl (1 mL, 5 M) was added. The aqueous layer was extracted with Et₂O (3 × 2 mL), dried with NaSO₄, and concentrated in vacuo to yield a crude residue. The residue was chromatographed (2:98 to 5:95 EtOAc:hexanes) to afford the desired product.

Ethyl 2-oxo-2-phenylacetate. (Table 2, entry 1) The general procedure was employed with ethyl 2-nitro-2-phenylacetate (25.0 mg, 0.120 mmol). The title compound was obtained as a yellow oil (15.5 mg, 72%). The spectral data were in agreement with reported literature values.^{47 1}H NMR (500 MHz, CDCl₃) δ 8.02 (dd, J = 1.1, 8.0 Hz, 2H), 7.67 (td, J =1.1, 7.8 Hz, 1H), 7.53 (dd, J = 7.8, 7.8 Hz, 2H), 4.47 (q, J = 7.2, 2H), 1.44 (t, J = 7.2 Hz, 3H).

Ethyl 2-oxo-2-(4-(trifluoromethyl)phenyl)acetate. (Table 2, entry 2) The general procedure was employed with 2-nitro-2-(4-(trifluoromethyl)phenyl)acetate (30.0 mg, 0.108 mmol). The title compound was obtained as a yellow oil (22.9 mg, 86%). ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J = 8.3 Hz, 2H), 7.79 (d, J = 8.3 Hz, 2H), 4.48 (q, J = 7.1, 2H), 1.45 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 185.1, 162.9, 136.0 (q, J = 33 Hz), 135.4, 130.6, 126.0 (q, J = 3.6 Hz), 123.5 (q, J = 273.1 Hz), 62.9, 14.2; IR (film) 2989, 2943, 1738, 1699, 1174, 1128, 1066, 1012 cm⁻¹; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₁H₁₀F₃O₃, 247.0582; found, 247.0575.

Ethyl 2-oxo-2-(p-tolyl)acetate. (Table 2, entry 3) The general procedure was employed with ethyl 2-nitro-2-(p-tolyl)acetate (27.1 mg, 0.120 mmol). The title compound was obtained as a yellow oil (15.4 mg, 67%). The spectral data were in agreement with reported literature values.^{47 1}H NMR (500 MHz, CDCl₃) δ 7.92 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 4.45 (q, J = 7.2, 2H), 2.45 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

Ethyl 2-(naphthalen-2-yl)-2-oxoacetate. (Table 2, entry 4) The general procedure was employed with ethyl 2-(naphthalen-2-yl)-2-nitroacetate (21.3 mg, 0.084 mmol). The title compound was obtained as a yellow oil (14.0 mg, 74%). The spectral data were in agreement with reported literature values.^{47 1}H NMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 7.70-7.57 (m, 2H), 8.10-7.89 (m, 4H), 4.53 (q, J = 7.2 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H).

Ethyl 2-(4-acetylphenyl)-2-oxoacetate. (Table 2, entry 5) The general procedure was employed with ethyl 2-(4-acetylphenyl)-2-nitroacetate (28.0 mg, 0.110 mmol). The title compound was obtained as a yellow oil (12.2 mg, 51%). ¹H NMR (500 MHz, CDCl₃) δ 8.13 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 4.48 (q, J = 7.1, 2H), 2.67 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ197.4, 185.6, 163.2, 141.5, 135.8, 130.5, 128.7, 62.82, 27.1, 14.3; IR (film) 2920, 2966, 1738, 1684, 1197, 1081, 1012 cm⁻¹; HRMS-CI (m/z): [M + H]⁺ calcd for C₁₂H₁₃O₄, 221.0814; found, 221.0814.

Ethyl 2-(1-methyl-1H-indol-5-yl)-2-oxoacetate. (Table 2, entry 6) The general procedure was employed with ethyl 2-(1-methyl-1H-indol-5-yl)-2-nitroacetate (29.8 mg, 0.110 mmol). A phosphate buffer (pH = 7) was used instead of aq HCl. The title compound was obtained as a yellow oil (16.8 mg, 66%). ¹H NMR (500 MHz, CDCl₃) δ 8.32 (d, J = 1.6 Hz, 1H), 7.92 (dd, J = 1.6, 8.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 3.2 Hz, 1H), 6.64 (d, J = 3.2 Hz, 1H), 4.49 (q, J = 7.1, 2H), 3.84 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 186.9, 165.2, 140.2, 131.1, 128.2, 126.1, 124.6, 123.0, 109.9, 103.8, 62.1, 33.3, 14.3; IR (film) 2935, 1730, 1668, 1607, 1097, 1020 cm⁻¹; HRMS-ESI (m/z): [M + Na]⁺ calcd for C₁₃H₁₃NO₃Na, 254.0793; found, 254.0793.

Ethyl 2-(4-methoxyphenyl)-2-oxoacetate. (Table 2, entry 7) The general procedure was employed with ethyl 2-(4-methoxyphenyl)-2-nitroacetate (24.7 mg, 0.103 mmol). The title compound was obtained as a yellow oil (17.7 mg, 80%). The spectral data were in agreement with reported literature values.^{47 1}H NMR (500 MHz, CDCl₃) δ 8.01 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 3.80 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).

Ethyl 2-(6-methoxynaphthalen-2-yl)-2-oxoacetate. (Table 2, entry 8) The general procedure was employed with ethyl 2-(6-methoxynaphthalen-2-yl)-2-nitroacetate (30.0 mg, 0.100 mmol). The title compound was obtained as a yellow oil (18.0 mg, 70%). The spectral data were in agreement with reported literature values.^{48 1}H NMR (500 MHz, CDCl₃) δ 8.48 (s, 1H), 8.03 (dd, J =8.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 7.17 (s, 1H), 4.51 (q, J = 7.2 Hz, 2H), 3.97 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H).

Ethyl 2-(3-methoxyphenyl)-2-oxoacetate. (Table 2, entry 9) The general procedure was employed with ethyl 2-(3-methoxyphenyl)-2-nitroacetate (52.0 mg, 0.220 mmol). The title compound was obtained as a light red oil (26.8 mg, 59%). ¹H NMR (500 MHz, CDCl₃) δ 7.55 (ddd, J = 1.5, 1.5, 8.0 Hz, 1H), 7.51 (dd, J = 1.5, 2.5 Hz, 1H), 7.39 (dd, J = 8.0, 8.0 Hz, 1H), 7.19 (ddd, J = 1.5, 2.5, 8.0 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ186.5, 164.0, 160.1, 133.9, 130.1, 123.3, 122.0, 113.5, 62.5, 55.7, 14.3; IR (film) 2982, 2839, 1736, 1687, 1192, 1095, 1022, 878, 751, 680 cm⁻¹; HRMS-ESI (m/z): [M + Na]⁺ calcd for C₁₁H₁₂O₄Na, 231.0633; found, 231.0651.

Formation of α-Amino Esters

To a flask was added nitroarylacetate as a solution in glacial AcOH (1 mL). To this solution was added purified zinc dust (4 × 6 equiv in 30 min intervals). The heterogeneous mixture was vigorously stirred for 16 h at rt. At this point, the reaction was quenched with saturated aq K₂CO₃, extracted with EtOAc (3 × 2 mL), dried with NaSO₄, and concentrated in vacuo to yield a crude residue. The residue was chromatographed (100% EtOAc) to afford the desired product.

Ethyl 2-amino-2-phenylacetate. (Table 4, entry 1) The general procedure was employed with ethyl 2-nitro-2-phenylacetate (30.0 mg, 0.140 mmol). The title compound was obtained as a yellow oil (18.0 mg, 85%). The spectral data were in agreement with reported literature values.^{49 1}H NMR (360 MHz, CDCl₃) δ 7.42-7.28 (m, 5H), 4.60 (s, 1H) 4.25-4.09 (m, 2H), 2.04 (bs, 2H), 1.21 (t, J = 7.1 Hz, 3H).

Ethyl 2-amino-2-(4-methoxyphenyl)acetate. (Table 4, entry 2) The general procedure was employed with ethyl 2-(4-methoxyphenyl)-2-nitroacetate (30.0 mg, 0.125 mmol). The title compound was obtained as a yellow oil (19.2 mg, 85%). The spectral data were in agreement with reported literature values.^{50 1}H NMR (500 MHz, CDCl₃) δ 7.31 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.55 (s, 1H) 4.22-4.11 (m, 2H), 3.81 (s, 3H), 2.04 (bs, 2H), 1.21 (t, J = 7.1 Hz, 3H).

Ethyl 2-amino-2-(p-tolyl)acetate. (Table 4, entry 3) The general procedure was employed with ethyl 2-nitro-2-(p-tolyl)acetate (23.6 mg, 0.110 mmol). The title compound was obtained as a yellow oil (15.2 mg, 71%). ¹H NMR (500 MHz, CDCl₃) δ 7.31 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.57 (s, 1H) 4.24-4.10 (m, 2H), 2.38 (s, 3H), 2.03 (bs, 2H), 1.25 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 174.0, 138.0, 137.2, 129.6, 126.8, 61.5, 58.6, 21.2, 14.2; IR (film) 3383, 3313, 2981, 2927, 2866, 1730, 1097, 1020 cm⁻¹; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₁H₁₆NO₂, 194.1181; found, 194.1178.

Ethyl 2-amino-2-(benzofuran-5-yl)acetate. (Table 4, entry 4) The general procedure was employed with ethyl 2-(benzofuran-5-yl)-2-nitroacetate (22.9 mg, 0.092 mmol). The title compound was obtained as a yellow oily solid (12.7 mg, 63%). ¹H NMR (500 MHz, CDCl₃) δ 7.63 (d, J = 2.1 Hz, 1H), 7.62 (d, J = 1.3 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 1.7, 8.5 Hz, 1H), 6.76 (dd, J = 1.3, 2.1 Hz, 1H), 4.71 (s, 1H), 4.23-4.11 (m, 2H), 2.31 (bs, 2H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 174.1, 154.5, 145.6, 135.0, 127.7, 123.1, 119.4, 111.5, 106.6, 61.3, 58.7, 14.0 ; IR (film) 3383, 3313, 2981, 2927, 1730, 1112, 1027 cm⁻¹; HRMS-ESI (m/z): [M – NH₂]⁺ calcd for C₁₂H₁₁O₃, 203.0708; found, 203.0718.

Ethyl 2-amino-2-(naphthalen-2-yl)acetate. (Table 4, entry 5) The general procedure was employed with ethyl 2-(naphthalen-2-yl)-2-nitroacetate (35.1 mg, 0.135 mmol). The title compound was obtained as a yellow oil (21.0 mg, 68%). ¹H NMR (500 MHz, CDCl₃) δ 7.85-7.83 (m, 4H), 7.52-7.48 (m, 3H), 4.78 (s, 1H), 4.24-4.13 (m, 2H), 2.11 (bs, 2H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 174.1, 137.9, 133.5, 133.2, 128.7, 128.1, 127.8, 126.5, 126.3, 125.9, 124.8, 61.6, 59.1, 14.3; IR (film) 3375. 3313, 3059, 2981, 2927, 1730, 1097, 1020 cm⁻¹; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₄H₁₆NO₂, 230.1181; found, 230.1185.

Ethyl 2-amino-2-(4-chlorophenyl)acetate. (Table 4, entry 6) The general procedure was employed with ethyl 2-(4-chlorophenyl)-2-nitroacetate (56.0 mg, 0.230 mmol). The title compound was obtained as a yellow oil (32.2 mg, 65%). ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.31 (m, 4H), 5.30 (s, 1H), 4.58-4.10 (m, 2H), 2.04 (bs, 2H), 1.21 (t, J = 7.1 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 173.7, 139.0, 134.0, 129.0, 128.4, 61.6, 58.3, 14.2; IR (film) 3383, 2981, 1736, 1178, 1092, 1015, 831, 764 cm⁻¹; HRMS-ESI (m/z): [M + H]⁺ calcd for C₁₀H₁₃ClNO₂, 214.0635; found, 214.0634.