2-Aryl-2-nitroacetates as central precursors to aryl nitromethanes, α-ketoesters, and α-amino acids

Article abstract of DOI:10.1021/jo302071s

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

Full text of DOI:10.1021/jo302071s

Note
pubs.acs.org/joc
2‑Aryl-2-nitroacetates as Central Precursors to Aryl Nitromethanes,
α‑Ketoesters, and α‑Amino Acids
Alison E. Metz and Marisa C. Kozlowski*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323,
United States
S
* Supporting Information
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
competing benzyl nitrite formation or disproportionation of the
phenyl nitromethane product to generate aldehyde. Purification
is also difficult as these byproducts coelute 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 that enables the
direct coupling of nitromethane with aryl bromides.8
Scheme 1. 2-Aryl-2-nitroacetates as Central Precursors
Hydrolysis and decarboxylation conditions were initially
optimized for the formation of phenylnitromethane and
comprised 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).
On the other hand, electron-rich substrates were more prone
to the Nef reaction (Scheme 3)12,13 forming an aldehyde
byproduct. 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).
2-aryl-2-nitroacetates2,3 is best accomplished by our previously
reported cross-coupling between nitroacetates and aryl
bromides (eq 1).4 In this paper, 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).
For aryl nitromethanes, current approaches (Scheme 2), with
yields from 30 to 60%, produce multiple byproducts and
require arduous purification.5−7 Low yields are a result of
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.
Scheme 2. Reported Syntheses of Arylnitromethanes
Received: September 20, 2012
© XXXX American Chemical Society
A
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Note
Table 1. Decarboxylation To Form Arylnitromethanes
(eq 2)
Table 2. Disproportionation of 2-Aryl-2-nitroacetates
(eq 3)
a
a
a
Reaction conditions. Method A: (1) 1 M NaOH, EtOH (0.14 M), 85
a
°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.
Reaction conditions: TBAF (5 mol %, 1 M 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
Scheme 3. Formation of Arylnitromethanes Instead of
Aldehyde
a
Table 3. Exploring Nef Reaction Conditions (eq 4)
b
entry
reagents
time (h)
conversion (%)
1
2
TBAF, MeI, KF
1
31
>95
6
2.25
2
3
TBAF, KF
4
4
50
6
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 arylalkynes (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 conditions25−28 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%
5
TBAF
2
6
TBAF, MeI
1
1
7
3
>74
0
8
KF
2
9
KF, MeI
TBAH, KF, MeI
2
0
10
2
>95
a
Reaction conditions: 5 mol % of TBAF (1 M solution in THF), MeI
b
(2.5 equiv), KF (12.5 equiv), THF (0.3M). Determined by 1H NMR
with respect an internal standard (mesitylene).
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
28
1
conversion by H NMR to the α-ketoester after 24 h.
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.
B
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Note
than 10% of the desired product observed. Tetrabutylammo-
nium hydroxide (TBAH) is also sufficient for the trans-
formation (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
nitroaryl acetate (pKa = 5.8). Notably, these conditions
produced the nitronic ester rather than the aldehyde or ketone
for phenylnitromethane or nitrodiphenyl methane.
Table 5. Identifying Conditions for Nitro Group Reduction
(eq 6)
a
entry
reaction conditions
1:2:3
1
2
NiCl2·6H2O, NaBH4, MeOH
Pt2O hydrate, H2 (1 atm), THF
Zn0, HCl, EtOH
5:1:0
16:3:1
1:0:2
0:0:1
2:1:1
0:1:1
10:1:3
0:2:7
0:1:0
0:1:0
1:0:0
1:0:0
2-Aryl-2-nitroacetates are also precursors for α-amino acids32
and arylacetic 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.
3
4
Zn0, AcOH, EtOH
5
Rh/Al2O3, H2 (1 atm), EtOAc
Rh/Al2O3, H2 (1 atm), EtOH
Raney Nickel, H2 (1 atm), EtOH
Raney Nickel, H2 (10 atm), EtOH
Pd/C, H2 (1 atm), EtOH
6
7
8
9
10
11
12
Pd/C, H2 (1 atm), EtOAc
Lindlar’s catalyst, H2 (1 atm), EtOAc
Fe0, AcOH, MeOH
Table 4. Reduction of 2-Aryl-2-nitroacetates to α-Amino
a
1
a
Determined by H NMR.
Esters (eq 5)
EXPERIMENTAL SECTION
■
Formation of Aryl Nitromethanes. Method A. To a flask was
added nitroaryl acetate 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 nitroaryl acetate) 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.
a
Reaction conditions: zinc dust (4 × 6 equiv added in 30 min
intervals), AcOH (glacial, 0.2 M).
Method B. To a flask was added nitroaryl acetate 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 were added THF (0.17 M with respect to the
nitroaryl acetate) 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.
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
(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 1H 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 1H 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 1H 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).
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 diazomethane, or a three-
step sequence from the benzyl halide involving displacement
with cyanide, cyanide hydrolysis, and esterification.42
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.
C
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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) δ 133.9, 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 1H 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).
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 1H 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 1H 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
1
as a yellow oil (12.2 mg, 51%): H 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 1H 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 1H
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,
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−
1
71 °C; H 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 cm−1; 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 1H 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
nitroaryl acetate 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 1H NMR (500 MHz, CDCl3) δ 8.02 (dd, J = 1.1,
D
dx.doi.org/10.1021/jo302071s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: marisa@sas.upenn.edu.
Formation of α-Amino Esters. To a flask was added nitroaryl
acetate 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 1H 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 1H 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).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NIH (RO1GM087605) for financial
support. Partial instrumentation support was provided by the
NIH for MS (1S10RR023444) and NMR (1S10RR022442).
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