Transition-metal-free decarboxylation of dimethyl malonate: An efficient construction of α-amino acid esters using TBAI/TBHP

Article abstract of DOI:10.1039/c5ob00109a

A transition-metal-free decarboxylation coupling process for the preparation of α-amino acid esters, which succeeded in merging hydrolysis/decarboxylation/nucleophilic substitution, is well described. This strategy uses commercially available inexpensive starting materials, catalysts and oxidants and has a wide substrate scope and operational simplicity. This journal is

Full text of DOI:10.1039/c5ob00109a

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Transition-metal-free decarboxylation of dimethyl
malonate: an efficient construction of α-amino acid
esters using TBAI/TBHP
Cite this: DOI: 10.1039/x0xx00000x
Jie Zhang,a Ying Shao,*b Yaxiong Wang,a Huihuang Li,a Dongmei Xu,*a and
Xiaobing Wan*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A transition-metal-free decarboxylation coupling process for the preparation of α-amino acid
esters, which succeeded in merging hydrolysis/decarboxylation/nucleophilic substitution, is
well described. This strategy uses commercially available inexpensive starting materials,
catalysts and oxidants and has a wide substrate scope and operational simplicity.
www.rsc.org/
Table 1 Optimization of reaction conditionsa
Introduction
O
H
N
O
O
OMe
Catalyst, Oxidant
90 oC, 12 h
The decarboxylative functionalizations have been developed as a
powerful strategy to construct new molecular skeletons.1 During the
course of the past decade, the impressive field has attracted
considerable attention and been studied systematically by a variety
of groups, such as those of Gooßen,2 Myers,3 Tunge,4 and others,5
thus providing many new opportunities for the convenient
construction of carbon–carbon or carbon–heteroatom bonds. Related
to conventional carboxylic acids as coupling reagents, ester was also
an ideal alternative because of its availability, solubility and
neutrality. Since the pioneering work from the groups of Tsuji6a and
Saegusa6b in the beginning of the 1980s, the palladium-catalyzed
decarboxylative allylic alkylation reaction of allylic ester has been
extensively applied to construct C‒C in organic synthesis.1b,4,6
However, other common esters were rarely employed as substrates
in decarboxylative reaction.7
N
MeO
OMe
3a
1a
2a
Yieldb (%)
Entry
Oxidant
Catalyst
TBAI
1
2
86
34
TBHP
H2O2
TBAI
3
4
5
6
TBAI
TBAI
N.D.c
N.D.
N.D.
N.D.
Oxone
O2
TBAI
DTBP
TBHP
n-Bu4NCl
7
8
n-Bu
4NBr
N.D.
69
TBHP
TBHP
KI
TBAI
9
N.D.
N.D.
10
TBHP
a0.5 mmol 1a, 7.5 mmol of dimethyl malonate 2a, 20 mol%
catalyst, 2.9 equiv oxidant in 1.0 mL MeCN and 1.0 mL H2O at
90 oC for 12 h.
bIsolated yield.
cNot detected.
Scheme 1 Our design to construct α-amino acid esters.
α-Amino acids and their derivatives are of great importance in
the areas of chemical, biochemical, and material science and
great endeavors have been devoted to the synthesis of these
compounds.8 The nucleophilic substitution of amines to α-
halogenated esters constitutes the conventional approach to this
ubiquitous molecules.9 Unfortunately, this method suffered
from the generation of stoichiometric halide waste. Recently,
we reported a new process for the preparation of α-amino acid
esters from amines and monomethyl malonate using Bu4NI as
We started our investigations by examining the oxidative
decarboxylation coupling reaction between N-methylaniline 1a and
dimethyl malonate 2a for this C‒N formation reaction. Following
extensive screenings, we found that the combination of Bu4NI (20
mol%) and tBuOOH (2.9 equiv, 70% aqueous solution) in
H2O/MeCN at 90 °C for 12 h afforded the desired product 3a in the
best yield of up to 86% (Table 1, entry 1). In the case of 30%
aqueous H2O2 chosen as the oxidant, the yield of 3a dropped from
86% to 34% (Table 1, entry 2). Other oxidants such as oxone,
molecular oxygen, and di-tert-butyl peroxide (DTBP) were also
examined and the reaction did not proceed smoothly (Table 1,
entries 3-5). Replacing Bu4NI with either Bu4NCl or Bu4NBr halted
the formation of compound 3a (Table 1, entries 6-7). Further
t
the catalyst and BuOOH as the oxidant,10 including sequential
iodination, decarboxylation, and nucleophilic substitution
reactions.11 Combining hydrolysis reactions of dimethyl
malonate and subsequent decarboxylation, we herein envision a
transition-metal-free entry to α-amino acid esters under mild
conditions (Scheme 1).
t
investigations indicated that both Bu4NI and BuOOH are crucial to
the efficient conversion and the reaction could not work in the
absence of Bu4NI or BuOOH (Table 1, entries 9-10). In addition, a
t
Results and discussion
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comparable yield was obtained when KI was used as the catalyst with ortho, meta or para substitutents on the aromatic ring could be
(Table 1, entry 8). Interestingly, compared to our previous work,11 converted to corresponding amino acid esters in moderate to good
base was unnecessary for the present transformation.
yields. Other N-alkyl substituted aromatic amines were also found to
be the effective reaction partners (products 3k-3q). A variety of
functional groups, such as alkoxyl (products 3b and 3e), alkyl
(products 3f, 3h and 3j), halide (products 3c, 3d and 3g), benzyl
(product 3k), and allyl (product 3p) group were tolerated under the
optimized conditions. It is noteworthy that aromatic amines bearing
electron-donating groups were found to give better results than those
with electron-withdrawing groups, presumably owing to the better
nucleophilicity. As a result, only trace amount of product 3i was
detected when 4-(methylamino)benzonitrile was subjected to this
reaction. To our delight, two secondary aliphatic amines were also
suitable reaction partners for this transformation and the
corresponding products 3r and 3s were furnished in moderate yields
under slightly modified conditions.
Table 2 Scope of secondary aminesa
20 mol % TBAI
R1
N
O
O
O
H
2.9 equiv TBHP
N
R1
R2
+
R2
OMe
MeO
OMe
H2O/MeCN, 90 o
C
3
1
2a
OMe
F
Cl
MeO
N
O
N
O
N
O
N
O
OMe
OMe
OMe
OMe
3b, yield: 81%
3d, yield: 72%
3c, yield: 53%
3e, yield: 84%
N
O
N
O
Cl
N
O
OMe
NC
N
O
To further explore the potential of the methodology, some selected
primary aromatic amines had also been employed as substrates, and
moderate results could be achieved when switching the solvent to
H2O/EA system (Table 3, 5a-5e).
OMe
OMe
OMe
3g, yield: 84%
3h, yield: 65%
3f, yield:77%
3i, yield: trace
Ph
Table 4 Scope of tertiary aromatic aminesa
N
O
N
O
N
O
N
O
OMe
OMe
OMe
OMe
3m, yield: 82%
3l, yield: 80%
3k, yield: 41%
3j, yield: 81%
N
N
O
N
O
N
O
OMe
O
OMe
OMe
OMe
3o, yield: 77%
3n, yield: 71%
3p, yield: 41%
3q, yield: 62%
OMe
OMe
N
N
N
O
N
O
N
3r, yield: 47%b
3s, yield: 47%b
aAll the reactions were carried out in 1.0 mL of MeCN and 1.0
mL of H2O, using 0.5 mmol of , 7.5 mmol of dimethyl
1
malonate 2a, 20 mol% of TBAI and 2.9 equiv of TBHP at 90
oC for 12 h.
t
b0.5 mL of BuOH and 1.5 mL of H2O were used as solvent at
aAll the reactions were carried out in 2.0mL of H2O, using 7.5
mmol of dimethyl malonate 2a, 0.5 mmol of 6, 20 mol% of
TBAI and 4.4 equiv of TBHP at 90 oC for 12 h.
80 oC.
Table 3 Scope of primary aromatic aminesa
In 1988, Murahashi and co-workers reported the pioneering
work of the transition-metal catalyzed N-dealkylation of tertiary
amines under oxidative conditions.12a However, further
transformation via dealkylation of tertiary amines was sparsely
reported. Li et al. recently demonstrated an iron catalyzed
amide formation by oxidative amidation between tertiary amine
and aldehyde.12b Continuing our study,11d we envisaged that the
tertiary amines could undergo a dealkylation process to
generate the secondary amines in situ, which subsequently
reacts with dimethyl malonate 2a to afford the desired product.
Then, N, N-dimethylaniline 6a was chosen as the source of
secondary amines, and to our delight, 3a could be isolated.
R1
HN
O
20 mol % TBAI
O
O
2.9 equiv TBHP
R1 NH2
+
OMe
MeO
OMe
H2O/EA, 80 o
C
5
4
2a
O
O
O
H
H
H
N
N
N
OMe
OMe
OMe
Cl
5c, R = Cl, yield: 60%
5b, R = Me, yield: 41%
5a, R = H, yield: 45%
O
O
H
H
N
N
OMe
OMe
t
OMe
When the amounts of BuOOH was incresaed to 4.4 equiv and
Br
H2O was used as the only solvent, a 55% yield was obtained
(Table 4, product 3a). The similar results could also be
achieved using other substituted N, N-dimethylanilines (Table
4).
5d, yield: 47%
5e, yield: 64%
aAll the reactions were carried out in 1.0 mL of ethyl acetate
(EA) and 1.0 mL of H2O, using 0.5 mmol of , 7.5 mmol of
4
dimethyl malonate 2a, 20 mol% of TBAI and 2.9 equiv of
TBHP at 80 oC for 12 h.
With the optimized conditions identified, a series of amines were
applied to this methodology as shown in Table 2. N-Methylanilines
2 | J. Name., 2012, 00, 1-3
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In summary, we have developed a transition-metal-free process
When diethyl malonate 2b was used as the reaction partner, for the synthesis of α-amino acid esters through a tandem
the corresponding product was given in lower yield compared Bu4NI-catalyzed hydrolysis/decarboxylation/nucleophlic
with dimethyl malonate 2a, presumably owing to the relative substitution. The advantages of this protocol include a wide
8
stability of diethyl malonate in hydrolysis (eq 1).
range of substrates, high practical convenience, and
commercially available materials. Compared to our previous
report, base was not necessary at all. Notably, the more
accessible and more stable dimethyl malonate, instead of
monomethyl malonate, were used as substrate and tertiary
amines were also adaptable substrates for this protocol via a C‒
N cleavage under mild conditions. Generally, we believe that
this method provides a promising complementary access to
previous methodologies.
Experimental
All manipulations were carried out under air atmosphere.
Column chromatography was generally performed on silica gel
(300-400 mesh) and reactions were monitored by thin layer
chromatography (TLC) using UV light to visualize the course
1
of the reactions. The H (300MHz or 400MHz) and 13C NMR
(75MHz or 100MHz) data were recorded using CDCl3 as
Scheme 2 Proposed catalytic cycle.
solvent. The chemical shifts (δ) are reported in ppm and
1
coupling constants (J) in Hz. H NMR spectra was recorded
with tetramethylsilane (δ= 0.00 ppm) as internal reference; 13C
NMR spectra was recorded with CDCl3 (δ = 77.00 ppm) as
internal reference.
General procedure for amines 1a-1q as substrates
Amine (0.5 mmol), dimethyl malonate (7.5 mmol), Bu4NI (0.1
mmol, 20 mol %), TBHP (1.45 mmol), 1.0 mL of MeCN and
1.0 mL of H2O were added to a test tube under air. The reaction
o
mixture was heated in an oil bath at 90 C for 12 h. It was then
quenched with saturated Na2SO3 solution (removal of excess
TBHP) and extracted with ethyl acetate. The organic layer was
combined and removed under vacuum followed by flash silica
gel column chromatographic purification using a mixture of
petroleum ether and ethyl acetate afforded the desired product.
Scheme 3 Investigations on mechanism.
Next,
transformation as depicted in Scheme 2. Initially, I- was
oxidized to hypoiodite
in the presence of TBHP,11,10d,10g-h, 10n
followed by the iodination of 3-methoxy-3-oxopropanoic acid
generated in situ from the hydrolysis of dimethyl malonate to
give the intermediate . Then, the intermediate could form
iodoacetate via decarboxylation. Finally, the desired α-amino
acids ester was delivered through the classic nucleophilic
substitution of amine to
with the release of I-.
a plausible mechanism was proposed for the
General procedures for amines 1r-1s as substrates
A
Amine (0.5 mmol), dimethyl malonate (7.5 mmol), Bu4NI (0.1
B
t
mmol, 20 mol %), TBHP (1.45 mmol), 0.5 mL of BuOH and
C
C
1.5 mL of H2O were added to a test tube under air. The reaction
D
o
mixture was heated in an oil bath at 80 C for 12 h. It was then
quenched with saturated Na2SO3 solution (removal of excess
TBHP) and extracted with ethyl acetate. The organic layer was
combined and removed under vacuum followed by flash silica
gel column chromatographic purification using a mixture of
petroleum ether and ethyl acetate afforded the desired product.
D
Some mechanistic experiments were conducted to better
understand this α-amino acid esters formation reaction (Scheme
3). The use of 2.2 equiv I2 and 4 equiv Bu4NOH10d,10g,10h,10n
resulted in the desired product 3a in 54% yield (Scheme 3a),
which suggested that hypoiodite generated in situ might be the
key catalytic species. To find out whether the hydrolysis of
dimethyl malonate played an important role in this reaction, we
removed the water from the model reaction using anhydrous
TBHP (5-6 M in decane) and MeCN as sole solvent (Scheme
3b). As expected, the desired product 3a could not be detected.
General procedures for amines 4a-4e as substrates
Amine (0.5 mmol), dimethyl malonate (7.5 mmol), Bu4NI (0.1
mmol, 20 mol %), TBHP (1.45 mmol), 1.0 mL of ethyl acetate
(EA) and 1.0 mL of H2O were added to a test tube under air.
o
The reaction mixture was heated in an oil bath at 80 C for 12 h.
It was then quenched with saturated Na2SO3 solution (removal
of excess TBHP) and extracted with ethyl acetate. The organic
layer was combined and removed under vacuum followed by
flash silica gel column chromatographic purification using a
mixture of petroleum ether and ethyl acetate afforded the
desired product.
Notably, when compound
9 was subjected to the standard
conditions, no desired product 3a was isolated, thus excluding
the possibility of 9 as reaction intermediate (Scheme 3c).
Conclusions
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129.7, 126.5, 112.5, 54.5, 51.7, 39.5, 20.2; MS (ESI): Anal.
Calcd. For C11H16NO2: 194, Found: 194 (M+H+); IR (KBr, cm-
General procedures for tertiary amines as substrates
Amine (0.5 mmol), dimethyl malonate (7.5 mmol), Bu4NI (0.1 1): υ 1748, 1619, 1522, 1199.
mmol, 20 mol %), TBHP (2.2 mmol), 2.0 mL of H2O were Methyl N-ethyl-N-(m-tolyl)glycinate (3j).11 Colorless liquid
1
added to a test tube under air. The reaction mixture was heated (84 mg, 81% yield); H NMR (300 MHz, CDCl3): δ 7.12 - 7.06
o
in an oil bath at 90 C for 12 h. It was then quenched with (m, 1H), 6.55 - 6.52 (m, 1H), 6.45 - 6.43 (m, 2H), 4.00 (s, 2H),
saturated Na2SO3 solution (removal of excess TBHP) and 3.71 (s, 3H), 3.47 - 3.40 (m, 2H), 2.29 (s, 3H), 1.19 (t, J = 7.5
extracted with ethyl acetate. The organic layer was combined Hz, 3H); MS (ESI): Anal. Calcd. For C12H18NO2 (M+H+): 208,
and removed under vacuum followed by flash silica gel column Found: 208; The data was in accordance with our previous
chromatographic purification using a mixture of petroleum report.
ether and ethyl acetate afforded the desired product.
Methyl N-benzyl-N-phenylglycinate (3k).11 Colorless liquid
(52 mg, 41% yield); H NMR (400 MHz, CDCl3): δ 7.32 - 7.18
1
Methyl N-methyl-N-phenylglycinate (3a).11 Colorless liquid (m, 7H), 6.76 - 6.67 (m, 3H), 4.64 (s, 2H), 4.08 (s, 2H), 3.72 (s,
(77 mg, 86% yield for amine 1a; 49 mg, 55% yield for amine 3H); MS (ESI): Anal. Calcd. For C16H18NO2 (M+H+): 256,
1
6a); H NMR (300 MHz, CDCl3): δ 7.24 - 7.19 (m, 2H), 6.76 - Found: 256; The data was in accordance with our previous
6.65 (m, 3H), 4.04 (s, 2H), 3.68 (s, 3H), 3.03 (s, 3H); MS (ESI): report.
Anal. Calcd. For C10H14NO2: 180, Found: 180(M+H+); The Methyl N-butyl-N-phenylglycinate (3l).11 Colorless liquid (89
data was in accordance with our previous report.
mg, 80% yield); 1H NMR (400 MHz, CDCl3): δ 7.21 - 7.17 (m,
Methyl N-(2-methoxyphenyl)-N-methylglycinate (3b).11 2H), 6.71 - 6.67 (m, 1H), 6.63 - 6.60 (m, 2H), 4.01 (s, 2H), 3.70
Colorless liquid (85 mg, 81% yield); 1H NMR (400 MHz, (s, 3H), 3.36 (t, J= 8.0 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.40 - 1.31
CDCl3): δ 7.02 - 7.00 (m, 1H), 6.96 - 6.88 (m, 2H), 6.83 - 6.81 (m, 2H), 0.95 (t, J= 8.0 Hz, 3H); MS (ESI): Anal. Calcd. For
(m, 1H), 4.00 (s, 2H), 3.82 (s, 3H), 3.66 (s, 3H), 2.96 (s, 3H); C13H20NO2 (M+H+): 222, Found: 222; The data was in
MS (ESI): Anal. Calcd. For C11H16NO3 (M+H+): 210, Found: accordance with our previous report.
210; The data was in accordance with our previous report.
Methyl N-(2-fluorophenyl)-N-methylglycinate
Methyl N-ethyl-N-phenylglycinate (3m).11 Colorless liquid
1
(3c).11 (79 mg, 82% yield); H NMR (300 MHz, CDCl3): δ 7.23 - 7.18
Colorless liquid (52 mg, 53% yield); 1H NMR (400 MHz, (m, 2H), 6.73 - 6.62 (m, 3H), 4.01 (s, 2H), 3.71 (s, 3H), 3.49 -
CDCl3): δ 7.04 - 6.91 (m, 3H), 6.85 - 6.79 (m, 1H), 4.02 (s, 3.42 (m, 2H), 1.19 (t, J = 6.0 Hz, 3H); MS (ESI): Anal. Calcd.
2H), 3.67 (s, 3H), 2.98 (s, 3H); MS (ESI): Anal. Calcd. For For C11H16NO2 (M+H+): 194, Found: 194; The data was in
C10H13FNO2 (M+H+): 198, Found: 198; The data was in accordance with our previous report.
accordance with our previous report.
Methyl N-(3-chlorophenyl)-N-methylglycinate
Methyl N-isopropyl-N-phenylglycinate (3n).11 Colorless
1
(3d).11 liquid (73 mg, 71% yield); H NMR (400 MHz, CDCl3): δ 7.23
Colorless liquid (77 mg, 72% yield for amine 1d; 57 mg, 53% - 7.19 (m, 2H), 6.73 - 6.66 (m, 3H), 4.19 - 4.12 (m, 1H), 3.93 (s,
1
yield for amine 6c); H NMR (400 MHz, CDCl3): δ 7.13 - 7.09 2H), 3.73 (s, 3H), 1.19 (d, J = 8.0 Hz, 6H); MS (ESI): Anal.
(m, 1H), 6.71 - 6.64 (m, 2H), 6.53 - 6.50 (m, 1H), 4.03 (s, 2H), Calcd. For C12H18NO2 (M+H+): 208, Found: 208; The data was
3.71 (s, 3H), 3.02 (s, 3H); MS (ESI): Anal. Calcd. For in accordance with our previous report.
C10H1335ClNO2 (M+H+): 214, Found: 214; For C10H1337ClNO2 Methyl N-cyclohexyl-N-phenylglycinate (3o).11 Colorless
1
(M+H+): 216, Found: 216; The data was in accordance with our liquid (95 mg, 77% yield); H NMR (400 MHz, CDCl3): δ 7.21
previous report.
- 7.17 (m, 2H), 6.71 - 6.64 (m, 3H), 3.96 (s, 2H), 3.71 - 3.62 (m,
4H), 1.94-1.67 (m, 5H), 1.43-1.08 (m, 5H); MS (ESI): Anal.
Methyl
N-(3-methoxyphenyl)-N-methylglycinate
(3e).
Colorless liquid (88 mg, 84% yield); 1H NMR (400 MHz, Calcd. For C15H22NO2 (M+H+): 248, Found: 248; The data was
CDCl3): δ 7.14 - 7.10 (m, 1H), 6.32 - 6.22 (m, 3H), 4.03 (s, 2H), in accordance with our previous report.
3.76 (s, 3H), 3.69 (s, 3H), 3.03 (s, 3H); 13C NMR (100 MHz, Methyl N-allyl-N-phenylglycinate (3p).11 Colorless liquid (42
CDCl3): δ 171.3, 160.6, 150.1, 129.8, 105.2, 102.0, 98.9, 54.9, mg, 41% yield); 1H NMR (400 MHz, CDCl3): δ 7.22 - 7.18 (m,
54.2, 51.7, 39.4; MS (ESI): Anal. Calcd. For C11H16NO3: 210, 2H), 6.74 - 6.64 (m, 3H), 5.92 - 5.83 (m, 1H), 5.25 - 5.15 (m,
Found: 210 (M+H+); IR (KBr, cm-1): υ 1750, 1613, 1502, 1201. 2H), 4.02 - 4.00 (m, 4H), 3.71 (s, 3H); MS (ESI): Anal. Calcd.
Methyl N-methyl-N-(m-tolyl)glycinate (3f). Colorless liquid For C12H16NO2 (M+H+): 206, Found: 206; The data was in
(74 mg, 77% yield for amine 1f, 50 mg, 52% yield for amine accordance with our previous report.
1
6c); H NMR (400 MHz, CDCl3): δ 7.13 - 7.09 (m, 1H), 6.58 - Methyl
2-(3,4-dihydroquinolin-1(2H)-yl)acetate
(3q).11
6.56 (m, 1H), 6.50 - 6.47 (m, 2H), 4.04 (s, 2H), 3.70 (s, 3H), Colorless liquid (64 mg, 62% yield); 1H NMR (400 MHz,
3.03 (s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ CDCl3): δ 7.03 - 6.95 (m, 2H), 6.63 - 6.59 (m, 1H), 6.40 - 6.38
171.5, 148.8, 138.8, 129.0, 118.3, 113.0, 109.4, 54.3, 51.8, 39.4, (m, 1H), 3.99 (s, 2H), 3.70 (s, 3H), 3.38 (t, J = 6.0 Hz, 2H),
21.8; MS (ESI): Anal. Calcd. For C11H16NO2: 194, Found: 194 2.78 (t, J = 6.0 Hz, 2H), 2.01 - 1.95 (m, 2H); MS (ESI): Anal.
(M+H+); IR (KBr, cm-1): υ 1750, 1605, 1499, 1202.
Calcd. For C12H16NO2 (M+H+): 206, Found: 206; The data was
Methyl
N-(4-chlorophenyl)-N-methylglycinate
(3g).11 in accordance with our previous report.
Colorless liquid (90 mg, 84% yield); 1H NMR (300 MHz, Methyl 2-(4-phenylpiperazin-1-yl)acetate (3r). Colorless
1
CDCl3): δ 7.17 - 7.14 (m, 2H), 6.60 - 6.57 (m, 2H), 4.03 (s, 2H), liquid (55 mg, 47% yield); H NMR (400 MHz, CDCl3): δ 7.28
3.70 (s, 3H), 3.02 (s, 3H); MS (ESI): Anal. Calcd. For - 7.24 (m, 2H), 6.94 - 6.92 (m, 2H), 6.88 - 6.84 (m, 1H), 3.74 (s,
C10H1335ClNO2 (M+H+): 214, Found: 214; For C10H1337ClNO2 3H), 3.29 (s, 2H), 3.25 (t, J = 5.0 Hz, 4H), 2.74 (t, J = 5.0 Hz,
(M+H+): 216, Found: 216; The data was in accordance with our 4H); 13C NMR (100 MHz, CDCl3): δ 170.5, 151.1, 129.0, 119.8,
previous report.
116.1, 59.3, 53.0, 51.7, 48.9; MS (ESI): Anal. Calcd. For
Methyl N-methyl-N-(p-tolyl)glycinate (3h). Colorless liquid C13H19N2O2: 235, Found: 235 (M+H+); IR (KBr, cm-1): υ 1750,
1
(63 mg, 65% yield); H NMR (300 MHz, CDCl3): δ 7.04 - 7.01 1600, 1502, 1202.
(m, 2H), 6.62 - 6.59 (m, 2H), 4.03 (s, 2H), 3.68 (s, 3H), 3.01 (s, Methyl
2-(4-(pyridin-2-yl)piperazin-1-yl)acetate
(3s).11
3H), 2.23 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 171.6, 146.7, Colorless liquid (55 mg, 47% yield); 1H NMR (400 MHz,
4 | J. Name., 2012, 00, 1-3
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ARTICLE
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of
Chemistry, Chemical Engineering and Materials Science, Soochow
University, 199 Renai Road, 215123 Suzhou, China. Fax: (+86) 512-6588-
CDCl3): δ 8.19 - 8.18 (m, 1H), 7.50 - 7.46 (m, 1H), 6.66 - 6.61
(m, 2H), 3.74 (s, 3H), 3.60 (t, J = 5.0 Hz, 4H), 3.28 (s, 2H),
2.69 (t, J = 5.0 Hz, 4H); MS (ESI): Anal. Calcd. For
C12H18N3O2 (M+H+) : 236, Found: 236; The data was in
accordance with our previous report.
0334;
wanxb@suda.edu.cn
bKey Laboratory of Advanced Catalytic Materials and Technology,
Changzhou University, Changzhou 213164, China. E-mail:
shaoying810724@163.com
Tel:
(+86)
512-6588-0334;
E-mail:
xdm.sd@163.com,
Methyl phenylglycinate (5a).11 Colorless liquid (37 mg, 45%
yield); 1H NMR (400 MHz, CDCl3): δ 7.24 - 7.17 (m, 2H), 6.77
- 6.59 (m, 3H), 3.90 (s, 2H), 3.77 (s, 3H); MS (ESI): Anal.
Calcd. For C9H12NO2 (M+H+): 166, Found: 166; The data was
in accordance with our previous report.
†Electronic Supplementary Information (ESI) available: Experimental
data and spectra of compounds. See DOI: 10.1039/b000000x
Methyl p-tolylglycinate (5b).11 Colorless liquid (37 mg, 41%
yield); 1H NMR (400 MHz, CDCl3): δ 7.01 - 6.99 (m, 2H), 6.54
- 6.52 (m, 2H), 3.88 (s, 2H), 3.76 (s, 3H), 2.23 (s, 3H); MS
(ESI): Anal. Calcd. For C10H14NO2 (M+H+): 180, Found: 180;
The data was in accordance with our previous report.
1
2
For reviews on this topic, see: (a) N. Rodríguez and L. J. Goossen,
Chem. Soc. Rev., 2011, 40, 5030; (b) J. D. Weaver, A. Recio, III, A.
J. Grenning and J. A. Tunge, Chem. Rev., 2011, 111, 1846.
(a) L. J. Gooßen, G. Deng and L. M. Levy, Science, 2006, 313, 662;
(b) S. Bhadra, W. I. Dzik and L. J. Goossen, J. Am. Chem. Soc.,
2012, 134, 9938; (c) S. Bhadra, W. I. Dzik and L. J. Gooßen, Angew.
Chem. Int. Ed., 2013, 52, 2959.
Methyl (4-chlorophenyl)glycinate (5c).11 Colorless liquid (60
mg, 60% yield); 1H NMR (400 MHz, CDCl3): δ 7.14 - 7.11 (m,
2H), 6.52 - 6.50 (m, 2H), 4.31 (s, 1H), 3.87 (s, 2H), 3.77 (s, 3H);
MS (ESI): Anal. Calcd. For C9H1135ClNO2 (M+1+): 200, Found:
200; For C9H1137ClNO2 (M+H+): 202, Found: 202; The data
was in accordance with our previous report.
3
4
5
(a) A. G. Myers, D. Tanaka and M. R. Mannion, J. Am. Chem. Soc.,
2002, 124, 11250; (b) D. Tanaka and A. G. Myers, Org. Lett., 2004, 6,
433; (c) D. Tanaka, S. P. Romeril and A. G. Myers, J. Am. Chem.
Soc., 2005, 127, 10323.
Methyl (4-bromophenyl)glycinate (5d).11 Colorless liquid (57
mg, 47% yield); 1H NMR (400 MHz, CDCl3): δ 7.27 - 7.25 (m,
2H), 6.48 - 6.46 (m, 2H), 4.31 (s, 1H), 3.86 (s, 2H), 3.77 (s, 3H);
MS (ESI): Anal. Calcd. For C9H1179BrNO2 (M+1+): 244, Found:
244; For C9H1181BrNO2 (M+H+): 246, Found: 246; The data
was in accordance with our previous report.
(a) E. C. Burger and J. A. Tunge, J. Am. Chem. Soc., 2006, 128,
10002; (b) R. Jana, J. J. Partridge and J. A. Tunge, Angew. Chem., Int.
Ed., 2011, 50, 5157; (c) S. B. Lang, K. M. O’Nele and J. A. Tunge, J.
Am. Chem. Soc., 2014, 136, 13606.
Methyl (2-methoxyphenyl)glycinate (5e).11 Colorless liquid
1
(62 mg, 64% yield); H NMR (400 MHz, CDCl3): δ 6.87 - 6.69
(m, 3H), 6.48 - 6.46 (m, 1H), 3.92 (s, 2H), 3.84 (s, 3H), 3.75 (s,
3H); MS (ESI): Anal. Calcd. For C10H14NO3 (M+H+): 196,
Found: 196; The data was in accordance with our previous
report.
Some recent examples reported by others, see: (a) P. Hu, M. Zhang,
X. Jie and W. Su, Angew. Chem. Int. Ed., 2012, 51, 227; (b) A. Shard,
N. Sharma, R. Bharti, S. Dadhwal, R. Kumar and A. K. Sinha, Angew.
Chem. Int. Ed., 2012, 51, 12250; (c) D. L. Priebbenow, P. Becker and
C. Bolm, Org. Lett., 2013, 15, 6155; (d) Y. Singjunla, J. Baudoux and
J. Rouden, Org. Lett., 2013, 15, 5770; (e) L. Chu, C. Ohta, Z. Zuo
and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136, 10886; (f) P.
Klahn, H. Erhardt, A. Kotthaus and S. F. Kirsch, Angew. Chem. Int.
Ed., 2014, 53, 7913; (g) H.-X. Zhang, J. Nie, H. Cai and J.-A. Ma,
Org. Lett., 2014, 16, 2542; (h) C. Li and B. Breit, J. Am. Chem. Soc.,
2014, 136, 862.
Methyl N-methyl-N-(o-tolyl)glycinate (7a). Colorless liquid
1
(54 mg, 56% yield); H NMR (400 MHz, CDCl3): δ 7.16 - 7.08
(m, 3H), 6.97 - 6.93 (m, 1H), 3.73 (s, 2H), 3.69 (s, 3H), 2.86 (s,
3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 171.4, 150.6,
132.0, 131.2, 126.3, 123.0, 120.1, 57.2, 51.5, 41.4, 18.3; MS
(ESI): Anal. Calcd. For C11H16NO2: 194, Found: 194 (M+H+);
IR (KBr, cm-1): υ 1755, 1600, 1494, 1201.
Methyl
N-(4-bromophenyl)-N-methylglycinate
(7b).
Colorless liquid (75 mg, 58% yield); 1H NMR (400 MHz,
CDCl3): δ 7.29 - 7.27 (m, 2H), 6.54 - 6.52 (m, 2H), 4.02 (s, 2H),
3.69 (s, 3H), 3.01 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
171.0, 147.8, 131.8, 113.8, 109.3, 54.1, 51.9, 39.5; MS (ESI):
Anal. Calcd. For C10H1379BrNO2: 258, Found: 258 (M+H+); For
C10H1381BrNO2: 260, Found 260 (M+H+); IR (KBr, cm-1): υ
1748, 1594, 1499, 1204.
6
(a) I. Shimizu, T. Yamada and J. Tsuji, Tetrahedron Lett., 1980, 21,
3199; (b) T. Tsuda, Y. Chujo, S. Nishi, K. Tawara and T. Saegusa, J.
Am. Chem. Soc., 1980, 102, 6381; (c) J. Fournier, O. Lozano, C.
Menozzi, S. Arseniyadis and J. Cossy, Angew. Chem. Int. Ed., 2013,
52, 1257; (d) C. J. Gartshore and D. W. Lupton, Angew. Chem. Int.
Ed., 2013, 52, 4113; (e) A. Khan, R. Zheng, Y. Kan, J. Ye, J. Xing
and Y. Zhang, Angew. Chem. Int. Ed., 2014, 53, 6439; (f) A. Hossian,
S. Singha and R. Jana, Org. Lett., 2014, 16, 3934.
Ethyl 2-(methyl(phenyl)amino)acetate (8).11 Colorless liquid
(49 mg, 51% yield); H NMR (400 MHz, CDCl3): δ 7.24-7.20
1
(m, 2H), 6.75 – 6.67 (m, 3H), 4.19- 4.14 (m, 2H), 4.04 (s, 2H),
3.05 (s, 3H), 1.23 (t, J = 8.0 Hz, 3H); MS (ESI): Anal. Calcd.
For C11H16NO2: 194, Found: 194 (M+H+); The data was in
accordance with our previous report.
7
8
(a) J. Wang, B. Liu, H. Zhao and J. Wang, Organometallics, 2012, 31,
8598; (b) M. K. Ghorai, R. Talukdar and D. P. Tiwari, Org. Lett.,
2014, 16, 2204.
For reviews on this topic, see: (a) F. A. Carey, Organic Chemistry,
4rd ed., McGraw-Hill Higher Education, New York, 2000, pp. 1051.
(b) K. Maruoka and T. Ooi, Chem. Rev., 2003, 103, 3013; (c) L.
Aurelio, R. T. C. Brownlee and A. B. Hughes, Chem. Rev., 2004, 104,
5823; (d) Y.-C. Luo, H.-H. Zhang, Y. Wang and P.-F. Xu, Acc. Chem.
Res., 2010, 43, 1317; For recent examples on amino acids synthesis,
see: (e) Z. Hou, J. Wang, P. He, J. Wang, B. Qin, X. Liu, L. Lin and
X. Feng, Angew. Chem. Int. Ed., 2010, 49, 4763; (f) R. Husmann, E.
Acknowledgements
A
Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD)
and NSFC (21272165).
Notes and references
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ARTICLE
Journal Name
Sugiono, S. Mersmann, G. Raabe, M. Rueping and C. Bolm, Org.
Lett., 2011, 13, 1044.
9
For representative examples, see: (a) Y. Zhang X., Gao, K.
Hardcastle and B. Wang, Chem. Eur. J., 2006, 12, 1377; (b) V.
Kumar, M. P. Kaushik and A. Mazumdar, Eur. J. Org. Chem., 2008,
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10 (a) L. Chen, E. Shi, Z. Liu, S. Chen, W. Wei, H. Li, K. Xu and X.
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Shi, Y. Shao, S. Chen, H. Hu, Z. Liu, J. Zhang and X. Wan, Org.
Lett., 2012, 14, 3384; (d) J. Zhang, J. Jiang, Y. Li and X. Wan, J. Org.
Chem., 2013, 78, 11366; (e) C. Zhang, C. Liu, Y. Shao, X. Bao and X.
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Q. Luo, J. Chen, D. Xu and X. Wan, Org. Lett., 2014, 16, 3312; (g)
M. Uyanik, H. Okamoto, T. Yasui and K. Ishihara, Science, 2010,
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Table of Content
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