Preparation of N-acetyl-2-arylglycin esters by N-H insertion reaction of aryldiazoacetates with acetamide

Article abstract of DOI:10.1080/00397910902964817

The intermolecular N-H insertion reaction of methyl α-diazo α-arylacetate with acetamide has been investigated using transition-metal complexes as catalysts. The Cu(II) complex Cu(hfacac)₂ (hfacac represents hexafluoroacetylacetonate) has prove

Full text of DOI:10.1080/00397910902964817

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Preparation of N-Acetyl-2-arylglycin
Esters by N-H Insertion Reaction of
Aryldiazoacetates with Acetamide
Dan Huang a b , Guo-Ming Jiang b , Hong-Xia Chen b & Wen-Dong Gao
a
a Key Laboratory of Eco-textile , Jiangnan University, Ministry of
Education , Wuxi , China
b Department of Chemistry and Chemical Engineering , Nantong
University , Nantong , Jiangsu , China
Published online: 29 Dec 2009.
To cite this article: Dan Huang , Guo-Ming Jiang , Hong-Xia Chen & Wen-Dong Gao (2009) Preparation
of N-Acetyl-2-arylglycin Esters by N-H Insertion Reaction of Aryldiazoacetates with Acetamide,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:2, 229-234, DOI: 10.1080/00397910902964817
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Synthetic Communications1, 40: 229–234, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902964817
PREPARATION OF N-ACETYL-2-ARYLGLYCIN ESTERS BY
N-H INSERTION REACTION OF ARYLDIAZOACETATES
WITH ACETAMIDE
Dan Huang,1,2 Guo-Ming Jiang,2 Hong-Xia Chen,2 and
Wen-Dong Gao1
1Key Laboratory of Eco-textile, Jiangnan University, Ministry of Education,
Wuxi, China
2Department of Chemistry and Chemical Engineering, Nantong University,
Nantong, Jiangsu, China
The intermolecular N-H insertion reaction of methyl a-diazo a-arylacetate with acetamide
has been investigated using transition-metal complexes as catalysts. The Cu(II) complex
Cu(hfacac)2 (hfacac represents hexafluoroacetylacetonate) has proven to be the most
active catalyst to yield methyl N-acetyl-2-phenylglycin in good isolated yield (73–80%)
with 3 mmol% of catalyst loading in reflux toluene. The catalyst is also valuable to the
substituted aryldiazoacetates at the 4-position on phenyl ring.
Keywords: Acetamide; a-diazo arylacetate ester; N-acetyl-2-arylglycin ester; N-H insertion; synthesis
a-Arylglycines are nonproteinogenic amino acids that play an important role in
chemistry and biology because of their function as building blocks of peptides and
many other natural compounds. Moreover, a-arylglycines and certain derivatives
have been widely applied in food, agrochemicals, and medicine as well as in coordi-
nation chemistry as metal-chelating agents.[1,2] The synthesis of arylglycines and their
derivatives has been a field of intensive research for years. The well-known and
powerful synthetic techniques were developed by Scho¨llkopf,[3] Seebach et al.,[4]
Evans and Nelson,[5] Williams and Hendrix,[6] and others.[7] However, the present
chemical synthetic routes have several disadvantages. They frequently require
low-temperature reaction steps and mostly need at least four reaction steps to yield
the desired amino acid starting from inexpensive reagents or require expensive or not
commercially available reactants. Recently, a general and convergent approach to
nonnatural amino acids was developed based on the the decomposition of a-diazo
compounds, resulting in highly active carbenes.[8]
Burger reported a one-step procedure for a-trifluoromethyl-substituted
a-amino acid derivatives using methyl 3,3,3-trifluoro-2-diazopropionate with
Received August 22, 2008.
Address correspondence to Dan Huang, School of Textiles and Clothing, Jiangnan University,
Wuxi, Jiangsu 214122, China. E-mail: Huangdan6@163.com
229

230
D. HUANG ET AL.
rhodium(II) acetate as catalyst at 80ꢀC.[9] Aller and coworkers described the use of
rhodium acetate for the formation of a-aminoacids and a-aminophosphonic acids as
well as an unprecedented preparation of peptides.[10] Morilla et al. studied the
insertion of ethyl diazoacetate (EDA) into nitrogen–hydrogen bonds of amines
and amides catalyzed by copper(I) complexes with homoscorpionate ligand (TpX)
and obtained glycinate derivatives in good yield.[11] Resently, Bachmann et al.
synthesized a-amino acid derivatives with Cu(I)-carbenoid and Ag(I)–Lewis acid
catalyst via asymmetric intermolecular insertion of a-diazo compounds into N-H
bonds.[12] Very resently, Lee and Fu[13] and Liu et al.[14] disclosed Cu-catalyzed asym-
metric N-H insertion reactons to a-amino acids derivatives. We have described syn-
thesis of c-keto ester, aziridine, and a-methoxyl-b-dicarbonyl compounds by the
reactions of a-diazo carbonyl compounds with enamines, imines, or alcohols, cata-
lyzed by copper or rhodium complexes.[15] In this article, we report the N-H insertion
reaction of a variety of aryldiazoacetates into acetamide to N-acetyl-2-arylglycin esters
in good yields.
The reaction of methyl a-diazo phenlacetate (1a) with acetamide catalyzed by
Rh2(OAc)4 provided methyl 2-acetamido-2-phenylacetate (2a) in 58% yield in reflux
toluene. Furthermore, the influence of solvent on the yield was investigated using
Rh2(OAc)4 as the catalyst, and the results are summarized in Table 1. The results
reveal that the greater boiling point of solvent afforded the greater chemical yield,
with the exception of Ph. It showed that the reaction was more effective with rise
of reaction temperature.
A variety of copper complexes and BF3 ꢁ Et2O were tested as catalysts, and the
results are summarized in Table 2. The reaction did not occur in the absence of a
catalyst (entry 1). The copper complex showed a profound effect on the yield. The
Cu(hfacac)2 was the best catalyst for yield and catalytic activity.
After careful examination of the effects of other reaction factors, the optimum
reaction conditions for this transformation were identified as following: slow
addition of a-diazo arylacetate ester[15b] (1.5 equiv.) to a stirred refluxing toluene
solution of acetamide (1.0 equiv) and Cu(hfacac)2 (3 mol%) under an argon
Table 1. Solvent effect in reaction of acetamide with 1aa
Entry
Solvent
PhH
Time (h)
Yield (%)b
1
2
3
4
5
2
2
2
6
2
25
39
46
53
58
CH2Cl2
ClCH2CH2Cl
THF
PhCH3
aThe reactions were carried out with 1.5 mmol diazo, 1.0 mmol acetamide, and 0.01 mmol Rh2(OAc)4
under reflux.
bIsolated yield after column chromatography.

PREPARATION OF N-ACETYL-2-ARYLGLYCIN ESTERS
231
Table 2. Catalysts in reaction of acetamide with 1aa
Entry
Catalyst
None
Rh2(OAc)4
Cat. (mol%)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
0
1
3
3
5
5
5
5
24
2.5
3
0
58
46
77
45
0
c
Cu(acac)2
Cu(hfacac)2
d
2
e
Cu(OTf)2
CuI
4
6
CuPF6
BF3 ꢁ Et2O
6
10
0
6
aThe reactions were carried out with 1.5 mmol diazo, 1.0 mmol aceamino in reflux with toluene.
bIsolated yields after column chromatography.
cCu(acac)2 ¼ acetylacetonate copper(II).
dCu(hfacac)2 ¼ copper(II)-bis-(hexafluoroacetylacetonate).
eCu(OTf)2 ¼ copper(II)-bis-(trifluoromethanesulfonate).
atmosphere. The scope of the reaction was explored with a variety of a-diazo
arylacetate esters, and the results are summarized in Table 3. Good yields were
obtained for all aryldiazoacetates and acetamide. The substituents on the 4-position
of the phenyl ring showed negligible effects on the yields. Attempts to effect N-H
insertion reactions on phthalimide, pyrrolidin-2-one, or azetidin-2-one using 1a were
unsuccessful, presumably because of their intense steric hindrance.
Table 3. Insertion reaction of a-diazo arylacetate estersa
Entry
Product
Time (h)
Yield (%)b
2a
2b
2c
2d
2e
2f
Ph
2
2
2
2
2
2
1
4
77
74
75
76
77
78
80
73
p-CH3OPh
p-CH3Ph
p-ClPh
p-BrPh
p-NO2Ph
2g
2h
N-Boc-b-indole
b-Naphthalenyl
aThe reactions were carried out with 1.5 mmol diazo and 1.0 mmol acetamide in refluxing toluene by
catalysis of 3 mmol% Cu(hfacac)2.
bIsolated yield after column chromatography.

232
D. HUANG ET AL.
In summary, we have developed a facile and efficient synthetic route to
arylglycine derivatives (N-acetyl-2-arylglycin ester) via the catalyzed N-H insertion
reaction of aryldiazoacetates and acetamide. The distinct advantages of this reaction
pathway are the simple reaction procedure (two steps from methyl 2-arylacetate) and
the good yields. Further efforts are under way to develop an asymmetric synthesis of
N-acetyl-2-arylglycin ester using a-diazo arylacetate ester as well as to explore the
application of products.
Typical Experimental Procedure and Characterization Results
Acetamide (0.059 g, 1.0 mmol), Cu(hfacac)2 (14.3 mg, 0.03 mmol), and toluene
(5 mL) were charged in a round-bottomed flask equipped with a stirrer and an
additional funnel under argon atmosphere. The reaction solution was heated in an
oil bath and kept refluxing. The addition funnel was charged with a solution of
methyl a-diazo phenlacetate (1a) (222.4 mg, 1.5 mmol) in toluene (5 mL), which
was added dropwise to the reaction solution over about 1 h. The reaction mixture
was refluxed for an additional 2 h. After the solvent was evaporated under vacuum,
the crude product was purified by flash-column chromatography (petroleum ether–
ethyl acetate 10:1) over silica gel to give methyl 2-acetamido-2-phenylacetate (2a) as
a light yellow solid (0.139 g, 77% yield), mp 115.2–117.3ꢀC. IR (KBr) (cmꢂ1): 750,
1
1380, 1705, 3050, 3441; H NMR (CDCl3, 400 MHz): d 7.57–7.26 (m, 5H), 5.51 (s,
1H), 4.90 (s, 1H), 3.74 (s, 3H), 2.19 (s, 3H). HRMS (EI) calcd. for C11H13NO3
207.0895; found 207.0890.
Methyl 2-acetamido-2-(4-methoxylphenyl)acetate (2b). Yellow solid;
yield: 74%; mp 125.2–126.8ꢀC; IR (KBr) (cmꢂ1): 814, 1179, 1514, 1655, 1742,
1
2839, 2980, 3287; H NMR (CDCl3, 400 MHz): d 7.25 (d, J ¼ 6.0 Hz, 2H), 6.84 (d,
J ¼ 6.0 Hz, 2H), 6.35 (d, J ¼ 6.0 Hz, 1H), 5.47 (d, J ¼ 3.0 Hz, 1H), 4.16 (3H, s),
3.78 (3H, s), 2.00 (3H, s). HRMS (EI) calcd. for C12H15NO4 237.1001; found
237.1090.
Methyl 2-acetamido-2-(4-methylphenyl)acetate (2c). Yellow oil; yield:
1
75%; H NMR (CDCl3, 400 MHz): d 7.35 (d, J ¼ 8.0 Hz, 2H), 7.22 (d, J ¼ 8.0 Hz,
2H), 5.48 (s, 1H), 4.86 (s, 1H), 3.64 (s, 3H), 2.35 (s, 3H), 2.20 (s, 3H). HRMS (EI)
calcd. for C12H15NO3 221.1052; found 221.1061.
Methyl 2-acetamido-2-(4-chlorophenyl)acetate (2d). Yellow oil; yield:
1
76%; H NMR (CDCl3, 400 MHz): d 7.52 (d, J ¼ 6.6 Hz, 2H), 7.33 (d, J ¼ 6.6 Hz,
2H), 5.51 (s, 1H), 4.80 (s, 1H), 3.61 (s, 3H), 2.20 (s, 3H). HRMS (EI) calcd. for
C11H12ClNO3 241.0506; found 241.1101.
Methyl 2-acetamido-2-(4-bromophenyl)acetate (2e). Fluorescent yellow
solid; yield: 77%; mp 150.1–152.6ꢀC; IR (KBr) (cmꢂ1): 818, 1010, 1073, 1154,
1
1269, 1488, 1708, 2950, 3340; H NMR (CDCl3, 400 MHz): d 7.59 (d, 2H), 7.35
(d, 2H), 5.52 (s, 1H), 4.79 (s, 1H), 3.54 (s, 3H), 2.21 (s, 3H). HRMS (EI) calcd.
for C11H12BrNO3 285.0001; found 285.0062.
Methyl 2-acetamido-2-(4-nitrophenyl)acetate (2f). Yellow solid; yield:
1
78%; H NMR (CDCl3, 400 MHz): d 8.35 (d, J ¼ 7.2 Hz, 2H), 7.72 (d, J ¼ 7.8 Hz,

PREPARATION OF N-ACETYL-2-ARYLGLYCIN ESTERS
233
2H), 5.61 (s, 1H), 4.89 (s, 1H), 3.60 (s, 3H), 2.25 (s, 3H). HRMS (EI) calcd. for
C11H12N2O5 252.0746; found 252.0795.
Methyl
2-acetamido-2-(1-tert-butyloxycarbonyl-indol-3-yl)-acetate
(2g). Yellow solid; yield: 80%; mp 188.6–189.2ꢀC; IR (KBr) (cmꢂ1): 755, 767,
1
1007, 1030, 1047, 1094, 1154, 1251, 1279, 1373, 1455, 1606, 1738, 2981, 3453; H
NMR (CDCl3, 400 MHz): d 8.18 (d, J ¼ 8.8 Hz, 1H), 7.78 (d, J ¼ 4.0 Hz, 1H), 7.51
(d, J ¼ 12.4 Hz, 1H), 7.35 (t, J ¼ 12.2 Hz, 2H), 7.25 (d, J ¼ 4.4 Hz, 1H), 4.07 (d,
J ¼ 4.4 Hz, 1H), 3.58 (d, J ¼ 4.4 Hz, 3H), 1.68 (d, J ¼ 4.0 Hz, 10H), 1.60 (s, 2H).
HRMS (EI) calcd. for C18H22N2O5, 346.1529; found 346.1532.
Methyl 2-acetamido-2-(naphthalen-2-yl)acetate (2h). Brown yellow solid;
yield: 73%; mp 162.0–164.2ꢀC; IR (KBr) (cmꢂ1): 755, 768, 1007, 1094, 1154, 1274,
1375, 1454, 1606, 1732, 2966, 3058, 3329; 1H NMR (CDCl3, 400 MHz): d
7.74–7.19 (m, 7H), 5.79 (s, 1H), 5.00 (s, 1H), 3.72 (s, 3H), 2.38 (s, 3H). HRMS
(EI) calcd. for C15H15NO3 257.1052; found 257.1090.
ACKNOWLEDGMENTS
Financial support from the Natural Science Foundation of Jiangsu (Project
KB2005043) and Jiangnan University (Project Q21050712) is gratefully acknowl-
edged. We thank Prof. Q. Shen and Prof. M. Yan for their useful suggestions.
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