Arylglycine-derivative synthesis via oxidative sp3 C-H functionalization of α-amino esters

Article abstract of DOI:10.3762/bjoc.8.178

An efficient method for the synthesis of arylglycine derivatives is described. The oxidative coupling reactions of naphthols and phenols with α-amino esters proceeded smoothly in the presence of meta- chloroperoxybenzoic acid as an oxidant under ambient c

Full text of DOI:10.3762/bjoc.8.178

Arylglycine-derivative synthesis via oxidative
sp3 C–H functionalization of α-amino esters
Zhanwei Xu, Xiaoqiang Yu*, Xiujuan Feng and Ming Bao*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1564–1568.
State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian 116023, China
doi:10.3762/bjoc.8.178
Received: 30 June 2012
Email:
Accepted: 09 August 2012
Published: 18 September 2012
Xiaoqiang Yu* - yuxiaoqiang@dlut.edu.cn; Ming Bao* -
mingbao@dlut.edu.cn
This article is part of the Thematic Series "C–H Functionalization".
Guest Editor: H. M. L. Davies
* Corresponding author
Keywords:
α-amino ester; arylglycine; C–H functionalization; oxidation; synthesis
© 2012 Xu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An efficient method for the synthesis of arylglycine derivatives is described. The oxidative coupling reactions of naphthols and
phenols with α-amino esters proceeded smoothly in the presence of meta-chloroperoxybenzoic acid as an oxidant under ambient
conditions, to produce arylglycine derivatives in satisfactory yields.
Findings
Arylglycine derivatives represent important synthetic intermedi- We have recently reported the copper-catalyzed oxidative
ates or building blocks for drug development and natural-prod- coupling reaction of alkynes with tertiary amine N-oxides [15].
uct synthesis [1,2]. The arylglycine moiety also occurs in This new strategy for the direct functionalization of sp3 C–H
several bioactive natural products [3]. Consequently, the devel- bonds adjacent to a nitrogen atom, via tertiary amine N-oxide
opment of convenient and efficient methods for the preparation intermediates, was successfully applied to the coupling reaction
of arylglycine derivatives has attracted considerable attention. of ethyl 2-(disubstituted amino)acetates with indoles to achieve
Over the past years, many methods have been developed for the indolylglycine derivatives (Scheme 2, reaction 1) [16]. In the
preparation of arylglycine derivatives [3]. Among these, the course of our continuous research on the direct functionaliza-
addition reaction of a carbon nucleophile to imines or iminium tion of sp3 C–H bonds, we found that this new strategy could
ions through Mannich-type reaction appears more useful also be applied to the coupling reaction of naphthols and
(Scheme 1, reactions 1–3). However, these reactions need phenols with ethyl 2-(disubstituted amino)acetates. The results
expensive arylboronic acids (Petasis reaction) [4-9] and suit- are reported in the current work (Scheme 2, reaction 2).
able leaving groups [10-12] as well as a metal catalyst
(Polonovsky reaction; this route requires the preparation of In our initial studies, the reaction of 2-naphthol (1a) with ethyl
amine N-oxide in advance) [13,14].
2-morpholinoacetate (2a) was chosen as a model for opti-
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Beilstein J. Org. Chem. 2012, 8, 1564–1568.
Scheme 1: Synthesis of arylglycine derivatives.
Scheme 2: Oxidative sp3 C–H functionalization of α-amino esters.
mizing the reaction conditions. The results are shown in 64–79%). These results indicated that both α-cyclic and acyclic
Table 1. The proportions of substrate 2a and oxidant meta- amino esters could be employed in this type oxidative coupling
chloroperoxybenzoic acid (mCPBA) were initially screened reaction. The desired products 3d–3f were obtained in yields of
with CH3CN as the solvent (Table 1, entries 1–3). The yield of 66–79% from the reactions of naphthols 1b–1d with 2a
3a was increased to 77% when 1.2 equiv of 2a and mCPBA (Table 2, entries 4–6). However, relatively low yields were
were used (Table 1, entry 2). Further increasing the amounts of observed from the reactions of phenols 1e–1h with 2a (Table 2,
2a and mCPBA or adding a copper catalyst could not improve entries 7–10, 30–55%). The poor reactivity of phenols 1e–1h
the yield of 3a (Table 1, entries 3 and 4). The solvents were was considered to be due to their lower electron density
then screened (Table 1, entries 5–10). The best result was compared to naphthols 1b–1d. No reaction was observed from
observed when CH2Cl2 was used as the solvent (79%, Table 1, the mixture of phenol 1i, bearing an electron-withdrawing Br
entry 5). Therefore, the subsequent reactions of naphthols and substituent on para-position, and 2a (Table 2, entry 11).
phenols with ethyl 2-(disubstituted amino)acetates were
performed in the presence of mCPBA (1.2 equiv) in CH2Cl2 The plausible mechanism for the coupling reaction of naph-
under ambient conditions.
thols and phenols with ethyl 2-aminoacetate derivatives is
shown in Scheme 3 [16-19]. mCPBA oxidized 2a to amine
The substrate scope was determined under the optimized reac- N-oxide 4 before being transformed into 3-chlorobenzoic acid.
tion conditions, and the results are shown in Table 2. As The interaction of 4 with 3-chlorobenzoic acid led to the gener-
expected, the reactions of ethyl 2-morpholinoacetate (2a), ethyl ation of the iminium ion 5 and 3-chlorobenzoate anion. The
2-(piperidin-1-yl)acetate (2b), and ethyl 2-(benzyl(methyl)- Mannich-type reaction of 5 with 2-naphthol may have occurred
amino)acetate (2c) proceeded smoothly to give the corres- to generate the coupling product 3a. The generated 3-chloro-
ponding products 3a–3c in good yields (Table 2, entries 1–3, benzoate anion acted as a proton acceptor.
1565

Beilstein J. Org. Chem. 2012, 8, 1564–1568.
Table 1: Optimization of reaction conditions.a
Entry
2a (equiv)
mCPBA (equiv)
Time (h)
Solvent
Yield of 3a (%)b
1
2
1.0
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.0
1.2
1.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
40
40
40
40
24
40
48
48
48
48
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
63
77
3
77
4c
5
75
79
6
65
7
dioxane
CH3CH2OH
toluene
DMF
16
8
14
9
70
10
trace
aReaction conditions: 2-naphthol (1a, 72.1 mg, 0.5 mmol), ethyl 2-morpholinoacetate (2a, 1.0 equiv to 1.5 equiv), and mCPBA (1.0 equiv to 1.5 equiv)
in solvent (3.0 mL) under air at 25 °C. bIsolated yield. c10 mol % Cu(OTf)2 was used as a catalyst.
Table 2: Oxidative coupling reaction of naphthols and phenols with α-amino esters.a
Entry
Phenol 1
Amine 2
Time (h)
Product 3
Yield (%)b
1
24
79
1a
2a
3a
2
3
24
36
64
64
1a
1a
2b
2c
3b
3c
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Beilstein J. Org. Chem. 2012, 8, 1564–1568.
Table 2: Oxidative coupling reaction of naphthols and phenols with α-amino esters.a (continued)
4
20
79
1b
2a
3d
5
20
75
1c
2a
3e
6
7
18
48
66
1d
1e
3f
2a
2a
30
3g
8
36
30
2a
1f
3h
9
24
16
35
1g
3i
2a
2a
10
55
1h
3j
11
48
0
2a
1i
3k
aReaction conditions: naphthols or phenols (1, 0.5 mmol), α-amino esters (2, 0.6 mmol, 1.2 equiv), and mCPBA (121.8 mg, 0.6 mmol, 85% purity) in
CH2Cl2 (3.0 mL) under air at 25 °C. bIsolated yield.
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Beilstein J. Org. Chem. 2012, 8, 1564–1568.
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In conclusion, a new strategy for the functionalization of sp3
C–H bonds of amino esters was successfully applied to the
coupling reaction of ethyl 2-(disubstituted amino)acetates with
naphthols and phenols. The proposed coupling reaction
proceeded smoothly in the presence of mCPBA as an oxidant
under ambient conditions to provide arylglycine derivatives in
satisfactory yields.
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General methods, characterization data and NMR spectra of
all synthesized compounds.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Nos. 21002010 and 21072023) for their financial
support.
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