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

  1. Zhanwei Xu,
  2. Xiaoqiang Yu,
  3. Xiujuan Feng and
  4. Ming Bao

State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China

  1. Corresponding author email

This article is part of the Thematic Series "C–H Functionalization".

Guest Editor: H. M. L. Davies
Beilstein J. Org. Chem. 2012, 8, 1564–1568. https://doi.org/10.3762/bjoc.8.178
Received 30 Jun 2012, Accepted 09 Aug 2012, Published 18 Sep 2012

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.

Keywords: α-amino ester; arylglycine; C–H functionalization; oxidation; synthesis

Findings

Arylglycine derivatives represent important synthetic intermediates or building blocks for drug development and natural-product synthesis [1,2]. The arylglycine moiety also occurs in several bioactive natural products [3]. Consequently, the development of convenient and efficient methods for the preparation of arylglycine derivatives has attracted considerable attention. Over the past years, many methods have been developed for the preparation of arylglycine derivatives [3]. Among these, the addition reaction of a carbon nucleophile to imines or iminium ions through Mannich-type reaction appears more useful (Scheme 1, reactions 1–3). However, these reactions need expensive arylboronic acids (Petasis reaction) [4-9] and suitable leaving groups [10-12] as well as a metal catalyst (Polonovsky reaction; this route requires the preparation of amine N-oxide in advance) [13,14].

[1860-5397-8-178-i1]

Scheme 1: Synthesis of arylglycine derivatives.

We have recently reported the copper-catalyzed oxidative coupling reaction of alkynes with tertiary amine N-oxides [15]. This new strategy for the direct functionalization of sp3 C–H bonds adjacent to a nitrogen atom, via tertiary amine N-oxide intermediates, was successfully applied to the coupling reaction of ethyl 2-(disubstituted amino)acetates with indoles to achieve indolylglycine derivatives (Scheme 2, reaction 1) [16]. In the course of our continuous research on the direct functionalization of sp3 C–H bonds, we found that this new strategy could also be applied to the coupling reaction of naphthols and phenols with ethyl 2-(disubstituted amino)acetates. The results are reported in the current work (Scheme 2, reaction 2).

[1860-5397-8-178-i2]

Scheme 2: Oxidative sp3 C–H functionalization of α-amino esters.

In our initial studies, the reaction of 2-naphthol (1a) with ethyl 2-morpholinoacetate (2a) was chosen as a model for optimizing the reaction conditions. The results are shown in Table 1. The proportions of substrate 2a and oxidant meta-chloroperoxybenzoic acid (mCPBA) were initially screened with CH3CN as the solvent (Table 1, entries 1–3). The yield of 3a was increased to 77% when 1.2 equiv of 2a and mCPBA were used (Table 1, entry 2). Further increasing the amounts of 2a and mCPBA or adding a copper catalyst could not improve the yield of 3a (Table 1, entries 3 and 4). The solvents were then screened (Table 1, entries 5–10). The best result was observed when CH2Cl2 was used as the solvent (79%, Table 1, entry 5). Therefore, the subsequent reactions of naphthols and phenols with ethyl 2-(disubstituted amino)acetates were performed in the presence of mCPBA (1.2 equiv) in CH2Cl2 under ambient conditions.

Table 1: Optimization of reaction conditions.a

[Graphic 1]
Entry 2a (equiv) mCPBA (equiv) Time (h) Solvent Yield of 3a (%)b
1 1.0 1.0 40 CH3CN 63
2 1.2 1.2 40 CH3CN 77
3 1.5 1.5 40 CH3CN 77
4c 1.2 1.2 40 CH3CN 75
5 1.2 1.2 24 CH2Cl2 79
6 1.2 1.2 40 THF 65
7 1.2 1.2 48 dioxane 16
8 1.2 1.2 48 CH3CH2OH 14
9 1.2 1.2 48 toluene 70
10 1.2 1.2 48 DMF 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.

The substrate scope was determined under the optimized reaction conditions, and the results are shown in Table 2. As expected, the reactions of ethyl 2-morpholinoacetate (2a), ethyl 2-(piperidin-1-yl)acetate (2b), and ethyl 2-(benzyl(methyl)amino)acetate (2c) proceeded smoothly to give the corresponding products 3a3c in good yields (Table 2, entries 1–3, 64–79%). These results indicated that both α-cyclic and acyclic amino esters could be employed in this type oxidative coupling reaction. The desired products 3d3f were obtained in yields of 66–79% from the reactions of naphthols 1b1d with 2a (Table 2, entries 4–6). However, relatively low yields were observed from the reactions of phenols 1e1h with 2a (Table 2, entries 7–10, 30–55%). The poor reactivity of phenols 1e1h was considered to be due to their lower electron density compared to naphthols 1b1d. No reaction was observed from the mixture of phenol 1i, bearing an electron-withdrawing Br substituent on para-position, and 2a (Table 2, entry 11).

Table 2: Oxidative coupling reaction of naphthols and phenols with α-amino esters.a

[Graphic 2]
Entry Phenol 1 Amine 2 Time (h) Product 3 Yield (%)b
1 [Graphic 3]
1a
[Graphic 4]
2a
24 [Graphic 5]
3a
79
2 [Graphic 6]
1a
[Graphic 7]
2b
24 [Graphic 8]
3b
64
3 [Graphic 9]
1a
[Graphic 10]
2c
36 [Graphic 11]
3c
64
4 [Graphic 12]
1b
[Graphic 13]
2a
20 [Graphic 14]
3d
79
5 [Graphic 15]
1c
[Graphic 16]
2a
20 [Graphic 17]
3e
75
6 [Graphic 18]
1d
[Graphic 19]
2a
18 [Graphic 20]
3f
66
7 [Graphic 21]
1e
[Graphic 22]
2a
48 [Graphic 23]
3g
30
8 [Graphic 24]
1f
[Graphic 25]
2a
36 [Graphic 26]
3h
30
9 [Graphic 27]
1g
[Graphic 28]
2a
24 [Graphic 29]
3i
35
10 [Graphic 30]
1h
[Graphic 31]
2a
16 [Graphic 32]
3j
55
11 [Graphic 33]
1i
[Graphic 34]
2a
48 [Graphic 35]
3k
0

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.

The plausible mechanism for the coupling reaction of naphthols and phenols with ethyl 2-aminoacetate derivatives is shown in Scheme 3 [16-19]. mCPBA oxidized 2a to amine N-oxide 4 before being transformed into 3-chlorobenzoic acid. The interaction of 4 with 3-chlorobenzoic acid led to the generation of the iminium ion 5 and 3-chlorobenzoate anion. The Mannich-type reaction of 5 with 2-naphthol may have occurred to generate the coupling product 3a. The generated 3-chlorobenzoate anion acted as a proton acceptor.

[1860-5397-8-178-i3]

Scheme 3: Proposed mechanism.

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.

Supporting Information

Supporting Information File 1: General methods, characterization data and NMR spectra of all synthesized compounds.
Format: PDF Size: 1.3 MB Download

Acknowledgements

We are grateful to the National Natural Science Foundation of China (Nos. 21002010 and 21072023) for their financial support.

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© 2012 Xu et al; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

 
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