Dehydrogenative Cross-Coupling Reaction between N-Aryl α-Amino Acid Esters and Phenols or Phenol Derivative for Synthesis of α-Aryl α-Amino Acid Esters

Article abstract of DOI:10.1021/acs.orglett.6b00162

A novel dehydrogenative cross-coupling (DCC) reaction between N-arylglycine esters and phenols or 1,3,5-trimethoxybenzene was developed by copper catalysis using di-tert-butyl peroxide (DTBP) as an oxidant. Under optimized conditions, a range of N-arylgly

Full text of DOI:10.1021/acs.orglett.6b00162

Letter
pubs.acs.org/OrgLett
Dehydrogenative Cross-Coupling Reaction between N‑Aryl α‑Amino
Acid Esters and Phenols or Phenol Derivative for Synthesis of α‑Aryl
α‑Amino Acid Esters
Muhammad Salman,† Zhi-Qiang Zhu,† and Zhi-Zhen Huang*,†,‡
†Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. China
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: A novel dehydrogenative cross-coupling (DCC) reaction between N-arylglycine esters and phenols or 1,3,5-
trimethoxybenzene was developed by copper catalysis using di-tert-butyl peroxide (DTBP) as an oxidant. Under optimized
conditions, a range of N-arylglycine esters 1 underwent the DCC reaction smoothly with various phenols 2 or 1,3,5-
trimethoxybenzene 4 to give desired α-aryl α -amino acid esters 3 or 5, respectively, with high ortho regioselectivities in a
moderate to excellent yield. A possible mechanism involving aromatic electrophilic substitution is proposed.
urrently, the use of only C−H bonds to undergo
esters with phenols bearing electron-withdrawing groups as well
as electron-donating groups on benzene rings or trimethox-
ybezene for the synthesis of α-aryl α-amino acid esters.
C
dehydrogenative cross-coupling (DCC) reactions is
thought of as a new generation of C−C bond formations
because DCC reactions avoid prefunctionalization of substrates
and are more atom economic and environmentally friendly.1
Among the DCC reactions, much attention has been paid to
the direct coupling of α-C(sp3)−H bonds of α-amino acid
derivatives with the C−H bonds of various nucleophiles for the
synthesis of various α-substituted α-amino acid derivatives.2−4
For example, in 2008, Li and co-workers found the first
example of DCC reaction between N-substituted glycine
derivatives and malonates by the catalysis of a copper
complex.2a In 2010, our group revealed a DCC reaction
between N-arylglycine esters and ketones under the cooperative
catalysis of copper salt and secondary amine.2b In 2011, Wang
et al. disclosed an asymmetric DCC reaction of N-arylglycine
esters with α-substituted β-ketoesters by a chiral copper
catalyst.2c In 2012, Bao and co-workers developed an oxidative
coupling reaction of N,N-disubstituted glycine esters with
naphthols to give the desired α-naphthylated α-amino acid
esters.3b Although some phenols bearing electron-donating
groups on benzene rings also performed the DCC readily, 4-
bromophenol as a sole example of a phenol bearing an electron-
withdrawing group on the benzene ring could not lead to the
desired coupling product. Herein, we present our recent work
on the DCC reaction of N-monosubstituted α-amino acid
Initially, we chose N-arylglycine ester 1a and phenol 2a as a
model reaction to explore and to optimize the DCC reaction
between them. When the reaction of N-arylglycine ester 1a
with phenol 2a was performed under the catalysis of 10 mol %
of CuBr using O2 as an oxidant in toluene at 60 °C, we were
pleased to find that the desired α-aryl α-amino acid ester 3aa
was formed, albeit in 26% yield (entry 1, Table 1). Then, other
transition-metal catalysts were probed, and Cu(OAc)2 proved
to be best with 45% yield for coupling product 3aa (compare
entries 1−4 with entry 3, Table 1; also see the Supporting
Information). A series of oxidants such as tert-butyl hydro-
peroxide (TBHP), dicumyl peroxide (DCP), tert-butyl
perbenzoate (TBPB), and di-tert-butyl peroxide (DTBP) were
examined, and DTBP showed the best efficiency with regard to
the yield of 3aa (compare entries 6 and 7 with entry 8, Table 1;
also see the SI). Among various solvents screened, dichloro-
ethane (DCE) led to the best yield of 3aa (compare entries 8
and 9 with entry 10, Table 1; also see SI). In the absence of
Cu(OAc)2, 3aa was isolated in only 7% yield (entry 11, Table
1). Increasing the amount of Cu(OAc)2 led to a reduction in
Received: January 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00162
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Table 1. Optimization of the DCC Reaction between N-
Arylglycine Ester 1a and Phenol 2a
Scheme 1. DCC Reaction between N-Arylglycine Ester 1a
and Phenol Derivatives 2a−n by Copper Catalysis
a
b
entry
[M] (10 mol %)
oxidant
solvent
yield (%)
1
CuBr
O2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
DCE
26
34
45
NP
12
15
40
49
25
56
7
2
Cu2O
O2
3
Cu(OAc)2
FeCl3
O2
4
O2
5
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
−
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
−
6
DCP
TBPB
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
7
8
9
10
11
DCE
c
12
DCE
31
28
39
64
d
13
DCE
e
14
DCE
f
15
DCE
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), catalyst (10
mol %), and solvent (2.0 mL) at 60 °C; under O2 (1 atm) or using
b
c
oxidant (1.0 equiv) for 24 h. Isolated yields. At 15 mol % Cu(OAc)2
d
e
f
At 80 °C. At 40 °C. 18 h.
the yield of 3aa (entry 12, Table 1). The optimization
experiment also indicated that raising the temperature to 80 °C
or lowering the temperature to 40 °C was not beneficial to the
DCC reaction (compare entries 13 and 14 with entry 11, Table
1).
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), and solvent (2
b
mL), at 60 °C; under oxidant for 18 h. Isolated yields.
Scheme 2. DCC Reaction between N-Arylglycine Esters 1a−i
and Phenol 2a by Copper Catalysis
On the basis of the screening of the reaction conditions, it
can be concluded that the optimized reaction should be
performed under catalysis of Cu(OAc)2 (10 mol %) using
DTBP (1.0 equiv) as an oxidant in DCE at 60 °C. Under the
optimized reaction conditions, we investigated the scope of
phenols in the DCC reaction with N-arylglycine ester 1a. It was
found that various phenols (2a−m) were able to undergo the
DCC reaction with N-arylglycine ester 1a, affording α-aryl α-
amino acid esters 3aa−am in 57−75% yields (Scheme 1).
Different from reported protocol,3b in the presented DCC
reaction, the phenols 2b−h bearing electron-withdrawing
groups also led to α-aryl α-amino acid esters 3ab−ah
expediently besides those 2i−m bearing electron-donating
groups. Under the optimized conditions, benzene did not
perform the DCC reaction with N-arylglycine ester 1a.
After the scope of phenols was examined, a series of N-
arylglycine esters 1a−i were investigated in the DCC reaction
with phenol 2a. It was found that under the optimized
conditions the DCC reaction proceeded smoothly to give α-
aryl α-amino acid esters 3aa−ia in 53−72% yields (Scheme 2).
The experimental results indicated that the DCC reaction has
high regioselectivities with ortho-coupling products 3aa−ia. No
para-coupling counterpart was isolated in the DCC reaction. A
range of N-arylglycine esters 1a−c bearing both electron-
donating groups and those 1e−f bearing electron-withdrawing
groups led to the desired coupling product 3aa−fa readily in
satisfactory yields. The experimental results also demonstrated
that methyl, isopropyl, and tert-butyl glycine esters 1g−i as well
as ethyl glycine ester 1a were able to perform the DCC reaction
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), and solvent (2
b
mL), at 60 °C; under oxidant for 18 h. Isolated yields.
with phenol 2a to give the desired coupling product 3ga−ia in
59−72% yields.
Moreover, 1,3,5-trimethoxybenzene 4 as an electron-rich
aromatic nucleophile performed the DCC reaction smoothly
with a variety of N-arylglycine esters 1a−i under the optimized
B
DOI: 10.1021/acs.orglett.6b00162
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Letter
conditions (Scheme 3). Moderate to excellent yields of desired
α-aryl α-amino acid esters 5a−i were achieved. When anisole
recycle by DTBP.5 Immediately, cation 6 can tautomerize to
iminium ion 7.2b Then, phenol 2a undergoes electrophilic
addition with iminium ion 7 to generate σ-complex 8, followed
by loss of a proton to give the desired α-aryl α-amino acid ester
3aa.
Scheme 3. DCC Reaction between N-Arylglycine Esters 1a−i
and 1,3,5-Trimethoxybenzene 4 by Copper Catalysis
In conclusion, we have developed a novel DCC reaction
between N-arylglycine esters 1 and phenols 2 by copper
catalysis using DTBP as an oxidant. A range of N-arylglycine
esters 1 undergo the DCC reaction with various phenols 2
bearing electron-withdrawing groups as well as electron-
donating groups on benzene rings, smoothly affording desired
α-aryl α-amino acid esters 3 with high ortho-regioselectivities in
53−75% yields. The optimized reaction conditions are also
suitable for 1,3,5-trimethoxybenzene to perform the DCC
reaction with a variety of N-arylglycine esters 1 to give α-aryl α-
amino acid esters 5 in moderate to excellent yields. A possible
mechanism involving aromatic electrophilic substitution is also
proposed. Further studies on the DCC reactions between other
α-amino acid derivatives and aromatic compounds and related
mechanisms are currently underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00162.
1
Experimental procedures, characterization data, and H
NMR, 13C NMR, and HRMS spectra for the DCC
products (PDF)
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), and solvent (2
b
mL), at 60 °C; under oxidant for 18 h. Isolated yields.
AUTHOR INFORMATION
Corresponding Author
■
was employed to perform the DCC reaction with glycine ester
1a, no desired coupling product was observed under the
optimized conditions.
*E-mail: huangzhizhen@zju.edu.cn.
Notes
When 2,6-di-tert-butyl-4-methylphenol (BHT), a radical
scavenger, was added into the reaction system of 4-methyl N-
arylglycine ester 1a with phenol 2a under optimized conditions,
the yield of coupling product 3aa was dramatically decreased to
18%. This result suggests that the reaction may undergo a
radical mechanism. A plausible mechanism of the reaction may
proceed as follows (Scheme 4). Initially, a tert-butoxyl radical
generated by the dissociation of DTBP may abstract α-
hydrogen of glycine ester 1a to form radical 5.2d A single-
electron transfer (SET) from 5 to copper(II) leads to cation 6
and copper(I), which can be oxidized to copper(II) for catalytic
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from MOST of China (973 program
2011CB808600) and the National Natural Science Foundation
of China (No. 21372195) are gratefully acknowledged.
REFERENCES
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