Metal-free intramolecular oxidative decarboxylative amination of primary α-amino acids with product selectivity

Article abstract of DOI:10.1039/c1cc12885j

A novel metal-free intramolecular oxidative decarboxylative coupling of primary α-amino acids with 2-aminobenzoketones under mild and neutral conditions was developed. Different quinazolines can be selectively obtained by various oxidants.

Full text of DOI:10.1039/c1cc12885j

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COMMUNICATION
Metal-free intramolecular oxidative decarboxylative amination of
primary a-amino acids with product selectivityw
Yizhe Yan and Zhiyong Wang*
Received 17th May 2011, Accepted 20th June 2011
DOI: 10.1039/c1cc12885j
A novel metal-free intramolecular oxidative decarboxylative
coupling of primary a-amino acids with 2-aminobenzoketones
under mild and neutral conditions was developed. Different
quinazolines can be selectively obtained by various oxidants.
intermolecular oxidative decarboxylative coupling of N-benzyl-
proline with various nucleophiles (Scheme 1A).9 Recently, Fu
reported a copper-catalyzed synthesis of quinazolinones via a
decarboxylative coupling of a-amino acids.10 To our knowledge,
metal-free intramolecular oxidative decarboxylative coupling
of primary a-amino acids remains a significant challenge.
Recently, we have reported a metal-free decarboxylative
cyclization from natural a-amino acids to construct pyridine
derivatives.11 On the basis of this work, we complete a novel
I2/oxidant-mediated intramolecular oxidative decarboxylative
coupling of primary a-amino acids with 2-aminobenzaldehydes
or 2-aminobenzoketones, affording a variety of quinazolines
(Scheme 1B). This reaction can be carried out smoothly under
mild and metal-free conditions. Moreover, the reaction could
tolerate water and air.
Transition metal-catalyzed decarboxylative couplings have
emerged as important synthetic methods for C–C or C–N
bond formation because of their high efficiency, selectivity and
convenience.1 For instance, many chemists have developed
transition metal-catalyzed intermolecular and intramolecular
decarboxylative couplings, in which carboxylic acids or esters
are directly employed as starting materials.2–6 A large number
of coupling products – the intermediates for the synthesis
of natural products – have been obtained. However, these
decarboxylative couplings are restricted to the transition
metal-assisted approach, requiring expensive transition metals,
complex ligands and harsh reaction conditions. To approach
the potential application of these methods, strategies with
lower cost, less waste and milder conditions are highly desirable.
Metal-free catalysis may be an attractive advance as a valuable
alternative to transition metal catalysis in decarboxylative
couplings.
Initially, we began our study with the reaction of 1 equiv. of
2-aminobenzophenone (1a) and 1.5 equiv. of phenylglycine
(2a), 2 equiv. of tert-butyl hydroperoxide (TBHP, 70% in
aqueous) as the oxidant and 50 mol% of molecular iodine as
the catalyst. The reaction mixture was heated in DMF under
air at 80 1C for 18 h. The coupling product 3a was obtained in
68% yield by GC-MS analysis (Table 1, entry 1). To improve
the reaction yield, various solvents were employed in this
reaction. Among these solvents, DMA proved to be the best
choice, with a yield of 85% (entries 2–5). When a transition
metal, such as copper or iron, replaced iodine as the catalyst,
no oxidative coupling product was obtained (entries 6–8).
After examination of various oxidants, such as TBHP,
DDQ, TEMPO and oxygen, TBHP gave the highest yield
(entries 9–11). In addition, we explored the influence
of temperature on the reaction efficacy. Either raising or
reducing the reaction temperature decreased the reaction
The synthesis of compounds containing nitrogen atoms has
attracted much attention because of their biological and
pharmaceutical properties. a-Amino acids are more readily
available and more stable than other starting materials from
nature. Therefore, the decarboxylative reaction of a-amino
acids provides a very efficient synthetic method for hetero-
cycles. For example, Cohen reported a decarboxylative reaction of
proline with sterically congested 2-hydroxyacetophenones in
1979.7 In 2008, Seidel and co-workers reported the reaction
of proline with 2-aminobenzaldehyde to form aminals.8a
Recently, they reported a three-component decarboxylative
a-functionalization of proline and aldehydes with nucleophiles.8b
After that, a related reaction was also reported.8c Concurrently,
Li and co-workers reported a copper or iron-catalyzed
Hefei National Laboratory for Physical Sciences at Microscale,
CAS Key Laboratory of Soft Matter Chemistry and Department of
Chemistry, University of Science and Technology of China, Hefei,
230026, P. R. China. E-mail: zwang3@ustc.edu.cn;
Fax: (+86) 551-360-3185
w Electronic supplementary information (ESI) available: Experimental
details and the characterization data for all compounds. See DOI:
10.1039/c1cc12885j
Scheme 1 The strategies for oxidative decarboxylative couplings of
a-amino acids.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9513–9515 9513

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Table 1 Optimization of the oxidative decarboxylative coupling of
phenylglycine with 2-aminobenzophenonea
Table 2 The substrate scope of I2/TBHP-mediated oxidative decar-
boxylative couplinga
Entry Oxidant
Catalyst
Temp (1C) Solvent
Yield (%)b
Entry R1
R2
R3
Ph(2a) 3a
Product Time (h) Yield (%)b
1
2
3
4
5
6
7
8
9
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DDQ
I2
I2
I2
I2
80
80
80
80
80
80
80
80
80
80
80
60
70
90
100
80
80
80
80
DMF
CH3CN
toluene
DMSO
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
68
0
10
55
85
0
0
0
0
32
5
75
77
58
56
63
66
64
84
1
2
3
4
5
6
Ph
H(1a)
H(1b)
H(1c)
H(1d)
18
18
18
18
18
36
78
78
78
79
11
trace
4-F–Ph
4-Br–Ph
4-Me–Ph
Ph
Ph
Ph
Ph
Ph
3b
3c
3d
3e
3f
I2
2,5-di-Me–Ph H(1e)
Cu(OAc)2
CuI
FeCl3
I2
2,4,6-
tri-Me–Ph
Et
H(1f)
7
8
H(1g)
H(1h)
H(1i)
H(1j)
H(1k) Ph
Ph
H(1m) Ph
5-Cl(1n) Ph
5-Br(1o) Ph
H(1p)
5-Cl(1q) Ph
H
H
H
H
5-Cl
5-Br
H
Ph
Ph
Ph
Ph
3g
3h
3i
18
18
18
18
18
18
18
86
85
80
86
85
78
76
n-Bu
10
11
12
13
14
15
16c
17d
18e
19f
TEMPO I2
9
hexadecyl
i-Pr
t-Bu
cyclopropyl H(1l)
cyclopentyl
Ph
Ph
H
H
Ph
4-F–Ph
4-Br–Ph
4-Me–Ph
Ph
Ph
Ph
oxygen
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
I2
I2
I2
I2
I2
I2
I2
I2
I2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
3j
3k
3l
3m
3n(3v) 18
3o(3w) 18
60(30)
70(20)
60
56
80
Ph
3p
3q
18
18
4
H(2b) 3r
a
H
H
H
H
H
3s
3t
3u
3v
3w
4
4
86
84
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (0.1 mmol),
b
oxidant (0.4 mmol), solvent (0.5 mL), 80 1C, 18 h. Determined by
4
69
GC-MS analysis using an internal standard. c 1 equiv. of iodine was used.
4
4
499
499
16(14)c
0(30)d
d
e
10 mol% of iodine was used. 4 equiv. of TBHP was used. 10 equiv. of
f
H2O was added.
Me(2c) 3x(3r) 24
i-Pr(2d) 3y(3r) 24
Ph
H
a
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), I2 (0.1 mmol),
b
c
yields (entries 12–15). Moreover, the amount of TBHP and
iodine were also optimized (entries 16–18). Notably, the addition
of 10 equiv. of water had little influence on this reaction
(entry 19). After optimization, the optimal reaction conditions
were selected: iodine as the catalyst, TBHP as the oxidant,
DMA as the reaction solvent and a reaction temperature
of 80 1C.
TBHP (0.4 mmol), DMA (0.5 mL), 80 1C. Isolated yield. 120 1C.
45% of 2-(4-phenylquinazolin-2-yl)propan-2-ol (4y) was obtained at
d
120 1C.
reaction pathway (Scheme 2, path b). Moreover, when 2-amino-
benzaldehyde and 2-amino-5-chloro-benzaldehyde were employed
as the substrates, only 60% of 3p and 56% of 3q were
obtained, respectively, due to the self-condensation of the
substrates and the generation of tert-butyl-2-aminobenzoate
(entries 16–17). Subsequently, phenylglycine was replaced with
glycine (2b) in this reaction. The reactions between 2-amino-
benzoketones and glycine gave the corresponding products
3r–3u in 69–86% yield (entries 18–21). It is noteworthy that
coupling products 3v and 3w were obtained in a quantitative
With the optimal reaction conditions in hand, we investigated
the substrate scope of the oxidative decarboxylative coupling
(Table 2). Various 2-aminobenzoketones and 2-aminobenzal-
dehydes (1a–1q) were reacted with phenylglycine (2a) to give
the corresponding 2-phenylquinazolines (3a–3q). When R1 was a
phenyl substituent, different substituents on the para-position
of the phenyl ring did not affect the reaction much (Table 2,
entries 1–4). However, the steric hindrance had a great
influence on this reaction. For example, substrate 1e, bearing
2,5-dimethyl substituents on the phenyl ring, only gave an
11% isolated yield of 3e (entry 5), while substrate 1f, bearing
2,4,6-trimethyl substituents on the phenyl ring, didn’t give the
desired product 3f (entry 6). When R1 was an aliphatic alkyl
group, the corresponding products were obtained with good to
excellent yields (entries 7–13). Among these alkyl substituents,
the chain alkyl afforded the desired products with higher yields
than cycloalkyl, perhaps due to the steric hindrance. In spite of
the complete conversion, only 60% of 3n and 70% of 3o were
obtained when a Cl and Br atom, respectively, were introduced
into the 5-position of 2-aminobenzophenone (entries 14 and
15). To our surprise, 3v and 3w were generated as minor
products. This cleavage of phenyl may occur via a different
Scheme 2 A plausible mechanism for the I2/oxidant-mediated intra-
molecular oxidative decarboxylative coupling.
c
9514 Chem. Commun., 2011, 47, 9513–9515
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yield when 1n and 1o were employed as the substrates
(entries 22–23). However, when alanine (2c) was used in the
reaction, only 16% of 3x was obtained. Meanwhile, 3r was
also generated in 14% yield because of the cleavage of methyl
(entry 24). Similarly, the reaction of 1a with valine (2d) gave 3r
in 30% yield and 2-(4-phenylquinazolin-2-yl)propan-2-ol (4y)
in 45% yield, which came from the further oxidation of 3y.
To obtain 3r exclusively, a product from the cleavage of
an alkyl, other oxidants were examined. When ammonium
persulfate was employed as an oxidant, the reaction of 1a with
2d gave 3r exclusively in 60% yield (Table ESI-2, entry 3). The
couplings of various 2-aminobenzoketones with a-amino acids
also afforded the corresponding products in moderate yields
(entries 1–8). When 1 equiv. of iodine was added, 6-iodo-4-
phenylquinazoline (4r) was obtained with 50% yield (entry 9).
These results indicated that the oxidation capacity of the
oxidants affected the selectivity of the product.
from the Chinese Academy of Sciences and the Graduate
Innovation Fund of USTC.
Notes and references
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To gain an insight into the reaction mechanism, several
preliminary studies were carried out (see ESI for detailsw).
Firstly, the effect of iodine in the decarboxylation was examined.
In the absence of iodine, the coupling product 3a was not
detected in the reaction of 1a with 2a. When N-iodosuccinimide
(NIS) was used as the catalyst, 42% of 3a was obtained but no
desired product was observed when PhI(OAc)2 was employed
as the catalyst. Therefore, a I2–I+ catalytic cycle may play an
important role in the oxidative decarboxylation. In addition,
when radical inhibitors, such as hydroquinone and benzoquinone,
were added to the reaction system, the yield of 3a was reduced
from 85% to less than 5%. This indicated that the reaction
may undergo a radical pathway.
On the basis of the results above and previous reports,9,12,13
a plausible mechanism for this oxidative decarboxylative
coupling is proposed (Scheme 2). Initially, imine A is formed
by the condensation of 1a with 2. Then I+, generated by the
oxidation of iodine, can oxidize A to form radical intermediate
B. Intermediate B eliminates one molecular CO2 to generate
radical C, which can be transformed following two pathways:
(a) a key azomethine ylides intermediate D1 is generated
through removing a hydrogen radical.9 This intermediate
can be further subjected to 1,6-H transfer and intramolecular
nucleophilic attack to give the coupling product F1. Finally,
the further oxidation of F1 by TBHP gives the quinazoline 3;
(b) D2 is generated through removing a R3 radical. Then 3r is
obtained via a similar process to path a.
5 (a) R. Shang, Y. Fu, J. B. Li, S. L. Zhang, Q. X. Guo and L. Liu,
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In summary, we have developed a metal-free intramolecular
oxidative decarboxylative coupling of a-amino acids under
mild conditions. The reaction products can be modulated
by using different oxidants. This reaction is applicable to
the synthesis of quinazolines that tolerate aryl and alkyl
substituents. Compared to traditional decarboxylative
couplings, this coupling displays many advantages, such as being
metal-free, water and air-tolerant, low toxicity and environmen-
tally benign. Further studies on the mechanism and application of
this reaction are under way in our laboratory.
12 J. T. Zhang, D. P. Zhu, C. M. Yu, C. F. Wan and Z. Y. Wang,
Org. Lett., 2010, 12, 2841.
13 For selected oxidative decarboxylations of a-amino acids, see:
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600; (b) A. Boto, R. Hernandez, Y. De Leon and E. Suarez,
J. Org. Chem., 2001, 66, 7796; (c) L. Liu, W. Zhou, J. Chruma
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1342.
We are grateful to the Natural Science Foundation of China
(20932002, 20972144, and 90813008) and the Ministry of
Science & Technology of China (2010CB912103), the support
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9513–9515 9515