A metal-free decarboxylative cyclization from natural α-amino acids to construct pyridine derivatives

Article abstract of DOI:10.1039/c0gc00753f

A metal-free decarboxylative cyclization from natural α-amino acids was developed and applied in the preparation of pyridine derivatives. By virtue of this method, a series of pyridines containing the moiety of natural α-amino acids can be synthesized efficiently from the corresponding natural α-amino acids. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0gc00753f

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COMMUNICATION
A metal-free decarboxylative cyclization from natural a-amino acids to
construct pyridine derivatives†
Qiang Wang, Changfeng Wan, Yang Gu, Jintang Zhang, Lingfeng Gao and Zhiyong Wang*
Received 31st October 2010, Accepted 11th January 2011
DOI: 10.1039/c0gc00753f
Table 1 Optimization of the reaction conditions
A metal-free decarboxylative cyclization from natural a-
amino acids was developed and applied in the preparation
of pyridine derivatives. By virtue of this method, a series
of pyridines containing the moiety of natural a-amino
acids can be synthesized efficiently from the corresponding
natural a-amino acids.
Entry Catalyst
Oxidant
Temp.b
Yield (%)c
1d
2d
3d
4
5
6
7
8
9
10
10% CuO
10% CuO
20% CuO
15% I2
TBHP
TBHP
TBHP
TBHP
70 ◦
80 ◦
70 ◦
70 ◦
70 ◦
60 ◦
70 ◦
70 ◦
70 ◦
70 ◦
C
C
C
C
C
C
C
C
C
C
40
33
32
51
48
54
70
Trace
<5
54
Pyridine derivatives play a significant role in medicinal
chemistry.1 In particular, many pyridine derivatives containing
the moiety of natural a-amino acids (Fig. 1) have various
bioactivities.2–4 Compound 1 can inhibit the interaction of
the estrogen receptor with coactivator peptides, while 2 and
3 can selectively bind to thyroid-hormone-receptor mutant
TRb(H435Y) to chemically treat some genetic diseases. More-
over, recent investigations indicated that various pyridine deriva-
tives present bioactivities against HIV.5–7 We have been focusing
on the search of small molecules to inhibit HIV transcription8,9
15% I2, 10% CuO TBHP
50% I2
50% I2
50% I2
—
TBHP
TBHP
—
TBHP
50% I2
Di-tert-butyl
peroxide
m-CPBA
11
12
50% I2
50% I2
70 ◦
C
C
27
42
2,2¢-Peroxybis- 70 ◦
(propane-2,2¢-
diyl)dibenzene
TBHP
TBHP
13
50% I2
50% I2
50 ◦
70 ◦
C
C
53
55
14e
a The reaction mixture of 0.32 mmol of L-Ala, 0.4 mmol of phenylac-
˚
etaldehyde, 0.4 mmol of oxidant, 2 mL of DMA, and 4 A MS was stirred
with different catalytic loadings under N2 for 1.5 h. The catalytic loading
was based on the amount of phenylacetaldehyde. b Slowly raised to the
desired temperature from room temperature. c Isolated yields based on
phenylacetaldehyde. d Reaction time 5 h. e 0.3 mmol of TBHP. TBHP =
tert-butylhydroperoxide.
and attempting to make use of the pyridines containing the
moiety of a-amino acids as a new kind of inhibitor for
HIV transcription. For a long time, the synthesis of pyridine
derivatives has involved NH3 and other N-containing substances
as nitrogen sources.10,11 It is difficult to adopt the previous
methods to prepare the pyridines which contain the moiety
of natural a-amino acids. On the other hand, decarboxylative
coupling reactions, including decarboxylative coupling of a-
amino acids, have developed remarkably in recent years,12,13–18
Generally, the decarboxylative coupling reactions can be clas-
sified into two categories in terms of reaction mechanism.
The first category is the transition metal (generally palla-
dium) mediated decarboxylative coupling,12c–e the mechanisms
of these coupling reactions are similar to that of the classic
Fig. 1 Pyridines bearing moiety of natural a-amino acids.
Hefei National Laboratory for Physical Sciences at Microscale, CAS
Key Laboratory of Soft Matter Chemistry, Joint Laboratory of Green
Synthetic Chemistry and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
E-mail: zwang3@ustc.edu.cn; Fax: +86 551-360-3185; Tel: +86
551-360-3185
† Electronic supplementary information (ESI) available: NMR data of
all products. See DOI: 10.1039/c0gc00753f
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Table 2 Oxidative decarboxylative cyclization of different a-amino acids and aryl-aldehydes
Entrya
1
A
B
C
Entrya
9
A
B
C
B1
2
3
B1
B1
10
11
B1
B1
4
5
6
B1
B1
B1
12
13
14b
15c
7
8
B1
B1
a Reaction scale and conditions: 0.32 mmol L-a-amino acids (unless stated), 0.4 mmol aldehydes, 0.1 mmol I2, 0.4 mmol TBHP, 2 mL DMA, powder
◦
4 A MS. Stirred and slowly raised to 70 C and kept for 1–2 h under N2. Catalysts amount were based on B. Isolated yields based on B. b Slowly
˚
raised to 50 ◦C and kept for 3 h. c Reaction was carried out for 5 h.
cross-coupling reactions such as Heck and Suzuki reactions,
involving oxidative addition and reductive elimination of the
transition metals in the reaction process. This kind of decar-
boxylative coupling reaction is generally carried out at high tem-
perature and the reactions are sensitive to the active hydrogens in
the reactants. The other category often involves the decarboxyla-
tive coupling reactions of amino acids. The mechanism of this
category possesses diversity according to different reactants and
conditions. Generally, metals, high temperature and oxidants
are necessary to achieve decarboxylation and form dipoles,
azomethine ylides and other active intermediates to enable the
coupling.12a,12b,13,15–19 Herein, we report a new decarboxylative
cyclization reaction to construct pyridines containing the moiety
of natural a-amino acids under metal-free conditions.
Initially, L-Ala and phenylacetaldehyde were employed as
model substrates and the reaction was carried out under the
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following conditions: 10% CuO as a catalyst, 1.0 equiv of TBHP
˚
as an oxidant, 4 A MS (molecular sieves) as a dehydrator, and
DMA (N,N-dimethylacetamide) as the reaction solvent. The
reaction mixture was stirred at 70 ◦C for 5 h under nitrogen, and
afforded the product 2-methyl-3,5-diphenylpyridine with a yield
of 40%. Subsequently the reaction conditions were optimized
in order to enhance the reaction yield. Experimental results
indicated that the oxidant and catalyst were necessary and TBHP
was a better oxidant in this reaction (Table 1, entries 7–12).
And, the combination of I2 with TBHP showed a better catalytic
activity in this decarboxylative cyclization (Table 1, entries 1–
7). Finally, the reaction was optimized and a yield of 70% was
obtained under metal-free conditions, as shown in entry 7 of
Table 1.
Scheme 1 Proposed mechanism of the oxidative decarboxylative
To examine the scope of this oxidative decarboxylative
cyclization, a series of natural a-amino acids were employed as
the reaction substrates. Normally, Ala (alanine), Asp (aspartate),
Glu-5-OMe (glutamic acid 5-methyl ester), Gly (glycin), Ile
(isoleucine), Leu (leucine), Nor-Leu (nor-leucine), Val (valine),
Nor-Val (nor-valine), Phe (phenylalanine), and Phg (phenyl-
glycine) performed well in this reaction to give the correspond-
ing pyridines with satisfactory yields (Table 2). However, the
decarboxylative cyclizations were not carried out when the a-
amino acids contained the active hydrogens on the side chains.
For example, the reaction did not work when Lys (lysine), Arg
(arginine), Ser (serine), and Thr (threonine) were employed
as the starting materials. Generally, electron-donating groups
favored this cyclization (Table 2, entries 1 and 2) while steric
hindrance impaired this reaction (Table 2, entries 4, 5, 6, 7 and
8). The phenyl group could present an electronic effect and
steric hindrance at the same time. When a phenyl group was
connected to the a-carbon atom of the amino acid, the electronic
effect played a crucial role because of the conjugation (Table 2,
entries 3). In contrast, when benzyl was connected to the a-
carbon atom of the amino acid, the steric effect was presented
since conjugation was blocked and the volume of the benzyl
group disfavored this cyclization (Table 2, entry 10). When
Asp, which containing two carboxyl groups, was employed
as the substrate (Table 2, entry 9), C1 (2-methyl-3,5-diphenyl-
pyridine) was obtained with a yield of 63%, which was the same
product as that in entry 1 of Table 2. Another two-carboxyl a-
amino acid, Glu, did not perform in this reaction, however, the
corresponding pyridine could be obtained after the esterification
of the g-COOH (Table 2, entry 11). As for aryl-acetaldehydes,
the substitution on the phenyl ring had a negative influence on
the reaction yield regardless of the electron-donating groups
or electron-withdrawing groups (Table 2, entries 12, 13), while
the reaction did not work when the aliphatic aldehydes were
employed as the reaction substrates (Table 2, entry 15).
cyclization.
acetaldehydes and totally non-toxic natural a-amino acids. In
this reaction a variety of pyridines containing the moiety of
a-amino acids can be prepared easily from facile a-amino
acids under mild conditions. Some of these pyridines may have
potential bio-activity since they contain various moieties of a-
amino acids. An investigation is underway to discover more
details about the reaction and the potential bio-activity of the
products.
We are grateful to the Natural Science Foundation of China
(20932002, 20972144, 20628202, 20772188 and 90813008) and
the support from the Chinese Academy of Sciences.
Notes and references
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In terms of our experimental results and the previous
publications,13,17 a possible mechanism was proposed (Scheme 1)
for this transformation. First, the amino group of a-amino acids
condense with aryl-acetaldehyde to form imide, and is followed
by amino acid-catalyzed aldol condensation to afford I.20 I is
converted into the intermediate II under the catalysis of I2 and
TBHP. Intermediate II can easily cyclize to give the intermediate
III, which is finally oxidized to give the pyridines.
In summary, we have developed a metal-free decarboxyla-
tive cyclization to construct pyridine derivatives from aryl-
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