Synthesis of 2,3,6-trisubstituted pyridines by transition-metal free cyclization of 1,3-diynes with amino acids

Article abstract of DOI:10.1016/j.tetlet.2017.06.080

Amino acids are firstly employed in transition-metal free heterocyclization reaction of 1,3-diynes in the presence of K₃PO₄ and DMSO at 120?°C. This method produces 2,3,6-trisubstituted pyridines with up to 86% yield. The –CO₂H group on the amino acids is crucial for this heterocyclization reaction. The mechanism of such a heterocyclization reaction is discussed, as well.

Full text of DOI:10.1016/j.tetlet.2017.06.080

Accepted Manuscript
Synthesis of 2,3,6-trisubstituted pyridines by transition-metal free cyclization
of 1,3-diynes with amino acids
Gang Zhou, Xiaoming Zhao, Wenyan Dan
PII:
S0040-4039(17)30820-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.080
TETL 49072
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 May 2017
23 June 2017
26 June 2017
Please cite this article as: Zhou, G., Zhao, X., Dan, W., Synthesis of 2,3,6-trisubstituted pyridines by transition-
metal free cyclization of 1,3-diynes with amino acids, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/
j.tetlet.2017.06.080
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Synthesis of 2,3,6-trisubstituted pyridines by
transition-metal free cyclization of 1,3-diynes
with amino acids
Leave this area blank for abstract info.
Gang Zhou, Xiaoming Zhao*, and Wenyan Dan
H2N
H2N
CO2H
CO2H
or
or
+
R1
N
R
CO2H
K3PO4
DMSO, 120 ºC, 12h
16 examples
H2N
R1
R1
R1
R1 = aryl and heteroaryl
up to 86% yield

1
Tetrahedron Letters
Synthesis of 2,3,6-trisubstituted pyridines by transition-metal free cyclization of 1,3-
diynes with amino acids
Gang Zhoua , Xiaoming Zhaoa,  and Wenyan Dana
a State Key Laboratory of Pollution Control and Resource Reuse, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092
Shanghai, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Amino acids are firstly employed in transition-metal free heterocyclization reaction of 1,3-
diynes in the presence of K3PO4 and DMSO at 120 °C. This method produces 2,3,6-
trisubstituted pyridines with up to 86% yield. The -CO2H group on the amino acids is crucial for
this heterocyclization reaction. The mechanism of such a heterocyclization reaction is discussed,
as well.
Available online
Keywords:
Amino acid
1,3-Diyne
2009 Elsevier Ltd. All rights reserved.
Cyclization
Pyridine
Transition-metal free
———
 Corresponding author.
E-mail: xmzhao08@mail.tongji.edu.cn

2
Tetrahedron
Introduction
(entry 13). DBU was not proper base for this reaction (entry 13).
The variation of the reaction temperature has a significant impact
on the result of the reaction (entries 12, 1415). Thus, we chose
entry 12 as the optimized conditions for the further investigation.
Pyridine moiety is frequently found in naturally occurring
compounds, pharmaceuticals, and functionalized materials, and
useful ligands in organic synthesis.1 For example, 2,3,6-
trisubsttued pyridines including Avoralstat,2 CC-115,3 Fluoro-
pioglitazone,4 and AZD-40175 exhibit excellent biological
activity (Fig. 1). In the past few decades, various methods for
the synthesis of pyridines were developed.6 Among them, there
are limited protocols for the synthesis of 2,3,6-trisubstituted
pyridines such as
Fig. 2 X-ray molecular structure of 3a.
Table 1: Optimizing reaction conditions. a
Figure 1. Four representative drugs with a pyridine ring
Ph
N
Me
Ph
solvent, temp
additive
CO2H
Ph
Ph
+
H2N
(1) palladium-catalyzed Suzuki cross-coupling reaction of 2,6-
dibromopyridines with arylboronic acid;7 (2) transition-metal (Fe
or Co or Ni or Au or Nb)-catalyzed cycloaddition of alkynes or
diene with nitriles;8 (3) 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU)-promoted ring expansion of 2-allyl-2H azirines;9 and (4)
Cu(OAc)2 or BF3-catalyzed cycloaddition of conjugated imine or
allyl amines with alkynes.10 Therefore, it is still highly desirable
to develop new practical method for the synthesis of 2,3,6-
trisubstituted pyridines.
2a
1a
3a
Entry
1
2
3
4
5
6
7
8
Catalyst
AgOAc
CuCl
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
dioxane
toluene
Additive
Temp, °C Yield of 3ab %
-
-
-
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
80
0
0
0
70
0
0
0
0
60
40
62
85
50
14
75
trace
Pd(OAc)2
-
-
-
-
-
-
-
-
-
-
-
-
-
Cs2CO3
-
Cs2CO3
Cs2CO3
Amino acids are the key building blocks in the organic
synthesis as well as play a very important role in the area of
biochemistry.11 To the best of our knowledge, amino acids are
not yet utilized in the synthesis of pyridines. In this paper, we
report a transition-metal free heterocyclization reaction of 1,3-
diynes with 3-aminopropanoic acid, glycine and 4-aminobutanoic
acid in the presence of K3PO4, which yields substituted pyridines.
1,2-DCE Cs2CO3
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
K2CO3
Na2CO3
NaOH
K3PO4
Na3PO4
DBU
10
11
12c
13
14
15
16
K3PO4
K3PO4
The present studies were initiated by exploring a reaction of 1,4-
diphenylbuta-1,3-diyne (1a) with β-amino acid such as 3-
aminopropanoic acid (2a) in the presence of AgOAc, CuCl and
Pd(OAc)2 in dimethyl sulfoxide (DMSO) at 120 °C, respectively,
and no reaction occurred (entries 13). To our delight, the
formation of 2-methyl-3,6-diphenylpyridine (3a) was observed
when Cs2CO3 was used (entry 4); in contrast, the
a Reaction conditions: 1a (0.2 mmol), 3-aminopropanoic acid (2a) (0.4 mmol
) and base (0.4 mmol) in solvent (2 mL) in a sealed tube at 120 °C for 24h .
b Isolated yields
c K3PO4 ( 0.8 mmol) was used in a sealed tube at 120 °C for 12h.
heterocyclization didn’t proceed in the absence of Cs2CO3 (entry
5). The molecular structure of 3a was also established by its X-
ray diffraction analysis (Fig. 2).12 Solvent examination revealed
that DMSO gave a superior yield; whereas other solvents
including dioxane, toluene, and 1,2-dichloroethane (1,2-DCE)
were not suitable (entries 68). Next, we explored a range of the
additives such as Cs2CO3, K2CO3, Na2CO3, NaOH, Na3PO4,
K3PO4, and DBU. The preliminary results indicated that the
nature of additives has a great influence on the yields of this
reaction;13 for instance, K3PO4 gave the best yield (entry 12).
Both alkali metal (Na, K and Cs) carbonate and NaOH led to fair
to good yield (entries 4, 911). Na3PO4 resulted in a 50% yield
Having established the optimized reaction conditions, we
subsequently examined the scope of the reaction of 3-
aminopropanoic acid (2a) with the diverse 1,3-diynes 1 (Table
2). The substrate (1a) and 1,3-diynes (1bi) with either electron-
donating group or electron-withdrawing group (e.g., p-Me, p-
MeO, p-pent-C6H4, m-Me, p-F, p-Cl, p-Br and m-F) led to 2,3,6-
trisubstituted pyridines (3ai) in good to high yield (Table 2).
Notably, the disfavorable ortho effect was observed when 1,4-
bis(2-fluorophenyl)buta-1,3-diyne (1j) was applied (Table 2). 2-
Thienyl-substituted 1,3-diyne 1i worked well and, however,
tetradeca-6,8-diyne 1l failed to proceed this reaction (Table 2).
1,4-Di(biphenyl-4-yl)buta-1,3-diyne (1m) provided 3,6-
di(biphenyl-4-yl)-2-methylpyridine (3m) in a 71% yield.
Interestingly, 1-chloro-4-((4-methoxyphenyl)buta-1,3-

3
Ph
Ph
N
diynyl)benzene (1n) was tested and it gave 3n (36% yield) along
with 3n’ (42% yield), which are separable (Table 2).
eq- 1
H2
N
CO2H
Ph
Ph
2b
2c
3o, 64%
K3PO4
N
COOH
eq-2
H2
N
CO2
H
+
Ph
Ph
Table 2: Scope of a variety of 1,3-diynes 1. a-b
DMSO, 120 ºC
12h
1a
3p
, 73%
R
N
Me
R
K3PO4
CO2H
R
R
H2N
eq-3
Complex
+
H2N
DMSO, 120
ºC, 12h
n = 0 or 1
2a
1
3
2d n = 1
2e n = 0
N
N
N
MeO
OMe
3b, 82%
Scheme 1. The amino acids 2b, 2c and the amines 2d and 2e used in the
3c, 70%
3a, 85%
reaction.
N
N
N
F
F
C5H11
C5H11
3d, 81%
3e, 76%
3f, 86%
CO2
F
F
HO2C
R1
N
R1
N
N
N
N
NH2
R1
Oxidation
-CO2
Cl
Cl Br
Br
2a
R1
R1
O
R1
120 o
3g, 82%
3i, 76%
3h, 80%
D
3
1
F
F
K3PO4
O2C
C
N
N
N
S
C5H11
C5H11
O
O
O
H
S
H
N
R1
3l, 0%
R1
R1
3j, 56%
3k, 73%
N
N
N
NH
R1
R1
Cl
OMe
R1
C
A
B
3n, 36%
3m, 71%
N
Scheme 2. Possible mechanism of the present reaction.
MeO
Cl
On the basis of our observations and other works14, a possible
mechanism was proposed in Scheme 2. The addition of 3-
aminopropanoic acid 2a to 1,3-dyine 1 in the presence of K3PO4
at 120 C gives a vinyl amine A, which undergoes a
tautomerization to form B. The deprotonation15 of B following
by a cyclization furnishes a conjugated C. Proton transfer from
CO2H group to the carbon anion on C takes place to give D. D
subsequently occurs the aromatization in the presence of
DMSO13b,16 and a decarboxylation reaction14 to provide the 2,3,6-
trisubstituted pyridine. Notably, DMSO not only serves as a
solvent, but also works as an oxidant in this reaction.13b,16 This is
in agreement with the results of the solvent survey in Table 1, as
well.
3n', 42%
a Reaction conditions: 1,3-diynes 1 (0.2 mmol), 3-aminopropanoic acid (2a)
(0.4 mmol ) and K3PO4 (0.8 mmol) in DMSO (2 mL) in a sealed tube at 120
°C.
b Isolated yields.
Interestingly, glycine (2b) was examined under the modified
conditions (e.g., 0.4 equivalent of 2b and 0.8 equivalent of
K3PO4) and it gave 2,5-diphenylpyridine (3o) in a 64% yield
(eq1 in Scheme 1). This is a new way for the synthesis of 2,5-
disubstituted pyridines. More significantly, we extended this
method to -amino acid such as 4-aminobutanoic acid (2c), 2-
I
n conclusions, we successfully developed a heterocyclization
(3,6-diphenylpyridin-2-yl)acetic acid (3p) was obtained in a 73%
yield. No decarboxylation reaction occurred in this cause of the
reaction (eq2 in Scheme 1).
reaction of 1,3-diynes 1 with amino acids 2 in the presence of
K3PO4, which provided 2,3,6-trisubstituted pyridines in good to
high yield. This method allows the use of aliphatic amino acids,
tolerates various functional groups, and affords a new approach
toward 2,3,6-trisubstituted pyridines. These are the first examples
in which amino acids are used in the synthesis of 2,3,6-
trisubstituted pyridines.
This is also a new one-pot method for the construction of
pyridines with an aliphatic carboxylic acid. In comparison with
above-mentioned reactions, either butan-1-amine (2d) or propyl
amine (2e) was also explored and it afforded the complex
mixture (eq3 in Scheme 1). These results strongly suggested
that the -CO2H group of amino acids is crucial for this
heterocyclization reaction.
Acknowledgments
We gratefully acknowledge the NSFC (21272175) for
generous financial support.
We carried out two controlled experiments in order to insight
into the pathway of this reaction. Under the optimized conditions,
the heterocyclization of 1a with 2a in either (CD3)2CO or DMSO
containing 5 L of D2O gave no deuterated pyridine 3a,
respectively.
References and notes
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4
Tetrahedron
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5
Highlights
 Synthesis of pyridines from 1,3-diynes and
amino acid was presented.

3-Aminopropanoic acid provided the desired
products.
 4-Aminobutanoic acid provided 2-(3,6-
diphenylpyridin-2-yl)acetic acid.
 Glycine afforded 2,5-diphenylpyridine.