Molecular Iodine-Mediated Chemoselective Synthesis of Multisubstituted Pyridines through Catabolism and Reconstruction Behavior of Natural Amino Acids

Article abstract of DOI:10.1021/acs.orglett.5b03037

A new process has been developed for the selective construction of 2,6-disubstituted, 2,4,6-trisubstituted, and 3,5-disubstituted pyridines based on the catabolism and reconstruction behaviors of amino acids. Molecular iodine was used as a tandem catalyst to trigger the decarboxylation-deamination of amino acids and to promote the subsequent formation of the pyridine products.

Full text of DOI:10.1021/acs.orglett.5b03037

Letter
pubs.acs.org/OrgLett
Molecular Iodine-Mediated Chemoselective Synthesis of
Multisubstituted Pyridines through Catabolism and Reconstruction
Behavior of Natural Amino Acids
Jia-Chen Xiang, Miao Wang, Yan Cheng, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Hubei, Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: A new process has been developed for the
selective construction of 2,6-disubstituted, 2,4,6-trisubstituted,
and 3,5-disubstituted pyridines based on the catabolism and
reconstruction behaviors of amino acids. Molecular iodine was
used as a tandem catalyst to trigger the decarboxylation−
deamination of amino acids and to promote the subsequent
formation of the pyridine products.
mino acids hold an important place in the annals of ligand
chemistry,1 chiral catalysis,2 and total synthesis.3 They
Pyridine is one of the most common N-containing aromatic
ring systems8 and can be found in a wide range of natural
products, pharmaceuticals, and functional materials.9 Pyridine
rings are traditionally prepared from aldehydes and amines via
multicomponent reactions10 or transition-metal-catalyzed
cycloaddition processes.11 However, the application of these
reactions can sometimes be limited by their requirements for
the use of toxic aldehydes or the need for extensive workup
procedures to remove residual metals. To address these
limitations, research efforts have recently been directed toward
the construction of pyridine skeletons via the oxidative cleavage
of the C−N bonds of amine derivatives12 (Figure 2, Column 1,
A
have also been used to develop an interesting array of synthetic
methodologies, with the majority of these studies being focused
on C−C bond-forming reactions via a decarboxylative coupling
process.4 However, nature is much more effective at affecting
the chemical transformations of amino acids. These compounds
are used in nature for many other reactions besides
decarboxylative coupling reactions since amino acids are
some of the most basic and versatile synthons available to
living organisms. During the biosynthesis of alkaloids, amino
acids can be catabolized into smaller fragments, which are
subsequently used as building blocks to reconstruct the core
skeletons of alkaloids under enzymatic conditions.5
A
representative example of this process is the biosynthesis of
haouamine A, which is a pyridine-based alkaloid that is widely
believed to be biogenetically derived from four identical
tyrosine congeners6 (Figure 1). The catabolism of these
Figure 2. Selected examples of pyridine synthesis and a brief
introduction of this work.
left side). Herein, we report an unprecedented I2-mediated
reaction for the in situ cleavage of the unreactive C−N bonds13
of natural amino acids to catabolize to the corresponding
aldehydes and amines, which subsequently undergo a
reconstruction process to afford 2,6-disubstituted, 2,4,6-
trisubstituted, and 3,5-disubstituted pyridines in a single step.
Given that the construction of pyridines from natural amino
Figure 1. Biosynthesis protocol of haouamine A.
tyrosine derivatives through sequential decarboxylation and
deamination reactions is thought to lead to the formation of the
corresponding phenylacetaldehyde derivatives and ammonia,
which might undergo a Chichibabin-type reaction to produce a
pyridinium core.7 To the best of our knowledge, there have
been no reports concerning the use of the catabolism and
reconstruction behaviors of natural amino acids as a leading
strategy for the development of novel synthetic methodologies.
Received: October 19, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03037
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acids under mild condition represents a rare transformation14
(Figure 2, Column 2, right side), this new method for the
selective synthesis of multisubstituted pyridines from different
kinds of amino acids will be of considerable practical value
(Figure 2, Column 2).
a b
,
Scheme 1. Scanning of Substrate Scope of Reaction 1
We initially investigated the reaction of glycine (1a) with
acetophenone (2a) as a model reaction in the presence of 1.0
equiv of I2 at 100 °C in DMF. Several bases were screened
against this transformation to optimize the reaction conditions
(for optimization details, please see Supporting Information
(SI)). The results of these screening experiments showed that
pyridine was critical to the success of the transformation (Table
1, entry 1). When the solvent was switched from DMF to
a
Table 1. Optimization of the Reaction 1
b
entry
solvent
I2 (equiv) additive (equiv) temp (°C) yield (%)
1
DMF
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.5
1.5
Pyridine (2.0)
100
100
100
100
100
100
100
110
120
120
120
120
31
2
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
Pyridine
−
61
3
DBU (2.0)
trace
36
a
Reaction conditions: 1 (2.0 mmol), 2 (2.0 mmol), I2 (2.0 mmol),
b
4
DMAP (2.0)
pyridine (2.0 mL), 120 °C for 12 h. Isolated yields. Reactions were
5
Cs2CO3 (1.0)
trace
23
carried out in a pressure vessel.
6
K2CO3 (1.0)
7
KOH (2.0)
27
in moderate yield (45%) which was unambiguously confirmed
by X-ray crystallography (please see SI). The optimized
conditions were also successfully applied to a wide variety of
heteroaryl ketones, including furanyl, thienyl, indolyl, and
benzofuryl methyl ketones, which generated the corresponding
heterocyclic substituted pyridines in good yields (3e, 3n, 3m,
3s, 3u, respectively). It is noteworthy that the reaction of
glycine with 1-phenyl-2-(phenylsulfonyl)ethan-1-one under the
optimized conditions led to the unexpected cleavage of one of
the two sulfonylbenzene groups and the formation of 2,3,6-
trisubstituted pyridine (3p) as the main product in 74% yield.
Several non-natural α-aromatic amino acids, such as 2-amino-2-
phenylacetic acid and related derivatives, were found to be
especially good substrates for this transformation (3q−t with
good yields in most cases) because of the electron-withdrawing
effect of their aromatic rings. Sterically hindered substituents
were also employed, and the results were satisfactory (3u and
3v). Cross-trapping product 3qv could be obtained using 2a
(1.0 mmol) together with 1-(9H-fluoren-3-yl)ethanone (1.0
mmol) as substrates.
Having evaluated the scope of this new method, we turned
our attention to the reaction of phenylalanine (4a) with
acetophenone (2a). However, this reaction did not generate
any of the desired product under the optimized conditions, but
it did result in the formation of a small amount of 3,5-
diphenylpyridine. Further investigation revealed that acetophe-
none did not participate in this transformation and that the 3,5-
diphenylpyridine product was therefore formed as a con-
sequence of the catabolism and homoreconstruction of
phenylalanine through a C−N cleavage process. Because of
this unusual transformation, we screened a variety of different
solvents with the aim of improving the yield of the 3,5-
diphenylpyridine product (for the optimization details, please
see SI). Only DMSO gave a relatively meaningful yield (Table
2, entry 1). The optimal temperature for the reaction was
determined to be 115 °C (Table 2, entry 2). The loading of I2
was also examined. Addition of 0.2 equiv of I2 led to a 20%
8
−
−
−
−
−
65
9
73
10
11
12
24
41
27
a
Reaction conditions: 1a (2.0 mmol, excessive dose), 2a (2.0 mmol),
b
additive, solvent (2.0 mL) for 12 h. Isolated yields based on 2a.
Reactions were carried out in a pressure vessel.
pyridine, the yield of the desired product 2,6-diphenylpyridine
(3a) increased significantly (Table 1, entry 2). Several other
bases were also evaluated but found to be ineffective (Table 1,
entries 3−7). The optimal temperature for this reaction was
determined to be 120 °C (Table 1, entry 9). Notably,
decreasing or increasing the loading of I2 led to a reduction
in the yield of the product, indicating that a loading of 1.0 equiv
was optimal.
With the optimized conditions in hand, we proceeded to
examine the scope of the reaction using a variety of different
substrates (Scheme 1). Several alkyl-branched amino acids,
including alanine (3f), 2-aminobutanoic acid (3g, 3h), leucine
(3i), and 2-aminohexanoic acid (3j−n), all reacted smoothly
under the optimized conditions to produce the corresponding
2,4,6-trisubstituted pyridines in moderate yields. Unfortunately,
the use of O-acetyl-L-serine hydrochlorideas (2o) or O-butyryl-
L-serine hydrochlorideas (2o′) as substrates failed to provide
the desired products. The unexpected cleavage of C−O bonds
led to 4-methyl-2,6-diphenylpyridine (3f) being the major
product. Furthermore, a wide range of acetophenones were
screened under the optimized conditions. Acetophenones
bearing an electron-withdrawing group on their phenyl ring
reacted well and produced the desired pyridine products in
good yields (e.g., 3d, 3k, 3l). Acetophenone substrates bearing
a halogen substituent on their benzene ring (e.g., 2-Cl, 4-Cl, 4-
Br: 3b, 3c, 3j) were well tolerated. Notably, 2-naphthyl methyl
ketone also reacted smoothly to give the desired product (3h)
B
DOI: 10.1021/acs.orglett.5b03037
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Organic Letters
Letter
a
visualized as a white fluorescent dot by TLC. Unfortunately,
histamine and tryptophan did not react in the same way.
The following control experiments were performed to
provide some insight into the mechanisms of these reactions
(for a detailed graphic, please see SI). For reaction 1,
acetophenone was treated with 1.0 equiv of I2 in the absence
of an amino acid in pyridine under the standard conditions for
6 h. This reaction produced 1-(2-oxo-2-phenylethyl)pyridin-1-
ium iodide (A) as a undissolved product in excellent yield.
Given that the generation of the pyridinium ylide equivalent A
would be an inevitable part of this reaction and pyridine was
found to be critical to the success of this transformation, it
seemed reasonable to assume that a pyridinium ylide was
formed as a crucial intermediate during this reaction. The
formation of 3q in 71% yield from the reaction of amino acid
1q with A in the absence of acetophenone provided further
proof of this idea. However, the yield of this reaction was lower
than that of the reaction shown in Scheme 3, which indicated
Table 2. Optimization of the Reaction 2
b
entry
I2 (equiv)
additive (1.0 equiv)
temp (°C)
yield (%)
1
2
3
1.0
1.0
0.2
0.2
0.4
0.5
1.0
1.5
0.5
0.5
0.5
0.5
−
−
−
−
−
−
−
−
100
115
115
115
115
115
115
115
115
115
115
115
31
46
20
c
4
65
5
25
6
61
7
33
8
trace
25
9
K2CO3
10
11
12
NaOAc
HOAc
trace
75
acetic anhydride
70
a
Reaction conditions: 4a (1.0 mmol), I2, additive, DMSO (3.0 mL) for
Scheme 3. Probable Mechanisms
b
c
6 h. Isolated yields. Reaction time extented to 24 h. Reactions were
carried out in a pressure vessel.
yield of the product (Table 2, entry 3). However, extension of
the reaction time to 24 h lead to a 65% yield which means I2
could be recycled by DMSO as a catalyst. The best result could
be achieved when using 0.5 equiv of I2 (Table 2, entry 6). An
increased dose of I2 lead to a dramatic reduction of desired
product. Additives such as acids and bases have been scanned,
and acetic acid was found to be optimal in reducing byproducts
and improving the yield of 5a (Table 2, entry 11).
Given that the yield of 3,5-diphenylpyridine achieved by this
reaction was pleasing compared with that of “abnormal”
Chichibabin pyridine synthesis,15 we proceeded to investigate
the scope of this conversion using a variety of phenylalanine
derivatives bearing sensitive halogen substituents (4-F, 4-Cl, 4-
Br, and 3-F; Scheme 2). All of these compounds gave the
desired products in good yields. It is noteworthy that the
reaction of tyrosine with a free hydroxyl group successfully
furnished the interleukin-6 inhibitor Sch-2141816 (5f) in 66%
yield. The use of tyrosine derivatives bearing a t-Bu protecting
group on their hydroxyl functionality gave 5g (70%), which was
a b
,
Scheme 2. Scanning of Substrate Scope of Reaction 2
that acetophenone played another role in the transformation.
The subsequent reaction of 1q with equal amounts of A and 2v
under the standard conditions gave the symmetrical products
3q and 3v in 7% and 34% yields, respectively. The cross-
trapping product 3qv was also obtained, as predicted, in a 45%
yield. For reaction 2, we repeated the first reaction using 2-
phenylethan-1-amine instead of phenylalanine (4a). However,
this reaction failed to produce any trace of the desired product
5a under standard conditions. This result suggests that the
driving force for this reaction was the decarboxylation of the
amino acid. The absence of a carboxyl group would make it
difficult to activate the C−N bond at the α position, therefore
preventing its oxidative cleavage by I2. This result also suggests
that this efficient I2-mediated catabolism process is unique to
amino acids. Furthermore, 2-phenylacetonitrile (B3), 2,4-
diphenylbut-2-enal (B4), and toluene could be detected by
GC-MS as intermediates.
a
Reaction conditions: 4 (2.0 mmol), HOAc (2.0 mmol), I2 (1.0
b
Based on the results described above and previous research,
we have proposed a plausible mechanism (Scheme 3). For
mmol), DMSO (3.0 mL), 115 °C for 6 h. Isolated yields. Reactions
were carried out in a pressure vessel.
C
DOI: 10.1021/acs.orglett.5b03037
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004,
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(3) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243
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(a) Bi, H. P.; Zhao, L.; Liang, Y. M.; Li, C. J. Angew. Chem., Int. Ed.
2009, 48, 792. (b) Zuo, Z. W.; MacMillan, D. W. C. J. Am. Chem. Soc.
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(5) For selected examples of some alkaloids which were
biosynthesized through catabolism and reconstruction behavior of
natural amino acids, please see: (a) Turner, N. J. Chem. Rev. 2011, 111,
4073. (b) Dagorn, F.; Yan, L. H.; Gravel, E.; Leblanc, K.; Maciuk, A.;
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(6) (a) Burns, N. Z.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47,
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6600.
(7) Chichibabin, A. E.; Zeide, O. A. J. Russ. Phys. Chem. Soc. 1914, 46,
1216.
(8) Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon:
Oxford, 1996; Vol. 5, p 167.
(9) (a) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223.
(b) Roth, H. J.; Kleemann, A. Pharmaceutical Chemistry (Drug
Synthesis); John-Wiley & Sons, Ltd.: New York, 1988; Vol. 1, pp
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(10) For selected examples see: (a) Li, Z. Y.; Huang, X. Q.; Chen, F.;
Zhang, C.; Wang, X. Y.; Jiao, N. Org. Lett. 2015, 17, 584. (b) Khanal,
H. D.; Lee, Y. R. Chem. Commun. 2015, 51, 9467. (c) Shen, L.; Cao, S.;
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(11) For selected reviews see: Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (b) Zeni,
G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (c) Varela, J. A.; Saa, C.
Chem. Rev. 2003, 103, 3787.
reaction 1, the acetophenone substrate would be initially
converted to 2-iodo-1-phenylethan-1-one, which would be
trapped by pyridine to afford 1-(2-oxo-2-phenylethyl)pyridin-1-
ium iodide (A). At the same time, I2 would trigger the
sequential decarboxylation and oxidation reactions of the amino
acid substrate to generate the corresponding imine species,
which would undergo a rapid hydrolysis reaction to give
ammonia and the corresponding aldehyde. The ammonia,
aldehyde, A, and residual acetophenone would converge via a
Krohnke type pyridine synthesis17 to reconstruct the desired
̈
2,6-disubstituted or 2,4,6-trisubstituted pyridine product in the
presence of I2. A similar mechanism would also occur for
reaction 2 (with phenylalanine as an example). Followed by
decarboxylation of carboxyl group, I2 promoted the oxidation of
the C−N bond to afford the unstable intermediate 2-
phenylethan-1-imine (B1). After hydrolysis, phenylalanine
catabolized to corresponding ammonia and 2-phenylacetalde-
hyde (B2). The combination of 3 equiv of B3 with 1 equiv of
ammonia (or 2 equiv of B3 with 1 equiv of B1) would allow for
the construction of the pyridine core in situ via a Chichibabin-
type pyridine synthesis. Finally, the 3,5-disubstituted pyridine
product could be obtained by a debenzylation/aromatizition
process.10a This process would allow for the regeneration of a
catalytic equivalent of I2 in the presence of DMSO.
In summary, we have developed a novel method for the
chemoselective synthesis of 2,6-disubstituted, 2,4,6-trisubsti-
tuted, and 3,5-disubstituted pyridines from natural amino acids.
These transformations featured a catabolism and reconstruction
reaction model including an unprecedented I2-mediated
oxidative cleavage of unreactive C−N bonds. In addition to
the inherent value offered by this reaction as a biomimetic
process, one of the main advantages of this environmentally
benign method is that it avoids the direct use of toxic aldehydes
and harsh conditions. Moreover, the transformation of biomass
materials into synthetically valuable scaffolds is ecologically and
economically beneficial.
(12) (a) Xi, L. Y.; Zhang, R. Y.; Liang, S.; Chen, S. Y.; Yu, X. Q. Org.
Lett. 2014, 16, 5269. (b) Wu, K.; Huang, Z. l.; Liu, C.; Zhang, H.; Lei,
A. W. Chem. Commun. 2015, 51, 2286.
(13) Extensive research reported that C−N bonds are inert; see:
(a) Ueno, S.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129,
6098. (b) Zhao, X. H.; Liu, D. L.; Guo, H.; Liu, Y. G.; Zhang, W. B. J.
Am. Chem. Soc. 2011, 133, 19354. (c) Kalutharage, N.; Yi, C. S. Angew.
Chem., Int. Ed. 2013, 52, 13651.
(14) Wang, Q.; Wan, C. F.; Gu, Y.; Zhang, J. T.; Gao, L. F.; Wang, Z.
Y. Green Chem. 2011, 13, 578.
(15) Heating an ammonia saturated solution of phenylacetaldehyde
in ethanol to 235 °C at 1150 psi for 6 h yields 13% 3,5-
diphenylpyridine: Eliel, E. L.; McBride, R. T.; Kaufmann, S. J. Am.
Chem. Soc. 1953, 75, 4291.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03037.
Experimental procedures, product characterizations,
crystallographic data, and copies of the 1H and 13C
NMR spectra (PDF)
Crystallographic data for 3h (CIF)
AUTHOR INFORMATION
(16) (a) Chuang, T. H.; Chen, Y. C.; Pola, S. J. Org. Chem. 2010, 75,
6625. (b) Tagat, J. R.; McCombie, S. W.; Barton, B. E.; Jackson, J.;
Shortall, J. Bioorg. Med. Chem. Lett. 1995, 5, 2143.
■
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
(17) Zecher, W.; Krohnke, F. Chem. Ber. 1961, 94, 690.
̈
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grants 21272085 and 21472056) for financial support.
REFERENCES
(1) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
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DOI: 10.1021/acs.orglett.5b03037
Org. Lett. XXXX, XXX, XXX−XXX