Oxidative Trimerization of Amino Acids: Selective Synthesis of 2,3,5-Trisubstituted Pyridines

Article abstract of DOI:10.1021/acs.orglett.7b01232

An oxidative trimerization of three amino acids has been realized to furnish 2,3,5-trisubstuitued pyridines in both cross- and homo-trimerization types. This method is capable of converting simple linear biomass material to heterocycles, which features in

Full text of DOI:10.1021/acs.orglett.7b01232

Letter
pubs.acs.org/OrgLett
Oxidative Trimerization of Amino Acids: Selective Synthesis of 2,3,5-
Trisubstituted Pyridines
Jia-Chen Xiang, Yan Cheng, Zi-Xuan Wang, Jin-Tian Ma, Miao Wang, Bo-Cheng Tang, Yan-Dong Wu,
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: An oxidative trimerization of three amino acids
has been realized to furnish 2,3,5-trisubstuitued pyridines in
both cross- and homo-trimerization types. This method is
capable of converting simple linear biomass material to
heterocycles, which features in the assembly of three amino
acid branched chains into one aromatic ring. Molecular iodine
triggers the sequential decarboxylation and deamination of
amino acids and then promotes the selective formation of new C−N and C−C bonds.
rimerization is a broadly existing and stimulating
1−3
Tmolecular behavior in chemistry.
This thermodynami-
cally favorable conversion is a powerful maneuver to assemble
three individual molecules into one linear or circular target
through an entropy-decreasing process.1b Compared with the
other oligomerization processes,2 cyclotrimerization attracts
more attention due to its capability of generating functionalized
ring-closure products.3 Comprehensive research has focused on
the cyclotrimerization of alkynes3a and olefins3b to produce
aromatic rings. Furthermore, extensive investigations have
disclosed trimerizations of other small-molecule synthons that
are similar in reaction models but differ in mechanisms.
Examples include the trimerization of isocyanates,3c trifluor-
oacetones,3d quinols,3e aldehydes,3f nitriles,3g and others3h−l
(Figure 1A).
However, as one of the most common and versatile
synthons, amino acids are infrequently used as trimerization
precursors. The trimerization behaviors of amino acids are
present in nature. For example, vicibactin can be biogenerated
from three naturally occurring ornithines via metabolic
sequences (Figure 1B).4 Previous endeavors using amino
acids to prepare cyclic compounds by chemical means are
few,5,6 and the direct preparation of aromatic rings through
trimerization of these renewable resources has yet to be
reported. By simulating biological catabolism approaches, we
Figure 1. Trimerization behaviors in nature and organic synthesis.
found that amino acids can be activated by specific oxidizing
phenylalanine to fill the research gap by switching the catalytic
system (Figure 1C).
The cross-trimerization reaction, which leads to a higher
diversity of products, was first investigated. Reactions of
phenylalanine (1a) and 2-amino-2-(2-chlorophenyl)acetic acid
(2b) were conducted for scanning the conditions (Table 1).
agents in situ. With this arsenal, we have disclosed an
unexpected oxidative cyclization reaction of phenylalanine to
afford 3,5-disubstituted pyridines.6 However, we failed to
achieve higher oligomers since the third amino acid branched
chain was not inserted into the final aromatic ring. Inspired by a
better understanding of amino acid reactivity from our prior
studies, this work focuses on the successful execution of the 2:1
cross-trimerization of amino acids to afford 2,3,5-trisubstituted
pyridines.7 Moreover, we accomplish the homotrimerization of
Received: April 24, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01232
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Scheme 1. Scope of Amino Acids in Cross-trimerization
b
I2
temp
(°C)
3ab
entry (equiv)
acid (equiv)
1a/2b
(%)
4 (%)
1
2
3
4
5
1.0
1.0
1.0
1.0
1.0
2:1
100
100
100
100
100
<10
32
61
40
29
1:1
1:1.3
1:1.3
1:1.3
37
c
HI (0.5)
45
sulfanilic acid
(0.5)
<10
6
1.0
1.0
0.2
1.5
1.0
1.0
1.0
1.0
1.0
1.0
TfOH (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.5)
TFA (0.2)
TFA (1.0)
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
100
100
100
100
rt
55
77
7
<10
8
<15
44
9
10
11
12
13
14
15
trace
trace
38
trace
trace
60
80
120
100
100
66
33
75
<10
a
Reaction conditions: 1a (1.0 mmol), 2b, acid, I2, and DMSO (3.0
mL) were combined in a pressure vessel and then stirred at 100 °C for
6 h. TfOH = trifluoromethanesulfonic acid, TFA = trifluoroacetic acid.
b
c
Isolated yields. Using hydriodic acid, 57 wt % solution in H2O.
Inspired by our previous studies, 1.0 equiv of oxidizing agent I2
was added, and DMSO was used as the solvent. When the
substrates ratio was determined as 1a/2b = 2:1, a formal
dimerized product 4 was isolated as the predominant product
(entry 1). When a 1:1 ratio of 1a/2b was used, 3ab was
obtained in low yield (entry 2, 32%). The generation of
byproduct 4 still affects the reaction efficiency. Excess 2b (1a/
2b = 1:1.3) weakens the formal dimerization and also induces
the cross-trimerization reaction to enhance the chemoselectivity
(entry 3). It was found that Brφnsted acid further improved the
yield of 3ab. As a result, several acids were investigated (entries
4−7), and trifluoroacetic acid (TFA) was chosen as the optimal
one with both high yield and selectivity. Next, we screened the
loading of I2 (entries 7−9). The results show that a
stoichiometric amount of I2 was decisive. However, the use of
excessive iodine was detrimental to the yield (entry 9, 44%).
The optimal reaction temperature was investigated. Under low-
temperature conditions (entries 10−12), the reaction medium
stays heterogeneous due to the poor solubility nature of amino
acids in cold solvent. Thus, the transformation is difficult to
trigger. However, a high temperature was ineffective (entry 13,
66%). At last, the loading of TFA was evaluated (entry 14 and
15). The results show that a 50 mol % amount of acid was
optimal in the cross-trimerization.
With the optimal conditions set, we tested the scope of the
reaction (Scheme 1). Substrate 2 bearing aromatic-ring
branched chains achieved the desired products in good yields
(59−81%). Sensitive groups such as halogens were tolerated
under these mild conditions, allowing further modifications
(3ab, 77%; 3ac, 81%). Moreover, conducted on 10 mmol scale,
this reaction allows gram-scale preparation of 3ab in 71% yield.
When electron-donating substrate 2-amino-2-(p-tolyl)acetic
acid was used as the substrate, the conversion provided 3ad
smoothly (59%). In addition, naturally occurring amino acids
with alkyl branched chains performed well in this conversion
a
Reaction conditions: 1 (1.0 mmol), 2 (1.3 mmol), TFA (50 mmol
%), I2 (1.0 mmol), and DMSO (3.0 mL) were combined in a pressure
vessel and then stirred at 100 °C for 6 h. Isolated yields. Conducted
on 10 mmol scale, isolated yield.
b
(3ae−al) to achieve cross-trimerized products in moderate
yields (44−71%). The substrate scope of 1 was further
examined. Phenylalanine derivatives bearing halogen groups
in all positions of aromatic rings provided the desired products
(3ba−fa) with little difference in yields (74−87%). Both
electron-donating and electron-withdrawing substituents on the
aromatic rings (3ga−ka, 40−81%) were compatible. Notably,
tyrosine was a valuable candidate in this reaction, providing a
trisubstituted pyridine with two hydroxyl groups (3ia, 55%).
Furthermore, the reaction using sterically hindered substituents
such as naphthalene and benzyl groups proceeded well (3la,
85%; 3ma, 62%).
From the above understanding of the scope in cross-
trimerization, we focused on the homotrimerization behavior of
three phenylalanines. When we used 2.3 equiv of phenyl-
alanines under standard conditions without addition of 2, the
major product obtained was formal homodimerization product
4. The third amino acid branched chain could not be inserted
into the target product. We suggest that 4′ is unstable under
B
DOI: 10.1021/acs.orglett.7b01232
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
these oxidative conditions. After extensive optimization of the
reaction conditions (see the Supporting Information (SI)),
homotrimerization was achieved to obtain 5 as a stable product
instead of 4′. The reaction was conducted at 60 °C with tert-
butyl hydroperoxide (TBHP) and phosphotungstic acid (PTA)
as combined additives (Scheme 2). On the basis of previous
which determined that 7 is a vital intermediate to achieve the
trimerization. The yield was poor because 1a would undertake
competing formal dimerization under these conditions in the
absence of excessive amounts of 2. Furthermore, I2 is critical to
achieve this step. Next, the origin of the nitrogen atom in the
pyridine product was investigated. L-Phenylalanine-15N was
employed under the standard conditions to furnish 15N-3ab
and 14N-3ab with 4:1 selectivity. The result of the isotope
experiment suggests that the source of the nitrogen atom in
pyridine comes from phenylalanine as a major pathway. A
nitrogen-transfer process in which the nitrogen source is
derived from phenylglycine could not be excluded.
a
Scheme 2. Homo-trimerization of Phenylalanine.
On the basis of the above results and related reports,6,7,9
a
preliminary mechanism proposal is proposed in Scheme 4. The
Scheme 4. Mechanistic Proposal
a
Reaction conditions: 1 (1.0 mmol), phosphotungstic acid (PTA) (20
mmol %), tert-butyl hydroperoxide (TBHP) (2.0 equiv), I2 (25 mmol
%), and DMSO/H2O = 4:1 (3.0 mL) were combined in a pressure
vessel and then stirred at 60 °C for 6 h. Isolated yields.
studies, this homotrimerized product was afforded by further
iodination and Kornblum oxidation of in situ generated 4′8 (for
the mechanism, see the SI). Moreover, additional examples
were synthesized7d to further verify this oligomeric selectivity.
Bearing halogen groups (−F, −Cl, −Br, −Cl2), 5b−e could be
obtained in medium yields (44−62%). Substrates with electron-
donating groups (−Me) remain applicable (5f, 52%). 2-Amino-
3-(naphthalen-2-yl)propanoic acid with a bulky electron-
withdrawing groups reacted smoothly to afford 5g in 74%
yield. Structures of both cross- (3da) and homo-trimerization
(5b) products were further confirmed by X-ray diffraction.
To illustrate the reaction mechanism, various control
experiments were performed (Scheme 3). The reaction of 1a
and 2b was conducted and stopped at 2 h, and three major
products, 3ab, 2-chlorobenzaldehyde (6), and α,β-unsaturated
aldehyde (7) were isolated. I2 triggered the catabolism of 2b to
afford 6 as an intermediate. Treating 7 with 1a under standard
conditions afforded 3ab in the presence of I2 with 57% yield,
reaction began with an I2-promoted decarboxylation and
oxidation reaction of amino acid to produce imine intermediate
A. Then, rapid hydrolysis occurred to transform A or
corresponding ammonium cation B into aldehyde species C.
This tandem process is the catabolism stage of amino acids.
According to that, phenylalanine (1) and phenylglycine (2)
generated phenylacetaldehyde (C1) and benzaldehyde (C2),
respectively. C1 could further react with dropped ammonia to
give A1′ and A2 as a couple of tautomers. Two catabolism
products, C1 and C2, underwent an aldol condensation to
afford α,β-unsaturated aldehyde (D). Linear dimer D was then
attacked by enamine (A2) in an aza-Michael addition followed
by aldol condensation to give M1. Subsequently, ring-closure
product M1 underwent elimination and oxidation under the
assistance of I2 and TFA. Finally, aromatic product 3 was
obtained by oxidative aromatization from regenerated I2. This
sequential three-component trimerization process was termed
the reconstruction pathway.
Scheme 3. Control Experiments
C
DOI: 10.1021/acs.orglett.7b01232
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Kunishima, M. Org. Lett. 2012, 14, 5026. (l) Pascal, R. A., Jr.; Mathai,
M. S.; Shen, X. F.; Ho, D. M. Angew. Chem., Int. Ed. 2001, 40, 4746.
(4) (a) Heemstra, J. R., Jr.; Walsh, C. T.; Sattely, E. S. J. Am. Chem.
Soc. 2009, 131, 15317.
(5) For recent reports on synthetic methods involving amino acids,
see: (a) Wang, H. Q.; Xu, W. T.; Xin, L. L.; Liu, W. M.; Wang, Z. Q.;
Xu, K. J. Org. Chem. 2016, 81, 3681. (b) Joshi, A.; Chandra Mohan, D.;
Adimurthy, S. Org. Lett. 2016, 18, 464. (c) Mai, D. N.; Baxter, R. D.
Org. Lett. 2016, 18, 3738.
In conclusion, we demonstrate a straightforward pyridine
synthesis from three amino acids. This new reaction reveals
unusual cross- and homo-trimerization behaviors of amino
acids which have potential synthetic utilities. This trans-
formation, driven by nonfossil carbon renewable resources,
features high chemoselectivity and good compatibility and is
user-friendly. Mechanistically, I2 activates amino acids in situ via
decarboxylation and deamination reactions to afford α,β-
unsaturated aldehyde intermediate. I2 further assists the
subsequent tandem process as a terminal oxidant to achieve
consecutive C−C and C−N bond formations. 2,3,5-Trisub-
stituted pyridines with diversified substitution patterns could be
readily prepared.
(6) Xiang, J. C.; Wang, M.; Cheng, Y.; Wu, A. X. Org. Lett. 2016, 18,
24 and references cited therein.
(7) For recent reports on pyridine synthesis, see: (a) Ye, F.; Haddad,
M.; Ratovelomanana-Vidal, V.; Michelet, V. Org. Lett. 2017, 19, 1104.
(b) Yi, Y. K.; Zhao, M. N.; Ren, Z. H.; Wang, Y. Y.; Guan, Z. H. Green
Chem. 2017, 19, 1023. (c) Hilf, J. A.; Holzwarth, M. S.; Rychnovsky, S.
D. J. Org. Chem. 2016, 81, 10376. (d) Li, Z. Y.; Huang, X. Q.; Chen, F.;
Zhang, C.; Wang, X. Y.; Jiao, N. Org. Lett. 2015, 17, 584. (e) Wu, K.;
Huang, Z. L.; Liu, C.; Zhang, H.; Lei, A. W. Chem. Commun. 2015, 51,
2286. (f) Yoshida, M.; Mizuguchi, T.; Namba, K. Angew. Chem., Int. Ed.
2014, 53, 14550. (g) Michlik, S.; Kempe, R. Angew. Chem., Int. Ed.
2013, 52, 6326. (h) Song, Z. D.; Huang, X.; Yi, W. B.; Zhang, W. Org.
Lett. 2016, 18, 5640. (i) Majee, D.; Biswas, S.; Mobin, S. M.; Samanta,
S. Org. Biomol. Chem. 2017, 15, 3286. (j) Hirai, S.; Horikawa, Y.;
Asahara, H.; Nishiwaki, N. Chem. Commun. 2017, 53, 2390.
(k) Guchhait, S. K.; Hura, N.; Sinha, K.; Panda, D. RSC Adv. 2017,
7, 8323.
(8) (a) Zhang, J. T.; Wang, Z. T.; Wang, Y.; Wan, C. F.; Zheng, X.
Q.; Wang, Z. Y. Green Chem. 2009, 11, 1973. (b) Hruszkewycz, D. P.;
Miles, K. C.; Thiel, O. R.; Stahl, S. S. Chem. Sci. 2017, 8, 1282.
(9) (a) Wypych, J. C.; Nguyen, T. M.; Nuhant, P.; Benechie, M.;
Marazano, C. Angew. Chem., Int. Ed. 2008, 47, 5418. (b) Usuki, T.;
Sugimura, T.; Komatsu, A.; Koseki, Y. Org. Lett. 2014, 16, 1672.
(c) Yu, L. B.; Chen, D.; Li, J.; Ramirez, J.; Wang, P. G.; Bott, S. G. J.
Org. Chem. 1997, 62, 208.
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.7b01232.
Experimental procedures, product characterization, crys-
1
tallographic data, and H and 13C spectra (PDF)
X-ray data for compound 3ba (CIF)
X-ray data for compound 5b (CIF)
X-ray data for compound 7 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
ORCID
An-Xin Wu: 0000-0001-7673-210X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21472056 and 21602070) and the
Fundamental Research Funds for the Central Universities
(CCNU15ZX002 and CCNU16A05002) for financial support.
This work was also supported by the 111 Project B17019. We
acknowledge an Excellent Doctoral Dissertation Cultivation
Grant from Central China Normal University (2015YBYB089).
REFERENCES
■
(1) (a) Hardesty, J. H.; Koerner, J. B.; Albright, T. A.; Lee, G. Y. J.
Am. Chem. Soc. 1999, 121, 6055. (b) Reichart, T. M.; Baksh, M. M.;
Rhee, J. K.; Fiedler, J. D.; Sligar, S. G.; Finn, M. G.; Zwick, M. B.;
Dawson, P. E. Angew. Chem., Int. Ed. 2016, 55, 2688.
(2) McGuinness, D. S. Chem. Rev. 2011, 111, 2321.
(3) (a) Lipschutz, M. I.; Chantarojsiri, T.; Dong, Y. Y.; Tilley, T. D. J.
Am. Chem. Soc. 2015, 137, 6366. (b) Zhou, P.; Huang, L. B.; Jiang, H.
F.; Wang, A. Z.; Li, X. W. J. Org. Chem. 2010, 75, 8279. (c) Paul, F.;
Moulin, S.; Piechaczyk, O.; Le Floch, P.; Osborn, J. A. J. Am. Chem.
Soc. 2007, 129, 7294. (d) Saaidi, P. L.; Guyonnet, M.; Jeanneau, E.;
Fleurat-Lessard, P.; Hasserodt, J. J. Org. Chem. 2008, 73, 1209.
(e) Carreno, M. C.; Ribagorda, M. Org. Lett. 2003, 5, 2425.
̃
(f) Kuninobu, Y.; Matsuki, T.; Takai, K. Org. Lett. 2010, 12, 2948.
(g) Cairns, T. L.; Larchar, A. W.; McKusick, B. C. J. Am. Chem. Soc.
1952, 74, 5633. (h) Ibad, M. F.; Langer, P.; Reiß, F.; Schulz, A.;
́ ́
Villinger, A. J. Am. Chem. Soc. 2012, 134, 17757. (i) Perez, D.; Guitian,
E. Chem. Soc. Rev. 2004, 33, 274. (j) Wang, M. W.; Jeng, R. J.; Lin, C.
H. Macromolecules 2015, 48, 2417. (k) Yamada, K.; Fujita, H.;
D
DOI: 10.1021/acs.orglett.7b01232
Org. Lett. XXXX, XXX, XXX−XXX