Chichibabin pyridinium synthesis

Article abstract of DOI:10.1016/j.tetlet.2019.01.011

Chichibabin pyridine synthesis involves the reaction of three aldehydes and ammonia to form 2,3,5-trisubstituted pyridines. This study examined the synthesis of tetrasubstituted pyridinium from aldehydes and an amine hydrochloride in the presence/absence of Pr(OTf)₃. Important insights into the reaction mechanisms of Chichibabin pyridinium synthesis were proposed through the investigation of reaction intermediates along with quantitative GC–MS analysis.

Full text of DOI:10.1016/j.tetlet.2019.01.011

Accepted Manuscript
Chichibabin pyridinium synthesis
Akiho Imura, Nao Tanaka, Toyonobu Usuki
PII:
S0040-4039(19)30012-7
https://doi.org/10.1016/j.tetlet.2019.01.011
TETL 50544
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 November 2018
27 December 2018
7 January 2019
Please cite this article as: Imura, A., Tanaka, N., Usuki, T., Chichibabin pyridinium synthesis, Tetrahedron
Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.01.011
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Chichibabin pyridinium synthesis
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Akiho Imura, Nao Tanaka, Toyonobu Usuki
N
N
5
0 mol%
Pr(OTf)3
w/ or w/o)
O
Ph
Ph
(
solvent
Ph
R
rt, 24 h
O
R = NH3Cl or NH2
N
N
Ph
Ph

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Chichibabin pyridinium synthesis
Akiho Imura, Nao Tanaka and Toyonobu Usuki 
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, 7-1 Kioicho, Chiyoda-ku, Tokyo 102-8554, Japan
—
——
ARTICLE INFO
ABSTRACT

Corresponding author. Tel.: +81-3-3238-3446; fax: +81-3-3238-3361; e-mail: t-usuki@sophia.ac.jp
Article history:
Received
Chichibabin pyridine synthesis involves the reaction of three aldehydes and ammonia to form
2,3,5-trisubstituted pyridines. This study examined the synthesis of tetrasubstituted pyridinium
Received in revised form
Accepted
Available online
3
from aldehydes and an amine hydrochloride in the presence/absence of Pr(OTf) . Important
insights into the reaction mechanisms of Chichibabin pyridinium synthesis were proposed
through the investigation of reaction intermediates along with quantitative GC-MS analysis.
2
009 Elsevier Ltd. All rights reserved.
Keywords:
Chichibabin pyridinium synthesis
Tetrasubstituted pyridinium
Pr(OTf)
3
Aldol condensation
Indroduction
In 1905, the Russian chemist Aleksei Yevgen'evich
Chichibabin reported the synthesis of 2,3,5-trisubstituted pyridine
from three equivalents of aldehyde and ammonia (Scheme 1)1
using high pressure and high temperature. Almost a century later,
Wang and co-workers screened several simple aldehydes, amine
hydrochlorides, and lanthanide triflates as catalytic Lewis acids
for their utility in this reaction. In 1997, they reported the
condensation of aldehydes and amine hydrochlorides at room
temperature in aqueous media in the presence of lanthanide
N
O
Ph
1
2
(4 eq)
3 (20%)
5
0 mol% Pr(OTf)3
H2O, rt, 24 h
2
Ph
NH3Cl
(1 eq)
N
Ph
trifluoromethanesulfonates (Ln(OTf)
tetrasubstituted pyridiniums and their dihydro-forms.
representative of this synthesis was the reaction of four
3
)
to give 1,2,3,5-
4 (62%)
Scheme
2.
2
A
2
Pr(OTf) -promoted Chichibabin pyridinium synthesis.
3
equivalents of hexanal (1) and one equivalent of benzylamine
hydrochloride (2) in the presence of 50 mol% Pr(OTf) in H O at
3 2
room temperature for 24 hours to afford 1,2,3,5-tetrasubstituted
pyridinium (3) in 20% yield and its 2,3-dihydropyridinium (4) in
3
In 2014, we described the Pr(OTf) -promoted Chichibabin
pyridinium synthesis of isodesmosine (7) and desmosine (8)
starting from protected allysine (5) and protected lysine
6
2% yield, respectively (Scheme 2).
3
hydrochloride (6). Compounds 7 and 8 are elastin crosslinking
amino acids and chronic obstractive pulmonary disease (COPD)
biomarkers and their yields in this synthesis were 37% and 3%,
respectively, after quantitative removal of the protecting groups
R
O
O
R
R
R

4
R
(Scheme 3). 1,2,3,5-Tetrasubstituted pyridinium is the typical
sealed
O
N
R
product of Chichibabin pyridinium synthesis and 1,3,4,5-
tetrasubstituted pyridinium can be regarded as an isomer. Several
biosynthetic studies on crosslinkers 7 and 8 have been reported
NH3
R = Me, Et, nPr
Scheme 1. Original Chichibabin pyridine synthesis.1
over the past several decades but the detailed mechanisms
5,6
underlying these synthetic strategies remain unclear. In this study
we therefore examined Chichibabin pyridinium synthesis using
hexanal
1 and benzylamine hydrochloride 2 as model
compounds.

2
Tetrahedron Letters
CO2H
CO2H
NH2
H2N
H2N
CO2H
N
NH2
CO2H
condensate 10 (the self-condensed product of 1) in 32% yield
N(Boc)2
CO2tBu
based on the amount of 2 as the main byproduct. We reduced the
number of equivalents of 1 from four to three to prevent side
reactions, although 10 was obtained in 32% yield along with 3, 4
and 9 in 19%, 25%, and 1% yield, respectively (entry 2).
Increasing the reaction temperature to 37 °C did not improve to
yields of 3, 4, 9 and 10 (18%, 22%, 1%, and 40% yield,
respectively) (entry 3). Reaction in the absence of 2 provided no
product, suggesting that 2 is involved in the formation of 10
(entry 4). Reactions were then conducted in organic solvent using
amine 2’ instead of 2 because of solubility issues. The non-polar
O
1
) 50 mol% Pr(OTf)3
isodesmosine (7, 37%)
5
6
(4 eq)
H2O, rt, 48 h
NH2
2
) TFA/H2O
rt, 2 h
NH(Boc)
CO2H
NH2
CO2H
ClH3N
CO2tBu
CO2H
CO2H
(1 eq)
H2N
H2N
N
desmosine (8, 3%)
aprotic solvent CH
DMF and MeCN were screened (entries 5-8). Conducting the
reaction in CH Cl interestingly, provided the 8-type pyridinium
2 2
Cl and the polar aprotic solvents DMSO,
3
Scheme 3. Pr(OTf) -promoted Chichibabin pyridinium synthesis of
isodesmosine (7) and desmosine (8).4
2
2,
9
in 20% yield and 3, 4, and 10 in 11%, 4%, and 39% yield,
respectively (entry 5). The use of DMSO resulted in a decreased
total yield of pyridiniums (entry 6) whereas the use of DMF and
MeCN afforded pyridiniums only as aromatized products (entries
7, 8). The results shown in Table 1 suggest that the preference for
certain pyridinium types changes depending on the solvent
system and that the yield of 10 is higher in organic solvent
Results and discussion
Chichibabin pyridinium synthesis was examined by altering
the reaction conditions, as shown in Table 1. We first repeated
Wang’s reaction conditions and obtained 3 and 4 in 29% and
2
4
1
2% yield, respectively (entry 1), as well as desmosine 8-type
,3,4,5-substituted pyridinium (9) in 2% yield and aldol
compared to in H
2
O.
Table 1. Investigation of Chichibabin pyridinium synthesis.
N
N
O
5
0 mol%
Ph
Ph
1
(3 eq)
Pr(OTf)3
3
4
rt, 24 h
Ph
R
conditions
2
2
: R = NH3Cl
': R = NH2
N
(
1 eq)
O
Ph
10
9
Entry
Nitrogen
source
Solvent
Temperature
Yield/%a
3
4
9
3+4+9
73
10
32
32
40
0
1b,c
2
2
H
H
H
H
O
O
O
O
rt
rt
rt
rt
rt
rt
rt
rt
29e
19e
18e
0
42
25
22
0
2e
2
2
2
2
2
1e
45
3
2
1e
41
4d
5
-
0
0
2’
2’
2’
2’
CH
2
Cl
2
11e
6e
4e
5e
0
20e
3e
35
39
42
48
40
6
DMSO
DMF
14
7
5e
15e
12e
20
8
MeCN
11e
0
23
aIsolated yield based on 2 or 2’ except mixture of 3, 4, and 9.
bSee ref. 2.
cFour equivalents of 1 were used.
dReaction conducted without 2.
e
1
Ratio was determined by H NMR.
Conducting the reaction under the same conditions as entry 2
Table 1) but without Pr(OTf) (Table 1) interestingly provided
,2,4,5-tetrasubstituted pyridinium 11 in 17% yield (entry 1,
Table 2). Unidentified oligomerization and polymerization of
aldol condensate were observed as other products. Compound 11
was not obtained when benzyl amine 2’ was used instead of 2
(entry 2), suggesting that acidic conditions are required for the
formation of 1,2,4,5-tetrasubstituted pyridiniums. Indeed,
Brønsted acid-promoted pyridinium synthesis was previously
(
1
3
7
reported starting from cyclic imine and aldehydes in AcOH. The

3
use of hexylamine hydrochloride 12 in place of 2 provided the
corresponding 1,2,4,5-substituted pyridinium 13 in 10% yield
5
0 mol% Pr(OTf)3
O
Ph
3
NH Cl
(entry 3).
1 (1 mmol)
2 (1 mmol)
O
H2O, rt, 24 h
10 (2 mmol)
Table 2. Investigation of Chichibabin pyridinium synthesis in
the absence of Pr(OTf) .
3
N
N
Ph
Ph
3
(1%)
4 (trace)
O
1
(3 eq)
H2O
N
rt, 24 h
nitrogen source
1 eq)
N
Ph
9 (23%)
(
R
a
Entry
nitrogen source
product
17
yield/%
Scheme 4. Chichibabin pyridinium synthesis with 10.
1
Ph
NH Cl
3
2
N
N
Ph
NH3Cl
50 mol% Pr(OTf)3
H2O, rt, 24 h
Ph
Ph
4 (1 eq)
2 (0.5 eq)
1
1
2
-
0
Ph
NH2
N
2
'
Ph
3
3
10
NH Cl
3
1
2
N
Scheme 5. Attempt to form 3 from 4.
1
3
aBased on the corresponding nitrogen source.
Based on the above results, we propose the reaction
mechanisms shown in Scheme 6. In the synthesis of 7-type
compounds 3 and 4, imine formation occurs first, followed by
8
Mannich reaction with enol 1 promoted by Pr(OTf)
3
. Subsequent
We quantified 10 by GC-MS analysis every two hours during
the reaction of three equivalents of 1 and one equivalent of 2 in
addition of 1 results in the formation of cyclized product 14.
Based on Scheme 5, compounds 3 and 4 are individually formed
from 14. For the formation of 8-type pyridinium 9, aldol
condensation likely occurs as the first step. Subsequent
H
2
3
O in the presence of 50 mol% Pr(OTf) at room temperature
(Figure S3, conditions for entry 2, Table 1). The amount of 10
initially increased rapidly, then remained constant after 6 hours.
It was suggested two possibilities; generated 10 was used to form
condensation between 10 and enamine, which is promoted by
8
Pr(OTf)
3
, then cyclization is promoted. Aromatization might
3
and 4; aldol condensation was completed without being used
for the formation of 3 and 4. Conducting Chichibabin pyridinium
synthesis from 1, 2, and 10 in H O interestingly afforded 8-type
pyridinium 9 in 23% yield and only trace amounts of 3 and 4
Scheme 4), probably suggesting that 10 is the intermediate of 9
proceed more easily with the precursor of 9 than with 14 due to
the resonance structure after dehydration of precursor of 9. The
solvent altered the type of pyridinium obtained because 10 is
soluble in organic solvents and not in H O, and thus the
2
substrates (including intermediate 10) were mixed in the organic
layer, and thereby 9 was obtained as a one of the main product. In
2
(
and not of either 3 or 4. In this reaction, ca. 2 mmol of 10 was
also obtained. In other word, 10 was not used for the formation of
contrast, imine is relatively dissolved in H
neat aldehydes resulted in the formation of 14 and the generation
of 3 and 4. The formation of 11 and 13 in the absence of Pr(OTf)
2
O and exposure to
3
and 4.
Isolated dihydropyridinium 4 was stirred with 0.5 equivalents
of 2 in H O in the presence of 50 mol% Pr(OTf) at room
2 3
temperature (Scheme 5). It was previously reported that the
3
resulted first in the generation of imine, followed by proton
assisted-nucleophilic attack by the imine on the aldehyde. This
promoted nucleophilic attack by enol on the iminium cation, or a
perycyclic-type reaction, to give 11 or 13 via cyclized product
synthesis of 3 from 4 was achieved by stirring under basic or
2
reflux conditions. However, in our case, aromatized pyridinium
1
5. Finally, dehydration and dehydrogenation occurred, similar to
3
was not obtained and starting material 4 was recovered
the synthesis of other pyridiniums.
quantitatively, indicating that 3 is not formed from 4 in this
reaction system.

4
Tetrahedron
7
8
.
.
Snider, B. B.; Neubert, B.
J. Org. Lett. 2005, 7,
2715-2718.
(a) Kobayashi, S.; Araki,
M.; Yasuda, M.
Tetrahedron Lett. 1995,
36, 5773-5776. (b)
Kobayashi, S.; Nagayama,
S. J. Org. Chem. 1997,
62, 232-233.
R
R
R
N
R
OH
R
OH
R
HO
R:
1 (enol)
R
- H2O
H2
R
R
N
N
R
-
R': Ph or C5H11
Ph
N
R
Ph
R'
Ph
1
5
11 or 13
H+
OH
1
R
R
R
3
R
R
O
-
H2O
- H2
R
R
2
R
N
1
HO
N
Ph
N
Supplementary Material
+
R
Ph
Ph
-
H2O
Pr(OTf)3
Ph
N
3
ClH3N
Ph
R
1
4
Supplementary data related
to this article can be found at
http://dx.doi.org/...
2
R
R
-
H2O
O
R
R
O
N
R
R
R
-
H2O
Ph
O
R
R
N
4
HN
Ph
Ph
H
N

Mechanistic
studies
Chichibabin
pyridinium synthesis
were examined.
Interesting
Ph
O
R
R
R
R
R
of
O
O
R
R
1
R
R
R
1 (enol)
R
R
O
R
R
- H2O
- H2
+
-
H2O
Pr(OTf)3
N
N
N
OH
1
0
Ph
1
Ph
Ph
9

pyridinium skeleton
was formed under several conditions.
GC-MS analysis of intermediate aldol
condensate was carried out.
Scheme 6. Proposed mechanisms of Chichibabin pyridinium
synthesis.

Conclusion
In conclusion, Chichibabin pyridinium syntheses under
various conditions were screened to obtain three types of
pyridinium isomers: isodesmosine-type 3, desmosine-type 9, and
the new types 11 and 13. Quantitative GC-MS analysis indicated
that the aldol condensate 10 is an intermediate of 9. Reaction
mechanisms for the synthesis of these pyridiniums were
proposed. Computational studies would be helpful to confirm
these proposed routes.
Acknowledgments
This work was supported in part by Grants-in-Aid from
KAKENHI (Grant No. 25750388 and JP17KO1953).
References and notes
1
.
(a) Chichibabin, A. Y. Zh. Russ. Fiz. -Khim. O-vA. 1905, 37,
1
9
229-1253. (b) Lewis, D. Angew. Chem. Int. Ed. 2017, 56, 9660-
668.
2
3
.
.
Yu, L.; Chen, D.; Li, J.; Ramirez, J.; Wang, P. G.; Bott, S. G. J.
Org. Chem. 1997, 62, 208-211.
(a) Partridge, S. M.; Elsden, D. F.; Thomas, J. Nature 1963, 197,
1
1
297-1298. (b) Thomas, J.; Elsden, D. F.; Partridge, S. M. Nature
963, 200, 651-652.
4
5
.
.
Usuki, T.; Sugimura, T.; Komastu, A.; Koseki, Y. Org. Lett. 2014,
6, 1672-1675.
(a) Akagawa, M.; Suyama, K. Connect. Tissue Res. 2000, 41, 131-
1
1
3
41. (b) Davis, N. R.; Anwer, R. A.; J. Am. Chem. Soc. 1970, 92,
778-3782.
6
.
Recently, we reported selective Chichibabin and IsoChichibabin
pyridinium syntheses of protected 7 and 8, see: Tanaka, N.;
Kurita, M.; Murakami, Y.; Usuki, T. Eur. J. Org. Chem. 2018, 21,
6
002-6009.