Novel synthesis of fully-substituted pyridine derivatives via self-condensation of cyclic ketones in aqueous ammonium chloride under hydrothermal conditions

Article abstract of DOI:10.1055/s-2001-16065

A new method for synthesizing fully-substituted pyridine derivatives was developed using the self-condensation of cyclic ketones in aqueous ammonium chloride under hydrothermal conditions.

Full text of DOI:10.1055/s-2001-16065

LETTER
1323
Novel Synthesis of Fully-Substituted Pyridine Derivatives via Self-
Condensation of Cyclic Ketones in Aqueous Ammonium Chloride under
Hydrothermal Conditions1
a
b
b
Hiyoshizo Kotsuki,* Barun K. Mehta, Kazumichi Yanagisawa
aLaboratory of Natural Products Synthesis, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
bResearch Laboratory of Hydrothermal Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Fax +81-88-844-8359; E-mail: kotsuki@cc.kochi-u.ac.jp
Received 15 May 2001
Table Preparation of Pyridine Derivatives via Self-condensation of
Abstract: A new method for synthesizing fully-substituted pyri-
dine derivatives was developed using the self-condensation of cy-
clic ketones in aqueous ammonium chloride under hydrothermal
conditions.
a
Cyclic Ketones in aq NH Cl
4
Temp. (°C)
Time (h)
Yield
(%)
Entry Ketone (1)
Product(s) (2)
b
Key words: self-condensation, cyclic ketones, fully-substituted
pyridines, aqueous ammonium chloride, hydrothermal reaction
O
2
4
50
8
1
1a
1b
2a
74
N
Pyridine ring systems are an important class of com-
pounds in heterocyclic chemistry because of their occur-
rence in nature as biologically active substances and their
applications in both pharmaceutical and agricultural
chemistry. As a consequence, for the past century, several
methods for the formation of pyridines have been report-
O
O
250
2
2b
70c, d
48
N
2
ed. However, while these are of great value, there is still
a need for a new method which would allow us to obtain
pyridine derivatives in an environment-friendly manner.
250
66 d, e
3
4
1c
1d
2c
48
N
As one approach toward this end, we were particularly in-
terested in the use of aqueous reaction media under hydro-
thermal conditions. Although there have been several
O
O
O
250
64c, d
investigations of the use of near-supercritical water (T
2d
c
48
3
water = 374 °C) for organic reactions, these are mostly
limited to the degradative combustion of organic materi-
als, and only a few studies directed toward an application
N
4
to organic synthesis have been reported. In the course of
300
39d
5
1e
2e
our own efforts in this field, we found that the self-con-
densation of cyclic ketones in hot aqueous ammonium
chloride provided a novel entry to fully-substituted pyri-
dine derivatives (Scheme 1). Although there is a report of
a similar type of transformation using cyclohexanone and
ammonia, this work only deals with the pyridine forma-
tion as a side reaction and its general utility is unclear.5
The purpose of this paper is to describe the great value of
hydrothermal reactions in the above field of pyridine syn-
thesis via the self-condensation of cyclic ketones. The re-
sults are summarized in the Table.
96
N
300
30d
6
7
1f
2f
96
N
O
250
tracef
1g
2g
24
N
a
X
All reactions were conducted in 30M aq NH Cl.
4
Isolated yield.
Isolated as a diastereomeric mixture.
Unreacted starting ketone was recovered.
X
b
c
aq NH Cl
4
O
X
X
d
O
X
∆
N
X
e
f
O
1: 1 dimer 8 was also obtained in 4% yield.
Aldol products 9 and 10 were obtained in 11% and 23% yields,
X = CH , (CH ) , (CH ) , CHR, CR
2
2 2
2 3
2
respectively.
Scheme 1
Synlett 2001, No. 8, 1323–1325 ISSN 0936-5214 © Thieme Stuttgart · New York

1
324
H. Kotsuki et al.
LETTER
References and Notes
(
(
1) Hydrothermal Organic Reactions. Part 1.
2) Jones, G. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Ed.; Pergamon Press: Oxford
1984; Vol. 2, Chap. 8, pp. 395-510; Jones, G. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.;
Rees, C. W.; Scriven, E. F. V., Ed.; Pergamon Press: Oxford
1
996; Vol. 5, Chap. 5.05, pp. 167-243.
To establish the optimum conditions, we first examined
the reaction of cyclohexanone (1a) with aqueous ammo-
nium chloride at 250 °C. The best results were obtained in
the presence of 30 M aqueous ammonium chloride,6
which after 48 h gave 6-pentyl-1,2,3,4,7,8,9,10-octahy-
(
3) For reviews see: Bröll, D.; Kaul, C.; Krämer, A.; Krammer, P.;
Richter, T.; Jung, M.; Vogel, H.; Zehner, P. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 2998; Savage, P. E. Chem. Rev. 1999,
99, 603.
(4) For reviews see: Siskin, M.; Katritzky, A. R. Science 1991,
254, 231; Katritzky, A. R.; Allin, S. M.; Siskin, M. Acc. Chem.
Res. 1996, 29, 399; Parsons, E. J. Chemtech 1996, 35; Siskin,
M.; Katritzky, A. R. Chem. Rev. 2001, 101, 825; Katritzky, A.
R.; Nichols, D. A.; Siskin, M.; Murugan, R.;
Balasubramanian, M. Chem. Rev. 2001, 101, 837.
5) Fan, L.; Liu, J.; Fujimoto, K. Sekiyu Gakkaishi 1999, 42, 201.
6) Under the similar conditions (250 °C, 24 h), the reactions of
drophenanthridine (2a) in an isolated yield of 74% (entry
7
1
). The hydrothermal reaction is undoubtedly quite effec-
tive as a new tool for promoting the desired pyridine for-
mation through the simple trimerization of cyclic ketones,
8
and is an efficient contribution to “green chemistry”. A
(
(
plausible mechanism for the formation of 2a is outlined in
5
Scheme 2. It can be easily understood that the reaction
1a with 10 M and 20 M aqueous NH Cl gave 2a in yields of
21% and 37%, respectively. The use of NH
4
should be initiated by the self-aldol condensation of 1a to
give dimer 3. The crucial step in this sequence might be
4
OAc or
(NH ) CO in place of NH Cl gave only a trace amount of 2a.
4 2
3
4
9
(7) All reactions were conducted in a Hasteloy-C autoclave
reaction vessel with cone and thread fittings and an internal
volume of 20 mL, designed to withstand temperatures up to
the Pictet-Spengler-type cyclization of the imino-inter-
mediate 6 followed by fragmentation of 7 through irre-
versible aromatization toward 2a.
4
00 °C.
Typical experimental procedure: Preparation of 2a (entry 1).
A mixture of cyclohexanone (1a; 440 mg, 4.5 mmol), NH Cl
8.0 g, 0.15 mol), and water (5 mL) was placed in a reaction
Under similar conditions, several cyclohexanone deriva-
10
4
tives 1b-1d gave 2b-2d in good yields (entries 2-4). Cy-
cloheptanone (1e) and cyclooctanone (1f) gave the
desired pyridine derivatives 2e and 2f in moderate yields
(
vessel, and reacted at 250 °C for 48 h. After quenching with
water, the mixture was extracted with AcOEt. The crude
product was purified by silica gel column chromatography
(hexane/AcOEt = 9: 1) to afford 2a (286 mg, 74%) as a thick
1
0
at higher temperatures (entries 5 and 6). Apparently, in-
creasing the hydrophobicity of the substrates causes a sig-
nificant decrease in the product yield, probably due to
their reduced solubility in the hot water system. Despite
our extensive efforts, only a trace amount of pyridine 2g
was formed from cyclopentanone (1g) (entry 7), which
implies that the initial aldol condensation product 9 is
colorless oil: R 0.30 (hexane/AcOEt = 4: 1); FTIR (neat) ν
f
-
1 1
1568, 1433, 1414 cm ; H NMR (400 MHz, CDCl ) δ 0.89
3
(
3H, t, J = 7.1 Hz), 1.30-1.42 (4H, m), 1.57-1.65 (2H, m),
1
2
2
.76-1.82 (8H, m), 2.52 (4H, brs), 2.67 (4H, t, J = 8.0 Hz),
.85 (2H, t, J = 5.6 Hz); C NMR (100 MHz, CDCl ) δ 14.03,
2.34, 22.57, 22.60, 22.91 ( 2), 25.24, 25.77, 26.17, 29.21,
13
3
1
1
quite insensitive toward ammonium chloride.
32.20, 32.80, 35.22, 127.02, 127.56, 144.40, 152.33, 157.12;
MS m/e 257 (M ).
+
In conclusion, we have found a novel method for prepar-
ing a variety of fully-substituted pyridine derivatives via
the self-condensation of cyclic ketones in aqueous ammo-
(
(
8) Green Chemistry. Designing Chemistry for the Environment;
Anastas, P. T.; Williamson, T. C., Ed.; American Chemical
Society: Washington DC 1996; Green Chemistry: Frontiers in
Benign Chemical Syntheses and Processes; Anastas, P. T.;
Williamson, T. C., Ed.; Oxford University Press: New York
1999.
1
2
nium chloride under hydrothermal conditions. The re-
sults illustrate the potential utility of this method as an
environment-friendly process, and further studies to elab-
orate a new effective way to derive a variety of heterocy-
clic compounds are now in progress.
9) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
NH4Cl
(-H2O)
O
1a
(-H2O)
O
NH
NH2
O
1a
3
4
5
H
1a
H+
(-H2O)
N
N
N
6
7
2a
Scheme 2
Synlett 2001, No. 8, 1323–1325 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Fully-Substituted Pyridine Derivatives
1325
(
10) Data for 2b (mixture of diastereomers): thick colorless oil; Rf
32.06, 32.13 and 32.24, 32.44 and 32.55, 32.59 and 32.66,
32.99 and 33.02, 35.16 and 35.36, 37.70 and 35.82, 40.97,
126.74 and 126.79, 127.00 and 127.11, 144.31 and 144.39,
0
.40 (hexane/AcOEt = 4: 1); FTIR (neat) ν 1568, 1456, 1433
-
1 1
cm ; H NMR (400 MHz, CDCl ) δ 0.89 (3H, t, J = 7.6 Hz),
3
+
0
.95 (3H, d, J = 6.1 Hz), 1.08 (3H, d, J = 6.6 Hz), 1.09 (3H, d,
J = 6.3 Hz), 1.13-1.50 (5H, m), 1.54-2.26 (8H, m), 2.38-2.91
8H, m); 13C NMR (100 MHz, CDCl ) δ 11.39, 19.10, 21.80
152.39 and 152.43, 157.46 and 157.51; MS m/e 341 (M ).
Data for 2e: thick colorless oil; R 0.40 (hexane/AcOEt = 4:
f
-1
1
(
1); FTIR (neat) ν 1564, 1453, 1418 cm ; H NMR (400 MHz,
3
and 21.94, 22.10 and 22.17, 25.85 and 26.56, 28.42 and 28.65,
CDCl ) δ 0.88 (3H, t, J = 7.1 Hz), 1.26-1.43 (6H, m), 1.53-
3
2
3
3
1
1
8.97 and 29.11, 29.36 and 29.41 and 29.44, 30.38 and 30.54,
1.07 and 31.22, 32.44 and 32.66, 33.08 and 33.10, 33.83 and
4.25, 34.29 and 34.41, 35.03, 36.21, 126.72 and 126.77,
27.00 and 127.14, 143.91 and 143.98, 152.10 and 152.13,
1.70 (10H, m), 1.76-1.85 (4H, m), 2.73-2.84 (8H, m), 2.98-
1
3
3.02 (2H, m); C NMR (100 MHz, CDCl ) δ 14.11, 22.64,
3
26.61, 26.70, 27.45, 27.49, 28.36, 28.91 ( 2), 29.63, 30.55,
31.54, 31.81, 32.10, 36.67, 38.89, 132.57, 133.46, 149.41,
+
+
57.29 and 157.32; MS m/e 299 (M ). Data for 2c: thick
154.66, 159.94; MS m/e 299 (M ). Data for 2f: thick colorless
colorless oil; R 0.41 (hexane/AcOEt = 4: 1); FTIR (neat) ν
oil; R 0.47 (hexane/AcOEt = 4: 1); FTIR (neat) ν 1562, 1453,
f
f
-
1
1
-1 1
1
570, 1458, 1431 cm ; H NMR (400 MHz, CDCl ) δ 0.85
1416 cm ; H NMR (400 MHz, CDCl ) δ 0.87 (3H, t, J = 7.1
3
3
(
3H, t, J = 7.6 Hz), 0.93, 0.98, 1.00 (each 6H, s), 1.32 (2H, q,
J = 7.6 Hz), 1.43-1.47 (4H, m), 1.55 (2H, t, J = 6.8 Hz), 1.61
2H, t, J = 6.8 Hz), 2.31, 2.43 (each 2H, s), 2.53 (2H, t, J = 6.8
Hz), 1.23-1.45 (16H, m), 1.59-1.71 (8H, m), 1.73-1.79 (2H,
m), 2.71-2.82 (8H, m), 2.91-2.94 (2H, m); C NMR (100
1
3
(
MHz, CDCl ) δ 14.12, 22.66, 25.96, 26.24, 26.41, 26.52,
3
1
3
Hz), 2.61-2.66 (2H, m), 2.89 (2H, t, J = 6.8 Hz); C NMR
100 MHz, CDCl ) δ 8.50, 23.83, 26.38 ( 2), 28.10 ( 2),
26.76, 26.96, 27.13, 29.34, 29.99, 30.47, 30.61, 30.78, 30.84,
31.05, 31.86, 35.64, 35.81, 129.98, 131.40, 147.58, 156.77,
(
3
+
2
3
1
8.54 ( 2), 28.72, 29.20, 29.62, 30.19, 33.11, 34.24, 34.85,
157.90; MS m/e 341 (M ).
5.53, 39.37, 39.61, 40.92, 126.33, 126.50, 143.49, 151.12,
(11) We cannot exclude the possibilities that 1g is less reactive
toward aldol condensation and also the tautomerization step
like 4 5 is fairly slow.
(12) Similar reactions using acyclic ketones such as 3-pentanone
gave only a complex mixture of products.
+
57.85; MS m/e 341 (M ). Data for 2d (mixture of
diastereomers): thick colorless oil; R 0.42 (hexane/
AcOEt = 4: 1); FTIR (neat) ν 1570, 1460, 1433 cm ; H NMR
f
-
1 1
(400 MHz, CDCl ) δ 0.88 (6H, t, J = 7.3 Hz), 0.99 (6H, t,
3
1
3
J = 7.3 Hz), 1.20-1.65 (15H, m), 1.92-2.95 (12H, m);
C
NMR (100 MHz, CDCl ) δ 10.88 ( 2), 11.43 and 11.49, 11.55
3
and 11.59, 25.28 ( 2), 25.80 and 26.50, 28.07 and 28.23,
Article Identifier:
28.61 and 28.74, 28.86 and 29.12, 29.24 and 29.39, 31.67 and
1437-2096,E;2001,0,08,1323,1325,ftx,en;Y09901ST.pdf
Synlett 2001, No. 8, 1323–1325 ISSN 0936-5214 © Thieme Stuttgart · New York