A facile one-pot synthesis of dicycloalkenopyridines at ambient temperature conditions

Article abstract of DOI:10.1016/j.tetlet.2012.09.134

An efficient synthesis of dicycloalkenopyridines was achieved via one-pot three-component condensation of aromatic aldehyde, cyclohexanone, and hydroxylamine hydrochloride using 3-nitrophenylboronic acid as an efficient catalyst under ambient condition. T

Full text of DOI:10.1016/j.tetlet.2012.09.134

Tetrahedron Letters 53 (2012) 6771–6774
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile one-pot synthesis of dicycloalkenopyridines at ambient
temperature conditions
⇑
Santosh V. Goswami, Prashant B. Thorat, Sudhakar R. Bhusare
Department of Chemistry, Dnyanopasak College, Parbhani 431 401, MS, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2012
Revised 27 September 2012
Accepted 29 September 2012
Available online 12 October 2012
An efficient synthesis of dicycloalkenopyridines was achieved via one-pot three-component condensa-
tion of aromatic aldehyde, cyclohexanone, and hydroxylamine hydrochloride using 3-nitrophenylboronic
acid as an efficient catalyst under ambient condition. The current methodology offers several advantages
such as high yields (78–90%) and simple experimental work-up at ambient temperature conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Dicycloalkenopyridines
Aromatic aldehyde
Cyclohexanone
Hydroxylamine hydrochloride
3-Nitrophenylboronic acid
Multi-component reactions (MCRs) are of increasing impor-
tance in organic and medicinal chemistry, because the strategies
of MCR offer significant advantages over conventional linear-type
synthesis.1,2 MCRs leading to interesting heterocyclic scaffolds
are particularly useful for the synthesis of drug-like molecules with
several degrees of structural diversity, since the combination of
three or more building blocks in a single operation leads to a high
combinatorial efficiency.3 The improvement of effective chemical
processes for the research of new biologically active molecules
constitutes a great challenge for chemists in organic synthesis.
The pyridine ring is a significant structural constituent in natu-
ral products and in many synthetic compounds of pharmaceutical
interest.4 Among the successful examples as drugs possessing pyr-
idine ring as a skeleton are streptonigrin, streptonigrone, and lav-
endamycin as anticancer drugs, and cerivastatin is reported as the
HMG-CoA enzyme inhibitor.5 Substituted pyridines are used as
leukotriene B-4 antagonists.6 Moreover pyridine derivatives are
used as chelating ligands in coordination chemistry, building
blocks in supramolecular chemistry, as metal-containing polymers,
molecular electronics, optoelectronic devices, solar cells, and as
photo-activated species.7 As a result, these facts are significant in
developing a new efficient and effective synthetic procedure for
the synthesis of pyridines.8 Many naturally occurring biologically
active compounds feature the presence of a cycloalkenopyridine
ring as basic skeleton. This observation produced the development
of new synthetic protocol to prepare pharmaceuticals and
agrochemicals, containing cycloalkenopyridine ring as a significant
building block.9 Substituted pyridines have been synthesized using
various methods and two methods have more advantages over
other procedures. One of the methods is the two-step Krohnke syn-
thesis10–12 via condensation of pyridinium salts with
a,b-unsatu-
rated ketones in the presence of a mixture of ammonium acetate
and acetic acid. The second method is Hantzsch type synthesis
via cyclo-condensation of aromatic aldehyde, acetophenone, and
a nitrogen derivative such as ammonium acetate or urea.13
Recently several new procedures have been developed for the
synthesis of pyridine derivatives including solvent-free reac-
tions,14,15 reactions in aqueous media,16 one-pot method under
microwave irradiation,17,18 and direct heating of
a,b-unsaturated
ketones with ammonium acetate in the presence of a catalytic
amount of acetic acid.19 Unfortunately, many of these processes
suffer some limitations such as harsh reaction conditions, low
yields, tedious work-up, and possibilities of several side reactions.
Organoboron compounds have been effectively used as a Lewis
acid catalyst in various organic transformations20–22 and in one-
pot synthetic organic chemistry.23,24 The phenylboronic acid, par-
ticularly those with electron-withdrawing substituent on aromatic
ring work as an efficient Lewis acid catalyst. Herein we describe a
novel one-pot three-component synthesis of dicycloalkenopyri-
dines starting from aromatic aldehyde, cyclohexanone, and
hydroxylamine hydrochloride using 3-nitrophenylboronic acid as
catalyst in methanol at room temperature conditions (Scheme 1).
In continuation of our interest in the synthesis of heterocycles
using organoboron compounds,25 herein we report for the first
time, a simple, mild, and efficient method for the synthesis of
⇑
Corresponding author.
E-mail address: bhusare71@yahoo.com (S.R. Bhusare).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.134

6772
S. V. Goswami et al. / Tetrahedron Letters 53 (2012) 6771–6774
O
Ar
N
O2N
B(OH)2
+
Ar-CHO
+ H2N-OH. HCl
MeOH, RT, 8-10h
1
3
2(a-l)
CH-Ar
CH-Ar
4(a-l) 78-90%
Scheme 1. One-pot multicomponent synthesis of dicycloalkenopyridines.
Table 1
Screening of the solvent in one-pot synthesis of dicycloalkenopyridinesa
Cl
O
CHO
O2N
B(OH)2
+
+
H2N-OH.HCl
Solvent, RT
N
Cl
1
2a
3
Cl
Cl
4a
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
Ethanol
15
12
28
28
30
22
64
78
48
50
38
58
Methanol
Chloroform
Dichloromethane
Water
Acetonitrile
a
Conditions: 4-Chlorobenzaldehyde (3 mmol), cyclohexanone (2 mmol), and hydroxylamine hydrochloride (3 g), 3-nitrophenylboronic acid
(10 mol %) at room temperature. The progress of reaction was monitored by thin layer chromatography.
b
Isolated yield.
dicycloalkenopyridines using 3-nitrophenylboronic acid as Lewis
acid catalyst at ambient temperature conditions in excellent
yields.26
Table 2
Screening of the catalytic loading in one-pot synthesis of dicycloalkenopyridinesa
Entry
3-Nitrophenylboronic acid (mol %)
Time (h)
Yieldb (%)
For initial optimization of the reaction conditions, we studied
the solvent effect on the model reaction of 4-chlorobenzaldehyde,
cyclohexanone, and hydroxylamine hydrochloride using 10 mol %
3-nitrophenylboronic acid as catalyst at room temperature condi-
tion. The polar protic solvents ethanol and methanol were found
to be the effective solvent for the reaction, especially methanol.
In the solvent methanol, product 4a was obtained in good yield
78% within 12 h (Table 1, entry 2). In the non-polar solvents like
chloroform and dichloromethane, the desired product 4a was ob-
tained in lower yield with extended reaction time (Table 1, entries
3 and 4, respectively). It was attributed to the less solubility of the
catalyst 3-nitrophenylboronic acid in these solvents. Moreover the
reaction in the solvents water and acetonitrile afforded 38 and 58%
yields, respectively with longer reaction time (Table 1, entries 5
and 6, respectively).
1
2
3
4
5
6
5
18
12
11
8
10
36
64
76
72
89
72
Trace
12
15
20
25
0
a
Conditions: 4-Chlorobenzaldehyde (3 mmol), cyclohexanone (2 mmol), and
hydroxylamine hydrochloride (3 g), methanol (15 ml) at room temperature. The
progress of reaction was monitored by thin layer chromatography.
b
Isolated yield.
reaction was sluggish (18 h) and afforded 64% yield of the product
4a (Table 2, entry 1). The reaction performance improved with the
increase in catalytic loading to 12 mol % and 15 mol %, the reaction
time was reduced and enhanced yield for the product 4a was ob-
tained (Table 2, entries 2 and 3, respectively). The best result for
the reaction was obtained at the catalytic loading of 20 mol % of
Subsequently, we investigated the influence of catalytic concen-
tration on the model reaction with methanol as solvent. Initially at
the catalytic loading of 5 mol % 3-nitrophenylboronic acid, the

S. V. Goswami et al. / Tetrahedron Letters 53 (2012) 6771–6774
6773
Table 3
hydroxylamine hydrochloride. All the reactions proceeded well
with a wide range of aromatic aldehydes affording good to excel-
lent yield of the corresponding products (Table 3).
One-pot synthesis of dicycloalkenopyridinesa
Entry
Ar
Product 4
Time (h)
MP
Yieldb (%)
From the mechanistic point of view, we propose a plausible
mechanism for the synthesis of dicycloalkenopyridines in
Scheme 2. The catalyst 3-nitrophenylboronic acid activates the
cyclohexanone ring through non-bonding interaction to form eno-
lized six membered intermediate I. The carbonyl carbon of aro-
matic aldehyde was attacked by an electron rich enol form of
cyclohexanone to afford intermediate II. The intermediate II on
further reaction with another molecule of aldehyde leads to inter-
mediate III. Intermediate III and intermediate II undergo Michael
addition reaction to form intermediate IV, which on cyclo-conden-
sation with hydroxylamine hydrochloride gives the final product 4
dicycloalkenopyridines.
In conclusion, we have demonstrated a facile and efficient
method for the synthesis of dicycloalkenopyridines using 3-nitro-
phenylboronic acid as catalyst under mild reaction conditions for
the first time. Arylboronic acids are usually crystalline solids, and
stable in air and moisture. Such evidence as exists indicates that
they are of relatively low toxicity and have low environmental
impact. The reaction proceeds smoothly at room temperature.
The key advantages of the present method include mild reaction
conditions, easy work-up, clean reaction profile, a wide range of
substrate applicability, high yields of products, and non-toxicity
of the reagents.
1
2
3
4
5
6
7
8
4-Cl
a
b
c
d
e
f
g
h
i
8
8
9
10
10
9
8
10
8
194–19615
224–22615
196–198
228–230
230–232
193–195
181–183
236–238
>250
89
82
88
79
86
89
90
88
84
78
84
87
4-OCH3
3-NO2
3,4-OCH3
4-F
4-NO2
2-Cl
3-Br
3-OCH3
H
9
10
11
12
j
k
l
9
8
9
157–15915
>25015
4-N(CH3)2
4-Br
198–199
a
Conditions: Aromatic aldehyde (3 mmol), cyclohexanone (2 mmol), hydroxyl-
amine hydrochloride (3 g), 3-nitrophenylboronic acid (20 mol %), and methanol
(15 ml) at room temperature. The progress of reaction was monitored by thin layer
chromatography.
b
Isolated yield.
the catalyst 3-nitrophenylboronic acid. The reaction was com-
pleted within 8 h and afforded the product 4a in excellent yield
of 89% (Table 2, entry 4). Further increase in the catalytic loading
of 25 mol % did not show significant improvement in the yield even
with extended reaction time (Table 2, entry 5).
To check the necessity of the catalyst 3-nitrophenylboronic acid
in the reaction, the same reaction was carried out without catalyst.
The reaction showed some progress after 36 h but the obtained
product was very poor in yield (Table 2, entry 6). Also, at the ele-
vated temperature the reaction showed no significant changes
with respect to yield and time in the absence of catalyst.
Acknowledgement
We acknowledge Dr. P. L. More and Dr. W. N. Jadhav, Dnyanop-
asak College, Parbhani for providing necessary facilities and finan-
cial support for this work by DST-SERC, New Delhi (SR/FT/CS-023/
2008) is highly appreciated.
Under the optimized reaction conditions, various aromatic
aldehydes were allowed to react with cyclohexanone and
NO2
NO2
NO2
HO
OH
HO
B
O
O
B
B
O
Ar
O
Ar
H
O
H
H
O
H
H
O
H
O
O
Ar
H2O
Ar
Ar
Ar
I
II
II
III
Ar
Ar
NH2OH.HCl
O
O
N
Ar
Ar
Ar
Ar
4
IV
Scheme 2. Mechanistic pathway for the synthesis of dicycloalkenopyridines.

6774
S. V. Goswami et al. / Tetrahedron Letters 53 (2012) 6771–6774
24. (a) Lopez-Ruiz, H.; Briseno-Ortega, H.; Rojas-Lima, S.; Santillan, R.; Farfan, N.
References and notes
Tetrahedron Lett. 2011, 52, 4308; (b) Tibhe, G. D.; Bedolla-Medrano, M.;
Cativiela, C.; Ordonez, M. Synlett. 1931, 2012, 23.
25. (a) Adude, R. N.; Tigote, R. M.; Goswami, S. V.; Bhusare, S. R. Int. J. Ind. Chem.
2012, 3, 6; (b) Goswami, S. V.; Thorat, P. B.; Kadam, V. N.; Bhusare, S. R. J. Chem.
Biol. Phys. Sci. 2011, 1, 164; (c) Goswami, S. V.; Thorat, P. B.; Dhone, S. S.;
Bhusare, S. R. J. Chem. Pharm. Res. 2011, 3, 632.
1. (a)Multicomponent Reactions; Zhu, J., Bienayme, H., Eds., 1st ed.; Wiley:
Weinheim: Germany, 2005; (b) Evdokimov, N. M.; Kireev, A. S.; Yakovenko,
A. A.; Antipin, M. Y.; Magedov, I. V.; Kornienko, A. J. Org. Chem. 2007, 72, 3443.
2. (a) Ugi, I. Pure Appl. Chem. 2001, 73, 187; (b) Nair, V.; Rajesh, C.; Vinod, A. U.;
Bindu, S.; Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36,
899; (c) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957.
3. (a) Domling, A. Chem. Rev. 2006, 106, 17; (b) Nuria, M.; Jordi, T.; Jose, I. B.;
Oliver, C. K. Tetrahedron Lett. 2003, 44, 5385; (c) Cui, S. L.; Lin, X. F.; Wang, Y. G.
J. Org. Chem. 2005, 70, 2866.
4. Ranu, B. C.; Jana, R.; Sowmiah, S. J. Org. Chem. 2007, 72, 3152.
5. Bringmann, G.; Reichert, Y.; Kane, V. V. Tetrahedron 2004, 60, 3539.
6. Zhou, Y.; Kijima, T.; Kuwahara, S.; Watanabe, M.; Izumi, T. Tetrahedron Lett.
2008, 49, 3757.
7. Kaes, C.; Katz, A.; Hosseini, M. W. Chem. Rev. 2000, 100, 3553.
8. Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 9297.
9. Thummel, R. P. Carbocyclic Annelated Pyridines. In Pyridine and its Derivatives,
Part 5; Newkome, G. R. (Ed.); in the series Newkome, G. R. The Chemistry of
Heterocyclic Compounds; 2008; Vol. 14.
10. (a) Krohnke, F. Angew. Chem., Int. Ed. 1963, 2, 225; (b) Krohnke, F.; Zecher, W.
Angew. Chem., Int. Ed. 1962, 1, 626; (c) Krohnke, F. Synthesis 1976, 1.
11. MacGillivray, L. R.; Diamente, P. R.; Reid, J. L.; Ripmeester, J. A. Chem. Commun.
2000, 359.
12. Yan, C. G.; Cai, X. M.; Wang, Q. F.; Wang, T. Y.; Zheng, M. Org. Biomol. Chem.
2007, 5, 945.
26. General procedure for the synthesis of dicycloalkenopyridines:
A mixture of
aromatic aldehyde (3.0 mmol), cyclohexanone (2.0 mmol), hydroxylamine
hydrochloride (3.0 g), and 3-nitrophenylboronic acid (20 mol %) as catalyst
was added in methanol (15 ml) solvent and the reaction mixture was stirred at
room temperature for appropriate time (Table 3). After completion of the
reaction as indicated by thin layer chromatography (pet ether: ethyl acetate
8:2), the reaction mixture was diluted with 50 ml of water and extracted with
ethyl acetate (3 Â 20 ml). The organic layer was dried over anhydrous Na2SO4,
concentrated, and the obtained product was purified by column
chromatography using silica gel mesh 80–120 to afford the pure product
(4a–l).
4,5-Bis(4-chlorobenzylidene)-9-(4-chlorophenyl)-1,2,3,4,5,6,7,8-octahydro-acridine
(4a): 1H NMR (300 MHz, CDCl3): d 7.96 (s, 2H), 7.30 (d, 4H, J = 7.6 Hz), 7.21–7.17
(m, 8H), 2.65 (t, 4H, J = 6.2 Hz), 2.32 (t, 4H, J = 6.6 Hz), 1.72 (m, 4H); 13C NMR
(300 MHz, CDCl3): d 152.7, 148.2, 141.2, 140.1, 135.3, 133.5, 131.97, 131.0,
128.4, 128.2, 128.0, 126.1, 125.2, 121.5, 120.1, 28.3, 27.6, 22.7; GC–MS, m/z: 541
(M+); Elemental Analysis: Anal. Calcd for C33H26Cl3N: C, 73.00; H, 4.83; N, 2.58%.
Found C, 73.03; H, 4.88; N, 2.60%.
4,5-Bis(3-nitrobenzylidene)-1,2,3,4,5,6,7,8-octahydro-9-(3-nitrophenyl)acridine
(4c): 1H NMR(300 MHz, CDCl3): d 8.12 (s, 2H), 7.90 (d, 4H, J = 8.2 Hz), 6.92 (d,
2H, J = 8.2 Hz), 6.86–6.80 (d, 6H, J = 8.0 Hz), 2.81 (t, 4H, J = 6.4 Hz), 2.40 (t, 4H,
J = 6.0 Hz), 1.68 (m, 4H); 13C NMR (300 MHz, CDCl3): d 159.5, 155.2, 144.9,
144.0, 140.4, 139.8, 136.2, 133.6, 129.9, 129.5, 129.0, 120.8, 120.5, 116.6,
115.0, 29.2, 27.9, 23.6; GC–MS, m/z: 574 (M+); Elemental Analysis: Anal.
Calcd for C33H26N4O6: C, 68.98; H, 4.56; N, 9.75%;. Found: C, 68.94; H, 4.61;
N, 9.79%.
4,5-Bis(4-fluorobenzylidene)-9-(4-fluorophenyl)-1,2,3,4,5,6,7,8-octahydroacridine
(4e): 1H NMR (300 MHz, CDCl3): d 7.88 (s, 2H), 7.42–7.38 (d, 6H, J = 6.8 Hz),
7.28–7.25 (d, 4H, J = 7.4 Hz), 6.95 (d, 2H, J = 7.4 Hz), 2.74 (t, 4H, J = 6.4 Hz), 2.38
(t, 4H, J = 6.4 Hz), 1.79 (m, 4H); 13C NMR(300 MHz, CDCl3): d 159.8, 155.4,
146.2, 141.6, 140.8, 139.2, 136.7, 133.1, 129.8, 126.9, 126.1, 123.7, 122.4,
116.0, 115.1, 29.1, 28.4, 23.2; GC–MS, m/z 493 (M+); Elemental Analysis: Anal.
Calcd for C33H26F3N: C, 80.30; H, 5.31; N, 2.84%; Found: C, 80.32; H, 5.34; N,
2.86%.
13. Ausins, A.; Durburs, D. G. Heterocycles 1988, 27, 291.
14. Tu, S.; Jia, R.; Jiang, B.; Zhang, J.; Zhang, Y.; Yao, C.; Ji, S. Tetrahedron 2007, 63,
381.
15. Tu, S.; Li, T.; Shi, F.; Fang, F.; Zhu, S.; Wei, X.; Zong, Z. Chem. Lett. 2005, 34, 732.
16. Tu, S.; Jiang, B.; Jia, R.; Zhang, J.; Zhang, Y. Tetrahedron Lett. 2007, 48, 1369.
17. (a) Singh, S. S.; Singh, K. N. J. Heterocycl. Chem. 2011, 48, 69; (b) Adib, M.;
Tahermansouri, H.; Koloogani, S. A.; Mohammdi, B.; Bijanzadeh, H. R.
Tetrahedron Lett. 2006, 47, 5957.
18. Wu, P.; Cai, X. M.; Wang, Q. F.; Yan, C. G. Synth. Commun. 2011, 41, 841.
19. Thummel, R. P.; Jahng, Y. J. Org. Chem. 1985, 50, 2407.
20. (a) Zheng, H.; Hall, D. G. Tetrahedron Lett. 2010, 51, 3561; (b) Frutos, R. P.;
Tampone, T.; Mulder, J. A.; Xu, Y.; Reeves, D.; Wang, X.-J.; Zhang, L.;
Krishnamurthy, D.; Senanayake, C. H. Tetrahedron Lett. 2011, 52, 2465; (c)
Zheng, H.; Lejkowski, M.; Hall, D. G. Chem. Sci. 2011, 2, 1305.
21. (a) Ishara, K.; Hall, D. G. Willey-VCH: Weinheim 2005, 377.; (b) Tale, R. H.;
Adude, R. N. Tetrahedron Lett. 2006, 47, 7263; (c) Tale, R. H.; Sagar, A. D.; Santan,
H. D.; Adude, R. N. Synlett. 2006, 3, 415; (d) McCubbin, J. A.; Hosseini, H.;
Krokhin, O. V. J. Org. Chem. 2010, 75, 959.
4,5-Bis(3-bromobenzylidene)-9-(3-bromophenyl)-1,2,3,4,5,6,7,8-octahydroacridine
(4h): 1H NMR(300 MHz, CDCl3): d 7.82 (s, 2H), 7.40 (d, 4H, J = 7.8 Hz), 6.88 (d,
2H, J = 7.8 Hz), 6.76–6,71 (m, 6H), 2.78 (t, 4H, J = 7.0 Hz), 2.32 (t, 4H, J = 7.0 Hz),
1.68 (m, 4H); 13C NMR (300 MHz, CDCl3): d 160.1, 158.9, 151.3, 135.4, 133.9,
130.6, 129.8, 126.6, 115.1, 114.2, 55.6, 29.4, 28.7, 22.5; GC–MS, m/z: 676 (M+);
Elemental Analysis: Anal. Calcd for C33H26Br3N: C, 58.61; H, 3.88; N, 2.07%;
Found: C, 58.66; H, 3.84; N, 2.11%.
22. Zheng, H.; Ghanbari, S.; Nakamura, S.; Hall, D. G. Angew. Chem. 2012, 124,
6291.
23. (a) Sridhar, R.; Perumal, P. T. Tetrahedron 2005, 61, 2465; (b) Debache, A.;
Boumoud, B.; Amimour, M.; Belfaitah, A.; Rhouatia, S.; Carbonib, B. Tetrahedron
Lett. 2006, 47, 5697; (c) Debache, A.; Boulcina, R.; Belfaitah, A.; Rhouati, S.;
Carboni, B. Synlett. 2008, 4, 509.