Microwave promoted synthesis of cycl[3.2.2]azines in water via a new three-component reaction

Article abstract of DOI:10.1016/j.tetlet.2010.12.036

A microwave-promoted and base-catalyzed synthesis of cycl[3.2.2]azines is accomplished in water via a three-component reaction (3-CR) of 2-picoline, α-bromoacetophenone and alkyne. The extension of the methodology to the synthesis of steroidal and carbocyclic cycl[3.2.2]azine is also reported.

Full text of DOI:10.1016/j.tetlet.2010.12.036

Tetrahedron Letters 52 (2011) 813–816
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Tetrahedron Letters
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Microwave promoted synthesis of cycl[3.2.2]azines in water via a new
three-component reaction
⇑
Shyamalee Gogoi, Mandakini Dutta, Junali Gogoi, Romesh Chandra Boruah
Medicinal Chemistry Division, North East Institute of Science & Technology (CSIR), Jorhat 785 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A microwave-promoted and base-catalyzed synthesis of cycl[3.2.2]azines is accomplished in water via a
Received 6 October 2010
Revised 7 December 2010
Accepted 9 December 2010
Available online 15 December 2010
three-component reaction (3-CR) of 2-picoline,
methodology to the synthesis of steroidal and carbocyclic cycl[3.2.2]azine is also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
a-bromoacetophenone and alkyne. The extension of the
The indolizine ring system is an important structural motif fre-
quently found in natural products and has been used as an impor-
tant skeleton in pharmaceutics because of their interesting and
promising biological properties.1 Synthetic indolizines have found
wide-spread application in drug design efforts, biological, and
pharmaceutical research.2 Several reports are available showing
the potential of indolizine derivatives as histamine H3 receptor
antagonists,3 antimicrobacterial agents,4 leucotriene synthesis
inhibitors,5 calcium entry blockers,6 and inhibitors of 15-lipooxy-
genase.7 The synthesis of indolizine derivatives has been actively
investigated and many synthetic strategies for producing indoli-
zine derivatives have been described in the literature.8 Perhaps
the most widely utilized method is the Tschitschibabin indolizine
synthesis, in which a quaternary pyridinium halide, resulting from
The cycl[3.2.2.]azine systems, which are tricyclic aromatic het-
erocycles having nitrogen as the central atom common to the three
rings, have attracted lots of attention due to their interesting phys-
ical and chemical properties.14 The most general method for the
synthesis of cycl[3.2.2]azine derivative is the (8 + 2)p cycloaddition
reaction of indolizines with acetylenes such as DMAD.15 However,
one of the discrepancies of this methodology is that it requires
costly and toxic metal catalysts (such as Pd on charcoal) as dehy-
drogenating agents in organic solvents.16 Hitherto, no report is
available for the synthesis of these cycl[3.2.2]azines using a mul-
ti-component reaction and water as the reaction media. Recently,
we have reported the synthesis of benzo[g]indoles from a-substi-
tuted acetophenone and naphthoquinone in the presence of urea
under microwave irradiation.17 In continuation of our interests,
herein we report an efficient and facile base-catalyzed preparation
of cycl[3.2.2]azines via a three-component reaction between an al-
the reaction of a 2-alkyl pyridine and an
a-halo carbonyl com-
pound undergoes an intramolecular condensation to the indolizine
product.9 However, in many cases, expensive and toxic metals, ex-
tended reaction times, elevated thermal conditions, and environ-
mentally hazardous organic solvents are used.
kyl pyridine, an
a-bromo carbonyl compound, and an alkyne in
water. Our synthetic approach, which involves the cycloaddition
of in situ generated Tschitschibabin indolizine in aqueous media,
turned out to be the first example of a metal-free preparation of
cycl[3.2.2]azines.
Typical reaction conditions for the preparation of the cy-
cl[3.2.2]azine system involve the treatment of alkylpyridines
The application of water as a solvent for performing organic
transformations under thermal and microwave heating has re-
ceived significant interest as a green alternative.10 Water offers
practical advantages over organic solvents as it is readily available,
cheap, non-flammable, and environmentally friendly. In addition,
the utility of unconventional microwave irradiation has been
increasingly recognized in organic synthesis in recent years. Micro-
wave-mediated multi-component reactions (MCRs) constitute a
particularly attractive synthetic strategy for rapid and efficient li-
brary generation, enhanced reaction rates, cleaner products, and
manipulative simplicity. The interest in this area is evidenced by
the large number of papers and reviews, which appeared in the lit-
erature in the past few years.11–13
(1a–c, 0.5 mmol) with
a-bromo carbonyl compounds (2a–f,
1.2 equiv) and alkynes (3a–b, 1.5 equiv) in the presence of a base
in a round bottomed flask open to air (Scheme 1). The product 2-
phenyl-4,5-dicarbmethoxy-cycl[3.2.2]azine (4a) was confirmed
by spectroscopic and analytical techniques.18 The effect of solvents
on the rate and yield of the reaction was evaluated using 1a, 2a,
and 3a as model substrates in the presence of K2CO3 and the results
are summarized in Table 1. Different aprotic solvents, such as,
CH2Cl2, DMF, DMSO, toluene, and CH3CN and protic solvents, such
as MeOH, EtOH, and H2O were examined. It was observed that
protic solvents were significantly preferred over aprotic solvents
and that the reaction in water was the fastest.
⇑
Corresponding author.
E-mail address: rc_boruah@yahoo.co.in (R.C. Boruah).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.036

814
S. Gogoi et al. / Tetrahedron Letters 52 (2011) 813–816
R3
R1
R1
O
Base
R2
Br
+
N
+
R2
N
Me
R3
R4
R4
4a-k
2a, R2 = Ph
1a , R1 = H
3a, R3 = R4 = COOMe
3b, R3 =H; R4 =COOEt
2b, R2 = 4-Me-C6H4
1b , R1 = 4-Me
2c, R2 = 4-Cl-C6H4
2d, R2 = 4-NO2-C6H4
2e, R2 = Androst-17-yl
2f, R2 = cyclohexenyl
1c , R1 = 3-Me
Scheme 1.
The versatility of the reaction was then evaluated in aqueous
medium under microwave irradiation using various 2-alkyl pyri-
dines, acyl bromides, and alkynes with modification at the pyridyl
ring, aromatic moiety of acetophenone and alkyne substituents
(Table 2). Hence, substrates with alkylpyridines (1a–c), substituted
acetophenones (2a–d) and alkynes (3a–b) afforded cycl[3.2.2]a-
zine products (4a–i) within 2–5 min in 20–92% yield.18,19 It was
observed that substrates bearing an electron releasing group at
the para position of the aromatic ring (2b) facilitated the enhance-
ment in yields of the products (entries 2 and 6), whereas electron
deficient 2d gave lower yields (entries 4 and 8). The three-compo-
nent reactions (3-CRs) in water were found sluggish when carried
out under thermal conditions (1–24 h) in comparison to micro-
wave heating wherein the reactions were very rapid (2–5 min).
In the light of the operational simplicity and mild condition of
our cycl[3.2.2]azine synthesis, we intended to expand the de-
scribed protocol to the preparation of steroidal and non-steroidal
derivatives. Reaction of 1a with 21-bromo-pregn-5,16-dieno-3-
acetate (2e) and 3a under identical conditions afforded 4j in 78%
Table 1
Effect of solvents on the formation of 4aa
O
Br
Base
Thermal
MeOOC
N
+
+
DMAD
N
COOMe
2a
3a
1a
4a
Solvent
% Yieldb
1 h
2 h
8 h
24 h
CH2Cl2
DMF
0
0
0
0
2
10
8
70
0
5
0
0
4
20
15
78
0
8
0
0
4
25
26
84
0
8
0
0
8
DMSO
Toluene
CH3CN
MeOH
EtOH
35
40
80
H2O
a
Reactions were carried out at 100 °C using 0.5 mmol of 2-picoline (1a) with
phenacylbromide (2a, 1.2 equiv), DMAD (3a, 1.5 equiv) and K2CO3 (1.5 mmol).
b
Yields are based on HPLC analysis compared to an analytical sample.
yield (Table 2, entry 10). Similarly
a-bromoacetyl-1-cyclohexene
Table 2
Synthesis of cycl[3.2.2]azines 4a–k in aqueous mediuma
Entry
Alkylpyridine
Acylbromide
Alkyne
Productb
Yieldc
Br
1a
N
N
N
2a
O
1
DMAD 3a
90
N
Me
4a
MeOOC
COOMe
COOMe
COOMe
COOMe
Br
Me
Me
Cl
2b
O
2
3
4
5
1a
3a
92
4b
MeOOC
MeOOC
Br
2c
Cl
O
1a
1a
1a
3a
60
4c
Br
2d
NO2
O2N
N
O
3a
20
4d
MeOOC
N
2a
2a
Ethyl propiolate 3b
78
4e
COOEt
N
Me
Me
6
3b
80
1b
4f
N
Me
COOEt

S. Gogoi et al. / Tetrahedron Letters 52 (2011) 813–816
815
Table 2 (continued)
Entry
Alkylpyridine
Acylbromide
Alkyne
Productb
Me
Yieldc
Me
N
7
1b
2b
3b
74
65
4g
COOEt
Me
Me
Me
1c
Cl
N
8
9
2c
3b
3b
N
4h
COOEt
Me
NO2
1c
2d
22
N
4i
COOEt
N
O
Br
4j
10
11
1a
1a
3a
3a
78
74
COOMe
MeOOC
MeOOC
2e
OAc
AcO
Br
2f
N
O
4k
COOMe
a
b
c
Conditions: 1 (1 mmol), 2 (1.2 mmol), 3 (1.5 mmol), K2CO3 (1.5 mmol), water (10 ml).
Reactions were carried out under microwave irradiation for 2–5 min at 100 °C.
Isolated yields.
(2f) reacted with 1a and 3b to yield 4k in good yield (74%, Table 2,
entry 11).
A plausible mechanism is proposed for the formation of 4a from
the water mediated three-component reaction (Scheme 2). The
quaternary salt (A), obtained from the reaction of 2-picoline (1a)
to afford 4a in good yield (88%).21 It was interesting to note that the
three-component reaction in water required no metal catalyst for
the oxidation of C to stable aromatic 4a in contrast to reactions
carried in organic solvents. All of our efforts to isolate dihydro-
cycl[3.2.2]azine (C) when performing the three-component reac-
tion under anaerobic condition failed as it solely led to 4a.
Moreover, the metal-free two-component reaction of B with 3a
in refluxing toluene failed in our hands.16a,16b
In conclusion, we have developed an efficient and fast reaction
for the synthesis of cycl[3.2.2]azines using water as a reaction
medium under microwave irradiation. The reaction proceeds via
the initial formation of the corresponding Tschitschibabin indoli-
zine, followed by a [3 + 2]cycloaddition with an alkyne with con-
comitant aerial oxidation. We have further shown that this
reaction can be applied to the synthesis of cycl[3.2.2]azine starting
from steroidal and carbocyclic acyl bromides. Our procedure in
aqueous medium is environmental friendly and devoid of organic
solvents and metal catalysts.
with a-bromoacetophenone (2a) initially undergoes cyclodehydra-
tion in the presence of base to afford the Tschitschibabin indolizine
(B), which then undergoes [3 + 2]cycloaddition with DMAD (3a) to
form dihydrocycl[3.2.2]azine (C). Finally, the oxidation of the latter
to 4a is rapidly accomplished under microwave irradiation in the
presence of air to form the stable 10p aromatic system. As a sup-
port of this hypothesis, we carried the reaction sequentially in or-
der to isolate the various intermediates. Hence, 2-picoline (1a) and
phenacyl bromide (2a) were first reacted under basic condition to
afford Tschitschibabin indolizine (B).20 The latter was then sub-
jected to DMAD (3a) in water under microwave irradiation to rap-
idly trigger the cycloaddition and the concomitant aerial oxidation
Base
_
Br
N
Me
O
Acknowledgment
+
Ph
2a
1a
+
N
We acknowledge the Department of Science & Technology
(DST) for their financial support and CSIR, New Delhi for the award
of JRF (to S.G. and M.D.). We are thankful to the Director of NEIST,
Jorhat for his keen interest.
(B)
Ph
(A)
(3a)
DMAD
Aerial oxidation
References and notes
Ph
Ph
N
N
H
H
1. (a) Flitsch, W. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
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Synthesis 1976, 4, 209.
COOMe
MeOOC
COOMe
MeOOC
(C)
4a
Scheme 2.

816
S. Gogoi et al. / Tetrahedron Letters 52 (2011) 813–816
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condition: To
a
mixture of 2-picoline (0.12 ml, 1 mmol),
a-
bromoacetophenone (240 mg, 1.2 mmol) and DMAD (0.18 ml, 1.5 mmol) in
water (10 ml) was added K2CO3 (207 mg, 1.5 mmol) and the mixture was
heated to 100 °C. The reaction was monitored by TLC and on completion of the
reaction after 1 h, the reaction mixture was cooled and extracted with CH2Cl2
(3 ꢀ 20 ml). The organic portion was washed with water, dried over anhydrous
Na2SO4 and the solvent was removed to obtain a crude product. Preparative
TLC separation using EtOAc/hexane (10:90) as eluant afforded 2-phenyl-4,5-
dicarbmethoxy-cycl[3.2.2]azine 4a in 70% yield. (b) Microwave condition: A
3. Chai, W.; Breitenbucher, J. W.; Kwok, A.; Li, X.; Wong, V.; Carruthers, N. I.;
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mixture of 2-picoline (0.12 ml, 1 mmol), a-bromoacetophenone (240 mg,
1.2 mmol), DMAD (0.18 ml, 1.5 mmol) and K2CO3 (207 mg, 1.5 mmol) was
taken in water (10 ml) and the mixture was irradiated in an open vessel of
Synthwave 402 Prolabo focused microwave reactor at 100 °C and power at 60%
(maximum output 300 W). The reaction was monitored by TLC and upon
completion of reaction after 2 min, the reaction mixture was cooled and
extracted with CH2Cl2 (3 ꢀ 20 ml). The organic portion was washed with
water, dried over anhydrous Na2SO4, and the solvent removed to obtain a
crude product. Preparative TLC separation using EtOAc/hexane (10:90) as
eluant afforded 4a in 90% yield.
7. (a) Gundersen, L.-L.; Malterud, K. E.; Negussie, A. H.; Rise, F. R.; Teklu, S.; stby,
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7973.
2-Phenyl-4,5-dicarbmethoxy-cycl[3.2.2]azine 4a: yellow needles, mp 139–42 °C
(dec); Rf = 0.5 (EtOAc/Hexane = 10:90); IR (CHCl3) cmꢁ1
:
m
2924, 2853, 1716,
1705, 1617, 1487, 1256, 1209, 1169, 1117, 1067, 772; 1H NMR (CDCl3,
300 MHz): d 7.93–8.42 (4H, m), 7.43–7.52 (5H, m), 4.02 (3H, s), 3.96 (3H, s). 13
C
NMR (CDCl3, 75 MHz): d 166.7, 164.3, 137.4, 134.1, 132.3, 129.6, 129.1, 128.8,
128.5, 125.6, 125.1, 122.6, 119.8, 116.4, 114.3, 112.2, 111.6, 100.4, 52.9, 51.8; EI
mass m/z = 333 [M+]. 2-Phenyl-4-carbethoxy-cycl[3.2.2]azine 4e: yellow needles,
mp 112–15 °C (dec); Rf = 0.55 (EtOAc/Hexane = 10:90): IR (CHCl3) cmꢁ1
: m
2924, 1698, 1610, 1505, 1256, 1176, 1097, 772; 1HNMR (CDCl3, 300 MHz) d
8.37 (1H, d, J = 4.7 Hz), 8.33 (1H, s), 8.05 (1H, d, J = 4.7 Hz), 7.90 (1H, d,
J = 4.6 Hz), 7.85 (3H, m), 7.51 (1H, s), 7.54 (1H, t, J = 4.6 Hz), 7.41 (1H, t,
J = 4.5 Hz), 4.50 (2H, q, J = 4.3 Hz), 1.51 (3H, t, J = 4.3 Hz); 13CNMR CDCl3,
75 MHz): d 165.2, 135.7, 134.1, 132.0, 129.9 (2C), 129.1, 128.5, 127.6 (2C),
124.4, 119.6, 114.7 (2C), 114.5, 113.1, 109.1, 60.2, 14.6; EI mass m/z 289 [M+].
2-(30-Acetoxy-50,160-dieno-androst-17-yl)-4,5-carbmethoxy-cycl[3.2.2]azine
4j: light yellow crystal, mp 203–05 °C (dec); Rf = 0.50 (EtOAc/Hexane = 10:90):
IR (CHCl3) cmꢁ1 2930, 1710, 1702, 1613, 1510, 1260, 1090, 770; 1HNMR
: m
(CDCl3, 300 MHz) d 8.28 (1H, d, J = 4.8 Hz), 8.17(1H, m), 8.02 (1H, d, J = 4.8 Hz),
7.51 (1H, s), 6.50 (1H, br s), 5.62 (1H, br s), 4.70 (1H, m), 4.10 (3H, s), 4.01 (3H,
s), 2.35–1.20 (17H, m), 2.10 (3H, s), 1.20 (3H, s), 1.03 (3H, s); 13CNMR CDCl3,
75 MHz): d 165.8, 164.9, 163.6, 153.4, 139.2, 139.0, 138.5, 127.8, 126.3 (2C),
125.6, 124.8, 122.4 (2C), 118.2, 113.3, 104.4, 72.5, 58.9, 55.1, 49.2, 46.8, 37.1,
35.8, 33.2, 31.7, 30.5, 29.1, 28.7, 26.4, 19.4, 18.6, 15.4, 15.3, 15.2; EI mass m/z
569 [M+].
19. The regioselectivity of the products 4e–i were in compliance with the reported
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(0.12 ml, 0.1 mmol),
a-bromoacetophenone (240 ml, 1.2 mmol), and K2CO3
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J. Am Chem. Soc. 1959, 81, 1459; (d) Galbraith, A.; Small, T.; Barner, R. A.;
Boekelheide, V. J. Am Chem. Soc. 1961, 83, 453; (e) Godfry, J. J. Org. Chem. 1959,
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582.
(207 mg, 1.5 mmol) was taken in water (10 ml) and irradiated in an open
vessel of Synthwave 402 Prolabo focused microwave reactor at 100 °C and
power at 60% (Maximum output 300 W). On completion of reaction after
1 min, the reaction mixture was cooled and extracted with CH2Cl2 (3 ꢀ 20 ml).
The organic portion was washed with water, dried over anhydrous Na2SO4, and
the solvent removed to obtain a crude product, which on purification afforded
B in 93% yield. mp 188–90 °C; Rf = 0.6 (EtOAc/Hexane = 05:95): IR (CHCl3)
cmꢁ1 2920, 1633, 1604, 1452, 1384, 1297, 1252, 781, 755; 1HNMR (CDCl3,
: m
300 MHz) d 7.88 (1H, d, J = 6.8 Hz), 7.65 (1H, d, J = 7.6 Hz), 7.56 (1H, s), 7.32
(3H, m), 7.25 (2H, J = 6.9 Hz), 6.69 (1H, s), 6.66 (1H, m), 6.44 (1H, m); 13CNMR
CDCl3, 75 MHz): d 135.0, 13.3, 129.1 (2C), 128.5, 226.2, 125.9, 125.6, 124.8,
118.7, 117.1, 110.2, 108.9, 96.3; ESI mass m/z 193 [M+].
21. Borthakur, M.; Barthakur, M. G.; Boruah, R. C. Steroids 2008, 73, 539.