The Baylis-Hillman bromides as versatile synthons: A facile one-pot synthesis of indolizine and benzofused indolizine frameworks

Article abstract of DOI:10.1055/s-0028-1087533

A facile one-pot synthesis of indolizine, benzofused indolizines {pyrrolo[1,2-a]quinoline and pyrrolo[1,2-a]isoquinoline} derivatives from the Baylis-Hillman (B-H) bromides, via an interesting strategy involving 1,5-cyclization of nitrogen ylides has been

Full text of DOI:10.1055/s-0028-1087533

LETTER
411
The Baylis–Hillman Bromides as Versatile Synthons: A Facile One-Pot
Synthesis of Indolizine and Benzofused Indolizine Frameworks
S
ynthesis of Indoli
e
zine and
B
e
e
nzofused
I
v
ndolizine Fra
i
meworks Basavaiah,* Badugu Devendar, Dandamudi V. Lenin, Tummanapalli Satyanarayana
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Fax +91(40)23012460; E-mail: dbsc@uohyd.ernet.in
Received 8 October 2008
densely functionalized molecules via an efficient atom-
economical, one-pot process.7,8 These densely functional-
ized molecules, which are commonly referred to as the
Baylis–Hillman adducts, have been meticulously and sys-
tematically employed in a variety of organic transforma-
tion methodologies and also in synthesis of a number of
bioactive compounds.7,8 Efforts were also made for the
facile transformation of the Baylis–Hillman adducts into
indolizine derivatives.6,9
Abstract: A facile one-pot synthesis of indolizine, benzofused in-
dolizines {pyrrolo[1,2-a]quinoline and pyrrolo[1,2-a]isoquinoline}
derivatives from the Baylis–Hillman (B–H) bromides, via an inter-
esting strategy involving 1,5-cyclization of nitrogen ylides has been
described.
Key words: Baylis–Hillman bromides, 1,5-cyclization strategy, in-
dolizines, benzofused indolizines, quinoline, isoquinoline
Indolizine framework has been and continues to be an in-
teresting and structurally challenging nitrogen heterocy-
clic moiety because of the presence of this skeleton in a
number of bioactive natural products1,2 such as amorine,1
erythraline,1 swainsonine,1 slaframine,1 crepidine,1 ge-
phyrotoxine,1 cryptaustoline,2 and cryptowoline.2 Several
indolizine derivatives, in fact, have been known to exhibit
various biological activities such as antibacterial activity
against mycobacterium tuberculosis,3a inhibitors of
phosphatase3b and aromatase,3c antioxidant,3d calcium en-
In 1972 Tamura and coworkers reported an elegant con-
version of 4-bromo-1,3-diphenylbut-2-en-1-one (involv-
ing 1,5-cyclization of nitrogen ylides) into the
corresponding indolizine and pyrrolo[1,2-a]isoquinoline
derivatives via the treatment with pyridine derivatives and
isoquinoline, respectively, in the presence of potassium
carbonate.4r Subsequently, Pohjala reported similar meth-
odology for obtaining dihydroindolizines and indolizine
derivatives in high yields. However, in some cases he ob-
tained mixtures of dihydroindolizine and indolizine deriv-
atives (Scheme 1).4q
try blockers,3e 5-hydroxytryptamine (5-HT3) receptor an-
tagonists,3f antidepressant,3g and antileukemic activities.3h
The biological and medicinal relevance of the indolizine
derivatives has created a need for the development of ef-
ficient synthetic strategies for obtaining such derivatives
and in fact, several systematic efforts have been made in
this direction.4 In continuation of our ongoing research
program in heterocyclic molecules5 and particularly in-
dolizine framework6 we herein report a simple and one-
pot methodology for obtaining indolizine, benzofused in-
dolizine, pyrrolo[1,2-a]quinoline and pyrrolo[1,2-a]iso-
quinoline derivatives using the Baylis–Hillman bromides
as synthons.
We were indeed fascinated by these wonderful publica-
tions.4q,r We were particularly pleased to know that allyl
bromides used by Pohjala4q were equivalent to the
present-day Baylis–Hillman bromides (they were not
known at that time with this name). It subsequently oc-
curred to us that this strategy would constitute a basis for
the preparation of various indolizine and benzofused in-
dolizine {pyrrolo[1,2-a]quinoline and pyrrolo[1,2-a]iso-
quinoline} frameworks using the B–H bromides (derived
from 2-methylene-3-hydroxy-3-arylpropanenitriles which
in turn can be easily prepared via the B–H coupling of
acrylonitrile with aryl aldehydes)8z as shown in the re-
trosynthetic scheme involving a 1,5-cyclization strategy
(Scheme 2).
In recent years the Baylis–Hillman reaction has become
one of the most popular carbon–carbon bond-forming re-
actions in synthetic organic chemistry for obtaining
R2
X
K2CO3
reflux
R2
N+
+
+
R2
R2
N
N
R1
X = Br, OAc
X–
N
R1
R1
R1
R1 = H, Ac, Ph, PhCO
2 = H, Ph, PhCO, 4-MeOC6H4
R
Scheme 1
SYNLETT 2009, No. 3, pp 0411–0416
x
x.
x
x.
2
0
0
9
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087533; Art ID: D35708ST
© Georg Thieme Verlag Stuttgart · New York

412
D. Basavaiah et al.
LETTER
Br–
CN
N+
N
1,5-cyclization
H
CN
R
R
OH
Br
H
CN
+ N
H
N
NC
Br–
R
R
CN
CN
R
1,5-cyclization
R
+ N
H
N
Br–
R
1,5-cyclization
CN
R
CN
Scheme 2 Retrosynthetic strategy for the synthesis of indolizine and benzofused indolizine derivatives
Accordingly, we first directed our studies towards the
transformation of 2-(bromomethyl)-3-phenylprop-2-ene-
nitrile (1a, as a mixture of E- and Z-isomers,10 the Baylis–
Hillman bromide derived from 3-hydroxy-3-phenyl-2-
methylenepropanenitrile, which in turn was prepared via
the B–H reaction between benzaldehyde and acrylo-
nitrile) into indolizine {1-aza-8-cyano-7-phenylbicyclo-
[4.3.0]nona-2,4,6,8-tetraene} 2a via the treatment with
pyridine. The best results in this approach were obtained
when 2-(bromomethyl)-3-phenylprop-2-enenitrile (1a)
was treated with pyridine for 15 minutes at room temper-
ature (for salt formation), followed by heating at 80 °C in
the presence of potassium carbonate for three hours, thus
Figure 1 ORTEP diagram of compound 2a
providing the desired 1-aza-8-cyano-7-phenylbicyclo-
[4.3.0]nona-2,4,6,8-tetraene (2a)11 in 52% isolated yield
after purification through column chromatography
(Table 1). We have also obtained single crystals for the
compound 2a and further confirmed the structure by sin-
gle-crystal X-ray data (see Figure 1 for the ORTEP repre-
sentation).12
ing at 80 °C for five hours in the presence of K2CO3, thus
providing 1-aza-12-cyano-11-phenyltricyclo[8.3.0.02,7]-
trideca-2,4,6,8,10,12-hexaene (3a) in 45% isolated
yield.13 We have also confirmed the structure of this mol-
ecule by single-crystal X-ray data (see Figure 2 for
ORTEP representation).12,14 In order to understand the
Encouraged by these results, we successfully transformed generality of this reaction strategy we have subjected var-
representative Baylis–Hillman bromides 1b–j into the ious Baylis–Hillman bromides 1b–d,f to the treatment
desired 1-aza-8-cyano-7-arylbicyclo[4.3.0]nona-2,4,6,8- with quinoline under similar conditions to provide 1-aza-
tetraenes 2b–j in 47–63% yields (Table 1). After develop- 12-cyano-11-aryltricyclo [8.3.0.02,7]tri-deca-2,4,6,8,10,12-
ing a simple one-pot methodology for the synthesis of in- hexaenes (pyrrolo[1,2-a]quinoline derivatives) 3b–e in
dolizine framework we have directed our attention 47–51% isolated yields (Table 2).
towards the synthesis of benzofused indolizine {pyrro-
Next we have focused our attention towards the synthesis
lo[1,2-a]quinoline} derivatives, namely 1-aza-12-cyano-
of benzofused indolizine {pyrrolo[1,2-a]isoquinoline de-
11-aryltricyclo[8.3.0.02,7]trideca-2,4,6,8,10,12-hexaenes.
riveatives} via the treatment of the Baylis–Hillman bro-
It appeared to us that this can in principle be achieved via
mides with isoquinoline. In this case also the best results
were obtained when the allyl bromides 1a–d,g were treated
with isoquinoline in DMF for one hour at room tempera-
ture followed by heating at 80 °C for five hours in the
the treatment of the B–H bromides with quinoline. In this
case also we have first selected 2-(bromomethyl)-3-
phenylprop-2-enenitrile (1a) for reaction with quinoline.
The best results in this strategy were obtained when the
Baylis–Hillman bromide 1a was treated with quinoline in
DMF for one hour at room temperature followed by heat-
presence of K2CO3, thus providing the required benzofused
indolizines (1-aza-12-cyano-11-aryltricyclo[8.3.0.04,9]trideca-
Synlett 2009, No. 3, 411–416 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolizine and Benzofused Indolizine Frameworks
413
Table 1 Synthesis of Indolizine Derivativesa
Br
H
1) r.t., 15 min
N
NC
+
2) K2CO3, DMF, 80 °C, 3 h
N
R
R
CN
1a–j
2a–j
Entry
B–H bromide
R
Productb
2ad,12
2b
Yield (%)c
1
2
1a
1b
1c
1d
1e
1f
H
52
54
59
55
47
60
58
54
63
49
4-Me
4-Et
4- i-Pr
4-NO2
2-Me
2-Cl
2-Br
3
2c
4
2d
5
2e
6
2f
7
1g
1h
1i
2g
8
2h
9
2,4-(Cl)2
3-Cl
2i
10
1j
2j
a All reactions were carried out on 1 mmol scale of the Baylis–Hillman bromides 1a–j with pyridine (3 mL).
b All the compounds 2a–j were obtained as colorless solids and fully characterized (see Supporting Information).
c Isolated yields of the pure products and based on the B–H bromides.
d Structure of this molecule was also established by the single-crystal X-ray data (see Supporting information).12
Table 2 Synthesis of Pyrrolo[1,2-a]quinoline Derivativesa
Br
H
1) DMF, r.t., 1 h
+
NC
2) K2CO3, 80 °C, 5 h
N
N
R
R
CN
1a–d,f
3a–e
Entry
B–H bromide
R
Productb
Yield (%)c
1
2
3
4
5
1a
1b
1c
1d
1f
H
3ad,12
3b
45
48
47
51
50
4-Me
4-Et
4-i-Pr
2-Me
3c
3d
3e
a All reactions were carried out on 1 mmol scale of the Baylis–-Hillman bromides 1a–d,f with quinoline (2 mmol) in DMF (3 mL).
b All the compounds 3a–e were obtained as colorless solids and fully characterized (see Supporting Information).
c Isolated yields of the pure products and based on the B–H bromides.
d Structure of this molecule was also established by the single-crystal X-ray data (see Supporting information).12,14
2,4,6,8,10,12-hexaenes) 4a–e in 52–68% isolated yields dihydroindolizine) derivatives formed in situ underwent
(Table 3). We have further confirmed the structure of 4a dehydrogenation during the course of the reaction to result
by single-crystal X-ray data (see Figure 2 for ORTEP rep- in the formation of indolizine (benzofused indolizine)
resentation).12,14
frameworks. Although the yields are not very high, this
methodology still offers utility in synthesis of pyrrole con-
taining heterocyclic compounds possessing much phar-
maceutical relevance.
A plausible mechanism (based on 1,5-cylization path-
way)4q,r for the preparation of indolizine and benzofused
indolizine derivatives is provided in the Scheme 3. It is in-
teresting to note that the dihydroindolizine (benzofused
Synlett 2009, No. 3, 411–416 © Thieme Stuttgart · New York

414
D. Basavaiah et al.
LETTER
Table 3 Synthesis of Pyrrolo[1,2-a]isoquinoline Derivativesa
Br
H
N
1) DMF, r.t., 1 h
+
NC
N
2) K2CO3, 80 °C, 5 h
CN
R
1a–d,g
4a–e
R
Entry
B–H bromide
R
Productb
4ad,12
4b
Yield (%)c
1
2
3
4
5
1a
1b
1c
1d
1g
H
68
63
60
63
52
4-Me
4-Et
4-i-Pr
2-Cl
4c
4d
4e
a All reactions were carried out on 1 mmol scale of the Baylis–Hillman bromides 1a–d,g with isoquinoline (2 mmol) in DMF (3 mL).
b All the compounds 4a–e were obtained as colorless solids and fully characterized (see Supporting Information).
c Isolated yields of the pure products and based on the B–H bromides.
d Structure of this molecule was also established from the single-crystal X-ray data (see Supporting information).12,14
H
H
N
N+
K2CO3
H
N
Br–
– H2
R
H
CN
R
CN
CN
1,5-cyclization
R
N
Br
H
H
H
K2CO3
N+
H
N
N
N
– H2
NC
Br–
H
R
CN
R
R
CN
CN
R
1,5-cyclization
N
Br–
H
N+
N
N
K2CO3
H
H
H
– H2
CN
CN
CN
R
R
R
1,5-cyclization
Scheme 3 A plausible mechanism for the synthesis of indolizine and benzofused indolizine derivatives
In conclusion, we have successfully developed a conve-
nient, facile, and one-pot procedure for the synthesis of in-
dolizine and benzofused indolizine {pyrrolo[1,2-
a]quinoline and pyrrolo[1,2-a]isoquinoline} frameworks
from the Baylis–Hillman bromides, thus further demon-
strating the applications of Baylis–Hillman bromides as
valuable synthons in synthetic organic and medicinal
chemistry.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Figure 2 ORTEP diagrams of compounds 3a and 4a
Synlett 2009, No. 3, 411–416 © Thieme Stuttgart · New York

LETTER
Synthesis of Indolizine and Benzofused Indolizine Frameworks
415
(5) (a) Basavaiah, D.; Roy, S. Org. Lett. 2008, 10, 1819.
Acknowledgment
(b) Basavaiah, D.; Reddy, R. J. Org. Biomol. Chem. 2008, 6,
1034. (c) Basavaiah, D.; Aravindu, K. Org. Lett. 2007, 9,
2453. (d) Basavaiah, D.; Reddy, K. R. Org. Lett. 2007, 9,
57. (e) Basavaiah, D.; Reddy, R. J.; Rao, J. S. Tetrahedron
Lett. 2006, 47, 73. (f) Basavaiah, D.; Rao, J. S.; Reddy, R. J.;
Rao, A. J. Chem Commun. 2005, 2621. (g) Basavaiah, D.;
Rao, J. S.; Reddy, R. J. J. Org. Chem. 2004, 69, 7379.
(h) Basavaiah, D.; Satyanarayana, T. Chem Commun. 2004,
32. (i) Basavaiah, D.; Sharada, D. S.; Veerendhar, A.
Tetrahedron Lett. 2004, 45, 3081. (j) Basavaiah, D.;
Kumaragurubaran, N.; Sharada, D. S.; Reddy, R. M.
Tetrahedron 2001, 57, 8167. (k) Basavaiah, D.;
We thank DST (New Delhi) for funding this project. B.D. thanks
CSIR (New Delhi) for his research fellowship. D.V.L. and T.S.
thank UGC (New Delhi) for their research fellowships. We thank
UGC (New Delhi) for support and for providing some instrumental
facilities. We thank the National Single-Crystal X-ray Facility fun-
ded by DST. We also thank Professor S. Pal, School of Chemistry,
University of Hyderabad, for helpful discussions regarding X-ray
data analysis.
References and Notes
Sreenivasulu, B.; Rao, J. S. Tetrahedron Lett. 2001, 42,
1147. (l) Basavaiah, D.; Satyanarayana, T. Org. Lett. 2001,
3, 3619.
(1) Comprehensive Heterocyclic Chemistry, Vol. 4; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984, 476.
(2) (a) Lotter, A. N. C.; Pathak, R.; Sello, T. S.; Fernandes,
M. A.; Van Otterlo, W. A. L.; de Koning, C. B. Tetrahedron
2007, 63, 2263. (b) Ewing, J.; Hughes, G. K.; Ritchie, E.;
Taylor, W. C. Nature (London) 1952, 169, 618.
(6) (a) Basavaiah, D.; Rao, A. J. Tetrahedron Lett. 2003, 44,
4365. (b) Basavaiah, D.; Rao, A. J. Chem Commun. 2003,
604.
(7) For leading reviews on the Baylis–Hillman reaction, see:
(a) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511.
(b) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev.
2007, 36, 1581. (c) Masson, G.; Housseman, C.; Zhu, J.
Angew. Chem. Int. Ed. 2007, 46, 4614. (d) Basavaiah, D.;
Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(e) Ciganek, E. Organic Reactions, Vol. 51; Paquette, L. A.,
Ed.; Wiley: New York, 1997, 201. (f) Basavaiah, D.;
Dharma Rao, P.; Suguna Hyma, R. Tetrahedron 1996, 52,
8001. (g) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988,
44, 4653.
(8) (a) Zhang, Y.; Liu, Y.-K.; Kang, T.-R.; Hu, Z.-K.; Chen,
Y.-C. J. Am. Chem. Soc. 2008, 130, 2456. (b) Winbush,
S. M.; Mergott, D. J.; Roush, W. R. J. Org. Chem. 2008, 73,
1818. (c) Shi, M.; Liu, X.-G. Org. Lett. 2008, 10, 1043.
(d) Amarante, G. W.; Rezende, P.; Cavallaro, M.; Coelho, F.
Tetrahedron Lett. 2008, 49, 3744. (e) Davoust, M.;
Cantagrel, F.; Metzner, P.; Briere, J.-F. Org. Biomol. Chem.
2008, 6, 1981. (f) Utsumi, N.; Zhang, H.; Tanaka, F.;
Barbas, C. F. III Angew. Chem. Int. Ed. 2007, 46, 1878.
(g) Shafiq, Z.; Liu, L.; Liu, Z.; Wang, D.; Chen, Y.-J. Org.
Lett. 2007, 9, 2525. (h) Chuprakov, S.; Malyshev, D. A.;
Trofimov, A.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129,
14868. (i) Pigge, F. C.; Dhanya, R.; Hoefgen, E. R. Angew.
Chem. Int. Ed. 2007, 46, 2887. (j) Myers, E. L.; Butts, C. P.;
Aggarwal, V. K. Chem. Commun. 2006, 4434. (k) Dadwal,
M.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothiri,
I. N. N. Chem. Commun. 2006, 338. (l) Krafft, M. E.;
Wright,
(3) (a) Gundersen, L. L.; Charnock, C.; Negussie, A. H.; Rise,
F.; Teklu, S. Eur. J. Pharm. Sci. 2007, 30, 26. (b) Wiede,
T.; Arve, L.; Prinz, H.; Waldmann, H.; Kessler, H. Bioorg.
Med. Chem. Lett. 2006, 16, 59. (c) Sonnet, P.; Dallemagne,
P.; Guillon, J.; Enguehard, C.; Stiebing, S.; Tanguy, J.;
Bureau, R.; Rault, S.; Auvray, P.; Moslemi, S.; Sourdaine,
P.; Seralini, G. E. Bioorg. Med. Chem. Lett. 2000, 8, 945.
(d) Ostby, O. B.; Dalhus, B.; Gundersen, L. L.; Rise, F.;
Bast, A.; Haenen, G. R. M. M. Eur. J. Org. Chem. 2000,
3763. (e) Gubin, J.; Vogelaer, H. D.; Inion, H.; Houben, C.;
Lucchetti, J.; Mahaux, J.; Rosseels, G.; Peiren, M.; Clinet,
M.; Polster, P.; Chatelain, P. J. Med. Chem. 1993, 36, 1425.
(f) Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.;
King, F. D.; Miner, W. D.; Sanger, G. J. J. Med. Chem. 1990,
33, 1924. (g) Maryanoff, B. E.; Vaught, J. L.; Shank, R. P.;
McComsey, D. F.; Costanzo, M. J.; Nortey, S. O. J. Med.
Chem. 1990, 33, 2793. (h) Anderson, W. K.; Heider, A. R.;
Raju, N.; Yucht, J. A. J. Med. Chem. 1988, 31, 2097.
(4) (a) Zhu, L.; Vimolratna, M.; Brown, S. P.; Medina, J. C.
Tetrahedron Lett. 2008, 49, 1768. (b) Hardin, A. R.;
Sarpong, R. Org. Lett. 2007, 9, 4547. (c) Chuprakov, S.;
Gevorgyan, V. Org. Lett. 2007, 9, 4463. (d) Smith, C. R.;
Bunnelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007,
9, 1169. (e) Przewloka, T.; Chen, S.; Xia, Z.; Li, H.; Zhang,
S.; Chimmananmada, D.; Kostik, E.; James, D.; Koya, K.;
Sun, L. Tetrahedron Lett. 2007, 48, 5739. (f) Seregin, I. V.;
Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050.
(g) Tielmann, P.; Hoenke, C. Tetrahedron Lett. 2006, 47,
261. (h) Marchalin, S.; Baumlova, B.; Baran, P.; Oulyadi,
H.; Daich, A. J. Org. Chem. 2006, 71, 9114. (i) Kaloko, J.;
Hayford, A. Org. Lett. 2005, 7, 4305. (j) Bora, U.; Saikia,
A.; Boruah, R. C. Org. Lett. 2003, 5, 435. (k) Katritzky,
A. R.; Qiu, G.; Yang, B.; He, H. Y. J. Org. Chem. 1999, 64,
7618. (l) Troll, T.; Beckel, H.; Bohm, C. L. Tetrahedron
1997, 53, 81. (m) Bonneau, R.; Romashin, Y. N.; Liu,
M. T. H.; MacPherson, S. E. J. Chem. Soc., Chem Commun.
1994, 509. (n) Eberbach, W.; Maier, W. Tetrahedron Lett.
1989, 30, 5591. (o) Matsumoto, K.; Uchida, T.; Konshi, H.;
Watanabe, Y.; Aoyama, K.; Asahi, M. Chem. Lett. 1987,
807. (p) Andeson, W. K.; DeRuiter, J.; Heider, A. R. J. Org.
Chem. 1985, 50, 722. (q) Pohjala, E. Tetrahedron Lett.
1972, 13, 2585. (r) Tamura, Y.; Tsujimoto, N.; Sumida, Y.;
Ikeda, M. Tetrahedron 1972, 28, 21. (s) Basketter, N.;
Plunkett, A. O. J. Chem. Soc., Chem. Commun. 1971, 1578.
(t) Krock, F. W.; Krohnke, F. Chem. Ber. 1971, 104, 1645.
J. A. Chem. Commun. 2006, 2977. (m) Rao, J. S.; Briere,
J.-F.; Metzner, P.; Basavaiah, D. Tetrahedron Lett. 2006, 47,
3553. (n) Berkessel, A.; Roland, K.; Neudorfl, J. M. Org.
Lett. 2006, 8, 4195. (o) Wang, J.; Li, H.; Yu, X.; Zu, L.;
Wang, W. Org. Lett. 2005, 7, 4293. (p) Turki, T.; Villieras,
J.; Amri, H. Tetrahedron Lett. 2005, 46, 3071. (q) Kabalka,
G. W.; Venkataiah, B. Tetrahedron Lett. 2005, 46, 7325.
(r) Gowri Shankar, S.; Lee, K. Y.; Lee, C. G.; Kim, J. N.
Tetrahedron Lett. 2004, 45, 6141. (s) Jellerichs, B. G.;
Kong, J. R.; Krische, M. J. J. Am. Chem. Soc. 2003, 125,
7758. (t) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc.
2003, 125, 12094. (u) Pei, W.; Wei, H. X.; Li, G. Chem.
Commun. 2002, 17, 1856. (v) Lee, W. D.; Yang, K. S.;
Chen, K. Chem. Commun. 2001, 1612. (w) Basavaiah, D.;
Muthukumaran, K.; Sreenivasulu, B. Synthesis 2000, 545.
(x) Basavaiah, D.; Suguna Hyma, R.; Padmaja, K.;
Krishnamacharyulu, M. Tetrahedron 1999, 55, 6971.
(y) Basavaiah, D.; Gowriswari, V. V. L.; Sarma, P. K. S.;
Rao, P. D. Tetrahedron Lett. 1990, 31, 1621. (z)Basavaiah,
D.; Gowriswari, V. V. L. Synth. Commun. 1987, 17, 587.
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416
D. Basavaiah et al.
LETTER
(9) (a) Bode, M. L.; Kaye, P. T. J. Chem. Soc., Perkin Trans. 1
1993, 1809. (b) Bode, M. L.; Kaye, P. T. J. Chem. Soc.,
Perkin Trans. 1 1990, 2612.
(10) Allyl bromides (as a mixture of E- and Z-isomers) were
prepared by treatment of the Baylis–Hillman alcohols with
HBr in the presence of H2SO4 following the literature
procedure. See: (a) Buchholz, R.; Hoffmann, H. M. R. Helv.
Chim. Acta 1991, 74, 1213. (b) Ameer, F.; Drewes, S. E.;
Emslie, N. D.; Kaye, P. T.; Mann, R. L. J. Chem. Soc.,
Perkin Trans. 1 1983, 2293.
LC-MS: m/z = 219 [M + H]+. Anal. Calcd for C15H10N2: C,
82.55; H, 4.62; N, 12.84. Found: C, 82.51; H, 4.65; N, 12.70.
(12) Detailed X-ray crystallographic data are available from the
CCDC, 12 Union road, Cambridge CB2 1EZ, UK; for
compounds 2a (CCDC # 693505), 3a (CCDC # 693506), 4a
(CCDC # 693507).
(13) 1-Aza-12-cyano-11-phenyltricyclo[8.3.0.02,7]trideca-2,4,-
6,8,10,12-hexaene (3a) – Representative Procedure
To a stirred solution of 2-(bromomethyl)-3-phenylprop-2-
enenitrile (1 mmol, 0.222 g) in DMF (3 mL) was added
quinoline (2 mmol, 0.258 g) at r.t. After stirring for 1 h (salt
formation was observed as evidenced by TLC), K2CO3 (5
mmol, 0.690 g) was added and heated for 5 h at 80 °C. The
reaction mixture was allowed to cool to r.t. and diluted with
sat. aq NaCl soln (5 mL) and extracted with CH2Cl2 (5 × 10
mL). The combined organic layers were dried over anhyd
Na2SO4. Solvent was evaporated, and the residue, thus
obtained, was purified by column chromatography (SiO2,
8% EtOAc in hexanes) to furnish the pure compound 3a as a
colorless solid. Yield 45% (0.120 g); mp 160–162 °C.
1H NMR (400 MHz, CDCl3): d = 7.11 (d, 1 H, J = 9.6 Hz),
7.34–7.68 (m, 9 H), 7.85 (d, 1 H, J = 8.4 Hz), 8.26 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 96.68, 114.43, 116.19,
117.35, 118.04, 120.39, 122.03, 124.52, 125.64, 127.50,
128.10, 128.84, 128.92, 129.00, 129.05, 132.28, 132.38.
IR (KBr): n = 2226 cm–1. LC-MS: m/z = 269 [M + H]+. Anal.
Calcd for C19H12N2: C, 85.05; H, 4.51; N, 10.44. Found: C,
85.11; H, 4.54; N, 10.57.
(11) 1-Aza-8-cyano-7-phenylbicyclo[4.3.0]nona-2,4,6,8-
tetraene (2a) – Representative Procedure
To 2-(bromomethyl)-3-phenylprop-2-enenitrile10 (1 mmol,
0.222 g) pyridine (3 mL) was added and stirred for 15 min
(formation of pyridinium salt was observed as shown by
TLC) at r.t. The reaction mixture was diluted with DMF (3
mL) and K2CO3 (5 mmol, 0.690 g) was added. The reaction
mixture was then heated at 80 °C for 3 h and was allowed to
cool to r.t. Saturated aq NaCl soln (5 mL) was added and
extracted with CH2Cl2 (5 × 10 mL). The combined organic
layer was dried over anhyd Na2SO4. Solvent was evaporated,
and the residue, thus obtained, was purified by column
chromatography (SiO2, 5% EtOAc in hexanes) to furnish the
pure compound 2a as a colorless solid. Yield 52% (0.114 g);
mp 128–130 °C. 1H NMR (400 MHz, CDCl3): d = 6.60–6.70
(m, 1 H), 6.77–6.86 (m, 1 H), 7.32–7.40 (m, 1 H), 7.46–7.53
(m, 2 H), 7.56–7.68 (m, 3 H), 7.74 (s, 1 H), 7.88 (d, 1 H,
J = 7.2 Hz). 13C NMR (100 MHz, CDCl3): d = 96.94, 113.60,
116.22, 117.46, 118.16, 118.92, 120.05, 125.31, 127.15,
128.67, 129.00, 129.68, 132.56. IR (KBr): n = 2222 cm–1.
(14) The single crystal X-ray structure revealed the presence of
two molecules in the asymmetric unit. For clarity we have
shown one molecule in the ORTEP diagram.
Synlett 2009, No. 3, 411–416 © Thieme Stuttgart · New York

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