Efficient one-pot synthesis of substituted 4,7-phenanthroline, pyrano-[3,2-f ]quinoline and pyrano[3,2-g]quinoline derivatives by aza-Diels - Alder reaction

Article abstract of DOI:10.1055/s-0030-1259105

A mild and efficient method for the synthesis of py-rano[3,2-f]quinoline and 4,7-phenanthroline derivatives via three-component domino reaction of heterocyclic amines, aldehydes, and terminal alkyne using BF₃OEt ₂ as Lewis acid catal

Full text of DOI:10.1055/s-0030-1259105

104
LETTER
Efficient One-Pot Synthesis of Substituted 4,7-Phenanthroline, Pyrano-
[3,2-f]quinoline and Pyrano[3,2-g]quinoline Derivatives by Aza-Diels–Alder
Reaction
S
ynthesis of Subst
.
itute
d
4,7-Ph
C
enanthrolin Deri
.vatives Majumdar,* Sudipta Ponra, Debankan Ghosh, Abu Taher
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
Received 15 August 2010
products and pharmaceuticals.4 Quinoline nucleus has
Abstract: A mild and efficient method for the synthesis of py-
rano[3,2-f]quinoline and 4,7-phenanthroline derivatives via three-
component domino reaction of heterocyclic amines, aldehydes, and
terminal alkyne using BF3·OEt2 as Lewis acid catalyst is described.
found broad application in drug development for the treat-
ment of melanin concentrating hormone (MCH)-receptor-
related disorder,5 cell proliferative diseases,6 transmis-
The features of this procedure are mild reaction conditions, good to sible spongiform encephalopatheies,7 malignant tumor,
high yields, and operational simplicity.
such as stomach cancer, brain tumor, and large instetine
cancer,8 and bacterial infections in mammals.9 They also
Key words: multicomponent reaction, BF3·OEt2, 4,7-phenanthro-
line, pyrano[3,2-f]quinoline, pyrano[3,2-g]quinoline, aromatic al-
find application in material science,10 bioorganometallic
processes,11 and agrochemicals and effect chemicals such
dehyde, phenyl acetylene
as dyestuffs and corrosion inhibitors.12 Moreover substi-
tuted quinolines show numerous biological activity as an-
Multicomponent reactions (MCR) have attracted consid- tagonists of endothelin,13 5HT3,14 and NK-3 receptors15
erable attention in combinatorial and medicinal chemistry and also function as inhibitors of gartric (H+/K+)-ATP-
and have been designed to produce elaborate biologically ase16 and dihydroorotate dehydrogenase.17 Moreover, it is
active compounds.1 Multicomponent reactions are con- expected that pyrano[3,2-f] quinoline, which contain both
vergent reactions, in which three or more starting materi- a quinoline ring and pyran moieties, afford unique biolog-
als react to give a highly complex product in one pot. The ical activities, such as psychotropic activity,18 antiallergic
multistep synthesis of a complex compound is laborious activity,19 anti-inflammatory activity,20 estrogenic activi-
and tedious, generating several equivalents of waste, salt ty,21 and are used as potential pharmaceuticals.22 Helieti-
and byproducts.2 Whereas multicomponent reaction gen- dine, dutadrupine, and geibalansine23 are examples of
erally occurs in one pot and exhibits high atom economy natural products containing pyranoquinoline core struc-
and selectivity and thus MCRs are advantageous com- ture. 4,7-Phenanthroline derivatives and its analogues ex-
pared to linear stepwise synthesis by reducing reaction hibit a high antibacterial activity and are used for
time, saving money and raw materials. Multicomponent treatment of gastrointestinal disease.24–29
reactions involving the simultaneous molecular interac-
In view of the importance of pyrano quinoline and its de-
tions of three or more components, selectivity is a partic-
rivatives, several methods were developed for the synthe-
ular concern because different products can be formed in
sis of pyrano quinoline by aza-Diels–Alder reaction.30
the reaction pathway.3 Moreover MCR are an ideal syn-
However, many of these synthetic protocols reported so
thetic tool for generating multiple molecular scaffolds and
far suffer from disadvantages, such as harsh reaction con-
to increase structural and skeletal diversity.
ditions, multistep reaction, expensive reagents and longer
The heterocyclic system quinoline represent an important reaction time, large amount of catalyst and lower yields.
class of alkaloids and are often found as structural frame- Therefore, a new protocol with reagent economy, one-pot
works in a large number of biologically active natural reaction, cheaper catalyst, and improved yields is desir-
Br
CHO
NH2
(i)
N
+
+
O
N
O
N
Me
Br
Me
1a
2a
3
4a
Scheme 1 Reagents and conditions: (i) BF3·OEt2, toluene, reflux, 4 h.
SYNLETT 2011, No. 1, pp 0104–0110
x
x.
x
x.
2
0
1
0
Advanced online publication: 10.12.2010
DOI: 10.1055/s-0030-1259105; Art ID: G24610ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Substituted 4,7-Phenanthrolin Derivatives
105
Table 1 Synthesis of Pyrano[3,2-f]quinoline and Phenanthroline
Derivatives under Various Experimental Conditions
able. In continuation of our work on the synthesis of quin-
oline-annulated heterocyclic compounds31 we became
interested to develop a methodology for the synthesis of
pyrano[3,2-f]quinoline and phenanthroline derivatives.
Herein, we present our recent investigation.
Entry Temp (°C) Acid catalyst
(mol%)a
Solvent
Time (h) Yield
(%)b
1
2
3
4c
5
6
7
8
9
r.t.
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
THF
24
24
24
4
0
Treatment of the aromatic aldehyde, 6-amino coumarin or
6-amino quinolone, and phenyl acetylene in the presence
of 10 mol% of BF3·OEt2 in toluene at reflux conditions af-
forded the corresponding pyrano quinoline derivatives or
phenanthroline derivatives in high yields (Scheme 1). In
our initial study the reaction of N-methyl 6-amino qui-
nolone (1), 4-bromo benzaldehyde (2), and phenyl acety-
lene (3) were used as a model reaction to optimize the
reaction conditions, and the results are presented in
Table 1.
reflux
r.t.
–
0
BF3·OEt2 (10)
BF3·OEt2 (10)
Yb(OTf)3 (10)
CuBr (10)
CuI (10)
0
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
87
61
35
48
55
51
72
69
75
61
84
81
4
6
6
TFA (10)
4
To obtain maximum yield of the product a small excess of
the amine and aromatic aldehyde with respect to phenyl
acetylene was required: 1.1 equivalents of both amine and
PTSA (10)
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (10)
BF3·OEt2 (20)
BF3·OEt2 (5)
4
aldehyde with respect to phenyl acetylene is sufficient to 10
4
bring about the improved yield. Further increase in molar
amounts resulted in side reactions. Having established the
11
4
optimized reaction conditions various aldehydes (2a–i)
were subjected to undergo the reaction with various het-
erocyclic amines (1a–d) to give the substituted quinolines
(4a–n) in high yields within few hours (Table 2). It is ob-
served that both electron-donating and electron-with-
drawing substituents on the aromatic aldehydes and
heterocyclic aldehydes gave the desired quinolines in high
12
13
14
15
DMF
4
EtOH
4
toluene
toluene
4
4
a Conditions: mol% of acid catalyst required relative to the phenyl
yields. The ortho, meta, and para substituents on the aro- acetylene in all the entries.
b Isolated yields.
matic ring of the aldehydes gave almost similar yields.
Reactions with alkynes like n-hexyne and n-heptyne did
c Optimized reaction conditions.
not give the desired products. Besides, aliphatic aldehydes
like formaldehyde and acetaldehyde did not undergo such
benzaldehyde (2c), phenyl acetylene (3) with 4-methyl-7-
reaction. A variety of substituted heterocyclic amines
were reacted with various aldehydes and phenyl acety-
lene, and in all the cases the desired products were ob-
tained in good yields. These multicomponent reactions
with excellent selectivity inspired us to react 4-methoxy-
aminocoumarin (1d). However, the expected cyclized
product 4n was obtained in only 53% yield. Perhaps this
lower yield is due to the less reactivity of 4-methyl-7-ami-
nocoumarin (1d) than that of the other amines (1a–c).
Table 2 Synthesis of Various Substituted Pyrano Coumarin and Phenanthroline Derivatives
Ph
Ar
NH2
BF3⋅OEt2, toluene
N
+
+
ArCHO
reflux, 4 h
Ph
O
X
1
2
3
O
X
4
Entry
Amines 1a–d
Aldehydes 2a–j
Products 4a–n
Yield (%)a
Br
NH2
Ph
CHO
N
1
87
O
N
Br
Me
2a
O
N
1a
Me
4a32
Synlett 2011, No. 1, 104–110 © Thieme Stuttgart · New York

106
K. C. Majumdar et al.
LETTER
Table 2 Synthesis of Various Substituted Pyrano Coumarin and Phenanthroline Derivatives (continued)
Ph
Ar
NH2
BF3⋅OEt2, toluene
N
+
+
ArCHO
reflux, 4 h
Ph
O
X
1
2
3
O
X
4
Entry
Amines 1a–d
Aldehydes 2a–j
Products 4a–n
Yield (%)a
CHO
Ph
NH2
Cl
N
2
81
O
N
Me
Cl
O
N
1a
2b
Me
4b
OMe
NH2
Ph
CHO
N
3
83
O
N
MeO
Me
2c
O
N
1a
Me
4c
Ph
NH2
S
N
CHO
4
5
80
86
O
N
S
Me
2d
O
N
1b
Me
4d
OMe
Ph
NH2
CHO
N
O
O
MeO
1b
2c
O
O
4e
Ph
NH2
NH2
NH2
CHO
6
7
8
84
81
79
N
O
O
O
O
2e
1b
O
O
4f
CHO
Ph
Cl
N
O
Cl
1b
O
O
2b
4g
Ph
O
CHO
N
O
O
2f
1b
O
O
4h
Synlett 2011, No. 1, 104–110 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 4,7-Phenanthrolin Derivatives
107
Table 2 Synthesis of Various Substituted Pyrano Coumarin and Phenanthroline Derivatives (continued)
Ph
Ar
NH2
BF3⋅OEt2, toluene
N
+
+
ArCHO
reflux, 4 h
Ph
O
X
1
2
3
O
X
4
Entry
Amines 1a–d
Aldehydes 2a–j
Products 4a–n
Yield (%)a
Cl
NH2
Ph
CHO
9
83
N
N
N
N
O
N
Cl
Et
2g
O
N
1c
Et
4i
Ph
NH2
CHO
10
11
12
79
77
77
O
N
Et
2e
O
N
1c
Et
4j
Ph
NH2
CHO
O
N
Et
2h
O
N
1c
Et
4k
Ph
NH2
CHO
Cl
Cl
O
N
Et
O
N
2i
1c
Et
4l
Ph
NH2
N
N
13
14
74
53
O
N
N
CHO
Et
2j
O
N
1c
Et
4m
Ph
N
CHO
OMe
O
O
O
O
NH2
OMe
1d
2c
4n
a Isolated yields.
Synlett 2011, No. 1, 104–110 © Thieme Stuttgart · New York

108
K. C. Majumdar et al.
LETTER
R
3
Ph
CHO
NH2
N
BF3⋅OEt2
+
R
O
X
O
X
1
2
A
R
R
R
Ph
Ph
Ph
H
NH
N
N
O
X
O
X
O
X
4
C
B
Scheme 2 The proposed mechanism for the synthesis of pyrano quinoline and phenanthroline derivatives
The reaction was first carried out in toluene without any in ionic liquids.41 However, there is no report of the syn-
catalyst at room temperature and refluxing conditions. It thesis of pyrano[3,2-f]quinoline, pyrano[3,2-g]quinoline,
was found that no product was formed without any cata- or phenanthroline derivatives avoiding preformed dienes
lyst (Table 1, entries 1 and 2). Similar reaction was at- by multicomponent domino reaction of heterocyclic
tempted in the presence of 5 mol%, 10 mol%, 20 mol% of amines, aromatic aldehydes, and unactivated alkyne in
BF3·OEt2 (entries 4, 14, 15) and found that the reaction one pot. According to our knowledge this is the first ex-
was completed at 10 mol% BF3·OEt2 at reflux in toluene ample of multicomponent aza-Diels–Alder reaction of un-
for four hours (entry 4). Lower or higher loading of the activated alkynes with any heterocyclic amines in the
catalyst had no significant effect on the reaction yield. To absence of any copper catalyst under conventional heating
find the optimum reaction conditions we used several avoiding microwave irradiation.
Lewis and Brønsted acids under the same reaction condi-
In conclusion we have demonstrated a novel, mild, and ef-
tions (entries 5–9). BF3·OEt2 gives better yield compared
ficient strategy for the synthesis of potentially biological-
to other Lewis acids. Brønsted acids give much lower
ly active pyrano[3,2-f]quinoline, pyrano[3,2-g]quinoline,
or phenanthroline derivatives by multicomponent aza-
yield compared to BF3·OEt2. In addition, MeCN, THF,
DMF, EtOH (entries 10–13) were also tested as solvents.
Diels–Alder reaction of various heterocyclic amines, al-
In these cases product 4a was formed in lower yield. Vari-
dehydes, and unactivated alkyne. The methodology is
ation of the catalyst and solvent showed that running the
simple, rapid, and inexpensive affording good to high
reaction in refluxing toluene using 10 mol% BF3·OEt2
yields with operational simplicity.
provides the best result.
Plausible rationalization for the formation of pyrano[3,2-
f]quinoline and phenanthroline derivatives is outlined in
Scheme 2. Initially, a BF3-catalyzed imine A is formed
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
which possess the aza-heterodiene moiety. This under-
goes intermolecular aza-Diels–Alder reaction with the
alkyne which is activated by BF3·OEt2 to give the prod-
ucts 4 via B´C.
Acknowledgment
We thank CSIR (New Delhi) and DST (New Delhi) for financial as-
sistance. Three of us (S.P., D.G., and A.T.) are grateful to CSIR
Chiral Lewis acid or chiral Brønsted acid catalyzed large (New Delhi) for their Research Fellowships. We also thank DST
(New Delhi) for providing Bruker NMR spectrometer (400 MHz)
number of asymmetric aza-hetero Diels–Alder reactions
and Perkin-Elmer CHN analyzer, UV-Vis, and Perkin-Elmer FTIR
are well known where active preformed diene are used as
spectrometer under the FIST program.
reaction component.33–38 The direct asymmetric aza-
hetero Diels–Alder reaction of alkynes which avoids the
use of preformed dienes, has been less extensively stud-
ied.39 Very recently Kulkarni and Török reported micro-
wave-assisted multicomponent domino cyclization–
aromatization for the synthesis of substituted quinolines.40
Gaddam and co-workers reported CuI/La(OTf)3-cata-
lyzed, one-pot synthesis of isomeric ellipticine derivatives
References and Notes
(1) For selected reviews, see: (a) Orru, R. V. A.; de Greef, M.
Synthesis 2003, 1471. (b) Balme, G.; Bossharth, E.;
Monteiro, N. Eur. J. Org. Chem. 2003, 4101. (c) Bräse, S.;
Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415.
(d) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168.
Synlett 2011, No. 1, 104–110 © Thieme Stuttgart · New York

LETTER
Synthesis of Substituted 4,7-Phenanthrolin Derivatives
(16) Ife, R. J.; Brown, T. H.; Keeling, D. J.; Leach, C. A.;
109
(2) (a) Vijjay, N. C.; Rajesh, A. U.; Vinod, S.; Bindu, A. R.;
Sreekanth, J. S.; Lakshmi, B. Acc. Chem. Res. 2003, 36,
899. (b) Tietze, L. F. Chem. Rev. 1996, 96, 115. (c) Padwa,
A.; Bur, S. K. Tetrahedron 2007, 63, 5341. (d) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed.
2006, 45, 7134. (e) Weber, L.; Illgen, K.; Almstetter, M.
Synlett 1999, 366. (f) Wang, Z.; Zhou, L.; El-Boubbou, K.;
Ye, X.-S.; Huang, X. J. Org. Chem. 2007, 72, 6409.
(3) (a) Wang, Z.; Zhou, L.; El-Boubbou, K.; Ye, X.-S.; Huang,
X. J. Org. Chem. 2007, 72, 6409. (b) Heravi, M. M.;
Baghernejad, B.; Oskooie, H. A.; Hekmatshoar, R.
Tetrahedron Lett. 2008, 49, 6101. (c) Willy, B.; Müller,
T. J. J. Eur. J. Org. Chem. 2008, 4157. (d) Umkehrer, M.;
Kolb, J.; Burdack, C.; Hiller, W. Synlett 2005, 79.
(4) Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996, 245.
Meeson, M. L.; Parsons, M. E.; Reavill, D. R.; Theobald,
C. J.; Wiggall, K. J. J. Med. Chem. 1992, 35, 3413.
(17) (a) Chen, S.-F.; Papp, L. M.; Ardecky, R. J.; Rao, G. V.;
Hesson, D. P.; Forbes, M.; Desxter, D. L. Biochem.
Pharmacol. 1990, 40, 709. (b) Zeevi, A.; Yao, G.-Z.;
Venkataramanan, R.; Duqesnoy, R. J.; Todo, S.; Fung, J. J.;
Starzl, T. E. Transplant. Proc. 1993, 25, 781.
(18) Nestrova, I. N.; Alekseeva, L. M.; Andreeva, N. I.; Glovira,
S. M.; V, G. Khim. Farm. Zh. 1995, 29, 31; Chem. Abstr.
1996, 124, 117128t.
(19) (a) Takahashi, K.; Arai, Y.; Kadowaki, S.; Shono, T.; Yuki,
S.; Kanayama, T.; Nishi, H.; Sugasawa, K.; Iwakura, M. Oyo
Yakuri 1986, 32, 233; Chem. Abstr. 1986, 105: 218691j.
(b) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K.
Biochem. Pharmacol. 1992, 44, 1211.
(20) Faber, K.; Strueckler, H.; Kappe, T. J. Heterocycl. Chem.
1984, 21, 1177.
(5) Frimurer, T. M.; Ulven, T.; Hoegberg, T.; Norregaard, P. K.;
Little, P. B.; Receveur, J.-M. WO 2004052371 A2, 2004.
(6) Leblond, B.; Petit, S.; Picard, V.; Taverne, T.;
Schweighoffer, F. WO 2004076445 A2, 2004.
(7) Murakami-Kubo, I.; Doh-ura, K.; Ishikawa, K.; Kawatake,
S.; Sasaki, K.; Kira, J.-I.; Ohta, S.; Iwaki, T. J. Virol. 2004,
78, 1281.
(21) Akhmed Khodzhaeva, Kh. S.; Besonova, I. A. Dokl. Akad.
Nauk Uzh. SSR 1982, 34; Chem. Abstr. 1983, 98, 83727q.
(22) Mohamed, E. A. Chem. Pap. 1984, 48, 261; Chem. Abstr.
1995, 123, 9315x.
(23) (a) Marco, J. L.; Carreiras, M. C. J. Med. Chem. 2003, 6,
518. (b) Puricelli, L.; Innocenti, G.; Delle Monache, G.;
Caniato, R.; Filippini, R.; Cappelletti, E. M. Nat. Prod. Lett.
2002, 16, 95. (c) Corral, R. A.; Orazi, O. O. Tetrahedron
Lett. 1967, 7, 583. (d) Sekar, M.; Rejendra Prasad, K. J.
J. Nat. Prod. 1998, 61, 294.
(8) Miwa, A.; Yoshino, T.; Osawa, T.; Sakai, T.; Shimizu, T.;
Fujiwara, Y. WO 2003033472 A1, 2003.
(9) Davies, D. T.; Jones, G. E.; Lightfoot, A. P.; Markwell,
R. E.; Pearson, N. D. WO 2002008224 A1, 2002.
(10) (a) Kim, H. M.; Jin, J.-L.; Lee, C. J.; Kim, N.; Park, K. H.
Bull. Chem. Soc. Jpn. 1998, 71, 2945. (b) Stille, J. K.
Macromolecules 1981, 14, 870. (c) Agrawal, A. K.;
Jenekhe, S. A. Macromolecules 1991, 24, 6806.
(d) Agrawal, A. K.; Jenekhe, S. A. Chem. Mater. 1992, 4,
95. (e) Agrawal, A. K.; Jenekhe, A. K.; Jenekhe, S. A. Chem.
Mater. 1993, 28, 895. (f) Agrawal, A. K.; Jenekhe, S. A.
Chem. Mater. 1993, 5, 633. (g) Jenekhe, S. A.; Lu, L.;
Alam, M. M. Macromolecules 2001, 34, 7315. (h)Agrawal,
A. K.; Jenekhe, S. A.; Vanherzeele, H.; Meth, J. S. J. Phys.
Chem. 1992, 96, 2837. (i) Jegou, G.; Jenekhe, S. A.
Macromolecules 2001, 34, 7926. (j) Lu, L.; Jenekhe, S. A.
Macromolecules 2001, 34, 6249. (k) Agrawal, A. K.;
Jenekhe, S. A. Chem. Mater. 1996, 8, 579. (l) Jenekhe, S.
A.; Zhang, X.; Chen, X. L.; Choong, V. E.; Gao, Y.; Hsieh,
B. R. Chem. Mater. 1997, 9, 409. (m) Zhang, X.; Shetty,
A. S.; Jenekhe, S. A. Macromolecules 1999, 32, 7422.
(n) Zhang, X.; Shetty, A. S.; Jenekhe, S. A. Macromolecules
2000, 33, 2069.
(11) (a) Saito, I.; Sando, S.; Nakatani, K. Bioorg. Med. Chem.
2001, 9, 2381. (b) He, C.; Lippard, S. J. J. Am. Chem. Soc.
2001, 40, 1414.
(12) Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996, 245.
(13) Cheng, X.-M.; Lee, C.; Klutchko, S.; Winters, T.; Reynolds,
E. E.; Welch, K. M.; Flynn, M. A.; Doherty, A. M. Bioorg.
Med. Chem. Lett. 1996, 6, 2999.
(14) Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.; Langer, T.;
Hamon, M.; Merahi, N.; Emerit, B. M.; Cagnotto, A.;
Skorupska, M.; Mennini, T.; Pinto, J. C. J. Med. Chem.
1995, 38, 2692.
(24) Husseini, R.; Stretton, R. J. Microbios 1981, 30, 7.
(25) Bailenger, J. Therapie 1961, 16, 287; Chem. Abstr. 1964, 60,
2222z.
(26) Mashkovskii, M. D. Lekarstvennye Veshchestva (Drugs),
Vol. 2; Khar’kov: Torsing, 1998, 313.
(27) Ordzhoni kidze, S. FRG Patent 1232156, 1967; Chem.
Abstr. 1967, 66, 115700h.
(28) CIBA Ltd. FR Patent 1369626, 1964; Chem. Abstr. 1965, 62,
1664i.
(29) PLIVA Tvornica Farmaceutskih i Kemijskih Proizvoda
FR Patent 1382542, 1964; Chem. Abstr. 1965, 63, 7912a.
(30) (a) Zhou, Y. L.; Jia, X. D.; Li, R.; Han, B.; Wu, L. M. Chin.
J. Chem. 2007, 25, 422. (b) Kantam, M. L.; Roy, M.; Roy,
S.; Subhas, M. S.; Sreedhar, B.; Choudary, B. M.; De R, L.
J. Mol. Catal. A: Chem. 2007, 265, 244. (c) More, S. V.;
Sastry, M. N. V.; Yao, C. F. Synlett 2006, 1399. (d) Das,
B.; Reddy, M. R.; Holla, H.; Ramu, R.; Venkateswarlu, K.;
Rao, Y. K. J. Chem. Res. 2005, 793. (e) Maiti, G.; Kundu,
P. Tetrahedron Lett. 2006, 47, 5733. (f) Lin, X. F.; Cui,
S. L.; Wang, Y. G. Tetrahedron Lett. 2006, 47, 4509.
(g) Zhang, W.; Guo, Y. P.; Yang, L.; Liu, Z. L. J. Chem. Res.
2004, 418. (h) Xia, M.; Lu, Y. D. Synlett 2005, 2357.
(i) Das, B.; Reddy, M. R.; Reddy, V. S.; Ramu, R. Chem.
Lett. 2004, 33, 1526. (j) Mahesh, M.; Reddy, Ch. V.; Reddy,
K. S.; Raju, P.; Reddy, V. V. Synth. Commun. 2004, 34,
4089. (k) Srinivas, K. V. N. S.; Das, B. Synlett 2004, 1715.
(l) Wang, Y. G.; Lin, X. F.; Cui, S. L. Synlett 2004, 1175.
(m) Kamal, A.; Prasad, B. R.; Ramana, A. V.; Babu, A. H.;
Reddy, K. S. Tetrahedron Lett. 2004, 45, 3507. (n) Yadav,
J. S.; Reddy, B. V. S.; Reddy, J. S. S.; Rao, R. S. Tetrahedron
2003, 59, 1599. (o) Yadav, J. S.; Reddy, B. V. S.; Sadasiv,
K.; Reddy, P. S. R. Tetrahedron Lett. 2002, 43, 3853.
(31) (a) Majumdar, K. C.; Taher, A.; Ponra, S. Synlett 2010, 735.
(b) Majumdar, K. C.; Taher, A.; Debnath, P. Synthesis 2009,
793. (c) Majumdar, K. C.; Chattopadhyay, B.; Taher, A.
Synthesis 2007, 3647. (d) Majumdar, K. C.; Debnath, P.;
Taher, A. Lett. Org. Chem. 2008, 5, 169.
(15) Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst, A.
D.; Grugni, M.; Raveglia, L. F.; Schmidt, D. B.; Rigolio, R.;
Luttmann, M.; Vecchietti, V.; Hay, D. W. P. J. Med. Chem.
1997, 50, 1794.
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K. C. Majumdar et al.
LETTER
(32) Synthesis of Compound 4a
C25H17BrN2O: C, 68.04; H, 3.88; N, 6.35. Found: C, 67.82;
H, 3.67; N, 6.37.
A mixture of the heterocyclic amine 1a (0.287 mmol) and
aromatic aldehyde 2a (0.287 mmol) was stirred in toluene at
r.t. for 10 min. After addition of 10 mol% BF3·OEt2 (mol%
calcd relative to the phenyl acetylene 3) phenyl acetylene (3,
0.261 mmol) was added, and the reaction mixture was
refluxed for 4 h. After completion of the reaction as
monitored by TLC the reaction mixture was cooled and
diluted with sat. NaHCO3 solution (40 mL). This was
extracted with EtOAc (3 × 20 mL). The combined organic
extract was washed with brine and dried over Na2SO4. The
solvent was distilled off. The resulting crude product was
purified by column chromatography over silica gel (60–120
mesh) using PE–EtOAc (4:1) as eluent to give the compound
4a. Yield 87%; colorless solid; mp 270–272 °C. IR (KBr):
1123, 1475, 1543, 1668, 2949 cm–1.1H NMR (400 MHz,
CDCl3): d = 3.89 (s, 3 H), 6.36 (d, J = 10.0 Hz, 1 H), 7.43 (q,
J = 2.7 Hz, 2 H), 7.50 (d, J = 10.0 Hz, 1 H), 7.54–7.55 (m, 3
H), 7.66 (d, J = 8.4 Hz, 2 H), 7.78 (s, 1 H), 7.89 (d, J = 8.8
Hz, 1 H), 8.10 (d, J = 8.4 Hz, 2 H), 8.38 (d, J = 9.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 30.4, 114.8, 118.8, 119.0,
122.5, 123.1, 124.1, 128.3, 128.7, 128.8, 129.4, 132.0,
133.8, 137.1, 137.4, 140.4, 141.7, 145.7, 148.1, 154.1,
161.7. MS: m/z = 441, 443 [M + H]+. Anal. Calcd (%) for
(33) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992, 57, 3264.
(34) (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem.
Int. Ed. 1998, 37, 979. (b) Kobayashi, S.; Kusakabe, K.;
Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220.
(c) Kobayashi, S.; Kusakabe, K.; Ishitani, H. Org. Lett.
2000, 2, 1225. (d) Yamashita, Y.; Mizuki, Y.; Kobayashi, S.
Tetrahedron Lett. 2005, 46, 1803.
(35) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem.Soc. 2003, 125, 4018.
(36) Mancheno, O. G.; Arrayas, R. G.; Carretero, J. C. J. Am.
Chem. Soc. 2004, 126, 456.
(37) (a) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem. Int. Ed. 1998, 37, 3121. (b) Yao, S.; Saaby,
S.; Hazell, R. G.; Jørgensen, K. A. Chem. Eur. J. 2000, 6,
2435.
(38) (a) Akiyama, T.; Itoh, J.; Fuchibe, K. Angew. Chem. Int. Ed.
2006, 45, 4796. (b) Akiyama, T.; Tamura, Y.; Itoh, J.;
Morita, H.; Fuchibe, K. Synlett 2006, 141.
(39) Fayol, A.; Zhu, J. Angew. Chem. Int. Ed. 2002, 41, 3633.
(40) Kulkarni, A.; Török, B. Green Chem. 2010, 12, 875.
(41) Gaddam, V.; Ramesh, S.; Nagarajan, R. Tetrahedron 2010,
66, 4218.
Synlett 2011, No. 1, 104–110 © Thieme Stuttgart · New York

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