A new three-carbon synthon for efficient synthesis of benzannelated and 1-(2-arylethenyl) heterocycles

Article abstract of DOI:10.1021/jo000946r

The novel three-carbon synthon 1-(1H-1,2,3-benzotriazol-1-yl)-3-chloroacetone for the synthesis of benzothiazoles, pyrido[1,2-a]indoles, and styryl-substituted indolizines and imidazo[1,2-a]pyridines is reported. The proposed routes are a general and efficient approach for heterocyclizations followed by benzannelations or attachment of arylethenyl pharmacophores.

Full text of DOI:10.1021/jo000946r

J . Org. Chem. 2000, 65, 8059-8062
8059
A New Th r ee-Ca r bon Syn th on for Efficien t Syn th esis of
Ben za n n ela ted a n d 1-(2-Ar yleth en yl) Heter ocycles
Alan R. Katritzky,*,§ Dmytro O. Tymoshenko,§ Daphne Monteux,§ Vladimir Vvedensky,§
George Nikonov,§ Christopher B. Cooper,‡ and Milind Deshpande|
Center for Heterocyclic Compounds, University of Florida, Department of Chemistry,
Gainesville, Florida 32611-7200, Bristol Myers Squibb Co., Pharmaceutical Research Institute,
Route 206 & Provinceline Road, Princeton, New J ersey 08563, and Bristol Myers Squibb Co.,
Pharmaceutical Research Institute, 5 Research Pkwy, Wallingford, Connecticut 06492
katritzky@chem.ufl.edu
Received J une 22, 2000
The novel three-carbon synthon 1-(1H-1,2,3-benzotriazol-1-yl)-3-chloroacetone for the synthesis of
benzothiazoles, pyrido[1,2-a]indoles, and styryl-substituted indolizines and imidazo[1,2-a]pyridines
is reported. The proposed routes are a general and efficient approach for heterocyclizations followed
by benzannelations or attachment of arylethenyl pharmacophores.
Sch em e 1
In tr od u ction
Benzannelation and the introduction of an arylethenyl
substituent are efficient methods for the diversification
of heterocycles of biological value. Benzo-fused 2-amino-
thiazoles (methabenzthiazuron, riluzole, sabeluzole, tiox-
idazole1), pyrido[1,2-a]benzimidazoles (rifaximin,1 poten-
tial anxiolytics,2a-2c antineoplastics,3 and anticancer
agents4), and pyrido[1,2-a]indoles5a-5c demonstrate activi-
ties comparable to those of the corresponding nonfused
systems. The introduction of arylethenyl substituents has
been used widely for the modification of drugs derived
from quinoline,6 pyridinium,7 thiazole,8 and thiazolium9
ring systems. These types of diversification each create
systems with additional conjugation and divergent syn-
theses from single precursors could allow a combinatorial
approach.
Most approaches to styryl heterocycles involve reac-
tions of heterocyclic activated methylene substrates with
aldehydes or their derivatives.10,11 This process is facili-
tated by an activating group in the methylene compo-
nent.12,13
Classically important methods for the preparation of
benzo-fused heterocycles normally involve construction
of a heterocycle onto a preformed benzene ring. 6,5,6-
Tricyclic type systems (2) are usually synthesized using
one of two general approaches (i and ii of Scheme 1).
Route (i) effects the closure of a five-membered ring in
substrates 1, containing an aryl group attached to a six-
membered heteroaromatic ring via carbon (X ) CR)14,15
or nitrogen (X ) N).16,17 This approach involves thermal-
17 or photodehydrocyclization16 and often affords systems
2 in low yields. Intermediates 1 are usually synthesized
starting from o-chloronitrobenzenes,18-20 which narrows
the scope for diversification in the fused target systems.
§ University of Florida.
‡ Bristol Myers Squibb Co., New J ersey.
| Bristol Myers Squibb Co., Connecticut.
(1) The Merck Index, 12th ed.; Chapman and Hall: London, 1996;
Ver. 12.1.
(2) (a) Maryanoff, B. E.; McComsey, D. F.; Ho, W.; Shank, R. P.;
Dubinsky, B. Bioorg. Med. Chem. Lett. 1996, 6, 333. (b) Cohen, J . H.;
Maryanoff, C. A.; Stefanick, S. M.; Sorgi, K. L.; Villani, F. J . Org.
Process Res. Dev. 1999, 3(4), 260. (c) Griebel, G.; Perrault, G.; Tan, S.;
Schoemaker, H.; Sanger, D. J . Behav. Pharmacol. 1999, 10(5), 483.
(3) Badawey, E.; Kappe, T. Eur. J . Med. Chem. 1995, 30, 327.
(4) El-Hawash, S. A. M.; Badawey, E.; Kappe, T. Pharmazie 1999,
54, 341.
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(b) Srivastava, S. K. et al. J . Med. Chem. 1999, 42, 1667. (c) Katsura,
Y.; Inoue, Y.; Nishino, S.; Tomoi, M.; Itoh, H.; Takasugi, H. Chem.
Pharm. Bull. 1992, 40(6), 1424.
(6) Rubtsov, M. V.; Pershin, G. N.; Yanbuktin, L. A.; Pelenitsina,
L. A.; Gurevich, T. J .; Novitskaya, N. A.; Milovanova, S. N.; Vich-
kanova, S. A. J . Med. Pharm. Chem. 1960, 2, 113.
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Abstr. 1963, 59, 2598g.
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O’Byrne P. M. J . Allergy Clin. Immunol. 1997, 2, 210.
(9) In Martindale. The extra Pharmacopoeia, 28th ed.; Reynolds, J .
E. F., Ed.; Pharmaceutical Press: London, 1982; p 1747.
(10) J ayabalan, L.; Shanmugam, P. Synthesis 1991, 217.
(11) Thumel, R. P.; Lefoulon, F.; Cantu, D.; Mahadevan, R. J . Org.
Chem. 1984, 49(12), 2208.
(12) Konakahara, T.; Takagi, Y. Tetrahedron Lett. 1980, 21(21),
2073.
(13) Konakahara, T.; Takagi, Y. Heterocycles 1984, 22(12), 2765.
(14) Soldatenkov, A. T.; Bagdadi, M. V.; Fomichev, A. A.; Prostakov,
N. S. Zh. Org. Khim. 1982, 18, 902.
(15) Ohsawa, A.; Kawaguchi, T.; Igeta, H. Chem. Lett. 1981, 1737.
(16) Baklanov, M. V.; Frolov, A. N. Zh. Org. Khim. 1991, 27, 638.
(17) Prostakov, N. S.; Varlamov, A. V.; Shendrik, I. V.; Anisimiv,
B. N.; Krapivko, A. P.; Lavani-Edogiaverie, S.; Fomichev, A. A. Khim.
Geterotsikl. Soedin. 1983, 1384.
10.1021/jo000946r CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

8060 J . Org. Chem., Vol. 65, No. 23, 2000
Katritzky et al.
Sch em e 2
The second route (ii) represents heteroring annelation
of intermediates 3 bearing a leaving group L, with three
carbon dielectrophiles (e.g., 1,3-diketones21,22 or propargyl
bromide23). This provides systems 2 in 10-40% yields,
but gives regioisomer mixtures at the intermediate step.23
Type 5,6-fused bicycles 6 have previously been pre-
pared by pathway (iv) from 5 via photodehydrocycliza-
tion24 or thermal25 dehydrocyclization, which gives mod-
erate to good yields of 5,6 systems 6, but frequently only
as the major component of complex mixtures.
To the best of our knowledge, the approaches shown
in synthetic routes (iii) and (v) were not previously
applied to systems of types 2 and 6. Pathways (iii) and
(v) require intermediates 4 and 7, respectively. Com-
pounds 4 and 7 could also be used for the introduction of
styryl substituents and are, thus, of interest as multi-
purpose precursors.
Our recent studies of the application of benzotri-
azoloalkyl(hetero)aromatics as benzoannelation precur-
sors in alternative approaches to benzo-fused five-
membered heterocycles have provided versatile new
synthesis of benzo[b]furans,26 benzo[b]thiophenes,27 and
5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines.28 In these trans-
formations, carbanions of the starting benzotriazolyl-
methyl-heterocycles (easily prepared from the correspond-
ing five-membered heteroaromatics) undergo Michael-
type addition to R,â-unsaturated ketones and subsequent
ring closure. Benzotriazolylmethyl heterocycles are also
convenient precursors of styryl heteroaromatics.27
We now present an efficient two-step method for the
preparation of 5,6- and 6,5,6-fused, and styryl-substitut-
ed, heteroaromatic systems based on common precursors
which should allow combinatorial approaches to their
synthesis. The new three-carbon synthon 1-(1H-1,2,3-
benzotriazol-1-yl)-3-chloroacetone (11) acts as a 1,2-
dielectrophile in the first step of [2 + 3]-type heterocy-
clizations to give 13, 14, and 15 (Scheme 2). In these
intermediates, the benzotriazoloalkyl(hetero)aromatic
structure intermediate reacts either as a 1,3-dinucleo-
philic moiety for the benzannelation step (to give 16, 17)
or as a benzotriazole activated methylene intermediate
to give heteroaromatic styryl systems 18 and 19.
Ta ble 1. 4-Ben zotr ia zolylm eth yl 2-Am in oth ia zoles 13
entry
R1
R2
yield, %
a
b
c
d
e
f
H
Ph
H
H
H
Ph
H
H
H
H
59
82
77
86
69
77
65
81
4-Cl-C6H4
Ph
4-NO2-C6H4
2-Cl-C6H4
4-CH3O-C6H4
1-naphthyl
g
h
Intermediate 11 was prepared in 84% yield by heating
neat chloroacetyl chloride with trimethylsilylmethylben-
zotriazole 10 (cf. ref 29). Further reaction of 11 with
thioureas 12a , 2-alkylpyridines 12b, and 2-aminopyr-
idines 12c as dinucleophiles led to novel benzotriazolyl-
methyl compounds 13a -h , 14a -e, and 15a -f. 4-(Ben-
zotriazolylmethyl)-2-aminothiazoles 13 were obtained in
good to excellent yields (Table 1). When thiourea was
reacted with 11 in DMF instead of ethanol only N-[4-
(1H-1,2,3-benzotriazol-1-ylmethyl)-1,3-thiazol-2-yl]form-
Ta ble 2. 2-Ben zotr ia zolylm eth yl In d olizin es 14
entry
R
R1
R2
yield, %
a
b
c
d
e
H
H
H
Me
H
H
Me
H
Me
H
H
H
62
66
64
54
32
H
(CH2)3
amide was isolated in 54% yield. In the case of 2-(ben-
zotriazolylmethyl)-indolizines 14 (Table 2), this transfor-
mation demanded harsher conditions (refluxing DMF
instead of ethanol for 13 and 15), and the reactivity of
substituted 2-alkylpyridines depended on the position of
the substituent in the starting pyridine. Thus, almost
quantitative conversion of the starting material was
achieved in 4, 0.5 and 0.75 h during the preparation of
compounds 14b -d , correspondingly. Benzotriazolyl-
substituted indolizines 14a -d were prepared in 54-66%
yields, while the yield of 14e was 32%. No reaction was
observed in the case of 2,6-dimethylpyridine. The yields
of 1-(imidazo[1,2-a]pyridin-2-ylmethyl)-1H-1,2,3-benzo-
triazoles 15a -f were 49-76% (Table 3).
(18) Anderson, D. J .; Taylor, A. J . J . Heterocycl. Chem. 1986, 23,
1091.
(19) Morgan, G. T.; Stewart, J . Chem. Ind. 1937, 670.
(20) Stephenson, L.; Warburton, W. K. J . Chem. Soc. C 1970, 1355.
(21) Popov, I. I. Khim. Geterotsikl. Soedin. 1989, 1695.
(22) Kuz’menko, V. V.; Komissarov, V. N.; Simonov, A. M. Khim.
Geterotsikl. Soedin. 1981, 1497.
(23) Bergerat, I.; Galons, H.; Rabaron, A.; Combet-Farnoux, C.;
Miocque, M. J . Heterocycl. Chem. 1985, 22, 369.
(24) Muthusamy, S.; Paramasivam, R.; Ramakrishnan, V. T. J .
Heterocycl. Chem. 1991, 28, 759.
(25) Tweit, R. C. J . Heterocycl. Chem. 1970, 687.
(26) Katritzky, A. R.; Fali, C. N.; Li, J . J . Org. Chem. 1997, 62, 8205.
(27) Katritzky, A. R.; Serdyuk, L.; Xie, L.; Ghiviriga, I. J . Org. Chem.
1997, 62, 6215.
(28) Katritzky, A. R.; Fali, C. N.; Li, J . J . Org. Chem. 1997, 62, 4148.
(29) Katritzky, A. R.; Lam, J . N. Heteroatom Chem. 1990, 1, 21.

Synthesis of Benzannelated Heterocycles
J . Org. Chem., Vol. 65, No. 23, 2000 8061
Ta ble 3. 1-(Im id a zo[1,2-a ]p yr id in -2-ylm eth yl)-1H-1,2,3-
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Am in o-
(4-ben zotr ia zolylm eth yl)th ia zoles 13. 1-(1H-1,2,3-Benzo-
triazol-1-yl)-3-chloropropan-2-one (11) (10 mmol) and the
corresponding thiourea (10 mmol) were stirred in EtOH (20
mL) under reflux for 12 h. After completion of the reaction
(TLC, hexanes/EtOAc ) 1:2), the reaction mixture was deluted
with water (20 mL), and the precipitate was filtered off and
recrystallized from methanol.
ben zotr ia zoles 15
entry
substituents
yield, %
a
b
c
d
e
f
H
7-Me
8-CH3
5,7-(CH3)2
8-OCH2C6H5
6-Cl
55
49
50
43
76
50
4-(1H -1,2,3-Ben zot r ia zol-1-ylm et h yl)-1,3-t h ia zol-2-yl-
a m in e (13a ): white microprisms; yield 59%; mp 189.0-192.0
1
°C; H NMR δ 5.96 (s, 2H), 6.52 (s, 1H), 6.86 (s, 2H), 7.35 (t,
Ta ble 4. 5,7-Disu bstitu ted 2-Am in oben zoth ia zoles 16
J ) 7.5 Hz, 1H), 7.47 (t, J ) 7.5 Hz, 1H), 7.73 (d, J ) 8.4 Hz,
1H), 7.96 (d, J ) 8.4 Hz, 1H); 13C NMR δ 46.4, 102.9, 109.1,
117.3, 121.9, 125.2, 131.1, 143.7, 143.8, 167.6. Anal. Calcd for
C10H9N5S: C, 51.93; H, 3.93. Found: C, 51.64; H, 4.07.
N-[4-(1H -1,2,3-Ben zot r ia zol-1-ylm et h yl)-1,3-t h ia zol-2-
yl]-N-p h en yla m in e (13b): white microprisms; yield 82%; mp
168.0 °C; 1H NMR δ 5.78 (s, 2H), 6.78 (t, J ) 7.5 Hz, 1H), 6.82
(s, 1H), 7.09 (t, J ) 7.2 Hz, 2H), 7.27-7.35 (m, 3H), 7.47 (t,
J ) 7.5 Hz, 1H), 7.86 (d, J ) 8.4 Hz, 1H), 7.93 (d, J ) 8.1 Hz,
1H), 10.10 (s, 1H); 13C NMR δ 47.7, 106.2, 111.4, 116.8, 119.1,
121.3, 123.9, 127.1, 128.8, 133.1, 140.9, 145.3, 146.0, 163.9.
Anal. Calcd for C16H13N5S: C, 62.52; H, 4.27; N, 22.79.
Found: C, 62.21; H, 4.24; N, 22.69.
entry
R1
R2
yield, %
a
b
c
d
e
Ph
Ph
74
63
59
72
25
4-CH3-C6H4
4-CH3O-C6H4
4-NO2-C6H4
4-Cl-C6H4
Ph
Ph
Ph
H
The structure of compounds 13-15 was confirmed by
1H and 13C NMR spectra.
Reaction of 13 with chalcones in ethanol in the pres-
ence of sodium ethoxide led to benzothiazoles 16a -d in
good yields (Table 4, Scheme 2). Reaction with cinnamic
aldehyde (R1 ) H, R2 ) Ph), which is prone to side
reactions in strong basic media, gave the desired N,5-
diphenyl-1,3-benzothiazole-2-amine (16e) in 25% yield.
We further extended this result to the synthesis of pyrido-
[1,2-a]indoles 17a ,b in 54% and 57% yields. Intermedi-
ates 14 demanded generation of carbanion by treatment
with BuLi and sequential cyclization of a Michael-type
product generated in situ and indicated by TLC under
acidic conditions. Intermediate 14c was further reacted
with (chloromethyl)arenes to afford 2-styryl indolizines
18a and 18b in 70 and 75% yields, correspondingly. This
sequence was further extended to the preparation of 2-(2-
arylethenyl)imidazo[1,2-a]pyridines 19a ,b which were
prepared in 71-75% yields.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(2-In -
d olizin ylm eth yl)-1H-1,2,3-ben zotr ia zoles 14. 1-(1H-1,2,3-
benzotriazol-1-yl)-3-chloropropan-2-one (11) (2 mmol) and the
corresponding 2-alkylpyridines (4 mmol) were stirred in DMF
(15 mL) under reflux for 40 min. The completion of the reaction
was monitored by TLC (hexanes/EtOAc ) 1:1). The reaction
mixture was diluted with ether (40 mL) and washed with
water (6 × 10 mL). Combined water layers were extracted with
ether (20 mL). Organic extracts were dried (MgSO4), concen-
trated in vacuo, and purified column chromatography (silica
gel, ethyl acetate/hexane ) 1:1) to give pure products.
1-(2-In d olizin ylm eth yl)-1H-1,2,3-ben zotr ia zole (14a ):
white plates; yield 62%; mp 150.0 °C; 1H NMR δ 5.94 (s, 2H),
6.35 (s, 1H), 6.43 (t, J ) 6.4 Hz, 1H), 6.62 (dd, J ) 6.5 Hz, 9.0
Hz, 1H), 7.25 (d, J ) 8.7 Hz, 2H), 7.29-7.49 (m, 3H), 7.78 (d,
J ) 6.8 Hz, 1H), 8.05 (d, J ) 8.1 Hz, 1H); 13C NMR δ 46.0,
98.4, 109.9, 110.7, 111.0, 117.7, 119.0, 119.9, 122.7, 123.7,
125.0, 127.1, 132.7, 133.1, 146.2. Anal. Calcd for C15H12N4: C,
72.56; H, 4.88; N, 22.57. Found: C, 72.27; H, 4.94; N, 22.43.
1-[(7-Meth yl-2-in d olizin yl)m eth yl]-1H-1,2,3-ben zotr ia -
Con clu sion
1
zole (14b): white plates; yield 66%; mp 162.0 °C; H NMR δ
A general and efficient approach to unified precursors
for the preparation of benzo-fused and styryl-substituted
heteroaromatic systems was developed. Such an ap-
proach is based on the novel three-carbon synthon 1-(1H-
1,2,3-benzotriazol-1-yl)-3-chloroacetone which resulted in
high yields of benzothiazoles 16, pyrido[1,2-a]indoles 17
and styryl-substituted indolizines 18 and imidazo[1,2-a]-
pyridines 19. The proposed routes open special oppor-
tunities for heterocyclizations followed by benzannela-
tions or attachment of arylethenyl pharmacophores.
2.21 (s, 3H), 5.91 (s, 2H), 6.20 (s, 1H), 6.37 (d, J ) 7.0 Hz,
1H), 7.00 (s, 1H), 7.15 (s, 1H), 7.26-7.47 (m, 3H), 7.68 (d, J )
7.2 Hz, 1H), 8.05 (d, J ) 8.0, 1H); 13C NMR δ 21.0, 46.1, 96.9,
110.0, 110.3, 113.5, 117.0, 120.0, 122.7, 123.7, 124.6, 127.0,
127.9, 132.7, 133.5, 146.3. Anal. Calcd for C16H14N4: C, 73.25;
H, 5.39; N, 21.36. Found: C, 73.20; H, 5.48; N, 21.36.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-(Im id a zo-
[1,2-a ]p yr id in -2-ylm et h yl)-1H -1,2,3-b en zot r ia zoles 15.
1-(1H-1,2,3-Benzotriazol-1-yl)-3-chloropropan-2-one (11) (10
mmol) and the corresponding 2-aminopyridines (10 mmol)
were stirred in EtOH (10 mL) under reflux for 12 h. After
completion of the reaction (TLC, hexanes/EtOAc ) 1:2), the
reaction mixture was evaporated under reduced pressure. The
crude mixture was then washed with water (10 mL) and
extracted with CH2Cl2 (2 × 10 mL). The organic layer was
dried (MgSO4) and concentrated under reduced pressure to
give the crude product, which was further purified by neutral
alumina column chromatography (hexanes/EtOAc ) 1:2) to
give pure products.
Exp er im en ta l Section
(Trimethylsilylmethyl)benzotriazole 10 was synthesized ac-
cording to the already reported procedure.29
P r ep a r a tion of 1-(1H-1,2,3-Ben zotr ia zol-1-yl)-3-ch lo-
r op r op a n -2-on e (11). 1-[(Trimethylsilyl)methyl]-1H-1,2,3-
benzotriazole (10) (2.05 g, 0.01 mol) was dissolved in chloro-
acetyl chloride (0.8 mL, 0.01 mol) at room temperature. After
10-20 s, the evolution of chlorotrimethylsilane was observed
and the mixture began to solidify. The solid obtained was
triturated with ether, filtered off, and washed with ether to
afford an analytically pure sample as pale yellow needles: mp
1-(Im id a zo[1,2-a ]p yr id in -2-ylm et h yl)-1H -1,2,3-b en zo-
tr ia zole (15a ): white microprisms; yield 55%; mp 173.0-174.0
1
°C; H NMR δ 6.04 (s, 2H), 6.77 (dd, J ) 6.7 Hz, 6.8 Hz, 1H),
7.18 (dd, J ) 7.3 Hz, 8.5 Hz, 1H), 7.33-7.37 (m, 2H), 7.45 (dd,
J ) 7.1 Hz, 7.9 Hz, 1H), 7.58 (d, J ) 9.2 Hz, 1H), 7.68 (d, J )
8.2 Hz, 1H), 7.99 (d, J ) 6.7 Hz, 1H), 8.06 (d, J ) 8.4 Hz, 1H);
13C NMR δ 46.8, 110.1, 110.5, 112.5, 117.4, 119.6, 123.8, 125.0,
125.7, 127.2, 132.8, 140.9, 145.0, 146.0. Anal. Calcd for
1
159.0 °C (84%); H NMR δ 4.72 (s, 2H), 5.86 (s, 2H), 7.30 (t,
J ) 7.5 Hz, 1 H), 7.44 (t, J ) 7.5 Hz, 1 H), 7.65 (d, J ) 8.1 Hz,
1 H), 7.95 (d, J ) 8.1 Hz, 1 H); 13C NMR δ 47.1, 54.3, 110.7,
119.1, 124.0, 127.4, 133.6, 145.0, 195.6. Anal. Calcd for C9H8-
ClN3O: C, 51.56; H, 3.85; N, 20.05. Found: C, 51.68; H, 3.65;
N, 20.01.
C
14H11N5: C, 67.45; H, 4.46. Found: C, 67.26; H, 4.73.
1-[(7-Meth ylim idazo[1,2-a ]pyr idin -2-yl)m eth yl]-1H-1,2,3-
ben zotr ia zole (15b): white microprisms; yield 49%; mp

8062 J . Org. Chem., Vol. 65, No. 23, 2000
Katritzky et al.
1
156.0-157.0 °C; H NMR δ 2.36 (s, 3H), 6.00 (s, 2H), 6.59 (d,
7.24 (dd, J ) 5.1, 1.0 Hz, 1H), 7.30-7.42 (m, 6H), 7.56 (d, J )
7.3 Hz, 1H), 8.02 (d, J ) 1.7 Hz, 1H); 13C NMR δ 18.58, 21.35,
91.1, 107.4, 116.4, 120.4, 121.2, 122.6, 124.2, 124.6, 126.8,
127.7, 127.9, 128.6, 129.0, 129.3, 129.4, 130.3, 136.6, 137.6,
139.0, 145.5. Anal. Calcd for C24H19NS: N, 3.96. Found: N,
3.65.
J ) 6.9 Hz, 1H), 7.28 (s, 1H), 7.31-7.37 (m, 2H), 7.43 (dd, J )
7.3 Hz, 7.7 Hz, 1H), 7.67 (d, J ) 8.2 Hz, 1H), 7.85 (d, J ) 6.8
Hz, 1H), 8.05 (d, J ) 8.3 Hz, 1H); 13C NMR δ 21.3, 47.0, 109.9,
110.2, 115.3, 115.8, 119.7, 123.8, 124.9, 127.3, 132.9, 136.1,
140.7, 145.6, 146.1. Anal. Calcd for C15H13N5: C, 68.42; H, 4.99.
Found: C, 68.42; H, 5.39.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ben zoth ia -
zole-2-a m in es 16. 4-Benzotriazolylmethyl 2-aminothiazole 13
(10 mmol) and the corresponding chalcone (10 mmol) were
stirred in the solution of sodium (0.23 g, 10 mmol) in EtOH
(30 mL) under reflux for 12 h. After completion of the reaction
(TLC, hexanes/EtOAc ) 1:4), the reaction mixture was evapo-
rated under reduced pressure. The mixture was then diluted
with water (10 mL), and the product filtered off and recrystal-
lized from acetone/methanol mixture to give pure products.
N,5,7-Tr ip h en yl-1,3-ben zoth ia zol-2-a m in e (16a ): white
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-[(E)-2-
Ar yleth en yl]in d olizin es 18 a n d 2-(2-P h en yleth en yl)im -
id a zo[1,2-a ]p yr id in es 19. n-BuLi (1 mmol, 0.66 mL of 1.5 N
solution in hexanes) was added dropwise to the solution of
indolizine 14c (0.262 g, 1 mmol) or imidazo[1,2-a]pyridine 15a
in dry THF (25 mL) under Ar at -78 °C. A deep-blue solution
formed and was kept at -78 °C for 2 h, and then benzyl
chloride (0.127 g, 1 mmol) was added. The reaction mixture
was allowed to warm to room temperature during 12 h and
monitored by TLC (hexanes/EtOAc ) 4:1). Then, t-BuOH (10
mL) and t-BuOK (1 g) were added, and the mixture was
refluxed for 72 h. The residue that formed after removal of
solvents was treated with water (15 mL) and extracted with
ether (3 × 10 mL). Crude material obtained after removal of
ether was recrystallized from ethanol to give pure product.
8-Meth yl-2-[(E)-2-p h en yleth en yl]in d olizin e (18a ): white
microprisms; yield 75%; mp 138.0 °C; 1H NMR δ 2.40 (s, 3H),
6.36 (t, J ) 6.7 Hz, 1 H), 6.44 (d, J ) 6.5, 1H), 6.58 (s, 1H),
7.03 (d, J ) 16.2 Hz, 1H), 7.16 (d, J ) 16.2 Hz, 1H), 7.20-
7.25 (m, 1H), 7.30-7.39 (m, 3H), 7.47-7.52 (m, 2H), 7.71 (d,
J ) 6.7, 1H); 13C NMR δ 18.1, 94.5, 110.4, 112.0, 116.7, 122.1,
122.9, 126.0, 126.6, 126.9, 127.5, 127.8, 128.5, 134.6, 137.8.
Anal. Calcd for C17H15N: N, 6.00. Found: N, 6.14.
1
microprisms; yield 74%; mp 215.0 °C; H NMR δ 7.02 (t, J )
7.5 Hz, 1H), 7.31-7.37 (m, 3H), 7.41-7.53 (m, 5H), 7.69-7.72
(m, 4H), 7.76-7.84 (m, 4H), 10.16 (br s, 1H); 13C NMR δ 115.6,
117.1, 119.9, 121.1, 125.8, 126.1, 126.3, 126.8, 127.4, 127.6,
127.7, 134.1, 138.3, 139.4, 139.5, 139.6, 152.6, 161.5. Anal.
Calcd for C25H18N2S: N, 7.40. Found: N, 7.24.
5-(4-Meth oxyp h en yl)-7-(4-m eth ylp h en yl)-N-p h en yl-1,3-
ben zoth ia zol-2-a m in e (16b): white microprisms; yield 63%;
mp 205.0 °C; 1H NMR δ 2.42 (s, 3H), 3.83 (s, 3H), 7.01 (t, J )
7.6 Hz, 1H), 7.31-7.37 (m, 3H), 7.41-7.53 (m, 5H), 7.69 (d,
J ) 6.5 Hz, 2H), 7.76-7.84 (m, 4H), 10.17 (bs, 1H); 13C NMR
δ 22.6, 41.7, 113.1, 114.3, 117.8, 118.6, 121.9, 123.6, 123.8,
124.7, 127.8, 131.8, 135.9, 137.6, 137.7, 142.2, 145.3, 150.5,
154.2, 158.8, 162.1. Anal. Calcd for C27H22N2OS: N, 6.63.
Found: N, 6.68.
Gen er a l P r oced u r e for th e P r ep a r a tion of 4,2-Disu b-
stitu ted P yr id o[1,2-a ]in d oles 17. 1-(2-Indolizinylmethyl)-
1H-1,2,3-benzotriazole 14 (1 mmol) was dissolved in 25 mL of
dry THF under Ar and cooled to -78 °C, and n-BuLi (1 mmol,
0.66 mL, 1.5 N solution in hexanes) was added dropwise. A
deep-blue solution formed was kept at -78 °C for 2 h, and
then the solution of chalcone (1 mmol) in 3 mL of dry THF
was added. The reaction mixture was allowed to warm to room
temperature over 12 h and monitored by TLC (hexanes/EtO-
Ac ) 25:1). After removal of the solvent the residue was
dissolved in 20 mL of 17% HCl and refluxed 4 h. The mixture
was neutralized with ammonia and extracted with ether (3 ×
20 mL). Crude material obtained after removal of ether was
purified on column (silica gel, hexanes/EtOAc ) 25:1) to give
pure product.
9-Meth yl-4-(4-m eth ylp h en yl)-2-p h en ylp yr id o[1,2-a ]in -
d ole (17a ): white microprisms; yield 54%; mp 147.0 °C; 1H
NMR δ 2.45 (s, 3H), 2.48 (s, 3H), 6.09 (t, J ) 6.8 Hz, 1H), 6.61
(d, J ) 6.2, 1H), 6.74 (br s, 1H), 7.30-7.35 (m, 4H), 7.39-7.47
(m, 4H), 7.62 (d, J ) 7.2 Hz, 1H), 7.72 (d, J ) 7.2, 2H), 8.00
(d, J ) 1.6 Hz, 1H); 13C NMR δ 18.6, 21.3, 91.1, 107.3, 117.6,
120.3, 122.3, 124.8, 126.7, 126.8, 127.5, 127.7, 128.6, 128.8,
129.3, 129.4, 130.4, 135.3, 136.9, 137.5, 138.9, 141.9. Anal.
Calcd. for C26H21N: N, 4.03. Found: N, 3.87.
9-Meth yl-2-(4-m eth ylp h en yl)-4-(2-th ien yl)p yr id o[1,2-a ]-
in d ole (17b): white plates; yield 57%; mp 112.0 °C; 1H NMR
δ 2.43 (s, 3H), 2.48 (s, 3H), 6.08 (t, J ) 6.8 Hz, 1H), 6.59 (d,
J ) 6.5 Hz, 1H), 6.70 (s, 1H), 7.07 (dd, J ) 3.7, 5.1 Hz, 1H),
8-Meth yl-2-[(E)-2-(1-n a p h th yl)eth en yl]in d olizin e (18b):
1
white microprisms; yield 70%; mp 109.0 °C; H NMR δ 2.42
(s, 3H), 6.37 (t, J ) 6.7 Hz, 1H), 6.46 (d, J ) 6.6 Hz, 1H), 6.68
(s, 1H), 7.22 (s, 1H), 7.41-7.56 (m, 4H), 7.70-7.88 (m, 5H),
8.28 (d, J ) 7.8 Hz, 1H); 13C NMR δ 18.2, 94.6, 110.5, 112.1,
112.2, 116.8, 122.9, 123.0, 123.9, 124.4, 125.0, 125.7, 125.8,
127.0, 127.7, 127.9, 128.5, 131.2, 133.7, 134.7,135.4. Anal.
Calcd for C21H17N: N, 4.94. Found: N, 4.99.
2-[(E)2-P h en ylet h en yl]im id a zo[1,2-a ]p yr id in e (19a ):
1
white microprisms; yield 71%; mp 160.0 °C; H NMR δ 6.75
(t, J ) 6.8 Hz, 1H), 7.11-7.20 (m, 2H), 7.24-7.28 (m, 2H),
7.34-7.39 (m, 2H), 7.52-7.62 (m, 4H), 8.06 (d, J ) 7.2 Hz,
1H); 13C NMR δ 110.9, 112.5, 117.5, 120.2, 125.3, 125.7, 126.9,
127.0, 128.0, 128.9, 130.8, 137.5, 144.5, 146.0. Anal. Calcd for
C
15H12N2: N, 12.72. Found: N, 12.68.
2-[(E)-2-(4-Ch lor op h en yl)et h en yl]im id a zo[1,2-a ]p yr i-
d in e (19b): white microprisms; yield 74%; mp 225.0 °C; 1H
NMR δ 6.75 (dt, J ) 1.0, 6.3 Hz, 1H), 7.08-7.20 (m, 2H), 7.30-
7.34 (m, 2H), 7.44-7.48 (m, 3H), 7.53-7.58 (m, 2H), 8.05 (dt,
J ) 1.0, 6.6 Hz, 1H); 13C NMR δ 111.3,112.5, 112.7, 117.7,
120.9, 125.6, 125.9, 128.2, 129.3, 129.6, 136.2, 144.2, 146.2.
Anal. Calcd for C15H11ClN2: C, 70.72; H, 4.36; N, 11.00.
Found: C, 70.79; H, 4.36; N, 11.05.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and CHN
analysis data for compounds 13c-h , 14c-e, 15c-f, and 16c-
e. This material is available free of charge via the Internet at
http://pubs.acs.org.
J O000946R