An efficient one-step method for the synthesis of 2-(indolizin-2-yl)benzimidazoles from quinoxalinones and α-picoline via a novel rearrangement

Article abstract of DOI:10.1016/j.tetlet.2008.08.032

A highly efficient one-step and versatile method for the synthesis of 2-(indolizin-2-yl)benzimidazoles has been developed on the basis of the novel ring contraction of 3-arylchloromethyl- and alkylchloromethylquinoxalin-2-ones with α-picoline.

Full text of DOI:10.1016/j.tetlet.2008.08.032

Tetrahedron Letters 49 (2008) 6231–6233
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An efficient one-step method for the synthesis of 2-(indolizin-2-yl)benzimi-
dazoles from quinoxalinones and a-picoline via a novel rearrangement
*
Vakhid A. Mamedov , Dina F. Saifina, Aidar T. Gubaidullin, Alina F. Saifina, Il’dar Kh. Rizvanov
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of the Russian Academy of Sciences, Arbuzov Str. 8, 420088 Kazan, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient one-step and versatile method for the synthesis of 2-(indolizin-2-yl)benzimidazoles has
been developed on the basis of the novel ring contraction of 3-arylchloromethyl- and alkylchlorometh-
ylquinoxalin-2-ones with a-picoline.
Received 25 June 2008
Revised 6 August 2008
Accepted 11 August 2008
Available online 14 August 2008
Ó 2008 Published by Elsevier Ltd.
Keywords:
Quinoxalin-2-one
Benzimidazole
a-Picoline
Ring contraction
Rearrangement
Indolizinylbenzimidazoles
1H NMR data
X-ray diffraction analysis
Benzimidazole-containing compounds exhibit a wide range of
biological properties. This class of heterocyclic systems has found
commercial applications in several therapeutic areas such as anti-
ulcer, antihypertensive, antiviral,1a,1b antifungal,1c antitumor,1d–h
and antihistamine agents1i as well as anthelmintic agents in veter-
inary medicine.1j–n Medicinal chemists consider these heterocycles
to be promising compounds.
Almost all the existing methods for the synthesis of benzimi-
dazoles1n,2a–j have some synthetic shortcomings, such as rigid con-
ditions and poor yields of target products, which limit their scope.
The one-step method of Fokas and co-workers3 is the most efficient
method for the synthesis of benzimidazoles, involving the Na2S2O4
reduction of o-nitroanilines in the presence of aldehydes in EtOH
or other appropriate solvents. However, the method is restricted
by its ability to synthesize a limited number of benzimidazole
derivatives.
Ar
O
N
N
Cl
+
N
-HCl
-H2O
N
H
N
H
N
Ar
1
2
3
Entry
Ar
Substrates
Product (yield) M.p., oC
1
2
3
4
5
4-NO2C6H4
Ph
2,4-Cl2C6H3 1c
3,5-Cl2C6H3 1d
1a
1b
2
3a (72%)
3b (78%)
3c (76%)
3d (65%)
3e (70%)
>300
2
2
2
2
246-248
160-162
170-172
155-157
CH2Ph
1e
Scheme 1.
In this Letter, a direct, efficient, and convenient approach to the
synthesis of 2-(indolizinyl)benzimidazoles is presented. The meth-
od is based on a new quinoxaline-benzimidazole rearrangement of
3-arylchloromethyl- 1a–d and alkylchloromethyl- 1e quinoxalin-
and N@C–Me fragments of quinoxaline 1 and
a
-picoline 2 are
involved in constructing the two new heterocyclic rings.
The structures of compounds 3a–e were deduced from their
elemental analyses and 1H NMR data.5 The mass spectra of these
compounds displayed molecular ion peaks at appropriate m/z val-
ues. Initial fragmentation involved scission of the benzimidazole
and indolizine ring systems.5
2-ones4 under the action of
noxalin-2-one 1 with
a-picoline 2. Thus, the reaction of qui-
a
-picoline 2 at reflux results in high yields of
the corresponding (indolizinyl)benzimidazoles 35 (Scheme 1). As is
evident from the structure of compounds 3, the C(2)–C(3)–C(Cl)Ar
The molecular structure of compound 3a was confirmed by a
single-crystal X-ray analysis (Fig. 1).6
Initially, complete dissolution of compounds 1 is observed in
* Corresponding author. Tel.: +7 843 2727304; fax: +7 843 2732253.
E-mail address: mamedov@iopc.kcn.ru (V. A. Mamedov).
refluxing
a-picoline solution, then an abundant precipitation of
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.08.032

6232
V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 6231–6233
Figure 2. ORTEP drawing of one of the independent molecules of compound 4c (the
compound crystallized in salt form with two independent molecules, two chlorine
anions, and acetic acid in the asymmetric part of the unit cell).
Figure 1. ORTEP drawing of one of the two independent molecules in the
asymmetric part of the unit cell of 3a. Displacement ellipsoids are drawn at the
30% probability level. H atoms are represented by circles of arbitrary size.
AcOH
2
3
4
3
Cl
Scheme 3.
Ar
+
N
H
N
10.97 ppm and two doublets at 3.91 and 4.67 ppm with 2J 18.5
Hz. The signals of the phenylene protons are shifted to stronger
fields as compared with the shifts of the protons of the phenylene
ring (7.33–7.82 ppm) of the quinoxalin-2(1H)-one 1.4 This demon-
strates the imine carbon atom involvement in the reaction, the
nitrogen becoming an electron-donating amine atom. These data
along with those already available to our group8 proved to be suf-
ficient to assign the structure of the spiro compound 4 to the prod-
uct formed at the first stage of the reaction (Scheme 2). IR
spectroscopy and mass spectrometric data also confirm this struc-
ture. The formation of spiro compound 4 was unambiguously con-
firmed by a single-crystal X-ray analysis of 4c (Fig. 2).9
2
1
+
3
+
N
H
O
4
4
Ar
Yield
10%
37%
41%
16%
M.p., oC
272-274
271-273
263-265
274-276
a
b
c
4-NO2C6H4
Ph
2,4-Cl2C6H3
3,5-Cl2C6H3
d
Scheme 2. Isolated and characterized spiro compounds, formed after reflux of the
reaction mixture for 1 h.
It should be noted that spiro compound 4 is quantitatively
transformed into 2-(3-arylindolizin-2-yl)benzimidazole 3 not only
crystals occurs rapidly which gradually dissolve during the course
of the reaction. The yield of crystalline products with a precise
melting point, obtained, for example, after refluxing quinoxalin-
in boiling a-picoline, but also in acetic acid (Scheme 3).
On the basis of the known chemistry of a a-haloi-
-picoline,10a–i
2(1H)-one 1c in
a
-picoline 2 for 1 h, is 41%7 (Scheme 2). The 1H
mines,11a–j and quinoxalinones,12a,b it is reasonable to assume that
the first stage involves nucleophilic substitution of the halogen
NMR spectrum of the product 4c showed signals for pyridinium,
phenyl, and phenylene rings at 7.98–8.67, 7.32–7.48 and 6.26–
6.69 ppm, respectively, three singlet signals at 6.73, 7.53, and
atom of the a-haloimine fragment by the nitrogen atom of the pyr-
idine ring with the formation of intermediate A. This is followed by
Cl
Cl
Ar
H
Ar
..
+
N
N
N
N
2
4
1
N
H
O
N
H
O
N
- HCl
N
A
Ar
H
Ar
H
N
Ar
N
N
NH
NH
3
-H2O
O
N
H
N
H
OH
OH
B
Scheme 4.

V. A. Mamedov et al. / Tetrahedron Letters 49 (2008) 6231–6233
6233
relative intensity less then 5% are not specified.) Anal. Calcd for C21H14N4O2: C,
71.18; H, 3.98; N, 15.81. Found: C, 70.80; H, 3.78; N, 16.00.
a cascade reaction involving (a) elimination of a proton from the
methyl group of -picoline, (b) nucleophilic attack of the methy-
a
6. The X-ray diffraction data for crystals of 3a were collected on a Smart Apex II
CCD diffractometer at 293 K. Crystallographic data for 3a. C21H14N4O2, two
independent molecules, dark pink prism crystal, formula weight 354.36,
monoclinic, P21, a = 10.8916(16), b = 15.042(2), c = 11.751(2) Å, b =
lene group on the C(3) atom of the quinoxalinone to form the
spiro-quinoxaline derivative 4, (c) intramolecular nucleophilic
attack by the N(4) nitrogen atom on the carbamoyl carbonyl group
with the formation of intermediate pentacyclic system B, (d) ring
contraction with cleavage of the C(3)–N(4) bond, and (e) elimina-
tion of water leading to the formation of the final product 3
(Scheme 4). It was shown that the reaction does not proceed in
neutral or aprotic solvents.
To summarize, we have found an efficient and versatile one-
step method for the preparation of a series of benzimidazoles as
well as other imidazole-containing ring systems. This was accom-
plished by a novel quinoxalinone-benzimidazole rearrangement of
3-chloroarylmethyl- and 3-chloroalkylmethyl-quinoxalin-2-ones
117.483(2)°, V = 1707.9(5) Å3, Z = 4,
0.092 mmꢁ1
R(int) = 0.0388, full-matrix least-squares on F2, parameters = 487, restraints =
q
calc = 1.378 g cmꢁ3
,
l(kMo K ) =
a
.
F(000) = 736, reflections collected = 28,590, unique = 8025,
1. Final indices R1 = 0.0884, wR2 = 0.2048 for 5660 reflections with I > 2r(I); R1
= 0.1252, wR2 = 0.2240 for all data, goodness-of-fit on F2 = 1.058, largest
difference in peak and hole (0.291 and ꢁ0.299 e Åꢁ3).
7. Typical procedure for the preparation of 4. A solution of 0.50 g (1.5 mmol) of 3-
(
a
-chloro-2,4-dichlorophenylmethyl)quinoxalin-2(1H)-one 1c in 4 mL of
picoline was heated while complete dissolution of compound 1c was observed
in the boiling -picoline solution. After ca. an hour an abundant precipitation of
a-
a
crystals occurred rapidly which were collected by suction filtration. Thus, 0.26
g (41%) of an analytically pure sample of 3-(2,4-dichloro)phenyl-1,2,3,1,2-
pentahydrospiro[quinoxalin-2,20-indolizin]-3(4H)-one 4c was obtained: 1H
NMR (600 MHz, DMSO-d6) d 3.91 (1H, d, CHAHB, Jab = 18.5 Hz); 4.67 (1H, d,
CHAHB, Jab = 18.5 Hz); 6.26 (1H, d, H(8), J = 7.7 Hz); 6.50 (1H, ddd, H(6), J = 7.7;
7.3; 1.5 Hz); 6.59 (1H, ddd, H(7), J = 7.7; 7.3; 1.5 Hz); 6.69 (1H, dd, H(5), J = 7.7;
1.1 Hz); 6.73 (1H, s, CH); 7.32–7.48 (3H, m, H(Ph3), H(Ph5), H(Ph6)); 7.53 (1H, br
s, N(1)H); 7.98 (1H, dd, H(50), J = 7.3; 6.6 Hz); 8.32 (1H, d, H(30), J = 8.1 Hz); 8.61
(1H, d, H(60), J = 6.2 Hz); 8.67 (1H, dd, H(40), J = 8.1; J = 7.7 Hz), 10.97 (1H, br s,
N(4)H). MS (EI*), m/z (I (%): 398(5), 397(18), 396(8) M+, 395(28), 367(7),
362(10), 361(8), 360(32), 344(20), 343(19), 342(61), 341(15), 334(5), 332(18),
307(9), 306(7), 305(6), 292(9), 291(11), 290(50), 289(18), 288(79), 281(5),
268(6), 261(7), 255(28), 254(20), 253(99), 252(13), 250(14), 240(5), 237(15),
236(28), 227(11), 226(9), 225(32), 224(6), 218(7), 216(16), 215(8), 214(39),
209(18), 208(100), 207(16), 206(5), 201(5), 197(9), 191(21), 190(28), 189(15),
188(6), 180(5), 179(6), 178(5), 172(11), 171(27), 163(8), 162(7), 161(13),
158(23), 153(7), 153(10), 148(6), 140(7), 123(5), 118(7), 104(6), 102(5), 94(5),
93(92), 92(35), 91(6), 90(9), 89(7), 80(10), 79(7), 78(29), 77(6), 66(28), 65(23)
38(17), 36(35) [HCl]). *(The peaks of ions with relative intensity less then 5%
are not specified.). Anal. Calcd for C21H16Cl3N3O: C, 58.29; H, 3.73; Cl, 24.58; N,
9.71. Found: C, 58.34; H, 3.97; Cl, 24.28; N, 9.52.
on exposure to
a-picoline. The reaction is readily applicable to
large scale synthesis. Application of this methodology to the syn-
thesis of other heterocyclic ring systems is currently under inves-
tigation and the results will be published in due course.
Acknowledgment
We thank the Russian Foundation for Basic Research (Grant No.
07-03-00613-a) for financial support.
References and notes
1. (a) Salluja, S.; Zou, R.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1996, 39, 881;
(b) Zarrinmayeh, H.; Zimmerman, D. M.; Cantrell, B. E.; Schober, D. A.; Bruns, R.
F.; Gackenheimer, S. L.; Oznstein, P. L.; Hipskind, P. A.; Britton, T. C.; Gehlert, D.
R. Bioorg. Med. Chem. Lett. 1999, 9, 647; (c) Taggart, P. J.; Cooke, L. R.; Mercer, P.
C.; Shaw, M. W. Crop Protection 1998, 17, 727; (d) Antonini, I.; Claudi, F.;
Cristalli, G.; Franchetti, P.; Grifantini, M.; Martelli, S. J. Med. Chem. 1988, 31,
260; (e) Skibo, E. B.; Schulz, W. G. J. Med. Chem. 1993, 36, 3050; (f) Skibo, E. B.
Curr. Med. Chem. 1996, 2, 900; (g) Zhou, R.; Skibo, E. B. J. Med. Chem. 1996, 39,
4321; (h) Craigo, W. A.; LeSueur, B. W.; Skibo, E. B. J. Med. Chem. 1999, 42, 3324;
(i) Janssens, F.; Torremans, J.; Janssen, M.; Stokbroekx, R.; Luyckx, M.; Janssen,
P. A. J. J. Med. Chem. 1985, 28, 1925; (j) Cedillo-Rivera, R.; Muñoz, O. J. Med.
Microbiol. 1992, 37; (k) Chavez, B.; Cedillo-Rivera, R.; Martinez-Palomo, A. J.
Protozool. 1992, 39, 510; (l) Fears, S. D.; O’Jare J. Antimicrob. Agents Chemother.
1998, 32, 144; (m) Spasov, A. A.; Yoshitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A.
Pharm. Chem. J. 1999, 33, 232; (n) Grimmett, M. R. In Comprehensive Heterocyclic
Chemistry II. Five-Membered Rings with Two Heteroatoms and Fused Carbocyclic
Derivatives; Elsevier, 1996. Vol. 3, Chapter 2.
2. (a) Wright, J. B. Chem. Rev. 1951, 48, 397; (b) Preston, P. N. Chem. Rev. 1974, 74,
279; (c) Gray, D. N. J. Heterocycl. Chem. 1970, 7, 947; (d) Hudkins, R. L.
Heterocycles 1995, 41, 1045; (e) Balasubramaniyan, V.; Balasubramaniyan, P.;
Patil, S. V. Indian J. Chem., Sect. B 1990, 29, 124; (f) Salakhov, M. S.; Umaeva, V.
S.; Salakhova, Y. S.; Idrisova, S. S. Russ. J. Org. Chem. 1999, 35, 397; (g) Hölljes, E.
L.; Wagner, E. C. J. Org. Chem. 1944, 9, 31; (h) King, F. E.; Acheson, R. M. J. Chem.
Soc. 1949, 1396; (i) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893;
(j) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814.
8. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A. Russ. Chem. Bull.,
Int. Ed. 2007, 56, 2386.
9. The X-ray diffraction data for crystal 4c (acceptable crystals for X-ray analysis
were obtained after crystallization from acetic acid) were collected on a Smart
Apex II CCD diffractometer at 293 K. Crystallographic data for 4c.
2(C21H16Cl2N3O+)ꢂ2(Clꢁ)ꢂC2H4O2, green plate crystal, formula weight 925.49,
ꢀ
triclinic, P1, a = 7.4352(13), b = 17.032(3), c = 17.361(3) Å,
a = 102.775(2)°,
b = 93.238(2)°,
c ,
= 98.979(2)°, V = 2108.4(6) Å3, Z = 2, qcalc = 1.458 g cmꢁ3
l
(kMo K ) = 0.460 mmꢁ1
.
F(000) = 952, reflections collected = 23,090,
a
unique = 9116, R(int) = 0.0241, full-matrix least-squares on F2, parameters =
557, restraints = 4. Final indices R1 = 0.0459, wR2 = 0.1190 for 6422 reflections
with I > 2r
(I); R1 = 0.0716, wR2 = 0.1327 for all data, goodness-of-fit on F2
= 1.018, largest difference in peak and hole (0.714 and ꢁ0.397 e Åꢁ3).
Crystallographic data (excluding structure factors) for the structures 3a and
4c in this Letter have been deposited with the Cambridge Crystallographic Data
Centre as Supplementary Publication Numbers CCDC 692009, 692010. Copies
of the data can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
10. (a) Fuks, L.; Gniazdowska, E.; Mieczkowski, J.; Narbutt, J.; Starosta, W.; Zasepa,
M. J. Organomet. Chem. 2004, 4751; (b) Carran, J.; Waschbuesch, R.; Savignac, P.
Phosphorus, Sulfur Silicon Relat. Elem. 1997, 209; (c) Arai, S.; Arai, H.; Tabuchi,
K.; Yamagishi, T.; Hida, M. J. Heterocycl. Chem. 1992, 215; (d) Hisano, T.; Yabuta,
Y. Chem. Pharm. Bull. 1973, 511; (e) Mamane, V.; Aubert, E.; Fort, Y.
J. Organomet. Chem. 2007, 7294; (f) Jiang, Y.; Zhou, G.-Ch.; He, G.-L.; He, L.;
Li, J.-L.; Zheng, Sh.-L. Synthesis 2007, 1459; (g) Natarajan, S. R.; Chen, M.-H.;
Heller, S.-T.; Tynebor, R. M.; Crawford, E. M.; Minxiang, C.; Kaizheng, H.; Dong,
J.; Hu, B.; Hao, W.; Chen, S.-H. Tetrahedron Lett. 2006, 5063; (h) Mohr, F.;
Binfield, S. A.; Fettinger, J. C.; Vedernikov, A. N. J. Org. Chem. 2005, 4833; (i)
Goel, Sh.; Parkash, S.; Goel, V. K. J. Indian Chem. Soc. 2004, 344.
3. Yang, D.; Fokas, D.; Li, J.; Yu, L.; Boldino, C. M. Synthesis 2005, 47.
4. Method for the synthesis of 1b: Mamedov, V. A.; Nuretdinov, I. A.; Sibgatullina,
F. G. Bull. Acad. Sci. USSR 1989, 38, 1294. Quinoxalinones 1a and 1c–e were
prepared by the method for 1b. Mp 235–238 °C (1c); 264–266 °C (1d), 199–200
°C (1e).
5. Typical procedure for the preparation of 3: A solution of 0.30 g (1.0 mmol) of 3-
(a-chloro-4-nitrophenylmethyl)quinoxalin-2(1H)-one 1a in 4 mL of a-picoline
11. (a) Jones, G. B.; Moody, C. J.; Padwa, A.; Kassir, J. M. J. Chem. Soc., Perkin Trans. 1
1991, 1721; (b) Biresaw, G.; Bunton, C. A. J. Phys. Chem. 1986, 5849; (c) Ishida,
M.; Ichikawa, K.; Asano, H.; Nakanishi, H.; Kato, Sh. Synthesis 1987, 349; (d)
Curran, W. V.; Sassiver, M. L.; Boothe, J. H.; Jacob, L. J. Heterocycl. Chem. 1985,
479; (e) Aszodi, J.; Bonnet, A.; Teutsch, G. Tetrahedron 1990, 1579; (f) Bosch, J.;
Salas, M.; Amat, M.; Alvarez, M.; Morgo, I.; Adrover, B. Tetrahedron 1991, 5269;
(g) Sakaizumi, T.; Nichikawa, M.; Ohashi, A. J. Mol. Spectrosc. 1995, 518; (h)
Miyabe, H.; Kanehiro, S.; Kume, K.; Kandori, H.; Naito, T. Tetrahedron 1998,
5883; (i) Grimmins, M. T.; Shamsad, M. Org. Lett. 2007, 149; (j) Korapala, Ch. S.;
Qin, J.; Friestad, G. K. Org. Lett. 2007, 4243.
was heated while complete dissolution of compounds 1a was first observed in
the boiling solution. After ca. an hour an abundant precipitation of crystals
occurred which gradually dissolved in the course of the reaction over 8 h. The
reaction solution was evaporated in vacuo. The resulting crude brown oil was
washed with water (2 ꢀ 5 mL), dried air, and after crystallization from AcOH
gave 0.24
g (72%) of an analytically pure sample of 2-[3-(4-nitro-
phenyl)]benzimidazole 3a: 1H NMR (600 MHz, DMSO-d6)
d 6.75 (1H, dd,
H(70), J = 7.0; 6.7 Hz); 6.97 (1 H, dd, H(60), J = 8.6; 7.0 Hz); 7.17–7.21 (3H, m,
H(10), H(5), H(6)); 7.50–7.54 (2H, m, H(4), H(7)); 7.69 (1H, d, H(80), J = 9.2 Hz);
7.91 (2H, d, H(Ph2), H(Ph6), J = 8.9 Hz); 8.22 (1H, d, H(50), J = 7.3 Hz); 8.37 (2H, d,
H(Ph3), H(Ph5), J = 8.6 Hz). MS (EI*), m/z (I (%): 355(19), 354(81) M+Å, 353(100),
309(5), 308(27), 307(74), 306(49), 305(21), 304(6), 295(7), 279(5), 265(13),
264(12), 262(8), 216(8), 203(6), 191(5), 190(5), 154(49), 153(54), 152(9),
140(10), 139(5), 126 (5), 112(5), 109(6), 98(6), 95(9)). * (The peaks of ions with
12. (a) Cheeseman, G. W. H.; Cookson, R. F. Condensed Pyrazines 1979, 35; (b)
Mamedov, V. A.; Kalinin, A. A.; Yanilkin, V. V.; Gubaidullin, A. T.; Latypov, Sh.
K.; Balandina, A. A.; Isaikina, O. G.; Toropchina, A. V.; Nastapova, N. V.;
Iglamova, N. A.; Litvinov, I. A. Russ. Chem. Bull., Int. Ed. 2005, 54, 2616.