1,5-electrocyclization of 1-alkyl-3-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]- 1H-benzimidazol-3-ium bromides

Article abstract of DOI:10.1007/s10593-011-0780-6

Cyclization of 1-alkyl-3-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]-1H- benzimidazol-3-ium bromides occurs in the presence of MeONa at a reduced temperature of 5-10°C via a 1,5-electrocyclization mechanism to give 3a,4-dihydro-3H-pyrrolo[1,2-a]benzimidazoles. T

Full text of DOI:10.1007/s10593-011-0780-6

Chemistry of Heterocyclic Compounds, Vol. 47, No. 4, July 2011 (Russian original Vol. 47, No. 4, April, 2011)
1,5-ELECTROCYCLIZATION OF 1-ALKYL-
3-[(2Z)-2,4-DIARYL-4-OXOBUT-2-EN-1-YL]-
1H-BENZIMIDAZOL-3-IUM BROMIDES
L. M. Potikha1*, A. R. Turelyk1, and V. A. Kovtunenko1
Cyclization of 1-alkyl-3-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]-1H-benzimidazol-3-ium bromides occurs in
the presence of MeONa at a reduced temperature of 5–10ºC via a 1,5-electrocyclization mechanism to
give 3a,4-dihydro-3H-pyrrolo[1,2-a]benzimidazoles. These are unstable under the reaction conditions and
are readily converted to {1-[2-(alkylamino)phenyl]-4-phenyl-1H-pyrrol-3-yl}(phenyl)methanones.
Keywords: benzimidazolium ylide, pyrido[1,2-a]benzimidazole, pyrrolo[1,2-a]benzimidazole, 1,5-elec-
trocyclization.
Cyclization of imidazolium and benzimidazolium ylides is involved in a number of general methods for
design condensed heterocyclic systems with a nodal nitrogen atom and whose mechanism of formation can in-
clude the participation of both the cyclic and the acyclic anion center of the ylide molecule [1]. The mechanism
of formation under the action of bases of pyrido[1,2-a]benzimidazole systems with cyclization of 1-R-3-[(2Z)-
2,4-diaryl-4-oxobut-2-en-1-yl]-1H-benzimidazol-3-ium bromides (1) also included an ylide formation stage [2,
3]. We have found [3] that, depending on the structure of the starting benzimidazolium salt and the reaction con-
ditions, two types of benzimidazolium ylides (2 or 3) can be formed and can cyclize to give the 5-R-2,4-diaryl-
5H-pyrido[1,2-a]benzimidazol-10-ium bromides (4). However, formation of the pyridobenzimidazolium salts 4
is not the only possible route for the cyclization of the benzimidazolium quaternary salts 1.
We have found that the cyclization of the benzimidazolium salts 1 in the presence of the strong base MeONa
can occur by two paths depending on the reaction conditions (process temperature) and on the nature of the
substituents on the nitrogen atoms. At room temperature or with gentle heating (up to 35ºC) of their solutions in
MeOH in the presence of MeONa the main reaction products are the pyridobenzimidazolium bromides 4. However,
in preparative mode this method is only realized in the case of the cyclization of the 1-benzyl- and 1-phenyl-
substituted benzimidazolium salts 1c,d. The products 4c,d were obtained in comparatively low yields (45 and 57%
respectively relatively to their yield (74–89%) when using morpholine or Et3N [3]) and with a high degree of purity.
For the salts 1e–g the yields of the pyridobenzimidazolium bromides 4e–g are even lower (< 25%) and the
benzimidazolium salts 1a,b are converted to an inseparable mixture of products. However, if the cyclization of salts
1a,b is carried out with cooling of their solutions to 5–10ºC, the amount of side products is decreased. The main
products then have the {1-[2-(alkylamino)phenyl]-4-phenyl-1H-pyrrol-3-yl}(phenyl)methanone structures 5a,b.
____________
*To whom correspondence should be addressed; e-mail: potikha_l@mail.ru.
1 Taras Shevchenko National University, 64 Volodymyrs'ka St., Kyiv 01033, Ukraine.
______________________________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 552–556, April, 2011. Original
article submitted April 7, 2010.
0009-3122/11/4704-0452©2011 Springer Science+Business Media, Inc.
452

Under these conditions (at 5–10ºC), the results of the reactions of salts 1c–g are the pyridobenzimidazolium bromides
4c–g but they are contaminated with a significant amount of the starting salt 1, even days after addition of the base to
its solutions.
Ar
_
Br
N+
COAr
H
N
R
1a–g
Ar
Ar
MeONa
H
N+
N+
COAr
COAr
H
Ar
_
N
R
N
Br
R
N+
6
2
25–35oC
Ar
N
R
Ar
Ar
4a–g
N+
H
N+
N
COAr
COAr
H
N
R
R
7
3
Ph
Ph
5–10oC
COPh
N
N
N
B:
H
COPh
H
NH
R
R
5a,b
8
1,4 ad Ar = Ph, a R = Me, b R = Et, c R = Bn, d R = Ph;
eg R = Me, e Ar = 4-MeOC6H4, f Ar = 4-ClC6H4, g Ar = 4-BrC6H4; 5 a R = Me, b R = Et
The structure of compounds 5a,b was proved from their IR and NMR data. The presence in the IR spec-
trum of a strong band at 1640 cm–1 points to the retention of a carbonyl in the reaction product molecule and that of
a broad band at 3380–3430 cm–1 to the presence of an NH, OH type group. The 1H NMR spectra primarily show
the presence of signals characterizing the NHAlkyl structural fragment as a quartet or triplet (3J = 5.0–5.5 Hz)
which exchanges with D2O at 5.08 or 4.80 ppm (NH) and a splitting of the signals for the N-methyl (doublet) or
N-ethyl group (CH2 multiplet). Convincing evidence of the structure of the N-arylpyrroles 5a,b was obtained
upon analysis of the COSY, NOESY, and HMBC homo- and heteronuclear correlations in the ethyl derivative
5b (see Figure 1). Thus, the presence in the compound studied of a benzene ring fragment was indicated by the
correlation of the ortho protons of one of the phenyl groups at 7.87 with the carbonyl carbon atom at 190.6 ppm.
The HMBC spectrum shows strong cross peaks linking the tertiary carbon atoms of the pyrrole fragment (123.9
and 131.6 ppm) and the protons bonded to them at 7.09 and 7.23 ppm and this is only possible in the case where
they are mutually distanced by three bonds. These protons also correlate with both of the quaternary ring carbon
453

atoms at 127.2 and 127.5 ppm. In combination with δC and δH chemical shift values these point to a
3,4-disubstituted pyrrole structure. The presence of the ortho phenyl fragment follows from the homonuclear
correlations seen in the COSY and NOESY spectra for the group of protons at 7.21–6.66 ppm, which form a
single AA'BB' type spin system.
The formation of the N-arylpyrroles 5a,b when the imidazolium salts 1a,b are cyclized can be explained
in the following way. Under the action of base, the N-alkyl-substituted quaternary benzimidazolium salts form
two types of ylides with localization of the negative charge on the endo- (C(2)) or the exocyclic carbon atom. In
our case (N-(2,4-diaryl-4-oxo-2-butenyl)benzimidazolium salts) four ylide structures are formed, as indicated
previously [3]. Two of these have the negative charge localized on the endo carbon (2 or 3) and two – localized
on the exo carbon of the butenyl fragment (6 or 7). Reaction of ylide 7 can be achieved by separation of the
proton at the C(2) atom to give ylide 3 with further cyclization to the pyrido[1,2-a]benzimidazole system or via
addition of the anion center to the electron-deficient C(2) atom to give the pyrrolo[1,2-a]benzimidazole system
8. The low stability of 3a,4-dihydro-3H-pyrrolo[1,2-a]benzimidazole derivatives with acceptor substituents in
the pyrrole ring in the presence of base has been noted previously [4, 5]. In the case of the intermediate
compound 8 the base initiates the cleavage of the N(4)–C(3a) bond to give the N-arylpyrroles 5a,b. A similar
1,5-electrocyclization mechanism involving an ylide of type 7 also explains the reaction of 1-[(2Z)-4-oxo-
2,4-diphenylbut-2-en-1-yl]pyridinium salts to indolizines under the action of base [6, 7].
128.9
7.28
H
7.46 H
135.1
127.2
127.5
7.09
H
7.15
O
123.9
H
122.2
190.6
N
6.66
H
7.87
H
131.6
7.23
140.3
126.1
129.9
H
143.7
7.46
H
H
4.80
7.21H
N
112.4
H
6.74
H
H
CH3
3.16
Fig. 1. Structurally significant HMBC correlations for compound 5b.
Differences in the behavior of salts 1a,b and 1c–g are mainly a result of the effect of the nature of the
substituent on the nitrogen atoms in the imidazolium salts 1 on the mobility of the proton at position 2. More
acceptor substituents at the N(1) atom (1c,d, R = Bn, Ph) or donor substituents in the benzene rings of the
butenyl fragment (1e) enable the cleavage of the H-2 proton, transition to ylide 2, and then to the pyrido-
[1,2-a]benzimidazole. The presence of acceptor substituents in the benzene rings of the butenyl fragment (1f,g)
on one hand facilitates the transition 2 → 6 → 7 but also increases the acceptor effect of the substituent at atom
N(3) in the type 7 structure which leads to ylide 3 and then to the pyrido[1,2-a]benzimidazoles. Evidently the
optimal combination of structural factors for the realization of the conversion 1 →7 →5 is only observed for
salts 1a,b. A type 7 structure is thermodynamically less stable than 3 with a smaller separation of charges.
Hence the likelihood of the transition 7 → 8 → 5 is only increased at lower temperature.
EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer Spectrum BX instrument for KBr tablets. 1H NMR spectra
1
and H and 13C NMR 2D correlation spectroscopic experiments were carried out on a Varian Mercury 400
454

instrument (400 and 100 MHz respectively) using DMSO-d6 with TMS as internal standard. Melting points were
determined on a Boetius heating block. Monitoring of the purity of compounds prepared was carried out by
HPLC mass spectrometry using an Agilent 1100 Series instrument with an Agilent LC/MSD SL detector
(sample introduced in a CF3COOH matrix, EI ionization).
The 1-R-3-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]-1H-benzimidazol-3-ium bromides 1a–g were prepared
1
by the method reported in [2, 3]. Melting points and H NMR spectroscopic data for compounds 4c,d agreed
with the literature [3].
5-R-2,4-Diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium Bromides 4c,d (General Method). Na
(0.25 g, 11.0 mmol) was dissolved in MeOH (15 ml). The salt 1c,d (2.5 mmol) was added with stirring to the
MeONa solution. Stirring was continued at 25–30ºC for 1.5 h. The precipitate formed on cooling was filtered off
and washed with 2-propanol to give the pyrido[1,2-a]benzimidazolium bromides in 45% (4c) or 57% (4d) yield.
{1-[2-(Alkylamino)phenyl]-4-phenyl-1H-pyrrol-3-yl}(phenyl)methanones 5a,b (General Method).
Na (0.25 g, 11.0 mmol) was dissolved in MeOH (15 ml) and cooled to 0–5ºC. The salt 1a,b (1.15 mmol) was
added with stirring. The mixture was held at 5–10ºC for a further 1.5 h. The precipitate was filtered off and
washed with 2-propanol.
Compound 5a. Yield 0.17 g (42%); mp 178–179ºC (MeCN). IR spectrum, , cm–1: 3430 (NH), 1640
1
3
(C=O), 1600, 1530, 1330, 1280, 900, 790, 700. H NMR spectrum, , ppm (J, Hz): 7.86 (2H, d, J = 8.0,
H-2',6'); 7.52 (1H, t, 3J = 8.0, H-4'); 7.44 (4H, m, H-3',5',2",6"); 7.29–7.20 (4H, m, H-3"-H-5", H-4"ʹ); 7.19 (1H,
d, J = 2.0, H-2); 7.14 (1H, d, J = 7.5, H-6"ʹ); 7.07 (1H, d, J = 2.0, H-5); 6.70–6.44 (2H, m, H-3"ʹ,5"ʹ); 5.08
4
3
4
(1H, q, J = 5.0, NH); 2.75 (3H, d, J = 5.0, NCH3). 13C NMR spectrum, , ppm: 190.3 (C=O), 144.3 (C-2"ʹ);
140.3 (C-1ʹ); 135.0 (C-1"); 132.1 (C-4ʹ); 131.3 (C-2); 130.3 (C-4"ʹ); 129.8 (C-2ʹ,6ʹ); 129.0 (C-3ʹ,5ʹ); 128.6
(C-2",6"); 128.3 (C-3",5"); 127.5 (C-3); 127.3 (C-4); 126.5 (C-4"); 126.2 (C-1"ʹ); 123.7 (C-5); 122.4 (C-6"ʹ);
116.9 (C-5"ʹ); 112.2 (C-3"ʹ), 30.9 (CH3). Found, %: C 81.71; H 5.69; N 7.98. C24H20N2O. Calculated, %:
C 81.79; H 5.72; N 7.95.
3
3
Compound 5b. Yield 0.19 g (44%); mp 124–125ºC (2-propanol). IR spectrum, , cm–1: 3380 (NH),
1640 (C=O), 1600, 1520, 1450, 1280, 790. H NMR spectrum, , ppm (J, Hz): 7.87 (2H, d, J = 8.0, H-2ʹ,6ʹ);
1
3
3
3
4
7.53 (1H, t, J = 8.0, H-4ʹ); 7.46 (4H, m, H-3ʹ,5ʹ,2",6"); 7.28 (2H, t, J = 8.0, H-3",5"); 7.23 (1H, d, J = 2.0,
3
4
3
H-2); 7.21 (2H, m, H-4",4"'); 7.15 (1H, d, J = 7.5, H-6"ʹ); 7.09 (1H, d, J = 2.0, H-5); 6.74 (1H, d, J = 7.5,
H-3"ʹ); 6.66 (1H, t, 3J = 7.5, H-5"ʹ); 4.80 (1H, t, 3J = 5.5, NH); 3.16 (2H, m, NCH2); 1.21 (3H, t, 3J = 7.0, CH3).
13C NMR spectrum, , ppm: 190.6 (C=O); 143.7 (C-2"ʹ); 140.3 (C-1ʹ); 135.1 (C-1"); 132.6 (C-4ʹ); 131.6 (C-2);
130.0 (C-4"ʹ); 129.9 (C-2ʹ,6ʹ); 129.1 (C-3ʹ,5ʹ); 128.9 (C-2",6"); 128.5 (C-3",5"); 127.5 (C-3); 127.2 (C-4); 126.7
(C-4"); 126.1 (C-1"ʹ); 123.9 (C-5); 122.2 (C-6"ʹ); 116.6 (C-5"ʹ), 112.4 (C-3"ʹ); 38.0 (NCH2); 14.9 (CH3). Found,
%: C 81.89; H 6.10; N 7.63. C25H22N2O. Calculated, %: C 81.94; H 6.05; N 7.64.
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