Unexpected formation of pyrrolo[1,2-a]quinoxaline derivatives during the multicomponent synthesis of pyrrolo[1,2-a]benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2013.01.036

New pyrrolo[1,2-a]benzimidazole and pyrrolo[1,2-a]quinoxaline derivatives are obtained via one-pot, three-component reactions from 1-benzylbenzimidazoles, α-bromocarbonyl compounds, and non-symmetrical activated acetylenic dipolarophiles in propylene oxide as both the reaction medium and acid scavenger, at room temperature. When the same reaction is performed in 1,2-epoxybutane at reflux temperature only the pyrrolo[1,2-a]benzimidazole derivative is obtained. Copyright

Full text of DOI:10.1016/j.tetlet.2013.01.036

Accepted Manuscript
Unexpected formation of pyrrolo[1,2-a]quinoxaline derivatives during the mul‐
ticomponent synthesis of pyrrolo[1,2-a]benzimidazoles
Alina Nicolescu, Calin Deleanu, Emilian Georgescu, Florentina Georgescu,
Ana-Maria Iurascu, Sergiu Shova, Petru Filip
PII:
S0040-4039(13)00072-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.01.036
TETL 42412
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
23 September 2012
26 December 2012
10 January 2013
Please cite this article as: Nicolescu, A., Deleanu, C., Georgescu, E., Georgescu, F., Iurascu, A-M., Shova, S., Filip,
P., Unexpected formation of pyrrolo[1,2-a]quinoxaline derivatives during the multicomponent synthesis of
pyrrolo[1,2-a]benzimidazoles, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.01.036
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Unexpected formation of pyrrolo[1,2-a]quinoxaline derivatives during the
multicomponent synthesis of pyrrolo[1,2-a]benzimidazoles
Alina Nicolescu a,b, Calin Deleanu a,b,*, Emilian Georgescu c, Florentina Georgescu c, Ana-Maria
Iurascu b, Sergiu Shova b,d, Petru Filip a
a “C. D. Neniţescu” Centre of Organic Chemistry of the Roumanian Academy, Spl. Independenţei 202-B, RO-060023 Bucharest, Romania
b “Petru Poni” Institute of Macromolecular Chemistry of the Roumanian Academy, Aleea Grigore Ghica Vodă 41-A, RO-700487 Iasi, Romania
c Research Center Oltchim, 1 Uzinei St., RO-240050 Râmnicu Vâlcea, Romania
d Institute of Chemistry, Academy of Sciences of the Republic of Moldova, Str. Academiei 3, MD-2028 Chişinău, Moldova
∗ Corresponding author. Tel.: +40-74-434-0456; fax: +40-21-312-1601; e-mail: calin.deleanu@yahoo.com
ABSTRACT
New pyrrolo[1,2-a]benzimidazole and pyrrolo[1,2-a]quinoxaline derivatives are obtained via one-pot, three-component reactions from 1-
benzylbenzimidazoles, α-bromocarbonyl compounds and non-symmetrical activated acetylenic dipolarophiles in propylene oxide as both the
reaction medium and acid scavenger, at room temperature. When the same reaction is performed in 1,2-epoxybutane at reflux temperature
only the pyrrolo[1,2-a]benzimidazole derivative is obtained.
KEY WORDS:
Pyrrolo[1,2-a]quinoxalines; Pyrrolo[1,2-a]benzimidazoles; Synthesis; 1H, 13C and 15N NMR; Single crystal X-ray
The increasing number of pyrrolo[1,2-a]benzimidazole derivatives having applications in biology and pharmacology,1-5
justifies interest in the development of efficient synthetic methods for these compounds.
Several synthetic routes have been reported for the synthesis of pyrrolo[1,2-a]benzimidazole derivatives.6-9 One of the most
important methods involves the 1,3-dipolar cycloaddition reaction of benzimidazolium ylides with electron-deficient alkynes
or alkenes.10-16 The classical multistep approach for the synthesis of pyrrolo[1,2-a]benzimidazoles, affording yields of up to
15%,10,11 starts with the preparation of benzimidazolium salts followed by their in situ conversion into benzimidazolium-N-
ylides in the presence of a base and the dipolarophile. Improved yields have been reported when oxidant promoters such as
CrO3 were used together with an organic base such as triethylamine.13
Our group has developed a one-pot synthetic strategy based on a consecutive quaternization, in situ generation of a
heterocyclic N-ylide, 1,3-dipolar cycloaddition and aromatization sequence.17-21 This is a three-component procedure starting
with almost equimolar amounts of an N-heterocyclic compound, an α-bromocarbonyl derivative and an electron deficient
alkyne in the presence of an epoxide, which plays the role of both the reaction medium and acid scavenger. This proved to be
a regiospecific, wide-in-scope synthesis, requiring simple reaction conditions and allowing final product separation through
crystallization.
In the case of 1-benzylbenzimidazole, using 1,2-epoxybutane at reflux temperature, we obtained better yields of
pyrrolo[1,2-a]benzimidazole derivatives. Thus, starting from 1-benzylbenzimidazole (1), phenacyl bromides 2a,b and electron
deficient alkynes 3a,b in 1,2-epoxybutane, we obtained pyrrolo[1,2-a]benzimidazole derivatives 5a,b in 68%, and 73% yields,
respectively (Scheme 1). The reaction was performed by mixing the components at reflux temperature for 24 hours, followed
by solvent evaporation and subsequent crystallization.
The reaction mechanism implies the formation of an intermediate benzimidazolium salt from 1-benzylbenzimidazole (1)
and the phenacyl bromide 2, followed by the generation of a benzimidazolium-N-ylide by the action of 1,2-epoxybutane, and
finally a 1,3-dipolar cycloaddition reaction of the intermediate benzimidazolium-N-ylide with the activated alkyne 3 to give
the corresponding dihydropyrrolo[1,2-a]benzimidazole 4 as the primary cycloadduct. Finally, the pyrrolo[1,2-a]benzimidazole
derivative 5 is obtained by spontaneous aromatization of the primary cycloadduct 4.
Surprisingly, if the same reactions were carried out in propylene oxide or 1,2-epoxybutane at room temperature for 60
hours, almost equal quantities of 4,5-dihydropyrrolo[1,2-a]quinoxaline derivatives 6a,b and pyrrolo[1,2-a]benzimidazole
derivatives 5a,b, the latter being the normal 1,3-dipolar cycloaddition products, were obtained (Scheme 1).

O
C
O
C
N
N
1,2-epoxybutane
2
1
HC
C
R
R
+
+
H C
2
Br
CH
2
2a b
,
3a b
,
Ph
O
1
N
>50 °C
O
R
1
R
N
H
O
CH
2
Ph
N
5a b
,
2
R
H
N
O
CH
2
Ph
Scheme 1. Pyrrolo[1,2-a]benzimidazoles 5a,b and 4,5-dihydropyrrolo[1,2-a]quinoxalines 6a,b prepared via the one-pot, three
component procedure.
Similar results were obtained starting from the corresponding benzimidazolium bromides and activated alkynes in an
epoxide, proving that the reaction was general.
All the structures reported were assigned based on NMR spectra and X-ray crystallography (see Supplementary
Information). The X-ray data showed that the three fused rings of heterocycles 5 are, as expected, perfectly planar, whereas
the three fused rings of heterocycles 6 are no longer planar with the central six-membered ring being distorted by the sp3
carbon (C-4). The NMR data for the two types of products have a few characteristic features depending on their structures.
Thus, in the 13C NMR spectra of compounds 6, a CO signal (around 182 ppm) is missing in comparison with compounds 5. A
signal for a saturated CH group (C-4) at around 59 ppm is present in the 13C NMR spectra of compounds 6, whereas this
signal is missing in the spectra of compounds 5. For compounds 6, the 1H NMR spectra show typical AB patterns for the two
non-equivalent benzylic protons (4.1 and 4.6 ppm), which can only be explained by the diastereotopic nature of these two
protons. In the case of compounds 5 the benzylic CH2 group gave rise to only one signal around 6 ppm indicating that the two
protons were equivalent. In the case of compounds 5, the 15N NMR spectra show two signals over 110 ppm, indicating
delocalization of the lone pair of electrons, whereas in the case of compounds 6, the N-5 signal is located at around 66 ppm
indicating no interaction of the nitrogen lone pair of electrons with other neighboring orbitals.
Ring-opening of the benzimidazole initiated by the deprotonation at C-1 of the primary cycloadduct 4 followed by ring-
closure involving the phenacyl C=O group could explain the formation of 4,5-dihydropyrrolo[1,2-a]quinoxalines 6a,b
(Scheme 2). A similar five-membered ring cleavage followed by a six-membered ring-closure mechanism has been proposed
to explain the formation of pyrroloquinoxalines in the 1,3-dipolar addition reaction of 1-methyl-3-
(ethoxycarbonylmethyl)benzimidazolium ylide and DMAD.22
The deoxygenation of the primary intermediate of the ring closure involving the phenacyl C=O group could be an
intermolecular process coupled with aromatisation of the pyrrole ring in 4. Several reductive amination reactions involving
subsequent hydroxyamines and iminium ions as intermediates have been reported.23-26 In our case, the fact that the final
product ratio of compounds 5 to 6 is 1:1, supports the possibility of an intermolecular hydrogen transfer.

O
O
O
R1
O
C
R1
R1
H
HC
C
R2
HC
N
HC
N
N
3a,b
H
R2
H
N
H
N
N
O
CH2
CH2
CH2
Ph
Ph
Ph
7a,b
4a,b
O
O
R2
O
O
R2
R2
R2
N
N
N
N
N
H
reduction
N
O
H
OH
-
H2O
N
NH
CH2
CH2
CH2
Ph
Ph
CH2
Ph
R1
R1
R1
Ph
R1
6a,b
a: R1 = H, R2 = CH3
b: R1 = Cl, R2 = OC2H5
Scheme 2. Proposed rationale for the formation of 4,5-dihydropyrrolo[1,2-a]quinoxalines 6.
In conclusion, the formation of pyrrolo[1,2-a]quinoxalines 6a,b in 1:1 molar ratio along with the expected pyrrolo[1,2-
a]benzimidazoles 5a,b was observed during the one-pot cycloaddition of 1-benzyl-3-phenacylbenzimidazolium ylides 7 to
electron-deficient alkynes 3a,b when an alkylene oxide was employed as the acid scavenger and solvent at room temperature.
At temperatures above 50 ºC, only the expected cycloaddition products, pyrrolo[1,2-a]benzimidazoles 5a,b, were obtained in
good yields. Further research is underway aimed at clarifying the reaction mechanism.
Electronic supplementary information (ESI) available: Experimental and analytical data, crystallographic data, and
supplementary figures. CCDC No: 895214 (5a), 895217 (5b), 895215 (6a), 895394 (6b).
Acknowledgement: This work was supported by a grant of the Romanian National Authority for Scientific Research, CNCS
– UEFISCDI, project number PN-II-ID-PCCE-2011-2-0028.
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Graphical Abstract
Unexpected formation of pyrrolo[1,2-a]quinoxaline derivatives during the
multicomponent synthesis of pyrrolo[1,2-a]benzimidazoles
Alina Nicolescu, Calin Deleanu, Emilian Georgescu, Florentina Georgescu, Ana-Maria Iurascu,
Sergiu Shova, Petru Filip
O
N
>50 °C
N
CH
2
O
C
O
C
Ph
N
N
2
1
5a
HC
C
R
R
+
+
H C
2
Br
CH
2
2a b
,
3a b
,
Ph
rt
+
5a b
,
1