Periselective intramolecular [4+2] cycloadditions of ketenimines: Synthesis of pyrido[1,2-a]benzimidazoles

Article abstract of DOI:10.1016/S0040-4039(00)01197-7

A new synthesis of pyrido[1,2-a]benzimidazole derivatives is described. Easily available N-(2-propenylideneaminophenyl)ketenimines underwent an intramolecular [4+2] cycloaddition reaction, in which the cumulated C=C bond of the ketenimine fragment acts as the 2π-electron component and the α, β-unsaturated imine function as the 4π-electron component, yielding the titled compounds in a periselective manner. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01197-7

Tetrahedron Letters 41 (2000) 7029±7032
Periselective intramolecular [4+2] cycloadditions of
ketenimines: synthesis of pyrido[1,2-a]benzimidazoles
Mateo Alajarõn,* Angel Vidal and Fulgencio Tovar
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Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Murcia, Campus de Espinardo,
Â
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30100 Murcia, Spain
Received 21 June 2000; accepted 18 July 2000
Abstract
A new synthesis of pyrido[1,2-a]benzimidazole derivatives is described. Easily available N-(2-propenyli-
deneaminophenyl)ketenimines underwent an intramolecular [4+2] cycloaddition reaction, in which the
cumulated CˆC bond of the ketenimine fragment acts as the 2p-electron component and the a,b-unsaturated
imine function as the 4p-electron component, yielding the titled compounds in a periselective manner.
# 2000 Elsevier Science Ltd. All rights reserved.
The last 20 years have witnessed the raise of a plethora of new reactions involving ketenimines
as substrates or intermediates for the synthesis of heterocyclic compounds.1 Amongst the
pericyclic reactions of ketenimines, [4+2] cycloadditions in which these heterocumulenes play the
role of the 4p-electron component have proven to be particularly useful and have been widely
reported as ecient methods for the synthesis of six-membered rings.2 By contrast, reports on the
use of ketenimines as 2p-electron components in [4+2] cycloadditions are notably scarce. In such
cases, either the CˆN or CˆC bond of the ketenimine could be the one involved in the cyclization
process. To our knowledge, a few examples of participation of the CˆN bond of ketenimines in
that kind of pericyclic reactions have been disclosed.3 Concerning the participation of the cumulated
CˆC bond, this has been shown to occur only when ketenimines are reacted intermolecularly
with a,b-unsaturated aldehydes,4 and intramolecularly with C-aryl hydrazones, when both
functionalities are linked by a proper tether.5
Herein we describe the successful intramolecular [4+2] cycloaddition of imino-ketenimines 3
where the CˆC bond of the ketenimine is the dienophile in respect to the a,b-unsaturated imino
function which acts as the diene. Both functional groups are linked by an ortho-phenylene tether
connecting the ketenimino and imino nitrogen atoms. This new cycloaddition reaction is also
* Corresponding author. Fax: +34 968 364149; e-mail: alajarin@fcu.um.es
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01197-7

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shown here to be periselective when other plausible pericyclic reaction paths of the same
substrates are ocurring.
A number of N-(2-azidophenyl)imines 2 were prepared by reaction of 2-azidoaniline 16 with
di€erent substituted cinnamaldehydes under standard reaction conditions (Scheme 1). A
Staudinger reaction7 of 2 with 1 equivalent of a 1 M toluene solution of trimethylphosphane, and
subsequent reaction of the resulting non-isolated trimethylphosphazene with an equivalent
amount of trimethylsilylketene in the same reaction ¯ask led to the corresponding 3-aryl-3,4-
dihydropyrido[1,2-a]benzimidazoles 4a±c in moderate yields, after chromatographic (column,
silica gel) puri®cation (Table 1, entries a±c).
Scheme 1. Reagents and conditions: (a) Ar±CHˆCH±CHO, EtOH, cat. AcOH, re¯ux, 30 min; (b) PMe3, toluene, rt,
30 min; (c) R1R2CˆCˆO, toluene, rt, 1 h
Table 1
Pyrido[1,2-a]benzimidazoles 4 and benzimidazo[1,2-b]isoquinolines 5 prepared

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Ketenimines 3 (R1=Me3Si, R2=H), resulting from the aza-Wittig reaction8 of the silylketene
with the phosphazene derived from 2, are reasonably the ®rst transient intermediates in the
sequence leading to 4a±c, which should then undergo the new type of intramolecular [4+2]
cycloaddition which results in the tricyclic pyrido[1,2-a]benzimidazole core. The protodesilylation
of 4 (R1=Me3Si, R2=H) to yield the ®nally isolated 4-unsubstituted 4a±c (R1=R2=H), an
uncommon but not unprecedented result,9 must occur during the chromatographic puri®cation
step. The analytical and spectroscopic data10 of the new compounds 4a±c were unequivocal in
assigning their structures.
The use of C-arylketenes instead of trimethylsilylketene in the sequence depicted in Scheme 1
opens the way to new pericyclic reaction paths. We have previously reported2 that imino-ketenimines
containing the same tether connecting both functionalities as that in imino-ketenimines 3, but
bearing two phenyl groups on the carbon terminus of the ketenimine function and one aryl group
on the iminic carbon atom, experimented an intramolecular [4+2] cycloaddition in which the C-
phenyl cumulenic unit behaved as the 4p-electron diene component, whereas the iminic CˆN
bond served as the dienophile, thus resulting in the formation of benzimidazo[1,2-b]isoquinolines
(similar to compounds 5 in Scheme 1).
When diphenyl (entries d±f) or methyl phenyl ketene (entries g±i) were employed as reactants in
step (c) of Scheme 1, mixtures of pyrido[1,2-a]benzimidazoles 4 and benzimidazo[1,2-b]iso-
quinolines 5 were obtained in good combined yields (71±91%) in which the tricyclic compounds 4
were clearly predominant, with the exception of the examples in entries f and i in which the ratio
of products was nearly 1:1. In all cases the mixtures were easily resolved into their pure
components by column chromatography (SiO2 gel, mixtures of hexane and ethyl acetate). For
entries g, h and i compounds 4 were obtained as nearly equimolecular mixtures of cis- and trans-
isomers. Compounds 5 were formed as mixtures of cis- and trans-isomers of variable ratios,
which equilibrated in solution as previously reported.2
These results illustrate the periselectivity of such reactions, in which the combination of the
a,b-unsaturated imino portion of intermediates 3 as the 1-azabutadiene component with the
dienophilic CˆC bond incorporated into the ketenimine function leading to 4 is preferred to
some extent to the alternative interaction between the iminic CˆN bond as heterodienophile with
the C-aryl ketenimine part of 3 as an all-carbon diene yielding 5. Whereas it is well-known that
azadienes are reluctant to participate in Diels±Alder reactions, it has been stated that the entropic
assistance provided by the intramolecular variant of that reaction is sucient in most instances to
override that reluctance.11 Moreover, the incorporation of the dienophile into a reactive system
(typically a heterocumulene, e.g. the ketenimine function of 3) has been shown to contribute
notoriously for allowing otherwise non-amenable cycloadditions.12 In the present case both
e€ects contribute to make possible and to favour the hetero-Diels±Alder process 3 to 4 over the
alternative pericyclic reaction path 3 to 5.
Acknowledgements
This work was supported by the Direccion General de Ensenanza Superior (Project PB95-1019),
Fundacion Seneca-CARM (Project PB/2/FS/99), and Acedesa (a division of Takasago). One of
us (F.T.) also thanks the MEC for a fellowship.

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References
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10. Satisfactory 1H, 13C NMR, mass spectra and elemental analyses were obtained for all new compounds.
Compound 4a: yellow prisms (diethyl ether). M.p. 140±142ꢀC; IR (Nujol) 1652 (CˆN), 1615, 1528, 1320, 1221,
1077, 966, 855, 742 cm^1; 1H NMR (CDCl3) ꢀ 3.20 (dd, J=16.6, 9.6 Hz, 1H), 3.45 (dd, J=16.6, 7.3 Hz, 1H), 3.87±
3.94 (m, 1H), 5.61 (dd, J=7.7, 3.7 Hz, 1H), 7.07 (dd, J=8.0, 2.1 Hz, 1H) 7.14±7.35 (m, 8H), 7.64±7.68 (m, 1H);
13C NMR (CDCl3) ꢀ 32.21 (t), 38.72 (d), 108.39 (d), 115.50 (d), 119.72 (d), 121.37 (d), 122.68 (d), 122.98 (d),
127.24 (d), 127.28 (d), 129.02 (d), 131.81 (s), 142.71 (s), 143.05 (s), 149.60 (s); MS m/e (EI) 246 (100, M+). Anal.
calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C, 82.78; H, 5.59; N, 11.63.
11. Boger, D. L. Chem. Rev. 1986, 86, 781±793.
12. (a) Boger, D. L. Tetrahedron 1983, 39, 2869±2939. (b) Ulrich, H. Cycloaddition Reactions of Heterocumulenes;
Academic Press: New York, 1967.