Base-catalyzed povarov reaction: An unusual [1,3] sigmatropic rearrangement to dihydropyrimidobenzimidazoles

Article abstract of DOI:10.1021/ol201985p

A novel base-catalyzed Povarov reaction of arylamines, aldehydes, and electron-deficient dienophiles has been developed. An unprecedented in situ [1,3] sigmatropic rearrangement leading to 4,10-dihydropyrimido[1,2-a] benzimidazoles has also been discovere

Full text of DOI:10.1021/ol201985p

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5120–5123
Base-Catalyzed Povarov Reaction: An
Unusual [1,3] Sigmatropic Rearrangement
to Dihydropyrimidobenzimidazoles
Chih-Hau Chen, Gorakh S. Yellol, Po-Tsung Lin, and Chung-Ming Sun*
Department of Applied Chemistry, National Chiao Tung University, Hsinchu, Taiwan
cmsun@mail.nctu.edu.tw
Received July 23, 2011
ABSTRACT
A novel base-catalyzed Povarov reaction of arylamines, aldehydes, and electron-deficient dienophiles has been developed. An unprecedented in
situ [1,3] sigmatropic rearrangement leading to 4,10-dihydropyrimido[1,2-a]benzimidazoles has also been discovered. An insight of the plausible
mechanism is discussed and supported by X-ray crystal study. This cascade reaction is achieved in a one-pot multicomponent fashion on soluble
support under microwave conditions.
Hetero-DielsꢀAlder cycloaddition is recognized as a
powerful reaction in the synthetic strategies of natural
and unnatural polyheterocycles owing to its rich synthetic
diversity.1 Since the pioneering works of Povarov, acid-
mediated [4 þ 2] hetero-DielsꢀAlder cycloaddition be-
tween the CdCꢀNdC azadiene moieties of N-arylimines
and dienophiles hasbecomeanestablishedroutetovarious
heterocycles.2 However, despite being an attractive strat-
egy, its application is limited to condensation of an amine
with an aldehyde and final cyclization between N-aryli-
mines and electron-rich dienophiles, which is usually cat-
alyzed by acids3 (method A, Scheme 1). A careful literature
survey revealed that the Povarov reaction has never been
explored under basic conditions and even not applied to
electron-deficient dienophiles. This encouraged us to in-
vestigate a base-catalyzed Povarov reaction as well as with
electron-deficient dienophiles (method B).
The ubiquity of polyheterocyclic systems in biomedi-
cally relevant molecules and natural products has stimu-
Scheme 1. Classical Povarov Reaction and Our Strategy
(1) (a) Desrat, S.; van de Weghe, P. J. Org. Chem. 2009, 74, 6728. (b)
Gaddam, V.; Nagarajan, R. Org. Lett. 2008, 10, 1975. (c) Schmidt, R. R.
Acc. Chem. Res. 1986, 19, 250.
ꢀ
(5) (a) Kaan, H. Y. K.; Ulaganathan, V.; Rath, O.; Prokopcova, H.;
(2) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(3) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
(4) Fischer, J., Ganellin, C. R., Eds. Analogue-Based Drug Discovery;
Wiley-VCH: Weinheim, 2002.
Dallinger, D.; Kappe, C. O.; Kozielski, F. J. Med. Chem. 2010, 53, 5676.
(b) Atwal, K. S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg,
A.; Gougoutus, J. Z.; Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990,
33, 1510.
r
10.1021/ol201985p
Published on Web 09/02/2011
2011 American Chemical Society

lated many efforts for their synthesis.4 The design concept
of the presently synthesized target has originated from the
recognition of the biological role of the dihydropyrimi-
dines and benzimidazoles which exhibits a wide range of
pharmacological properties5 including nociceptin/orpha-
nin FQ receptor agonism6 and HIV-1 integrase inhibition.7
Thus, the generation of a fused heterocyclic skeleton
resembling druglike molecules has a substantial intellec-
tual appeal and thus provoked us to synthesize benzimi-
dazolyl-fused dihydropyrimidines.
Scheme 2. Base-Catalyzed Povarov Reaction and
Rearrangement
Modern synergetic approaches integrating the soluble
polymer-supported synthesis with microwave synthesis
provides a powerful strategy to generate a diversified
molecular library to speed up initial drug discovery.8
Microwave heating greatly accelerates the rate of reac-
tions, while polymer support facilitates purifications by a
simple precipitation technique.9 Our laboratory is fasci-
nated by the application of such eco-friendly technologies
to develop rapid synthetic methods for biologically pro-
mising molecules.10 In continuation of our studies, here we
disclose an unprecedented base-catalyzed Povarov reac-
tion of heteroarylimines with electron-deficient dieno-
philes and subsequent unusual [1,3] sigmatropic rearrange-
ment and the development of a multicomponent strategy
toward the soluble support for synthesis of the dihydro-
pyrimido[1,2-a]benzimidazole library.
The most promising method to investigate the Povarov
reaction under basic conditions is to synthesize the aryli-
mine first and then treat it with various dienophiles. At the
outset of our studies, the viability of the imination was first
attempted by a reaction of 2-aminobenzimidazole 1a with
benzaldehyde 2a (optimization table provided in the Sup-
porting Information). The desired imine formation was
not observed under thermal reflux conditions in toluene,
using trifluoroacetic acid in dichloromethane and utilizing
scandium triflate as a Lewis acid catalyst in methanol,
chloroform, and toluene under reflux as well as microwave
conditions. However, use of the ammonium chloride in
toluene under thermal and microwave conditions affords
imine in moderate yields. Our investigation of the intended
base-catalyzed Povarov reaction led us to investigate
piperidine as a catalyst for imine preparation. The use of
piperidine (0.5 equiv) in toluene under microwave condi-
tions was found to provide the best results. Mechanisti-
cally, condensation of aldehyde with piperidine provides
the piperidinium hydroxide salt.11 The nucleophilic
addition of benzimidazol-2-amine 1a to piperidinium hy-
droxide salt with expulsion of water and a piperidine unit
affords benzimidazole-2-imine derivative 3a.
To investigate the Povarov reaction under basic condi-
tions, as a model reaction, it was decided to use methyl
propiolate as reactive dienophile and piperidine as a base
catalyst. Consequently, benzimidazole-2-imine 3a was
treated with methyl propiolate and piperidine in toluene
under microwave conditions at 120 °C. After 5 min,
benzimidazole-fused dihydropyrimidine was obtained as
a product, whose structure was considered as 4a according
to the anticipated results (Scheme 2).
Figure 1. ORTEP diagram and key NOE enhancements of 5a.
In addition to spectroscopic studies, additional 1D NOE
studies were carried out for the confirmation of structure
and regioselectivity of the resulting tricyclic heterocycle.
Peculiarly, the results of 1D NOE experiments did not
correspond to the structure of proposed Povarov reaction
product 4a. The irradiation of proton Ha in fused tricyclic
heterocycle enhances the signals of phenyl protons by
2.10%. However, the irradiation of Hb proton enhanced
the signals of phenyl proton by 4.79% as well as shows
enhancement of Hc proton by 2.90% (Figure 1). These
observations indicate that the phenyl group could be in
proximity of the Hb proton rather than the expected Ha
proton. With this ambiguity, the structure of the fused
(6) Hayashi, S.; Hirao, A.; Imai, A.; Nakamura, H.; Murata, Y.;
Ohashi, K.; Nakata, E. J. Med. Chem. 2009, 52, 610.
(7) Jones, E. D.; Vandegraaff, N.; Le, G.; Choi, N.; Issa, W.;
Macfarlane, K.; Thienthong, N.; Winfield, L. J.; Coates, J. A. V.; Lu,
L.; Li, X.; Feng, X.; Yu, C.; Rhodes, D. I.; Deadman, J. J. Bioorg. Med.
Chem. Lett. 2010, 20, 5913.
(8) Hsiao, Y. S.; Yellol, G. S.; Chen, L. H.; Sun, C. M. J. Comb.
Chem. 2010, 12, 723.
(9) (a) Zhang, W. Chem. Rev. 2009, 109, 749. (b) Presset, M.;
Coquerel, Y.; Rodriguez, J. Org. Lett. 2009, 11, 5706.
(10) (a) Chen, C. H.; Kuo, J.; Yellol, G. S.; Sun, C. M. Chem. Asian J.
2011, 6, 1557. (b) Yellol, G. S.; Chung, T. W.; Sun, C. M. Chem.
Commun. 2010, 46, 9170. (c) Lai, J. J.; Salunke, D. B.; Sun, C. M. Org.
Lett. 2010, 12, 2174.
(11) Correa, W. H.; Edwards, J. K.; McCluskey, A.; McKinnon, I.;
Scott, J. L. Green Chem. 2003, 5, 30.
Org. Lett., Vol. 13, No. 19, 2011
5121

triheterocyclic product was further analyzed by an X-ray
crystallographic study. Surprisingly, the X-ray crystallo-
graphic data revealed that the product structure is 5a
rather than expected 4a. The ORTEP diagram of com-
pound 5a is depicted in Figure 1 (crystallographic data in
the Supporting Information). The phenyl group is linked
to the C10 carbon rather than the expected C8 carbon
atom. The results of 1D NOE experiments absolutely
match the structure 5a. This combined study clearly in-
dicates the rearrangement of Povarov reaction product 4a
to dihydropyrimidobenzimidazole 5a. The phenyl group
was migrated from the C8 carbon to the C10 carbon
through electronic rearrangement in the dihydropyrimi-
dine ring system. This is the first report of this kind of
unusual [1,3] sigmatropic rearrangement.
Table 1. Exploring Povarov ReactionꢀRearrangement
Strategya
Scheme 3. Plausible Mechanism for Base-Catalyzed Povarov
Reaction and [1,3] Sigmatropic Rearrangement
a Only representative examples are shown in this table. All examples
are included in the Supporting Information. b Yields of the isolated
product. c Reactions carried out in sealed tube.
various aldehydes 2 smoothly afforded the corresponding
imines 3 with good yields over 5 min under microwave
irradiation. While ketones required harsh conditions (the
reaction was carried out with sodium hydride for 10 min)
to deliver the corresponding imine as compared to alde-
hydes. The generality of the Povarov cascade reaction
was further investigated with different dienophiles. The
electron-withdrawing monosubstituted alkynes reacted
smoothly to furnish the corresponding rearranged trihe-
terocyclic product 5 (entries 1ꢀ2). Electron-donating die-
nophiles were also investigated under the base-catalyzed
Povarov cascade reaction. Benzo[d]imidazole-2-imine 3
was treated with 2,3-dihydrofuran under basic conditions
(reaction carried out in a sealed tube for 24 h) to produce
Povarov product 6 regioselectively. The subsequent rear-
rangement was not observed due to unsuitable electronic
requirements and the rigid nature of the Povarov reaction
product (entry 3). To the best of our knowledge, this is the
first report of the synthesis of this novel tetra-heterocyclic
scaffold 6. Ketones instead of aldehydes were also exam-
ined in the Povarov cascade reaction, which furnished the
corresponding Povarov reaction product 4(entries4and5).
However, the [1,3] sigmatropic shift of the alkyl or aryl
group was not observed with ketones and disubstituted
alkyne dienophiles because both its electron-withdrawing
groups stabilize the Povarov reaction product through
conjugation. Remarkably, the sequential process worked
Plausible steps involved in the base-catalyzed Povarov
reaction and in situ [1,3] sigmatropic rearrangement are
depicted in Scheme 3. Initially, electron-deficient dieno-
phile would activate through the base. Piperidine reacts
with ethyl propiolate to form reactive allene adduct A, which
spontaneously reacts with imine 2 to afford the adduct B. The
subsequent cyclization by 1,4-Mannich-type addition delivers
ionic intermediate C. Expulsion of the piperidine molecule
from adduct C furnished Povarov reaction product 4. The
mechanism of the further [1,3] sigmatropic rearrangement of 4
was envisioned through a series of electronic revolvement for
the formation of more stable conjugate system 5. The
electronic rearrangement could be initialized through lone
pairs of benzimidazolyl nitrogen of 4 to form the ionic
intermediate D. Finally, the [1,3] sigmatropic transfer of aryl
or alkyl group could triggered by the electron transfer on the
acrylate to form a fully conjugated stable system through
stabilization of the ionic intermediate to furnish dihydro-
pyrimido[1,2-a]benzimidazole 5.
Having achieved inspiring results for the base-catalyzed
regioselective Povarov reaction and in situ sigmatropic
rearrangement in a model reaction, we explored its scope
and limitations with various aldehydes and dienophiles
(Table 1). The reaction of 2-aminobenzimidazoles 1 with
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Org. Lett., Vol. 13, No. 19, 2011

well with a broad range of aldehydes and dienophiles to
give the corresponding products in good yields with high
regioselectivity.
microwave irradiation and PEG support greatly accelerate the
reaction in multicomponent fashion. Additionally, the PEG
support allows the progress of the reaction to be easily
monitored by regular proton NMR. It furthermore obviates
the need for purification along the way since the excess reagents
are removed in the precipitation process.
Scheme 4. PEG-Supported Multicomponent Povarov Reaction
Table 2. Scope of Povarov Multicomponet Reactiona
With successful exploration of stepwise imine formation
and a Povarov reaction followed by a [1,3] sigmatropic
rearrangement reaction under basic conditions, we next
focused our attention on a one-pot multicomponent
reaction of heteroarylamine, aldehydes, and dienophiles
to produce dihydropyrimidineꢀbenzimidazole. Unfortunately,
various attempts to achieve the multicomponent reaction are
unsuccessful at providing the desired product. On the basis of
previous experience, it was contemplated that the synergetic
effect of microwave irradiation and PEG support may offer an
opportunity to access the Povarov reaction in a multicompo-
nent fashion. Accordingly, PEG-immobilized 2-aminobenzi-
midazole 7 was prepared through a four-step synthetic
procedure with built-in diversity (R1).8 To investigate the
multicomponent reaction, PEG-linked 2-aminobenzimidazole
7 was treated with aldehyde, alkyne, and piperidine in toluene
at 120 °C under microwave irradiation. Gratifyingly, polymer-
supported dihydropyrimido[1,2-a]benzimidazole 9 was ob-
tained in 10 min through a multicomponent Povarov reaction
and in situ [1,3] sigmatropic rearrangement (Scheme 4). The
acceleration of the multicomponent Povarov reaction kinetics
could be interpreted by the fact that the polyethylene glycol
support provided a microwave absorption environment which
could efficiently conduct the microwave energy to the reactants.
PEG-bound compound 9 was purified by precipitation and
washing with cold ether to remove excess reagents and by-
product. Finally, polymer support was cleaved in the metha-
nolic solution of ammonia to furnish 4,10-dihydropyrimido-
[1,2-a]benzimidazoles 5 in good yields. Table 2 shows repre-
sentative examples to demonstrate the feasibility of this novel
multicomponent cascade reaction to provide dihydropyrimi-
dobenzimidazole analogues with manifold appendages. In
sharp contrast to conventional Povarov reaction which in-
volves acid-catalyzed reaction of aromatic aldehydes and
electron-rich dienophiles, we have demonstrated the piperi-
dine-catalyzed Povarov protocol can be applied to electron-
deficient acetylenes as well as a variety of aldehydes includ-
ing aliphatic aldehydes and ketones. The synergetic effect of
a Only representative examples are shown in this table. A library of
the 21 compounds is included in the Supporting Information. b HPLC
purity. c Yields were determined on the weight of purified samples.
In summary, we have successfully achieved four goals
that comprise (i) a base-catalyzed Povarov reaction
of heteroaryl amines, aldehydes, and alkynes; (ii) utiliza-
tion of electron-deficient dienophiles in a Povarov reac-
tion; (iii) discovery of an unprecedented [1,3] sigmatropic
rearrangement; and (iv) a soluble polymer-supported short
route by one-pot Povarov multicomponent reaction under
microwave conditions. The strategy provides an efficient
chemical pathway to access dihydropyrimido[1,2-a]-
benzimidazoles in highyields withexcellent regioselectivity
that is compatible with a wide range of substrates. The
extension of this method with different arylamines,
carbonyl components, and dienophiles will certainly pro-
vide ample opportunities for the synthesis of a wide
range of relevant compounds with potential biological
interest.
Acknowledgment. We thank the National Science
Council of Taiwan for financial assistance.
Supporting Information Available. Full experimental
1
details and copies of H and 13C NMR, mass, and IR
spectra for 4ꢀ6. This material is available free of charge
via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 19, 2011
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