Intramolecular cyclization of alkylimidazoles

Article abstract of DOI:10.1016/j.tetlet.2014.12.074

1,2-Dialkylimidazoles can be converted to nucleophilic 2-alkylidene imidazolines upon treatment with (BOC)₂O under mild conditions. Incorporation of a β-keto amide carbonyl electrophile in the 2-alkylimidazole side chain results in intramolecul

Full text of DOI:10.1016/j.tetlet.2014.12.074

Accepted Manuscript
Intramolecular cyclization of alkylimidazoles
Madhur S. Joshi, Ashabha I. Lansakara, F. Christopher Pigge
PII:
S0040-4039(14)02140-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.074
TETL 45598
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
25 November 2014
11 December 2014
12 December 2014
Please cite this article as: Joshi, M.S., Lansakara, A.I., Christopher Pigge, F., Intramolecular cyclization of
alkylimidazoles, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.074
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Intramolecular cyclization of alkylimidazoles
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Madhur S. Joshi, Ashabha I. Lansakara, F. Christopher Pigge*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Intramolecular cyclization of alkylimidazoles
Madhur S. Joshi, Ashabha I. Lansakara, and F. Christopher Pigge*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
1,2-Dialkylimidazoles can be converted to nucleophilic 2-alkylidene imidazolines upon
treatment with (BOC) O under mild conditions. Incorporation of a β-keto amide carbonyl
2
Received in revised form
Accepted
electrophile in the 2-alkylimidazole side chain results in intramolecular aldol-like cyclization to
afford imidazole-functionalized γ-lactams. Positioning of a ketone electrophile in a 1-alkyl side
chain results in cyclization at the 2-position to afford fused ring imidazoles through a similar
reaction manifold. Efficient transfer of a BOC group from an intermediate N-acyl imidazolium
species to a nucleophilic center in the cyclized product appears to be an important feature of
these reactions.
Available online
Keywords:
Imidazole
Imidazoline
2
009 Elsevier Ltd. All rights reserved.
Anhydrobase
Azaheterocycle
N-Heterocyclic carbene
1
. Introduction
have explored the reactivity of methylene and alkylidene
8
imidazolines toward various transition metal fragments.
Azaheterocycles occupy positions of unparalleled importance
Notably, imidazolines such as 1 represent deoxy analogues of
intermediates potentially encountered in imidazolium-based N-
heterocyclic carbene-catalyzed transformations of aldehydes (i.e.,
Breslow intermediates), thus further stimulating interest in
1
in natural product and medicinal chemistry. Owing to the wide
range of biological activities exhibited by N-heterocyclic natural
products and unnatural pharmacologic agents, developing new
synthetic strategies to both synthesize azaheterocycles and
manipulate existing azaheterocyclic ring systems remain
important objectives.
9
reactive species of this type.
R
R
R
O
O
O
O
O
In this context, we have begun examining the reactivity of
aromatic N-heterocycles, such as pyridine, toward new
dearomatization
ClCO2Et
NEt
NEt
NEt
(a)
manifolds
leading
to
functionalized
iPr2NEt
2
,3
dihydropyridines and piperidines. As part of these studies, we
have also begun examining the reactivity of alkylidene
dihydropyridines (anhydrobases) with the aim of expanding the
(
ref. 4a)
N
N
N
CO Et
2
4
synthetic utility of these readily accessible intermediates.
O
O
O
O
O
Toward this end, we recently reported successful intramolecular
benzylic cyclizations of 4-substituted pyridines via anhydrobase
intermediates generated by transient electrophilic activation of
HO
NEt
NEt
NEt
TfOH (10 mol%)
dioxane, 120 o
ref. 4c)
(b)
4
a,b
pyridine substrates with ethyl chloroformate (Scheme 1a).
Subsequently, we found that similar cyclizations could be
effected in the presence of Brønsted acid catalysts, presumably
C
(
N
N
N
H
4
c
via formation of enamine-like intermediates (Scheme 1b).
E
R2
N
N
electrophile (E)
base
N
Imidazoles offer similar opportunities for generation of
nucleophilic alkylidene imidazolines (1) via electrophilic
2
3
CHR R
(c)
R3
N
5
activation (Scheme 1c). Consequently, appropriately substituted
R1
R1
1
2-alkylimidazoles and/or 1,2-dialkylimidazoles should also be
capable of participating in intramolecular cyclizations analogous
to those depicted in Scheme 1a,b. Indeed, a few examples of
intermolecular aldol- and Mannich-type condensations involving
nucleophilic alkylidene
imidazoline
electrophilic activation of 1,2-dialkyl imidazoles have been
6
Scheme 1
reported.
imidazolines toward other electrophiles (e.g., activated alkyl
More recently, the reactivity of alkylidene
7
halides) has been examined as well. Finally, several studies

2
Tetrahedron
Given the general importance of imidazole-based
was isolated in good yield (51%, as a ~1:1 mixture of
12
diastereomers ) after purification by flash column
1
0
heterocycles in natural product/medicinal chemistry coupled
with increasing interest in the chemistry of alkylidene
imidazolines and our previous experiences with pyridine
anhydrobases, we set out to explore intramolecular reaction
manifolds available to relatively simple 1,2-disubstituted
imidazoles in the presence of electrophilic activating agents. We
report the preliminary results of this study that has resulted in
identification of reaction conditions leading to successful
preparation of imidazole-substituted lactams from 2-
alkylimidazole precursors and formation of pyrrolo[1,2-
a]imidazoles from 1-alkylimidazoles.
chromatography (Scheme 3). The formation of 9 is consistent
with the expected reaction manifold involving imidazole
2
activation by (BOC) O followed by deprotonation to generate a
nucleophilic imidazoline (8a) that reacts with the pendant
carbonyl electrophile. Transfer of the BOC group to the resulting
oxyanion (by intra- and/or intermolecular acylation) then
completes the transformation.
Slow evaporation of an
EtOAc/hexane solution of 9 deposited single crystals suitable for
X-ray analysis. Fortuitously, both diastereomers were found to
be present in the crystal as shown in Figure 1 (relative occupancy
0.6:0.4), thus establishing the relative stereochemistry of both
13
products.
2. Results and discussion
Our study began with the straightforward preparation of
imidazole 2 starting from 1-methylimidazole-2-carboxaldehyde
11
(
Scheme 2).
This compound was then subjected to reaction
conditions previously found to be effective in promoting
formation and intramolecular aldol-like cyclization of pyridine-
4
a
derived anhydrobases. In this instance, however, none of the
expected imidazole-substituted lactam was obtained, instead
lactam 3 was isolated, albeit in modest yield. We speculate that 3
arises from electrophilic activation of the imidazole ring with
i
2 2
Scheme 3. Reagents and conditions. (a) (BOC) O (1.5 equiv), Pr NEt (2
equiv), DCE, reflux, 51%.
2
EtO CCl followed by nucleophilic addition of the activated
methylene to afford spirocyclic intermediate 5. Base-promoted
elimination/ring opening of the imidazoline then gives 6.
Addition of TFA/H
observed product. Consistent with this mechanistic rationale,
changing the electrophilic activating agent to (BOC) O and
2
O induces enamine hydrolysis to yield the
2
omitting the acid treatment resulted in conversion of 2 to
spirocycle 7, although again in modest isolated yield.
Figure 1. X-ray structure of 9 showing the molecular structure of both
diastereomers that differ in relative configuration at C9/C9’ (Scheme 3).
Several other imidazoles bearing α-alkyl-β-ketoamide
substituents at the 2-position were subjected to these cyclization
conditions as well, and the results are summarized in Eq. 1 and
Scheme 4. In each case diastereomeric ratios were estimated by
.
1
comparison of H-NMR resonances corresponding to H
a
Relative stereochemistry in 11a (Eq. 1) was assigned by analogy
to 9 (vide supra). Cyclopentanone-derived substrate 10b did not
undergo cyclization (Scheme 4). The other cycloalkanone-
imidazoles (10c-e) gave the reaction to afford imidazole-
substituted lactams (11c-e) in comparable yields, each as
inseparable mixtures of two diastereomers. A NOESY spectrum
obtained on cycloheptyl adduct 11d allowed assignment of
relative stereochemistry in both the major and minor
diastereomer according to the correlations indicated in Figure 2.
The presumed reactive conformations leading to these
Scheme 2. Reagents and conditions. (a) (i) p-CH
3
OC
6
H
4
CH
, reflux, 75%. (c)
4
(0.5 equiv), THF, reflux;
2 2
NH , mol.
sieves; (ii) NaBH , 76%. (b) methyl 3-oxovalerate, PhCH
4
3
i
CCl (1.5 equiv), Pr
i
(
i) EtO
2
2
NEt (2 equiv), Ti(O Pr)
2
O (1.5 equiv), Pr NEt (2 equiv),
i
(ii) TFA, H
DCE, reflux, 41%.
2
O, reflux, 25%. (d) (BOC)
2
diastereomeric products are also illustrated.
Relative
stereochemistry of the major diastereomer in 11c and 11e has
been tentatively assigned as shown in Scheme 4 by analogy to
11d.
In previous studies involving manipulation of pyridine
anhydrobases equipped with β-amido carbonyl side chains, it was
observed that substituents on the activated methylene group
promoted benzylic cyclization at the expense of competing
4a
spirocyclization. To probe for similar effects in the imidazole
series, substrate 8, bearing a methyl group at the dicarbonyl-
i
O and Pr
activated carbon, was treated with (BOC)
refluxing DCE. Disappearance of starting material was observed
2
2
NEt in
to be complete after ~12 h, and imidazole-substituted lactam 9

3
of 12 to 13, however, necessitates formation of an intermediate
oxyanion that is structurally impeded from participating in an
intramolecular acyl transfer involving BOC-substituted
a
imidazolium species (16). To probe the importance of this
feature in reactions leading to fused-ring imidazo products, 2-
2
unsubstituted imidazoles 17 were treated with (BOC) O with the
aim of generating nucleophilic acyl imidazolium carbenes
capable of participating in intramolecular cyclizations to give
1
7
oxyanion intermediates. Indeed, both 17a,b were transformed
to the pyrrolo[1,2-a]imidazoles 18a,b in virtually quantitative
yield according to NMR analysis of crude products (Scheme 6).
Unfortunately, both compounds proved to be unstable, readily
decomposing upon attempted purification, thus characterization
was performed on impure material obtained directly from
reaction mixtures. Nonetheless, the difference in reactivity
between 17 and 12 seemingly supports the notion that a pathway
for facile conversion of acyl imidazolium intermediates to stable
imidazoles is an important parameter in successful intramolecular
cyclizations of in situ-generated 2-alkylidene imidazolines and
imidazolium carbenes.
i
O (1.5 equiv), Pr
Scheme 4. Reagents and conditions. (a) (BOC)
equiv), DCE, reflux.
2
2
NEt (2
PMB
N
H
H
O
OR
H3C
H3C
H
H
H
N
N
H
O
N
H
N
O
N
PMB
H
BOC
major diastereomer
H
H
H
OR
H
3
H C
O
H3C
H
N
H
N
N
H
O
O
N
N
PMB
PMB
minor diastereomer
Figure 2. NOESY correlations in 11e (R = BOC).
N
BOC
H
We next turned our attention to the preparation of fused-ring
imidazo-derivatives via intramolecular cyclization of N-alkyl-2-
methylimidazoles under reaction conditions expected to generate
2 3
Scheme 6. Reagents and conditions. (a) (BOC) O, CH CN, rt, 12 h, 100%.
1
4
nucleophilic imidazoline intermediates. Thus, exposure of 12
to (BOC) O in refluxing DCE resulted in complete consumption
of starting material within 30 minutes, and imidazo[1,2-
3
. Conclusions
In conclusion, we have demonstrated that nucleophilic 2-
2
a]dihydropyridine 13 was obtained, albeit in impure form, in
alkylidene imidazolines can be generated from 1,2-
dialkylimidazoles under mild conditions and that these reactive
intermediates are capable of participating in intramolecular
cyclization reactions with appropriately positioned electrophiles.
Specifically, aldol-like cyclizations of keto-amide side chains
attached to the 2-position of imidazole substrates were found to
proceed in reasonable yield to deliver imidazole-substituted γ-
lactam products. Results from attempts to prepare fused ring
imidazo[1,2-a]dihydropyridines and pyrrolo[1,2-a]imidazoles via
intramolecular cyclization of 2-methylimidazoles and 2-
unsubstituted imidazoles, respectively, indicate that the ability to
regenerate a stable imidazole at the conclusion of the cyclization
event by transfer of an acyl activating group to a nucleophilic
center in the newly-formed ring may be an important feature of
successful transformations. These results show the potential to
generate functionalized imidazole derivatives by manipulation of
peripheral substituents. Current studies seek to further define the
synthetic utility of alkylidene imidazolines in organic and
organometallic reaction manifolds.
1
5
4% yield after chromatography (Scheme 5). No added base
4
was used in this process as tert-butoxide anion should be
6b,c,16
2
generated upon reaction of the imidazole with (BOC) O.
Efforts to improve this transformation revealed that performing
the reaction at room temperature in acetonitrile gave comparable
results, but the yield of 13 never rose above ~40%. Moreover,
structurally related substrates such as 14 and 15 afforded
intractable reaction mixtures under both sets of conditions.
Acknowledgments
Scheme 5. Reagents and conditons. (a) (BOC)
(
2
O, DCE, reflux, 44%. (b)
BOC) O, CH CN, rt, 41%.
2
3
This paper is dedicated to the memory of Harry H.
Wasserman. We thank the U.S. National Science Foundation
A common feature in successful intramolecular cyclization
reactions involving imidazoline intermediates described above
Schemes 3-4) and mechanistically analogous intermolecular
transformations of 2-alkylimidazoles reported previously is the
transfer of an electrophilic activating group (e.g., tert-butoxy
carbonyl) from an imidazolium ring to a nucleophilic oxygen
generated in the course of aldol-like condensation. Conversion
(
CHE-1265488) for generous financial support. We thank Dr.
(
Dale C. Swenson for assistance with X-ray crystallography and
Mr. Vic Parcell for assistance with mass spectrometry.
6
*
Corresponding author. Tel.: +1 319 335 3805; fax: +1 319 335 1270; email: chris-pigge@uiowa.edu

4
Tetrahedron
Supplementary Material
(d) Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.;
Mal’kina, A. G.; Nikitina, L. P.; Afonin, A. V.; Ushakov, I. A.
Eur. J. Org. Chem. 2010, 1772-1777. (e) Cruz-Acosta, F.; de
Armas, P.; García-Tellado, F. Synlett 2010, 2421-2424.
Experimental procedures, compound characterization data,
13
H-, C-NMR spectra, and crystallization data (cif file) can be
1
found in the online version of this article at doi:
1
0.1016/j.tetlet.xxxx.xx.xxx.
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4
1. A UV active PMB protecting group was employed to aid TLC
analysis of reaction mixtures.
2. Diastereomeric ratio was estimated based on relative integration of
1
singlets corresponding to H
a
in the H-NMR spectrum.
3. This structure has been deposited with the Cambridge Structural
Database. CCDC No. 1035872
4. Liu, B. K.; Wu, Q.; Qian, X. Q.; Lv, D. S.; Lin, X. F. Synthesis
2
5. The structure of 13 was assigned on the basis of H-, C-NMR
007, 2653-2659.
1
13
1
and HRMS. Impurities appearing in the aliphatic region of the H-
NMR spectrum are attributed to the presence of (BOC) O in the
reaction. Numerous attempts to obtain a homogeneous sample by
2
repeated column chromatography and distillation were
i
CCl and Pr
unsuccessful. Interestingly, using EtO
(
2
2
NEt in place of
BOC) O led to formation of I in low yield.
2
N
N
CO2Et
EtO2CCl
iPr2NEt
12
DCE, reflux
I (24%)
1
1
2
6. (BOC) O alone may be sufficient to mediate the cyclizations
illustrated in Schemes 2-4 as well, but this was not attempted.
7. For related intermolecular transformations, see reference 6b,c and:
(
a) Zhao, Y.; Lei, M.; Yang, L.; Han, F.; Li, Z.; Xia, C. Org.
Biomol. Chem. 2012, 10, 8956-8959. (b) Joyce, E.; McArdle, P.;
Aldabbagh, F. Synlett 2011, 1097-1100. (c) Shen, Y.; Cai, S.; He,
C.; Lin, X.; Lu, P.; Wang, Y. Tetrahedron 2011, 67, 8338-8342.