Direct access to functionalized benzotropones, azepanes, and piperidines by reductive cross-coupling of α-bromo enones with α-bromo enamides

Article abstract of DOI:10.1039/c5ob00517e

The synthesis of functionalized azepenes and piperidines bearing an α-cycloheptenone or benzotropone derivative has been accomplished through direct reductive cross-coupling of α-bromo eneformamides or enecarbamates with highly versatile α-bromo benzotrop

Full text of DOI:10.1039/c5ob00517e

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Direct access to functionalized benzotropones,
azepanes, and piperidines by reductive cross-
coupling of α-bromo enones with α-bromo
enamides†
Cite this: DOI: 10.1039/c5ob00517e
Received 16th March 2015,
Accepted 7th April 2015
DOI: 10.1039/c5ob00517e
Timothy K. Beng,* Kayla Sincavage, Ann Wens V. Silaire, Amir Alwali,
Daniel P. Bassler, Laura E. Spence and Oliver Beale
www.rsc.org/obc
The synthesis of functionalized azepenes and piperidines bearing
Fittingly, key features such as structural diversity and
an α-cycloheptenone or benzotropone derivative has been accom- biological relevance continue to inspire researchers toward
plished through direct reductive cross-coupling of α-bromo ene- developing increasingly more efficient strategies for the
formamides or enecarbamates with highly versatile α-bromo construction and functionalization. of (benzo)tropone,5 cyclo-
benzotropone derivatives, under cobalt catalysis. The coupling heptenone,6 azepane,7–9 and piperidine9–13 derivatives. If two
products have been further elaborated to other synthetically or more of the aforementioned motifs are coupled together, it
useful aza-heterocyclic frameworks.
is recognized that the structural space for the discovery of
novel scaffolds with medicinal value would be greatly
expanded. The conventional cross-coupling of nucleophilic
coupling partners such as vinyl stannanes and aryl boronic
acids (see I, Fig. 2A) with α-halo enones such as II has pre-
viously been accomplished under forcing conditions.14 Given
the now established reactivity series of α-halo enones relative
to the unsubstituted counterpart (Fig. 2B),15 conventional
cross-coupling strategies featuring the latter, under less
forcing conditions, have subsequently emerged.16 Our interest
in functionalized azaheterocycles11,12,17,18 led us to the discov-
ery that α-halo eneformamides such as IV may be satisfactorily
coupled with aryl, alkenyl, and alkynyl nucleophiles.7,18 Very
recently, we have disclosed that cyclic α-bromo eneformamides
and enecarbamates are amenable to cobalt-catalyzed reductive
cross-coupling with aryl or vinyl bromides (Fig. 2C).19 In this
umpolung process, the catalyst (rather than the substrate) is
reduced, thus, obviating the need for the pregeneration of
difficult-to-handle, expensive, or toxic organometallic reagents.
Seeking an efficient strategy that would provide access to func-
tionalized azaheterocycles bearing a benzotropone derivative
(Fig. 2D) or a β-amino substituent (Fig. 2E), we reasoned that
direct reductive cross-coupling of two readily available, stable,
and easy to handle electrophilic organic bromides, under
transition metal-catalysis, offered an attractive approach.20
Communicated herein, are our current efforts toward the
realization of the proposed plan.
Functionalized benzotropones, cycloheptenones, azacyclohept-
anes (i.e., azepanes), and azacyclohexanes (i.e., piperidines) are
ubiquitous structural motifs in bioactive natural products and
pharmaceuticals including perovskatone A (from Perovskia atri-
plificifolia, Fig. 1),1 colchicine (from Colchicum automnale),2
longeracinphyllin
B
(from Daphniphyllum yunnanense),3
stenine (from Stemona tuberosa), and nominine (from Aconi-
tum sanyoense).4
Fig. 1 Examples of functionalized tropone, cycloheptenone, azepane,
and piperidine alkaloids and pharmaceuticals.
Our studies on the reductive cross-coupling of α-bromo
enones (examples of which are depicted in Fig. 3) with
α-bromo eneformamides and enecarbamates commenced with
the search for the best phosphine-based ligand and transition
metal catalyst.
Department of Chemistry, Susquehanna University, 514 University Avenue,
Selinsgrove, PA 17870, USA. E-mail: beng@susqu.edu
†Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/c5ob00517e
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arenes19 to the current scenario, we were pleased to find that
the coupling of bromo enecarbamate 10 with bromo enone 1
proceeds efficiently at room temperature using the conditions
described in Scheme 1A (see 13). As a testament to the gener-
ality of the transformation, methoxy-bearing bromo enone 2
and chlorine-containing enone 3 both furnish the α-vinylated
adducts in good yield (see 14 & 15). This is noteworthy, since
either substituent (i.e., the methoxy or chlorine substituent)
could serve as a place-holder or functional handle for late-
stage diversification. The marginal increase in the efficacy
and rate of coupling of 2 with 10 suggests that electron-rich
bromo enones have a beneficial effect on the transformation.
This is somewhat understandable given the general reactivity
of α-halo enones (see Fig. 2B). Encouragingly, despite
being less stable and enolizable, bromo enone 4 still couples
Fig. 2 Proposed plan for accessing functionalized azaheterocycles
containing at least one cycloheptenone derivative.
Fig. 3 Selected enone derivatives employed in these studies.
Cognizant of the high tolerance for carbonyl-containing
functional groups in reductive cross-couplings and hoping to
apply some of the lessons learned from our recent report on
Co-catalyzed cross-coupling of bromo enamides with bromo-
Scheme 1 Co-catalyzed reductive cross-coupling of α-bromo enones
with organic bromides.
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with bromo enecarbamate 10, affording imino diene 16 in
acceptable yield, following acid-mediated cleavage of the Boc-
group. The importance of having a benzannulated bromo
enone (which aids to slow down reactivity, thus, mitigating
undesirable homocoupling) is supported by the observation
that the reaction of α-bromocycloheptenone 5 with bromo
enecarbamate 10 affords mostly the homocoupling product,
even when the former is introduced slowly over the course
of an hour. Consistent with our previous findings on the
superiority of bromo eneformamide 11 (relative to bromo
enecarbamate 10) as
a coupling partner in reductive
cross-couplings,19 we find that it couples modestly with 5
(see 17).
As further illustrated in Scheme 1A, azepane-derived bromo
eneformamide 12 is also amenable to Co-catalyzed reductive
cross-coupling with α-bromo enones (see 18–20). Understand-
ably (especially from a stability standpoint), dibromonaphtho-
quinone 6 couples inefficiently with 10 under the identified
conditions (Scheme 1B). These studies have also revealed that
highly versatile α-bromo enaminones such as 7, 8, or 9
undergo satisfactory co-catalyzed cross-electrophile-coupling
with bromo styrenes, bromo acrylates, bromoarenes, and
allylic bromides (Scheme 1C). The latter example (i.e., for-
mation of 25) features net regioselective β-allylation of an
enaminone. This is noteworthy since the presence of an allyl
moiety on a piperidine skeleton offers several advantages for
the synthesis of piperidine alkaloids and pharmaceuticals.
For example, as has been demonstrated for 2-allyl piperidine
derivatives, the double bond on the allyl moiety can be
reduced,11,21 oxidized,11,22 engaged in metathesis reactions,13
or carbolithiated.23
Scheme 2 Elaboration of reductive coupling products to other functio-
nalized azaheterocycles.
Desiring to broaden the synthetic utility of the reductive
coupling methodology described herein, we have shown that
further elaboration of the coupling products depicted in
Scheme 1 to other synthetically important molecular architec-
tures is possible. For example, chemoselective reduction of the
double bond resident in the allyl moiety of allylated enami-
none 26 (prepared in the same way as 25, see Scheme 1C)
affords β-alkylated derivative 27 in high yield, without any
complications arising from benzonolysis, conjugate, or 1,2-
reduction of the enaminone motif (Scheme 2A). Additionally,
N-acyl iminium reduction of N-formyl amino diene 17 affords
piperidine derivative 28 (Scheme 2B). Furthermore, cleavage of
the Boc-group in 14 quantitatively furnishes α-functionalized
cyclic imine 29 (not shown), which upon subjection to sequen-
tial α-acylation and α-methylation of the corresponding aza-
enolate, affords 3,3-difunctionalized 1,2-dehydropiperidine 30
in 59% overall yield (Scheme 2C). In another significant
outcome, we have found that electronically frustrated imino
Conclusions
In summary, the cobalt-catalyzed reductive cross-coupling of
versatile α-bromo enones with cyclic α-bromo enamides has
been accomplished under mild conditions. The 2-substituted
benzotropone and cycloheptenone derivatives are amenable to
further functionalization under different modes of reactivity,
including chemoselective catalytic hydrogenation, N-acyl
iminium reduction, [4 + 2]-cycloaddition, and α-acylation/
methylation. These short synthetic sequences set the stage for
the synthesis of functionalized piperidine or azepane alkaloids
and pharmaceuticals bearing
details of which will be disclosed later.
a benzotropone derivative,
Acknowledgements
dienes such as 31 (obtained from 18, see Scheme 1A) are We are grateful to the Chemistry Department and the Commit-
amenable to a [4 + 2] cycloaddition with activated dienophiles tee for Faculty Scholarship at Susquehanna University for
such as ester quinone 32. For example, treatment of 31 with 32 funding. Professor Bill Dougherty is greatly acknowledged for
under thermal conditions affords highly functionalized penta- making it logistically possible for us to perform experiments
cycle 33 (Scheme 2D). Primarily due to challenges associated involving air- and moisture-sensitive reagents at SU. T.K.B. is
with stability, the relative configuration of 33 hasn’t been particularly thankful to Miss Sarah Pursley Beng for some stra-
unambiguously established at this point.
tegic comments during the incipient stages of this project.
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