Unstabilized azomethine ylides for the stereoselective synthesis of substituted piperidines, tropanes, and azabicyclo[3.1.0] systems

Article abstract of DOI:10.1021/ja312311k

Acid treatment of densely substituted 2-silyl-1,2-dihydropyridines provides a new and convenient entry to reactive azomethine ylides that can (1) be protonated and reduced with high stereoselectivity to give piperidines, (2) participate in [3 + 2] dipolar

Full text of DOI:10.1021/ja312311k

Communication
pubs.acs.org/JACS
Unstabilized Azomethine Ylides for the Stereoselective Synthesis of
Substituted Piperidines, Tropanes, and Azabicyclo[3.1.0] Systems
Michael A. Ischay,† Michael K. Takase,† Robert G. Bergman,‡ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Division of Chemical Sciences, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California,
Berkeley, California 94720, United States
S
* Supporting Information
this process is the requirement that internal alkynes be used,
ABSTRACT: Acid treatment of densely substituted 2-
silyl-1,2-dihydropyridines provides a new and convenient
entry to reactive azomethine ylides that can (1) be
protonated and reduced with high stereoselectivity to give
piperidines, (2) participate in [3 + 2] dipolar cycloaddition
to give tropanes, and (3) undergo a Nazarov-like 6-π
electrocyclization that upon reduction give 2-azabicy-
clo[3.1.0] systems.
which necessarily introduces substitution at the 6-position.
Terminal alkynes would be attractive coupling partners but are
not viable due to competitive homocoupling leading to complex
mixtures of products.7 Herein, we report a strategy for using
TMS acetylenes as terminal alkyne surrogates for the convergent
assembly of diverse tetrahydropyridines with high stereo- and
regiocontrol. This class of alkynes provides access to piperidines
with a substitution pattern commonly found in drugs and natural
products.8 Moreover, mechanistic inquiry reveals that the
intermediate silyl-dihydropyridine can function as a new and
convenient azomethine ylide precursor enabling rapid entry into
highly substituted tropanes, and through an unprecedented
rearrangement, 2-azabicyclo[3.1.0] systems.
onaromatic nitrogen heterocycles such as piperidines,
Ntropanes, and pyrrolidines are valuable, ubiquitous
structural motifs in biologically active alkaloids as well as drugs
that have had a major impact on disease.1 While C−H bond
functionalization strategies have been extensively applied to the
synthesis and elaboration of aromatic nitrogen heterocycles,2 few
applications to nonaromatic frameworks have been reported.3
Recently, we disclosed a highly diastereoselective process that
enables the formation of densely substituted tetrahydropyr-
idines4,5 from α,β-unsaturated imines and alkynes using Rh(I)
catalyzed C−H activation6 (Scheme 1). A current limitation of
Treatment of imine 1 (eq 1) with 1.5 equiv of 1-phenyl-2-
trimethylsilylacetylene, 2.5 mol % of [RhCl(coe)2]2 and 5 mol %
Scheme 1. Rapid Entry into Substituted Piperidine, Tropane
and 2-Azabicyclo[3.1.0] Frameworks
of 4-Me2N-C6H4-PEt2 in toluene (1 M) at 100 °C for 1 h resulted
in alkenylation to give azatriene 2 that undergoes a 6-π
electrocyclization in situ leading to the clean formation of silyl-
dihydropyridine 3 as a single detectable regioisomer, as assessed
1
by H NMR. When the reduction sequence was carried out
according to previously optimized conditions (HOAc and
NaBH(OAc)3 in MeOH/PhCH3 from 0 °C to rt),4 desired
product ( )-4 was formed in modest yield and with a
considerable amount of olefin isomerization (7:1 mixture of
inseparable isomers).
Investigation of different acids and hydride sources established
that direct addition of Me4NBH(OAc)3 in CH2Cl2 followed by
(PhO)2PO2H to the Rh(I)-catalyzed reaction mixture provided
clean formation of ( )-4 in excellent overall yield as a single
observable diastereomer and regioisomer (eq 1). The relative
configuration of ( )-4 was determined by single crystal X-ray
analysis of the hydrochloride salt.4 This stereoselective
protonation/reduction sequence proceeds with concomitant
Received: December 31, 2012
Published: February 11, 2013
© 2013 American Chemical Society
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a
Table 1. Convergent Assembly of Piperidines with Terminal Acetylene Equivalent
a
Yields correspond to isolated product after silica gel chromatography and represent overall yields from the imine precursor 6. Diastereoselectivity
b
1
was determined by H NMR of the crude reaction mixture. Conducted using HF-pyridine in THF at 0 °C.
cleavage of the trimethysilyl moiety to formally introduce a
terminal acetylene unit with complete regiocontrol in one pot
from the TMS acetylene and imine starting materials. This
strategy consequently addresses a major synthetic limitation to
our previously published reports.
tion under the standard reaction conditions. We reasoned that
the aldiminium intermediate is sufficiently reactive that hydride
delivery to 8 (R3 = H) competes with desilylation (vide infra).
For these substrates, we found it beneficial to conduct the
reaction in THF using pyridinium fluoride as the acid source to
give the desired tetrahydropyridines 9q,r with complete
desilylation.
We envisioned that upon protonation of the dihydropyridine
7, desilylation could occur through two possible reaction
pathways (Scheme 2). In scenario A, iminium 8 would be
An important feature of this approach is the vast number of
readily available TMS acetylene and α,β-unsaturated ketone
inputs that enable the rapid assembly of a range of piperidine
analogs. To this end, a number of TMS acetylenes and α,β-
unsaturated imines have been surveyed to establish broad
reaction scope (Table 1). Alkyne components containing
electron-rich and -deficient aromatic as well as heteroaromatic
groups are tolerated and result in the desired tetrahydropyridines
in excellent yield and diastereoselectivity (9a−d). Alkynes
bearing aliphatic groups also react efficiently under the reaction
conditions (9e,f). Furthermore, functional groups such as Boc-
protected primary amines (9h), phthalimides (9g), and silyl
ethers (9i) that are sensitive to either strongly acidic or reducing
conditions are viable coupling partners for this process and
provide a platform for further diversification.
Scheme 2. Proposed Mechanistic Pathways
The substitution pattern of the α,β-unsaturated imine was also
explored. Imines bearing no substitution in the β-position (9j)
and differential substitution patterns (9k) react efficiently
enabling the site-specific functionalization of the piperidine
core. Furthermore, a piperidine bearing different substitution at
each position of the ring (9l) could be constructed by
appropriate choice of imine and acetylene inputs. Bicyclic
tetrahydropyridines can be accessed from a cyclic α,β-
unsaturated imine precursor (9m−p). Moreover, consistent
with our previous work,4 this process is not restricted to benzyl
imines as N-cyclopropylmethyl (9o) and N-cyclohexyl (9p)
imines are also suitable directing groups.
reduced to 10 followed by protonation/desilylation to give the
observed product 9. Alternatively, 8 could undergo desilylation
resulting in the intermediacy of unstabilized azomethine ylide 11.
Subsequent protonation followed by reduction of 11 would also
account for the formation of the desired product. In support of
pathway B, Padwa has leveraged species 12 to access unstabilized
azomethine ylides under acidic conditions for [3 + 2]-dipolar
While this method works exceedingly well for ketimine
precursors, aldimine substrates underwent incomplete desilyla-
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cycloadditions.10 This class of dipoles has been widely utilized for
the synthesis of substituted pyrrolidines including those found in
natural products and drugs.11,12 However, approaches for
generating more highly substituted azomethine ylides typically
require the presence of a stabilizing electron withdrawing group.
To distinguish between the two proposed mechanisms, we
first resubmitted a silyl-substituted tetrahydropyridine, isolated
as a byproduct during early optimization experiments, to the
(PhO)2PO2H and TMABH(OAc)3 reaction conditions (eq 2).
Cleavage of the silyl group was not observed ruling out pathway
A.
A number of substituted tropanes were then constructed using
this new transformation, showing broad scope in both the imine
and trimethylsilyl alkyne inputs (Table 2, 13a−e). Utilization of
the unsymmetrical alkyne methyl propiolate also resulted in
moderate to good regioselectivity for the dipolar cycloaddition
(13f and g), with the regioisomers readily separated by silica gel
chromatography. This process represents a new strategy for rapid
entry into structurally dense tropanes that would otherwise be
challenging to prepare.
A subsequent investigation of the effect of acid strength on
reaction yield uncovered an unanticipated reaction product
(Scheme 3). Treatment of DHP-3 with PhSO3H in dichloro-
Scheme 3. Nazarov-like Electrocyclization
We therefore set out to intercept the transient azomethine
ylide in pathway B with a dipolarophile. In support of its
intermediacy, direct addition of the [Rh]-reaction mixture
containing crude DHP 3 to a solution of 1.2 equiv of
(PhO)2PO2H and 2 equiv of dimethylacetylene dicarboxylate
(DMAD) at 0 °C resulted in the clean formation of tropane 13a
(Table 2), which was characterized by 2D NMR spectroscopy
a
Table 2. Tropane Synthesis via Azomethine
methane at room temperature resulted in an intractable mixture
1
of products as determined by H NMR. However, by adding
PhSO3H and Me4NBH(OAc)3 at −78 °C with slow warming to
room temperature, a new product was formed in good yield. On
the basis of extensive NMR spectroscopy, we assigned the
structure as the 2-azabicyclo[3.1.0] system ( )-15a, which was
unambiguously confirmed through single crystal X-ray diffrac-
tion of the hydrochloride salt. Use of an alkyl rather than an aryl
substituted TMS acetylene input also provided the related
bridged pyrrolidine 15b, in a one pot process. This core
structural motif has significant relevance to drug discovery. For
example, it was specifically introduced into the approved drug
Saxagliptin to enhance metabolic stability.14
Variable temperature NMR was performed to gain insight into
the formation of 15a from 3. The presence of 1.05 equiv of
PhSO3H resulted in the rapid and persistent generation of the N-
protonated dihydropyridine 16 between −78 and −20 °C. This
was converted to a complex mixture of products upon gradual
warming between −20 and +23 °C. In the presence of
Me4NBH(OAc)3, we observed the formation of iminium 17
starting at −20 °C. Upon warming to +5 °C, we observed the
gradual formation of 15a.
a
Yields correspond to isolated product after silica gel chromatography
and represent overall yields from the imine precursor 6. Diaster-
eoselectivity was determined by 1H NMR of the crude reaction
b
mixture. Conducted at −78 °C in toluene.
On the basis of these studies, we conclude that this reaction
proceeds through N-protonation of the dihydropyridine
followed by proton transfer to generate C-protonated
ketiminium 17. Assisted desilylation, either by the sulfate
counteranion or hydride, induces a torquoselective disrotatory
Nazarov-like15 6-π electrocyclization to form enamine 18,16
which could undergo subsequent stereoselective protonation
and reduction resulting in the desired product 15a. This
and single crystal X-ray diffraction. While [3 + 2]-dipolar
cycloadditions of azomethine ylides have been widely employed
in pyrrolidine synthesis, relatively few examples that provide
access to tropanes have been disclosed.13 Furthermore, dipole
generation, which proceeds through protonation of the enamine
followed by desilylation, represents a new entry into unstabilized
azomethine ylides.
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(c) Harrison, D. P.; Iovan, D. A.; Myers, W. H.; Sabat, M.; Wang, S.;
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serendipitous finding provides a new avenue for the preparation
of highly substituted derivatives of this azabicyclic framework.
In summary, densely substituted 2-silyl 1,2-dihydropyridines
are readily prepared from α,β-unsaturated imines and TMS
acetylenes by a C−H bond functionalization and electro-
cyclization sequence. Without any purification or isolation,
treatment with acid generates unstabilized azomethine ylides as
versatile intermediates that lead to valuable nitrogen hetero-
cycles. In situ protonation and reduction provides tetrahydro-
pyridines with a substitution pattern matching that expected for
terminal alkyne incorporation. Alternatively, azomethine gen-
eration in the presence of a dipolarophile provides highly
substituted tropanes. Finally, by selectively tuning the acid in the
protonation step, an unprecedented rearrangement was observed
that can be used to produce 2-azabicyclo[3.1.0] systems.
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ASSOCIATED CONTENT
* Supporting Information
Full experimental details and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
jonathan.ellman@yale.edu
■
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH Grant GM069559 (to J.A.E.).
R.G.B. acknowledges funding from The Director, Office of
Energy Research, Office of Basic Energy Sciences, Chemical
Sciences Division, U.S. Department of Energy, under Contract
DE-AC02-05CH11231. M.A.I. also acknowledges support from
an NRSA postdoctoral fellowship (F32GM090661).
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