Highly diastereoselective synthesis of tetrahydropyridines by a C-H activation-cyclization-reduction cascade

Article abstract of DOI:10.1021/ja2119833

A versatile reaction cascade leading to highly substituted 1,2,3,6-tetrahydropyridines has been developed. It comprises rhodium(I)-catalyzed C-H activation-alkyne coupling followed by electrocyclization and subsequent acid/borohydride-promoted reduction. This one-pot procedure affords the target compounds in up to 95% yield with >95% diastereomeric purity.

Full text of DOI:10.1021/ja2119833

Communication
pubs.acs.org/JACS
Highly Diastereoselective Synthesis of Tetrahydropyridines by a C−H
Activation−Cyclization−Reduction Cascade
Simon Duttwyler,† Colin Lu,† Arnold L. Rheingold,‡ Robert G. Bergman,*,§ and Jonathan A. Ellman*,†
†Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States
‡Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, 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
substitution that to our knowledge has not previously been
reported.6
ABSTRACT: A versatile reaction cascade leading to highly
substituted 1,2,3,6-tetrahydropyridines has been developed.
It comprises rhodium(I)-catalyzed C−H activation−alkyne
coupling followed by electrocyclization and subsequent
acid/borohydride-promoted reduction. This one-pot proce-
dure affords the target compounds in up to 95% yield with
>95% diastereomeric purity.
Rh-catalyzed β-C−H bond activation of α,β-unsaturated
imines 1 followed by addition across alkynes 2 gives azatriene
intermediates 3, which undergo electrocyclization in situ to
give 1,2-dihydropyridines 4.3b−d We envisioned that these
1,2-dihydropyridines 4 could serve as very useful intermediates
in a sequence leading to highly substituted piperidine deriva-
tives as long as selective functionalization of the double bonds
could be accomplished with high stereoselectivity. One avenue
for achieving this goal would be stereoselective protonation
of the enamine double bond followed by stereoselective
reduction of the resulting iminium intermediate 5 to provide
1,2,3,6-tetrahydropyridines 6 (Scheme 1). The reduction of
−H bond functionalization has proven to be a powerful
Cstrategy for the assembly of pharmaceutically relevant
classes of nitrogen heterocycles from simple and readily available
precursors.1,2 We and others have capitalized upon this approach
to prepare highly substituted pyridines from alkynes and α,β-
unsaturated imines, which in turn are derived from amines and
diverse enones and enals (eq 1).3 Resonance stabilization of the
Scheme 1. Reaction Cascade for the One-Pot Stereoselective
Synthesis of Piperidine Derivatives
N-alkyl-1,2-dihydropyridines to 1,2,3,6-tetrahydropyridines via
iminium intermediates has been documented to proceed in
good yields.7 However, in the vast majority of examples no stereo-
centers are introduced, and we could not identify any examples
where this reduction sequence resulted in the introduction of two
new stereocenters.
We therefore first chose to investigate reduction conditions
using dihydropyridine 4e as a test substrate. Alkenylation of
imine 1e in toluene at 80 °C using 2.5 mol % of [Rh(coe)2Cl]2
and 5 mol % of 4-Me2N-C6H4-PEt2 ligand followed by in situ
heteroaromatic product provides a key driving force that enables
this overall transformation to be accomplished by multiple
mechanistically distinct pathways.
In this work, we utilized the same readily available starting
materials to provide efficient access to highly substituted
piperidine derivatives, a class of heterocycles that is prevalent
in a large number of bioactive natural products and drugs.4,5
Specifically, we report here a one-pot cascade process for
preparing tetrahydropyridines substituted at multiple sites in
good yields with very high diastereoselectivities (eq 2). This
sequence enables the preparation of fully differentiated
hexasubstituted piperidine derivatives, a level of differential
Received: December 22, 2011
Published: February 22, 2012
© 2012 American Chemical Society
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Communication
a
Table 1. Influence of the Reduction Conditions on the Yield
and dr of Tetrahydropyridine 6e
Table 2. Substrate Scope of the Cascade Transformation
a
b
c
c
entry
reducing agent
solvent/acid
yield (%)
dr
d
d
1
NaBH4
PhMe-EtOH/none
PhMe-EtOH/AcOH
PhMe-EtOH/pivOH
PhMe-EtOH/AcOH
PhMe-EtOH/AcOH
PhMe-EtOH/AcOH
(77)
(54:46)
94:6
2
NaBH4
86
84
85
87
85
78
81
3
NaBH4
65:35
92:8
4
Bu4NBH4
Na(CN)BH3
Na(AcO)3BH
5
68:32
95:5
6
7
Me4N(AcO)3BH PhMe-EtOH/AcOH
Me4N(AcO)3BH PhMe-CH2Cl2/AcOH
96:4
8
89:11
(54:46)
(27:73)
d
d
9
Na(AcO)3BH
Na(AcO)3BH
PhMe-EtOH/TsOH
PhMe-EtOH/TFA
(35)
10
17
a
Reduction conditions: 20 μmol of dihydropyridine, 5 equiv of acid,
3 equiv of reducing agent, 0 °C for 2 h, then 0 °C to RT overnight.
b
PhMe from Rh-mediated reaction, PhMe-EtOH or PhMe-CH2Cl2 =
1:1; pivOH = pivalic acid, TsOH = p-toluenesulfonic acid; TFA =
c
trifluoroacetic acid. Determined by GC/MS using 2,6-dimethoxy-
toluene as an internal standard; yield = total yield of tetrahydropyr-
idine isomers with regard to imine starting material, dr = ratio of
depicted all-cis product to sum of other diastereomers. The estimated
d
error for GC integrals is 3%. Approximate values; unidentified
byproducts with overlapping retention times were also formed.
electrocyclization proceeded cleanly within 2 h to give 4e
in >90% NMR yield. Dihydropyridine 4e was then subjected
to a variety of reduction conditions (Table 1). At the outset,
a toluene solution of 4e was added to a suspension of NaBH4 in
ethanol at 0 °C, a procedure based upon previously reported
conditions for reducing 1,2-dihydropyridines unsubstituted at
the 5- and 6-positions. Unfortunately, only partial reduction to
a mixture of tetrahydropyridines along with unidentified
byproducts was observed (Table 1, entry 1).7 However, when
the toluene solution of 4e and an excess of acetic acid were
added to the NaBH4 suspension, GC/MS analysis indicated a
much cleaner conversion to a mixture of four products, the
major component of which was identified as 6e (see below).
Apparently, regio- and stereoselective protonation−reduction
was considerably facilitated by a Brønsted acid.
Optimization of the reduction conditions indicated that both
the nature of the acid and the reducing agent had an influence
on the product distribution, but no significant counterion effect
was observed (Table 1, entries 3−5). In addition, we suspected
that the actual reducing species in entry 2 was (AcO)3BH−.8
Indeed, the use of (AcO)3BH−/AcOH afforded 6e in high
yield and diastereoselectivity; stronger acids led to markedly
worse results (entries 6−10). On the basis of these findings,
the conditions listed in entry 6 were chosen for reductions
involving other dihydropyridines.
Diverse sets of imines 1 and alkynes 2 were next evaluated to
test the scope of the cascade reaction (Table 2). The imines
were obtained by condensation of primary amines and α,β-
unsaturated ketones that were commercially available or readily
accessible by an aldol condensation.9 Upon completion of the
alkenylation and cyclization steps, crude solutions of the
dihydropyridines and acetic acid were added to a suspension of
Na(AcO)3BH in ethanol at 0 °C, and the resulting reaction
mixtures were stirred at 0 °C to ambient temperature overnight.
a
Yields correspond to the overall yields of analytically pure products
after silica gel chromatography and are based upon the α,β-unsaturated
imine starting material. The diastereoselectivities were determined by
1H NMR analyses of clearly resolved piperidine hydrogens. For full
b
experimental details, see the Supporting Information. Alkyne
regioselectivity 2:1, combined yield for separated regioisomers.
c
Combined yield for regioisomerically pure diastereomeric mixture.
Under the optimized reaction conditions, less-substituted
imines 1a−c afforded tetrahydropyridines 6a−c in excellent
overall yields. For 6c, where a single additional stereocenter was
introduced, good diastereoselectivity was also observed. Most
importantly, all of the hexasubstituted products showed out-
standing diastereoselectivities, with only a single diastereomer
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1
detectable by H and 13C NMR spectroscopy except for the
substituents, the conformation with C(5)−Et in a pseudoaxial
position is preferred. Approach of the acid and proton transfer
then occur in an anti fashion, affording cis-iminium ion 5e. This
species is eventually reduced by (AcO)3BH−, which delivers its
hydride from the less-hindered side to give all-cis product 6e.
Additionally, we sought to extend the synthetic utility of the
cascade sequence by providing an initial demonstration that
nucleophiles other than hydride can be added to protonated
dihydropyridines with high selectivity. Specifically, when
isolated 4e was treated stepwise with 2-naphthylsulfonic acid
and allylcerium chloride, heptasubstituted piperidine derivative
8 was obtained in good yield as a single diastereomer (eq 3).15,16
hindered tert-butyl-substituted product 6j and bicyclic product
6l, for which 10:5:3 and 10:1:1 ratios of stereoisomers were
observed, respectively.10a
A variety of N substituents were well-tolerated, including N-
benzyl (6a−e,h−q), branched N-alkyl (6f), and N-phenyl (6g)
derivatives. Although 3-hexyne was employed as the alkyne input
for the majority of examples, diphenylacetylene also provided
tetrahydropyridine 6h in high yield with excellent stereo-
selectivity. The unsymmetrical alkyne isopropyl methyl acetylene
(2c) afforded a 2:1 regioisomeric mixture of products that could
be separated by silica gel chromatography.10b In contrast, tert-
butyl methyl acetylene (2d) gave a single regioisomer upon
C−H activation−cyclization; however, a mixture of diaste-
reomers was obtained after reduction (see below). Notably,
unsymmetrical alkyne 2e bearing an ester functionality afforded
6k as a single regio- and diastereoisomer.10c A number of
4-phenyl and 4-heteroaryl tetrahydropyridines have been
recognized as pharmacologically potent compounds.2,11 For
this reason, we prepared imines 1i−l containing furyl, pyrrolyl,
and indolyl moieties, respectively, in addition to the phenyl-
substituted derivatives 1b−d. The corresponding tetrahydropyr-
idine products were isolated in 52−95% yield (6b−d and
6m−q). For 6p, no over-reduction of the indole ring system was
observed.12 The combination of imine 1e and alkyne 2e served
to highlight the potential of the cascade process for introducing
a maximum number of different piperidine substituents in a
concise sequence. To the best of our knowledge, 6q is the first
example of a hexasubstituted, fully differentiated piperidine
derivative.
The relative configuration of 8 was established by X-ray cry-
stallography and points to a mechanism similar to that operative
in the reactions leading to tetrahydropyridines 6.
The relative configuration of the saturated ring carbon atoms
was established by X-ray crystallography; the structure of 6h
was solved as the free amine and those of 6e and 6g were
solved as the corresponding ammonium salts, unambiguously
confirmed all-cis stereochemistry.13 On the basis of these
results and the similarities of the NMR spectra of all of the
tetrahydropyridines, in addition to the assumption of similar
reduction pathways, we assigned the all-cis configuration to the
other products by analogy.
In conclusion, we have developed a cascade transformation
that enables the one-pot preparation of highly substituted
piperidine derivatives 6 starting from imines and alkynes in
good overall yields with uniformly excellent diastereoselectiv-
ities. The broad scope and versatility of the cascade process was
demonstrated by the introduction of a variety of alkyl, aryl, and
heteroaryl substituents at multiple sites in the tetrahydropyr-
idine products.
The synthetic potential of dihydropyridine intermediates 4
was further accentuated by the demonstration that in addition
to hydride, carbon nucleophiles can be added with high dia-
stereoselectivity to give heptasubstituted piperidine derivative 8.
Further expansion of this sequence to a broader set of carbon
nucleophiles is being actively pursued, as is the application of
this cascade transformation to the rapid preparation of bioactive
compounds.
We rationalize the observed stereochemical outcome by a
kinetically controlled protonation followed by face-selective
borohydride reduction (shown for product 6e in Scheme 2).
Scheme 2. Proposed Mechanism for the Stereoselective
13
Reduction and Ball-and-Stick Representation of [6e-H]+
ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental details and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*jonathan.ellman@yale.edu; rbergman@berkeley.edu
The transition state 7e leading from dihydropyridine 4e to
iminium ion 5e exhibits N−C(2) double-bond character.14
Because of allylic strain between the N-benzyl and C(5)-ethyl
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by NIH Grant GM069559 (to J.A.E.).
The Director, Office of Energy Research, Office of Basic Energy
Sciences, Chemical Sciences Division, U.S. Department of
Energy, under Contract DE-AC02-05CH11231 is acknowl-
edged by R.G.B. S.D. is grateful to the Swiss National Science
Foundation for a postdoctoral fellowship (PBZHP2-130-966).
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