Regio- and stereoselective 1,2-dihydropyridine alkylation/addition sequence for the synthesis of piperidines with quaternary centers

Article abstract of DOI:10.1002/anie.201310517

The first example of C alkylation of 1,2-dihydropyridines with alkyl triflates and Michael acceptors was developed to introduce quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeded with high diastereoselectivity. Carbon nucleophile addition results in an unprecedented level of substitution to provide piperidine rings with adjacent tetrasubstituted carbon atoms. Pipe up: Alkylation of readily prepared 1,2-dihydropyridines with alkyl triflates and Michael acceptors introduces quaternary carbon centers with high regio- and diastereoselectivity. Hydride or carbon nucleophile addition to the resultant iminium ion also proceeds with high diastereoselectivity. For carbon nucleophile addition, an unprecedented level of substitution is achieved to provide piperidine rings with contiguous tetrasubstituted carbon atoms.

Full text of DOI:10.1002/anie.201310517

Angewandte
Chemie
DOI: 10.1002/anie.201310517
Synthetic Methods
Regio- and Stereoselective 1,2-Dihydropyridine Alkylation/Addition
Sequence for the Synthesis of Piperidines with Quaternary Centers**
Simon Duttwyler, Shuming Chen, Colin Lu, Brandon Q. Mercado, Robert G. Bergman, and
Jonathan A. Ellman*
Abstract: The first example of C alkylation of 1,2-dihydropyr-
idines with alkyl triflates and Michael acceptors was developed
to introduce quaternary carbon centers with high regio- and
diastereoselectivity. Hydride or carbon nucleophile addition to
the resultant iminium ion also proceeded with high diastereo-
selectivity. Carbon nucleophile addition results in an unprece-
dented level of substitution to provide piperidine rings with
adjacent tetrasubstituted carbon atoms.
P
iperidines are valuable and prevalent substructures in
Scheme 1. a) Previously reported 1,2-dihydropyridine protonation and
nucleophilic addition sequence. b) Transformation developed in this
study: Reaction with carbon electrophiles (R+) followed by addition of
hydride or carbon nucleophiles.
biologically active natural products and in medicines which
have been enormously important in managing disease.[1–3] As
an entry to this important class of compounds, a number of
powerful methods for the synthesis of 1,2-dihydropyridines
have been developed.[4,5] In this context, we previously
disclosed an approach to rapidly assemble highly substituted
Table 1: Optimization of dihydropyridine alkylation conditions.
À
1,2-dihydropyridines by a rhodium(I)-catalyzed C H alkeny-
lation/electrocyclization cascade from readily available a,b-
unsaturated imines and alkynes.[6] We have also recently
described that these 1,2-dihydropyridine products are versa-
tile intermediates for the preparation of highly substituted
tetrahydropyridines by regio- and diastereoselective proto-
nation with subsequent hydride or carbon nucleophile
addition (Scheme 1a).[7–9] Herein, we demonstrate that C al-
kylation of 1,2-dihydropyridines, a reaction which to our
knowledge has not previously been reported, can be achieved
with alkyl triflates and Michael acceptors with high regio- and
diastereoselectivity to provide quaternary carbon centers
within the piperidine core (Scheme 1b).[10–12] Moreover,
reduction or carbon nucleophile addition to the resultant
iminium ion can also be accomplished with high diastereose-
lectivity. In the case of carbon nucleophile addition, an
unprecedented level of substitution is achieved to provide
piperidine rings with adjacent tetrasubstituted carbon atoms.
Entry
R
R’X
Solvent
t [h]
d.r.[a]
Conv. [%][b]
1
2
3
4
5
6
7
8
Me
Me
H
Me
Me
H
MeOTf
EtOTf
MeOTf
MeOTf
EtOTf
MeOTf
EtOTf
BnCl
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
16
14
18
1.5
1.5
1.5
1.5
16
16
2
–
>95
–
–
>95
–
>95
>95
>95
>95
>95
>55
>95
<5
H
>95
Me
Me
Me
n.d.
n.d.
>90
9
BnBr
BnBr
<5
>95
10[c]
[a] Where applicable, the reaction d.r. value was determined by 1H NMR
analysis. [b] The reaction conversion was established by H NMR
analysis. [c] With ZrCl4 as a Lewis acid additive, À788C to RT.
1
[*] S. Duttwyler, S. Chen, C. Lu, B. Q. Mercado, Prof. Dr. J. A. Ellman
Department of Chemistry, Yale University
We initially explored the addition of methyl iodide and
dimethyl sulfate to the dihydropyridine 1 (R = Me; Table 1).
However, methylation was not observed using a variety of
solvents such as THF, toluene, and CH2Cl2 even with heating
to 608C in a sealed reaction vessel (data not shown). We
consequently evaluated the considerably more reactive
methyl triflate, which resulted in complete conversion into
the methylated iminium product at room temperature
(entry 1). Successful alkylation with ethyl triflate demon-
strated that less-reactive alkylating agents also couple effi-
ciently (entry 2). Moreover, ethylation established that the
reaction proceeds with very high diastereoselectivity. To
225 Prospect St., New Haven, CT 06520 (USA)
E-mail: jonathan.ellman@yale.edu
Prof. Dr. R. G. Bergman
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720-1416 (USA)
and
Lawrence Berkeley National Laboratory
1 Cyclotron Road, Berkeley, CA 94720 (USA)
[**] This work was supported by the NIH Grant GM069559 (to J.A.E.).
R.G.B. acknowledges funding from the DOE, DE-AC02-05CH11231.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310517.
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Table 2: One-pot dihydropyridine alkylation and reduction.[a]
further test the generality of the alkylation protocol, the
reactivity of 1, where R = H, was investigated because it
results in a more highly destabilized aldiminium product
(entry 3). While generally complete and stereoselective
alkylation was observed in toluene with a 14–18 h reaction
time, at shorter reaction times using CH2Cl2 as the solvent
proved to be more effective (entry 4–7). Given the instability
of benzyl triflates, benzyl chloride and bromide were instead
evaluated, but no alkylation was observed for either reagent
(entries 8 and 9). Lewis-acid-mediated activation of benzyl
bromide was therefore investigated, with ZrCl4 providing the
benzylated product in greater than 95% conversion within
2 hours at À788C to room temperature, and with good
diastereoselectivity (entry 10).
With the feasibility of the key alkylation step established,
we next focused on the preparation of the desired tetrahy-
dropyridines 3 by reduction of the reactive iminium ion 2
(Table 2). We first explored the alkylation/reduction
sequence for the 1,2-dihydropyridines 1, which are unsubsti-
tuted at the R2 position (R2 = H), because this avoids
introducing a stereocenter in the reduction step. After
alkylation, Me4NBH(OAc)3 served as a mild and inexpensive
reducing agent for the synthesis of the tetrahydropyridines
3a–f in good to high overall yields. Notably, in the key
alkylation step, methyl (3a and 3d), ethyl (3b and 3e),
functionalized 2-methoxyethyl (3c), and benzyl (3 f) groups
were all successfully incorporated. The overall yields for the
methylation products 3a and 3d were somewhat lower than
for the other electrophiles because of competitive methyl-
ation at nitrogen when R2 = H. However, for all of the other
alkylating agents, which are less reactive than methyl triflate,
no alkylation at nitrogen was detected and high diastereose-
lectivities were observed. For ethylation (3b and 3e) and 2-
methoxyethylation (3c), only a single diastereomer was
obtained. Alkylation consistently occurs opposite to the R6
group as rigorously established by X-ray structural analysis of
3e as well as for multiple other alkylation products (3g, 3m,
3n, 3p, 6d, and 6g).[13] The Lewis-acid-mediated benzylation
provided a more modest 5:1 ratio (3 f).
We next investigated the alkylation/reduction sequence
for 1,2-dihydropyridines substituted at the R2 position, which
introduces added complexity because a stereocenter is
generated in the reduction step (3g–r; Table 2). The sequence
was first performed by methylating the dihydropyridines 1,
where R3 = Me, such that a stereocenter is only introduced in
the reduction step (3g–l). In all cases only a single diastereo-
mer was produced as determined by 1H NMR analysis.
Hydride addition opposite the R6 group was rigorously
established for 3g by X-ray structural analysis and is
consistent with the face selectivity observed for reduction in
our previously reported protonation/reduction sequence.[7]
The methylation/reduction sequence proceeded in excellent
overall yields for a range of substituents with diverse steric
and electronic properties (75–94%). For the R1 group on the
nitrogen atom both N benzyl (3g) and the comparatively
deactivating N phenyl (3h) group provided high yields. The
R4 position could be substituted with alkyl (3g, h, k, and l),
phenyl (3i), and furanyl (3j) groups, while alkyl and phenyl
groups could be used for both R5 and R6 groups (3g versus
[a] Yields are those of products isolated after purification by chroma-
tography. Diastereoselectivities were determined by NMR analysis.
[b] Unless otherwise indicated, alkylation was performed with the
corresponding triflate (1.5–2 equiv). [c] Benzylation was accomplished
using BnBr (2.5 equiv) and ZrCl4 (1.7 equiv) at À788C with warming to
RT. [d] Reduction was performed by addition of K(iPrO)3BH in THF at
À788C with warming to RT. [e] Reduction was performed by addition of
LiEt3BH in THF at À788C with warming to RT. [f] For details and other
crystal structures unequivocally establishing relative configurations of
the products, see Figures S1–S7 in the Supporting Information.
3k). A 91% yield was observed when R6 was a tert-butyl
group (3l), although reduction with K(iPrO)3BH at À788C
instead of Me4NBH(OAc)3 at 08C was necessary to achieve
high selectivity.
For the products 3m–r, two stereocenters are introduced,
the first in the alkylation step and the second in the reduction
step. High overall yields and good stereoselectivities were
observed for methylation (3r), ethylation (3m to 3o),
benzylation (3p), and introduction of the 2-methoxyethyl
group (3q). Moreover, different R2–R4 groups were tolerated,
including a bicyclic dihydropyridine which resulted in the cis-
fused product 3r. However, to achieve high reduction
stereoselectivity for many of these substrates, it was necessary
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Table 3: One-pot dihydropyridine alkylation and carbon nucleophile
to use more-reactive hydride reagents at À788C. In particular,
for 3m–o, reduction with LiBEt3H was optimal, and for 3l,
3p, and 3q, reduction with K(iPrO)3BH proved to be the most
effective. The relative configurations of the two newly formed
stereocenters were rigorously determined by X-ray structural
analysis for the ethylation/reduction products 3m and 3n and
the benzylation/reduction product 3p.[13] These X-ray struc-
tures establish that upon introducing alkyl groups (R) larger
than a methyl group, steric interactions, which result from the
newly formed and adjacent quaternary stereocenter, control
the face selectivity of reduction rather than the more distant
R6 substituent.
addition.[a]
Michael additions to a,b-unsaturated esters were explored
to introduce the ester group as a versatile functionality for
further elaboration (Scheme 2). Direct addition of the
[a] Yields are those of products isolated after purification by chroma-
tography. Diastereoselectivities were determined by NMR analysis.
[b] Alkylation was performed with the corresponding triflate (1.5–
2 equiv). [c] PhMgBr in ether (7 equiv) was used to prepare 6a and 6b.
AlkynylMgCl in ether (6–9 equiv) was used to prepare 6c–e. Allylcerium
chloride in THF (9 equiv) was used to prepare 6 f and 6g. [d] For details
and other crystal structures unequivocally establishing relative config-
urations of the products, see Figures S1–S7.
Scheme 2. Michael addition of dihydropyridines to methyl acrylate.
dihydropyridine to methyl acrylate did not proceed, but
after evaluating a variety of Lewis acids, we established that
TMSOTf results in high conversion into the silyl enol ether
intermediate 4 as an approximately 1:1 E/Z isomer mixture.
To obtain the tetrahydropyridine 5a, reduction with
Me4NBH(OAc)3 was most effective, while for 5b LiBHEt3
provided the highest diastereoselectivity and overall yield.
We next investigated the addition of carbon nucleophiles
rather than hydride (Table 3). We first evaluated additions to
the 1,2-dihydropyridines 1 unsubstituted at the R2 position,
because the iminium intermediate that is generated upon
alkylation lacks a-hydrogen atoms and therefore cannot
undergo competitive a-deprotonation. For these substrates
phenyl Grignard adds cleanly to give 6a and 6b, with the yield
for 6a being somewhat lower because of the competitive
N methylation of the dihydropyridine in the alkylation step
(see previous discussion for 3a and 3d). While high diaste-
reoselectivity was observed for 6a, an attenuated 81:19
selectivity was observed for 6b.
The remaining carbon nucleophile addition products (6c–
g) were prepared from 1,2-dihydropyridines having carbon
substituents as R2, and results in adjacent tetrasubstituted
stereocenters being introduced in the alkylation/nucleophilic
addition sequence. Each of these substrates has the potential
for competitive a-deprotonation in the carbon nucleophile
addition step. For this reason, less basic and more covalent
organometallic reagents were more effective. Phenyl-, alkyl-,
and silyloxymethyl-substituted alkynyl Grignard reagents all
added diastereoselectively and in good yields (6a–e).[14] Allyl
cerium reagents also added in high yields and with excellent
diastereoselectivities (6 f,g),[15] including for the preparation
of the cis-fused bicyclic piperidine 6g with tetrasubstituted
carbon atoms at the two bridgehead positions. Finally, X-ray
structural analysis of 6d and 6g[13] establishes that when the
alkylation step introduces a stereocenter the face selectivity
for nucleophilic attack is controlled by steric interactions at
this adjacent quaternary site and is consistent with that
previously observed in the alkylation/reduction sequence.
In conclusion, a 1,2-dihydropyridine alkylation/nucleo-
phile addition sequence has been developed and proceeds in
good yields and with high levels of regio- and diastereoselec-
tivity to provide piperidine derivatives with unprecedented
levels of substitution, including products with adjacent
tetrasubstituted ring carbon atoms. Because the 1,2-dihydro-
pyridine starting materials are prepared in one step from
À
simple precursors by a tandem C H alkenylation/electro-
cyclization reaction cascade, the described alkylation/nucle-
ophile addition sequence provides rapid access to densely
substituted piperidines which would be extremely difficult to
prepare by alternative methods.
Received: December 4, 2013
Published online: March 6, 2014
Keywords: alkylation · diastereoselectivity · heterocycles ·
.
reduction · synthetic methods
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described in the Supporting Information. CCDC 974855 (3e),
974821 (3g), 974854 (3m), 974857 (3n), 974819 (3p), 974856
(6d), and 974820 (6g) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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