Expedient synthesis of a-heteroaryl piperidines using a pd-catalyzed suzuki cross-coupling-reduction sequence

Article abstract of DOI:10.1021/ol403367b

A method for the modular synthesis of a-heteroaryl piperidines is reported. The two-step procedure consists of an initial Pd-catalyzed Suzuki cross-coupling of the heteroaryl bromide with a boronate ester derived from N-Boc piperidone, followed by subsequ

Full text of DOI:10.1021/ol403367b

Letter
pubs.acs.org/OrgLett
Expedient Synthesis of α‑Heteroaryl Piperidines Using a
Pd‑Catalyzed Suzuki Cross-Coupling−Reduction Sequence
Kevin D. Hesp,* Dilinie P. Fernando, Wenhua Jiao, and Allyn T. Londregan
Pfizer Worldwide Medicinal Chemistry, Eastern Point Road, Groton, Connecticut 06340, United States
*
S Supporting Information
ABSTRACT: A method for the modular synthesis of α-
heteroaryl piperidines is reported. The two-step procedure
consists of an initial Pd-catalyzed Suzuki cross-coupling of the
heteroaryl bromide with a boronate ester derived from N-Boc
piperidone, followed by subsequent tetrahydropyridine reduc-
tion. Using this method, α-heteroaryl piperidine products
featuring a broad range of pharmaceutically relevant azine and diazine substitutions have been prepared.
iperidines featuring α-aryl substitution are frequently
sought after pharmacophores that are well-represented in
Building from the precedent set by Campos and others for
the enantioselective α-arylation of N-Boc pyrrolidines, the α-
4
P
both successfully marketed drugs and in chemical series being
arylation of N-Boc piperidines with aryl bromides has been
1
3g
3i
pursued in drug discovery (Figure 1). As a result of the
achieved by Gawley and Coldham via an α-deprotonation,
transmetalation to ZnCl , and Pd-catalyzed Negishi coupling
2
sequence (Scheme 1a). Due to the hydrolytic instability of the
Scheme 1. Alternative Syntheses of 2-Aryl Piperidines
intermediate organolithium species, an inherent limitation of
this method is the requirement for rigorously dried solvents and
reagents. This necessity invariably limits the usage and success
of this method in the context of rapid analogue generation for
driving structure−activity relationships (SARs) in drug
discovery. As an alternative approach, the diastereoselective
synthesis of α-aryl pyrrolidines and piperidines by reductive
cyclization of substituted N-sulfinyl ketimines with pendant
alkyl chlorides was described by Reddy and co-workers
Figure 1. Selected examples of α-aryl piperidines found in biologically
active compounds.
2
importance of this structural motif in pharmaceutical research,
the development of robust synthetic methods that allow access
to a diverse scope of α-heteroaryl piperidines is a thriving area
of investigation. Typically, 2-aryl piperidines are prepared
through reduction of the corresponding 2-aryl pyridines under
3
h
(
Scheme 1b).
Despite showing excellent control of
diastereoselectivity, this method incorporates the diversified
aromatic moiety early in the synthetic sequence, thus
introducing additional manipulations per analogue. Whereas
both approaches provide powerful asymmetric syntheses of α-
aryl piperidines, the ability to rapidly screen an array of
heteroaromatics neither is facile nor has been described in the
1c
catalytic hydrogenation conditions. However, this approach is
inherently limited, as the synthesis of piperidines featuring α-
pyridyl substitution is not feasible due to undesired over-
reduction of both pyridines. Initially the known procedures for
accessing this privileged scaffold suffered from long synthetic
sequences, low yields, and poor selectivity; however, there have
since been several recent reports that have addressed some of
Received: November 20, 2013
3
these limitations.
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403367b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
literature. Furthermore, the broad compatibility of such
methods with heteroaromatic halides has yet to be demon-
strated for piperidine substrates. In this context, the
with established success in challenging Suzuki cross-coupling
7
reactions, such as electron-rich phosphines (PCy and SPhos)
3
5
or bidentate phosphines (BINAP and DPPF), provided inferior
identification of a robust method for the coupling of a versatile,
bench-stable synthetic intermediate with a large feedstock of
heteroaromatic halides would be ideal for rapidly exploring the
chemical space associated with this privileged pharmacophore.
In surveying the literature for suitable conditions to address
this limitation, we identified the δ-valerolactam derived
boronate ester 1 as a promising intermediate that was poised
for rapid coupling with a diverse set of heteroaromatics. The
Suzuki coupling of 1 with simple substituted aryl bromides and
triflates was initially developed by Occhiato and co-workers for
yields of product (entries 2−5; 7−45%). The use of P(o-tolyl) ,
3
a ligand with a larger steric profile, showed a significant drop in
yield when compared with PPh (Table 1, entry 1 vs 6).
3
Eventually, it was observed that improvements in yield showed
a more subtle reliance on the electronic features of the
triarylphosphine ligands employed. Whereas the use of p-OMe-
and p-CF -substituted triarylphosphines showed similar yields
3
of 2a to that observed for PPh (entries 7 and 8), a modest
3
increase in yield to 72% was achieved when employing P(p-
C H F) (entry 9). In contrast, moving to the perfluorinated
6
4
3
6
the preparation of 2-aryl tetrahydropyridines; however,
ligand, P(C F ) , showed a dramatic decrease in yield (entry
6 5 3
attempts to extend this methodology to include heteroaromatic
bromides were met with poor yields and incomplete
conversions, specifically when employing 2-pyridyl bromides
10). After further investigation into base and solvent effects
8
(entries 11−13), we identified that the combination of
Pd(OAc) and P(p-C H F) in toluene solvent with CsOH·
2
6
4
3
(
<50% yield). Given this limitation and the importance of
H O as the base provided near-quantitative conversion of 1 to
2
9
,10
substituted azines in drug discovery, where control of
lipophilicity is critical for the optimization of drug-like
properties, we initiated a focused study on the development
of a robust synthetic route to efficiently access these motifs.
Herein, we report the optimization of a catalyst system capable
of coupling a breadth of azine heteroaryl bromides to 1, as well
as conditions for the subsequent tetrahydropyridine reduction
to access the desired α-heteroaryl piperidines.
tetrahydropyridine 2a. Finally, the successful reduction of 2a
to the desired α-pyridyl piperidine 3a was realized using either
catalytic hydrogenation under H or transfer hydrogenation
2
conditions (Scheme 2).
a
Scheme 2. Tetrahydropyridine Reduction Conditions
6b
Building on conditions previously reported by Occhiato
and co-workers (Table 1, entry 1), we initiated our studies by
Table 1. Optimization of α-Heteroaryl Tetrahydropyridine
a
Synthesis
a
1
Yield determined by H NMR relative to 2,6-dimethoxytoluene as an
internal standard.
Having defined a highly effective two-step sequence for the
preparation of 3a, a selection of other azine heteroaryl
bromides was pursued to highlight the scope of α-heteroaryl
piperidine synthesis using this method (Scheme 3). Other 3-
pyridyl bromide substrates featuring pyrrolidinyl (3b) and
methyl ester (3c) substitutions were successful in generating
the desired piperidines (60 and 44% yield respectively). In
addition, the use of 2- and 4-pyridyl substrates with electron-
donating methoxy (3d) or electron-withdrawing fluoro (3f)
and trifluoromethyl (3e, 3g) groups was also tolerated using the
optimized conditions. Using the two-step protocol, the α-
diazine piperidines derived from 2-bromo-5-methylpyrazine
(3h), 4-bromopyridazine (3i), and 5-bromopyrimidine (3j)
were isolated in good yields following reduction (48−76%
yield). In addition to substituted pyridines, the two-step
procedure also translated well to related fused heteroaromatic
substrates, such as quinoline (3k), isoquinoline (3l), and
azaindole (3m) providing the desired piperidines in good yields
b
entry
ligand
base
yield
1
2
3
4
5
6
7
8
9
PPh3
PCy3
K PO ·H O
61
7
3
4
2
K PO ·H O
3
4
2
SPhos
BINAP
DPPF
K PO ·H O
18
45
37
22
63
60
72
3
4
2
K PO ·H O
3
4
2
K PO ·H O
3
4
2
P(o-tolyl)3
K PO ·H O
3 4 2
K PO ·H O
3 4 2
K PO ·H O
3 4 2
K PO ·H O
3 4 2
P(p-C H OMe)
6
4
3
P(p-C H CF )
6
4
3
3
P(p-C H F)
6
4
3
10
11
12
13
P(C F )
K PO ·H O
<5
6
5
3
3
4
2
P(p-C H F)
Na CO (2 M, aq)
24
6
4
3
3
2
3
P(p-C H F)
CsOH·H O
83
6
4
2
c
d
P(p-C H F)
CsOH·H O
>95 (91)
6
4
3
2
a
Conditions: 1/ArBr/base = 1:1.5:2 (0.11 mmol scale), 5 mol % [Pd],
b
Pd/L = 1:2, [1] = 0.2 M in 1,4-dioxane at 100 °C for 2 h. Yield
determined by 1H NMR relative to 2,6-dimethoxytoluene as an
c
internal standard. Toluene used in place of 1,4-dioxane as solvent.
(
66−78% yield). Importantly, this method provides a robust
d
Isolated yield of 2a using a 0.3 mmol scale of 1.
strategy for accessing α-azine piperidines, which would
otherwise be incompatible with standard 2-aryl pyridine
reduction approaches.
In summary, we have developed a facile method for the
synthesis of α-heteroaryl piperidines by enabling a robust two-
step procedure involving initial Suzuki cross-coupling of lactam-
derived boronate 1 with a variety of azine heteroaryl bromides
and subsequent tetrahydropyridine reduction. Importantly, a
1c
evaluating a series of related triarylphosphine ligands with
subtle steric and electronic differences for the Pd-catalyzed
Suzuki coupling of vinyl boronate 1 with 3-bromopyridine,
employing 5 mol % Pd(OAc) and 10 mol % ligand with
2
K PO ·H O (2 equiv) at 100 °C in 1,4-dioxane for 2 h (Table
3
4
2
1). Initial attempts to improve the yield of 2a by using ligands
B
dx.doi.org/10.1021/ol403367b | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 3. Scope of α-Heteroaryl Piperidine Synthesis
2
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EtOH, rt, 16 h.
broad range of pharmaceutically relevant azine and diazine
substrates were shown to be compatible with this method. In
view of the stability of the boronate ester and the ease of
reaction setup, this protocol is a useful and practical synthetic
sequence that should help fuel rapid SAR studies around this
important pharmacophore in drug discovery programs.
(
5) Several heteroaryl halides of pharmaceutical relevance were used
for the arylation of pyrrolidines in ref 4a.
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(
7
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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.
(e) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(8) See Supporting Information for further reaction optimization
details.
(9) For lead references describing the use of hydroxide bases for
AUTHOR INFORMATION
Corresponding Author
transmetalation in Pd-catalyzed Suzuki reactions, see: (a) Lennox, A. J.
J.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2013, 52, 7362.
■
*
(
(
b) Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 2116.
c) Amatore, C.; Jutand, A.; Le Duc, G. Chem.Eur. J. 2011, 17, 2492.
E-mail: kevin.hesp@pfizer.com.
Notes
(10) Notably, the use PPh with the optimized base (CsOH·H O)
3 2
and solvent (toluene) also provided improved results, affording 2a in
quantitative yield ( H NMR).
The authors declare no competing financial interest.
1
ACKNOWLEDGMENTS
■
We thank Dr. Vincent Mascitti and Dr. Adam Kamlet for
reviewing this manuscript and Jason Ramsay for high resolution
mass spectrometry determination. All colleagues acknowledged
are affliated with Pfizer, Inc., Groton, CT, USA.
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dx.doi.org/10.1021/ol403367b | Org. Lett. XXXX, XXX, XXX−XXX