Directed functionalization of 1,2-dihydropyridines: Stereoselective synthesis of 2,6-disubstituted piperidines

Article abstract of DOI:10.1039/c4cc02220c

A practical and highly stereoselective approach to access 2,6-disubstituted piperidines using an amidine auxiliary is reported. Following the diastereoselective addition of Grignard reagents at the 2-position of an activated pyridinium salt, the amidine group directs a regioselective metalation at the 6-position, enabling further functionalization. A subsequent electrophilic quench or a Negishi cross-coupling could be performed, resulting in 2,6-disubstituted dihydropyridines. These were reduced to the saturated piperidine rings with high diastereoselectivity. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02220c

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Directed functionalization of 1,2-dihydropyridines:
stereoselective synthesis of 2,6-disubstituted
piperidines†
Cite this: Chem. Commun., 2014,
50, 6883
Received 25th March 2014,
Accepted 30th April 2014
Guillaume Pelletier, Lea Constantineau-Forget and Andre B. Charette*
´
´
DOI: 10.1039/c4cc02220c
www.rsc.org/chemcomm
A
practical and highly stereoselective approach to access
2,6-disubstituted piperidines using an amidine auxiliary is reported.
Following the diastereoselective addition of Grignard reagents at
the 2-position of an activated pyridinium salt, the amidine group
directs a regioselective metalation at the 6-position, enabling further
functionalization. A subsequent electrophilic quench or a Negishi
cross-coupling could be performed, resulting in 2,6-disubstituted
dihydropyridines. These were reduced to the saturated piperidine
rings with high diastereoselectivity.
Enantioenriched piperidines are often components of pharmaco-
logically active compounds.1 The broad interest in these saturated
heterocycles can be accounted for by the fact that they are more
diversified and more complex than their aromatic pyridine counter-
parts.2,3 However, the full potential of chiral polysubstituted piper-
Scheme 1 Synthesis of 2,5-cis-disubstituted piperidines, 3-aryl-3-
piperidinol and 2,6-disubstituted piperidines from dihydropyridines.
idines as pharmacophores is yet to be discovered. In that sense, a employing the dearomatization of a chiral N-imidoylpyridinium salt
recent survey of SAR studies executed by different pharmaceutical (Scheme 1).10
companies (AstraZeneca, GlaxoSmithKline and Pfizer) demonstrated
More precisely, these units could be accessed via an electro-
that the majority of encountered piperidine residues in drug lead philic iodination/Suzuki cross-coupling sequence or direct aryl-
candidates are either monosubstituted at the nitrogen position or ation of 1,2,3,4-tetrahydropyridines (2). Following these results, we
1,4-disubstituted.4,5 One of the reasons associated with this poor were interested in developing a divergent approach that could
representation can be attributed to the lack of reliable, stereoselective provide access to 2,6-disubstituted piperidines (7) from a common
and versatile methods available for their synthesis. Therefore, rapid synthetic intermediate. This alternative substitution pattern is
and general routes aimed toward generating libraries of chiral frequently found in the structure of natural alkaloids (Fig. 1).11
enantioenriched polysubstituted piperidines are highly desirable.
To do so, we initially recognized that the amidine protecting
Substituted piperidines can be accessed via different approaches.6 group on the 1,2-dihydropyridines (1) could be an efficient directing
In this regard, our group has disclosed various asymmetric syntheses tether for lithiation of aryl and alkyl C–H bonds12 and direct
of piperidines employing either aziridinium ring expansions of a-arylation of pyrrolidines and piperidines.13 In particular, we
prolinol derivatives,7 Grob fragmentations of azabicyclo[2.2.2]- anticipated that a chiral Schiff base variant, developed by Meyers,12
octenes,8 or dearomatization of N-activated pyridinium salts.9 For could be used to direct deprotonation at the 6 position of 1 using
example, we recently reported the synthesis of enantioenriched
2,5-cis-disubstituted piperidines (4) and 3-aryl-3-piperidinols (5) by
FRQNT Centre in Green Chemistry and Catalysis, Faculty of Arts and Sciences,
´
´
Department of Chemistry, Universite de Montreal, PO Box 6128, Station Downtown,
´
´
Montreal, Quebec, Canada H3C 3J7. E-mail: andre.charette@umontreal.ca;
Fax: +1 514 343 7586; Tel: +1 514 343 6283
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc02220c
Fig. 1 Naturally occurring 2,6-disubstituted piperidines.
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n-BuLi, where the transient 6-lithio-1,2-dihydropyridine could be PhSSPh reacted well under the optimal conditions. The methyl
trapped with various electrophiles in order to diversify the hetero- substituent at the 2-position could be varied for other alkyl groups
cycle substitution pattern.14 This hypothesis can be closely asso- (1b–1c) without a significant effect on the yield. Unfortunately, 2-aryl-
ciated with a previously popularized strategy developed by Comins substituted dihydropyridine 1d afforded a complex mixture of pro-
et al. using variously substituted N-Boc a-lithiated dihydro- ducts when treated with n-BuLi. In order to access aryl-substituted
pyridines.15 The latter technique was applied successively for dihydropyridines, we performed an alternative sequence where the
the total synthesis of many nitrogen containing alkaloids such as 6-lithio-1,2-dihydropyridines would undergo a transmetallation/
(+)-myrtine,15e (+)-epi-myrtine,15f and spirolucidine.15c
Negishi cross-coupling.17 We initially optimized the 2-step, 1-pot
This strategy was explored by deprotonating the model sequence with 4-bromoanisole and 1a under classic palladium-
1,2-dihydropyridine 1a9f at 0 1C with a slight excess of n-BuLi catalyzed Negishi conditions (Scheme 3).18 After transmetallation
(1.2 equiv.), and then quenching the anion with D2O. Analysis with ZnBr2 at rt, the resulting organozinc reagent derived from 1a
of the crude reaction mixture by 1H NMR showed complete was treated with Pd(OAc)2 (2.5 mol%) and PPh3 (5.0 mol%) in the
deuterium incorporation at the 6 position (6a, 495% D incor- presence of 1.5 equiv. of 4-bromoanisole, which furnished the desired
poration). Deuterium oxide was then substituted by different 6-aryl-1,2-dihydropyridine 6o in 68% yield. To explore the scope of
electrophiles in order to evaluate the reactivity of the 6-lithio- this reaction, we replaced 4-bromoanisole by different aryl bromides.
1,2-dihydropyridine (Scheme 2). Alkyl iodides and activated In general, aryl bromides bearing electron withdrawing or electron
alkyl bromides reacted well with the anion of 1a, as the donating substituents gave modest to good yields for the corre-
corresponding 2,6-dialkyl-1,2-dihydropyridines 6b, 6c and 6n sponding 6-aryl-1,2-dihydropyridines. Interestingly, 1H NMR analysis
were isolated in good yields (72%, 75%, and 85%).
of compounds 6o–6x revealed that the protons associated with the
Although 6-halo-2-alkyl-1,2-dihydropyridines 6d–6f could be phenyl ring of the amidine broaden in comparison with 1a. Alter-
synthesized effectively, they were found to be unstable on silica gel natively, with a 6-cis-prop-1-enyl substituent (6y), or with the previous
and decomposed after a few hours if stored at room temperature.16 examples depicted in Scheme 2, this phenomenon was not observed.
Electrophiles such as TMSBr, Me2N = CH2+IÀ, ClCONMe2 and
To demonstrate the utility of the 2,6-disubstituted 1,2-dihydro-
pyridine derivatives synthesized as precursors of chiral polysubsti-
tuted piperidines, various hydrogenation conditions were explored.
This strategy was employed in some of our previous studies directed
toward the synthesis of indolizidines, quinolizidines and other
piperidine rings.10,19 However, treating different 2,6-disubstituted
dihydropyridines (6) under ambient pressure of hydrogen (1 atm)
Scheme 2 Directed lithiation/electrophilic quench. a Reaction performed
b
on a 1.0 mmol scale. Isolated yield. 1.1 equiv. of the electrophile was used
a
instead of 1.5 equiv. NFSI N-fluorobenzenesulfonimide; NIS: N-iodosuccinimide.
NCS: N-chlorosuccinimide; Elec = electrophile.
Scheme 3 Directed lithiation/Negishi cross-coupling sequence. Reaction
performed on a 1.0 mmol scale. Isolated yield.
6884 | Chem. Commun., 2014, 50, 6883--6885
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Table 1 Diastereoselective hydrogenation of the 1,2-dihydropyridine diene
¨
given drug: H. Schonherr and T. Cernak, Angew. Chem., Int. Ed.,
2013, 52, 12256.
6 For recent reviews concerning the synthesis of enantioenriched
piperidines, see: (a) C. Escolano, M. Amat and J. Bosch, Chem. –
Eur. J., 2006, 12, 8198; (b) J. Cossy, Chem. Rec., 2005, 5, 70;
(c) M. G. P. Buffat, Tetrahedron, 2004, 60, 1701; (d) P. M. Weintraub,
J. S. Sabol, J. M. Kane and D. R. Borcherding, Tetrahedron, 2003, 59, 2953;
(e) S. Laschat and T. Dickner, Synthesis, 2000, 1781; ( f ) A. Mitchinson and
A. Nadin, J. Chem. Soc., Perkin Trans. 1, 2000, 2862.
7 (a) S. B. D. Jarvis and A. B. Charette, Org. Lett., 2011, 13, 3830. See
also: (b) J. Cossy, O. Mirguet and D. G. Pardo, Synlett, 2001, 1575;
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11, 1935.
Entry
R1
R2
d.r.a (cis : trans)
Yieldb (%)
1
2
3
4
Me
Me
Et
4-FPh
4-MeOPh
Me
420 : 1
17 : 1
420 : 1
1 : 2
57 (8a)
62 (8b)
70 (8c)
73 (8d)
8 (a) G. Lemonnier and A. B. Charette, J. Org. Chem., 2012, 77, 5832;
(b) G. Lemonnier and A. B. Charette, J. Org. Chem., 2010, 75, 7465;
(c) G. Barbe, M. St-Onge and A. B. Charette, Org. Lett., 2008, 10, 5497.
9 (a) A. Lemire and A. B. Charette, J. Org. Chem., 2010, 75, 2077;
(b) A. Lemire and A. B. Charette, Org. Lett., 2005, 7, 2747;
(c) C. Legault and A. B. Charette, J. Am. Chem. Soc., 2005,
125, 8966; (d) C. Legault and A. B. Charette, J. Am. Chem. Soc.,
2005, 125, 6360; (e) A. Lemire, M. Grenon, M. Pourashraf and
A. B. Charette, Org. Lett., 2004, 6, 3517; ( f ) A. B. Charette,
M. Grenon, A. Lemire, M. Pourashraf and J. Martel, J. Am. Chem.
Soc., 2001, 123, 11829. For recent reviews of the literature, see:
(g) D. L. Comins, K. Higuchi and D. W. Young, Adv. Heterocycl.
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G. Pelletier and A. B. Charette, Chem. Rev., 2012, 112, 2642;
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Comins and S. O’Connor, in Progress in Heterocyclic Chemistry, ed.
G. Gribble and J. Joule, Elsevier Ltd., Oxford, U.K., 2004, vol. 16,
p. 309.
Me
D
a
Diastereoselective ratios were determined by analysis of the crude
b
reaction mixture. Isolated yield.
with Pd/C resulted only in partial hydrogenation of the
3,4-unsaturation to the 1,2,3,4-tetrahydropyridines. In order
to have complete conversion to the fully saturated piperidines,
an atmosphere of 700 to 1000 psi of hydrogen was needed
(Table 1). Fortunately, high diastereoselectivity for the cis iso-
mer was observed for the piperidines synthesized (17 : 1 to
420 : 1). Curiously, poor selectivity favoring the trans isomer
was observed when the 6-substituent is deuterium (2 : 1 trans :
cis, 8d). The relative stereochemistry of the centers at the 2 and
6 positions was confirmed by selective nOe analysis.18
A rapid and stereoselective synthetic method for the genera-
tion of 2,6-cis-disubstituted piperidines was developed. Regio-
selective lithiation at the 6-position of 1,2-dihydropyridines was
enabled by a chiral amidine directing group. The in situ gener-
ated anions were treated with various electrophiles or used in a
transmetallation/Negishi coupling sequence. The obtained
2,6-disubstituted 1,2-dihydropyridines underwent diastereoselec-
tive hydrogenation to generate 2,6-cis-disubstituted piperidines.
´
10 (a) G. Pelletier, A. Larivee and A. B. Charette, Org. Lett., 2008,
´
10, 4791; (b) A. Larivee and A. B. Charette, Org. Lett., 2006, 8, 3955.
11 For potent biologically active 2,6-disubstituted piperidines, see:
(a) S. Leclercq, J. C. Braekman, D. Daloze and J. M. Pasteels, Prog.
Chem. Org. Nat. Prod., 2000, 79, 115; (b) A. Pianaro, E. G. P. Fox,
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12 (a) A. I. Meyers and J. Guiles, Heterocycles, 1989, 28, 295. For reviews
on a-lithiation of piperidines, see: (b) P. Beak and A. I. Meyers, Acc.
Chem. Res., 1986, 19, 356; (c) A. I. Meyers, Tetrahedron Lett., 1992,
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Weisenburger, Acc. Chem. Res., 2000, 33, 715.
´
´
This work was supported by Universite de Montreal, the
Natural Science and Engineering Council of Canada (NSERC),
the Canada Research Chair Program and the Canada Foundation
for Innovation. The authors would like to thank Prof. Stephen
Hanessian (Universite de Montreal) for supplying some starting
electrophiles as well as Sylvie Bilodeau for support in some NMR
13 (a) S. J. Pastine, D. V. Gribkov and D. Sames, J. Am. Chem. Soc., 2006,
´
126, 14220; (b) H. Prokopcova, S. D. Bergman, K. Aelvoet, V. Smout,
W. Herrebout, B. Van der Veken, L. Meerpoel and B. U. W. Maes,
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14 V. Snieckus, Chem. Rev., 1990, 90, 879.
´
´
15 (a) J. J. Sahn and D. L. Comins, J. Org. Chem., 2010, 75, 6728;
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Chem. Rev., 1984, 84, 471.
´
studies. G.P. would like to thank NSERC, FRQNT and Universite
de Montreal for postgraduate scholarships.
´
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5 A recent review correlates the profound effect of installing a chiral 18 See ESI† for more information and for optimization tables.
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This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 6883--6885 | 6885