Communication
Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes
by Rh(III)-Catalyzed C−H Activation
Fedor Romanov-Michailidis, Kassandra F. Sedillo, Jamie M. Neely, and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
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* Supporting Information
synthesis of N-unprotected 2,3-dihydropyridines.8 This con-
stitutes a handicap to the synthetic community, given the
potential number of transformations in which such inter-
mediates can engage.
In recent years, Rh(III)-catalyzed C−H activation has
become a method of choice for constructing nitrogen
heterocycles.9,10 In particular, coupling of α,β-unsaturated
imines and oximes with alkynes represents a useful approach
to pyridines.11 We recently demonstrated that high regiose-
lectivities are obtainable when electronically biased alkenes are
used in place of alkynes as coupling partners (Scheme 1, eq
ABSTRACT: α,β-Unsaturated oxime pivalates are pro-
posed to undergo reversible C(sp2)−H insertion with
cationic Rh(III) complexes to furnish five-membered
metallacycles. In the presence of 1,1-disubstituted olefins,
these species participate in irreversible migratory insertion
to give, after reductive elimination, 2,3-dihydropyridine
products in good yields. Catalytic hydrogenation can then
be used to convert these molecules into piperidines, which
are important structural components of numerous
pharmaceuticals.
Scheme 1. Rh(III)-Catalyzed Synthesis of 2,3-
Dihydropyridines
itrogen heterocycles are among the most abundant
N
structural components of pharmaceuticals.1 Because of
their omnipresence in biologically active molecules, the
synthesis of nitrogen heterocycles has attracted considerable
attention in the synthetic community. Pyridines represent one
of the most prevalent scaffolds encountered in medicinal
chemistry.1b,c Removal of one unsaturation from a pyridine ring
affords a dihydropyridine.2 Dihydropyridines come as three
double-bond isomers: 1,4-dihydropyridine (1), 2,3-dihydropyr-
idine (2), and 1,2-dihydropyridine (3) (Figure 1). The first
Figure 1. Structures of dihydropyridines.
synthesis of a 1,4-dihydropyridine is attributed to Arthur
Hantzsch for work done over a century ago.3 The importance
of this motif is highlighted by its presence in nicotinamide
adenine dinucleotide (NADH), a universal biological reducing
agent. Interest in 1,4-dihydropyridines has been further
stimulated after their incorporation into calcium channel
blockers.4
In stark contrast to 1,4-dihydropyridines, which are stable
structures, the 2,3- and 1,2-congeners are kinetically labile and
thus are not found in bioactive molecules as such. Nevertheless,
they have been implicated as versatile intermediates in
biosynthetic pathways leading to alkaloid natural products.
Recent examples include the proposed biosynthesis of the
marine natural product symbioimine5 as well as the
isoquinuclidine alkaloids keramaphidin B and manzamine A.6
While N-alkyl-2,3-dihydropyridinium salts are well-docu-
mented and even isolable,7 there is scarce information on the
1).11a Furthermore, substituted acrylic acids were shown to give
the complementary regioisomers of the pyridine products,
where the carboxylate acts as a traceless directing group (eq
2).11b In a conceptually distinct approach, Bergman and Ellman
showed that Rh(I)-catalyzed coupling of unsaturated imines
with internal alkynes followed by iminium formation and
reduction can deliver complementary tetrahydropyridines
depending on nature of the acid (eq 3).11c This latter reaction
was proposed to proceed through dihydropyridine intermedi-
ates.
Received: May 12, 2015
© XXXX American Chemical Society
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX