Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/jacs.5b04946

α,β-Unsaturated oxime pivalates are proposed 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.

Full text of DOI:10.1021/jacs.5b04946

Communication
pubs.acs.org/JACS
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
S
* 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
A
DOI: 10.1021/jacs.5b04946
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
In our initial work (eq 1), we never observed the presumed
intermediate dihydropyridine adducts even in the absence of
external oxidants. We speculated that the instability of the 2,3-
dihydropyridine was responsible and that rapid in situ oxidation
to the pyridine was faster than the initial annulation.12 We
envisioned that the use of 1,1-disubstituted alkenes would
prevent oxidation and deliver 2,3-dihydropyridines as isolable
outcomes of the reaction (eq 4). Herein we disclose our results.
We commenced our investigation by subjecting α,β-
unsaturated oxime pivalate 1a and alkene 2a to catalytic
amounts of various CpRh(III) diacetates13 in hexafluoroiso-
propanol (HFIP) at 60 °C (Table 1). As can be seen from the
Scheme 2. α,β-Unsaturated Oxime Pivalate Scope
a
Table 1. Optimization of the Reaction Conditions
Turning our attention to the scope of the alkenes, we found
that various 1,1-disubstituted olefins are competent substrates
for 2,3-dihydropyridine synthesis (Scheme 3). Functional
Scheme 3. Alkene Scope
d
entry
Rh(III)
additive
yield (%)
b
c
1
2
3
4
5
6
7
8
[Cp*RhCl2]2
AgOAc
<12
A1
A1
A1
A2
A3
A4
B3
B3
none
55
72
81
91
99
92
99
99
b
p-TsOH
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
e
9
a
Reaction conditions: 1a (1.0 equiv), 2a (1.2 equiv), additive (2.0
equiv), and Rh(III) catalyst (5 mol %) in HFIP (0.3 M) at 60 °C for
b
c
16 h. 10 mol % additive was used. Determined by 1H NMR
d
e
spectroscopy. Yields of isolated products. The catalyst loading was
decreased to 2 mol %, and the reaction temperature was decreased to
50 °C.
table, replacing the Cp* ligand (A1) with its more sterically
congested tert-butyl-substituted congener (A2) increased the
yield of the 2,3-dihydropyridine product (3aa) from 81% to
91%. The product yield was further enhanced when electron-
deficient Cp ligand A3 bearing a trifluoromethyl10b substituent
was used. When CsOAc was employed as an additive, product
3aa was isolated in 99% yield when 5 mol % A3 was used.
The use of Rh(III) diacetates is problematic for some Cp
ligands because of their hygroscopicity. Fortunately, use of the
more easily handled cationic tris(acetonitrile) Rh(III) pre-
catalyst B3 bearing a trifluoromethyl-substituted Cp* ligand did
not deteriorate the yield of the 2,3-dihydropyridine. Interest-
ingly, the dinuclear complex [Cp*RhCl2]2 did not promote the
title transformation with either CsOAc or AgOAc as an
additive.
With the optimal conditions in hand, we examined the scope
of the reaction (Scheme 2). α,β-Unsaturated oxime pivalates 1
bearing various linear or branched alkyl substituents at
positions 2 and 3 were tolerated (3aa−3da). Substrates bearing
an aromatic ring at position 3 were also competent (3ha−3na),
as well as functional groups such as silylated alcohols (3fa) and
halides (3ga and 3la).
groups including esters (3ab), ketones (3ac), ethers (3ad),
and protected amines (3am) were tolerated. With methyl-
enecyclopentanes and cyclohexanes as substrates, spiro-bicyclic
2,3-dihydropyridines were obtained in good yields (3dj−3ao).
Finally, exo-methylenecyclohexanes bearing a prostereogenic
carbon at the 4-position furnished the corresponding 2,3-
dihydropyridines (3an and 3ao) with high levels of
diastereocontrol (up to 10:1 dr).
To demonstrate the synthetic utility of the 2,3-dihydropyr-
idines, we turned our attention to derivatization of the
products. Stimulated by the wide abundance of piperidines in
biologically active compounds,1a attention was placed on the
reduction of C−C and C−N double bonds. We successfully
developed a single-pot protocol wherein the Rh(III)-catalyzed
coupling of imines and alkenes was sequenced with Pd-
catalyzed hydrogenation to deliver high overall yields of
piperidine products (Scheme 4). Surprisingly, the major
B
DOI: 10.1021/jacs.5b04946
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Journal of the American Chemical Society
Communication
a
Scheme 4. One-Pot Synthesis of Piperidines
Scheme 6. Postulated Catalytic Cycle
a
Values in parentheses denote yields and diastereomeric ratios after
recrystallization.
diastereomer formed proved to have the trans relationship
between the substituents at the 2 and 3 positions, although the
level of selectivity seemed to be modestly substrate-dependent
(compare 6mi vs 6hi). The relative configurations of products
6am and 6ao were unambiguously assigned by X-ray
crystallography.13
Labeling studies provided valuable insight into the
mechanism of the reaction. A small primary kinetic isotopic
effect (KIE = 1.41) was observed when deuterated oxime
pivalate d5-1j was used (Scheme 5). This observation may be
ation−deprotonation mechanism. The resultant five-membered
metallacycle II then undergoes rate-limiting migratory insertion
to give the seven-membered metallacycle IV. Reductive
elimination/N−O bond cleavage furnishes the 2,3-dihydropyr-
idine and regenerates the catalyst.
In conclusion, we have described an efficient Rh(III)-
catalyzed synthesis of semisaturated nitrogen heterocycles. A
significant effect of the ligand on the reactivity was observed,
Scheme 5. Observation of Kinetic Isotope Effects
with the electron-deficient trifluoromethyl-substituted Cp*CF
3
ligand being optimal. The scope of the transformation is
large,16 and many of the obtained 2,3-dihydropyridines were
successfully reduced to piperidines with good levels of
diastereocontrol. Mechanistically, it was established that the
reaction follows overall second-order kinetics, migratory
insertion being the turnover-limiting step.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic characterization of
compounds, X-ray crystal structures (CIF), and detailed
mechanistic studies. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/jacs.5b04946.
explained by evoking a reversible C−H activation event and
incorporation of deuterium from solvent rather than as a direct
indicator of a rate difference.14 A rather large inverse KIE
(0.74) was observed with deuterated alkene d2-2f, which is
consistent with rate-determining olefin insertion.
A Hammett study provided further support that olefin
insertion is the slow step.13 A large and negative value of the
reaction constant (ρ = −1.2) indicates that positive charge
builds up at the reaction site during the rate-limiting step.
Preliminary kinetic analysis15 of the reaction revealed a first-
order dependence of the rate on both the catalyst and the
oxime. Furthermore, a first-order dependence on the alkene
was also seen at low concentrations; higher concentrations
demonstrated some evidence of an inhibitory effect.13
In order to account for the observed mechanistic data, the
following catalytic cycle is proposed (Scheme 6). Following the
formation of the active Rh(III) diacetate complex, C−H
activation takes place reversibly through a concerted metal-
AUTHOR INFORMATION
Corresponding Author
*rovis@colostate.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIGMS (GM80442) for support. F.R.-M. thanks the
Swiss National Science Foundation for fellowship support.
K.F.S. thanks NIGMS for a supplement. We thank Johnson
Matthey for a generous loan of Rh salts, Christopher D. Rithner
and Karolien Denef (CSU) for assistance with NMR
C
DOI: 10.1021/jacs.5b04946
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Journal of the American Chemical Society
Communication
spectroscopy, Brian Newell (CSU) for solving X-ray crystal
structures, and Maria Romanova-Michaelides (University of
Geneva) for assistance with mathematical analysis.
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D
DOI: 10.1021/jacs.5b04946
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