Rh(III)-catalyzed regioselective synthesis of pyridines from alkenes and α,β-unsaturated oxime esters

Article abstract of DOI:10.1021/ja3104389

α,β-Unsaturated O-pivaloyl oximes are coupled to alkenes by Rh(III) catalysis to afford substituted pyridines. The reaction with activated alkenes is exceptionally regioselective and high-yielding. Mechanistic studies suggest that heterocycle formation proceeds via reversible C-H activation, alkene insertion, and a C-N bond formation/N-O bond cleavage process.

Full text of DOI:10.1021/ja3104389

Communication
pubs.acs.org/JACS
Rh(III)-Catalyzed Regioselective Synthesis of Pyridines from Alkenes
and α,β-Unsaturated Oxime Esters
Jamie M. Neely and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
however, suffer from low regioselectivities. Investigations by our
ABSTRACT: α,β-Unsaturated O-pivaloyl oximes are
coupled to alkenes by Rh(III) catalysis to afford
substituted pyridines. The reaction with activated alkenes
is exceptionally regioselective and high-yielding. Mecha-
nistic studies suggest that heterocycle formation proceeds
via reversible C−H activation, alkene insertion, and a C−
N bond formation/N−O bond cleavage process.
group found that a bulky tert-butylcyclopentadienyl ligand
allowed for enhanced selectivity with unsymmetrical internal
alkynes.6d
Despite these advances, inconsistent regioselectivities and
restricted terminal alkyne scope still limit this methodology. We
envisioned that the use of an alkene in place of the alkyne, with
an external oxidant in addition to the N−O bond internal
oxidant,9,10 could potentially address these problems and
provide a complementary method for pyridine synthesis (eq 3).
We chose to examine the reaction of oxime derivatives of 1-
acetyl-1-cyclohexene (1a) with ethyl acrylate (2a) in the
presence of [RhCp*Cl2]2 (Cp* = pentamethylcyclopentadien-
yl) in 2,2,2-trifluoroethanol (TFE) (Table 1). With silver(I)
ubstituted pyridines are the most abundant heteroaromatic
S
structures in medicinal chemistry.1 Consequently, extensive
research has focused on the development of methods to access
this motif.2 Limitations associated with more established
carbonyl condensation3 and [2 + 2 + 2] cycloaddition4
strategies have inspired new approaches to the pyridine core,
and several elegant reports demonstrate the recent progress in
this field.5
a
Table 1. Reaction Optimization
Rhodium-catalyzed coupling of α,β-unsaturated oximes and
alkynes (eqs 1 and 2) represents a particularly useful
b
yield (%)
entry
R
solvent
TFE
T (°C)
3aa
4
1
2
3
4
H
74
74
74
85
85
0
0
35
35
0
Ac
TFE
c
Piv
Piv
Piv
TFE
30
DCE/AcOH
45
0
d
5
DCE/AcOH
65
0
a
b
1.2 equiv of 2a, 0.15 M solution. Determined by 1H NMR analysis.
c
d
Formed as a ∼4:1 mixture of Et and CF3CH2 esters. 0.3 M solution.
acetate as an oxidant, the parent oxime afforded none of the
desired pyridine 3aa, instead undergoing intramolecular
cyclization to give isoxazole 4 (entry 1). Isoxazole formation
was similarly observed with the O-acetyl oxime ester of 1a
(entry 2). On the other hand, the O-pivaloyl derivative [Piv =
C(O)tBu] furnished the desired pyridine 3aa in 30% yield
(entry 3). Importantly, the 6-substituted pyridine was formed
as a single regioisomer. An extensive screen of reaction
conditions (see the Supporting Information) revealed a 0.3
M solution in 2:1 dichloroethane (DCE)/acetic acid (AcOH)
to be optimal, providing 3aa in 65% yield (entry 5).
contribution to pyridine synthesis.6,7 In a recent report,
Cheng demonstrated the Rh(I)-catalyzed synthesis of poly-
substituted pyridines from α,β-unsaturated oximes and sym-
metrical internal alkynes.6a Several terminal alkynes, historically
avoided because of their propensity to undergo side reactions,8
were reported by Bergman and Ellman to be competent
substrates with a Rh(I)/phosphite system (eq 2).6e The
reactions with terminal and unsymmetrical internal alkynes,
With these optimized conditions in hand, we examined the
reactions of various O-pivaloyl ketoximes 1 with 2a (Chart 1).11
Received: October 25, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja3104389 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Chart 1. Oxime Ester Scope
Chart 2. Activated Alkene Scope
a
Conditions: 1 (0.21 mmol), 2a (0.25 mmol), [RhCp*Cl2]2 (0.005
mmol), and AgOAc (0.44 mmol) in 0.7 mL of 2:1 DCE/AcOH for 14
b
h. 0.12 mmol scale.
The oxime ester substrates were accessed easily from the
corresponding ketones, hydroxylamine hydrochloride, and
pivaloyl chloride. The reactivity dramatically increases when 1
lacks substitution at the β-position. α-Alkyl and α-aryl
substrates afford the 2,3,6-trisubstituted pyridines in excellent
yields. Vinyl oxime ester 1h delivers disubstituted pyridine 3ha,
but in lower yield. Notably, primary alkyl chloride 1e is
tolerated in the presence of the Ag(I) oxidant, giving 3ea in
good yield. In all cases, 6-substituted pyridines are formed with
complete selectivity.
We next investigated the alkene component of the reaction
(Chart 2). Electron-deficient alkenes afford the desired
products in excellent yields as single regioisomers. The reaction
of 1c and styrene is also completely regioselective; however, the
6-phenylpyridine product 3cf undergoes a second C−H
activation event,12 resulting in a mixture of 3cf and 2-
styrenyl-3cf (eq 4). On the other hand, product alkenylation
a
b
Conditions: see Chart 1. For 1g, 1.05 equiv of 2 was used. 1.2 equiv
c
of 1c. 75 °C.
a
Table 2. Alkyl Alkene Scope
b
entry
alkene
R
3:5
yield (%)
1
2
3
4
5
6
2m
2n
2o
2p
2q
2r
CH2OPh
nHex
Cyp
2.2:1
1:1.3
1.3:1
7.2:1
3.4:1
<1:20
66
72
67
69
Cy
c
is not observed with oxime ester 1g. Presumably, the slightly
larger ortho substituent in 3gf discourages alkenylation.13 The
reactions of oxime 1g with various substituted styrenes provides
the corresponding 2-arylpyridines as single regioisomers.
Alkyl alkenes are also competent coupling partners but
produce separable mixtures of the 6- and 5-substituted
pyridines 3 and 5 (Table 2).14 Surprisingly, the reaction with
vinylcyclohexane (2p) is significantly more selective for 3 than
that with vinylcyclopentane (2o; Cyp = cyclopentyl), while
intermediate selectivity is observed with 3-methylpentene (2q)
(entries 3−5). The reason for this anomaly is currently under
investigation. Notably, the reaction of 3,3-dimethylbutene (2r)
affords the 5-substituted product 5cr exclusively, albeit in low
yield, suggesting that there is a steric component to the control
of regioselectivity.
sBu
50
cd
,
tBu
17
c
a
b
Conditions: see Chart 1. Determined by 1H NMR analysis. 5 equiv
of 2 was used. 0.54 mmol scale.
d
with 1c to afford the corresponding tetrasubstituted pyridine in
similar yields. The reaction is selective for the 2-picolinate
product (7) even when the β-substituent of the alkene is a
ketone (6c; entry 5).
Contemplating the mechanism of the reaction, we
considered two general pathways for C−N bond formation
from rhodacycle A (Figure 1). In pathway A, β-hydride
elimination generates azatriene B, and subsequent electro-
cyclization and elimination of PivOH furnishes 3. Such Rh-
catalyzed C−H alkenylations have been demonstrated with
various directing groups,10b,12,15−17 including oxime ethers.18
β-Substituted acrylates 6 could also participate as the alkene
component (Table 3). The Z and E isomers of 6 both react
B
dx.doi.org/10.1021/ja3104389 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 3. Internal Alkene Scope
b
entry
alkene
CO2R
R
7:8
yield (%)
1
2
(Z)-6a
(E)-6a
(Z)-6b
(E)-6b
(E)-6c
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
CO2Me
Me
n/a
n/a
71
54
47
51
methyl of 3ca signals a deprotonation step; since there was no
deuteration at the same position of 1c, the deprotonation most
likely occurs after the first irreversible step of the reaction.22
With these observations in mind, we propose the reaction
mechanism in Scheme 1. After generation of acetate catalyst I,
c
3
>20:1
>20:1
4.7:1
c
4
Me
5
CO2Me
C(O)Me
41
c
a
b
1
Conditions: see Chart 1. Determined by H NMR analysis. 5 mol
% [RhCp*Cl2]2.
Scheme 1. Proposed Reaction Mechanism
Figure 1. Two possible pathways for C−N bond formation.
Moreover, 6π-electrocyclization of an azatriene intermediate19
has been proposed in the Rh(I)-catalyzed reaction of oximes
and alkynes.6a,b,e To probe the possibility of pathway A, we
used cis-fused 1,2-dihydronaphthalene as our alkene compo-
nent (eq 5). If pathway A were operational, no product would
reversible C−H activation forms rhodacycle II. Dissociation of
an acetate ligand leads to cationic complex III, which may be in
equilibrium with chelated complex III′. Alkene coordination
and presumed irreversible migratory insertion provides rhoda-
cycle V, and deprotonation at the α-position gives neutral
complex VI. It is possible that chelation of the O-pivalate
substituent prevents β-hydride elimination at this stage as a
result of coordinative saturation.23 Instead, a C−N bond
formation/N−O bond cleavage event provides complex VII
after tautomerization.24 Final β-hydride elimination furnishes
the pyridine product. Reductive elimination of complex VIII
followed by oxidation of the Rh(I) species regenerates the
active catalyst.25
In conclusion, we have developed a novel synthesis of
pyridines from α,β-unsaturated O-pivaloyl oximes and alkenes.
The reaction is general, efficient, and highly regioselective with
activated alkenes. Mechanistic studies support a pathway that
proceeds by reversible C−H activation, alkene insertion, and a
C−N bond formation/N−O bond cleavage process.
be expected, since a trans relationship between rhodium and
the β-hydride in intermediate A would preclude β-hydride
elimination.20 In fact, tricyclic product 10 is formed in 32%
yield, implicating an alternate pathway for C−N bond
formation.
Pathway B in Figure 1 depicts a C−N bond formation/N−O
bond cleavage event that is followed by oxidative aromatization
to give 3. This type of process has been invoked in the Rh(III)-
catalyzed synthesis of pyridines from oximes and alkynes6c,d
and analogous reactions of hydroxamic acid derivatives.10 In
particular, Glorius demonstrated that the product of the
reaction of N-oxybenzamides and alkenes hinges upon the O
substituent.10b Specifically, N-methoxybenzamides afford olefi-
nated products while N-pivaloxybenzamides form tetrahydroi-
soquinolones, presumably via pathways analogous to A and B,
respectively. Accordingly, the O-methyl derivative of 1a does
not afford the pyridine product under our conditions.
Isotope experiments provided further insight into the
mechanism of pyridine formation.21 In particular, when the
reaction was performed with AcOD to ∼50% conversion,
deuterium incorporation was observed at the β-position of 1c
and the 2-methyl and 5-H of 3ca (eq 6). The observed
deuteration at the β-position of 1c implies that C−H activation
is reversible. Nearly complete deuterium incorporation at the 2-
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, compound characterization, and
additional experiments. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
■
C
dx.doi.org/10.1021/ja3104389 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank NIGMS (GM80442) for support, Amgen and Roche
for unrestricted support, and Johnson Matthey for a generous
loan of rhodium salts.
.
(14) Aspects of the terminal alkyne methodology (ref 6e) should be
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D
dx.doi.org/10.1021/ja3104389 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX