Pyridine synthesis from oximes and alkynes via rhodium(iii) catalysis: Cp* and Cpt provide complementary selectivity

Article abstract of DOI:10.1039/c1cc15248c

The synthesis of pyridines from readily available α,β- unsaturated oximes and alkynes under mild conditions and low temperatures using Rh(iii) catalysis has been developed. It was found that the use of sterically different ligands allows for complementary selectivities to be achieved.

Full text of DOI:10.1039/c1cc15248c

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COMMUNICATION
Pyridine synthesis from oximes and alkynes via rhodium(III) catalysis:
Cp* and Cpt provide complementary selectivitywz
Todd K. Hyster and Tomislav Rovis*
Received 23rd August 2011, Accepted 21st September 2011
DOI: 10.1039/c1cc15248c
The synthesis of pyridines from readily available a,b-unsaturated
oximes and alkynes under mild conditions and low temperatures
using Rh(III) catalysis has been developed. It was found that the
use of sterically different ligands allows for complementary
selectivities to be achieved.
Table 1 describes modification to our standard reaction
conditions. We found that oxime 1a and alkyne 2a in the
presence of K2CO3 and [RhCptCl2]2 in 2,2,2-trifluoroethanol
(TFE) at 45 1C provide pyridine 3a in 87% yield with 4 : 1
regioselectivity. By comparison, the Rh(I) approach gives a
similar yield, but 1.6 : 1 regioselectivity.18 The use of [RhCptCl2]2
is preferred, as [RhCp*Cl2]2 delivers similar yields but low
regioselectivity (Table 1, entry 7).6b Importantly, the use of
Cpt gives the alkyne regiosomer opposite of what is typically
observed in Rh(III) CꢀH activation chemistry. Oxime methyl
ethers afford no reaction (Table 1, entry 2). Furthermore, the
acetyl oxime ester decomposes under the reaction to yield the
free oxime within minutes.20 A base screen revealed CsOAc
also functions well (Table 1, entry 3), but the reaction requires
some base, presumably because the CꢀH activation proceeds
through a concerted metallation-deprotonation (CMD) mecha-
nsim (Table 1, entry 4).21 More electron deficent ligands (Table 1,
entry 8) are tolerated, but afford lower regioselectivity and yield.
The enhanced selectivity provided by Cpt is likely due to steric
interactions.
Poly-substituted pyridines rank as one of the most common
heterocycles encountered by medicinal chemists.1,2 The fre-
quency with which this motif appears has necessitated the
development of numerous approaches for generating pyridines
of different substitution patterns.3 Transition metal catalysis is
a powerful tool for this problem.4 Based on our experience
with heteroatom containing metallacycles,5 we imagined we
could use a nitrogen containing rhodacycle to access pyridines.
Our group,6 and others,7 have independently demonstrated
that benzamides and acrylamides can be coupled with alkynes
to access isoquinolones and pyridones using Rh(III) catalysis.8
This method affords access to a variety of nitrogen containing
heterocycles including indoles,9 pyrroles,10 isoquinolines,11
and dihydro-isoquinolones.12 We envisioned that pyridines
could be accessed from a,b-unsaturated oximes13 and alkynes,
with the NꢀO bond of the oxime acting as an internal oxidant.
NꢀO bonds have been shown to function as internal
oxidants in other CꢀH activation protocols.14–17 Guimond
and Fagnou7a,b were the first to demonstrate that Rh(III) CꢀH
activation functions with internal oxidants to prepare iso-
quinolones and dihydroisoquinolones. Inspired by this work, we
believed that oximes might allow access to a similar 7-membered
rhodacycle that can decompose to form pyridines with cleavage
of the NꢀO bond. Notably, Cheng and workers have demon-
strated a clever synthesis of pyridines using a,b-unsaturated
oximes and alkynes under Rh(I) catalysis.18 Under these con-
ditions unsymmetrical alkynes give low regioselectivity while
requiring high temperatures (130 1C). We speculated that our
approach would render more mild conditions and a broader
substrate scope.19
With optimized conditions in hand, we began a screen of the
oxime components with 1-phenyl-1-propyne. The oxime was
Table 1 Reaction optimizationa
Yield
Entry Variations from ‘‘standard conditions’’ (%)b Regioselectivity
1
2
3
4
5
6
7
8
none
R=Me
CsOAc instead of K2CO3
No K2CO3
87
4 : 1
—
2.2 : 1
—
2.1 : 1
4 : 1
1 : 2
1 : 1
n.r.c
65
n.r.
68
70
83
MeOH instead of TFE
(4 : 1) H2O/TFE instead of TFE
[RhCp*Cl2]2 instead of [RhCptCl2]2
[RhCpCF3Cl2]2 instead of [RhCptCl2]2 20
Department of Chemistry, Colorado State University, Fort Collins,
CO 80523. E-mail: rovis@lamar.colostate.edu;
Fax: (+1) 970-491-1801; Tel: (+1) 970-491-7208
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and spectroscopic data. See DOI: 10.1039/
c1cc15248c
a
Standard Reaction Conditions: oxime (0.2 mmol), alkyne
(0.22 mmol), catalyst (0.005 mmol), base (0.4 mmol) in solvent (3 ml)
b
stirred for 16 h. Yields determined by GC/MS. n.r. = no reaction.
c
z This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
c
11846 Chem. Commun., 2011, 47, 11846–11848
This journal is The Royal Society of Chemistry 2011

screened with [RhCptCl2]2 and [RhCp*Cl2]2 to determine the
effect the ligand has on regioselectivity. Alkyl substituted oximes
function well in this reaction with regioselectivities increasing
when the Cpt ligand is employed (Table 2, entries 1–3).22
Aldoximes are tolerated under the reaction conditions, a con-
straint of the Cheng methodology (Table 2, entry 6).23 In contrast
to alkyl-substituted oximes, b-aryl substituted oximes display
higher selectivity when Cp* is used (Table 1, entries 4,5, and 7).
Beyond giving high selectivity with Cp*, b-aryl groups also allow
access to the opposite regioisomer in moderate regioselectivity.
When electron-withdrawing groups are placed at the b-position
of the substrate Cp* is a better ligand with good to excellent yield
and regioselectivity (Table 2, entries 8 and 9).
alcohols function well under the reaction conditions, albeit
with slightly lower regioselectivity (Table 2, entry 10). A variety
of alkyl/aryl alkynes participate with good selectivity, including
pyridine- and cyclopropyl-substituted alkynes. Phenyl propiolates
provide pyridines in good yield and excellent regioselectivity
(Table 2, entry 12). Dialkyl alkynes gave excellent selectivity.
Pyridines 3r, 3s were isolated in high yield and excellent
regioselectivity. In these cases the larger group is at the 2-position
of the pyridine.
Previously, excellent work by Chiba demonstrated that O-Ac
oximes can be used to access isoquinolones.11b Later, Li11a and
Guimond/Fagnou11d demonstrated that free oximes can func-
tion as directing groups for this reaction. Using our conditions
we were delighted to access isoquinolines. A variety of substitu-
tion is tolerated off the 1-position of the oxime, ranging from
aryl, alkyl, and vinyl groups (Scheme 1, 5a–5c). We felt this
method might also allow us to perform cyclizations with hetero-
cyclic oximes. We were pleased to find that pyrroles, thiophenes,
furans, and benzofurans are all tolerated in excellent yield
(Scheme 1, 5d–5i). In most cases the regioselectivities with Cp*
are quite pedestrian. Interestingly, changing to Cpt alters the
intrinsic selectivities to favor the opposite isomer. In addition
to these heterocycles, we found that pyridines are tolerated
in this reaction. This is striking in light of the relatively few
examples of Rh(III) CꢀH activation on heterocycles contain-
ing basic nitrogen.24 Furthermore, the CꢀH activation occurs
predominately at the position adjacent to the nitrogen, appar-
ently due to the increased kinetic acidity of that proton.
Additionally we found a kinetic isotope effect of 18 in this
transformation. While rare, a similar value was observed by
Guimond/Fagnou in their internal oxidant rhodium(III) studies.7a
With CꢀH activation as the turnover-limiting event, we were
interested in determining the mechanism of internal redox. In
particular, we sought to probe the possibility of a 6p-electro-
cyclization event. Since a,b,g,d-unsaturated oximes undergo
electro-cyclizations under mild conditions,25 we elected to generate
We explored a variety of alkyne components for the reaction
with oxime 1h in the presence of [RhCp*Cl2]2. Protected propargyl
Table 2 Pyridine scopea
a
Standard Conditions: see Table 1. Cp* = [RhCp*Cl2]2, Cpt
=
[RhCptCl2]2. Reaction run at 80 1C with K2CO3 (50 mol%).
b
Scheme 1 Isoquinoline scope.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11846–11848 11847

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¨
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Scheme 2
the intermediate derived from an isoquinoline. Upon subjection of
the 6p intermediate to our standard reaction conditions, we did
not observe any pyridine product, suggesting that this reaction
does not occur via a 6p-electrocyclization (see the ESIw).
A possible product of this reaction is a polysubstituted
pyridine N-oxide. This species could oxidize Rh(I) to Rh(III)
under the reaction conditions and provide the desired product.
When the reaction is conducted in the presence of 4-phenyl
pyridine N-oxide, none of the reduced 4-phenyl pyridine is
observed, suggesting that if the reductive elimination path
is occurring, inner sphere oxidation is inherently rapid and
the dominant pathway for reoxidizing Rh. Alternately, and
perhaps more reasonably, N–O bond reduction occurs in
concert with the C–N bond-forming event, as proposed by
Guimond/Fagnou.7b
12 (a) S. Rakshit, C. Grohmann, T. Besset and F. Glorius, J. Am.
Chem. Soc., 2011, 133, 2350; (b) Ref. 7a.
13 For select examples, see: (a) S. R. Neufeldt and M. S. Sanford,
Org. Lett., 2010, 12, 532; (b) L. V. Desai, K. L. Hull and M. S.
Sanford, J. Am. Chem. Soc., 2004, 126, 9542; (c) L. V. Desai,
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With these insights in hand, we propose the following
mechanism. The monomeric rhodium catalyst coordinates to
the basic nitrogen of the oxime A. A turnover limiting CꢀH
activation event occurs, presumably facilitated by carbonate,
to provide a 5-membered rhodacycle B. This metallacycle can
insert an equivalent of alkyne to generate a 7-membered
metallacycle, which undergoes a CꢀN bond formation with
concomitant N–O bond cleavage C.
We thank NIGMS (GM80442) for support and Johnson
Matthey for a loan of Rh salts. We thank Marie Trujillo
(CSU) for early experiments.
Notes and references
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11848 Chem. Commun., 2011, 47, 11846–11848
This journal is The Royal Society of Chemistry 2011