One-pot synthesis of highly functionalized pyridines via a rhodium carbenoid induced ring expansion of isoxazoles

Article abstract of DOI:10.1021/ja803139k

A concise one-pot synthesis of highly functionalized pyridines has been developed. The first step in the reaction sequence is the formal insertion of rhodium vinylcarbenoids across the N-O bond of isoxazoles. Upon heating, the insertion products undergo a

Full text of DOI:10.1021/ja803139k

Published on Web 06/13/2008
One-Pot Synthesis of Highly Functionalized Pyridines via a Rhodium
Carbenoid Induced Ring Expansion of Isoxazoles
James R. Manning and Huw M. L. Davies*
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York, Buffalo, New York 14260-3000
Received April 28, 2008; E-mail: hdavies@buffalo.edu
Functionalized pyridine and 1,4-dihydropyridine derivatives have
long been known as important biologically active compounds.1,2
While the 1,4-dihydropyridines have been extensively used as
calcium channel modulators,1b their oxidized counterparts target a
wide variety of biological receptors.2 Due to the prevalence of
pyridines in pharmaceuticals, agrochemicals, and natural products,
their synthesis remains an area of intense current interest to the
chemical community.3 Many of the methods for preparing substi-
tuted pyridines rely on the Hantzsch reaction4 between amines and
carbonyl compounds, necessarily restricting functionality at the 3
and 5 positions to carboxyl groups. Other common methods include
multicomponent condensation reactions,3d cycloadditions3b,g,i,k and
the electrocyclization of azatrienes.3a,c,f We herein report a
conceptually distinct approach to the synthesis of highly substituted
pyridines from isoxazoles. This approach is based upon a rhodium
carbenoid induced ring expansion of isoxazoles, followed by
rearrangement to a dihydropyridine and oxidation to the corre-
sponding pyridine.
likely proceeds through one of two distinct mechanistic pathways
outlined below (eq 4). Upon heating, the N-O insertion product 9
could undergo a Claisen rearrangement to directly give 3,4-
dihydropyridine 10. Alternatively, 9 could undergo an electrocyclic
ring opening to azatriene 11, followed by a 6π electrocyclization
to give 10. Tautomerization of 10 then leads to the isolated 1,4-
dihydropyridine product 12.
We recently reported that isoxazoles are capable of undergoing
efficient ring expansion reactions with the donor/acceptor-
substituted rhodium carbenoid derived from methyl phenyldiaz-
oacetate 1 (eq 1).5 The isoxazole ring expansion likely proceeds
through an ylide intermediate.6
Having demonstrated that the N-O insertion product of an
isoxazole with a vinylcarbenoid could successfully rearrange to a
1,4-dihydropyridine, the next step was to develop a one-pot
synthesis of the corresponding pyridine. The reaction conditions
were carefully chosen according to the following criteria: (1)
reversible coordination of the isoxazole nitrogen lone pair to the
Rh(II) catalyst necessitates conducting the diazo compound addition
at elevated temperatures to ensure decomposition to the carbenoid;
(2) vinyldiazo compounds are prone to undergo a 6π electrocy-
clization reaction to form pyrazoles at elevated temperatures;7 and
(3) the solvent must have a high boiling point to efficiently promote
the subsequent rearrangement and must not react with the carbenoid.
As such, the optimal conditions for most of the examples shown
require a 30 min syringe pump addition of the diazo compound to
the solution of catalyst and isoxazole at 60 °C in toluene. The
solution is then heated at reflux for 4 h before being cooled to
ambient temperature for the DDQ oxidation.
The results of this study are shown in Table 1. The reaction is
very efficient for most of the reactions with substituted arylvinyl-
diazoacetates and 5, with the yields being slightly higher for
electron-deficient aromatics (15a-15j). The standard reactions were
conducted with 2 mol % of catalyst, but in many cases, the reactions
could be conducted with just 0.5 mol % of catalyst without any
loss in yield. A good yield can also be obtained using an
arylvinyldiazo ketone (15k) and a diester-substituted vinyl diazo
compound (15w). The electron-rich heteroaromatic vinyldiazoac-
etates (15m-15q) gave lower yields with the exception of the Boc-
protected indolylvinyldiazoacetate (15o). A particularly attractive
feature of this method is the ready access of 3,5-disubstituted
isoxazoles using the copper-catalyzed process developed by Fokin
and co-workers.8 Thus, the pyridines can be widely varied by use
of a two-step, three-component coupling protocol (eq 5), as
We reasoned that, if the same reaction were conducted with a
vinyldiazomethane, the resulting product might then be capable of
undergoing a rearrangement to form a 3,4-dihydropyridine. To test
this hypothesis, the ring expansion product 6 of 3,5-dimethylisox-
azole (5) with (E)-styrylvinyldiazoacetate 4 was prepared in 79%
yield via the Rh2(OAc)4-catalyzed reaction (eq 2). When 6 was
heated in toluene, it underwent rearrangement, but the isolated
product was 1,4-dihydropyridine 7, not the expected 3,4-dihydro-
pyridine 8 (eq 3).
This isomeric product was likely formed by a facile tautomer-
ization of the putative rearrangement product 8. The transformation
9
8602 J. AM. CHEM. SOC. 2008, 130, 8602–8603
10.1021/ja803139k CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 1. One-Pot Synthesis of Highly Functionalized Pyridines
Uniform conditions unless otherwise noted: 2 equiv of diazo compound, 2 mol % of Rh2(OAc)4, 30 min diazo compound addition at 60 °C, then
reflux for 4 h, then rt DDQ addition. a With 0.5 mol % of Rh2(OAc)4 used. b With 4 equiv of diazo compound used. c Diazo compound added at reflux.
d With 3 equiv of diazo compound used. e Refluxed overnight after diazo compound addition.
illustrated in products 15r-15y. A protected 2-aminopyridine 15z
was also synthesized from a protected 3-aminoisoxazole. The
References
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Acknowledgment. The National Institutes of Health (GM080337)
is gratefully acknowledged. J.R.M. thanks the National Institutes
of Health for a Ruth L. Kirschstein predoctoral fellowship
(DA019287). We thank Mateusz Pitak and Milan Gembicky for
the X-ray crystallographic analysis.
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(9) The X-ray crystallographic data have been submitted to the Cambridge
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Supporting Information Available: Full experimental data for the
compounds described in this paper; X-ray crystallographic file in CIF
format. This material is available free of charge via the Internet at http://
pubs.acs.org.
JA803139K
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J. AM. CHEM. SOC. VOL. 130, NO. 27, 2008 8603