Heteroaromatic synthesis via olefin cross-metathesis: Entry to polysubstituted pyridines

Article abstract of DOI:10.1021/ol103088r

The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of α,β-unsaturated 1,5-dicarbonyl derivatives which then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within macrocycles, as exemplified by an efficient synthesis of (R)-(+)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile substituent variation are all notable aspects of this methodology.(Figure Presented)

Full text of DOI:10.1021/ol103088r

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1036–1039
Heteroaromatic Synthesis via Olefin
Cross-Metathesis: Entry to
Polysubstituted Pyridines
†
ꢀ
Timothy J. Donohoe,* Jose A. Basutto, John F. Bower, and Akshat Rathi
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K.
timothy.donohoe@chem.ox.ac.uk
Received December 21, 2010
ABSTRACT
The olefin cross-metathesis reaction provides a rapid and efficient method for the synthesis of R,β-unsaturated 1,5-dicarbonyl derivatives which
then serve as effective precursors to mono-tetrasubstituted pyridines. Manipulation of the key 1,5-dicarbonyl intermediate allows access to
pyridines with a wide range of substitution patterns. An extension of this methodology facilitates the preparation of pyridines embedded within
macrocycles, as exemplified by an efficient synthesis of (R)-(þ)-muscopyridine. High levels of regiocontrol, short reaction sequences, and facile
substituent variation are all notable aspects of this methodology.
Of all heteroaromatic compounds, pyridines are unri-
valled in terms of their pharmacological significance.1,2
Consequently, the development of methods for the prep-
aration of highly substituted pyridine derivatives is of
importance to medicinal chemistry and represents a worth-
while goal of organic synthesis. Substantial and exciting
progress has been made in the derivatization of pre-exisiting
pyridine frameworks using metal-catalyzed cross-coupling
protocols.3 However, another flexible and also comple-
mentary approach involves the development of de novo
pyridine methodologies.4 Ideally, any new method should
enable the concise combination of readily available materials
in a convergent, predictable, and regiocontrolled manner.
Recent studies from our laboratory,5,6 and others,7 have
focused upon incorporating the olefin metathesis reaction
into methodologies for the synthesis of heteroarenes. In
(4) For a review, see: Henry, G. D. Tetrahedron 2004, 60, 6043. For
some recent and pertinent examples, see: Aulakh, V. S.; Ciufolini, M. A.
J. Org. Chem. 2009, 74, 5750. Manning, J. R.; Davies, H. M. L. J. Am.
Chem. Soc. 2008, 130, 8602. Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc.
2008, 130, 6918. Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007,
2459. Dash, J.; Lechel, T.; Reissig, H.-U. Org. Lett. 2007, 9, 5541.
Movassaghi, M.; Hill, M. D.; Ahmad, O. K. J. Am. Chem. Soc. 2007,
129, 10096.
† Author for correspondence regarding the X-ray structures.
(1) Pharmaceutical Chemistry. Drug Synthesis, Vol. 1.; Roth, H. J.,
Kleemann, A., Eds.; Prentice Hall Europe: London, 1988; p 407.
(5) Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem., Int. Ed.
2006, 45, 2664.
(6) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem.;Eur. J.
ꢀ
(2) See ref 1 within: Bonnet, V.; Mongin, F.; Trecourt, F.; Breton, G.;
ꢀ
Marsais, F.; Knochel, P.; Queguiner, G. Synlett 2002, 1008.
2008, 14, 5716.
€
(3) For representative examples, see: Schroter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. Cho, S. H.; Hwang, S. J.; Chang, S. J. Am.
Chem. Soc. 2008, 130, 9254. Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.;
Campeau, L.-C.; Fagnou, K. J. Org. Chem. 2010, 75, 8180. Mousseau,
J. J.; Bull, J. A.; Charette, A. B. Angew. Chem., Int. Ed. 2010, 49, 1115.
For a review, see: Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036.
(7) For a comprehensive review, see: van Otterlo, W. A. L.;
de Koning, C. B. Chem. Rev. 2009, 109, 3743. See also: Fujimura, O.;
Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029. Yoshida, K.;
Kawagoe, F.; Hayashi, K.; Horiuchi, S.; Imamoto, T.; Yanagisawa, A.
Org. Lett. 2009, 11, 515.
r
10.1021/ol103088r
Published on Web 01/26/2011
2011 American Chemical Society

Scheme 1. Olefin CM for the Synthesis of Pyridines
Scheme 2. Substituted Pyridines via Enone-Enone CM
particular, protocols based upon ring-closing olefin me-
tathesis (RCM) provide efficient access to a range of
heteroaromatic classes.8 Most recently, we have applied
the powerful olefin cross-metathesis process (CM)9 to the
synthesisof heteroaromatic derivativesand reported meth-
ods for the synthesis of di- and trisubstituted furans and
pyrroles.10 An attractive aspect of CM-based strategies
resides in the utilization of metathesis for both convergent
fragment coupling and provision of unsaturation for the
aromatic target. Herein, we report an extension of this
concept to the synthesis of pyridines.
Our approach to pyridines involves an olefin CM-based
protocol for the synthesis of substituted R,β-unsaturated
1,5-dicarbonyl derivatives 3 (Scheme 1). These are as-
sembled from homoallylic alcohol precursors 1 by oxida-
tion and then olefin CM with an R,β-enone component 2.
Alternatively, inversion of the alcohol oxidation and
CM events provides equally concise access to 3. Treatment
with ammonia then converts the 1,5-dicarbonyl intermedi-
ate 3 directly to the pyridine target.11 Modification of
3 through enolate chemistries enables access to higher
substitution patterns. In all cases, the CM sequence allows
the combination of simple precursors and reactions to
provide complex pyridines with high levels of substitution
and regiocontrol.
Our initial investigations centered upon the CM of β,
γ-enones with R,β-enones to afford the required 1,5-dicar-
bonyl derivatives directly (Scheme 2). Under optimized
conditions, the CM of β,γ-enone 5 with methyl vinyl ketone
proceeded in 73% yield using the Zhan 1B catalyst.12 The
dicarbonyl intermediate 6, formed as an inconsequential
mixture of alkene regioisomers, was then converted to
the pyridine 7 upon exposure to NH4OAc under mildly
acidic conditions. This chemistry provides a general meth-
od for the introduction of substituents at the 2- and
6-positions of the pyridine ring, although extension to
more highly substituted variants was problematic. For
example, CM of sterically encumbered β,γ-enone 11 with
methyl vinyl ketone afforded dicarbonyl 12 in 14% yield;
these inefficiencies prompted the investigation of alterna-
tive reaction sequences.
Olefins bearing proximal alcohol groups have emerged
as a special substrate class for CM. Enhanced levels of
reaction efficiency may be due to hydrogen bonding
between thehydroxyl groupand the chloride ligandsonthe
metathesis catalyst.13 Accordingly, CM of homoallylic
alcohol 14 with methyl vinyl ketone was efficient, and
upon completion,11 Dess-Martin periodinane (DMP)
was added to the reaction to afford the dicarbonyl 9 in
one pot (Scheme 3: compare the CM of 4 and 11 to that of
4 and 18). As before, conversion to pyridine 10 occurred with
NH4OAc.11 Extension to more highly substituted deriva-
tives, based upon more complex homoallylic alcohols,
(8) Donohoe, T. J.; Bower, J. F.; Basutto, J. A.; Fishlock, L. P.;
Procopiou, P. A.; Callens, C. K. A. Tetrahedron 2009, 65, 8969.
Donohoe, T. J.; Fishlock, L. P.; Basutto, J. A.; Bower, J. F.; Procopiou,
P. A.; Thompson, A. L. Chem. Commun. 2009, 3008. Donohoe, T. J.;
Kershaw, N. M.; Orr, A. J.; Wheelhouse (nee Gosby), K. M. P.; Fishlock,
L. P.; Lacy, A. R.; Bingham, M.; Procopiou, P. A. Tetrahedron 2008, 64,
809. Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10,
285.
(9) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J.
Am. Chem. Soc. 2003, 125, 11360. Morrill, C.; Funk, T. W.; Grubbs,
R. H. Tetrahedron Lett. 2004, 45, 7733. Stewart, I. C.; Douglas, C. J.;
Grubbs, R. H. Org. Lett. 2008, 10, 441. For a recent review, see: Nolan,
S. P.; Clavier, H. Chem. Soc. Rev. 2010, 39, 3305.
(10) Donohoe, T. J.; Bower, J. F. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 3373. Donohoe, T. J.; Race, N. J.; Bower, J. F.; Callens, C. K. A.
Org. Lett. 2010, 12, 4094. See also: Shafi, S.; Ke-dziorek, M.; Grela, K.
Synlett 2011, 124.
(11) This transformation is well established. For a recent example,
see: Tokuji, S.; Takahashi, Y.; Shinmori, H.; Shinokubo, H.; Osuka, A.
Chem. Commun. 2009, 1028.
(12) Zhan, Z.-Y. J. U.S. Patent, 2007, 20070043180; this catalyst is
commercially available. It was necessary to use 5 equiv of the enone
component to ensure maximum yields from the CM reaction.
(13) Hoveyda, A. H.; Lombardi, P. J.; O’Brien, R. V.; Zhugralin,
A. R. J. Am. Chem. Soc. 2009, 131, 8378.
Org. Lett., Vol. 13, No. 5, 2011
1037

Scheme 3. Substituted Pyridines via Homoallylic Alcohol-Enone CM
a Hoveyda-Grubbs II catalyst was used at 80 °C in PhMe.
meant that mono-, di-, and trisubstituted pyridines could
be prepared. This methodology is efficient for the intro-
duction of alkyl and aryl groups onto the pyridine and also
allows the introduction of heteroatom groups such as
alkoxy substituents (31).
Scheme 4. Substituted Pyridines via Acetal CM
The formation of pyridines without a substituent at R5 is
more challenging as the requisite aldehydic unsaturated
1,5-dicarbonyl intermediates were found to be sensitive to
purification. However, cross-metathesis of, for example, 8
with acrolein diethylacetal 3514 was reasonably efficient
and afforded intermediate 36 which, upon exposure to
NH4OAc, delivered monosubstituted pyridine 37 in good
yield (Scheme 4).
Similarly, CM of β,γ-enone 11 with vinyldioxolane 38
(this CM partner was less sensitive to steric hindrance)
afforded 2,3-disubstituted pyridine 40. Here, oxidation to
the β,γ-enone prior to CM was more efficient than oxida-
tion after CM of the analogous homoallylic alcohol.
Tetrasubstituted pyridines are not directly attainable via
this methodology due to inefficiencies associated with the
demanding CM of 1,1-disubstituted olefins. Trisubstituted
R,β-unsaturated 1,5-dicarbonyl intermediates (formed via
the CM-oxidation sequence) are, however, readily ma-
nipulated to allow the eventual installation of an extra
substitutent onto the pyridine core (Scheme 5). For exam-
ple, Pd-catalyzed R-arylation of 12, 20, and 23 with a range
of aryl bromides afforded, after exposure of the products
to NH4OAc, diverse tetrasubstituted pyridines 41-44 bear-
ingarylmoietiesatC(5).15 Single regioisomers were obtained
from the R-arylation event, and Heck arylation of the olefinic
moiety was not observed; the structures of both 42 and 43
were confirmed by X-ray crystallographic analysis. Similarly,
base-promoted alkylation of the dicarbonyl derivative
(14) O’Leary, D. J.; Blackwell, H. E.; Washenfelder, R. A.; Miura,
K.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 1091. An excess of the
acetal component was required to maximize the yield of cross-metath-
esis.
(15) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010,
49, 676. Hama, T.; Hartwig, J. F. Org. Lett. 2008, 10, 1545.
1038
Org. Lett., Vol. 13, No. 5, 2011

Scheme 5. R-Functionalization of R,β-Unsaturated 1,5-Dicar-
bonyl Intermediates
Scheme 6. Intramolecular “CM-Based” Approach to Muscopyridine
shown proceeds in 17% yield over eight steps and com-
pares well to the most efficient asymmetric syntheses
reported to date.20
The olefin CM reaction provides a straightforward
method for the synthesis of R,β-unsaturated 1,5-dicar-
bonyl derivatives which then serve as effective precursors
to mono-, di-, and trisubstituted pyridines. Tetrasubstituted
pyridines are available via further manipulation of the
key 1,5-dicarbonyl intermediate. A related intramolecular
strategy facilitates the preparation of pyridines embedded
within macrocycles, as exemplified by a highly efficient
synthesis of (R)-(þ)-muscopyridine. High levels of regio-
control, short reaction sequences, and facile substituent
variation are all notable aspects of this pyridine methodol-
ogy. Consequently, this chemistry provides an attractive
strategy for medicinal chemistry applications.
12 ultimately provided pyridine 45 bearing an alkyl group
at C(5). It is important to note that the transformations
outlined in Scheme 5 are representative of a much broader
range of potential manipulations for the introduction of
extra substituents onto the pyridine target.
Further extension of this chemistry affords macrocyclic
pyridines, such as (R)-(þ)-muscopyridine,16 via utilization
of the key metathesis event for macrocyclization (Scheme 6).
Accordingly, Wadsworth-Emmons olefination of com-
mercially available undecenal provided acrylate 47 which
was subjected to asymmetric copper catalyzed addition of
a methyl Grignard to provide ester 48 in high yield and
with excellent levels of enantiopurity (g95% ee).17 This
intermediate was then advanced to the key metathesis
precursor 50 over four steps involving (i) Weinreb amide
formation,18 (ii) olefin epoxidation, (iii) double addition of
a vinyl Grignard, and (iv) Dess-Martin oxidation. Exposure
of 50 to the metathesis-based pyridine formation sequence,
but employing high dilution for the metathesis step, afforded
Acknowledgment. We thank the EPSRC for financial
support and the Oxford Chemical Crystallography Service
for use of instrumentation.
1
Supporting Information Available. Copies of H and
13C NMR spectra and experimental procedures are avail-
able. The structure of pyridines 7, 10, 13, 17, 27, 37, 40,
and (R)-(þ)-muscopyridine were determined by compar-
ison of the spectroscopic data reported in the literature.
The structure of pyridines 21, 34, 41, and 45 were deter-
mined by characteristic NOE enhancements. The struc-
ture of pyridines 42 and 43 were determined by X-ray
crystallographic analysis. The structure of pyridines 24,
31, 34, and 44 were assigned by analogy to the aforemen-
tioned compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
25
(R)-(þ)-muscopyridine {[R]D þ10.8 (c 0.5, CHCl3); lit.
23
[R]D þ12.5 (c 1.8, CHCl3)19} in 42% yield. An alternative
end game, involving macrocyclization of the corresponding
homoallylic alcohol, was less successful: while RCM was
efficient, the ensuing oxidation was problematic. The route
(16) Schinz, H.; Ruzicka, L.; Geyer, U.; Prelog, V. Helv. Chim. Acta
1946, 29, 1524.
(17) Wang, S.-Y.; Ji, S.-J.; Loh, T.-P. J. Am. Chem. Soc. 2007, 129,
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2008, 350, 673.
(18) Weinreb, S. M.; Nahm, S. M. Tetrahedron Lett. 1981, 22, 3815.
Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling,
U. H.; Grabowski, E. J. Tetrahedron Lett. 1995, 36, 5461.
(19) Hagiwara, H.; Katsumi, T.; Kamat, V. P.; Hoshi, T.; Suzuki, T.;
Ando, M. J. Org. Chem. 2000, 65, 7231.
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