Synthesis of 2,4,6-trisubstituted pyridines via an olefin cross-metathesis/Heck-cyclisation-elimination sequence

Article abstract of DOI:10.1039/c1cc14257g

Heck reactions were performed on α,β-unsaturated-δ- sulfonamido intermediates, derived from cross metathesis, to allow the instalment of substituents at the β position. Subsequent one-pot cyclisation/elimination provides an operationally simple, catalytic and convergent synthesis of 2,4,6-trisubstituted pyridines.

Full text of DOI:10.1039/c1cc14257g

View Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 10611–10613
www.rsc.org/chemcomm
COMMUNICATION
Synthesis of 2,4,6-trisubstituted pyridines via an olefin cross-metathesis/
Heck–cyclisation–elimination sequencew
a
a
a
a
´
Timothy J. Donohoe,* John F. Bower, David B. Baker, Jose A. Basutto,
Louis K. M. Chana and Peter Gallagherb
Received 14th July 2011, Accepted 9th August 2011
DOI: 10.1039/c1cc14257g
Heck reactions were performed on a,b-unsaturated-d-sulfonamido
intermediates, derived from cross metathesis, to allow the
instalment of substituents at the b position. Subsequent one-pot
cyclisation/elimination provides an operationally simple, catalytic
and convergent synthesis of 2,4,6-trisubstituted pyridines.
Substituted pyridines are a unique class of compounds that
feature heavily in several pharmaceutical targets, as well as
being a common motif in many natural products.1 In addition,
many ligands used in transition metal catalysis also contain
substituted pyridines.2 Consequently, a range of de novo
methods for pyridine synthesis have emerged.3,4 As a counter-
point to this approach, methods for the functionalisation of
existing pyridines are also well documented.5 Recently de-
scribed methods for the catalytic direct functionalisation of
pyridine and its derivatives have also proved attractive but are
mainly limited to the C-2 and C-3 positions,6 although an
isolated example has been reported for the direct functionali-
sation of pyridines at the C-4 position.7
We have previously demonstrated that a disconnection
using a tandem cross metathesis (CM)/Heck coupling could
Scheme 1 Cross metathesis approach for the synthesis of unsymmetrical
provide a facile entry into highly substituted furans and
pyrroles.8 Extension of this strategy should also provide a
regio-controlled, catalytic route to multi-substituted pyridines
in a convergent manner (Scheme 1a). Recent work in our
laboratory has demonstrated that using the CM between
I and II could provide 1,5-dicarbonyl intermediates III (Scheme 1b).
Further functionalisation using a Pd catalysed a-arylation
reaction led to a short route into 2,3,5,6-tetrasubstituted
pyridines IV.9 However, the introduction of a substituent at
C-4 was not possible via this chemistry. We were interested in
further investigating the utility of the CM-based approach for
synthesising pyridines with different substitution patterns,
especially those allowing access to the C-4 position.
2,4,6-trisubstituted pyridines.
With this goal in mind, we envisaged that the CM between
homoallylic sulfonamides 1 with vinyl ketones 2 would provide
a,b-unsaturated-d-sulfonamido ketones 3, as key synthetic
intermediates for elaboration (Scheme 1c). Further functiona-
lisation using the Heck reaction should allow the introduction
of substitution at the 4-position. Therefore, the proposed route
provides a complementary substitution pattern around the
pyridine ring when compared to our previous work. Note that the
success of this method relies on the well-established inversion
of the double bond geometry during the Heck reaction to
provide a ‘(Z)’-trisubstituted alkene 5 (Scheme 1d).10 Cyclisa-
tion promoted by acidic conditions should take place to
form 6 and subsequent elimination of sulfinate would allow
the formation of the desired trisubstituted pyridines.11
a Department of Chemistry, University of Oxford, Chemistry Research
Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
E-mail: timothy.donohoe@chem.ox.ac.uk;
We were pleased to find that cross metathesis using the air
stable Hoveyda–Grubbs 2nd generation (H-G II) catalyst with
homoallylic sulfonamide 1a and methyl vinyl ketone 2a
afforded 3a. It was found that 7.5 mol% of H-G II catalyst
with 5 equivalents of the vinyl ketone 2a were optimal to drive
the formation of the CM product (Scheme 2, entry 1).12 It was
Tel: +44 (0) 1865 275649
b Eli Lilly Ltd., Erl Wood Manor, Sunninghill Road, Windlesham,
Surrey GU20 6PH, UK
w Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra and experimental procedures are available.
CCDC 834833. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc14257g
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10611–10613 10611

View Online
Scheme 2 Cross metathesis of 1a and 2a.
possible to obtain as good yields of the CM product by either
lowering the catalyst loading to 3 mol% or reducing the
stoichiometry of 2a, but longer reaction times were required
(entries 2 and 3).
Upon examining the scope of the Heck reaction, it was
found that electron neutral (4a,b), electron rich (4c) and
electron deficient (4d–f) aryl bromides worked well in the Heck
reaction (Scheme 3).z Typical conditions for the Heck reaction
require 5 mol% of Pd2(dba)3 and 20 mol% P(t-Bu)3HBF4, as a
monodentate bulky electron rich ligand.13 The cyclisation/
elimination procedure was also optimised such that upon
completion of the Heck reaction by TLC analysis, sequential
addition of trifluoroacetic acid (TFA) and then 1,8-diazabi-
cycloundec-7-ene (DBU) would furnish directly the desired
pyridines conveniently in a one-pot process, without the need
to isolate the intermediates 5 or 6.14 We were delighted to find
that heteroaromatics such as N-methylindole also underwent
the one-pot Heck/cyclisation/elimination to give 4g in a
respectable 65% yield.
Despite the extensive use of vinyl halides in Pd(0) catalysed
cross coupling reactions, we were surprised to find that only
limited examples of intermolecular Heck reactions have been
reported using vinyl halides.15 Our efforts into effecting a
one-pot pyridine formation from 3a that involves a vinyl
substitution at the C-4 position were not successful. However,
a low yield of the Heck intermediate 5h could be isolated.
Cyclisation/elimination to give 4h were also performed but
Scheme 4 Scope of the R2 and R6 components in the pyridine
a
formation. 10 mol% Pd2(dba)3, 40 mol% P(t-Bu)3HBF4 were used.
again a poor yield was obtained. Thus, at the current time the
introduction of substitution at C-4 is most effective with
aromatic groups.
To further expand the utility of this reaction, a range of homo-
allylic sulfonamides 1a–i were subjected to CM with different vinyl
ketones 2a–c (Scheme 4). We found that CM reactions under these
conditions are highly reliable and gave good to excellent yields of
3i–r.16 When the optimised one-pot procedure (steps 2–4) was carried
out with bromotoluene as the Heck coupling partner, we found that
intermediates with aryl (3i–k) and ester (3l) moieties as the R2
component worked well in the Heck reaction/cyclisation/elimination
reaction to furnish 4i–l in moderate to good yields over three steps.17
Surprisingly, when the R6 substituents on 3m were bulky
aliphatic or aryl components, it was found that the Heck/
cyclisation sequence became very stubborn.18 Lower yields of
4m were obtained despite increased loading of the catalyst
(Scheme 4). In order to overcome this problem, bulky aliphatic
groups could be installed as the R2 components instead. We
were pleased to find that the Heck reaction/cyclisation (steps 2
and 3) with R2 = n-alkyl (3n,o) and s-alkyl (3p–r) all worked
well to furnish 6n–r in good yields. Due to the absence of a
neighbouring trigonal centre in these cases, R2 does not benefit
from a lowered pKa (in 6n–r) and so the elimination (step 4)
was modified such that upon isolation of 5n–r, treatment with
either KHMDS/toluene or KOH/EtOH gave the desired
trisubstituted pyridines in good yields.
We have successfully extended our investigation into using a
cross metathesis approach for the synthesis of heteraromatics
Scheme 3 Scope of the one-pot Heck-reaction/cyclisation/elimination
on 3a. a10 mol% Pd2(dba)3, 40 mol% P(t-Bu)3HBF4 were used.
c
10612 Chem. Commun., 2011, 47, 10611–10613
This journal is The Royal Society of Chemistry 2011

View Online
and a representative library of unsymmetrical 2,4,6-trisub-
stituted pyridines has been synthesised. Problems with C-4
functionalisation that we have previously encountered were
overcome using a Heck reaction following the cross metathesis.
Such key catalytic carbon–carbon bond formation steps
(CM and Heck) described herein provide a simple, convergent
and regio-controlled synthesis.
(e) A. M. Berman, J. C. Lewis, R. G. Bergman and J. A. Ellman,
J. Am. Chem. Soc., 2008, 130, 14926; (f) Y. Nakao, K. S. Kanyiva
and T. Hiyama, J. Am. Chem. Soc., 2008, 130, 2448.
7 Y. Nakao, Y. Yamada, N. Kashihara and T. Hiyama, J. Am.
Chem. Soc., 2010, 132, 13666.
8 (a) T. J. Donohoe and J. F. Bower, Proc. Natl. Acad. Sci. U. S. A.,
2010, 107, 3373; (b) T. J. Donohoe, N. J. Race, J. F. Bower and
C. K. A. Callens, Org. Lett., 2010, 12, 4094; (c) T. J. Donohoe,
J. F. Bower and J. A. Basutto, Nat. Protoc., 2010, 5, 2005.
9 T. J. Donohoe, J. A. Basutto, J. F. Bower and A. Rathi, Org. Lett.,
2011, 13, 1036.
The authors would like to thank the EPSRC and Eli Lilly
Ltd. for financial support.
10 (a) Geometric inversion of the alkene during the Heck reaction has
previously been reported: A. F. Littke and G. C. Fu, J. Am. Chem.
Soc., 2001, 123, 6989; (b) NOE experiments from our previous
work also proved that inversion occurs under the Heck reaction to
allow cyclisation to form furans: see ref. 8a.
Notes and references
z Single crystal diffraction data for 4f were collected at 150 K19 using a
Nonius Kappa CCD Diffractometer (l = 0.71073 A). Data were
reduced using DENZO/SCALEPACK.20 The structure was solved
with SuperFlip21 and refined by full-matrix least squares on F2 using
CRYSTALS.22 All non-hydrogen atoms were refined with anisotropic
displacement parameters and hydrogen atoms were treated in the
usual manner.23 See ESIw for full refinement details; CCDC 834833.
11 (a) L. Alcaraz, J. J. Hamett, C. Mioskowski, J. P. Madel, T. Le
Gall, D.-S. Shin and J. R. Falck, Tetrahedron Lett., 1994, 35, 5449;
(b) A. Fustner, M. D. B. Fenster, B. Fasching, C. Godbout and
¨
K. Radkowski, Angew. Chem., 2006, 118, 5636 (Angew. Chem., Int.
Ed., 2006, 45, 5510).
12 A. K. Chatterjee, T.-L. Choi, D. P. Sanders and R. H. Grubbs,
J. Am. Chem. Soc., 2003, 125, 11360.
13 G. C. Fu, Acc. Chem. Res., 2008, 41, 1555.
14 Intermediates associated with the synthesis of 4a (5a and 6a) were
isolated. See ESIw for full characterisation details.
15 Examples found upon a literature survey: (a) L. Liao, R. Jana,
K. B. Urkalan and M. S. Sigman, J. Am. Chem. Soc., 2011,
133, 5784; (b) Z. Owczarczyk, F. Lamaty, E. Vawter and
E. Negishi, J. Am. Chem. Soc., 1992, 114, 10091; (c) L. Harris,
K. Jarowicki, P. Kocienski and R. Bell, Synlett, 1996, 903;
%
Single crystal data: C19H14N2O6, Mr = 270.33, triclinic, P1. a =
8.0582(2) A, b = 9.9181(3) A, c = 9.9557(3) A, a = 62.2103(15)1, b =
85.9715(14)1, g = 87.9363(12)1, V = 702.17(4) A, data/restraints/
parameters—3194/0/190, Rint = 0.019, final R1 = 0.0431, wR2 =
0.1084 (I 4 2s(I)), Drmin,max = ꢀ0.22, +0.29 e A3.
1 (a) Pharmaceutical Chemistry. Drug Synthesis, ed. H. J. Roth and
A. Kleemann, Prentice Hall Europe, London, vol. 1, 1988, p. 407;
´
(b) V. Bonnet, F. Mongin, F. Trecourt, G. Breton, F. Marsais,
P. Knochel and G. Queguiner, Synlett, 2002, 1008.
2 For representative reviews: (a) G. Chelucci, Chem. Soc. Rev., 2006,
35, 1230; (b) C. G. Arena and G. Arico, Curr. Org. Chem., 2010,
14, 546; (c) A. von Zelewsky, Coord. Chem. Rev., 1999, 190, 811.
3 For reviews of pyridine synthesis: (a) G. D. Henry, Tetrahedron,
2004, 60, 6043; (b) M. Hill, Chem.–Eur. J., 2010, 16, 12052; (c) For
a representative de novo method: O. G. Dediu, N. A. M. Yehia,
(d) T. Frenzel, M. Brunjes, M. Quitschalle and A. Kirschning,
¨
Org. Lett., 2006, 8, 135.
16 See ESIw for results with lower catalyst/vinyl ketone loadings.
17 The structure of pyridine 4l was confirmed by characteristic NOE
enhancements. See ESIw for full details.
18 Despite an efficient cross metathesis (step 1), our efforts to
persuade other substrates to undergo a one pot Heck (step 2) and
cyclisation (step 3) resulted either in low conversion or decomposi-
tion. Ongoing work to widen the scope will be reported in due
course
T. Oeser, K. Polborn and T. J. J. Muller, Eur. J. Org. Chem., 2005,
1834.
¨
4 For ring closing metathesis based syntheses of heteroaromatic
compounds: (a) T. J. Donohoe, J. F. Bower, J. A. Basutto,
L. P. Fishlock, P. A. Procopiou and C. K. A. Callens, Tetrahedron,
2009, 65, 8969; (b) T. J. Donohoe, L. P. Fishlock, J. A. Basutto,
J. F. Bower, P. A. Procopiou and A. L. Thompson, Chem.
Commun., 2009, 3008; (c) K. Yoshida, F. Kawagoe, K. Hayashi,
S. Horiuchi, T. Imamoto and A. Yanagisawa, Org. Lett., 2009,
11, 515; (d) T. J. Donohoe, N. M. Kershaw, A. J. Orr, K. M.
P. Wheelhouse (nee Gosby), L. P. Fishlock, A. R. Lacy,
M. Bingham and P. A. Procopiou, Tetrahedron, 2008, 64, 809;
(e) T. J. Donohoe, L. P. Fishlock and P. A. Procopiou, Org. Lett.,
2008, 10, 285; (f) O. Fujimura, G. C. Fu and R. H. Grubbs, J. Org.
Chem., 1994, 59, 4029; (g) For a review: W. A. L. van Otterlo and
C. B. de Koning, Chem. Rev., 2009, 109, 3743.
5 For a recent report: M. Jaric, B. A. Haag, S. M. Manolikakes and
P. Knochel, Org. Lett., 2011, 13, 2306 and references therein.
6 For recent representative examples: (a) M. C. Ye, G. L. Gao and
J. Q. Yu, J. Am. Chem. Soc., 2011, 133, 6964; (b) R. E. Beveridge
and B. A. Arndtsen, Synthesis, 2010, 1000; (c) J. J. Mousseau,
J. A. Bull and A. B. Charette, Angew. Chem., Int. Ed., 2010,
49, 1115; (d) H.-Y. Sun, S. I. Gorelsky, D. R. Stuart,
L.-C. Campeau and K. Fagnou, J. Org. Chem., 2010, 75, 8180;
.
19 J. Cosier and A. M. Glazer, J. Appl. Crystallogr., 1986, 19, 105.
20 Z. Otwinowski and W. Minor, Processing of X-ray diffraction data
collected in oscillation mode, ed. C. W. Carter and R. M. Sweet,
Methods Enzymol., 1997, 276, Academic Press.
21 L. Palatinus and G. Chapuis, J. Appl. Crystallogr., 1997, 40, 786.
22 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout and
D. J. Watkin, J. Appl. Crystallogr., 2003, 36, 1487.
23 R. I. Cooper, A. L. Thompson and D. J. Watkin, J. Appl. Crystal-
logr., 2010, 43, 1100.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10611–10613 10613