Direct and regioselective c-h alkenylation of tetrahydropyrido[1,2-a] pyrimidines

Article abstract of DOI:10.1021/ol900627q

The electrophilic C-H palladation and Heck-type alkenylation of the tetrahydro[1,2-a]pyrimidine scaffold leads to exclusive formation of the C(7) adducts, and this palladium-catalyzed process is applicable to a broad range of alkenyl components. Mechanist

Full text of DOI:10.1021/ol900627q

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2639-2641
Direct and Regioselective C-H
Alkenylation of
Tetrahydropyrido[1,2-a]pyrimidines
Dachen Cheng and Timothy Gallagher*
School of Chemistry, UniVersity of Bristol, Bristol, BS8 1TS, United Kingdom
t.gallagher@bristol.ac.uk
Received March 25, 2009
ABSTRACT
The electrophilic C-H palladation and Heck-type alkenylation of the tetrahydro[1,2-a]pyrimidine scaffold leads to exclusive formation of the
C(7) adducts, and this palladium-catalyzed process is applicable to a broad range of alkenyl components. Mechanistic studies suggest that
palladation is selective for C(7), and there was no evidence for C(9) metalation; the latter corresponds to the pathway observed previously
with N-methylpyridone.
Bicyclic pyridones 1 belong to a class of pharmacologically
active heterocycles that have attracted attention initially as
potential analgesics and anti-inflammatory agents.1 More
recently, both Bayer AG2 and Amgen Inc.3 have disclosed
bicyclic pyridones analogous to 1 to be useful in the
prophylaxis and treatment of diseases mediated via TNF-R,
IL-1ꢀ, IL-6, and/or IL-8.
We have recently described two novel approaches to the
Figure 1. Target bicyclic pyridone scaffolds.
synthesis of the [5,6], [6,6], and [7,6] bicyclic pyridones
1a-c, respectively, which encompass versatile methods for
achieving aryl substitution within the pyridone ring of these
heterocyclic scaffolds (Figure 1).4
A key objective of our studies in this area was to define
flexible methods for the further substitution and functional-
ization of these bicyclic scaffolds, and while Suzuki arylation
was achieved, alkenylation (via a Heck or analogous process)
was more attractive given the significantly increased range
of functionality that Heck products offer. The advantages
of the Heck reaction lie in the use of a catalytic process to
introduce easily manipulated functionality (e.g., CdC, esters)
and low molecular weight units, but as with other Pd-
mediated couplings, this reaction usually also necessitates
participation of a haloarene (i.e., halopyridone) component.
Direct metalation (palladation) of C-H bonds5 associated
with (often but not exclusively) electron-rich arenes offers
a very effective alternative to halide-based Heck alkenylation
that has attracted widespread interest.6-8 Itahara’s work in
(1) Kubo, K.; Ito, N.; Isomura, Y.; Sozu, I.; Homma, H.; Murakami,
M. Chem. Pharm. Bull. 1979, 27, 1207. Kubo, K.; Ito, N.; Isomura, Y.;
Sozu, I.; Homma, H.; Murakami, M. Yakugaku Zasshi. 1979, 99, 880; Chem.
Abstr. 1980, 92, 58685t.
(2) Alonso-Alija, C.; Michels, M.; Schirok, H.; Schlemmer, K.-H.; Dodd,
S.; Fitzgerald, M.; Bell, J.; Gill, A. WO2003053967A1, 2003.
(3) Frohn, M. J.; Hong, F.-T.; Liu, L.; Lopez, P.; Siegmund, A. C.;
Tadesse, S.; Tamayo, N. WO 2005/070932A2, 2005.
(5) For pioneering work in this field, see: Moritani, I.; Fujiwara, Y.
Tetrahedron Lett. 1967, 1119. Fujiwara, Y.; Moritani, I.; Danno, S.; Asano,
R.; Teranishi, S. J. Am. Chem. Soc. 1969, 91, 7166. Jia, C.; Piao, D.;
Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992.
Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633.
(4) Cheng, D.; Croft, L.; Abdi, M.; Lightfoot, A.; Gallagher, T. Org.
Lett. 2007, 9, 5175.
10.1021/ol900627q CCC: $40.75
Published on Web 05/27/2009
 2009 American Chemical Society

the 1980s is particularly relevant here.7 For example,
alkenylation (using ethyl acrylate) of N-toluenesulfonyl
indole at C(3) was achieved using palladium(II) acetate (10
mol %) in combination with an excess of copper(II) acetate
as the reoxidant (to regenerate Pd(II) after the alkenylation
step). More recently, Gaunt8 has reported that regiocontrol
(C(2) vs C(3)) in the oxidative Heck alkenylation of indole
itself using butyl acrylate is solvent dependent; a switch from
C(3) (as observed by Itahara) to C(2) substitution was
achieved by changing the reaction medium from DMF/
DMSO to dioxane/acetic acid.
Scheme 1. Oxidative Heck Alkenylation of Bicycle 2a
The application of this C-H activation variant of the Heck
reaction to pyridones is, however, less straightforward.
Itahara applied direct C-H palladation and Heck alkenylation
to N-methyl-2-pyridone, and (using acrylates) the C(5)
adducts were the exclusive products (see below).7 However,
this chemistry reported use of stoichiometric amounts of
palladium(II) and failed for other (useful) alkenyl substrates,
such as styrene and methyl vinyl ketone. More recently, one
example of an oxidative Heck alkenylation (using catalytic
Pd(II)) of a dihydro-4-pyridone using methyl acrylate has
been described.9
Building on Itahara’s initial studies with N-methyl-2-
pyridone, we have sought to develop an efficient and
economical method for C-H palladation and functionaliza-
tion of bicyclic pyridones 1. Using N-benzylated tetrahy-
dropyrido[1,2-a]pyrimidine 2a as a representative substrate,
reaction with tert-butyl acrylate, a variety of alkenylation
conditions were examined (Scheme 1 and Table 1).
Optimal conditions proved to be palladium(II) acetate (5
mol %) and copper(II) acetate (200 mol %) in DMF for 10 h
at 90 °C (entry 3, Table 1), which gave the C(7)-substituted
adduct 3a in 93% yield. The impact of an acidic solvent
was also examined (entries 4-6, Table 1), but this only
resulted in slower and less efficient reactions; no change in
regiochemistry or product distribution was observed. Inter-
estingly, none of the isomeric C(9) adduct 4 was observed
under any of the conditions examined; this isomer corre-
sponds to the regioisomer observed by Itahara with N-methyl-
2-pyridone.7
The scope of this process (in terms of the range of
compatible alkenes) has been explored, and a series of C(7)
alkenylated adducts (3b-e, Figure 2) have been prepared
using ethyl acrylate, methyl vinyl ketone, styrene, and
2-cyclohenylethene, respectively. These reactions proceed in
good yield under essentially the same conditions as described
for 3a, and this is particularly noteworthy in the case of 3e,
which involves a simple alkyl-substituted alkene, which are
traditionally regarded as poor substrates for Heck reactions.
Interestingly, 2-vinylpyridine failed to give the expected
Heck adduct 3f, and based on Narahashi and Shimizu’s
earlier work, it is likely that palladation is followed by
formation of a stable chelate 5 (involving the pyridine lone
Table 1. Optimization of Oxidative Alkenylation of 2a
entrya
solvent
Pd(OAc)2 (x mol %) time (h) 3ab (%)
(6) For examples of Pd-mediated C-H activation and alkenylation of
aryl and heteroaryl substrates, see: Trost, B. M.; Godleski, S. A.; Genet,
J. P. J. Am. Chem. Soc. 1978, 100, 3930. Boele, M. D. K.; van Strijdonck,
G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.; van Leeuwen,
P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. Baran, P.; Corey, E. J.
J. Am. Chem. Soc. 2002, 124, 7904. Dams, M.; De Vos, D. E.; Celen, S.;
Jacobs, P. A. Angew. Chem., Int. Ed. 2003, 42, 3512. Ma, S.; Yu, S.
Tetrahedron Lett. 2004, 45, 8419. Capito, E.; Brown, J. M.; Ricci, A. Chem.
Commun. 2005, 1854. Wang, J.-R.; Yang, C.-T.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2007, 48, 5449. Cai, G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z.
J. Am. Chem. Soc. 2007, 129, 7666. Maehara, A.; Satoh, T.; Miura, M.
Tetrahedron 2008, 64, 5982. Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2008, 47, 6452. Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem.
Soc. 2008, 130, 9254. Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne,
M. R.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008,
130, 10066. Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
131, 5072.
1
2
3
4
5
6
DMF
DMF
DMF
AcOH
dioxane/AcOH
DMSO/AcOH
0
10
5
6
2
10
10
10
10
0
92
93
35
45
51
20
10
10
a No evidence was observed for formation of the C(9) adduct 4 under
any of these conditions. b Isolated yield.
(7) (a) Itahara, T. Chem. Commun. 1981, 254. (b) Itahara, T. Chem.
Commun. 1981, 859. (c) Itahara, T.; Kawasaki, K.; Ouseto, F. Bull. Chem.
Soc. Jpn. 1984, 57, 3488. (d) Itahara, T. J. Org. Chem. 1985, 50, 5272. (e)
Itahara, T.; Ouseto, F. Synthesis 1984, 488. (f) Itahara, T.; Kawasaki, K.;
Ouseto, F. Synthesis 1984, 236.
(8) Grimster, N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2005, 44, 3125. For analogous regioselectivity studies
associated with pyrroles and application to total synthesis, see: Beck, E. M.;
Grimster, N. P.; Hatley, R.; Gaunt, M. J. J. Am. Chem. Soc. 2006, 128,
2528. Beck, E. M.; Hatley, R.; Gaunt, M. J. Angew. Chem., Int. Ed. 2008,
47, 3004.
Figure 2. Alkenylation products derived from 2a.
(9) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008, 130,
3708.
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Org. Lett., Vol. 11, No. 12, 2009

1
Scheme 2
.
Oxidative Alkenylation: 2- vs 4-Vinylpyridine
Scheme 3. Palladation Pathway Observed by H NMR
Scheme 4. Failed Attempt To Trap a C(9)-Palladated Species
pair and the adjacent π-bond) that retard this process (Scheme
2).10 The corresponding 4-subsituted pyridine did, however,
give the expected Heck adduct 3g in 86% isolated yield.
Mechanistic options11 associated with this process have
also been studied. As pointed out above, increasing the
acidity of the solvent system (which has been associated with
the interconversion of σ-Pd intermediates) had no impact
on the distribution of regioisomers (entries 4-6, Table 1).
In our hands, the C(9) adduct was never detected, although
electrophilic halogenation of 2a (and 2b) does produce both
the C(7) and C(9) regioisomers.12
yields of the C(7) alkenylation products (i.e., 3) that we have
observed. Further support for a lack of involvement of a C(9)-
palladated species comes from a failure of the N-allylated variant
8 (prepared from 2b) to undergo an internal (5-exo) Heck
reaction14 (via 9) under these oxidative conditions (Scheme 4).
In summary, the oxidative Heck reaction which likely
involves initial and highly regioselective electrophilic pal-
ladation (given the electron-rich nature of 2a), provides a
robust, efficient and economical method for the functional-
ization of bicyclic pyridone scaffolds, as represented by
N-benzyltetrahydropyrido[1,2-a]pyrimidine 2a. The inter-
mediate σ-Pd species 6 has been characterized by 1H NMR
and regeneration of the key electrophilic Pd(II) reagent is
readily achieved using Cu(II) as oxidant.
The initial interaction of Pd(II) with 2a was examined by 1H
NMR (in DMSO-d6). Using 20 mol % of Pd(OAc)2, the
resulting spectrum showed formation of approximately 16% of
the C(7) σ-Pd species 6 (with the remainder being unreacted
2a) (Scheme 3). With 1 equiv of Pd(OAc)2 (and after 4 h), a
10:1 ratio of 6 to 2a was observed (see the Supporting
Information for details of assignments and copies of relevant
spectra). We obtained no evidence for the formation or
intermediacy of the C(9)-palladated adduct 7, although these
experiments cannot exclude involvement of this species.13
Nevertheless, if formed, 7 would need to be unstable with
respect to protiodemetalation in order to account for the high
(10) Narahashi, H.; Yamamoto, A.; Shimizu, I. Chem. Lett. 2004, 33,
348.
Acknowledgment. Financial support from the University
of Bristol is gratefully acknowledged.
(11) Various mechanistic possibilities exist for C-H activation with
Pd(II). These most frequently link electrophilic aromatic substitution to
electron-rich, π-excessive (hetero)arenes and, more recently, concerted
metalation-deprotonation for simple and electron-deficient arenes. For a
summary of mechanistic possibilities and leading references, see: Gorelsky,
S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008, 130, 10848.
(12) Reaction of 2a with NCS or NBS gave mixtures of C(7) and C(9)
regioisomers and C(7)/C(9) bishalogenation products: Cheng, D. Unpub-
lished results.
Supporting Information Available: . Experimental de-
1
tails and spectroscopic data for all new compounds and H
NMR studies relating to the regioselective palladation of 2a
are available. This material is available free of charge via
the Internet at http://pubs.acs.org.
(13) The possibility that the CdO group directs palladation at C(7) has
been rasied by a reviewer, and carbonyl directing effects have been recently
reported: Giri, R.; Yu, J.-Q J. Am. Chem. Soc. 2008, 130, 14082. Delcamp,
J. H.; Brucks, A. P.; White, C. M. J. Am. Chem. Soc. 2008, 130, 11270.
However, such a directing effect should also have operated in Itahara’s
work, but this does not appear to be the case.7
OL900627Q
(14) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
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