Synthesis of 2-substituted pyridines via a regiospecific alkylation, alkynylation, and arylation of pyridine N-oxides

Article abstract of DOI:10.1021/ol070184n

Figure presented Sequential addition of Grignard reagents to pyridine N-oxides in THF at room temperature followed by treatment with acetic anhydride at 120°C afforded 2-substituted pyridines in good to high yields. Furthermore, by exchanging acetic anhydride for DMF in the second step, 2-substituted pyridine N-oxides were obtained, as intermediates suitable for addition of a second Grignard reagent for the synthesis of 2,6-disubstituted pyridines.

Full text of DOI:10.1021/ol070184n

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1335-1337
Synthesis of 2-Substituted Pyridines via
a Regiospecific Alkylation, Alkynylation,
and Arylation of Pyridine N-Oxides
Hans Andersson,† Fredrik Almqvist,*,† and Roger Olsson*,‡
Department of Chemistry, Umeå UniVersity, SE-901 87 Umeå, Sweden, and
ACADIA Pharmaceuticals AB, Medeon Science Park S-20512, Malmo¨, Sweden
fredrik.almqVist@chem.umu.se; roger@acadia-pharm.com
Received January 24, 2007
ABSTRACT
Sequential addition of Grignard reagents to pyridine N-oxides in THF at room temperature followed by treatment with acetic anhydride at
120 C afforded 2-substituted pyridines in good to high yields. Furthermore, by exchanging acetic anhydride for DMF in the second step,
°
2-substituted pyridine N-oxides were obtained, as intermediates suitable for addition of a second Grignard reagent for the synthesis of 2,6-
disubstituted pyridines.
Herein, we report on the transition-metal free regiospecific
synthesis of 2-substituted alkyl, alkynyl, and arylpyridines,
a class of compounds prominent in medicinal chemistry and
materials.1 Sequential addition of Grignard reagents to
pyridine N-oxides followed by treatment of the resulting 2,4-
dienal oximes2 with acetic anhydride affords a range of
2-substituted pyridines in good to high yields (eq 1). In 1965,
Kato reported the reaction of pyridine N-oxides with phen-
ylmagnesium bromide as the sole reagent, giving 2-phen-
The addition of organometallic reagents to acyl- and alkyl-
ylpyridine in 43% yield via a 1,2-dihydropyridine interme-
activated pyridines has been developed into an expedient
diate.2b The 4-methyl-2-phenylpyridine was reported in 23%
method for the synthesis of substituted pyridines. However,
yield. Interested in the stereospecificity, Kellogg revisited
the formation of isomeric mixtures of 2- and 4-substituted
the reaction and found it to proceed via a ring-opened 2,4-
products has limited the application of this methodology.
dienal oxime intermediate; however, the subsequent 2-arylpy-
Although some selective additions to the 4-position have
ridines formed were reported in yields below 24%.2c
been achieved,3 additions to the 2-positions have only been
synthetically useful when the 4-position is blocked.4 Re-
cently, Fagnou and co-workers published the Pd-catalyzed
direct arylation of pyridine N-oxides followed by a Pd-
catalyzed reduction reaction with ammonium formate yield-
† Umeå University.
‡ ACADIA Pharmaceuticals AB.
(1) (a) Abass, M. Heterocycles 2005, 65, 901. (b) Henry, G. D.
Tetrahedron 2004, 60, 6043. (c) Fang, A. G.; Mello, J. V.; Finney, N. S.
Org. Lett. 2003, 5, 967. (d) Davies, I. W.; Marcoux, J. F.; Reider, P. J.
Org. Lett. 2001, 3, 209.
(2) (a) Andersson, H.; Wang, X.; Bjo¨rklund, M.; Olsson, R.; Almqvist,
F. Manuscript. (b) Kato, T.; Yamanaka, H. J. Org. Chem. 1965, 30, 910.
Kato, T.; Yamanaka, H.; Adachi, T.; Hiranuma, H. J. Org. Chem. 1967,
32, 3788. (c) Kellogg, R. M.; Van Bergen, T. J. J. Org. Chem. 1971, 36,
1705.
(3) (a) Wang, X.; Kauppi, A. M.; Olsson, R.; Almqvist, F. Eur. J. Org.
Chem. 2003, 4586. (b) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982,
47, 4315.
(4) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27, 2219.
10.1021/ol070184n CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/01/2007

ing 2-arylpyridines in good to high yields (64-86%) based
on the arylbromide; however, 4 equiv of the pyridine N-oxide
was used in the reaction.5 The availability of the pyridine
N-oxide could be the limiting starting material, even though
there is a wealth of commercially available pyridine N-
oxides.
In our previous report on the synthesis of 2,4-dienal
oximes, the fast addition of the Grignard reagents to the
pyridine N-oxide THF solution was identified to be key for
achieving high yields of the dienal oxime.2a A range of alkyl,
aryl, and alkynyl Grignard reagents were added to pyridine
N-oxides in THF. After consumption of the pyridine N-oxide,
a liquid-liquid extractive workup followed by dissolving
the residue in Ac2O and further heating under microwave
conditions (120 °C, 4 min) afforded 2-substituted pyridines
in good to high yields (37-86%, Table 1).6 The unsubstituted
by adding the corresponding Grignard reagents to pyridine
N-oxides (1a-d). Complete consumption of the pyridine
N-oxide was achieved with aryl, heteroaryl, and alkynyl
Grignards. However, alkyl Grignards resulted at best in only
modest yields of 38%, 45%, and 37% of pyridines 2d, 2l,
and 2m, respectively, by increasing the amount of Grignard
reagent to 2 equiv; beyond that, no improvement was seen.
The starting materials, pyridine N-oxides, were isolated in
around 40% yields. Starting out with 4-substituted pyridine
N-oxides 1b-d yielded the 2,4-disubstituted pyridines 2e-n
(entries 5-15, Table 1). Substituted 4-chloropyridines are
predisposed for further transformations such as nucleophilic
substitutions and cross-couplings. A limitation using this
strategy for the synthesis of substituted pyridines is the
availability of substituted 4-chloropyridines. The 74% yield
achieved with 4-chloropyridine N-oxide (1d) is an improve-
ment compared to the published 55% yield using phenoxy-
carbonyl-activated 4-chloropyridine (entry 15, Table 1).7
Conventional heating in the second step and cyclizing the
dienal oxime gave a comparable yield to that using micro-
wave heating (compare entries 5 and 6, Table 1).
Table 1. Synthesis of 2-Substituted and 2,4-Disubstituted
Pyridinesa
2-Substituted pyridine N-oxides have one less reactive
R-site (i.e., 2- and 6-postions) that potentially could drive
the reaction to give 4-substituted products. Phenylmagnesium
chloride was added to 2-methyl pyridine N-oxide 1e, and
the 2,6-disubstituted pyridine 2o was formed in high yield
(87%). The 2,4-substituted pyridine was not observed which
is the major isomer formed using acylpyridinium salts3b
(Scheme 1). This method is an alternative to using 2-halo-
entry
R1 (N-oxide)
R2
product
yieldb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H (1a)
H (1a)
H (1a)
H (1a)
Ph
2a
2b
2c
2d
2e
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
63%
83%
83%
38%
86%
81%c
75%
78%
86%
73%
82%
79%
45%
37%
74%
p-MeOPh
p-MePh
Bn
Scheme 1. Synthesis of 2,6-Disubstituted Pyridines
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
BnO (1c)
BnO (1c)
BnO (1c)
BnO (1c)
Cl (1d)
Ph
Ph
naphthalen-2-yl
PhCC
cy-propylCC
thiophen-2-yl
Ph
naphthalen-2-yl
iso-propyl
Me
pyridines and a Pd catalyst published by Wolf (2-Br, 61%
yield)8 and Knochel (2-Cl, 96% yield).9
Ph
Having established that the two-step protocol worked with
unsubstituted as well as with 2- and 4-substituted pyridine
N-oxides, 3-substituted pyridine N-oxides were reacted using
the developed conditions (Scheme 2). Interestingly, the 2,4-
dienal intermediate was not formed by adding Grignard
reagents to 3-substituted pyridine N-oxides. The correspond-
ing 2,3-disubstituted pyridine was formed directly. Addition
to the 3-methyl derivative 1f gave the sterically more
congested 2,3-disubstituted pyridine 2p as the major product
in moderate 43% yield but with excellent selectivity; the
minor 2,5-disubstituted isomer was formed in trace amounts.
Interestingly, although smaller Grignard reagents (e.g.,
a
Conditions: (1) pyridine N-oxide (1 equiv), Grignard reagents (1.5
b
equiv) in THF at 25 °C. (2) Ac2O, 120 °C, 4 min. Isolated yields, two
steps. Conventional heating at 120-140 °C for 1 h.
c
N-oxide 1a, having the potential of forming 4-addition
products, yielded exclusively 2-substituted pyridines (entries
1-4, Table 1). Both the p-MeOPh derivative 2b and p-MePh
2c were isolated in the same high yield (83%), and the
p-MePh 2c result was comparable with the 86% yield
reported by using direct arylation.5 In addition to 2-arylpy-
ridines (entries 1-7, 11, 12, and 15; Table 1), 2-alkynyl
(entries 8 and 9, Table 1), heteroaryl (entry 10, Table 1),
and alkyl (entries 4, 13, and 14; Table 1) were also accessible
(7) (a) Comins, D. L.; Mantlo, N. B. J. Org. Chem. 1985, 50, 4410. (b)
Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697. (c) Karig, G.; Spencer,
J. A.; Gallagher, T. Org. Lett. 2001, 3, 835.
(5) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020.
(6) Exothermic onset temperature (T0) for pyridine N-oxide is 288 °C.
(8) Wolf, C.; Lerebours, R. J. Org. Chem. 2003, 68, 7551.
(9) Bonnet, V.; Mongin, F.; Trecourt, F.; Queguiner, G.; Knochel, P.
Tetrahedron 2002, 58, 4429.
1336
Org. Lett., Vol. 9, No. 7, 2007

was dissolved in DMF and heated to give the 2-phenyl
pyridine N-oxide 1h in 86% yield. A subsequent phenyl-
magnesium chloride addition to pyridine N-oxide 1h yielded
the 2,6-diphenyl-substituted pyridine 2r in 73% yield (Scheme
3). However, addition of p-tolylmagnesium chloride to 1h
Scheme 2. Synthesis of 2,3-Disubstituted and
2,3,5-Trisubstituted Pyridines
Scheme 3. Sequential Addition to Pyridine N-Oxide
ethylmagnesium chloride) when added to acyl pyridinium
salts have been reported to preferentially add to the 2-position
and not to the less-hindered 6-position, using the larger
phenylmagnesium halides, 6-substitution predominates over
2-substitution.10 This is a diversification from our results that
gives practically only the 2-substituted product. However,
more importantly, an isomeric mixture of 2-, 4-, and
6-substituted products is formed using acyl-activated py-
ridines. The 3,5-dimethyl-substituted pyridine N-oxide 1g
gave the 2,3,5-trisubstituted pyridine 2q in excellent 91%
yield.
furnished the 2,6-unsymmetrical substituted pyridine 2s in
63% yield.
The sequential synthesis of unsymmetrical 2,6-disubsti-
tuted pyridines from the symmetrical ones has been scarcely
reported, and the few examples reported so far have mostly
relied on the 2,6-dihalo pyridines.11 Pyridine N-oxides are
easily synthesized by a number of methods12 which would
open up for the use of 2-substituted pyridines (e.g., see
Scheme 1) in the synthesis of 2,6-disubstituted pyridines.
However, forming the pyridine N-oxide directly from the
2,4-dienal oxime formed after the first addition of the
Grignard reagents would give an attractive synthesis that
would be able to start from 2,6-unsubstituted pyridine
N-oxides. Although sequential addition can be achieved with
the Fagnou methodology, the use of 4 equiv of the pyridine
N-oxide makes it less attractive. During the methodology
development presented herein, it was noticed that by heating
the dienal oximes the corresponding pyridine N-oxides were
formed. Thus, the synthesis of unsymmetrical 2,6-disubsti-
tuted unsymmetrical pyridines would be straightforward.
After the first Grignard addition to 1c, the crude product
Neither pyridine 2r nor the corresponding p-tolyl-disub-
stituted pyridine was observed in the latter reaction. In
addition to the efficient synthesis of 2,6-disubstituted py-
ridines, this procedure is also well suited for sequential
addition of Grignard reagents with very similar structural
properties, which potentially could render purification prob-
lems by the formation of the symmetrical 2,6-disubstituted
pyridine.
In summary, we have developed a general, high-yielding
synthesis of 2-substituted pyridines. The reaction is com-
pletely selective, exclusively forming one regioisomer, which
simplifies the purification step. Alkyl, alkynyl, and aryl
2-substituted pyridines can potentially be synthesized using
2-, 3-, and 4-substituted pyridine N-oxides as starting mater-
ials. With the exception of 3-methyl pyridine N-oxide, the
pyridines are formed via an intermediate 2,4-dienal oxime.
Acknowledgment. We thank the Swedish Natural Sci-
ence Research Council and the Knut and Alice Wallenberg
foundation for financial support.
(10) Comins, D. L.; Abdullah, A. H. J. Org. Chem. 1982, 47, 4315.
(11) Wang, J.; Hanan, G. S. Synlett 2005, 1251.
(12) (a) Coperet, C.; Adolfsson, H.; Khuong, T.-A. V.; Yudin, A. K.;
Sharpless, K. B. J. Org. Chem. 1998, 63, 1740. (b) Caron, S.; Do, N. M.;
Sieser, J. E. Tetrahedron Lett. 2000, 41, 2299. (c) Youssif, S. ARKIVOC
[online computer file] 2001, 2, 242. (d) Winkeljohn, W. R.; Vasquez, P.
C.; Strekowski, L.; Baumstark, A. L. Tetrahedron Lett. 2004, 45, 8295.
Supporting Information Available: Synthetic procedures
and the characterization of compounds 2a-s. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL070184N
Org. Lett., Vol. 9, No. 7, 2007
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