Efficient, mild and completely regioselective synthesis of substituted pyridines

Article abstract of DOI:10.1039/c000748j

Addition of Grignard reagents to pyridine N-oxides in THF at low temperature (-78 to -20 °C) and treatment with TFAA provides an efficient general procedure for synthesis of substituted pyridines. The method is compatible with a range of functional groups such as esters, halogens and nitriles.

Full text of DOI:10.1039/c000748j

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Efficient, mild and completely regioselective synthesis of substituted
pyridinesw
Hans Andersson,a Thomas Sainte-Luce Banchelin,a Sajal Das,a Roger Olsson*bc and
Fredrik Almqvist*a
Received (in Cambridge, UK) 12th January 2010, Accepted 16th February 2010
First published as an Advance Article on the web 16th March 2010
DOI: 10.1039/c000748j
Addition of Grignard reagents to pyridine N-oxides in THF at
low temperature (ꢀ78 to ꢀ20 1C) and treatment with TFAA
provides an efficient general procedure for synthesis of
substituted pyridines. The method is compatible with a range
of functional groups such as esters, halogens and nitriles.
However, the protocol developed was based on the available
knowledge at the time, namely that reacting Grignard reagents
with pyridine N-oxides results in ring-opening products.6 After
the formation and work-up of the ring-opened intermediate, a
second step, at a higher temperature (120–140 1C), is necessary
to ring-close and form the substituted pyridine.
The method presented here is based on our recent (2009)
discovery that reacting pyridine N-oxides with Grignard
reagents at low temperature prevents the formation of the
ring-opened products.7 The reaction was found to be efficient
at temperatures ranging from ꢀ78 to ꢀ20 1C; at higher
temperatures the ring-opened product started to form, and
at 0 1C a 1 : 1 mixture of the corresponding heterocycle and
ring-opened dienal-oxime was detected. Hence, performing the
reaction below ꢀ20 1C and aromatizing the dihydropyridine
formed in the addition reaction would potentially afford a
convenient scalable method for the synthesis of substituted
pyridines. The rationale was to add an acylating agent to the
initially formed dihydropyridine N-oxide, which could then
react with the oxygen resulting in a good leaving group that
ultimately would lead to a formation of the desired pyridine.
However, to ensure that no competing 2,3-addition occurred,7a
one equivalent of methanol should be added prior to the
acylating agent. To assess the utility of this procedure, test
reactions were performed by allowing 4-phenylpyridine
N-oxide (1a) to react with phenylmagnesium chloride at
ꢀ40 1C, quenching with approximately one equivalent of
methanol then adding one of the four electrophilic acylating
agents listed in Table 1.
Substituted pyridines are privileged scaffolds that occupy a
central position in biologically active compounds and in
material science.1 Consequently, methods for their synthesis
are of great interest. Herein, we report an efficient, mild, and
transition-metal free, complete regioselective synthesis of
2-substituted vinyl- and arylpyridines. This reaction exhibits
all the advantages of direct arylation reactions and of
our previous reported method,2 but with the additional
advantages of short reaction times, single-step, and mild
reaction temperatures. Recently, direct arylation at the ortho
position in pyridines and pyridine N-oxides has been
described.3 This method eliminates the need for the preparation
and isolation of 2-pyridyl organometallics or 2-pyridyl
halogens, a step that is necessary in the more traditional
transition-metal-catalyzed cross-couplings.4 However, direct
arylations require high temperatures (i.e., 110–190 1C) and
long reaction times (i.e., 12–24 h). Furthermore, the pyridines
or the pyridine N-oxides are used in excess (3–6 equiv), which
makes the reaction unattractive when these starting materials
are valuable. The formation of isomeric mixtures of 2- and
4-substituted products has limited the applicability of organo-
metallic additions to acyl- and alkyl-activated pyridines in the
synthesis of 2-substituted pyridines.5 We recently reported a
transition-metal free complete regioselective synthesis of
2-substituted pyridines, achieved by a two-step reaction
between pyridine N-oxide and Grignard reagents.2 In addition
to the advantages represented by the direct arylation
methodology, this reaction used close to stoichiometric
amounts of reagents and avoids the use of a transition-metal
catalyst that can be costly and potentially toxic, which may
complicate its use in late stages of pharmaceutical synthesis.
Table 1 Investigation of the aromatizationa
Entry
Electrophile
Yieldb (%)
a
˚ ˚
Department of Chemistry, Umea University, SE-90187 Umea,
Sweden. E-mail: Fredrik-almqvist@chem.umu.se;
Fax: +46-90-786 7655; Tel: +46-90-786 6925
1
2
3
4
AcCl
Ac2O
Vilsmeier salt
TFAA
67
69
28
76
b ACADIA Pharmaceuticals AB, Medeon Science Park S-20512,
Malmo, Sweden. E-mail: roger@acadia-pharm.com
¨
a
c Department of Chemistry, University of Gothenburg,
SE-41296 Gothenburg, Sweden. E-mail: oroger@chem.gu.se;
Fax: +46 31 772 38 40; Tel: +46 736 25 34 87
Reaction conditions: N-oxide (1 equiv.) in THF, PhMgCl (1.2 equiv.),
quenched with MeOH (1.3 equiv.), followed by addition of
the electrophile (1.1 equiv.) and warming to ambient temperature.
b
w Electronic supplementary information (ESI) available: Experimental
details and spectroscopic data for compounds 2a–2n. See DOI:
10.1039/c000748j
Average isolated yields based on at least two experiments. TFAA,
trifluoroacetic anhydride.
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3384 | Chem. Commun., 2010, 46, 3384–3386

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Acetyl chloride and acetic anhydride gave comparable yields
(67 and 69%, respectively) of the pyridine 2a (entries 1 and 2,
Table 1). The Vilsmeier salt8 afforded the pyridine 2a in a low
yield of 28% (entry 3), and the yield was highest (76%) using
trifluoroacetic anhydride (TFAA; entry 4).
reaction, we turned to investigate 3-substituted pyridine
N-oxides as starting materials. In our previous protocol,
injecting phenyl Grignard reagents to a solution of 3-methyl-
pyridine N-oxide (1i) or 3,5-dimethylpyridine N-oxide at rt
gave the corresponding 2,3-substituted pyridine 2l and the
2,3,5-substituted pyridine in 43 and 91% yields, respectively.2
Interestingly, these pyridines were formed directly rather than
by the general route via the ring-opened intermediate.2
Furthermore, 1i gave the more sterically congested 2,3-
substituted pyridine 2l a stereochemical preference consistent
with the major isomer, with other methodology, using activated
3-substituted pyridines, with 3-substituents as alkyls, methoxy
and halogens.10 However, when picoline N-oxide 1i was
reacted according to the present (low temperature) protocol
only trace amounts of the corresponding 2,3-disubstituted
pyridine 2l were observed (Scheme 1). In contrast, 3-cyano-
pyridine N-oxide (1j) gave the 2,5-disubstituted pyridine 2m in
60% yield, and the expected 2,3-substituted regioisomer was
not observed (Scheme 1). Fagnou et al. recently described the
direct arylation of 1j, and depending on the catalytic system
this reaction gave different ratios of isomeric mixtures (>9.5 : 1),
however, the major isomer was 3-cyano-2-arylpyridine
N-oxide.3b These two methods complement each other nicely.
Synthesis of polysubstituted pyridines by sequential addi-
tions would be possible if the intermediate aromatization
occurred without cleavage of the N–O bond. Reacting pyr-
idine N-oxide 1d with 4-methoxyphenylmagnesium chloride
followed by an oxidation using chloranil resulted in pyridine
N-oxide 1k in 75% yield (Scheme 2). After the consumption of
1d, acetic acid and the chloroanil were added directly to the
reaction mixture at ꢀ40 1C, the reaction mixture was then
warmed to ambient temperature, yielding 1k in 75% yield.
Subsequent treatment of pyridine N-oxide 1k with vinyl-
magnesium chloride followed by quenching with methanol
and addition of TFAA resulted in the trisubsubstituted
pyridine 2m in excellent (92%) isolated yield.
The scope of the reaction was further studied using a variety
of substituted pyridine N-oxides and phenylmagnesium
chloride followed by addition of TFAA. Pyridine N-oxide
(1b) gave 2-phenylpyridine (2a) in 54% yield (entry 1,
Table 2). Both electron-donating (entries 2 and 3) and electron-
withdrawing substituents (entries 4 and 5), are compatible
with the reaction conditions. Grignard addition to the
functionalized 4-chloropyridine N-oxide (1e) and the
4-methoxycarbonylpyridine N-oxide (1f), gave the corresponding
2,4-disubstituted pyridines in good yields; 68 and 63%,
respectively (entries 4 and 5). The possibility of using reactive
functional groups towards Grignard reagents as the methyl
esters (1f) is a attractive feature of this procedure, and
increasing its generality compared with the previous method
performed at rt. 2-Picoline N-oxide (1g), in which one of the
two 2-positions is blocked that could potentially drive the
reaction towards the formation of 4-addition products,
also gave only one regioisomer, 2g in 62% yield (entry 6).
When 2-phenylpyridine N-oxide (1h) was reacted with phe-
nylmagnesium chloride the 2,6-disubstituted pyridine 2h was
isolated in an excellent yield of 85% (entry 7). This reaction
gave basically the same yield of 2h when performed at gram
scale. Next, the influence of different Grignard reagents was
investigated. Reagents with electron-donating and electron-
withdrawing aryl substituents worked equally well, 4-methoxy-
and 4-fluorophenylmagnesium chloride gave 79% yields of 2i
and 2j, respectively, in the reaction with pyridine N-oxide 1h
(entries 8 and 9). Vinylmagnesium chloride yielded pyridine 2k
in a good 77% yield (entry 10). Since alkyl Grignard reagents
are prone to undergo hydrogen abstraction,9 adding a vinyl
group can provide a way to introduce alkyl substituents by
adding a subsequent reduction step.7
In summary, we have shown that addition of Grignard
reagents to pyridine N-oxides affords an efficient, general
method for the synthesis of substituted pyridines. This reaction
is compatible with reagents with a wide range of substitution
patterns and substituents (e.g., methyl esters and nitriles).
Furthermore, the reaction is completely regioselective, exclusively
forming one regioisomer and no transition-metal catalyst is
required, which simplifies the purification procedure. In addition,
polysubstituted pyridines can be synthesized by an intermediate
oxidation using chloranil followed by a second addition
of Grignard reagent. All this taken together with the mild
reaction conditions, generally, ꢀ78 to ꢀ20 1C and in some
cases (e.g., for 3-methylpyridine N-oxide) up to ambient
Having worked out a procedure for using pyridine N-oxide,
and a selection of 2- and 4-substituted pyridine N-oxides in the
Table 2 Synthesis of substituted pyridinesa
Entry
R (N-oxide)
R0
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
H (1b)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2b
2c
2d
2e
2f
2g
2h
2i
54
68
66
68
63
62
85
79
79
77
4-OBn (1c)
4-OMe (1d)
4-Cl (1e)
4-CO2Me (1f)
2-Me (1g)
2-Ph (1h)
2-Ph (1h)
2-Ph (1h)
2-Ph (1h)
4-MeOC6H4
4-FC6H4
Vinyl
2j
2k
a
Reaction conditions: N-oxide (1 equiv.) in THF, PhMgCl (1.2 equiv.),
quenched with MeOH (1.3 equiv.), followed by addition of trifluoro-
b
acetic anhydride (1.1 equiv.). Isolated yields.
Scheme 1 Synthesis of 2,3- and 2,5-substituted pyridines.
Chem. Commun., 2010, 46, 3384–3386 | 3385
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Scheme 2 Synthesis of polysubstituted pyridines.
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We thank the Swedish Natural Science Research Council
and the Knut and Alice Wallenberg foundation for financial
support. We are also grateful to Umea Centre for Microbial
Research (UCMR) for financial support to T. S.-L. B.
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´
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This journal is The Royal Society of Chemistry 2010
3386 | Chem. Commun., 2010, 46, 3384–3386