Reaction of pyridine N-oxides with Grignard reagents: a stereodefined synthesis of substituted dienal oximes

Article abstract of DOI:10.1016/j.tetlet.2007.07.161

Rapid addition of Grignard reagents to pyridine N-oxides under mild conditions gave stereodefined dienal oximes in good to excellent yields. This reaction provides an efficient access to substituted olefins with defined stereochemistry that are potentiall

Full text of DOI:10.1016/j.tetlet.2007.07.161

Tetrahedron Letters 48 (2007) 6941–6944
Reaction of pyridine N-oxides with Grignard reagents: a
stereodefined synthesis of substituted dienal oximes
Hans Andersson,a Xiaoyang Wang,a Mikael Bjo¨rklund,a Roger Olssonb,* and
Fredrik Almqvista,*
a
˚
˚
Department of Chemistry, Umea University, SE-90187 Umea, Sweden
bACADIA Pharmaceuticals AB, Medeon Science Park S-20512, Malmo¨, Sweden
Received 12 June 2007; revised 20 July 2007; accepted 25 July 2007
Available online 28 July 2007
Abstract—Rapid addition of Grignard reagents to pyridine N-oxides under mild conditions gave stereodefined dienal oximes in
good to excellent yields. This reaction provides an efficient access to substituted olefins with defined stereochemistry that are poten-
tially of interest as bioactives themselves or as versatile synthetic intermediates.
Ó 2007 Elsevier Ltd. All rights reserved.
Pyridine N-oxides are potential starting materials for the
synthesis of a multitude of target molecules.1–3 While
the addition of organometallic reagents to acyl or alkyl
activated pyridines have been developed into an
expedient method for the synthesis of substituted piperi-
dines,4–8 the analogous nucleophilic addition to pyridine
N-oxides has been scarcely reported.9–14 Focusing on the
structural elucidation of the products from the reaction
of aryl Grignard reagents with pyridine N-oxide 1, Kel-
log et al. reported on the formation of dienal oximes 2
(10–48% yields).12 The low yields obtained probably
hampered further exploration of the reaction. Provided
that the yields could be improved, dienal oximes 2 with
the inherent stereodefined unsaturated system appeared
to us to be attractive intermediates for further transfor-
mations. Thus, depending on the substitution pattern
present in pyridine N-oxide 1 and the synthetic transfor-
mations used, a diverse set of compounds would be
obtainable within a few steps. Furthermore, the wealth
of commercially available substituted pyridine N-oxides
1 in combination with their easy synthesis15–17 make
them attractive as starting materials. Herein we report
on the development of a synthetic methodology that
generates dienal oximes 2 in high yields by the regiospec-
ific addition of Grignard reagents to pyridine N-oxides
1. These key intermediates were transformed into a di-
verse range of compounds, for example, substituted ali-
phatic amines 4 and enaminones 7.
Initial studies show that organozinc reagents in combi-
nation with copper cyanide used in the synthesis of
4-substituted piperidines via addition to N-acyl pyr-
idinium salts,7 or the use of organolithium reagents,
resulted in either no reaction or complex reaction
mixtures when reacted with pyridine N-oxides. How-
ever, an earlier publication by Kellog et al. reported
low yields using Grignard reagents.12 Also in our hands
slow addition of the Grignard reagent (PhMgCl in
THF) at temperatures ranging from À50 °C to room
temperature gave a moderate isolated yield of dienal
oxime 2 (<40%) confirming Kellog’s results. However,
by rapidly adding the phenylmagnesium chloride to pyr-
idine N-oxide 1a dissolved in THF at room temperature,
a clean transformation was observed, and after stirring
the reaction mixture for an additional 30–60 min the
reaction was quenched and dienal oxime 2a was isolated
in 85% yield (Table 1). The reaction was monitored via
NMR experiments and it was shown that the transfor-
mation to the desired dienal oxime did not occur until
water was added to the reaction mixture (see Fig. 1,
Supplementary data).
The conditions developed for the addition of phenyl-
magnesium chloride were used in the addition of meth-
ylmagnesium chloride and iso-propylmagnesium
chloride to pyridine N-oxides 1a and 1b. Unfortunately,
this time, a complex reaction mixture was formed and
*
Corresponding authors. Tel.: +46 90 786 6925; fax: +46 90 138885
(F.A.); e-mail: fredrik.almqvist@chem.umu.se
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.161

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H. Andersson et al. / Tetrahedron Letters 48 (2007) 6941–6944
Table 1. Investigation of the formation of dienal oximes 2 derived
from pyridine N-oxide 1 and a mild in situ transformation to
conjugated nitriles 3
Substituted pyridine N-oxides, for example, the picoline
N-oxide series 1c–e were reacted with phenylmagnesium
chloride (Table 2). High yields of dienal oximes were ob-
tained with 2- and 4-substituted pyridine N-oxides and
5-substituted ketoxime 2d and aldoxime 2f were isolated
in a 79% and 81% yields, respectively (Table 2). 2-
Substituted pyridine N-oxides are easily obtained by
the present method, via sequential addition of Grignard
reagents to pyridine N-oxides followed by mild oxida-
tion (air, DMF, 120 °C, 8 h).19 Thus, substituted stereo-
defined dienal ketoximes are obtainable. 3-Substituted
picoline N-oxide 1d, on the other hand, gave no dienal
oxime when reacted with phenylmagnesium chloride, in-
stead the major isolated product was 2-phenyl-3-methyl
pyridine.19
R
R
R1 MgCl
THF, rt
1)
R
R1 MgCl
THF, rt
R1
R1
Cl
2)
N
N
O
N
3
2
CN
Cl
OH
DCM, rt
R1
Ph
1
Entry
1
R
Oxime 2
(yield)a
Nitrile 3
(yield, %)a
1
2
3
1a
1a
1b
H
2a (85%)
2b (trace)
2c (trace)
3a (74)b
3b (49)
3c (64)
H
Ph
CH(Me)2
Me
a Isolated yields calculated from pyridine N-oxide 1.
Phenyl, phenylethynyl- and thienylmagnesium chloride
also reacted well and the phenyl and alkynyl and hetero-
aryl dienal oximes 2g–i were isolated in 83%, 77% and
66% yields, respectively, when reacted with 1b (Scheme
1). All the dienal oximes were obtained as single isomers,
the stereodefined 5-substituted (1E,2Z,4E)-penta-2,4-
b Obtained as an isomeric mixture of cis–trans and trans–trans diene-
nitrile in a 20:3 ratio, respectively, according to NMR spectroscopy.
only traces of the desired dienal oximes were observed
(Table 1). However, the corresponding nitriles 3a–c were
accessible in 74%, 49% and 64% isolated yields, respec-
tively, via a mild in situ transformation of the oxime
functionality using the Vilsmeier–Haack salt18 (Table
1). This showed that in addition to aryl Grignards the
reaction worked with alkyl Grignard reagents as well.
The dienal oximes are probably formed initially and
the low yields of isolated alkyl substituted dienal oximes
instead were attributed to the lower stability of alkyl
substituted dienal oximes compared to aryl substituted
dienal oximes.
1
dienaloxime was formed in all cases according to H
NMR analysis.20
With an efficient synthetic protocol to stereodefined di-
enal oximes in hand we wished to perform further trans-
formations to a diverse set of molecules. In general, we
observed that dienal oximes 2 were prone to form dihy-
dropyridines at elevated temperature. Therefore, mild
transformations of the oxime functionality were desired.
Encouraged by the successful formation of nitriles 3a–c
we investigated the possibility of reducing dienal oximes
to the corresponding substituted saturated primary
amines. The practical hydrogen transfer method (Pd/
C, ammonium acetate in MeOH) used to reduce dihy-
dropyridines to piperidines7 did not give the primary
amine 6, instead secondary amine 4 was isolated as the
major product in a 48% yield.21 A significant improve-
ment was seen when a combination of t-BuNH2–BH3
with Pd/C22 was used giving secondary amine 4 in an
isolated yield of 62% from 2g (Scheme 2). Other meth-
ods that had been reported to selectively reduce oximes
to amines were tested only to find that reagents such as
Table 2. Investigation of the formation of dienal oximes 2 derived
from picoline N-oxides 1c–e
R3
R3
R2
R2
R1
Ph
PhMgCl
THF, rt
R1
N
N
O
OH
2
1
Entry
1
R1
R2
R3
Oxime 2 (yield, %)a
23
24
1
2
3
1c
1d
1e
Me
H
H
H
Me
H
H
H
Me
2d (79)
2e (0)
2f (81)
NaCNBH3 or LiAlH4 returned the starting material
25
while BH3–SMe2 gave a complex reaction mixture.
However, Zn dust in acetic acid26 gave a rapid and clean
a Isolated yields.
conversion to the unsaturated primary amine 5 (Scheme
Ph
Ph-MgCl
or
Ph
PhCC MgCl
or
Ph
Ph
H
H
N
OH
2g (83%)
MgCl
S
N
O
Ph
N
S
OH
2h (77%)
THF, rt
1b
H
N
OH
2i (66%)
Scheme 1. Aryl-, phenylethynyl- and thiophene-substituted dienal oximes.

H. Andersson et al. / Tetrahedron Letters 48 (2007) 6941–6944
6943
OBn
Ph
O
NH2
Ph
Ph
t
-Bu-NH2-BH3
Pd/C
NH4CO2H
Ph
Pd/C
Ph
N
H
Ph
2g
MeOH, rt
MeOH, rt
N
N
2k
7 (78%)
4 (62%)
OH
OH
Zn
AcOH, rt
N2H4*H2O
MeOH
MWI
(120 °C 120 s)
Ph
Ph
Pd/C
H2
NH
N
Ph
NH2
6 (100%)
Ph
MeOH, rt
5 (86%)
NH2
8 (71%)
cis
: trans 1: 2
Scheme 3. Synthesis of substituted enaminone 7 and pyrazole 8.
Scheme 2. Reduction of dienal oximes.
oxy substituted intermediate 2k gave no dimerization
and instead enaminone 7 was isolated in high yield
78% (Scheme 3). To illustrate the potential of this inter-
mediate in heterocycle synthesis, enaminone 7 was
reacted with hydrazine hydrate under microwave irradi-
ation to give pyrazole 8 in 71% yield (Scheme 3).31
2). NMR spectroscopy showed a 2:1 mixture of E/Z iso-
mers. This mixture was then easily converted to primary
amine 6 in quantitative yield (86% from 2g) by using Pd/
C, H2 in methanol (Scheme 2).
So far, the substituents at pyridine N-oxide had been
either alkyl or aryl in various positions. In all cases,
the Grignard reagent had selectively added to the 2-po-
sition and no addition at the 4-position had been
observed. This was also the case using 4-chloro substi-
tuted N-oxide 1f. Hence, the chloro substituted dienal
oxime 2j was obtained in an excellent yield of 86% and
no product formed by substituting chloride was detected
(Table 3). Also 4-benzyloxy substituted pyridine
N-oxide 1g gave the corresponding dienal oximes in high
to excellent yields on reaction with aryl, heteroaryl
and alkynyl Grignard reagents (Table 3, 76–95%,
entries 2–5).
In conclusion, we have shown that rapid addition of
aryl, alkynyl and alkyl Grignard reagents to pyridine
N-oxides can be used to synthesize substituted stereo-
defined olefins in high yields. The cis, trans configura-
tion obtained is of considerable interest, (e.g., the
anticarcinogenic and antioxidative effects seen with con-
jugated lineloic acids has been attributed to the cis, trans
isomers).32 Moreover, in a few steps, the conjugated
dienal oximes can be converted into a diverse set of
compounds exemplified herein by nitriles, amines,
enaminones and pyrazoles. Thus, this methodology con-
stitutes an excellent platform to design and perform
diversity-oriented synthesis.
A selective debenzylation together with reduction of the
oxime functionality would provide a novel method to
generate substituted enaminones from 4-benzyloxy
substituted pyridine N-oxides. Enaminones are versatile
intermediates that combine the ambident nucleophilicity
of enamines together with the ambident electrophilicity
of enones. This makes enaminones very important in
the synthesis of heterocycles.27–30 Previous attempts to
reduce the oximes using Pd/C and ammonium formate
in methanol gave the secondary amines 4 as the major
products. However, applying this method on the benzyl-
Acknowledgements
We thank the Swedish Natural Science Research Coun-
cil and the Knut and Alice Wallenberg foundation for
financial support.
Supplementary data
Detailed experimental procedures and compound char-
acterization data are available. Supplementary data
associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2007.07.161.
Table 3. Reaction of functionalized pyridine N-oxides
R1
R1
R2 MgCl
THF, rt
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