Selective synthesis of 2-substituted pyridine N-oxides via directed ortho-metallation using Grignard reagents

Article abstract of DOI:10.1016/j.tetlet.2008.09.104

Addition of i-PrMgCl to pyridine N-oxides in THF at -78 °C generates selectively an ortho-metallated species, which can be trapped with various electrophiles to generate 2-substituted pyridine N-oxides. Furthermore, by applying a double metal-catalyzed cross-coupling, direct arylation of the pyridine N-oxides is achieved.

Full text of DOI:10.1016/j.tetlet.2008.09.104

Tetrahedron Letters 49 (2008) 6901–6903
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Tetrahedron Letters
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Selective synthesis of 2-substituted pyridine N-oxides via
directed ortho-metallation using Grignard reagents
a,
Hans Andersson a, Magnus Gustafsson b, Roger Olsson b, , Fredrik Almqvist
*
*
a Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden
b ACADIA Pharmaceuticals AB, Medeon Science Park, S-20512 Malmö, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Addition of i-PrMgCl to pyridine N-oxides in THF at À78 °C generates selectively an ortho-metallated
species, which can be trapped with various electrophiles to generate 2-substituted pyridine N-oxides.
Furthermore, by applying a double metal-catalyzed cross-coupling, direct arylation of the pyridine
N-oxides is achieved.
Received 17 August 2008
Revised 16 September 2008
Accepted 17 September 2008
Available online 20 September 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Herein, we report an efficient one-pot synthesis of 2-substi-
tuted pyridine N-oxides via directed ortho-metallation using Grig-
nard reagents in combination with a diverse set of electrophiles.
Synthesis of functionalized pyridine N-oxides constitutes a practi-
cal way to achieve substituted pyridines which are prominent in
medicinal chemistry1–3 and materials.4 Transition metal-catalyzed
C–H activation has proven to be efficient for the functionalization
of pyridine N-oxides.5–7 Although synthetically elegant, the meth-
od is limited to arylations, requires high temperatures, long reac-
tions times, and the use of excess pyridine N-oxide (4 equiv, in
general). The use of organolithium reagents, that is, butyllithium,
for deprotonation of pyridine N-oxides followed by addition of an
electrophile has been thoroughly studied, but so far only poor to
moderate yields (14–45%) have been reported along with 2,6-
disubstitution as major by-products.8–14 The reaction between pyr-
idine N-oxides and Grignard reagents has generally been reported
to give rise to nucleophilic attack followed by ring-opening.15–17 As
a result, pyridine N-oxides were not regarded as suitable starting
materials for the synthesis of substituted piperidines using Grig-
nard reagents. Instead, another method was developed, that is,
the synthesis of 2-substituted piperidines by addition of Grignard
reagents to N-benzoyliminopyridinium ylides.18
Recently, we took advantage of the fact that pyridine N-oxides
undergo rearrangement after a rapid addition of Grignard reagents
at room temperature. This led to improved syntheses of both die-
nal oximes and 2-substituted pyridines.19,20 However, during those
studies, instead of the normal addition-rearrangement, a proton
abstraction was observed when treating the N-oxides with alkyl
Grignard reagents at À78 °C. This could potentially lead to a mild
regioselective methodology for the synthesis of substituted pyri-
dine N-oxides and correspondingly, to pyridines with a broad
range of substituents.
Exploration of the reaction conditions was initiated by the addi-
tion of n-butylmagnesium chloride at À78 °C to pyridine N-oxide
1a followed by quenching with deuterium oxide. A regioselective
incorporation of deuterium at the 2-position was observed in more
than 90% according to crude-NMR, 2a (Table 1, entry 1). Thus, by
using n-BuMgCl, the disubstituted by-products previously reported
with n-BuLi were avoided. Switching the electrophile to benzalde-
hyde gave a significant drop in yield, and product 2b was isolated
in 45% yield (Table 1, entry 2). However, the yield was improved to
Table 1
Preparation of 2-substituted pyridine N-oxides
R2
R2
1)
-BuMgCl
THF, -78 o
i-PrMgCl or
R1
R3
R1
R3
E
n
C
2) E+, THF,
-78 oC to rt
N
O
N
O
2a-g
1a-e
Entry
N-Oxide
R1
R2
R3
E
Product
Yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1d
1e
H
H
H
H
H
H
Me
H
OBn
OBn
OBn
OBn
H
H
H
Ph
H
H
H
H
Me
OMe
Me
H
D
2a
2b
2b
2c
2d
2e
2f
90b,c
45b
65
PhCHOH
PhCHOH
I
PhCHOH
PhCHOH
I
67
61d
86
92
38
PhCHOH
2g
Conditions: (1) pyridine N-oxide (1 equiv), Grignard reagent (1.7 equiv) in THF at
À78 °C stirred for 1 h. (2) Benzaldehyde (2.0 equiv) added at À78 °C and allowed to
reach rt and stirred for another 30 min.
a
Isolated yields.
n-BuMgCl used for deprotonation.
Yield determined by crude-NMR.
Isolated as an isomeric mixture of 2,3- and 3,6-substituted N-oxides in a 1:1.5
b
c
d
* Corresponding authors. Tel.: +46 90 786 6925; fax: +46 90 138885.
E-mail address: fredrik.almqvist@chem.umu.se (F. Almqvist).
ratio.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.104

6902
H. Andersson et al. / Tetrahedron Letters 49 (2008) 6901–6903
65% by exchanging n-BuMgCl with iso-propylmagnesium chloride
(i-PrMgCl) (entry 3, Table 1). Results for the deprotonation of
substituted pyridine N-oxides 1a–e using 1.7 equiv of i-PrMgCl fol-
lowed by quenching with benzaldehyde or iodine (entries 3–8) are
summarized in Table 1.
isolated 7% yield using n-BuLi.10 Analogously 2i and 2j were iso-
lated in improved yields of 32% and 36%, respectively (Table 2, en-
tries 2 and 3). In comparison, using alkyllithiums, the yields were
0% and 21%, respectively, and resulted in alkylation on the methyl
groups.10 Furthermore, the corresponding 3,5-dimethyl pyridine
N-oxide 1d gave rise to the hydroxy-cyclohexyl substituted N-
oxide 2k in 81% yield (Table 2, entry 4). Pyridine N-oxides 1i and
1k, with 2-methoxy- and 2-chloro substituents, respectively, gave
rise to a complex reaction mixture when reacted in the same man-
ner (Table 2, entries 5 and 8). However, when 4-methoxy- and 4-
chloro-substituted N-oxides 1j and 1l were used, the desired prod-
ucts 2n and 2p were isolated in 22% and 20% yields, respectively
(Table 2, entries 7 and 9). The 3-methoxy pyridine N-oxide 1c
and 4-benzyloxy N-oxide 1a underwent the desired deprotonation
in good to excellent yields, and the tertiary alcohol-substituted
pyridine N-oxides 2m and 2q were isolated in 90% and 62% yields,
respectively, after the addition of cyclohexanone. High yields were
obtained when 3-methoxy-substituted pyridine N-oxide 1c was
deprotonated and trapped with various electrophiles. To further
prove the robustness of the reaction, another three electrophiles
were trapped with intermediate 3 (Scheme 1).
Incorporation of substituents such as piperidinone moieties is of
great interest due to their known potency in biological systems.21–25
The direct trapping of intermediate 3 using Boc-protected piperidi-
none resulted in an excellent 93% isolated yield of 2r (Scheme 1).
Moreover, the introduction of halogens on heterocycles is of signif-
icant importance because of their versatility as synthetic intermedi-
ates, for example, in cross-couplings such as Heck,26,27 Suzuki28 or
Stille.29,30 Indeed, the addition of iodine to intermediate 3 yielded
the corresponding 2-iodopyridine N-oxide 2s in 96% yield (Scheme
1). Finally, by trapping intermediate 3 with phenylisocyanate, the
amide substituted pyridine N-oxide 2t was obtained in 81% yield.
Bearing in mind the large amount of commercially available
ketones, aldehydes and isocyanates, these results indicate a great
potential to synthesize libraries of pyridine N-oxides with diverse
substituents and properties (Scheme 1).
When iodine was used as the electrophile in the reaction with
ortho-metallated pyridine N-oxide 1a, a similar yield as for the
reaction with benzaldehyde (2b, 65%) was observed, and 2c was
isolated in 67% yield (Table 1, entry 4). Thereafter, the unsymmet-
ric 3-picoline N-oxide 1b was deprotonated and allowed to react
with benzaldehyde. This yielded a 1:1.5 mixture of 2- and 6-substi-
tuted isomers 2d, respectively, in a 61% isolated yield (Table 1, en-
try 5). However, by switching the methyl group to a methoxy
group as in 1c, with potential directing properties, a better result
was obtained, and the 2,3-substituted pyridine N-oxide 2e was iso-
lated in 86% yield as the sole product (Table 1, entry 6). The sym-
metric 3,5-dimethyl-substituted N-oxide (1d) was deprotonated
and reacted with iodine yielding the tri-substituted pyridine N-
oxide 2f in an excellent isolated yield of 92% (Table 1, entry 7). A
selective monohalogenation was observed which stands in strong
contrast to the reaction performed using alkyllithium, which is re-
ported to give mainly dihalogenated products.10 The 4-phenyl
substituted pyridine N-oxide 1e showed a different reactivity when
treated with i-PrMgCl at À78 °C followed by trapping with benzal-
dehyde. The major product was the result of direct nucleophilic at-
tack followed by an oxidation to yield 2-isopropyl-4-phenyl
substituted pyridine N-oxide in 56% yield and the expected prod-
uct 2g was obtained in 38% yield (Table 1, entry 8).
To further investigate the potential of the method and to make
it more practical, we wanted to reduce the number of equivalents
of the Grignard reagent. In addition, a sterically more demanding
electrophile other than benzaldehyde was studied. Therefore, var-
ious pyridine N-oxides were reacted with 1.2 equiv of i-PrMgCl,
followed by in situ trapping with cyclohexanone, which in addition
to being more sterically hindered has acidic a-protons (Table 2). By
using cyclohexanone as an electrophile, it was also possible to
compare the alkylmagnesium reaction with butyllithium more
directly.10
Regioselective 2-substitution of pyridine N-oxide 1f was
achieved with cyclohexanone to yield 38% of product 2h (Table
2, entry 1), which is an improvement compared to the previously
Finally, in order to expand the scope to include cross-coupling
reactions and, thus, gain access to 2-aryl-substituted pyridine N-
oxides, we explored the utility of the generated metallated pyri-
dine N-oxide in combination with aryl halides. These types of reac-
tions have been described extensively in the literature, for
example, the use of palladium,31 iron,32 as well as copper33 in com-
bination with Grignard reagents and different halides. Unfortu-
nately, both iron and copper reagents, which are easier to handle
and are inexpensive, only resulted in isolation of starting material
in attempts to couple intermediate 4 with different aryl halides.
Alternatively, as to aryl halides, the use of bench-stable diaryliod-
Table 2
ortho-Metallation followed by trapping using cyclohexanone
R3
R3
R2
R1
R4
R2
R1
R4
1)
i-PrMgCl
THF, -78 o
C
OH
2) Cyclohexanone,
THF, -78 oC to rt
N
O
N
O
OMe
O
OH
1a,c,d,f-l
2h-q
N
N
Entry
N-Oxide
R1
R2
R3
R4
Product
Yielda (%)
O
N
Boc
Boc
2r, 93%
1
2
3
4
5
6
7
8
9
1f
H
Me
H
H
OMe
H
H
Cl
H
H
H
H
Me
H
H
H
H
H
H
H
H
Me
H
H
H
OMe
H
Cl
OBn
H
H
H
Me
H
OMe
H
H
H
H
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
38
32
36
81
0
90
22
0
OMe
OMe
MgCl
OMe
1g
1h
1d
1i
1c
1j
1k
1l
1a
I2
i
-PrMgCl
THF, -78 o
C
N
O
N
O
N
O
I
PhNCO
1c
2s, 96%
OMe
3
H
20
62
N
10
H
N
O
O
Conditions: (1) pyridine N-oxide (1 equiv), Grignard reagent (1.2 equiv) in THF at
À78 °C stirred for 1 h. (2) Cyclohexanone (1.5 equiv) added at À78 °C and allowed
to attain rt and stirred for another 30 min.
2t, 81%
a
Isolated yields.
Scheme 1.

H. Andersson et al. / Tetrahedron Letters 49 (2008) 6901–6903
6903
with this article can be found, in the online version, at doi:
10.1016/j.tetlet.2008.09.104.
Pd(PPh3)4,
ZnCl2, THF, 5
i
-PrMgCl
MWI 70 o
10 min
C
THF, -78 oC
N
O
N
O
N
O
MgCl
References and notes
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Supplementary data
Supplementary data (detailed experimental procedures and
compound characterization data of compounds 2a–u) associated