Table 1. Reactions of 4-Nitropyridine N-Oxides with Grignard
Reagentsa
Scheme 1. Possible Reactions of Grignard Reagent with 4-Ni-
tro-2-picoline N-Oxide
entry
R0 (1)
Ar (R)
productb
yieldc
material science.8 It is of high interest to develop synthetic
methodologies for the facile pyridine N-oxide intermediate
preparations. Recently, direct arylation of pyridine N-
oxides via transition-metal-catalyzed CꢀH activation has
been reported.9 This method was only limited to arylation
and requires harsh reaction conditions, extended reaction
times, and excess pyridine N-oxide as well as expensive
transition-metal catalysts. Alternatively, an efficient and
transition-metal-free arylation and alkylation of pyridine
N-oxides was achieved through the reactions of Grignard
reagents with pyridine N-oxides.10,11 Although nitropyr-
idine N-oxides constitute a significant class of heterocyclic
N-oxides,6 the reactions of Grignard reagents with nitro-
pyridine N-oxides have not yet been reported to date. It is
expected that these reactions are challenging because at
least four possible reactions could take place (in Scheme 1).
We herein reporta robust direct arylation and alkylation
of nitropyridine N-oxides, which is a one-pot transition-
metal-free reaction of a Grignard reagent with nitropyr-
idine N-oxides. We expect that this protocol will signifi-
cantly extend the scope of the reactions of Grignard
reagents in the presence of a nitro group as well as the
arylation or alkylation of pyridine N-oxides.
1
2-Me(1a)
1a
Ph
3aa (6-)
3ab (6-)
3ac (6-)
3ad (6-)
3ae (6-)
3af (6-)
3ag (6-)
3ah (6-)
3ai (6-)
3ba (2-)
3bh (2-)
3ca (2-)
3cj (2-)
3db (6-)
3dg (6-)
3ea (2-)
3ak (3-)
3am (3-)
3bn (3-)
3bo (3-)
92%
85%
82%
78%
76%
79%
69%
70%
69%
69%d
64%d
91%
74%
80%
90%
78%
47%
32%
45%
35%
2
4-MeC6H4
3-MeC6H4
2-MeC6H4
2,4,6-(Me)3C6H2
naphthalen-1-yl
thiophen-2-yl
pyridin-3-yl
2-MeOOCC6H4
Ph
3
1a
4
1a
5
1a
6
1a
7
1a
8
1a
9
1a
10
11
12
13
14
15
16
17
18
19
20
H(1b)
1b
pyridin-3-yl
Ph
3-Me(1c)
1c
1de
1d
1ef
2-CNC6H4
4-MeC6H4
thiophen-2-yl
Ph
1a
Me
1a
Et
1b
i-Pr
1b
cyclohexyl
a 4-Nitropyridine N-oxide was treated with Grignard reagent (1.2
equiv) in THF at ꢀ60 °C. After the addition reaction was completed
(1ꢀ2 h), DDQ (1.2 equiv) was added. The mixture was allowed to come
to room temperature and stirred for 4ꢀ6 h. b The arylated or alkylated
position in product is given in parentheses. c Yield of isolated product.
d About 10% diarylated product was isolated. e 2-Diisopropylcarba-
moylpyridine N-oxide. f 4-Nitroquinoline N-oxide.
(7) For naturally occurring N-oxides, see: (a) Karwno, L. B. S.;
Angerhofer, C. K.; Tsauri, S.; Padmawinata, K.; Pezzuto, J. M.;
Kinghorn, A. D. J. Nat. Prod. 1991, 54, 1360. (b) Nicholas, G. M.; Blunt,
J. W.; Munro, M. H. G. J. Nat. Prod. 2001, 64, 341. (c) Donnell, G. O.;
Poeschl, R.; Zimhony, O.; Gunaratnam, M.; Moreira, J. B. C.; Neidle,
S.; Evangelopoulos, D.; Bhakta, S.; Malkinson, J. P.; Boshoff, H. I.;
Lenaerts, A.; Gibbons, S. J. Nat. Prod. 2009, 72, 360. For biologically
active N-oxides, see:(d) Oberwinkler, S. M.; Nowicki, B.; Pike, V. W.;
Halldin, C.; Sandell, J.; Chou, Y. H.; Gulyas, B.; Brennum, L. T.;
Fardec, L.; Wikstroma, H. V. Bioorg. Med. Chem. 2005, 13, 883. (e)
Haginoya, N.; Kobayashi, S.; Komoriya, S.; Yoshino, T.; Nagata, T.;
Hirokawab, Y.; Nagaharab, T. Bioorg. Med. Chem. 2004, 12, 5579. For
chiral N-oxide catalyzed asymmetric reactions, see:(f) Malkov, A. V.;
Kocovsky, P. Eur. J. Org. Chem. 2007, 29. (g) Takenaka, N.; Sarangthem,
R. S.; Captain, B. Angew. Chem., Int. Ed. 2008, 47, 9708. (h) Chen, J.;
Takenaka, N. Chem.;Eur. J. 2009, 15, 7268.
In a preliminary experiment, a complex mixture was
obtained when 4-nitro-2-picoline N-oxide (1a) was treated
with phenylmagnesium bromide (2a) at ꢀ20 °C. However,
at lowered reaction temperature, 6-phenyl-4-nitro-2-pico-
line (3aa) was mainly obtained, in yields of 27% and 51%
atꢀ40or ꢀ60°C respectively. The resultsuggestedthat the
addition of phenylmagnesium bromide to the N-oxide
group could take place predominantly at a low tempera-
ture. Various oxidants (KMnO4, FeCl3, Cu(NO3)2, DDQ,
and air) were then screened to oxidize the adduct dihy-
dropyridine N-oxide10d into corresponding pyridine
N-oxide in situ. The best result was obtained when DDQ
was used, where 3aa was isolated in a 92% yield (Table 1
entry 1). This simple, transition-metal-free and highly
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Sons: 2010. (b) Abass, M. Heterocycles 2005, 65, 901.
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Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291. (b) Schipper, D. J.;
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2011, 9, 337. (b) Andersson, H.; Banchelin, T. S. L.; Das, S.; Olsson, R.;
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Org. Lett., Vol. 13, No. 22, 2011
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