Azopyridines as New Reagents for Mitsunobu Reaction
SCHEME 1
TABLE 1. Esterification of 4-Nitrobenzoic Acid with Benzyl
Alcohol in the Presence of PPh3 and Azo Compounds (2a-c, 3a-g)
under Different Reaction Conditions
reduce these problems, and along with our continued interest
mainly on the modification of Mitsunobu reaction in our
laboratory,11 we studied the possibility of using azopyridines
(2a-c) and their pyridinium salts ionic liquids (ILs) (3a-g)
(Scheme 1) as a new class of reagents for Mitsunobu esterifi-
cation reactions.
In this paper, we have presented the application of azopy-
ridines (2a-c) and also their pyrdinium salts ionic liquids
(3a-g) as new alternatives for diethyl azodicarboxylate (DEAD)
to perform the Mitsunobu esterification reactions.
Azo compound
PPh3
Reaction Yield % of Benzyl-
Entry (molar equiv) (molar equiv) Time (h)
4-nitrobenzoate
1a
2a
3a
4a
5a
6a
7a
8b
9a
10a
2a (1.2)
2b (1.2)
2c (1.3)
3a (1.3)
3b (1.3)
3c (1.3)
3d (1.3)
3e (3)
1.2
1.2
1.3
1.3
1.3
1.3
1.3
3
2
2
3
6
6
6
6
6
6
6
93
90
50
50
6
50
52
65
20
20
Azopyridines (2a-c) were simply prepared according to the
literature procedure by oxidation of their corresponding ami-
nopyridines with sodium hypochlorite at 0 °C.12 These azo
compounds were then converted to their methyl, n-butyl, and
3f (1.2)
3g (1.2)
1.2
1.2
a The reaction was performed in refluxing acetonitrile. b The ionic
liquid azo compound was used as solvent of the reaction at 80-90 °C.
n-octyl pyridinium salts having Br-, PF6-, CH3SO4-, and NTf2
-
as counterions (Scheme 1). Azopyridines (2a-c) were then used
as reagent (1.2-1.3 equimolar) in conjunction with PPh3
(1.2-1.3 equimolar) for the esterification of 4-nitrobenzoic acid
with benzyl alcohol in refluxing acetonitrile. The results are
tabulated in Table 1. However, their pyridinium salts (3a-g)
which are liquid upon heating to 80-90 °C were used either as
reagent in refluxing acetonitrile or as an ionic liquid media and
reagent for esterification of 4-nitrobenzoic acid.
Our studies showed that 2- and 4-azopyridines are nearly
equally efficient reagents and are more reactive than their
3-isomer for esterification of 4-nitrobenzoic acid with benzyl
alcohol (Table 1, entries 1-3). This can be explained on the
basis of the stabilization of the produced negative charge after
reaction with PPh3 through the resonance effect of the nitrogen
atom in the 2- and 4-positions of azpys (2a,b) (Scheme 2, I).
The lower reactivity of the pyridinium salts of azpys (3a-g)
compared to that of the azo pyridines (2a-c) in the esterification
of 4-nitrobenzoic acid with benzyl alcohol (Table 1, entries
4-10) again can be rationalized by electronic effects. In the
pyridinium salts of azopyridines, the electrophilicity of azo
groups is increased for the reaction with PPh3 due to the
presence of positive charge on the ring’s nitrogen. However,
the negative charge which is produced by the addition of PPh3
to the azo group (Scheme 2, III) is greatly dispersed by the
positive charge on the nitrogen in 4- and 2-positions of the
pyridinium ring. This causes severe reduction of the basicity
of adduct III obtained from the reaction of PPh3 and the azo
functionality of the pyridinium salts and seriously decreases their
reactivity compared to I for deprotonation of carboxylic acids
which is the crucial step in the Mitsunobu esterification reaction.
In support of this suggestion, our NMR study showed that
azopyridine (2a) is not protonated by 4-nitrobenzoic acid, and
therefore the lower reactivity of the alkyl pyridinium salts is
attributed to the presence of the positive charge on the nitrogen
atom of their aromatic ring.
Among the studied azo compounds, 2,2′- and 4,4′-azopyridine
(2a) were found to be the most efficient and suitable alternatives
for DEAD in the Mitsunobu reaction. However, since the yield
of the reaction for synthesis of 2a is much higher than for 2b,
this compound was chosen as the reagent of choice in this
reaction. We therefore focused our attention toward esterification
of various acids and alcohols and observed that 4,4′-azopyridine
(2a) as an easily prepared solid azo compound is very efficient
(Scheme 3) and useful for this purpose under our optimized
reaction conditions. Apart from the ease of handling and
preparation of 2a, its produced hydrazine byproduct from this
(7) (a) Toy, P. H.; But, T. Y. S. J. Am. Chem. Soc. 2006, 128, 9636–9637.
(b) Ve´liz, E. A.; Beal, P. A. Tetrahedron Lett. 2006, 47, 3153–3156. (c) Ba´lint,
´
A. M.; Bodor, A.; Go¨mo¨ry, A.; Ve´key, K.; Szabo´, D.; Ra´bai, J. J. Fluorine
Chem. 2005, 126, 1524–1530. (d) Szabo´, D.; Bonto, A. M.; Ko¨vesdi, I.; Go¨mo¨ry,
´
A.; Ra´bai, J. J. Fluorine Chem. 2005, 126, 641–652. (e) Harned, A. M.; He,
H. S.; Toy, P. H.; Flynn, D. L.; Hanson, P. R. J. Am. Chem. Soc. 2005, 127,
52–53. (f) Dandapani, S.; Curran, D. P. Chem.—Eur. J. 2004, 10, 3130–3138.
(g) Dembinski, R. Eur. J. Org. Chem. 2004, 2763–2772. (h) Dandapani, S.;
Curran, D. P. Tetrahedron 2002, 58, 3855–3864. (i) Dobbs, A. P.; McGregor-
Johnson, C. Tetrahedron Lett. 2002, 43, 2807–2810. (j) Pelletier, J. C.; Kincaid,
S. Tetrahedron Lett. 2000, 41, 797–800 .
(8) Yoakim, C.; Guse, I.; O’Meara, J. A.; Thavonekham, B. Synlett 2003,
473–476.
(9) Lipshutz, B. H.; Chung, D. W.; Rich, B.; Corral, R. Org. Lett. 2006, 8,
5069–5072.
(10) (a) Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003, 3, 317–334,
a/blmoldead.htm.
(11) (a) Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N. Tetrahedron 2006, 62,
5498–5501. (b) Iranpoor, N.; Firouzabadi, H.; Nowrouzi, N. Tetrahedron Lett.
2006, 47, 8247–8250. (c) Iranpoor, N.; Firouzabadi, H.; Akhlaghinia, B.;
Nowrouzi, N. Tetrahedron Lett. 2004, 45, 3291–3294. (d) Iranpoor, N.;
Firouzabadi, H.; Akhlaghinia, B.; Azadi, R. Synthesis 2004, 1, 92–96. (e)
Iranpoor, N.; Firouzabadi, H.; Aghapour, G. H.; Vaez Zadeh, A. R. Tetrahedron
2002, 58, 8689–8693.
(12) Launay, J. P.; Tourrel-Paggis, M.; Lipskier, J. F.; Marvaud, V.; Joachim,
C. Inorg. Chem. 1991, 30, 1033–1038.
J. Org. Chem. Vol. 73, No. 13, 2008 4883