conversions are found to occur in significantly short dura-
tions. Owing to the readily available starting materials from
Friedel-Crafts acylation,11 this method could expand the
scope of the formation of primary amides and simplify
synthetic procedures.
Scheme 1
.
Preparation of Primary Amides from Various
Compounds
Initially, we investigated the favorable condition of the
transformation reaction from methyl ketones to the corre-
sponding primary amides using acetophenone as a model
substrate in the presence of molecular iodine and aqueous
ammonia (25%) in various solvents (entries 1-9, Table 1).
catalysts including homogeneous and heterogeneous com-
plexes (Path II).4 The rearrangement of aldoximes to the
primary amides using transition metal catalysts has also been
reported (Path III).5 Recently, one example of oxidative
primary amide synthesis has been achieved from terminal
alkynes catalyzed by metalloporphyrins (Path IV).6 Further-
more, two excellent transformations, heterogeneously ruthe-
nium-catalyzed dehydrogenative coupling of primary alco-
hols with amines (Path V)7 and oxygenation of primary
amines to amides (Path VI),8 have been reported, sequen-
tially.
Table 1. Optimization Studies in the Synthesis of Benzamidea
entry
amine
T (°C) solvent time (h) yield (%)b
1
2
3
4
5
6
7
8
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
NH3·H2O
(NH4)2CO3
(NH4)2SO4
NH4Cl
60
60
60
60
60
60
60
60
60
20
90
60
60
60
60
60
60
MeOH
MeCN
THF
CH2Cl2
DME
DMF
EtOAc
DMSO
H2O
H2O
H2O
H2O
H2O
4
4
4
4
4
4
4
4
1
72
1
1
2
4
5
1
5
<5
<5
<5
<5
<5
<5
<5
<5
86
23
85
28
Water is essential for the survival of all known forms of
life and it covers 71% of the Earth’s surface. Compared to
reactions in organic solvents, there are many potential
advantages using water as a solvent for organic reactions:
cheap, nontoxic, environmental friendly, etc. In the last two
decades, a series of novel synthetic methodologies have been
developed in aqueous media.9 In the course of our continuing
studies on self-sorting tandem reactions,10 a novel transfor-
mation to access primary amides in aqueous media has been
put forward. The wider application of amides and the
precipitation of partially converted amides led us to explore
this new protocol. In this paper, we show that a novel and
direct transformation of methyl ketones or carbinols to the
corresponding primary amides smoothly occurred in the
presence of molecular iodine by employing aqueous am-
monia. In addition to the simplicity of this procedure, the
9
10
11
12c
13
14
15
16
17
NRd
NRd
NRd
NRd
NRd
H2O
H2O
H2O
H2O
HCOONH4
CH3COONH4
a Reaction conducted with 1 mmol of acetophenone, 10 mmol of amine
and 3 mmol of I2 in 25 mL solvent. b Isolated yields. c Only 1 mmol of I2
was used. d No reaction.
Benzamide was obtained with 5% yields when MeOH,
MeCN, THF, CH2Cl2, DME, DMF, EtOAc or DMSO was
used as solvent. It was notable, however, that this transfor-
mation occurred smoothly in H2O, with 86% yields.12 Next,
the effect of reaction temperature on the yield of the primary
amide product 2a was examined. A lower conversion was
observed upon heating the reaction mixture to 90 °C or from
performing the reaction at 20 °C when the reaction was
carried out in water (entries 10-11, Table 1). Furthermore,
the experimental data indicated that the reaction was not
completed when the reaction time was less than 1 h at 60
°C. The number of equivalents of iodine had an influence
on isolated yields of the reaction. In entry 12, the yields
changed from 86 to 28% when the mole ratios between
iodine and acetophenone were changed from 3:1 to 1:1. Then,
(5) (a) Field, L.; Hughmark, P. B.; Shumaker, S. H.; Marshall, W. S.
J. Am. Chem. Soc. 1961, 83, 1983. (b) Leusink, A. J.; Meerbeek, T. G.;
Notles, J. G. Recueil TraV. Chim. Pays-Bas 1976, 95, 123. (c) Park, S.;
Choi, Y.; Han, H.; Yang, S. H.; Chang, S. Chem. Commun. 2003, 1936.
(d) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9,
3599. (e) Fujiwara, H.; Ogasawara, Y.; Yamaguchi, K.; Mizuno, N. Angew.
Chem., Int. Ed. 2007, 46, 5202. (f) Owston, N. A.; Parker, A. J.; Williams,
J. M. J. Org. Lett. 2007, 9, 73.
(6) Chan, W. K.; Ho, C. M.; Wong, M. K.; Che, C. M. J. Am. Chem.
Soc. 2006, 128, 14796.
(7) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (b) Zweifel, T.; Naubron, J. V.; Gru¨tzmacher, H. Angew. Chem., Int.
Ed. 2009, 48, 559.
(8) (a) Mori, K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K.
Chem. Commun. 2001, 461. (b) Kim, J. W.; Yamaguchi, K.; Mizuno, N.
Angew. Chem., Int. Ed. 2008, 47, 9249.
(9) (a) Li, C. J.; Chen, L. Chem. Soc. ReV. 2006, 35, 68. (b) Li, C. J.;
Chan, T. H. ComprehensiVe Organic Reactions in Aqueous Media, 2nd
ed.; Wiley-VCH: New York, 2007.
(10) (a) Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan, Y. J.
Org. Lett. 2006, 8, 2245. (b) Yin, G. D.; Wang, Z. H.; Chen, A. H.; Gao,
M.; Wu, A. X.; Pan, Y. J. J. Org. Chem. 2008, 73, 3377.
(11) (a) Friedel, C.; Crafts, J. M. Compt. Rend. 1877, 84, 1392. (b) Li,
J. J. Name Reaction: A Collection of Detailed Reaction Mechanisms, 3rd
ed.; Springer-Verlag: Berlin, 2006; p 240.
(12) The combination of ammonia and iodine in aqueous media may
lead to the formation of explosive NI3. Synthesis and properties of NI3,
see: Klapo¨tke, T.; Tornieporth-Oetting, I. Angew. Chem., Int. Ed. 1990,
29, 677.
Org. Lett., Vol. 11, No. 17, 2009
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