An effective method for the synthesis of carboxamides by using tetrakis(pyridine-2-yloxy)silane as a mild coupling reagent

Article abstract of DOI:10.1246/cl.2005.1334

Tetrakis(pyridin-2-yloxy)silane [Si(OPy)₄] is easily prepared by trans-silylation between silicon tetrachloride and trimethyl(pyridin-2-yloxy) silane in the molar ratio of 1:4. This novel reagent is effectively employed as a mild dehydrating reagent in forming various carboxamides from the corresponding carboxylic acids and amines that involve secondary or tertiary alkyl substituted ones in good to high yields without using any basic promoters such as tertiary amines or 4-(dimethylamino)pyridine. Copyright

Full text of DOI:10.1246/cl.2005.1334

1334
Chemistry Letters Vol.34, No.10 (2005)
An Effective Method for the Synthesis of Carboxamides
by Using Tetrakis(pyridine-2-yloxy)silane as a Mild Coupling Reagent
Takashi Tozawa,y;yy Yoshinobu Yamane,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received July 7, 2005; CL-050877)
Tetrakis(pyridin-2-yloxy)silane [Si(OPy)4] is easily pre-
moters such as DMAP.5 These reactions by using reactive carbo-
nates as condensation reagents require a strict stepwise proce-
dure since the unreacted carbonates react directly with amines
to form undesired by-products such as ureas, carbamates, or
isothiocyanates that are often difficult to remove from the reac-
tion mixture.
In the course of our continuous investigations on the prepa-
ration of silicon-containing heterocycles and their application to
dehydration reactions, the use of pyridin-2-yloxysilane was fo-
cused upon. Now, we would like to report a mild and convenient
procedure for the synthesis of carboxamides from the corre-
sponding carboxylic acids and amines that involve secondary
or tertiary alkyl substituted ones by using tetrakis(pyridin-2-
yloxy)silane [Si(OPy)4], a novel dehydrating reagent.
pared by trans-silylation between silicon tetrachloride and trime-
thyl(pyridin-2-yloxy)silane in the molar ratio of 1:4. This novel
reagent is effectively employed as a mild dehydrating reagent in
forming various carboxamides from the corresponding carboxyl-
ic acids and amines that involve secondary or tertiary alkyl sub-
stituted ones in good to high yields without using any basic pro-
moters such as tertiary amines or 4-(dimethylamino)pyridine.
In our preceding paper, it was reported that various imida-
zolylsilane derivatives were easily synthesized by trans-silyla-
tion between 1-(trimethylsilyl)imidazoles and chlorosilanes.1 It
was revealed there that the novel reagents having silicon–imi-
dazole linkage were effectively utilized as dehydrating reagents
to form carboxamides from free carboxylic acids and amines via
the formation of active 1-acylimidazole intermediates under
mild conditions. While a classical azolide method by using
1,10-carbonyldiimidazole (CDI) as a condensation reagent re-
quires a strict stepwise operation so as to prevent the side reac-
tion of forming undesired urea,2 a new method with novel dehy-
drating reagents having silicon–imidazole linkage successfully
proceeds just by mixing carboxylic acids, amines, and imida-
zolylsilanes at a time. The desired carboxamides are afforded
then in good yields without accompanying any side-products
even when an excess amount of the dehydrating reagent is used.
Further, it is noted that the work-up procedure is quite simple
and carboxamides are obtained in almost pure form if tetra-
kis(2-methylimidazol-1-yl)silane [Si(2-Me-Im)4] is used since
the co-products of the reaction are 2-methylimidazole and silica
[(SiO2)n]. 2-Methylimidazole can be removed by washing with
dilute acid and the silica thus formed is removed easily just by
filtration since it is insoluble in any common solvents.
Based on our previously reported procedure employed for
the preparation of Si(2-Me-Im)4,1 tetrakis(pyridin-2-yloxy)-
silane [Si(OPy)4] was synthesized in almost quantitative yield
Table 1. Preparation of various carboxamides by using
Si(OPy)4
Si(OPy)4
O
O
(0.6 equiv.)
HNR2R3
+
R1
OH
R1
NR2R3
THF, rt, 24h
1
2
3
(1.2 equiv.)
(1.0 equiv.)
Entry
Carboxylic acid
Amine
Yielda/%
1
2
Ph(CH2)2CO2H
1a Ph(CH2)3NH2 2a
98
95b
61c
traced
96
1a
2a
2a
2a
3
1a
4
1a
5
1a
PhCH2NH2
Ph2CHNH2
2b
2c
6
1a
89
In the meantime, dehydrating reagents having 2-oxypyridine
moiety have been studied intensively, and it was demonstrated
that a convenient method for the synthesis of carboxamides or
dipeptides was attained in high yields from the corresponding
carboxylic acids and amines or ꢀ-amino acids by using di(2-
pyridyl) carbonate (DPC) or O,O-di(2-pyridyl) thiocarbonate
(DPTC) in the presence of a catalytic amount of 4-(dimethyl-
amino)pyridine (DMAP).3,4 Further, a still more efficient
method by employing 1,10-carbonyldioxydi[2(1H)-pyridone]
(CDOP) has also been accomplished in the absence of basic pro-
7
1a
PhCHMeNH2 2d
PhCH2NHMe 2e
95
8
1a
93
9
1a
Piperidine
2f
97
10
11
12
13
14
15
16
17
18
19
1a
PhNH2
2g
2h
86e
62e
90
1a
c-C6H11CO2H
1b
t-BuNH2
1b
1c
1d
2a
2f
85
t-BuCO2H
1c
2a
2b
2a
2f
80e
86e
84
PhCO2H
1d
73
(E)-MeCH=CHCO2H 1e
(Z)-MeCH=CMeCO2H 1f
2a
2a
86
SiCl4
+
Si
74
Me3SiO
N
4
O
N
−4Me3SiCl
aIsolated yield. bSi(OPy)4 (1.0 equiv.) was used. cSi(OPy)4 (0.3
equiv.) was used. dMe3SiOPy (1.0 equiv.) was used instead of
Si(OPy)4. eCarboxylic acid (1.5 equiv.) was used.
[Si(OPy)4]
(1.0 equiv.)
(4.0 equiv.)
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.10 (2005)
1335
or tertiary alkyl substituted ones in good to high yields under
very mild conditions. Further, its experimental procedure is quite
simple and the desired carboxamides are obtained in almost pure
form just by removing co-products, 2-hydroxypyridine (2-
PyOH) and silica [(SiO2)n], through extraction with water and
filtration.
O
O
R1
OH
R1
NR2R3
1
Si(OPy)4
2
O
X
X
X
+
3
+
Si
R1
O
A
−2-PyOH
HNR2R3
(SiO2)n
X = OPy, OSi, OCOR1, NR2R3
2
+
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
O
2-PyOH
R1
OPy
B
References and Notes
1
Scheme 2.
T. Tozawa, Y. Yamane, and T. Mukaiyama, Chem. Lett., 34,
734 (2005).
by trans-silylation between silicon tetrachloride (SiCl4) and tri-
methyl(pyridin-2-yloxy)silane (Me3SiOPy)6 in the molar ratio of
1:4 in dry toluene (Scheme 1). After removal of the solvent and
thus formed chlorotrimethylsilane (Me3SiCl), the resulting solid
product that can be stored without decomposition for several
weeks in a sealed bottle would be used directly for the next con-
densation reactions.7
2
a) H. A. Staab, H. Bauer, and K. M. Schneider, ‘‘Azolides in
Organic Synthesis and Biochemistry,’’ Wiley-VCH, Wein-
heim (1998), pp 129–208. b) H. A. Staab, Angew. Chem.,
Int. Ed. Engl., 1, 351 (1962). c) T. Kitagawa, H. Kuroda,
H. Sasaki, and K. Kawasaki, Chem. Pharm. Bull., 35, 4294
(1987). d) A. K. Saha, P. Schultz, and H. Rapoport, J. Am.
Chem. Soc., 111, 4856 (1989). e) R. Paul and G. W.
Anderson, J. Am. Chem. Soc., 82, 4596 (1960).
I. Shiina, Y. Suenaga, M. Nakano, and T. Mukaiyama, Bull.
Chem. Soc. Jpn., 73, 2811 (2000).
I. Shiina, K. Saitoh, M. Nakano, Y. Suenaga, and T.
Mukaiyama, Collect. Czech. Chem. Commun., 65, 621
(2000).
I. Shiina and Y. Kawakita, Tetrahedron Lett., 44, 1951
(2003).
a) A. R. Bassindale, M. Borbaruah, S. J. Glynn, D. J. Parker,
and P. G. Taylor, J. Chem. Soc., Perkin Trans. 2, 1999, 2099.
b) M. J. Buchanan, R. H. Cragg, and A. Steltner, J. Organo-
met. Chem., 120, 189 (1976).
As a preliminary experiment, the reaction of 3-phenylpropa-
noic acid 1a (1.2 equiv.) and 3-phenylpropylamine 2a (1.0
equiv.) was examined in THF by using Si(OPy)4 (0.6 equiv.)
at room temperature, and the corresponding carboxamide was
obtained in 98% yield (Table 1, Entry 1). When Me3SiOPy
was used instead of Si(OPy)4, on the other hand, only a trace
amount of the desired carboxamide was formed (Entry 4). Sev-
eral examples of carboxamides 3 obtained by using Si(OPy)4 as
a dehydrating reagent are listed in Table 1.8 In most cases, the
reactions proceeded smoothly at room temperature to form the
corresponding carboxamides 3 in good to high yields even when
highly hindered carboxylic acids or amines such as pivalic acid
1c or tert-butylamine 2h were used. In addition, it was found that
no substantial isomerization took place either when base-sensi-
tive substrates such as crotonic acid 1e or angelic acid 1f were
used (Entries 18 and 19).5 This is because the present reactions
are carried out without using any bases such as tertiary amines or
DMAP.
The proposed mechanism for the formation of carboxamides
from free carboxylic acids and amines by using Si(OPy)4 is as
follows (Scheme 2). Free carboxylic acids 1 react readily with
Si(OPy)4 to form silyl ester intermediates A along with elimina-
tion of 2-hydroxypyridine [2(1H)-pyridone]. In the case when
Si(2-Me-Im)4 is used as a dehydrating reagent, in situ formed
silyl ester intermediates are smoothly transformed into the corre-
sponding 1-acyl-2-methylimidazoles by nucleophilic attack of
2-methylimidazole to the carbonyl carbon.1 In this reaction by
using Si(OPy)4, other active intermediates such as 2-pyridyl
esters B are not detected at all because 2-hydroxypyridine [2-
(1H)-pyridone] is a weakly nucleophilic substance. Therefore,
it is considered that reactive silyl ester intermediates A directly
undergo the subsequent condensation with amines 2 to afford the
desired carboxamides 3.
3
4
5
6
7
Preparation of tetrakis(pyridin-2-yloxy)silane [Si(OPy)4]
(Scheme 1). To a solution of Me3SiOPy (10.5 g, 62.8 mmol)
in toluene (5 mL) was added slowly SiCl4 (1.46 mL, 12.7
mmol) at room temperature under argon. The precipitation
of a white solid was observed. After the mixture was stirred
at 80 ꢁC for 1 h, the generated Me3SiCl and the solvent were
removed under reduced pressure to give a white powder
in almost quantitative yield (6.35 g). The reagent can be
handled for brief periods in the air though it is sensitive to
moisture. 1H NMR (270 MHz, CDCl3) ꢁ 8.02 (brs, 1H),
7.56 (brs, 1H), 6.99 (brs, 1H), 6.82 (brs, 1H); 13C NMR
(67.8 MHz, CDCl3) ꢁ 159.5, 147.1, 139.0, 118.2, 113.0.
General procedure for the preparation of carboxamides by
using Si(OPy)4 (Table 1); To a stirred suspension of
Si(OPy)4 (0.3 mmol) in THF (0.75 mL) was successively
added a carboxylic acid (0.6 mmol) and a solution of an
amine (0.5 mmol) in THF (0.75 mL) at room temperature.
The reaction mixture was stirred for 24 h at the same temper-
ature, followed by the addition of water. Precipitated silica
was filtered and washed with EtOAc, and then the filtrate
was extracted with EtOAc. The organic layer was washed
with 1 M HCl aq, saturated NaHCO3 aq, and brine, dried
over anhydrous Na2SO4. After filtration, the solvent was
removed under reduced pressure to afford an almost pure
8
Thus, a novel dehydrating reagent, Si(OPy)4, was easily pre-
pared by trans-silylation between SiCl4 and Me3SiOPy, and was
used conveniently for the preparation of various carboxamides
from free carboxylic acids and amines that involve secondary
1
(by H NMR and TLC) carboxamide.
Published on the web (Advance View) September 3, 2005; DOI 10.1246/cl.2005.1334