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Facile conversion of carboxamides to nitriles
Tetrahedron Letters,Vo1.27,No.2O,pp printed in Great Britain
2203-2206,1986
0040-4039/86 $3.00 + .OO Pergamon Journals Ltd.
FACILE CONVERSION OF CARBOXAMIOES TO NITRILES
Khuong Mai* and Ghanshyam Section
of Medicinal/Organic
American
Summary: readily
Alkyl,
require
aralkyl,
converted
trichloromethyl
Supply
chloroformate,
extraction,
American
Corporation,
aryl, heteroaryl
to the corresponding
McGaw Park,
carboxamides
nitriles
as dehydrating
Critical
bearing
in good yields
Care Division
Illinois
various
60085
functionalities
using the liquid
are
"diphosgene",
In many cases, the procedure does not
agent.
and hence offers a very simple work-up.
The preparation Certain
Hospital
Chemistry,
Patil
of nitriles
by the dehydration
of carboxamides
is very well documented.1-24
amides
conditions
have been converted to nitriles with the basic reagents, where relative drastic l-4 have been employed. Some examples have involved mesitamide with sodium hydroxide
in refluxing
ethylene
phenylacetamide for several
glycol,l
benzamide
with 3.3 equivalents
hours.4
with
"deficient"
of n-butyl
On the other hand acidic
amount of lithium aluminum
lithium,3
reagents
and benzamide
appear
hydride,2
with silazanes
to offer milder
conditions
at 220' and
trimethylsilyl polyphosphate,7 chloride,5 ethyl polyphosphate,6 8 lo tricyanuric chloride/dimethylformamide, Vilsmeier reagent,' triethoxydiiodophosphorane, 12 fluoroacetic anhydride,l' triphenylphosphine ditriflate, titanium tetrachloride,13 triphenylbetter yields:
Trichloroacetyl
phosphine, l4 boron trifluoride,15 /dimethylformamide,18 phosphorous dine,20 the development
phosphoryl
chlorosilane,16
chlorosulfonyl
carboxamides good yields
of new, mild methods
bearing
procedure
In a well-ventilated
of the reaction
to nitriles
using
aryl, and heteroaryl
to the corresponding
nitriles
in
Preparation
of 3,5_dinitrobenzonitrile
(CAlJTION).25
chloroformate 26 (2 ml) was added dropwise
of 3,5_dinitrobenzamide
(2.1 g; 10 mmol)
in trimethyl
to a cold
phosphate
(6.3
was then slowly heated to 60' for 5 minutes to ensure the completion 27 After cooling down in an iceand also to drive away any generated phosgene. mixture
to eliminate
127-129',
from isopropyl
were converted
aralkyl,
1.
is as follows:
troy any trace of phosgene
(96%), m.p.
of carboxamides
Alkyl,
mixture
bath, the reaction
hed with water
chloroformate.
functionalities
hood, trichloromethyl
solution
ml). The reaction
water
various
there still exists a need for
for this conversion.
trichloromethyl
as shown in TABLE
(O-5'), stirred
chloride
chloridelpyridine, However,
"diphosgene",
A typical
thionyl
pentoxide, and thionylchlori~~~Pminum ch10ridey20tosy' chloride'pyri-
In this paper, we wish to report a simple dehydration the liquid
isocyanate,17
was vigorously
and chloroformate.
stirred
The precipitated
trace of HCl and trimethyl
IR and NMR are consistent
ether gave an analytically
and ice-water
2203
solid product was filtered,
phosphate,
with the assigned
pure product,
m.p.
(10 g) was added to des-
and air-dried; structure.
130-131'.
yield:
was-
1.88 g
Recrystallization
2204
TABLE
1:
Conversion
of Carboxamides
to Nitriles
#
CARBOXAMIOE
PRODUCTa
YIELD
1
(CH3)3CONH2
(CH3)3CN
76b
105o/755
2
H2NCO(CH2)6CONH2
NC(CH2)6CNC
87
120°/o.1
3
dl-Thioctic
dl-Thioctonitrile
92
4
c-C3H5CONH2
c-C3H5CN
86
13501755
5
c-C6HllCONH2
c-C6HllCN
93
47'/1.2
6
1-Naphthylacetamide
I-Naphthylacetonitrile
96
107O/o.3
7
2-MeOC6H4CH2CONH2
2-MeOC6H4CH2CN
91
67-69'
8
trans-Cinnamamide
trans-Cinnamonitrile
79
84'/0.3
9
C6H5QC-CONH2
C6H5C3C-CN
90
37-39O
10
2-HOC6H4CONH2
2-HOC6H4CN
89
96-97'
11
4-HOC6H4CONH2
4-HOC6H4CN
94
114-115O
12
4-MeOC6H4CONH2
4-MeOC6H4CN
97
58-60'
13
2-02NC6H4CONH2
2-02NC6H4CN
93
108-110'
14
3,5-(02N)2C6H3CONH2
3,5-(02N)2C6H3CN
96
130-131°
15
2-CIC6H4CONH2
2-C1C6H4CN
91
45-46'
16
2,6-C12C6H3CONH2
2,6-C12C6H3CN
95
143-144O
17
4-BrC6H4CONH2
4-BrC6H4CN
95
113-114O
18
2-IC6H4CONH2
2-IC6H4CN
88
54-55O
19
I-Naphthalenecarboxamide
1-Cyanonaphthalene
79
106'/0.2
20
2-Naphthalenecarboxamide
2-Cyanonaphthalene
97
65-66'
21
9-Anthracenecarboxamide
9-Cyanoanthracene
86
177-179O
22
2-Thiophenecarboxamide
2-Thiophenecarbonitrile
77
46'/1.0
23
2-Furancarboxamide
2-Furancarbonitrile
81
15001755
24
Nicotinamide
3-Cyanopyridine
Acid Amide
0
(%)
MP. or BP.('C)/Torr
__ d
__
2205
a) All known nitriles show physical and spectral properties identical to those reported in the literature. b) The low yield is probably due to the volatility of the product. c) Double amounts of trichloromethylchloroformate were employed. d) Isolated as an oil, NMR and IR data are consistent with the assigned structure.
In cases where the product separated as an oil, ether was added and the organic layer was washed with water, 5% sodium bicarbonate, brine, dried over magnesium sulfate, and evaporated to an oil. In all cases, the IR spectra showed the disappearance of the carbonyl absorption and the appearance of the nitrile group. By analogy to the general mechanism proposed for this type of dehydration by a derivatized acidic reagent, the reaction probably undergoes according to the pathway and the stoichiometry shown in the following scheme:
R-C-NH2 II 0
-co*
,A
R-C=NH I OH
+
c13c0c0c1
-HCl __)
R-C=&H ~~,s,,,,
Cl t
R-CGN
+
3
8
H-O--E-Cl
R-CEN
-
+
HCl
+
c12co
Cl
Overall:
RCONH2
+
c13cococ1
-
RCN
+
2HCl
+
CO2
+
c12co
We believe that the liberated phosgene (Cl2CO) does not further react with another molecule of carboxamide since in a separate experiment under similar conditions, carboxamide remained intact in the presence of excess amount of phosgene. In fact, it has been reported that carbo24 23 xamides react with phosgene only in the presence of pyridine, or at higher temperature. Interestinglyenough, P-hydroxybenzamide(entry # 10) dehydrated easily to 2-cyanophenol in good yield without any contamination of the expected cyclic adduct.
0 a
CNOH
Athough the reaction appears to be fairly general, it should be mentioned that pentafluorobenzamide reacted very slowly with C13COCOCl (only 10% completion after 2 hours); also nicotinamide remained intact after heating for 2 hours; this is probably due to the insolubility of ’ nicotinamide.HCl in trimethyl phosphate (HCl salt is formed in situ). When dioxane, acetonitrile, and tetrahydrofuranwere used as solvents, the reaction seems to slow down dramatically as shown in TABLE 2:
2206 TABLE 2:
Solvent Effect for the Dehydration of ~arboxamides
Substrate
So‘lvent
Time to Completiona
Condition
trans"~~nnamam~de
(MeO)3PO
I5 minutes
60°
Dioxane
120
#I
7o"
CH3CN
150
II
ReflUX
THF
300
Ii
Reflux
5
'&
R.T.
DiOXi3fKZ
120
'I
7o"
CH3CN
120
Ii
Reflux
THF
240
ti
Reflux
(MeO~3PO
2
'I
R+T*
THF
2
'*
R.T.
(~e~}3P~
Trimethy~acetamjde
a) The progress of the reaction was followed by TLC. In conclusion, the good yield, the short reaction period, the simple work-up, and the fairly mild condition demonstrate the usefulness and the versatility of this synthetic method. This report therefore offers an alternative to the well documented dehydration of carboxam~des. REFERENCES and NOTES: M. S, Ne~an, T. Fukunaga, J. Am. Chem, Sot. 82, 693 (196G). L,Tsai, T. Mfwa, M, S. Newman, 3, Am. Chem. Sot. 79, 2530 (1957 MI.Kaiser, R. L.Vaulx, C. R. Hauser, J. Org. Chem. 32, 3640 i967). E. Dennis, J. Org. Chem. 3B, 3253 (IQ?O). Saednya, Synthesis 1985, 184, Imamoto, T. Takaota, M. Yokoyama, Synthesis 1983, 142, Yokoyama, S. Yoshida, T. Imamoto, Synthesis m, 591. A. Olah, S. C. Narang, A. P. Fung, B. G. B. Gupta, Synthesis 1980, 657. M. BargarB C. M. Riley, Synth. Commun. a, 479 (1980). Cooper, S. Trippet, Tetrahedron Lett. 1979, 1725. Campagna, A. Carroti, 6. Casini, Tetrahedron Lett. 1977, 1813, 3. Hendrickson, S. M. Schwartzman, Tetrahedron Lettrm, 277. Lehnert, Tetrahedron Lett. 192_1,1501. Yamato, S. Sugasawa. Tetrahedron Lett. '1970,4383. Kanaoka, T, Kuga, K. Tanizawa, Ehem. PhK Bull. lJ_*397 (1970). E. Dennis, 3. Org. Chem. 35, 3253 (1970). A. Olah, Y, D. Qankar, A. Garcialuna, Synthesis 1979, 227, C. Thurman, Chem. Ind. (London) 1964, 752. Ser. Sci. Chem. lo, 227 (1962); C.A. 59, 4031 (1963). Libereck, Bull. Acd. Polon. Sci., Pesson et al., Bull. Sot. Chim. Fr. 1965, 2262. B. Reisner, E. C, Corning, Org. Synth. Coil. Vol. IV_,144 (1963). A. Krynitsky, H. W. Carhart, Org. Synth. COT?. Vol. IQ, 436 (1963). E. Ficken, H. France, R. P. Linstead, J. Chem. Sot. n54, 3730 Greenhalgh, Brit. Patent # 488,036; C.A. 33, P:178(3). CADTIOX: Paper soaked with a solution of 10% p-dimethy~aminoban~a~debyde and colorless d~p[~~ny~arnin~ in ethanol, then dried, wilf turn from yellow to deep orange in the presence of the maximum allowable concentrationof phosgene. See the Merk Index for further details and precautions. 26. Purchased from Fluka Chemical Corp., Haupp~~ge, New York 11787* 27. To ensure the dehydration, the reaction mixture was coofed to +IOo; another 1 ml of trich~oromethy~cb~o~fo~ate was added, and heating was resumed for another 5 minutes, fl?e\teceived in USA 3 January 1986)
2203-2206,1986
0040-4039/86 $3.00 + .OO Pergamon Journals Ltd.
FACILE CONVERSION OF CARBOXAMIOES TO NITRILES
Khuong Mai* and Ghanshyam Section
of Medicinal/Organic
American
Summary: readily
Alkyl,
require
aralkyl,
converted
trichloromethyl
Supply
chloroformate,
extraction,
American
Corporation,
aryl, heteroaryl
to the corresponding
McGaw Park,
carboxamides
nitriles
as dehydrating
Critical
bearing
in good yields
Care Division
Illinois
various
60085
functionalities
using the liquid
are
"diphosgene",
In many cases, the procedure does not
agent.
and hence offers a very simple work-up.
The preparation Certain
Hospital
Chemistry,
Patil
of nitriles
by the dehydration
of carboxamides
is very well documented.1-24
amides
conditions
have been converted to nitriles with the basic reagents, where relative drastic l-4 have been employed. Some examples have involved mesitamide with sodium hydroxide
in refluxing
ethylene
phenylacetamide for several
glycol,l
benzamide
with 3.3 equivalents
hours.4
with
"deficient"
of n-butyl
On the other hand acidic
amount of lithium aluminum
lithium,3
reagents
and benzamide
appear
hydride,2
with silazanes
to offer milder
conditions
at 220' and
trimethylsilyl polyphosphate,7 chloride,5 ethyl polyphosphate,6 8 lo tricyanuric chloride/dimethylformamide, Vilsmeier reagent,' triethoxydiiodophosphorane, 12 fluoroacetic anhydride,l' triphenylphosphine ditriflate, titanium tetrachloride,13 triphenylbetter yields:
Trichloroacetyl
phosphine, l4 boron trifluoride,15 /dimethylformamide,18 phosphorous dine,20 the development
phosphoryl
chlorosilane,16
chlorosulfonyl
carboxamides good yields
of new, mild methods
bearing
procedure
In a well-ventilated
of the reaction
to nitriles
using
aryl, and heteroaryl
to the corresponding
nitriles
in
Preparation
of 3,5_dinitrobenzonitrile
(CAlJTION).25
chloroformate 26 (2 ml) was added dropwise
of 3,5_dinitrobenzamide
(2.1 g; 10 mmol)
in trimethyl
to a cold
phosphate
(6.3
was then slowly heated to 60' for 5 minutes to ensure the completion 27 After cooling down in an iceand also to drive away any generated phosgene. mixture
to eliminate
127-129',
from isopropyl
were converted
aralkyl,
1.
is as follows:
troy any trace of phosgene
(96%), m.p.
of carboxamides
Alkyl,
mixture
bath, the reaction
hed with water
chloroformate.
functionalities
hood, trichloromethyl
solution
ml). The reaction
water
various
there still exists a need for
for this conversion.
trichloromethyl
as shown in TABLE
(O-5'), stirred
chloride
chloridelpyridine, However,
"diphosgene",
A typical
thionyl
pentoxide, and thionylchlori~~~Pminum ch10ridey20tosy' chloride'pyri-
In this paper, we wish to report a simple dehydration the liquid
isocyanate,17
was vigorously
and chloroformate.
stirred
The precipitated
trace of HCl and trimethyl
IR and NMR are consistent
ether gave an analytically
and ice-water
2203
solid product was filtered,
phosphate,
with the assigned
pure product,
m.p.
(10 g) was added to des-
and air-dried; structure.
130-131'.
yield:
was-
1.88 g
Recrystallization
2204
TABLE
1:
Conversion
of Carboxamides
to Nitriles
#
CARBOXAMIOE
PRODUCTa
YIELD
1
(CH3)3CONH2
(CH3)3CN
76b
105o/755
2
H2NCO(CH2)6CONH2
NC(CH2)6CNC
87
120°/o.1
3
dl-Thioctic
dl-Thioctonitrile
92
4
c-C3H5CONH2
c-C3H5CN
86
13501755
5
c-C6HllCONH2
c-C6HllCN
93
47'/1.2
6
1-Naphthylacetamide
I-Naphthylacetonitrile
96
107O/o.3
7
2-MeOC6H4CH2CONH2
2-MeOC6H4CH2CN
91
67-69'
8
trans-Cinnamamide
trans-Cinnamonitrile
79
84'/0.3
9
C6H5QC-CONH2
C6H5C3C-CN
90
37-39O
10
2-HOC6H4CONH2
2-HOC6H4CN
89
96-97'
11
4-HOC6H4CONH2
4-HOC6H4CN
94
114-115O
12
4-MeOC6H4CONH2
4-MeOC6H4CN
97
58-60'
13
2-02NC6H4CONH2
2-02NC6H4CN
93
108-110'
14
3,5-(02N)2C6H3CONH2
3,5-(02N)2C6H3CN
96
130-131°
15
2-CIC6H4CONH2
2-C1C6H4CN
91
45-46'
16
2,6-C12C6H3CONH2
2,6-C12C6H3CN
95
143-144O
17
4-BrC6H4CONH2
4-BrC6H4CN
95
113-114O
18
2-IC6H4CONH2
2-IC6H4CN
88
54-55O
19
I-Naphthalenecarboxamide
1-Cyanonaphthalene
79
106'/0.2
20
2-Naphthalenecarboxamide
2-Cyanonaphthalene
97
65-66'
21
9-Anthracenecarboxamide
9-Cyanoanthracene
86
177-179O
22
2-Thiophenecarboxamide
2-Thiophenecarbonitrile
77
46'/1.0
23
2-Furancarboxamide
2-Furancarbonitrile
81
15001755
24
Nicotinamide
3-Cyanopyridine
Acid Amide
0
(%)
MP. or BP.('C)/Torr
__ d
__
2205
a) All known nitriles show physical and spectral properties identical to those reported in the literature. b) The low yield is probably due to the volatility of the product. c) Double amounts of trichloromethylchloroformate were employed. d) Isolated as an oil, NMR and IR data are consistent with the assigned structure.
In cases where the product separated as an oil, ether was added and the organic layer was washed with water, 5% sodium bicarbonate, brine, dried over magnesium sulfate, and evaporated to an oil. In all cases, the IR spectra showed the disappearance of the carbonyl absorption and the appearance of the nitrile group. By analogy to the general mechanism proposed for this type of dehydration by a derivatized acidic reagent, the reaction probably undergoes according to the pathway and the stoichiometry shown in the following scheme:
R-C-NH2 II 0
-co*
,A
R-C=NH I OH
+
c13c0c0c1
-HCl __)
R-C=&H ~~,s,,,,
Cl t
R-CGN
+
3
8
H-O--E-Cl
R-CEN
-
+
HCl
+
c12co
Cl
Overall:
RCONH2
+
c13cococ1
-
RCN
+
2HCl
+
CO2
+
c12co
We believe that the liberated phosgene (Cl2CO) does not further react with another molecule of carboxamide since in a separate experiment under similar conditions, carboxamide remained intact in the presence of excess amount of phosgene. In fact, it has been reported that carbo24 23 xamides react with phosgene only in the presence of pyridine, or at higher temperature. Interestinglyenough, P-hydroxybenzamide(entry # 10) dehydrated easily to 2-cyanophenol in good yield without any contamination of the expected cyclic adduct.
0 a
CNOH
Athough the reaction appears to be fairly general, it should be mentioned that pentafluorobenzamide reacted very slowly with C13COCOCl (only 10% completion after 2 hours); also nicotinamide remained intact after heating for 2 hours; this is probably due to the insolubility of ’ nicotinamide.HCl in trimethyl phosphate (HCl salt is formed in situ). When dioxane, acetonitrile, and tetrahydrofuranwere used as solvents, the reaction seems to slow down dramatically as shown in TABLE 2:
2206 TABLE 2:
Solvent Effect for the Dehydration of ~arboxamides
Substrate
So‘lvent
Time to Completiona
Condition
trans"~~nnamam~de
(MeO)3PO
I5 minutes
60°
Dioxane
120
#I
7o"
CH3CN
150
II
ReflUX
THF
300
Ii
Reflux
5
'&
R.T.
DiOXi3fKZ
120
'I
7o"
CH3CN
120
Ii
Reflux
THF
240
ti
Reflux
(MeO~3PO
2
'I
R+T*
THF
2
'*
R.T.
(~e~}3P~
Trimethy~acetamjde
a) The progress of the reaction was followed by TLC. In conclusion, the good yield, the short reaction period, the simple work-up, and the fairly mild condition demonstrate the usefulness and the versatility of this synthetic method. This report therefore offers an alternative to the well documented dehydration of carboxam~des. REFERENCES and NOTES: M. S, Ne~an, T. Fukunaga, J. Am. Chem, Sot. 82, 693 (196G). L,Tsai, T. Mfwa, M, S. Newman, 3, Am. Chem. Sot. 79, 2530 (1957 MI.Kaiser, R. L.Vaulx, C. R. Hauser, J. Org. Chem. 32, 3640 i967). E. Dennis, J. Org. Chem. 3B, 3253 (IQ?O). Saednya, Synthesis 1985, 184, Imamoto, T. Takaota, M. Yokoyama, Synthesis 1983, 142, Yokoyama, S. Yoshida, T. Imamoto, Synthesis m, 591. A. Olah, S. C. Narang, A. P. Fung, B. G. B. Gupta, Synthesis 1980, 657. M. BargarB C. M. Riley, Synth. Commun. a, 479 (1980). Cooper, S. Trippet, Tetrahedron Lett. 1979, 1725. Campagna, A. Carroti, 6. Casini, Tetrahedron Lett. 1977, 1813, 3. Hendrickson, S. M. Schwartzman, Tetrahedron Lettrm, 277. Lehnert, Tetrahedron Lett. 192_1,1501. Yamato, S. Sugasawa. Tetrahedron Lett. '1970,4383. Kanaoka, T, Kuga, K. Tanizawa, Ehem. PhK Bull. lJ_*397 (1970). E. Dennis, 3. Org. Chem. 35, 3253 (1970). A. Olah, Y, D. Qankar, A. Garcialuna, Synthesis 1979, 227, C. Thurman, Chem. Ind. (London) 1964, 752. Ser. Sci. Chem. lo, 227 (1962); C.A. 59, 4031 (1963). Libereck, Bull. Acd. Polon. Sci., Pesson et al., Bull. Sot. Chim. Fr. 1965, 2262. B. Reisner, E. C, Corning, Org. Synth. Coil. Vol. IV_,144 (1963). A. Krynitsky, H. W. Carhart, Org. Synth. COT?. Vol. IQ, 436 (1963). E. Ficken, H. France, R. P. Linstead, J. Chem. Sot. n54, 3730 Greenhalgh, Brit. Patent # 488,036; C.A. 33, P:178(3). CADTIOX: Paper soaked with a solution of 10% p-dimethy~aminoban~a~debyde and colorless d~p[~~ny~arnin~ in ethanol, then dried, wilf turn from yellow to deep orange in the presence of the maximum allowable concentrationof phosgene. See the Merk Index for further details and precautions. 26. Purchased from Fluka Chemical Corp., Haupp~~ge, New York 11787* 27. To ensure the dehydration, the reaction mixture was coofed to +IOo; another 1 ml of trich~oromethy~cb~o~fo~ate was added, and heating was resumed for another 5 minutes, fl?e\teceived in USA 3 January 1986)