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The action of substituted formamides on arylformylacetonitriles
Tmhd~dron.
Vol. 26. pp 2377 lo 2381.
Pcrgamon Rer,
1972.
Rioted in Great Britain
THE ACTION OF SUBSTITUTED FORMAMIDES ARYLFORMYLACETONITRILES J. D. Department0
BON-E
and R. R. MATUDA
de Quimica OrgBnica. Facultad de Farmacia y Bioquimica. Buenos Aires. Argentina.
(Received in the USA 30 August 197 1; Received in the UKforpublication
Abstraeformamides
ON
Universidad de
18 Jamcary 1972)
The reaction between phenyl- or p-methoxy phenylformylacetonitrile and monosubstituted results in enaminonitriles. In some instances a simultaneous deformylation is observed.
Formic acid is produced during the reaction and its origin was investigated. PHENYLFORMYLACETONITRILE (1) reacts with formamide’ or N,N-disubstituted formamides’ giving enamines To complete the study, the action of N-monosubstituted formamides on 1 was investigated. R
C II
H
JN
H/%H 1-2 R l=H 2=OMe
+
L=o k-H \
C' H/
CN
!i\ N /
\
RI 3-l
8-15
RI 3=Me 4 = Et 5 = -CHz phenyl
see table
H R, -
t C% I CN
m-21 R 2O=H 21 = OMe
6 = cyclohexyl 7 = -phenyl
Compound 1 was heated at 160” with a fourfold excess of 3, for several hours. The IR spectrum of product (8) showed bands at 3367 (NH), 2208 (conjugated nitrile), 1637 and 897 (trisubstituted C=C), 752 and 690 cm-’ (monosubstituted benzene). The NMR spectrum of 8 supported the enamine structure, giving peaks centered at 6: 3.07 (3H, d, .I : 5 cps, N-Me), 7.03 (lH, vinyl) and 7.28 ppm (5H, m, aromatic) : its UV spectrum, (EtOH) gave absorption at 213.1 (log E: 353), 226.6 (log E: 364), 239.1 (log E: 3*32),252.7 (log E: 3*45),265.2 (log E: 3*35),293.4 (log E: 3*77), 301.7 (log E: 3*71)and314*1 nm(loge: 3.74). The synthesis was extended to p-methoxyphenylformylacetonitrile (2) and other mono- and disubstituted formamides, and in every instance the analytical and spectrophotometrical data of the products was consistent with those of the parent compounds. However, besides the formation of enamines, the reaction also gave simultaneous deformylation of 1. This secondary reaction took place only with aliphatic mono2377
TABLE 1.
C H
,CN
01s
R,
Found H
ChlC.
Enamine
R
38.0 51.0 81.0 72.1 81.6 89.1 753 73.1 75.1
75.92 76.74 82.02 7960 81.81 71.27 74.97 76.78 71.27
637 697 602 8.01 5.45 6.97 7.86 5.63 697
17.70 16.27 11.96 12.39 12.72 13.84 1092 11.18 13.84
76.01 1689 82Q8 79.67 81.92 71.50 15.30 7650 71.35
6.42 7.03 6.12 8.09 5.41 7.07 7.82 5% 7.41
17.60 16.20 1190
3
87-88
704
7439
7.49
11.55
74.50
7.40
11.75
W
124-125
78.0
68.83
660
1146
68.70
6.13
11.31
167.5-168.5
64.5
85.11
5.44
9,49
85.1
5.22
9 10 11 12 13 14 15 16 17
--OMe
-N-N
18
-0Me
.-N-
19
H
-N(Ph),
- .._ -
-. l
Bibliog.’ 157-l 58”
C
99.5-1005 53-54 150-I51 1X-127 157.5-158.5. 120-121 90-91 160-161 87.5-88.5
--NH(Me) -NH(Et) -NH(Bz) -NH(GH,J - NH(Ph) -NH@) -NH(C,H,,) -NH(Ph) - N(Me),
H
N
Yields”/,
H H H H H AIlMe A)Me -0Me -0Me
8
C
M.p.
RI
~.
N
..-
--
m S
Si g
12.28 12.68 14.05
&
1@85
P
14.18 1109
940 .-
+ a
;
5 >
J. D. BONAFEDEand R. R. MATUDA
2380
transformed into a singlet. H-D exchange was very slow and the doublet disappeared only after several hours. In order to check the ability of other amides to be used as a source of enamines, the reaction between 1 and N,Ndi-methylacetamide (DMA) was investigated. Examination of the products by TLC gave four spots, identified as unreacted 1 (R, = O), a-phenylacetoacetonitrile (24), enamine 23 and 20 by NMR, and IR comparison with authentic samples
I+
Me I,0 C’ \/Me \
C’
H 1 ,CN
CN
H’
Id
Me
‘N’ \
MC
+
c Me NC* 0
+29
Me
23
24
The presence of both 24 and 20 in the reaction media accounts for the somewhat lower yield of 23. As 24 does not react with DMF and since 1 is deformylated under the reaction conditions, it is possible that amide exchange did take place. The DMF so formed can react with 1 to give enamine 23. H 1
+
DMA
-24+
This scheme also explains why AcOH is produced in almost negligible amounts. Lack of reactivity of 24 towards formamides was further verified when we tried to make it react with other formamides (aliphatic, alicyclic or aromatic), but 24 was always recovered unchanged. EXPERIMENTAL Mps were made on a Thomas-Hoover Unimelt apparatus and are uncorrected. Yields of enamines refer to crude products. IR spectra were taken as Nujol mulls or neat liquids on NaCl plates with a PerkinElmer 137-E Infracord or KBr discs with a Beckman IR-20 apparatus UV spectra were obtained with a Beckman DB-G spectrophotometer using EtOH as solvent. NMR spectra were run on a Varian T-60 or Perk&Elmer R-12A instruments using CC14 or CDCl, as solvents and TMS as internal standard. Phenylformylacetonitrile,* p-methoxyphenylformylacetonitrile,9 and u-phenylacetoacetonitrile’O were obtained by reaction of the appropriate arylacetonitrile with ethyl formate or acetate and EtONa.” DMF and diphenylformamide (commercial products) were used without further purification. The rest of the amides were synthetired by the method of Auerbach. ’ ’ TLC and PLC separations were carried out on silica gel G (Merck) plates with F 254 indicator using CHCI, as eluant. Synthesis of enomines. General procedure: a suspension of the oitrile (005 mole) in the appropriate formamide (0142 mole) was heated at 140-160” until evolution of HCOOH ceased. If crystals separated after cooling, the mixture was filtered and solid washed with cold EtOH or benzene. If no crystals formed, excess amide was removed in uccuo and the residue dissolved in benzne and precipitated with light petroleum ether, then recrystallizd from ligroine.
The action of substituted formamides on arylformylacetonitriles
2381
Enamines 8-9 were distilled at reduced pressure before recrystallization: their bps were 142-ISO”/ mm and 170-172’/3 mm respectively. Synthesis of 24. A suspension of 1 (3.65 g: 0025 mole) in DMA (8.7 g: 01 mole) was heated for 8 hr at 175”. Excess DMA was removed giving 602 g of dark oil which crystallimd at 0”. TLC showed four spots atR,:O:@36:@6and@8 An aliquot of the reaction products was dissolved in CHCI, and this solution was used for PLC. After elution, the components were visualimd by short wave UV light and worked up as usual. Band I : R,: 0, unreacted phenylformylacetonitrile 1. Band II : R,: 036, a-phenylacetoacetonitrile. Band III : R,: @6,enamine 23. Band IV : R,: 08, benzyl cyanide 20. All compounds were identified by IR and NMR spectra and comparison with authentic samples by TLC. Acknowledgements.-This work was supported by grants from the Consejo National de Investigaciones Cientificas y T&micas and the Facultad de Farmacia y Bioquimica (U.B.A.). The authors arc indebted to the Instituto National de Farmacologia y Bromatologia for the T-60 NMR spectra The R-12A spectrometer was purchased with a grant of the Fondo Especial para la Investigaci6n Cientifica (U.B.A.).
’ 2 a 4 5 6 ’ * ’ i” ”
REFERENCES F. Eiden and B. S. Nagr, Arch. Pharm. 297 (1964) A. Novelli, A. P. G. dc Varcla and J. D. Bonafcdc. Tetrahedron 24.2481 (1968) E. E. Garcia, J. G. Riley and R. I. Fryer, J. Org. Chem 33.2268 (1968) M. Lamant and M. Lemoine, Bull. Sot. Chim Fr. 1144 (1961) H. Ahlbrecht and S. Fischer, Tetrahedron 26.2837 (1970) Y. Shvo and H. Shanan-Atidi, J. Am. Chem Sot. 9L6683.6689 (1969) A. Berger, A. Loewenstein and S. Meiboon, Ibid. 81,63 (1959) R. Walthar and P. G. Schikler, J. Prakt. Chem. (2)X$331 (1897) I. Ch. Badhwar, W. Baker, B. K. Menon and K. Venkataraman, J. Chem Sot. 1541(1931) P. L Julian, J. J. Oliver, R. H. Kimball, A. B. Puke y G. D. Jefferson, Org. Syn Coil. 2.48 1 (1943) M. Auerbach and R. Wolffenstein, Ber. Dtsch. Chem Ges. 32 2518 (1899)
Vol. 26. pp 2377 lo 2381.
Pcrgamon Rer,
1972.
Rioted in Great Britain
THE ACTION OF SUBSTITUTED FORMAMIDES ARYLFORMYLACETONITRILES J. D. Department0
BON-E
and R. R. MATUDA
de Quimica OrgBnica. Facultad de Farmacia y Bioquimica. Buenos Aires. Argentina.
(Received in the USA 30 August 197 1; Received in the UKforpublication
Abstraeformamides
ON
Universidad de
18 Jamcary 1972)
The reaction between phenyl- or p-methoxy phenylformylacetonitrile and monosubstituted results in enaminonitriles. In some instances a simultaneous deformylation is observed.
Formic acid is produced during the reaction and its origin was investigated. PHENYLFORMYLACETONITRILE (1) reacts with formamide’ or N,N-disubstituted formamides’ giving enamines To complete the study, the action of N-monosubstituted formamides on 1 was investigated. R
C II
H
JN
H/%H 1-2 R l=H 2=OMe
+
L=o k-H \
C' H/
CN
!i\ N /
\
RI 3-l
8-15
RI 3=Me 4 = Et 5 = -CHz phenyl
see table
H R, -
t C% I CN
m-21 R 2O=H 21 = OMe
6 = cyclohexyl 7 = -phenyl
Compound 1 was heated at 160” with a fourfold excess of 3, for several hours. The IR spectrum of product (8) showed bands at 3367 (NH), 2208 (conjugated nitrile), 1637 and 897 (trisubstituted C=C), 752 and 690 cm-’ (monosubstituted benzene). The NMR spectrum of 8 supported the enamine structure, giving peaks centered at 6: 3.07 (3H, d, .I : 5 cps, N-Me), 7.03 (lH, vinyl) and 7.28 ppm (5H, m, aromatic) : its UV spectrum, (EtOH) gave absorption at 213.1 (log E: 353), 226.6 (log E: 364), 239.1 (log E: 3*32),252.7 (log E: 3*45),265.2 (log E: 3*35),293.4 (log E: 3*77), 301.7 (log E: 3*71)and314*1 nm(loge: 3.74). The synthesis was extended to p-methoxyphenylformylacetonitrile (2) and other mono- and disubstituted formamides, and in every instance the analytical and spectrophotometrical data of the products was consistent with those of the parent compounds. However, besides the formation of enamines, the reaction also gave simultaneous deformylation of 1. This secondary reaction took place only with aliphatic mono2377
TABLE 1.
C H
,CN
01s
R,
Found H
ChlC.
Enamine
R
38.0 51.0 81.0 72.1 81.6 89.1 753 73.1 75.1
75.92 76.74 82.02 7960 81.81 71.27 74.97 76.78 71.27
637 697 602 8.01 5.45 6.97 7.86 5.63 697
17.70 16.27 11.96 12.39 12.72 13.84 1092 11.18 13.84
76.01 1689 82Q8 79.67 81.92 71.50 15.30 7650 71.35
6.42 7.03 6.12 8.09 5.41 7.07 7.82 5% 7.41
17.60 16.20 1190
3
87-88
704
7439
7.49
11.55
74.50
7.40
11.75
W
124-125
78.0
68.83
660
1146
68.70
6.13
11.31
167.5-168.5
64.5
85.11
5.44
9,49
85.1
5.22
9 10 11 12 13 14 15 16 17
--OMe
-N-N
18
-0Me
.-N-
19
H
-N(Ph),
- .._ -
-. l
Bibliog.’ 157-l 58”
C
99.5-1005 53-54 150-I51 1X-127 157.5-158.5. 120-121 90-91 160-161 87.5-88.5
--NH(Me) -NH(Et) -NH(Bz) -NH(GH,J - NH(Ph) -NH@) -NH(C,H,,) -NH(Ph) - N(Me),
H
N
Yields”/,
H H H H H AIlMe A)Me -0Me -0Me
8
C
M.p.
RI
~.
N
..-
--
m S
Si g
12.28 12.68 14.05
&
1@85
P
14.18 1109
940 .-
+ a
;
5 >
J. D. BONAFEDEand R. R. MATUDA
2380
transformed into a singlet. H-D exchange was very slow and the doublet disappeared only after several hours. In order to check the ability of other amides to be used as a source of enamines, the reaction between 1 and N,Ndi-methylacetamide (DMA) was investigated. Examination of the products by TLC gave four spots, identified as unreacted 1 (R, = O), a-phenylacetoacetonitrile (24), enamine 23 and 20 by NMR, and IR comparison with authentic samples
I+
Me I,0 C’ \/Me \
C’
H 1 ,CN
CN
H’
Id
Me
‘N’ \
MC
+
c Me NC* 0
+29
Me
23
24
The presence of both 24 and 20 in the reaction media accounts for the somewhat lower yield of 23. As 24 does not react with DMF and since 1 is deformylated under the reaction conditions, it is possible that amide exchange did take place. The DMF so formed can react with 1 to give enamine 23. H 1
+
DMA
-24+
This scheme also explains why AcOH is produced in almost negligible amounts. Lack of reactivity of 24 towards formamides was further verified when we tried to make it react with other formamides (aliphatic, alicyclic or aromatic), but 24 was always recovered unchanged. EXPERIMENTAL Mps were made on a Thomas-Hoover Unimelt apparatus and are uncorrected. Yields of enamines refer to crude products. IR spectra were taken as Nujol mulls or neat liquids on NaCl plates with a PerkinElmer 137-E Infracord or KBr discs with a Beckman IR-20 apparatus UV spectra were obtained with a Beckman DB-G spectrophotometer using EtOH as solvent. NMR spectra were run on a Varian T-60 or Perk&Elmer R-12A instruments using CC14 or CDCl, as solvents and TMS as internal standard. Phenylformylacetonitrile,* p-methoxyphenylformylacetonitrile,9 and u-phenylacetoacetonitrile’O were obtained by reaction of the appropriate arylacetonitrile with ethyl formate or acetate and EtONa.” DMF and diphenylformamide (commercial products) were used without further purification. The rest of the amides were synthetired by the method of Auerbach. ’ ’ TLC and PLC separations were carried out on silica gel G (Merck) plates with F 254 indicator using CHCI, as eluant. Synthesis of enomines. General procedure: a suspension of the oitrile (005 mole) in the appropriate formamide (0142 mole) was heated at 140-160” until evolution of HCOOH ceased. If crystals separated after cooling, the mixture was filtered and solid washed with cold EtOH or benzene. If no crystals formed, excess amide was removed in uccuo and the residue dissolved in benzne and precipitated with light petroleum ether, then recrystallizd from ligroine.
The action of substituted formamides on arylformylacetonitriles
2381
Enamines 8-9 were distilled at reduced pressure before recrystallization: their bps were 142-ISO”/ mm and 170-172’/3 mm respectively. Synthesis of 24. A suspension of 1 (3.65 g: 0025 mole) in DMA (8.7 g: 01 mole) was heated for 8 hr at 175”. Excess DMA was removed giving 602 g of dark oil which crystallimd at 0”. TLC showed four spots atR,:O:@36:@6and@8 An aliquot of the reaction products was dissolved in CHCI, and this solution was used for PLC. After elution, the components were visualimd by short wave UV light and worked up as usual. Band I : R,: 0, unreacted phenylformylacetonitrile 1. Band II : R,: 036, a-phenylacetoacetonitrile. Band III : R,: @6,enamine 23. Band IV : R,: 08, benzyl cyanide 20. All compounds were identified by IR and NMR spectra and comparison with authentic samples by TLC. Acknowledgements.-This work was supported by grants from the Consejo National de Investigaciones Cientificas y T&micas and the Facultad de Farmacia y Bioquimica (U.B.A.). The authors arc indebted to the Instituto National de Farmacologia y Bromatologia for the T-60 NMR spectra The R-12A spectrometer was purchased with a grant of the Fondo Especial para la Investigaci6n Cientifica (U.B.A.).
’ 2 a 4 5 6 ’ * ’ i” ”
REFERENCES F. Eiden and B. S. Nagr, Arch. Pharm. 297 (1964) A. Novelli, A. P. G. dc Varcla and J. D. Bonafcdc. Tetrahedron 24.2481 (1968) E. E. Garcia, J. G. Riley and R. I. Fryer, J. Org. Chem 33.2268 (1968) M. Lamant and M. Lemoine, Bull. Sot. Chim Fr. 1144 (1961) H. Ahlbrecht and S. Fischer, Tetrahedron 26.2837 (1970) Y. Shvo and H. Shanan-Atidi, J. Am. Chem Sot. 9L6683.6689 (1969) A. Berger, A. Loewenstein and S. Meiboon, Ibid. 81,63 (1959) R. Walthar and P. G. Schikler, J. Prakt. Chem. (2)X$331 (1897) I. Ch. Badhwar, W. Baker, B. K. Menon and K. Venkataraman, J. Chem Sot. 1541(1931) P. L Julian, J. J. Oliver, R. H. Kimball, A. B. Puke y G. D. Jefferson, Org. Syn Coil. 2.48 1 (1943) M. Auerbach and R. Wolffenstein, Ber. Dtsch. Chem Ges. 32 2518 (1899)