Synthesis of 3,3-Disu bstitu ted Gluta rimides I. LALEZARI, N. SHARGHI, and P. ZlAlAN Faculty of Pharmacy, University of Tehran, Iran The following 3,3-disubstituted glutarimides have been synthesized, and their intermediate compounds prepared: 3-p-methylmercaptophenyl-3-methylglutarimide, 3-p-nitrophenyl-3-methyl glutarimide, 3-cyclohexyl-3-methylglutarimide, 3-p-fluorophenyl-3-ethylglutarimide, and 3-m-trifluoromethylphenyl-3-ethylglutarimide. The infrared and NMR spectra of 3J-disubstituted glutarimides were recorded and assignments have been given.
T O STUDY their pharmacological effects, several 3,3disubstituted glutarimides, summarized in Table V, were prepared. 3,3-Disubstituted glutaric acids (Table 111) were synthesized by the method of McElvain and coworkers ( I ) . Alkylidene derivatives (Table I ) were obtained by treating appropriate ketones with ethyl cyanoacetate, which, after reaction with cyanoacetamide in sodium ethoxide solution gave corresponding dicyanoglutarimides (Table I I ) , which were hydrolyzed to 3,3-disubstituted glutaric acids (Table 111).
These acids, when boiled with acetic anhydride, gave 3,3disubstituted glutaric anhydrides (Table IV) . Related glutarimides were prepared by reaction of glutaric anhydrides with urea (Table V). The infrared spectra of glutarimides, recorded on a Leitz Model I11 Spectrograph (KBr wafer), include two strong bands a t 5.9 and 6 . 0 ~due to carbonyl groups, The characteristic skeletal absorption is two strong bands a t 11.5 and 11.6~.Imide group absorption is a strong band near 7 . 8 ~ .The infrared spectra of deuterated glutarimides do not show appreciable shifts of imide absorption.
Table I. Ethyl Alkylidenecyonoacetates
R
Ch
\
/
c=c
Analyses
B.P., C.
R
R’
(Mm. of Hg)
p-CHBCfiH, p-NO2CsHa CsHii p-FCsH, m-CF.?CsH,
CH? CH? CH3 CzHs CzHs
210(2.2) 154(4.6) 156(2.5) 167(5.5)
Carbon, 3’ 2
Hydrogen,
7
Yield, %
Calcd.
Found
Calcd.
Found
57 78 88 64 67
64.36 59.77 70.58 68.01 60.60
64.55 60.20 70.30 68.26 60.34
5.74 4.98 8.59 5.66 4.71
5.90 4.81 8.35 5.78 4.50
“M.P. 156°C. Table II. 3,3-Disubstituted 2,4-Dicyanoglutarimides /CH(CN)Co
C‘
’4
‘C“(CN)CO
\ /
”
Analyses
R P-CH~SC~H, p-NOzCsHa CfiHii p-FCsHa m-CF3CsHa
Hydrogen, 7
Carbon, %
R‘
B.P., “C.
Yield, 70
Calcd.
CH3 CHs CH3 C2Hs CzHs
262 290-3 270 234-5 282
80 70 65 99 69
60.20 56.38 64.86 63.15 57.31
Found 59.98 56.18 65.22 63.10 57.12
Calcd. 4.34 3.38 6.56 4.21 3.58
Found 4.30 3.46 6.60 4.02 3.43
Table Ill. 3,3-Disubstituted Glutaric Acids R,C
,CII,COCIH
Analyses
R p-CHsSCsHa p-NOzCsH, csH11 p-FCsH, m-CFaCsH,
288
R‘ CH3 CH3 CHs CzHs CzHs
Carbon, 70
Hydrogen, %
M.P., OC.
Yield, 70
Calcd.
Found
Calcd.
Found
110 148 156 122-4 160-1
15 48 45 35 30
58.20 53.93 63.15 61.41 55.26
58.66 53.85 63.08 61.42 55.16
5.97 4.86 8.77 5.90 4.93
5.59 4.92 8.72 5.64 4.96
JOURNAL OF CHEMICAL AND ENGINEERING DATA
Table IV. 3,3-Disubstituted Glutaric Anhydrides
'\
/CH2Co C
\ Analyses
R
R'
P-CHSCsH, p-NO,CsH, CGHII P-FCsH, m-CF iCsH4
CH? CH i CH? CJL CzHs
Carbon, YO
Hydrogen, 70
M.P.,
Yield,
"C.
70
Calcd.
Found
Calcd.
Found
96-100 161-2 50 78 69
Quant. Quant. Quant. Quant. Quant.
62.40 57.83 68.57 66.10 58.74
62.34 57.25 68.45 66.29 58.90
5.60 4.41 8.57 5.50 4.54
5.80 4.35 8.48 5.12 4.78
Table V. 3,3-Disubstituted Glutarimides
Analyses R p-CHiSCsH4 p-I%OnCsHa CsHii m-FCsH, m-CFjCeH,
R' CH? CH, CH, CnH, CzH,
M.P., OC. 189-90 189-90 186 156-9 148-9
90
Carbon, 70 Calcd. Found
40 45 52 62 50
62.65 58.06 68.89 66.38 58.94
Yield,
62.44 58.23 70.21 68.33 60.64
Hydrogen, 7" Calcd. Found 6.02 4.83 9.09 5.95 4.91
6.06 5.09 9.58 6.09 5.42
IR,
M~~
C=O
NH
5.8,6.0 5.8,5.95 5.8,5.95 5.8,5.95 5.8,5.90
7.8 7.9 7.8 7.85 7.9
KBr, f i n Skeletal 11.55 11.65 11.70 11.55 11.60
NMR, NH 1.5 1.5 1.65 1.45 1.58
TO
"Refer to the text for details on I R and NMR.
The N M R spectra of glutarimides in CDCL solution were recorded on a Varian A60A Spectrometer using T M S as internal standard. The NH proton absorption of the imide group, for which not many examples can be found in literature, was studied carefully. Deuteration was accomplished by adding D 2 0 to samples dissolved in CDCls. The imide proton absorption disappeared rapidly. After evaporation of solvent, pure deuterated glutarimides were obtained. The NH proton absorption in all cases, including the case of
VOL. 13, No. 2, APRIL 1968
3,3-methylethylglutarimide, is a very broad band a t 1.65.
T
1.45-
(1) McElvain, S.M., Clemens, D.H., J . A m . Chem. SOC.80, 3915 (1958). RECEIVED for review July 20, 1967. Accepted December 5, 1967.
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