J. Org. Chem. 1981,46, 3945-3949 the fiter cake was washed with hot dimethylformamide (4 X 10 mL). The filtrate and washings were combined and evaporated to dryness in vacuo. The residue was crystallized from aqueous DMF (water/DMF, 46,v/v) to yield 60 mg (69.2%) of 7: mp 250 "C dec; 'H N M R (MeaO-dd 6 5.10 (t, 1, H i , Jr,'?= 6.0 Hz, Jr8 = 6.0 Hz), 6.25 (d, 1, H i , J1, = 6.0 Hz), 7.22 (br s,2,NHZ), 8.22 (8, 1, Hz or Hs), 8.91 (s, 1, HI, or Hz). Anal. Calcd for C13H1,NB06~1.5H20 (verified by 'H NMR): C, 43.21; H, 4.71; N, 23.27. Found C, 43.58; H, 4.47; N, 22.97. General Procedure.u Method A. The o-aminonitrile was dissolved in pyridine, and 1 mL of liquefied carbonyl sulfide was added to the solution at -70 O C . The reaction mixture was then sealed in a steel vessel and heated for a suitable period of time. The reaction v e a d was cooled to room temperature and the excarbonyl sulfide was allowed to slowly evaporate. The reaction mixture wm coevaporatedseveraltimea with 2-propanol to remove the pyridine. The remaining solid was dissolved in a 1 N NaOH solution, activated charcoal was added, and the reaulting mixture was fiitered through a Celite bed. The pH of the filtrate was adjusted to 6.0 with a 1 N HC1 solution and the solid that sep~~~
~
(24) See Tables I and I1 for the exact quantities used and the results obtained.
3945
arated was collected by filtration. Analytical samples were obtained by one additional reprecipitation. GeneralProcedure.N Method B. Carbonyl sulfide was slowly bubbled through a 1 N sodium ethoxide solution for 10 min. The appropriate o-aminonitrile was added to this solution and the reaction mixture was heated to reflux temperature. After a suitable period of time, any solid that had formed was diesolved in a small amount of water and the volume of the reaction mixture was concentrated to ca,4 mL. Activated c h c o a l was added, the mixture was fiitered through a Celite bed, and the pH of the filtrate was adjusted to 6.0 with a 1 N HC1 solution. One additional reprecipitation from a basic solution afforded analytical samples of the respective products.
Acknowledgment. This investigation was supported by research grant Rol-CA 28381 from the National Cancer Institute, NIH, and by DR & D Research Contract NIH NCI-CM-77142 from DCT, NCI, NIH, and PHS and by CONICIT. Registry No. 2, 57071-61-1;3, 74754-48-6;3 disodium salt, 78479-71-7; 4,74754-49-7; 5,73851-57-7; 6,74754-50-0;7,74764-51-1; loa, 4651-82-5;lob,4623-55-6;lla,78479-72-8;llb, 78479-73-9;12, 16617-46-2;13,5334-33-8;14,28745-14-4;15,28745-15-6.
Metalation of Diazepam and Use of the Resulting Carbanion Intermediate in a New Synthesis of 3-Substituted Diazepam Derivativesla*c Barbara E. Reitter,lb Yesh P. Sachdeva, and James F. Wolfe* Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 Received April 9, 1981
Treatment of 7-chloro-l-methyld-phenyl-l,3-dihydro-W-1,4-benzodiezepin-2-one (diazepam, 1) with 1 equiv of LDA in THF-hexane produces an equilibrium mixture consisting of equal amounts of 1 and its monolithio salt 2 as shown by 'H NMR and D20quenching. With 2 equiv of LDA, 2 is formed in sufficient concentration to react with alkyl halides, aldehydes, ketones, and eaters to give 3-substituted derivatives of 1. 'H N M R studies of T H F - d 8 solutions prepared from 1 and 2-3 equiv of LDA indicate partial twofold metalation of 1 in which both hydrogens at Csare removed to form dilithio derivative 10. The present metalations provide a convenient new method for direct modification of diazepam, without requiring the more cumbersome ring closure procedures traditionally employed for such syntheses.
As part of a program directed toward the preparation In these cases, the original a substituent of the acylating agent appears at the 3-position of the resulting diazepiof new anticonvulsant agents, we sought a direct, general none. Certain 3-substituted 1,4-benzodiazepin-2-ones method for the synthesis of various 3-substituted derivacan tives of 7-chloro-l-methyl-5-phenyl-l,3-dihydro-2H-1,4- also be prepared from 3-hydroxy-l,4-benzodiazepin-2benzodiazepin-2-one (diazepam, 1).2 Current syntheses ones,' which are available through reaction of 1,3-diof such compounds usually involve extensions of methods hydro-2H-1,4-benzodiazepin-2-one 4-oxides with acetic employed for the preparation of 1 such as condensations anhydride followed by hydrolysis: by base-catalyzed cyof 2-amino-5-chlorobenzophenone with a-substituted aclization of the syn oximes of 2-(haloacetamido)-5m i n o acids (estersIsor a-substituted a-haloacyl halides? chlorobenzophenones,8and by oxygenation of 1 and related compounds in the presence of potassium tert-butoxide.' The present study was based on the concept that 3(1) (a) Supported by Grant No. NS 10197 from the National Institute substituted diazepams might be available directly from 1 of Neurological and Communicative Disorders and Stroke. (b) Taken in through metalated derivative 2. Subsequent reactions of part from the MS thesis of B.E.R., Virginia Polytechnic Institute and State University, Aug 1979. (c) Presented in part at the l8lst National 2 with electrophilic reagents could then lead to introducMeeting of the American Chemical SocietyAtlanta GA, Mar 1981;ORGN tion of 3-substituents without requiring construction of the 15. diazepinone ring from acylic precursors each time a dif(2) (a) Rassi, G.F.; Rocco, C. D.; Maira, G.; Meglio, M. "The Benzo-
diazepinea";Garattini, S., Mussini, E., Randall, L. O., Eda.; Raven Preea: New York, 1973; p 461. (b) For recent references see: Berger, J. G.; Iorio, L. C. In "Annual Reporta in Medicinal Chemistry"; Hess,H.J., Ed.; Academic Press: New York, 1979; Chapter 3; 1980, Chapter 3. (3) (a) Stembach, L. H.;Fryer, R. I.; Metlesica, W.; Reeder, E.; Sach, G.;Saucy, G.; Stempel, A. J. Org. Chem. 1962,27,3788. (b) Bell, S. C.; Sulkomti, T. 5.;Gochman, C.; Childreas, S. J. Zbid. 1962,27, 562. (c) Falk, J. L.; Swise Patent 417614,1967;Chem. Abstr. 1967,67,21948. (d) Sunjic, V.; Kajfez, F.; Stomar, I.; B h v i c , N.; Kolbah, D. J. Heterocycl. CheM. 1973,10, 591.
(4) For ah example of this approach see: Selletedt,J. H.J. Org. Chem. 1975,40, 1508 and references cited therein. (5) Bell, S. C.; Gochman, C.; Childreas, S.J. J. Org. Chem. 1963,28, 3010. (6) Stempel, A.; Dovan, I.; M e r , E.; Stembach, L. H.J. Org. Chem. 1967,32, 2417. (7) Gall,M.; Kamdar, B. V.; Colliine, R. J. J. Med. Chem. 1978,21, 1290.
0022-326318111946-3945$01.25/00 1981 American Chemical Society
3946 J,Org. Chem., Vol. 46,No. 20, 1981
Reitter, Sachdeva, and Wolfe
were complete in 3 h or less. Attempts to prepare 3,3dialkyldiazepams by treatment of 3a or 3d with 2 equiv of LDA followed by methyl iodide failed to afford isolable amounts of the desired 3,3-dialkyl derivatives, even in the presence of HMPA. Quenching with DzO indicated that metalation was
