81
J. Org. Chem. 1985,50, 81-84 threo), 4.85 (1 H, HC(OH), AB system, J = 5.4 Hz, erythro), 7.0-7.35 (10 H, Ph H, m); mass spectrum (70 eV), mle 210 (M' - HZO), 178, 121, 107. 2,3-Di-2-pyridyl-2,3-butanediol(14u) a n d 2,3-Di-4pyridyl-2,3-butanediol(14v). For detailed separation of dl and meso isomers and spectroscopic assignments see ref 18. Registry No. (*)-12g, 93453-79-3; (&)-12h, 93453-80-6; (*)-12n, 57377-60-3; 12g, 91-01-0; dl-l3a, 93453-74-8; meso-l3a, 62154-11-4; dl-l3b, 22985-88-2; meso-l3b, 22985-87-1; dl-13c, 22985-90-6; meso-ltc, 4217-65-6; dl-l3d, 93453-75-9; meso- 13d, 93453-77-1; dl-l3e, 93528-45-1; meso-l3e, 93528-46-2; dl-l3f, 93453-76-0; meso-l3f, 93453-78-2; dl-l3m, 16020-87-4; meso-l3m,
16020-86-3; dl-1311, 63882-18-8; meso-l3n, 63846-48-0; dl-l3p, 93453-81-7; meso-l3p, 93453-82-8; 13g, 464-72-2; dl-llr, 655-48-1; meso-llr, 579-43-1; threo-llt, 50778-88-6; erythro-llt, 50778-87-5; d l - l l u , 20445-39-0; meso-llu, 20445-38-9; dl-llv, 83179-65-1; meso-llv, 83179-64-0; TiCl,, 7705-07-9; p-MeOC6H4C(0)CH3, 100-06-1; p-MeC6H4C(0)CH3,122-00-9; PhC(0)CH3, 98-86-2; p-ClCBH,C(O)CH3, 99-91-2; P-CF&H~C(O)CH~,709-63-7; p CNC6H,C(O)CH,, 1443-80-7; PhC(O)C(O)Ph, 134-81-6; (*)PhC(O)CH(OH)Ph, 579-44-2; (*)-PhC(O)CH(OMe)Ph, 5987-95-1; 2-PyC(O)CH3, 1122-62-9; 4-PyC(O)CH,, 1122-54-9; p HOC6H,C(O)CH3, 99-93-4; p-NH&H,C(O)CH,, 99-92-3; p NH3'C6H4C(O)CH,,93453-73-7; PhC(O)CH&H,, 93-55-0; PhC(O)CHzPh,451-40-1;PhC(0)-t-Bu,938-16-9; PhC(O)Ph, 119-61-9.
New Preparation and Controlled Alkaline Hydrolysis of 21-Bromo-20-ketopregnenes.A Facile Synthesis of Deoxycorticoids' Mitsuteru Numazawa* and Masao Nagaoka Tohoku College of Pharmacy, 4-1 Komatsushima-4-chome, Sendai 983, Japan Received May 4, 1984 Syntheses of deoxycorticoids 7b, Sb, and 9b are described. Treatment of 20-oxo steroid 1 with 3 mol equiv of CuBrz in MeOH in the presence or absence of pyridine gave the 21-bromide 4a or the 17a-methoxide 2 in high yields, respectively. When 6 mol equiv of the brominating reagent was used in the absence of pyridine, the 21-bromo 17a-methoxide 5a was formed. l7a-Hydroxy 20-ones 3 could be similarly converted to the 21-bromides 6a and 6b. Oxidation of la, 5a, and 6a with Cr03 and subsequent isomerization of a double bond a t C-5 with acid gave the corresponding 4-en-3-ones 7a, Sa, and 9a, of which 7a and 9a were efficiently hydrolyzed to 7b and 9b under controlled conditions with a KzC03-HzO-acetone system. On the other hand, Sa was converted to 8b by reaction with NaOCH, in MeOH.
Introduction of the 21-hydroxyl function into the 17acetyl side chain of a 20-ketopregnene is of central importance in the partial synthesis of corticoids. One of the attractive chemical methods involves direct C-21 halogenation of a 20-ketopregnane and subsequent displacement of the resulting 21-halo compound by acetate or hydroxide. Direct halogenation of a 20-oxo steroid lacking a substituent (e.g., OH or CHJ at C-17 with the common reagent such as Br2 generally does not give a satisfactory yield of the 21-bromo derivative,2 although Ringold and Stork3 reported a versatile method for direct C-21 iodination of 20-ketopregneneswith a 4-en-3-one or 5-en-30-01 system. While displacement of a 21-bromo 20-one by hydroxyl can be accomplished by careful control of reaction conditions,4 it is preferable to use acetate instead, because a Favorskii rearrangement5 is involved in the reaction and the product, 21-hydroxy 20-one, is sensitive to basic reagents. Glazier6 reported that the reaction of 30-hydroxy-5pregnen-20-one (1) with CuBr, in MeOH resulted in the formation of l7a-methoxy derivative (2) in a modest yield without affecting the integrity of the olefinic bond at (2-5. We recently discovered a high yield and controlled stereoselective alkaline hydrolysis of steroidal 16a-bromo 17-0nes',~and 2a-bromo 3-0nes.~ (1)Preliminary communication: Numazawa, M.; Nagaoka, M. J. Chem. SOC.,Chem. Commun. 1983, 127. (2)For a review see: Oliveto, E. P. "Organic Reactions in Steroid Chemistry"; Fried, J., Edwards, J. A., Eds.; Van Norstrand Reinhold: New York, 1972; Vol. 11, p 127. (3) Ringold, H. J.; Stork, G. J. Am. Chem. SOC. 1958, BO, 250. (4)Kritchevsky, T.H.;Gallagher, T. F. J . Am. Chem. SOC.1951, 73, 184. (5)Kirk, D. N.; Hartahorn, M. P. "Steroid Reaction Mechanism"; Elsevier Publishing Co.: Amsterdam, 1968; p 388. (6)Glazier, E. R. J. Org. Chem. 1962,27, 4397.
0022-3263/85/1950-0081$01.50/0
Chart I
&
--OCH3
Ro
HO 1
2
HO 4 a, R = B r
3 a,R=H
b, R = O H
b, R =COCH3
C H R' ~
RO 5 a,R=H , R'= Br b,R=COCHj, R'= Br c, R= H , R'= OH
4' 6 a,R=H,R'= Br b,R=COCH3, R ' = B r c , R = C O C H 3 ,R'=OH
We now report the previously unreported direct bromination at C-21 of 20-ketopregnenes 1, 2, and 3 with (7) Numazawa, M.; Osawa, Y. J. Am. Chem. SOC.1980, 102, 5402.
0 1985 American Chemical Society
82 J. Org. Chem., Vol. 50, No. 1, 1985
Numazawa and Nagaoka Chart I1
Table I. Bromination of 20-Oxo Steroids 1,2, and 3 with CuBr," condition CuBrz, isolated no. mol equiv solvent CnHnN time, h product yield, % 1 3 no 24 2 MeOH 65 1 3 MeOH 71 yes 24 4a 1 6 no 24 5a MeOH 54 no 24 5a 78 2 3 MeOH 2 3 MeOH
