1618 J.C.S. Perkin I Steroidal Heterocycles : 2'-Thiocyanatoandrosteno-3,2-dpyrimidines and -I 7,16-dpyrimidines By Joginder S. Bajwa and Peter J. Sykes," Department of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ The preparation of steroidal heterocycles containing the 2'-thiocyanatopyrirnidine ring fused to the 2.3-position or 16.1 7-position of the steroid nucleus is described. These are prepared by the reaction of 2-arnino-l.3.4-thia-diazole with 2 -hydroxymethylene- 3-0x0 -steroids and 16 -hydroxymethylene-17-oxo-steroids. ITwas of interest to prepare fused steroidal pyrimidines since other heterocyclic fused steroids have been shown to exhibit modified or accentuated hormonal activities1 Various pyrimidine bases in the steroid series have already been obtained by reactions involving the con- densation of 2-hydroxymethylene-3-oxo-steroidswith guanidine, urea, and thiourea2 or by the treatment of ketones with trisformylaminomethane and cyano-g~anidine.~2 a-Cyano-3-oxo-steroids and their enol ethers have also been used as starting materials for the preparation of pyrimidine bases2 This paper describes another convenient synthesis of some androsteno-3,2-dpyrimidines and androstenol7,16-dpyrimidines by the reaction of 2-amino-l,3,4-thiadiazole(1) with steroidal p-diketones.The condensation of 17p-hydroxy-2-hydroxy-methylene-5a-androstan-3-one (2) with 2-amino-l,3,4-thiadiazole (1) in refluxing toluene in the presence of a catalytic amount of toluene-9-sulphonic acid gave 17 p-hydroxy-2'-thiocyanato-5a-androst-2-eno3,2-dpyrimi-dine (4) in 60 yield.The i.r. spectrum of this com- 1 R. E. Counsel1 and P. D. Klimstra, ' Medicinal Chemistry,' ed. by A. Burger, Wiley-Interscience, New York, 1970, 3rd edn., Part 11, p. 923. P. de Ruggieri, C. Landolfi, and D. Chiaramonti, Gazzetla, 1962, 92, 768. 9 H. Bredereck, R. Gompper, and B. Geiger, Ber., 1960, 93, 1402. pound exhibited a strong band at 2 160 cm-l indicative of a thiocyanate group and also bands at 1 565, 1555infl, 1 545infl, 1415, 1365, and 755 cm-l characteristic of a pyrimidine ring. The lH n.m.r. spectrum showed a singlet at 6 8.25 confirming the 6'-hydrogen of the pyrimidine ring. It is apparent that the final dehydration of the initial condensation product (3) results in a rearrangement furnishing the thiocyanato-pyrimidine ring system.Indeed a similar rearrangement has been reported during the reaction between S-amino-l,3,4-thiadiazole and the simple 1,3-dicarbonyl compound, acetylacetone, resulting in the formation of 2-thiocyanato-4,6-dimethyl-pyrimidine. The intermediate condensation product (3) could not be isolated and it is, therefore, possible that it might have an isomeric structure based upon an initial reaction between the amino-group of (1)and the 3-carbonyl group of the steroid. However fission of the N-N bond in the dehydration step of either of the possible intermediates will yield the same product. The thiocyanate group is known to isomerise to the isothiocyanate structure on refluxing in acetonitrile, L.L. Smith, D. M. Teller, and T. H. Foell, J. Medicin. Clzem., 1963, 6, 330. R. F. Lauer and G. Zenchoff, J. Heterocyclic Chem., 1976, 13, 291. 1978 1619 benzene, and toluene.6 However, no such isomerisation 3-one (10) gave the expected 2’-thiocyanatopyrimidine was observed in the above synthesis, the 2’-thiocyanate (11) accompanied by a variable amount of 17,17-dime t h yl-2'-thioc yanat 0-18-norandros t-2,13-dieno- 3,2-dpyrimidine (12) depending upon the quantity of toluene-p-sulphonic acid used in the reaction. N -N The reaction was also successfully applied to two steroids with a A4-double bond, namely 17p-hydroxy-2- HoHcR2 +0 ~~2 hydroxymethyleneandrost-4-en-3-one and 2-hydroxy-H (2) R1=OH,R2xH (5) R)R~=H (7 1 R -c~H,,, R?= H (10) R’=OH ,R~=~i N* N0 HU $?i’(tOH (1) 1 k (3) i methylenecholest-4-en-3-one, but the yields of the products, 17 p-hydroxy-2‘-t hiocyanatoandrost -2 ,kdieno- 3,dpyrimidine (13) and 2’-thiocyanatocholest-2,4-dieno3,2-dpyrimidine (14) were lower, being in the range 3540.Analogously fused 3p-hydroxy-2‘-thiocyanato-5a-androst-l6-eno17,16-dpyrimidine (15), and 3-methoxy-2’- thioc yanato-oestra- 1,3,5 (lo), 16- tetra- enol7,16-dpyrimidine (17) were prepared from 3p-hydroxy-16-h ydrox ymethylene-5a-androstan- 17-one and 16-h ydroxy-methylene-3-met hoxyoestra-l,3,5( 10)-trien-17-one respectively.Acetylation of the 3-hydroxy-steroid (15) gave the corresponding acetyl derivative (16) whilst oxidation by Jones reagent furnished the 3-ox0 derivative (18). The reaction of 17p-hydroxy-2-ethoxycarbonyl-(hydroxy) meth ylene- 17a-methyl-5a-androst an-3-one with (1)under the same conditions furnished the expec- ted 17p-hydrox y-17a-met hyl-6‘-( 1,3,4-thiadiazol-2- ylcarbamoyl)-2‘-thiocyanato-5a-androst-2-eno3,2-d-pyrimidine (19). A further example of this reaction was illustrated by the conversion of 2-ethoxycarbonyl-(hydrox y)met hylene-5a-cholest an-3-one into 6’-(1,3,4-thiadiazol-2-ylcarbamoyl)-2’-t hiocyanat 0-5 a-cholest-2- eno3,2-dpyrimidine (20). Under the same reaction conditions 2a-acet yl-17p-.#R hydroxy-5a-androstan-3-onefailed to yield any con-NCSkN A N0 NCSk PI (9) SCN NR-N N/ NCSkN A (4)R’= OH R~=H (6) R’= R2= H (81 R’= CaH17,R2= H (11) R’= OH, RZ.M~ dR2 ti NC:< (13) R’=OH ,R?= H (151 R: OH ,R2=H (14)I?’= CaH,, ,R2s H (16) R= OAc ,R2= H (181R1R; 0 Me0SCN (17) N-N ..H 1(19) R=OH, R2=Me 2(20)R1=C,H,, ,R = H group remaining intact even after prolonged heating in refluxing xylene. A.bsence of isomerisation to isothio- cyanate was confirmed in that the product failed to react with a primary amine. In a similar manner 2’-thiocyanato-5a-androst-2-eno-3,2-dpyrimidine (6), 2’-thiocyanato-5a-cholest-2-eno-3,2-dpyrimidine (8), and 1l-oxo-2‘-thiocyanato-5a-spirostan-2-eno3,2-dpyrimidine(9) were prepared from the corresponding 2-hydroxymethylene-3-0x0-steroids (5), (7), and 2-hydroxymethylene-5a-spirostane-3,ll-dione respectively.Using the reaction conditions for the con-densation product, probably because ketones, in this densation reaction, a 2-hydroxymethylene-3-oxo-steroid the za-acetyl group, generally react with amines having a tertiary hydroxy-group at C-17, also undergoes a Wagner-Meerwein rearrangement. For l7P-6 U. Tonellato, 0.Rossetto, and A. Fava, J. Org. Chem., 1969,hydroxy-2-hydroxymethy1ene-17a-methy1-5a-androstan-34,4032. 1620 J.C.S. Perkin I much more slowly than aldehydes (the 2-formyl group) to 3,ll-dione (3.5 g, 66), m.p. 165-166. 1.r. (CHBr,) yield Schiff's bases.' vmX.2 930, 2 870, 1 700 (C=O), 1 640, 1 585 (COC=CHOH), 1 450, 1 385, and 1 375 cm-'; lH n.m.r. 6 0.72, 0.82,0.95,EXPERIMENTAL SECTION 1.00 (methyl groups), and 8.60 (s, 1 H, 2=CHO) (Found: C, M.p.s were determined on Gallenkamp apparatus and are 73.20;H, 8.91. Calc. for C,,H,,O,: C, 73.68; H, 8.77). uncorrected. 1.r.spectra were recorded in bromoform on a General Procedure for the Condensation Reaction.-A Perkin-Elmer 157 G Spectrometer. 'H N.m.r. spectra solution of steroidal P-diketone (0.001 mol), 2-amino-1,3,4- were recorded in deuteriated chloroform using tetramethyl- thiadiazole (0.0015 mol), and toluene-p-sulphonic acid (20 silane as an internal standard on a Nuclear Magnetic mg) in dry toluene (50 ml) was refluxed and stirred overnight. Resonance Ltd EM360 (60 MHz) or a Varian HA 100 (100 The reaction rnixture was cooled and the solvent was High resolution AnalysisYield M.p.mass spectrum Characteristic 'H N.m.r. (6) Found () Calculated (yo) () ("C) Found Calculated i.r. abs (v/cm l) 6'-H 18-CH. 19-CHa C H N C H N 60 213-215 383.202 537 383.203 123 2 160(SCN), . 8.20 0.75 -0.75 69.0 7.6 11.1 68.89 7.63 10.96 1565,755 85 210-212 367.205 933 367.207 136 2 160 ISCN). 8.30 0.70 0.75 71.7 8.0 11.65 71.89 7.96 11.44 1565,'755 " 70 159-160 479.331 357 479.333 404 2 160 (SCN), 8.30 75.3 9.45 8.55 75.10 9.46 8.76 1565,755 68 241-243 521.271 406 521.271 198 2 160 (SCN), 8.30 68.75 7.95 8.1 69.06 7.54 8.08 1695 (COI.i 565,'fG" 0.80 11 125-127 379.208 494 379.308 203 2 160 (SCN), 8.30 17-gem 1.00 72.75 7.85 10.5 72.78 7.71 10.71 1565,755 dimethyl41 185-187 381.186 086 381.187 474 2 160 (SCN).8.20 0.80 1.00 68.75 7.25 10.8 68.25 7.13 11.02 1620,'l 575; 750 38 184-186 477.316 335 477.317 754 2 160 (SCN), 8.20 75.25 8.9 8.5 75.42 9.08 8.80 1620,1565, 7 70 75 192-194 383.203 289 383.203 123 2 160 (SCN), 8.35 0.85 0.97 69.1 7.75 10.95 68.89 7.63 10.96 1580, 790 72 177-179 377.154 981 377.156 176 2 160 (SCN), 8.35 1.00 69.65 6.25 10.65 69.99 6.15 11.13 1605,1575, 780 80 226-228 381.187 281 381.187 474 2 160(SCN), 8.50 1.00 1.10 68.95 7.25 10.75 69.26 7.14 11.02 1700 lC0l. 1575,'790' 53 175-177 425.214 789 425.213 686 2 160 (SCN), 8.50 0.90 1.00 67.4 7.0 9.9 67.73 7.29 9.87 1720 (CO),1580,900 65 244-246 524.204 927 524.202 805 3 330 (NH), 8.90 0.77 0.87 59.7 4.2 16.2 59.51 4.41 16.09 2 160 (SCN), (6"-H), (1.20,1690 (CO), 12.0 (NH) 17-Me)1510, 745 71 311-314 606.317 398 606.317 434 3 330 (NH), 8.90 64.95 7.5 13.5 65.31 7.68 13.85 2 160 (SCN), (5"-H)1690 (CO), 12.00 (NH)1500,735 85 172-1 7 3 397.218 722 397.218 773 2 160 (SCN), 8.20 0.75 0.90 69.5 7.85 10.95 69.48 7.86 10.57 1565,755 (1.2017-Me) a Methylene chloride was used for the elution of these compounds over silica gel.Q Methylene chloride-ethanol (95 : 5) was used for elution of these compounds. MHz) spectrometer. Mass spectrometry was carried out on removed under reduced pressure to leave a residue which AEI MS 902 instrument. was chromatographed over silica gel (50 g; 80-200 mesh) All the starting materials except 2-hydroxymethylene-5a- using either methylene chloride or methylene chloride- spirostane-3,l l-dione, which has not been reported so far, ethanol (95 :5).A summary of results is given in the were prepared by the known literature methods. Table. Compounds (4) and (6) were recrystallised from 2-Hydroxymethylene-5a-spirostane-3,ll-dione.-Sodium benzene and acetone respectively whilst all other products hydride (1.5 g) was added to a solution of 5a-androstane-were recrystallised from ethanol. 3,l l-dione (5g) in benzene (100 ml) and ethyl formate (5 ml) 17p-Hydroxy- 1 7a-uutethyl-2'-thiocyanato-5u-androst-2-eno-and the reaction mixture was set aside under nitrogen for 3,2-d-pyrimidine ( 11) and 17,17-Dimebhyl-2'-thiocyanato-one day.Methanol (10 ml) was added to decompose the 18-narandrost-2,13-dieno3,2-dpyrimidine( 12) .-The crude excess of sodium hydride and the solution was diluted with product from the condensation reaction was chromato-water (300 ml). The layers were separated and the basic graphed over silica gel. Elution with methylene chloride solution was extracted with ether to remove the neutral gave the rearranged steroid ( 12) which was recrystallised material. The aqueous layer was then acidified with 3M- from ethanol whilst further elution with methylene chloride- hydrochloric acid (40 ml) and the liberated enol extracted ethanol (95 : 5) mixture gave the expected condensation with ether. The ether layer was washed with water and product ( 11) which was recrystallised from ethanol. saturated sodium chloride solution, dried (MgSO,), and 8/506 Received, 20th March, 1978)evaporated to dryness. The crude product was recrystal- lised from ethanol to give 2-hydroxymethylene-5a-spirostane-7 R.W. Hayes, Chem. Rev., 1963, 63,489.
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