March 1970 NOTES 309

Com- pound

1 2 3 4

6 7 h 9.

1 0 e 11 12 13 14 1 .5 16 17 l h 19 20 21

2s 24 4 -5 46 47

1

.9.> - ,~

TABLE I -1LKYLATED A S D NOS.\LECYL.\TED DERIVATIVES O F 1 ,2 ,3 ,4 -TI~TR.~HYDROCaKshzoLE-3-C*RBoXrLIC ,%CID

R

COOCHa COOC2Hs COOCsHi COOCaHg COOCjHii CH?COOC?H: ( CHp),COOC?Hj COOCH:] COOC?Hs OCHi COOC?Ha COOCjHi CHZCOOCrH, ( CH?)?COOC?H; C0OC.H: CO(>C?H:, COOC?Hj COOC?Hj COOC2Hs COOC?Ha COOCzHj CH?COOC?H; I CH?),COOC,Hj COSIC2Hi)r CHIS( C?H.,)r CH?OH

COOH R'

H H H H H H H H H H H c Hj CH CH., CHs (CHr)3S(CHa)z (CH?)?N(CrHs)? (CH,)nN(CHa)2 (cH,),?:(cH~)~' (CH?)ZS(CH?)iOn (CH2)iS ( CH,L)jP i CH? )aS(CpHi)2 (CH,)sS(CHa)? (CH?):qS1CHs):, H H H

L1Ip or bp, 'C (mm)

196-198' 68-69 5' 94 t5-96d 102-104c 126 5-127 5 . 74 3-75 ,5c 127 3-128c

192-193

107 .i-llOc

167-173 (0 13) 1.56-160 (0 025) 16-5-173 (0 03-5)

200-202 (0 06)

179-180'

157-163 (0 03)

162-169 (0 08) 161-170 (0 05) 16.5-170 10 03) 1.59-166 (0 02.5) 18i-19.5 (0 03) 173-18.5 (0 04) 172-180 (0 04) 178-188 (0 06) 173-183 10 0 .5 ) 130- 1 3 1 1.30-1.5.5 (0 5 ) 93 .5-98l

Yield, L/c

88.0 83.9 86 .4 8 2 . 3 84 .4 79.8 8 7 . 8 84 .4 82.6 81.0 78.6 70.6 71.9 82 . 6 72.6 6 2 , 3 61. :j 3 . 2 10.6 4 8 . 2 46 .9 37.6 .57 3 4.1 9 69.6 87.9 92.4

- -

Method

A A -4, B, C A A 9 A A A f Ai A .I, B B A B

Analyses"

C, H , S C, H, S c, H C, H , ?: C, H, K C, H , N C, H, T C, H, S C, H, X C, H, S C, H, S c, €1, s C, H, S C, H, S C, H, ?; C, H , h- C, H, X C, H, S C, H, S C, H , S C, H , S C, H, S C, H, S C, H , ?; C, H, S C, H, T C, H, S

;inalytical results obtained for the indicated elements were within +0.4% of the theoretical values. Glacial AcOH. CH3OH. e Benzo[b] 1,2,3,4-tetrahydrocarbazole. f From naphthylhydraxine by addition of ketone to refluxing hydra-

zine. g Hydrochloride, mp 200-200.1O; Anal. (C20H2&1S202) C, H, C1, N. Methiodide, mp 144-146"; -4nal. (CZ~H~I IXZOZ) I . Methiodide, mp 185-

187", -4nal. (C?oH?JN20~) I. Pyrrolidinoethyl. Naleate, mp 144-145"; Anal. (C2&2N206) C, H, N. Morpholinoethyl. hIal- eate, mp 160-161 ' , I n a l . (C2jH3jX~o;) C, H, X. Fum- arate, mp 119-12l0: Anal. (C&a6?r'206) C, H, ?;. * Hydrochloride, mp 140"; Bnal. (C21H31ClN02) C1. t EtzO. u Hydrochloride, nip 2221-224" ; -4 naT. (C17H?,CIS?)C1.

Petroleum ether-C&

Maleate, mp 123-124'; Anal. (C2,H34N206) C, H, N. Methiodide, mp 148-148.5'; Snal. ( C Z Z H ~ ~ I X Z O ~ ) I.

P Piperidinoethyl. q hlaleate, mp 153-155'; L4nal. (C26H34S206) C, H, N.

21 Et20-ligroin.

I

(CH,)

C-R I - -

Compound R R' Alp, OC Yield (%) Formula"

2 ,5 COUCH, s 10.5-106, .ib 82.2 CiiHirNnOr 26 COOClHr, N 90-92c 8.5.6 CuH?aN,O:! 27 COOCZH; S 91. .5-93h 84.4 C ~ S H P ~ N ~ O ? 28 COOCiH 9 s 77-77. .id 82.4 C~OHUNPO? 29 C0OC;HiI h- 78-79* 79.7 CI IH~GNZO~ 30 CH,COOC;tH: K 60-61 ..ib 70.9 CieHvzXn.02 3 1 COOCH:, p\' 168-164. ?ih 74.6 C?iH2&~02 :j2 COOH OOH 165-166.5' 71.6 C16HliKO,

Analytical results obtained for the indicated elements were within 10.4';; of the theoretical values. All compounds were analyzed for C, H, X. * IIeOH. e Petr ether-MeOH. * Petr ether-C& e Benxo[b] 1,2,3,4-tetrahydrocarbazole. f EtOAc.

25 ml of DMF. =ifter 1.5 hr, 6.1 g (0.05 mol) of Me2S(CH2)3C1 Distillation of the residual oil n-ae added s l o ~ l y , maintaining constant temperature. The gave 16, 10.2 g, 62.37, [bp 162-169" (0.8 mm)] . Compounds mixtiire was ytirred overnight and an additional 3.1 g (0.03 mol) of Anal. chloride added aiid heated for 1 hr at 70". After cooling, i t wad The hydrochloride of 16 had mp 200-

worked up in the usual manner.

17-24 i n Table I were also prepared by this procedure. (CZOH~,?~' ,O~) C, H, N.

3larch 19'70 NOTES 311

= (CHz)ZN(C2Hj)2.-Compoiiiid 3 (70 g. 0.30 mol) was dissolved in 850 ml of xylene and added over 15 niin to a cool mixture of EtZS(CHt)*OH (0.60 mol and 2 g 10.10 g-atom) of ?\'a. After refluxing for 5 hr, the condenser Tyai diacoiinected and 100 ml of distillate collected. Fresh xylene (100 nil) was added and the reaction proceeded overnight. The solvents were removed until about 50 ml remained. Aft.er cooling, the re>idue was triturated wit,h concentrated HC1 (200 mi) until a solid residue formed. This solid was dissolved in EtO.Ic-Et20 ( 5 : 1) and treated with 20% XaOH unt,il basic. The aqueou- e w a c t s were reextracted with EtOAc-Et20 (2: l), and the organic layers were combined, washed with saturated SaCI, and dried r C'aClr). Evaporation of t,he solvents and t,reatmerit of the w-idiie with alcoholic HC1, and Et& and refrigeration, yielded critde 38. HCI, which on treatment with C and recrystallization from abmlute Et80H gave 17.4 g, 16.!5%, of 38, nip 190-191". A n d . tCIJH?iCIN~Ot) C, H, C1, N .

Method B. 3-(3-Dimethylaminopropyl)-S-methyl-1,2,3,4- tetrahydrocarbazole-3-carboxylate 142 [V, R' = CH,: R = (CHa)3N(CH3)~].-Conipoiind 12, 43 g (0.20 mol), was dis- solved in 150 ml of absolute ETOH a i d added to a solution of KOH (11.2 g, 0.20 mol) in 250 nil r~i absolute EtOH. After refluxing for 1.5 hr, the solveiit removed in mcuo, the K salt (111, R' = CH3; R = I<, 16 g. 0.07 mol) was aiispeiided in 300 ml of dry toluene, stirred, and heated to reflux, and 10 g (0.07 mol) of (Me)2N(CHl)pC1 in 50 ml of dry toluene added over 1 hr. After 8 hr an additional 5 g of chloride was added and the mixture refluxed for a total of 72 hr. The mixture was cooled and worked up in t,he usual manner. llistillation produced an oil, 13.4 g, 60.9CG [bp 180-187' (0.07 mm)]. A n a / . tC19H26?J?0?) C, H, N. The hydrochloride of 42 had mp 188-190" IEtOH). A n a l . (C19- H&lP;,Or) C , H, C1, N. Compouiid., 4045 in Table I11 were syntherized by this method. 3-Diethylcarboxamido-l,2,3,4-tetrahydrocarbazole (&).-To a

500-ml aliqnot of the acid chloride of 111 rR = R' = H, ea. 30.6 g, 0.14 mol) in a 1-1. flask n-a. added a 3 31 excess (30.7 g) of EtJH and the solution refluxed for 1 hr. After cooling, the zolution was washed (105, HCl. H.O. 10' aOH, and saturated SaC1). The organic layer was dried I?; 04) and evaporated tmo an oil which, aft,er distillation [bp 213 0" (0.2 mm)], solid- ified into a glass; yield, 22 g, 69.9'7. Recrystallization pro- duced crystals, mp 130-131" (Et?O\. .4nal. (C17H22SZO) C, H, N. 3-Diethylaminomethyl-1,2,3,4-tetrahydrocarbazole (46) (VII).

-The amide 45 (6 g, 0.02 mol), di.;oived in a mixture of dry CsHG (100 ml) and anhyd Et& (100 nil,, rvah added to a solution contaiiiiiig 3.5 g of L.4H i n anhyd Etr(). After refluxing overnight, the mixture was deconipw?d wit,h H10 and worked up in the usual manner. The reiidlie iva- &tilled [bp 150-155' (0.5 mm)] to produce a yellox oil, 4 . 5 g \ 37.9y0). ((317-

HzaNt) C, H, iY. 46.HCl had mp 221-224" iEtOH). And . (Ci7HzCINt) CI. 3-Hydroxymethyl-l,2,3,4-tetrahydrocarbazole r47).--Reduc-

tiori of 12.5 g (0.05 mol) of 3 with 7 g of L.IH occurred 011 refluxing overnight. The carbinol, 47, mp 95.5-98,' (Et20-ligroin), 9.7 g, 92.4%, was obtained on distillation of the residue [bp 167-177" (0.1 mm)]. dnai. (CI3HljNO) C, H, S.

Acknowledgment.-The author.* wish t'o express their thanks to the Institute of l l en ta l Health, S. I. H., for Grant' So. AIH 11331, which .supported this \vorl<.

d n a i .

16-Oxygenated 17a-RIethyl-53-androstanes

Divis ion of Organic Chemistry , Tokyo College of Pharmacy , Tokyo , Jupcin

Received October PO, 1969

Very recently, we have denion.trnted that in rabbits 17a-methyltestosterone, a more potent androgen than testosterone in oral therapj-, i- converted into 16- oxygenated 17a-methyl-;i~-atidro*tanes, 1 and 4, in

high yields, and 6 in verymirior yield.' The preferential formation of the 16P-hydroxy-$-steroid to its 16a- hydroxy isomer was the first instance with respect to the metabolism of CI9 and other steroids in the animal body and seemed to be attributable to a steric effect of the 17cu-3Ie since 16-hydroxylation of C19 steroids is known to occur at a tn t h o 2 and in ~ l i t r . o . ~ - ~ Our attention, therefore, has been focused on the role of the 17a-Ile in the conversion of l'ia-methyltestosterone into 1 and interconversion of 1 into 6 through 4. J'urther systematic invedigations on this problem were required on these 16-oxygenated \teroids, of which 1 has already been synthesized in good yield from 3a,17- dihydroxy-5p-androst-16-ene diacetate.' We now wiqh to report the synthesis of 4, 6, and their derivatives.

4 , R = H 5, R = COPh

1, R, = Rz = R3 = H

Z , R I = C O P ~ ; R ~ -

3,R1 = COPh;R* = R3 = H

R2- \C/CH~ ' \ C H ,

Ro,*&

H RO'. H

6 , R = H 7 ,R=Ac

8 , R = H 9,R=Ac

OAc

10 11

The 16a-hydroxy steroid 6 was synthesized by the acid treatment of 10,l followed by the Grignard reaction of the resulting 16a-acetoxy-17-ketosteroid 11. The reaction of 11 with M e l l g I did not proceed stereo- selectively and gave a mixture of two triols, 6 and 8, in a ratio of 3: 1 , while the same Grignard reaction of 16- epimer of 11 resulted in specific production of 1 . This indicates an interfering effect of the 16a-OH on the a-side attack of the reagent at the li-C=O. Assign- ment of the structures of both triols was carried out by the acetonide formation test and comparison of chemi- cal shift value of 18-Me protons of their diacetates, 7

(1) T. Watabe, S. ragishita, and S. Hara, Biochem. Pharmacol., in press. (2) R. Xeher and G. Stark, Ezperientia, 17, 510 (1961). (3) W. E. Easterling. J r . , H. H. Simmer, IT. J. Dignam, hI. 1'. Flankland,

(4) -4. H. Conney and A . Klutch, J . Bid. Chem., 238, 1611 (1963). ( 5 ) G. Pangels and H. Breuer, ~ ~ u t u l . ~ i s s e n s c h a ~ ~ f t e n , 49, 106 (1962). (6) W. L. Heinrichs, H. H. Feder, and A. Cblas, Steroids, 7, 91 (1966).

and F. ?;aftdin. Steroids, 8 , 157 (1966).