141
KOTES
January 1970
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4
I
1 E:1MgBr. 25
2. tI ,o+,100
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(17.9 g, 0.20 mole) were added and the suspension was stirred a t reflux under Nzfor 4 hr. Before cooling the mixture was filtered, the solids were washed wit,h hot C&s, and the filtrat,e was evaporated to yield a crystalline residue (20.6 g), mp 85-89", containing thioxanthene and thioxant,heri-9-oneJ as well as the desired nitrile (t,lc). One recrystallization from hexane removed thioxarrtherie and one recryst,allization from i-PrOH removed most of the thioxant.hen-9-one to provide 13.6 g (617,) of 3a, mp 92.595', which was pure enough to be used as a synthetic int,ermediate. Three addit,ional recrystallizations from i-PrOH provided pure 3a: nip 97-98', ir (KBr) C=N stretching eit,her weak or absent; uv max (EtOH) 262 mp (log e 4.0). Anal. (CldHsNS) C, H, K. 2-Chloro-9-thioxanthenecarbonitriie (3b) was prepared by the same procedure in 64% yield, mp 13G-136" (Me2CO-hexane), ir (KBr) 4.49 p (C=?r', very weak), uv max (Et.OH) 266 mp (log e4.1). Anal. (CldH&lK'S) C, H , S . Method A. 9- [2-(Dimethylamino)ethyl] -9-thioxanthenecarbonitrile (4a).--A solution of 3a (11.2 g, 0.050 mole) in 50 ml of anhydrous DMF under S:!was treated with 4970 KaH in oil (2.5 g, 0.050 mole). After ea. 10 miii HZ evolution subsided and 2-chlo~o-?;~I\j-dimethglethylamine (8.5 g, 0.070 mole) was added to the deep red carbanion solution. The mixture v a s stirred a t 95' for 15 min daring which time the color discharged. After dilution by 2 vol of HIO, the prodiicts were extracted into EtOAc. The EtOAc extracts were washed twice with H10, then extracted by t,hree 30-ml portions of 1 S aqueous HC1. The combined acidic extracts were treated wit,h 10 iY aqueous KaOH to pH 11 and t,he product was extracted with EtOAc. The residue dissolved in EtzO afforded a crystalline salt upon treat,ment, wit,h HC1-Et20. One recryst,allization from i-PrOH provided 10.0 g (60%) of pure 4a,HCl, mp 232-234', uv max (EtOH) 263mp (log 64.1). ilnal. (ClaH18S,S.HC1) C, H, K. 2-Chloro-9- [2-(dimethylamino)ethyl] -9-thioxanthenecarbonitrile (4b) n-as prepared in 73% yield from 3b via method A: mp 71.5-i3' (hexane). The hydrochloride crystallized from i-PrOH: nip 260-261.5", uv max (EtOH) 270 mp (log E 4.1). Anal. (Ci8Hi7CINzS.HCl) C , H, N. 1- { 9- [2-(Dimethylamino)ethyl] thioxanthen-9-yl ) -1-propanone (5a).--A solntion of 4a (4.1 g, 0.014 mole) in 60 ml of anhydrous C6H, was added to a solution of EtIlIgBr (from 3.3 g of EtBr, 0.73 g of Llg, and 15 ml of anhydrous Et2O) under K Pat such a rate so as to maintain the reaction t,emperature below 5". After stirring a t 25' for 18 hr, the pale green suspension was treated with 30 ml of 3 N aqueous HC1 and heated for 0.5 hr on a steam
6
8
bath while the Et20 and CsHe were allowed to distil away from the react'ion mixture. The mixture was cooled and the oily hydrochloride was extracted into CHCb. Two recryst,allizatioris from C&-hexane afforded 3.05 g (50%) of pure 5a.HC1,l0 mp 178-180', ir (KBr), 5.81 p (C=O), uv max (EtOH) 274 mp (log e 4.0). Anal. (C20H2aNOS.HCl) C, H, N. 1-(2-Chloro-9- [2-(dimethylamino)ethyl]thioxanthen-9-yll-lpropanone (5b) was prepared in 41Yc yield from 4b by the same, procedure but was isolated as the maleate salt: nip 18&190", ir (KBr) 5.85 p (C=O), uv max (EtOH) 277 mp (log e 4.1). Anal. (CiaHzpClKOS.C~H404)C, H, N. 2-Chloro-N,N-dimethyIthioxanthene-9-ethylamine(6), the major product if the Grignard mixture is heated t o 100' before addition of the aqueous HC1, rvas isolated as the hydrochloride, mp 257-258.501 uv max (EtOH) 272 mp (log e 4.1). Anal. (C17HisClNS.HCl) C, H, X. 9- [2-(Dimethylamino)propyl] -9-thioxanthenecarbonitrile (7) was prepared from 11.2 g of 3a and 2-chloro-S,N-dimethylpropylamine by method A. The crude residue (11.8 g) derived from the EtOAc extract was dissolved in hexane and chromakographed on 300 g of neutral AlzOs (Woelm, activity I). Elution with 2% Et20-hexane provided 3.0 g of an oil, which was greatly enriched (cu. 9: 1) in the less polar (LP) isomer. Subsequent elution by Et20 yielded 8.7 g of a mixt,ure slightly enriched (ca. 6:4) in the more polar (AIP) isomer, The 90% L P fraction was converted to the hydrochloride salt, in Et20 and t,wice recrystallized from EtOH t o yield 1.2 g of pure 7.HCl: mp 276-277" dec; nnir (CDCla)S 2.42 (broad singlet, +SCH,), 1.20 (d, 3 H, J = 6 CPS, CCH,). Anal. (Cl~HzOXzS.HCl) C, H, N. 9- [l-(Dimethylamino)-2-propyl] -9-thioxanthenecarbonitrile (8) was obtained by rechromatographing the above Et20 eluate on 90 g of neut,ral A1203,eluting with C6H6 to remove all LP isomer, then eluting the hIP isomer with hIe2CO. The JIe2C0 eluate was treated u-ith HC1 and the insolitble salt'was recrystallized from EtOH to afford 1.4 g of pure 8.HC1: mp 241.5-243' dec; nmr (CDCI,) 6 2.46 (sharp singlet, +SCH,), 1.29 (d, 3 H, J = 7 cps, CCH3). Anal. (C1gH20NYS.HCl)C, H, E.
Acknowledgment.-I wish t'o express my appreciation for the valuable technical assistance contributed by Mr. Hans Wiedermann. (IO) Compound Sa previously reported is the maleate salt: C. L. Zirkle,
U.S . Patent 3,095,425 (1963); Chem. Abstr., 69, 128420 (1963).
