THIETANE 1 DI DIOXIDES
July 1966
489
Thietane 1,l-Dioxides’ JACK
s.WELLS AND FRANK 8. ABBOTT
Department of Medicinal Chemistry, School of Pharmacy and Pharmacal Sciences, Purdue University, Lafayette, Indiana Received January 13, 1966 Cyclization of methanesulfonyl chloride with the appropriate enamine in the presence of triethylamine gave 3-alkylamino-2-phenylthietane1,l-dioxides (IIa-e). I n addition to cyclic products the acyclic derivatives, 2dimethylamino- and 2-pyrrolidino-1-methanesulfonyl-1-phenylethylene (111and I V ) were isolated. Some properties and chemistry are discussed. Reduction of the thietane 1,l-dioxides to the corresponding thietanes was unsuccessful. The thietane 1,l-dioxides were of interest as possible MA0 inhibitors. None of the compounds tested showed significant i n vitro MA0 inhibitory activity.
It has been postulated that the potent monoamine oxidase (hIAO) inhibitory activity exhibited by 2phenylcyclopropylamine might be explained in terms of the electronic and steric properties of the cyclopropane ring system. Cyclobutyl and larger cycloalkyl analogs of 2-phenylcyclopropylamine are much less active -1IdO inhibitors presumably for steric reasons and because of a change of electronic properties of the ring system. For a review of structure-activity relationships of AlAO inhibitors in the phenycyclopropylainine series see Zirkle and Kaiser. Heterocyclic analogs of cyclopropane have also shown bIAO inhibition activity in v i t y o . Paget and Davis4reported activity of phenyldiaziridines and more recently Shirodkar5 found 1-phenethyl- and I-isopropyl-2-phenylaziridine to be potent in vitro M A 0 inhibitors. These compounds are unique in that the amine nitrogen is an integral part of the ring system and may lend further support to the theory that a small, electron-dense ring system serves as a point of attachment or attraction to the enzyme, AIAO. I n order to further investigate this theory it appeared that heterocyclic analogs of 2-phenylcycloalkylamines in which the hetero atom could provide the electron density would merit study for -1IAO inhibitory activity. During the course of pursuing thietane derivatives for ;\I40 inhibition studies a number of 3-dialkylamino-2phenylthietane 1,l-dioxides (IIa-e) were synthesized and the chemistry and properties of these derivatives are reported here. Since these compounds are heterocyclic analogs of 2-phenylcyclobutylamine, they appeared worthy of a screen for in v i t y o JIAO inhibition activity. Nethanesulfonyl chloride was cyclized with the appropriate enamine (Ia-f) in the presence of triethylamine to give the corresponding thietane 1,l-dioxide (IIa-e) (Chart I). This cyclization is considered to occur via a sulfene The cyclization reactions were performed in anhydrous ether under the general reaction conditions described for these reactions.’ The thietane 1,ldioxides (IIa-e) were obtained as white, crystalline, (1) (a) T h e support of this n o r k by a research grant from the Purdue Research Foundation is gratefully acknoaledged. (b) From the Ph.D. Thesis of F. S.Ahbott, Purdue Unirersity. (2) (a) B. Belleau and J. Rloran, J . M e d . Pharm. Chem , 6 , 215 (19621, (b) Ann. N . Y . Acad. Sa.,107, 822 (1963). (3) C. L. Zirkle and C. Kaiser in “Psychopharmacological Agents,” Vol I , W. Gordon, Ed., Academic Press Inc., New York. N. E ., 1964, p 445. (4) C J. Paget and C. S D a \ i s , J . M e d . Chem., 7 , 626 (1964) (5) J. N. Wells A. V. Shirodkar, a n d A. M. Knevel, J . Med. Chem., 9, 195 (1966). (6) R. H. Hasek, R. H. Aleen, and J C. Martin, J . Org. C h e m , S O , 1495 (1965). ( i )G. Opitz, H. bchempy, and H. Adolph, Ann. Chem., 684, 92 (1965).
IIa-e % ’ yield of IIa-f
--Solvent---
c,
K Z O
EtnO
CHsCN
47
75
35
75
51
55
24
36
..
Xi1
..
water-insoluble solids. None of the compounds rapidly decolorized 1% KAlnOc solution. Infrared spectra showed no olefinic absorption. Strong sulfone bands occured at 7.6 and 8.9 p with a third strong band around 8.4 p (possible contribution by C-IY stretch). Xmr spectra were in accord with the ring structure, all compounds showing a signal for the benzylic proton (Ha) a t 6 5.3 (doublet), ring methylene protons (H,) a t 4.05 (multiplet with the appearance of a triplet), and the remaining ring proton (Hb) at 3.35 (quartet). The causative agent for the unusual triplet for the ring methylene protons (H,) is not known.
$+He O2 H,
A similar observation has been reported.8 The thietane 1,l-dioxides (IIa-e) are soluble in dilute acids and are readily precipitated from solution by the addition of base, a useful procedure for the isolation and purification of these derivatives from the crude oils or resinous solids often obtained in the cyclization reactions. I n the cyclization reactions for the dimethylamino (IIa) and pyrrolidino (IIb) derivatives, the acyclic products, 2-dimethylamino-1-methanesulfonyl-1-phenethylene (111) and 2-pyrrolidino-l-methanesulfonyl-l(8) L. A. Paquette, J . O r g . Chem., 29, 2854 (1964).
Pyrolysis of the S-oxide of 8-diinetliylxniiiio-L'phenyltliietanr~ 1,l-dioxide (IIa) gave 2-l)hetiylt liictcb 1,l-dioxide (VIII) (Chart 111). I I a could he rrcovered from treatmmt of S'III with ai1 ethaiiolic +olutioii of tliiiicthylnminc.. Thr reaction of VI11 with 5yL S a O H in :~queousnict1i:iiiol gave benzyl methyl sulfonc~(VI). 'l'hc reaction p:tthw:ty may be the same as that pro1)osed for the actioii of aqueous base on thiete l,1-clioside.9 I
VI
COIlver~lOliof' :tti ~ - : ~ l l ~ ~ ~ t ~ ~ ~ u ltoi othe ~ ~SUI~l:tl~l~~h~d~~ fone uitli 1 0 v of foi~ii:itcuntlei. the influencc of base ha$ Ring ol)eiiing of ~~-diiiictli~latiiiiio-2-~,hcl!ylthiet:tnc hceii tlchcribed :t> : L I I : ~ ~ O Ut $o :L rcv('r.c aldol condens:t1,l-dioxidc (IIa) occurred under the itifluciicck 01 tion.9 secoiid 1)roduct IT ar i-olutcd in sniall quantity :queoua 1):thc. t o give L'-diiiic~tl~ylamino-l-lrhenyniethfrom the cyclization iwiction i n the synthesis of 3:tnesulfonylctliglciie (X) (Chart IY). Acid hydrolysi.+ inorpholirio-2-pheii~~lthietaiie1,l-dioxide (IIc). This solid rapidly decolorized 1% I-\-dtalri, 109". The iimr spectriim gave aigrials a t 6 7 . 5 (siiiglet, phcnyly lo), 5.4 (triplet, benzylic protons, 2), 3.65 (triplet, reniainirig ring proton, 1j, and 1.HY (singlet, ?;-methyls, 6). .4na/. Calcd for C17H19NO2S: C, 67.74; T I , 6.35. Foiuid: (:, 67.59; H, 6.19. 3-Phenylthiete 1,l-Dioxide (VIII).-:3-l~irneth~-laniiiio-~ptietiylt hiet,ane 1,l-dioxide (2.25 g, 0.01 mole) wa3 dissolved in a tiiisture of 5 nil of glacial acetic acid and 3 nil of acetic aiihydride i~intaiiiedi i i a 50-ml erlenrneyer flask and the solutioti was cooled t,n 0' iri :til ice --salt-water bath. To this was added dropwise wit,h stirriiig 2.:2 g of 30% H20?solutioii. The reaction mixture \vas stirred an additional 12 hr at 2,5", again cooled in ice, atid rieutralized wit,h concentrated NaOH. The mixture was heated in :I water bath with stirring under ured pressure (water piimp) for 1-2 hr or until practically c STater (20 nil) wa! added itnd the mixture was extracted h two 20-ml portions of chloroform. The CHCll extraiets were dried (XazCOs) :tiid ev:iporat,ed in CUCZLO to give 1.5 g (%3tX) of white solid ( I T I I ) . Ilecrystallizat,ion from hexane-ethati ave white needles, nip 96'. The infrared spectriim showed iig absorptions at 7 . 6 3 , $3,8.8 (sulfone), and a atroiig baiid :it 12.2 p (olefin). The iiltraviolet, spectrum gave A':, 26:: nip ( F 14,000). The nnir r
l
' / A
spectrum showed signals :tt 6 7.4s (singlet, plieiiyl, a), 7.0 (triplet, olefinic prototi, 1 ) i J = 2 i p s ) , :itid 4.54 (doublet, rnethylene protolie, 2 ) i J = 2 cpa).
I
.
heated on a steam bath until moat o f had cv:rpornted. The mixtiire as cooled and 0.275 g ~iilitl \T:IS cdlected by filtration. Itecrystallizaticiii frwni Iiexaiit, c~thariol gave white needles, nip 126- 126.5". .\ inistiire iiielting poiut with benzyl methyl sulfone was not. tiepresscci. .\ sohition of \-I11 (1.0 g ) iti LOO nil of ethatiol s:itiiratetf with diinet tiyl:iiiiiiLe \v:w :rllowed to stand for 5 days. The (~t1i:iiii)I~-n,5ciwpiiratrti :tnd the resulting d i d was extr: wit,h 1 .I. TI('1. Tlic iiiwliihle porlion wits removed liy filtr x i i d ~ l i filtrati, r tnniie ba-ic. wit,h NaOIl t o give a white precipit:itv talliaatioir from ltesaiie-ethaiiol gave 0.7 g tiylaniiIto-Y-pheiiylthietarie I,l-dioxide, IIIII 110-117' ( IIO tielires&ri of niixtiire melting point with IIaj. 2-Dimethylamino-1-phenylmethanesulfonylethylene(X 1. - A .iiluiioii of 11:) ( 2 . 2 5 g, 0.01 mole) i t i 50 nil o f r i i c ~ t h : i i i o l i'oiii:iiiiiiig 0.5ti g ((0.W rncile) of S a R H a (or 1 g of Y a O l I ) \v:I> tefliisecl 6 hr: 5(l nil of n-ater w a s added, arid the solutiori wz+ heated o i i ;i >icitni 11:it Ii iilitil riioit of the tnethanol had e v q i i i rated. Tho ~ i i ~ i i~oluti~iii t ~ i ~ iwis ~ i~rioletiin a freezer :inti filieiwl \ i i give. 1.8 g of white solid, nip 80 3". The solid wah r.e:tdiljwliihle in ttiluk IIC'I :tiid r:tpidly decolorized KLltiOl ,sohition. Several recryzlalliaatio,lfi from ether-petroleum ether g:tvc llitie S ,nip 85-ii6". Infrared analysis showed htroiig at 6.15 iolefin). 7.7--7.'3, : i t i d 9.2 p (sulfone). Thr idtrsviolet hpectniin gave x ~ ~ ~ ' 251 ~ : : : " nip ( e 22,600). The timr spectriim sho\vetl aigids :it 6 7.45 (singlet, pheiiyl, 5 ) , 6.!)5 (doliblet, vinyl priitmt, 1 ) (.T = 1:3 i y s ) , 4.68 (doliblet, vinyl prot,on> 1) i , / = 13 c p ) , 4.24 (siiiglet, rnethylene, 2 ) , :tiid 2.R3 (singlet, ?\'-rtiethyl~,ti). A n a l . Calcd for ('llH15S02S: (:, 5S.M; 11, 6.71. Foiititl: c, 58.hl; TI, 6.83. "\ soliiti(iii o f 0.25 g of S in 10 nil of 1 .V IICI was Iieuted fIJr several miniltr-. \ v h c ~cool ~ the d u l i o n was satiirat ed with YaC1 and extrurtetl with two IO-nil portions of chloroform. Tho CIIC13extract dried (Xa,SOa) and evaporated to give x few of colorless oil. Treatment, of the oil with 2,4diriitroreageiit gave :tn oraiige 'L,-l-diiiitrophenylhydralization from ethyl acetate gave orange crystals, A >ample analyzed as t he 2,Cdinitrophenyltiydrazcitic of ~~lit~ii~lmethaiiesiilfon~~lacetaldehyde (XI). . I n n / . C:ilui for (:I;HI~N40&: C, 47.,52; H, 3.72. Polrtrtl: C, 47.2!): 11, Y.78. IIydroly& iif S i i i 1 .\- HC:l followed kiy adjusiinent of the pH i o 12 wit,h NaOH gave Ivhite needles, ~ n p125-127', identified tis I)enz;\.l methyl hiilfoiic hy mixtiire meltiiig point ttnd comparison of infrared spectra. Lithium Aluminum Hydride Reduction of Ila and I1 g, 0.04 tiiolc) rlis-iilvcti i:i 60 ml o f anhydrous THF iiriipwi.c> t o 4.5 K (11.12 tiicile) of powdered 1,iAlHa sti I I I I S 'I'HF :it 0'. The reaitioti mixture was stirred 2.5' for 11' hr, :iii11 final refused for 1 hr. .4niiiie T l i ~w:ii,tiiiii r iiixtui w1.s clecmnposed by thr i t i o i i ( I f 4.5 nil of H?O, 4 I l l l IJf 20"1, Pu'aOH, t i l l d 15.7 r i l l o f \+-:iter, i i i thut order. Tlie i~rystallitic~ mlti \vt>rt, Icrnoved 11). fi1lr:itioii :iiid w a h d TTith ether, and the ether filrate :tiid n-:ichiiig.s were CVap
