nient in this investigation, to Dr. Paul E. Thompson, Mr. Jack E. Meisenhelder, and Dr. Haig Yajarian for the antischistosome testing, and to nIiss 11. Virginia l-Ch]oro-2-methyl.3-(4-phenylazo-l-naphthylamino).2.proDudley, A h . Zoe Gavrilis, 31i-s. ?tIary K. Martin, 11iss pano1.-Vtilizing the procedure described above for the preparaJoan D. nlulthaup, Rliss Josephine Rarity, Mrs. Doris tion of l-~hl0r0-3-(4-phenylazo-l-naphthylamino)-2-~~0~an0~, R. Thomas, and I\Iiss E. A. Weinstein for synthesizirlg miline (3.25 g, 0.035 mole) and l-chloro-2-methyl-3-( l-naphthylseveral of the compounds described herein. We also ami11o)-2-propanol~~ (10.0 g, 0.035 mole) gave 7.8 g (63%) of thank n h . TvTiilliam Pearlman for carrying out the hydroniaroon crystal>, nip 130-131”. .inal. Calcd for C,oH20C15~0.C, 67.88; H, 5.70, K, 11.88. genations, l l r . C. E. Childs and associates for the Found: C, 67.98; H, 5.6i, 9 , 12.05. microanalyses, arid Dr. J. 11. T’andenbelt and coworkers f i r determination of the infrared and ultraviolet Acknowledgments.-The authors wish to express absorption spectra. their appreciation to Dr. Loren 31. Long for encourage-
was crystallized from ethanol to give 12.2 g (72%) of a reddish brown solid, mp 140-141”. A n a l . Calcd for CisHlsCINaO: C, 67.15; H, 5.34; C1, 10.44; ?i, 12.37. Found: C, 67.45; H, 5.55, C1, 10.58; X, 12.26.
Reactions of Mercaptoamines. 111. Synthesis of N-Monosubstituted 2-Mercaptoethylamines1J h’FHUH
1’. 1 ” E R H I S , 3 0. LEROYSALERX1,I A N D BEVERLY A.
SCHUTZ
AI d u e s t Research Institute, K a n s a s City,JIissouri 64110 Received September 29, 1965 As part of a program on the synthesis of antiradiation drugs, a four-step novel synthesis of N-monosubstituted 2-mercaptoethylamines has been developed. The synthesis involves (1) conversion of 2-mercaptoethylamine by reaction with nitriles to 2-substituted 2-thiazolines (I), ( 2 ) quaternization of the thiasolines by tosylate esters to thiazoliniiim salts (11),(3) alkaline hydrolysis of the salts to an XT-(2-mercaptoethy1)acetamide derivative (111), and (4) hydrolysis of the amides in concentrated HC1 and glacial acetic acid to N-monosubstituted 2-mercaptoethylamines (IT’).
Because of the potential use of 2-niercaptoethylamines as antiradiation drugs,j-s it has become iinperative that additional synthetic routes to compounds of this class be devised. Previous studies of the reactions of mercaptoamines have shown that many compounds capable of reacting with the amine function also react with the mercaptan f u i ~ c t i o n . In ~ ~the ~ ~ work reported here, a method was devised for protecting the mercaptan function in 2mercaptoethylamine, allowing the amine function to react, and then regenerating the free mercaptan. SMonosubstituted 2-mereaptoethylamines were thereby obtained.
L-:H3 @
I
e
p-O,SC,H,CH,
NaOH then H,OC
I1
(1) This work u a s supported by the V. 8 . Army RIedical Research and l)evelopment Command, Department of the .lrmy, under Contract No. Dh-~Y-193-3ID-2174. 12) Presented in part a t the Sixteenth h n n u a l Midwest Chemistry Conference, Kansas City, Mo., Nov 19, 1964. (3) Deceased. (4) To whom requests for reprints should be addressed. (5) Cf. Symposium on Radiation-Protective Agents, 141st National Meeting of the American Chemical Society, Washington, D. C., 3Iarch 1962. (6) D. D. Reynolds, D. L. Fields, and D . L. Johnson, J . Oru. Chem., 26, 5120 (1961).
( I ) R . J. Wineman. 11.H. Gollis, J. C. James, and A . h l . Pomponi, ihid., 27, 4222 (1962). (8) F. I. Carroll, H. h l . Dickson, and 31. E. \Vall, i b i d . , 30, 33 (1965). (9) Paper I : A . F. Ferris and H. A . Schutz, %bid.,28, 3140 (1963). (10) Paper 11: A . F. Ferris and R. A . Schutz, d i d , , 29, 201 (1964).
Two recent investigations have independently shown that 2-mercaptoethylamine reacts with nitriles to give 2-substituted 2-thiazolines.” l 2 It had been shown earlier that 2-thiazolines are quaternized with alkyl iodides or p-tol~enesulfonates.1~It was found that low molecular weight alkyl iodides indeed gave good yields of solid quaternary thiazolinium iodides when heated with 2-methyl-2-thiazoline (I) in refluxing absolute ethanol. However, when more coniplex halides were used, the reaction appeared to be sluggish. Benzyl chloride and 2-bromoethylamine hydrobromide both gave ill-defined syrups with 2-methyl-2-thiazoline, and chloroacetone gave a tarry product. I t became apparent that only active alkylating agents would serve to quaternize the thiazoline. Since esters of ptoluenesulfonic acid (“tosylates”) are known to be more effective in displacement reactions than alkyl halides (ie., the tosylate anion is a better “leaving group” than any of the halide anions), they seemed a likely choice for the thiazoline quaternization. I n the first experiments, refluxing absolute ethanol was used as solvent and ethyl and n-heptyl tosylates were the alkylating agents. The same solid product was obtained in both reactions, and it proved to be the simple tosylate ralt of 2-methyl-2-thiazoline. From the reaction with heptyl tosylate, a liquid product was isolated and identified as ethyl n-heptyl ether. The isolation of this compound provided a basis for explaining what had happened in these reactions. The tosylate ester had alkylated the solvent in preference l o the thiazoline, and the latter had acted merely as an acid acceptor. When refluxing dry acetonitrile (11) R. Kuhn and F. D r a u e r t , German Patent 937,231 (Dec 29, 1955), Chem Abstr , 63,409 (1959). (12) T Kurihaia. K Suzuki, and h l Oklta, Tohoku Yakka Daakago Kiyo, 6 , 43 (19581, Chem Abslr., 68, 10176 (1959). (13) L. G . S . Brocker, J . Am. Chem. SOC.,68, 662 (19.36).
w:ii u-cd as the solveiit, tlie h i r e d thiazolinium qalt was obtairied in poor yield.. From the reaction of l-icl)tyl tosylate a r i d 2-methyl-2-t liiazoline wai obtained a 38c/cyield of 3-n-lie~~ty1-'2-iiictliyl-2-thiazoliiie tosylat c aiid considerable unidentified liquid by-product. L-qe
of chlorobeiizenc solveiit (2x5 rccoiiiniended by Lempcrt and %auer14 for the quaternizatiori of nitrogen-contairiiiig heterocyclic molecule-) i i i the ciuaternizatioii of 2-methy1-2-thinzoliiie r e d t e d in vcry marked iiiiI)roveincnt in yields over m y other solvent tried. l'or example, the quaternizatioii n it11 heptyl tosylatc p v e a .S4yc yield of thimoliriiuni salt (11) 1s. 3BC2 in acetonitrile. Witli octyl and '2-benzyloxyethyl to-yl:itcs, yields of salt were 62 :ind 855,. reqpectively. Airecciit study': has deiiioiiitrated that quaterriizetl 2-osazoliiie- nrc cleaved t o eiteri of ninino alcoholq on . Thus, hytl~dysibof the quaternary halt to the S-2-(iiiercaptoethyl) acet aniid (111) wa.; carried out by atltlirig :I 3 X ex :ti 70" to the quntcriixy coinpouiitl i i :ltliio-phcrc. I'or ~ x a i ~ i p l e ,~-illetliyI-8-(:3-1,lieli~li~roi)yl)thinzoliiiiuiiito.ylnte :~fforckd~ i 8i 8 5 yield ot S-(2-nicrc:iptoct hyl)-S-(:3-plienyli)roi)yl):tt>ctuiiiitle. ,It teiiil)t, to hydrolyze the :uiiide to the correqmndiiig :uiiiii(>11it11 e x c c ~a1l;nli or C, S HC1 under reflux for 8 Iir f:iiletl, 1 !I(. ainicle being rec,ovcrecl i r i e:icli (YW. Hon c w r , Iiytlroly\i- with a 1: 1 mixture of coilcentrated HC'l -glnc*ial :rcvtic :acid uriclcr reflux for '24 lir in a i i i t rogcvi ntino.l)here (lid roiivert t h c miide to the de>\ i r c ~ l:tiiiiric> (IV). 111 tlii- u:iy S-('2-mercal)toethyl)S-(:l-~~liciiyll~ro~,yl)~~cctaiiiitlc u:i\ ronvertctl to S(2-iiivrcal)t octliy1)-~-1-~1henyl~~ro~~yl,~1iiiiie i u 647; yield. Hydroly.1. of (lie thiazoliiiiiun y:ilt. (II) vcry 1)roh:tMy pro(~e(1si i i :I muirier Giiiiilx to that 1)oitulatecl by l I : w t i i i I f ) for liydroly of 2--all;yltlii:~zoli1ie\. Hn.r oiwiou+ -liift\ the c( 1ihri:i -0 t h a t thc re:icatioii ~ ~ i ~ o:ic*mrrlirig w ( ~ 1 ~to 1 ~ 1 t Th. t h o (lrivitig forw for ( ' S
-
\ l l e i i , Jr , d i i , l I Ginoz J I< I ( . \lartiri I? I\ IIrciii :il).orptioii but elid reveal abqorptioii :it 1700 ( . i i i r 1 ( , I doc. S-ncetyliiicrca~~toacetorie):uid b:iiid\ :ii 810. 1003, :ml 10%i charactcriiticy of toiyliiiel : i i i i o ~ i \ . ~ ~ l'iirtlierniore. hylrolydq of crude 2-iiietliyl-~~-(~-i~i(~t1ioxyethyl)tIiiiizoliriiuiii tosylatc with water :tiit1 t1ic11 (iS HC'l gave :i poor yield (13c;) of S-(2-inethoqc~tliyl)-2-iiierc:i~~toct~~yl~~iiiirie. The :iiniiicl n11i-t :iIiiio-f certainly Iiave heen foriiicd by i)>ith TI, iiri(ir t l i c x :iiiiidc\ (1)ath I) (lo not hptlrolyzc to the :iiniii(xk 1111c1(~1 the-e condition.. The thiazoliiiiuni d t 5 were not all w y h t allix:ibl(~ d d . . Thoqc iihich ~ v e r ecrystalline were c~1iar:tclciizetl by melting \)oilit deterniinatiori and :trialyzctl. The i1ifr:irctl .I)cc*tr:i of the thiazoliiiiuni \:ilt.; all ITve:dctl iiiteiiv t)niicl; at 1003 arid 1020 m r l , chariwtc.t*iitic of tosplat anion bands.'' Reyults are rclportetl in Table I. Sot all tlie tliiaxoliiiium salts oould be (*onv c r t d t o S-iiioiio.uhitituted ~ - m e r c ~ p t o ~ ~ t h p l n i i i i ~ i ~ ~ ~ . (hi the ot1ic.r li:m(l, :I number of tliiazoliniuiii -:I11 \VI iicah c~)ultlI l ( J t I)c cryytallized u~idermcrit IiycIroIy~i~
-
JIay 19G6
nIERCAPTOAMINES.
111
393
TABLEI1 N-~IOSOSUBSTITUTED 2-lIERCAPTOETHYLAMIXES HSCHZCHZNHR Overall" yield,
7 - 7 0 yield.imide
Amine
CaHa(Ck11n)r CnHs(CH?)J
68 88
60
% 18
64
23
C2IlsOCH&IIl CHa(CH?jaOCH?CHr
58 73
22 51
2Y
64
38
7
56
18
10
R
CH,+-CHI CHs(CH*jaO(CH2)20CH?CH?
JISILCHLH, p-(CHa)aCCsHnOCHzCH?
P-CIC~H~OCH~CH~~
Alcohol -+ amine.
12
Amine bp, OC (mm) 81-SZ(O.2) 107-110 (0.15) 78-81(4.4) Si-100 (2.7)
C
iO-i3(0.2) 99.5-100
46
22
100
40
20 17
(0.2) 136.5 (0.2)
for amine,
H
1.4690 1.4668
54
42
7-Calcd 66.25 67.64
(0.4) Y5.5-96 (0.3) 143.5-144
92
Amine n% 1.5512 1.5401
8.34
x-7
N
--Found
C
S
for amine, %---
H
K
5 17.8i
8.78
7.73 7.17
17.69 16.41
66.47 67.87
8.34 8.96
7.72 7.11
16.1Y
48.28 54.19
10.13 10.80
9.39 7.90
21.48
18.08
48.18 54.44
9.97 11.07
9.24 7.99
21.63 18.01
1.4926
64.11
11.30
7.48
17.11
63.97
11.47
7.54
16.98
1.4677
54.26
10.4i
6.33
14.48
54.09
10.35
6.17
14.64
1.5656
51.29
6.Y9
7.48
34.23
51.41
7.10
7.58
34.10
1.5314
66.36
9.15
5.53
12.65
66.23
9.03
5.62
12.32
1.5618
51.83
6.09
6.05
13.84
52.02
6.13
5.96
13.67
Anal. Calcd: C1, 15.30. Found: C1, 15.10.
TABLEI11 x-lIONOSCBSTITUTED
N-( 2-RIERCAPTOETIIY I.) ACETAMIDES
___--
'5 R
CHdCH,), C?HaOCH2CH2 QCH
CH2
CH,(CH?)aOCH2CHz NECCH~CH? CHaO( CHz)rOCH,CHr CH,CH( OCHa)CH,CH? C?HsOCH,CHzOCHsCH,
Calcd, 7G-----H N S
>ield
RP, " C (mm)
n2*n
39 58
145-150(0 04) 102-103(0 07)
1 4815 1 4884
64.81 11.27 50.23 8.96
5.40 12.36 7.32 16.76
54
150-155(0 05)
1 5687
52.37
6,59
61 43 45 19 18
iis-120(0 176-177(0 138-140(0 108-110(0 128-132(0
1 4830 1 5169 1 4906 1 4888 1 4823
54.76 48.81 48.84 52.65 51.04
10) 05) 5) 23) 23)
satisfactorily to give the appropriate X-monosubstituted 2-mercaptoethylaniines. -411 the distillable monosubstituted mercaptoethylamine derivatives which \yere prepared are listed in Table 11. The infrared spectra of these compounds all revealed mercaptan peaks at 2550 cni-1,18 and were void of amide absorption. The properties of the amides which were isolated and distilled are listed separately in Table 111. Tlie infrared spectra of these substances mere consiitent with the desired structure and showed amide (1640 cni-I) and mercaptan absorption (2550 em-'). For the reasons noted, the "R" groups do not necessarily correspond in the different tables. Biological Activity.-The nine S-monosubstituted mercaptoethylamines listed in Table I1 have been examined for protective activity against radiation lethality in mice. The compound where R is phenethyl was found to have a protective effectiveness described as good. The compound where R is 2-(2-thienyl)ethyl possessed activity described as fair. Slight activity was assigned to those compounds where R is p-t-butylphenoxyethyl, p-chlorophenoxyethyl, and 3phenoxypropyl. The other N-monosubstituted mercaptoethylamines were inactive. The thiazolinium salts listed in Table I and the acetamide derivatives (Table 111) were also examined for protective activity against lethal doses of radiation. ,411 these compounds were inactive. The thiazolinium salts mere tested on (18) L. .J. Uellamy, "Tlie Infrared Spectra of Complex 3Iolecules," John IViley and dons. Inc., New York, S . T..1958, p 360.
C
C
I'ound, c/o-----H N
5
64.91 11.25 50.50 9 . 0 8
5 . 4 6 12.15 7.23 16.07
6.11 27.96
52.60
6.75
6.08 27.83
9 . 6 5 6.39 14.62 7.02 16.27 18.62 8 . 6 5 6 . 3 3 14.49 9.33 6.82 15.62 8.99 5.95 13.62
54.91 49.00 48.59 52.89 51.21
9.74 6.37 1 4 . 5 i 7 . 1 9 16.50 18.38 8 47 6.46 14.63 9 . 4 1 6.86 15.40 9 . 0 6 6.11 13.90
the premise that they may undergo in vivo hydrolysis to the corresponding S-monosubstituted mercaptoethylamine. The following dose levels were employed in testing the compounds for biological activity: 51-150 mg/kg for all the IT-monosubstituted 2-mercaptoethylamines except those where R = 2-(n-butoxyethoxy)ethyl and phenethyl, which lvere tested at less than 50 mg/kg; 51-150 mg/kg for the acetamide derivatives except those where R = 2-(n-butoxyethoxy)ethyl and 2-(2-methoxyethyl)ethyl, which were tested at 150-350 mg/kg; 51-130 mg/lig for the thiazolinium salts except the compound where R = decyl, which was tested at less than 50 mg/kg. The conipounds were administered intraperitoneally to mice which \yere tested for 30-day survival against lethal radiation of 1000 r. Complete details are described by Field and co-workers.lg Experimental Sectionz0 Oiily typical procedures are described here. All alcohol. were converted to their tosylste esters by the method of Marvel and Sekera.21 2-Methyl-3-(2-phenethyl)thiazolinium Tosy1ate.-A solution of 55.2 g (0.20 mole) of crude phenethyl tobylate and 20.2 g (0.20 (19) L. Field, A. Ferretti, R. Crenshaw, and T. Owen, J . J f e d . Chem., 7 , 42 (1964). (20) Melting points are corrected and boiling points are uncorrected. Nicroanalyses were performed b y Galbraith Laboratories. Knoxville, Tenn. Infrared spectra were recorded on a Perkin-Elmer Model 137 Infracord recording spectrophotometer. (21) C. 8.Marvel and V. C . Sekera, "Organic Syntheses," CON. Vol. 111, John IViley and Sons, Inc., ?ieu- T o r k , N. T.,1955, p 366.
