0.
n. ~IOI)IG), R . l?. ('OJ.LIE;H,
.\VI)
11. I\.
s( I T I , \ ' ~ Z E I {
Pyridine Chemistry. 11. Further Studies on the Smiles Rearrangemen t of the 3-riniiiio-Z,Z'-clipy~idylSulfide System. The SyiiLhesis of Some 1,6-I)iazaphenothiazines~
.Iddit ioii:Ll studie.; oii fart,i)r*-nl'rei~i~lg tlie Smile, rearraiiyeiiieiil ( i f ~ - n ~ ~ ~ i ~ ~ ~ j - ~ sulfides ~ ~ ' - ( are l i ~reported, ~~ri(lyl nloiig nit,h B ,superior prepnralioii iJf tlie thiolact.:tins 4a a i d b. The c:oiiveriion of these thiolactmis to 1,Bdia~apheiiothiaziiie~ of potential biological interest is discussed, including it11 unusual synthetic approach t o the 10-aryl derivatives. The reactions of several of I he thiaaiiies iri it,anrlard antiinflamrtmtory a.11dcentral nervou.: system tests are given.
In a previous publication2 we reported on the Smilestype rearrangement < which 3-amino-2,2'-dipyridyl -illfidei (e.g., 3a and b) undergo in acidic, hasic., and neutral media, inveitigation, n k c ~ hyielded compounds oi i t ructure 4. The continuing intere-t in the relationships between the chemical st rurture of plienothiazlne~ and their actions upon specific physiological and p5yc-hophysiological function- inducd us to -tudy the conversion of these substancci t o the corresponding 1,G diazapheriothiazines (5). 4 The heretofore preferred preparation for the ihio amide5 derivatires 4 involve- the base-catalyzed condensations of 3-aniilio-lH-pSridiriethione (1) i with the vorreyponding (Bhloropyridinr 2, folloncd by the a(%(Latalyzed rearrangement- of the tin\iiiiig dipyridyl sillfidw (Chart I) 2 I t ha, nox k~ecnfound that amine5 of type 4 can be prepared in good yield directly from tho corresponding pyridinethionos and pyridyl chloride- hy heating tlieqe reac+anii in alcohol nith, or withoiit. a small amount of added hydrochloric arid. Conipounds 4a and b were prepared by this method. In the course of thiy work, it nas of intrinsic intereit t o examine the rearrangemeni aptitude of tlie diaminoof the nitro dipyridyl sulfide 6, -inw lllc co~ivcr~ion group t o an amine function ihould disfavor the nucleophilic~rearrangeniciit The ziilfidc 6 waq readily prcp a i d by the iron-acetic. acid rcductioii of the nitro ( 1 ) (a) bupported I>\ Research G i a n t G-11388 of ~ h rNational Sciencr Foundation (11) Taken in part the 1I.P Thesis of R E Collier, CnirPrsity of Virginia 1962, and tlie l'h D Dissertation of R I\ Schlatzer, Uni\ersity of Virginia. 1966 (2) Paper I 0. R Rodig, R E Collier and R Chem 29, 2652 (19641 ( 3 ) Ear example, see 11. Gordon P ;2, Craig, and C L Zirkle, Idranccs in Chemistry Series, N o 45, 4meriran Chemiral Societv, Washington, 13 C , 1964, p 140, for a recent revirv (4) T h e nuinbering used is t h a t recommended b y L T Capell and D I Walker, J r , "The Ring Index " Lmencan Chemical Societv, Wa-hinpton I). P,, 1st Supplement, 1967, namelv
aFcj H
N
S
( 5 ) In response t o a recent suggestion [A. R. Katritrky, Chem. Ind. (London), 331 (1965)l "2-mercaptopyridine" derivatives reported in this communication are depicted and named t o conform t o t h e prevalent tautomeric form. In the present case, this is the thiolactam structure in each instance, a s evidenced by tlie presence of a thiocarhonyl stretching hand near 1140 c m . 3 [E. Spinner, .I. Chem. Soc., 1237 (1960)], as well as t h e absence of -SH absorption in the infrared spectra of these compounds. (6) At sufficiently high acid concentrations, the protonation of one of the primary amino groiips might, occur, which would negate its deactivating influence. Yet, from the known pK, values for 3-aminopyridines [A. Albert, ihtd., 1020 (1960)], this should not happen t,o a n y extent until hot11 ring nitrogen atoms have heen protonated.
CIIARI'
I
H
H
[
/
4a, b
3a, b
KOH, EtOH,
Sa.b
9c, d , e
10
a,R=H b,R=CHa C , R = CH,CH(CHa)CH,N(CH,)J d, R = C H ~ C H ~ C H L N ( C H J ) L e, R =
ns0' x
f,
R
nSH2 N
group in 3a and was found to rearrange to the thio amide 7 when treated with 10% hydrochloric acid, although at a considerably slower rate than did thc rorrespondiiig nitro compound. The strucaturcl of' thc
PYRIDINE CHEMISTRY.I1
Jaiiuary 1966
thiolactam 7 was confirmed by its preparation from the pyridinethione 4a by the reduction of the nitro group with iron in acetic acid. The diazaphenothiazines 5a and b could be obtained from the N-acetyl-2,2'-dipyridyl sulfides Sa and b2 \vlien these compounds were heated in ethanolic potashium hydroxide. Under these conditions, however, the sulfide 8a yielded about 25% of the uncyclized product 4a a,' well. When the thiolactam 4a was treated in like manner, no ring closure occurred, even when the reaction mixture was heated at reflux for an extended period of time.
13a, R
= KO2; R' = H b, It = KO?; R' = CHI C, R = H ; R' SO2 d, R = CH3; R' = NO1
X similar observation was reported by r\laki7who tried to convcmrt the chloro derivatives 128to the corresponding diazaphenothiazines by the same method. He attributed the failure of the cyclization to the presence of strong hydrogen bonding between the amino hydrogen atom and the o-nitro group in each case.$ This argument is embraced by abundant evidence which supports the fact that nitro groups can hydrogen bondlo and apparently do so quite strongly if a resonating system prevails, as is the case in the nitroamines 4a and b. l 1 Yet, it seemed to us remarkable that this bonding is indeed of such a magnitude as to preclude the formation of diazaphenothiazines under the conditions investigated. In an effort to shed additional light on this question, the X-H stretching frequencies of the thiomethyl derivatives 13a-d2 were studied. The results observed in both the solid and the liquid phases are shown in Table I. The CC14solution spectra distinctly show that TABLE I ?;-H
S T R E T C H I S G F R E Q U E N C I E S ' IN THE I N F R A R E D SPECTR.4 OF SOME
Compd.
3- .\SD5 - N I T R O - 2 , 3 ' - D I P Y R I D Y L . ~ ~ I ~ E S
KDS
Medium CClP
CClr
+ DAIS0
3306(*) 3289 (b), 3340 (sh) 3295(5) 3285 ( b ) ,3350 (sh) 3180,3231 3155 (b), 3185 (sh) 3378 (s) 3380(a) 3394 ( 9 ) 3200 (sh), 3240 5 = sharp, b = broad, sh = shoulder; values are in reciprocal centimeters.
13a 13b 13c 13d
( 7 ) T.N a k i . J . Pharm. Soc. J a p a n , 77, 485 (1957). (8) By analogy with our compounds pyridinethione structures are assumed for these suhstances, rather t h a n the mercaptodipyridylamine structiires reported by 31aki.7 (9) T h e possibility of such a n effect has also been entertained by 0. L. Urady and C. Waller [ J . Chem. Soc., 1218 (1930)l t o explain t h e previously observed inability of certain o-(Z-nitroanilino)phenols t o cyclize in basic media to yield phenoxazines. Hovever, in order t o satisfy all of the known facts, they found i t necessary t o abandon this argument in favor of a purely steric one. I n t h e case of phenoxazines, it now appears t h a t both hydrogen bonding and steric effects play a n important role in t h e cyclization Drocess [cf. K. C. Roberts and H. B. Clark, ibid., 1312 (1935)l. (10) For example, see W. F. Baitinger. P. yon R. Schleyer, T. S. S. R Rlurty, and I,. Robinson, Tetrahedron. 20, 1635 (1964), and references cited therein. (11) These compounds can be compared t o the o-nitroanilines, t h e intramolecular hydrogen bonding of which has been extensively studied. See tootnote 21 in ref. 10.
117
the amino group is int'rainolecularly hydrogen bonded in compounds 13a and b, while it is not so in dipyridylamines 13c and d. These effects are also noted in the solid state spectra for compounds 13a, b, and d, but 13c gave a typical hydrogen-bonded spectrum, the bonding presumably occurring via an intermolecular process. In view of these findings, a reagent was sought which might compete successfully wit'h the nit'ro group for tmhe amino hydrogen at'om when added t'o t'he reaction medium, thus sufficiently freeing the nitro group to assure success of the cyclization process. Dimethyl sulfoxide was studied as one such possibility,'Z and when a small amount of this reagent mas added to the solution samples of 13c and d used for infrared studies, a pronounced shift to lower frequency of the N-H stretching mode was observed (see Table I). Clearly, dimethyl sulfoxide hydrogen bonds with the amino groups, and possibly more strongly (absorption a t lower freq~ency'~) than does the nitro group. Indeed, when the reaction was carried out in t'he presence of this reagent, the diazaphenothiazines 5a and b were obtained in good yield. The dimet'hyl sulfoxide may also serve to increase the nucleophilic character of the sulfide ion, since anions are at most only weakly solvated by this reagent.'* The dimet'hylamiriopropyl and -butyl side chains were added by treating the diazaphenothiazine 5a with the corresponding dimethylaminoalkyl chloride in the presence of sodium hydride. Under these conditions, alkylation occurs mainly a t position 10, rat'her than at positions 1 or 6,15and infrared and ultraviolet absorption data supported this premise. The dimethylaminobutyl derivative 9c was obtained as a rvell-defined solid, m.p. 99-101", aft'er purification as the dihydrochloride. On the other hand, the dimethylaminopropyl derivative 9d was obt'ained as an oil which could not be crystallized. It yielded both a solid dihydrochloride and a solid picrate, however. It was intriguing to att'empt the synthesis of aryl side-chain derivatives of 9 (R = aryl) from the thio amide 4a by a process involving a Smiles rearrangement. The method is exemplified by the following sequence and may at times prove to be the method of choice for preparing such thiazines. The thio amide 4a was treated with 2-chloro-3-nitropyridine under basic conditions, whereby the condensation product 10 was obtained. More vigorous treatment of this product with base effected t'he rearrangement and ring closure, giving the diazaphenothiazine 9e in good yield. The amine 9f was readily prepared by the reduction of the (12) T h e strong hydrogen-bonding properties of dimethyl sulfoxide are well known. For example, see D. Barnard, J. Fabian, and H. Koch, J . Chem. Soc., 2442 (1949); 0. L. Chapman and R. W. King, J . A m . Chem. Soc.. 86, 1256 (1964); 4 . Allerhand and P. von R. Schleyer. i b i d . , 86, 1715 (1963). For such bonding concerned specifically with amines, see W. Impoiiiid showed an iiifrared baiid a t 1134 mi.-' attril)lrted t i l the C=S stretching mode. When NaHCO., \vas d d e d l o the iriother liquor until pH 7. 0.17 1 g. ( 14Yc) of cnide :i-aniiir11-:3'-llitro-2,2'-dipyridyl dfidc (3a) prec*ipitated: t i aii ortinge wlid, m.p. 162.5-165' (lit.* m.p. 1(ii-.l68"). 3- [ (5-Methyl-3-nitro-2-pyridyl )amino]-2( 1 H)-pyridinethione (4b).---A mixture of 282 my. (2.23 mmoles) of 1,2,5383 mg. (2.21'
iiirrioles) of 2-chloro-3-iiitr0-5-1nethylpyridine (2b),2119 nil. of :it>soluteethanol, 10 ml. of water, and 1.0 ml. of coricentrated HCL wits heated to gentle boiling in a n opeii flask on a steam bat'h, allowing some of the solvent to boil off. After 35 min., the sohitioii had turiied dark and a bright red solid had precipitated. The mixture was cooled in ice aiid the solid was removed by filtration, washed with water (wash added to the filtrate), and (16) For reported antiinflammatory characteristics of phenothiazine derivatives, see V. S. Mitrofanor, Z. .\, Popenkova, N.S. Tolmacheva. and A. hf. Chernukh, Uch. Zap., Inst. Farmakol. i Khimioterap. Akad. M e d . .\'auk, 1, 167 (1958); B i d . Abstr.. 46, 64654 (1964); J. C . Siucki and C. R. Thompson. An. J . P h ~ s i o l . , 193, 275 (1958): L. Kato and R. Gozsy, J . Pharmacal. Ezptl. lherap., 129, 231 (1960) : G. Vogel, Arzneimittel-Forsch. 11,978 (1961). (17) All melting points were taken in a heated oil bath and are corrected. Although not usually specified, infrared spectra were taken of all compounds, using a Perkin-Elmer Nodel 21, 137, or 837 instrument. T h e spectra nere taken in a K B r matrix unless indicated otherwise and \yere used in rimjunction with melting points i o determine the structures of all produrts. I n addition, the spectra reported in Tahle I and for compounds Sa, b, and 9c-f mere determined on a Perkin-Elmer l l o d e l 521 instrument calibrated against a polystyrene standard (TV = weak, m = medium, s = strong). T h e ultraviolet absorption spectra were determined in 95% ethanol w i t h a Tary Model 11 spectrophotometer, hlicroanalyses mere performed b s Mrs. W. E. Coyne and Bfrs. J. D. Reed of this laboratory. and by Galbraith Laboratories, I n c . Knoxville, Tenn. (18) T h e solid state infrared spectrum of this compound showed a band a t 1131 cm.-l attributed to the C=S stretching mode. (19) Light and Co., Ltd., Colnbrook, Buckinghamshire. England. (20) T h e melting point of this compound mas found t o h e dependent on t h r rate of heating of the melting point, 1,aili. That reported was taken with a heating rate of 2-3O/min. 121) 9. J. Ciiililresa and R. 1,. h I c l C t ~ ,.I. .1m Chum. Soc.. 73, 3501 (19,51).
4b, 1ti.p. 246-255O tl('i.. .I 11'dried, yielding 505 Ing. (87' crystallization from acetoiie the meltiiig poiiit i o 23:L'--L'.i.?'' dec.20 (lit.? 1n.p. 25;-257.5" infrared hillid :lt ll:$fj ( ' t i i . I :t>sigried t o tlie CI-S stretohiiig mode. 0 1 1 standing fur 5 days, t,he filtrat,e yielded :iii :tdi.litiiiiiiil 4!1 I I I ~ . (,S(;i j of somewhat less pure 4b, m.p. 230-234' del,. 3,3'-Diamino-2,2'-dipyridylSulfide (6).--A mixture of 529 iiig. ( 2.13 mnioles) of 3-amino-3'-nitro-2,2'-dipyridyl sulfide (3a), 1048 ing. of powdered iron (100 mesh), :tnd 6.0 inl. of glacial :ic,etic* acid was genily warmed oii a steam bath for 5 r n i i i . \\':iter ( 5 ml. with added a i d heating was coiltinlid for :til additioiial 10 n i i t i . 'I'tir hot niixtiirr was filtered and the re-idire rem:titiitig o i i t l i ( , filler was wa*hetl with liot water (wtisliiiigs added t o the filtrat c I . Tlie ;icidity of the filtrates was adjusted to applosimately pH .i liy (lie :itldiiic~ti ol solid KOH (:%pellet.), produc~iiig:i roltirlc+Tlie solid w:i* srpar:ttetf I-iy f i l ~ r : i ~ i i i i i , Of 6! I l l . ] ) . 2O,-i-?I I O with prwioiis (LeUJllltllimt ion friiiii : I q t i e i 1113 riirit h i iiol p i v~ iioii,
.I
NU/.
Fiiiiiid:
(':ilid. ior ('lnH1,
C', t5.j.lJ:i;
ti, 4.ti2: 1,?>.ti:.
C,5.i.2L: I i , 4.54; N,25.S:;.
\Their the riiother liqtiiir was f l i r t tier treated nit11 (:4 pellets) aiid cooled iii ice, ail iidtlitiorial 59 mg. (1:3 with previoiis decomposit i o i i ohtniiied, m.p. 205-?O~~o -1tliliydrochloritlc~\v:i- prepared by addiiig several d r o p ut' v i i i i relitrated HC1 to 6 dissolved iii liot absolute ethanol. O n rooliiig as obtaiiied as :I pale yellow 185' but ttieii resolidi y decomposed :it 220 Recrystallizatitiii o f the prodLict f r o m aqiieoiii eth:tiiul d change its melting poilit. i1na1. Calcd. for Cl,,H12C12X~S: (1! 41.25; H, 4.1;. I~(ititii1: C?4O.!X3: H,4.24. 3- [(3-Amino-2-pyridyl)amino]-2( la)-pyridinethione (7). A. From the Reduction of the Thiolactam 4a.-A mixture of 214 111g. (0.862 mmole) of 4a, 368 ing. of powdered iron (100 mesh), 5.0 nil. of glacial acetic: acid, arid 5.0 ml. of water was heated on a ateaiii tmth for 5 riiiti. ' T l i r b litit mixture was filtered and tlie r e d i i c o i i the filter 1v:ia \v:~.-liedwitti h o t water (washings added to the, filtrate). W a t w (11)nil.) was added t o the filtrate aiid the acidity \vas theii ttdjusled to :ipproxiurately pH 4 by tlie addition of solid KOH ( 8 pellets), wlierr~tiythe prodtict precipitated. The solid wi>c,ollrc~tedhy filtmtioii, waslied wit,h water, a i i d r i'roiii :tqiir;oii+ tiieth:tiicil (c,harc*oal1, yielding 4.5 nig. :i> pale )-ellon- iietdle;-, tii,l), 1'Ot)-205° dec. Wheii t, t I i c inother liquor via> tidjuated t o :ipproxiinately pH tioiial d i d KOH, :L precipitate w;is ohtained whic*hwas tjrc;ilctl inatiiier n- that described above, j-ieldiiig rttiot81ier I!) of 7, III.~. 20:3--20Fo dw. The rombiried r r o p w w i ~ d t1vic.e from :iqiieous iiietliaiiol, wliivh i,trinrd 1 tic melting poiiit t o 203-20S' tier. Thiy r i i t n p o i i i i t l stici\vrd :LII infrared I i a i i d :it I l:+l c i n - l whic~hi i g t i d t o the (':--S htretiahitig nioclr. .\f!aE. (':ll('d. fiJr ( ~ l ~ k ~ ~ " C ~' , ~55.i);k f ? 11, 4.62; s,2:l.(iy. Foritid: ('>53.04: H, 4.56; N, 25.37. .-~&litioiialprodiict xvah obtaiiied ivlieii the inother liqtior W:L> made hasic t o approximately pH X t)y adding KOH aiid theti XaHCOs. The mixtiire extracted with ether, tlie etlicr la)-ers were c.ombiriet1 :uid dried, a i d the >iilveiit The pale yellow solid which re1n:ritled w:i> recq :iqiieoiis rrieth:iiiol t o give :I Eiirther I!) m y . f IO('; ) 20.5" t l ~ . B. From the Smiles Rearrangement of 3,3'-Diamino-2,2'dipyridyl Sulfide (6).---.4 solution of 73.9 mg. (0.334 intiiole) of 6 in 3.0 ml. of lop; H('1 w t s heated a t reflux for 1.25 tir. A ( ~ c ~ l o t i c : (20 ml.) ~v:istheii added Fvliereby :ipale yellow solid precipit:itetl. This was separat,ed by filtration, washed with acetoiie, ntid dried, yielding 60.0 mg. of 6 tiihydrochloride, which partially melled alitl rewlidified to an orailge-j-ellow solid a t 190" followed by decorriposition a t 213-329". R h e i i ari aqueous solution of the dihydrochloride \ w s iieutrtrlized with XaHCOs, the free amine 6 was rerovered. Tlie filtrate 1~3thc-ciiiceiitrated 011 a steam bath to remove most of the acetoile. -4sniall amount of water wa hy 1 hr ;iclditioti i l i ' S;iHCOs iuitil COr evolritioii yellow solid which had separated was collected by filtratiuti, w a h c d with water, niitl dried, yielding 22.6 mg. of crude thio1:tct:trli 7, I I I . ~ .l92--J!Ni0 de(,. llecrystallimtiur~of this materid
,J:itiusry 1Wti
PYRIDINE CHE~WBTRY. I1
from aqueous methanol gave 13.1 nig. (4770)22of the desired product as yellow-tan needles, m.p. 203-205" dec. A second crop yielded an additional 3.1 mg. ( 1 1 % ) 2 2 of 7, m.p. 193-204" dec. ITo attempt was made to obtain optimum yields in this case, but in view of the large amount of starting material recovered, it appears that a longer reaction time should prove beneficial to the yield of rearranged product. lOH-Dipyrido[2,3-b:2',3'-e] [1,4]thiazine (5a). A. From 3-Acetamido-3'-nitro-2,2'-dipyridyl Sulfide (Sa).-A solution of 337 mg. (1.16 mmoles) of Sa and 160 mg. of KOH in 15 ml. of ethanol was heated a t reflux for 40 min. When the mixture was cooled in ice, dark crystals separated. These were collected by filtration and recrystallized from an ethanol-ether solvent pair, giving 82.9 mg. (25%) of the potassium salt of 3-[(3nitro-2-pyridyl)amino]-2( lH)-pyridinethione having an ill-defined melting point wit,h decomposition occurring a t 244". When this material was treated a-ith water, it gave back the thio amide 4a. Water was added to the mother liquor and the mixture was coiiceiitrated on a hteani bath. Successive cooling in ice caused several crops of product to heparate which were combined arid llized from aqueous ethanol, yielding 101 mg. (43%7,!of sa, m.p. 223-225". An analytical sample was recrystallized 239 nip (log E 4.42), 337.5 mp from ethanol; m.p. 225'; : : : "A (log E 3.99); (l/X)i:: (principal peaks, em.?) 3196 (w), 3144 (w), 308'2 (w), 3053 (w), 1599 (m), 1589 (m), 1555 (m), 1517 (m), 1433 (s), 1123 (m), 780 (m), 751 (m). Anal. Calcd. for CloHiN$: C, 59.68; H, 3.51; N, 20.88. Found: C, 59.80; H, 3.85; N, 20.39. B. From 3- [( 3-Nitro-2-pyridyl)amino] -2( 1H)-pyridinethione (4a).-TO 50 ml. of dimethyl sulfoxide was added 1.84 g. of KOH and enough absolute ethanol (approximately 50 ml.) to dissolve the base when the mixture was heated on a steam bath. This hot basic solution was then added to a stirred mixture of 7.83 g. (0.0315 mole) of 4a in 20 ml. of dimethyl sulfoxide. The maroon mixture was heated at reflux for 7 hr. and the ethanol was then removed by distillation over a 0.5-hr. peroid. The greenish tan residue was allowed to cool and was poured into 150 ml. of water, whereby 5.81 g. (92%) of the thiazine 5a separated, m.p. 222.5-224.5". h Yimilar run, differing in that the reflux step was eliminat'ed and the ethanol was distilled over a 20-min. period, gave an Si% yield of the thiazine, m.p. 220-224". An attempt to prepare 5a by heating 4a in ethanolic KOH solution for 4 hr. produced only the potassium salt of 2-mercapto-3'iiitro-3,2'-dipyridylamine as black crystals, m.p. 251-254' dec. This salt appeared to decompose partly in protic solvents aiid itt t enipts to purify it for analysis (e.y., by recrystallization from nbiolrite ethanol) were unsuccessful. 3-Methyl-lOH-dipyrido[2,3-b:2',3'-e] [1,4]thiazine (5b). A. From 3-Acetamido-3'-nitro-5'-methyl-2,2'-dipyridyl Sulfide (8b). A solution of 1.00 g. (0.00329 mole) of 8b and 0.25 g. of KOH in ethanol was heated a t reflux for 30 min. The solution was then taken to dryness under reduced pressure and the residue was treated with hot ethanol. The inorganic salts were removed b g filtration and, on cooling, the filtrate yielded 0.51 g. ( 7 2 7 , ) of the thiazine 5b as a tan crystalline solid, m.p. 205-208". Recry,stallizatioii from ethanol raised the me1t)ing point to 217-218; X",EP," 289 mp (log E 4.41), 341 mp (log E 3.99); (l/X):tC (principal peaks, ~ n i . - ~3224 ) (w), 3152 (w),2979 (w),1600 (m), 1434 (s), 790 (m), 6112 (m). Anal. Calcd. for CllHgN3S: C, 61.37; H, 4.21; Tu', 19.52. Found: C, 61.04; H, 3.97; N, 19.29. B. From the Pyridinethione 4b.-In a flask equipped with a distilling head were placed 437 mg. (1.67 mmoles) of 4b, 5 ml. of dimethyl sulfoxide, and a solution of 90 mg. of KOH in 15 ml. of absolute ethanol. The deep purple mixture was heated a t such a rate that the ethanol distilled over a 20-min. period. The browti soliitio~iwas cooled and 20 ml. of water was added, causing it solid ti, previpitate. After cooling iu an ice bath, the solid was wllec.ted by filtratioii, wanhed with water (washings added to filtrate), aiid recrystallized from aqueous ethanol (charcoal), yielding 260 mg. (72%) of the thiazine 5b as a tan solid, m.p. 216-219'. 0 1 1 standing, the filtrat,e deposited an additional 25 mg. ( 7 % ) of less pure product, m.p. 207-216". lo-( 2-Methyl-3-dimethylamino-l-n-propyl)dipyrido[Z,3b : 2',3'-s] [1,4]thiazine (9c).-A solution of 7.57 g. (0.0377 mole) [1,4]thiazine (5a) in 200 nil. of dry of lOH-dipyrido[2,3-b:3',3'-e] benzene was placed in a three-necked flask fitted with a stirrer, _____ (22) Yield based on recovered starting material.
119
dropping funnel, dry-nitrogen inlet, and a reflux condenser. Two grams of 52.7% NaH in mineral oilz3was added, the system was flushed with dry nitrogen, and the stirred niixture was heated a t reflux for 3 hr. Heating was then discontinued and a benzene solution of 3-chloro-2-methyl-l-dimethylaminopropa1ie was added to the reaction mixture. The chloramine solution was prepared by neutralizing 6.50 g. (0.0378 mole) of 3-chloro-2methyl-1-dimethylaminopropane hydrochloride24 with aqueous KOH solution extracting the free amine with three 50-ml. portions of benzene and drying the combined benzene extracts (NazSW. The mixture was heat,ed a t reflux for an additional 16:hr., after which time a second portion of the chloramine in benzene was added without discontinuing the heating. This second portion was prepared as described above from 3.00 g. (0.0174 mole) of the hydrochloride, the free amine being extracted wit,h 35 ml. of benzene. After heating at reflux for an additional 8 hr., the reaction mixture was cooled to room temperature, washed with water, and extracted with 10% HC1. The combined acid extracts were washed with benzene, filtered and made basic by adding (with cooling) solid KOH, and the acidity was then adjusted to approximately p H 4 with dilute HC1. The solid which precipitated was collected by filtration, yielding 2.89 g. (38%) of uiireacted thiazine, m.p. 222-225". The filtrate was made basic by adding additional KOH, followed by extraction with ether. Removal of the ether from the combined and dried (NazSO,) extracts left an oily solid which was trit,urated with 50 ml. of absolute ethanol. The remaining solid was separated by filtration, and washed on the filter with 35 ml. of absolute ethanol, yielding an additional 0.28 g. (47,)of unreacted thiazine, m.p. 221-224". The filtrate was treated with charcoal, followed by the addition of 40 ml. of absolute ethanol, 10 ml. of concentrated HC1, 200 ml. of ether, and 100 ml. of acetone. The precipitated oil slowly solidified, was collected by filtration, and washed with acetone, yielding 5.03 g. (62%)22of 9c dihydrochloride, m.p. 208-214'. The hygroscopic product was recrystallized for analysis from an absolute ethanol-ether mixture, giving yellow crystals, softening a t 200", m.p. 210-215". Anal. Calcd. for C16Hd212NaS: C, 51.47; H, 5.94; N, 15.01. Found: C, 51.83; H, 5.79; N, 15.99. An aqueous solution containing 3.96 g. of the thiazine dihydrochloride was made basic by adding solid KOH. An oil separated which solidified on cooling. The solid was collected by filtration and recrystallized from aqueous ethanol (with charcoal treatment), giving 2.93 g. of the thiazine 9c as a pale tan crystalline solid, m.p. 99-101'. When this product was recrystallized from aqueous methanol (charcoal), colorless crystals were re243.5 mp covered with no change in the melting point,;' : : A (principal peaks, (log E 4.32), 328.5 mp (log e 3.94); (l/X)E;: cm.-]) 3050 (w), 2818 (m), 2761 (m), 1585 (m), 1434 (m), 1400 (s), 1210 (m), 1038 (m), 799 (m), 787 (m), 760 (m). Anal. Calcd. for C ~ ~ H ~ O N C,~63.97; S: H, 6.71; N, 18.65. Found: C, 63.68; H, 6.54; N, 18.48. lo-( 3-Dimethylamino-1 -n-propy1)dipyrido[2,3-b:2',3'-e] [1,41thiazine (9d)Dihydrochloride.-The thiazine 9d dihydrochloride was prepared in a manner similar to that described for Se, with the following major procedural differences. The quantities used were thiazine 5a, 4.21 g. (0.0210 mole); dry benzene, 300 ml.; NaH, 1.00 g. (52.7'% in mineral 0il)~3;first portion of 3-chloro-ldimethylaminopropane hydrochloride,24 6.00 g. (0.0380 mole); 50 ml. of dry benzene; reflux period after addition of the first chloramine portion, 2.5 hr. ; second portion of 3-chloro-1-dimethylaminopropane hydrochloride, 6.70 g. (0.0424 mole); 50 ml. of dry benzene; reflux period after second chloramine addition, 27 hr. The reaction mixture was then allowed to cool, washed with water, and extracted with 5% HC1. The combined acid extracts were cooled in ice and made basir by adding solid KOH. The yelloworange oil which separat'ed was taken up in ether and the ether solution was dried (Na*S04), followed by removal of the solvent under reduced pressure. The residual orange oil was dissolved in absolute ethanol, the solution was filtered and then acidified by adding 10 ml. of concentrated HC1. The mixture was cooled in ice and the yellow solid which had precipitated was collected by filtration, yielding 6.00 g. ( 8 0 5 ) of 9d dihydrochlo___
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(23) Metal Hydrides. Inc.. Beverly, Mass. (24) We wish t o thank Dr. James Kerwin of Smith Kline and French Laboratories, Philadelphia, Pa., for a generous supply of this compound.
