'E'HE SYfiTfiESES G? SQME WQ-TERfiARY AMENE $AL?S 05 SUBSTETG‘FSE} AC‘I’Lc3-AMSNQ‘E‘E‘EEOPE‘iEE‘éES Thesis for She Dem“ 3% M. S. Mimim STA}? UNEV‘ERSETY mm Sfiafiord’ “Fae? 5%? -' ‘UIBRAR y \S g . . FE; chhxgan State University I.\ '1; -I En.) 1» L13 1" .‘ {.1} NC) , :y I: \. L v |, ~. . .‘ N I.l In“: mi .‘iQflN T1717,“ T“ "‘71' "‘3'- " “IT J’WT 7.“ liu QLL\-~i-..;J~.¢_A)J rJLL.-.~J ‘fltr- ‘x m "-73:71 at) r v. "‘1’? r: armcw C"! cg'rTi‘wr'i Farm 73:) Ci'A-‘LGJL-LH‘S—n LLLY ALLL‘- LA‘A-J ”‘44:; .‘J lb U L. M J L I J- L, .L H, ACYL-B—AKITOTHIOEHlKJS By Arthur Stafford Teot A THSSIS Submitted to Kichigan State University in partial fulfillment of the requirements for the degree of EASTER CF SCIfififlE Department of Chemistry 1961 1-2 5 33: 1C‘ T paw. 7.“. —‘~' . 1—"? 4.31.3 QLL‘.....‘..: .-...m) x... -C--.) L;.1;;\J-‘.—‘_il_i.'.--.‘--c-£iL ? _._,’__ .-_.' A ~— r-q‘ “1 Aw—‘I C‘V’w: :1 —, T'-" - 'p‘~7-—- ‘7 ‘ -» .1-7—~ ~- A — l-‘Io --—— /—_ 1.- ~--'-.~< 1‘ I 'S \‘ _ I . ‘ k H L" ...-1, _ ' ',—"—‘ I v—’ “ L..— ,J (\J-..‘ ....»J -.-. NJ .- J.....-....\. -...) ---...‘J (J1.-.... ...—--—\'¢...--_.'u._.4._J by Arthur 5. Teot The furpose of this investigation was to de— , l V- .L_‘.\.“‘ .0 1. .,_ .,1,“‘. ynthetic metio1s lor tie fijdlm < (“‘1 H O "J (D C? series of thicPhene derivatives hi in: the follOfiinr enhlgfl_:3tructure: It Wis RnllCl“ ted tirit such compounds would sho hi‘h physiological activity with such an amide group based on studies rejorted in tFe literature wi i sini— lar phenyl compounds. The sturtinvfrmfixarial for tfe svnthcsis of these conqwiunds vwhs B—tlfinnruidc. .lnis ;rx3 brengfi;d Jimw1 IS-Umathylifliiogdyfiie tt':a sianliixicgdiTon.<3F C: ;g;i rwa's - 1‘ q 4, .- proceaur€< ’. o—Tuena31ue was 117.0 ed TO updg IQO a 1” Hr . .-. ,1 -- .. , A q 1 nofmxnn rearrnn eie t «ed the re uitL , e.ine wdu ~ fl '1'“ ' -5.- ‘3 '1 - ". \v T ' . r x ‘ . 1' 'l'1r1li.e libel TSJCLJUJ Ledli flltd ‘31 ll..J (3 C’ L< ‘ 1 (D F ( I‘ I w - f "— r~ ‘:K C V 1- _ U 13‘ 'J either chloro:--xcetyl chloride Cr fl—c37:.l0‘z?orro::ioryl chloride. The /§—ccloro—2—oror‘oriridotrfioon ne Wis . (w ‘ J I) 'L‘ -’\ ’I 1'1““,(3 - ~ 7 13-" Yr [1 1') g ‘l I' —‘ r— —d-i 1M r. "'5‘ .. ‘ .5 . ' ' IN 1;?) U -n . U KLO- C I; ll]. ”'“u‘ L) DC] 0 .1- ; 163' . - f), :7" 1.- 1.")- OHIO 11.2.151‘ ."__—n :1- LI‘U . ’~ -: '-. I" x a R 4 ' 1‘ <'- . v ,1 -< \ D :I ““ ‘ ‘ "‘, .‘ "vv '- ‘W "' I‘ll’l‘. Slio’gtui. lagL‘C. CIJIVLVV 'Lblvr’xjo 0-1. /—U1.‘L’1Lgai 41.116 n'e-Y'e L.) ‘ - ‘v: A "u 4--1.\ ‘\ \ \ ‘ I" r‘ " -" '“1 .1") fl. ‘3 I ~\ 1 precared fOllOJLDQ t:e Trocedures of Cl ,,l 1e JLQ (1“ Ci‘ ‘. In- . .7;__' gil‘L-lu3 2120 l t‘ 1 synthesized, in drv dioxune solution at room teaser— eture, by displacement of tie QJ—chlorine with excess piperidine, diethylurine or morpholiee respectively. mhe rroiucts were separated from the diOXine solvent and the excess sec01d4rv amine was removed bv steam "' . I“ '.'." 3 " ‘. 'Vr'. . ""2 ‘ 11“ L“, -_ .‘ "L‘ *1 ~ ." .1 If: 'I" '\ ll:Ltion or bi fliCCiglClblkfl wlUJ Muubr dad Lever pl Fl. (1 E—j—I ‘0' Irv“ ' (‘14- n -" "‘ *1 r . -~ 4“ -: ' , - ’1 ~ v- r -- ,._ 1": -. '3‘ . - . ‘maofllLu or the r Cl:*uleo Alter several deuitionul 'Y‘\“]'Y). 10'; fit‘wi"? ”‘13 (W J” ‘r‘.'-\ ""1. v") "D. “‘u)-] T. ,1 \f7- 1 'u‘!‘(‘1 1-1r\“r‘./') 11' u‘flffl It") ‘I 44’ L1..- 1- -.. ..- \1 Li. ). (.11 ’1 5;} ‘..' L3 -‘g‘: , 'u 1 J;- _'.. .1 £19.-.. J . («11' L, L; i.) s: C} {J C- : l-,..;. ‘40 bl _ ized either as their hydrochloride r quaternary rethyl- iodide salts. Results of piwrwicolo ic el testi ng of ct hese compounds till be 1e mo ted clsexnere. 2- The nenide was sud‘eCLed to a Eof inn re;rrunge— ment bu t fiiled to re:act thus confirming Campaigne's previous results (2 ). Additional studies on the 2— thienyl series included an attempted preparation of .3 Ziee Q.) N—bromo-2— thenamide, the synthesis of R—thenoyl and an attempted Curtius re leafi‘é“ nt of the litter which failed to give a defindtive result. References (1) C“7;3;;nez_E et al, Org. Syntleses, 47, 5;, and 9: (13;) (2) Carpuigne, E. and Konroe, P.A., J. An. Chem. 600°, 25.‘ 2447 (1954). DEDICATION To Ky'flife ii ACKNOULEDGMLNT The author wishes to express his apnreciation for the aid and guidance given by Professor Robert D. Schuetz and to The Dow Chemical Company for granting a leave of absence which made possible the completion of this work. iii III-III: “II"?I‘” v-1 .1. .U ‘o' ' T'r'“.’::rf'1‘T'/V'T .LL...”:J ‘...L..L\/.'.1.L_J DTA'ITH'T L 7-H? .....‘Jx/br‘JL-5a. ' L¢| 5 :- Y ': \ '1"/ -Aflln0o fl—c w -:‘. ,I\ - ‘i'. —7 5- p-TL\ “eh? 2—6uhstitute —.‘ -—uu-‘~~--1 1 ,. .7 s” '1 . : .44.“; 4......L- .....J... .4. “Au “....‘n... ..- ..TW‘ “— —p'._‘._, :kdr‘ ..J...L-A—J»I Van—4:) 75v?) 1" A. a.» J O >|"‘:‘1 A‘ --J-— r\'-1 m l 7' , o .L -1. .1144“; L'J.‘ (Di; CLOUILLO} "M 11C W ”‘ieh_riij 11337-1 ..- f1 1' K; k ' l V L; [I hloro acwfl—I—an c:‘<fi “ ‘ I :V‘.._~;i .ll ................. I ,_.’... ‘Ar‘J iV‘\rls ...... \ "r Cj-nC”l—j- awn o VK « A lifilOITfifllGS . _, '\_. In ~ 1‘4 .L , . ‘v‘vH‘w ’- RLQ ilA'QJI’ble .ldGLOU -.. r1 ‘ :ted vb é mw (-"J. r1‘):]() ... O O O. D ’\ Ol H I’L) .k 5‘ . II’T'E‘I] “'_I'§1CT, o sti tuije I 7 ./ A 1“:er H -’l"he- n :8 ‘5- rfi -: w I A ‘ I. i . O 7“" L .A‘,\ . :“ra - .“ “VI"? "'1 7' C3 \ n ‘ . ‘. .1 -._ . ,# .'._a. 7 4-. .... . w L).\ ‘ .(5 A J Anni o t . :_i oh 1-: i :3 e from 3 5e iron . .I44_ -0 t) L‘IJU Oi HUTO n of K-ZTOUO- . _ \ ,4 \. -1”: ._\_ (l, o o o 0 IL- . fl b 0 sh 0| ‘4 '_.Jo l (‘ bJ t (,3 (D }__J (D \H I . \N \3 /’ / 61 1— —— -“.--“ (—x wfi F" . —‘__ r. (.‘1' LLxJ-L v—L _l.--.;~_'_---4 Table ‘ 7“ \~ I’ ’)I' J - ’ C. 7‘. 1I "v I“ .1" ~ -. :- r" ‘r “.\ - IA 0 ..t‘r64-‘IJI J b]. 11 O i 141...]...31) {I l L- u ocd a -C 111C730— '7 fl-\' 3—. . ... ': fi :_:._ _o . V." H r‘ ;\:—:4..O;-)1.01’1:L- ;_'-UOL 'LOLW;1L':J(?S O o o o o O o 0 o o O ...} I3. Erepa atio; f Substituted ,G—Cllloro- on 3 O P -: ‘7 ,~.‘ . ‘1 4—} j. 7‘" L d c -" I‘ MLO C«-;LlCLOU-J-O_-L.)41'.Iieu o o o o o o o o o o 0 \JJ 1—5 N) .3 II. Proyerties and Ana yscs of Substituted f3-Chloro-3—Propionafiidothioph;mes . III. Pref-Inition Off W—Tet‘tiu?y .—3.«":Ei:”:(.: .c.',.-_._ L‘s ' of Substituted Acyl—E- , -.- 3 ~‘ 1' o w ~, .- ~<-‘ ’. iLllEJOtH10911\'l'US o o o o o o o o o o o o o o o o o o o 0 IV. Properties of 09—Tertiary gnino Salts of Substituted gogl—E- Aminothiopbcnes .................... ’r-: L fl r.) \N C.) \H }_J [U \I‘.‘ 4 \J INTRODUCTION 2. The relationships between chenical structure and physiological effect in organic mate;ials have inter- ested man since the beginnings of the science of chemical therepeutics. In 1937, lofgren general- ized the structural reguirements for an organic chem- ical which would have local anesthetic preperties, as A-K—éCH29ENR2 where A represents an aryl group and M is a heteroatom or a group having one or more such atoms. The length of the polymethylene chain (ie., the value of "n") between the aromatic and tertiary amine groups is important but the Optimum value of n varies with the remainder of the chemical structure. Usually, how- ever it is 2 or 5. In the majority of the commer- cially important local anesthetics, A is a phenyl or substituted phenyl group and M is an ester link- " or "Novocaine" which age. For example, "Irocaine was first synthesized and shown to be superior to - n - n n- w (2) the naturally occurring Cocaine by Linnorn has the structure: N -C—O-CH CH H 2 2’N’(C2H5)2 The thiophene analog of "Procaine"(5) and a number of other esters of 2— and 5- thenoic acids<4> have been prepared and tested pharmacologically. 7» It was the primary purpose of this investigation to synthesise thiOphene derivatives which might possess outstanding local anesthetic preperties by replacing the ester linkage with an amide group. The compounds prepared in this study can be represented by the seneral formula: 0 II N 110%H993NR 2 X 5/ Y Anticipation for high physiological activity with the amide group can be found in the recent literature. "Lidocaine",u)-diethylamino-2,6-dimethyl-acetanilide has been found to have twice the potency of "Procaine", (5). With less toxic and fewer side effects Further it was the purpose of the present investigation to deter- mine the effect of various substituents on the thiophene ring, length of hydrocarbon residue (value of "n") and the importance of the tertiary amine grouping on the anesthetic properties. This thesis, however, will concern itself with the preparation of the heterocyclic amides as th pharmacological results will be reported elsewhere. A comparison of the physiological effects of certain benzene and thiophene c0Wpounds has aroused considerable interest for several years an“ the status a of the field has been reviewed by Blinke<6> and more C”) recently by Campaigne ’ . Some work has been reported substituting the thiophene for the benzene nucleus in local anesthetics, mostly arleQs of effective phenyl compounds. Dann<5> made and tested the 2-thienyl ana- log of "Procaine" and reported an average duration of anesthesia of 120 minutes for the 5—amino-2-thienyl ester as compared to 100 minutes for "Procaine" in the rabbit cornea test. The most complete study was that of Campaigne and Q LeSuer(b) who prepared a series of compounds having the formula S substituted in both the 2 and 5 positions of the thienyl ring. The only two compounds having local an- esthetic activity were the 2— and B-thienyl derivatives where n=3 and Rzn—butyl. In the corneal irrigation test, both compounds gave 20 — 22 minutes of anesthesia which is in the range for "Butyn". The general type of compounds investigated in the present study can be represented by the general formula: u NEG-€0H2}ENR2 X s Y It is to be noted that they are acylated amines, rath- er than amides of 2- and E—thenoic acid, and hence might be expected to snow a greater difference in their physiological properties than just the substitution of an amide linkage fer an ester group. The work report— ed in this thesis deals with the synthesis of these co—alkylamino substituted acyl aminothiOphenes and does not include the physiological studies, which will be reported elsewhere.. The first step in the preparation of the desired compounds was to obtain the aminethiOphenes. Both 2— and B-aminothiophenes have been prepared in fair yield by the reduction of the corresponding nitrothiophenes and their isolation as a double salt of stannic chlo— Q ride(/) (10) (11) according to the following equation: Sn - .T . N02 WET—'9 G‘I‘TH2 hC l SnC 14 ' S The free 2-aminothi0phene has been distilled in an . (10) .. - inert atmosphere but rapidly becomes a gummy tar in an ordinary atmosphere. The hydrochloride salt of 0 a ' 1 w a H 1 l2 2-aminotniopnene nas supposedly been made by Tonl< > 7. but it was "too hygrosc0pic" to obtain a melting point. The E—aminotniophene has not been isolated either as the free amine or as its hydrochloride or by Hofmann rearrangement of E—thenamide(15). NaOH _,\1‘ 0 Th 0m ?_ _ .- l 3H2 h“ anl4 + AC2O Ether‘) l |-hh%-CH5 O 3 s -C-NH -NH —NHCCH “ 2 NaOEr 2 Ac 0 | ' 5 O W ——92 O 3 N2 3 ‘ S The isomeric 2—acetamidothi0phene has been synthesiz- F - ed both from the double salt and by a Beckmann , . . lO rearrangement of the OXime of 2-acetylthiophene( ). NOH PCl O -C-CH— ntaer —NHC—CH 3 5 0 OC 5 5 Nuclear substitution reactions of 2—acetamido- thiOphene were first described by SteinKOpf(ll) and more recently in the studies by Hurd et al(14) (15) Nitration, brominaticn, sulfonatien and mercuration occur first in the 5-position of the thiophene ring with a second substituent entering the 5-position. 0:) o A nitro group can be displaced by a chloro, the :— un. position being the most susceptible an azo dye readily formed when 2-acetamidothi0phene was coupled . . . . .: 16 With }’-nitrobenzenediazonium chloride< >. -NHC—CH | u 5 2 O = S O ‘v't 1"" Twrf"? 7" 02N_ —h=m— s -hhoCn5 (13) Campaigne et al have carried out bromination, chlorination, iodination, nitration and coupling re— actions with B-acetamidothiOphene. Substitution occurs initially in the 2-positien while a second group attacks the S-position. Reaction of the ca-chloro group in a cu—chloro— alhylphenyl sulfide with a secondary amine has been carried out previously by Kim and Schuetz to obtain tertiary amine derivatives of mixed phenyl alkyl sulfides. -s—(-CH —}—Ci + R NH CsHe / \ -3405 Hm 2 n 2' —l——; 2 n”? A two mole excess of the secondary amine was employed which, together with removal of the hydrosen cnloride g) formed in the reaction as the secondary amine hydro- chloride salt, pletion. served to drive DISC T353 I Ci“: IO. ll. '1‘ w —\~-. T 5—1;}. IITC_--IOE'LLZ’L .iJ...Ji’..L .3i;IV;_:S The aninoalkyl substituted acyl- ~3-aminothio- phenes studied in this investigation H€“€ prepared by ie following sequence of react'ons: (3103? 0399—0001 "5 (D VI IHC CH 9-—-CH2 Cl + H NH Dioxai 2n 2 X Y [\J on O O 0 o mac—eclia—eeau 2 X Y Y = H, Br, NCD R9 = piperydyl, morpholyl, diethylamino. 13-Chloro acyl—B-Aminothiochenes The AP-Chloro substituted acyl—E—avinothiophenes were synthesized by carrying out a i‘i ofm Lifin rearrange— ment on B—thenamide and acylating directly the result- ing amine with an cd—chloro—acid chloride without iso- lation of the intermediate amine following the pro- cedure of Campaigne and Konroe(15). A sodium hypro— bromite solution was prepared by adding bromine to an . o i -. . . . ice cold (O-lO C.) aqueous haOH solution containing l2. excess NaOH. The solution of the B—thehamide or sub— stituted B-thenamide was stirred under a nitrogen atmosphere for about an hour after the amide had dis- solved. Usually the reaction solution darkened and warmed Spontaneously to 50-400 C. The rearrangement was completed by heating the alkaline reaction mix— ture for 50—60 minutes at 70—850 C. During this time, the B-thenamide reaction mixture remained clear and took on a deep red coloration althou;h the 2,5-dibromo— B-thenamide turned black and an insoluble product form— ed. After immediately cooling the reaction mixture in an ice bath, the am'ne was acylated directly with an aJ—chloro acid chloride without attempting isolation of the free amine. The product was recovered by filtra- tion, washed with water and recrystallized from a hot water-ethanol mixture, decolorizing with activated car— bon. The Hofmann rearrangement was carried out many times (Table I A) and the yield is usually 25—50%. The principal side reaction is presumably polymeriz- (15) ation of the aiine but some decomposition also occurs during the recrystallization as evidenced by darkening in color of the product and formation of a small amount of a tarry materia . Darkenin; of the aqueous solution of the product has even been observed while it was set aside at room temperature in the dark. The thiophene nucleus was substituted in the 2— position with a nitro group and in the 2,5-positions {(3 J ' ' ‘ 1 V‘. - . -~ ‘- h n‘ —1' ’ ’A '3 ‘ '1 -‘ . "- ."— . "*r K‘ I\ ‘u . ‘thfl bro 1L6. Usually tee euos 1; tion ufia cariie - , ~ «if . , -..... ...i. , , * .. A, r.- *' r out after the HOIMHHN rearran e ent Out e,;—dibromo— * .‘ v. :1, -r\ . ' r r" . H ‘L‘ ‘1” . -, 1 .*~ -~ " r“ .—~~ .‘ ~~‘ V . 3 —C‘ _'_CI'1 O-/—_LJI‘OPJ-OII«12111010bi 10913-30?) i1. :18 ell L40 bi”: 'L’il TD]- @- 1 .. -» f.‘ (..., m . A! _ .4 '-t_ a “ .‘_:_ ' i e, .1- _ ,:‘ : ‘,\ ._ . .1 -3 ,. pared Pf rearrank £31 .vhl? Oi Jli‘C; 5110;; ml in! unit Q-!. ...;‘I! '.?_.'.l_L‘_-';) . "‘1/x I E: 1 . ' V'V‘ 7 "" tr - s . 1 1 . I '1‘ s ~*‘ “ ’. ' .(“1 L y“. ‘3". A -~ (“i ~ A ‘LiLC 1?, ,}-Q11\)I‘OIHO—:i-LJ.l“:‘DOlC L’lCld. this: i. .1. I. Q U l t‘ ’_1T'\,‘Q 5., c ‘_ _2_ o ...._ W" -, _‘_-s’ "x . I r I -‘ o . r. ’ o ‘ r" .‘l_ fic ,-.‘ u by brOtlndtlLQ 9—tren0ic aCid in MluClJl acoti doid at room temperature. This was converted to the amide its acid chloride and the Hofmann rearranvement V vi $0 was carried out with tie 2,5—dibromo—5—tlenamice in a manner similar to that erployed for the B—taenanide. Tle overall yield of tie amide from E-thenoic acid was I rather low, #.9fl. Conducting the Hofrann rearran;e- ment on the unsubstitutedemnde and broninatin; tfio [g-chloro-E—propionawidothiophene in Vlacial acetic acid gave a 7.83 overall yield from E-tbenoic acid. (Tables I A and I B). This difference in the violds of the amide obtainable from t*e two rrocedures is no significant since it is based on only a single set of experiments. Nitration in the 2-position (I the thiophene ring was accomplished by very slowly adding concentrat— ed HNO5 to ‘9—chloro—3—pr0pionaiidothiophene dissolved _5o.<15> in acetic anhydride at -lS to The product was isolated by ipmediately pouring tte reaction mix- 1 ture into ice water and neutralising t.e anhydride With NEQCOE. The product was rccovered'd; filtration,t washing it with water and recrystallizin; it from a water-etha 14. nol mixture follo ins treatnent of the latter L-) with activated carbon (Table I B). 1 1| v’ Tue r J. (.0 1y- ica il, ole ical proneities and analyses of the /?—CLJUL0-WCVl-l‘4Hl ot11i034;5es are u marised - r r 1 1 . 4.». ’7- ' . -.1 44;. t: .1 ' 1 fl ,,- in Janie II. Both the a—nitro and twe 3,9—ii- aiomo— A%chloro—§—proni ”01%; CO 6“ ID ni=i dothio: 1’.es have been :ro“*r(d O 2». —l- . rul' r. ~ I- . - , - o 1 ~ ‘. \-‘- -- n, I I] r1 1 —' r“. 'I-1\ . ‘ “at nLuinei'cif tan es (.trii, L;G ,atikh, of iris (,2 t L3 (_ l H HI (1‘ L“ r CT :1 (I \_ R, H C: H O C} d W [—1. o H U) H {3" H ,§_(‘.lOT‘-(.I O CO? :}OL..:CL "3313-13 I E). C is IlOt ‘ - ' ‘7. ‘I 3 ‘N -:-‘ 1 .-‘-‘ w. “" -'. ‘ 7‘) --t‘ I’ 'wr bulb is euc prlnlely LO 4“ JnCiexsed ~- 2.. : a 1 .w :- .m ,Hr: -v : .s, 1P TGJCUL n OP iEbb thCO 'OJLulUn in v.0 ‘ A .i' ' i -\ s‘ ' 1. , _._-‘._ ' r- ' .1 . 5-... .1.‘_ i ‘, '___ -1l lsOlatlmfl DJ tse inudaeS. i LU .eie t'e latter, tue . "\ ww- -- .‘ .‘~ r‘ - . 3:3 2‘ -'- - ~ r'. ‘ ‘1 p' ‘\ } 1" v~r , -. \ -—\ -‘ S t]. 1.1. l O ‘LZ‘I‘ C]. L' Pt}; #3 .1 2‘»; -14.; CI .. t-) Grist]. Hi.) in J v L4 DC" .1 C 0;! .lU LUILI could legitimatelv be cansidornd avu t e {tier l con— _V: (31,1 m U" —-- v «— K]- . A- , a i CCCOTHOJLDWT ‘- C'r . u —\ - . 2 ,~ ._ "n 0 ‘1 ~, " " m _'_.“‘ V“ ' ‘ ":1 a ‘ r poly KM Flffiltlifll o: u e .n4i1x; bwlhy icii»ed) .motlii be .i- ‘l— _1 “— 1- ' v ‘ ' " ~ - \ 2.1 I -. . x “n '- ‘. - 'I“ v ’ . “r 'l . '—"“' l" l‘ (x ‘ pectea bO 5»,U t.c or white eyes? OL it.aality. it iCK ‘ 13f a nuclix>__i:ilic :mxi'ent jroups in group saould be facilitated s w- 1 U1 Therefore hydrolysis would be easier sith the B—EOq compound aid the expected yield should be poorer. E; (0-K,N-(Dialkylavino)-Acyl-§-Amircthiophenes Initially the tertiary anine salts were synthesiz— ed ac cordin to the method of Kim and Schuetz which the co-cbloro compound was refluxed in dry toluene with excess secondary amine 3rd t_e e: :cess amine was separated by steam distillaticn from e re action mix— ture. hntensive QECOR.Ob‘thH occuired with this pro- cedure as evidenced by t e acid insolubi lity and black, tarry appearance of the product which reM'ined in the distillation ila 34 thus necessitatin; de vcloraent of an alternative wetLod for tne orcoaiation of these compounds. The following successful preparation was ever tually deveIOped. The amid tion was peiicrmeu in dry dioxane at room terne‘“"u7e during at least a 15 hour period in the presence of a tie molar excess or the secondary to dissolve the Reine hydrochloride and precipitate the hi :herr loe cula r xveifiit product, 3 —Iriorp1':olyl—§— rosionamidothiophene was an excepticn in that it had to be steam distilled. The precipitate was then t or— uyhly washed with water to remove any rewainin: second— ary amine. It was tsen dissolved in alueous hydrogen "‘ . ’7‘ a“ ‘ I “ ' I". l I" I“ “q V“ ."‘ ”v.4“ ‘3 -, ‘ u - . “I 'i . I 1 ' . :1 chloriue 42d any DHTuiCtud stiitim. iwrerill ans re— ‘7) moved by ext actidn with other. The a;ucous phase was mafe alkaline ether extracted, use EtHCP ldyqr dried :ith anhydrous sodium sulfate, filtered :nd tisry '*i e precipitated with gaseous hydro;;n Clloride. A variety of solvents (usually drv iso;ropyl alcohol or etl nol) " used for recrystallisution of the :Iydro- chloride salts. One product (;9-dnrthy :arino-fi-propion— amidothiophone) failed to yield a solid hydrochloride A(l:) b7 "It so a quarternsry Silt was prepared 3 air atin: an ether solution of the ”3-0 10‘0—3-jr09io1 i 0t~iool“de with excess methyl iodide ior Ev n1urs at room tenper— ature. Tde crude product was a sticky solid :jdering to the bottom of the flask 1:3 fins isolated by decant- ing the selvert, dissolvirs tie residue in absolute alcohol, treating giti activated carbon, riitering and allo;inf the salt to recrystallise. Tze prepar— artiorhs oi"the QJ—(ll,Eluiislflqvlasiiio)-icyCL-§-quiirMittde- phenes are summarised in Table III and the properties 7 and analysis o tie Tydrocnlorioe o'd netnyl iodide (L; quart rniry salts are tabulated in Table IV. T e econ F1tl“fl of a<-piperidyl—§—acetdridothio— phene differed from the propanamido derivative in that the intermediate chloro compound from the c loroac etyl chloride acylation of the Z— ‘m1_OblLOUI e formed by the Hofmann rearrgn;eheit was not purified and isolated to pre vc he hydrolysis of c a(-c loro atom in o<—chloroacetamidothiOphodc. she a irdtion rein tion 17. with piperidine was accomplished as usual in a dr' dioxane solution but some difficulty was eXperienced with recrystallization of the product and the yield was only 6.6%, possibly because of the impure start- ing material. There is no pattern discernible regarding the yields of the various salts but the melting points are in the order morpholyl > piperidyl.) diethylamino. Regarding the influence of ring substituents on the melting point; the unsubstituted ring compounds have the highest melting points, the 2—nitro derivatives are intermediate and the 2,5—dibrouo conpounds have the lowest melting points. 9; B-Thcral Campaigne et 31(20) (21) describe a method of pre— paring B—thenal from 3—methylthi0phene in satisfactory yields according to the eguations given on page 49. The first step in this synthesis was the preparation of B-thenyl bromide by the free radical bromination of the methyl group with N-bromosuccinimide in benvene t“) as a solvent. Isolation 0 tie B—theny bromide is hazardous because it is a powerful lachrymator and has been known to explode durin; listillation. The Sommelet reaction was utilized to convert the E—thenyl bromide to E—thenal, Le, a quaternary br ride was formed with hexamethylenetetraanine which was decomposed to the ”l ‘\ \«dx - k » . aldehyde and amines by steam distillation. The aldehyde sas extracted into ether from an acid solution and distilli‘GLo Seen the aldehyde is desired, a simplified pro- cedure givin; comparable yields has been deveIOped. _I'\ Following preparation oi the E—thenyl bromide and re- moval of the succiniuide by filtration, the quaternary bromide was forged by adding hexamethylenetetramine to the benzene solutitn employed in synthesis of the E—thenyl bromide. The mixture was usually allowed to react overnight at room temperature and completed by warming it to 500 C. for a couple of hours. The remaind£HT3)(2’+) '_l _ l7 - .. n s konroe< )>. TLC preparation Ci 2— tner lished by the follo in; series of reaccions + A020 HEPO4 70—950 0. 3 u 5 D0012 Conc' \ T :r———-—9 \ VH .w —CCOh heflux -COCl an‘n 7 -cc::, 8 r- The process is trai htfornard and will not be described here in detail (experimental section). he overall yield for the four steps, based on a sir le triel, was 49.7%. ‘his compares with a Zl.7% yield for the six step 83 Wntaesis (only three products were isolated) of ~thenamide from 3—methyltni0phene. The Hofmann reirrlnl cent of 2— t enaeide was 20. attempted employing the identical procedure as that used successfully for fi—tnenamide except that the acylating agent was acetic anhydride and the temper- ature was not allowed to rise above 570 C. Only a small amount of an unidentified, very water soluble solid and about 6% of unreacted amide were recovered. Campaigns and honroe also failed to isolate any 2-acetamidothi0phene. Jhen heated to 60—700 0., they observed ammonia evolution and 2—thenoic acid was recovered in about 80% yield. 1 Y Since it is known that the first step in tze the formation of a N-bromo }. U} Hofrann rearrangement N-bromo-Q-thenamide was at- H) compound, preparation 0 tempted in chloroform to eliminate hydrolysis which could occur in the alkaline hypobromite solution. The 2-thenamide and bromine were heated to reflux in a chloroform solution, cooled, potassium hydroxide was added and the precipitate which formed was recrystallized from water. From the melting point of this material (1650 C.), it was concluded that bromination of the thiophene ring had occurred. After failure of the Hoftann rearrangement with 2—thenamide, a Curtius rearrangement of 2-thenoyl aside was attempted. The aside was prepared in accordance (25>, with the equation 21. I l' + NaNB Acetone; -CCl H O ‘ - P u 9 c ‘—- N O 1000. O The sodium azide was dissolved in ice water ano the 2—-thenoyl chloride dissolved in acetone was added portionwise, during a period of l - 1.5 hours. The azide ,roduct :as recovered by filtration and dried in a vacuum dessicator (75.5% yield). The Curtius rearrangement was accomplished in refluxing benzene as a reaction mixture under a nitropen atmosphere to give a-Lnlenyl isocyanaue which supposedly could be hydrolysed to 2-aminotnio- phene. 2 L ‘lr_,~:., T501 Vrr.1' a. ’T ’3.- -‘ ,. o 7 \~_ “ L 4; .' mi...) —Cl\\ CLLLIC'Le —i“_C:C\ LI 7; Acetic , . Ant '\ dride 7 ”m - S/J—sd ‘J ‘\\$ dine-Ch.g H / so? late v:x3:fllwned but K) 0 {b It is thought that ;*e in ; alkaline hydrolyse and warning with acetic anhydride failed to yield any 2-acetauidothiophene. An acid hydrolysis of the isocyanate was also tried and re- action of the sun osed amine with chloroacctyl chloride gave a tarry material. Ho pure co pounés could be ii Obtained from the tarry m terial. It is :orth lescribing an experimental observation R) ’D L 0 which should be investigated further axd could lead to some interesting dye hemistry. Following the Hofmann rearrangement, crude 6’-chloro-5-proyionamido- amidcthiOEhene was customarily treated with activated carbon in a hot water-alcohol nixtire and vacuum filtered through a fritted glass funrel. Part of the time, a solid which was only slowly soluble in acetone (A?—chloro-5-propionamidothiopheae is very soluble) t...- collected on the unders de of tie f lter. If this i (0 treated :ith a warm concentrated nitric acid, a a rilliant blue color is formed. The color 's soon oi 1.55 (D Irir¢tai ‘VVUEfllfiifl31j'i331TP’ CUilGJJZUGr o; tee Iiitm"ic t.) “' , acido H-fi V: ’T‘"1“9T‘- - n‘y“ ‘- r“‘ n‘ J . ‘4‘ i ‘ , g ,_ ' _ , ‘. 1.5.4. ...LLI..L.'I-.L'J.L9 .. ..‘L P.) \N o 24. (TL? CEO CE, TFxT‘f‘ 1:5“! 1“ "" ”it“ fl—‘J¢-L ’is. ’- B—E;- LL.- -._.. .K.’ .1—1— ‘:__._._--.___4 \\5 500 ml., three—necked, rornd bottom flask elilip— ped with standard tager joints and fitted with a N eas inlet tube, stirrer, dropping I nel and support— ed in an ice bath was charged with 22‘. (0.55 moles) of NaOH dissolved in 130 ml. distilled water. a 25.5 g. (0.145 moles) quantity of bronine was added slowly :Le ice cold al‘alir solution. The flow of nitro— d O (-+ gen was started, the ice bath was re;‘ oved and 12.,9 9. (0.1 moles) of 5—thenamide were added to the eaction mixture. The amide dissolved vhile the reactiin temperature was allowed to rise during a period of about 1 hour to 50 - 400 C. The reaction solution then was heated at 70 — 800 0. until its color be- came dark red (about 45 minutes). The flask was im- meo diately cooled with an ice bath to below 100 0. and 12. g. (0.1 moles) of Ay—chloropropionyl chloride were added dronwise during about 5 minutes while a sloa flon of nitrogen was Wilqutlfl ed. After stir- ring the Lixture for 10 - 15 minutes, tre brown pre- cipitate was recovered by filtration, washed, heated to boiling in 600 m1. of water and enou;h alcohol was added to dissolve all the solid, The solution was then decolorized with activated carbon and filtered 25. hot through a fritted glass filter precoated with filter-aid. Upon cooling in ice water, a flocculant white precipitate formed, which after filtering and drying overnijnt in a convection oven at 500 0., gave a.light tan colored powder. Additional product was obtained by washing the filter cake with acetone and alcohol until the effluent was substantially color— less, adding the amber soluticn to 500 — 600 ml. of water and evaporating it on a hot plate until the first sign of a precipitate began to appear. The activated carbon from the previous crystallization was employed to decolorize the product and the previously described recovery procedure was used. The combined product weighed 4.1 g., 21.8% of the theoretical, and melted at 159 — e10 0. Anal.*: Calc'd. for C H ClNOB: c, 42.5 8 O H U 1...: 0) 0 \l (X) 7 s, 16.9. Found: c, 44.24; H, 4.51; 01, 15.55; 3, 16.79. 2,5 DIERCLC—13—0LL020—5—EACZICILLIDCTIICEAQIL 0 - ._ “ -..- . -NhC—Ch20n2-Cl Br Br To a 500 ml., three necked flask eguipped as described were added 8 3. (0.0422 moles) of ,G—Chloro- (*) All micro analyses performed by Kicro—Tech Labora- - tories, chokie, Ill. 20. 5- -pr opi on1m1dot11o nene and 95 ml. of glacial acetic acid. 1 solution containing 15.5 g. (0.054 M0188) of \ bromine dissolved in 70 ml. glacial acetic acid was placed in t:e dropping fennel an added to the thio- phene derivative durin a period of 20 minutes. Dur- ing the addition of the halogen, the solution cleared and darkened and, after stirring an adoit 1 a1 20 cured into a liter of ice water. A minutes, it was p pink colored emulsion resulted which became a sticky material as it was warmed but eventually formed a flocculant, easily filtered nrcc1o1t1te. This was heated with an equal volume of water and alcohol, but part of the solid fused to the bottom of the beaker so the Clear, yellow liquid was decanted and cooled. . 1 o o1y111g in an oven at 50 C., 2.5 OJ After filteri1 r" an 5. of a tan colored crystalline material in the form of needles was obtained which melted at 120 — 1210 with darkening. The fused solid was dissolved in hot alcohol, water added until the initial turbidity appear ed and, after decoloriz 1:5 with activated carbon, fil- tration was attempted. Difficulty was experienced with solidification of the product in the filter which ne— cessitated cleaning the filter with acetone and re— peating the crystallization procedure. Eventually, 5.5 g. of tan colored powder was obtained which melted at 120 - 1210 with darkening. The combined product wei:hed 6 5., which is 41. 4% of the theoretical. Ana1.: Calc'd for CgthrgClNOS: C, 24.2; H, 1.75; p—J A; '2 \fi U1 0 a a Halogen, 56 .51; Found: C, 24.51; H, 1.95; Halogen, 56.15; N, 4.07; S, 9.25. The 2,5—d1broro—le—c~lcro 1r0pionaaidoth10phene can also be prepared by the Lofmann rear1 n ewwqt of 2 ,5-dibromo- -5— thtnaride. Following the same general procedure as employed in rearranging the unsubstituted —thenamide, a solution of: aojr was prep M18 by dis— solving 8.6 g. (0.215 moles) of: daOH in 70 ml. of ice water and slowly addin3 9.1 3. (0.058 moles) of bromine. The ice bath M1s removed, the flow of nitrogen gas was started and 11.1 5. (0.059 moles) of 2,5-dibromo—5— thenamide was added to the reaction mixture. As the solution warmed, it took on a bright yellow coloration sreen and a prec1p1t1te settled to the k.) vhich turned 1 1 bottom of tne flask. After an additional hour of stirring, the solution had become quite dark in appear— ance and apparently was homogeneous. It was then heat— ed for approximately a half hour during which time a black precipitate was observed to form. Then, after cooling it in an ice bath, 4.8 3. (0.053 moles) of ,chhlorOpropionyl chloride has added to Cl e re action mixture. The black colored solution was :‘ilte Jed, the precipitate was washed with water, dissolved in hot w1ter COUoilLifiz some alcohol, t1 ea ted 1th activated carbon, filtered and the filtrate on cooling precipi- ’3’»? C“\__/ . tated a crystalline solid. Recrys allization of the crude product was repeated twice and gave, after dry— f‘ L)“ \.)-J ing 2.1 3. of yellow colored powder. Another 0. of product was recovered by concentratin3 the mother liquor to about one third its original volume and cooling. The total weight of product was 2.4 3., which is 17.8% of the theoretical. The compound melted sharply at 120 — 1210 C., which is the same as tha obtained above by an alternative synthesis. 2—FITRC-,8—ChLGRO-5-PHOPIONALIDOTHIOPEENE 0 H —NHC—CHQCH201 ‘102 F—J 5 In a 500 m1., three necked flask equipped with a stirrer, thermometer and drOppin3 funnel, were placed 8.4 g. (0.045 moles) ,6—chloro—5—pr0panidothiophene and 140 ml. of acetic anhydride and this mixture was cooled to ~150 C. with a dry ice—isopropyl alcohol bath. The dropping funnel was charged :ith 12.6 3. of concentrated HR 5 (0.14 moles HHOB). This was added to the reaction mixture very slowly a drop at a time while applying and withdrawing the cooling . ,, ,, , 1 1 ho bath to control tae reaCtion temperature between —15 C. q u o o 1 . . . . . . and —5 C. Tne nitric ac1d addition required 40 min— utes, the reaction mixture was stirred an additional 20 29. minutes while holding the temperature within the pre— scribed limits and then the mixture was poured into 600 m1. of ice water. The quenched mixture was neu— tralized with solid sodium carbonate. This Ins very slow because of excessive foaming, but the latter served to indicate when all the acid had been neu- tralized. The neutralized solution was filtered and the black precipitate was rashed with water and dissolv— ed in hot alcohol. Sufficient water was adied to the hot solution to 3ive a slight turbidity and it was ct hen treated with activated carbon, filtered anf the filtrate on cooling precipitated a crystalline solid which was recovered by filtration. The filtrate was concentrated and crystallisation again occurred. This procedure was repeated twice, which TATE, after drvirs, the following four fractiamsof material: 1.5 3. of a yellow colored powder, m. n. 108 — 1390; 2.8 g. of a crystalline solid in the form of long yellow needles, m. p. 118 - 1200; 0.8 3. of a dark colored yellow crystalline solid in the form of needles, m. p. 108 — 1090 and 0.9 3. of an amber colored powder, m. p. 107 - 10800 The total wei3ht of product was 6.0 3., which is 57.7% of the theoretical. An :1 l .: Calc'd. for 07H ClNQOES: Cl, 15.1; N, 11.92; 7 S, 150{:50 Found: Cl, 15.1; H, 11.35; S, 15.8. mmmmm| >4 tr! H. CD '1 Am; 2: 3 A3 u 0 emawm H>n wumvmunwpo: on mccmdpucamn muQUHOHOIuuwuouuoumap00¢SHovSmamm 3333112135: |»< w H. U“! '1 muQSHowonwnovHoaww QUHOHme zowmm zmom o.mm 0.mm H.:m 0.4: 0.4u 0.MH 0.H: sz END :00 Hmo :mm m:w m:o 40 :m 0.Hm 0.Hm , o.um 0.Hm 0.Hm 0.0m 0.0: 0 .. IZWIOIQNMIONMQH o.H: 0.0: meowwmamwwuuma macs m announmnvmsow apxncum wmuea o: zmumvd on unarmamapam ow m.mnouaaoaouu|¢5eamapom. m.mLUHuuoaonwua5msmsuoo. mnuudfimm Heat. zpsm. o o :mnmo mnwo :mumo muwo mo Honwm moudo mnwo mosqo mnwo mo mnwo mo mnwo mmmcmmH emafl. 393m. o o :m woumo mo uonmo mo umnmw mo uoumo m0 woumo we wouao Hm wouflo mm.m :m.m Am; :3 E 0: A3 ; UH amuwm Hm“ wumvmumwpo: ow mcdmwpnfiama muQUHOHouwuwaovpoamaHQO¢UHbSm=mm 0 -zm-m-0m»-0mnop x _ _.m m mowo 0m 40 mm 0.0; mum 0.0m mo>o mm 40 we 0.0m mu» 0.:0 mo>o pm: you 20» 0.0: 020.030 0.0A00 >o»0 0:0 - :0» 0.00 mzoo3v 0.HHA00 >o~0 am - 20» 0.0: mzoufiv 0.5?v >ono Hum . 20» . 0.0m mzoufiv 0pm?v >o~0 H04 - mnovpoaouuuwdovpoumapaonSpovsmam women on zmpmvd ow muoswououuuvdovpoamBHQO¢SHousze wmowwmamwpunma 0005 m tmcodnmavmsOH apxdcaa aoa mzom omwoswmaea um H00* 0200 womodpoa Heat. o 0 Spam. mm :0 mm m0 mm um um 00 nwm m0 3 mm 2 mo 2 mm a KHQHQ Wayne” :H.: :w.m :4.m m4.q mm.0 mm.w mm.: 0» 603.0 HM" 3.303000 .50 Egon on 9500000000 uéonouuugpgofigg o 5.0.8.0008 am an m . . Ea... . L0 0 MP .0. 05mm... 0 u m 0 IN! lulu 08.80. I. . .0. 0.00.0. 0.950 03.0.0. 1950 :28 03.0.0. 0.950 03.0.0. 0950 050.0. 3.50 m. a 90.828 50.90: £70.. #5 f3 0.» 8 00.0 5.4» - .. 5.3 00.0 0.. E. 0.0.9.0808 000.83 2.3 0...» 0.3 rd 083 0.0.3 “0.0.. ...3 .78 0.8.. 0.0» m :0. 90.002090 50-00:; - - .. .. 8 5.0 5L 5.00. 3.0» 5.0 5.00 A: 300355.300 3 30030005 0.000.. 265.0. H5950»... A5 ...—000400050000 3.0- . 300700685“— 505.0. ‘htrt'w “VI ‘7 ’3 ' N "* ““ A “v .. fl -.LJJ-.L _;-4-IJJ_L l-j-i -f': .2. ..L 4.0:“.— .i—JC. J.fliJ-L_ ...—-.. .1) -10. “I- .» u__.i.L‘ ...}..‘J 1 of 7.0 3. (0.027 moles) Cd‘[3-€fiLOlO-3-9U0plUHRVldO- ‘1 . ‘0’“ \ .~ fl . .‘u “u /‘ 0 fl "' ~F‘ r.’ W? L' " - ‘ 4' f“ tIXLO:N1be3 tfiluLAJ1VTML l“! a zllxreu_kfi Oi ‘ ~ .' 1" r r: r V‘."’ - | a"- 2' .‘l‘ - a“. . ’3? ~ ‘ r' v~ .". a “A 7 ~ v Loose-neon fincgbOI and Swlgldjt conde; er a.i vie . ~ .. ~ - a‘ '_‘I n' '| . L‘ ‘L r» 'fi "q u“ ‘ ’W "I. .0 . “. ‘ ~' ‘ O .~. . Sblffer -itn a COUle , Iiitted «less std: .f 101 in— - .-. L.-w h- K” 1:. .rvum_m m.. ”.2 H t JECthH Of SUWAJ. The TUJCFluU MLQLm16 Hi0 ugde 11h;— 4 line with dilute, agueous NaOH solution and steam cis- tillation begun to VA”C” twe excess )1PBT171N8 and the organic solvents. From time to time, the Simon's color test for second“ y amine s distillate and aevrox; at;ly 5 1. of distillate had to be collected before a negative Sinon's test was obtained. Pufficic nt conc. hCl was anced to tle dis— J— . 1 r“ 'L' . , ~, 0 ’3 . ‘0 4" tr. r“ ‘v I" 4- ,~~ ,-~q " w. n. bllidulufl r‘blflde uO JALU bme 31UBOUb p,- the major part oi the olick colored oil failed to Cis- solve. The aqueous pkl 1se was extracted three tires ‘with chloroform, made alkaline yith a EQCH solution, ex FECth JSEiH with chloroform, dried with cmnrorou' NaGSCQ and filtered. The chloroform was removef on a L. sttem bdth, and ether was added but tFe a_iie precipi— tated so sufficie21t CHC J W13 ddled to the ether solu— U) tion to make homo;eaou . Gaseous H01 was passed into the solution and a sti leYar precipitate formed which be— came filterable af_ter bein3 set aside oveini h_t. The solid was separated by filtration, dissolved in hot, dry isogronl alcohol, treated with fictivated cxrbon, filtered and allowed to crystallize. The product was . . , . , _ . -0 , recrystallized 2331n, dried 4 Hours in a 49 oven and 1 Fr 9 r' 4 ’7'“. -.‘- 3 " v'l" j y‘ j "v A d ' lo“; :2. 0-1. 1 1-L.:_)LL Ltin {1(1)}.(JMV‘J L O vU‘JI‘, 1.4. 0 L509 _ 5.3-0 - -- a,“ mi: . 7 ‘1” o 1 1 a 2.: .t - - ,- v‘nlS COL-111161. 1.1.11.8 l)..,,-) 01 bite L,.=..,OO;‘€LJ1C:.1 yield. Anal.: Ca Hc' for C 1n~1chqOJz C, 52.7; 1:, ’é‘loi’fl; Cl, 12.C6; s, 11.7. Found: C, 52.01; H, 6.94; Cl, 12.76; B, 11.45. 13 —LOLV1‘*VL~5—EEOLICE;;ILKHEZUlflidib EYE; distiljs ‘\ 1.3” f‘. T? '7' ‘ ° ’3“ -lI;.'_V_'v'Ll/\C " "' N o :lv t_ A 250 m1., round bottcm, single necked flask was chirgd with 4.7 :3. ( 50248 moles) of ,3 —c7;1lo:"o—5— ' ..T- ' 4' -- .: 1- 7., . x ,3 , -__,- .1“ M v 7 it- :v .1 1, , 1. ' DrOblonamlmOLlLOrLUfld agd Ed $1. of erg d oisre. Tnis z / \Jl was stirred by a ragnetic stirrer but only part of the solid dissolved, however a clear solution was obtained upon the addition of 6.5 - .(O .075 moles) of morpholine. A large dropping funnel sei 'Jed as an air condenser. In about an hour a precipitate began to form, Sulr‘lF“ was continued at roon terperature for 24 hours and tnen ECO ml. of water was added to the reaction mizcture but no precipitation occurred. The turbid yellow color ed solution was steam distilled (about 5.5 l. of distillate collected) and the residue in the distillation flas k ,as made alkaline “v'ith DaOEi. The amine was extracted with ether and the latter was shaken three times Jith androximately 10% aqueous 301 which caused the yellow color to shift to the acid layer. The latter was then extracted once with ether, neutralized with HaOH and again ether extracted. The filtered ether layer was dried xi th anhydrousi 1900,, and gaseous HCl was passed into it to obtain a white dispersion. The ether was allowed to evaporate at room temperature and the tan colored solid which form— ed was dried in a 500 oven. This was recrys allized from absolute ethanol, dried nd 0.6 g. of a very Q) lig ht tan colored crystalline solid was obtained (8.8% of the theoretical yield). The salt melted at 230.5 - o n n , . 251 and was analyzed to give tne lOllOWlH: results. Anal.: Calc' d. for CllH17C 1H2023: C, 47.6; H,6.lq; Found: C, 47.;3; J, 6.18; Cl, 11.67; N, 10.3 ; k s, 13.01. [3-D ItrIIi I o 5—P11tHIC-iIItc-nitiinfj :3;L:L 103113 5) Using the apfiaratus described in the previous “1:310 "C::2C:131T(CZE 12.5) C:l~vI 02E? example, 6.7 g. (0.055 moles) of'XQ—chloro—fi—propion— amidothiOphene was disrerse in 20 m1. dry dioxane and 9.1 g. (0.13 moles) of diethylamine was added. fter a few minutes of stirring, the mixture becare clear and within 15 minutes there was evidence of a precipi— tate being formed. The reaction was carried out dul— ing 21 hours at room temperature. At this point, about 100 ml. of water was added to the reaction mixture and a brown oil separated. This was VJater— washed th Iree times in a separatory funnel and shaken with dilute hCl in which Host of tfle oil was soluble. The acid solution U s extracted three ti as with ether, made alkaline with KaCH and the a ine product was extracted into the ether lyer. This was dried with I,n1Wdrous Na SO filte Ie d and tIe ted with gas— eous :01 which gave an emulsion. Evaporation of the ether left an oil residue which »"as taken up in dry isorroryl alcohol, treated Lit? :tciivafied CLrhon and cooled. Cry """" a11i7 :tion cou_id not Ow 10 need so the alcohol was evaporated at 500. The residuar 1 azoer colored oil was dissolved in water and made alkaline with dilute K303. The nrtc1n1t1t was extracted into ether, dried with anhydrous EaQSOQ, filtered and placed in a magnetically stirred, 250 m1., round bottom flask. To this was added 10 3. (0.071M01 s) of CH5: and the solution was stirred at room terncrature for 59 hours at which ti2e th re was a sticky solid adhering to the bottom of the flask. The essentially clear liguid was decanted; t1_1e solid was dissolved in absolute alcohol, . I, V, J. A and, following the 00011 aCLlVioLQ ca roon treatu 1t, C) filtration and drying, a pale yellox colored powder was obtained. The product was recrystallized again and gave 0.45 g. nale, yellow colored solid in the f 1 F5 17-70 (Z 5’” «'41»; um Iorm O nL€0 LS, m.p. a - um , I \u OL one LnLO- retical). Ana1.: Calc'd for C ’ 1H 03: C, 38.9; H, 6.22; I, 54.5. Found: C, 39.2; H, 6.06; I, 5k.12. 2,5-D13?1K0-K9-PIPLZIDYL— Br m H _‘I\‘\ " .‘ "- 1““, “I '1‘ -~". 1‘ 'VT '. '.I..\ '1 ‘V. ‘1‘3 ~ Lmrloylfl; the na neoicilly sLIIied eodiuucnt discu1ssed prov10u 1y, G j. (0.017 moles) of 5,5—dibromo— ;rE-ca Gus dissolved in I O 5 H o H o l \N +23 H o *0 l.) o *5 H O o a [3" "_ l l 27 ml. of dry dioxane crd 5.2 3. (0.031 moles) of piperidine was added to the solution. lhe solution was stirret for 44 hours at room .tmreruture during wricn tine piperidine hydrochloride precijitnted. About 100 ml. of water was added to the re;cticn mixture to complete tne nreciuitaticn of ale product. This was recovered by filtration aid throughly washed 'with water. The solid practically all dissolved in a moderately strong HCl solution (ca. 15%) but, after standing a few minutes, a flocculdnt precipitate form— ed transforming tie s lutien into a thigetrogic paste. This was made alkaline with KaOH and LVe resultant slurry was ether extracted. use ether solution was q dried with anhfdrous N32804, filtered are t sated Wlth H .1 'L. anhydrous HCl gas which formed a copious unite precipi— tate. This wss filtered, crystallized twice from dry 0 isoproryl alcohol, decolorizin? with activated carbon x.) _\ eacn time. The solid was Wiven a tnird crvstsllisation C) d y— from dbsolute alcohol. Additional product was recover— ed from the filtrate by concentration of the letter. A total of 0.9 g. of colorless powder was obtained (12% of the theoretical), m.p. 17o - 1720 C. Anals: Calc'd for C ’Hl7BrQClNECS; C, 33.40; H, 5.95; Halogen, 45. Found: C 757%.le \ O 7.2'. \N /'\ I» /O 2, 5-1313). “21.;0—fl— .-Li’i’IXJLIL- 3-:%C-ICIiII“”LMltiUs V KYEHCCi CLIEE c n —1IIIII III—II CII —- o °II01 Br Br L \L__J/ The general rrocedure and apparatus were tVe same as used in tie previous prefaratien. A 5.7 3. (0.0ll moles) quantity of 2,5—dibroro—xf—cblor0w5— prepionaridothiOpnene was readily dissolved in 20 nl. of dry di rays, and 2.3 0.032 moles) of morpholine wss added to it. The reactien mixture was stirred at room temperature for about 33 hours. There was no evidence of heat evolution when tWe .orurolIre was added. The rreviously described product isolation procedure was followed. Jater was added to the re— ction mixture and tae precipitated product was filter— m ed. It was water—washed, dissolved in hCl solution and ether extracted to remove any unreacted Ir1aterial. The aqueous layer was made alkaliwe with HaCH and ' 7 ether extracted again; tne latter was drie DJ ‘0 H3 *4 o l’—‘ C1“ Li (D Q4 and treated with gaseous HCl to obtain a white emulsion. [‘11 . . 1 - O I :1 _ I . . .1. Tne etner mas evaporated at 5a and tee resultant brown colored solid was recrystallized twice from dry 2- E—Jo pronanol, trea n: t~e solution with acti Jate d c roon each time. The light, tan colored powder weighed 0.7 which was 15.1% of the the 17s0 with dIHscolorati n. Anal. : Calc'd :or 011E153 Halogen, 45.01; (3 “3 Found: C, 50.91, F‘l 0, 70240 2, 5-2:33<:.1:o-/6 5—PHCEIOEAMIDOTHIOE o H —NEC— CH Br Br 5.7 g. (0.011 moles fi-chloro-E-propionamidoth 20 m1. of dry dioxane foll (0.052 moles) of diethylami _‘ was set aside for 72 hours ing stirred during a; roxi After precipitation of tle the waxy solid was recover physical characteristics ing it with water rather la tion nloceuulc w the 1 I.) previous ereparation creep .lization from dry isofrofyl alcohol After being set Y El, aside overnifi 40. .fi oretical and melted at aC 6.. 7. T -.. 1N,02 s: c, t’. 55 7 ./-));:. 1T, '\"\ l :1 :2. LA.I TO— *H. -.L 1: TI: 3 .L‘__‘. HYDROC lLCHIDE l ‘ CH 2NCO 2H5)2°HCl ’3 (. ) quantity of 2,5-dihromo- iophene was dis solved in o ed.by the addition of 2.5 "’1 C; m! If; .3 ‘5 '2" .1 V 7‘ —' 7' z- - “f" ...‘b . Li—‘U I‘CQCL’»3~~2"1‘1 I._1.}Luu.x€ 4.. at room te.pcrgture, te- nately a third of this time. prodiurt by'2nlflnv ed by filter Ition. ‘ n— C‘ te made was erecieita iffleU1t. T“e product iso— : t out 11r% in EEG 't ifiiat a; sidifilez CTj/stcul— “ployed. “e “Io net seearated ht, '9) 41. as a thick yellow colored solid in tLe form of needles which, when dried, weiyhed 1.8 g. and melted at 155 - 340 Anal.: Calc'd for C11H17Br201N205: C, 51.56; H, 4.04; Halo;en,4 46.:2; S, 7.61. FOUDd‘ Ca 51-45; H, 4.07; Halo en, 46.45; I“! I“ "f" 31), /0900 —E?1 ‘“*I”“"TT“’1 -Lif.O-' “1.1.- .....l‘..._.'..«‘l '- —5-T LOTICLT‘; IsCL--ICi.L _. 1-1:L‘LLCC--LcI.-1I:L3 9 I —"r"- —CHQCH?— ’ECl —.L‘.'L.'.\/ I l .1300 W1 Usin: the eauipnent described aoove, 5.8 a. (0.024 moles) of 2—nitro—f3-chloro-5—propionaiido- thioghene £33 dissolved in 25 21. ery dioxane. Lo this so ution was a:eed 6 g. (0.071 roles) of piperi— reaction mixture be- e ci’e at roan te “er;tuIe T? ....A.-- , v .— are warm Spontaneously, a precipitate formed and stirrifiv was coxtinued OVGFHlQQt. The product was precipitated with water, ‘Ilt rad, reared, dissolved in dilute E01 and extracted with ether. -he agueous solution mas made alkalire usinv LaCE 3:1 ether extracted again. Home difficulty was encountered in obtaining a good separation of the chases becau e of the increased Viscositv. Alter isolwtlng 3'0 HTIEO, U 42. the -ydroc-lo ri 1:35 L. I n,— tre1' t of t v‘yp', \,.- lution by colored The d1rk times from absolute each tine with activa' (32.7% yield) of 1 greenish \ 1\ 4w l) H‘ .v (TAD 204- (d1rkened) C) .2. An 5, 10.01. Found: Cl, I l 7‘7 ix 3 02 A Inter1ction of 5.2 1nd amidothiophene 2 0 ml. of cry dioxane w1s of 14 hours of dioxane had to oe 1dded reaction bec3 As the The product 11s isol:1 ted b r, NJ. .'.-‘v. .._. ' ° 3-4- ,1 - - 1 tiut bbe eleCiniU1te whicn lution made W Li 5:3 The littLr precipit1t alcohol, ted carbon. Ob - n '1 F ‘41 n -9: 1.. 011c d lor Cl2h1bClJ50 3 at room terperature. y formed in the ether ,' ‘l—l‘ -r ‘\ Eltfl ggseous '3 \"rw" \J -.' .44 {I} recry ‘“~viii# t‘e A total 1..-A rber colored [75111.1 Cd 0 , Cl, 11.12; N 2 ..LiiiC IL— 'g417'1):"r“ .‘7'1 ”"r‘; 111 ......c v_,...-.. 1%... 141.4 —N O 'ECl (. solut so— ECl. stellized three ion (0.06 moles) of norpholine di b ‘53 E3 :1 c1rried out durin} fl LL All soon after 1: [18 -L Tr. LJ ‘6 ... formed when a uldifigioruil beginning 1su11 procedure dgueous (0.02 moles) of 2-nitrwwfg—ctloro—3—pr0pion— ssolved in eriod ) —5 ml. t he slurry became too heavy to stir. exceft SO- 11kaline proved to be irsoluble in 215. ether. Theemflne was extrscted with CEClB, dried with anhydrous N12304, Liltered, and the latter was treated with gaseous H01. The sticky *rfcln t1. vas set aside for several 11;; it rorm temperature and 1 bright yellow colored dry powder resulted. This 11s dissolved in a mixture of hot istropyl alcohol 11d sufficient W1ter to just bring esout soluailiid, decolo rized Ii tn 1ctiv1ted carbon and allowed to slowly crgst1llise overnight. The yellow ) }_J colored solid was rtcrystal ized from tVe sane solvent \ mixture to yield 2.8 3., after uryin , of a yellow colored solid in the form of plates (45.4% of the theo- ' 1 I ' r— O ' J reticel). Tne nroduct melted at 217 — 217 Wluh d1rk— enin:. xi) £0 An11.: Calc'd for C H 11 013? 5045: c, 41.: ; N, 4. 115 C1, 10.89 . Found: C, 40. \O s; H, 4.91; Cl, 11.03. 2-1‘3’1 :‘RC- 8 —D IETHVLi'ugILTO— 5-PRCPICY1 "110311035532 HYDECCHLCIIDE 0 “IV ITIC-CIIQCI (Ur- LIE) 2 .ITIC]. ' I NC 3 2 To 1 solution of 5.2 g. (0.014 moles) of 2—nitro— [3-Ch1oro—5-pr0pionsmidothiophene d ssolved in 20 m1. of dry diox1ne w1s adied 5 g. (0.041 moles) of diethyl- amine Heat 11s evolv ri115 the mixture ‘cr added to it W SC (3 1‘ 1173.5 24 41“ 0 ed syont1neously. ho to precipitate This was purified by tfie procedure previously describ- ed. The only difficulty encountered the separath1 of the ether 1nd aqueo The vdroc’nloride s1lt absolute alcohol, {71‘ , .1. 11(4) activated carbon. 0.5 Calc'd for C 4.; ll tre-tin .(11.,;r3 of the 037;), em h1s the extraction. (D us 3 8 during 1s recryst1llised twice from 11 V- 'e solutio1 e1ch time with "\J lifit in colored yo der weighed eltcd at 175 - 1750 with 1. If) Q. T7 C‘.‘_—. ler-l CZ"). C, l‘iLIQLJ, 4., 5.1.4), / Cl, 1105114"; I‘\, l/Oxzrg; K's, lOo/ilo Found: C, 42.91; H, R.8@; Cl, 11.,5; I, lfi.d5; 3, 10058. Q(-EIEZRIDIL-E—10LT3_ICIHTCIL;;; IYDlC-“lt1_D —l‘?I~IC-CIL3—N 'I-ZCl l .’ L. O E“ ejx11"1ti-wr1 oi? -523 CCm‘EHDLMIC (lijffc=cedl 1“or-1 t}: propion1 ldOtIflfififllfil\gg11VTthCo in t31t tie inler‘ mediate chloro comp011rd H13 not isollied S‘UCG it would be expected to u1ier‘o easv lfurol sis of t-e l -C chlorine. In a 50 0 ml. :1ree—nec Fed rou Wottom flask fitted with a siirrer nitro‘en Sparper end (0.196 moles) of bromine was added followed by 11.1 i. }..J \L (0.067 mo 63) 01 fi—tieruhide. The l ._ -1. ..., ,1. m: ., .u‘, . , ,_._.‘ , meet 3&5 conducted fOlqulq t e Sgre peserll cedure discussed previousl excegt acylstion of tie ‘x‘f u —auiuotuio; one oreseut in toe solution after re- \N c r“ ‘ \ 'L‘ ' .— ‘ -\ . v " ‘ " i: '.' . 1 3' \ " fa“ r v~ arrangement His accom411sueu Lite ,.9 ;. (O.oc moles) chloroucetyl chloride. The crude o(—ckloro-3—dcet— nmidotriOFhmre Wes filtered while tie solution was still cold, wdslgc :itq ice water, dissolved in di- oxene, treste with activated carbon, filtered, dried with anhydrous fiaBSOq, and filtered afflin. This so— lution was placed in tie magnetically stirred appa— ratus described previously. A 10 e. (0.12 moles) V ’3 quantity of piperidine wus added and the reaction mixture was set aside at room temperature for a week (a shorter time could have been used). ister was added to precipitate tte product and this was isolated and converted to the hydrochloride salt as previously described. A little difficulty was efjerierced with recrystallization but it was decouplisbed eventually from isoprOpyl alcohol, decolorisisg the solution Wice with activated carbon. A final crystallization was carried out from a peutuue—absolute alcohol mixture I '1 l lull “ 4'0. yielding 1.5 g. (3.5% of theory) of the desired product which melted at 198 - 1990. .- a: ‘5'“ 'j — ) TI T w: .r“, ...T no . Cl, 15.5; N, 10.7; S, 12.1. Found: C, 50.61; H, 6.52; Cl, 15.55; N, 10.55; s, 12.08. oouuaouo no. A“. £35.. «3!. - 8:88 H3030: 8.: 0338058: 2. 08. 0083 3.».- gaqoo a: 85...... 3.0830 .85 08380288.. 3. . 8:88 8088: 8.8 0032358.. 8. 3: 03.88080? 3 .850 803.... .3 a. 80 oggooiafiag-n-838.n on £38: 8 0:8 20 8300880833§A03890 3 3 0.0 . .. 00H .. 0n .3 «do a H 2: 18...:on n C. 0.: .. .. 6 .. 0a 8.0 8.0 0 A3 canflaoa a0: 3 ..n. .. .. z .. .9. 00.0 8.0 a :5 H2398: .0: 5 sun .. .. 2 .. mm 8.0 «0.0 m :0. 83802 .0: 3 ..on .. .. 2. .. 0m no.0 8.0 o E 032008 .8 3 1.3 .. .. on .. 00 no.0 8.0 m :5 ”330.5. an 3 odd .. .. .3 .. 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I: a::: n: Immmbfiammmm N 1;. \O ‘7 "WT '- - 9‘- 0L; 2:.._‘JL LLLJJLuhL Dg -CH NB3* l —CH03r 7) ' I / Benzee- \ ' Benzoyl Peroxi Ce / 5// 3 Refll: GEE—$23411. \ r—'- ‘Ll’W(C fining”) Er ”4.1—. . —CIIO S "1 The initial svnthesis of y—t e20loe1vHe from E—nietbyltbiogflxene is that described by L. Cdmf .1 ne ’3 ’"~ ’3 et al(”b)(”l> and has 0» en c:1rn‘. ed out sts-.:ise with * [I O with an average yield 0; 54% (literature r ports 53 - 57%). A modified procedocc has been developer which saves consi Tible ti.e erd will be described in detail In a well ventilated hood, 3 5 1. three necked flash ”*3 14 C? (J (0 K J 1.1 :1. H (‘\ I..._J 9 OD x.) (standxrd ta er joints)‘wds condenser, stireer, Heating mantle and a srecial 10" long condenser for solids addition neving a cylindrical 0.5" d C”€tcr o_e in:. A SOlL7tiCn containif“ 275 3. (2.81 moles) of 5—metbyltbiopbene, 5 3. (O. O.fl 6 roles) of benzoyl peroxide and 875 ml. of dry benzene wes hee‘ ted to vigorous reflux. In a large 0: stillizing dish were dry blended 4&5 5. (2.fl8 oles ) of N-bromo- * N—Bromosuccinimide 50. succinimide and 7 5. (0.3206 moles) of bensoyl per— oxid . This Was added to Lle reaction wizture portion— Wise through the liFfi; e bore condenSLr as rapidly as .‘ would pernit and pusne J down tee condenser with "W r'“ ‘V a glass rod. The addition of the brominatiig agent re uired about 40 minutes. ;ne mantle was replaced 1 first by a water and then by an ice bath to reduce the solubility of the succinimide. The succinimide was 4-‘, removed by filtration and washed with dry enzene. The yellow colored filtrate Wis returned to the reaction ' l flask and 306 D. (2.18 Inoles) of denahctnal ne tetramine was added. The slurry was stirred for about a half hour, set aside overnimdt and the n leated for an ad— ditional 2 hours at 50 — 600 C. About 600 ml. of water was added and t’e water layer was separated in a large funnel. The benzene layer Was €"b racted taice With water and the combined water extracts were placed in a 2 1. three necked flask equipyed for steam distil— lation. Uhen the distillate showed no turbidity (about 4 1. had been collected), it U15 acidified with HCl and ext racted three tires filth et er. The ether extracts were combined, dried with anhydrous nlqocw, filtered and distilled throuyh a 10" column p c¢ed With glass helices. The ether W45 rehoved at atmos- nheri lC pressure and the B—tnen Ulcet"de di ' till;d at “,0 1 a 0 7O - 73 /l2 mm. The breduct was a olo rless ligUi j KL, I“ —2 1.5875 (Campaigne repo t Cf; C)! _ r d 1 . 41—ch 1.5::L—L) web tool: 51. on a yellow coloration even when stored in an umber bottle. The yleld was 195.2 3. (@9-7% Of thCOYJ - 5 "li-«:- I: IS its ID —CCCH Silver oxide was preJi red b3! slov ly addinf a I \J solutien containing 503 g. (l.77 moles) of 52:05 in 600 ml. of water to a solution containing 140 g. 3.5 i in ~00 ul. of water; the latter be'ng "I -l moles) of Lac con,uinLcLi115122 1. three necked_idgxfli e;uip:3d witkl an atitator. The bro n, semi— solid susjension was cooled with an ice bath and 95 L. (0.?9 moles) of —tnenal was added in small portions from a drOfping funnel. The slu 3?ry was stirred for 5 — lO Linutes Mter aoLit LOB of the 5-5 L_J ‘ J (D . l (D Qt ,3 in C" (T CJ ,_J ) (Vs «— U l J I‘H 4 ‘1 J l.‘ susgwnniion was IkxyLVVsod by'V€mnnrn.filtratiiqi'throu;h a fine, fritted .l: s funnel. ine filteredke was washed with "wet" steam from an untrar_ed lire, the combin d filtrates were heated to coagulate colloidal silver thich cane throu;h tne filter anL he . oluifi mo serilizered efioloylnr a filter—aid coated *‘Q d- funnel. The cold filtrate on acidifi3a330n with concentrated HCl gave a voluminous :hite preci which was recovered by filtrati on and dried at 5L for 12 hours. The White VO'mcred frod ct WGifiied 93-7 8-, 52. end had a m.p. of l5? — 1530. en udditiendl 7.4 g. of product wes recovc'zred from the filtrate by waking; it alkaline, concentrutinj to two thirds of its voluve and reecidifinj. Total weijht of groduc' was 100 3., which is 99.4% of the theoretical. Cempuigne and LeSuer<27><25), whose procedure was used in the above preperetion, reported a melting point of 137 — ”.0 . ~ . » 150 They SEVQO'Ft a yield of 95 - 97m. 0 / “I > A4 :1 .LJ 5-.L::..J:‘¢ ‘. .I’ Into a 500 ml., single necked flask fitted with a reflux condenser and heeting mantle were placed ll 0.5 g. (3.852 moles) of 5—thenoic acid end 275 ml. (5. 70 moles) of 8001?. These were heated gently for 5.5 hours while the major pert of the gas evolution ..‘ was occurridg u d tlen the mixture was heated at its reflux temperature for erotker 4.5 hours. After cool— ing, the reflux conode1i1s :r was renldced with a distil— lation heed and the exces- 3 30012 was rewoved at atmospheric pressure. While still were, the dark colored residual liquid res joured, in Siell portions, nto enerOV1mutely l l. of a well stirrel concentrated HI TH4CH solution contained in a l5CQ h]. heukcr. A Visorous reaction 0 terred with ewch admit on of acid ' . r1: 1 “v.11; ' -1 . .. .' q 1. -. 3-. .- ,1 1”. CthI‘lL ‘3 . .Lll'd 13’-‘~- bi, .L_-_. l L 11 {3 ud d' l\ e w cap 1. xiz-COV a; .1. c U- QJ’ . " I'w“‘. ‘ - 1.. ‘- . . x .’ ." '1 ‘ I ‘ 4 ’V 1 ‘l r. i ‘ v‘ I ‘v ‘1 ‘ fllLT..b-Lx.fl, «cit/Cl“ E’Jctlulh'b 'J‘ixi IK‘JCY,w1;.u;i]_i...btfkl iICJu. ciQOut 1 890 nl. of Lot ther. After cooli;;, filteriL; 3rd drying, 66.8 g. (67.9% yield of a tan colored product 0 \O i: tte form of need les 1 p. 178 — 17 'N15 obtained. Ciflpiigne and Lonroeu“— .Ju root tc 1«;r Hula, iii; coitcnts 3.1 1.1 ,. r- “”1, ., ._ .1 :1' (Mr/1 :1 ° ..,. .3 0; rue ildoh ”a e nouzcd i!«o pUU ml. or ice filter. 3 (“t "€)’ ‘ rr 2 1-3 ~ ~ 77:.IT1' ~n-“i ]_ er.) I‘OU' .40. DJ :1". \._'__1' . ‘iL4-L.\) LLL;LJ... ‘-v 1‘ ’) A I ,3 r- "1 ,l (D ‘M ,1! [3 Excess brim the bromine color was dlSCnl“ ed. The product was . . . , _ o , _ recovered by fil‘rmtlor and cried gt no , Tue 9.? Q- / 54. i1mww“o—§-flnysoic :mzid 1;H3 CONVIJVCGL 1x3 its amide by the prOCUddre described in the fires ration of 71—‘t‘m’3nargide. The snide was recrystallizcd from a Ezfi meter— et hzxnol mixture to give 7.6 5. oi lo ss product (69.153 yield), m.p. 146 - 147 . P 1‘. nn-qh‘ fi'i-Y‘ r-V-v-v H-rw-f‘ .—.“L\J.L_'1.Ll:m .LCL ii- ...J 1 Tme 2-1cety1thiophcne was nrep:red by tie nethod 11(99) . of Kosdk and Hartoup n 252 .(5 inoles quantity of redistilled thiophene and 117 .(1. 1 moles) of acetic anhydride mere nlaced i a l 1., three necked flask fitted with a reflux condenser, stirrer, ther- mometer, heating mantle and 125 ml. dropgiig funnel contsifiiig 10 g. (0.037 moles) of 85% H7P04. The flask ’ 2 -"\O - ‘. -' ._ . *1 1. - was heated to 7o and tne cotalgst was added which , r L4 .1 11., ,. -. -.. 4. ' 4. (no cnused the redcticn t.; erdtdie to rise U0 ,u . After th :e initi:: l res cti;n had subsided, tan solution mas - r . ~—O . ECRtCQ at its reflux tennerature (99 ) for 2 hours. 7 r -3 3.1“ _ ”4 _ ,1 ..‘_ , . -3 f" _ 1“”), 4, n ‘ .. m ._ -.. ._ ,-.. ~ ‘ ‘ \ It thug unen COoleo, Lflkflhxfiirlcd UO 3 Em 13.1torv funnel and extrictcd_511xit'n1tfi 2~Z‘) m1. (n.13n3ti1led wuter a E“ [.71 g (1 16. “"‘ ‘ '3 J.“ 'r‘ 3‘ . I fi‘~‘)‘ ' “‘ .. ».-.- A then With 230 11. oi d log iguCOus 110w z 5.. /' The orthic 113Vr was PLHCSH in a dist11_itirn anna- . " ‘ ‘ ’ ’ ," “‘7, "~ ’L‘- . " " ‘. “r v~ '( 1' l ’ I" "“ H " A .~ .- "~ " V" 1‘ (N Tit/US 1111 13 1*: U ' -1 1T" C €1,111 {VF-‘1' ~31 LI 1.7 1? c1511: 01.; 1.1-1130 J " 11 1, (31*. C (3’ .1) ...) '1.“ _° .yh“ . . 7-. - .. - 1 »-_V J- 1‘ 1: --‘ 1117-" . “.‘n ‘ b ‘ 1 1 ‘71 m1 »’ tLLOpflufle were Te10Ved at stressitiic gresuhie. l1e A _ . ,,. _1_‘ - “1., »/. ,1 ’j ' .9. ° 1. we, ;; .. \ - _.o W _ d-UCQtJlLDlOyflCMS mfin cistiileu UHULC 3 Ar. L1 ;1:bQUC€ .. ,- m (“r/'1" — r-s- .1 ° 1 , 1 -7 :Q and 108.2 5. Com of theory) distilled oetween be — . 9._ ,, 700’s“ 7% 15::uo (liter atui e renortsfin €91.5tc7). 1U r“71‘ H ”“fl ‘ "—1 u“ TN —.._;L._J.: TC—J --JJ—LU Into a 4 l. beaker t1; iced on a large 0 runee mas placed 440 g. (11 moles) of NaOE, €00 ul. of water and 2500 3. of ice. chlorine sas was bubbled into the had been absorbed. 1> . \n F3 0 1.: (D U) v solution until 522 o. ( This solution was the“ transferred to a 5 1., three necked flask equipped with a stirrer, therrorwici, drOpping funnel and heating men: 1e. The contents of the f ask were heated to 600, tbe muntle redo vod nrd 123 g. (1 mole) of 2-acetjlt-ic> :ene aidJi at such a rate that the reaction temperature was held between 60 - 700 with the aid of a water bath. The solution was allo ed to cool, 100 3. of KaESOz dissolved in 200 m1. of water was added and the reaction mixture was aci‘fi fied with concentrated H01. The white, fluffy «recipitate was removed by filtration, re— crysta11ized from about 1200 m1. of hot water, and dried to yield ;8 g. of a white or; stulline solid (needles). An additional §.7 3. of acid was obtained / the 3c1d from not pdltF. -ne tot3l yield has 50.3; . .2 1 - ,--- . .. n C "‘00 ”K :' ......“ ..-. of eve theoretic l, m.,. 1 7 - 120 (:rrd 3nd nlclnd o T‘flX‘Y‘xOTA“;_ (“z/q (7 r1 -r> 1AI7 Ar“.] 1..T-\ Iii--01. ‘3' 1.. ~ hp)w“O yfl'tfyd 4. \l ; .. \J VEL Vt ... . .L O V‘ , - \ «Li. ,J. L} J V“; __ ’v l .. ' ~4 , Us ch 3 m.p. 13o — 13; . r‘rfi‘ r. 73 -" ‘ «j —-——-—_A le—J V-L.L4\rh~—L.~.L_J {U 1 qt: V" ‘j ‘4' I 3 ‘1 "P. «.""" v.'. v V In 3 evil-fil., Sin 1e luflfi-y3 113s , 3:11:5tt1e of _) e. _. r: -- ’3 L1 :, : 1 ,3 '1. l ",5‘ 103.4 3. (0.3 holes) of e—tgtnelc -«cld 3:3 300 3. 6;;3 i.) moles) of 00019 was heated at its reflur tcrgvr ture -J. .5 hours. Distillqtioi of tfie egcti n Wlkture removed excess 52019 folloaed by 99.1 g. of cleer C. 1131d beilie; between 780 5 10 mo. 3nd 3/ at 2 In. }__1 report an "almost guuntit3tive" giild by tile pro— 1 ‘ 1‘3 ‘ I a ‘ r} O I ‘V‘I cedure 33C 3 o.e. {7 /10 mg. m 71‘ 7r...- T . T.r\\fi L. A.--——J~..-.L... ...LJA—J -cer:q L. m ( ~v- ‘ 4 ‘ r‘ .—V 1 "‘ . ,~ I‘ n : F“ vw‘ "‘5 lo 3 dell stirred solution 01 / u 11. or con 0“ cont i~ed in e 2 l. benker was slowly .3 .\ 3 - ‘r. «I ‘ (I. 4:? p-.~ -. 4“ f) ... ’ 7 .. " 1“ “ . 7‘ — acced ;5 e. ( .3o .oles) 01 n-tu;godl orlcriee. e -- ~ . . ,7 "f 4- 4—: .\ . .- . ,7 amide }¢UnirGCOVL:;Wl\1V Ill ratirq1.xflc crgstzllixmmi 1-1. (1’ from ljfixlgul. of Inn: gazer‘:vx111ried irram1 oven. +2190) - .1 ’) -~ 4~‘» o: m “ an n# v-. v\ v . «\L 1 ;.eilhod_,iw./ ;. c,. ”1,,ielcj, 7.gm. 1,, . rtOL -1- Q a (\ reports a m.p. 1Uv . ind-rm '7 - 1 m . . __ ‘ ~ ~ 1 P -. .1” ran --4.-._1..-;_ ,V_;_J __,\, 4‘ 1;; L! 14.. ..."..M‘hd". -1“; .HU K. -. 2-—~¢.-.~.-.-;.....‘-4J...‘J A EaCBr soluuion ads oreysrec dii$ olved in lSO ml. of rater 5nd 21.1 f. of bromide 33 described previously in the synthesis of chloro- 5—pro:iona.110tiionncne d . 'hhile passii; d of nitrogen tflr0tgh tFe KaOBr solution, l2.7 ;. (0.1 moles ) of 2-1““1ml(9 was added. TWe reaction mixture 45 ninutes later c4 allowed to vsrm up spontaneously $130 the temperature had res ched 77o durinj which time a precim tate har1 forue ed. The dark nixture was coole* to 200, 20 m1. (0.2l Toles) acetic 11 1ydri‘e was add- ed, and it was stirred for about 2 hours and then filtered. The solid ”as crystallized from 110t vzater 1") after ect iW ted c:;rbon troqtrént and ;;Ve 0.8 g. o unreacted amide, m.p. 1790. Ether extraction of the a: ueous layer gave only a small amount 0 identified, very water uUlJLl solid. u - -.~.. .‘ w—--\ .- 7‘“ v ~gr ~1-v— ’- vv f\. vv-n .- >v- - -—\-—-1 oz- :Lmtm P- , . . OF N— Q_~_m T 1 -&o-— .—--L.a. .,.L 4..“ .A. .J.‘ -.-..‘.A‘._._ ...\, - l - .L;-—J..t~:_1 .¢ ..r‘J ~C C131 .5 C) L) 5 ’3 the procedure .:_'.?ZT‘ 010311]; .. a , ‘ r" n (51) 4 4.- CK ntottom :‘ ‘1“’ -'1\:' I \ p ‘f 1 ‘. Y‘ '1 .."‘,"r r“, r" ‘— -.'\ ‘ 101" L11 1.? S‘v;1‘u '.‘\',‘._;._.-S (/1 .L —01 O: U 02;}. (:1 if. 108 , .l ' l- UN“; 01 "J r“ A, 1 - D ’) 4-: . r V 4 j ’7 ‘., , L.. / :7. (0.]. 1.11010) 0.1. (—.'Uilxi?:r_';i.'__1.‘c'.(:, 1k.) L1. (0.1 I C15) Of brOfiine :;d 150 g. Of CHCl 1 J—— a .0 .r-. ~ .‘ '1 p ’. ~. '. -..-x ‘ -:~ 1 ootai CG. hitbr COQllL; 0H8 —? ‘ .. r: C (‘7‘ ,- "- a_.r--L' 1., /"..‘-.J L). (00].- .‘O].'_}) 01 G'.I,1QI‘:.LLI.1.L'€‘ 081-018 c”. 110.1. ..., I ‘ J cgenous solution was ndgixxce a schmfixni con- issolved in 50 U1. Tr’I‘VT —. .LiUL'. (.1 .0 zya' r‘ "'- r‘v r 3‘. 1“! ‘ “I a .‘1‘1 7' '3 ’('> :1 '3’ ' )‘l": ,"‘\ Q "."t " oi Hater ”as added L,rduuallT in s cll go.t1ons WlUJ \ I . l‘ 'V i ' “V: v“ "‘ '3'1' ’1’“ I " ‘. " "1 . J‘ “'7“. Fj‘v‘ " ' a .1 occawyions1.:mm1ni a; of Lune lc:K3UlUD.1JJCuU e. i flichlu- o u I n J“ r» 1*“ 0 ..-.-(V‘, a r‘ _’\—"' 0 ”K. _1_.- ._ D ‘ 3t 1011 OI L: (x: (i 414]. l C- '3. U, “GK... LL " i L. Clfijl L113. u C t O .1. 033,11. FT. ' . .— .. w -' J liis was chstallised (n 1 l O ,. O O (V >ed1es), m.i ' . L1 ."7‘ .L small quantity 0' t m gave no precipitate. bly S—bromo-E-thenamide, m.p. 1670 (52). 2-thenaxide, m.p. The procedure employed w (25) from Organic Reactions. \ f; taining 7 b. (0.108 of water was cooled moles) of 2—thenoyl chloride acetone were added. Hater giViag he product dissolved in wate The_recovercd pro moles) of in an ice A precipitate formed ’3 1 solid ‘. .' :11) e The addition of $3305 r ., 1 CL 1U. ct was proba- o 1650 C“) or 4,5-dibromo— as an adaptation taken A a“ .. All 1‘? .1111 7) J bath and 14.7 3. (0.1 dissolved in 30 ml. of almost 50 m1. of mater :53 added to U10 rea tioa solutiOL an o I , -« _- . .- I ’q‘ ‘ Q“ q the preCinitate ma; removed by llltTflblCH Sud niessed .Y_ 0 «;-‘_-\ {5 ' '1 t ‘ '3' ‘ Y“: 3| {‘*_ ‘ " ',’)‘ ‘ "\ ,n 1'10“ ...l_- “Jr $1-1- o -‘.i as]? \‘i‘ :1.-. U. . ' . l- ‘ v ' ... _-_ U ‘LJ 9 m a H ; C, r [)3 .J o 1...: 3 in a vacuum dcuolnqbflr at room temperature, 11.2 g. of the aside was obtained (73.30 of Ce ory) Tue .., _, ( "x in, ) / / melting point was not Iakea for fear of exflosion . - ‘ -'—. -.. . ~ — ._ -r— w‘. - V_ ~ - ,7 _- Tm - — r ~- A- - — V‘rw— r - . -fil ,‘ 1nr|1 _ .‘l "1 CTT _V.. ' ...-TT'S ‘ ‘ 3,1“ "g .r‘) , .-‘- T 4' ‘1vl (.1\':41 f)__31:_ 1. C1 1' ‘ 1’, ’ \ 4 ...‘L...L.....L-_.‘.. ...—MD thL‘M ..._;J-L‘._.._:-.- \—‘—-J¢--_¢—J-—>~ .- L ....‘L-._._.. *1.) --»J-._...J.A_l ride $/-1t'::ce::1—:5 ”1‘ 1‘ r .-~. -: "‘ .-. - , - . r1 J‘ "-1“ . \ - Tr ~. 3" iae r 1r tn :ent or twe aside LO t-e isocuenate _u1 its nydimfl_y s:is to tbe afidxnrxvere chVU <1 out by w ' ’3 ollowin“ the (We cri3i tion given in "Organic Ee“c ions“ ) \_/ W 0 ml. three necked flask was char ed with 5.1 3. \J y. P \N O ‘x -1 3 roles) of tie Q—thenoyl aside and 90 m1. of or? x U \H (0.0 1 r "r. ' . a. ,1. m; - benzene. while sparuini 1 M L.) , tee solution was latee U) at its I8fl1K te*m :erature for 2 iour” durin? which time it took on a maroon coloration. Tee so 011 tion was kept at its reflux teaterature about 2 hours after adding 50 r1. of 153 agueous NaCH to it. It was then transferrc d to a separatory funnel. The benzene layer 60. was separated, dried, warmed with 10 n1. (0.11 roles) of acetic anhydride and poured into water. Ho pre- cipitate formed. A solid was precipitated from the . 4—7 n *7 water layer by the addition of E01 but oflls gas not investigated further. Followic; this failure, an acid hyvrolysis was attempted. Employing the sane eeneral procedure as just described except that a reaction period of 4 hours was used, 6.1 3. (0.039 moles) of 2-thenoyl aside were rearranged in 50 ml. of benzene. Con— centrated HCl (50 3.) was then added, the reaction mixture was heated for 1.5 hours at 50 — 600 and the water layer was cooled and made alkaline. Tke green— ish colored benzene layer was se arated, dried a“d warmed with 10 e (0.11 moles) of acetic anhydride. .J. There was no Visible change in tle benzen: solution a so tiitittle c‘lmmwaacetgl.ci'1oride THUS a dec L‘J . IL vigoeous reacticn occurred and tarry material formed ... . in the bottom oi the ilask. Acidification of tie J. aqueous layer caused it to take on a turbidity but no precipitation occurred. “WW—... - .-.. fa 7. ., ,. .4 , . ..Lg- 4‘..ng ’V‘ .a—lnd 12 15. 14. ... 1/ ,0 (3’3 1“. C.“ n '1‘ " I 1 ' ‘ ..-. 1‘ ,1: ~ A ’ TV“ , ' ' V“. ’r r :— . 14:1...11-vfl'741171 L4. :7; .1) IO}- "(3.‘1, 1" o , n-J'V (tw'lbr‘i £15."... .1. 3 I, f‘,‘ ." —- (2;, r—ly I (V1 ‘ U 'W . fl r~ .L- ‘ _‘ '_ 3“ 7 fit,“ r‘“ 1 ;\ -~ [j 3" 1 ) (l; )r), VLUI‘ :o “Dobrmbbb, 9 , {.2 '4 (1;:I/)o —-~. . , I“ .1 1 - T1,. _ - .. '17 24131111111, :1. Cilia 'Illft‘lCt-r, .LJO , A-lllfll. , 5? D3““’ 0°, 3..., 26, 419 (1343). V". -- "—111.71 1 ,. . - 1 .' 1 . .- .. .- ..,,.n :1‘1111C/L4: Fl EQD. , .L" ;_L):‘.‘;'I.EI.-“:_3 H] llJQ DC: 1 V -11 l‘fCuJ , Inters01gnce "unlisners, Inc., new York, K.K., Jilson, 0.0. :3n1 Gisvo1 d, C., "Textbook of Org' icinal and rU.TWdC€uthxl C: .=*istry", 3- L , J.B. Lippincott Co., railudelpnia, 31., #34 (1936). H‘rtou a, 111) , "T1.iopnere and_ Its DeriV1tives", e ~tic; ence Fuelisv rs, Inc., Row York / le“JlTP€, 3., J. nfl. Phnrr. assec., HE, 129 (1957). i;ne E. nd Lesuer, J.K., J. Am. Chem. 50c., '70"? / [4-513 (1(d') Stadler, 0., Ber., 13, 1490 (1885 Steink03f, U., Ann., 403, 17 (1914). 1'! Steink03f, a. and Hopner, T., inn., 501, 173 (1933). Tohl, 1., Ber., 29, 2217 (1395). Campaifne, E. and Ionroe, P.A., J. an. Cher. $00., 7—37, ".l! 11"" 13,1: /:, awe/ (13; )- Hurd C. D. and fioffat, J., J. Am. Chem. 500., 1a-? 7' . T“ 1..”? .3 1’3 T ' . ‘,--1«r. 7.“ a IlVKJ+1TVr 1101... '1110 1-1er, \JoJo, J. -1 o C 1131'. POOL/o, :2, 117: (194?). -- c1 - - 1 ~\ ~ "g I‘ll/TU, (JOE. 1:; W” I \J[ , C’OJJO, U 0 .5- o (J . \JOCO, (TC ,'.L1i-. (‘ I, \ l1, _/‘/’ (1"1/1./ O 74., " . * 1 -- ’ o “ 1 I‘X!."!, I-.-J-. j .4 J ‘f L} , *5.U., d. o‘ O C . JD, 0, "jn C ’3 CIT“ [[3, lrJ‘_ (l//‘_ . ''''' H -: 4 \ 1 ' ., P! -r- m CH' .- 1- ; C9, ....10 1. ‘(J W- ;Oqu, ... 0 (Va, U0 - 0 L1 1- o ’3'! 'Lj I @000, ,’ , ‘L/ly ”(J-1‘; 1). ’" /' \J(.:: £11.:L.) \fJ, [1:03 LAA'C‘ u x..-.. -n, ‘k0-4-0, JO ~ I. ‘J 2 O JC’C/O, E191 - O a . h .\ n b t n s o n . , a o u u . 1 . v n p u u 1 a ‘ 1\ u . . . D . . . 1 O 0 w n u ~ u n . . ‘ ‘ , . J . .- J . . O D . a u C . . 1 o a . a O J - . a . Q a x C U 9 a 'U C) 7\_) I _J .NK ) [U Q UJ '\ \\)\J m VJ Q1 VJ C I r" ‘r"\ . .3 , I '1" I ‘> 1 l D 77-. C . 1 <7 2 v. ‘,a 1' ' ‘ :'_; " r. ’ ’ . “NHL 12...“...1v, J4. L '4. ..L LII , ..o‘ o , .x. ‘ 0 mid o , _,_/, I." /‘ v- _ —’ ‘\ \_.1’\. 1 \3 ’3 / " “‘ / / ./ J . C J ‘ 7" ii 7L :3 “,(‘x J .7 , , | C; 7-,} f} “I (I; C' ‘73- '31; «' JI- C .7; -. “ -.. , Q , .... - x t. , ..u. . O .3- . \4t 4.- . u», ~J . .U' , . . O , '\ _ / L‘ i <1 . . - -y ) ‘ I - - TI r _/ ; ’ L '7‘ U . "Ju . , l y , z ”7 "" / r J . TE— L" c - '7 .- ..,.. - \<, T. :-. A ". ‘ ' 1 .7 ' T_T 'A‘ “ "z '- -7 t'r 7' t? :< l). ”,7; .1". , ..‘L O U 0 .1Li \xL ...‘flL! t! L) L). 7-4 L , 4.4. o \J 0 L71 (_,) O I‘JQ -1. , :l , ( :1 ‘7‘ 1, €th —— - J ”7‘ ._,-" . ITr, ‘ .‘ i' . IF1‘~? .‘A.‘.\ ,.N 3 ._ H I - , LgIImr»,r, L.D., -J.LO.¢W&€ ;V&I ILS DLIjAf tivoL” , n w u ‘7', ‘7‘ *: r‘-.'~ "N 3. '7': ~vvv ‘77 ‘r - w IWUFI~01~PIP gobl L oIs, Ino., “ta IorI, h.f., EQS (13);). T ., r. A .-l,.. I T_‘ -.I .7 n P1", ,»r.» (101168, “-04. =1". (7. 1L7uilj7‘4, 'u 0.1)., J. 4177. U.;‘\;"..o 2.2000, A3, fwwu (1;. L) . —: ‘7'. I‘, 7 7—77 4- 'm) - "‘ " "‘ '. T: ' ("s 4" P- - a I! 1.7. - “- Lowgs, no of Co I ~rQI.Io no Cbluno :oL. III, 1 “° , u. . ”if, 7" fif,,. Kr _ 7- 7 xr ,‘FW r ' JOth. ..‘llOQ-l Li. J~ _ JOE’S, III/Clo , .L‘va‘f lCJq:-o A. 0.1. o , (Hr/4' (3.:4I) 353:3, Roger at 31, "Organic Re3oti ‘;s" Vol. III, " I"r1:d Ekxms, Ino., I31? YOIWC, I§.Y., . ., J?t50d.IKfP IdCIflLLficaticnl of Pure Crgxfiio Corjouods" Vol. II, John 5413” and Sons, Inc., Fox York, K.Y., ”(I Q. p..— r g H L...) H '7 D U W W k‘ r“ .--, u< - 1' ¢' / I 7 - ~- I' V_._ 7“. ”a v- "”| ,no L. 2n_l5 Les U;I , J.;., 5. My. bheu. goo., FOTC], 1 0V . 'j‘qu E»: “0.7::13T, D o , J. CEIHZI . iJOC o , AI‘KL’WO (1957). n H w m cU - M1 fr :1 I I . , 4— - \h! too 5, 5.3., IoIO'bLJL dLlViulVGg7, e 1