OVERDUE FINES; I .. .1. o 25¢ per day per item "4 ( RETURNING LIBRARY MATERIALS: EX?” .i~j 133‘?” ' Place in book return to remove \‘v‘kx'm ~ W charge from circulation records STUDIES TOWARD THE SYNTHESIS OF ORGANIC CONDUCTORS 139 Larry Lewis Klein A THESIS Submitted to Michigan State Universitu in partial Fulfillment of the requirements For the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1980 It /I ABSTRACT STUDIES TOWARD THE SYNTHESIS OF ORGANIC CONDUCTORS Bu Larrg Lewis Klein with the discoverg in 1973 that tetracganoquinodimeth- ane. TCNG, and tetrathiaFulvalene, TTF. Form an electricallg conducting complex. there arose a need For compounds analo— gous to these in order to optimize the conductivitg. Ne re- port here our attempt to prepare hetero-analogs 09- these systems. The First area explored was that of the azine ring sus— tems. Potassium 4~dicuanomethglpgridine 1-dicqanomethglide was prepared From 4-chloropgridine. Various carbon. nitro- gen. and sulFur protected malononitriles were prepared and used as nucleophiles with 3.6-dichloropgridazine. The work performed on the pgrimidine ring sustem led to the synthesis of the ethglene ketal and the ethulene dithioketal of 1.3-diaminoacetone along with N.N’-dia1kgl derivatives of the former Reta]. Sgnthesis of the sodium and tetrabutglam- monium salts 0F B-dicganomethgl~b—methulthio-1.2.4,S-tetra- Larry Lewis Klein zine was also successful. Several new 2.5-disubstituted derivatives 0F the thienoE3.2—blthiophene ring system were prepared. Synthesis of the corresponding diacid, bis-carbomethoxy. bis-carboethoxy. bis-hydroxymethyl. bis-chloromethyl. bis-cyanomethyl. and bis—(carboethoxy)cyanomethyl are de- scribed. Two potential donor molecules were also prepared From rondensatxons of 2.5-thienoE3.2~blthiophene dicarboxal— dehyde with 1,2“benzenedithiol. and 4~methylbenzene-1.2-di- thiol Followed by oxidation. Synthetic efforts toward 3.4.7.8-tetrathiopyridazin- o[4.5—d]pyridazine are described including the preparation of several new tetra—alkylthio derivatives of this ring sys- tem. Finally. construction of the skeleton OF a bis~benzannulated diaza-azulene was achieved: providing a key step toward the goal of synthesizing a tetracyano diazawazulene quinone. TABLE OF CONTENTS Page INTRODUCTION ......................................... 1 RESULTS AND DISCUSSION I. PYRIDINE NUCLEUS ............................... 10 II. PYRIDAZINE NUCLEUS ............................ 17 III. PYRIMIDINE NUCLEUS ........................... 32 IV. TETRAZINE NUCLEUS ............................. 51 V. THIENOE3.2~b]THIOPHENE NUCLEUS ................. 58 _VI. PYRIDAZINDE4.5-dJPYRIDAZINE NUCLEUS ........... 72 VII. DIAZIPENOE4.5.6.7-d.e.¥lFLUORENE NUCLEUS ..... 79 EXPERIMENTAL General procedures ................................. 83 4-Chloropyrid1ne 1*dicyanomethylide ngl ........... ~83 Potassium 4—dicyanomethylpyridine 1-dicyanomethylide LIZ; ............................................... B4 4—Ethoxypyridine 1-dicyanomethylide £18; ........... 85 4—t~Butyldicyanomethylpyridine 1-dicyanomethylide lel ............................................... 85 4-Bis(ethoxycarbonyl)methylpyridine 1-dicyanomethylide nglu .............................................. 86 4-Aminopyridine 1-dicyanomethylide ................. 86 BdDicyanomethyl—awchloropyridazine nggl ........... 87 2-N-Methylr3-dicyanomethylene-b-chloropyridazine ngl ............................................... B7 3,eris-(t-butyldicyanomethyl)pyridazine Lgfll ...... 88 3,6~Bis~(methylsulFonyl)pyridazine Leg; ..... ' ....... 89 3~DicyanomethyI-bmt-butyldicyanomethylpyridazine (313_ ............................................... 89 TABLE OF CONTENTS (continued) Page Phenylthiomalononitrile L221 ....................... 9O n-Butyl toluenethiolsulFonate L31; ................. 9O Benzyl toluenethiolsulfonate ngl .................. 91 Benzylthiomalononitrile £421 ....................... 92 2-Dicyanomethyl~3,S-dihydroxy-4”methylpyrimidine LQQQL ......... . ................................. 92 2—Dicyanomethylw3,5~dihydroxyr4~phenylpyrimidine LQQQL ......... .. ................................. 93 I2—Dicyanomethy1ene piperimidine LQQL ............... 93 5—Hydroxy-2-dicyanomethylene piperimidine L69; ..... 94 2-Dicyanomethylene piperimidine-S-mesylate £911.... 94 2-Dicyanomethylene piperimidine-5~tosylate (62).... 94 5-Trimethylsiloxy-Q—dicyanomethylene piperimidine L631 .......................................... , ..... 95 2-Dicyanomethyl-(3H.4H)-dihydropyrimidine L62; ..... 96 2.2rDicarboethoxy 1.3-dithiolane £611 .............. 96 2.2~Biscarbamoyl 1,3-dithiolane Légal .............. 97 2.2~Bis and 1-N—ethyl—2-dicyanomethylene-S— piperimidone ethylene ketal £85; ................... 102 1.3~N.N’~Diethy1~2—dicyanomethylene-S—piperimidone L§§3_ ............................................... 103 N.N’-Bisbenzoy1—1.3-diamino—2—propanol (fig; ........ 103 113~Bisbenzamidoacetone (89) ....................... 104 I1.3-Bisbenzamidoacetone ethylene ketal LEQL ........ 104 1.3-Bis(benzylamino)acetone ethylene ketal £211.... 105 1,3~Bisacetamido-Q-propanol 12g; ................... 105 3-Dicyanomethyl~6—methylthio-1,2.4;5~tetrazine sodium salt L102) ......................................... 106 3-Dicyanomethyl—6-methylthio 1.2.4.5—tetra- zine tetrabutylammonium salt (103) ................. 107 3-Dicyanomethyl—6~methylthio-1.2.4,S-tetrazine (1011 .............................................. 107 3~Bis 9.954 @ N ‘3 '9 O '3 "SCH New 2 FIGURE 2: First attempted route toward 9. most cases the pyridine nucleus is far too electron rich to 10 11 undergo nucleophilic substitution. and this problem has been countered in two ways. Smith and EvansE20] succeeded in substituting this chlorine with 5-alky1 barbituric acid de— rivatives in the presence of acetic anhydride(Figure 3). Presumedly. initial acetylation of the pyridine nitrogen ac- tivated the ring allowing attack by nucleophiles. The sec- ond method of activation is shown by the substitution of FIGURE 3; Nucleophilic substitutions of 4—chloropyridines. chlorine in 14 by sodio diethylmalonate(Figure 3)[21]. The ortho nitro groUp accelerates the attack. possibly via elec- tron transfer. Subsequent removal of this activating group would be necessary. so this method was not studied further. Howevery in 1975. PollackE22] showed that direct reac- tion of malononitrile anion in dimethyl sulfoxide with I2~chloropyridine yields the compound 15. shown in the fa- vored tautomeric Form(Figure 4). Under these same N ' O + M.) N Cl NDMSO LS FIGURE 4: Reaction of 2~chloropyridine with malononitrile. N H conditions. though. reaction with lg led to a cyano contain- ing water soluble dye. This result was repeatedly attained From the many attempts to react A; with the malononitrile anion. The autoquaternization of 4—chloropyridine is known to occur slowly at room temperature and is inhibited in basic solution. A possible reason that Lg could be prepared under these conditions is that the site a? reactivity. the nitrogen. is blocked. All other efforts toward substitution 0? the chlorine in ;§ with diFFerent bases led to the same result The second route to §.(Figure 5) takes advantage of the ylide structure in lg to activate the ring toward the final substitution. 4~Chlor0pyridine was prepared K0. I cu NeN 9’ +~c N QC M, Na Nag-9Q '25 " NC‘N NeN L} 1§ ll FlGUHt a: Second attempted route toward Q. 13 by neutralization of its commercially available hydrochlo- ride salt followed by extraction with ether. Evaporation o? the ether and addition of dry reaction solvent completed the procedure used in most cases when the Free base was needed. Its reaction with tetracyanoethylene oxide yielded a bright yellow crystalline compound. lg. Reaction conditions proved critical as the yields ranged From 10% to 70%. Reaction of the activated chlorine in $9 with the malo- nonitrile anion led to a high melting (}BOO°) very insoluble salt. To generate the malononitrile anion. sodium methoxide in methanol or benzene. sodium hydroxide in ethanol. potas- sium t-butoxide in tetrahydroFuran. and sodium hydride in toluene were used. The product of each process exhibited an infrared spectrum showing the ylide structure. a gala sub- stituted 'pyridine ring. loss of the aromatic chlorine and a multiple cyano peak at 2130cm-1 and 2200cm-1. The PMR in dimethyl sulfoxide shows doublets at 66.7 and 67.7 as an 'AA’BB’ pattern. Other variations using hindered amines left tarry oils as products. Attempts to silylate or alkylate this anion went For naught as it was quite unreactive. Only the potassium salt. L1. could be obtained in crystallized Form as purple needles by evaporating an acetone solution. An elemental analysis (CHN) of this salt was consistant with its formulation. 14 Further evidence for this structure was achieved by an alternate synthesis shown in Figure 6. The use of t-butyl-malononitrile I ' 5* NC NCHN Na @+NC——CN_2§>O T O '—‘> NCtCN 19 1- | G O A 0 NC?" "‘5?“ Mc”6\cn FIGURE 6: Alternate route toward 11. as a protected malononitrile equivalent has precedence in the work of Hheland and MartinthJ. Since there is no hy- drogen a to the cyano groups in the adduct. further reaction of this site in the basic medium is prevented. In the syn- thesis of polyhalo TCNO’s. these workers found that by using t-butyl malononitrile as a masked dicyano moiety. a dis- placement of the halide on the electron deficient ring can occur. The t-butyl group is then removed thermally under neutral conditions as isobutylene. Because the ylide struc— ture decreases the electron density of the chloropyridine ring. this process seemed applicable to 19. Milder condi- tions were first attempted using sodium ethoxide as the base. However. this resulted in a mixture of two products. Ag and $2., the ethoxy compound being the.maJor product. with sodium hydride. 12 was produced in 81% as a bright yel— low powder. mp 218°C. 15 From PMR data. the pyrolytic cleavage of the t-butyl group seems to take place most readily in dimethyl sulfox- ide. rather than mesitylene or propionic acid. The reaction can be conveniently monitored by heating a sample of 12 in a, PMR tube in deuterated dimethyl sulfoxide. As the intensity of the t-butyl signal decreases. the aromatic proton pattern of two doublets changes. The downfield doublet centered at 68.45. corresponding to the 3.5-protons in ii. disappears. and a doublet at 66.7 appears. The signal for the 2.6—protons retains the same chemical shift in both samples. The PMR of the product after warming 10-40 hours at 110°C. shows the same spectrum as that shown by the previously de- scribed salt. 11. giving further evidence for its structure. A final alternate synthesis should be mentioned. It was thought that if the diester. g9. could be made. ammono- lysis followed by dehydration could afford the conJugate acid of Q
c 35 26 FIGURE 11: Alkylation of dicyanopyridazine. 23a. a singlet at 64.15 and an AB quartet centered at 67.42 in a ratio of three to two. From previous studies of the methyl- ation of tautomeric 3.6-disubstituted pyridazines. it is as- sumed that the alkylation has taken place on the ring nitro- genEQBJ. Treatment of this "protected" pyridazine with ma- lononitrile anion at reflux for 2 hours provided a deeply colored mixture of products which was not further character- ized. Protected malononitrile groups have already been de- ' / scribed with the use of t-butylrmalononitrile in the produc- tion of tetrafluoro TCNG. 28b(Figure 12)[10]. Upon heating. 2 a loses two equivalents of isobutylene to give a dihydro precursor of gay. This scheme was repeated by reacting two moles of the conJugate base F.) N NC N I! N NC bk .1; F JELZ,,F F + “H9 -—> r N H N F F F NC N Nc N Nc . 2_8a 2:85 FIGURE 12: Synthesis of tetrafluoro-TCNG. of t—butyl-malononitrile with gg. After purification by co- lumn chromatography. 31% of Q2 was isolated as white flakes(Figure 13). The PMR. 0 L2 ”3 FIGURE 13: Synthesis of tetracyano-pyridazine g2. IR and mass spectral values were all those expected for 3.6-bis(t-butyldicyanomethyl)pyridazine. Attempts to increase the yield by increasing the labil- 12 'n «1;: ity of the leaving group. i.e. from chlorine to methylsul- fonyl as shown. led to 3.6-bis(methylsu1fonyl)pyridazine. Q9. However. when the same reaction conditions used for gg were applied to gg. no replacement of methyl sulfonyl groups. was observed. The thermolysis of 23 was effected under varying condi- tions. but only one maJor product was isolated in each in- stance. this being the monart—butyl compound. Q1. The color of this compound. bright yellow. can be used to detect its presence. and in most cases mild heating induced this color change. A list of reaction solvents and their results are shown here in Table 3. Run 6 was chosen as the best proce- dure as the yield (61%) was highest. Pyridazine Q; was also shown by TLC to be the main product in the other runs. Nhen Q; was isolated and purified. its infrared spectral data were very similar to the chloro compound. gag. and its PMR spectrum showed two singlets of ratio nine to two appearing at 61.12 and 67.3. respectively in dimethyl sulfoxide. The signal due to the tautomeric proton was not seen. Resubmitting g; to the same reaction conditions re- turned starting material along with a small amount of an or- ange solid. This compound was isolated by column chromatog- raphy and showed a base peak in the mass spectrum of only m/e149. The infrared spectrum exhibited only a very broad 24 A —__.9 I NC :1: TABLE 1:11 ENTRY SOLVENT ES TIMEQLIIQ RESULI 5.01 m ANISOLE l52 300 29 3| MESITYLENE I62 600 Lil DECALIN I95 . 30 :11 TRIGLYME 222 ISO an QUINOLINE 237 5 .1: PHENYL EI'HER 259 5 :3: 60% SULFOLANE 285 20 _ — (BuiNOBae I20 5 .1: DMSO l20. 360 "— signal in the cyano region. and this product appeared to be due to a degradative process. It is possible that the de- sired product may not be stable under these thermolytic con- ditions. however if so. there is still only a very small. amount of it being formed. Since the trbutyl group proved to be troublesome to re- move. methodology directed toward different protected malo- nonitriles was sought. A solution to this problem would have utility not only for this problem but also for various other a—haloazines such as QQ. QQ or Qi(Figure 14). FIGURE 14: Other potential targets of malononitrile anion. It was thought that by making the attached carbon group more bulky or by stabilizing the alkene which forms on ther- molytic cleavage. the reaction would go to completion. To this end. various substituted malononitriles QQazg were pre— pared by sodium borohydride or trimethylammonium formateEBlJ reduction of the condensation products of the corresponding carbonyl compound and malononitrile (Figure 15). However. under the same 26 N N <-~e=< as N NTEAF 151R=¢CHZ- 5R QC?!- ‘ R 175099 d R :pac- conditions used for t-butyl—malononitrile. even benzylmalo- FIGURE 15: Substituted malononitriles. nonitrile anion was unable to act as a substituting moiety on the pyridazine ring. Another approach involved substitution of QQ by dicyano ketene diethyl and ethylene ketals. 36a.b(Figure 16). shown below. 0R N :H:Me ORWeH—-—1-0Ff2 R—‘fi—a 09' on CN 36aR:(CH22 R’: crycn; M :N. — bRZ-‘R'ZCH3 M:K FIGURE 16: Dicyanoketene dialkyl acetals. Hydrolysis of Q2 would give an acid which should spontane- ously decarboxylate to yield the 3.6-bismalononitrile pyri- dazine. Preparation of QQ was straight forward. yielding the saltst32l as powders stable towards air and moisture. However. the high acidity of the proton of the conJugate acids and the hindered nucleophilic site combine to heighten the stability of this base. Thus it resisted all efforts to effect reaction with 22 under various conditions. a—Heteroatomic malononitrile molecules were then in- vestigated as possible synthons. The synthesis of N.N-dimethylaminomalononitrile QQ.(Figure 17) started with 'wedeecligii. 3“" FIGURE 17: Synthesis of N.N~dimethylamino malononitrile. the preparation of N.Nrdimethy1—N~chloromethylammonium chlo- ride from phosgene and dimethylformamideESBJ. Addition of excess copper cyanide yielded the product as a fairly stable liquid. Reports on the chemistry of QQ warned of the ambi- dent nucleophilic nature of in this anionE34J. When the anion was reacted with 22. a tarry mixture of products was obtained. Separation and isolation of these products was abandoned in order to pursue more viable routes. The second class of heteroatomic malononitriles inves- tigated was that incorporating a sulfur in the position. This work was based on the assumption that mild Raney nickel or nickel boride desulfurization of this synthon. following its attachment to an aromatic ring. would lead to the de- sired product. Initially four compounds of this type were known. QQESSJ. 1QC363. 41(36]. and 3QE36J (Figure 18). 15%| Phenylthiomalononitrile. I N N .5 N oNHz 425: t 59 " 4.9 028 — — FIGURE 18: a—Sulfenylated active methylene compounds. was synthesized in a number of ways. the best one being a new. more general method shown in Figure 19. using phenyl toluenethiosulfonateE37]. 1Q. as a ”amt“ +(fHA33‘g—S e I .19 FIGURE 19: New synthesis of phenylthiomalononitrile. sulfenylating agent. A previously reported synthesis of Q3. which was said to proceed in 98% yield. gave in our hands a mixture of monosulfenylated and disulfenylated productsEBS]. Phenylthiomalononitrile is converted to a stable anion upon treatment with sodium hydride in tetrahydrofuran. However. this anion failed to react with QQ and 1Q. even on refluxing for long periods. Assuming steric interference does not account entirely for this failure to react. the stability of the anion must be so great as to preclude this desired substitution. Therefore it was thought that ethyl (phenylthio) cyanoace-A tate. 1Q. or (phenylthio) cyanoacetamide. £1. might yield stronger nucleophiles. and they were reacted initially with sodium hydride in tetrahydrofuran or hexamethylphosphoram— ide. followed by combination with QQ. Again. only starting material was recovered from these reactions. To overcome both the steric and anion stabilizing ef- fects of the phenyl moiety. the next choice of substituent was an alkylthio group. The synthesis of alkylthiomalononi- triles has yet to be reported. Attempts toward the syn- thesis of methylthiomalononitrile. 13. include direct nucle- CH3SSCH3 N + NAH Gs—sfchaix“ CH; N \Y’ chE—s—cs 44 N * 45 — _. ‘ N " “*‘i‘s'li. + NAH n-Bu—s N —- N FIGURE 20; Froposed synthesis of methylthiomalononitrile 30 ophilic attack of the malononitrile anion on dimethyl disul- fide (Figure 20) both with and without the presence of silver ion as a catalyst. and using unsymmetrical disulfides as the sulfenylating agent (as in 1:). These reactions gave only disulfide residues as products of oxidation. Even when methyl toluenethiosulfonatet37]. 46. was prepared. sulfenyl- —_ ation of the active methylene carbon of malononitrile did not occur. This was also the case when n—butyl thiosulfon- ate. 11. was used. It is possible that disulfenylation may be occuring. since toluenesulfonic acid can usually be re- trieved from the products. Another malononitrile equivalent is the benzylthio de- rivative. 32. Duplication of the syntheses of sulfenylating agents 1Q. 39. and 31. using benzyl disulfide gave the cor- responding thiolsulfonate. 3Q. in 9OZ
=:<:E‘H NH 2 )NH 5% _> NO REACTION ’0 IO \k E} COMPLEX MIXT URE 028 NC a) 12%., NC : a“ . 35 23) [41]. Bu using this methodologg with 1.1-bismethglthio 2.2-dicganoethg1ene. fig. as the dielectrophile. we hoped that derivatives 0F fifi would be produced. :Hsz H H2 HN , X ———->x:d>:<:—>—>fi H2 +0555 ”HE C C “is: —-> CFC: c s N 54HZ H3 \_/ ___.) "cm N 2 § _GKJ; 5 {3 FIGURE 23: Methods For sunthesis of tetrahydropgrimidines. 2 Depending upon the nature 0? X
29: WW a. o cr—EcH ('— N KN A?) ”2:0 fi7 m FIGURE 24: First preparation of 1.3-diaminoacetone. The preparation of fiZ shown in Figure 24 is troublesome. and the intermediates are diFFicult to characterize. Onlg one report of the use 0F this compound in heteroatomic sgnthesis has arisen.” namelg a cgclization with carbon disulfide in the presence 0? baseE45]. The alleged product. however. was not theracterized. A similar cgclization 0F 57 prepared in this manner with 52 under various conditions was attempted. but Failed. Since diaminoacetone dihgdrochloride was useless as a 1.5—dinuc1eophile. a commerciallg available precursor. 1.3-diamino-2-propanol. 58. was chosen as a starting materi- al. The planned sgnthetic route is shown in Figure 25. H NHZ c N N Ho + ”EFL—f ———-> H "z CHSS‘ on ’CN .523- H N 5.2.8 OQN §.0 [0] ’—‘CN _5_? N H Nc NH N <: N. 5 <——‘°] 2=C>=< <——" o O- _ N H N H N FIGURE 25: Attempted sgnthesis of fi From diaminopropanol. Cgclization 0F fig with fig. or the ethglene glgcol deriva- tive. fig. oFfered the alcohol. 99. in 72% and 84% gield. respectively. This compound showed its expected molecular ion From mass spectral analgsis at m/elb4. Its infrared spectrum exhibited bands at BSOOcm-l. 324Ucm-l.(O-H. N~H). 2210cm—1. 2170cm~1(CsN). and its PMR had resonances at 53.15(br s. CH23.53.92(br tr. HCD). 65.18(br .s. 0H). 67.44 (br 5. NH) in dimethyl sulfoxide. This alcohol was soluble in solvents such as dimethyl sulFoxide or dimethgl Formamide 38 and showed remarkable stability toward oxidative conditions. After numerous attempts to convert go to the ketone with the reagents listed in Table 5. eFForts toward this oxidation were halted. TABLE I may OXImzmg AfiENI in lime mam. . “03142504 RT I00 20mm “590% Z " RT um. our 3 n '00 7hr: ” 4 HQ ' CROaCle " 40min CHZCIZ s 2 ” - 0120;?- RT 24!... our 6 DMSO- Dcc-Hapq . . . . ‘6"5 7 DMso- DCC-TFA .. .. .. a omso- 08-90 - TEA -4o 2“,, 0,202 9 c180 . TEA 0 RT 5.... m.- l0 some 0 100 am PYRIDINE n Ncs- PYRIDINE IOO 5min ‘6”6 I2 iBUOCI RT mm tauOH '3 EfOzC‘N=N'C02Ei ' ’ 3 day: our '4 MN 02 N H I o '5 A9N03,hv(350nn~9 " 4m DMSQ/HZO Derivatization of the alcohol. 60. proceeded with mesyl * chloride and pyridine to the mesylate. 61. while the tosy- .— late. gg. and the trimethyl silyl ether. 63. were prepared. - though in much lower yieldiFigure 26). Attempted oxidation. 0? the acct-<2 viii-o " " \ H / NH NL/ 60 \J ” NH N H N as 65 NH N C H wig-OCH” + Nc N Mi) c H H H FIGURE 2': Derivatization of alcohol go. " ESIO mesyl and tosyl compounds in dimethyl sulFoxide Failed as did the reaction oF the silyl ether. Qfi. with trityl Fluoro- boratet46]. when the preparation 0F the triflate was at- tempted. the only product isolated From the basic reaction mixture was the alkene. fifi. in 412. Nucleophilic displace— ment of the mesylate with malononitrile anion yielded only the mesylate and the original alcohol on workup. However. a similar reaction with t-butyl~malononitrile resulted in 63% 40 of the substitution product. 95, Compound 95 proved to be useless as an intermediate product toward the synthesis of fi and thus. was abandoned. A thioketal is another synthetically useful carbonyl synthon. Approach to the synthesis of age began with the preparation of 2.2-biscarboethoxy~l.3~dithiolane. 91. from ethylene dithiotosylate. Q9I47]. and malonic ester in quan~ titative yield. A Japanese groupE48] failed to prepare this compound when sodium ethoxide was used as base. Due to the lability of the alkyl dithiotosylate. a less nucleophilic base such as acetate was necessary. He hoped to synthesize the bisamide. éfia.(Figure 27) and reduce this compound to the 1.3 diamine. a useful diamino acetone synthon. Without further purification. the low melting diester. -Tos I: + Mm.) L l 95] -T05 5* (:3)? egg ' E? ? lNH40H NE gN EPoo!a L—‘I EH” [—1 . R><,‘ 7O 6__8aR= corii: NHZ R: H 63R- 5 ‘ 333:th FIGURE 27: Synthesis of diamino thioketal gig. 41 fiZ. was warmed with ammonium hydroxide and precipitated a white solid which was characterized not as fififi. but instead. as the monoamide. gag. This monoamide was also produced when malonamide was refluxed with the sulfenylating agent. This thermal decarbamylation has been noted to occur with a variety of sulfenylated malonamidesE48]. However. by com- bining the diester with ammonium hydroxide at 0° C for 7 hours. the bisamide. 68a. was isolated in 80%. Lithium aluminum hydride reduction of the bisamide figa. yielded an oil which showed signs of dithiolane ring opening by PMR analysis. Similar results arose from the use of so- dium acyloxyborohydridet49]. Nhen diborane in tetrahydrofu- ran was used at reflux for 8 hours with a 5:1 molar ratio of reducing agent to diamide. an oil was isolated which conta- ined 2~aminomethyl dithiolane. 69b. and the desired bisami- nomethyl dithiolane. 69a. By running this reaction at 0°C for 30 hours. the quantity of side product. fiflfi. was minim- ized. The bisamide. gig. was dehydrated with phosphorus ox— ychloride to yield the novel dithiolane. ZQ. albeit in 7.7% yield. Reduction with various reducing agents caused decom- position of Zfi without isolation of any diamine. 69a. Rather than purify this diamine. it was combined with the cyclizing agent fig.(Figure 28) in ethanol. thereby pre- cipitating the thioketal Zl. in 53%. _. .5 m. —-> (H at “Cad CH5 5 N (5 3 ‘2 " H FIGURE 28: Synthesis of thioketal Zl. The PMR spectrum showed three signals at 63.8(s.S-CH2). 63.4b(br s.NCHZ). and 58.00(br s.NH). The infrared spectrum has a cyano pattern very similar to that of the alcohol. QQ. Hydrolysis of thioketal Z; to the desired ketone was attempted with various reagents; however. most yielded only starting material. The use of mercuric chloride and mercu- ric oxide in methanol or mercuric chloride and cadmium car- bonate in dimethyl sulfoxide at both room temperature and 50°C. returned the ketal. 2;, Chloramine T. ceric ammonium nitrate. N-bromo succinimide in acetonitrile. sodium perio- date. thallium nitrate and magic methyl also gave 1;. while N—chloro succinimide and silver nitrate photolysis afforded no isolable products. The variety of deprotecting methods reflects the difficulties involved in the customary removal of thioketal functions. The use_of a more easily hydrolyzed function such as a ketal. may allow formation of the desired ketone. The diam- inoacetone synthon. Zfi.(Figure 29) is unknown. and several 43 routes toward its synthesis were studied. Initially. sub- stitutions of the . W136: Ex: +5; C ' H3 LZJX :Cl 74C max :0 bx :3 _ _bX :Br FIGURE 29: Attempts toward the synthesis of Zfi. accessible ketal chloride. Zfig. and bromide. zgg. by various nitrogen nucleophiles such as ammonia at high temperature and pressure. ammonium hydroxide and azide ion all yielded only starting materials. It was anticipated that displace- ment of these neopentyl type groups would be slow. In order to reduce the steric hindrance in this substitution. the ethylene ketals of 1.3~dichloroacetone. Zfifi. and 1.3-dibromoacetone. Zfifi. were prepared in 43% and 39% yield. respectively. These. too. were completely unreactive toward ammonia. ammonium hydroxide and azide ion. A new amine syn- thesis utilizing the anion of bisbenzenesulfenimideESO] as a strong nucleophile also failed. The second route to 11 relied upon the successful work in the synthesis of thioketal 92;. A preparationlfil] of the ethylene ketal of diethyl oxomalonate was attained by azeo- tropic removal of water. but was very dependent upon the particular acidic catalyst used. Due to these difficulties 44 and the cost of the starting material. a more convenient. though lower yield method of procuring the diethyl ketal was used. Diethyl malonate was brominated directly to the di- bromide. Z; in 7OZE52]. The ensuing substitution with sodi-- um ethoxide afforded the required ketal. 19. in 16%(Figure 30)[53]. 2&3: 4%? fie" W; " ”a E? no E? t 8 "2 H2 71» 14c 225 225 7:7 E30 N no N _8 FIGURE 30: Second attempt toward synthesis of 15. The use of ammonium hydroxide at 0°C with 19 led to only partial ammonolysis. whereas ammonia in a sealed bomb af~ forded the bisamide 21 in 49% yield. Unfortunately. reduc- tion of this ketal amide as before with lithium aluminum hy- dride. bismethoxyethoxysodio aluminohydride. sodium acyloxy— borohydride. diborane - tetrahydrofuran. and diborane - di- methyl sulfide failed. Expecting that the dinitrile. ZQ. would lead to a more facile reduction. dehydration of 21 was attempted with both acetic anhydride and its trifluoro deri- vative. but” resulted in extensive decomposition of the starting material. 45 The third route toward 13 was designed around a recent convenient synthesis of diaminoacetone dihydrochloride. 57E54]. The synthesis is shown below in Figure 31. and succeeds through four steps from glycine ethyl H2 NHCHO c (HOE H i (:le E 2 E} CIkJET (liar (—..... 5'7 OZHCI 9 (RC 3 g Z9Anch3 R H H R a 3:03 FIGURE 31: Recent synthesis of Q1. ester in 36%. Since quantities of :1 were available. direct neutralization of the hydrochloride and attempts at cycliza- tion were studied under various conditions. None led to the desired ketone. The synthesis of the bisacetamido ketone. Zia. was notedESS]. and this procedure was modified to cre- ate the bistrifluoroacetamido ketone. 22;: It was presumed that either of these compounds could be ketalized. and hy- drolyzed to the corresponding diamine. Ketalization of the highly insoluble 79b was unsuccess- 4e ful in various solvents. However. bisacetamide 79a afforded the ketal QQ in 85% by simple azeotropic water removal in benzene with a catalytic amount of hydrochloric acid(Figure q 3;). This bisacetamido ketal was hydrolyzed to the FIGURE 32: Preparation of diaminoacetone synthon 74b. diamine. 74b. by refluxing in 30% potassium hydroxide for 1 hour. The crude diamine showed a very clean PMR spectrum with three singlets at 63.95(0CH2). 62.72(NCH2). and 61.2(NH2). without further purification. this compound was combined with the cyclizing agent. gg. and yielded a pure white powder. El. and which showed the expected molecular ion in its mass spectra. Its PMR and infrared spectra were also similar to the cyclized alcohol. QQ. and thioketal. Z}. Again. hydrolysis of this ketal. gl. condensation of the ke- tone with malononitrile followed by oxidation. should yield the target molecule. Q. 47 All hydrolytic methods applied to ketal El failed to produce the desired ketone. with various acids. solvents. and temperatures. the starting material was the lone product isolated from the mixtures. When El was heated in dimethyl, sulfoxide~102 hydrochloric acid for 10 hours at 90°. com- plete decomposition into water soluble products occured. It was suspected that the amide—like N-H group in E1 was the cause of failure of these reactions. probably by more favorable coordination with the hydrolytic reagent. Substitution of these hydrogens by alkyl groups would res- trict this coordination and also disallow any tautomeric equilibria. Several methods of acylation were performed on Si. but to no avail. as the starting material was always re- covered. Another synthetic pathway to these alkylated deri- vatives of a; could be envisioned as starting from the bis-N.N’—dialkyl~1.3-diamines. as shown in Figure 33. If the blocking group is labile. e.g. benzyl. perhaps deketal- ization to ketone 3g and condensation to tetracyano compound 3Q could be carried out. Subsequent removal of the blocking group and ring oxidation could then provide the quinone 5. The first point to consider in this scheme is whether the cyclization of the more hindered bis-secondary amines. 2Q. with reagent gg. would be possible. In order to answer 48 SCI—edge: emdgnge: FIGURE 33: Proposed synthesis of Q via dialkyl diamines. this question. diamine a; (Figure 34) was prepared by reduc- E: £13m ESE: s... CQEC FIGURE 34: Synthesis of N.N’-disubstituted piperimidines. tion of bis-amide Zma. The cyclization of a; yielded two products. a; and 33. which were separated by chromatography. The unsymmetrical diamine Si. was isolated in very low yield and arises from reductive cleavage of the acyl group in Zia. when hydrolysis of ketal S3 was attempted by. heating with 10% hydrochloric acid and the ketone Q2 was isolated as 49 white needles in 20Z*30% yield. Under these conditions de- struction of a3 to water soluble products causes the sub- stantial losses. Nevertheless. upon warming the ketone §§ with malononitrile and water in the presence of alanine. the. tetracyano compound. 86. was isolated from a mixture of pro- ducts. albeit. in low yield. Since construction of the desired carbon skeleton is now possible. use of diamines with potentially removable groups was studied. The source of such diamines would be dependent upon the long synthetic scheme to diamino acetoneA.¢HCN ——>A.¢(CN),_ ——->A.cl-I(£:N)z 1 FIGURE 36: 1.2.4.5~Tetrazine analog to TCNQ. Classically. 3.6-disubstituted tetrazines have been prepared by reacting hydrazine with nitriles. imidates. ami- dines. or thioamides as shown in Figure 37(553. These meth- ods would also be inappropriate for formation of Z. as the desired nitrile groups in the sidechain of R would not tol- erate these conditions. Therefore the dicyanomethyl moiety would best be introduced onto the tetrazine ring in one 51 FIGURE 37: Syntheses of 3.6-disubstituted tetrazines. step. or possibly. the tetrazine ring should be cyclized with previously incorporated dicyanomethyl groups. Only the former route will be described here. In 1977. Mangiat57l synthesized 1.2.4.5-tetrazines hav- ing the potential for systematic nucleophilic substitution at both the 3 position and 6 position. . Previously. 1.2.4.5-tetrazines having replacable functionalities at both positions were unknown. His work described the preparation of 3.6 bis—methylthio-1.2.4.5-tetrazine. This tetrazine derivative. 199. can undergo substitution of one methylthio group by hydrazine. Subsequent oxidation in the presence of halide ion affords the halide 19; which can. in turn. be substituted by an appropriate nucleophile: Manzia proposed that the second methylthio group can be dealt with in an an- alogous manner. thus resulting in 3.6 disubstituted deriva~ tives. The preparation of AQQ shown in Figure 38 was also accomplished for the present work. 53 HZWZ ‘ CH3 WI}. r I?" . as 11" H \zcozn . CH3 F0011 HNHZ c O 5%- iO Mi iO CH3 |_Ql CH3 (:3 IQO FIGURE 38: Synthesis of 3.6—bismethylthiotetrazine 100. The proposed synthesis of Z used malononitrile anion as the nucleophilic species in this method(Figure 39). It was r Ncg'eécn N . . as“ I“ 3 < ~ ~ ~ 0:1 193 “I T‘" “ /7 '— “gr'z \CH3 <. D? FIGURE 39: Reaction of 101 with malononitrile. not certain whether the first malononitrile group introduced would be stable toward conditions necessary to replace the second methylthio group. when 3-bromo-6-methylthio—1.2.4.5 tetrazine was reacted with sodiomalononitrile in benzene. a purple powder precipitated from the reaction mixture. This 54 solid ishowed infrared bands at 3400cm-1(water). 2200cm-1. 2160cm-1(CEN). and PMR signals in dimethyl sulfoxide at 52.52(S-CH3) and 63.3(water). Even when the solvent and solid were extensively dried. a signal due to water ap-_ peared. The actual precipitation of this salt would not occur until the system was exposed to water or simply atmos- pheric moisture overnight. Treatment of this violet solid with tetrabutylammonium iodide in warm water precipitated the metathesized organic salt. 103. After recrystallization from ethanol-water. this compound was collected as shiny violet plates. The sodium salt was acidified with 10% hydrochloric acid to yield LQfl as a violet oil. This oil. however. was unstable. and any trace of base immediately returned the salt. 103. The substitution of the second methylthio group has proven to be difficult. due. primarily. to the enhanced a- cidity of $93. Reaction of 19g or $93 with hydrazine failed to give the substitution product. yielding instead. starting material in the first case. and a residue containing the methylthio group in the latter. The use of a protected malononitrile such as t-butyl-malononitrile. failed to yield any substitution product. but did cause decomposition of the ring system... A corresponding substitution with sodio diethylmalonate yielded 105(Figure 40) as a red oil which was isolated by acidification of the reaction mixture and extraction into 1:“! IQI “3 FIGURE 40: Synthesis of diester 10 . ether. The acidic proton in 105 appeared at 65.15 in the PMR spectrum. Further modification of this diester failed to produce isolable compounds. Another possible route to tetrazines might. be through use of 1.1-diamino—2.2-dicyanoethylene. 199(401. Coupling of the nitrogens would yield the tetracyano compound. AQZ (Figure 41) which presumedly could be oxidized to the prod- uct Z. N Hangs. "It?” ——-—> Rik: -‘—>Q’ _2.>=<: " race H2 NC '95’b :19]H _ FIGURE 41: Alternate route toward synthesis of Z. 56 It was thought. at first. that monochlorination of each of the geminal nitrogens in the presence of a tertiary amine base could remove two moles of hydrogen chloride. yielding the condensation product. It was found through various man-y ipulations that the amino groups in L96 are quite non-nucleophilic. due most probably to the predominating re- sonance form. ZQQQ. This compound showed no reaction when combined with thionyl chloride or ethyl chloroformate. al— though n-butyl lithium caused the precipitation of an amor— phous polymer. Nevertheless. chlorination with chlorine gas introduced into a suspension of 106 in acetonitrile at ~20?C. caused dissolution of the solid after several minutes. -Norkup yielded a yellow oil which crystallized to whitish needles. N '93‘Hc1 N N> CHI H? Cl C R Cf IV NC H2 ti 0 cu —-) H :> _44: ‘7 c/"‘\ '96 cNC IOBI. Hz 0 N '99 N FIGURE 42: Chlorination of 106. " The mass spectrum exhibited a molecular ion containing two chlorines at m/e 176 which may correspond to either 108a or 108b(Figure ‘42). The infrared spectrum has bands at 3430cm—1. 3340cm-1. 3220cm-1. 3150cm-1. along with a satu- rated nitrile band at 2252cm~1 and a broad band at 1650cm—1 57 suggesting structure logy. Difficulties in reproducing the initial conditions have arisen. and yields of 193 have been inconsistant. Addition of sodium hydroxide. sodium bicarbo- nate. or even basic alumina to log causes the white solid to‘ dissolve into a bright yellow solution. However. isolation of products from these solutions have failed thus far. Besides intermolecular condensation. intramolecular reaction may be occurring to form $93. This molecule may be stable enough to exist since its main resonance form leads to an aromatic system. V. THIENOE3.2-DJTHIDPHENE NUCLEUS ThienoC3.2-b]thiophenes are aromatic systems similar in many physical and chemical properties to napthalene. Their‘ syntheses have been reviewed recentlyESB] and mainly stem from the thiophene nucleus. However. work on the elabora- tion of sidechains has been quite limited. A recent articleE59J dealing with the synthesis and properties of 2.5-dihydroxy thienoE3.2-blthiophenes. L10. showed that oxi- dation of the corresponding dianion led to solutions of stable radical anions (Figure 43). With this in mind. we attempted to synthesize quinone Q. an analog of tetracyano- napthaquinodimethane. TNAP. N \ . N I) NaOH ° _ _ <99“ —+ °<<>E>3 .336» FIGURE 43: Known radical anion of thienothiophene system. In previous work the dicyanomethyl group has been in- corporated onto a thiophene ring by a peculiar condensation of 2.5edibromothiophene with tetracyano ethylene oxide as in Figure 44(60]. This reaction yielded only starting material when repeated with 2.5—dibromothienoE3.2-thhiophene. All attempts at ‘the direct substitution of bromine in Zia with sodio malononitrile also failed. 58 59 NC N 3.10%. + m Preparation of thiophene analog to TCNG. FIGURE 44: which reflects the high electron density of these rings use of a classical The synthetic approach to a made route that had been utilized in the synthesis of TNAP. 120(Figure 45).[61] should Reduction of the 2.5 dialdehyde. 131 which through halogenation and substi- yield the diol. ;&_. [Tl CIC woo? "302%" H H .. O 3 __)~ ,54—9 5. FIGURE 45: Classical route to tetracyanoquinones. 6O tution by cyanide ion would yield the bis-acetonitrile. leg. Carboalkoxylation of 12 . ammonolysis to the amide. and dehydration of this amide. possibly would provide the tetra- cyano compound a. The standard preparation of the parent ring system. thieno[3.2-blthiophene. ZZZ. an important intermediate for further functionalization. is shown in Figure 46(623. <33" {CT —-> @557?“ l_l_2 we... Qfi‘w‘ “we | |_ 5 \ |_l_6 ”-4 . m U] FIGURE 46: Preparation of thienoE3.2-b]thiophene. Several problems arose when this procedure was repeated in large quantities. First. the separation of ester 1;; and aldehyde iii through fractional distillation is rarely com- plete. Analysis of the reaction mixtures were performed by thin layer chromatography on silica gel. The subsequent cyclization reaction leading to acid 115. allowed retrieval of this product in a pure state. without traces of either 61 112. 113. or 114. Therefore. for large scale preparations.the intermediate products were used directly to prepare acid 11; without further purification. Secondly. the cyclization to the acid 115 was accompan- ied by hydrolysis of the ester 113 to yield the open chain acid 116. These acids are separated by initial acidifica- tion to pH 5. precipitating the cyclized acid. 115. Further addition of hydrochloric acid affords the side product. 116. This thiophene acid. however. can be recycled to the ester by using methyl iodide and sodium bicarbonate stirred in di- methyl acetamide. In this way. the ester 113. is produced in 94%. The decarboxylation of 112 and brominationt63] are done without purifying the parent compound. 11Z. and in 83% yield(Figure 47). The dialdehyde. 129. has recently been synthesized in two steps from the dibromide. 11g. Combination of 11s with two moles of n~butyl lithium pro— vides 2.5-dilithio thienot3.2~blthiophene. 112. which gives the dialdehyde when reacted with dimethyl formamide. This highly insoluble dialdehyde was reduced with lithium alumi- num hydride to yield the diol. 121. as light tan flakes in 77%. Compound 123 was also prepared in lower yield directly from the dianion 119. by quenching with paraformaldehyde. Although this latter method involved fewer steps. it was not 62 as efficient or reproducible as the former route. so Ne» Boo» Ll" '18 VLnBuLI meow w woo» I_2..0 W“ ch0 H9 H0 HZC Q ”20“ FIGURE 47: Preparation of diol 121. The tedious synthesis of the diol. 1 1. could be shor- tened if direct functionalization of the acid 11:. could be attained. Treatment of this acid with two moles of base to form its dianion. 122 (Figure 48). could be followed by ad- dition of carbon dioxide. esterification of this diacid and reduction. affording the dial 121. It was found that upon addition of two moles of lithium diisopropylamide to acid (Dad 735(1)“? €02“ me‘?“ l_l5 .. ZL122 . 7:23AM BR-C C R=E1H3 FIGURE 48: Preparation of diacid 123a. 63 H 15 at ~78°C. followed by warming to -10° C and quenching E ith carbon dioxide. the diacid. 1222. was prepared in 73% yield. Quantitative esterification to the diester. 1221. with diazomethane succeeded as did lithium aluminum hydride‘ reduction to afford the diol. 121. in 80%. This demon- strates a new and convenient method of functionalizing the thienothiophene ring system. The 2.5-bis(chloromethyl) thienoE3.2-b]thiophene. 1242. was prepared from dial 121 with thionyl chloride and pyri- dine in 96%(Figure 49). when sodium cyanide in aqueous ace- tone was used to make the dicyanide. 125. only a 7% yield woos FIGURE 49: Preparation of bis-acetonitrile 125 was produced. Using dimethyl sulfoxide led to a higher yield of 16%. when potassium cyanide in methanol was used. a 53% yield of 2.5~dimethoxymethyl thieno[3.2-thhiophene. pa 2 . resulted with no trace of 125. Upon checking the lit- erature for analogous disubstituted systems. this bis-benzylic displacement was found to be of only fair or 64 poor yield. In the case of TNAP. the published result in dimethyl sulfoxide is 8%[64]. Changing the solvent to meth- anol in that case gave 25% of the product. It is possible that the cyanide ion may be acting as a base to deprotonate_ the product or may Just be less reactive under such polar conditions. The preparation of tetraethylammonium cyanide. TEACN. by the metathesis of potassium cyanide and tetraethyl fluo~ roborate was employed as previously describedC65]. TEACN is soluble in methylene chloride. as is the dichloride 123a. Addition of 1242 to a solution of TEACN led to rapid darken- ing of the mixture and production of product 122 in at most 26% yield after chromatography. p... By changing the leaving group to bromide as in 24b lH through the use of phosphorus tribromide on the dial 1 H approximately the same yield of 12; was acquired. Since the bis-bromide was less stable than the corresponding chloro derivative. no advantage was to be gained through this meth- od. An attempt to prepare the iodide via trimethyl silyl iodide led to the isolation of a product which darkened on exposure to moisture and decomposed while eluting on silica gel. Reaction of a solution of this bis—iodide led to 125. but in very. low yield. Tosylation and mesylation of the diol was attempted by utilizing the respective sulphonyl 65 chlorides and pyridine. but isolation of these reactive ma- terials was not successful. Other indirect methods of preparing bis-acetonitrileA groups were investigated. A classical method toward this end is the Erlenmeyer azalactone synthesis(Figure 50). In this H 0R . ”2 + RCHO ———> 0"-ng7.« R=CH3 “META. a :1:ch M20 R'CHZCN (312$ R'CHzgcozl-l FIGURE 50: Erlenmeyer azalactone synthesis. process. an aldehyde is condensed with aceturic acid. 12Z§XFigure 50. R= CH3). or hippuric acid. 12Z9(R= phenyl) to afford the azalactone. Initial hydrolysis with base fol— lowed by treatment with acid produces the fl-keto acid. These derivatives are known to yield acetonitriles when warmed in the presence of aqueous hydroxylaminet66]. Other variations include the use of rhodanine which can be treated as aceturic acid had been to yield the productE67J. Only one report of these methods dealt with an aryl dialdehyde. terephthaldehyde. though its hydrolysis or any further reac— tions were not reported. When the dialdehyde 129 was heated with acetic anhydride and aceturic acid.(Figure 51) an ex- 66 tremely insoluble red product was isolated which exhibited molecular ion peaks in its mass spectrum for the monoazalac- tone and bis-azalactone. 129. Similar results accompanied the exper- iments employing rhodanine as the homologating agent. Presumedly. the mono-cyclized product was so insoluble that further reaction was unlikely. Both these methods worked well for thiophene producing a fair yield of thienyl aceto- nitrile in two steps from 2-thiophene carboxaldehyde. A new method of preparing homologated nitriles from ke- tones and some aldehydes was reported recentlyE68]. It dealt with the use of toluenesulfonylmethyl isocyanide. TOSMIC. as the condensing agent with carbonyls to yield the tosylalkenylformamides. Upon treatment with sodium in meth- anol. these compounds undergo a rearrangement to the aceto- nitriles. as shown in Figure 52E69I. Again. no examples of difunctional molecules were reported. Thiophene gave 75% of 129 when treated with TOSMIC and potassium t-butoxide in tetrahydrofuran. Terephthaldehyde was also used as a model 67 0 system and yielded 68% of the bis-amide. Treatment of 12_ under the same conditions. led mainly to the recovery of starting material. HCHO RCHO + (:2: —-—> RC —->RCH,_CN 9] _2_9 HCHO [go FIGURE 52: Recent synthesis of arylacetonitriles. When a mixture of dimethyl sulfoxide and tetrahydrofuran was used as the solvents. terephthaldehyde gave 84% of the bis-amide. and the dialdehyde. 129. yielded only one pro- duct. its corresponding bis-amide. 199. in 77% yield. Rearrangement of 129 under basic conditions. followed by pu- rification. led to 14.5% yield of the desired dicyanide. 129. This quantity could not be increased by varying condi- tions of either step. Since this was. in total. less effi- cient than the previous reduction. halogenation. cyanation sequence. further application of this potentially useful re- action was regected. The addition of a carboxy group to of 1 5 results in 68 the bis-cyanoester. 1 1 (Figure 53). being produced in 72% m Mm. :le "tom? |25 FIGURE 53: Attempted ammonolysis of ester 131. yield. The ammonolysis of 131 with ammonium hydroxide at room temperature or liquid ammonia at 0°C. on workup mainly returns starting material. It is thought that the cyanoes- ter 131. may be more acidic than its benzene or napthalene analogs. The greater pKa would stabilize the resultant anion and thus. slow attack of ammonia upon the ester carbo- nyl. This could also explain lower yields due to side prod- ucts in the use of cyanide ion as a nucleophile. Nevertheless. in order to proceed on the synthetic route toward 9. an alternate method designed by Wheland and Martin at du Pont was usedElOJ. Rather than transform the carboethoxy group into a cyano group. the method obtains the conJugate base of the cyanoester(See Figure 36). and cyan- ates with cyanogen chloride. Thus. in a stepwise manner. a protected malononitrile group has been prepared. The pro- cess continues with the aqueous base hydrolysis of the ester and acidification. to release carbon dioxide and obtain the aryl malononitrile. Oxidation in situ is normally used to directly provide the quinone. 8. Cyanation of ester 131 has 69 led to the dicyano acetate 122 in low yield. Purification of this compound has been complicated by its reactivity with various chromatographic supports. The crude 122 was com- bined without further purification with aqueous base yield- ing a highly fluorescent solution after dissolution of the solid 122 with heat. Acidification of this mixture in order to isolate 122 (Figure 54). or direct oxidation of the acid- ified solution to yield 2 has failed. Only highly £102 coze ctozc (1028 l_2_5 -——9 Ne cu moE “We" 8 ISI "C " " —- I92 FIGURE 54: Synthesis of diester l 2. insoluble products have been obtained from the. fluorescent solutions. This fluorescence fades upon standing overnight at room temperature. and the solids which precipitate have not yet been successfully characterized. Access to the dialdehyde 120 encouraged efforts toward the synthesis of derivatives of TTF with extended a frameworks. e.g. 134(Figure 55). The availability of 3.4- dimercaptotoluene 135. promoted its use in our work. .. meager . FIGURE 55: Synthetic target system of thienothiophene. 70 Upon refluxing 129 in benzene with two moles of 122. and a catalytic amount of toluenesulfonic acid. there precipitates a tan solid whose mass spectrum exhibits a molecular ion peak at m/e 472. corresponding to the bis-dithiole. 136(Figure 56). However. when 1.2 dimercaptobenzene. 137. was used in “3.: + ohcmcm ". —> © 5 I35 IZO “‘3 © FIGURE 56: Synthesis of bis(methylbenzo)dithiole 140. m this same way only the mono benzdithiole. 122. was isolated in low yield (Figure 57). Either the insolubility of 122 or the lower stability of the dithiol may have caused this loss in yield. Changing the reaction conditions by stirring the dithiol 122 in ethanol. saturated with hydrogen chloride at room temperature. led to a 73% yield of 122 being produced. No trace of the oxidized product 159 or of any disulfides was present from PMR and mass spectral 71 I_2_o + 0::__> W I37 \ awn 0 22:25 0 S 5 MI FIGURE 57: Synthesis of bis-benzodithiole 141. analysis. Application of these same conditions to the un- stable dithiol. 1_Z. led to a 62% yield of 122. When 122 and 122 was treated with a solution of dichlo- ro dicyano quinone in tetrahydrofuran. dark solids precipi- tated and show molecular ions at m/e 470 and m/e 442 agree- ing with that expected of the oxidized products. 139 and _11. Unfortunately. most of the product consists of very insoluble and non~volatile compounds which may be the charge transfer complexes of 199 and 141 with DDG. VI. PYRIDAZINOE4.5*dJPYRIDAZINE NUCLEUS As shown in Table I. the napthalene bis disulfide. _A_ (Figure 58) forms a highly conducting complex with TCNG. The substitution of heteroatoms in this ring system as in 19 may result in equally interesting electronic properties. We ‘—_5 00 IO 0' N S__—S '15 IO FIGURE 58: TTN. 145. and proposed analog. 19. attempted to synthesize 19 since it should be quite accessi- ble from the known tetrachloro compound. 144. prepared as shown below (Figure 59)[71]. 025: e c 5' EtOZC‘ toza CI l zoo <11 ..C cu I-’-_I_4 FIGURE 59: Tetrachloro-tetra—azanapthalene. 144. 72 73 Since positions a to an aromatic nitrogen as in 195 are easily functionalized. the synthesis of 19 should be less arduous than that of the carbocyclic system. Numerous meth- ods of introducing sulfur to these positions are present in» the literature. Furthermore. thiol sulfurs that are posi- tioned peri to each other have been shown to be easily oxi- dized to the cyclic disulfide. From initial experiments. 112 was found to be quite reactive toward nucleophiles. Displacement of one chlorine by a hydroxy group had been found to occur while it was stirred with aqueous sodium car- bonate at room temperature. Fusion of 1&9 with sulfur using conditions similar to preparations of 1_2 failed to give any 19. In fact.-treat- ing 191 with sulfur in various nucleophilic forms. KSH or dipotassium sulfide. 132. and even potassium ethylxanthate. 147. or potassium thiolacetic acid yielded insoluble red—brown powders (Figure 60). The mass spectra of these CI Cl JE'g-Eli) RS SR N N LO Q g Lg. RZK.0I' H Cl C C O . '14 We R SR FIGURE 60: Attempts at sulfur incorporation of 134. samples often exhibited a molecular ion at m/e 256. 74 Although this is the correct weight for 19. it is also that for elemental sulfur. All samples were washed with exces- sive amounts of carbon disulfide to extract out any sulfu- rous residues. however. this did not change the spectral re-_ sults. Identification through the study of the fragmenta- tion ions is complicated by the coincidental weight of m/e 128 for the desulfurated ring nucleus of 19 and 84. an im- portant fragment of sulfur itself. A recent method involving the in situ production of a dilithio disulfide species in the absence of larger sulfur fragments was also used with 144 (Figure 61). A stoichime- tric amount of sulfur FIGURE 61: Attempted synthesis of 19. and of lithium triethylborohydride in tetrahydrofuran were mixed together yielding a clear solution of 148. However. when this solution was added to 144. a resinous product re- sulted which. after chromatography. showed a large fragment ion for ethyl in its mass spectrum. Treatment of the known tetramethoxy 149. or tetrahy- droxy compounds 150 (Figure 62). with phosphorus pentasul- 75 fide under various conditions gave products displaying sul- fur-containing mass spectra after washing with water. FIGURE 62: Oxygen derivatives of 144. hot carbon disulfide and ether. When 199 was reacted with thiourea similar intractable products were obtained. These reactions took place immediately. and the solution darkened long before all reagent was added. In most cases. no start- ing material could be recovered. If the problem was one of the initially formed mercap- tide ion. 151 (Figure 63). undergoing an intermolecular sub- stitution. then utilizing a protected sulfur nucleophile '59 Cl N ' O N CI CI FIGURE 63: Possible intermediate from sulfurization of 1_1. would obstruct this side reaction. Although potassium thio- cyanate in ethanol was used with 144 under various condi- 76 tions. it failed to produce the tetrasubstituted compound. It has been shown in the 3.6-dichloropyridazine systemt72] that that only one thiocyanate group will substitute on the ring. The protection of protein thiol groups has gained im- portance recently. and studies in this field have utilized a number of compounds that 1) can act as a protected sulfur nucleophile. and 2) after substitution. allow facile removal of this groupE733. One of the more well known protected thiols is t-butyl mercaptan. When this thiol is mixed with potassium hydroxide in ethanol and reacted with 1_1. there resulted a bright yellow compound. 12_. in 48%(Figure 64). Mass spectral analysis 0 '1 e416: E©©I A; >300°i IR (NUJol): 2200. 2160. 2125. 1620. B75; ~PMR (DMSD): 6.75 (d. 2H). 7.8 (d. 2H). Anal. Calcd For 11: C. 53.86; H. 1.643 N. 28.55: Found: C. 54.055 H. 1.675 N. 29.04. 85 4-Ethoxypyridine l-dicyanomethulide (18) Sodium (0.159. 6.52 mmoles) is added to absolute etha- nol (10ml). and once dissolved. 16 (0.579. 3.22 mmoles) is added all at once. The solution is stirred For 2 hours at room temperature. The reaction mixture is then Filtered and the mother liquor is evaporated to a yellow brown solid. Recrystallization of this solid with ethanol yields 0.269 (43%) of 18: mp 145°; IR (NUJol): 2190. 2150. 1030. 8003 PMR (ChloroForm): 1.44 (tr. 3H). 4.17 (q. 2H). 7.0 (d. 2H). 8,23 (d. 2H); MS: m/e = 187 (parent). 4-t-Butyldicuanomethulpuridine 1-dicuanomethylige 1121 To sodium hydride (0.29. 50% in mineral oil. 4.16 mmoles) is added dry ether (10ml) under nitrogen. To this stirred suspension is added t-butylmalononitrile (0.29. 1.64mmoles) in dry ether (5ml). It is allowed to stir at room temperature For 1 hour. All at once. 16 (0.2289. 1.29 mmoles) is added. and the mixture is stirred overnight. Excess sodium hydride is decomposed by cautious addition of water. and the solution is tiltered. The bright yellow solid is rinsed with cold ether and vacuum, dried to give 0.279 (81%) o? 19: mp 218°; IR (NUJol) :. 2200. 2160. 860; PMR (DMSO): 1.15 (s. 9H). 7.65 (d. 2H). 8.38 (d. 2H); M8: m/e = 263 (parent). 86 4-Bis(ethoxycgrbonul)methylpyridine 1—dic9gnomgthulidg 1291 Sodium (0.0169. 0.7 mmoles) is dissolved in absolute ethanol (3ml). Diethyl malonate (0.059. 0.34mmoles) is dis— solved in ethanol (lml). and this solution is added all at, once to the basic solution. The mixture is stirred at room temperature for 5 minutes and then 19 (0.0609. 0.34 mmoles) in THF (5ml) is added. After 1 hour. the ethanol is evapo- rated. and ether and 5% sodium hydroxide are added to dis- solve all solids. The ethereal layer is extracted twice with 5% sodium hydroxide (5ml). and the aqueous layers are separated. combined and acidified with 5% hydrochloric acid at which point a light yellow solid precipitates. This solid is collected by filtration. and the acidic aqueous layer is extracted twice with ether. Evaporation of the solvent leaves a solid which. combined with the previous solid. can be recrystallized from ethanol yielding 42.6mg (41%) of 99: mp l73-174°; IR (NUJ01)2 2200. 2160. 1740. 1160. 1045; PMR (chloroform): 1.15 (tr. 6H). 4.08 (q. 4H). 4.62 (s. 1H). 7.6 (d. 2H). 8.38 (d. 2H); MS: m/e = 301 (parent). 4-Aminop9ridine l-dicggnomethylide To concentrated ammonium hydroxide solution (1.62ml of 58%) is added 99 (0.04269. 0.14 mmoles) and this mixture is warmed on a steam bath for 1.5 hours. water is added to the cooled solution. and the precipitated solid is filtered. 87 More solid can be attained by ether extraction of the aque- ous layer: IR (NUJol): 3250. 2260. 2180. 16255 PMR (chlo- roform): 2.52 (s. 2H). 7.3 (d. 2H). 8.32 (d. 2H). ms: m/e = 158 (parent). 3-Dicyanomethul-6—chloropyridgzine 12991 To a suspension of sodium hydride (3.89. 50% in mineral oil. 0.079 moles) in dry THF (150ml). malononitrile (5.29. 0.079 moles) in THF (50ml) is added dropwise with stirring under nitrogen at room temperature. To this white suspen- sion is quickly added 3.6-dichloropyridazine (59. 0.0335 moles) in THF (75ml). The mixture is refluxed overnight. cooled. and the solvent is evaporated. The solid is tritu- rated with ether and collected by filtration.. Dissolution of this solid in water (200ml) with stirring gives a solu- tion that is filtered. acidified with concentrated hydro- chloric acid. and refiltered. This filtered solid is washed several times with water and is vacuum dried yielding 4.229 (71%): mp 258°; IR (NUJol): 3050. 2225. 2180. 1610. 1560. 1255. 1020. 820; PMR (DMSO): 7.45 (s. 2H). 13.3 (br s. 1H). MS: m/e = 178 (parent). ng—Methyl-3~dicyéflomethulene-6-chloropuridazing 1291 To a stirred suspension of sodium hydride (0.1359. 50% in mineral oil. 2.8 mmoles) in THF (10ml). is added 23a 88 (0.59. 2.8 mmoles) as a solid at room temperature under ni- trogen. The mixture is refluxed 0.5 hours and cooled in ice while triethyloxonium fluoroborate (0.419. 2.8 mmoles) dis- solved in THF (70ml) is added dropwise. The ice bath is re- moved. and the reaction is stirred overnight. The solvent is evaporated. water added. and the remaining solid is fil- tered. triturated with ether and refiltered leaving 0.22g (41%) of 99: mp 142—142.5°i IR (NUJOI): 3100. 2201. 16255 PMR (chloroform): 4.15 (s. 3H). 6.9 (d. 1H). 7.46 (d. 1H): MS: m/e = 192 (parent). 3.6-Bis-(t~butyldicygnomgthyl)pyridézing 1991 To a suspension of potassium hydride (4.29. 25% in min- eral oil. 0.027 moles) in THF (25ml). is added dropwise a solution of t-butyl malononitrile (3.39. 0.027 moles) in THF (25ml). After the initial reaction is over. the mixture is stirred until the evolution of hydrogen has quelled. At this point. 3.6-dichloropyridazine (29. 0.0134 moles) in THF (20ml) is added quickly. and the mixture is refluxed for 60 hours. Afterwards. the solvent is evaporated. and water is cautiously added. The aqueous mixture is extracted with chloroform until it extracts no more color. Evaporation of the solvent gives a dark brown solid. Column chromatography of this solid on neutral alumina with chloroform yields a solid which can be recrystallized from ethanol. 1.359 (31%): mp 22l-222°i IR (NUJol): 2245. 1415. 1175. 940; 89 PMR (chloroform): 1.27 (s. 9H). 7.84 (s. 1H) 3 HS: m/e = 264 (parent - isobutylene). 3.6-Bis-(methylsulfonul)pyridgline (30) Chlorine gas was slowly entered into a solution of 3.6-bis-(methylthio)pyridazine (7.49. 8.14 mmoles) in metha- nol (140ml) and water (0.6ml) cooled to -5°. A white pre- cipitate gradually forms. After 25 minutes. the mixture is cooled to -20°. and the solid is collected by filtration giving 1.59 (832) of 39: mp 250°. IR (NUJol): 3100. 3030. 3005. 1550. 1310. 852i PMR (DMSD): 3.53 (s. 3H). 8.5 (s. 1H); MS: m/e = 236 (parent). 3-Dicy9nomethul-6~t*butuldicygnomethglpurid911ng 1911 To a solution of refluxing phenyl ether (20ml) is added all at once. 99.(0.2g. 0.625 moles). After 5 minutes. the solution is cooled to room temperature. The reaction mix- ture is treated with 5% sodium bicarbonate. and these aque- ous solutions are extracted several times with ether to re- move the residual phenyl ether. Acidification of this aque- ous layer with 5% hydrochloric acid precipitates a solid which is collected by filtration and washed thoroughly with water. After drying in a vacuum for several hours. there remains 0.19' (61%) 31: mp 235-24o°. IR (NUJol): 3150. 2201: 21751 15401 1585! 8053 PMR (CthT‘O‘FOT‘M): 1. 27 (5! 9O 9H). 7.12 (s. 2H). 7.45 (s. 1H); MS: m/e = 264 (parent). Phegglthiomélononitrile (39) Sodium hydride (0.3649. 50% in mineral oil. 7.6 mmoles) is suspended in THF (10ml) and to this ice cooled solution is added malononitrile (0.59. 7.6 mmoles) dissolved in THF (5ml). After evolution of hydrogen is complete. the mixture is warmed to room temperature and pipetted with an eye dropper into a stirred solution of phenyl toluenethiosulfon- ate (29. 7.6 mmoles) in THF (100ml). As the anion adds. a dense white precipitate forms. The thick suspension is stirred overnight. and the solvent is evaporated. Water is added and the mixture is extracted three times with ether. The organic solution is dried over sodium sulfate and evapo- rated to an oil which crystallizes on standing to yield 30% of 99. All spectral data concur with literature valuest38].. n-Butul toluenethiolsulfongfig 1911 Silver nitrate (2.169. 12.7 mmoles) is dissolved in water (10ml). n-Butyl disulfide (1.889. 10.5 mmoles) is dissolved in acetone (30ml). and this solution is combined with the aqueous solution. The mixture is stirred at room temperature ‘in an open flask. Sodium toluenesulfinate (2.079. 11.7 mmoles) is added as a solid to the stirred mix- 91 ture and immediately creates a thick precipitate. The mix- ture is stirred for 2 hours. filtered. and the inorganic solids are washed with acetone. The mother liquor and ace- tone are concentrated. and the remaining slush is extracted three times with ether. This organic solution is dried over sodium sulfate and the solvent is evaporated. The crude oil is flash chromatographed on silica gel with methylene chlo- ride yielding 1.549 (51%) of 91: IR (Neat): 2950. 1600. 1350. 1140. 812. PMR (chloroform): 0.33 (tr. 3H). 1.42 (m. 4H). 2.4 (s. 2H). 2.9 (tr. 2H). 7.13 (d. 2H). 7.62 (d. 2H); MS: m/e = 260 (parent). fignzyl toluenethiolsulfon919 1991 The same procedure was used as that shown above for 91. Using silver nitrate (10.49. 0.061 moles). benzyl disulfide (12.39. 0.05 moles) in acetone (200ml) and water (75ml) to- gether with sodium thiolsulfinate (109. 0.056 moles) yielded 12.49 (89%) of 19. The crude material can be purified by flash chromatography on silica gel using pet etherzethyl acetate. 3:1. as the eluent: mp 56-57°i IR (NUJOI): 1590. 1325. 1135. 700; PMR (chloroform): 2.36 (s. 3H). 4.15 (s. 2H). 7.05 (s. 5H). 7.1 (d. 2H). 7.55 (d. 2H); MS: m/e = 278 (parent). Benzulthiomélononitrile (49) 92 Malononitrile (2.379. 0.036 moles) dissolved in THF (10ml) is added to a suspension of sodium hydride (1.759. 50% in mineral oil. 0 036 moles) in THF (20ml) cooled by an ice bath. After evolution of the hydrogen had ceased. an eyedropper was used to add the anion dropwise into a solu- tion of 99 in THF (200ml). As it adds. a dense white pre- cipitate forms. and after stirring at room temperature for 1 hour. the solid is filtered and washed with ether. The or- ganic solvents are evaporated to a moist solid that is col- lected by filtration with pentane. The crude solid is flash chromatographed over silica gel with methylene chloride yielding 2.7g (40%) of 99: mp 66-69°f IR (NUJol): 2275. 1180. 1020; PMR (chloroform): 4.06 (s. 2H). 4.12 (s. 1H). 7.12 (s. 5H); MS: m/e = 188 (parent). 2-D19999omethyl-3.5—dihydroxu—4-methylpggim1919e 19991 A solution of sodium ethoxide is prepared by dissolving sodium (0.1679. 7.26 mmoles) in ethanol (25ml). To this so- lution is added diethyl methylmalonate (1.219. 6.95 mmoles) and 1.1-diamino-2.2-dicyanoethylenet40] (0.759. 6.95 mmoles). The mixture is refluxed for 2.5 hours and precipi- tates a white solid. This solid is collected by filtration and dried by washing with ether. The solid is dissolved in water and acidified. precipitating a white solid that was collected by filtraytion and washed with water. After dry- ing in vacuum there was given 0.219 (16%) of SOD: mp 300°; 93 IR (NUJ01)Z 3530. 3460. 2235. 2220. 1750. PMR (DMSO): 1.7 (s). other signals are very broad due to solvent. MS: m/e = 190 (parent). 9+Dicy9nomethyl-3.5-dihydroxy-4-phen91purimiding 19991 The same procedure was used as for 999. In this way 1.1-diamino-2.a~dicyano ethylene (0 59. 4.6 mmoles). diethyl phenylmalonate (1.19. 4.6 mmoles) were added to sodium (0.119. 4.6 mmoles) in ethanol resulting in 0.39 (26%) of 50c: mp 250°. IR (NUJol): 3375. 3ooo. 2225. 2200. 1550. PMR (DMSO): 7.2 (s. 5H). 11.17 (s. 3H). other signals are very broad due to solvent; MS: m/e = 252 (parent). 9:91999nomethylene piperimidine (55) To a warm solution of 1.1-bismethylmercapto 2.2-dicyanoethylene. 99. (19. 5.88 mmoles) in ethanol (50ml). is added 1.3-diaminopropane (0.4359. 5.88mmoles) in ethanol (10ml) dropwise with stirring. The mixture is stirred for 0.5 hour and cooled before filtering the precip- itated solid. This solid is washed with ether to dryness to yield 0.79 (81%) of 99: mp 300°. IR (NUJol): 3290. 2190. 2160. 1585. 1200; PMR (DMSD): 1.79 (p. 2H). 3.2 (tr. 4H). 7.5 (br s. 2H); MS: m/e = 148 (parent). 5—Hydroxy-2-dicggnomethulene piperimigine (60) 94 A solution of 1.3-diamino-2—propanol (0.59. 5.55 mmoles) in ethanol (25ml) is stirred at room temperature. To this solution is added an equimolar amount of 99 or dicy- anoketene ethylene acetal. 99E40]. either in solution or as solids. The respective mixtures are refluxed for 2 hours and allowed to cool slightly before the precipitated solids are collected by filtration. This solid is washed to dry- ness with ether giving 0.749 (81%) of 99: mp 267°. IR (NUJol): 3300. 3050. 2205. 2170. 1601. 1580. 12001 PMR (DMSD): 3.15 (br s. 4H). 3.9 (p. 1H). 5.15 (br s. 1H). 7.4 (br s. 2H). MS: m/e = 164 (parent). 999199§nomethylene piperimidine-S-mesu1919 1911 A solution of 99 (19. 6.1 mmoles) in pyridine (15ml) is stirred at 0° while methanesulfonyl chloride (0.6959. 6.1 mmoles) is added dropwise. The mixture is stirred for two hours before quenching with water. The precipitated solid is washed with water and vacuum dried to yield 1.49 (95%) of 91: mp 240°. IR (NUJol): 3230. 3045. 2200. 2170. 1630. 1590. 1350. 930. PMR (DMSO): 3.28 (s. 3H). 3.42 (br s. 4H). 5.1 (br s. 1H). 7.7 (br s. 2H); MS: m/e = 242 (par- ent). 2-DiC9gnomethylene giperimidine-S—tosylate (62) A solution of 99 (0.59. 3.05 mmoles) in pyridine (10ml) 95 is cooled to 0°and stirred while toluenesulfonyl chloride (0.589. 3.05 mmoles) is added as a solid over several mi- nutes. After stirring for 1 hour. the yellow mixture is evaporated and combined with water and ether. Some suspend- ed solid is filtered from these layers. and the organic layer is then separated. The aqueous layer is extracted twice with ether. The organic layers are combined and eva- porated to an oil which is crystallized by addition of a small amount of water. The white crystalline solid is dried in a vacuum overnight: mp 230°; IR (NUJol): 3275. 2220. 2200. 1630. 1600. 1155. MS: m/e = 318 (parent). 5-Trimethylsiloxy-2-dic9999methy1999 piperimiding 1991 A solution of 99 (0.59. 3.05 mmoles) in pyridine. (5ml) is stirred at room temperature while trimethylsilyl chloride (0.339. 3.05 mmoles) is added dropwise. After 1 hour. the mixture was evaporated. and the residue was warmed with chloroform. Undissolved solids are filtered. and the mother liquor is combined with pet ether and cooled in order to precipitate the product: mp 265~267°i IR (NUJol): 3300. 2200. 2165. 1620. 1600. 1200. 875. PMR (DMSD): 0.17 (s. 9H). 3.2 (m. 4H). 4.2 (br s. 1H). 7.45 (br s. 2H). HS: m/e = 236 (parent). 9;Dicy9nomethul-(3H.4H)-dihydronurimidin9 (65) 96 Into a flask chilled to 0°and protected by a drying tube. is charged 99 (0.419. 2.5 mmoles) and pyridine (3.5ml). To this stirred solution is added trifluoromethan- esulfonyl anhydride (0.719. 2.5 mmoles) dropwise. The yel-r low suspension is stirred for 3 hours at room temperature before quenching with water (40ml). The precipitated solid is collected by filtration and washed with water and rinsed dry with ether yielding 0.159 (41%) of 99: mp 285-289°i IR (NUJol): 3290. 3075. 2220. 2190. 1700. 1680. 1225; PMR (DMSO): 3.78 (m. 2H). 4.9 (m. 1H). 5.97 (m. 1H). 7.7 (br s. 1H). 9.0 (br s. 1H). MS: m/e = 146 (parent). 9197Dicgrboethoxu 1.3-dith101999 1911 Ethylene dithiolsulfonate (39. 7.46 mmoles). diethyl malonate (1.259. 7.81 mmoles). and potassium acetate (29. 20.2 mmoles) are combined and refluxed in ethanol (50ml) for 6 hours. The ethanol is evaporated and the oily solid is extracted into ether. The organic layer is washed once with 10% sodium carbonate. and once with saturated sodium chlo- ride solution. After drying with sodium sulfate. evapora- tion of the solvent leaves an oil that is of adequate purity for further reactions. 1.869 (95%): IR (Neat): 2980. 1740. 1230. 1030. 'RMR (chloroform): 1.33 (tr. 3H). 3.45 (s. 2H). 4.27 (q. 2H); MS: m/e = 250 (parent). 97 2.2-Biscarbamoyl 1.3-dithio1999 19991 A solution of 91 (3.19. 12.4 mmoles) in the minimum a- mount of ether is poured into concentrated ammonium hydrox- ide (50ml) at 0°. The mixture is vigorously stirred at this temperature for 1 hour. then allowed to warm to room temper- ature for 4 hours. The white solid is filtered and rinsed dry with ether. The mother liquor is evaporated to leave a residue which contains a 50:50 mixture of the product diam- ide and the side product. 2-carbam0y1 1.3-dithiolane. Total yield of product 999_is 1.9g (80%): mp 247°. IR (NUJol): 3400. 3200. 1650. 1350. PMR (DMSO): 3.25 (s. 4H). 7.26 (br s. 4H). MS: m/e = 192 (parent). 2.2-Bis(9minomethyl)-1.3-dithiolane dihydrochlorjdg (6992 Diborane:tetrahydrofuran complex (43.5ml of 0.94" solu- tion. 41 mmoles) is stirred under nitrogen at 0°while 999 (1.579. 8.12 mmoles) is added as a solid. The mixture is stirred at room temperature for 24 hours. The recooled so- lution is quenched with 10% hydrochloric acid (6.6ml). and the solvents are evaporated to a slush. With cooling. water (5ml) is first added followed by several pellets of potassi- um hydroxide. making the mixture alkaline. The basic aque- ous layer is then extracted three times with chloroform. and this organic_ solution is dried over sodium sulfate. The oily diamine can be used for further reactions by evapora- tion of the solvent. Isolation of the dihydrochloride salt 98 can be accomplished by entering dry hydrogen chloride into the cooled chloroform solution. Filtration of the solid and regassing of the clear mother liquor is repeated until no further solid precipitates. This method yields 0.959 (50%) of 999:2HCl : mp>300°. IR (NUJol): 3000. 2100. 1585. 1050. 970. PMR (chloroform): 2.18 (s. 4H). 2.88 (s. 4H). 3.21 (s. 4H). 19:0icy9no-1.3—dithiolane (70) "U Acetamide (1.049. 17.6 mmoles) and 999 (0.89. 4.2 mmoles) are combined with phosphorus oxychloride (2m1) and refluxed for 2 hours. The dark tarry mixture is cooled. and some ice is cautiously added until all solids dissolve. This mixture is extracted three times with ether. and the organic layer is. in turn. washed with water and dried over sodium sulfate. Evaporation of the solvent leaves an orange oil which crystallizes on standing. The solid residue is recrystallized from carbon tetrachloride with darco to yield 0.059 (7.7%) of 19: mp 76-77°. IR (NUJOI)! 2225. 1455. 1280. PMR (chloroform): 3.68 (s). MS: m/e = 156 (par- ent). 2-Dicu9nomethylene—5-piperimidone ethglene 9ithioke§al (Z12 A solution of the oily 99; (1.629. 9.37 mmoles) in eth- anol (25ml) is combined with 99 (1.689. 9.87 mmoles) and re- 99 fluxed for 2 hours. The mixture is allowed to cool slight- ly. and the precipitated solid is collected by filtration. This solid is washed with ether to dryness yielding 0.659 (53%) of 11: mp >260°. IR (NUJol): 3280. 2250. 2160. 1620. 1580. PMR (DMSO): 3.35 (s. 4H). 3.42 (br s. 4H). 8.0 (br s. 2H). MS: m/e = 238 (parent). 919-3199minomethyl~1.3-dioxo1999 11991 A mixture of 99 (3 19. 14.4 mmoles) is refluxed in 30% potassium hydroxide solution (25ml) for 1 hour. The clear mixture is cooled and saturated with several pellets of po- tassium hydroxide. The basic aqueous solution is extracted three times with chloroform. This organic solution is dried over anhydrous sodium carbonate. and the solvent is evapo- rated to a clear Oil weighing 2.259 (84%). This diamine is used without further purification for subsequent reactions: IR (Neat): 3360. 1600. 1025. PMR (chloroform): 1.2 (s. 4H). 2.72 (s. 4H). 3.96 (s. 4H). Diethoxymélongmide (74c) Ammonia (25ml) is condensed into a stainless steel bomb cooled to -78°in a dry ice/ acetone bath. Diethyl diethoxy- malonatet53] (109. 52.1 mmoles) is dissolved in a minimum of ethanol and 'slowly combined with the ammonia. The bomb is sealed and allowed to warm to room temperature for 48 hours. 100 The bomb is then recooled. opened. and its contents are emp- tied by washing several times with boiling ethanol. One re- crystallization of the crude solid from ethanol yields 4.39 (56%) of 199 contaminated with a trace of the corresponding acetamide: mp 206-207°. IR (NUJ01)Z 3470. 3400. 3380. 1670. 1125. 1080. PMR (DMSD): 1.2 (tr. 6H). 3.4 (q. 4H). 7.13 (br d. 3H). M8: m/e = 190 (parent). 1.3-Bistrifluor99cet9midog§etone (79b) 1.3-Diaminoacetone dihydrochloride (29. 11.2 mmoles) and sodium acetate (1.849. 22.4 mmoles) are stirred in ether (30ml) in a flask cooled in an ice bath and protected by a drying tube. To this suspension is added trifluoroacetic anhydride (14.99. 70.9 mmoles) dropwise. The mixture is al- lowed to warm to room temperature for 8 hours. The solid is collected by filtration. triturated in 1% hydrochloric acid solution (25ml). refiltered. and rinsed to dryness with ether. After vacuum drying for several hours. there is pro- duced 2g (64%) of 199: mp 223-226°. IR (NUJol): 3300. 3100. 1730. 1700. 1560. 1175. 1030. PMR (DMSD): 4.18 (d. 4H). 9.54 (br tr. 2H). M8: m/e = 281 (parent). 1.3-Di9cgt9midogcetone ethylene ketal (80) Ethylene glycol (6.8ml). three drops of. concentrated hydrochloric acid. and 1.3-diacetamidoacetone155] (3 4g. 101 19.8 mmoles) are refluxed in benzene (150ml) with a water separator. After 5 hours. the mixture is cooled. and the solvent is evaporated. The residue is triturated with 4:1 ether acetone. yielding. after drying. 3.7g (87%)-of 99: mp. 162-163°. IR (NUJ01)2 3290. 3060. 1700. 1570. 1220. PMR (DMSO): 1.99 (s. 6H). 3.3 (d. 4H). 3.93 (s. 4H). 6.3 (br s. 2H). MS: m/e = 216 (parent). 9;91999nomethulene~5-piperimidone ethylene 99191 1911 The diamine. 119 (2.05. 15.5 mmoles). is dissolved in ethanol (20ml). and to this solution is added 99 (2.659. 15.5 mmoles) all at once. This mixture is refluxed for 0.5 hours and allowed to cool slightly before collecting the precipitated solid by filtration. This solid is washed with ether to dryness yielding 1.689 (53%) of 91: mp >300°. IR (NUJOI): 3250. 3040. 2205. 2170. 1625. 1585. 860. PMR (DMSD): 3.1 (d. 4H). 3.9 (s. 4H). 7.68 (br s. 2H). MS: m/e = 206 (parent). N.N’-Diethul-1.3-di9min0999tone ethyleng ketal 1991 The ketal 99 (1.149. 5 mmoles). is added as a solid to a suspension of lithium aluminum hydride (0.59. 13.15 mmoles) in tetrahydrofuran (25ml) stirred at room tempera- ture. After' the addition. the mixture is refluxed for 8 hours. The suspension is tRen cooled. and water (0.5m1). 15% potassium hydroxide solution (0.5m1). and water (1.5ml) are cautiously added in order. After stirring For 1 hour. the inorganic solids are collected by Filtration and washed with THF. The solvent is evaporated. and the residue is combined with enough water (lml) to dissolve several pellets of potassium hydroxide. The basic aqueous layer is extract- ed three times with ether. The ether solution is dried over anhydrous sodium carbonate and upon evaporation of the sol- vent. there results an oil. 0.929 (93%) o? 88. This diamine is used in subsequent reactions without further purification: PMR (chloroform): 1.08 (tr. 6H). 1.48 (br s. 2H). 2.6 (q. 4H). 2.72 (s. 4H). 3.9 (s. 4H); M8: m/e = 188 (parent). 1.3-N.N’—Diethyl:27dicuénomethulene—S-oioerimidone ethyleng £938; £88; and l-N-ethulzg~dicu§nomethulene-S-piperimidong ethylene ketal £811 The ketal 88 (0.799. 4.2 mmoles) is combined with 88 (0.7149. 4.2 mmoles) in ethanol (20ml) and refluxed for 1 hour. The precipitated solid is Filtered From the reddish reaction mixture and yields 0.319 (51%) of 88: mp 150-152? IR (NUJol): 2190. 2170. 1560. 1520. 900. 8133 PMR (chloro- Form): 1.3 (tr. 6H). 3.1 (s. 4H). 3.35 (q. 4H). 3.92 (5. 4H); MS: m4e = 262 (parent). Evaporation of the mother liquor gives a mixture of 88 along with another product which can be separated by column 1er 103 chromatography. Elution of the crude solid with ethyl ace- tate on alumina absorption isolates 83: mp 140-141°i IR (NUJOI): 3250. 2190. 2170. 1575. PMR (chloroform): 1.3 (tr. 3H). 3.1 (br s. 4H). 3.6 (q. 2H). 3.99 (s. 4H). 6.0 (br s. 1H); M8: m/e = 234 (parent). 1.3-N.N’-Diethul~8;digyanomethyleng-fi-pipgrimiggng $852 The ketal 88 (0.39. 1.15 mmoles) is combined with 10% hydrochloric acid (10ml) and heated on a steam bath for 5 hours. The mixture is filtered hot from any suspended solid and cooled in ice to precipitate clear needles. The product is collected by Filtration and vacuum dried to give 88: mp 198—200°. IR (NUJol): 2190. 2170. 1750. 1530. 15003 PMR (DMSD):. 1.2 (tr. 6H). 3.48 (q. 4H). 3.85 (s. 4H): M8: m/e = 218 (parent). N.N’-Bisbenzou1-1.B—Qigmino-2-propgnol (88) 1.3—Diamino-2wpropanol (19. 11.1 mmoles) is dissolved in methanol (15ml) with stirring. To this solution is added benzoic anhydride (5.19. 22.5 mmoles) within 5 minutes warm- ing the solution considerably. After 0.5 hours. the sol- vents are evaporated and saturated sodium bicarbonate is added to the residue. The white solid is collected by fil- tration and washed. first with water. followed by ether. After vacuum drying there remains 2.69 (80%) of 88: mp 104 134-135.5°. IR (NUJOI): 3480. 3300. 1e40, 1530. 1115. 800. PMR (DMSD). 3.3 (hr tr. 4H): 3.78 (m: 1H): 5.13 (br 5: 1H): 7.3 (m. 6H). 7.78 (m. 4H). 8.32 (br s. 2H); HS: m/e = 280 (parent - water). 1.3-Bisbenzamidogggtone (89) The alcohol 88 (0.3g. 1 mmole) is dissolved in dimeth- ylformamide (2ml) and added at once into a similar solution of pyridinium dichromatet79] (0.579. 1.5 mmoles). The dark red mixture is capped and stirred at room temperature for 48 hours. water is added to precipitate a solid that is washed with water and vacuum dried yielding 0.179 (57%) of 88: mp 191-192.5°i IR (NUJOI): 3300. 1740. 1640. 13003 PMR (DMSO): 4.12 (d. 4H). 7.3 (m. 6H). 7.78 (m. 4H). 8365 (br tr. 2H); M8: m/e = 191 (parent - benzoylL 1.3-Bisbenzamidoacetone gtfiylggg L938; L281 Ethylene glycol (0.1429. 2.3 mmoles) and ketone 82 (0.119. 0.37 mmoles) are combined in benzene (15ml) along with one drOp of concentrated hydrochloric acid. A water separator and drying tube are used as this mixture is re- fluxed for 12 hours. As the mixture cools a solid precipi- tates and is collected by filtration. Saturated sodium chloride solution is added to the mother liquor. and the or- ganic layer is separated. dried over anhydrous sodium carbo- 105 nate and evaporated to yield a white solid. The two solids are combined to yield 0.1059 (842) of 88: mp 173-176°5 IR (NUJol): 3300. 1640. 1550. 1310. 690; PMR (DMSO): 3.6 (d. 4H). 4.0 (s. 4H). 7.22 (br m. 8H). 7.78 (m. 4H): M8: m/e = 340 (parent). 1.3-Bis(benzylaminglécetone ethylene ketgl LZLL The ketal 98 (0 19. 0.29 mmoles) is dissolved in THF (5ml) and added dropwise to a stirred suspension of lithium aluminum hydride (0.0289. 0.74 mmoles) in THF (10ml) under nitrogen. After refluxing for 4 hours. the mixture is then cooled and to it is added. water (0.05ml). 15% sodium hy- droxide (0 05ml). and water (0.15ml) in order. The solids are filtered and washed with THF. Evaporation of the com- bined solvents leaves an oily residue. water (1m1) and sev- eral pellets of potassium hydroxide are added to this resir due before it is extracted twice with ether. The organic solution is dried with sodium sulfate and evaporated to a light yellow oil. The crude yield is 0.099 (100%) of 2;: PMR (chloroform): 2.1 (s. 2H). 2.78 (s. 4H). 3.72 (s. 4H). 3.85 (s. 4H). 7.15 (s. 10). This diamine was used in subse— quent reactions without further purification. 1.3-Bisacetamido-g-propanol (92) 1.3-Diamino-2-propanol (19. 11.1 mmoles) is dissolved 106 in methanol with stirring. To this solution is added acetic anhydride (2.59. 24.5 mmoles) within 5 minutes warming the solution considerably. After 1 hour. the solvents are eva- porated. leaving an oil which is crystallized by adding methylene chloride. The yield of white crystalline 88 is 1.419 (73%). The product can be recrystallized by ad- ding methylene chloride/pet ether: mp 98-100°5 IR (NUJol): 3380. 3320. 3100. 1660. 1580. 11255 PMR (DMSD): 1.8 (s. 6H). 3.0 (hr tr. 5H). 4.9 (d. 1H). 7.7 (br s. 2H): MS: m/e = 174 (parent). 3-Dic9anomethul~6-methulthio—1.2.4.5-tgtraging ggiigm salt (102) Sodium hydride (1.3g. 50% in mineral oil. (27.1 mmoles) was suspended in benzene (25ml) and malononitrile (0.169. 2.43 mmoles) in benzene (10ml) was added dropwise with stir- ring under nitrogen at room temperature. To this anion is added 3-bromo—6-methylthio~1.2.4.5-tetrazine. 18;, (0.59. 2.43m moles) in benzene (10ml) in a dropwise manner. Following this addition. the vessel is opened to the air and stirred vigorously for 2 hours. From the red solution a dark solid precipitates which is collected by filtration and rinsed dry with ether yielding 0.959 of a hydrated violet powder: mp 2300°i IR (NUJol): 3400. 2200i 2180. 2160. 16203 PMR (DMSD): 2.52 (s). 3.3 (water). 107 3-Dicyanomethu1-6—methylthio 182.4.5-tet;gzing tetrabutgl ammonium éél£ £188; The sodium salt 188 is dissolved in water and to this solution is added a warm clear solution of a slight excess, of tetrabutylammonium iodide in water. Upon combination. a violet solid precipitates. This metathesized solid is col- lected by filtration and is recrystallized from 95% ethanol: mp 114-115°; IR (NUJol): 2180. 2155. 1200. 1050. 3eDicy§nomethul~6~methylthio-lég.4.§:tetrgzing £191; The sodium salt 188 (1.259) is dissolved in water (50ml) and is then treated with 10% hydrochloric acid to pH 2. Extraction with ether several times gives a dark tarry oil which reverts into the anionic form upon standing over- night in glassware: PMR (chloroform): 2.53 (s). 5.77 (br s). 3-Bis(carboethoxy)*6-methulthio-1.8:4.5-tgtrgging LLQQL Sodium hydride (0.139. 50% in mineral oil. 2.7 mmoles) is suspended in benzene (10ml) and diethyl malonate (0.49. 2.5 mmoles) is dissolved in benzene (10ml) and added drop- wise causing evolution of gas. To the suspension of the anion is added a solution of 18; (0.59. 2.43 mmoles) in ben- zene (20ml):' Addition causes darker solution to occur. After stirring 1 hour at room temperature. solids are col- 108 lected by filtration. These solids are dissolved in 5% so- dium hydroxide solution and extracted with ether. The basic aqueous layer is acidified with 10% hydrochloric acid and extracted three times with ether. The ether solution is_ dried over sodium sulfate and evaporated to give a red oil as the product. 188: IR (NUJol): 1725. 1370. 1160. 1025; PMR (carbon tetrachloride): 1.32 (tr. 6H). 2.75 (s. 3H). 4.3 (q. 4H). 5.15 (s. 1H); MS: m/e = 286 (parent). Chloringtion grodqgg 99 1.1~di§mino-2.2-dicyanoeth91ene (106) 1.1-Diamino-2.2—dicyanoethylene (0.29. 1.85 mmoles) is suspended in dry acetonitrile (20ml) cooled to -20°with a dry ice/carbon tetrachloride bath. Chlorine gas is entered into the mixture with stirring at a steady rate and after several minutes a light yellow precipitate is seen. Soon all of the solids dissolve as chlorine is bubbled in for a total of 0.5 hours. The mixture is allowed to warm to room temperature. and the solvents are evaporated. Water is added along with ether and the organic layer is separated. dried over magnesium sulfate and evaporated to leave a pale yellow oil. This oil crystallizes upon standing and is col- lected by filtration with hexane. Column chromatography with silica 931 and ether as the eluent proceeds to afford the purified product: IR (NUJol): 3430. 3340. 3220. 3150. 2252. 1650; MS: m/e = 176. 109 3—(Thienyl-2~carbo;§ldehyde)-mercgptogcetic 2211 £113; The preparation of thienoE3.2-b]thiophene 2-carboxylic acid was followed as in reference 62. To the basic aqueous layer. 10% hydrochloric acid is added until a pH of 5 is reached. The precipitate is collected by filtration. and the mother liquor is acidified further to pH of 1-3. The latter solid that precipitates is mainly that of 118: PMR (DMSO): 3.88 (s. 2H). 7.15 (d. 1H). 7.97 (d. 1H). 9.72 (s. 1H). ThienoE3L8:b]thioohene-8.5~dic§rboxulic gcig (123a) ThienoC3.2~thhiophene—2-carboxylic acidt62J (19. 4.39 mmoles) is added as a solid to a solution of lithium diiso- propyl amide (7.47m1 1.6M n-BuLi. 1.219 diisopropylamine) in THF (50ml) at -78°under nitrogen. The stirred suspension is allowed to warm to ~10°for 0.5 hours at which time an excess of dry carbon dioxide is bubbled into the mixture. After 0.5 hours. the solvents are evaporated. and the remaining solids are vacuum dried overnight. The product is dissolved in a minimum of water and extracted two times with ether. The basic aqueous layer is cooled in an ice bath and acidi- fied by dropwise addition of 10% hydrochloric acid. The mixture is stirred for 10 minutes. and the precipitated solid is collected by filtration and vacuum dried yielding 0.99 (73%) of 188;: mp >300°i IR (NUJol): 3100. 1660. 1300. 1150. 7505 PMR (DMSD): 8.0 (5); MS: m/e = 228 110 (parent). Diethyl thienoE3Lg~thhiophene-2.5-dicarboxylate (123b) The diacid 1888 (0.29. 0.88 mmoles) is suspended in' methylene chloride (25ml) and to this mixture is added dii- sopropylethylamine (0.2269. 1.75 mmoles) and triethyloxonium fluoroborate (0.379. 1.94 mmoles). The mixture is capped and stirred for 24 hours. Extraction three times with 1N hydrochloric acid. three times with 1N sodium bicarbonate. and once with saturated sodium chloride gave an organic so- lution that was dried over sodium sulfate and evaporated to yield 0.129 (48%) of 1889;: IR (NUJol): 3090. 1702. 12355 PMR (DMSD): 1.4 (tr. 6H). 4.32 (q. 4H). 7.8 (s. 2H); MS: m/e = 256 (parent - ethyl). Dimethul thienoC3L2~blthiophene-gi5-dichboxylate (123C) The diacid 123a is added as a solid to a cold solution of distilled diazomethane (from N.N’-dimethyl-N.N’ dinitro- soterephthalimidet78] 2.59). The mixture is stirred over- night at room temperature. Acetic acid is added dropwise to destroy excess diazomethane. Evaporation of the solvent and trituration of the solid with water followed by drying in vacuum gave 0.189 (80%) of 123c: mp 233°; IR (NUJol): 1720. 1230. 'PMR (chloroform): 3.32 (s. 6H).. 7.97 (s. 2H); MS: m/e = 256 (parent). 111 2.5~Bis(hydroxymethyl)thienot888-b3thiophene L181; ThienoE3.2~blthiophene*2.5-dicarboxaldehyde 189 (22.159. 0.113 moles) is added as a solid to a suspension o lithium aluminum hydride (17.069. 0.449 moles) in THF (400ml) at 0°. The mixture is stirred at room temperature overnight. To the recooled mixture is then added water (34ml). 15% sodium hydroxide (34ml). and water (34ml) in order. The inorganic solids are collected by filtration and washed several times with hot THF. The organic solution is evaporated to yield 17.459 (77%) of the crude 181 which can be used without further purification for subsequent steps. This diol can be purified from THF and darco. by filtration and precipitation with hexane: mp 145°; IR (NUJol): 3200. 1635. 1145. 1040. 1000. 820 5 PMR (DMSD): 4.6 (d. 4H). 5.4 (tr. 2H). 7.11 (s. 2H). MS: m/e = 200 (parent). 0. 2.5-Bis(chloromgthul)thignoE3L8:9]thioohgflg (124a) The dial 181 (17.459. 87.25 mmoles) is combined in chloroform (250ml) with pyridine (13.1ml). To this stirred suspension is added thionyl chloride (18.9ml) in chloroform (50ml) under nitrogen. The hot mixture is refluxed for 0.5 hours. cooled. and quenched by pouring cautiously onto ice and is stirred for 0.5 hours. The organic layer is separat- ed and washed.with 10% hydrochloric acid (50ml). with 10% sodium carbonate (50ml). and with water (50ml). The organic solution is then warmed with calcium chloride and darco. and 112 filtered. The organic solution is evaporated to yield 17.99 (87%) of crude 1818. Further purification is possible by column chromatography with silica gel using ether as the eluent: mp 136-137°i IR (NUJol): 1465. 1250. 1150. 1120. 8355 PMR (DMSD): 5.12 (s. 4H). 7.5 (s. 2H); MS: m/e = 236 (parent). 8.5-Bis(bromomethyl)thienot3.8:b]thiophene (1240) The dial 181 (1g. 5 mmoles) is dissolved in THF (25ml). and to this solution is added dropwise at 0°a solution of phosphorus tribromide (lml) in THF (10ml). The mixture is stirred for 2 hours at 0°. 1 hour at room temperature. and then quenched by pouring on ice. The precipitated solid is filtered and vacuum dried. The organic solvent is evaporat- ed and more solid is collected. yielding 0.6g (70%) of 1888: PMR (chloroform): 5.2 (s. 4H). 7.4 (s. 2H); MS: m/e = 345 (parent). 8.5-Bis(gggnomethul)thieno[818-b]thiopheng_11881 The bis-chloromethyl compound 1818 (16.759. 0.071 moles) is dissolved in dry methylene chloride (700ml) in a flask equipped with a drying tube. To this stirred solution at room temperature is added tetraethylammonium cyanide (22.359. 0.143 moles) in dry methylene chloride (350ml). and this mixture is refluxed for 2 hours. The solvent is evapo— 113 rated. and the residue is chromatographed on silica gel with methylene chloride/ether 50:1. yielding 4g (26%) of 125: mp 155-158°; IR (NUJol): 2250. 1215. 825. PMR (DMSO): 4.35 (s. 4H). 7.3 (s. 2H); MS: m/e = 218 (parent). Reaction 91 potggsium cyanide 1n methgnol with 124a The bis-chloromethyl compound 1818 (0.599. 2.5 mmoles) is dissolved in methanol (25ml) and to this solution is added. all at once with stirring. a solution of potassium cyanide (0.3359. 5.1 mmoles) in methanol (50ml). The mix- ture is refluxed overnight. cooled. and the solvent is eva- porated. The residue is triturated with water. and the aqueous mixture is extracted three times with ether. The organic solution is dried over sodium carbonate. heated with darco. filtered and evaporated to yield 0.39 (53%) of 2.5-bis(methoxymethy1) thienot3.2—thhiophene. 188: mp 60-70°i PMR (chloroform): 3.32 (s. 4H). 4.57 (s. 4H). 7.0 (s. 2H); MS: m/e = 228 (parent). 8.5-Bis(ggrboethoxycyanomethyl)-thieno[3.8erthiopngng 11811 The bis-cyanomethyl compound 188 (0 59. 2.3 mmoles) is dissolved in THF (15ml) along with dimethyl carbonate (0.4139. 4.6 mmoles). and this solution is added dropwise under nitrogen to a room temperature suspension of sodium hydride (0.229. 50% in mineral oil. 4.58 mmoles) in THF 114 (10ml). After 10 hours the solvent is evaporated. and the residue is acidified with acetic acid and is extracted 4 times with chloroform. The organic solution is washed with water and warmed over sodium sulfate and darco. Once f