SYNTHESIS OF THIENYL AND THIANAPHTHENYL DIOXOLANES AND THIENYL DICARBONYLS Thesis for the Degree of Ph. D. MICHIGAN STATE UNIVERSITY ALBERT JOSEPH MUELLER 1968 (H 9.29.5 LIBRARY Michigan State University This is to certify that the thesis entitled SYNTHESIS OF THIENYL AND THIANAPHTHENYL DIOXOLANES AND THIENYL DICARBONYLS presented by Albert Joseph Mueller has been accepted towards fulfillment of the requirements for __.Eh_.D_._degree in_Chemis.try c J I4 t i" I \. fl" 1 _ . [A I‘mfir rilqu-LLC/ \ Major Wiener Da‘e May , 1 9 68 0-169 I HUM: & suns' .- .: snox amour me. Liam-v IIIIHCDQ ‘3 ‘ . ‘ I I 3" “gal“! _‘7‘ _ "N: 7‘ J Few St‘ thleni’l a“: this invest routes for acetyl and 1: was anti undergo CYC heteroCYClj tlon, usinc. 2~methyl 01 ml; re! naphthenyli I < g, R ~ T J, ‘ I? I: \. \ ABSTRACT SYNTHESIS OF THIENYL AND THIANAPHTHENYL DIOXOLANES AND THIENYL DICARBONYLS BY Albert Joseph Mueller Few studies have been reported on the syntheses of thienyl and thianaphthenyl dicarbonyls. An objective of this investigation was to explore and develop new synthetic routes for the preparation of vicinally disubstituted formyl, acetyl and benzoylthi0phenes and thianaphthenes. Further, it was anticipated that such dicarbonyl compounds would undergo cyclization reactions to yield thienothiepins, a new heterocyclic system. The hydrogen-metal interchange reac- tion, using n-butyllithium in hexane-ether, of 2-hydrogen, 2—methyl or 2-phenyl—2-(5'-thienyl)-1,5-diosolanes I}! El and ii; respectively) and 2-methyl or 2-phenyl-2-(5'-thia- naphthenyl)-1,34dioxolanes (I! and_y_respectively) occurred R\ /0 H2 R\ /0 H2 C / \ H2 \O/H2 fl N/ _I_I R i H IV, R = CH3 III, R = C6H5 -' 6 5 rpidli’ 1“ nea. 9-position Of :icxelanes we the interacti: .ltnmms with 93’ .3 N,N—dir.et sizenyl and t 7‘ I g' swelcarbom A it. ' ne‘metal 3157 q ‘HEQ Albert Joseph Mueller rapidly in nearly quantitative yields at the more hindered 2-position of thiOphene and thianaphthene. Nine formyl, acetyl and benzoyl thienyl, El, and thianaphthenyl, VII; I I R“~C//O:]H2 R‘\‘c//O\IH2 ,/ \\ H2 H2 / \ O \O/ ‘COR OR \\\s VI VII dioxolanes were obtained in isolated yields of 32-81%, upon the interaction of thienyl and thianaphthenyl dioxolane lithiums with N,N-dimethylformamide, N,N-dimethylacetamide and N,N-dimethy1benzamide. Hydrolysis of carbonyl substituted thienyl and thianaphthenyl dioxolanes readily gave the 2,3-dicarbonyl thiophenes and thianaphthenes. Z-Phenyl-Z-(Z'-formyl-5'-thienyl, y;;;, and 5'—thia- naphthenyl, iz)—1,5-dioxolanes failed to survive hydrolysis conditions and did not yield stable isolatable products. 2-(4'-Bromo-3'-thienyl)—1,3-dioxolane,_§, was subjected to a H © 0 H2 @\ /0 H2 \ / H2 :;C<:; H2 ‘ Br 2 4 / \§_CHQO O CHO <3 VIII IX X _ — bromine-metal interchange reaction with n-butyllithium. The lithium dioxolane on reaction with N,N-dimethylformamide yielded a 5,4-diformy1thi0phene. Produc spectral da hydrogens 'w auction of 2-:henal a: at 8-17 ml "ere also 0 Thieno “‘leno I2, 3-: with z u,4-dif 2,5. . Albert Joseph Mueller Product structures were assigned from UV, IR and NMR spectral data. Coupling constants of the thiophene ring hydrogens were determined to be (ops): J45=5.O-5.2, J25: 2.9-5.1, J24=1.5-1.7 and J = 0.85-1.4. The intro- (CH0)2‘5 duction of sterically larger groups into the 3-position of 2-thenal and 2-thienyl ketones produced hypsochromic shifts at 8-17 mu in the carbonyl band of the UV spectra. Corres- ponding shifts of 10-50 cm‘1 in the carbonyl band of the IR were also observed for these same compounds. Thieno[3,4-d]thiepin—2,4-dicarboxylic acid, XI, was COgH SA. — \\\C;> '::: \R 52 this molecule possesses "extended conjugation" by its unusual UV Spectrum (13 maxima from 210 mu to 390 mu). Thieno[3,4-d]- thiepin was also Shown to have unusual stability toward therm- al desulfurization; whereas, benzo[d]thiepin derivatives are easily desulfurized thermally to naphthalene derivatives (13-17). In view of the potential applicability of vicinally sub- stituted dicarbonyl thiOphenes and thianaphthenes, an investigation of a general synthesis scheme to produce these compounds would seem to be of value. For this purpose, the hydrogen-metal interchange reactions of Z-Substituted 2-(3'-thienyl, £23, and 3'-thianaphthenyl, §!;;)-1,3-dioxo- lanes were studied using n—butyllithium. R\\C//O H2 \\O,/H2 / For the we to study 2:- the hydro; ring. An ad: these interme react furthe: precursors o: Spectroscopi: these precur. 1,3-dioxolam 2.3-dic. 355+ ' For the thiOphene derivatives, one specific purpose was to study the substituent effects of the dioxolane moiety on the hydrogen-metal interchange reaction of the thiophene ring. An additional objective was to study the ability of these intermediate thienyl and thianaphenyl lithiums to react further with several N,N-dimethylacylamides to produce precursors of dicarbonyl thiophenes and thianaphthenes. Spectroscopic evidence will be presented which shows that these precursors are 2—substituted-2-(2'-acyl-3'-thienyl)- 1,3-dioxolanes, XVIII, which upon acid hydrolysis in acetone, give 2,3-dicarbonyl thiOphenes, I. I R \ /0 H2 6 . C H Egg L COR // ’/’ \\ 2 acetone 75 QCOR \s COR XVIII I A short study was made to determine the feasibility of preparing thienothiepins and thienoéxepins by base catalyzed condensation of 2,3-diformyl and 3,4-diformylthiophenes with ethyl thiodiglycolate and dimethyl diglycolate; the results of this study are described in the Results and Discussion section of this thesis. The met reported by ‘ tative yield 3.; mechanis 3:“ the metal appears to o Iciety to tk the thiOphez: Cl‘Jsive meta mg and Wit (‘3: 3) PCsit Rene “meet! the Carbonat mrdinates Metallation iinaSi/I‘ HISTORY The Metallation of Thiophene The metallation of thiophene with n—butyllithium, reported by Gilman, yields 2-thienyllithium in nearly quanti- tative yield (18). Gronowitz (19) has suggested the follow- ing mechanism for this metallation reaction. Coordination of the metallating agent to the sulfur of the thiophene ring appears to occur first, followed by attack of the carbanion moiety to the most "acid like" proton alpha to the sulfur on the thiOphene ring. Such a mechanism is in accord with ex- clusive metallation of the alpha position on the thiOphene ring and with directive effects of substituents in the beta (or 3) position of thiOphene (20). Using the furyl thio- phene mixed heterocyclic system, Klinke (21) has Shown by the carbonation products that thiophene in furyl thiophenes coordinates a mono equivalent of n-butyllithium exclusively. Metallation of isotope labeled thiophene gave a KH/KT of 16.i 4 and a KH/KD of 6.6.i 0.3, in accord with the nucleophilic character of n-butyllithium, indicating that elimination of hydrogen, or alpha carbon-hydrogen bond breaking, is the rate determining step (22). this alpha sel (23-26), Z-met and alkyl the: i-position of observed with substitution . E-methylthio— n-butyllithiu 3PM carbonat tfins showing 93 Competitix hIOCREd: this O .3 (“9'1") Li + \ S + n-C4H9Li _+ : I —'>' S L. This alpha selectivity was Shown by the fact that 2-alkyl (23-26), 2-methoxy (24,27) and 2-alkylthio-thi0phenes (26) and alkyl thenyl sulfides (28,29) were all metallated in the 5-position of the thiophene ring. This selectivity was not observed with conventional reagents in electrophilic aromatic substitution. Metallation of a mixture of thiophene and 2-methylthio-thiophene with a half molar equivalence of n-butyllithium gave exclusively 5-methylthio-2-thenoic acid upon carbonation of the intermediate thienyllithium (26). thus Showing the activating effect of the methylthio group on competitive metallation. When both alpha positions were blocked, this highly specific reactivity disappeared and metallation with n-butyllithium depended on the nature of substituents present. While'2,5-dimethyl thiOphene was not metallated, 2-methoxy-5-methyl thiophene was metallated readily (27) in the 3—position due to the coordination effect of the methoxyl oxygen. Gronowitz and his associates have studied n-butyllithium metallation of a number of 3-substituted thiOpheneS to de- termine the mechanism of the reaction and to study its syn- thetic utility (3). 3-Methylthi0phene was metallated in the 5-position; competitive experiments with thiOphene show S-nethylthio thiephene (1 {anold's te preferential iesreases th p.3tons of E correspondir Ea-tethylthic in the Z-pos and during t Ltcreased t} strong, as . lithium and hindered 2‘} n'butyllith; 3-methylthiophene to be metallated at a Slower rate than thiophene (19,24,30). This is expected as the + I effect (Ingold's terminology (31)) of the methyl group increases preferentially the electron density of the 2-position and decreases the "acidity" of this proton. Both the 2 and 5 protons of 3-methylthiophene are less acidic than the corresponding hydrogens of thiophene (19). 3-Methoxy (28), 3-methylthio (25) and 3—bromothiophenes (19) were metallated in the 2-position, which has been ascribed to -I effects and during the reaction, corresponding inductomeric effects increased this mode of reactivity. This influence is quite strong, as 3-t-butoxythiophene was metallated with n-butyl- lithium and carbonated exclusively to the considerably more hindered 2-position (29). A secondary coordination of n-butyllithium to these electron rich 3-Substituents may also aid in 2-position substitution (29). Gronowitz has used this effect in the metallation of 2-(3'-thienyl)-1,3-dioxolane to prepare 3-formyl-2-thenoic acid exclusively, thus estab- lishing no trace of 5-position metallation (32). Metal-Halogen Interchange of Halogenated Thiophenes Halogen-metal interconversion between bromothiOphenes and n-butyllithium can be defined as a nucleophilic substi- tution of halogen. This reaction occurs readily at tempera- tures as low as -700 (19,33-35).. This fact is important as Grignards of bromothiOphenes are prepared in small yield by entrainmen bromide (35,3 E-bromothiop} could be pre} Gronowi' :hLenyllithi' 3,5-dibromot not replace by entrainment with a co-Grignard such as ethyl magnesium bromide (33,34,36-38). By the use of n—butyllithium with 3-bromothiophene, a whole range of typical Grignard products could be prepared in the 3-position. Gronowitz and Moses (35) have studied the stability of thienyllithiums derived from 3-bromothiOphene and 3,4- and 2,3-dibromothi0phenes. In these reactions, the lithium did not replace the acidic alpha hydrogens of thiophene, which Br Li ((;>) + n—C3H9Li ‘*f>' Z<§>S + n—C4H9Br Br Br Li + n-C4H9Li _> 20; + n-C4H9Br S Br . r <:> + n-C4H9L1 -——$» + n-C4H9Br " Br 0 Li S S indicated that these were kinetically controlled reactions. Br ©l This was further amplified by the fact that the intermediate thienyllithium had been found stable at -700 for ten hours, but did rearrange to complex mixtures as the temperature was raised (38). The ease of halogen-metal exchange over alpha hydrogen abstraction was Shown by the observation that 2—bromo, 2,3- and 2,4—dibromo and 2,3,5-tribromo easily and selectively underwent halogen-metal exchange at low tempera— tures (39). The reaction of tribromothiophene and n-butyl- lithium Showed the added inductive effect of the 3—bromo sub- stituent on the direction of the metallation reaction (35). 1O (<:>hBr + n-C4H9Li -—€P' <;> S Z >“L r _ r + n-C4H9L1 ‘——%> <:> + n-C4HgBr r L + n-C4H9Li .——e7 (:3 Br (:> S 3 Br B (CL, (6}. S i + n—C4H9Br Br + n-C4H9Br + n-C4H9Li ——€>' + n-C4H9Br i B Li r Br Br 1 The stability of the thienyllithiums derived from 2,3-, 2,4- and 3,4-dibromothiophene at —700 has made them very useful for preparing isomer free difunctional group deriva- tives, Since halogen-metal interchange with n—butyllithium can be done individually with each bromine atom. For example, 4-methylthio-3—thenaLIXIXJ(24) and 3-formyl-4-thenoic acid, _§§,(40) have been prepared from 3,4-dibromothiophene using dimethyl disulfide and N,N—dimethylformamide. Br 0 Wire 1) n-C4H9LI s 2) DMF r . CH3“S’)2 Br Br Br 1 OHC7F_:§~SCH3 O O 1)DMF XIX H2 s s 2N m a ' (-CH20H)2 Q \0 2 1) n-EeHsLi p-TSOH 2) C02 5) H20 H020: -cHo O X_X The ree TN-dimethy everal met‘ sfn-butyll Cfthis rea afnucleopt formanilide GrOnok‘it Z 1 1" PrEPari- Lamyl the PDH § In ' v 11 Previous Synthesis of Thigphene Dicarbonyl Compounds The reaction of thienyllithiums with compounds such as N,N-dimethylformamide and N-methylformanilide is one of several methods to obtain thenals. Before the availability of n-butyllithium, Gatterman (41) first described a variation of this reaction whereby a 70% yield was obtained by attack of nucleophilic 2-thienyl magnesium bromide upon N-methyl- formanilide. e .3 - 0L1 ’ 0 )-CH0 + R(CH3)NCHO —+— . Haoa \s < O >—Li \<> -N-R ‘ + S H CH3 R(CH3)NH R = CH3, CBHS Gronowitz used this reaction with n—butyllithium extensively in preparing unsubstituted (42) 3-thenal and the isomeric formyl thenoic acids (32,40); the latter were synthesized by repeated metallations of various dibromothiOphenes by n-butyllithium, followed by reaction with N,N-dimethylform- amide and carbon dioxide. Previous studies of dicarbonyl thiophenes had been limited for the most part to the synthesis of the four known thiophene dicarboxaldehydes. The synthesis of 2,5-thiOphene biscarboxaldehyde was initially reported by two groups of investigators using an identical synthetic scheme (43,44). Bis-chloromethylthiophene was allowed to react with pyridine to obtain a bispyridinium hydrochloride,XXI, which in turn h‘ n.13mn a ‘v’ar‘ was treated wi intermediate )3 in aqueous hyd bexaldehyde, I ClCH2© ( (CH3) all-C Gol'dfar be. - tarboXalde r-thenal dime G‘PCsitiOn w~f «:1tCH(ocH 53:3 H L. HCl 8 and MC let)? Of 12 was treated with N,N-dimethyl—p-nitroso aniline to yield an intermediate bisnitrone, XXII. The nitrone was decomposed in aqueous hydrochloric acid to give 2,5-thiophenedicar- boxaldehyde, XXIII, 9 C16 c1 0 ———>- o - (Ole - o CICHZ-[Q— CH2C]. CN CH2 S H2 N 6 a 20—H- 2ON-© -N(CH3) 2 (CH3) 2N-©-§=CH___©CH=g- © -N(CH3) 2 o s XXII 2N a OHC—©—CHO HC]. S XXIII Gol'dfarb and Rogovik (45) have synthesized 2,5-thiophene biscarboxaldehyde using the n—butyllithium metallation of 2-thenal dimethylacetal, XXIV, followed by formylation of the 5-position with N,N-dimethylformamide. n-CgHaLi; DMF. .1, ZQLCHWCHa) 2 - Li @Hmws) 2 XXIV OHC ©‘CH(OCH3) 2 5 H01 ' C© _—_——>. H20/EtOH OH 5 CH0 Thames and McCleSkey (46) used the same procedure to prepare a variety of 5—substituted -2-thenals and 2-acetothienones. Recent thiophenes El'tsov anc' thiephene, :ethylthio; and sodium 3,4-biseth: utrogen t: chlorornethj Z‘PIOpiony “3‘Pb(No W‘Y‘fi “TOURS w. .\ CHO ~h3 m L 4‘ "so 1 81Ce: ‘ (J n 13 Recently, several researchers have synthesized dicarbonyl thiophenes by oxidation of apprOpriate chloromethylthiophenes. El'tsov and Ginesina (47) prepared 3,4-diformyl-2,S-dimethyl- thiOphene, XXVI, by oxidation of 3,4—bischloromethyl-2,3-di- methylthiophene, XXV, using 2-nitropropane, potassium iodide and sodium ethoxide. Dimroth et al., (48) previously synthe- sized 3,4-diformyl-2,5—dimethylthiophene by oxidation of 3,4—bisethoxymethy1-2,5—dimethylthi0phene, XXVII, using di— nitrogen tetraxide in chloroform. Janda and Dvorak (4) chloromethylated 2—propionylthi0phene to obtain S-chloromethyl- 2-propionylthiophene. Subsequent oxidation of this compound with Pb(N03)2 gave 5—formyl-2-propionylthi0phene. This latter compound was reported to possess antibiotic properties. CH3 H2Cl CH3 7‘ CH3 /’ . \‘ CHO H2Cl 1—PrN02, KI and I_ CH0 ’— \ S / W CH3 NaOEt/EtOH S ’/ CHO CH3 :éé! NaOEt CH3 CH3 EtOH XXVI \ \ CI-IgoEt N204, ""— S CHC13 ” CHZOEt .CH3 XXVII Gronowitz (40) in his studies on the synthesis of the isomers of formyl thenoic acid has Shown that the ethylene glycol acetal of 3-thenal is metallated and subsequently carbonated in the 2-position. Pastour-(493 et al. have been able to pre} the diethyl TN-dimethyfl H(CX321 O Gol'dfarb et :arboxaldehx zflaminated t thenal, The .c a bromine .cfi" sVilOkled by M . -\~~, with N do}, ba‘fde h’as C acetal. O + \ C S HO n‘ ‘\Séfiéfli£~s 14 able to prepare 2,3-thiophene biscarboxaldehyde, XXIX, via the diethyl acetal of 3-thenal—2-lithium, XXVIII, using N,N-dimethylformamide. H(OC2H5)2 CH(OC3H5)2 1)DMF O W- : [OK > n 4 9 .1. S Li 2) H20 HO XXVIII @HO XXIX Gol'dfarb et al. (50) have synthesized thiophene-2,4—bis- carboxaldehyde in a rather unusual manner. 2—Thenal was mono— brominated using AlC13 as a catalyst, to obtain 4-bromo-2- thenal. The diethyl acetal of 4-bromo-2-thenal was subjected to a bromine—metal interchange reaction using n-butyllithium followed by treatment of the resulting lithium derivative, XXX, with N,N-dimethylformamide. Thiophene-2,4—biscarboxal— dehyde was obtained by hydrolysis of the resulting aldehyde acetal. Br + Br2 AlClg >—- HC(OC2H5)3 L <:> CHO <:> CHO ’7 S S Br ZOLCH(OC2H5) 2 S 2 ye ——>= 70%: n-C H Li. 0 H(OC2H5)2 2) H20 \ HO 4 9 y S S XXX The red: aluminum hydr thiophene bi5< thiophene-3 , 4- :f the cones reported the reduction of aluminum hvdr 15 The reduction of thiophene bisnitriles using diisobutyl aluminum hydride has been reported in two cases to yield thiophene biscarboxaldehydes. Trofimenko (51) has prepared thiophene-3,4—biscarboxaldehyde in a 23% yield by reduction of the corresponding dinitrile. Pastour (49) et al. have reported the synthesis of thiOphene-Z,4-biscarboxaldehyde by reduction of thiophene-2,4—bisnitrile using diisobutyl aluminum hydride. NC_ (i—C4H9) 2A1—N=CH-— ©~2N +( i-C4H9) 2A1-H —>— /\®-CH=N-Al- (i‘C4H9)2 H O OHC— 5 Synthesis of Thiophene Biscarboxaldehydes from Dilithiated Thiophenes When thiophene or dihalogenated thiOpheneS are treated with two equivalents of n-butyllithium, thiophene dilithiums have been reported. Taft (52) has reported that thiophene 2,5-dilithium gave a 32% yield of thiophene—2,S-biscarboxal- dehyde on reaction of two equivalents of n-butyllithium with 2,5-diiodothiophene followed by treatment with N,N-dimethyl— formamide. Iodine-metal conversion of 2,5-diiodothiophene using phenyllithium to the dilithium derivative was reported by Campaigne and Foye (53) as shown by a 53% yield of thi0phene 2,5-biscarboxylic acid upon carbonation. Ostman (54) has shown that dicarboxyl lithium f0 (59, have by treatme equivalent ELK-dineth produced 5 J by t first with reaction w in. “53) :aCSO2 ‘lodcthio 16 shown that 3-bromothiophene gives rise to thiophene—2,3— dicarboxylic acid upon addition of an excess of n-butyl— lithium followed by carbonation. Recently, Robba et al. (55), have successfully synthesized 2,3—diformylthiophene by treatment of thiophene-2,3-dilithium (prepared from two equivalents of n—butyllithium and 3—bromothiophene) with N,N-dimethylformamide. Fedorov and Stoyanovich (56) have produced 5-t—butylsulfonylthiophene-2,4-biscarboxaldehyde, ‘XXXI, by the direct treatment of t—butyl 2-thienyl sulfone, first with two equivalents of n-butyllithium followed by reaction with two equivalents of N,N-dimethylformamide. i 5 Li ZU‘C4H9LI . (CH3)3CSOg- Q 7‘: (CH3)3CSOE_IQ)—-Ll 1) DMF OHC l y 2 H —'CH0 ) 20 (CH3) 3C-802 2;) XXXI The use of a double iodine-metal interconversion of diiodothiophenes with two equivalents of n—butyllithium followed by addition of the organo metallic complex to N,N-dimethylformamide has been successfully applied by Robba et al. (57) to the synthesis of each of the four thiophene biscarboxaldehydes. Winn and Bordwell (58) recently have prepared 3,4-diformyl-3,5—dimethylthiophene by the double iodine-metal interchange reaction with n-butyllithium upon 3,4-diiodo-2,5—dimethylthiophene, followed by reaction of the thiophene-3,4-dilithium with N,N-dimethylformamide. 1L .‘although the isexpected ' Ialdehydes 1 added featun introduced . Thiaz The met, Shirley and ¢ Ofthe lithir Shirley and 1 t3 the Synthe lutemediate 17 Although the yields were not reported in these studies, it is expected that these procedures for producing thiophene dialdehydes probably give low yield and do not have the added feature of allowing variation of the carbonyl groups introduced. Thianaphthene Metallation and Thianaphthene- 2,3-biscarboxaldehydes The metallation of thianaphthene was first reported by Shirley and Cameron (59) using n-butyllithium. Carbonation of the lithium complex gave 2-thianaphthene carboxylic acid. Shirley and Danzig (60) later applied this reaction procedure to the synthesis of 2-thianaphthene carboxaldehyde using the intermediate 2-thianaphthene lithium and N-methylformanilide. 1) C02 © S S l 1) DMF S OOH Reid and Bender (61) prepared thianaphthenyl-2,3-dilithium by two different methods and carbonated the organo lithium salt to the known thianaphthene-2,3-dicarboxylic acid. This was accomplished experimentally by treatment of 2,3-dibromo- thianaphthene with a single equivalent of n—butyllithium followed by addition of finely divided lithium metal to ex- change the second halogen atom. The alternate procedure utilized . lithium t: step. I: was dis thianaphth of N‘methy ‘1 I ‘Y Synth. A» V“ d“fermylth. thianaphthe “His .913 cc Chloride ‘dimEthy filtrOne gav 18 utilized S-bromothianaphthene and two equivalents of n-butyl- lithium to obtain thianaphthenyl-2,S—dilithium in a single step. Br Br , . 2L1 + n—C4H9Li .___a». | L_ :; S =r Li Li G | + LiBr Li Br Br Q + {1"C4H9Li ——+— Q I Li U‘C4H9Li\_ H ,. S Li It was also observed that no dialdehyde was produced when thianaphthenyl-2,3-dilithium was added to two equivalents of N—methylformanilide. Reid and Bender have reported the only synthesis of a thianaphthenyl biscarboxaldehyde, 2,3— diformylthianaphthene, xxxy, (61). Bischloromethylation of thianaphthene gave 2,3-bischloromethylthianaphthene,‘zzgll. This was converted to the corresponding bispyridinum hydro- chloride, XXXIII. The hydrochloride intermediate was then converted to its bisnitrone, XXXIV, by interaction with N,N-dimethyl-p-nitrosoaniline. Acid hydrolysis of the bis- nitrone gave the biscarboxaldehyde derivative. 19 CHZO H2Cl ZCSHSN‘; II + + -—+‘ H C]. 7’ S HCl 2 XXXIII XXXII 2 0N.N (C6H5)3P-CH2- o ——3—9» (C5H5)3P = Bre EH30H (BrCI—I2 ) 20 G CH-OCHg-P(C5H5)3 9 Br XLI CH3 + ____.3__y X—Ll CHO CH30H 9' 5g CH3 XLII 6,8-dimethylthieno[3,4-d]oxepin,_§L;1J using 3,4-diformyl- 2,5-dimethylthiophene (see above) and the Wittig salt, KEL- Several condensations of unsubstituted and substituted 2,5- and 5,4-diformylthi0phenes have been reported. Both Winn and Bordwell (58) and El'tsov and Ginesina (47) have 21 prepared the 1,3,5,7-tetramethyl 2-thiaazulenium salts, XLIII, by condensation of 2,S-dimethyl—S,4—diformylthiophene and S-pentanone in the presence of base. Robba et al., (55,57) and El'tsov and Ginesino (47) have prepared several CH3 /§H3 CH3 CH3 CH3 CHO \\ “ . e ' e + (C2H5) 2C0 C=O 1) LlAlHA 00 C104 ,/ CHO b // __ 2) HClo4 ase CH3 5 CH3 CH3 H3 CH3 XLIII differently substituted thieno[2,5-d]pyridazines, XLIV, and thieno[3,4-d]pyridazines, XLV, by condensation of vicinally substituted dicarbonyl thiophenes with hydrazines; these compounds were synthesized for pharmaceutical study. R R H . \\ ‘\ S ‘\i/ ' R I XL IV XLV Recently, Schlessinger and Ponticello (12) have syn- thesized thieno[3,4-d]thiepin, xy, by treating 4,5-dihydro thieno[3,4-d]thiepin-3-oxide, Egygl, with acetic anhydride. The sulfoxide, zgylg, was prepared readily from the previ- ously known 4,54dihydrothieno[5,4-d]thiepin, XLVI, (65). Eglintor YT (71- a - . 2‘ '31-'41?“ "A ! ‘V l ‘t,3‘2 It ‘ 1 ft‘c‘fr Ix n ‘ 22 Eglinton et al. (65) have synthesized this precurser, i.e., GO -*—> 530.0% d? /' /’ __ H2 H2 H2 H2 XLVI XLVI XVI 4.5-dihydro thieno[5,4-d]thiepin, by a base catalyzed ((CH3)3COK) isomerization of 1,6—dithiacyclodeca-5,8-diyne, XLVIII, which in turn was prepared by the reaction of 1,4-dichloro-2-butyne and ammonium sulfide. / CH2 'CEC "CH2 2ClCH2CECCH2Cl +(NH4)2s-———e>- s “s ‘\CH2-CEC-CH2/’ XLVIII \~ {fig / H2 H2 XLVI XLVIII (CH3)3COK>; The condensation of thianaphthene-2,S-biscarboxaldehyde with acetone dicarboxylic acid diethyl ester has been reported by Reid and Bender (61) to give thianaphtheno-Z',3':- 4.5-2,6-cycloheptadienone—2,7-dicarboxylic acid, xggx, with 1,4-cyclohexadione, thianaphthene-2,S-biscarboxaldehydes gave two isomeric bisthianaphtheno anthraquinones, L and LI. 25 HO 4C H ONa L_ 0 II + CO(CH2C02C2H5) 2 2 5 r // HO S CHO NaOC2H5\ 20 ti + r0 CHO S s l l The s jicarbonyl lanes usi Drgano li Ubstitut hl'i‘lolysj initial 3 S‘brorct} 2313 a ha. RESULTS AND DISCUSSION The syntheses of 2,3—thienyl and 2,3—thianaphthenyl dicarbonyls was accomplished through hydrogen-metal inter- change of the "activated" 2' position of 2-substituted 2-(3'-thienyl,_§y, and 3'—thianaphthenyl, gy;)-1,5-dioxo— lanes using n-butyllithium. Treatment of these intermediate organo lithiums with N,N-dimethylacylamides yielded carbonyl substituted thienyl and thianaphthanyl dioxolanes, which on hydrolysis gave the corresponding dicarbonyl compounds. The initial S—thienyl aldehydes or ketones were prepared from S-bromothiophene, using the method described by Taft (52), via a halogen-metal interchange reaction using n-butyllithium. The 3-thienyllithium was then converted to an aldehyde or ketone using N,N-dimethylformamide and N,N-dimethylacylamides. S—BromothiOphene was prepared by the procedure described by Gronowitz (66,67) from 2,5,5-tribromothiophene. The S-thia- naphthenyl ketones were prepared by direct acylation by the method of Farrar and Levine (68), which occurred predominately in the 5-position of thianaphthene. Z-Thienyl and S-Thianaphthenyl Monocarbonyls and Dioxolanes The preparation of S-bromothiophene was synthesized using a method developed by Gronowitz (67). Tribromination of 24 25 thiophene with elemental bromine occurred readily without a catalyst. 2,3,5-Tribromothiophene, isolated by steam distillation, was debrominated(zinc-acetic acid) in the 2,5-positions to obtain 43% of pure S-bromothiophene based on the initial amount of thiOphene used in the reaction. The preparations of S-thenal, S-acetothienone and S-benzoylthiophene were accomplished by using methods described initially by Taft (52); S-thenal and S—acetothienone were obtained on treatment of S—thienyllithium with N,N-di- methylformamide and N,N-dimethylacetamide. The use of S—thienyllithium and N,N—dimethybenzamide to prepare S-benzoyl- thiOphene represented an extension of Taft's work. These procedures resulted in the formation of S-thenal, S—acetothienone and S-benzoylthiophene respectively in iso- lated yields of 76, 68 and 94 percent. The reported physical properties and infrared spectra of S-thenal (42,69), S-acetothienone (70) and S-benzoylthiophene (66) agreed with the physical properties of the compounds prepared in this study. The use of these distinctly different N,N-dimethyl- acylamides in this experimental procedure, demonstrates the general applicability of this synthetic method for the preparation of ketones. The aldehyde and both ketones were then converted to dioxolane derivatives by the procedure of Bergmann et al. (71) using ethylene glycol, p-toluenesulfonic acid in a benzene reaction solvent in yields of 65-81 per- cent. Both 2-(3'—thienyl)-1,5-dioxolane, LIII, (52) and 26 2-methyl-2-(3'-thienyl)-1,3-dioxolanes, LIV, (55) have been synthesized and their physical properties agreed with those reported. 2—Phenyl-2-(5'—thienyl)-1,5-dioxolane, £1, is a new compound synthesized for this present study. R\~ //O P C\ / O/Hg LIII, R - H LV, R = CeHs The use of S-thienyllithium and N,N-dimethylacylamides represented a significant departure from past practice in the synthesis of sulfur heterocyclic ketones. Gronowitz (70) prepared S-acetothienone by converting S-thienyllithium first to the corresponding Grignard reagent using magnesium bromide etherate followed by treatment of the Grignard with acetic anhydride. ' M Br COCH Id“ e (CD79 > <67 3 G r 0" S 70 ,ether S ether, 70 S + [CH3C02MgBr] Gronowitz (66) also treated S-thienyllithium with acetaldehyde to obtain the intermediate 3-thienyl methyl carbinol, which on oxidation with chromic oxide in acetic acid gave 27 S-acetothienone. S-Benzoylthiophene had been previously prepared (70) in a 75 percent yield by the interaction of benzonitrile with S—thienyllithium. It is interesting to note that the reaction of 5-thienyllithium with acetonitrile gave very small amounts 0 (70). A strong base, viz. of S-acetothienone at —70 S-thienyllithium, could be expected to readily abstract an alpha hydrogen from acetonitrile. However, S-thienyllithium added readily to the carbonyl carbon of N,N—dimethylacetamide H COCH QTCCC (ol 3 i /*z’ 3 {(:)S + CH3CN s ‘-7$"Z<:)l + Li6 (CH2CN)e yielding S-acetothienone, rather than reacting to abstract hydrogen from the alpha carbon of N,N—dimethylacetamide to give thiophene and the lithium salt of N,N-dimethylacetamide. This is surprising, since Hauser et al. (72) have reported /0 N(CH3)2 ((;))H + CH:-C O—N(CH3)2 that two equivalents of n—butyllithium and one equivalent of Li fl (<:); + CH3C-N(CH3)2 s acetanilide react rapidly and quantitatively below 00 to 28 give a dicarbanion. Since the addition of 5-thienyllithium to (rather than hydrogen abstraction from) N,N—dimethyl- acetamide appears complete within minutes at -700, it appears that addition is a kinetically favored process over that of hydrogen abstraction. The preparation of S-acetyl and S-benzoylthianaphthene was accomplished by the method of Badger and Christie (75). using the appropriate acyl chlorides and stannic tetra— chloride as the catalyst with benzene as the reaction solvent. S-Acetylthianaphthene was separated from the 2-isomer by fractional crystallization of the reaction product from 95% aqueous ethanol following the procedure of Farrar and Levine (68). In the case of 2-benzoylthianaphthene, it could not be separated from minor amounts of the 2-isomer formed by fractional crystallization, since 2-benzoylthianaphthene is reported to be a liquid (74), solidifying to a glass at room temperatures. Following the usual ketalization reaction using ethylene glycol, etc., the distilled reaction mixture on being set aside for three months, eventually crystallized to a mass of crystals in the oily distillate. Recrystalliza— tion of this crystalline material from 95% aqueous ethanol, gave 55% of pure 2-phenyl-2-(5'-thianaphthenyl)-1,5-dioxolane, LZII, based on initial thianaphthene used in its synthesis. The isomer was shown to be pure by thin-plate, silica-gel chromatography (benzene eluent). This dioxolane represents the first crystalline derivative obtained using the carbonyl group of S-benzoylthianaphthene. Attempts to prepare oximes 29 and phenylhydrazone derivatives have reportedly failed (74). 2-Methyl-2-(3'—thianaphthenyl)-1,5-dioxolane, LEI, was readily prepared in an 86 percent yield based on the amount of S-acetylthianaphthene used in the synthesis. Both 2— methyl and 2-phenyl—2-(3'-thianaphthenyl)-1,5—dioxolanes were new compounds which were synthesized for this present study. H C 3 ‘\C/’O H2 C /’ :lHe m \o C LVI LVII Spectral Properties of 2-Substituted-2-(5'-Thienyl and S-thianaphthenyl)-1,3-dioxolanes The infrared and ultraviolet spectra and physical prop- erties of 2—(3'-thienyl)-1,5-dioxolane were identical to those previously reported (50). The NMR resonance spectrum of 2-(5'-thienyl)-1,3—dioxolane (20 w./v. percent in CC14), which was not reported, showed complex absorption, typical of an ABX pattern, with H2 at 2.75 T; H4, 2.98 T; H5, 2.90 T. The acetal hydrogen appeared at 4.22 T as a barely resolved doublet (J=O.7 cps) coupled to hydrogen 2 of thiophene. The hydrogens of the dioxolane ring appeared centered at 6.16 T as a symmetrical A2B2 multiplet, showing hydrogens both cis 50 and trans to the thiophene ring. Figure 1 shows the aromatic portion of this NMR spectrum. The coupling constants are J45=5.2 cps, J25=3.1 cps, J24=1.4 cps and J = 0.7 cps. CH—2 The infrared spectra indicated the absence of carbonyl absorp- tion at 1691 cm’1 and strong C-O-C stretching absorption at 1100 cm‘l. The preparation of 2-methyl and 2-phenyl-2-(5'-thienyl)- 1,3-dioxolanes was easily accomplished as already described. Following distillation of the reaction products at reduced pressures, the two dioxolanes were crystallized from aqueous ethanol. They had melting points respectively of 55-40 and 79.5—800. The infrared spectra of 2-methyl and 2—phenyl-2- (3'—thienyl)-1,5-dioxolanes are reproduced as Figures 2 and 5. While the physical properties of 2-methyl-2-(3'-thienyl)- 1,5-dioxolane prepared in this study agreed with those re- ported by Robba et al., (55), it is interesting to note that no spectral evidence was reported. The description of these spectral prOperties, together with those for 2~phenyl-2- (3')thienyl)-1,3-dioxolane follows. For 2—methyl-2~(3'- thienyl)-1,5-dioxolane, the carbonyl stretching frequency at 1688 cm’1 has disappeared and been replaced by the C-O-C stretching and methylenic carbon-hydrogen stretching fre- quencies at 1055 cm“1 and 2875 cm‘1 respectively. Likewise with 2-phenyl-2—(5'-thienyl)-1,5-dioxolane, the carbonyl stretching frequency at 1656 cm’1 has been replaced by C-O—C stretching and methylenic carbon-hydrogen stretching .AR .Ho> omv eaoo an coxMH mcmHoxOlem.alAamcmflnul.mvlm mo mommouowc oaumeoum mo Esuuommm mzz .a musmflm mm.m oo.m e mw.m bl - r r ? mlflh m N t .. e - . N 30h. l 5 6< < / I? Mlfih. «m 52 .eeoo ea memeoxoeeum.auAssemenu-.mvumuemeeme-m mo eduuumdm ewemuucH .m deemed Ae|Euv > owe oom oooa coma cows come oome _\ ooom comm w .p 4 m w fl ” K n _, . mmog V\ omaa moms cam oom omma ommfi owns omm case a memm moom omm _ umee C mmwd .eeou an mdeoxoeeum.auflamemenuu_mvumuesedednm mo edeuummm rmumumcH .m mesmem 55 AHIEUV > omm oom oooe come ooee come come \A\eoomm.ooom oomm 0 u r. .1 x ” ewe,“ " “ omoe “recomOH mob 0mm I mace . mesa mmme rmomee meme odofi mmm mmee ommm # v 0mm . Omvfi OmmN : omm come new (ma r 54 frequencies of 1090 cm“1 and 2880 cm'l. The sterically larger phenyl group compared to the methyl group has created additional strain in the molecule, shifting the C-O-C stretching frequency to shorter wavelengths by approximately 40 cm’l. The UV spectra of 2-methyl and 2-phenyl-2-(5'-thienyl)- 1,5-dioxolanes in ethanol showed maxima at 252 mu (65840) and 256, 269 mu ($7490, 2760) respectively. Gronowitz (75) has reported that 2— and some 5—substituted thiophenes show two maxima, which are bathochromic shifts of maxima of unsubsti— tuted thiophene, i.e., 215 mu and 255 mu (log 65.5, 5.85) arising through a w -—,'w* excitation. Many 5-substituted thiOphenes show only a single maximum as in 2-methyl-2—(5'- thienyl)-1,5-dioxolane. This condition is thought to be due to a coalescing of these two maxima, or in this case a greater shift of the 215 mu band than the 255 mu band. The NMR spectra of 2—methyl and 2-phenyl-2—(5'-thienyl)~ 1,5—dioxolanes showed the dioxolane hydrogens as a symmetrical A2B2 complex at 6.05—6.15 T in either CC14 or CH3CN solvents. The methyl group of the methyl dioxolane is observed at 8.40 T and 8.44 T respectively in CH3CN and CC14, considerably more upfield than is the case with 5—acetothienone (i.e., 7.56 T in CCl4). A portion of the NMR spectrum is reproduced in Figure 4 for the aromatic region of 2-methyl—2-(5'-thienyl)- 1,5-dioxolane in CC14 and CH3CN solvents. The spectrum for the three aromatic protons in these solvents consisted of 55 . .zommo &.>\.3 0m Amo he5o & .>\.3 om Add "mcmHoxOlem.HsAamcmflnul.mvlmiawnumalm mo mommoupwn UHuMEoum mo Esupoomm mzz .w musmflm P .m oo.m o~.m O¢.N b . p d d 5 O ant-bf) Ase Amv two quarte CH3CN. Ii to hydroge 2-(5'-thie acceptable unusually Gronowitz associated ing that t Since the "ill not 5 that the 5. Usually co: (Sl‘thieny resonance < thlgphene ) The ir 3~acetyl ar SOllds' 59 liEntiCal PhthCnyl) ~" 4 IT” can men‘s SPeCtra o f ,4- «DSEnCe O f ( 56 two quartets which are separable by use of a polar solvent, CH3CN. If an assignment of the lower quartet could be made to hydrogen 2 of the thiophene ring, as in the case of 2-(5'-thienyl)-1,5—dioxolane, the observed splitting would be Jf4.0 cps and J=2.8 cps. A value of J=4.0 Cps would be acceptable for J25. However, J=2.8 cps for J24 would be unusually large in light of all the examples studied by Gronowitz (ref. 5, p. 8). A large "singlet" appears to be associated with this downfield quartet. It is also interest- ing that the upfield quartet has the same coupling constants. Since the methyl group is unsplit, the thiophene protons will not show further coupling. Gronowitz (52) has indicated that the Spectra of 2-(5')thienyl)-1,5-dioxolane was un- usually complex (at 40 MC.). The NMR spectra of 2—phenyl-2- (5'-thienyl)1,5-dioxolane is complicated by the overlapping resonance of the phenyl protons and assignments for the thiOphene hydrogens cannot be made unequivocally. The introduction of the dioxolane ring system into the 5-acetyl and 5-benzoylthianaphthene, produced lower melting solids, 59.5-40.5O and 78-90 respectively, which were almost identical to the thiophene analogs. 2-Phenyl—2-(5'-thiana— phthenyl)-1,5-dioxolane represents a crystalline derivative of a "non-solid" 5-benzoylthianaphthene. The infrared spectra of 2-methyl and 2-phenyl-2-(5'-thianaphthenyl)-1,5- dioxolane are shown in Figures 5 and 6. These showed the absence of carbonyl stretching frequencies and the appearance é2<é\/\\ < 57 0A0>\0301—HV dH00 CH mcmHoonplm.alAamcmnuSQMCMHSpI.mvnmlamnmeIN mo muuommw UmHMHMCH .m musmflm A750 .3 0mm oom OOOH OONH 0 ea H OmH m 000m 0 mm . _ P, F on 00w 0 _ L\@% N _ W . q 4 . a 1 (. KR. . omma OONfi 1 mmma :mmwa . ooom mam _ 00m 1 fi mesa Com 1 mafia omma owm a , OQMH Omom A Ommfi I 1 V _ mmma \$/\\\)(\ £m 58 daou CH mamaoxOHUIm.HlAamcmanQMGMHnul.mvlmlawcmnmlm mo mnpommm pmumumoH ow musmflm one com 0006 come coed cows come 3\ comm opmm — P L b r — a V“ a a a . 4 J . 4 mmoe mmoe m e oeoe mmee a sweeee mooa owed 4 names come mm H mm o mmme ommm . ONNH O©¢H . cede mam ommm omom coma mam C mane mmme meme >xs/p mum of a diOXO ing freque the methyl the phenyl dentical milar sh stituents . naphthenyl unsubstitu‘ r\) 9C) and 50: As the Z-me groups apps Of the 3—5: said to mak of the UV e The NH Phthenyl) - A 59 of a dioxolane C-O-C and methylene carbon-hydrogen stretch— ing frequencies respectively at 1050 cm"1 and 2900 cm"1 for the methyl derivative and at 1085 cm‘1 and 2890 cm"1 for the phenyl derivative. These frequencies are essentially identical to those of the thiophene analogs, which have a similar shift to a shorter wavelength for the phenyl sub- stituents. The UV spectra in ethanol for these two thia- naphthenyl compounds, which appeared almost identical to unsubstituted thianaphthene, showed maxima at 220, 260, 280, 290 and 500 mu with little change in extinction coefficients. As the 2—methyl—2-dioxolanyl and the 2-phenyl—2-dioxolanyl groups appeared to make a slight change in the UV spectra of the 5-substituted thianaphthene, these groups can be said to make only minimal contributions to the stabilization of the UV excited states of these molecules. The NMR spectra of 2-methyl and 2—phenyl-2-(5'-thiana— Iphthenyl)-1,5-dioxolanes in CCl4 (10 w./v. percent) showed absorption for the aromatic and dioxolane hydrogens at 1.97 T - 2.94 T, 6.22 T and 2.26 T - 5.00 T, 6.06 T respec— tively. The methyl group of the former compound appeared as a sharp singlet at 8.28 T. The dioxolane hydrogens in 2—methyl-2-(5'—thianaphthenyl)-1,5-dioxolane appeared as a symmetrical A2B2 multiplet of approximately 50 Cps in width, while the dioxolane hydrogens in the 2-phenyl derivative appeared as a sharp singlet. With the introduction of a sterically larger phenyl group to the dioxolane ring, which should ass' average in dioxolane r a fairly ri | car cn-carb ting of the Table 40 should assist rotation of the carbon—oxygen bonds, a zero average in the chemical shift of the four hydrogens in the dioxolane ring is observed. Models of dioxolane indicated a fairly rigid ring system with severe rotation about the carbon-carbon and carbon-oxygen bond (76). However, split- ting of the A2B2 system of dioxolane was not observed (76). Table 1 summarizes UV and IR spectral data of these thienyl and thianaphthenyl dioxolanes. Table 2 summarizes their NMR spectral data. Syntheses of Carbonyl Substituted Thienyl and Thianaphthenyl Dioxolanes In the preparation of larger amounts of 5-thenal, 5-acetothienone and 5-benzoylthi0phene using the procedure of Taft (52), the direct preparation of n-butyllithium from two gram equivalents of lithium per equivalent of n-butyl bromide was economical, convenient and preferred. In the hydrogen—metal interchange reaction of smaller amounts (e.g., 10 mmoles) of 2-(5'—thienyl)-1,5-dioxolane, 2-methyl and 2-phenyl-2-(5'—thienyl)-1,5-dioxolanes and 2-methyl and 2-phenyl-2-(5'—thianaphthenyl)—1,5-dioxolanes, the procedures of Gronowitz (40) and Pastour (49) were used to obtain the intermediate thienyl and thianaphthenyl lithiums. In this work, commercial n—butyllithium in hexane was found to be an excellent alternative to synthetic material, and gave identi- cal yields of product when compared to the synthetic material used in the preparations of 5-thenal and 5—benzoylthi0phene. IIIIIIIIIIIF|| AUIOIUV) WHIIPCMUV ONO) “demz MUMVHMHNCH AHIEUVx ,CJC A»; CIK UCCCGNSOOUQUflle AlEv A m. N XQE< UCSOQE AmocsrumS >3 00 Ir.pi-fl~.flhuvfiofia Hiauub—atorafln-Unhflw.‘-—.~.. .14!an ~ \fl-e,i.fi.n~.- Canal“ Flu“ man: d 9.1.“ errJtfiiphW IN NLVH§1J >x~ I N, 8.! ~4~Bvr~u ii] 41 .mmaa .mmma ..oom .Emcu .h .mxwum .2 .h Ucm mppom .b .m .mflumflnnu .b .m .ummpmm .2 .0 .cofluucfiuxm umwmuma OGHBOQm pawn wuwfiflum** * Lose.m .ome.m .omm.m .oea.e .ooe.mmv memHoxoeo-m.e mmoe -- oom .omm .emm .omm .Hmm -Aememeerdmemene-.mo-N-Hsemre-m loom.m .omm.m .mmo.m .omm.m .oom.meo mcmaoxoee-m.H-Aemdmze omofi -- mam .omm .emm .omm .mmm -edmemerp-.mV-m-Hmrpmz-m 10mm.m home.e hOBS h031m “oem.mev -- -- “mam “0mm “0mm “0mm “mmm *umemnerdmemena mcmaoxOHU omoe -- Acme.m .ome.ev mmm .mmm -m.a-Assamese-.mV-N-Hmemed-N mcmHoxoaU mmoe -- loam.mv mmm -m.e-Assamese-.mV-m-Hmremz-m -- ewes Aomm.meo mmm memedoeeeemouemm-m -- mmmfi Aomo.mfiv omm meoemeeeoumua-m AHIEwp*AoIOIUV> AaIEov ouo> A189 A w,v meK pcsomfioo MEHXNZ mum-HMHM CH Aeoemsumv >D mwcmHoonQ Hmcmnunmmcmana pom Hmcmflna now mama Hmuuummm mH pom >5 .fi CHQMB : u u u t u at g o: a uu ra.m-ns.m veou un.eu~exeuecsw.ncum UCDOQEOU F Away-UV ha ... men mwo vmo NANZUOV: A:IUv: A3205: UHquOu< uco>~0m h. 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I.» 0 pkg ~ on - uuvuluvn~1flc 7,sz o uukd .t ~9-NIK..~. 42 .umHmCHm * * .umameuase mmmd * mcmHOxOHU -m.e-Aemcmrendme - - - mo.m - - oo-m-mm.m eeoo -mH:e-.mV-N-Hmcmzm-m mcmHoxOHp -m.fi-AH>cmrunmmd - - - mm.m - mm.m em.N-em.fi uauo -mege-.mo-m-H>:em2-m - - - mo.m - - oo.m-mn.m zommu memeoxOHB-m.a - - - Ne.m - - mo.m-oe.m «Hod -AH>cmere-.mV-m-Hscmrd-m - - - me.e - oe.m mo.m-em.m memaoxoee-m.e - - - me.e - ee.m me.m-me.m aeou -AH»emHnH-.mV-m-H>nem2-m e.m m.m m.e - - em.s me.m-oo.m «Hod meoemerpoumod-m o.m o.m e.a mo.m ma.e - we.N-mm.m zommo memeoxoae m.m H.m m.a mfi.m mm.e - mm.m-me.m ueoo -m.H-AH>eerH-.mV-N mun mmb umb mammoovm Am-ovm wnmovm oeumeoud uco>aom chOQEOo Ammuv h .#l P mocmHoonQ HmcwCuSQMCMHSB pom Hmcmflna How mama Hmuuommm mzz .m magma The dioxolé at -3o° wit" in ether 0‘: readily acc naphthenyl hydrolysis Z-(2'-acety 3" aqueous lane ring. indicated 2, discussion These r solvent by d Particularly the Sl'nthesi {X 2‘(2'-b (2 "formy1-5 (2‘~formy1-3 win 63/53 /t" x H [‘4 r-v r“ /L:/L 1:5 A: >mE< UEDOQEOU 1100c mH :5me >3 mn,~—~flu.~.fidvfi.0u~.Q — \fl—no3-n— cafwnflwfnfiw d ~71. «Ian-ls 4 >..r.u «:75 uJWn a w. .u .1 d a..ufi~...fln d \finhaaWh LVHMU .Hau‘H Hm. 1. -.fi,~ W 9%-. ”unvfiwnwm v~ ~ ~,un-w. \{u I «h... g 173-135. 46 Aomm.md hOmmda “ohm.mdv mcmHoxOHUIm.fi omoa cams son “0mm “mmm I“Hmcmruammcmanuu.muasauoun.mvumuamcmgmum Acum.om k2.0.3 rooa.mac mamaoxounum.a mmoa coma mom “mmm “mmm ufiascmnugmmamuguu.muamauomu.mvnmuamrpmzum mcmHOxOHU oaaa mmmfi Acme.aav mmm um.aaAuscmunuu.mnamoucmnn.mvnmuamcmamum . mamaoxoap rm mmoa .mmoa mama imam.oav msm um.a-hamcmflgpn.muamauouu.mvumuascmamum Aomm.m “om¢.mav mcmHOxoflp mmoa mama nmsmm "Nmm um.auAuscmflauu.mnamoucmnn.mcumuasnumzum - xiii! - mcmHoxOflU omoa owed Aooo.aav ohm um.anAfiscmflnuu.muH>8uomu.mvumuamnumzum Aoma.fifi “oam.mav oaaa omma smm .mmm mcmHoonenm.auAuscmflruu.mnamoucmmu.mvum Aoam.mfi romp.mav mmoa .maaa mama Armvomm “mom mamaoxofloum.anAamcmuapu.muamuwo«-.mcum Aomm.oa “osm.omv omoa .mfifia coma Armvmmm “mam mcmHoononm.fiuhamcmflgus.muam5uomu.mvum AHIEUVAUIOIUV> AaIEUVAOHUV> niev va meA UCDOQEOU Awaoov AmOumv >3 mmcmaoxoan Hmcmzunmmcmflcfi Ucm H>C¢H£B Umusuflumflsm H%COQHMU How mama Hmuuommm mH Ucm >D .m magma The UV spe< thienyl) -l respective bands whic? These valun respective Z-benzoylt the Z-diox the thiOph 3'5 the car PfESence 0 5m- for 2 lanes, in thiengnes phenyl gro lane ring lnCreaSed in the lat 47 The UV spectra of 2-(2-formyl, 2'—acetyl and 2'-benzoyl-5'- thienyl)-l,5-dioxolanes, LVIII, LIX and_L§, show maxima respectively at 268, 268 and 263 mu together with secondary bands which appear as shoulders in the former two compounds. These values compare to the maxima of 260, 260 and 263 mu respectively for 2—thenal (75), 2-acetothienone (75), and 2—benzoylthi0phene (77). Apparently, the introduction of the 2—dioxolanyl group into the 5' (or ortho) position of the thiophene ring has done little to interfere with resonance of the carbonyl function into the thiophene ring. The presence of the dioxolanyl ring gave a bathochromic shift of 8 mu for 2-(2'-formyl and 2'-acetyl—5'-thienyl)-1,5-dioxo- lanes, in comparison to unsubstituted 2-thenal and 2—aceto- thienones (see Figure 7). The substitution of methyl and phenyl groups for hydrogen in the 2-position of the dioxo- lane ring in 2-(2'-formyl-5'—thienyl)-1,5-dioxolane shows an increased bathochromic shift; a shift of 10 mu is observed in the latter case when a phenyl is substituted for hydrogen. The size of the 2-phenyl—2—dioxolanyl group in the 3-position of 2-thenal does not greatly affect the resonance ability of the carbonyl function with thiophene, or in other words, this group does not appear to stabilize the excited states observed in the UV spectrum (see Figure 8). The steric effect in hindering a carbonyl group's resonance is shown in 2-phenyl-2-(2'-benzoyl-5'-thienyl)-1,5-dioxolane where a hypsochromic shift of 11 mu is observed in substituting the (“I I ( J l\_) (I! “Tare 7 Log 6 5. 2 48 — 2-thenal -—---— 2-(2'-formy1—3'-thienyl)— 1,5-dioxolane ----— 2-(2'-acetyl—3'—thieny1)- 1,5-dioxolane 5" —-——-— 2—(2'-benzoyl-3'-thienyl)— 1,5-dioxolane O-D— 5-. 0+ u 5 l :7 200 ' 250 l (mu) %* 500 525 Figure 7. Ultraviolet spectra of 2—thenal and some 2—(2'-acyl—3'-thienyl)-1,5-dioxolanes. -4. .0& an.» 0 Log 6 49 2-(2'-formyl—5'-thienyl)- 1,5-dioxolane -—---—- 2-(2'—methyl-3'—thienyl)- 1,5-dioxolane -'--“- 2-(2'-benzoyl—3'—thienyl)- 1,5—dioxolane ,Sl .O~- .54- 00-0- .5 l i % 200 250 500 525 l (mu) Figure 8. Ultraviolet spectra of some 2-substituted-2— (2'-formyl-5'—thienyl)-1,5-dioxolanes. E-phenyl- phene (St 2-(2'-fo: four max: ; ‘reqUeQ 9:4: «'38 ‘Jlana Phth. 50 2-phenyl-2-dioxolany1 in the 5-position of 2-benzoylthio- phene (see Figure 9). In the case of 2-methyl and 2-phenyl- 2-(2'-formyl—5'-thianaphthenyl)-1,5—dioxolanes, the latter four maxima at longer wavelengths of thianaphthene (see Table l) are submerged by the higher extinction w -—> w* and n ——> W* transitions, respectively at 250 mu and 505 mu. of the carbonyl group substituted in thianaphthene. In the infrared spectra of the carbonyl substituted thienyl and thianaphthenyl dioxolanes, the effect of 2- hydrogen, 2—methyl and 2-phenyl-2-dioxolanyl groups in the 5-position of 2—thenal, 2-acetothienone and 2—benzoylthiophene follows the same general pattern as was shown in their UV spectra. For example, the carbonyl stretching frequency of 2-(2'—formyl-5—thienyl)-l,5-dioxolane and 2-methyl-2-(2'- formyl-5'-thienyl)-l,5-dioxolane, shows a shift to longer 1 when compared to the wavelengths of approximately 10 cm“ carbonyl frequency of 1675 cm‘1 for 2-thenal (78); it has shifted 15 cm‘1 to shorter wavelengths in 2—phenyl-2-(2'- formyl-5'—thienyl)-l,5-dioxolane. A similar effect is also seen in the successive substitution of the 2-dioxolanyl, 2-methyl-2-dioxolanyl and 2-phenyl-2-dioxolanyl groups in the 5-position of 2-benzoylthi0phene, whereas shifts to higher -1 frequencies of 50-51 cm are observed from the monosubsti- tuted 2-benzoylthi0phene value of 1656 cm‘l. The opposite effect was found in 2-methyl and 2—phenyl-2—(2'-formyl-5'- thianaphthenyl)-1,5-dioxolanes where substitution of the Log e 51 2-(2'—benzoyl—5'—thienyl)- 1,5—dioxolane —’“——° 2-methyl—2-(2'-benzoyl-5'- thienyl)-1,5—dioxolane ~—-—~— 2—phenyl—2-(2'-benzoy1—5'- 4,5q— thienyl)—1,5-dioxolane 4.0-- 5.5—- 2 - 5 L ' 4' e : 200 250 500 525 l (mu) Figure 9. Ultraviolet spectra of some-2-substituted- 2-(2'-benzoyl-5'—thienyl)-1,5—dioxolanes. larger 2- dioxolany only thos ~e~11remer Shl ft to c 52 larger 2-phenyl-2—dioxolanyl group for the 2—methyl-2- dioxolanyl group gave a carbonyl frequency shift to longer wavelengths of 20 cm‘l. Maxima observed for the dioxolane asymmetric C-O—C stretching are also given in Table 5. These maxima can ap- pear as a multiplet of 4-5 bands, however in this study, only those bands with the largest extinction are listed. Little variation appears in the principal C-O—C stretching band by changing substituent groups in the 2-position of the dioxolane ring. However, the presence of a methyl rather than hydrogen or phenyl causes a shift to longer wavelengths of approximately 55-60 cm‘l. In general, as the steric requirement of a substituent or group becomes larger, a shift to shorter wavelengths is observed in the C—O—C stretch— ing frequency of the dioxolanes. The infrared spectra of carbonyl substituted thienyl and thianaphthenyl dioxolanes determined as 10 (w./v.) percent solutions are reproduced in Figures 10-18. The studies of NMR spectra of thiophenes has attracted considerable interest since substituted thiophenes contain only a few hydrogens, and as a consequence are readily ana- lyzed giving information of electron distribution about chemically (or magnetically) non-equivalent hydrogen. From such information, considerable knowledge has been obtained and unequivocal structure assignments for the positions of substituents on the thiOphene ring can be made based on the- .eaoo CA cwxmu mcmHoonUIm.alAamcmHQuI.MIH%EHom1.NVIN mo mnpommm pmHMHmcH .OH musmflm 0mm . oom oooa obma AH: oowa 809 > oboe H coma \oomm oo.om bomm 55 mum Nb 0mm om 0mm mwm mafia Ono omoa g ma NH H owma omwd omma owmd Coma . k . 00mm ommm 0am < < oosm fRK .\|\¢ 54 00> .wHUo CH :wxmu mamHOxOAUIm.HIAawcwHSuI.MIHMmeMI.NVIN mo mupummm UmumumcH .HH musmflm me «O Doha ma a mom mmob mm a Coma 0mm mama ONNfi A.-aoc . ooWa oowfi OOWH \ a 00mm OOWM 0mmm 1‘ 0 #fi mea mt? : 00mm mam fifiom oowm .aaoo ca cmxmu mcmHoxOHUIm.alAamcoa£w|.mlamoucmnu.NVIN mo muuommm UmamumcH .NH musmam ia-er > oMo opo ooma ocma oowa oowa ooma ,cx boom ooom oomm - T a a + 3 dl V\u - q omoa omwa ooma 5 mos s .oma oooramooa mama mmoa mmo u 2 o oa ooaa ooo aaa ooom . m o a. oooa ooom /¢ £ woaa mama m C o aa ¥ mom 56 .eaoo ca cmxmu mamaoxoaplm.filAamcmanul.muahEu0m:.mvlmlamnuoE|N mo mauummm pmHMHMCH .mfi magmam ia-soc > ooo ooo oooa ooma ooaa oooa ooma (\ omm omom oomm T A n ” fi ,fi 4 v a o oo a oooa _ moma omaa moo iomma ooo oooa maoj moaa oaaa oooa moo , oosa ooom moma maaa ama C m ma am a Ommm .eaoo ca 57 cmxmu mamHoxOHUIm.HIAamcmanul.MIH>ONch|.mvlmlahnumalm mo mupommm UmHMHMQH .«H musmfim A.-eUc > oMm ohm coma coma omwd ODmH coma owmw omom 03mm A 1 A a A a J 4 mmma V _ mam4<%sma j moma ooh own mom mmaa ooaa oomammaa omm oo oso oaaa ( 00 D coma mm ONMH a I , . fl _ oooa ooom mom ooom .mca oao : Cw o H omom .eaoo ca cmxmu mcmHoxoaplm.HlAamcmanul.mlamanom1.NV|NIHmcm£mlm mo muuommm UmumumcH .mfi magmam AaIEUV > omo ooo oooa ooma ooaa oooa oomaL\ oomm ooom oomm 3 m 4.. 4. T » u a : (oooa mmaa oak oaoa omma , oooa maoa oaa osma ooo moo Nana moo ooo ooo 4 oama ooaa ooom 8 i 5 a m a oaom mo C : (oooa no; mma o C 0 ma {soon 59 .eaoo ca cmxmu mcmHOxoaUIm.HlAahcmagul.m1H%oucmnl.mvlmlamcmnmlm mo mauummm pmumnwcH .md magmam AaIEUV > . omo ooo omoa omma oowa oooa ooma owmm onom oomm « A 4 5 A A A V! d d oooa osma : mos oaaa ooh omoa 9 mama mmaa . oooa: em as A #oo ooaa omo . mooL oaa omma oooa ! _ ooom as : oooa ooom ; ooaa i oaom : oooa _ i i ‘ m H .«Hoo cfl cmxmu mcmHoxOlem.HlAawcogpQQMGMHnul.mlawauowl.NVINIH%£u®EIN mo mupommm UmHMHMCH .na musmflm AH-EUV > 0mm 0mm oooa coma owwa oowa cama‘xx comm oooa onmm q % A . 1 . d \W . _ T oomfi ommfi mmo mnfifi 2 j omma , . omwa P 0mm cmab omma cam owna _ r mafia 00mm , . o ommm 6 mmm mmfifi owwfi mam nNMH A cmmfi 5 omm mw m ma Q _ 4 L coon mcmHOXOHUIm.aIhahcmSpSQMCMHSuI.mIH%EHOMI.NVINIH>:m£mIN .«Hoo a“ cmxmu mo muwommm UmumumcH .md musmflm 61 Aflnaov > [mMm cam oooa coma oowfi coma coma .b N ooon owmm q q a. d " .fi 1 \ a w — 0¢md coma o«oa om a omafi ommfi mow maca .mfij : was : obma omm HWH ( n N mm¢fi 0¢¢H oomm owmfi mmm g oxma . ~A mm a cape ommm momg mom 62 splitting or coupling constants of the thiOphene hydrogens. Gronowitz (ref. 5, p. 8) has observed, based on the study of 56 monosubstituted and 65 disubstituted thiOphenes, that the coupling constants, all of equal sign, fall in four dis- tinct regions: J35 = 1.25-1.70 Cps; J25 = 5.20-5.65 cps; J34 = 5.45-4.55 cps and J45 = 4.90-5.80 cps. Structural assignments are made on the basis of these observations. Table 4 summarizes the NMR data on the carbonyl substituted thienyl and thianaphthenyl dioxolanes, prepared in the course of this investigation. One of the more interesting spectra, that of 2-(2'-formyl—5'—thienyl)-1,5-dioxolane in CH3CN is shown as Figure 19 and demonstrated the applicability of the NMR to structure determination in these types of compounds. The coupling constant for the aldehydic proton at —O.24 T (or 11.76 5) is 1.2 cps and is coupled with hydrogen 5 of the thiophene ring. Hydrogen 5 is also split by hydrogen 4 (J24 = 5.15 ops); by the aldehydic hydrogen (JCH02_5 = 1.2 cps) and to a slight degree, it is split by the acetal hydro- gen (J g'O.5 cps). It is interesting to note that by chang- ing to a non—polar solvent, CC14, the latter slight coupling by the acetal hydrogen to hydrogen 5 disappeared. Hydrogen 4 shows coupling with hydrogen 5 plus coupling with the acetal hydrogen (J g 0.55). Again this latter slight coupling CH-4 also disappeared when the spectrum was determined in CCl4. For this compound and 2-(2'-acetyl-5-thienyl)-1,5-dioxolane and 2-methyl-2—(2'-formyl—5'-thienyl)-1,5-dioxolane, the .pmamauasfi Hmoauumeahm mmm¢ mo Hmucmo .pcw>aom Hmcnwuca m mm pom: mamaam Hwnumemuume ** mmCMaOXOHQ chmnuSQMCMHSB Ucm HhcmHSB Umusuflumflsm HNCOQHMO MOM Mqu Hmuuummm MHZ * 11 mcmaoxowo nu- a»- In- N0.m In- 50.0- In- In: zommo um.auaamcmnunmmcmunu II. In- In: 00.0 In- mp.0n nu: 1.: «H00 I.muamsnoma.mvumuamcmnmum Ammuv -u- nu- In- 00.0 06.0 05.0- Ill uuu zummo mamaoxouc Ammov Im.HIAHm:m£p£mocmw£u [In I.. ll. 00.0 00.0 00.0- In- In- «H00 u.m-a>&uomu.mcumuamnumz-m In- nu- 0N.m 50.0 In- In- 1-- mm.m zommo mamaoxououm.auiamcmflgu In- nu- 0m.m 00.0 -n- .n. -n- mfi.m anon I.muamowcmn-.mvumuamcmnmum nu- e.fi 0m.m 00.0 In: 00.0-Ahm.msm>.m zommo mcmnox0H0um.auAH>:mflnp -u- 0.5 0N.m 50.0 In- mm.0ufiom.mvmm.m ¢H00 n.muasauom-.msumnamcmnmum Ammos In: In: 0H.m mm.0 em.m In: Ama.mv>m.m zommo ‘ Ammov mcmHox0H0nm.duAH>:mflzu 3 In- .I. 0m.m 00.0 0e.0 nu- Ams.m500.m .Hoo u.muamoucmn-.mvumuamnmenm 6 Ammov nu- m.a 0m.m 00.0 mm.0 00.0- mm.m he.m zommo Ammov mCMHOXOHUIm.fiIAH%cmH£u In- 0.5 0m.m 00.0 mm.m 00.0- ma.m 00.m d.50 n.mIHmEuom-.anmuamsumzum 1-- In- 0m.m 00.0 00.0 In- In- 05.m 200mm mcmHoxoucum.a In- In: mm.m 0H.0 00.0 In: In- 00.N ¢Hoo IAamcmngpu.muamowcmmu.mvnm ammimow Ammoc 0 mm.0 In: mm.m No.0 00.m mm.» mm.m 00.m zommo Ammov mamaox0H0u0.a .. 0.0 nu- 0m.m No.0 00.0 00.5 00.m ~>.m «H00 uramcmflnun.muamumo¢.mvum N0W0 n a n A moovmun 0.0 N.a mfi.m 00.0 0a.m em.0u mm.m 05.0 zommo mamaox0H0-m.fi .. u: N.a 0a.m «0.0 00.0 0m.0n mm.m 00.m «H00 uAamcmflnun.muamsuomu.mvum IN N I N m - m A moovmoh m omon mv0 ** A moovm mm mm mm «m ucm>aom vasomaoo b *9 .0 means .zoomo ca cmxmu mamHoxOHUIm.HIAawcmflnul.m1H>EHowl.anm mo mupommm mzz .mH musmflm Apmm.mv bv Aea>.mvam m m EUI mm _\ M mmomm.o|._w1l mmo m. m . muomo _ _ mmo mm.©lu mmo N a n h _ _ Ammoovmo ml b m . u I m o m a 0306 mmu ma.m u m¢b 1900.0-0 QMU ANN.N "Ev mm 65 coupling constants were found to be J45 = 5.10-5.25, J = 1.2, indicating these compounds are definitely CHO-5 2,5-disubstituted thiOphenes. In these NMR studies, the appearance of the aromatic protons appeared between 2.00-5.5 T and the acetal hydrogen appeared at 5.60 T - 5.95 T (generally as a singlet). The ketal methyl group at 8.28 T - 8.40 T (singlet) was consider- ably upfield from acetyl methyl which appeared as a sharp unsplit singlet at 7.58 T — 7.50 T. The dioxolane hydrogen appeared as a symmetrical A2B2 multiplet of varying band width; the center of these multiplets varied from 5.88 T - 6.55 T. The effect of changing the solvent from CCl4 to a polar solvent CHSCN, generally shifted the more "acidic" protons downfield. The problem of assigning the T values for thiophene hydrogens in compounds containing phenyl substituents is complicated by the overlapping resonances of the phenyl protons. Portions of the aromatic region in the NMR spectrum in CCl4 and CH3CN solvents are reproduced in Figures 20-25 respectively for 2-(2'-benzoyl-5'~thienyl)—1,5-dioxolane, Lg, 2-methyl-2-(2'—benzoyl-5'-thienyl)-1,5-dioxolane,‘lel, 2-phenyl-2-(2'—formyl—5'-thienyl)-1,5-dioxolane, 2511;! and 2-phenyl-2-(2'-benzoyl-5'-thienyl)1,5—dioxolane, gzgy. A common NMR characteristic for these types of compounds, appears to be a doublet in the upfield portion of the aromatic region. This characteristic is quite evident in Figure 21 and 25. The couplings for these doublets are 5.10-5.20 cps mwwuwr! , ,xil! .ucm>aom ZUmmU ca RA.>\.BV om Amv uucm>H0m ¢HUU ca RA.>\.BV om Adv "mamaoxOHU Im.alAamcmwnul.mnamoucmnl.mvlm mo mammoupmn Uflumeonm mnu mo Esuuommm mzz .om musmflm P Ownm om.m mmnm . q a mfib A5 66 o~.N om.N mN.N fl Md‘h. EV u KIN-{al.flo r0... .ucm>aom ZUmmU CA &.>\.3 ON Amv u«H00 ca R.>\.3 om Adv ”mamaoxoaplm.a IAamcmfl£u|.mlamoucmnl.mvlmlamzumelm mo mammonpmz oaumEonm on» no Esuuommm mzz .HN musmflm oo.m e m>.m om.m i m Ar 3. mfih. oo.m s. mum om.m II I 4.19, T I l ‘ 1 7 6 mash... EV 68 .ucm>aom 20mmo :H RA.>\.3VON Amv “waoo GH RA.>\.BVON A¢V "mamaoxowwlm.fi IAawcmazul.mna>€u0mu.mvlmlamcm£mlm mo mammonomn Uflumeoum mnu mo Esuuommm mzz .NN wusmflm 00.0 m».m P om.m p b . a 1 )Iltb ‘ ‘I‘ mauhu ”ARV m¢h4 Amv .u:m>aom Zoomo RA.>\QNVON Amv uucm>aom ¢HOU RA.>\.3VON Aflv ”mamaoxOflolm.a IAawcmflnpl.mua>oucm£n.NVINlawcmsmlN mo mammonoms UHumaoum mnu mo Esuuommm mzz .mN musmflm .0 mi. N 0 +0 [‘0 "’-" ’ b. '7’), b. I’D I ' “ “‘ 1 ‘1 Q mmwha 69 ‘I ‘- mhvh. S , 70 and are attributed to hydrogen 4 of the thiOphene ring. The recent work of both Kaper et al., (79) and Martin et al., (80) have indicated that the chemical shift of hydrogen 4 of the thiophene ring of several 2—benzoylthi0phenes was consistently observed in the upfield portion of the aromatic region of the NMR spectrum. The coupling constants were also found to be similar to those observed in this work, i.e., J = 5.0 - 5.4 Cps. In Figure 22 the partial spectra of 2-phenyl-2—(2'-formyl-5'-thienyl)-1,5-dioxolane in CH3CN, the downfield quartet appears to be hydrogen 5 as the observed splitting is J = 1.4 cps and 5.2 cps. Though the evidence is not unequivocal in the case of these compounds, there are strong indications that these compounds are in- deed 2,5-disubstituted thiophenes. Both 2-methyl and 2-phenyl-2—(2'-formyl-5'-thiana— phthenyl)-1,5-dioxolanes show the 2-aldehydic hydrogen at slightly downfield values (-0.68 T to -0.78 T) than their corresponding thienyl analogs. There is little reason to doubt the 2,5-disubstituted thianaphthene structure, due more so to chemical reasons, i.e., occurrence of metallation in the benzene part of thianaphthene appears unlikely when the 2-position of thianaphthene is available for hydrogen-metal interchange. 71 Hydrolysis of Carbonyl Substituted Thienyl and Thianaphthenyl Dioxolanes Hydrolysis of the carbonyl substituted thienyl and thianaphthenyl dioxolanes to their corresponding 2,5-thienyl and 2,5-thianaphthenyl dicarbonyls was accomplished under rather mild conditions. For example, 80-100 ml. of a 0.5 molar solution of the carbonyl thienyl or thianaphthenyl dioxolane in acetone was stirred for two to two and one—half E hours at ambient temperatures in contact with 5-10 ml. of g 10% aqueous hydrochloric acid. This procedure was sufficient ’ to hydrolyze all the dioxolanes in nearly quantitative yields with isolatable yields of 65-90%. The products obtained were clean crystalline materials with two exceptions, 2-benzoyl-5-formylthi0phene, L§;§_and 2-formyl-5-acetyl- thianaphthene, LXXIV. ,’COR COR ©COR' @ O CHO S B. Bf g LXVII H H LXXIV CH3 LXVIII H CH3 Lm C3H5 LXIX H C5H5 LXX CH3 H LXXI CH3 C5H5 LXXII CBHS H LXXIII CSHS C5H5 72 The former compound was isolated from the hydrolysis reac- tion as a dark yellow-brown colored crystalline mass compared to the light yellow colors of other 2,5—thienyl dicarbonyls prepared in the course of this work. The use of activated charcoal in hexane—ether crystallization solvent gave an acceptable product. 2-Formyl-5-acetylthianaphthene was ob- tained from the hydrolysis mixture as a dark brown colored semi-crystalline mass. This thianaphthenyl dicarbonyl was readily purified by sublimination at 50-700 and 0.1 mm. Hg. of pressure. Two disappointing exceptions to these hydrolysis pro- cedures were the attempted preparations of 2-formyl-5- benzoylthiOphene, ggglg, and 2-formyl-2-benzoylthianaphthene, szy. Initial hydrolysis attempts yielded only very dark brown resinous oils. The NMR spectra of these oils showed the characteristic 4:1 integrated ratio of dioxolane and aldehyde protons in 2-phenyl-2-(2'-formyl-5'-thienyl or 5'- thianaphthenyl)-1,5-dioxolanes, indicating the absence of a dicarbonyl. With the presence of the latter group, the 4:1 ratio would be less than this or the appearance of another aldehyde peak would possibly have been noted. The continued hydrolysis of these two dioxolanyl aldehydes gave further rEduction in the intensity of the 4:1 ratio of dioxolane- aldehyde proton peaks. Eventually, the only observable proton absorption in the NMR was in the aromatic region (2.2 T — 3.0 T). Apparently as both dicarbonyls were formed, they 75 were sufficiently unstable to prevent their isolation and their decomposition products did not show aldehydic protons in their NMR spectrum. It is also of interest to note that these final hydrolysis products did not show the presence of any carbonyl stretching frequencies in their infrared spectra. The disappearance of both IR carbonyl and NMR :71 aldehyde-dioxolane bands could also be followed as a function of time. The use of a nitrogen atmosphere in these hydrolyses attempts did not improve the procedure and allow the isolation of the products. These dicarbonyl thiOphenes and thiana- E phthene are all new materials, with the exception of the two isomers, 2-formyl-5-acetylthiophene, Egg, and‘2-acetyl-5- formylthiophene, LXVIII. Robba et al., (55) had recently prepared these two compounds by acid hydrolysis from their respective dioxolane precursors, as described above. Again Robba et al., presented little spectroscopic evidence for these compounds; i.e., no ultraviolet or NMR data and little data on their infrared spectra. These data, obtained in this work, are discussed below. 5,4-Diformylthiophene The synthesis of 5,4-diformylthiophene showed that this eXperimental approach may be applicable to the synthesis of other 5,4-thiophene dicarbonyls. The approach consisted of two consecutive bromine-metal interchange reactions with 5,4-dibromothiophene similar to the methods reported by 74 Gronowitz et al. (24,40,66) for the syntheses of 4-methyl- thio-5—thenal and 4-formyl-5-thenoic acid. Treatment with N,N-dimethylformamide at -700, gave 5,4-diformylthiophene in a 54% yield based on 2-(4'-bromo—5'-thienyl)-1,5-dioxolane. The expected 2-(4'-formyl—5'-thienyl)-1,5-dioxolane was not obtained, which was unusual since the hydrolysis medium in this case was water. 5,4-Diformylthi0phene is identical to the compound prepared by Trofimenko (51) by the reduction of 5,4—dicyanothiophene with diisobutyl aluminum hydride. Spectral Properties of Thienyl and Thianaphthenyl Dicarbonyls The summary of ultraviolet and infrared data is given in Table 5. Surprisingly, all the ultraviolet maxima recorded in ethanol showed little variation (272 mu-280 mu). In gen- eral, these maxima were all shifted to longer wavelengths by 10-15 mu in comparison to the corresponding carbonyl substi- tuted 5-thienyl dioxolanes. In the case of the single pair of thianaphthenyl derivatives, the shift to longer wavelengths was only 5 mu. In the case of 5,4-diformylthiophene, an addi- tional maximum appeared at 250 mu having a high extinction coefficient. This could be the displaced 215 mu primary band of thiOphene caused by the dicarbonyl group. As groups ortho to each other become sterically larger, resonance becomes more difficult and hypsochromic shifts were seen; for example, the maxima for 2-benzoyl-5-acetylthiophene, ngl, and 2,5— dibenzoylthiOphene, LXXIII, appear respectively at 261 and 75 mnmd anmvomma .mmmd Onwa .Nmmfi .OHNH mmwa .ommfi ome .ommfi wwwfi Nmma Anmvmwwfi..ommfi .Anmvmmmfl “ohm.m “me.OH hoom§Nv 00m ume ume A®¢¢.mmv dwN AO¢>.> “0mm.mav omN “HwN Aomm.aav omN AON>.Ndv th Amma.m “om¢.OHv Azmvoam “th Aowm.Na h030$ mew “00m. AomN.OHV NNN moo:unanswezua%umUMIm1a>EHOMIN mdmsmoenuH>0Ndeeonm.m mquQOHQuawmeMImla%oucmmlN mC0£QOH£UH%U®OMLMIHWEHOWIN mcm3m0H£uHNEHONIMIamoucmmIN mcm£m0H£uH>EHOMImIH%umoEHomaQIm.N AOHUV > meflxmz UmumnwcH “moans Awe, xmsz MEmeE >3 pcsomfioo mahconumuan Hmcmnunmmcmflna pom chmflna How mama Hmnuoomm mH pom >2 .m magma 76 264 mu (see Figure 24). 2-Formyl-5-acetylthianaphthene, ngly, shows a typical absorption for a carbonyl group sub— stitution, i.e., two maxima at 257 mu and 507 mu which represent respectively the w ->'w* and n ->'W* transitions of the carbonyl group. The band at 254 mu is probably the 'v-i" I. high extinction primary band which occurs at 220 mu in un- 'Ffi substituted thianaphthene, shifted by the presence of the ; two carbonyl groups. The infrared spectra of these thienyl and thianaphthenyl dicarbonyls (Figures 25-52) were characterized by maxima with i smaller extinction coefficients than in spectra discussed previously. The one exception were the carbonyl stretching frequencies. The carbonyl frequencies range from 1690 cm-1 to 1650 cm'l. Since carbonyls substituted in the 2-positions of thiophene have greater resonance capabilities with the thiophene ring compared to the 5-position (thus shifting to longer wavelengths), it is not surprising to find 2-benzoyl- 5-formylthiophene, LKIEI and 2—formyl—5-acetylthiophene, LEE, with distinct doublets as carbonyl stretching frequencies. In these cases, the absorption at longer wavelengths was assigned to carbonyl at the 2-position. The Spectrum of 5,4- diformylthiophene showed very few maxima, due to its high degree of symmetry. The spectrum of 2-benzoyl—5-acetylthio— phene, Lzzl, showed a strong peak at 1710 cm‘l. This most likely is not a carbonyl stretching frequency. Gronowitz (78) has explained these bands as Fermi resonance overtones of the Log e 77 2-benzyl-5—formylthiophene -—---—- 2-benzoyl—5-acetylthiophene _._..—u-2,5-dibenzoylthi0phene 4.5‘" 4.0-+ 5.5-- 5.0-- 2.5 % i i 200 250 500 525 A (mu) Figure 24. Ultraviolet Spectra of some 5-acyl-2-benzoyl- thiophenes. ‘ nan: .0000 C0 cmxmu mconmownuamfiuom0©Im.N mo mnuommm pmumumcH .mN musmflm \ “ 78 AHIEUV > 0M0 000 0300 00W0 0000 00m0 0b00 \0000 0900 0000 a .J 4 _ q a J ~V1 a q 0000 0000 0000 0000 0000 0000 a 20000 0000 0000 0000 000 000 _ . 000 0000 0000 0 N00 fr¥ N00 .0000 CH cmxmu mcmnm00£00>800m0610.m mo muuommm UmHMHMCH .mN musmflm A.-edc > 000 000 0000 00w0 0000 0000 0000 \0000 0000 0000 0 r I . . 0 0 a u 51 . a 0000 m 0000 0000 0000 0000 000 00000000 0000 0000 0000 000 00000000 0000 00 0000 000 0000 —. r‘ .0000 CH :mxmu 0cm£000500>5000Inlamumomnm mo muuowmm pmumuwcH .NN 005000 001500 > 000 000 0000 00m0 0000 0000‘ 0000 0000 0000 0000 r — — P _ . . A a a a 0 - _ . VN . 0 0000 0000 0000 1 00mw00 0000 0000 O 8 000 0000 000 0000 0000 ‘J 000 C 0000 No i 0000 ooam Om m 81 .0000 :0 cwxmu mcmgm00£u0%EHOMIMIHmONQmQIN mo mnuommm omnmnmcH .mN mHDmHm 00:500 > 0mm 00m 0000 OONH 0000 0000 coma lemmN ooom 00mm P _ p . . _ . _ a A F a d a VN - — ommfi mmmfi ommd mMNH 0N0 mob 00m mm H mNm NNma 000 0000 0000 000 000 0000 00000000 mace om mmad mwbfi 000 001 C m0m i oomN omom 0 H .0000 Q0 cmep mamSQOHSuahumUMIMIH>EHOMIN mo mnpommm UmHMHMCH .mN ousmflm 82 00:53 > 000 000 0000 0000 0000 0000 0000 00 0900 0000 . . p . b p c 1 _ . 0 .4 5 A a _ V 000000000 O‘Na A 0000 0000 0000 0000 000 I 0000 000 OwHH 1 000 i C 000 000 0 00 60 000 ._ 0 0000 \ @000 C_ - .0000 00 00000 000000000000000u0u0monc0nu0 00 0000000 00000000 .00 000000 85 AHIEUV > . 000 000 0000 0.000 0000 0000 0000 K0r00 00.00 0000 1 a a - 4 q a V v4 0 . 0000 0000 0000 0000. 0000 000 000 0000000 000 000 000 0000 0 0000 00 0 000 0mm 0mm 3 0000 C 0000 0000 000 . 00 0 . 00 0 0000 0000 / .0000 :0 cmxmu mamQQOHSuamoucmnflolm~m mo mupummm ©0000MCH .Hm m0smfim A0IEUV > 000 000 0000 0000 0000 0000 0000 0000 0000 0000 L p - 0 - p r p r k — - _ 0 0 -u 0 0 0 , _ 0 v M. . _ 0000 0000 000 2 > 2 oomr 000 0000 0000 0000 4 8 0000 0000 A 0000 J 000 4 J 0000 0000 0000 0000 00 0 g _ 0 00m 000 rg F\. 0000 5 f/r\/<)(<. ,\g’fl 0.00 000 0000 00.00 0000 S»: 0m00 2000.0 0000 0000 a A % a 4 J — ow M 1 u all 0000 0000 0000 5 8 0000 0000 0000 0000 0000 000 0000 0000 000 000 0000 000 000 0000 86 carbonyl band and bands appearing at 830 -850 cm‘l. These overtones are also found in the spectrum of 2-benzoyl-5- formylthiophene EXEE: The NMR spectral data of these compounds are summarized in Table 6. In general, the T values for the thiophene pro- tons appear at somewhat lower values (2.00 — 2.70 T) than F3 in the corresponding carbonyl substituted thienyl and thiana- phthenyl dioxolanes, due undoubtedly to the deshielding effect of an added carbonyl group present in the thiophene molecule. The methyl of the acetyl groups appeared at 7.22 — g 7.71 T and the aldehydic protons, being considerably more deshielded, appeared at —O.15 to -O.62 T. The use of a polar solvent, CH3CN as compared to CC14 for determining spectra: showed little effect on the T values. The range of coupling constants found for these dicarbonyl compounds were: J45 = = 0.30- 5.10-5.20 cps, = 0.85-1.10 cps and J J(CHO)2-5 (CHO)3-5 0.70 cps. There was nothing unusual regarding the coupling constants, other than J appeared somewhat smaller than (CHO)2-5 in previous examples discussed. The dicarbonyls, which have a benzene moiety, did not show resolvable positions.for the thiophene protons, due to deshielding of the 4 proton by the additional carbonyl at the S-position of the thiOphene ring. These values are given for the aromatic range in which aro— matic protons appear. 87 n o . . 1 2.... ’J 5.)- .. u 1“... .COHmmu 00008000 :0 c000m00090 cououm mo mmcmm ** .manm>aommulcoz * ::: ::: ::: ::: 00.0 00.0: ::: ::: 20000 000000000 ::: ::: ::: ::: 00.0 00.0: ::: ::: 0000 :000000:0:0>00om:0 ::: ::: ::: ::: ::: ::: 00.0: 00.0 20000 00000O000 . ::: ::: ::: ::: ::: ::: 00.0: 00.0 0000 :000000000:0.0. ::: ::: ::: ::: 00.0 ::4 **00.0: 00.0 . . 000000000 ::: ::: ::: ::: 00.0 ::: **00.0: 00.0 0.000:;000000000000:0. ::: 00.0 00.0 ::: 00.0 00.0: .00.0 00.0 00000 000000000 ::: 00.0 00.0 ::: 00.0 00.0: 00.0 00.0 0000 :000000:0:000000:0 00.0 ::: ::: 00.0: ::: ::: *000.0: 00.0 .20000 000000000000000 00.0 ::: ::: 00.0: ::: ::: *000.0: 0000 0000 :0:000000m:0 00.0 ::: 00.0 00.0: 00.0 ::: 00.0 00.0 00000. 000000000 00.0 ::: 00.0 00.0: 00.0 ::: 00.0 00.0 0.000 :000000:0:000000:0 ::: ::: ::: 00.0: ::: ::: 00.0 ::: 00000 000000000 ::: ::: ::: 00.0: ::: ::: 00.0 ::: 0000 :00000000:0.0 *.0.z "0:0000000 00.0 00.0 00.0 00.0: ::: 00.0: 00.0 00.0 20000 0 0.0 "0: Aomuvb mcm£m0050 00.0 00.0 00.0 00.0: ::: 00.0: 00.0 00.0 0000 :00000000:0.0 l0 IN N. m. N 11 0 000000Hu0 .000000 000 000000 A 0000 000000 00 «m 000>0om 00000000 Ammwv b H mawcoflumofla Hmcmnusmmc00£a Ucm Hmcmflne How mumn Hmuuwmmm MSZ .m magma 88 Condensation Reactions of Thiophene biscarboxal— dehydes under Hinsberg Conditions A cursory attempt was made to investigate the condensa~ tion products of 3,4-diformylthiophene and 2,3—diformylthio- phene with diethyl thiodiglycolate and dimethyl diglycolate as catalyzed by sodium methoxide. 3,4-Diformylthiophene and diethy1 thiodiglycolate reacted in the presence of sodium methoxide in methanol at 100, giving a base soluble compound which on the basis of elemental analysis and spectral prOper- ties has been assigned to structure, thieno[3,4—d]thiepin- 2,4-dicarboxylic acid. Figure 33 shows the infrared spectra of this compound. It has bands in the hydroxyl (3500 cm‘l), carbonyl (1665 cm'l) and olefinic (1595 cm'l) regions. The Spectra is of rather poor quality and was determined as a "mull" in CCl4. The NMR spectrum of the material taken in N,N-dimethylacetamide showed three singlets of equal inten- sity at —O.89 T (carboxyl hydrogens), 2.28 T (6,.8 hydrogens) and 2.43 T (1,5 hydrogens). The UV spectrum showed clearly defined maxima, well into the visible range. The bands are (ethanol): 218 m0 (14,300), 252 mu sh (15,460), 284 m0 (34,100), 331 mu (2,390), 348 m0 sh (2,070) and 368 m0 sh (1,180). The extension of the visible absorption is seen even into the infrared, where increasing transparency was observed from the 2 to the 6 micron region. An attempt to prepare thieno[3,4-d]oxepin-2,4-dicarboxylic acid and thieno[2,3-d]thiepin-2,4-dicarboxylic acid were 89 .0000 :0 00000 0000 000>xon00UHUlw.NI00000Q0HUI0.m_000000 00 0000000 0000000H .mm 003000 00-000 > 0mm 00m oooa coma 0000 0900 ooma\ \.oomm Gown 09mm 0. 0 0 0 0 0 0 m u‘ 3 J 1 mama 00mm 90 unsuccessful when conducted under similar experimental con- ditions. In the former case, a resinous polymeric product insoluble in a variety of solvents, e.g., CC14 and DMF, was obtained. In the latter case, a black intractable product was obtained and continued to form as the reaction proceeded, together with a strong odor of hydrogen sulfide evolution. 1? 0' 'Wq. ‘ - u ‘3‘- n Microanalytical Data All the compounds prepared in the course of this study W1“ were submitted for microanalytical analysis to Micro-Tech Laboratories, Skokie, Illinois. These analytical data are summarized in Tables 7 and 8. All results were within the accepted accuracy of 0.2% of the calculated values. 91 mummy. haymmv .0000000H .00xoxm .000000000000 £00BIO0002 >9 00800000m 0003 000%00cfi0 0 1 _ Ammoo oumufimmoovo 00.00 mm.m 00.00 mm.mm 00.0 nm.>0 _mm0Oomoao umo\\ my: 00 00.00 00.0 mm.0m mm.mm mm.m 00.00 mmO0moo omo: 000: m 0m.00 00.0 00.00 >m.00 00.0 mm.n~ 000000000 0: mmoooou mmoooou 00.00 00.0 00.00 mm.m0 00.0 00.00 000000000 m: 00000» mmoooo: 00.0w mm.m 00.00 00.00 00.0 00.00 mmOombo m: @0000: 000: 00.00 00.0 00.00 00.00 00.0 00.00 mmOmmmflo m: 000: mmoooou 00.00 00.0 00.00 00.00 mm.m 00.00 mnemmbo m: 000: @0000: 00.00 00.0 00.00 00.00 m0.m m0.0m mm00moo mu , 000: 000: m0.m 00.0 00.00 mm.m m>.0 00.00 mmOofimomo mu NANmoonmmoou mmoooon 00.00 00.0 00.00 mm.m0 00.0 mm.0m mmomam0flo mu «Ammoovmmeoou 000: 00.00 00.0 00.00 00.00 m0.m 00.00 mmO000mHo 0n mammoovmmoon mmmooon 00.00 00.0 00.00 00.00 00.0 00.00 moOodmmo 0: «0000000000: 000: m0.m0 00.0 00.00 00.00 00.0 mm.0m mmom000flo 0: 000000000: mmoooon 00.00 00.0 00.00 00.00 00.0 mm.0m uncoflmmo 0: 000000000: m”0000.. mm.~0 00.0 00.mm 00.00 00.0 00.00 0000000 0: mhmmoovmon omou 0m.m0 mm.m 00.00 om.m0 00.0 00.00 mmomdmmao m: NANmoovmmoooul, 0- 00.00 00.0 00.00 00.00 mm.m 00.00 mmoodmmo m: «AmmooVAomovo- 0- 0:00am 00m000>m £00000 0:00am c0mO0©>m £00000 005E0om. 0m 0m 0m Uczom 0000090000 0 m «mahkwfimm 000C0£Q00£B 00050000030 000 000D 00000%00C< 00002 “B 00008 92 i .I — a mn;. 0.07 .0000000H .00xoxm .000000000000 0008100002 >0 005000000 0003 0000000000 fi . 00.00 00.0 00.00 00.00 00.0 00.00 00000000 00000. 000: 00.00 00.0 00.00 00.00 00.0 00.00 000000000 000000000000. 000: 00.00 00.0 00.00 00.00 00.0 00.00 000000000 «0000000000: 000: 00.00 00.0 00.00 00.00 00.0 00.00 000000000 000000000000. 0- 00.00 00.0 00.00 00.00 00.0 00.00 000m00m00 mAmmuovmmoou 0- 030030 000000wm 000000 030030 00mo00>m 000000 0038000. 00 .0 Hm 0030& 0000030000 ii 0 :T 00 N. 00000000m000008 00030000030 000 0000 00000M000¢ 00002 .0 00008 EXPERIMENTAL Apparatus used with n-butyllithium solutions were flamed under a stream of dry nitrogen prior to start of a reaction. Dry nitrogen was obtained by passing "pre-purified" nitrogen through twin towers of sulfuric acid, a tower of solid potas- sium hydroxide and a final tower of anhydrous calcium sulfate. Thiophene was obtained from Pennsalt Chemicals Inc., Phila- delphia, Penn., and the thianaphthene was secured from Columbis Organic Chemicals Inc., Columbia, S. C. These were purified by distillation through a glass helices packed column. Bromine was of a technical grade supplied by the Dow Chemical Co., Midland, Mich. N, N-Dimethylformamide and N,N-dimethylacetamide were obtained as practical grade chemi- cals from the Matheson, Coleman and Bell Co., Norwood, Ohio. These amides were treated initially with solid potassium hydroXide and then with calcium hydroxide. followed by distil- lation at reduced pressure. NMR spectra were determined in a Varian A—60 high resolu- tion spectrometer at 60 mo Operating at room temperature. Infrared absorption spectra were determined with either a Beckman IReS or a Unicam SP-ZOO instrument. Ultraviolet spectra were determined with a Beckman DB instrument. 95 f. if?! 94 All melting points are uncorrected. Analyses reported were determined by Micro-Tech Laboratories, Skokie, Ill. The Preparation of N,N-Dimethylbenzamide A 100 g. (2.2 moles) quantity of gaseous dimethylamine was condensed into a one liter, three-necked flask at 500 Ir: (dry ice/iSOpropanol) equipped with a stirrer, dr0pping funnel and a suitable low temperature thermometer. The chilled amine, was dissolved in 100 ml. of anhydrous etheg and 140 g. (1.0 mole) of freshly distilled benzoyl chloride y in 500 ml. ether were added drOpwise during three hours to the ether solution of amine. The mixture was warmed to room temperature, then heated at its reflux temperature for fif- teen minutes and poured into 800 m1. of water. The aqueous layer was extracted with two 200 ml. portions of ether. The combined organic layers were washed with 5% aqueous hydrochloric acid and dried over anhydrous magnesium sulfate. Distillation, after solvent removal in a Rinco evaporator, gave 148 g. (0.99 mole, 99% yield) of pure N,N-dimethyl— benzamide boiling at lZZO/Smm., m.p. 44.5045.50 (recrystal- lized from hexane-ether). Literature value is: m.p. 45-450 (81). S-Bromothiophene Into a two liter, three-necked flask equipped with a stirrer, dropping funnel and reflux condenser fitted by a length of tubing which led to a suitable gas trap, were 95 placed 578 g. (4.5 moles) of freshly distilled thiophene. To the stirred thiophene, at room temperature, 2,196 g. (15.8 mole, 710 ml.) of bromine were added drOpwise during nine hours at a rate sufficient to cause a steady ebullition of hydrogen bromide gas. Following the addition of the bromine, the reaction mixture was stirred for one day to PA purge the system of hydrogen bromide. A solution containing 720 g. (12.8 moles) of potassium hydroxide in 1500 ml. methanol was prepared and placed into a five liter, three-necked flask equipped with a stirrer and g reflux condenser. The brominated thiophene mixture was cautiously added to the alkaline methanol solution and the basic solution was refluxed for a three hour period. The organic residue was then exhaustively steam distilled until traces of tetrabromothiophene appeared in the condensate, at which point 1104 g. of an oily product had been collected. The oil was placed in a five liter, three-necked flask equipped with two reflux condensers, 600 ml. of glacial acetic acid, 2700 ml. of water and 555 g. (5.1 g. atom) of zinc dust. The suspension became warm and after being set aside for one hour, the mixture was refluxed for one day. The reaction mixture was then steam distilled to obtain an oil which was washed with water, then with 5% aqueous sodium bicarbonate and again with water and then dried over anhydrous magnesium sulfate. The oil was fractionally distilled using a heated, 40 cm. glass spiral column to obtain 515.8 g. 96 (0.65 mmole, 42.8% based on the initial thiOphene) of S-bromo- thiophene boiling 70-710/54mm., n§°= 1.5868. Literature Vnalues for S—bromothiophene, b.p. 157-80/1 atm; n30 1.5861 (see ref. 1, p. 208). A 267.3 g. (1.11 moles, 24.6% based on initial thio- Iplaene) of dibromothiophenes, presumably the 2,4 and 2,5- isomers, boiling at 93-960/15 mm. were also obtained. B—Thenal A 14.0 g. quantity (2.0 g. atoms) of clean lithium metal (Fisher Scientific Co., Fairlawn, N. J.) was cut into Chips (approx. 1 cm. x 1 cm. x 0.5 cm) and placed in 600 ml. anhydrous ether contained in a previously dried two liter, three-necked flask equipped with a dry nitrogen inlet tube, thermometer (-2000 to 500) , a 500 ml. pressure equilibrating dropping funnel and a stirrer. A 165.0 g. quantity (1.2 moles) of n-butyl bromide in 250 ml. ether was added dropwise to the lithium-ether suspension precooled to ~50 to -200 by immersion in a dry ice/iSOpropanol bath and stirred until the last traces of lithium had reacted (three to five hours). The etheral solution of n-butyllithium was thoroughly cooled to -700 and 165.0 g. (1.0 mole) of 5-bromothiophene in 200 ml. Sther were slowly added to the alkyllithium and stirred for an additional fifteen minutes. To the cold 5-thienyllithium Solution, 88.0 g. (1.2 moles) of freshly distilled N,N- Ciimethylformamide in 250 ml. ether were added during a period 97 <3:E one hour and the stirred reaction solution was allowed to Vvaarm to room temperature overnight. It was then poured into one liter of a saturated aqueous eannmonium chloride solution. The aqueous layer was separated Eirld extracted with 600 ml. ether. The combined extract calrganic layer was dried over anhydrous magnesium sulfate. I)j_stillation of the residue after removal of the ether, gave 6363.0 g. (0.76 mole, 76%) of 2-thiophenecarboxaldehyde: b.p. '723-800/15 mm.; n2O 1.5875. Literature values for S-thiophene- D c221rboxaldehyde are; b.p. 72-780/12 mm.; n30 1.5860 (82). 5-Acetothienone One mole of S-thienyllithium was prepared in the manner EDITeviously described from 14.0 g. (2 9. atom) of freshly CZIJt lithium metal, 165 g. (1.2 moles) n-butyl bromide, 165 $3 - (1.0 mole) of 5-bromothi0phene and 600 ml. anhydrous €31:her. The addition of the acylating agent, 110.6 g. (1.2 In(Dles) of N,N-dimethylacetamide, in 200 ml. ether was accom— E>]_ished in one-half hour at —70°, after which the mixture was Seat aside at room temperature overnight. The hydrolysis was done in the usual manner with 10% a~queous hydrochloric acid, followed by extraction of the a(Iueous layer once with ether. The combined organic layers were washed with 10% aqueous sodium bicarbonate and water, ddried over anhydrous magnesium sulfate and fractionated in v’iacuo. The product, 87.0 g. (0.68 mole, 68%) S—acetylthiophene, 98 vvas obtained at 71-20 (5.0 mm. Hg): m.p. 56-70 (70% aqueous eathanol). Literature values for 5-acetylthiophene are: 1>.p. 88-90 (11 mm. Hg): m.p. 57.5-58.50 (70). 54Benzoylthiophene The preparation of 5~benzoylthiophene was accomplished jgn an identical manner to that used for the previous two ssyntheses, from 7.0 g. (1.0 9. atom) lithium metal, 82.5 g. ((3.6 mole) n-butyl bromide, 81.5 g. (0.5 mole) 5-bromothio- Eahene, 90.0 g. (0.6 mole) of N,N-dimethylbenzamide and 500 Inld anhydrous ether. Distillation of the reaction residue, Eifter the removal of the solvent, gave 88.7 g. (0.47 mole, 534.5%) of 5-benzoylthi0phene as a clear oil boiling at 3415-200 (0.5 mm. Hg) which solidified upon being set aside (Ivernight; m.p. 62-65.5O (70%, aqueous ethanol). Literature \Ialues for 5-benzoylthiophene are: b.p. 129-500 (5 mm. Hg); lTl.p. 65-40 (85). 2-(5'-Thienyl)-1,5-dioxolane, LIII A 500 ml., one-necked flask equipped with a Dean and EStark water separator, reflux condenser and a calcium chloride Cirying tube, was charged with 86.0 g. (0.76 mole) 5-thi0phene- (Zarboxaldehyde, 75 ml. ethylene glycol, a few crystals of Ip—toluenesulfonic acid monohydrate and 250 ml. benzene. The lvent removal, distillation of the residue gave a tacky, Iaimown material which solidified in forty-eight hours. This VJEiS easily recrystallized from methanol on refrigeration of 1:}1e solution to yield 1.82 g. (7.0 mmoles, 52%) of 2-phenyl- 23—-(2'-formyl-5'-thienyl%4q5-dioxolane as light yellow <2<3ilored crystals: m.p. 55-707 kmax (ethanol) 278 mu ( 6 10,512); (cm—1%“:1X (0014) 5060, 2970, 2890, 1712, 1688. 3.55255, 1505, 1485, 1460, 1452, 1595, 1570, 1520, 1270, 1250. 31ZLLSO, 1095, 1085, 1040, 1015, 960, 950, 890, 850, 710, 695. ESEBCD. Anal. Calc'd for C14H12038: C, 64.59: H, 4.65; S, 12.52. Found: C, 64.82; H, 4.70; 8, 12.26. 2-Phenyl-2-(2'—benzoyl-5'-thienyl)- 1,5—dioxolane, LXIV A 500 ml., three—necked flask equipped with a magnetic ss‘tlj.rrer, reflux condenser and dropping funnel was charged ‘Frj~1:h 5.0 g (22 mmoles) of 2-phenyl-2-(5'-thienyl)-1,5- €le(bxolane dissolved in 75 ml. of anhydrous ether. To the cooled solution (-250), 15.5 ml. (25 mmoles) of Si 11.6N n-butyllithium solution were added drOpwise followed ‘kDEZ' heating the reaction mixture under reflux for ten minutes. 110 qflae resulting solution of 2—phenyl-2—(5'-thienyl)-1,5- diioxolane—2'-lithium in ether was recooled to -250, and 5.5 c;. (25 mmoles) of N,N-dimethylbenzamide in 20 ml. ether were sslowly added. The reaction was completed by heating under Ireflux for ten minutes. The reaction was hydrolyzed with a ssaturated aqueous ammonium chloride solution and the product Em iJsolation was conducted in the usual manner. Removal of the solvent from the dried (anhyd. magnesium sstnlfate) solution produced a crystalline mass. This was Jreecrystallized twice from methanol to obtain 5.5 g. (10.4 E rnITuoles, 47.5%) of pure 2-phenyl-2-(2'benzoyl-5'-thienyl)- :L.,.3-dioxolane: m.p. 101.5-1020; kmax (ethanol) 252 mu ( 6 14,420; v (cm-1)max (0a.) 5070, 2980, 2690, 1665, 1600. _1_ES£35, 1545, 1500, 1480, 1455, 1520, 1270, 1225, 1180, 1140. 11£fl_CDO, 1085, 1050, 1008, 960, 905, 875, 840, 708, 702, 685. Anal. Calc'd for C20H15038: C, 71.40; H, 4.79; S, 9.55. Found: C, 71.45; H, 4.86; S, 9.48. 2-Methyl-2-(2'—formyl-5'-thianaphthenyl)- 1,5—dioxolane, LXV A 500 ml., three—necked flask equipped with a magnetic EstZ-irrer and 100 ml. dropping funnel, were charged with 10.0 g; - (45 mmoles) of 2-methyl-2-(5'-thianaphtheny&)-1,5-dioxo- Jreilne in 100 ml. anhydrous ether. To the cooled (-250, dry i‘<2£e/i50propanol) solution, 51.4 ml. (50 mmoles) of a 1.6N Irl“1nnqdlithium in pentane was slowly added. The resulting Czc>1dmixture, was stirred for an additional one-quarter hour 111 aarud 5.65 g. (50 mmoles) of N,N-dimethylformamide in 25 ml. aarflnydrous ether were added drOpwiseu .The mixture was then ssert aside, at room temperature overnight with continuous st:irring. Hydrolysis of the reaction metal complex was accom— E>14ished using 100 ml. of a saturated ammonium chloride solu- t;i<)n. Removal of solvent from the dried (anhyd. magnesium Stilete) solution produced a crystalline mass. Recrystal- SLszation of this twice from 95% ethanol gave 9.01 g. (56.5 Innuoles, 80.8%) of pure 2-methyl—2-(2'-formyl—5'-thiana- IQTrthenyl)~1,5-dioxolane: m.p. 110-110; xmax (ethanol) 255, 252 and 502 mu (6 18,100, 15.040 and 20,570 respectively): Vnuax (CC14) 5.28(sh). 5.56, 5.45, 6.01, 6.62, 6.99, 7.27. '7-£50, 7.61, 7.91, 8.40, 8.54, 9.00, 9.61, 10.54, 11.22. 11L -52, 14.60 and 14.92(sh) u. Anal. Calc'd for C13H12038: C, 62.88; H, 4.87; S, 12.91. Found; C, 62.79; H, 5.02; S, 12.86. 2-Phenyl-2-(2'~formyl-5'—thianaphthenyl)- 1,5—dioxolane, LXVI A 500 ml., three-necked flask was equipped with a mag- n6i'tic stirrer and a 100 ml. dropping funnel and charged with 13-.5 g. (40 mmoles) of 2-phenyl—2-(5'-thianaphthenyl)-1,5- Clioxolane in 100 ml. anhydrous ether. To the cooled solution (~200), 25.5 ml. (40 mmoles) of a 1.6N n-butyllithium solu- tion in hexane was slowly added. Following an additional Stirring of the mixture for one—half hour, 2.5 g. (40 mmoles) 112 of N,N-dimethylformamide were added dropwise and the mixture was set aside at room temperature overnight. Following the hydrolysis of the organo lithium complex using saturated aqueous ammonium chloride, removal of the solvent produced an oil which slowly crystallized during two days. Recrystal- lization of the crude product twice from 95% ethanol using activated charcoal, gave 7.06 g. (22.8 mmoles, 57%) of 2-phenyl-2-(2'—formyl—5'-thianaphthenyl)-1,5—dioxolane as light yellow, short needles; m.p. 111.0-12.50; xmax (ethanol) 252, 250 and 507 mu (6 15,870, 10,980 and 15,520 respectively); v (cm'l)max (0014) 5060, 2950, 2900, 1710, 1640, 1692, 1620. 1600, 1458, 1440, 1565, 1540, 1520, 1270, 1220, 1200, 1185. 1150, 1110, 1080, 1060, 1040, 1018, 960, 955, 910, 705, 675. Anal. Calc'd for C18H14038: C, 69.66; H, 4.55; S, 10.55. Found: c, 69.59; H, 4.65, 9, 10.45. The Hydrolysis of 2-(2'-Formyl-5'-thienyl)- 1,5-dioxolane ‘ An 88 ml. volume of acetone and 20 ml. of 10% aqueous laydrochloric acid, together with 12 g. (65.2 mmoles) of 2-(2'-formyl—5'-thienyl)-1,5-dioxolane were placed in a 250 Inl. Erlenmeyer flask. The contents were stirred for two luours at room temperature. The acetone was removed by evap- <3ration under a gentle stream of air leaving a crystalline nnass. This was dissolved in 50 ml. of ether, separated from 12he residual water and dried over anhydrous magnesium Snalfate. Removal of the ether and recrystallization of the 115 reusidue from CCl4 yielded 8.2 g. (58.6 mmoles, 90%) of pure m.p. 77.5-78.00; tlLiOphene—Z,5-dicarboxaldehyde, LXVII: (cc14) 2850, (ethanol) 272 m1 (6 10,280);v (cm‘l) max A rna9< 1511. 1455. 1400. 1568. 1240. 2720, 1688(sh). 1680. 1575(sh). 1025. 865. 842. 675. 122.5, 1182. 1162. C, 51.42; H, 2.89; 8, Anal. Calc'd for C6H402S: H, 5.15; S, 22.75. 22.88. Found: C, 51.67; The Hydrolysis of 2-(2'-Acetyl-5'—thienyl)- 1,5-dioxolane A 50 ml. Erlenmeyer flask was charged with 15 ml. of Eicxetone and 2 ml. of 10% aqueous hydrochloric acid together VViiih 1.08 g. (5.5 mmoles) of 2-(2'-acetyl—5'—thienyl)-1.3- Ciioxolane. The reaction was stirred for two hours and the acxetone was removed by evaporation. The residual semi-solid ITlass was treated in the manner described previously to Cflbtain 0.78 g. (5.1 mmoles, 92%) of 2—acetyl-5-formylthio- Efllene, LXVIII, as pale greenish-white crystals. The product VVets further purified by recrystallization from methanol: (ethanol) 278 and 510(sh) mu (6 10,450 and H‘sp. 46-70; Kmax 5.198 respectively); v (cm‘l)max (CC14) 5560, 5000, 2880, 3L678, 1550, 1520, 1450, 1592, 1575, 1560. 1240, 1060, 1050. Literature values for 2-acetyl- 662. 1) doublet 1688 max 11010. 940. 920. 855. m.p. 480; V (cm- :5-formylthiophene are: and 1670 (55). 20.80. Anal. Calc'd for C7H5023: C, 54.42; H, 5.92; 2, Found: C, 54.67; H, 4.00; S, 20.56. 114 The Hydrolysis of 2-(2'-Benzoyl—5'-thienyl)- 1,5-dioxolane Acetone (50 ml.) and 10 ml. of 10% aqueous hydrochloric a<:id were used to hydrolyze 4.0 g. (15.4 mmoles) of 2-(2'- loenazoyl-5'-thienyD-1,5-dioxolane by the procedure just rmylthiophene, Lglg. This was recrystallized twice from Tlexxane-ether using activated charcoal to obtain a pure rnerterial, in the forms of off-white colored short needles: m-p. 55.5-54.00; lmax (ethanol) 276 mu (e 12,720); v (cm'l)max ((2C14) 5050, 2900, 1765, 1708(sh). 1690, 1650, 1600, 1580. 1&522, 1458, 1458, 1592, 1522, 1268, 1255, 1185, 1140, 1080. 1015, 980, 945, 925, 890, 850, 720, 705, 670. Anal. Calc'd for C12H502S: C, 66.65; H, 5.75; S, 14.85. Found: C, 66.75; H, 5.84; S, 15.05.' The Hydrolysis of 2-Methyl~2-(2'-formyl- 5'-thienyl)-1.5-dioxolane A 125 ml. Erlenmeyer flask was charged with 80 ml. eacetone, 20 ml. of 10% aqueous hydrochloric acid, and 7.8 g. (59.4 mmoles) of 2-methyl-2-(2'—formyl-5'-thienyl)-1.5- dioxolane. The contents were stirred at ambient temperatures for six hours. After the acetone had been removed under a gentle stream of air, the residue was dissolved in 50 ml. ether, separated 115 frxom the aqueous material and dried over anhydrous magnesium SLJlfate. Removal of the ether and recrystallization of the czriide product from methanol gave 5.2 g. (55.7 mmoles, 85.5%) c>f’ 2—formyl-5-acetylthiOphene, LXX, in the form of short g>aLLe greenish—white needles: m.p. 61-20; xmax (ethanol) 280 mud. (6 11,650); v (cm-l)max (CCl4) 5000, 2880. 1680. 1665. 1.5%20, 1425, 1588. 1565. 1250. 1200. 1160. 1090. 1025. 1005. $1115, 848, 708, 680. Literature values for 2-formyl-5—acetyl- m.p. 610; v (cm-1) 1671 (55). max th 1 Ophene are 2 Anal. Calc'd for C7H502S: C, 54.52, H, 5.92; S, 20.80. Found: C, 54.57; H, 5.96; 8, 21.01. The Hydrolysis of 2-Methyl-2-(2'-benzoyl~5'- thienyl)-1,5-dioxolane The hydrolysis of 1.77 g. (6.5 mmoles) of 2—methyl—2— (23'-benzoyl-5'-thienyl)—1,5-dioxolane required 25 ml. acetone, 11) ml. water and 5 ml. of 10% aqueous hydrochloric acid. Tfiie hydrolysis solution was stirred for five hours at room txemperature and the product was isolated in the manner The crude product was crystallized (5.45 IDreviously described. IErom CCl4 (using refirgeration) to obtain 1.25 g. Hunoles, 84%) of pure 2-benzoyl—5-acetylthiophene, LXXI, in m.p. 87.5—87.70; A (ethanol) ‘the form of small needles: max ZEfl.and 290 mu (6 15,660 and 7,740 respectively)? V (cm-l)max (CC14) 5080. 5020. 2950. 1680. 1660. 1600. 1582. 1515. 1485. 1055. 1028. 945, 905. 900. 720. 700. 116 Anal. Calc'd for clsnloogs: c, 67.80; H, 4.58; 9, 15.95. Found: C, 67.74; H, 4.57; S, 14.08. The Hydrolysis of 2—Phenyl—2-(2'-benzoyl-5'- thienyl)-1,5—dioxolane A 50 ml. Erlenmeyer flask was charged with 10 ml. of 10% aqueous acetone, a few drOps of concentrated hydrochloric acid and 1.0 g. (2.97 mmoles) of 2-phenyl—2-(2'—benzoyl-5'- thienyl)-1,5-dioxolane. The hydrolysis mixture was stirred for two hours at ambient temperature, and the acetone was removed under a gentle stream of air. The residue was dis- solved in ether, washed with 5% aqueous sodium bicarbonate and water and the ether solution was dried over anhydrous Inagnesium sulfate. Removal of the ether left a crystalline Inass which was recrystallized twice from 95% ethanol to <3btain 0.6 g. (2.05 mmoles, 69.2%) of pure 2,5-dibenzoyl~ thiOphene, LXXIII, in the form of short prisms: m.p. 80.5- 81.0°; )max (ethanol) 264 mu (e 55.440); v (cm‘l)max (0014) 5096, 5077, 5040, 1665, 1600, 1582, 1520, 1455, 1418, 1585. 1522, 1280, 1190, 1140, 1085, 1018, 1005(sh), 948(sh). 955. 890, 720, 700(sh). 670. Anal. Calc'd for C18H1202S: Sc, 75.95; H, 4.14; S, 10.97. Found: C, 75.87; H, 4.21; S, 10.97. The Hydrolysis of 2-Methyl-2-(2'-formyl—5'- thianaphthenyl)-1,5-dioxolane In a 125 ml. Erlenmeyer flask, a mixture of 5.52 g. <:EP..14 mmoles) of 2~methyl—2-(2'-formyl~5'-thianaphthenyl)- 117 :1,5-dioxolane, 40 ml. of acetone and 5 ml. of 10% aqueous liydrochloric acid was stirred at room temperature for ten laours. Removal of the acetone was accomplished with a gentle stream of air to obtain a dark brown residue. The residue (mas dissolved in ether, washed with 5% aqueous sodium hydroxide and then with water. The ether solution was dried over anhy- drous magnesium sulfate. Removal of the ether, followed by vacuum sublimation of the residue (0.1 mm Hg, 50-700) yielded a semi-solid crystalline material which on recrystallization from methanol yielded 2.81 g. (1.57 mmoles, 64.2%) of pure 2-formyl-5-acetylthianaphthene, nggy, in the form of long pale green-white needles: m.p. 107-80; Kmax (ethanol) 254. 257, and 507 mu (6 27,600, 10,670 and 9,570 respectively): v (cm-1) (C014) 5010, 5007, 2940, 1675, 1600, 1560, 1510, max 1472. 1440. 1565. 1550. 1280. 1205. 1080. 970. 940. 890. 870. 680. Anal: Calc'd for C11H802S: C. 64.68; H, 5.957 3, 15.70. Found: C, 64.96; H, 4.05; S, 15.59. The Synthesis of Thiophene—5,4—biscarboxaldehyde The preparation of the necessary intermediates for the synthesis of this heterocyclic were carried out first. 5,4-DibromothiOphene was prepared from thiophene via the tetrabromothiophene following the method of Gronowitz, Moses and Hakansson (66). 4-Bromo-5-thiophenecarboxaldehyde was prepared from 5,4-dibromothiophene by the method of Gronowitz. 118 rdoses, Hornfeldt and Hakansson (24). The bromo-aldehyde was ireadily converted to the corresponding ethylene acetal as ciescribed by Gronowitz, Biezais and Mathiasson (40). The :synthesis of the thiophenedicarboxaldehyde was then conducted as follows . A one liter, three—necked flask was equipped with a Inechanical stirrer, dry nitrogen inlet tube and a drOpping funnel. This flask was connected by a small length of Tygon 'tubing to a second two-liter, three-necked flask using rubber .stOppers fitted with small glass tubes. This two liter flask xvas also equipped with a mechanical stirrer and a drying ‘tube. The apparatus was thoroughly dried by flaming it with ea Bunsen burner while continuously purging the apparatus with (dry nitrogen. The liter flask was charged with 512 ml. (0.5 mole) of a.1.6N n-butyllithium solution in hexane and cooled to ~700 (dry ice/is0prOpanol bath). To the cold stirred solution of ‘nebutyllithium, 100 g. (0.45 mole) of 2-(4'-bromo-5'-thienyl)- 1,5-dioxolane in 150 ml. of anhydrous ether were added slowly to avoid any excessive rise in the reaction temperature (forty-five minutes). Following the addition of the dioxo- lane solution, the heavy white mixture was stirred an addi- tional fifteen minutes. A two liter flask was charged with 55.0 g (0.75 mole) (of N,N-dimethylformamide and 150 ml of anhydrous ether and . o . . . lts contents were cooled to —70 by immerSlon in a 119 ciry ice/isopropanol bath. The mixture in the one liter flask <:ontaining 2—(5'—thienyl)-1,5—dioxolane-4'—lithium was slowly poured through the Tygon tubing into the N,N-dimethyl~ formamide-ether solution, during ten minutes. Cold, dry ether was used to wash the last solid residue from the one liter flask into the two liter flask. The combined mixture in the two liter flask was stirred overnight at room temper— ature. The resulting clear green solution was poured into an equal volume of water and two phases were separated. The aqueous phase was extracted twice with 100 ml. portions of ether. The combined organic phases were washed twice with 5% aqueous hydrochloric acid, once with 10% aqueous sodium 'bicarbonate and finally with water, and then dried over an— hydrous magnesium sulfate. After filtering, the ether was removed to yield a solid residue. This was crystallized from hexane-ether to obtain 52.0 g. in the form of long white needles (0.25 mole, 54% based on the bromo-acetal) of pure thiophene-5,4-biscarboxaldehyde: m.p. 79-800; A (ethanol) max 250 and 278 mu (6 22.640 and 12.940 respectively); v (cm'l) max (CCl4) 5120, 2900, 2850, 2700(sh). 1692, 1515, 1448, 1740(sh). 1565, 1185, 1165, 1120, 905, 885, 840, 670. Anal. Calc'd for C5H4028: C, 51.42, H, 2.89; S, 22.88. Found: C, 51.22; H, 2.91; S, 25.05. Trofimenko (48) reported only a m.p. of 78-800 and NMR values of -0.56 T and 1.69 T for thiophene-5,4—biscarboxal- dehyde. g’ev- " I .' '3 IO 120 The Synthesis of Thieno[5,4-d]thiepin- 2,4-dicarboxylic acid A solution of 9.00 g. [45.7 mmoles] of diethyl thiodi- glycolate and 6.15 g. [45.7 mmoles] of thiOphene-5,4—bis- carboxaldehyde in 20 ml. absolute methanol was added dropwise into a 500 ml., three—necked flask equipped with a magnetic stirrer, drOpping funnel and dry nitrogen inlet, containing a cold (0-50) sodium methoxide solution prepared from 4.2 g. (0.176 g. atom) of freshly cut sodium in 60 ml. of absolute methanol. The rate of the addition of the sodium alkoxide solution was regulated to hold the reaction temperature ‘below 80. The mixture was stirred an additional two hours at ice bath temperatures, then concentrated to a total volume of 40 ml. using a water aspirator at room temperature. The Inixture was then diluted with 90 ml. of water and acidified vdth 18% aqueous hydrochloric acid under rigorous stirring until no further precipitation occurred. The precipitate (was recovered by filtration and dried in a vacuum desiccator over sulfuric acid for twenty-four hours to obtain 5.7 g. (22.4 mmoles, 51.5%) of crude thieno[5,4-d]thiepin42,4n (dicarboxylic acid. Recrystallization of the crude product was accomplished in two equal portions by adding each to 200 ml. of boiling {30% aqueous ethanol and stirring rapidly for thirty seconds. (Concentrated,hydrochloric acid (4 ml.) was added and the :solution was again stirred vigorously. Before the last traces 121 (of residue had dissolved, the solutions were quickly filtered into flasks immersed in an ice bath. After setting the fil- trate aside in a refrigerator for one-half hour, the products ‘were then collected by filtration and dried. By this pro- cedure, 1.8 g. of pure thieno[5,4—d]thiepin-2,4-dicarboxylic acid were collected and an additional quantity of 0.54 g. product were obtained by concentration of the mother liquor. The melting point of the product was stable at 2500, showed initial decomposition at 2800 and had undergone decomposition at 2950. The crystalline material was a deep, velvet red in color, insoluble in carbon disulfide, carbon tetrachloride, water and cold ethanol but was soluble in aqueous base, dimethylsulfoxide, N,N—dimethylformamide and N,N-dimethyl- acetamide: xmax (ethanol) 218, 252, 284, 551, 548 and 568 mu (6 14,500, 15,460, 54,100, 2,590, 2,070 and 1,180 respec— tively); max (CC14) 2.90, 5.20, 5.58, 5.80, 6.00, 6.22. 6.70, 8.02, 7.10, 7.78, 7.91, 8.16, 8.58, 9.87, 11.15, 11.54. 12.21, 15.05, 15.26, 15.77, 14.17, 14.85, and 15.66 u. Anal. Calc'd for C10H50432: C, 47.25; H, 2.58; S, 25.22. Found: c, 47.25; H, 2.65; s, 25.04. Attempted Hydrolysis of 2-Phenyl—2—(2'- formyl-5'-thienyl)-1,5-dioxolane A 50 ml., Erlenmeyer flask was charged with 1.5 g. (5.0 'mmoles) of 2-phenyl—2-(2'-formyl-5'-thienyl)-1,5~dioxolane, 2 ml. of 10% aqueous hydrochloric acid and 20 ml. of acetone. The reaction solution was stirred under a nitrogen atmosphere 1.4-.49 [- 122 at room temperature for two hours. The acetone was removed under a gentle stream of air and the residue was dissolved in ether, washed twice with water and dried over anhydrous magnesium sulfate. Removal of the ether yielded an oil which was shown to be identical to starting material by its identi— cal infrared and NMR spectra. This oil was redissolved in 20 ml. of acetone and 2 ml. of 10% aqueous hydrochloric acid and allowed to stir an additional twelve hours under a nitro- gen atmOSphere. Following a product isolation procedure as described above, a brownish black "tarry" residue was ob- ' tained. An NMR spectrum of the residue in carbon tetra— chloride, exhibited only complex absorption in the aromatic region (2.2 T - 5.0 T) and an aldehydic proton and ketal proton absorption (1:4 ratio) which together approximated less than 5% of the total proton absorption. The Attempted Hydrolysis of 2-Phenyl~2-(2'~ formyl-5'-thianaphthenyl):1,5-dioxolane In a 125 ml. Erlenmeyer flask were placed, 4.68 g. (1.5 mmoles) of 2-phenyl—2-(2'~formyl-5'-thianaphthenyl)-1,5~ dioxolane, 40 ml. of acetone and 15 ml. of 10% aqueous hydro- chloric acid. The reaction mixture was stirred for twelve hours under a nitrogen atmosphere. The acetone was removed by an air stream. The residue was dissolved in 20 ml. of ether, washed twice with water and dried over anhydrous mag- nesium sulfate. Removal of the ether gave a residue which was shown to be identical to the starting material. 125 (The hydrolysis procedure was repeated under identical condi- tions for an additional twenty-four hours (total thirty—six 'hours) to yield a ”tarry" brown residue which resembled the starting material as indicated from its NMR spectrum. To a 100 ml., three—necked flask equipped with a reflux condenser and nitrogen inlet gas tube was charged with 2.4 g. (0.8 mmole) of 2-phenyl—2-(2'—formyl—5'-thianaphthenyl)—1,5-dioxo- lane, 40 ml. acetone and 10 ml. of 10% aqueous hydrochloric acid. The contents were heated under reflux in a nitrogen atmosphere for eighteen hours. Product isolation procedures were carried out in the previously described manner. Removal of the ether left a tarry residue. Determination of its NMR Spectrum in CCl4 showed a complex absorption of protons in the aromatic region (2.2—5.0 T). Proton absorption attribut- able to the aldehyde and ketal hydrogens in a 1 to 4 ratio compared to aromatic protons indicated that the reaction had progressed to the extent of approximately 90%. The Attempted Synthesis of Thieno[5,4—dlr oxepin-2,4-dicarboxylic acid To a 500 ml., three-necked flask equipped with a magnetic stirrer, dry—nitrogen gas inlet and a pressure equilibrating dropping funnel capped with an attached drying tube of calcium sulfate, a solution of 6.15 g. (45.7 mmoles) of dimethyl diglycolate in 20 ml. anhydrous methanol was added to a vigorously stirred solution of sodium ethoxide prepared from 4.2 g. (0.18 g. atom) of freshly cut sodium in 60 ml. 124 absolute methanol. The rate of addition of the alkoxide was adjusted to maintain the reaction temperature below 100. The light yellow reaction mixture was stirred an additional two hours at 50 and overnight at ambient temperature to com- plete the reaction. The reaction solution was concentrated to 40 ml. volume under vacuum (water aspirator) and 50 ml. water was added to partially dissolve the residue. The con- tents of the flask were filtered to yield a clear filtrate. This on acidification with concentrated hydrochloric acid produced a precipitate which when collected by filtration and dried, could not be dissolved in methanol, ethanol, ace- tone, dimethylsulfoxide or N,N-dimethylformamide. The pre- cipitate was redissolved in 10% aqueous sodium hydroxide. The original insoluble material, obtained on concentration of the reaction solution, could not be dissolved in any of the aforementioned solvents. Both precipitates exhibited melting points with initial decomposition at 2950 and severe darkening at 510-5150. The base soluble precipitate (7.2 g.) was subjected to carbon-hydrogen analysis. Anal. Calc'd for C10H4OSS: C, 50.42; H, 2.54; S, 15.46. Found: C, 48.74; 48.75; H. 5.99, 5.87; S, 9.88. No ash or residue was reported. The Attempted Synthesis of Thien012,5~dl— thiepin-2,4-dicarboxylic acid A 500 ml., three-necked flask was equipped with a mag~ netic stirrer, dry-nitrogen gas inlet and a pressure 125 equilibrating dropping funnel. A sodium ethoxide solution containing 2.1 g. (0.09 9. atom) of freshly cut sodium in 40 ml. anhydrous methanol was prepared in the flask under dry nitrogen and cooled to 00. To the chilled alkoxide solution, a mixture of 4.5 g. (21.9 mmoles) of diethyl thiodiglycolate and 5.00 g. (21.4 mmoles) of thiophene-2,5—biscarboxaldehyde in 40 ml. anhydrous methanol was added drOpwise during one- quarter hour. No turbidity or precipitate was noted initially, as was also true with thieno[5,4—d]thiepin-2,4-dicarboxylic acid where an orange disodium salt was observed. However, as the reaction progressed at 0-50, globules of dark brown-black resinous material was formed and deposited in the reaction vessel. After twelve hours, this material had partially solidified. This material (0.42 g.) was recovered by filtra- tion and found to be insoluble in N,N-dimethylacetamide, dimethylsulfoxide, carbon tetrachloride, water and 10% aque- ous base and acid. A strong odor of hydrogen sulfide was noted toward the end of the reaction period. The filtrate was acidified using concentrated hydrochloric acid. Reduction of the volume followed by addition of water pro- duced no precipitate. 10. 11. 12. 15. 14. LITERATURE CITED . H. D. Hartough, "Thiophene and Its Derivatives," science Publishers, Inc., New York, 1952. H. D. Hartough and S. L. Meisel, ThiOphene Rings," 1954. 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