m SYNTHESIS AND REACTIONS or sow: ' THIENYL mums ' imwmmdmm , mm * (STATE W .- ‘ --uww;xrmk. ' ; ' 1963 * * IJRRARY «'1‘: "f "11% I f .1 A‘ ’d f— MECHIGAN STATE UMVZ-Rr mm IANSRG, MICHIGAN .f, ABSTRACT THE SYNI'HESIS'AND REACTIONS OF SOME THIENYL FURANS by David J. Klinke The purpose of this investigation was to study the chemical .behayior of some mixed heterocyclic biaryls. 2-(2'-Thienyl)-furan .and.5-(2'eThienyl)-furan were prepared by the ring closure methods of Benary.and Burness respectively. Although these.compounds were found.to be air oxidizable, they were quite stable.under a nitrogen atmosphere. ._These.biaryls were subjected to metalation,aacylation, and free.radical bromination. Preferential coordination of the metal- .atingnagent with thewsulfur.hetero atom prior to.hydrogen metal interchangeicontrols the.location of substitution, only that a position whichnis proximate to the sulfur.atom undergoing metala- tion- iAqylation and bromination occurtpreferentially in the ' less aromatic furanmnucleus. .Substitution occurring in the a position ortho to the thienyl.8ubstituent thus characterizing that Substituent as an Ortho para director.I David J. Klinke .Product structures were assigned with the aid of the characteristic spinaspin coupling constants of the aromatic protons, which in this work were found to be (c.p.s.): thiophene, J23 = h.5-5.53 J24 = 1.2-1.9; .J34,= 5.u-u.1, furan,.J23 = 1.6-2.1, J24 = 0.7-0.9, J25 = 1.5-1.7, J34 5.h-5.9. The Campaigne.and Hinsberg methods of ring closure are discussed. The attempted conversion of 2-nitro-thiophene to B-thenoic acid via a .Von Richter reaction is also outlined. THE SYNTHESIS AND REACTIONS OF SOME THIENYL FURANS By David J. Klinke A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Chemistry 1965 ACKNOWLEDGMENTS The author wishes to express his sincere appreciation to Professor Robert D. Schuetz for his counsel and friend- ship.throughout the course of this investigation. Grateful acknowledgment is extended to Dr. G. J. Karabatsos for many helpful discussions and suggestions. Appreciation is also extended to Mrs. V. Harper for her kind assistance in the preparation of the manuscript. ii TABLE OF CONTENTS INTRODUCTION AND HISTORICAL. . . . . . . . . . . . ‘Methods of preparation of heterocyclic biaryls. Reactions of heterocyclic biaryls . . . . . . Assignment of product structures. . . . . . . RESULTS AND DISCUSSION . . . . . . . . . . . . . . . Preparation Preparation of 2-(2’-Thienyl)-furan (IV). . of 5-(2'-Thienyl)-furan (XVII). . Reactions of 2-(2’-Thienyl)-furan (IV). . . . Reactions of 5-(2'-Thienyl)-furan (XVII). . . . Studies of the Nuclear Magnetic Resonance ’~Spectra.. . EXPERIMENTAL . . Preparation 0 O O O O O I I O O O O O O O O I '0 of 5-(2'-Furyl)-2-mercapto-2,h— pentadienoic.Acid (I) . . . . . . . . . . . . Preparation of 2,2’-Dithiobis-[5-(2"efuryl)-2;u' pentadienoic.Acid] (II) . . . . . . . . . . . . Preparation Preparation Preparation (V) 0.- oa . ‘ Preparation Preparation of 2-(2'-Furyl)-5-thenoic Acid (III) Of 2" (2 '-']Ih.ienyl)_furan (IV). 0 o o of Ethyl 2-(2’—Thienyl)—5-furoate of 2-(2'-Thienyl)-5-furoic.Acid (VI) of 2-(2'-Thienyl)~furan (IV). . . Nitration of 2-(2'-Furyl)-5—thenoic Acid. . . . Acylation of 2—(2'-Thienyl)-furan . { . . . . iii Page 15 15 21 28 58 A9 59 59 59 60 61 61 62 65- 65 64 TABLE OF CONTENTS - Continued .Page Acylation of Ethyl 2-(2'—Thienyl)-5—furoate. . 6h Metalation of 2-(2'-Thienyl)-furan . . . . . . 65 Bromination of 2-(2'-Thienyl)-furan. . . . . . 66 ‘Preparation of 2—(2' -Thienyl)— 5- furoic Acid (XII). . . . . . . . . . . . . . . . 67 Preparation of l,l-Dimethoxy~3-oxo-5-(2’— thienyl)-propane (XIII). . . . . . . . . . . . 68 Preparation of l-Methoxy—B— oxo- ~5—(2' ~thienyl)- l-propene (XIV). . . . . . . . . . . . . . 69 Preparation of Methyl 5—(2'—Ihieny1)-2- furoate (XV) . . . . . . . . . . . . . . . . . 70 Preparation of 3—(2'-Thienyl)~2-furoic Acid (XVI) . . . . . . . . . . . . . . . . . . 70 Preparation of 5-(2'-Thienyl)-furan (XVII) . . 70 Acylation of 5-(2'-Thienyl)-furan (XVII) . . . 71 Metalation of 5-(2'-Thienyl)-furan (XVII). . . 72 Bromination of 3-(2'-Thienyl)-furan (XVII) . . 72 Bromination of XVII in the presence of benzoyl peroxide . . . . . . . . . . . . . . . . . . . 72 Attempted condensation of thienyl glyoxal with methyl diglycolate . . . . . . . . . . . . . . 75 Attempted Von Richter reaction on 2-nitro- thiophene. . . . . . . . . . . . . . . . . . . 7h SUMMARY . . . . . . . . . . . . . . . . . . . . . . 76 LITERATURECITED 77 iv II. III. V. LIST OF TABLES -Spin-spin coupling constants for furan, pyrrole, and fluqmam-.. .Substituted effects in the ring-proton chemical shifts of furans. Physical constants for 5—(2’-thienyl)-furans . Physical constants for 2-(2'-thienyl)-furans . Spin-spin coupling constants and chemical shifts of aromatic protons in 2-(2'-thienyl)-furans. . -Spin-spin coupling constants and chemical shifts of aromatic protons in 3—(2'-thienyl)-furans. Page- II 52 54 55 57 FIGURE 5a. 5b. ha. Ab. 10. ll. 12a. 12b. 15. 1A. LIST OF FIGURES Infrared Spectrum of 5-(2'-Furyl)—2-mercapto-2,h-pentadienoic Acid (I) taken in chloroform. . . . . . . . . . . . . . Infrared Spectrum of [5- (2"- furyl)- 2,h-pentadienoic Acid] (II) taken" as Nujol Mull . . . . . . . . . . . . . . . . Infrared Spectrum of 2- (2 -Fury1)- S-thenoic acid (III) taken as Nujol Mull . . . . . . . . . . . . . . . . . N;m.r. Spectrum of 2-(2'-Furyl)-5-thenoic Acid (III) in Dioxane taken at sweep width of lOO c.p.s.. . . . . . . . . . . . . Infrared Spectrum of 2-(2'-Thienyl)-furan (IV). N.m.r. Spectrum of 2-(2'-Thienyl)-furan (IV) in 0014 taken at sweep width of lOO c.p.s . . . . . . . . . . . . . . . Infrared Spectrum of Ethyl 2-(2'-Thienyl)-5 furoate (V) . Infrared Spectrum of 2- (2' -Thienyl)- 5- furoic Acid (VI) taken as Nujol Mull. . . . . . . . . . . . . . . . . . . . _Infrared Spectrum of l- -Methoxy- 5- 0x0- -5- (2' -thienyl-)- l-propene (XIV) taken as Nujol Mull . Infrared Spectrum of Phrified Residue from the Preparation of XIV taken as a Nujol Mull . . . . . . . . . . . . . . Infrared Spectrum of l,l-Dimethoxy-5-oxo-5-(2'-thienyl)-propane (XIII). . . . . . . . . . . . . . . . . . . . . . . . . Infrared Spectrum of Methyl 5-(2'-Thienyl)-2-furoate (XV) . Infrared Spectrum of 5-(2’-Thienyl)—2-furoic Acid (XVI) taken as a Nujol Mull . . . . . . . . . . . . . . . . . . . . . . . Infrared Spectrum of 5-(2'-Thienyl)-furan (XVII). N’.m. r. Spectrum of 5- (2' -Thienyl)- furan in CCl4 taken at a sweep width of lOO c. p. s. . . . . . . . . . Infrared Spectrum of 2- (5' -Carboxy- 2'- thienyl)— 5- furoic Acid (X) taken as Nujol Mull . . . . . . . . . . . . . . . . . Infrared Spectrum of s-Butyry1-2-(2'-thieny1)-furan (VII) vi Page 1h 15 l6 l7 l8 19 2O 22 25 27 29 5O 51 52 55 55 57 LIST.OF FIGURES - Continued FIGURE 15. 16a. 16b. 17. l8. I9. 20. Infrared Spectrum of 5- Bromo- 2- (2'- thienyl—)- furan (XI) taken in Carbon Tetrachloride . . . . . . . Infrared Spectrum of 2-(2'-Thienyl)-5-furoic Acid (XII) taken as a Nujol Mull.. . . . . . . . . . . . . . sz.r..Spectrum of 2-(2'—Thienyl)-5-furoic.Acid (XII) in dioxane taken.at a sweep width of 100 c.p.s.. . . . Infrared Sp.ectrum of 5- Nitro- 2— (5'-carboxy-2' -thienyl)- furan (XXIII) taken as a Nujol mu11 . . . . . . . Infrared Spectrum of 2-Butyry1-5-(5'-butyry1-2'-tnieny1)- furan (XXI) taken as a Nujol Mull . . . . . Infrared Spectrum of 2- Bromo- 5- (2'- thienyl)- furan (XXII) taken mCarbon Tetrachloride . N m.r. Spectrum of Crude Mixture of 57% XVI (A) and A5% XVIII (B) in Acetone taken at Sweep Width of 100 c.p.s. . . . vii Page 59~ :A0 ‘41 A2 A6 #7 A8 INTRODUCTION.AND HISTORICAL .The directing influence of a substituent on an aromatic nucleus on a .suhsequent:substitution on the ring is well known. The directive influences -ofmmany.substituents in arene hydrocarbons have been.determined-and are familiar.knowledge. However, the orienting effects of the heteroaromatics furan, pyrrole, and thiophene as substituents have been more difficult to .ascertain experimentally. Due to the greater reactivity of the hetero— .qyclics relative to benzene, compounds such as I‘ or II' undergo further {/X\E :: :: [TO X‘=O,.S, orNH 1' II' substitution in the hetero ring, which gives no information on the directing effect of the hetero ring as a substituent. Thus, if the directing influence of a hetero ring in substitution reactions is to be determined it must be used as a substituent on a more reactive nucleus. In a search for such a nucleus the possibility of using another heterocyclic ring immediately suggests itself. Substitution reactions of the heterocyclic aromatic com- pounds, furan, pyrrole, and thiophene are known to occur preferentially in;a position a to the heteroatom when that position is open. 3' B .When-onesof the B positions is substituted moreover” this B substituent directs the incoming group to the adjacent a or opposite a' position in -a manner.similar to that found in the benzene systems Thus, ortho, para directing substituents direct the incoming group to the adjacent a positionv while a meta director leads to substitution at the alternate o' position. Therefore, the substitution reactions of compounds of types III' and IV', where the reactivity of ring A is greater than, or equal to /A\ /f\ AAA ABV that of.ring B, Should yield important information regarding the directive influence of ring B to substitution reactions on ring A. Mbthods of preparation of heterocyclic biaryls. (a) a substituted compounds. wynberg has developed synthetic procedures (2,5) for the preparation of compounds of structure type III'. 0 OH iii—j R R ___ R RMgBr Z 5 2 E 2/ \E X = O or S X a X i X X .In.this, or a Similar manner he has.prepared compounds where X:Y=S, (2) X=S .and Rap, (2)_X:O.and Rs¢ (5) and in unpuinshed work (1,4) the compound where X:O and.X=S. Burness has also developed an excellent route (5,6,7) to the B substituted furans. O CICH20020H3 ‘ 1 H R-C-CHg-CH(OCH3)2 R-CQCHQ—CH(OCH3)2 -—7§—a> / \ é/O CH3020 O l l COgCHa He has Shown this reaction to be quite general by utilizing it to prepare compounds where R = methyl or phenyl° Alternatively Hinsberg’s (15) studies of the.reaction between aedioxo compounds and diglycolic or thiodiglycolic --acids or their esters, R CHg-C02R" , .)\t=o | R R l + X -——————) ’ZZ—i§;\ X = 0,.S, or Se 0:0 I . R"02C 002R" // CH 002R" X 2- B! may give a third method for the synthesis of type III' structures. While Becker and Stevens (16) used this procedure to prepare the 5,A-diphenyl- furan, — thiophene, and —selenophenes, Dodson (9) utilized it to prepare the S,B‘-di-Ohthienyl-thiophene. (b) a’substituted compounds. Compounds of type IV' on the other hand should be capable of preparation by the method of Campaigne (8), R-CH=CH-CH=CSHC02H ——la—+> R-JQTIEX—COEH -————9~ jR_1/ \S S S Who used this method to prepare the R = phenyl compound. Dodson (9) has prepared the R = a-thienyl compound by the same procedure. An alternative procedure for the preparation of a type IV” structure could be adaptation of the method developed by Renary (IO,ll,l2) for the preparation of.a—substituted uB-furoates and pyrrole carboxylates. _O C2H502 H02C ClCHgCHO \» / \ base 7 R X R RQ beam. While Gilman (l2) used this.method to prepare the 2-methyl—5-furoate, Kondo u R—C-CH2-00202H5 and Suzulsi (15) used it to prepare the 2-phenyl-5-furoate. Johnson (1h) however while using this and other methods reported that the 2-phenyl furanS which they prepared turned dark on standing, indicating a degree of in- stability of aromatic substituted furans. . Reactions of heterocyclic biaryls. Reactions of 2—5' bithienyl V’, and 2—2' bithienyl VI', . /A\ (/A\§ [/B\§ S S V' VI' i.e., structures III’ and IV' where X = Y = S, have been studied by.Wynberg (1). While both acylation (17) and metalation of compound VI“ resulted in mono- and dinsubstitution in the 5 and 5' positions as expected, s / \ / \ 5882:3723 M00211 + HOgCMCOgH S acylation of V' resulted in substitution into the open 5 position of ring B. _Attempted acylation of ring A by using more drastic methods resulted in the formation of an intractable polymer. /\ /\fi OCH 8 (CHsCO)20 . / \ 3 H3PO4 ’ / S) S jMetaIation of V', however, resulted in substitution at either the 2‘ or 5' position of ring A. HOEC 38% / \ S COgH 52% wynherg ascribes the electrophilic attack at the 5 position in V' to steric interference by the ortho thiophene to substitution at the 2' position and to conjugative interactions with the other ring which are possible for substituion at the 5 position but which cannot easily be formulated if initial attack occurs at the 5' position. /+ /\ s +—-—> Hetc. + /\ ° R \s‘__> These results give little information as to the directive influence of a ,thiophene ring to electrophilic substitution. The.results of the hydrogen metal interchange were ascribed tofi (a) greater electronegativity of the 5 position, as illustrated by the electro- philic substitution, than that of the 5' position, (b) the electron attraction of thiophene as an ortho substituent, (c) possibility of co- ordination of the lithium atom with the sulfur atom of either ring prior to exdhange, and /\ /\ s and S H l 1 Li-u-CSH5 (d) a decrease in basicity of the sulfur atom in ring B, therefore, a decrease in ability to coordinate with the lithium atom, caused by electron attraction by thiophene. The work of Gronowitz (25,2A,25) on electrophilic aromatic substitutions has Shown metalation to occur at a position ortho to a substituent which contains a pair of unshared electrons, independent of the directing influence of that substituent. Thus, the initial step in metalation of thiophenes is a coordination of the metal of the metalating agent with the unshared electron pair of the sulfur atom. By reactions on unsubstituted, 5-bromo, and 5-methyl thiophenes, Gronowitz determined that ‘the orientation and reaction rates were the same as would be predicted by inductive effect, i.e., (55 > C) > (.3) 1 l l (cg-Zr Q COQH Hogc Q These results are consistent with additional work (26) in which the same CH3 investigator.metalated thiophene with nebutyl lithium in trace amounts of thiophene—2-t, and observed a kinetic isotope effect of KH/KT = 5.9. These facts.have been interpreted by Gronowitz to indicate that the rate determin- ing.step is a nucleophilic attack on H by the carbanion, a mechanism similar to that proposed by wynberg and discussed previously. _ Assignment of product structures. Nuclear magnetic resonance studies (20) have been made on several substi- tuted furans, pyrroles (22) and thiophenes (l8,l9,2l). The data obtained indicate. that these heterocycles have characteristic proton Spin-spin coupling constants which are quite consistent regardless of the substituent which may be present. Gronowitz (18), in a study of twenty, 2 and 5 substituted thiophenes, has found this ring’s proton spin coupling constants to be (c.p.s.‘): J23 = 5.1+ _+_ 0.6, J34 = 5.8 i 0.5; J25 = 2.5 1 0.1+; J35 = 1.6 i 0.5. In another study (27) of twenty, 2 substituted and sixteen, 5 substituted thiophenes, Gronowitz attempted to establish the influence of the.anisotrqpic susceptibilities of the substituents on the chemical shifts. . These were.found to contributetonly in a minor degree to the chemical shifts. . Thus,whe decided that the Shifts are largely determined by local contribu- . tionswand-as.suCh are directly related to the electron densities on the various hydrogenss The shift data were discussed in terms of inductive effects and by -using simple resonance theory. Smaller Shifts of the A position compared to those.of the 2 position, in 5 substituted thiophenes, and the larger Shifts .of the 2.position, in 5 substituted thiOphenes, compared.to the shifts of the 5 position, in 2 substituted thiophenes, were also interpreted in these terms. Evidence was given for a.more extensive conjugation of mesomeric substituents to the 5 position than to the 5 position and for an alternating inductive .effect in 2-substituted thiophenes. He also determined some ring coupling constants in nineteen, 2,5-, seventeen 2,5-, eighteen 2,h- and eleven 5,4- disubstituted thiophenes. They are: J34 = 5.u5 - A.55; J45 e u.90 - 5.80; J35 = 1.25 — 1.70; J25 = 5.20 - 5.65 all.: 0.15 c.p.s. Bernstein (20) moreover in a summary of several studies has reported the following ring proton spin coupling constants (c.p.s.); Table I J19 1;”st .‘ J23 J24; Jam . J25 Ftran 1.80 (.09) 0.80 (10) 5.55 (.15) 1.55 (.1) Pyrro1e 2.45 (.16) 2.A5 (.2A) 2.65 (.05) 1.4a (.05) 5.A2 (.A2) Thiophene 5.2 (.5 ) 1.5 ((.5) 5.6 (.5) 2.7 (.5) 10 In his paper Bernstein also concludes from data for 2-substituted furans in _ acetonem(Table.II),.that.the chemical shift of a proton Signal is dependent on two factors: (a) the electronegativity of a substituent being greater than that of hydrogen caused a Shift of all Signals to a lower field, the .closestlproton to the substituent being shifted the greatest; the effect being ..attenuated as the distance.from the substituent increases; and (b) because of.its.ability to donate or withdraw electrons from "aromatic"*rings, the .suhstituentmcan cause the signals to move to high or low field, respectively. Thislmesomeric effect probably behaves in a fashion analogous to that in the parent compound, affecting all positions in the same-qualitative way (i.e., all increase in n.electron density or all decrease). Thus, in a semi- .quantitative way he distinguishes between the effect of electron donating and .withdrawing substituents. In the case of the former, the electronegativity of.the substituent shifts the Signals to low field but the mesomeric effect .increases.the.n electron density, causing greater shielding which causes the signal to move to higher field. In the case of electron withdrawing substi— tuents, however, both the electronegativity and mesomeric effect operate to Shift the signals to a low field. .All substituents which he studied were of greater electronegativity than methyl, which due to its donpr property and low electronegativity caused a shift to a high field relative to furan, and thus these substituents caused the proton signals to be found at a lower field than in 2-methyl furan. With stronger electron withdrawing substituents the proton Signals appeared at increasingly lower fields. He also observed that the effect of multiple substitution is very nearly additive. Table-II;. Substituent.effects in the ring-proton chemical shifts of furans (results are given in parts per 107). L_‘ ~ ‘ ' ' ' W1 L‘— p ‘ .._ J; J. 45 _ 2=methylfuran + h.55 + 1.55—. + 2.05 22furfurylamine + 2.A2 + 1.00 + 1.57 2-furfuro1 + 1.51 + 0.76 + 0.89 furan 0.00 0.00 0.00 2-furanacrylic acid - h.08 - 1.4h - l.56 2efuran acrolein - 5.51 - 2.09 - 2.26 ethyl furoate - 7.7M - 1.85 - 2.26 2-furoic acid - 7.95 - 1.81 - 2.20 furfurol - 9.87 - 2.9M - 5.66 2-nitro furan -10.65 - A.02 _ - 5.18 2-furoyl tri fluoromethyl ketone ~11.98 — 5.75 — 5.55 (a) results were determined at 60 Mc/s in 10% solutions of acetone using the acetone Signal as reference, the reproducibility from three independent spectra for each solution was i 0.2 c.p.s., i.e., : 0.05 parts per 107. (b) actual furan value -5h.82.(a:protons)3 —h5.58 (B protons). With this information on the directing influence, and the n.m.r. spectra characteristics of substituted furans, pyrroles, and thiophenes, it was de- cided to synthesize the compounds VII' and VIII'. It was anticipated that / \ / .\ /’S\ / \ 0 VII' VIII' these compounds should facilitate the determination of the directive ”Jinfluence of a.five. L 3 heterocyclic ring on the substitution reactions .whichranother aromatic.nucleus might undergo. The differences in chemical .shiftnof.the thiophene protons versus the furan protons, plus the charac- teristic.spinnspin coupling constants of substituted thiophenes and furans of .known.structure,.could be used as a convenient method for the assignment of the structures of compounds reSulting from substitution reactions which biaryls VII' and VIII' would undergo. RESULTS.AND DISCUSSION '2.-,(2 ' -.uIiieny1)-furan(Iv ) . .In.an attempt to gain an entry into the defurydrosthiophene biaryl system,.the Campaigne (8) procedure for the preparation of 5-substituted-2- thenoic.acids was used to obtain the compound 2-(2'-furyl)-5-thenoic acid(III). (Equation 10, Fig. 1,2,5). H C-C’H u u {/03 33:05 “‘2" Moo? /0\ /s\ ‘1‘” I III IV _Although acid III was Obtained in rather low yield, it was found to be .quite stable and was subsequently stored in the open with no precautions to, .exclude oxygen or sunlight. The bright yellow white fluorescence which resulted from exposure of the compound to ultraviolet light was consistent with its high extinction coefficient (Table IV). Decarboxylation of III gave the un— _substituted, biaryl IV (Fig- A) in high yield. Like 2sphenyl-furan (1A) which turns dark upon standing, 2-(2'-thieny1)furan(IV) turned to a dark blue—black , color upon exposure to the atmosphere at room temperature. This biaryl IV, however, was stored for several weeks in the cold under nitrogen without the occurance of Significant decomposition. .Although III and IV were prepared through the use of the Campaigne method of ring closure, this route to the 6-701" biaryl system was found to be awkward experimentally and therefore an alternate route was sought. The Benary (11,12) method of preparation of aesubstituted-B—furoates was subsequently used to prepare ethyl 2-(2'-thieny1)—5-furoate (V, Fig. 5) from ethyl 5-(2-thienyl)—5-oxopropanoate in a 55% yield (equation 11). 15 1h +2” 8.8.8.818 sH sweep AHV 30¢ oflosofiompsmmuzamuOPQmoaoaamuAHung:.myum .Ho asepoomm 66.8.55” msosodz sfl Spmooaourmz NH, OH w m .H enemas _ _ _ _ 15 Has: Honsz mm stamp AHHV leans oaosoacmpsma-s.m-AHassa-smv-mlmanoassao-.m.m so assaooam cosmsasH msoaoflz as mesoam>m3. as ma OH w c .m madmflh _ a _ a . 16 :H Has: Homsz no stamp AHHHV oao< oaosmss-m-fiaassa-.mvum so Sassooam emsmsasH mqoaoflz QH npmomao>m3 ma 0H m 8 .mm osswflm I _ _ _ 17 .mdo 8H .8 are? ocean at amass. osmxoam s... CH: Boa. oaosofiAAHssanmvm .8 556QO sea on games » Also: Jam m2. 2:. ems. wk. _ 9&3 _ L :\ JR o :1 I r o r I L 411 a\ .1 .I l8 1: A>Hv GradyufiahsoflcBusmvum Mo Bespommm eosmaesH mQOHOHS SH £pmnoam>m3 OH w .m: oasmflm _ _ _\O l9 . 0 90H E m o mmmzm SH thazE m Edhpomo Z O N ’H v u o A cma5% « wlfl Smxmp y H Pm Pfiflz. OH . .9.0 o H S O m was , 9H5 as 45m Mwa. k h: $m.d mm.w E. A 2O .A>v opmoasa mrfiaasoflcan.mvum Heapm Mo esspooam emsmsMQH moosoflzflsfi prooao>m3 mu 2” r .m 05mg _ _ ; 00202H5 0 _ cogcghg 83H + '23:“ L / \ / \ ———> (11> o—o ——» m VI T.’ Although V was also found to be readily air oxidized to a blue-black color, it was stable to storage under nitrogen in the cold. Saponification of this ester gave the stable acid VI (Fig. 6) and subsequent decarboxylation of this acid produced IV in good yield. This product was Shown to be identi- cal to that made previously by the Campaigne procedure, by comparison of ultraviolet, infra red and n.m.r. Spectra. The Benary procedure which, therefore, gave the substituted biaryl V in 10% overall yield in three clean steps from thiophene was preferred over the more awkward Campaigne method which yielded the biaryl III in an 8% overall yield through four steps from furfural. 5-(2'-Ihieny1)-§pran(XVII>. Ihe synthesis of 5-(2'-thienyl)-furan was first attempted through the base catalyzed condensation of thienyl glyoxal with methyl diglycolate (equation 12). (/ )—C :20 CH2C02CH3 _ / \ (12) S 0H 5 S 1/ \ I + 0 z ! CH30 C 0020H3 H"C O CH2C02CH3 2 0 22 .HHSS HOnSZ mm Grasp AH>V eflo< oeosfitumiflahsmficau.mvum to soupoomm emsmsmsH moosoflz SH Spwsoao>m3 mu 3 m m .m madmflm _ m l 3.5 Aithough. thienyl glyoxal is known (59) to react with base under reflux to give) a.quantitative yield of (2ethieny1)nglycolic acid (equation 15), 08-8-31 —O—-> /s\ (15) H C- COEH O H it was.thought that the competing reaction with methyl diglycolate might yield some.biary1 as indicated by.equation 12. A variety of reaction conditions in several.attempts to achieve the condensation failed, however, to effect any conversion to isolatable biaryl. .At this point due to the possibility of an alternate procedure the Hinsberg method was set aside. .Ihegmethods of Royals (5H) and Borness (5,7) were then used to prepare . methyl 5-(2 '-thieny1)-2-furoat:e‘.'(XV)(,(.e-quationf 1A). 0 0 /S\ 0 (11+) Z Eu '0' ml ClCH2C02CH3 NaOCHs *T- fl—C-Cflg-CH(OCH3)2 s .x. l. 0 XV 0'020H3 Although Royals was able to prepare 1,1-dimethoxy-5-butanone (equation 15), :0 , 0 0 0 0 H " NaocH H H CH3 OH H CH30CH3 + HCOCH3 ———§-—’ CHs- -C— C—Ha— CH T7 .CHsC-CH2-0H(-OCH3)2 (15) the same procedure, however, led to the formation of a vinyl ether (equation 16) when a synthesis of the analogous phenyl ketone acetal was attempted. 21+ 0 0 ‘ 0 II II II II II {ZS-cam, + HCOCHs M (ZS-.C-CHa-CH % ¢—C-CH=CHOCH3 (16) v-o~-n \ In our hands, an attempted preparation of the thienyl ketone acetal by Royals’ procedure led similarly (equation 17) to the vinyl ether (XIV, Fig. 7) in 10% yield. 0 O (:53... . .30.... goat.» 3- a. '0'. (17) 0 Z/ \5." C-CH=CHOCH3 S . XIV The distillation residue from this reaction also yielded a large quantity of a crystalline material in the empirical formula C7H2.gSO . It had a low solubility in organic solvents and also had a rather high melting point, i.e., nhp- 209-5~2ll.5°a This material is thought to have been produced by a base catalyzed polymerization of the vinyl ether to give a polymer with the possible unit structures IX' and X'. —-(—C=c—)-n ‘ ——(—--CC—)— . it IX' X Uhit IX' being formed from XIV by a normal polymerization mechanism (equation 18) followed by a base cataLyzed loss of methanol. 25 .HHSS acmsz mm cmxmp A>Hxv mummosmnaufiazsmflsyu.mvunaoxo muhxospmzna go Esspommm cmawamsH mQOMOHS SH Spmsmam>m3 ma 3 w m .> $de . . fl _ 0:3 ?CH3 A- U 3 @CH3 0H” C M —-—* Seé—lé—a—n —-—>+ (18> H H o 0 We ——> N -(——o—c—+n Foxes; an i Unit Xi, however, might be formed by the loss of methoxide ion from the semi stable anion (equation l9) causing chain termination. O _ O E E A - (l9) / S\ I?‘ (:CHs ___) Q? t?CH3 £13...) H-CzC-H H-C-C'I 4—9—— . 21H /s\ " a, __J£l_, /s\ ? ¥ H---c-==C—)-— —+——C'J———C———9— H 4,1 The alkene (XI') thus formed would also be subject to attack by another anion leading to chain branching. This hypothesis is supported by the infra red spectrum.(Fig. 8) and by its low solubility in organic solvents which prohibited n.m.r. or mass spectrum studies. Since Royals' procedure involved neutralization of the adidic acetal mixture until basic to litmus before distillation of the acetal product, it was thought that the slight excess of base could be deprotonating the acetal ketone with subsequent loss of methanol (equation 20) upon distillation. o o o w-CHg-CH(OCH3)2 JAE—r [Z/ \X- gl-CH-CH(OCH3)%—zy9 Z/ \Xg-CH=CHOCH3 (2o) - s ~S ‘S e 27 i .HHSE Hensz m we moms» >Hx %o soapwammmam map 809% msoflmmm doflMHsom a0 soapommm emamswsH mochoflz QH :pmcwam>m3 NH 3 w m .w msowflh . _ _ _ > 28 Support.fior this was found in the Change in color of the acetal mixture, .during neutralization of the.excess acid, from a bright yellow to an intense blood.red near a pH of 7. .Subsequent neutralization of the acidic acetal .mixture,.however, only to a pH of 6 and distillation of the acetal (Fig. 9) .gave XIII.in 70% yield from 2—aceto—thienone. .Subsequent preparation of the glycidic ester was followed by heating to l55° causing methanol to distill from the mixture while ring closure was affected. Vacuum distillation then yielded the biaryl ester XV (Fig. .10) in 17% overall yield from thiophene. Upon standing XV was quite readily air oxidized to a red viscous oil. However, its storage in the cold under nitrogen gave no decomposition. Saponification and decarboxylation gave successively XVI (Fig. ll) and XVII (Fig. 12) in high yield. Although the acid XVI was stable to the atmosphere, XVII reacted in a manner similar to XV.in the air and thus had to be stored under nitrogen in the cold. Reactions of 2—(2‘-Thienyl)—furan(IV). 2-(2'-Thienyl)-furan was subjected to metalation, acylation, and free radical bromination. 29 :H .AHHHNV oqmgosguAHhsmfizpn.mvnmuoNOImnhxonpmaHmnHeH e0 asapommm omHmHMsH moosowz ow Spmooam>m3 NH OH w w .m madwflm _ _ d _ 50 .25 optoefidAieoefismYm fleets .Ho soeeooem Begum .3 2&3 msoaoflz SH Spwsoao>m3 ma 3 w b _wd- . _ i _ 3]. .332 Howe/H e we ooaop 3.53 Boa. oeouoemAfiooEeJmYm so 558% awesome” . .1 usage mocked; ofl flawsoamgroz NH OH w e l _ _ fl _ J 32 ea NH .AHHES QMHSHIAHKHQoHHHuEvum .Ho €590QO doamHMoH . moosodz QH npmooH 9%: 0H. m b ’ .ome mesmea _ _ m J 55 6.9.0 OOH .Ho epHcHB @925 m pm Somme wHoo SH QoHSHuAHKHQmHQBJNVum .Ho 85.8.0QO 678.2 .QNH oHSmHh .i a rlJ‘L M.._ fl. oz $5M. >o.m We.“ mm.” Me...“ ”\Nx £1 5 _I { i I [I o < I dI -f y a J 5h Ceca. OC2H5 /\/\-fi W°/\/\ S JVIII 0 CC3H7 S V H020 / \ / \ :N02 CGZCZHS 0 002H SXXIII 0 IX VI 0 CH30® 20 N33 l 1 4b -L§OBGAZ_7§L_JQT_S> /S\fl /o\ B. «_— O/S\WU/.\ 2° 2, s If. 0 2: 25:? W1 WWW Hydrogen metal interchange followed by carbonation was found to yield' 2—(2'—furyl)-5-thenoic acid (III) (identical to a previously prepared sample by u.v., IR, n.m.r. and m.p.), and the dicarboxylic acid K (Fig. 15). Although the.open.a>position on the furan nucleus in IV has a lower electron density than.the corresponding open a thiophene position, as predicted by the appearance of this .a—iuiyl hydrogen atom farther downfield (7’: 2.711) in the n.m.r. spectrum than the corresponding hydrogen atom (7’: 2. 91+) in the thio- phene nucleus, hydrogen metal interchange was found to occur only in the thiophene ring. This result, however, is consistent with the mechanism pro- posed by wynberg (l) where the metalating agent coordinates with the hetero atom prior to hydrogen metal exchange. /\ /\HS S I ’\ Li 05H5 55 .Haas Honoz on gonna Axv eaoe oaoaae-m-Aasooaep-.m-sxoenoo-.mv-m to eanoooam eoaeaoaH .ma oaomaa msoaodz QH npwooH o>m3 ea we OH w m a 56 With IV, therefore, coordination must occur only with the more available electrons on the sulfur atom allowing proton abstraction at a.position~a-to .the.sulfur atom only. When coordination occurs, the electron density at the eLposition is decreased and hydrogen abstraction by the n-butylide anion is facilitated. Secondary metalation of the molecule to yield K (Fig. 15) can then.occur.because of the increased electron density at the oxygen hetero atom, dnemto.the'presence of a now.less electronegative metalated thienyl substi- tuent, facilitating coordination with the n~butyl lithium» “Acylation with n-butyric anhydride on the other hand occurred only on the furan nucleus to yield VII (Fig. 1h). Though a lower electron density might .be.present in.the position a to the oxygen atom than would be evident in the .alternatecacthiophene position, the lower aromaticity of the furan ring relative to that of the thiOphene ring would lower the activation energy of the transition state leading to substitution in the furan ring. .Acylation of the ester V, however, led to substitution in both rings, in 60% yield. The furan nucleus having been sufficiently deactivated by the carboethoxy substi- tuent to cause 60% furyl acylation and MO% substitution in the thiophene ringf 'tAs determined by integration of the n.m.r. spectra of the crude and distillate_ mixtures (the two keto esters were not isolated from each other). 57 l: .AHH>V QMHSMuAHthanuamv-muHhhhpomum Ho aohpoogm UmamaMQH mooaon sH npmomHo>m3 NH OH w .:H oasta i a _ ——J\O 538 Bromination of IV with N-bromo—succinimide led quantitatively (no trace of IV was present in the n.m.r. spectrum of the crude reaction mixture after 2.5 hrs. of reflux) to 5-bromo-2(2‘—thienyl)-furan (XI, Fig. 15). _Again the furan nucleus with lower aromaticity requires less activation energy for substitution than does the thiophene nucleus. The thienyl-bromo—furan.(XI), like other'bromo furans, was found to be quite.unstable upon isolation. When the carbon tetrachloride reaction solvent was removed from the crude XI the bromide-began to decompose within a .few minutes with a seemingly self catalyzed spattering and fuming to form an amorphous tar. However, XI was stable in solution and although metal halogen interchange.could not be effected by either lithium or magnesium at lhO°, the interchange was effected at -70° by reacting the bromide with n-butyl lithium, forza limited time to reduce the possibility of metalation of the thiophene ring. Carbonation of this biaryl lithium.produced thienyl furoic acid x11 (Fig. 16). Reactions of 52(2'-Thienyl)-furan (XVII). The biaryl XVII was also subjected to metalation, acylation, and free radical bromination. 59 .ooHAOHsowapeB sopaoo SH QoMMP AHNV stSMIAHhsoHSPI_mvumuoeoamum Mo anpoomm onMHHQH i NH. mQOMOHS QH SPmeHo>m3 . OH O .mH madman, I_II.I|||. _ _) ho .Hasz Homes as sores AHHxv eaoa oaoasc-m-massoaeg-.mv-m to saacooam eonsaasH OH mQOHOHS sH gemsoHo>m3 w .me mHSMHm _ a —..\O — .m.m.o OOH Mo SpoHs macaw a pm scare onwKOHo QH AHHNVcHo<_OHosdyumnAHasoHeaa.mvnm Ho aospoomm_.a.auz .QOH osome ’41 rl. oI . 4.0 . . n tan do m em 3% a. 4 so . _ r f L a} «I p T L ‘ b r: b: Abe .Hass Hoesz s as sores AHHHxxV soasa-flassoacc-.m-sxoeasc-.mv-m-oncaz-m so asasooam eonsaasH .sa enemas msoaoHE QH nemQMHoEE» ea ma ca w m a _ a _ _ _ _ H02C S XVIII H02C O XVI XXI thalation of XVII with n-butyl lithium gave a mixture of mono acids in 90% yield, consisting of 45% XVI and 57% XVIII (as determined by integration of the nemerv.spectrum~ofl theECrudeqmixture,aFig. 20911 AgaihfibbbrdinatianOf the metalating agent before proton abstraction appears to be the rate determining factor. Coordination occurring only with the sulfur hetero atom, however, there are now two protons in the correct proximity for abstraction by the carbanion. /\ /\ Hs-/\ “3—, s /\ 7(1 0 I110 Chg --- Li Lil-‘54H9 Although the n.m.r. spectrum of XVII shows the furan hydrogens to be at lower field, therefore having a lower electron density and probably therefore more prone to abstraction, the hydrogen a to the sulfur atom is abstracted duh the.most.readily (57% vs. M5%). However, although this.hydrogen atom is always .in close prosimity to the butyl carbanion due to metal coordination with the -sulfur, any rotation of the molecule about the thienyl furan carbon-carbon bond, .removes the competing furan a hydrogen from the vicinity of the butyl carbanion, /\ ‘_ S-/\ _‘—’ (‘ f O 04H9----Li Li--C4H9 thereby reducing its possibility of abstraction. Considering the relative infrequency of the proper conformation for abstraction (a 7 center transition state is required) the amount of furan dehydrogen abstraction is quite high. .Acyflation of XVII produced two mono-acylated biaryls and one diacylated biaryl in h5% and 14% yields respectively. Of the mono-acylated material, electrophilic attack on the.furan nucleus at the a position ortho to the thienyl substituent,.was favored over attack on the open thiophene a position. .Furan acylation gave XIX (79%), while thiophene substitution produced XX (2T%) (as determined by integration of the n.m.r. spectra of the crude and distillate mixtures, the mono ketones were not separated from each other). Again the lower aromaticity of the furan nucleus leading to predominant substitution on that ring. The presence of the bulky ortho thienyl substituent however re- duces the reactivity of this site to the extent that substitution on the thiophene ring becomes competitive. It should be noted, however, that substi- tution on the furan nucleus occurs only at the a position ortho to the thienyl substituent (XIX), thus characterizing the thienyl substituent as an ortho- para director, in that a meta.director would in turn have led to substitution #5 at the alternate a position on the furan ring (XXIV). /\ /\ S'c;/\ ‘5 /\,S’ Cng’C O - 0 CCsH7 XIX XXIV A second acylation of either XIX or XX in turn gives the diketone XXI (Fig. 18). Eromination of XVII with NBS, with or without benzoyl peroxide present, led to a single substitution product (XXII, Fig. 19). Again the lower aro- maticity of the furan nucleus allowing a lower activation energy than would be found.for.substitution in the thiophene ring. The a position ortho to the thienyl substituent being attacked because of the possibility of conjugative interactions between that substituent and the a position ortho to it, /\ /\ Qflrgm‘r Br 0 Br 0 while such interactions cannot be incorporated in a structure where attack ‘5‘7' etc. occurs meta to the thienyl substituent. U) {I} .HHSS Henoz o mm. seams AUOS smsoyuAHaquopu.mannEchcru.mvumuHcPEHpomnm Ho 85.50QO omnmafifi. .OH 933% mooacHE sH ememHoEmz :H. NH 0H m m 1+6 —...-:1' _ _ _ _ H 1+7 ea .meHHOHaomame oopamo QH cease AHHNXV QMHSHIAHasmngu.NV:muosoamnN Ho asepommm emamaaoH NH OH msoaoflz QH apmsmHo>m3 w .ma mammaa _ fl _ p—»\O 1+8 ss amass ososoo<_ss Amv ssssx em: ens .Aav H>x see so .m.a.o cos so apes: scram masts”: @630 so $5.510QO 9.8.2 .ON 93me 33m . . Rafi To: 0%.“ INN.“ "\mx _ . L {JI r!) <4 ma" T... I r 3.3.. wd.“ Mid nm< "k. . i . . \ {Ix f I s meI (ml 1.9 The bromide XXII was found to have a stability similar to that of XI, and was therefore not isolated but was instead subjected to halogen metal inter- change in order to obtain the corresponding acid XVI. Studies of the Nuclear Magnetic Resonance Spectra. The structure assignments of the thienylwfuransjprepared and studied in this work were made through a first approximation of the n.m.r. spectra to first order splitting. The proton spinmspin coupling constants for these biaryls arei thiophene, J23 = u.5 - 5.5; J24 = 1.2 - 1.9; J34 e u.l3 furan, J23 = 1.6 - 2.1; J24 = 0.7 - 0.9; J25 : 1.5 - 1.73 J34 s 5.u m 5.9.(c.p.s.). These results were found to be quite consistent With the coupling constants' obtained by Gronowitz (18,27) and Bernstein (20). The chemical shifts of the aromatic protons (Tables V and VI) of the substituted biaryls were also found to be dependent upon the inductive character of the substituents on the rings. The effect of a substituent on one ring is in turn felt by the protons on the other ring. The n.m.r. spectra of the unsubstituted biaryls were of particular interest. While the absorption signals of protons 3 and M in IV, and 5 and 7 in XVII were found at lower field than are those 155.0 of the corresponding protons in the unsubstituted heterocycles (#0), 2.96 0 :2: (CI the signals of the remaining protons have been shifted to a higher field. To the extent that structures involving interconjugation between the two coupled heterocyclic rings contributes to the ground state of IV or XVII, M ._, m ._, IV XVII the loops of electrons in the aromatic rings are disturbed with a subse- quent reduction of deshielding as caused by the inter atomic diamagnetic term. #51 Although this reduction in interatomic diamagnetic effect would cause a shift of the absorption signals of all of the.aromatic protons to a higher field, any protons capable of hydrogen bonding (i.e., protons 5 and h in IV, and 5 and 7. in. XVII) are deshielded and their absorption signals are, therefore, found at a lower field «_ strength. (Fig. 11b, 12b). The proximity of these protons to the adjacent heterocyclic ring also can lead to_additional deshielding due to the diamagnetic effect of the other ring. However,.the extent of this diamagnetic term appears to be of minor consequence as is indicated by a lack of deshielding of the proton at position 5 in XVII, .which though it can not hydrogen bond, should be influenced by the anisotropic effect of both rings. .52 cmsoHpsoo more mom mw.m mmm wacm.a Ase s.ov owns ---- wo.e wmm haemoo a >x o m .m m / \ m m / \ m H I sashes em... ream moss so wA/m\w so. a mm.m mwm . m mesa Ase 8.8 .mm ---- ace 8m mammoovmohmbéC HE .. / \ o wm.a man u u n u o teases mes mom mlT a w mo so 51A. / \V H cameo .a- -5..- .832: MM mmm mwooAmmvoumomoumPfl/o \./\ H 18 OMB .nH.m .942 .w won—H dag 6 _ Bessemer ._.. casoasoo HHH 0.3mm. ‘w—m . ~7.~:. H Casey-4v uh NH: #1 p ».N.NN HIV..\\ .npmsmH 0>m3 smpsoflm pm sdeSOQm mHors>Homossoz w.-- fl. ...... Ii: a: nu: OmwN sm m HE em.e can mm.e smm --- ---- .oss-mos mo.a omm Asa-sv-w Asa-sv-w Has 0 0 Vet Ase sowov --- .mma-moa --- ---- --- m Asa-sv-w Max 0 Ass mo.ov --- .mma-mos ---- ---- --- Asa-sv-w m xHx o --- u--- ---- nit: --- m mmoo HHpr sm.m Hem . so.s smm emmm.s Ass m.ev .ew ---- mo.a omm m a Hs>x so.:. was --- ---- .eea-sea so.s emm ewoo m ssx 18 0%: .m .m .9 .2 w, .wOH . .088 .K 9309800 laces ewes. Lu? eossassool- HHH oases -- --- sea-woe am.s mam race a a HHx -- -- -- -- -- am m m Hx --- ---- eon-mom mm.e emm mace m ewoo x Ass mo.ov -- omaH-HJH -- -- -- m mmNONOO Asa-sv-w NH 0 Ass mo.ov -- omaH-HJH -- -- -- Asa-QV-m mmNONOO m HHH> 0 rs mm.s can :5 He.n new mmam.a Ass wo.ov once one-mm ow.m omm Asa-sv-w m m HH> o ms.e mam --- ---- .m.mma-mms am.m saw a race a H> mam Hemm.a Ass mo.ov .maa ---- om.m mam m mmmomoo a > as so as Homm.a Ass osv .m.sm ---- ma.e mom a m m >H .m.ewa om.e wmm -- ---- -m.mra ew.m saw a m mmoo HHH ohm H m m m ..m m own as as m was Cass IRE .. . assesses / \ / \ >.H mHHMB 11$ 1 {1| ...((.6_. .\ ain't-0k < .flo ED.vHHu-Hm HGUHE~0n~U WIN .3 inn-UM 03.4auvmnoo MSHHQHJQU Saw-mlfinfimc pk? Vin-nip“ ewdsHpsoo --- as.m mm.m -- ma.m mm.m -- save -- m.a -- -- 0.: --- -- Aomcmmcmaoo-a m -mmwomoo-sv as -- -- rs.m -- mm.a mo.m mm.m save -- -- --- -- r.m m.a o.m Ammommowmoc-m . a -nmwomoo-sv HHH> -- -- mm.m mm.m ms.m os.m ow.m save -- -- --- m.m m.m m.s o.onmommommoo-mv HH> :5 = .9 o ---- ma.m aa.m --- e®.a em.m oa.m ososoos --- o.m -- -- m.m m.a m.m Amoco-av H> -- ms.m am.m -- mm.a oo.m oe.m save --- m.a -- -- m.m m.a m.m Anmwomoo-ev > -- ow.m ms.m mm.m me.m ma.m ---- more em -- s.a r.o s.m w.m -- -- = HHH -- ma.m wa.m am.m ms.m om.m --- ossaoae -- m.a s.o m.m s.s -- -- s HHH -- oa.m aa.m ma.m sw.m on.m -- ososoos -- m.a s.o a.m 0.: -- -- Amoco-HO HHH -- as.m ms.m me.m er.m ma.m am.m race -- m.a r.o a.m e.n e.a m.m A.smasusav >H e as m /. \a M/, \ m em om mm em as we as assoeaom sob one new new owe was was essoasoo *msosoas.oasssoa< so assaem asossono * “HA.m.m.oV mpsdpmqoo wQHHmsoo sflmm-Qflmw .> oHme (ll-II); -- | W: ~w-s N Q -a,».\V \a .l. \.RV JVv 0809.9 :0 .0 “I. mH mQOHpssHssmpmo PsHQm HmOHEmso so aosaooos aOH u.kw«dsmeswpm stameH as me some mm: mstHHmHsewosmspmH* .mmHoao N.O H.mfl mQOHpssflfismpod 05Hm> b so sods500<+ .thHHQSHom 30H 0p 05d smeared QOHpmHPsmosoop 6 5 .6090: mm psmoxm &ON-OH mama wows mQOHPmeQoosoos -- -- 0m.m aa.m 0e.m 0m.m -- aosmxoae -- -- -- 0.m 0.: -- -- Am0z-e -mmoo-av HHHax -- -- sw.m Ha.m mm.m m0.m m0.m osssoae -- -- -- 0.m m.m m.a H.m Ammoo-ev HHN ---- --- m0.m ms.m m0.m sa.m sm.m saoc -- --- -- e.m m.m m.a m.m Ass-0O Hx . -- -- am.m H0.m 00.m m0.m -- m0az em -- -- -- m.m r.m -- -- Amm00-m -mm00-av _x Fm mm mm Wm mm mm Hm MP8>HOM 50H. mmh QIVH. mavH. ONHq , OHH. NHH. 630.9500 003380 - > oases doosHpsoo ---- 00.m m0.m ---- sa.m 0m.m --.- aososoos --- 0.m --- --- 0.: --- --- Aerodrommcm-s 0 -mmommommoo-HV Hex __ 0 mm.m m0.m s:.m ---- mm.m :0.m ---- eaoo m.a m.a 0.0 --- 0.: --- ---Aom0mm0mm00-HO xx in ---- m0.m 0m.m ---- 00.m m0.m me.m ssoo --- 0.H -- --- 0.m m.a m.mAnm0mm0mm00-sv ass .7, w s0.a sm.m 0m.m ---- 0m.m ms.m ---- ososoos m.: m.a m.0 -- 0.: -- -- Amm00-HO Hassx -- a0.m sm.m -- 0m.m m0.m ms.m eaoo -- 0.a -- -- 0.m m.a n.m Anemomoo-sv sx -- mm.m m0.m -- ma.m ww.m 0:.0 ososoos -- 0.a -- -- w.m m.a m.m Assoc-s“ Hex m:.m. m0.m mm.m -- :0.m :H.m m0.m sa00 s.a 0.H m.0 -- s.m m.a m.: A.suasassv sssx 0m.m 0m.m mm.m -- :m.m m0.m ss.m ososoos 0.a 0.H 0.0 -- m.m :.H m.: A.sapsassv Hssx s m/\ a: m/ \m hm mm mm mm mm mm am mps0>H0m bmh mmh hmb mwh mmb new New assomsoo *msoposm.0Hpm50s< s0 messsm HmUHsmeO m .m.s.oV mpswpmsou wsHHmsoo sHmm-sHmw .H> mHQmH ea .mmHoao N.OH mH mQOprsHssmp e 03Hm> b so sowH500 panes EXPERIMENTAL* 5—(23-Furyl)-2-mercapto-2,h-pentadienoic Acid (I). ..A-7;1 g. (0-05 mole) quantity of the rhodanine derivative (28) of 2- furylacrolein (29) and 60 m1. of 10% NaOH were placed in a 250 ml. flask. The-alkaline reaction mixture was.heated until solution was complete (10-15 min.),.then cooled in ice water and acidified by the addition of #0 m1. of lO%.HCl in one portion. The precipitated mercapto-acid was recovered by filtration, washed with water and dried to obtain u.u g. (0.022 mole), 75%, of I- .A portion for analysis was purified by sublimation in order to obtain light yellow needles which melted at lh8-l50°. Anal. Calc'd. for CgHgsogz C, 55.09; H, 4.11; s, 16.5u. Fbund: c, 5h.9u; H, 4.55; s, 16.u0. g,2‘-Dithiobis-[5-(2"-fury1)-2,u-pentadienoio_Acid] (II). To a stirred solution of 0.5 g. (0.0025 mole) of crude I dissolved in .a.minimum of absolution ethanol at 0° was added 0.55 g. (0.001u mole) of iodine. The oxidation was allowed to continue for an hour at 0°; the mix- ture was filtered and the disulfide precipitate washed with a minimum of cold ethanol. Recrystallization of the crude disulfide from an ethanol water *All reactions were conducted under dry nitrogen. N.m.r. spectra were obtained on a varian A-6O high resolution spectrometer, infrared spectra from a Perkin- Elmer model 2l, and ultraviolet spectra were obtained on either a Beckman DK-2 or a Cary model ll. 59 .60 mixture yielded the pure.product II (0.55.g., 0-0018 mole, 70%) as an orange colored.crystalline solid melting at 191 to 195°. Anal- oalctd. for clghlgsaog: C, 55.57; H, 5-61; 3, 16-45. .Found: C, 55.22; H, 5.86; S, 16.65. Neutralization equivalent. Calc'd.: 195. Found: 196. 2—(2'-Fury1)-5-thenoic.Acid (III). .A 6 g-.(0-05.mole) quantity of I was added to a stirred solution prepared from 7.5 g. (0.05 mole) of iodine dissolved in 100 ml. of absolute ethanol and.contained in a 250 ml. Erlenmeyer flask. The temperature of the flask was maintained at 75° for 5 hrs..after which the contents were poured into a liter of water. Unreacted iodine was destroyed by adding excess granular NaHSOS. Powdered charcoal was then added, the mixture was warmed to effect solution of the organic material, and the hot mixture was filtered through fluted filter paper. The cooled filtrate was extracted with one 200 m1. and two 100 ml. portions of ether. The combined ether extracts on evaporation yielded 1.6 g. (0.0082 mole, 27%) of crude III. .A sample for analysis was purified by recrystallization from an ethanol-water mixture and then sublimed at 110° (0.08 mm.) to obtain a pale yellow solid in the form of needles which melted at 186.5 to 187.5° Anal. Calc'd. for chgsogz c, 55.66; H, 5.12; 3, 16.51. Found: C, 55.59; H, 5.54; S, 16.57. Neutralization equivalent. Calc'd.: 194. Found: 197. .61 2-(2!-Thienyl)-furan(IV). Into a.25 ml. three neck flask equipped with a nitrogen inlet tube, and a.20 cmm.vacuum insulated vigereaux column attached to a.distilling head were placed 5.6 g. (0.029 mole) of III, 0.5 g. powdered copper, and 10 g. of puri- fied.quinoline. The reaction mixture was heated to its reflux temperature while the flask was swept with nitrogen until C02 evolution had ceased (2 hours)- .The resulting thienylfuran-quinoline mixture was subjected to vacuum distillation, the portion boiling.at 90-1lO° (10 mm.) being collected. The distillate.was dissolved in 20 ml. of ether and the ether solution was washed twice with 5 ml. portions of water, and dried. The ether was removed and the residue distilled in vacuo to obtain 2.55 g. (0.017 mole, 59%) of IV, b.p. 97-5° (10 mml), nfio 1.6201, which was readily oxidized by air. Anal. Calc'd. for CgHSSO: C, 65.97; H, h.05;~s, 21.5u. Found: C, 6u.10; H, n.11; 8, 21.29. . Ethyl 2-(2'-Thieny1)-5-furoate(V) (11). Into a liter three necked flask containing a nitrogen inlet tube, mechanical stirrer, and a dropping funnel, were placed 56.5 g. (0.286 mole) of ethyl 5-(2'-thieny1)-5-oxopropionate (51), 50 g. (0.515 mole) of 1,2- dichloroethylethyl ether, and 500 m1. of ether. The vigorously stirred mixture was cooled to 0° and a solution of 55 g. KOH dissolved in 200 m1. of ethanol was added to it over a period of an hour. The reaction mixture was stirred for an additional hour and then 50 m1. of 10% HCl was added to it. The insoluble salt (K01) was removed by filtration, followed by removal of the ether on a rotary evaporator. The heavier, lower, organic layer was 62 separated, dried and distilled.in vacuo, and the fraction boiling.in.the _range16oal4o° (0.5.mm.).was collected. The distillate was diluted with four .timesmitscvolume of ether, chilled in ice, and washed five.times with 50 m1. portionslofs2%aNa0H, then with dilute HCl, and finally with water and.dried. “Vacuum"distillation of the resulting.ethereal solution of essentially pure ester.gave.20.7l.g.(0.095 mole, 53%) of V, b.p. 115-119° (0.09 mm.),-' n30 1.5941. . Asa- { Calcfid. for CllHloSOS: C, 59.42; H, $.55; 8, 14.45. .Fbund: C, 59.45; H, 4.46; 5, 14.49. 2-(2'-Thieny1)-5-furoic Acid (VI). A 5 g. (0.0225 mole) quantity of ester (V) was saponified by heating at its reflux temperature a solution of the ester with 2 g. (0.056mole) of KOH, dissolved in 75 m1. of 65% ethanol, under a nitrogen atmosphere for 20 min. The ethanol was removed from the aqueous acid salt of VI by vacuum distillation with a water aspirator, concentrating the alkaline solution to a volume of 15 to 20 ml. .A 100 m1. volume of water was then added to the concentrated solution and the basic solution was cooled. .Acidification with 20 m1. of 10% H01, followed by filtration, washing of the precipitate with copious quantities of ice water, and drying, gave 4.4 g. (0.022 mole), 98%, of a stable colorless organic acid, VI. .Sublimation of a portion of the acid for analysis at 100° (0.08 mm.) gave colorless needles melting at 155 to 155.5°. 65 Anal. Calc'd. for 09H68032 C, 55.66; H, 5.12; 5, 16.51. Found: C, 55.92; H, 5.54; S, 16.41. 24(2lqghiemyl)sfurant(IV). 22(2'-Thienyl)-5-furoic.Acid (IV) was decarboxylated by the procedure utilized for the decarboxylation of 2-(2'—furyl)-5-thenoic acid (III). ,A 17.7 g. (0.091 mole) quantity of VI yielded 12.9 g. (0.086 mole) of IV. The latter was shown to be identical to the material obtained by the decarboxyla- tion of III by infrared, n.m.r., b.p., and refractive index determinations. Nitration of 2-(2'-Fury1)-5-thenoic Acid. Following the experimental procedure outlined by H. Gilman (57), 9.7 g. (0.05 mole) of 2-(2'-fury1)-5-thenoic acid (III) was added in portions at -15° to a well stirred nitrating mixture prepared from 18.5 g. of fuming nitric acid (sp. gr. 1 51) dissolved in 59 m1. of acetic anhydride. The reaction mixturc.was stirred for an hour at -15° and then poured into 500 m1. of ice water. The precipitated nitro acid was recovered by filtration to obtain 5.7 g. (0.024.mole) of the crude acid XXIII. Sublimation of a portion of the acid for analysis gave orange Colored needles of pure acid which melted at 262-265°, and had a low solubility in most organic solvents. .Anal. Calc'd. for C9H5N058: c, 45.19; H, 2.11; 3, 15.41; N, 5.86. Found: C, 45.20; H, 2.283 S, 15.65; N, 5.84. 64 .Acylation of 2-(2'-Thienyl)-furan (52). Into a.10 m1. flask which.had been fitted with a reflux condenser, a drying.tube, a thermometer, a magnetic stirring bar, and a nitrogen inlet tube, were placed 2.75.g. (0.0182) mole) of IV and 5.50 g..(0.029 mole) of butyric anhydride. To this solution was added 0.25 g. (0.50 ml.) of BFa- etherate while nitrogen was passed over the stirred mixture. The tempera- .ture of the dark blue solution immediately rose and was maintained at 110° for 2 min. The solution was then allowed to cool while stirring was continued for an additional 50 min., and the reaction was then quenched by the addition of 2 m1. of water. .A saturated aqueous solution of Na2003 was then_added to the reaction.mixture until it was basic to litmus. .The mixture was extracted with ether and the combined organic extracts were dried with Na2804. Removal of the ether and vacuum distillation of the residue yielded 1.0 g. (0.0045 mole) of the ketone VII, b.p. 105° (0.08 mm.), m.p. 52-55°, n30 1.6152, (28% based on unreclaimed IV). Anal. .Calc'd. for 012H12S02: C, 65.45; H, 5.45; 3, 14.55. Found: C, 65.21; H, 5.70; S, 14.45. Acylation of Ethyl 2-(2'—Thieny1)-5-furoate. Acylation of ethyl 2-(2'-thienyl)-5-furoate (V) was accomplished by the procedure outlined for IV above. By reacting 2.22 g. (0.01 mole) of V with 1.82 g. (0.0115 mole) of butyric anhydride and 0.14 g. (0.165 ml.) of BF3- etherate, 1.7 g. (0.0077 mole) of a product, b.p. 141-145° (0.05 mm.), 60% was obtained, consisting of a mixture of keto-esters VIII and IX, melting at 65 59—62°. .This mixture was subjected to elemental analysis. .Anal. Calc'd. for C15H16804: C, 61.64; H, 5.48; 8, 10.96. Found: C, 61.92; H, 5.67; 8, 10.77. thalation of 2-(2'-Thienyl)-furan. .A mixture of 0.50 g. (0.0455 mole) of lithium metal pellets and 10 ml. of anhydrous ether was placed under nitrogen in a 25 ml. 5 neck flask whidh . was equipped with a magnetic stirrer, a -100 to + 50° thermometer and a _pressure.equalizing dropping.funne1. A solution of 2.74 g. (0.02 mole) of nebutyl bromide dissolved in 5 ml. of anhydrous ether was placed in the dropping funnel and a few drops of the latter mixture were added to the lithium mixture. The stirrer was started and after 5 to 10 minutes, the _liquid.in.the.f1ask became cloudy and bright spots appeared on the lithium. The temperature of the reaction mixture was lowered to -20° by immersion of the reaction flask in-a dry ice acetone bath, and the remainder of the bromo- butane was added at an even rate during approximately an hour. .The mixture was stirred for an additional hour while the temperature was allowed to rise to t10°., The unreacted lithium was removed and the remaining solution was .cooled to -50°- ”A solution of 5.0 g. (0.02 moles) of thienylfuran (IV) in . .5 ml. of.anhydrous ether was placed in the dropping funnel and this mixture .was allowed to drop into the reaction flask during a half hour while the temperature of the reaction mixture was maintained below -20°. The reaction mixture was stirred for an additional hour while the temperature was allowed to rise to 0°, at which point it was poured into a slurry of 25 g. of dry ice in 15 ml. of ether. The dry ice was allowed to evaporate and the remaining 66 .ether mixture was washed three times with 20 ml. portions of water. The _ .combined water extracts were waShed once with 10 ml. of.ether, placed in .a flask and acidified to a pH of 4.2 (pH meter) to obtain the mono-acid III, 2.5 g. (0.0129 mole), 65%, (identified by comparison of m.p., and n.m.r. and.infrared.spectra.with data for previously prepared III). The filtrate was treated with.norite.and.further acidification yielded 0.5 g. (0.0015 mole), 6%,.of.pure dicarboxylic acid X melting at 502-504°. .Anal- Calc'd- for ClngSOS: C, 50.42; H, 2.54; S, 15.46. Found: C, 50.54; H, 2.61; s, 15 77. Bromination of 2-(2'-Thienyl)-furan (55). Into a 100 ml. 5 neck flask equipped with a reflux condenser, a nitrogen inlet.tube, and a magnetic stirrer, was placed 5 g. (0.02 mole) of IV dissolved in 40 m1. of purified 0014. To this solution was added 5.5 g. (0-02 mole) of N-bromosuccinimide and the resulting mixture was heated at its.ref1ux temperature for 2.5 hrs., then cooled and the succinimide removed by filtration. The filtrate was washed twice with 10 m1. portions of water .and dried with Drierite. Infrared and n.m.r. spectra taken of this solution showed the reaction to be essentially quantitative. Evaporation of the solvent on a rotary evaporator gave a greenish-yellow colored liquid which decomposed with a seemingly self-catalyzed spattering and fuming, commencing about 5 minutes after removal of the C014, producing a black amorphous tar. 67 2-(2'-Thieny1)-5-furoic.Acid (XII). 5-Bromo-2-(2'-thienyl)-furan (approx. 0.02 mole) in 0014, from the _previous reaction was placed in a 100 ml. 5 neck flask which had been fitted with a.nitrogen inlet tube and a vigereaux column with distilling head .attached. .A 40 m1. quantity of dry di-n-butyl ether was added and the C01; was removed from the mixture by distillation until the vapor temperature reached 40° (50 mm.). The di-n-butyl ether solution was cooled and added in one portion to 0.02 mole of n-butyl-lithium dissolved in 50 ml. of diethyl ether.at -70°. The resulting mixture was stirred for 2.5 minutes and the reaction mixture was then.poured into a slurry consisting of 25 g. of dry ice in 25 ml. of anhydrous diethyl ether. The excess dry ice was allowed to vaporize and the remaining ether mixture was washed 5 times with 50 m1. portions of water. The combined aqueous portions were extracted once with 20.ml- of ether and then acidified with 10% HCl. The crude organic acid was separated by filtration (1.89 g., m.p. 162—164°), and again dissolved in aqueous base, treated with Norite and reacidified. Filtration of the ' resulting white flocculant acid and drying gave XII which melted at 166- 167°. The 41% yield based on IV, should be increased by longer reaction time as considerable unreacted bromide remained in the ether layer. A portion of the acid for analysis was sublimed with no further improvement in melting point. Anal. Calc'd. for C9H6803: C, 55.66; H, 5 12; 3, 16.51. Found: C, 55.46; H, 5.26; 8, 16.52. 68 .l,léDimethoxy15-oxo—5-(2'-thienyl)-propane (XIII) (54). Into a dry 2 liter 5 neck flask, equipped with a reflux condenser with an_attached drying tube, A Hirshberg stirrer, a vacuum take off, and a nitrogen inlet tube, was placed 250 ml. of anhydrous methanol. To this was added 25 g. (1 mole) of sodium metal chips. -After the reaction was com- plete the excess methanol was removed by vacuum distillation from the stirred mixture.until powdering was complete.* A 1.5 liter volume of anhydrous ether was then added to the cooled flask and a solution of 126 g. (1 mole) of acetothienone dissolved in 72 g. (1.2 mole) of methyl formate (distilled from P205) was added at a rate sufficient to maintain a gentle refluxing (50 min.) of the well stirred thickening yellow-white mixture. The reaction mixture was stirred for an additional 1.5 hrs., at which point most of the ether was removed by vacuum distillation from the very thick mass (stirring was continued for as long as practical). Methanol (6 moles) was then added .to the solid sodium hydroxymethylene ketone followed by the addition of a .solution of 2 moles of anhydrous H01 dissolved in 4 moles of methanol. The temperature of the mixture rose on addition of acid and was lowered to 20° .by cooling. The acidified mixture was stirred for an additional 2 hrs. at 20°. .A solution of KOH dissolved in a minimum of methanol was then added, while the stirred reaction.mixture cooled in an ice bath, until a pH of 6 (moistened Hydrion Paper) was attained. .A mixture of 200 m1. of 0014 and *Commercial sodium methylate would not catalyze the desired condensation. 69 450 ml. of water was then added and the resulting aqueous brine layer was removed.and washed with two 50 ml. portions of CC14. The organic layers were combined and washed twice with 150 ml. portions of a half saturated brine solution. The.organic layer was separated and dried with Mg804, and the solvent was removed by means of a rotary evaporator and vacuum dis- tillation of the residue from a simple distillation flask gave XIII (141 g.) 70%, b.p. 95° (0.07 mm.) (oil bath temperature 115°). Anal. Calc'd. for 09H12803: C, 55.97; H, 6.04; S, 16.01. Found: C, 54.18; H, 5.94; S, 16.24. l:thhoxy-5—oxo-5-(2'—thienyl)-lwpropene (XIV) (54). The procedure for the preparation of XIII was followed with the following modifications. The acidic methanolic acetal solution was neutralized with a saturated solution of KOH dissolved in methanol until .the.mixture was basic to litmus. At this point the coloration of the mixture had changed from a yellow to a blood red color. Filtration of the precipitated inorganic salts, followed by vacuum distillation of the filtrate from a simple distillation flask, resulted in the isolation of 10 g- of distillate, b.p. 120° (0.7 mm ), consisting of a mixture of XIII and XIV, which solidified in the collection flask. Recrystallization of this solid.distillate four times from CC14 with Norite treatment resulted in the isolation of 4.0 g. of pure XIV, m.p. 72 5-75 5°. Anal. Calc'd. for CgHgsogz C, 57.12; H, 4 79; S, 19 07. Found: C, 56.61; H, 4.66; S, 19.55. 70 methyl 5-(2'-Thienyl)-2-furoate (XV). The.procedure outlined by Burness (5,7) for the preparation of B- substituted methyl a—furoates was utilized for the synthesis of XV. .In this manner 200 g. (1 mole) of XIII was converted to (66 g.) of XV, 52%, b.p. 156° (0.7 mm.), n50 1.6098 by distillation from a simple distillation flask without purification of the glycidic ester intermediate. _Anal.= Calc'd. for C10H8503: C, 57.67; H, 5.87; 3, 15.40. Found: C, 57.42; H, 5.92; 3, 15.22. 5-(2'-Thienyl)-2-furoic Acid (XVI). The procedure followed has been outlined for the saponification of V. By this method 100 g. (0.48 mole) of ester was converted to 84 g. (0.45 mole), 90%, of crude, cream colored acid melting at l68-l69°. A 4.0 g. portion of the acid for analysis was dissolved in base, treated with Norite at 25°, and acidified to obtain 5.2 g. of colorless acid melting at l7l-l72° on a Kofler block. Anal. Calc'd. for C9H5803: C, 55.66; H, 5.12; S, 16.51. Found: C, 55.65; H, 5.16; 8, 16.71. 5-(2'-Thienyl) furan (XVII). By the method used above for the conversion of VI to IV, 61 g. (0.515 mole) of acid XVI was converted to 42.1 g. (0.28 mole), 89%, of XVII, b.p. 84° (4.2 mm.), n50 1.5924. 71 .Anal. Calc‘d. for CgHgSO: C, 65.97; H,.4.05; S, 21.54. Found: C, 64.50; H, 5.92; 8, 21.00. Acylation of 5-(2'-Thienyl)—furan (XVII). By the procedure used above for the acylation of IV, 9 g. (0.06 mole) of XVII, 10.92 g. (0.069 mole) of n-butyric anhydride, and 0.99 ml. of BFg-etherate were allowed to react for 5 minutes at 110° and the solution was then allowed to cool while stirring was continued for an additional hour. .A 12 ml. volume of water was added and the solution was made basic by the addition of a saturated Na2C03 solution. .Ether (10 ml.) was then added and the crystals of almost colorless diketone XXI (2.4 g., 14%) were recovered by filtration and rinsed with ether. Sublimation of a portion of the crude XXI gave cubic crystals melting at 109-110°. .Anal. Calc'd. for Clengsosz C, 66.18; H, 6.25; 3, 11.04. Found: C, 66.28; H, 6.56; 8, 11.14. The filtrate after isolation of XXI was extracted with ether and the organic layer was dried over MgSO4. Removal of the ether and vacuum _distillation of the residue gave a mixture (5.9 g-, 45%) of ketones consisting of 79% XIX and 21% XX, b.p. 105—122° (0.06 mm.) with XX pre- dominating at the higher temperature. .Anal. Calc'd. for 012H12502: C, 65.45; H, 5.45; 5, 14.55. Found: C, 66.01; H, 5.75; S, 14.50. 72 ~Metalation of 5-(2’-Thienyl)-furan (XVII). .By the procedure previously discussed for the metalation of IV, a 6 g. (0.04 mole)quantity of XVII was converted to 5.95 g. (2.04 mole), 51%, of .a.crude.acid.(90% based on.unreacted XVII). Sublimation of.a portion of the _acid for analysis at 110° (0.05 mm.) yielded a mixture of monoacids con- sisting of 45% XVI and 57% XVIII. Anal. Calc'd. for C9H68032 C, 55 66; H, 5.12; 5, 16.51. Found: 0, 55.85; H, 5.16; 5, 16.78. .Bromination of 5—(2'-Thienyl)-furan (XVII). By the procedure outlined earlier for the bromination of IV, a 5 g. .quantity (0.02 mole) of XVII was allowed to react with 5.5 g. of NBS in .40.ml. of.0014, to yield quantitatively (as determined by n.m.r.) in 1.5 hrs , 2ebromo-5-(2’-thienyl)-furan (XXII). Due to the instability of XXII it was converted to.the corresponding acid XVI (2.25 g., 58%) by the previously described procedure to convert XI to XII. Bromination of XVII in the_presence of benzoyl peroxide. In a manner similar to that above, 5 g. (0.02 mole) of XVII was allowed to react with 5.5 g. (0.02 mole) of NBS, and 0.2 g. of benzoyl peroxide in 40 ml. of purified 0014. Again XVII was converted quanti- tatively (by n.m.r.) in 1.5 hrs. to XXII, at the reflux temperature of the reaction mixture. '75 ”Attempted condensation of thienyl glyoxal with1methyl diglycolate. . The Hinsberg (16,50) method for the preparation of substituted furans was used in an.attempt to prepare a substituted 5-(2'-thienyl)-furan. Utilizing this previously described experimental method 5.5 g. (0.025 mole) of thienylglyoxal (55,56) and 4.05 g. (0.025. mole).of methyl di- glycolate.dissolved in 20.ml-.of anhydrous methanol were added to a .solutionncontaining.7-25 g- (0.115 mole) of freshly prepared sodium methylate dissolved in 45 ml. of anhydrous methanol. The resulting mixture was set aside under nitrogen at room temperature for 7 days. The dark blue reaction mixture was then poured into water and concentrated .by.heating on.a steam bath- .Acidification of the cooled alkaline mixture -gave an.aqueous suspension of.a dark amorphous material from,which no .substituted.furoic acid could be isolated. Modifications of this pro- -oedure were also.attempted. The reaction mixture was heated at its reflux temperature under nitrogen for 4 hrs., poured into water and then concentrated on a steam bath. >The brown basic mixture was acidified and .the isolation of any resulting furoic acid was again unsuccessful. A 7 g. (0.05 mole) quantity of thienyl glyoxal and 8.1 g. (0.05 mole) of ester were dissolved in.a mixture of 75 ml. of ether and 25 m1. of methanol. This solution was cooled to 0° and a second solution containing 14. 5 g. (0. 225 mole) of freshly prepared sodium methylate in 67 m1. of methanol was slowly.added to the stirred mixture. The cold mixture was stirred for an additional 2 hours, then poured onto ice, and the resulting mixture extracted three times with ether. The organic layers were combined, washed with dilute acid, then with water and dried. The ether was evaporated and the residue was distilled in vacuo. The starting material -which distilled.at 85° (0.1.mm.), consisted mainly of methyl diglycolate, the remaining material was undistillable, at a pressure of.0.l mm., although the still bath temperature was raised to 200°. _Attempted isolation of ester ..orlacid.from this residue was unsuccessful. .A 7 g..(0a05 mole) quantity of thienyl glyoxal and.8.l.g. of methyl diglycolate were dissolved in 20 ml. of dimethyl sulfoxide and 1 ml. of triethylamine was added. The resulting dark blue mixture was stirred at room temperature for 50 hrs., and 40 ml. of 10%-Na0H.solution was then.added. The basic mixture was heated at its reflux.temperature for 15 minutes. The triethylamine was removed by vacuum .distillation from.the mixture and 200 ml. of water was added. The resulting .solution was treated with Norite, and then acidified. .Attempted isolation of a thienyl-furoic.acid from the resulting dark colored mixture gave no positive results. Attempted Von Richter reaction on 2-nitrothiophene. .The.Von Richter-(17,58) reaction conditions were used in an attempt to convert.2-nitro thiophene to 5-thenoic acid. In this manner 4 g. of 2- nitrothiophene was combined with 15 g. of KCN in 75 ml. of 48% ethanol.. The resulting.mixture was refluxed for 1.5 hrs-,.and then poured into 100 ml. of _water and made strongly basic with NaOH. The ethanol was removed by steam distillation.and the residue was acidified. Steam distillation of the acidic sclution gave a cloudy distillate, which was extracted with ether. .Evapora- tion of the solvent from the ether extract yielded no 5-thenoic acid. In a subsequent attempt to carry out the Von Richter reaction with 2-nitrothiophene, CuCN was used in place of the KCN with no positive results; and the KCN '75 .aqueous ethanol solution was.buffered with KH2P04 to a.pH of 718. In neither of these.modifications of the reaction conditions was any 5-thenoic acid iSOlated. SUMMARY Theimixed biaryls 2-(2’-thienyl)-furan.and.5-(2'-thienyl)-furan were prepared,-and though air.oxidizable, they were quite stable under a nitrogen atmosphere. These biaryls were subjected to metalation, acylation, and.free radical bromination- While coordination of the.metalating agent with the sulfur hetero atom controlled the position of hydrogen metal ex- change, acylation and bromination occurred.preferentially in the less aromatic furan.nucleus. »Substitution took place in the a.position ortho to the thienyl substituent in the B substituted furans, and in the alternate a (para) position in.a substituted furans. Product structures were assigned with the aid of the characteristic ,spinespin.coupling constants of the various aromatic protons, which in this work were found to be: thiophene - J23 = 4.5 - 5.5; J24 = 1.2 - 1.9; 5.4 - 4.1; furan - J23 = 1.6 - 2.1; J24 = 0.7 - 0.9; J25 = 1.5 - 1.7; J34 J34 5.4 - 5.9 (c.p.s.). 76 LJIWERJAIWJRJQ(3PTEHD 1- H. wynberg, J..Am..Chem..Soc.,;§2, 1447 (1960). 2. H. wynberg, J..Am. Chem. Soc., 79, 1972 (1957). 5. H. wynberg, J-.Am. Chem. Soc., 89, 564 (1958). 4. H.-wynberg,.Abstracts,offiPapers,.Division-of Organic Chemistry, 155th National Meeting :American Chemical Society, Boston, Massachusetts (April. 5-10,1959), p. 75. 5- D. M. Burness, Org. Syn., Vol. 59, p. 49. .6. D. M. Burness, Org. Syn., Vol. 59, p. 46. 7. D :M. Burness, J. Org- 0hem.,.gl, 102 (1956). 8. E..Campaigne, J.-0rg. Chem.,;§£, 59 (1956). 9. A. Dodson, Ph.D. Thesis, Michigan State University (1961) 10. E..Benary, Ger., 44, 495 (1911). 11. T. Reichstein, Helv.,Chim. 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