Initial n n‘ rues. out..- I 09'- 0- ”n- -c r“ {'1' ,fi , 1.;aq ~ “'1'” ‘R .1. ' ' ~ in ' '~‘I ‘ "I 1" ‘ I Q'.‘ -- - -( ' "I ‘l 31" (V .1 9“qu _-: .3“; e ‘ I\l.:._'w‘;s€ £5-23! -u...:. um: ..'_\(~‘ ~-:". d‘doa'ia ’r’l: ': .. o ' ‘. P .‘v. '! ~ I ~ ‘ ' " . ‘ r- - f. I ; ’A- .‘ ’- ‘ 1 ‘_ V ~ -\-ba‘ '0. 5|.» ‘6564.’ J: . " "" ' ' ' ‘ . I? w:- rot m-s s-.—1.. .- ..,. ..‘ I I‘U-l-fl‘ 1 if Q :1 . - ";:"‘ o 'o . ‘5 n ‘ ‘ ' c I ‘I , ’ ' Hug-Ht" .' .3.A.- 4...a.u...¢atu ! " _z. ;- {:3 f‘ .f‘ fQ. “‘g . a; ’O". -r >7 L h: .' .5 : Q-V' - v. \ l ..‘.- - .. \. ' o ’ . , . a l 8" v. :mgsts LIBRARY Michigan State University . .4 rape." THE SYNTHESIS AND REACTLONS OF SOHE BIHETEROCYCLIC SYSTEJS BY John S. Perz A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1965 ACKNOWLED3EHENT3 The author wishes to exoress his sincere an reciation to l k Professor Robert D. Schuetz for his interest and guidance throughout the course of this investigation. *#*#***$#**#*** TABLE OF CON TENTS II\II1‘RODUCTION ATVTD IiISTORICAL....O.OOOOOO....OOOOOOCOOO ..... 0.0.1 EXPERE'mITA-Looo0.0000000000000000...oooooo00.000000000000000005 NOMOR. SPECTRAOOOOOOOOOOOOO0.0.0....00.000000000000000.0.0.0.018 ESULTS AND DI.3CUSSIONOOOOO.000.0.0.0....00....000.00.000.0000027 SUL'E‘IAEHOOOOOOOOOOOO...00.0.0...0.0.0.0000...OOOOOOOOOOOOOOOOOOBLP REFEREEQCESOOOOOOOOOOO00.0.00...0......I0......0.0.0.000000000035 INTRODUCTION AND HISTORICAL In recent years, considerable work has been'undcrtaken in these laboratories on the syntheses and investigation of biheterocyclic compounds. One objective of this research wws to utilize these compounds in determining the orienting effects of the hetero- aromatics furan, pyrrole, and thiophene as substituents in substitution reactions. Some progress has been made in these studies in that the biheterocyclic systems 2-(2'-thienyl)-furan and 3—(2'-thienyl)-furan have been synthesized in sufficient quantities to permit orientation studies.(l). However, the yields have been small due to the necessity of employing a multistepped reaction sequence in their preparation. It would be very helpful to the investigation of the properties and chemistry of biheterocyclic compounds to develops a synthetic method to such systems capable of yielding substantial amounts of symmetrical and mixed biheterocyclics. In the present research, investigations of two possible reaction sequences to the synthesis of biheterocyclics were examined. The first of these deit with an examination of a coupling reaction reported by Gronowitz (2), utilizing an oxidation reduction coupling procedure involving the lithium derivative of the heterocyclic molecule and anhydrous cupric chloride. Gronowitz employed this method to synthesize 2,2'-bithienyl and 3,3'—bithienyl in yields substantially higher than any preparation previously described in the literature (3). The present investigation extended this coupling procedure to the synthesis of the furan and N;methylpyrrole biheterocyclic systems. The preparation of 2,2'_bifuryl was initially accomplished in 1926 by Kondo and Suzuki (4) through the decarboxylation of 2,2i-bifuryl-3—carboxylic acid. The acid was obtained in approximately a twenty percent yield by a two step synthesis involving furoylacetate and Z—chloroethanal as starting materials. 90202115 00202H5 COOH cno ,CHZ NaOH Cl 0 Since that time, little work has been reported in the literature on the 2,2'-bifuryl system, especially with respect to the deve10pement of a simple synthesis of this material. A tirough search of the chemical literature shows that the synthesis of 2,2'ebi—N;methylpyrrole has not been as yet accomplished; or at least it has not been reported. In the present research, investigations were carried out to synthesize derivatives of the biheterocyclic systems 2,2'—bifuryl and 2,2'—N-methylpyrrole. The intermediate utilized to synthesize all derivatives was the metalated biheterocyclic lithium compound. The use of this intennediate lead directly to the carboxylic acid, carboxaldehyde, and methyl ketone of the two biheterocyclic compounds described above, with all of the substituent groups located in the 5 position. The 5-carhoxylic acid and 5—carboxaldehyde of 2,2'-bifuryl were initially prepared by Reichstein, Grussner, and Zschokke in 1932 (5). These investigators synthesized the aldehyde via the action of hydrogen cyanide and dry hydrogen chloride on 2,2'-bifuryl. The aldehyde was then oxidized to the carboxylic acid. 1 HON, HCl x 2 H20 7 CHO Q Q . Q U \r The second reaction pathway to the preparation of bihetero- cyclic systems investigated involved the coupling of the lithium derivative of a heterocyclic molecule with the same or another heterocyclic halide. This procedure had been investigated recently by Ramanathan and Levine (6). These invastigators reacted 2-thienyllithium with a series of alkyl bromides and a haloaromatic compound, bromobenzene. .The alkyl halides coupled with the thienyllithium giving excellent yields of the alkyl thiophenes. The reaction of Z-thienyllithium with bromobonzene gave a thirty percent yield of 2-phenylthiophene, and a small amount of 2,5- diphenylthiOphene. Ramanathan and Levine (7) extended their - Q.) coupling reactions to furan, but limited their studies here to reactions with alkyl halides. The coupling reactions investigated in the present work were conducted in tetrahydrofuran as well as in ether as reaction solvents. The tetrahydrofuran was the better of the two solvents with regard to product yield in the reactions investigated by Ramanathan and Levine. No 2—phenylthiophene was produced when ether was employed as the reaction solvent. Hith the successful arylation of thiOphene with the fairly unreactive bromobenzene, it seemed reasonable that the synthesis of biheterocyclics utilizing heterocyclic halides, specifically halothiophenes, could be successful and should be investigated. \i't ”VD-#11 r 5-0.1". . 1' 113’s; LAILE'AJ‘: LILL Z—Furyllithium, cua3Lio: n.w. 73.99 The method of Ramanathan and Levine (7) was utilized in the preparation of 2-furyllithium. A 20.# g. quantity of furan (0.30 mole) was added to 0.25 moles of n—butyllithium in 400 ml. of anhydrous ether during a half hour period. The reaction was carried out in a nitrogen atmosphere by a continuous passage of nitrogen through the one liter three—necked reaction vessel at —20°. fter the addition of the furan, the reaction mixture was allowed to warm to room temperature, and was then heated at its reflux temperature an additional four hours to complete the reaction. The yield of the organoheterocyclic, 76%, was based upon the amount of 2—furoic acid produced by addition of the 2-furyllithium to an ether slurry of carbon dioxide. 2,2'—Bifuryl, C8H602: M.w; 13t.1o A solution of 2—furyllithium was prepared as previously described by the addition of 20.4 g. (0.30 mole) of furan to 0.25 moles of n—butyllithium in ether. The total volume of the reaction mixture vas increased to a half liter by the addition of 100 ml. ether following the formation of the 2-furyllithium. The reaction m. 1:312:31: WWI -‘39‘ 1 All melting and boiling points are uncorrected. mixture was cooled to -100, and 33.6 g. (0.25 mole) of anhydrous cupric chloride was added to the 2—furyllithium other solution from a dropping funnel during a half hour period. Initially the reaction mixture turned a dark green from a pale green in a matter of a few minutes, after which it was stirred rapidly at 00 for three and a half hours and then poured into 300 ml. of a saturated aqueous ammonium chloride solution. The aqueous layer was separated and extracted twice with 250 ml. of other, and the combined other layers were dried over anhydrous calcium sulfate. The ether was removed by distillation, and the liquid residue was vacuum distilled to obtain 7.06 g. (0.052 mole, 42%) of pure product as a colorless liquid; b.p. 62-63°/ll mm. Literature (5) value, b.p. 63-6u0/ll mm. 2-. Lithiutl—N-methylpyrrole, C5H6LiN: MAI. 87.03 The method of Shirley (8) was modified to obtain this compound. ‘N-methylpyrrole, 32.4 g. (0.40 mole), in 50 ml. anhydrous ether was added during a period of a half hour to a solution containing 0.37 moles n—butyllithium in 630 ml. of anhydrous ether. The reaction was conducted in a one liter three-necked flask under a nitrogen atmosphere at a reaction temperature of ~250. Following the additiqn of the heterocyclic other solution, the reaction mixture was allowed to warm to room temperature, and heated at its reflux temperature for twelve hours. The work of Shirley indicates a maximum yield of 42$ based on the amount of Z-N;methylpyrrole earboxylic acid produced by carbonation of the lithium derivative with an ether slurry of solid carbon dioxide. 2,2'—Bi—N-methylpyrrole, ClOHlZUZ: w.w; 160.37 \ n An coder solution of 2-lithium-N-methylpy role was prepared as described above by adding 32.4 g. (0.40 mole) N9methylpyrrole to 0.37 moles n—butyllithimn. After heating the reaction mixture at its reflux temperature for twelve hours, it was cooled to -100, and 50.4 g. (0.37 mole) cupric chloride was added to it during a half hour period. The reaction solution turned a dark grey from a pale yellow on addition of the cupric ciloride. The reaction was allowed to continue for an additional three hours at 0°. The reaction mixture was then poured into 403 ml. of saturated aqueous ammonium chloride. The water layer was extracted twice with 200 ml. ether, and the combined ether extracts were dried over anhydrous calcium sulfate. The ether was removed by evaporation and the residue, a dark blue oil, was distilled under reduced pressure to obtain 12.1 g. (0.075 mole, 42%) of the desired product; b.p. 860/1 mm. Anal: Calculated for ClOHlZNZ: C, 75.00; H, 7.50; N, 17.50 1 Found: C, 74.73; H, 7.70; N, 16.71 2,2'_BL—N_methylpyrrolo,5-carhoxaldehyde, Cllfilengo‘ h.W} 188.37 2,2'_Bi—N-methylpyrrole, 12.1 g. (0.075 mole) in 40 ml. 0f “-0-. -—-—.— .—-r---—-.—_- .u.——- Eflemental analyses were performed by Micro-Tech Laboratories, kokie, Illinois. ether, was ad ed during a period of 15 minutes to 0.08 moles ln—butyllithiun at —250. The re at on use conducted in a 500 ml. three-necked flask under a nitrogen atmosphere with vigrous stirring. Following the addition of the heteroeyclic, the reaction mixture was allowed to warm to room temperature, and heated at its reflux temperature for seven hours. The other solution of the lithium derivative of the bi—H_mcthylpyrrole was cooled to -400, and 5.84 g. (0.08 mole) N,N-dimethy1fbrmamide in 30 ml. ether was added to it slowly. A white fluffy solid separated from solution immediately. The suspensi n was stirred for a half hour during which it warmed to room temperature, and then it was poured into 200 ml. of a saturated afiueous ammonium chloride solution. The water layer was extracted twice with 50 ml. ether, and the combined ether extracts were dried over anhydrous calcium sulfate. The ether was removed by evaporation, and the residue was vacuum distilled to obtain 4.1 g. (0.022 mole, 32%) of a yellow oily product boiling at ll3°/0.07 mm. The oil crystalized on being set aside at room temperature. Recrystalization of the crude product from ligroin gave a colorless crystalline product. It melted at 50-50.5°, and had a sharp carbonyl peak at 5.9812in the infrared. Anal: Calculated for CllHlZNZO: C, 70.21; H, 6.33; N, 14.89 Found: c, 70.03; H, 6.49; N, 14.74 2,2‘-3i-E_methylpyrrole,5-methyl ketono,(agfhaIbCh H.W. 202.38 in 11.5 g. (0.072 mole) quantity of 2,2'-bi—N-methy1pyrrole in 30 ml. ether was added to 0.085 moles n—butyllithium in ether. The apparatus and Cchrimental reaction conditions employed here were those described for the preparation of 2,2'—bi—N—methylpyrrole,5- aldehyde. The quantities of reactants used were 7.0 g. (0.072 mole) f N,H—dimethylacetahide in 40 ml. ether added to the lithium heterocyclic solution at -25°. A white solid precipitated immediately; however the reaction was allowed to continue for two hours during which the reaction mixture heated to room temperature. Product isolation was carried out as previously described in the preparation of the aldehyde. Distillation of the crude product yielded 3.? g. (0.018 mole, 268) of a light yellow oil boiling at 110°/0.07 mm. The oil crystalized upon being set aside at room temperature; m.p. 44.44.50. Recrystaliaation of the crude product from ligroin gave a colorless crystalline material with a sharp carbonyl peak at 6.01/uin the infrared. Anal: Calculated for ClghlaNZO: c, 71.28; H, 6.93; N, 13.86 Found: C, 71.12; H. 7.17; N. 13-59 2,2'-Bi—N;methylpyrrole,5—carboxylic acid, C11312N202: F.W. 204.35 An 11.0 g. (0.068 mole) quantity of 2,2'—bi~N;methylpyrrole in 40 ml. ether was added to 0.072 moles n—butyllithium in other at -20°. The reaction mixture was warmed to room temperature, and then heated at the reflux temperature for seven hours. The reaction mixture was cooled to room temperature, and was poured onto an ether slurry of solid carbon dioxide. A yellow precipitate was 10 felmed imnc ediately, and was dissolved in water by the addition of 200 ml. cold water to the ether—precipitate mixture. The ether layer was extracted twice with 103 ml. water, and ¢.e combined water extracts acidified with twenty percent hydrochloric acid to a pH of four. A precipitate was obtained whici was recrystalized from methanol—water to yield 6.0 g. (0.03 mole, 433) of white crystalline product; m. p, 124 —l25°. The compound had a Sharp carbonyl peak at 5.974Ain the infrared. Anal: Calculated for cllnlzngog: c, 64.70; H, .88 ;N, 13.72 Found: C, 64.90; h, 6.12; N, 13.23 2,2',5j2",5",2"LTetra—N—methylpyrrole,CZOHdzNa: M.U. 318.45 A 10.58 g. (0.066 mole) quantity of bi-N—metl wylr rrole in 40 ml. ether was added to 0.066 moles of n-butyllithium in other at -25°under a nitrogen atmosphere. The reaction mixture was warmed 0 room temperature, and hea" bOd at its reflux temperature for nine hours. Then 8.8 g. (0.066 mole) of anhydrous cupric chloride was added to the reaction mixture at —15°, and it was stirred at 0° for an additional two and a half hours. The light yellow reaction mixture turned a deep purple in color following the addition <>f the chloride salt. The reaction mixture was poured into 250 ml. of’saturated aqueous ammonium chloride solution, and the product ‘Uas isolated as described above for the other derivatives of bipyrroles. iv Mt r drying the reaction mixture, the at or and unH‘e cted 2.,2' —ul-n—heoayleyrrole were re:.10ved by dis til ation under reduced pressure. The residue, a dark brown semi-solid, was dissolved 11 in lijroin, treated with Norite, and filtered to obtain a clear solution. The eroduct was crystalized from the li;roin by cooling, and collected via fi tration. The yield of pure product obtained was 0.75 3. (0.0024 mole, 7.1%) as a white powdery solid melting at 89-910. Anal: Calculated for C20322N4: C, 75.47; H, 6.92 Found: C, 75.41; H, 7.01 ‘1 LT 2,2'—Bifuryl-5_carboxaldehyde, 095603: u.«. 162.14 An other solution of 2,2'-bifuryl was prepared by the addition of 6.9 g. (0.052 mole) of 2,2'-bifuryl to 150 m1. of anhydrous ether. The ether solution of bifuryl was cooled to -250, and 0.057 mole of n-butyllithium in hexane was added during a half hour period. The reaction mixture was allowed to warm to room temperature, and then was heated at its reflux temperature for four hours. The reaction mixture was cooled to -3o°, and 4.04 3. (0.055 mole) .N,N-dimethylformanide in 30 ml. ether was added during ten ruinutes. A white precipitate was obtained. The reaction mixture Ifas allowed to warm to room temperature during three hours, and 1;hen it was poured into an aqueous solution of amnonium chloride. 'The other layer was separated from the water layer, and the water layer was washed twice with 75 ml. portions of other. The C=Om‘bined organic layers were dried over anhydrous sodium sulfate. 'The et er solvent was removed by evaporation to yield 5.5 g. of ‘3Pude product, m.p. 52-530. The dark yellow crude material was recrystalized twice from methanol to obtain 5.0 g. (0.031 mole, 1. .Ir, .’ 4 a '.L . 57.5 e) of pale yellow colored crystals, n.p. 53.; . Literature 0 . v ‘ i value, m.p. 54 (5). The pure product snowed an infrared carbonyl absorption at 5.9251. 2,2'—Bifuryl—5-methyl ketone, ClOHSO : H.fl. 176.16 ’3 J t--] he lithixm derivative of 5.4 g. (0.0% mole) 2,2'—bifuryl was prepared in the manner described under the synthesis of 2,2'-bifuryl—5—carboxaldehyde. Following the addition of 0.043 mole n—butyllithium in ether and refluxing for four hours, the reaction mixture was cooled to —30°, and 3.8 g. (2.043 mole) N,N—dimethylacetamide was added in 50 ml. anhydrous ether. The reaction mixture was stirred at room temperature for four hours, and the product isolation was as described in the synthesis of 2,2'~bifuryl-5-carbcxaldehyde. The solvent was removed by evaporation to yield 3.8 g. crude product. A single recrystalization from methanol gave 3.4 g. (0.019 mole, 48.3 %) of bright yellow colored crystals; m.p. 500. The product showed a sharp carbonyl absorption at 5.94A4in the infrared. .Anal: Calculated for C10H303: Ch 68.13; H, 4.55 Found: C, 67.97; H, 4.64 .Attempted synthesis of 2-(2'—thieny1)-furan uccessive portions of 10.2 g. (0.15 mole) fur n in 50 ml. (J) Other and 12.6 g. (0.15 mole) thioehene in 50 ml. other were added 0 no.1. ‘ ‘ 'vfi' - A (luring a half hour at —26 to 0.20 mole n—outyllitaium in 300 ml. 13 ether. The reaction mixture was allowed to warm to room temperature, q I ux tenperature for four hours. F’) and teen was heated at its re The reaction temserature was then lowered to 00, and 40.3 g. (0.30 mole) of wanpdreus cupric chloride was added quickly. The reactibn mixture was stirred at 00 for two and one half hours, and then poured into 500 m1. saturated annonium chloride solution. The organic layer was separated from the aqueous layer, washed ‘W with 200 ml. portions of water twice, and cried ovrr anhwdrous sodium sulfate. The ether was renoved by evaporation, an. c:e residue was distilled under vacuum to obtain 1.85 g. (0.014 mole, 18.5 3) of pure 2,2'-bifuryl and 5.3 3. of crude 2,2'—bithienyl. The 2,2'—bithieny1 was recrystalized from ligroin to obtain 4.6 g. (0.028 mole, 36.8 5) of 2,2'—bithienyl; m.p. 31.50. Literature value, m.p. 32° (2). Attempted synthesis of 2—(2'—furyl)-N—nethylpyrrole To an other solution of 0.30 mole n-butyllithium in 200 m1. anhydrous ether was ad'ed 13.8 g. (0.18 mole) of N-methylpyrrole and 13.2 g. (0.18 mole) of furan in the stated order. Both heterocyclics were initially dissolved in 50 ml. other before addition to the n-butyllithimn solution which occurred at -200 during a period of an hour. The reaction mixture was warmed to .room temperature, and then heated at its reflux temperature for six hours. The mixture was cooled to -200, and 40.3 g. (0.30 mole) of anhydrous culrie chloride was added during a quarter of an hour. The reaction mixture was stirred at 0° for lfi three hours, and then poured into #50 m1. of aeueous aiaonium chloride. The other layer was seuarated and the water layer was washed tsice with 100 m1. ether. The combined other extracts and organic layer were dried over anhydrous calcium sulfate. The ether was removed by evaporation, and the residue was distilled under vacuum to obtain b.54 g. (0.03% mole, 25 g) of pure 2,2'-bifuryl. No other product could be isolated from the residue, a dark semi—solid. The 2,2'_hifnrvl was identified by Means of infrared spectroscopy. .Attempted synthesis of 2,2'-bithienyl The method of Ramanathan and Levine (6) was used to synthesize 0.2 mole of thienyllithium in 100 m1. anhydrous tetrahydrofuran. To this solution was added 42.0 g. (0.2 mole) of 2—iedothiophene dissolved in 90 ml. tetrahydrefuran at —l5° during a half hour. he reaction mixture was allowed to warm to room temperature, and then it was heated at its reflux temperature for an hour. The mixture was poured into 300 g. crushed ice, and the organic phase was separated. The water layer we washed with two portions of 50 ml. ether, and the combined extracts and organic layer were (iried over anhydrous sodium sulfate. The other, tetrahydrofuran, 41nd 25.6 g. (60 %) of the 2—iodothiophene were recovered by vacuum (iistillation. The residue was dissolved in 25 ml. of anhydrous either, treated with Norite, and the ether was redeved by evaporation. :Light yellow crystals, 4.3 g. (equal to 32 g of the unrecovered I ‘ Q I ‘ ‘ I O ' Q 1 I O 23-ioeota10paene) of 2,5 eiiodotaiopnene were recovered, m.p. 39-40 . 15 Literature value, m.p. 40.50 (9). The conpeund had an infrared spectrum wiich was identicle to a known sample of 2,5-diiodothiophene. ttemated synthesis of 2,2',5'-terfihicnjl A solution of 0.2 mole of thienyllithium in 190 m1. anhydrous tetrahydrofuran was prepared as previously described in the attempted synthesis of 2,2'—bithienyl. The thienyllithium seluoion gas cooled oe -;e , --i 2,5—dibr methionhene was added during a one half hour. The reaction mixture was allowed to wann to room temperature, and then it was heated at its reflux temperature for three hours. The product isolation procedure used here was that used on the 2,2'-bithieny1 synthesis, except that the distillation residue, 22.6 3., was chromatographed on 140 g. of activated alumina. 4After eluting the column with 365 m1. of dry hexane in ten :fractions, the hexane was removed by evaporation to yield 2.4 g. 2<<$3é¥<¥§e§5§3$>§é _. _--.. --—... . __ _ _——_.._..—_——-. - *MM, [—— ."".. :1 3 r' 4.— mo.— lill‘lllrliulll“ . 1.. an: n»- 3/- . .. .. f .. i . x. ., arcaarcr;apasahxflxn_mnm we suspect 4 Iv .4“. CC m .firlilll v . I ‘7‘ . nuns... ...:HJ t... . ,m ..E... .3. l r:a . MO I r.\ r\| \ p r\ ex..\)l ....)s .... p\ J r. .... . ..a . a _ r). g )3 ..\¥>\~§§I~>M .29).?» . — _ .. * u. \ _ m . l _ . p ._ _ _ _ fl _ . . _ . . _ .. J _ a a . ivy“! . .- ---, i 4 .. .. .. -:5... -.. ,2 ... .1 a s. . . ... vase“. ....m trot: (.-. .....- 41:13:25. _:0 :L :C .L .N m 90 Ezkleozu «H i -. 1 -. ..- I) \o ...). ...o\. .... 9.0 m (R m. ...r O 1J\ It .. a. -....>)\ x .399?) x J .l «1...... all .r ) ...>. if...) 923 .. _ . . .r . . ... 4.7.9.933 .5... 5. _ 2;. $7.2..- .. __ .... l... . o D . r III'I. !l‘l. i itiobll} IIIOIJlAtU‘x V- toil ii.l‘lfi I ll. ‘I 24 V iiiixii.'ilil l- .__7 _- it: s . !-' l'. :3.€<.rr<.i>\ )3. .LADKJS ......)x.:.\,v> J§< ”\HPR. . -r.... .. V FUD. .Ur hair... _ ..lJ , OI: .LN. m (L C im\ 0 —___. ...- w~.——J—— o . H a. . l 1... ... i .... H, t. a. ; will... i... 3 :2 T :3 2. m. . i: L. 3:. a Z . )Naesa/xxE/zfixaeéxe Reg/.... \(%\><\va. .... .CCK, ii)» \ .73.... 0...... «L .m.....H.GH.fi. n- No ‘4 c .. Fete; Otto 7-1!..- \ .1)\<\n).).\}\\1. 11>\‘...~v¥.). p We. H\J\P\\Jw 2|-.JK\- I? ( r p / f ~.-_ 1. Ill'ol.ll . DI'III'VIII ...»...m 26 {.3 <5) .../9).)... “.1 ‘ “‘— M a a o \\<)2252 «1-1.... ...... .I r, l, .... l \\<...... .... KS... .3. 33... .... . . ... . -3 x .. .... x 2:: ...... a a. a \i-“ . a e ...h ) ..- a) . x O . -... .-....5 -n . . o 1 . In! K m 446 ...rw.\~..(fl1¢lvb r? .k. _. ..1 . ._ tr C I. I'll ll‘llrllii'l‘lfilllll It!!! 32.8.3.8.3/ / C a‘ I... n . .x....<--.\...._....\).... ...)KS/TI V.JLT3 it) 3133333 on The a kylation and arylation of thiophene via the coupling of 2-thienyllithium and alkyl or aryl halides was carried out . ‘1‘ «'7‘ -‘ u / ...: 3...... .... .,- -§\,. «74-; succeSSLuiiy sy 1ev1ne and Ramanathan (o), with tie oust Lean-.. obtained in anhydrous tetrahydrofuran as a reactian solvent. '....' _' . .. . ‘ ._ '5. .' _". ‘. arylation, coupling occurred eaeiusiVeif in tetrahydrofuran. In the case of heterocyclic arylation, investigated in the there was an exclusive preference for halogen- lithiun excnanze to occur. The above was indicated in the reactions between 2—thienyllithium and the heterocyclic halides, 2—iodothiophene and 2,5—dibromothiaphene. In the case of 2-iodothiOphene, the only new species obtained H. was 2,5—di odothionhene. An explanation for the formation of a" reaction 5,]. I .L‘.. "3.4.- ,...,.‘. .1. H. ' ,. . 4.3. . ‘ ., tae latter essence .an be based on buC follow. & L“ .,_ .fl "\ .21 ‘0 I Y‘C’ (a 1.1;.lb ‘A 13 t o“lt ‘ :. if I‘d-3 oi W -. “(A Lllc u....LO~ Uk’q V" 2—iodo— S- litaium t 1):] (..LAJ Z—LLJLBZAJ illuulufl :31‘8 SC" ionhene can then CD N ..1. . 4.3. -; , . - .. —'.-. .:. .1. ~ to see that ae .i e zeaition is 4.0«Jabea _.-_:_ '. ~ - .'.‘-- ,.\ - .4”, ._.' -.'..1.. , attacx cue to the electron situaraxal .x.‘ .1- ('1' :‘c. , {..i. “afi‘ .fi <«.31.; ... .'._, 4.x . (1110 ‘3‘.) A. ‘1}. J.'. .0 rlcvufvxhba O.)...'4....O“ .A'- utien ( resulting ndcrjo metal—halorer 8A _) A xel.an3e with additional 2-iodothiophene present in the reaction -...L mi..ture. .he fact t V 1at an iodohe wrocyclic compound will ‘ndergo ‘r _ F. V ’ fl .' ‘ ‘_ ‘ ‘ .‘ _I H _ _‘ ’1 '0- ' ‘fi ' _- .zf‘ _ ‘ ‘ C‘.C L-h‘-‘Ql3 has .L‘lL-‘U-LOI‘ CBVJflCuCGu Dy lSOJ. Lil-0L1 OJ. (.1 U KaAAbJ ‘7’“. ”\1’1 2 r 3 "'5 an r. Ar, “‘A'L HA1 .-"‘G “n, - J' we, \Q'x . w' 3- O”: ‘. -" .111 v...b LL 0... -- OQOU.L-'-C- .r... 'LLV A-;._(1A.D 1.1.3.71 -A'v J. ' .Lb~\ AA ' -.O.L.. ... ' c—‘\ A q a: I A: Q- . a‘ h f~- A 1 «A- -1 ‘ q ' r‘ 4‘ euanULbLeS 0L Q-iLu A..A.LL.I ..i .43.): L‘) LhAA';.Lg.A (111/1 "..- LONG 01; ‘5'“0 ) 100.6. l/’\ 62/, }~———. / *‘—-‘ I l I. a: I. ‘ I ‘ 'I i I' it // \\ " ' 3‘ 1 1'" i? / \ I 5"; 2“" -..-2.: l )7" L ' V \S/; 'LJ'L + \\/ J- 130.; “L W‘ \5 \7/ ... L1 " s be) I c' —L— - .7 a 44. I‘d“. Clan-LI onal studi the br nohetero 2,2',5‘—terthienyl from the only compound isolat + 2 TEfCliC CO' TITDOU... .dSo -.‘fl‘ 1. \. ‘. es with metal—haloeen couplin' 1- .J yrewfe once towa-d exchange with In the att0h.uca sylthcs is of S—QibronOthioo1-ne and2 -—eh enyllithiwn, Q ed was 2-bromothiophene. mww -~ \ reflux Mm -. ‘ ~ I f\ fi f‘ A '- F- v ' ‘ "Q r-n «4" O I) ' E‘ E ”"I. .' I f‘ \vf1 . Y 7 L1 -. 3, I . . -'(... _ .. 3’ _ . .— . -- '. . ... | L‘. b.1k) ._, \lt.‘ L .L; ,0 \JJ. U.-O )T' .. 1 l ...) -... (-IJ. - , .... ’J -\.-‘._'; L;-‘A.L.t‘1u..4., a». La.. \JA‘I './J ' 3," A3 , .', _'_ A1 .I.‘. Z , ., .... -: - ’.. -;. v—n —. .u ,A.‘ .-. A,- O 'I . Duo oe:Cen' y-e-d of tee Z—QPJAOLJLOQuCHG .-- in”. emu 110m bAG W O f.) O C " 'rJ. L) J ixture. . A o - ‘,.‘I- ' - r-L .‘ . - A‘fi" 43-:- Ao- 4' F”. " ~' ' n |“ ‘ \“I . ’c I... ."'l llvtpnIUl-CLLLIlJI] “as CUAAVC‘tl\IUDd U0 Lbu ' ' L‘Ju (A (1' L.'.-.1 .1: 3 OJ. — "L ‘1: 55‘. 1 ‘ 1" w . 'L , . 5" v ‘- x A ‘ ‘ Q—bromotuiognene aha Z—tdlonflllbfl u.. -t was NO cu t ./ les. reactive 3 .osition on the thiophene nucleus .IOUld resist exchanfe and in 350 d eou~le to 3 ive the unsymme Carieal 2,3'- ' -..' n .' , . -4 .. ...:.....',_' -uudL. .ue react; n gave only st &I‘L-.3 mleeriul ox- , . ,- . J" .‘ 4““. '2’ ": ‘bfin A ‘A ‘L 1:. ' rr" ‘ indicatini tuwu c-3nunve nod not occurred. More‘ 3 under tne .) J 1 ‘ - resetion eonditi ens utilich, the 3-bm‘01ot11ioniene was also too J ~'.‘ I- ~‘- -~ ' ’r‘ - .~ ‘* '- '- . V 0.. J‘ "H J“ 1 ‘A‘~) '- ‘ r " .1\.‘ "i 1 Slroe m... "(.er .,.C.-...C“JCC1 '.‘-'.J.. .. :18 1150 O... O....'1..."_“OLIS' CL.__.‘:.‘.LC e..ior'ic.e a? a co plin3 event. 1.0 compom us 2,2‘—bifuryl and 2,2'-Di-u—zetnvioy.“o e were obtained in a fourty percent yield by the interaction between the iieteroevclie lithi a compound and the cupric salt. to \ / t’ P. (D Ci‘ _ If 0 '9 If; 5 (‘3 }.J _Io ) O W O’Tl .\ 2 / \Li ethelrfoo’ / \ 5? s A! An A‘ ‘ : l "--v ,‘-- fl -. v...) u;.’_ Uls’: "n. r 1‘ ‘l a' 'L‘.’ . ’1‘ . . “ ‘L‘ “ ‘ . ‘,"‘. '1 f '! '11 ~ a J. ‘ i ..V- .-Q q]! -.3. "G Of c.1153 UrOCCH‘JI‘G 1108 111 pm} 111 ,.. fi< Klein 03. bl’lO 01f ‘ “4" “P. fi-i 3" " .‘T l: f‘ 3 f1 "'"r or} .J— "“4 ,- " ' -»\ ~ a ' ".9 -~ QJuIJLIU‘ ACIC~+ illC 'v'vloc.) C J.u (.11le Lil 0 .L ACU ‘JLliv.LI vA-LJ l‘JtJ. 4L+QLI involves a Sin le stop. a; previous repo;eed s‘ntuesss o; H,Z‘—bi£uryl g7ve low Viel”s and involved multi_stco reaction -.A “.1. ' '7." .~.- .,.-.-.-..: , .- , 4‘ n: ..- ' LO I'm-Colon CO xhlbiOnS 1101‘; 04‘.Q.!1.L4.C‘i_fl ..l‘l CiiOib uO 1-.!. .--.- . ° .‘ .‘J' .- m ... -v- 3,33. -... 4-10:. '1 CduCrHLhe opt eimum Concioions. nesul s iuii3abed only low 4. w -'._ 4:7 -..-.i n w J.‘ . 4" -- 3 belg 'L_1(I L'.‘.;‘~: x) (J..A».7i 1"; " L LsA.~Lt.U.L.Ji—1 lilvorca L1. ow - - 5 ".I 1. J kl —' ‘:.‘; C)... k' a“. ‘ . ‘ :3 ~~ ‘ ‘ V - '3‘ .Q A. J y . - "I 0.053.qu 00.1 JOLLLCLS Q" ‘CLLLlCl. ‘ L, e Inajor CO. .- Suing J. “A. ulOAl, ’ .-'I"I'": V3“ ‘ ‘ \ V .1 '0“ ' ‘ ~r "‘ "hA' ‘ -. '7 nolfidcrismcion. “VH3: r 5 disc louse c0 so relunaolo OVer 1- as _y_ _._ ‘._-’:_ f. _ r‘ t ‘ beurgudufO_UFdfl as fine solvenL mecia. S _-I {4.1 I», o ”rocuce Solvent lean. Cone. p Yield (03} x " ) ‘5. 2,2'—;i—I_nethyl- Ether Reflux 1.25 25.0 pyrrole ” zeflux 0.42 28.0 t E EDI "5 (J " filler O 0 .11’2 11:2 0 O This coupling mroccdur as expended to the svncacsis Oi . '-~. .. 7' ‘ ' ‘ '7 .‘ - 3 .'. _ f) ‘ _ V' .‘ ‘ I | ‘ ' ‘I A q I - r ‘ ‘ v ’ l v 8.:10 \3..' ‘2‘. E). Iruh A~ILILj~fiHL 3,..ALO LIKJ- 0(fl1'L:.L4-C (.l')rtQILI\-.‘l, ~14, l - ‘_CJ—-AI-AILC r -L:)U‘rrr0 e. ".1 ‘ . - I J. . .. . ~ . ‘ - .. . l‘ ’1 fi . - .. 3. n J. ‘ ‘1 . . " . , '. ‘- ‘ fl ‘4 “ " " lue .L..m....u... “-._“:LVVC {H.314 OJ. .. ,3 ‘31-14—.quL.'.l-T.fi‘i O-I.O . ob ci‘c‘fl'nCel ‘4. L‘. with cupric chlo ride to oceain a seven percent yield of cue I 2,?',5‘,2”,5”,2"—ueeri-j-nenu{lsj7relc. «LI-31") _\ .. stT/ Launch. , V Kevin; obtained the biheterocyclic svstens of 2,2‘—bifuryl 3.1 Q,fl‘_bi—I~nel?;lyjrrole in good yield, fine 5 ,esiticn TIHKLM deriv etives of each were synthesized by interaction with n—“utjllithhng. '3 e lithiua Q”._V”El”e" we"e then treated with a carben dioxide—ether slurry, with N,N—dinethvlferns‘7dc, and with fi,f-diiecnrl77~tenide to sgntlesize 2,2‘ —bi3u:fl—5-cerboxyi acid, 2,2’_bi£u:zfi -5—cefl Xelecufce, 2,.'-oifurv1—5—r1ethvl ketone, 2,~‘-bi—H-methylprrr7lt—S—ccrbe“‘-ic cicl, 2,2'-bi—H“mcthylpgrrrele-5_ arbexeldegl do, and i,”‘—bi—3_methjlpyrrele_5-;'r etlfl ketone. All of these products were obtair ed in yields vervi n3 from t we 1ty-si:-: to siitv—tnl ee percent. The derivatives of 2,2'—bifuryl q ~1- ‘L .2 V A ’I. - 4' 1" ‘A p ' W m‘- . W 7' ‘ I" J. ' F C: t. J, mere oeeained in tie ”l 'rner yieids. idlS may be ruulonulLZUu ‘ as a functlozz of he ex*ent to which the individaal Dino teroeyclic (J) {to (7 F C. 0.. o ystezs co did be metal In previous Stu‘ies on the netslation furtn and “—Mccu lpyrrole, fur7n was metalated in substantially ; 0 F4 higher yields and under milder reaction conditions (7,8). ‘ The 3.3.3. spectra of the biheterocyclic eeriwetives - .. ._ w .- ‘1 4. .. 1. .u'. c. 2. 4. . W1] .4 ‘73 gA ‘ .- . ,I‘ ,"," ~«fl " H1‘v"7‘ A ,Al-w 4‘ re "y’l‘flr‘ ~~1filr~ (O ‘ "‘ t“, ulv‘_ J ._ .r . .. .. .L An|'_‘. l-n_.’_dr U0 |)\ \ )UthAti'AL/v ll..k L— .3U... LI: \; .__ ~4x). Stu. . btoe ST ' ‘fl _ J :5 - r) r?! s - \y - _ '1 - o . . , . A A A ‘ ‘A e. ‘- . - —-- \v’lr ' ~-‘ ““ Ir- —.- l—‘ -- A... ,- l\o.ioL'-o a J "v L;.L a 0;. uni? R4, —L).L-l‘c'-.1UL;E. -‘. fr; 1.0.1.0 \LL.-....r«. 11403 Q. 8 . 1“ .:_'-._ U 7.’ . , .:\ 1 -n....." ._, J.‘...fi ~ .‘ .. ewe u.n.3. spectrdm oi 2,2'-Oliu.fi-5-m0buyl xetone mere . - . - -- >. ~‘- ‘ '~ A -_\~~ ‘ L J- ‘ f‘ w ‘- 14". {L 5.0 1. - , ... . ...oJ L. .U ‘33 3030C; .JoI'LlC .11. mo. . ...1 1... L. CHCoI‘OD . I.- ~ ‘ ’5 . _ v ...-... ‘- ‘. .-.- _, ‘.- -.‘ - 1— .L“ .0 u ”0‘ >- ‘ .0 >." I) 3 I s-v l.’ ‘ .V‘ \ '1’- ». .L VA—K‘.;.L:¢. ~IJ “-11.; 4.1.1k.) 'sAL ) X) {.28 ...;‘a {14.10 D 130 S; [\J L 1" 0.5. 11120 2 , A“\./ r- ~q': .. - ___ ,'_ f. 1‘ 'v‘ ,- '- ' 1 n ‘-F n ‘ -‘ :“ .‘\ ' ‘; ‘ '- r“ r " . . ~.' 7 \ ‘NJ‘ aSbl“ 11' 'u 1.0 9.10 .LlluC 'rate d. .110...‘:,7'-'. -‘O....‘.S, ....lu. 1. Send u-..LL) u:J.--l-')ILT.C.'1L., -:- “. d ‘P' ~ -‘-\ I ‘f‘ '06 -\rj ‘ ". "' ..1 3‘ .x 1 ‘ Vr“ "/I“ 'lp‘fi (‘- fi ‘A ""1'1-7 r‘ v) 1' j P" 4 U-AU JALLLLJ‘VA. OJ. '. \“.L1.-I‘I-A-OJLL-.L [1",- (\A-L.‘\)VAVIQ .-.:A U-AC .IAO-L‘.\ L.g .1 \.O|'..L.\A -J‘\: ‘t‘ A m, ‘7 I: r. ~ ‘- - -~-'- ‘1! ‘— A ‘ ‘J' o h a calculated. ine av TOeOn conceit CuCCnUQ Ohb in all cases. J u rat. _ 1‘" 7. f ' .L . .. .2." r’ H :‘ H O H ~'- ,-.J- - K" -.- J- I. 1.3; “uni?" SyGCofl-Lm 0.2. 7 2' ,j' ,2 ,j ,H ‘—ooc1‘C.—..~.£€-L,11§fl— —' L. A .. _._ r- J. r . . em,r ole as used to suost mcl te tu- Sb ueture oi bulS compound —. . . V , . w o . -‘ - r ‘ "fi 1 s . 1 . .L. . _. . . .- . . . r- "~. ‘ ,- . ' ' ~" . - v‘ ‘ h \*.-v.- m —. .-_- - -.-. - 4 4 a .‘I P- v -,. , - . .-». 1 -- .-A 3 w -‘ f . c~---~IV I tub)~.'L&.'s.L‘A U ..‘...a :2». \J O _){.\_,‘. ....)U‘ IL.»‘.._I xx}. ‘4’ u.v'J \o. .... .1 -. V'A, ‘._..u|..) . A‘."‘,“‘j . ,. yeaks should so fIresent. Furthermore, the relative ratio of “ \» .—- , -’~n»1 «,4. r. --L .9 ". ' V' . ,1- ‘~ .1,‘ If" .‘I. .,. ‘ ...! , J. ”0 J. ‘ . A,‘ . one, aid till he on- to one Ior only de propos-1 so; cturo. {'1.‘ . r. ~-r :- "I' t 7' h 'f’ 1“ :1 ”‘1‘“ P'"‘ :3 --n" "1 'v‘ A-“ "3‘. 41 "- ' .4. 5) ....) . WAki t v LL " .. .4- UCIAJ .~”L.-.U.A. 11 U UJ.’ 1~i o o 1 t e se uion u u 0 o 1 c 1 trum. ~" ~ [- .: _' - J. a 4. 1‘ “3‘ I. o ‘1. A '_ -.. ’ ‘ .L 1 Jul Eli-At ...olOfi, C...C CllOCL; Oi uhe Suusoluhv .u .5301. Jo on one lei‘rn- m-.- «T‘nc var- .2.-. ‘ r- -.-c- nAJ‘4fl‘3' ,:.,._1 was A. LUUCJ. U\4;y.\’.1_-Lkzv Incl») 1.1.feSUiullm LI IJQ. :55 ‘u‘. 3-0 CLIJDAbfi‘uLx‘J'--V-L’ bL-D 4L,” \, vv': L‘.,1.r‘ '4‘ f - 11 A 1 fl ave-2 3-: A I‘ I C i all 54+UAALA‘CI .-l‘i ’ (‘8 L1 ’10 5 :n-JO Dual— L011 04.. \l-J‘V 1 r .1 | I; H 1"; I- '- -. .1 fl .1 v- ‘ § ~or - “ - t ‘D I. ' ': "J‘ .-...- . I‘.O~ 'D'Cllp 1.13.1.CC‘d- C ‘ "(Educ/l C .1. '- .1 '2. Cu ' . r". x .1 S .. u “‘1‘ , u -- - Q‘ — -. ‘. ". , ..- .1 I‘ —~ ~ ‘ 1 .' "‘ ’. "" J. " ' ‘ inc} L150 0;. CuL-’.‘...-u C 1.4.03.1.00 as 3. COdpLLTI; afguflb L0 00 Elm e13 was els investigate Q. O 3.2.- . '1 . “Rik-‘- ie x .' 2-tiica;rllic;ium Jere prod ced on the seditiou w. euiric calor de. '. I' -. - #r ‘i"- r~ -~ fi‘-\ 1‘ U. I —. - - A~—‘ r‘ J. . 1": j ..., ' H. '3‘ "~-. fl 1.x. beget... .. .4:.:.>L.:.._.1J....\.: «2 91.390 'v a ratio 0.1. 0110 T40 U110 90 b: 0 OJ. r" I ... -I -\~‘ _ —r'— fi V _I ... 1“. . I , _2_ ‘I ,-'-sluu:.l, s,;'—o_cu o1Vl, and 2-\2'_1m rL)-bd*0 Leno to oe ,— -'- ,. 3 ... r. J ' J- '- . . 3- ° . -'- --' J- ‘a A J- 3 .. ... ' ...-J- . - A O LI.‘..LAA'../.« 3.2.1 Loni) COLI )LL'J reac Lil-on. 110'. :CVC‘T ’ v.10 IQGLAC (1.1.0AA bibs Ulti‘U ---“ ... ..,,.w ’3 A: "l n~-.u un-‘d' 41d ‘40 CO:\U£~;A¢ 11:.er ,2 t-bif ‘ /’ (21“; Mia": —O);-.‘:J‘A—LC;‘:I in -5 .v. .' ." . A ...:..i 1:. ,3”. - , 4. t, '2“ ._ a gaUlo o; 33,30lllaoulf one no J . lad 3“ v‘\ 'l" .' ’- ~~~ '- \P‘l ~ . 1"" - '\“‘~~ - a“ f“ ""l"’.1J‘ 1 "fl '2 1";~S 2...; “'U . JUU~A :41Vu1 e'; .‘n-HA J-u~.fi .\_ g.¢1bu— I‘Juh‘gb O... \.' -.s n . ..73 -~ - “I. ., . I1 "4 A Ol -LRCH auu “-mcbdylwfl;ole. 1 Bgls casu, g N 'l‘ A“ .Q“ J... l- q- 9. sq ... ’\ -o v .: ‘1' “qu 11; 17. Line. “ff—“A x) \Jufcun f-‘-'.,-._-\_'.. nTl’ ._ J. . '1 " .‘ J-‘ “a .1- van J- . | , -," , -~ . nr~ h' \I ;‘n‘.U ——Ooo""- - ... 1: Unitace L F. o A y rv ‘ L1 - A ~-~.-' "- o ‘ - ‘4’. .0 Cu fills; fwaCL;Jn In Gain of £39 reactions automated, the most stable metalatcd cospound was one I a v 1 u I u r O I s - 0V - 50'- ? 3 ~- ’r- 7 "-~ '1 W". "‘ '- .“ E“ ‘ one blwlng use Hudol- y o; Lne ls©lfl¢£q UlflC .- ., -,'--.—. ‘ -. -\ “-.. ,..,*,1‘ -..-..1..\ .-‘._v.,“';-,. ¢-- LVV*-.-Ull UL 'J-Akr u‘kc’ .‘LLJ AJ‘I\§IJ-n\l N)‘ J|-AA(J_ At UhL —--A.-L -1 .'... f _ (‘1‘. 11‘}.- “DOB! C 1 LC). 1.10 ‘.'nr ., f'. ,' ','\ ‘i-fr . .5. , ._'_.1. ‘J ~Jv‘u.‘A 1Lq{)\l n-‘PL -'-'L p n '. ‘L ‘ W'L’ ”ll, “numb lor any unreacucd Ho;cro(yc ic molecule Li+ ——————>/\+ ‘j' J-.L 7.3.7-3. , 4 .2 " .. .-°. ,‘ ho abbeAi~;Ju via-.5 LACL‘C go is ...-3.90 tue Sharulfl .. - .uUa. 4.3.13 :Ln C110 ,- ~- 4' ‘. fl ' (~. "’.'~"fi . ‘- 7 "I P1 rc ’2 -A h --- "‘ ~. '9 i "' 1" “A -: relculuu- elldlnbc. One au“¢t; cull eAIlanauton lo: “40 lalluro (‘1‘ O 0 0‘ ci‘ {.3 F1. :5 B 5.) 02 3 '0 c r rical heterocyclic systems ‘1 :2 P O y. (1 :5 0 OJ } ’I '0. ') "5 0 <2 K O 1,..1 |,_I. O :13 '\‘ ”S'J‘.r "1‘ ‘~.~~ v m‘ ‘ J- . ‘;‘ eunwlvqua UflglOJCd. Lae unsymmeurl cal Olli- been too uzstable osurvive. 1 J-‘ ‘I‘ may ‘0 ~16 6:30 W’E A fl . u . -r~ ’\ . _n. an A ~1'- n . OvaULe aolyme rlzes dulc: buo TOnglOfl c‘oc7cl ics may have {1 0‘. .2 ’1‘" C“ P ‘9 fi‘f Oi. LL-bi r1 _ x-n-L" 4,... 9 V, .L‘ fiJC, o 3...]. .,-: ”A1 “1.1,: . .' --,_ .‘ .L .3 an; uLAOLu) 1.0; 1,110 SJ. '11.; :01 015 v 0... “mow. .. 'IuJ. 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