The Chemistry of Heterocycles

Home , Hydrogen selenide, Selenophene, Sulfolene

Mohammad Jafarzadeh Faculty of Chemistry, Razi University

The Chemistry of Heterocycles, (Second Edition). By Theophil Eicher and Siegfried Hauptmann, Wiley-VCH Veriag GmbH, 2003 1 80 5 Five-Membered Heterocycles

5.7 Benzo[A]thiophene 80 5 Five-Membered Heterocycles 5.7 Benzo[b]thiophene

5.7 [A]Benzo[A]thiophenBenzo[b]thiophene wase previously named thionaphthene. It has the following spectroscopic data:

Benzo[6]thiophene was previously named thionaphthene. It has the following spectroscopic data:

Benzo[6]thiophenUV (ethanol) e was previously name1H-NMd thionaphtheneR (CCU) . It has the followin13C-NMg spectroscopiR (CDCIsc) data:

1 13 UV (ethanol227(4.40) ) 289(3.22) H-NMR (CCUH-2) : 7.33 H-6: (7.23) C-NMR (CDCIs0-2:126.) 2 C-6: 124.2 249(3.83) 296(3.50) H-3: 7.23 H-7: (7.29) 0-3:123.8 C-7: 12 258(3.83) H-4: 7.72 0-4: 123.6 C-3a: 139.6 227(4.40) 289(3.22) H-2: 7.33 H-6: (7.23) 0-2:126.2 C-6: 124.2 265(3.63) H-5: 7.25 0-5: 124.1 C-7a: 139.7 249(3.83) 296(3.50) H-3: 7.23 H-7: (7.29) 0-3:123.8 C-7: 12 258(3.83) H-4: 7.72 0-4: 123.6 C-3a: 139.6 265(3.63TheTh) e NMRNMR chemicalchemical shifshiftt H-5valuevalues: 7.2s 5hardl hardlyy diffedifferr frofromm thosthosee o0-5fof benzo[£]furan: benzo[124.1 bC-7a]furan.: 139.. 7

The NMR chemicaBenzo[Z?]thiophenl shift values hardle yis diffe somewhar from tthos leses oreactivf benzo[£]furane in electrophili. c substitutions than thiophene, and also less reactive than benzo[£]furan. Moreover, regioselectivity is poor, giving rise to mixtures. 2 Benzo[Z?]thiophenFrequently, the e3-positio is somewhan ist lesattackes reactivd preferentialle in electrophiliy ovec substitutionr the 2-positions than, thiophenee.g. in halogenation, and , nitration alsano lesd sacylation reactive .tha Onln benzo[£]furany the reactio.n Moreover with n-butyllithiu, regioselectivitm yis isregioselective poor, giving ris, egivin to mixturesg 2-lithiate. d benzo[6]- Frequentlythiophene, the 3-positio. n is attacked preferentially over the 2-position, e.g. in halogenation, nitration and acylationBenzo[6]thiophene. Only the reactiosn undergwith n-butyllithiuo photochemicam is regioselectivel [2+2] cycloaddition, giving 2-lithiate, for instancd benzo[6]e wit- h 1,2-dichloro- thiopheneethen. e in the presence of benzophenone as sensitizer: Benzo[6]thiophenes undergo photochemical [2+2] cycloaddition, for instance with 1,2-dichloroethene in the presence of benzophenone as sensitizer:

hv,

Oxidation of benzo[Z?]thiophene with peroxy acids leads to the 1,1-dioxide. Oxidation of benzo[Z?]thiophene with peroxy acids leads to the 1,1-dioxide. By analogy with benzo[Z?]furans, benzo[fr]thiophenes can be obtained from thiophenolates and By analoga-haly witoh ketones benzo[Z?]furans: , benzo[fr]thiophenes can be obtained from thiophenolates and a-halo ketones:

w - N a X w - N a X SNa SNaX X 80 5 Five-Membered Heterocycles 80 5 Five-Membered Heterocycles 5.7 Benzo[A]thiophene 5.7 Benzo[A]thiophene

Benzo[6]thiophene was previously named thionaphthene. It has the following spectroscopic Benzo[6]thiophendata: e was previously named thionaphthene. It has the following spectroscopic data: UV (ethanol) 1H-NMR (CCU) 13C-NMR (CDCIs) UV (ethanol) 1H-NMR (CCU) 13C-NMR (CDCIs)

227(4.40) 289(3.22) H-2: 7.33 H-6: (7.23) 0-2:126.2 C-6: 124.2 227(4.40) 289(3.22) H-2: 7.33 H-6: (7.23) 0-2:126.2 C-6: 124.2 249(3.83) 296(3.50) H-3: 7.23 H-7: (7.29) 0-3:123.8 C-7: 12 249(3.83) 296(3.50) H-3: 7.23 H-7: (7.29) 0-3:123.8 C-7: 12 258(3.83) H-4: 7.72 0-4: 123.6 C-3a: 139.6 258(3.83) H-4: 7.72 0-4: 123.6 C-3a: 139.6 265(3.63) H-5: 7.25 0-5: 124.1 C-7a: 139.7 265(3.63) H-5: 7.25 0-5: 124.1 C-7a: 139.7

ThThee NMNMRR chemica chemical lshif shift valuet values hardls hardly diffey differ fror mfro thosm those ofe benzo[£]furan of benzo[£]furan. . [B] Benzo[b]thiophene is somewhat less reactive in electrophilic substitutions than thiophene, and also less reactive than benzo[b]furanBenzo[Z?]thiophenBenzo[Z?]thiophen. Moreover,e regioselectivityeis isomewhas somewhat lest sles reactiviss reactivpoor,e ine giving electrophiliin electrophilirisec tosubstitutioncmixtures substitutions .thans thiophenethan thiophene, and , and alsalsoo les less sreactiv reactive etha than benzo[£]furann benzo[£]furan. Moreover. Moreover, regioselectivit, regioselectivity is poory is ,poor givin, ggivin rise gt oris mixturese to mixtures. . Frequently, the 3-positionFrequentlyFrequentlyis attacked, ,th the e3-positio 3-positiopreferentiallyn nis iattackes attackedover preferentialld preferentiallthe 2-yposition, ovey over ther 2-positionthee. g2-position. in ,halogenation, e.g., ie.gn halogenation. in halogenationnitration, nitratio, nitration n and acylation. Only theanandd acylationreactionacylation. .Onl Onlwithy yth then e-reactiobutyllithium reaction nwit with n-butyllithiuhis n-butyllithiuregioselective,m ims regioselectiveis regioselectivegiving, givin2-lithiated, giving 2-lithiateg 2-lithiatebenzo[d benzo[6]db ]benzo[6]- - - thiophene. thiophenethiophene.. Benzo[6]thiopheneBenzo[6]thiophenes sunderg undergo ophotochemica photochemical [2+2l [2+2] cycloaddition] cycloaddition, for, instancfor instance witeh wit1,2-dichloroh 1,2-dichloro- - Benzo[b]thiophenes undergoethenethenee i ninphotochemical th thee presenc presence eo fo benzophenonf benzophenon[2+2] cycloaddition,e aes sensitizeras sensitizer:for:instance with 1,2-dichloroethene in the presence of benzophenone as sensitizer:

hv, hv,

Oxidation of benzo[Z?]thiophene with peroxy acids leads to the 1,1-dioxide. Oxidation of benzo[Z?]thiophene with peroxy acids leads to the 1,1-dioxide. Oxidation of benzo[b]thiophene with peroxy acids leads to the 1,1-dioxide. By analogy with benzo[Z?]furans, benzo[fr]thiophenes can be obtained from thiophenolates and a-halBy oanalog ketonesy wit: h benzo[Z?]furans, benzo[fr]thiophenes can be obtained from thiophenolates and [C] By analogy with benzo[ba-hal]furans,o ketonesbenzo[: b]thiophenes can be obtained from thiophenolates and �- halo ketones:

w - N a X SNa X w - N a X SNa X 3 5.7 Benzo[b]thiophene 81 5.7 Benzo[b]thiophene 81

[D] Benzo[b]thiophene, Benzo[£]thiophenecolorless crystals,, colourlesmp 32s crystals°C, bp, mp221 32°C°C,, bphas 221°Ca , smellhas a smelsimilarl similato rthat to thaoft of naphthalene. It is presentnaphthaleneBenzo[£]thiophenein the .naphthalene It is presen, colourlest infraction sth crystalse naphthalen,of mpcoal 32°Ce fractiotar, bpand n221°C of cancoa, hal betas ra anpreparedsmeld cal nsimila be preparefromr to thasodiumdt ofrof m so- thiophenolate anddiubromoacetaldehydem thiophenolatnaphthalene. eIt anis dpresen bromoacetaldehyddiethylt in theacetal naphthalene. diethyBenzo[e fractiol acetalbn]thiophene o.f Benzo[&]thiophencoal tar anoccursd can bee inprepareoccurroasteds di nfro roastem coffeesod- coffee beans. diubeansm thiophenolat. e and bromoacetaldehyde diethyl acetal. Benzo[&]thiophene occurs in roasted coffee beansVariou. s Pharmaceuticals and biocides are derived from benzo[£]thiophene, and it is found to be b i o - Various Pharmaceuticals and biocides are derived from benzo[£]thiopheneL , and it is found to be b i o - Various Pharmaceuticalsisosteric witandh naphthalenbiocidese areand indolederived. Mobafromm 1benzo[ [4-(AL methylcarbamoyl)benzo[6]thiopheneb]thiophene, and it is found] tois aben in- bioisosteric with naphthaleneisosterisecticidce wit which naphthalenhand is asindole effective an.de Mobam indoleas carbary. Moba1l 2[m4. -Bot1( N[4-(Ah-methylcarbamoyl compoundmethylcarbamoyl)benzo[6]thiophenes inhibit th)benzo[e enzymbe]thiophene] acetylcholinesterase] is an inis- an . secticide which is as effective as carbaryl 2. Both compounds inhibit the enzyme acetylcholinesterase. insecticide which is as effective as carbaryl 2. Both compounds inhibit the enzyme acetylcholinesterase. V ff O—C—NHCHV 3 ff O—C—NHCH3 O—C—NHCH3 O—C—NHCH3

Benzo[b]-3-thienylaceticBenzo[6]-3-thienylacetiacid 3 promotesc caci acid plant3d promote3 promotegrowth,s plans plant asgrowtht growthdoes, as ,doethe ass doe correspondingthes correspondin the corresponding indolindolege indol compoundcompounde compound. . 3. - (2-Aminoethyl)benzo[3-(2-Aminoethyl)benzo[6]thiophenb]thiophene 4 has an evene e4 ha4stronger sha ans evean neve strongeactionn stronger actioonr actionthe on nthcentral oen centra the central nervousnervoul nervous systesystemsm syste thanmthan than tryptamin. tryptamin.. CH2—COOH CH2—CH2—NH2 CH2—COOH CH2—CH2—NH2

4 Several compounds which are known as thioindigo dyes are derived fromm benzo[Z?]thiophene. Thio- indigSeverao 6l compounditself is mads ewhic fromh 2-sulfanylbenzoi are known as thioindigc acid viao benzo[£]thiophen-3(2//)-on dyes are derived fromm benzo[Z?]thiophenee 5 (thioindoxyl) by. Thio- thindige followino 6 itselg stepf is smad (FRIEDLANDEe from 2-sulfanylbenzoiR 1905): c acid via benzo[£]thiophen-3(2//)-one 5 (thioindoxyl) by the following steps (FRIEDLANDER 1905):

COOH CICH2COOH

COOH CICH- HCI2COOH

- HCI

-2H2O

Thioindigo, a vat dye, f o r m s red needles and its vat is bright yellow. As a dye, i t has a blue-red colour. Thioindigo dyes were produced in large quantities until the fifties, but since then they have become lesThioindigos important, a. vat dye, f o r m s red needles and its vat is bright yellow. As a dye, i t has a blue-red colour. Thioindigo dyes were produced in large quantities until the fifties, but since then they have become less important. 5.7 Benzo[b]thiophene 81

Benzo[£]thiophene, colourless crystals, mp 32°C, bp 221°C, has a smell similar to that of naphthalene. It is present in the naphthalene fraction of coal tar and can be prepared from sodium thiophenolate and bromoacetaldehyde diethyl acetal. Benzo[&]thiophene occurs in roasted coffee beans. Various Pharmaceuticals and biocides are derived from benzo[£]thiophene, and it is found to be b i o - isosteric with naphthalene and indole. Mobam 1 [4-(ALmethylcarbamoyl)benzo[6]thiophene] is an insecticide which is as effective as carbaryl 2. Both compounds inhibit the enzyme acetylcholinesterase.

V ff O—C—NHCH3 O—C—NHCH3

Benzo[6]-3-thienylacetic acid 3 promotes plant growth, as does the corresponding indole compound. 3-(2-Aminoethyl)benzo[6]thiophene 4 has an even stronger action on the central nervous system than tryptamin.

CH2—COOH CH2—CH2—NH2

Several compounds which are known as thioindigo dyes are derived fromm benzo[Z?]thiophene. Thio- Several compoundsindigowhich 6 itselfare is madknowne from as2-sulfanylbenzoithioindigo cdyes acid viarea benzo[£]thiophen-3(2//)-onderived from benzo[be ]thiophene5 (thioindoxyl. ) by Thioindigo 6 itselfthise followinmade fromg step2s- sulfanylbenzoic(FRIEDLANDER 1905)acid: via benzo[b]thiophen-3(2H)-one 5 (thioindoxyl) by the following steps (FRIEDLANDER 1905):

COOH CICH2COOH

- HCI

-2H2O

Thioindigo, a vat dye, f o r m s red needles and its vat is bright yellow. As a dye, i t has a blue-red colour. Thioindigo, a vat dye, forms red needles and its vat is bright yellow. As a dye, it has a blue-red color. Thioindigo dyes were produced in large quantities until the fifties, but since then they have become Thioindigo dyes were produced in large quantities until the fifties, but since then they have become less important. less important.

5 82 5 Five-Membered Heterocycles

5.8 Benzo [c] thiophene

5.8 Benzo[c]thiopheneA |-| This system lacks a benzene ring and has a o-quinonoid structure. Unlike benzo[c]furan, 82 5 [AFive-Membere-D] This systemd lacksHeterocycle—~ a 1benzene benzo[c]thiophens ring ande hahass beena isolatedo-quinonoid. Its synthesistructures proceede. Unliked by thbenzo[e followinc]furan,g route, starting benzo[c]thiophene hasfrobeenm 1,2-bis(bromomethyl)benzeneisolated. Its synthesis proceeded: by the following route, starting from 1,2- 5.8 Benzo [c] thiophenebis(bromomethyl)benzene: + Na2S -2 NaBr

AI203.A

-H20 A |-| This system lacks a benzene ring and has a o-quinonoid structure. Unlike benzo[c]furan, —~ 1 benzo[c]thiophene has been 1isolated,3-Dihydrobenzo[. Its synthesib]thiophenesl,3-Dihydrobenzo[6]thiophene-2-oxid proceede-2-doxide by thise heatedfollowining arouteesublimation is, heatestartind ign apparatusa sublimatiowithn apparatualuminiums with aluminiuoxide inm oxide in vacuo, resulting in thevacuosublimation, resulting inof thebenzo[ sublimatioc]thiophenen of benzo[c]thiophene. The compound. The compounis isolatedd is isolateas colorlessd as colourless crys- from 1,2-bis(bromomethyl)benzene: crystals of mp 53-55 °Ctal.sIt oitf mthermallyp 53-55°Cunstable. It it thermalland ydecomposes, unstable and decomposeseven at -30, eve°C,n underat -30°Cnitrogen, under nitrogewithinn within a a few days. Its stabilityfeisw increaseddays. Its stabilitby substituentsy is increased biny thesubstiruent1,3-positionss in the 1,3-positionas in benzo[s asc ]furanin benzo[c]furan. . l,3-Diphenylbenzo[c]thiophene, yellow needles, mp 118°C, is thermally stable. Its solution displays a + Na S 2 1,3-Diphenylbenzo[cgree]thiophenen fluorescence, yellow. Thneedles,e compounmpd118 can° C,beis preparethermallyd bystable ring . transformatioIts solution ndisplays of 1,3-diphenyl- -2 NaBra green fluorescenceisobenzofuran. The compound with P4Sicano in CS2be -prepared by ring transformation of 1,3-diphenyl- isobenzofuran with P4Sl,3-Dichlorobenzo[c]thiophene10 in CS2. , bright yellow crystals, mp 54°C, was made from phthaloyl dichloride

[32]: 6

AI203.A

-H20 N82S rV\ PCI5,POCI3 l,3-Dihydrobenzo[6]thiophene-2-oxide is heated in a sublimation apparatus with aluminium oxide in vacuo, resulting in the sublimation of benzo[c]thiophene. The compound is isolated as colourless crystals of mp 53-55°C. It it thermally unstable and decomposes, even at -30°C, under nitrogen within a few days. Its stability is increased by substiruents in the 1,3-positions as in benzo[c]furan. l,3-Diphenylbenzo[c]thiophene, yellow needles, mp 118°C, is thermally stable. ItCsl solution displays a green fluorescence. The compound can be prepared b[4+2y ]rin Cycloadditiong transformatios are typican lo fof r benzo[c]thiophenes1,3-diphenyl- , e.g.: isobenzofuran with P4Sio in CS2- l,3-Dichlorobenzo[c]thiophene, bright yellow crystals, mp 54°C, was made from phthaloyl dichloride [32]: s + II o *

N82S rV\ PCI5,POCI3

[4+2] Cycloadditions are typical for benzo[c]thiophenes, e.g.:

s + II o *

io 82 5 Five-Membered Heterocycles

5.8 Benzo [c] thiophene 82 5 Five-Membered Heterocycles

5.8 Benzo [c] thiophene

A |-| This system lacks a benzene ring and has a o-quinonoid structure. Unlike benzo[c]furan, —~ 1 benzo[c]thiophene has been isolated. Its synthesis proceeded by the following route, starting from 1,2-bis(bromomethyl)benzene: A |-| This system lacks a benzene ring and has a o-quinonoid structure. Unlike benzo[c]furan,

+ Na2S —~ 1 benzo[c]thiophene has been isolated. Its synthesis proceeded by the following route, starting -2 NaBr from 1,2-bis(bromomethyl)benzene:

+ Na2S

AI203.A -2 NaBr

-H20

l,3-Dihydrobenzo[6]thiophene-2-oxide is heated in a sublimation apparatus with aluminiuAIm20 3oxid.A e in vacuo, resulting in the sublimation of benzo[c]thiophene. The compound is isolated as colourles-H20 s crystals of mp 53-55°C. It it thermally unstable and decomposes, even at -30°C, under nitrogen within a few days. Its stability is increased by substiruents in the 1,3-positions as in benzo[c]furanl,3-Dihydrobenzo[6]thiophene-2-oxid. e is heated in a sublimation apparatus with aluminium oxide in l,3-Diphenylbenzo[c]thiophene, yellow needles, mp 118°C, is thermally vacuostable,. resultinIts solutiog inn thdisplaye sublimatios a n of benzo[c]thiophene. The compound is isolated as colourless crys- green fluorescence. The compound can be prepared by ring transformatiotals of mnp 53-55°Cof 1,3-diphenyl. It it thermall- y unstable and decomposes, even at -30°C, under nitrogen within a isobenzofuran with P4Sio in CS2- few days. Its stability is increased by substiruents in the 1,3-positions as in benzo[c]furan. l,3-Dichlorobenzo[c]thiophene, bright yellow crystals, mp 54°C, was madl,3-Diphenylbenzo[c]thiophenee from phthaloyl dichloride , yellow needles, mp 118°C, is thermally stable. Its solution displays a [32]: green fluorescence. The compound can be prepared by ring transformation of 1,3-diphenyl- isobenzofuran with P4Sio in CS2- l,3-Dichlorobenzo[c]thiophene, bright yellow crystals, mp 54°C, was made from phthaloyl dichloride [32]: N82S rV\ PCI5,POCI3

1,3-Dichlorobenzo[c]thiophene, bright yellow N82S rV\ PCI5,POCI3 crystals, mp 54 °C, was made from phthaloyl dichloride:

Cl [4+2] Cycloadditions are typical for [4+2] Cycloadditions are typical for benzo[c]thiophenes, e.g.: benzo[c]thiophenes, e.g.: Cl 5.9 2,5-DihydrothJophene 83

Mixture[4+2] Cycloadditions of endo- ans dar exo-diastereomere typical for benzo[c]thiopheness are usually formed, e.g.:. The reactivity of l,3-diphenylbenzo[c]- s + II o * thiophene in [4+2] cycloadditions is distinctly lower. Acetylene dienophiles yield adducts which, on i heating, are converted into the corresponding substituted naphthalenes with loss of sulfur: o s + II o * COOEt I io . Mixtures of endo- and exo-diastereomers are C ^ A usually formed. The reactivity of 1,3- ^COOEt COOEt diphenylbenzo[c]thiophene in [4+2] cycloadditions is distinctly lower. Acetylene dienophiles yield adducts which, on heating, are converted into the corresponding substituted naphthalenes with loss of sulfur: 7

5.9 2,5-Dihydrothiophene

The names A3-thiole and 3-thiole have previously been used for 2,5-dihydrothiophene. A general synthesis for 2,5-dihydrothiophenes with different substituents is based on the MICHAEL addition of a-sulfanylcarbonyl compounds to vinyl phosphonium salts, followed by an intramolecular WITTIG reaction:

1 6 1 R \ R R \^0 R! ,PPh3®X MEt,

*a * Y 3 4 SH R4^R5 R^S^R

2,5-Dihydrothiophenes are oxidized to 1,1-dioxides by m-chloroperoxybenzoic acid. These compounds are also accessible by [4+1] cycloaddition of 1,3-dienes and sulfur dioxide. For instance, butadiene reacts even at room temperature with liquid sulfur dioxide to give an adduct 2,5-dihydrothiophene 1,1- dioxide, commonly known by the trivial name 3-sulfolene: - Q 02

Following WOODWARD, such conversions are called cheletropic reactions. The LUMO of the 1,3-diene surrounds the nonbonding electron pair of sulfur like the claws of a crab (Greek: chele). 3-Sulfolenes are masked 1,3-dienes [33]. At about 150°C they undergo [4+1] cycloreversion (cyclo- elimination) into 1,3-dienes and sulfur dioxide. As this is a thermal concerted reaction, it proceeds in a 5.9 2,5-DihydrothJophene 83

Mixtures of endo- and exo-diastereomers are usually formed. The reactivity of l,3-diphenylbenzo[c]- thiophene in [4+2] cycloadditions is distinctly lower. Acetylene dienophiles yield adducts which, on heating, are converted into the corresponding substituted naphthalenes with loss of sulfur:

COOEt I 5.9 2,5-DihydrothJophene .83 C ^ A Mixtures of endo- and exo-diastereomers are usually formed. The reactivity of l,3-diphenylbenzo[c]- ^COOEt thiophene in [4+2] cycloadditionCOOEst is distinctly lower. Acetylene dienophiles yield adducts which, on heating, are converted into the corresponding substituted naphthalenes with loss of sulfur:

COOEt I . 5.9 2,5-DihydrothJophene C 83 ^ A

^COOEt Mixtures of endo- and exo-diastereomers are usually formed. The reactivity of l,3-diphenylbenzo[c]COOEt - thiophene in [4+2] cycloadditions is distinctly lower. Acetylene dienophiles yield adducts which, on heating, are converted into the corresponding substituted naphthalenes with loss of sulfur:

COOEt I . C 5.9 2,5-Dihydrothiophen^ Ae ^COOEt COOEt

5.9 2,5-Dihydrothiophene

The names A3-thiole and 3-thiole have previously been used for 2,5-dihydrothiophene. A 5.9 2,5-Dihydrothiophenegeneral synthesis for 2,5-dihydrothiophenes with different substituents is based on the MICHAEL addition ofTh a-sulfanylcarbonye names A3-thiole anl dcompound 3-thiole havse tpreviouslo vinyly phosphoniu been used fomr 2,5-dihydrothiophene salts, followed b. yA an in- [A-D] The names �3-thiole and 3-thiole have previously been used for 2,5-dihydrothiophene. A general tramolecular WITTIG generareactionl synthesi: s for 2,5-dihydrothiophenes with different substituents is based on the synthesis for 2,5-dihydrothiophenes with different substituents is based on the MICHAEL addition of �- MICHAEL addition of a-sulfanylcarbonyl compounds to vinyl phosphonium salts, followed by an in- sulfanylcarbonyl compounds to vinyl phosphonium salts, followed by an intramolecular1 WITTIG6 tramolecula1 r WITTIG reaction: R \ R R \^0 R! ,PPh3®X 5.9 2,5-Dihydrothiophenreaction: e MEt, 1 6 1 R \ R R \^0 R! ,PPh3®X *a * Y MEt, 3 4 SH R4^R5 R^S^R *a * Y 3 4 SH R4^R5 R^S^R

The names A3-thiole and 3-thiole have previously been used for 2,5-dihydrothiophene. A general synthesis fo2r ,52,5-dihydrothiophene-Dihydrothiophenes2,5-Dihydrothiophene2,5-Dihydrothiophenes arewitoxidizedh differens areto oxidizet 1substituent,1s -ardioxidese doxidize to s1,1-dioxide bydis tombase -1,1-dioxidechloroperoxybenzoicd osn bthys ebm-chloroperoxybenzoiy m-chloroperoxybenzoiacid. c acidc acid. Thes. These compounde compounds s MICHAEL addition of a-sulfanylcarbonyarle compound also accessiblsar teo alsvinyeo accessibllb yphosphoniu [4+1e ]b ycycloadditio m[4+1 salts] cycloadditio, followen odf nb1,3-diene yo fa n1,3-diene in- s ans and dsulfu sulfurr dioxidedioxide. Fo. For instancer instance, butadien, butadiene e These compounds are also accessible by [4+1] cycloaddition of 1,3-dienes and sulfur dioxide. tramolecular WITTIG reaction: reacts even areactt roos meve temperaturn at room temperature with eliqui withd liqui sulfud sulfur dioxidr dioxide teo t ogiv givee aann adduct t2,5-dihydrothiophen 2,5-dihydrothiophene 1,1-e 1,1-

For instance,dioxidebutadiene, commonldioxidereactsy, commonlknowevenn ybat yknow roomth1 en trivia btemperaturey th6 el trivianamle nam 3-sulfolenewithe 3-sulfoleneliquid :sulfur: dioxide to give an adduct 1 R \ R R \^0 2,5-dihydrothiopheneR! ,PPh3®X 1,1- dioxide, commonly known by the trivial name 3-sulfolene: MEt,

*a * Y 3 4 SH R4^R5 R^S^R - Q - Q02 02 8 2,5-Dihydrothiophenes are oxidized to 1,1-dioxides bFollowiny m-chloroperoxybenzoig WOODWARD, succ acidh conversion. These compounds are calleds cheletropic reactions. The LUMO of the 1,3-diene surrounds the nonbonding electron pair of sulfur like the claws of a crab (Greek: chele). are also accessible by [4+1] cycloaddition of 1,3-dienes and sulfur dioxide. For instance, butadiene Following WOODWARD3-Sulfolenes ,ar suce maskeh conversiond 1,3-dieness ar[33]e calle. At aboud cheletropit 150°C thec yreactions undergo [4+1. Th]e cycloreversioLUMO ofn th (cycloe 1,3-dien- e reacts even at room temperature with liquid sulfur dioxide to give an adduct 2,5-dihydrothiophene 1,1- surrounds theelimination nonbondin) intgo electro1,3-dienens paiandr sulfuof sulfur dioxider lik. eA ths thie sclaw is a stherma of a lcra concerteb (Greekd reaction: chele), it proceed. s in a dioxide, commonly known by the trivia3-Sulfolenel name 3-sulfolenes are: masked 1,3-dienes [33]. At about 150°C they undergo [4+1] cycloreversion (cyclo- elimination) into 1,3-dienes and sulfur dioxide. As this is a thermal concerted reaction, it proceeds in a - Q 02

3-Sulfolenes are masked 1,3-dienes. At about 150 °C they undergo [4+1] cycloreversion (cyclo- elimination) into841 ,3-dienes and sulfur dioxide5 . Five-Membered Heterocycles As this is a thermal concerted reaction, it proceeds in a dis-rotatory manner according to the disrotatory manner according to the WOODWARD-HOFFMANN rules. Thus a cw-2,5-disubstituted 3- WOODWARD-HOFFMANN rules. Thus a cis-2,5-disubstituted 3-sulfolene stereospecifically yields an sulfolene stereospecifically yields an (E,E)- 1,3-diene, while the toms-diastereomer gives an (£,Z)- 1,3- (E,E)-1,3-diene, while the trans-diastereomer gives an (E,Z)-1,3-diene: diene: A

- so2 02

For multistep Fosynthesesr multistepthat syntheseincludes that aincludDIELSe a -DIELS-ALDEALDER reaction,R reactioncorresponding, corresponding1 ,1,3-diene3-dieness araree necessary. necessary. They can be prepared by the method described. In many cases, the 1,3-diene is not They can be prepared by the method described. In many cases, the 1,3-diene is not isolated, but the isolated, but the DIELS-ALDER reaction is carried out with 3-sulfolene and dienophile in boiling xylene. DIELS-ALDER reaction is carried out with 3-sulfolene and dienophile in boiling xylene. 9

5.10 Thiolane

The bond lengths in thiolane (tetrahydrothiophene) are the same as those in dialkyl sulfides. As in tetrahydrofuran (see p 67), the ring is nonplanar and conformationally flexible. The twist con- formation is, however, preferred because of the larger heteroatom. The activation energy for pseudoro- tation is greater than that for tetrahydrofuran. The chemical shifts in the NMR spectrum correspond to those observed for cycloalkanes and dialkyl sulfides.

Thiolanes behave like dialkyl sulfides. With haloalkanes or alcohols in the presence of BRÖNSTED acids, tertiary sulfonium salts are formed:

o xe

These compounds are good alkylation agents. Ring fission occurs with compounds possessing CH- acidity, e.g.: 84 5 Five-Membered Heterocycles

disrotatory manner according to the WOODWARD-HOFFMANN rules. Thus a cw-2,5-disubstituted 3- sulfolene stereospecifically yields an (E,E)- 1,3-diene, while the toms-diastereomer gives an (£,Z)- 1,3- diene: A

- so2 02

84 5 Five-Membered Heterocycles 02 disrotatory manner according to thFoer multisteWOODWARD-HOFFMANp syntheses that includN rulese a . DIELS-ALDEThus a cw-2,5-disubstituteR reaction, correspondind 3-g 1,3-dienes are necessary. sulfolene stereospecifically yields aThen (E,E)-y can b1,3-dienee prepare,d whil by the eth methoe toms-diastereomed described. In rman givey casess an, (£,Z)the 1,3-dien- 1,3- e is not isolated, but the diene: DIELS-ALDER reaction is carried out with 3-sulfolene and dienophile in boiling xylene. A

- so2 02 5.10 Thiolane

For multiste5.10 Thiolanep syntheses that include a DIELS-ALDEThe bond lengthR reactions in thiolan, correspondine (tetrahydrothiopheneg 1,3-diene) sar are the enecessary same as thos. e in dialkyl sulfides. As They can be prepared by the method describedin tetrahydrofura. In mann y(se casese p 67), th, the e1,3-dien ring is nonplanae is notr anisolatedd conformationall, but the y flexible. The twist con- [A] The bond lengths in thiolaneformatio(tetrahydrothiophene)n is, however, preferrearedthe becaussamee ofas thethose larger inheteroatomdialkyl sulfides. The activatio. As inn energy for pseudoro- DIELS-ALDER reaction is carried out with 3-sulfolene and dienophile in boiling xylene. tetrahydrofuran, the ring is nonplanartation is andgreateconformationallyr than that for tetrahydrofuranflexible. The. Thtwiste chemicaconformationl shifts inis thpreferrede NMR spectrum correspond to because of the larger heteroatomthose. observeThe activationd for cycloalkaneenergys anford dialkypseudorotationl sulfides. is greater than that for tetrahydrofuran. The chemical shifts in the NMR spectrumThiolanecorresponds behave liktoe thosedialkylobserved sulfides. forWitcycloalkanesh haloalkanes andor alcoholdialkyl s in the presence of sulfides. BRÖNSTED acids, tertiary sulfonium salts are formed: 5.10[B] ThiolanesThiolanbehavee like dialkyl sulfides. With haloalkanes or alcohols in the presence of BRÖNSTED acids, tertiary sulfonium salts are formed: o xe 5.11 Selenophene 85 These compounds are good alkylation agents. Ring fission occurs with compounds possessing CH- acidity,The bone.gd.: lengths in thiolaneThes (tetrahydrothiophenee compounds are goo) ard ealkylatio the samn eagents as thos. Rine ign fissiodialkyn loccur sulfidess wit. hA compounds s possessing CH- in tetrahydrofuran (see p 67)acidity, the rin, e.g.g i:s nonplanar and conformationally flexible. The twist con- formatioFurthern is, methylation,however, preferrefollowedd becausby e of the larger heteroatom. The activation energy for pseudoro- the action of sodium ethoxide in tation is greater than that for tetrahydrofuran. The chemical shifts in the NMR spectrum correspond to ethanol, leads to substituted (NC) CH thosecyclopentanes observed for .cycloalkanes and dialkyl2 sulfides. 10 Thiolanes behave like dialkyl sulfides. With haloalkanes or alcohols in the presence of BRÖNSTED acids, tertiary Furthesulfoniur methylationm salts ar, followee formedd by: the action of sodium ethoxide in ethanol, leads to substituted cyclopentanes. Thiolanes can be oxidized to sulfoxides and subsequently to sulfones.

The reaction of 1,4-dibromo- or 1,4-diiodoalkanes with sodium or potassium sulfide provides e o thiolanes in good yield: x

R - - -2 NaBr These compounds are good alkylation agents. Ring fissioBr nB r occurs with compounds possessing CH- acidity, e.g.: The ring transformation of tetrahydrofurans into thiolanes proceeds with hydrogen sulfide in the presence of aluminium oxide at 400°C: O

Thiolane is a colourless, water-insoluble liquid of bp 121°C. It has a distinctive odour similar to town gas. In combination with other compounds, it is responsible for the typical odour of urine after consumption of asparagus. Thiolane 1,1-dioxide, known by the trivial name sulfolane, is obtained industrially by catalytic hydrogenation of 3-sulfolene. Sulfolane, colourless crystals, nip 27.5°C, bp 285°C, is water soluble. Sul- folane is a polar aprotic solvent and is used for the extraction of sulfur compounds from industrial gases and for the extraction of aromatic substances from pyrolysis fractions. It also serves as a solvent for cellulose acetate, polyvinyl chloride, polystyrene, and polyacrylonitrile.

5.11 Selenophene

The selenophene molecule is planar. The chemical shifts in the NMR spectra are found in the region typical for aromatic compounds. The synthesis of selenophenes uses a modified FIESSELMANN synthesis for thiophenes and proceeds as follows: 5.11 Selenophene 85

5.11 Selenophene 85

(NC)2CH

Further methylation(NC), 2CfolloweH d by the action of sodium ethoxide in ethanol, leads to substituted cyclopentanes. Thiolanes can be oxidized to sulfoxides and subsequently to sulfones. Further methylation, followed by the action of sodium ethoxide in ethanol, leads to substituted Thcyclopentanese reaction .of 1,4-dibromo- or 1,4-diiodoalkanes with sodium or potassium sulfide provides thiolaneThiolanes in sgoo cand b eyield oxidize: d to sulfoxides and subsequently to sulfones.

Thiolanes can be oxidizedThe reactioto sulfoxidesn of 1,4-dibromoand subsequently- or 1,4-diiodoalkaneto sulfoness. with sodium or potassium sulfide provides thiolanes in gooR d yield: - - -2 NaBr [C] The reaction of 1,4-dibromo- or 1B,r4 -diiodoalkanesBr with sodium or potassium sulfide provides thiolanes in good yield: R - - -2 NaBr The ring transformation of tetrahydrofuranBr Br s into thiolanes proceeds with hydrogen sulfide in the presence of aluminium oxide at 400°C: The ring transformationThe ring transformatioof tetrahydrofuransn of tetrahydrofuraninto thiolaness into thiolaneproceedss proceedwith hydrogens with hydrogesulfiden sulfidin ethe in the pres- presence of aluminium oxide at 400 °C: ence of aluminium oxide at 400°C: O O [D] Thiolane isThiolana colorless,e is awater colourless-insoluble, water-insolublliquid of bp 121e liqui°C. Itdhas of bapdistinctive 121°C. Iodort has similara distinctivto towne odour similar gas. In combination with other compounds, it is responsible for the typical odor of urine after consumption tofo asparagustown Thiolangas. Ine combinatiois a colourlessn , witwater-insolublh other compoundse liquid of b, pi t121°C is responsibl. It has a edistinctiv for thee odoutypicar similal odour r of urine after consumptioto town gasn o. fI nasparagus combinatio. n with other compounds, it is responsible for the typical odour of ThiolaneThiolan1,1-dioxideeurin 1,1-dioxidee afte, rknown consumptio, knowby thenn o bf trivialyasparagus the trivianame. l namsulfolanee sulfolane, is obtained, is obtaineindustriallyd industriallby catalyticy by catalytic hydro- hydrogenation of 3-sulfolene. Sulfolane, colorless crystals, mp 27.5 °C, bp 285 °C, is water soluble. genation Thiolanof 3-sulfolenee 1,1-dioxide. Sulfolane, known b, ycolourles the trivials namcrystalse sulfolane, nip, 27.5°Cis obtaine, db pindustriall 285°C,y ibsy watecatalytir solublec hydro-. Sul- Sulfolanefolanisea ipolarsgenatio a polaaproticn ro faproti 3-sulfolenesolventc solvenand. Sulfolaneist usedand i,fors colourles usethed extractionfos r crystalsthe extractioof, nisulfurp 27.5°Cncompounds of, bsulfup 285°Cr compoundfrom, is industrialwater ssoluble from . industriaSul- l gases and for folanthe extractione is a polarof aprotiaromaticc solvensubstancest and is usefromd for pyrolysisthe extractiofractionsn of sulfu. It ralso compoundservess froasma industrial gases andgase fosr anthde foextractior the extraction of naromati of aromatic substancec substances sfro fromm pyrolysipyrolysiss fractionsfractions. I.t Ialst also serveo serves as sa asolvens a solvent t solvent for cellulose acetate, polyvinyl chloride, polystyrene, and polyacrylonitrile. 11 for cellulosfor ecellulos acetatee ,acetate polyviny, polyvinyl chloridel chloride, polystyrene, polystyrene, an, andd polyacrylonitrile polyacrylonitrile. .

5.11 5.1Selenophen1 Selenophene e

The selenophene molecule is planar. The chemical shifts in the NMR spectra are found in The selenophenthe region typicae molecull for aromatie is planarc compounds. The chemica. l shifts in the NMR spectra are found in Ththe esynthesi regions typicaof selenophenel for aromatis usesc a compoundsmodified FIESSELMAN. N synthesis for thiophenes and proceeds as The synthesifollowss o: f selenophenes uses a modified FIESSELMANN synthesis for thiophenes and proceeds as follows: 5.11 Selenophene 85

(NC)2CH

Further methylation, followed by the action of sodium ethoxide in ethanol, leads to substituted cyclopentanes. Thiolanes can be oxidized to sulfoxides and subsequently to sulfones.

The reaction of 1,4-dibromo- or 1,4-diiodoalkanes with sodium or potassium sulfide provides thiolanes in good yield:

R - - -2 NaBr Br Br

The ring transformation of tetrahydrofurans into thiolanes proceeds with hydrogen sulfide in the presence of aluminium oxide at 400°C: O

Thiolane is a colourless, water-insoluble liquid of bp 121°C. It has a distinctive odour similar to town gas. In combination with other compounds, it is responsible for the typical odour of urine after consumption of asparagus. Thiolane 1,1-dioxide, known by the trivial name sulfolane, is obtained industrially by catalytic hydrogenation of 3-sulfolene. Sulfolane, colourless crystals, nip 27.5°C, bp 285°C, is water soluble. Sul- folane is a polar aprotic solvent an5d. 11is useSelenophened for the extraction of sulfur compounds from industrial gases and for the extraction of aromatic substances from pyrolysis fractions. It also serves as a solvent for cellulose acetate, polyvinyl chloride[A-D], polystyreneThe selenophene, and polyacrylonitrilemolecule is planar. . The chemical shifts in the NMR spectra are found in the region typical for aromatic compounds. The synthesis of selenophenes86 uses a modified5 FIESSELMANNFive-Memberesynthesisd Heterocyclefor thiopheness and proceeds 5.11 Selenophene as follows:

+ + HO Na2Se V-CHO BrCH2COOEt R - NaCI - -NaBr,-H20 Cl SeNa

Acetylene reacts at 350-370°C with selenium to produce selenophene. Ring transformation of furan Acetylene reacts at 350-370 °C with selenium to produce selenophene. Ring transformation of furan The selenophene moleculintoe isselenophene planar. The occurschemicainto selenophenwithl shifthydrogens e ioccurn thesselenide NMwithR hydroge spectroverna aluminiumselenid are foune ovedat r ialuminiun400 °Cm. at 400°C. the region typical for aromatic compounds. The synthesis of selenophenes usesSelenophene a modified FIESSELMAN, a colorlessSelenopheneN liquid,synthesi, awhich, colourless for inthiophenescontrast liquid, swhich toandthiophene, ,proceed in contrass hasats to anthiopheneunpleasant, has asmell,n unpleasanhastmp smell-38, has mp -38°C and bp 110°C and is insoluble in water. Selenophene undergoes electrophilic substitution reac- follows: °C and bp 110 °C and is insoluble in water. tions typical of furan and thiophene. It reacts faster than thiophene but much more slowly than furan. Selenophene undergoesSubstitutioelectrophilicn occurs regioselectivelsubstitutiony ireactionsn the 2- or 2typical, 5 -positionsof furan. and thiophene. It reacts faster than thiophene but much more slowly than furan. Substitution occurs regioselectively in the 2- or 2,5-positions. Tellurophenes have not been examined in great detail. Their synthesis is analogous to that described for selenophenes, but uses Na2Te instead of Na2Se. Tellurophenes are more sensitive toward12 s acids than selenophenes or even thiophenes. Benzofb] selenophenes and -tellurophenes, as well as the corresponding dibenzo-condensed systems, are known. Natural products derived from selenophene or tellurophene have so far not been discovered, which is in contrast to furan and thiophene. Selenophene proves to be bioisosteric with benzene, thiophene and pyrrole, as in the case of 2- amino-3-(benzo[6]selenophen-3-yl)propionic acid and the proteinogenic amino acid tryptophan:

CH2— C H - C O O H

NH2

5.12 Pyrrole

The univalent radical derived from pyrrole is known as pyrrolyl. All atoms of the pyrrole molecule lie in a plane and the ring forms an almost regular pentagon (see Fig. 5.5). 86 5 Five-Membered Heterocycles

+ + HO Na2Se V-CHO BrCH2COOEt R - NaCI - -NaBr,-H20 Cl SeNa

Acetylene reacts at 350-370°C with selenium to produce selenophene. Ring transformation of furan into selenophene occurs with hydrogen selenide over aluminium at 400°C.

Selenophene, a colourless liquid, which, in contrast to thiophene, has an unpleasant smell, has mp -38°C and bp 110°C and is insoluble in water. Selenophene undergoes electrophilic substitution reactions typical of furan and thiophene. It reacts faster than thiophene but much more slowly than furan. Substitution occurs regioselectively in the 2- or 2, 5 -positions.

Tellurophenes have not been examinedTellurophenein great details hav. Theire not synthesisbeen examineis analogousd in great todetailthat. Theidescribedr synthesis is analogous to that described for selenophenes, but uses Na2Te insteadfor selenophenesof Na2Se. Tellurophenes, but uses Na2Taree insteamoredsensitive of Na2Setowards. Telluropheneacids s are more sensitive towards acids than selenophenes or even thiophenestha. n selenophenes or even thiophenes. Benzo[b]selenophenes and -tellurophenes,Benzofbas well] selenopheneas the correspondings and -tellurophenesdibenzo,- condensedas well as thsystems,e corresponding dibenzo-condensed systems, are known. are known. Natural products derived from selenophene or tellurophene have so far not been discovered, which is Natural products derived from selenophenein contrasor tellurophenet to furan andhave thiopheneso far. not been discovered, which is in contrast to furan and thiophene. Selenophene proves to be bioisosteric with benzene, thiophene and pyrrole, as in the case of 2- Selenophene proves to be bioisostericamino-3-(benzo[6]selenophen-3-yl)propioniwith benzene, thiophene and pyrrole, as inc theacidcase and thofe2 proteinogeni-amino- c amino acid tryptophan: 3-(benzo[b]selenophen-3-yl)propionic acid and the proteinogenic amino acid tryptophan:

CH2— C H - C O O H

NH2

5.12 Pyrrole 13

The univalent radical derived from pyrrole is known as pyrrolyl. All atoms of the pyrrole molecule lie in a plane and the ring forms an almost regular pentagon (see Fig. 5.5).