Chapter 9 N S. Thiophenes

Transcription

1 Chapter 9 N Thiophenes 1

2 The simple thiophenes are stable liquids that closely resemble the corresponding benzene compounds in boiling points and even in smell. They occur in coaltar distillates the discovery of thiophene in coal-tar benzene provides one of the classic anecdotes of organic chemistry. 2

3 TIPENE eactions with electrophiles at C Preferably at C-2 / C-5 (α-positions) X E X E X E X E E E E m o s t s t a b l e X : N,, X X 3

4 -Protonation Much more stable under acidic conditions than pyrroles and furans Protonation at C-2 /C-5 100% 3 P 4 90 o C 4

5 The action of hot phosphoric acid on thiophene leads to a trimer; its structure suggests that, in contrast with pyrrole, the electrophile involved in the first C C bonding step is the α-protonated cation. C

6 Nitration Not complete selectivity Not N 3 (explosions) Nitration of thiophene needs to be conducted in the absence of nitrous acid, which can lead to an explosive reaction; the use of acetyl nitrate or nitronium tetrafluoroborate is satisfactory 6

7 eactions with electrophiles at C Further nitration of either 2- or 3-nitrothiophenes also leads to mixtures: equal amounts of 2,4- and 2,5- dinitrothiophenes from the 2- isomer, and mainly 2,4- dinitrothiophene from 3- nitrothiophene. " N + 2 " N 2 2 N N N N 2 ca 1 : 1 N 2 N 2 " N + 2 " 2 N N 2 : m-directing 7

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9 alogenation alogenation of thiophene occurs very readily at room temperature and is rapid even at 30 C in the dark; tetrasubstitution occurs easily. The rate of halogenation of thiophene at 25 C is about 10 8 times that of benzene. 2-Bromo-, 2-chloro- and 2-iodothiophenes and 2,5- dibromo - and 2,5- dichlorothiophenes can be produced cleanly under various controlled conditions. 9

10 eactions with electrophiles at C Bromination 2 Br 2, 48% Br o C Br 2 Br 2, 48% Br -10 r.t Br Br ne interpretation of the selective reductive removal is that it involves, first, electron transfer to the bromine, then transient anions, thus halogen can be selectively removed from that position where such an anion is best stabilised normally an α-position NaB 4 DM, r.t. Br Br 3 Br 2, 48% Br 75 o C Br Br Br Br NaB 4, Pd(0) MeCN, Br Zn Ac, Br Multibromination occurs readily at room temperature and even at -30 C Careful control or reaction conditions is required to ensure mono-bromination 10

11 Br CuCl DMF Cl Iodination I 2, N 3 (aq) 90 o C I Br CuI DMF I 11

12 The Friedel Crafts acylation of thiophenes is a much - used reaction and generally gives good yields under controlled conditions, despite the fact that aluminium chloride reacts with thiophene to generate tars; this problem can be avoided by using tin tetrachloride and adding the catalyst to a mixture of the thiophene and the acylating agent. Acylation with anhydrides, catalysed by phosphoric acid is an efficient method. (strong Lewis acid, AlCl 3 leads to polym.) CCl ncl 4 FC acyl. ketone PCl 3, DMF (Vilsmeier) aldehyde 12

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15 Condensation with carbonyl compounds Acid-catalysed reaction of thiophene with aldehydes and ketones is not a viable route to hydroxyalkyl - thiophenes, for these are unstable under the reaction conditions. ' ' + res forms - ' Decomp 15

16 Condensation with carbonyl comps, cont. C 2, conc. Cl 0 o C Cl 16

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18 Condensation with imines / iminium ions Thiophene (and furan): Preformed reagent generally required Me 2 N=C 2 Cl MeCN, N But: 2 C (aq) N 4 Cl N 2 18

19 The Petasis reaction Another device for bringing thiophenes into reaction with Mannich intermediates is to utilise thiophene boronic acids the Petasis reaction; primary aromatic amines can also be used as the amine component. 19

20 eactions with electrophiles at ulfur E E Possible for thiophene; in 3rd row Not possible for furan / pyrrole; and N in 2nd row Probably sp 3. tetrahedral Works best for electron rich thiophenes Me Me Me Me Me F Me Me Me Me Me F NaPF 6 Me Me Me Me Me PF 6 + F 3 Na 20

21 eactions with electrophiles at ulfur eact. with carbenes N N 2 C C 2 N N h 2 ( A c ) 4 -N 2 2 C C 2 C a r b e n e 9 5 % 2 C C 2 t a b l e y l i d e 2 C C 2 2 C C 2 2 C C 2 60 o C C 2 C 2 C 2 C 2 21

22 eactions with electrophiles at ulfur eact. with carbenes N N C 2 1 ) h 2 ( A c ) 4 2 ) C 2 C 2 C 2?????? C 2 22

23 xidation [ox] [ox] Not aromatic 23

24 xidation The oxidation of thiophene derivatives by hydrogen peroxide is catalyzed by methyltrioxorhenium(vii) (C 3 e 3 ). This compound reacts with hydrogen peroxide to form 1:1 and 1:2 rhenium peroxides, each of which transfers an oxygen atom to the sulfur atom of thiophene and its derivatives. Complete oxidation to the sulfone occurs readily by way of its sulfoxide intermediate. Inorg. Chem., 1996, 35 (25), pp

25 xidation mcpba rel. stable EWG EWG EWG- 25

26 eactions with nucleophiles Nitro substituents activate the displacement of leaving groups like halide, as in benzene chemistry, and extensive use of this has been made in thiophene work. uch nucleophilic displacements proceed at least 10 2 times faster than for benzenoid counterparts, and this may be accounted for by participation of the sulfur in the delocalisation of charge in the Meisenheimer intermediate. X N Nu X N Nu N 2 Nu ulfur stab. neg, charge on α-c Nu X N 26

27 eactions with nucleophiles 27

28 eactions with nucleophiles Nitrogroups also permit the operation of VN processes, as illustrated below: V i c a r i o u s N u s u b s t ( V N ) N E W G X E W G X N B a s e E W G N E W G N 2 28

29 Copper and copper(i) salts have been used extensively in thiophene chemistry to catalyse displacement of bromine and iodine, but not chlorine, in simpler halo thiophenes. B r C u X X = C l, I X C u B r M e N a M e 29

30 C-metallation and further reactions In the 2 / 5 pos. n-buli 1 equiv. Li "E + " E n-buli 2 equivs. Li Li "E + " E E 3-Litiation with DG n-buli C 2 Li Li LDA Li C 2 Li 30

31 C-metallation and further reactions 31

32 Metal alogen Exchange Bromine and iodine at either α - or β - positions undergo exchange with alkyllithiums giving lithiated thiophenes. B r n - B u l i L i " E + " E - 70 o C t a b l e i n h e x a n e 32

33 Metal alogen Exchange ieke metals are highly reactive metal powders prepared by the methods developed by euben D. ieke. ieke metals are highly reactive because they have high surface area and lack surface oxides which retard reaction. ieke metals are usually prepared by a reduction of a TF suspension of an anhydrous metal chloride with an alkali metal. Typical alkali metals used in this method are potassium, sodium, and lithium. For example, the preparation of ieke magnesium employs potassium as the reductant: MgCl K Mg + 2 KCl 33

34 In Et 2 over -25 o C: Met Li Li Met: ZnX, MgX table at T 34

35 eaction with radicals, eldom synthetically usefull adicals generated in various ways have been utilised in elaborating thiophenes and in ring - closing reactions; examples are shown below: 35

36 Catalytic reductions of the thiophene ring, or of substituents attached to it, are complicated by two factors: 1- poisoning of the catalyst and 2- the possibility of competing hydrogenolysis reductive removal of sulfur, particularly with aney nickel Indeed the use of thiophenes as templates on which to elaborate a structure, followed finally by desulfurisation, is an important synthetic strategy. 36

37 Cycloadditions Unactivated thiophenes show little tendency to react as 4 π components in a Diels Alder sense; however, maleic anhydride will react with thiophene to produce an adduct in high yield, under extreme conditions. 37

38 Electrophilic alkynes will react with thiophenes under vigorous conditions, though the initial adduct extrudes sulfur, and substituted benzenes are obtained as products. Thus, both α - and β - methoxy - substituted thiophenes react with dimethyl acetylenedicarboxylate in xylene to give modest yields of phthalates resulting from sulfur extrusion from initial adducts; in acetic acid as solvent, only substitution products are obtained. 38

39 xythiophenes 39

40 Aminothiophenes N 2 N 2 c.f. Aminopyrroles -Amino (not iminoform) - unstable nly amino Generally unstable 40

41 ynthesis of Thiophenes a b c d 41

42 Carbonyl condensations trategy a: L ± - 2 L: Lawesons reagent Me P P Me 42

43 trategy a, cont.: eactions with electrophiles at ulfur When the process is applied to 1,4 - dicarboxylic acids, a reduction must occur at some stage, for thiophenes, and not 2- or 5-oxygenated thiophenes result. P N a N a 43

44 Use of conjugated diynes Much use has been made of conjugated diynes, which are also at the oxidation level of 1,4 dicarbonyl compounds, which react smoothly with hydrosulfide or sulfide, under mild conditions, to give 3,4-unsubstituted thiophenes. ' 2, Na ' ' 44

45 3,4-ethylenedioxythiophene 45

46 From α-thio - Carbonyl Compounds trategy b: P h 3 P P h 3 P W i t t i g [ o x ] ( c h l o r o a n i l ) 46

47 Chloranil: 47

48 From Thioglycolates and 1,3 - Dicarbonyl Compounds trategy c: C 2 48

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50 Fiesselmann Thiophene ynthesis The Fiesselmann thiophene synthesis involves the condensation reaction of thioglycolic acid derivatives with acetylenic esters, which upon treatment with base results in the formation of 3-hydroxy-2- thiophenecarboxylic acid derivatives.

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53 trategy d d 53

54 Mechanism: 2 C C 2 Base 2 C C 2 2 C 2 C Bsae 2 C C 2 2 C C 2 2 C Base 2 C - 2 C C 2 54

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56 Miscellaneous carbonyl reactions Using Carbon Disulfide: ' ' 1) Base 2) =C= ' ' Base ' ' Br ' ' Base '' ' ' Water elim. -alylation (''X) ' ' ' ' 56

57 Miscellaneous carbonyl reactions From Thio Diketones: 4 3 TiCl 4 Zn