1,3-Prototropic rearrangements

The mechanism of the indolization of aniline 5 with methylthio-2-propanone 6 is illustrated below. Aniline 5 reacts with f-BuOCl to provide A-chloroaniline 9. This chloroaniline 9 reacts with sulfide 6 to yield azasulfonium salt 10. Deprotonation of the carbon atom adjacent to the sulfur provides the ylide 11. Intramolecular attack of the nucleophilic portion of the ylide 11 in a Sommelet-Hauser type rearrangement produces 12. Proton transfer and re-aromatization leads to 13 after which intramolecular addition of the amine to the carbonyl function generates the carbinolamine 14. Dehydration of 14 by prototropic rearrangement eventually furnishes the indole 8. 

Accounting for this effect, it was possible to apply dynamic NMR spectroscopy to measure energy barriers to the prototropic rearrangements of pyrazoles. Temperature-variable spectra of a series of 4-substituted pyra-zoles 5 and 6 have been studied in methanol-d4 solutions and the free energy barriers of the degenerate type 2a 2b tautomerization reported (93CJC1443). 

Research into the mechanism of diazotization was based on Bamberger s supposition (1894 b) that the reaction corresponds to the formation of A-nitroso-A-alkyl-arylamines. The TV-nitrosation of secondary amines finishes at the nitrosoamine stage (because protolysis is not possible), but primary nitrosoamines are quickly transformed into diazo compounds in a moderately to strongly acidic medium. The process probably takes place by a prototropic rearrangement to the diazohydroxide, which is then attacked by a hydroxonium ion to yield the diazonium salt (Scheme 3-1 see also Sec. 3.4). 

The stereochemistry of dienes has been found to have a pronounced effect in the concerted cyclo-additions with benzyne 64>65h A concerted disrotatory cyclo-addition of tetrafluorobenzyne, leading for example with trans- (3-methylstyrene to (63, R = Me), is likely and in accord with the conservation of orbital symmetry 68>. However while the electro-cyclic rearrangement of (63, R = H) to (65, R = H) is not allowed, base catalysed prototropic rearrangement is possible. A carbanion (64, R = H) cannot have more than a transient existence in the reaction of tetrafluorobenzyne with styrene because no deuterium incorporation in (65) was detected when either the reaction mixture was quenched with deuterium oxide or when the reaction was conducted in the presence of a ten molar excess of deuteriopentafluorobenzene. 

In contrast with the normal behaviour of aliphatic thioketones, 3-exo,3 -exo-(lR,l R)-bithiocamphor cannot exist as enethiol, since the latter is obtained by reduction of its 1,2-dithiine, immediately stabilized by 1,5-prototropic rearrangement.6... 

Reactions of arylsulfonylallenes with 3,5-dichloro-2,4,6-trimethylbenzonitrile oxide (227) proceed in a manner similar to that of the above-mentioned sulfides. Probably, both 4- and 5-alkylidene-4,5-dihydroisoxazole cycloadducts are initially formed which then undergo different transformations. 4-Alkylidene isomers give spiro adducts such as 60 with an additional molecule of nitrile oxide, while 5-isomers convert to isoxazoles 61, products of their prototropic rearrangement. 

Only two general methods have been developed for the synthesis of the macrocyclic annulenes.9 The first of these, developed by Sondheimer and co-workers, involves the oxidative coupling of a suitable terminal diacetylene to a macrocyclic polyacetylene of required ring size, using typically cupric acetate in pyridine. The cyclic compound is then transformed to a dehydroannulene, usually by prototropic rearrangement effected by potassium i-butoxide. Finally, partial catalytic hydrogenation of the triple bonds to double bonds leads to the annulene. 

The isomerization of the smallest alkynes 80 with halogens in a propargylic position has been described for chlorine [151, 152], bromine [153] and iodine [154] (Scheme 1.35), but often might proceed by an SN2 -type substitution rather than a prototropic rearrangement [155-159]. On the other hand, transformations such as 82 —> 83 [160] or 84 —> 85 [161] are clearly prototropic (Scheme 1.36). This is also true for propargylic halides such as 86 with its additional ester group assisting the prototropic isomerization [162,163] (Scheme 1.37). 

For stannanes, there exists one example of a rearrangement (133 —> 134) which at first sight resembles a prototropic rearrangement, but is in fact a radical chain reaction [341] (Scheme 1.59). 

The field of allenes bearing phosphorus is dominated by sigmatropic rearrangements (see Section 1.3.1). Nevertheless, some examples of prototropic rearrangements are known. 

There exist early examples of this transformation [507, 508], but due to the symmetric structure of the alkene part, only isotope labeling, etc., allowed the exclusion of a prototropic rearrangement. Furthermore, due to the high reaction temperatures of 340 °C and above, several different products are formed. A low-temperature version (77 K) of this reaction via the radical cation has been reported [509]. The chirality transfer has been studied and a detailed mechanistic investigation has been conducted [510] typical experiments in that context were the reactions of substrates such as 155 and 157 (Scheme 1.70). 

The acidity of the propargylic proton of the starting compound 18 allows the equilibration with the allene 19 induced by bases such as tertiary amines or alcoholates (Scheme 7.4). Such prototropic rearrangements furnish the title compounds 19 with at least one proton at the terminal carbon atom, often in good yields. The EWG group involves carboxylic acids [33], esters [34], ketones [35, 36], isonitriles [37], sul-fones [38], sulfoxides [39, 40] and phosphonates [41], The oxidation of easily accessi-... 

In the case of carboxylic acids [33], ketones [47] or sulfones [49], it was possible to prove a further prototropic rearrangement of allenes 19 with R2 = H yielding the alkynes 20. In other examples, the prototropic isomerization of the triple bond leads to conjugated dienes directly thus the allene of type 19 could only be postulated as an intermediate [50]. Braverman et al. showed that the allenes generated by prototropic isomerization of dipropargylic sulfones or sulfoxides, for example 24, are unstable. They are transferred rapidly via diradical intermediates to polycycles such as 27 [51-53],... 

Scheme 20.18 Enyne-allenes via prototropic rearrangement of enediynyl sulfones.

The cyclic enediynyl sulfide 93 is also prone to undergo prototropic rearrangement (Scheme 20.21) [57]. When the l,8-diazabicydo[5.4.0]undec-7-ene (DBU)-induced isomerization was conducted in carbon tetrachloride, three cycloaromatized products, 96 to 98, were isolated, indicating the formation of the biradical 95a as a transient intermediate. In a polar solvent, such as methanol or ethanol, the formation of 99 can best be accounted for by regarding the biradical 95a as the zwitterion ion 95b. A related process involving the oxidation of 93 with selenium dioxide has also been reported [58],... 

A similar process involving an all-carbon cyclic system has also been investigated [59]. Other examples involving the prototropic rearrangement of enediynes having an imino or a keto substituent at the propargylic position to form the corresponding enyne-allenes have also been observed [60, 61]. 

The propargylic alcohol 102, prepared by condensation between 100 and the lithium acetylide 101, was efficiently reduced to the hydrocarbon 103, which on treatment with potassium tert-butoxide was isomerized to the benzannulated enyne-allene 104 (Scheme 20.22) [62], At room temperature, the formation of 104 was detected. In refluxing toluene, the Schmittel cyclization occurs readily to generate the biradical 105, which then undergoes intramolecular radical-radical coupling to give 106 and, after a prototropic rearrangement, the llJ-f-benzo[fo]fluorene 107. Several other HJ-f-benzo[fo]fluorenes were likewise synthesized from cyclic aromatic ketones. 

Scheme 20.22 Synthesis of 11 H-benzo[fo]fluorenes via prototropic rearrangement of benzannulated enediynes.

Treatment of the propargylic alcohol 144, readily prepared from condensation between benzophenone (143) and the lithium acetylide 101, with thionyl chloride promoted a sequence of reactions with an initial formation of the chlorosulfite 145 followed by an SNi reaction to produce in situ the chlorinated and the benzannulated enyne-allene 146 (Scheme 20.30) [62], A spontaneous Schmittel cyclization then generated the biradical 147, which in turn underwent a radical-radical coupling to form the formal [4+ 2]-cycloaddition product 148 and subsequently, after a prototropic rearrangement, 149. The chloride 149 is prone to hydrolysis to give the corresponding 11 H-bcnzo h fluoren-ll-ol 150 in 85% overall yield from 144. Several other llff-benzo[fc]fluoren-ll-ols were likewise synthesized from benzophenone derivatives. 

In addition to the example depicted in Scheme 20.40 and examples involving a prototropic rearrangement [61], the use of trimethylsilyl trifluoromethanesulfonate to induce the transformation of 212 afforded 213 bearing a keto substituent at the allenic terminus (Scheme 20.44) [81]. Thermolysis of 213 promoted the Myers-Saito cyclization leading to 216. 

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