Dipolarophiles thiocarbonyls

In the absence of a dipolarophile, thiocarbonyl ylide 84 undergoes a 1,4-hydrogen shift to give the naphthoannelated thiophene derivative 85. Many examples of related syntheses have been reported (139-143). The photolysis of tetraarylthiiranes in the presence of tetracyanoethene represents an approach to tetrahydrothiophenes via a SET mechanism (75,76). 

The 2,5-dihydro-l,3,4-thiadiazole 79 reacts with a range of acetylenic dipolarophiles to afford the 2,5-dihydrothio-phenes 80 in 25-75% yields (Equation 19) <2002HCA451>. The thermal extrusion of dinitrogen from the thiadia-zole affords a thiocarbonyl ylide, which reacts with the dipolarophiles to form the thiophenes. 

Oxidation of sulfur atom of pyrazolo[l,5-c]thiazole 64 into sulfoxide 65 followed by Pummerer-type dehydration furnished the transient nonclassical pyrazolo[ 1,5-c]thiazole, the thiocarbonyl ylide 67, which could react with various dipolarophiles such as Ar-pheny 1 ma 1 eiinide (Equations 27 and 28) <2000T10011>. In an excess of oxidizing agent, pyrazolo[l,5-c]thiazole 64 was readily converted to sulfone 66 (Equation 27) <2001J(P1)1795>. 

The desilylation methodology for the generation of 1,3-dipoles, developed by Vedejs and West (29) with regard to azomethine ylides, was successfully applied by Achiwa and co-workers (30) to the field of thiocarbonyl ylides. This approach allowed the generation of the parent thioformaldehyde (5)-methylide (la) and its use for preparative purposes (31,32). Generation of la in the presence of C=C dipolarophiles led to tetrahydrothiophenes (19) in high yield (Scheme 5.4). 

Reaction with acetylenic dipolarophiles represents an efficient method for the preparation of 2,5-dUiydrothiophenes. These products can be either isolated or directly converted to thiophene derivatives by dehydration procedures. The most frequently used dipolarophile is dimethyl acetylenedicarboxylate (DMAD), which easily combines with thiocarbonyl yhdes generated by the extrusion of nitrogen from 2,5-dihydro-1,3,4-thiadiazoles (8,25,28,36,41,92,94,152). Other methods involve the desUylation (31,53,129) protocol as well as the reaction with 1,3-dithiohum-4-olates and l,3-thiazolium-4-olates (153-158). Cycloaddition of (5)-methylides formed by the N2-extmsion or desilylation method leads to stable 2,5-dUiydrothiophenes of type 98 and 99. In contrast, bicyclic cycloadducts of type 100 usually decompose to give thiophene (101) or pyridine derivatives (102) (Scheme 5.37). 

Based on a series of kinetic studies, Huisgen et al. (91-93) established that thiocarbonyl compounds, especially aromatic thioketones, function as very active dipolarophiles (superdipolarophiles) toward thiocarbonyl ylides. In fact, the trapping reaction of thiocarbonyl ylides with thiocarbonyl compounds represents an excellent method for the preparation of 1,3-dithiolanes. 

Only a few examples of the [3 + 2] cycloaddition of thiocarbonyl ylides with C=N compounds have been reported so far. By comparison with aldehydes, imines are poor dipolarophiles. For example, Al-benzylidene methylamine and adamanta-nethione (5)-methylide (52) produce 1,3-thiazolidine (129) in only 13% yield (163). An alternative and efficient approach to 1,3-thiazohdines involves the [3 + 2] cycloaddition of azomethine ylides with thiocarbonyl compounds [cf. (169)]. 

Reactions of thiocarbonyl ylides with nitriles are scarce. Simple nitriles do not undergo bimolecular cycloaddition (171). There is, however, a single example of an intramolecular case that was reported by Potts and Dery (24c,62). By analogy to the intramolecular cycloaddition with acetylenic dipolarophiles (Scheme 5.40), the primary product derived from the reaction of a thiocarbonyl ylide with a nitrile group undergoes a subsequent elimination of phenylisocyanate to give the fused 1,3-thiazole (131). 

The following types of dipolarophiles have been used successfully to synthesize five-membered heterocycles containing three heteroatoms by [3 + 2]-cycloaddition of thiocarbonyl ylides azo compounds, nitroso compounds, sulfur dioxide, and Al-sulfiny-lamines. As was reported by Huisgen and co-workers (91), azodicarboxylates were noted to be superior dipolarophiles in reactions with thiocarbonyl ylides. Differently substituted l,3,4-thiadiazolidine-3,4-dicarboxylates of type 132 have been prepared using aromatic and aliphatic thioketone (5)-methylides (172). Bicyclic products (133) were also obtained using A-phenyl l,2,4-triazoline-3,5-dione (173,174). 

Nitroso compounds are seldom used as dipolarophiles for trapping reactions with thiocarbonyl ylides. However, Sheradsky and Itzhak (175) did report one example where nitrosobenzene reacts with a thioisomiinchnone to give 134 as the major product. 

A-Sulfinylamines (R—N=S=0) are known to function as reactive dienophiles and dipolarophiles, and some examples of [3 + 2] cycloaddition with thiocarbonyl ylides have been reported (176). For example, the reaction of thiobenzophenone (5)-methylide (16) with both A-phenyl and N-tosylsulfinylamines occurs regiose-lectively to give 1,3,4-dithiazolidine 3-oxides (135). In the case of thiocarbonyl ylide 69, reaction with N-phenyl sulfinylamine selectively afforded the analogous product 136 (R = Ph). However, the corresponding reaction with Al-tosyl sulfinylamine resulted in a mixture of the N,S-adduct (136) (R =Tos) and the 0,S-adduct 137. Formation of a mixture of products is compatible with a stepwise reaction via a zwitterionic intermediate. 

The thiocarbonyl group is a highly reactive dipolarophile and in general this group dominates the reactivity of nonenolisable exocyclic thioketones as illustrated for the systems shown 5-methylene-2-thioxo-l,3-thiazolinin-4-one (260) (161), pyrimidone-2- and -4-thiones (261, 262) (134), pyrazolo[l,5,4-e/][l,5]benzodi-azepin-6-thione (263) (162). 2-Thiono-4-imidazolidinone (264) also gave a C=S cycloadduct as expected but, in the case of the analogue 265 with an additional exocyclic methylene group, the latter proved to be more reactive (163). 

The isomeric adamantane-spirothiadiazolines (145 and 146) (Scheme 8.34) exhibit different thermal stability [145 Xi/2 = 33 min at 45 °C 146 Xi/2 = 25.6 min at 110 °C (206a)]. Elimination of N2 from 145 generates thiocarbonyl ylide 147 that was trapped not only with the dipolarophiles mentioned above for 140, but also with aldehydes and imines (206a) (147 —> 149). Without a trapping reagent, thiirane 151 was formed from both 145 (at 80 °C) and 146. In the latter case, the extrusion probably proceeds via intermediate 148 and is accompanied by homo-adamantanethione 152 and a trace of methyleneadamantane. When 145 was decomposed at 45°C rather than at 80 °C, dimer 150 was also obtained. The isolation of 150 suggests that ylide 147 is also able to act as a base toward its precursor 145 (213). In fact, 147 can also be trapped with other protic nucleophiles. 

Interception of photochemically generated thiocarbonyl ylides with reactive dipolarophiles (e.g., A-phenylmaleinimide) has been used for the preparation of polycyclic tetrahydrothiophenes of type 83 (139). An example is shown in Scheme 5.30. 

V-Sulfinylamines (R—N=S=0) are known to function as reactive dienophiles and dipolarophiles, and some examples of [3 + 2] cycloaddition with thiocarbonyl ylides have been reported (176). For example, the reaction of thiobenzophenone ... 

Other alkenic dipolarophiles like N- phenylmaleimide behaved in an analogous fashion, the reaction displaying both kinetic and thermodynamic product control in the formation of the azomethine adduct (132) at low temperatures and the thiocarbonyl adduct (133) at high temperatures. Thermal loss of H2S from adduct (133) was not, however, observed. 

When acrylonitrile or ethyl acrylate was used as the dipolarophile, the azomethine adducts (134) and (135) were formed no thiocarbonyl ylide addition products were isolable in refluxing toluene or xylene, although the isoindoles (136a) and (136b) derived from them were isolated. In contrast to the reactions with fumaronitrile or AT-phenylmaleimide, the azomethine adducts (134) and (135) were still present at higher reaction temperatures — almost 50% in toluene and 4-5% in xylene. Under the same reaction conditions other electron-deficient dipolarophiles like dimethyl fumarate, norbornene, dimethyl maleate, phenyl isocyanate, phenyl isothiocyanate, benzoyl isothiocyanate, p-tosyl isocyanate and diphenylcyclopropenone failed to undergo cycloaddition to thienopyrrole (13), presumably due to steric interactions (77HC(30)317). 

Calculations have shown that the HOMO in the [3,4-c]-annelated A,B-diheteropen-talenes is closely related to the nonbonding MO, thereby allowing ready reaction with electron-deficient dipolarophiles. In the case of the systems with two discrete ylide moieties as in thieno[3,4-c]pyrrole derivatives, it is not only the nature of the HOMO which directs the mode of addition, but also the thermodynamic stability of the adduct, leading to addition across the thiocarbonyl ylide at elevated temperatures and to the azomethine ylide at low temperatures (Section 3.18.4.2.1) (77T3203). 

Thiocarbonyl ylides are the 1,3-dipoles with the highest ir-MO energies.28,29 Huisgen described the cycloadditions of 2,2,4,4-tetramethyl-l-oxocyclobutane-3-thione S-methylide (10) and of adamantane-thione S-methylide (11) to dimethyl 2,3-dicyanofumarate which proceed in a nonstereospecific manner (Scheme 4).27 The presence of four electron-attracting substituents in the dipolarophile significantly lowers the MO energy of the ethylenic dipolarophile. Thus, in this particular case, the pair of reactants ful-... 

Another route which has recently been used to generate thiocarbonyl ylides involves the bromodesilyl-ation reaction of a-bromosilyl silyl sulfide (189). This process is related to the methodology first developed by Padwa for the preparation of azomethine ylides. Thus, heating a sample of (189) generates thiocarbonyl ylide (190) which can be trapped with various dipolarophiles to give cycloadducts of type (191 Scheme 44). 

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