Desulfurative cyclization

Treatment of bisbenzenesulfonylmethane and a ketone with Smia leads to a /3-hydroxy sulfone. Allylic sulfones are a source of allyl anions because they are cleaved by Sml2 in HMPA thus a new preparative method for homoallylic alcohols is available. However, the desulfurative cyclization of allylic sulfides toward a carbonyl group may belong to a different mechanistic category. 

Gassman and co-workers developed a synthetic route from anilines to indoles and oxindoles which involves [2.3]-sigmatropic rearrangement of anilinosul-fonium ylides. These can be prepared from Ai-chloroanilines and ot-thiomcthyl-ketones or from an aniline and a chlorosulfonium salt[l]. The latter sequence is preferable for anilines with ER substituents. Rearrangement and cyclizalion occurs on treatment of the anilinosulfonium salts with EtjN. The initial cyclization product is a 3-(methylthio)indole and these can be desulfurized with Raney nickel. Use of 2-(methylthio)acetaldehyde generates 2,3-unsubstituled indoles after desulfurization[2]. Treatment of 3-methylthioindoles with tri-fiuoroacetic acid/thiosalieylie acid is a possible alternative to Raney nickel for desulfurization[3]. 

The synthesis of 3-acyl- and 3-aroyl-l,2-benzisoxazoles was accomplished by the desulfurization of (562). The dithioacetal (562) was prepared by the addition of the lithium salt of propenedithioacetal to an isocyanate with subsequent base cyclization (equation 61) (B-79MI41609). 

In addition there are certain other methods for the preparation such compounds. Upon heating of the thionocarbonate 2 with a trivalent phosphorus compound e.g. trimethyl phosphite, a -elimination reaction takes place to yield the olefin 3. A nucleophilic addition of the phosphorus to sulfur leads to the zwitterionic species 6, which is likely to react to the phosphorus ylide 7 via cyclization and subsequent desulfurization. An alternative pathway for the formation of 7 via a 2-carbena-l,3-dioxolane 8 has been formulated. From the ylide 7 the olefin 3 is formed stereospecifically by a concerted 1,3-dipolar cycloreversion (see 1,3-dipolar cycloaddition), together with the unstable phosphorus compound 9, which decomposes into carbon dioxide and R3P. The latter is finally obtained as R3PS ... 

Friedel-Crafts cyclization of the dibasic acid gives thiaxanthone 4. Note that the symmetry of this intermediate assures formation of a single product. Desulfurization by means of Raney nickel leads, finally, to the antiinflammatory agent, ketopirofen... 

A variation of the pathway in which 2 -hydroxybiphenyl-2-sulfinate is converted to 2 -hydroxybiphenyl-2-sulfonate (HBPSo) has been reported [26,62], In this alternate desulfurization pathway, the HBPSo further spontaneously cyclizes to sultone , BPSo. The latter is a substrate for DszA (Fig. 2), and is desulfurized to 2, 2 -dihydroxybiphenyl (DHBP) and sulfite. 

The reaction sequence outlined in Scheme 12 illustrates how macrocyclic polyether-thiono diesters such as RR)-lfi6 can be prepared (184) from 0,0-dimethyl 2,6-pyridinedicaibothiolate and (RR)-S4, Potassium thiocyanate forms a 1 1 crystalline complex with (RR)-1S6 and presumably the potassium ion serves as a template for the (1 -I-1) cyclization. Raney nickel desulfurization of (/ R)-186 yields the chiral pyridino-18-crown-6 derivative RR)-191. 

Reductive desulfurization was used by the present authors to establish the structures of the products formed by AlClj-catalyzed cyclization of 2-acetonylthio-5-ethylthiophene. The mixture obtained of 5-ethyl-3-methylthieno[2,3-i]thiophene (26) and 5-ethyl-3-methylthieno-[3,2-h]thiophene (27) was converted (AcCl/SnCl4) into 2-acetyl-5-ethyl-... 

The last synthesis to evolve which is due to Ito and his coworkers is interesting in that it relies on a stereospecific skeletal rearrangement of a bicyclo[2.2.2]octane system which in turn was prepared by Diels-Alder methodology (Scheme XLVIII) Heating of a toluene solution of cyclopentene 1,2-dicarboxylic anhydride and 4-methylcyclohexa-l,4-dienyl methyl ether in the presence of a catalytic quantity of p-toluenesulfonic acid afforded 589. Demethylation was followed by reduction and cyclization to sulfide 590. Desulfurization set the stage for peracid oxidation and arrival at 591. Chromatography of this intermediate on alumina induced isomerization to keto alcohol 592. Jones oxidation afforded diketone 593 which had earlier been transformed into gymnomitrol. 

Scheme 1.64). The Ag(I)-mediated cyclization afforded dipole 306 for 1,3-dipolar cycloaddition with methyl vinyl ketone to yield adducts 307 and the C(2) epimer as a 1 1 mixture (48%). Hydrogenolytic N—O cleavage and simultaneous intramolecular reductive amination of the pendant ketone of the former dipolarophile afforded a mixture of alcohol 308 and the C(6) epimer. Oxidation to a single ketone was followed by carbonyl removal by conversion to the dithiolane and desulfurization with Raney nickel to afford the target compound 305 (299). By this methodology, a seven-membered nitrone (309) was prepared for a dipolar cycloaddition reaction with Al-methyl maleimide or styrene (301). 

Ring closure to an episulfide is a feasible reaction for thiocarbonyl ylides. In most cases, the sulfur is further extruded under the reaction conditions to afford an olefin as the final product. This cascade transformation has been utilized by Danishefsky and co-workers in their total synthesis of ( )-indolizomycin (Scheme 16)." In the Danishefsky s approach, diazo ketone 137 is treated with a catalytic amount of Rh2(OAc)4 to generate thiocarbonyl ylide 138, which cyclizes to give episulfide 139. This episulfide isomerizes to mercaptan 140, which is then desulfurized by partially deactivated W-2 Raney nickel. 

An alternative synthesis from the Glaxo patents involves Fnedel-Crafts acylation of the 3-position of the indole intermediate 22 (Scheme 5) Reaction of hydrazine 10 with (phenylthio)acetaldehyde gave hydrazone 20, which was subjected to the Fischer indole reaction to give 3-thiophenylindole 21. It is noteworthy that this Fischer cyclization took place at room temperature because most require heat. Reductive desulfurization of 21 using Raney nickel provided indole 22. Acylation of the 3-position... 

V-(Arylsulfonamidino)thioureas (108) afford the expected 5-amino-3-sulfonamido-l,2,4-thiadiazoles (109). The cyclization occurs almost quantitatively under the influence of bromine, but fails with hydrogen peroxide, which cleaves part of the starting material to sulfonylguanidine (110), and desulfurizes part to sulfonamidinourea (111).116. 

An approach to the synthesis of angularly substituted polycyclics through the Diels-Alder cycloaddition of dihydrothiophenes has been devised (69JA7780). The easily prepared 2,5-dihydro-4-methoxycarbonyl-2-thiopheneacetic acid methyl ester (316) was heated at 180 °C with excess butadiene to yield (317). Desulfurization and double bond reduction of the cycloadduct with W-5 Raney nickel gave (318) which was characterized by conversion to the corresponding diacid and comparison with an authentic sample. Dieckmann cyclization of (318) is known to lead to the 5-methyl-1-hydrindanone (319 Scheme 68). The use of other dienes in the [4 + 2] cycloaddition process will, of course, produce more highly functionalized hydrindanones. 

A number of mesoionic l,2,4-triazolo[4,3-a]pyrimidines (15) were obtained upon desulfurization of l-methyl-l-(4,6-dimethylpyrimidin-2-yl)thiosemicarbazides (13) with dicyclohexylcarbodiimide (DCC) [88JCS(CC)506 93JCS(P1)705] or by cyclization of l-alkyl-l-(4,6-dimethylpyrimidin-2-yl)hydrazines (14) with carbon disulfide or phosgene [88JCS(P1)351] (Scheme 8). 

The dithiane derivative 60 (Scheme 14) is such a compound, it being made from 2,3 5,6-di-0-isopropylidene-D-mannose by treatment with 2-lithio-l,3-dithiane to give a heptose dithioacetal that was refunctionalized at C-2-C-3 by way of the C-l anion and then converted to the 6,7-epoxide following selective acid-catalyzed cleavage of the 6,7-acetal ring. Treated with n-butyllithium it gives, in 70% yield, the cyclized 61, which is efficiently convertible into validatol 62, a component of validamycin A, by desulfurization with Raney nickel and de-O-protection by use of boron tribromide in dichloromethane [31]. 

The chlorosulfonium compounds can also be used for the synthesis of oxindoles, the stable tautomeric form of 2-hydroxyindoles. The a -methylthio ketone is replaced by ethyl methylthioacetate and the products of the Sommelet-Hauser rearrangement are cyclized to 3-methylthiooxindoles. The methylthiooxindoles are reductively desulfurized with Raney nickel (equation 102) (74JA5508). 

Both of the above approaches employed a metal ion as a template about which the corrin cyclization was performed, but the nickel or cobalt ions could not subsequently be removed. In order to obtain metal-free corrins, a new route was therefore devised (67AG865) which employed the novel principle of sulfide contraction (Scheme 22). Thus the sodium salt of the precorrin (284) (Scheme 23) was transformed into the thiolactam (285), and loose complexation with zinc(II) ions caused cyclization to give (286), which was treated with benzoyl peroxide and acid to give the ring-expanded compound (287). Contraction with TFA/DMF gave the corrins (288) and (289), and the major of these (289) was desulfurized with triphenylphosphine and acid to give (288). Finally, demetallation with TFA gave the required metal-free corrin (290), a source for a whole variety of metal derivatives. 

The recent synthesis of ( ) 8-coniceine (190) involved a pyrroline derivative (191) as a key intermediate as it was relatively stable. It was cyclized with methanolic hydrogen chloride, desulfurized with Raney... 

In the total synthesis of indolizomycin700, one of the key steps involved the cyclization of a thiolactam with an intramolecular a-di azoketone moiety, catalyzed by rhodium acetate (equation 195). The molecule is desulfurized by treatment with Raney nickel, giving a good yield of the required target. 

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