Cyclizations ylides

When thiocarbonyl and ot-diazocarbonyl compounds are combined, acyl-substituted thiocarbonyl ylides 158 are generated from a nonisolable 3-acyl-1,2,4-thiadiazoline 157 (Scheme 8.36). In addition to giving acylthiiranes 159 and 1,3-dithiolanes 160, dipoles 158 can also 1,5-cyclize to produce 1,3-oxathioles 161. Acyl-thiocarbonyl ylides derived from diazoketones [e.g., HC(0)C(N2)R, R = Ph, f-Bu (219,220) 2-diazocyclohexanone (221)] produce 1,3-oxathioles [e.g., 162 (220), Scheme 8.36], while those derived from diazoesters (218,222,223) lead to thiiranes by 1,3-cyclization. Ylides derived from a-diazocarboxamides form 1,3-oxathioles (e.g., 163) and thiiranes (e.g., 159, R = f-Bu, R = NMePh, R = R" = Ph), depending on the nature of the substituents (220). A related 1,5-cyclization of an aminomethyl-thiocarbonyl ylide formed from dimethyl 3-anilino-2-diazobutanedioate was also reported (224). 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

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]. 

Dimethylsulfonium phenacylide (574) underwent C-alkylation with a-chloronitroso compounds such as (575). The intermediate (576) immediately cyclized to the isoxazoline (577). With a more basic ylide such as dimethylsulfonium methoxycarbonylmethylide the initial alkylation product underwent elimination of the sulfonium group to an alkene rather than its displacement (72T3845). 

Carbanions in the form of ylides also add to azirines. For example, treatment of 1-azirine (227) with dimethylsulfonium methylide gives 1-azabicyclobutane (229) in good yield (72JA2758). The addition of the methylene group occurs by initial nucleophilic attack by the ylide to give intermediate (228) which cyclizes with expulsion of dimethyl sulfide. 

Cyclization of the diazo compound (108) with a copper catalyst affords the clavulanic acid derivatives (110) and (111), possibly via rearrangement of the sulfur ylide (109) (80H(14)1999). Similar reactions have been reported in the recent literature (80H(14)1967, 81H(16)1305, 80TL31). 

Recently, Burger devised an improved method of carrying out mild, regiospecific cyclizations that involve an intermediate that acts as a synthon for a nitrile ylide of HCN [47 (equation 48). With this methodology, cycloadditions with activated alkenes, alkynes, and azo compounds were earned out [47] (equation 49). All such reported reactions were regiospecific and had the same orientational preference... 

The cyclizations of conjugated nitrile ylides forming substituted oxazoles and thiazoles were computed up to the MP4/6-31H-G level [OOJOC47]. Relative to 23, oxazole-4-carboxylic acid24 is stabilized by about -38.1 kcal/mol (Scheme 18). 

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 ... 

The initial step of olefin formation is a nucleophilic addition of the negatively polarized ylide carbon center (see the resonance structure 1 above) to the carbonyl carbon center of an aldehyde or ketone. A betain 8 is thus formed, which can cyclize to give the oxaphosphetane 9 as an intermediate. The latter decomposes to yield a trisubstituted phosphine oxide 4—e.g. triphenylphosphine oxide (with R = Ph) and an alkene 3. The driving force for that reaction is the formation of the strong double bond between phosphorus and oxygen ... 

Unlike alk-2-enylbenzonitrile ylides. which on thermolysis yield isolablecyclopropa[c]isoquino-lines, the thiophene analogs 2 and 5, generated from the respective imidoyl chloride, 1 and 4, cyclize directly to thienoazepine 3 and 6, respectively.40... 

Although the exact mechanism of the Tschitschibabin cyclisation has not been elucidated, it is reasonable, as shown in Scheme 4, to assume a series of reversible steps from the vinylogous ylide (or methylide) to a methine and an enol-betaine intermediate and then finally an irreversible dehydration to the indolizine nucleus. The reaction might be related to the modern electrocyclic 1,5 dipolar cyclization. 

The thermolysis of various substituted phosphonium ylides between 600 °C and 900 °C can afford either substituted alkynes [16,25,27] or cyclic dienes [20] by extrusion of PhjPO, or new stabilized ylides by cyclization of the functional groups [27,28]. 

Particularly interesting are the results obtained with the phosphonium ylides including an acyl rest derived from aminoacid if the N-H bond reactivity is blocked by an amide protection, the alkyne formation takes place [25,27], but if the N-H bond is not deactivated, an intramolecular cyclization occurs to give a new stabilized ylide [27,28]. 

Key features of the cyclopropanation include the ylide acting as a mild base to isomerize the 1,2-dioxines into cis-y-hydroxy enones, followed by Michael addition of the ylide and last by cyclization of the intermediate enolate [35]. It must be noted that the trans-y-hydroxyenones do not give the cyclopropanation. 

Olefination Reactions Involving Phosphonium Ylides. The synthetic potential of phosphonium ylides was developed initially by G. Wittig and his associates at the University of Heidelberg. The reaction of a phosphonium ylide with an aldehyde or ketone introduces a carbon-carbon double bond in place of the carbonyl bond. The mechanism originally proposed involves an addition of the nucleophilic ylide carbon to the carbonyl group to form a dipolar intermediate (a betaine), followed by elimination of a phosphine oxide. The elimination is presumed to occur after formation of a four-membered oxaphosphetane intermediate. An alternative mechanism proposes direct formation of the oxaphosphetane by a cycloaddition reaction.236 There have been several computational studies that find the oxaphosphetane structure to be an intermediate.237 Oxaphosphetane intermediates have been observed by NMR studies at low temperature.238 Betaine intermediates have been observed only under special conditions that retard the cyclization and elimination steps.239... 

A mechanistic interpretation for the formation of 35 is depicted in Scheme 5. Deprotonation of an allylic proton yields ylide intermediate 36. This then adds to methyl acrylate to give intermediate 37, which cyclizes to construct a cyclopropane ring together with the fission of the S-C bond to afford the final adduct 35. 

An intramolecular azomethine ylide-mediated cyclization has been used to access the core 5 6 5 angular tricyclic structure of martinellic acid by Snider (Equation 113) <20010L4217>. Reaction of IV-benzylglycine 420 with the aldehyde 419 led to intramolecular cyclization, giving 421 in good yield. 

The reaction of 196 with phenyl chlorocarbene 198 illustrates the synthesis of indolizines by cyclization of pyridinium ylides (Scheme 7). Cyclization of ylide rotamer 199 generates the intermediate product 200, which undergoes elimination of chloride to provide compound 201 <2005EJ01532>. 

Diazo compounds 107 were heated to reflux in the presence of a rhodium catalyst giving rise to the carbene followed by intramolecular cyclization to give the diastereomeric pairs of ylides 5 and 108 (Equation 22) <2006T1459>. 

Some functionalized thiophenes have been investigated in order to assess the scope of ylide-derived chemistry. As already mentioned, 2-(hydroxymethyl)thiophene still gives the S-ylide upon Rh2(OAe)4-catalyzed reaction with dimethyl diazomalonate 146 but O/H insertion instead of ylide formation seems to have been observed by other workers (Footnote 4 in Ref. 2S4)). From the room temperature reaction of 2-(aminomethyl)thiophene and dimethyl diazomalonate, however, salt 271 was isolated quite unexpectedly 254). Rh2(OAc)4, perhaps deactivated by the substrate, is useless in terms of the anticipated earbenoid reactions. Formation of a diazo-malonic ester amide and amine-catalyzed cyclization to a 5-hydroxytriazole seem to take place instead. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

Electrocyclization of 1,4-dienes is an efficient process when a heteroatom with a lone pair of electrons is placed in the 3-position, as in 77 (Scheme 20)38. Photoexcitation of these systems generally results in efficient formation of a C—C bond via 6e conrotatory cyclization to afford the ylide 78. These reactive intermediates can undergo a variety of processes, including H-transfer (via a suprafacial 1,4-H transfer) to 79 or oxidation to 80. In a spectacular example of reaction, and the potential it holds for complex molecule synthesis, Dittami and coworkers found that the zwitterion formed by photolysis of divinyl ether 81 could be efficiently trapped in an intramolecular [3 + 2] cycloaddition by the... 

The Cu(I)-catalyzed cyclization for the formation of ethyl ( )-tetrahydro-4-methylene-2-phenyl-3-(phenylsulfonyl)furan-3-carboxylate 82 has been accomplished starting from propargyl alcohol and ethyl 2-phenylsulfonyl cinnamate. Upon treatment with Pd(0) and phenylvinyl zinc chloride as shown in the following scheme, the methylenetetrahydrofuran 82 can be converted to a 2,3,4-trisubstituted 2,5-dihydrofuran. In this manner, a number of substituents (aryl, vinyl and alkyl) can be introduced to C4 <00EJO1711>. Moderate yields of 2-(a-substituted N-tosyIaminomethyl)-2,5-dihydrofurans can be realized when N-tosylimines are treated with a 4-hydroxy-cis-butenyl arsonium salt or a sulfonium salt in the presence of KOH in acetonitrile. The mechanism is believed to involve a new ylide cyclization process <00T2967>. 

Acid- and base-promoted methods have also been used in the syntheses of pyrazoles. Hydrogenation of methyl 2-Cbz(hydrazine)-3-hydroxy-4,4-dimethoxybutanoate 11 followed by cyclization in the presence of trifluoroacetic acid afforded the first asymmetric synthesis of the (4S,5.R)-5-carbomethoxy-4-hydroxy-A2-pyrazoline 12 <00TL8795>. Reaction of 2-nitrobenzyl triphenylphosphonium ylide (13) with aiyl isocyanates afforded 2-aryl-2H-indazoles 14 <00TL9893>. Base-promoted reaction of nitrobenzenes 15 with aryl imines 16 afforded aryl pyrazoles 17 . 

W(CO)6 in toluene at room temperature gave the tricyclic adduct 190a in 94% yield after acidic workup. This reaction forms the tungsten-containing azomethine ylide 191, which undergoes the [3 + 2]-cycloaddition with 189a. The rhodium(n)-catalyzed cyclization of the ene-yne-aldimine 192 with alkene 193 into the cyclopropane 194 was reported by Uemura and Ohe (Scheme 32).42c... 

Another interesting example of a photochemi-cally induced domino process is the combination of the photocyclization of aryl vinyl sulfides with an intramolecular addition as described by Dittami et al. [901 as intermediate a thiocarbonyl ylide can be assumed. The domino-Norrish I-Knoevenagel-allyl-silane cyclization developed by us allows the efficient stereoselective formation of 1,2-trans-subsituted five- and six-membered carbocycles.1911 A photochemical cycloaddition of enamino-aldehydes and enamino-ketones with the intermediate formation of an iminium salt followed by addition to allylsilanes gives access to novel bicyclic heterocy-des. New examples of photochemically induced... 

M. A. Marx, A.-L. Grillot, C. T. Louer, K. A. Beaver, P. A. Bartlett, Synthetic Design for Combinatorial Chemistry. Solution and Polymer-Supported Synthesis of Polycyclic Lactams by Intramolecular Cyclization of Azo-methine Ylides , J. Am. Chem Soc. 1997,119, 6153-6167. 

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