Ynolates reactions

An efficient preparation of hexahydro-isoxazolo[2,3- ]pyridin-2-ones relies on the anionic addition of nucleophiles at the electrophilic carbon of the nitrone followed by cyclization of the resulting Ar-oxide. As shown by results collected in Scheme 31, various nucleophiles can be engaged in the reaction and include enolates 95 <20020L3119> or 98 <2000BML1811>, silyl acetals 101 <2003TL2817>, or ynolates 103 <20020L3119> (Scheme 31). 

Lithium phenylethynolate (520) has been prepared in a rather intriguing fashion through the elimination of benzonitrile from 5-lithio-3,4-diphenylisoxazole (519) (75AG(E)765). Reaction of the ynolate with an aldehyde or ketone was shown to afford a metallated /3-lactone (521). Treatment of this intermediate in turn with an electrophilic reagent such as benzyl bromide produced a tri- or tetra-substituted /3-lactone (522 Scheme 114). 

Tetrasubstituted alkenes (214) were obtained with high Z selectivity (>99 1) by reaction of ynolates (211) with a-oxy- and a-amino-ketones (212 X = OR, NR2) (g) at room temperature. According to experimental and theoretical studies, the high Z selectivity is induced by orbital interactions in the ring opening of the /3-lactone enolate intermediate (213), rather than by the initially presumed chelation of the lithium atom.260... 

In a new benzannulation procedure, the 4 + 2-cycloaddition of lithium ynolates (131) with (trialkylsilyl)vinylketenes (132) yields, via an intermediate 3-(oxido)dienyl-ketene (133), the highly substituted phenols (134), which can be converted to ben-zofurans and benzopyrans (Scheme 37).135 The reaction of buta-2,3-dienoate with vinylketenimine yields the expected Diels-Alder adduct together with an unexpected aniline formed by a competing 2 + 2-cycloaddition.136 The first example of a... 

Ynolate anions react with acylsilanes at low temperature to give P-lactones 48 in good yields. When the reaction is conducted at room temperature the isolated product is a (1-silyl-a,p-unsaturated ester via a P-lactone enolate intermediate <02JACS6840>. 

When the 3-position of the isoxazole is blocked, but the 5-position free, ring opening is again either concurrent with deprotonation or takes place under very mild conditions. In these substrates fission of both the N—O bond and the C3—C4 bond occurs, giving a nitrile and an ynolate ion (49). The latter is usually hydrolyzed on work-up to a carboxylic acid, R CH2C02H,1 but can be trapped at low temperatures. As exemplified by Scheme 7, such reactions could provide useful syntheses of ketenes and /Mactones.159... 

One of the best methods to synthesize cyclopentenone derivatives is the Pauson-Khand procedure. However, Shindo s group have recently developed a domino process consisting of a [2+2] cycloaddition of a ketone with an ynolate, followed by a Dieckmann condensation to give a (3-lactone as 4-190 which is decarboxylated under reflux in toluene in the presence of silica gel to afford cyclopentenones [64a]. Thus, the reaction of 4-188 and 4-189 led to 4-190, which on heating furnished the linear cucumin 4-191 (Scheme 4.41). This natural product has been isolated from the mycelial cultures of the agaric Macrocystidia cucumis [65, 66]. The domino procedure described was also used to synthesize dihydrojasmone and a-cuparenone. Moreover, the [2+2] cycloaddition can be combined with a Michael reaction [64b]. 

A review on ynolates, including the synthesis of p-lactones, has appeared <03S2275>. Morita-Baylis-Hillman-type adducts have been converted into a-alkylidene-p-lactones 65, which on reaction with dimethyltitanocene can be transformed into 3-alkylidene-2-methyleneoxetanes <03OL399>. Lactones 66 have been obtained via the cinchona alkaloid-catalyzed dimerization of monosubstituted ketenes <03OL4745>. The PdCh-promoted synthesis of P-lactones 67 have been achieved via cyclocarbonylation of 2-alkynols <03OL4429>. 

Another relevant phenomenon is the reaction of carbon monoxide with the lithium trimethylsilyldiazomethanide (MesSiCNaLi) to form either an ynolate (MesSiC COLi) or a ketenide (Me3SiC(Li)=C=0) derivative. The corresponding neutral species Mes SiCHN2 reacts with CO, in the presence of Co2(CO)s, to form Me3SiCH=C=0 . Neither reaction was studied calorimetrically. Accordingly, they cannot be compared with the energetics of the reaction of HCNi with CO to form HCCO and N2, a quantity indirectly obtainable from the deprotonation enthalpies of diazomethane and ketene. ... 

B. Lithium Ynolate-initiated Cascade Reactions Leading to Multisubstimted... 

Metal ynolates are not as easy to prepare in a similar fashion as metal enolates, because the intermediates may be labile monosubstituted ketenes. Several preparative methods for alkali metal ynolates have been reported, among which some have been used as intermediate steps in one-pot organic syntheses. Silyl ynolates have been prepared from lithium ynolates. There have been few reports on the other metal ynolates. Since there is no universal method to determine the yield of metal ynolates, the efficiency of preparation is estimated from the results of some of the following reactions. 

Flash photolysis of phenylhydroxypropenone (51) in aqueous solution gives pheny-lacetic acid 53 through the ynolate 52 as a short-lived reaction intermediate (equation 21) ". Kinetic experiments revealed that the corresponding aryl ynols ArC=COH are strong acids with pKa < 2.8 5,... 

Since metal ynolates are ambient nucleophiles, with oxygen being a hard nucleophilic center and carbon a soft one, the position of attack at O or C would therefore depend on the hard/soft character of the electrophile (equation 24). When metal ynolates react as C-nucleophiles, they are regarded as metallated ketenes 59. Ynolates are also considered as electron-rich alkynes. In this section, the unique reactions of metal ynolates induced by these characteristic features are summarized. 

In the same way, electrophilic reactions can be applied to the tandem reaction. The ynolate-initiated tandem [2 + 2] cycloaddition-Michael reaction followed by decarboxylation furnished the polysubstituted five-, six- and seven-membered cycloalkenes in good overall yield (equation 33) . The ester enolate intermediates 77 are nucleophilic, and further bond formation is possible. 

Asymmetric cycloadditions of the chiral non-racemic nitrones 101 and 103 afford the isoxazolidinones 102 and 104 respectively, with high diastereoselectivity. This process can lead to an efficient asymmetric synthesis of /3-amino acids (equations 42 and 43) . This is the first example of asymmetric reactions with ynolates. It is noteworthy that the ynolates show higher reactivity and stereoselectivity than the corresponding lithium ester enolates and demonstrate the high potential of lithium ynolates in asymmetric reactions. 

There has been only a few reports on reactions of small rings with metal ynolates. Oxiranes are much less electrophilic than carbonyls and sometimes need activation by Lewis acids or Lewis-acidic organometals. The lithium-trimethylaluminum ate complex of i/ZyZ-substituted ynolate 105 reacts with the oxirane 106 to give the y-lactone 107 (equation 44), while lithium silyl-substituted ynolates are inert to oxiranes. There have been no reports using carbon-substituted metal ynolates. 

The y-lactam 110 is prepared by the reaction of the lithium silyl-substituted ynolate 105 with the aziridine 108 activated by a p-toluenesulfonyl group. The initial product is the enolate 109, which can be acidified to yield the a-silyl-y-lactam 110. Intermediate 109 can be trapped by aldehydes to afford the a-alkylidene-y-lactams 111 via a Peterson reaction (equation 45) . These reactions may be considered to be formal [3 + 2] cycloadditions as well as tandem reactions involving nucleophilic ring opening and cyclization. 

Although the Michael addition of metal ynolates to a,/ -unsaturated carbonyl compounds is expected to give six-membered cycloadducts, 1,2-addition to carbonyl groups usually precedes 1,4-addition. The cycloaddition of the lithium-aluminum ate complex of silyl-substimted ynolate 112 with ethyl benzylideneacetoacetate (113), which is doubly activated by the ester and keto functions, gives the y-lactone 114 via a [4 4- 2] type cycloaddition (equation 46). Diethyl benzylidenemalonate (115) affords the uncyclized ketene 116 by reaction with 112 (equation 47). This could be taken as evidence for a stepwise mechanism for equation 46. ... 

Styryl isocyanate (117) reacts with ynolates to provide the 4-hydroxypyridone 119 in moderate yield via a formal [4 + 2] cycloaddition (eqnation 48). This reaction also indicated the participation of the ketene intermediate IIS. ... 

The reaction of thiol esters with lithium ynolates (equation 67) takes place by a route different than the one shown in equation 65 for alcohol esters. Thiol esters (162) undergo a two-carbon homologation to S-keto thiol esters 165 in good yield. Intermediates 163 undergo a two-step rearrangement to a S-keto thiol ester enolate (165), via elimination of lithium thiolate to yield a ketene (164), followed by the nucleophilic attack of the thiolate on 164. Finally, the homologated S-keto thioester (165 ) is obtained on acidification of the reaction mixture . ... 

Since sUyl ynol ethers have an electron-rich triple bond, they are useful for Lewis acid catalyzed synthetic reactions. Lithium ynolates 175 are silylated by TIPSCl or TIPSOTf and TBSCl to afford the corresponding silyl ynol ethers 176 and 177, which are thermally stable and isolable, but sensitive toward acids (equation 71) . See also equations 9 and 10 in Section ll.C. An experimentally improved procedure for the purification of 176 derived from Kowalski s method is described. Lithium ynolate derived from Julia s method is also used for the preparation of 176. TMSCl and TESCl provide silyl ketenes 179, however, by C-silylation. These small silyl chlorides primarily gave the silyl ynol ethers 178, but, upon warming the reaction mixture, isomerization to the more stable silyl ketenes takes place. The soft electrophilic silyl chlorides like PhsSiCl afford silyl ketenes. Disi-lyl ynol ethers, prepared from ynolate dianions, are rearranged to disilylketenes mediated by salts . 

Nucleophilic reactions of lithium thioalkynolates with electrophiles mostly occur at the 3 -position to afford alkynyl sulfides. For example, 3 -silylation and 3 -stannation are shown in equation 80 the synthesis and -alkylation of a quaternary ammonium thioalkynolate are shown in equation 81. Exceptionally, lithium thioalkynolates add to ketones to form -thiolactones, which are converted into alkenes on elimination of carbon oxysulfide (equation 82). Contrary to lithium ynolates, thioalkynolates do not react with aldehydes. ... 

---