Amide thioacetals

Alkylmercaptomethyleneiminium salts as well as alkoxymethyleneiminium salts are transformed to amide thioacetals (443 equation 206) by alkali metal thiolates and thiols. - The action of alcoholic alkoxides on 2-alkoxy-2-dialkylaminocarbonitriles (444 equation 207) produces amide acetalsJ Spi-locyclic amide acetals (446 Scheme 82) were prepared from oxazolium salts (445) and substituted sal-icyl aldehydes. The addition of alcohols to the l,3-oxazolium-4-olate (447) affords heterocyclic amide acetals (448). ... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

The Wittig reaction efficiently olefinates aldehydes and ketones, but not esters or amides. Several early-transition-metal approaches have been taken to this problem. Recently, Takeshi Takeda of the Tokyo University of Agriculture and Technology reported (Tetrahedron Lett. 44 5571,2003) that the titanocene reagent can effect the condensation of an amide 10 with a thioacetal 11 to give the enamine 12. On hydrolysis, 12 is converted into the ketone 13. When the reaction is intramolecular, reduction proceeds all the way, to give the pyrrolidine IS. 

Cyclization of benzophenones having an o -thioacetic acid, ester or amide group has been used in structure studies and to synthesize 3-phenylbenzo[6 ]thiophenes with specific substituents. Thus (57) was readily converted to (58 X = OH, OEt or NH2) as precursors to a variety of benzo[6 ]thiophenes (57AC(R)705>, and as precursor to the unequivocal synthesis of 3-phenylbenzo[6 jthiophene, to demonstrate a remarkable sulfur-catalyzed rearrangement (59AJC218). 

Schlessinger has shown that the addition of ester enolates to sulfur stabilized acceptors, e.g. ketene di-thioacetal monoxide (151) and methyl a-(methylthio)acrylate (187), is highly efficient for the synthesis of Y-ketoesters.148 Similarly, Ahlbrecht and Seebach have reported that amide and ester enolate additions to nitrogen stabilized acceptors, e.g. nitroalkenes (40) and 2-(/V-methylanilino)acrylonitrile (59 Scheme 72), are highly efficient.149... 

Trialkyloxonium ions have been extensively used to carry out O-alkylation of lactams, amides, sulfoxides, oxo-sulfonium ylides, iV-alkylation of iV-heterocycles, 5-alkylation of thioethers, thioacetals, thioamides, and thiolactams.1,90 Although trialkyloxonium ions do not alkylate benzene or toluene directly, alkylations readily occur in combination with highly ionizing superacids such as HS03F-SbF5. This may indicate protosolvation of a nonbonded electron pair on oxygen in the superacid medium. 

In contrast to other methods, functional groups such as esters, amides, nitriles, alkenes, alkynes, etc. were unaffected, under these conditions. In pure methanol, ethanol or ethylene glycol, thioacetals were converted to acetals. The use of [bis(trichloroacetoxy)iodo]benzene gave equally good results [44]. Generally, since trichloroacetic acid is 3 times cheaper than trifluoroacetic acid on a mole basis, [bis(trichloroacetoxy)iodo]benzene may be an alternative to BTI. 

Pivaloyloxymethyl (Pom) esters are useful as prodrugs of penicillin and other 0-lactam antibiotics owing to their easy hydrolysis in vivo by ubiquitous non-specific esterases. Mascaretti and co-workers showed that Pom esters can also by cleaved under mild conditions with 2 equivalents of bis(tri-/i-butyltin)oxide as shown in Scheme 6.32. The intermediate tributylstannyl esters are readily hydrolysed on treatment with water to release the carboxylic acid. Functional groups such as aldehydes, thioacetals, amides, vinyl bromides, and nitro compounds are compatible.22... 

The liberation of the (3-sulfanyl group of cysteine is achieved by means of PGA-mediated hydrolysis of phenylacetamides.P " °l For this purpose, the thiol group is masked with the phenylacetamidomethyl (Phacm) blocking function. After penicillin acylase catalyzed hydrolysis of the amide incorporated in the acylated thioacetal, the labile 5-aminomethyl compound is formed and immediately liberates the desired thiol. This method has been used in a synthesis of glutathione which is isolated as its disulfide 6 (Scheme 12). 

Boron enolates generated from a-heterosubstituted thioacetates by treatment with 105 undergo highly enantioselective and diastereoselective condensations. On the other hand, chiral esters 106 and 107, and amides 108 behave differently. V-Acyl derivatives of the bicyclic isoxazolidine 109 ° readily undergo syn-selective aldol reactions via enol borates. 

Protection and deprotection oj 0-acetylation of alcohols and accu Trityl ethers are cleaved by ITV not affected. Discrimination of ary l (alkyl TBS ethers are selectively hy such amides by brief treatment witf Thioacetals are converted to car lodinations. In the preparat added. lodination of aromatic 1 -(tosyloxy)-1,2-benziodoxol-3( 1H iodination of 3,4-bis(trimethylsilyl i a combination of iodine and sih unsymmetrical 3,4-diarylthiophene a-Methoxy-a,P-unsaturated et (1 -methoxyalkylidene)-mngsten(O) the unsaturated esters. When iodim low. 

The addition reaction of fert-butyl thioacetate-derived silyl ketene acetal produces the corresponding aldol adducts in 84% yield and up to 96% enantiomeric excess (Eq. 16). The enantioselectivity of the products was observed to be optimal with toluene as solvent the use of the more polar dichloromethane consistently produced adducts with 10-15% lower enantiomeric excess. The bulkier ferf-butylthioacetate-derived enol silane was found to lead to uniformly higher levels of enantioselectivity than the smaller S-ethyl thioketene acetal. This process is impressive in that it tolerates a wide range of aldehyde substrates for instance, the aldol addition reaction has been successfully conducted with aldehydes substituted with polar functionaUty such as N-Boc amides, chlorides, esters, and 0-benzyl ethers. A key feature of this system when compared to previously reported processes was the abiUty to achieve high levels of stereoselectivity at 0 °C, in contrast to other processes that commonly prescribe operating temperatures of -78 °C. 

A wide variety of functional groups such as hydroxy and amino groups, esters, amides, carbamates, acetals, thioacetals, and isolated double bonds are tolerated. Sulfonamides, which are labile towards other reductive reagents such as Na/Hg,144 are unreactive.145 On the other hand, Al/Hg reduces aromatic nitro compounds to the corresponding anilines, a feature that has been used in the... 

While further studies and the discussion are planned to be published elsewhere, it can be concluded that trifluorothioacetamides, their amidium salts, their amide chlorides, their thioacetals and 1,3-dipoles are useful reagents with CF3-substitution. The trifluoromethyl iminium salts, the trifluoroethyl-t-butyl sulfoxide, and the already mentioned trifluoro-dithioacetates are treated in the following sections. 

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