Aldehydes thioamides

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

Owing to the instability of a-halogenoaldehydes it is occasionally preferable to use more stable derivatives, such as enol acetate prepared according to Bedoukian s method (204) and a-bromoacetals (4, 8, 10, 16, 22, 67, 101, 426). An advantage is said to be in the yield however, this appears to be slight. The derivatives react in the same sense as the aldehydes themselves, that is, the acetal group as the more polarized reacts first and enters the C-4 position. It is likely that the condensation and cyclization occur by direct displacement of alkoxide ions. Ethyl-a,/3-dihalogeno ethers (159, 164, 177, 248) have also been used in place of the free aldehydes in condensation with thioamides. 

The presence of a halogen may indicate a haloid salt of a base, alky-l, alkylcue, or aryl halide, add halide, haloid derivative of an aldehyde or aad. Some substances, like mustard oils, amino- uilphonic atids and thioamides, contain both nitiogen and sulphur. 

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. 

Another frequently used multicomponent reaction is the Kindler thioamide synthesis (the condensation of an aldehyde, an amine, and sulfur). The Kappe group has described a microwave-assisted protocol utilizing a diverse selection of 13 aldehyde and 12 amine precursors in the construction of a representative 34-member library of substituted thioamides (Scheme 6.114) [226]. The three-component con-... 

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

The three component condensations of aldehydes, amines and elemental sulfur using 1-methyl-2-pyrrolidone as solvent employing microwave flash heating 100-180 °C for 2-20 min give the corresponding primary, secondary and tertiary thioamides (Scheme 6).23... 

Katritzky offers a general one-pot alternative approach to polysubstituted pyrroles utilizing disubstituted olefins of which a wider variety is commercially available compared to acetylenes . Thus, thioamides 32 were subjected to Mannich condensation with aldehydes and BtH to yield functionalized thioamides 33 which were then treated with base... 

Thioamides were converted to aldehydes by cautious desulfurization with Raney nickel [1137, 1138] or by treatment with iron and acetic acid [172]. More intensive desulfurization with Raney nickel [1139], electroreduction [172], and reduction with lithium aluminum hydride [1138], with sodium borohydride [1140] or with sodium cyanoborohydride [1140] gave amines in good to excellent yields. 

Secondary amides have the advantage over tertiary amides that they are relatively easy to remove. It is quite difficult to stop the addition products from aldehydes, ketones, amides, epoxides and nitriles cyclizing directly to give a variety of lactone derivatives (by attack of OH on the secondary amide) or lactam derivatives (by attack of the secondary amide on the new electrophihc centre). Thioamides behave similarly . 

Although introduced over 40 years ago, Hurd and Mori s synthesis of 1,2,3-thiadiazoles remains the most widely used for the synthesis of 1,2,3-thiadiazoles. The simplicity of the method has contributed to its popularity. A variety of ketones and aldehydes have been converted into their corresponding hydrazones (tosyl and acyl), and thioamides have been converted into thio-carbazonate esters. The carbonyl derivatives are then treated with thionyl chloride to yield 1,2,3-thiadiazoles in high yields. When one is faced with the task of synthesizing new 1,2,3-thiadiazoles, Hurd and Mori s method should always receive attention. 

A -Silylmethyl-amidines and -thioamides (42) (X=NR or S) undergo alkylation at X with, for example methyl triflate, and then fluorodesilylation to give the azomethine ylides 43 (identical with 38 for the thioamides) (25,26). Cycloaddition followed by elimination of an amine or thiol, respectively, again leads to formal nitrile ylide adducts. These species again showed the opposite regioselectivity in reaction with aldehydes to that of true nitrile ylides. The thioamides were generally thought to be better for use in synthesis than the amidines and this route leads to better yields and less substituent dependence than the water-induced desilylation discussed above. 

TABLE 5. Stereochemistry of aldol reaction of magnesium enolates derived from thioamides with aldehydes... 

If thioamide enolates are prepared by conjugate addition of Grignard reagents to a,/3-unsaturated thioamides of secondary amines, the reaction of these enolates with aldehydes affords anti aldols. These results are rationalized by the formation of a boat-like, chelate transition state" Representative examples are provided in equation 112 and Table 16. 

Other routes to 1,3-oxazines employ condensation reactions between /3-chloroketones and nitriles or between chloroalkyl amides and alkynes <69LA(723)ill) (Scheme 62). Thiazines are available through similar condensations between thioamides, aldehydes and acetylenes (74G849), and AH- 1,3-benzoxazines may be prepared from 2-hydroxybenzyl alcohols and nitriles in the presence of either perchloric or sulfuric acids (Schemes 63 and 64) (68MIP22700). 

Peptide aldehydes can be synthesized via hydrolysis of thiazolidine precursors with mercury or copper salts (Scheme 10). 56 The Phe-thiazolidine derivative 27 was prepared from reduction of dihydrothiazole ring in 26, which was formed from a (5-hydroxy thioamide cyclization of 25 using the Mitsunobu reaction. N-Terminal Boc and Z groups on thiazolidine pseudopeptides such as Boc-Ala-Phe-thiazolidine and Z-Phe-Tyr-thiazolidine are stable to hydrolysis that affords Boc-Ala-Phe-H and Z-Phe-Tyr-H. 56 ... 

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