Thioamides as useful synthons in the synthesis of heterocycles.

Reactions of carbonyl compounds with (monohalo) methyleniminium salts (vilsmeier reagents)

The invention relates to processes for preparing compounds having the formula (I) and crystalline forms thereof, wherein Ar is aryl or heteroaryl, L is an optional alkylene linker, and R2, R3, R4, and R5, are as defined in the specification herein, which compounds are useful as kinase inhibitors, in particular, inhibitors of protein tyrosine kinase and p38 kinase.

Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors

A Simple Route to N,N‐Dialkyl Derivatives of 2‐Amino‐5‐thiophenecarboxylates

This chapter extends the discussion to reactions between the Vilsmeier-Haack reagent (subsequently referred to as the Vilsmeier reagent for brevity) and any other compounds in which a carbon-carbon bond is formed. The discussion thus excludes reactions in which the Vilsmeier reagent acts as a chlorinating agent (for example in the preparation of acid chlorides), or in which it forms carbon-oxygen or carbon-nitrogen bonds, unless these are accompanied by formation of a carbon-carbon bond. For a discussion of the nature of the reagent and of the mechanism of the reaction, the earlier chapter in vol. 49 should be consulted. There are also a number of reviews that deal at length with mechanisms of reactions involving the Vilsmeier reagent, notably those by Jutz and Marson, and hence this chapter will concentrate on applications, with brief mention of mechanisms when necessary.



Wizinger has pointed out that alkenes could react with the Vilsmeier reagent, but his only examples were styrenes where the intermediate carbocation has considerable stability.



Hydrolysis gives the cinnamaldehyde. In principle, any alkene which is not too sterically hindered can undergo this reaction, but the Vilsmeier reagent has low reactivity as an electrophile, and in practice activation is often necessary. The addition depends on the HOMO of the alkene, and anything increasing the HOMO energy will aid reaction, as for example further conjugation (dienes, trienes, etc.) or the presence of an electron-donating substituent. Hence aldehydes and ketones are active in their enol forms, and enol ethers and enamines are good substrates. Indeed, all additions covered by this chapter can be regarded as alkene additions, even those on active methyl groups attached to electron-deficient rings. As with any reaction involving carbocation intermediates, rearrangements are possible; the initial products are sometimes enamines, and this can give rise to polysubstitution. The substrates are grouped into eleven major subsections; references to reviews of particular relevance will be found in the appropriate subsection.


Keywords:

vilsmeier reaction;
non-aromatics;
alkenes;
dienes;
polyenes;
heteroatoms;
substituents;
enamines;
enamides;
alkynes;
aldehydes;
ketones;
imines;
hydrazones;
semicarbazones;
oximes;
carboxylic acids;
anhydrides;
acid chlorides;
esters;
lactones;
amides;
lactams;
imides;
nitriles;
methyl groups;
methylene groups;
adjacent rings;
comparison of methods;
experimental conditions;
experimental procedures;
tabular survey

The Vilsmeier Reaction of Non‐Aromatic Compounds

3-Aminothioacrylamides are a class of organic sulfur containing compounds that are easily available and exhibit polyfunctional reaction behaviour. They can be used widely in the synthesis of a variety of heterocyclic and open chain compounds. The synthetic utility of 3-aminothioacrylamides can be further extended if additional functionalities are incorporated.

The chemistry of 3-aminothioacrylamides; part ii: 3-aminothioacrylamides as useful synthons in organic synthesis

Formylation products of thioamides. VII: Synthesis of new N-(3-aminothioacryloyl)-formamidines and N,N'-bis[aminomethylidene] thioureas by bis-iminoformylation of thioacetamides and thiourea with formamide acetals

Compounds possessing 3-aminothioacrylamide structures have gained great interest in synthetic organic chemistry. In the present report the methods employed to synthesize 3-aminothioacrylamides are reviewed. The classification is in accordance with the bond which is formed in the final step of the reaction sequence. A short summary of typical physical and spectroscopic properties of 3-aminothioacrylamides is included. The wide application of 3-aminothioacrylamides as building blocks in the synthesis of openchained and especially heterocyclic compounds will be reviewed in a separate publication.

Chemie der 3-Amino-thioacrylsäureamide; Synthesen und Eigenschaften†

N, N′-Bis(aminomethylidene)thioureas 1 react with electron acceptor substituted methyl halides 2 under the formation of 2-formamidinothiazoles 4. The reaction of N-(3-aminothioacryloyl)-formamidines 5 with substituted methyl halides 2 gives either 2-formamidinothiophenes 7 or 2-aminovinylthiazoles 8. The 8 can be hydrolysed to corresponding 2-hydroxyvinylthiazoles 9. 2-Aminovinylthiazoles 11 bearing primary amino groups are obtained by transamination of the N-(3-aminothioacryloyl)-formamidines 5 and subsequent reaction of the resulting 10 with substituted methyl halides 2.

Formylation products of thioamides. XIV. Synthesis of Substituted Thiazoles and Thiophenes by the reaction of N, N′-bis(aminomethylidene)thioureas or N-(3-aminothioacryloyl)-formamidines with alkylating reagents

N-(3-Aminothioacryloyl)-formamidines 3 react with primary amines to give either 4(1H)-pyrimidinthiones 6 or transaminated N-(3-aminothioacryloyl)-formamidines 5. Alkylation of the latter compounds gives rise to cyclised 6(1H)-pyrimidinimines 7. The 4(1H)-pyrimidinthiones 6 can be S-alkylated to 4-alkylmercaptopyrimidinium salts 8. Subsequent substitution of the alkylmercapto group of the 8 results in the formation of 4-aminopyrimidinium salts 9, which can also be obtained starting from the 3 by a reversed reaction sequence that is first by S-alkylation to 3-alkylmercapto-2-azapentamethinium salts 10 and subsequent reaction with primary amines.

Alexander Knoll

Papers

The chemistry of 3-aminothioacrylamides; part ii: 3-aminothioacrylamides as useful synthons in organic synthesis

Formylation products of thioamides. VII: Synthesis of new N-(3-aminothioacryloyl)-formamidines and N,N'-bis[aminomethylidene] thioureas by bis-iminoformylation of thioacetamides and thiourea with formamide acetals

Chemie der 3-Amino-thioacrylsäureamide; Synthesen und Eigenschaften†

Formylation products of thioamides. XIV. Synthesis of Substituted Thiazoles and Thiophenes by the reaction of N, N′-bis(aminomethylidene)thioureas or N-(3-aminothioacryloyl)-formamidines with alkylating reagents

Formylation products of thioamides. XIII. Reaction of N‐(3‐aminothioacryloyl)‐formamidines with amines – Synthesis of Pyrimidine Derivatives