Asinger reaction

Ugi and Domling have shown that the U-4CR can also be combined with other MCRs, thus creating sequences which involve up to nine different substrates [33]. An example of such an approach is the combination of an Ugi-4CR with the as-yet not mentioned Asinger reaction (A-3CR or A-4CR). The latter allows the formation of thiazolines from ammonia, carbonyl compounds and sulfides [34]. As shown in Scheme 9.7, a mixture of a-bromoisobutyraldehyde, isobutyraldehyde, sodium hy-drogensulfide and ammonia yields the imine 9-38 which, by reaction with t-butyl-isocyanide, methanol, and C02, led to the final product 9-39 [35]. 

The condensation reaction between a 1,3-oxazine 134 and 3-hydroxy-2,2-dimethylpropionaldehyde generates an intermediate product 135 which undergoes intramolecular cyclization via the Asinger reaction to give compound 136 (Scheme 16) <1995ZSK976>. 

The enantiomerically pure 3-thiazoline 50, obtained via Asinger reaction using a galactose-derived chiral auxiliary, was successfully submitted to an Ugi condensation affording the trans adduct 51 with good stereoselectivity, as reported in Scheme 1.19 [56],... 

A synthesis of an enantiomerically and diastereomerically pure 3-thiazoline 214 from 215 has been reported via a modified Asinger reaction. The use of a galactose-derived chiral auxiliary 216 was involved (Scheme 85) <2000TL7289>. 

Schlemminger, I, Janknecht, H H, Maison, W, Saak, W, Martens, J, Synthesis of the first enantiomerically pure 3-thiazolines via Asinger reaction. Tetrahedron Lett., 41, 7289-7292, 2000. 

Being an MCR, the Asinger reaction shares similarities with other MCRs (e.g., Ugi, Gewald) in that more than one bond is formed in the final product. These reactions are shown here. ... 

Other references related to the Asinger reaction are cited in the literature. ... 

The four-component Asinger reaction between a-chloroisobutyraldehyde, ammonia, acetone, NaSH (X.=S) or water (X=0), was used to create 3-thiazoline and 3-oxazoline, which were used as building blocks for the realization of poly-oxa(thia)zolidine polymers 191 and 192 (14MCP412). 

Asinger and Thiel (473) use an aldehyde and ammonia instead of nitrile. Thus the reaction of mercaptoacetone. with benzaldehyde and ammonia gives 4 methyl-2-phenylthiazole in 80% yield and 4-methyl-2-pheny]-A-4-thiazoline as the main by-product. 

The reaction between ketones, sulfur, and ammonia can also lead to heterocyclic compounds. For a review, see Asinger, F. Offermanns, H. Angew. Chem. Int. Ed. Engl., 1967, 6, 907. 

Early attempts by Asinger to enlarge the scope of hydroalumination by the use of transition metal catalysts included the conversion of mixtures of isomeric linear alkenes into linear alcohols by hydroalumination with BU3AI or BU2AIH at temperatures as high as 110°C and subsequent oxidation of the formed organoaluminum compounds [12]. Simple transition metal salts were used as catalysts, including tita-nium(IV) and zirconium(IV) chlorides and oxochlorides. The role of the transition metal in these reactions is likely limited to the isomerization of internal alkenes to terminal ones since no catalyst is required for the hydroalumination of a terminal alkene under these reaction conditions. 

The [l,3]oxazino[4,3- ][l,3]oxazine 387 was obtained as the main product of a combined Asinger and Ugi multi-component reaction from MeOH, NH3, 2,2-dimethyl-3-hydroxypropanal, allyl isocyanate, and C02 in 40% yield. As shown by NMR spectroscopy and X-ray crystallography, 387 is formed as a single diastereomer <1998ACS107>. 

Sulfur-containing Heterocycles from the Reaction of Carbonyl Compounds with Sulfur, Ammonia or Amines F. Asinger, W. Leuchtenberger and H. Offermanns, Chem.-Ztg., 1974, 98, 610-615. 

Finally, in the most complex multicomponent reaction involving isocyanides, the 7-CC proposed by Ugi in 1993 [93], a moderate diastereoselectivity, leading to a 2 1 mixture of epimeric thiazolidines 109 was observed. The reaction is a combination between an Asinger condensation, involving an a-mercaptoaldehyde (generated from the a-bromoaldehyde and SH ) and an Ugi-type 4-CC with a monoalkyl car-boxylate as acid component (Scheme 1.38). Although the relative configuration of the major stereoisomer was not demonstrated, it is probably trans, in line with the results of Ugi condensation with chiral thiazolines, reported above in Scheme 1.19. 

The earliest reports of constrained Ugi adducts derived from bi-functional precursors appeared in the 1960s with the preparation of penicillin derivatives such as 68, involving sequential Asinger and Ugi four-component reactions (Scheme 11.13). As such, the synthesis represents the shortest preparation of a known penicillin derivative [65], The /Mactam ring is formed after isocyanide addition to the cyclic Schiff base, followed by carboxylate nitrilium ion trapping and acyl transfer to give the final penicillin core. In this example, the amine and carboxylic acid inputs may be considered tethered. 

For purposes of organization, a distinction is made between oxidation-reduction processes and nonoxidative-reduction processes. The former is illustrated by summarizing briefly the work of Asinger and his associates who over the course of twenty-five years investigated the low-temperature oxidative-reductive reactions of ketones and elemental sulfur in the presence of ammonia or amines. This work deviates from hydrous conditions in nearly all cases. Nevertheless it is apropos both in relation to the temperatures employed and the variety of heterocycles produced. It points the way to reinvestigation under hydrous conditions. 

Asinger s studies demonstrated that product formation is sensitive to the ratio of sulfur to ketone (1), the structure of the ketone, the replacement of ammonia by amines, the temperature and the medium. Room temperature (20-25 °C) reactions in which the ratio of sulfur to ketones is 0.5 favors the formation of 3-thiazoline, 2, as shown in Figure 1. The formation of 5-alkylidene-3-thiazolines, 3, sometimes competes with the formation of 3-thiazolines such is the case when aryl ketones such as l-phenylpropan-2-one and l-phenylbutan-2-one are employed (4). Also the additional presence of hydrogen sulfide promotes the generation of 1,2,4-trithiolanes and 1,2,4,5-tetrathiolanes from ketones ana aldehydes at the expense of 3-thiazoline formation (11-12). Increasing the S/ketone ratio to 8 favors the formation of the 3-imidazoline-5-thione (5), a product which has a greater tendency to result from aryl methyl ketones (3). 

A-3CR (A-4CR) Asinger three (four)-component reaction Ac acetyl... 

The combination of MCRs in one pot is not new. It was first introduced by Domling and Ugi who developed a 7-component reaction (7CR), that was basically a one-pot combination of a modified Asinger 4CR and U CR (Scheme 15) [100, 101]. In this 7CR, an a- or (3-bromo/chloro aldehyde 158, NaSH/NaOH, NH3, another aldehyde 161, an isocyanide 166, CO2, and a primary alcohol (solvent) are combined to afford 167 efficiently. However, NaSH/NaOH, NH3 and CO2 are invariable components in this reaction which limits the substitutional diversity (appendage diversity) and thereby the scope of the MCR. 

The Mannich reaction l and the related a-aminoalkylations of nucleophilic anions of weak acids are also examples of MCRs of type I,t whereas ring closures to heterocycles, e.g. the Hantzschf l and Radziszewkit l reactions, correspond to MCRs of type II. The Asinger reactiont sometimes belongs to type I and in some other cases to type II MCRs. 

Carbohydrate-linked aldehydes or isocyanides have also been employed to perform Ugi [124-126], Strecker [127] and Asinger [128] reactions, but the diastereoselectivities observed had been unsatisfying. 

---