Aldehydes, reaction with TosMic

The development of the key intermediate, 5-(2-methoxy-4-nitrophenyl)oxazole (25), in the preparation of the hepatitis C drug candidate, VX-497, utilizes a van Leusen reaction of aldehyde 24 with TosMIC. ... 

Reductive cyanation (5, 684 6, 600).1 The original conditions for conversion of ketones into nitriles give low yields when applied to aldehydes. Satisfactory results are obtained, however, if the initial reaction with TosMIC is conducted at 50° in DME before addition of methanol and reflux. Yields of 50-70% are then possible. 

Reaction of aldehyde 1477 with TosMIC and NaCN yields tosyl-substituted oxazoline 1478, which is converted into imidazole 1479 with ammonia at elevated temperature (Scheme 382) (see also van Leusen imidazole synthesis in Section 4.02.9.2(ii)(h)) <2005JME2100, 2003JME5445, 1999JME1115>. 

A two-step synthesis of 1,4-disubstituted imidazoles (8) from TOSMIC (1) plus an aldehyde, followed by reaction with ammonia or a primary amine, proceeds via a 4-tosyloxazoline (11). The reaction sequence could be classified as 1,2 and 1,5 bond formation, 1,5 bond formation, or transformation of another heterocycle. There are, however, analogies to the aldimine reactions, and so the process is detailed at this stage. Certainly the synthesis is carried out in two steps often with isolation of the oxazoline (see also Chapter 6). Heating (11) with a saturated solution of methanolic ammonia gives a 4-substituted imidazole with methanolic methylamine a 1,4-disubstituted product is isolated as a single regioisomer (Scheme 4.2.4). Some of the oxazolines cannot be isolated as they are unstable oils which have to be heated immediately with the amino compound [12]. Related is the synthesis of 2-carbamoyl-4-(2 -deoxy- 0-D-ribofuranosyl)imidazole [13]. 

Tosylmethyl isocyanide (TosMIC) (75 R = H), a versatile reagent in synthesis, can also be used as an acyl anion equivalent. For instance symmetrical and unsymmetrical diketones were prepared by using this TosMIC synthon (equation 40). Ketones are homologated to enones by alkylating the condensation product derived from TosMIC, followed by acid hydrolysis (Scheme 46). 1-Isocyano-l-tosyl-l-alkenes (76), formed by the reaction of TosMIC with an aldehyde or ketone, react with a primary amine or ammonia to give 1,5-disubstituted (or 5-monosubstituted) imidazoles in high yield (Scheme 47). ... 

Reactions of aromatic or heteroaromatic aldehydes 144 with a ROMPgel Tosmic reagent 143, available from the ring opening metathesis of 142, allowed the preparation of a small library of oxazoles 145 in high yields and with minimal purification <01OL271>. 

An atom economic route for the preparation of fludioxonil (2) has been patented [18]. Known 2,2-difluorobenzodioxole 12 is regioselectively lithiated to form 13 (Scheme 15.2.3). In a one-pot reaction intermediate 13 is directly quenched with 14 followed by conversion of the formed intermediate 15 with TosMIC into the desired fludioxonil (2). Alternatively intermediate 13 can be quenched with DMF to form aldehyde 16 which is, similar to the above process, stepwise reacted with a cyanoacetic acid derivative to obtain 15 followed by ring formation using TosMIC to deliver fludioxonil (2). Table 15.2.1 lists the chemical and physical properties of fenpiclonil (1) and fludioxonil (2). 

P. R. Krishna, K. Lopinti, Synlett 2007, 83-86. Diastereo-selective Passerini reaction of chiral 2,3-epoxy aldehydes with TosMIC. 

Diverse sugar-derived aldehydes 15 (Scheme 11.6) were used as chiral auxiliaries to perform the diastereoselective three-component Passerini reaction by reaction with p-toluenesulfonylmethyl isocyanide (17a, TosMIC) and carboxylic acids 16, giving... 

Oxazoles are a common structural motif foxmd in numerous molecules that display antiviral, antifungal, antibacterial, and antiproliferative activities [150,151]. Classical methods for oxazole synthesis include Robinson-Gabriel synthesis by dehydration of 2-acylaminokefones, Fischer oxazole synthesis from cyanohydrins and aldehydes, Bre-dereck reaction with a-haloketones and formamide. Van Leusen reaction with aldehydes and TosMIC, Hantzsch reaction, and aza-Wittig reaction [152]. 

The van Leusen reaction forms 5-substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (1, TosMIC) with aldehydes in protic solvents at refluxing temperatures. Thus 5-phenyloxazole (2) is prepared in 91% yield by reacting equimolar quantities of TosMIC and benzaldehyde with potassium carbonate in refluxing methanol for 2 hrs. ... 

Substituted oxazoles through the reaction of p-tolylsulfonylmethyl isocyanide (TosMIC) with aldehydes in protic solvents at refluxing temperatures. 

Also in 2009, an elegant combination of two original van Leusen reactions was reported, leading to a MCR toward 4,5-disubstituted oxazoles (19) [136]. The MCR involves the base-induced mono-alkylation of TosMIC (8a) followed by the formal cycloaddition with an aldehyde (Fig. 9). Although dialkylation is a problem often... 

The Passerini reaction is a useful method for the synthesis of substituted a-acyloxy carbocyclic acids. This is another reaction that one might assume an epoxide would not survive. Reaction of an epoxy aldehyde with benzoic and TosMIC provided the Passerini product in good yield as a mixture of diastereomers <07SL83>. 

To a stirred suspension of TOSMIC (5.0mmol) and the aldehyde (5.1 mmol) in dry ethanol (15 ml) is added finely powdered sodium cyanide (0.5 mmol). Within minutes a slightly exothermic reaction gives a clear solution from which the oxazoline separates ( 15min). Stirring is continued for an additional 10 min, or until TLC (dichloromethane diethyl ether, 95 5) shows that all of the TOSMIC has disappeared. The mixture is filtered, the crystals are washed with ether-hexanc (1 1, 15 ml) and dried. A second crop is obtained by concentration of the mother liquors and trituration with ether-hexane (1 5). 

The most recent synthetically useful modification of TOSMIC reactions involves the cycloaddition of Af-trimethylsilylimines with lithiotosylmethyl isocyanides. This allows the preparation of 4-mono- and 4,5-disubstituted imidazoles from readily accessible aldehydes and organolithium compounds in a one-pot reaction. Although yields are only moderate, there are advantages which accrue from the easy availability of the starting... 

Tosylmethylisocyanide (TosMIC) reacts with aldehydes via a [3+2] pathway, under basic conditions, to give 5-substituted oxazoles. In one example, the resulting oxazole product was used in the synthesis of a key intermediate for the hepatitis C drug candidate VX-497 (Scheme 56) <20020PD677>. K2CO3 is usually the base of choice for this reaction since stronger bases such as KO/-Bu lead to a cyanide product. 

PS-p-toluenesulfonylmethyl isocyanide (TosMIC) reagent, developed by Barrett et al. was found to be effective for the conversion of a range of aryl aldehydes into highly pure 4-aryl oxazoles in the presence of BTMG (2) [79] (Scheme 4.29b). A typical procedure involved the reaction of aldehyde with the gel (4 equiv.) in acetonitrile (0.2M sol) and BTMG (2) (4 equiv.) for 12 h at 65 °C. ... 

The Barton-Zard reaction refers to the base-induced reaction of nitroalkenes with alkyl a-isocyanoacetates to afford pyrroles. Solvents used are THF or alcohols (or mixtures), and the reaction often proceeds at room temperature. The Barton-Zard pyrrole synthesis is similar both to the van Leusen pyrrole synthesis that uses Michael acceptors and TosMIC and to the Montforts pyrrole synthesis that uses a,P unsaturated sulfones and alkyl a-isocyanoacetates. An alternative to the use of the reactive nitroalkenes is their in situ generation from P-acetoxy nitroalkanes, which are readily prepared via the Henry reaction between an aldehyde and a nitroalkane followed by acetylation. 

Yu et al. reported the synthesis of oxazoles 76 via the van Leusen reaction [148] with tosylisocyanide (TOSMIC) using ILs (Scheme 33). The authors carried out alkylation of tosylisocyanide followed by in situ treatment with different aldehydes to afford oxazoles in 75-90% yield. The authors also cited for complete recovery and reuse of IL [BMIM][Br], however, a slight decrease in the yield was observed throughout the six consecutive runs [149]. 

BetMIC is characterized by two key properties first, the good leaving ability of the benzotriazole (Bet) moiety and, second, the high acidity of the methylene protons. BetMIC is reactive with ketones to afford 4-ethoxy-2-oxazolines (94), which can be hydrolyzed to synthetically useful a-hydroxyaldehydes (95). It must be noted that unlike TosMIC, BetMIC forms 94/96 without the presence of highly toxic thallium alkoxides. The reaction works well in the absence of ethanol and provides better yields when using aliphatic ketones. With aromatic ketones, for example, ben-zophenone, partial conversion to oxazoline occurs probably due to steric effects. Reaction of BetMIC with aldehydes typically generates oxazoles 97 (Scheme 7.24) [43,44]. 

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