TosMIC

Ketones can be converted to nitriles with an additional carbon atom with the aid of the TosMIC reagent (J.R. BuU, 1975 O.H. Oldenziel, 1973). 

After the umpolung of an aldehyde group by conversion to a l,3 dithian-2-ide anion (p. 17) it can be combined with a carbonyl group (D. Seebach, 1969, 1979 B.-T. GrO-bel, 1977 B). Analogous reagents are tosylmethyl isocyanide (TosMIC), which can be applied in the nucleophilic formylation of ketones (O.H. Oldenziel, 1974), and dichloromethyl lithium (G. KObrich, 1969 P. Blumbergs, 1972 H. Taguchi, 1973),... 

The use of a vinylphosphonium salt as the source of the QQ fragment instead of the more commonly employed 1,2-dicarbonyl substrate is illustrated by the pyrrole synthesis in Scheme 79b (8UOC2570). A particularly interesting feature is the intramolecular Wittig reaction with an amide carbonyl group. A very useful synthesis of pyrroles depends upon the addition of the anion of p-toluenesulfonylmethyl isocyanide (TOSMIC) to a,/3-unsatur-... 

A one-step synthesis o( mtnles from carbonyls by a reductive cyanation with tosylmethyl isocyanide (TosMIC), also synthesis of 1,3-azole or of ketones... 

In some cases, potassium carbonate is superior to DBU and tetramethylguanidine (TMG) in the BZ reaction. Thus 7 reacts with TosMIC (19) in the presence of K2CO3 to afford pyrrole 20 in excellent yield. The yield of 20 using DBU is 62%. 

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. ... 

In 1972, van Leusen, Hoogenboom and Siderius introduced the utility of TosMIC for the synthesis of azoles (pyrroles, oxazoles, imidazoles, thiazoles, etc.) by delivering a C-N-C fragment to polarized double bonds. In addition to the synthesis of 5-phenyloxazole, they also described reaction of TosMIC with /7-nitro- and /7-chloro-benzaldehyde (3) to provide analogous oxazoles 4 in 91% and 57% yield, respectively. Reaction of TosMIC with acid chlorides, anhydrides, or esters leads to oxazoles in which the tosyl group is retained. For example, reaction of acetic anhydride and TosMIC furnish oxazole 5 in 73% yield. ... 

Van Leusen and co-workers also demonstrated the condensation of heteroaromatic aldehydes with TosMIC. Table 6.7.1 shows the 5-heteroaryloxazoles 6 prepared in 47-88% yield in the presence of equimolar amounts of potassium carbonate in refluxing methanol. 

Van Leusen and co-workers also demonstrated the utility of dilithio-tosylmethyl isocyanide (dilithio-TosMIC) to extend the scope of the application. Dilithio-TosMIC is readily formed from TosMIC and two equivalents of n-butyllithium (BuLi) in THF at -70"C. Dilithio-TosMIC converts ethyl benzoate to oxazole 14 in 70% yield whereas TosMIC monoanion does not react. In addition, unsaturated, conjugated esters (15) react with dilithio-TosMIC exclusively through the ester carbonyl to provide oxazoles (16). On the other hand, use of the softer TosMIC-monoanion provides pyrroles through reaction of the carbon-carbon double bond in the Michael acceptor. 

TosMIC reagents. For example, glyoxylic acid ethyl ester undergoes cycloaddition with (2-naphthyl) tosylmethyl isonitrile (17) to produce oxazole 18 in good yield. ... 

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. ... 

Barton and Zard found that the base-catalyzed reacdon of nitroalkenes or fi-n v/ith alkyl isocyanoacetate or TosMIC gives pyrrole-3-carboxylates or 3-suifonylpyrroles, respecdvely fsee Eqs 10 18 and 10 19) This reacdon is very convenient for the synthesis of... 

Based on a known synthesis of spiro compounds with six-membered rings [63] we succeeded in the stepwise assembly of terminal substituted mono-[64] and dispiranes [65]. Hereby the cyclisation of the dibromide 35 with TOSMIC (Iter. 1) is the keystep of the reaction sequence as the initial ketone functional group (36) is recovered. Four subsequent reactions led to the spirodibromide 40 (Iter. 2). Final spirocyclisation afforded the dispirane 41, representing a precursor for new calamitic liquid crystals (Fig. 16) [66]. 

Isonitrile cyclization provides a useful alternative method of the Knorr type cyclization for pyrrole synthesis. In 1972, Leusen and coworkers reported pyrrole synthesis based on the reaction of tosylmethyl isocyanide (TosMIC) with electron-deficient alkenes (Eq. 10.12).15... 

The most important advantage of this procedure is that a-free pyrroles are obtained directly. Reaction of nitroalkenes with TosMIC gives 3-nitropyrroles in 55-85% yield (Eq. 10.13).16 The... 

Total synthesis of phytochromobilin starting from 2-tosylpyrroles, which are prepared by (3-nitro acetates with TosMIC (Scheme 10.4) has been reported.28 Phytochrome is a chromoprotein concerned in a variety of processes in higher plants such as growth, development, and morphogenesis, 29... 

Reaction of pyrrolopyridines 241 with tosylmethyl isocyanide (TosMIC) in the presence of a phase transfer catalyst tetra- -butylammonium iodide (TBAI) provides the tricyclic pyrimidopyrrolopyrimidine derivatives 242 (Equation 30) <20000L3253, 2004JOC4974, 2005JOC4879>. 

Monosubstituted and 4,5-disubstituted oxazoles were easily obtained from aryl-substituted tosylmethyl isocyanides and aldehydes . Tosyloxazoles 107, prepared from TosMIC 106 and carboxylic acid chlorides, led to 5-substituted derivatives 108 through ultrasound-promoted desulfonylation <00JCS(P1)527>. 

The biologically active oxazole compounds were synthesized by Wang et al. [34], and two types of isomers were described those with N1 pointing towards the A-ring (e.g., 54) and those with N1 positioned closest to the B-ring (e.g., 55), Scheme 10. Tosmic reagents 12 and 13 were used for this synthesis as described in Sect. 2.1.1, Scheme 1. The chemistry described... 

The reaction of the 3-(bromomethyl)pyrazole 276 with various alkyl derivatives of tosylmethyl isocyanide (TosMIC) 277 affords the products 278 (Equation 56) and requires phase-transfer conditions for success <2005JOC4879>. This reaction was also used for the synthesis of ring system 68, but in lower yield (25%). 

Catalysed alkylation of tosylmethylisocyanate (TOSMIC) [63, 64] has extended its versatility in the preparation of l, 4-dicarbonyl compounds and as a l, 3-dipolar precursor for the synthesis of heterocyclic compounds. The alkylation reactions should not be conducted in carbon disulphide, as nucleophilic attack by the methylene group on the carbon disulphide leads, after ring closure and S-alkylation, to a 4-alkylthio-1,3-thiazole system [65]. 

Method A (in the absence ofCS2) TOSMIC (0.97 g, 5 mmol), the alkylating agent (5.5 mmol) andTBA-Br (0.32 g, l mmol) in CH2Cl2 (15 ml) are stirred at 0°C with aqueous NaOH (35%, 12 ml) for 3 h and then at room temperature for 6 h. The mixture is poured into H20 (20 ml) and extracted with CH2Cl2 (3 x 20 ml). The organic extracts are washed well with H20, dried (Na2S04), and evaporated to yield the alkylated derivative. 

---