Aldehydes TosMIC

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 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. ... 

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. 

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. ... 

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>. 

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

The first MCR involving the explicit use of a-acidic isonitriles was reported in 1998 by Sisko [131]. The reaction involves the cycloaddition of aTosMIC derivative (8) to an (in situ-generated) imine (10) followed by the elimination of p-toluenesulfinic acid (TsH) as described in 1977 by van Leusen for preformed imines (Fig. 5, scaffold P) [119]. Although several potential pitfalls for the conversion of the traditional van Leusen [3 + 2] cycloaddition to the so-called van Leusen three-component reaction (vL-3CR) of imidazoles were expected by the author, simply stirring the aldehyde and amine for 20 min followed by addition of the TosMIC derivative and base resulted in the isolation of the corresponding imidazole (9) in high yield [131]. 

In 2009, the MCR between o-phenylenediamines (13), aldehydes, and TosMIC (8a) which yields 2,6,7-trisubstituted quinozalines (14) has been described [135]. The mechanism probably proceeds via the initial attack of deprotonated TosMIC at the in situ-generated imine affording intermediate 16 (Fig. 8). Apparently, attack of the secondary amine in 16 at the terminal isonitrile C-atom that yields the... 

Fig. 7 Formation of 2,6,7-trisubstituted quinozalines (14) from the MCR between o-phenylene-diamines (13), aldehydes, and TosMIC (8a)...

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... 

Fig. 9 MCR between TosMIC (8a), aliphatic halides (18), and aldehydes which yields 4,5-disubstituted oxazoles (19)...

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. 

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>. 

The synthesis of oxazole C-nucleosides in moderate yields by Tosmic addition to sugar derived aldehydes and concomitant cyclization has been reported. In particular, aldehyde 130 gave 131 in 48% yield <03SL1619>. 

From the interaction at low temperatures in basic medium of an aldehyde or ketone and tosylmethyl isocyanide ( tosmic ), iV-(l-tosyl-l-alkenyl)formamides are formed. When these are dehydrated they produce 1-isocyano-l-tosylalkenes (66) which react with primary amines to form imidazoles in high yields (Scheme 35) (79RTC258). 

When TOSMIC reacts with an aldehyde or ketone the products formed are A-(l-tosyl-l-alkenyl)formamidcs (8) (yields are high, 50-85%), which can be dehydrated in 54-77% yields to give 1-isocyano-l-tosyl-l-alkenes (9)... 

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]. 

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). 

Imidazoles (8) made from TOSMIC with aldehydes and amino compounds [12]... 

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... 

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>. 

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. 

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). ... 

TosMIC can be efriciently alkylated with primary alkyl halides, isopropyl iodide and benzyl bromide both to the corresponding mono- or di-alkyl derivatives using NaH in DMSO or 40% aq. NaOH in and in the presence of Bu"4NI (Scheme 125). The resulting compounds have then been transformed to aldehydes and ketones, including cycloalkanones, and the method has been successfully applied to the synthesis of optically active 2-methylcyclobutanone from the chiral sulfonylmethyl isocyanide and 1,3-dibromobutane. ... 

Oxazole syntheses employing isocyanides as starting materials are of considerable preparative value. In the van Leusen synthesis, tosylmethyl isocyanide (TosMIC) reacts with aldehydes under base catalysis, e.g. in the presence of K2CO3. The primary products are 4,5-dihydro-1,3-oxazoles 12, which are converted into oxazoles by elimination of sulfinic acid (see p 172) ... 

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. ... 

About 30 years ago van Leusen and co-workers pioneered the condensation of TosMIC with aldehydes and ketones to prepare 4,5-disubstituted oxazolines that eliminate toluenesulfinic acid to yield 5-substituted oxazoles. This process continues today as an important method for constructing such analogues, as evidenced by the following examples. 

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