Isocyano-esters

DBU IS most widely employed as the base m the Barton-Zard reaction Stronger nonionic bases such as PrMeNCH-,CH-j,N and the phosphazene base Csiipplied by Flukai are more effective to induce pyrrole formadon in the reaction of nitroalkenes v/ith isocyano esters than DBU Sterically hindered nitroalkenes are converted into the corresponding pyrroles using these bases, as shovm in Eq 10 35, but DBU is not effective in this transformation... 

For the dehydration of TV-formylamino compounds to give isocyanides the CDI is activated by protonation into its bisimidazolium form (CH3CN, room temperature, 4h). Thus, chiral a-isocyano esters and other base-sensitive isocyanides are obtained in high yield. CDI itself did not produce this dehydration. 

Among the a-acidic isocyanides, isocyano esters (1) (for the first isolated example of a-acidic isocyano ester see [24]), isocyano amides (2) (for the first isolated example of a-acidic isocyano amide see [25]), and arylsulfonyl methyl isocyanides (3) (for the first report of TosMlC see [26]) have been studied predominantly, and therefore this mini review will mainly focus on the MCRs involving these species. 

Fig. 3 General methods for the preparation of isocyano esters (1), isocyano amides (2), and arylsulfonyl methyl isocyanides (3) (R = afkyl and/or H)...

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

Arylsulfonyl methyl isocyanides (3) and isocyano esters (1) can also be prepared by the deprotonation of alkylisocyanides (5) by strong bases (nBuLi or NaH) followed by the addition of TosF and dialkyl carbonates or ethyl chloroformate, respectively (pathB) [37, 38]. However, the use of small and foul-smelling alkyl isocyanides makes this route less attractive. 

Finally, isocyano esters can be converted to the corresponding amides upon treatment with an amine (typically just stirring in MeOH) [32, 43, 47, 67-71]. Although this procedure (path D) works well for a,a-unsubstituted isocyano esters and for a wide variety of primary and secondary amines, steric bulk around both the a-carbon and the amine component should be avoided. 

Fig. 4 Selected examples for the formation of heterocycles starting from isocyano esters...

Finally, treatment of a-acidic isocyano esters (1) with base in the absence of other reagents is reported to furnish 5-alkoxy oxazoles (K) via ring closure [113, 114]. 

For arylsulfonyl methyl isocyanides (3), [3 + 2] cycloadditions with aldehydes yielding 4,5-disubstituted oxazoles (N) have been reported [115]. The cycloaddition takes place in the same manner as with the use of isocyano esters (A, = H) ... 

Fig. 13 Scope of isocyano esters in the MCR toward trisubstituted oxazoles...

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

In 2006, our research group reported a novel MCR based on the reactivity of a-acidic isocyano esters (1) toward 1-azadienes (84) generated by the 3CR between phosphonates, nitriles, and aldehydes [169]. Remarkably, the dihydropyridone products (85) for this 4CR contained the intact isonitrile function at C3. The exceptional formation of the 3-isocyano dihydropyridone scaffold can be explained by the Michael-attack of the a-deprotonated isonitrile (1) to the (protonated) 1-azadiene (84), followed by lactamization via attack of the ester function by the intermediate enamine. Although in principle the isocyano functionality is not required for the formation of the dihydropyridone (85) scaffold, all attempts using differently functionalized esters (e.g., malonates, ot-nitro, and a-cyano esters) gave lower yields of the dihydropyridone analogs [170] (Fig. 26). 

Recently, our group also contributed to CBD as a tool for DOS. By judicious selection of the reaction conditions, the 3CR between ot-acidic isocyanides 145 (isocyano amides and isocyano esters " ), carbonyl components 6 and primary amines 146 could be directed towards either 2//-2-imidazolines 150 or trisubsti-tuted oxazoles 152 (Scheme 13) [98]. 

It has to be noted that the formation of oxazoles using isocyano amides has been well studied by Zhu and co-workers (see [58, 59]). With the work of Elders et al. the oxazole MCR has been expanded with a wide range of isocyano esters. The MCR with isocyano amides can now also he directed to the 2-imidazolines. 

The directing properties of the MCR involving isocyano esters could exclusively be performed using a-aryl isocyano esters, since the use of a-alkyl isocyano esters always resulted in the formation of 2-imidazolines, in various solvents, even without AgOAc, see [96] and [97]. 

In 2009, our group demonstrated that the MCR strategy can also be used to obtain complexity as well as scaffold diversity (Scheme 17) [103]. The strategy is based on the abovementioned 3CR to 2//-2-imidazolines (reacting an isocyano ester, aldehyde or ketone and an amine) that shows extraordinary FG and solvent compatibility [96]. By incorporation of a second orthogonally reactive group in one of the starting materials, this MCR can be coupled to a second MCR. 

Rearrangement of allylic a-isocyano esters Y. Ito, H. Higuchi and M. Murakami, Tetrahedron Lett., 1988, 29, 5151. 

Synthesis of pyrroles form nitroolefins or p-acetoxy nitro compounds with a-isocyano esters in the presence of an organic base. 

Early development of the Passerini reaction focused on the convergent synthesis of complex depsipeptide derivatives. In 1962 Ugi described the use of isopropyl a-isocyano ester 40 as a glycine precursor to prepare the simple... 

A novel route to a-isocyano-esters involves a ring-opening reaction of 5-alkoxyoxazoles (Scheme 33) isolated yields are ca. 80%. a-Trimethylsilyl esters cannot normally be obtained directly from ester enolates owing to the preference for O- rather than C-silylation. This can be overcome by treating a-chloroacyl silanes with lithium alkoxides (Scheme 34) yields are ca. 80%. 

The synthesis of glycidic esters in a two-phase solid-liquid system has been reported yields of between 32 and 92 % are obtained for eleven examples. 2,3-Dibromoalkyl esters react with excess sodium azide on heating to give 2-azido-2-alkenoic esters in 71 to 87 % yield over five examples. The chiral formamido-ester (71) reacts with oxomethylenebis-(3 f+-imidazolium) bis(methanesulphon-ate) (72), a non-basic dehydrating agent, to give the a-isocyano-ester (73) in 80 % yield with only 1 % racemization, as shown by the re-hydration of the product (73) (Scheme 38). ... 

Scheme 5.80 Hayashi s gold-catalyzed direct aldol reaction of isocyano ester 281.

Cycloalk-l-enylglycines, useful in some penicillin syntheses, are available from A-formylcycloalkylideneglycinates, themselves prepared from methyl iso-cyanoacetate and cycloalkanones (Scheme 56). ° a-Alkylated homologues (193) of cycloalk-l-enyl-glycines may be obtained from the enolate of the unsaturated isocyano-esters (192). ° ... 

The first catalytic asymmetric 1,3-dipolar cycloaddition of a-substituted isocyano-esters and nitrooleflns was reported by Gong et al., in 2008 [40]. This process was based on the use of cinchona alkaloid derivatives, such as 23 (Figure 37.3), as... 

Pyrroles.—Formation. Toluene-p-sulphonyl-alkyl isocyanides react with electron-poor olefins to furnish pyrroles thus compound (279) and methyl cinnamate give the ester (280). Treatment of the isocyano-ester MeCH=C(NC)C02Et with Li" CH(NC)C02Et affords the pyrrole derivative (281). A series of amino-nitriles (282 R = alkyl, Ph, etc.) has been prepared by the action of... 

They have shown that these isocyano esters can be utilized in the U-4CCR and the resulting acyclic product 175 can be converted to the corresponding ester 176 quantitatively under Armstrong s conditions (Scheme 7.60). 

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