Isocyanides electron withdrawing group

A third property that characterizes the reactivity of isocyanides is their a-acidity. Introduction of an electron withdrawing group (EWG) at the a-position of isocyanides considerably lowers the pKa-value of the a-hydrogens. Consequently, a-acidic isocyanides have, besides the aheady unusual reactivity of the isocyanide functional group, an additional nucleophilic center upon proton abstraction. This opens different reaction paths towards a range of interesting products, including heterocycles. 

Ito and co-workers have also used the Pd(OAc)2/t-alkyl isocyanide catalyst to affect the double silylation of carbon-carbon multiple bonds in an intramolecular system to yield silacarbocycles.59 Alkenes or alkynes that are tethered to a disilanyl group through a carbon chain, an ether linkage, or an amine functionality undergo intramolecular addition of the disilane moiety to the multiple bond. Activation of the disilane by the presence of electron-withdrawing groups on silicon is not necessary for the reaction to... 

A recent discovery has been the unprecedented double insertion of isocyanides into 1,4-dihydropyridines, bearing an electron-withdrawing group at the 3-position, resulting in the formation of substituted benzimidazolium salts 298 (Scheme 68) <2007AGE3043>. 

In a project on electron-deficient isocyanides, Lentz studied the reactivity of pentafluorophenyl isocyanide 4a, isocyanoacetonitrile 4b, pentacarbonylchromium diisocyanomethane 4c, and 2,2,2-trifluoroethylisocyanide 4d toward bis[tris(trimethylsilyl)methyl] diphosphene 3. Combination of the reactants in pentane or diethyl ether at ambient temperature led to the formation of the expected diphosphirane imines 5a-5d as yellow crystals in moderate yields (Equation 2). For the success of this process very bulky substituents at the P=P unit and electron-withdrawing groups at the nitrogen atom are required, which is evident by the decrease of thermostability in the series 5c m 5a >5b>5d <1998JFC73, 1999ZFA1934>. 

Pyridine iV-oxides can be aminated with isocyanides (Scheme 33). The reaction proceeds through an N-formylaminopyridine intermediate that can be isolated or hydrolyzed with acid to provide the aminopyridines.The reaction works with a number of substituted pyridines however, with electron-withdrawing groups the yields are lower. With C-3 substituted pyridine iV-oxides, a mixture of regioisomers was produced. The C-2 product predominated with aryl isocyanides. Steric hindrance did appear to impact the yield for both aryl and aliphatic isocyanides. Finally, isoquinoline AT-oxide reacted under these conditions to form the aminoisoquinoline in good yield (60%). If both the two and six positions were blocked, the reaction failed to proceed (14JOC2274). 

Mironov and Mokrushin described the extraordinary formation of 35 from the reaction between triethylamine and aryl isocyanides bearing electron-withdrawing groups (Entry 7) [14], An x-ray crystal determination of 35 (R =R =H, R =R =CFj) confirmed the structure of this 2-triethylammonium-3-arylaminoindolate. Even more bizarre is the isolation, and x-ray crystal structure, of N-lithioindole 36 from the reaction of phenyl isocyanide and LiCH(TMS), (Entry 8) [15],... 

Choice of base can play a crucial role in the success of the Schdllkopf reaction, as the reactivity of a-metalated isocyanides varies as a function of the metal counterion. For example, although lithium ethyl isocyanoacetate (8) condenses readily with a wide range of acid chlorides, lithio-8 fails to react with less reactive ester electrophiles and affords only isocyanide dimerization products. Likewise, only a-metalated alkyl isocyanides lacking electron-withdrawing groups at the a-position are sufficiently nucleophilic to react with amide electrophiles in the Schdllkopf reaction. ... 

Isocyanide ligands containing electron-withdrawing groups form stronger redonor... 

Yamamoto reported the Cu(I)-catalyzed synthesis of 2,4-di- and 2,3,4-tri-substi-tuted pyrroles 317 (Scheme 8.111) [309]. Target products were obtained in modest to good yields via a 3 + 2 cycloaddition reaction between isonitriles 315 and activated alkynes 316. Steric congestion around the triple bond of 316 decreases the reaction efficiency. It was also demonstrated that alkynes activated with electron-withdrawing groups other than carbalkoxy were somewhat inefficient in this cascade transformation. However, much better compatibility of electron-withdrawing substituents on isocyanide 315 was observed. The reaction mechanism is outlined in Scheme 8.112. 

Imidazo[l,2-(j]pyridines can be prepared from a multicomponent reaction of alcohols, 2-aminopyridines, and isocyanides (Scheme 53) (13TL95). The alcohols are oxidized by DMSO and propylphosphonic anhydride, which also catalyzes the nucleophilic addition with isocyanides. Aromatic alcohols with electron-donating and electron-withdrawing groups can provide the desired... 

The S5mthesis of furopyrimidines has received a little attention in spite of their wide range of associated bioactivities including antimicrobial, antiviral, antimicotic, and antiplatelet [84-86]. Shaabani et al. reported a three-component condensation reaction of N,N -dimethylbarbituric acid with aldehydes and alkyl or aryl isocyanides at room temperature (RT) in the presence of [BMIM][Br] in a molar ratio of 1 1 (reactant/IL) to afford furo[2,3-d]pyrimidine-2,4(lH,3H)-diones 32 (Scheme 6). The authors cited that the presence of an electron-withdrawing group was necessary and addition of [BMIM][Br] was crucial for the formation of the desired product in high yield [87]. 

The first synthesis of pentasubstituted pyrroles was achieved by using PylC (Ik) in the U-4CR on a solid phase [50], According to Mjalli and coworkers, pyridine was necessary as a cosolvent in the U-4CR as it helped buffer the reaction mixture and stabilize the isocyanide. The acyclic Ugi product 108 can be directly converted to the miinchnone 109 by heating (100°C) in acetic anhydride and trapped in situ with alkynes bearing electron-withdrawing groups via 1,3-diploar cycloaddition to afford pyrrole 110 (Scheme 7.29). 

Aziridines react with enolates, " phosphine ylides, lithium trimethylsilyl-acetylide, lithiated 4-methoxybenzyl isocyanide, and other organometallics if, and only if, the nitrogen atom bears a powerful electron-withdrawing group such as p-toluenesulfonyl. When the A-tosylaziridine carries additional substitution at the 2-position, only the vacant 3-position is attacked under ring opening (Scheme 1-90). 3-(Trimethylsilyl)allyllithium connects with the 3-position of 2,2-dimethyl-AT-tosylaziridine... 

Cl, N02) undergoes cod substitutions with isocyanides and phosphines.190 However, when R is the strongly electron withdrawing N02 group, reaction with PEt3 leads to nucleophilic attack on the coordinated cod ligand affording (63) instead of cod substitution. 

In general, the hydrolysis of amides requires conditions that are not compatible with the survival of several functional groups [10]. If the amide nitrogen is linked to an electron-withdrawing moiety, alkaline hydrolysis of the amide group is easier. Following this observation Martens and co-workers used 4-methoxy-2-nitrophenyl isocyanide 14 (or 2-methoxy-4-nitrophenyl isocyanide) as a convertible isocyanide for the preparation of Peptide Nucleic Acid (PNA) monomers [8a] (for another example, see Ref. [11]). The Ugi-4CR between isocyanide 14, carboxymethyl nucleo-... 

Other electron-withdrawing substituents which have been used to stabilize cyclopropyl anions are the acyl, ° carboxy, ° nitro, and isocyanide groups. With one exception, the first three were unsuccessful, partly because other reactions took place. Thus, cyclopropanecarboxylic acid undergoes dimerization to l-(cyclopropylcarbonyl)cyclo-propanecarboxylic acid, and this reaction predominates above room temperature. When ni-trocyelopropane was treated with base spontaneous dimerization oceurred, yielding mixtures of 1-nitro-l-nitrosobicyclopropyland l,l -dinitrobicyclopropyl. The yields of the two products were dependent on the workup procedure employed. 

---