Isocyano substituents

Stereoselective synthesis of b/S-alkyl-penicillanates, using reductive removal of a 6/3-isocyano substituent with tributyltin hydride, has been described/ Stereocontrol in the formation of 6-hydroxyalkyl /8-lactam antibiotics by trans-metallation between benzyl 6,6-dibromopenicillanate esters and metal alkyls. 

Modification of the 5 -hydroxyl of ddU to the 5 -0-methanephosphonate (ddU-5 -OCH2POjNa2) did not significantly improve the poor activity of Ae parent compound. Replacement of the hydroxyl group at the 5 -position of AzddU by an isocyano substituent greatly diminished activity. Compounds in which the 5 -hydroxyl of 2 -deoxyuridine was substituted by amino, azido, or isocyano moieties were inactive. 

In a like manner the 6/3-isocyano group can be utilized to activate the C(6) proton (79JCS(P1)2455), an example of which is shown in Scheme 43. It was also possible to introduce the 6a-methylthio substituent by reacting the intermediate anion with methyl methoxycarbonyl disulfide The 6a-methylthio group could subsequently be converted to the 6a-methoxy group by treatment with CI2 and MeOH. 

This chapter embraces quinoxalines bearing nitrogenous substituents that are joined to the quinoxaline nucleus through their nitrogen atom. However, isocyano-, isocyanato-, and isothiocyanatoquinoxalines will be found in Chapter 7 to ensure that they are adjacent to quinoxalinecarbonitriles. 

The 7,15-diisocyano isomer (101) of 95 (-NC substituents at C-7 and -20), and 8-isocyano-10-cycloamphilectene (102) are also Amphimedon metabolites. 

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]. 

The scope of the aldehyde inputs includes a wide range of (hetero)aromatic aldehydes as well as a,(3-unsaturated aldehydes. With the use of aliphatic aldehydes, side products due to aldol condensations could be observed. Allowed ot-substituents at the isocyano acetate (1) includes R" = Ph, H, Me, Et, Bn, iBu, iPr. The scope according to the nitrile input includes aromatic, heteroaromatic, and aliphatic nitriles. However, the use of primary aliphatic nitriles should be avoided. 

The fate of isocyanosulfide (70) depends on the nature of the substituent originally at C-4 of the isothiazole ring. If R is aryl, as in 55, the extended conjugation of the sulfide and the aryl group is expected to lower the basicity of the sulfide resulting in reprotonation at the isocyano carbon to yield 71. Protonation at this site renders the carbon more susceptible to nucleophilic attack by the negative sulfur. As a result, these substituted isocyanides spontaneously cyclize to 4-arylthiazoles 73 (R=Ar). 

Structural elucidation of the terpenoid constituents of marine plants and animals has revealed the presence of several compounds whose novel structures often have chlorine, bromine, or isocyanide substituents (cf. pp. 65 and 89). 9-Isocyano-pupukeanone (273) is a recent example of a marine sesquiterpenoid isolated from a... 

By introducing a substituent, especially an aryl group, into the a-position of an a-isocyanoacetate (e.g., 13) and using a primary amine as reaction partner of an aldehyde, a completely different product was obtained by Orru s group (Scheme 5.7) [21]. The reaction was also initiated by nucleophilic addition ofthe enolate anion of 13 to the imine (iminium) however, the lack of an additional acidic proton a to the ester group in the intermediate 14 (Mannich adduct) made P-elimination impossible. Therefore, the secondary amine would attack intramolecularly the divalent isocyano carbon leading,... 

In a short section the electronic effect of the isocyano group is discussed. The possibility of including unipolar substituents in Hammett and similar treatments has long been a matter of controversy and this problem is discussed with special reference to the N2 substituent. The effects of acetylenic groups are examined in some detail and various unsatisfactory aspects are uncovered. Multiparameter treatments such as the Yukawa-Tsuno equation and the dual substituent-parameter equation have long been important and further treatments have been devised in recent years. A final section is devoted to some of these, with an indication of the place of CN, and to a lesser extent of the other groups of interest, in these treatments. 

Electronic effects of cyano, isocyano, acetylenic and diazonio groups 267 TABLE 6. a and values for substituents containing... 

From the linear correlation between and op or the Taft polar o substituent constants recognized for a number of ferrocene derivatives, it was possible to estimate such constants for various isocyanide groups aixl the (high) values obtained (e.g., o ca. 2.8 for -N=C) substantiate the strong electron withdrawing ability of the isocyano group [21]. 

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