Nitriles functionalized, synthesis

Tiazofurine (142) is an antimetabolite with antineoplastic activity. It preferentially affects leukemic lymphocytes over normal cells due to selective activation by formation of its adenine dinucleotide by transformed cells. Of the syntheses available, one starts by conversion of iniidate 138 to methyl 2,5-anhydroallonothioate (139). Next, condensation with ethyl 2-amino-2-cyanoac-etate leads to the thioamide which undergoes thiol addition to the nitrile function to produce the amminothiazolecarboxyester system of 140 directly. Sodium nitrite in aqueous hypophosphorus acid eliminates the superfluous amino group via the diazonium transformation to give 141. This synthesis of tiazofurine (142) concludes by ester amide exchange in methanolic ammonia [48]. 

The use of o-aminonitriles as ring precursors in this field is illustrated by Equation (85) <2003PS(178)649>, although the nitrile functionality is not always directly involved in the ring synthesis <2005JHC169>, for example, as in Equation (86). 

Taylor and Patel describe a quinazoline synthesis (Scheme 93) transforming the iminophosphorane of anthranonitrile with isocyanate to car-bodiimide 254. Addition of ammonia in tetrahydrofuran (THF) leads to guanidine 255, which affords with the adjacent nitrile function quinazoline derivatives 256 (91JHC1857). 

POLYHYDROGEN FLUORIDE REAGENT 1-FLUORO-ADAMANTANE. Dichloroalkane synthesis is shown in cis-DI-CHLOROALKANES FROM EPOXIDES cis-1,2-DICHLORO-CYCLOHEXANE. Nitrile functionality can be introduced from a ketone, as in NITRILES FROM KETONES CYCLOHEXANENITRILE, or from a reactive diene, as shown in 2,3-DICYANOBUTADIENE AS A REACTIVE INTERMEDIATE BY in situ GENERATION FROM 1,2-DICYANO CYCLOBUTENE 2,3-DICYANO-1,4,4a,9a -TETRAHYDRO-FLUORENE. 

As mentioned above, the synthesis of cyanohydrins from ketones is difficult due to the unfavorable equilibrium. However, it can be achieved. When methyl ketones were treated with only 1.5 equivalents of HCN in an emulsion of citrate buffer (pH 4.0) and MTBE, the S-selective Manihot esculenta HNL catalyzed the synthesis of the corresponding cyanohydrins with good yields (85-97%) and en-antioselectivities (69-98%). The corresponding esters were then used in a second carbon-carbon bond forming reaction. Since cyanohydrins from ketones cannot be deprotonated adjacent to the nitrile group, the esters could be selectively deprotonated and then a ring closing attack on the nitrile function yielded the unsaturated lactones (Scheme 5.6). When the nitrile function was first con-... 

Cyclocondensation of the nitrile 62 with the (/ )-2-methylcysteine building block 5b provides the thiazoline ester 63. After conversion of the ester to the nitrile 64, cyclocondensation with 5b leads to the bis(thiazoline) 65. The subsequent conversion of the ester to the nitrile function (65 66) nearly failed, with 10 % yield. In the last synthetic sequence the bis(thiazo-line) compound 66 is coupled with the oxazole compound 61 to provide the third and last thiazoline ring. Formation of the methylamide is the final step of the thiangazole synthesis of Patten-den. 

Several new routes involve formation of one carbon-carbon bond in pre-formed substrates. Palladium-catalyzed cyclization of /3-hydroxyenamine derivatives has been employed in a route to substituted pyrroles and 4,5,6,7-tetrahy-droindoles with multiple substituents by formation of the C-3-C-4 bond as the key feature, as illustrated by construction of the molecule 534 (Equation 146) <2006T8533>. Zinc perchlorate-catalyzed addition of alcohols to the nitrile functionality of a-cyanomethyl-/3-ketoesters, followed by annulation gave access to a series of substituted ethyl 5-alkoxypyrrole-3-carboxylates <2007T461>. Similar chemistry has also been used for synthesis of a related set of pyrrole-3-phosphonates <2007T4156>. A study on preparation of 3,5,7-functionalized indoles by Heck cyclization of suitable A-allyl substituted 2-haloanilines has also appeared <2006S3467>. In addition, indole-3-acetic acid derivatives have been prepared by base induced annulation of 2-aminocinnamic acid esters (available for instance from 2-iodoani-lines) <2006OL4473>. 

Zhao D, Fei Z, ScopeUiti R, et al. Synthesis and characterization of ionic hquids incorporating the nitrile functionality. Inorg. Chem. 

Zhao D B, Fei Z F, Geldbach T J, et al. Nitrile-functionalized pyridi-nium ionic liquids Synthesis, characterization, and their application in carbon-carbon coupling reactions. J. Am. Chem. Soc. 2004. 126, 15876-15882. 

In 1998, Dupont et al. [68] reported the synthesis of [C4mim]2[PdCl4] (Fig. 11). Solid IL-coordinated Pd2+ complex 13 was synthesized by the reaction of a nitrile functionalized ionic liquid with PdCl2 at room temperature. [69] Shreeve and co-workers [70] synthesized the IL-coordinated compound 14 (Fig. 11). 

The nitrile functional group is, formally, a dehydrated primary amide. (In fact, u little-used nitrile synthesis involves amide dehydration ... 

Diazines.—The utility of N-cyano-amidine derivatives of malonic acid in pyrimidine synthesis has been extended by the use of the ester (221). The nitrile function can be selectively attacked by water or secondary amines and the products then cyclized to pyrimidine derivatives (Scheme 87). ... 

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