Nitrile surrogates

Aliphatic and aromatic nitriles are often converted to the corresponding imidates that then react with amino alcohols to provide oxazolines. This two-step process offers milder conditions. Generally, a mixture of the imidate (free base or hydrochloride) is allowed to react with the amino alcohol in a solvent (alcohols, CH2CI2, CHCI3) with or without a tertiary base. As expected, the cylization proceeds with retention of stereochemistry when chiral amino alcohols are used. Representative examples are shown in Table g 17 33,62,63,139,216-225 ready availability of benzimidates and trimethyl orthobenzoates make them ideal surrogates for benzonitrile. ... 

In Fig. 1.11, one sees the insertion of unusual peptide bond surrogates for lead seeking. Such residues include peptide boronates, peptide hydroxamates, peptide aldehydes, peptide trifluoromethylketone hydrates, peptide nitriles, peptide phosphonates, and so on. One could also add to this list inclusion of j3-tum mimics, j3-sheet analogs, and so on. This is at present a very active subfield of medicinal chemistry. 

An elegant and flexible strategy for the assembly of a synthon for the ort/to-hydroxyaryl-1,3-diketone required for a chromone synthesis depends on the use of an isoxazole as surrogate for the 1,3-diketone unit (25.7). An isoxazole was produced by the cycloaddition (25.12.1.2) of an aryl nitrile oxide to tri-n-butylstannylacetylene, the product coupled with 2,4,6-trihydroxyiodobenzene and then the N-0 bond hydrogenolytically cleaved. ... 

With the success of reducing nitriles in the presence of a 1,3-diamine to make hexahydropyrimidines, we turned our attention to the use of 3-hydroxy-1-aminopropane (22) as a surrogate for the 1,3-diamine. Hydrogenation of aceton-trile with Raney Ni in the presence of 22 in a 1 1 mole ratio at 95 °C and 500 psig produced tetrahydro-2-methyl-l,3-oxazine (23) in 90% selectivity and 70% conversion of 22 by intramolecular cyclization of the hydroxy to the intermediate enamine. This synthesis is quite different from other syntheses (7) which involve Pd or Pt homogeneous complexes for the intramolecular hydroamination of ami-nopropyl vinyl ether to give 23. 

H" " Surrogate. TMSCl can function similarly to a Br0nsted acid or can generate a Br0nsted acid in situ in various reactions. For example, addition of 2 equiv of TMSCl and 2 equiv of water to various nitriles furnishes the corresponding amides in good yield under ambient conditions (eq 59). Furthermore, heating a... 

Cyanide is always an excellent source of nitrogen for amino acid derivatives and acid hydrolysis of nitriles allows them to function as carboxyl surrogates as well (see section 1.3.A.i). The examples in this section will focus on using the cyano moiety as an amine surrogate. 

This section is concluded with a different type of reaction that gives products similar to those observed above. In this study, acetonitrile was first reacted with HCl and then with Meldrum s acid (1.141) to give 1.142 in a Pinner synthesis. Hydrolysis was followed by decarboxylation (in situ) to give ethyl 3-aminobut-2-enoate, 1.143 This reaction used a nitrile as an amine surrogate (acetonitrile) and... 

A related route reacted enamino-nitrile I.I7S with phosgene (another carboxyl surrogate) to give 7.27d. 5 Methanolysis of the acid chloride gave methyl 3-amino-... 

As applied to an amino acid synthesis, the ester enolate must react with another molecule that contains a nitrogen moiety. In one example, methyl 2-methylpropan-oate was treated with lithium diisopropylamide and then with 4-bromobutanenitrile to give 4.68. Catalytic hydrogenation of the cyano group gave methyl 6-amino-2,2-dimethylhexanoate (4.dP).35a in this case, the nitrile was the amine surrogate and the ester was the acid precursor. 

Another type of carboxylate surrogate is the nitrile moiety, although it can also be converted to an aminomethyl group. This section will include amino acids that are prepared by methods using the enolate of alkyl niuiles in alkylation reactions or... 

Nitrile enolates can also react with carbonyl derivatives such as oxalate, which serves as a carboxyl surrogate. Reaction of 2-phenylacetonitrile and diethyl oxalate, in the presence of sodium amide, gave 4.99. " Catalytic hydrogenation of the cyano group and hydrolysis led to ethyl 2-phenyl-3-aminopropanoate, 4.100. In this case also, the nitrile moiety was an amine surrogate. Other a-aryl acetonitrile derivatives... 

More recently, Jin et al. discovered an efficient copper-catalyzed cyanation of arenes 119 nsing benzyl nitrile as a cyanide anion surrogate, which fiunishes aromatic nitriles 120 (Scheme 5.84) [85]. The process involves at least three steps, where (1) benzyl nitrile undergoes a copper-catalyzed oxidation with air to generate A and B, accompanied by the generation of Cu(II) species (2) cyanide anion is formed throngh a retro-cyanohydrination of A or/and hydrolysis of B and (3) the in situ-generated cyanide anion participates in the copper(II)-catalyzed aerobic oxidative C—H fnnctionalization to afford the cyanation product. 

An efficient palladium-catalyzed protocol for the hydration of alkyl and aryl nitriles to amides has been disclosed, employing acetaldoxime as efficient water delivering surrogate to nitrile. A plausible mechanism was suggested involving Pd(ll)-catalyzed nitrile-oxime coupling followed by disruption of the intermediate into benzamide and acetonitrile in a concerted manner [81-83] (Scheme 39). 

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