Directing groups nitrile

Buchwald and co-workers reported a directed zirconium-mediated /// -acylation of various aromatic compounds, bearing a directing group, with different nitriles.150 One representative example is shown in Equation (14). 

This chelation-assisted C-H/olefin and C-H/acetylene coupling can be applied to a variety of aromatic compounds with a directing group such as ester, aldehyde, imine, azo, oxazolyl, pyridyl, and nitrile [7]. In this section, we describe the coupling reactions of aromatic carbonyl compounds with olefins using a transition metal catalyst. 

For the chelation-assisted catalytic reaction, Jt-electrons in a nitrile group are able to function as a directing group. The ruthenium-catalyzed alkylation of aromatic nitriles with triethoxyvinylsilane takes place predominantly at the ortho position (Eq. 9.10) [24]. This regioselectivity indicates the possibility of Jt-coordination of the CN group to the ruthenium in the catalytic cycle. 

An indirect method involves the reaction of an aromatic ring with tert-butyl-lithium, particularly when there is a directing group (see 13-17), followed by reaction with PhOCN (phenyl cyanate) to give the aryl nitrile. another indirect method involve the palladium catalyzed reaction of aryl bromides with the cyanohydrin of acetone [Me2C(OH)CN] to give ArCN. ... 

In spite of the acidity impaited to the ortho position by a cyano group (Table 1), little use has been made of it as a directing group. Two examples are shown in Scheme 14. Because of the susceptibility of the nitrile function to addition by oiganometallics, the bases used are lithium amides. - ... 

By designing suitable directing groups containing nitrile substituents, Yu et al. were able to devise an efficient chelation control for the functionalisation of toluene and hydrocinnamic acid derivatives, phenols, " and amines. 

Rh-catalyzed direct C-H cyanation of aryl oximes with the cyano transfer group JV-cyano-A/ -phenyl-/)-toluenesulfonamide has tilso been reported [84]. This was the first report of a Rh-catalyzed-directed C-H cyanation reaction for the synthesis of aromatic nitriles. JV-Cyano-JV-phenyl-/)-toluenesulfonamide, a user-friendly cyanation reagent, was used in the transformation. Many different directing groups can be used in this C-H cyanation process, and the reaction tolerates a variety of synthetically important functional groups. This methodology was nicely used for the synthesis of the cyanated derivative of the nonsteroidal anti-inflammatory drug zaltoprofen in a yield of 74% (Scheme 4.12). 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

Constitution. Pelletierine behaves as a secondary amine and the oxygen atom of the alkaloid is present in the form of an aldehyde group, since the base yields an oxime, convertible by the action of phosphorus pentachloride into a nitrile, b.p. 104-6°/13 mm., which is hydrolysed by caustic potash in alcohol to an acid, the ethyl ester of which is Loffler and Kaim s ethyl -2-piperidylpropionate. Pelletierine is not directly oxidisable to this acid. It also yields a liquid hydrazone, b.p. 130°/20 ram., which with sodium in alcohol at 136-70° reduces to dZ-eoniine. These reactions are explained by the following formulas, in which pelletierine is represented as -2-piperidylpropionaldehyde. 

It is often advantageous to proceed to a desired product through two nucleophilic displacements rather than directly when one can exploit a difference in the reactivity of two leaving groups. An example is the conversion of 4-chloro-2,6-dimethoxypyrimidine (109) (not satisfactorily reactive with sulfanilamide anion) by means of trimethylamine into the more reactive trimethylammonio derivative 110. Conversion of chloro-quinohnes and -pyrimi-dines into nitriles is best accomplished by conversion (with sulfite) into the sulfonic acids before reaction with cyanide. 

A thiazole derivative that incorporates a fragment of the amphetamine molecule shows some CNS stimulant activity more specifically, the compound antagonizes the depression caused by overdoses of barbiturates and narcotics. Reaction of benzalde-hyde with sodium cyanide and benzenesulfonyl chloride gives the toluenesulfony1 ester of the cyanohydrin (141). Reaction of this with thiourea leads directly to aminophenazole (143) It is probable the reaction proceeds by displacement of the tosylate by the thiourea sulfur to give 142 addition of the amino group to the nitrile followed by tautomerization affords the observed product. ... 

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 methyl groups adjacent to the pyridine nitrogens can also be modified without changing calcium channel blocking activity. The most significant change involves replacement of methyl by a nitrile group. Hantsch type condensation of the nitrobenzaldehyde 43 with methyl acetoacetate and the vinyl amine 44 from isopropyl 3-cyano-3-ketopropionate leads directly to nilvadipine (45) [13]. 

The cyano group in aromatic nitriles can be converted directly to a methyl group in vapor phase over 30% Ni-on-AljOj prereduced by hydrogen i>i situ... 

It has been shown52 that under similar conditions reduction of the nitrile groups in cellulose ethyl cyanate and of those in the copolymer of vinylidene cyanide with vinyl acetate, proceed simultaneously in two directions with the formation of aldehyde and amine groups. g+ g ... 

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