Addition of nitriles

Addition of hydrogen cyanide or nitriles to olefins in the presence of concentrated sulfuric acid or some other strong acid is a preparatively important method of synthesizing alkylated amides containing secondary or tertiary alkyl groups on the nitrogen atom (the Graf-Ritter reaction) 20-26 

This reaction takes place in glacial acetic acid or in dibutyl ether at room temperature or on moderate warming and gives good yields. 

As an example of the ready reaction the preparation of N-acetyl-a-methyl-benzylamine20 may be cited  

Styrene (10.4 g) and acetonitrile (6.1 g) are mixed and added to a solution of benzene-sulfonic acid (17 g) in glacial acetic acid (50 ml). The whole is set aside for 15 h, then poured on crushed ice (200 g) and neutralized with aqueous ammonia. A viscous oil that separates is extracted three times with ether (100-ml portions). The extracts are united, dried over potassium carbonate, and freed from ether. The residue is distilled (b.p. 175-180°/7 mm). Recrystallization of the distillate from light petroleum gives the product (7 g, 43 %), m.p. 72 to 73°. 

The formamides resulting from the use of hydrogen cyanide can be particularly easily hydrolysed to the amines, thus providing an elegant method for synthesis of tertiary alkylamines that are otherwise difficult of access.21 The reaction is capable of very wide generalization and is suitable also for the preparation of other classes of compound such as A-acylamino acids,23 isoquinolines,24 and oxazolines.25 

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Cycloahphatics capable of tertiary carbocation formation are candidates for nucleophilic addition of nitriles. HCN in strong sulfuric acid transforms 1-methyl-1-cyclohexanol to 1-methyl-1-cyclohexylamine through the formamide (47). The terpenes pinene (14) [2437-95-8] and limonene [5989-27-5] (15) each undergo a double addition of HCN to provide, after hydrolysis, the cycloahphatic diamine 1,8-menthanediamine (16) (48). 

A useful synthesis of polysubstituted pyridines (i.e., 11) is based on the legioselective addition of Uthiated -enaminophosphonates to unsaturated carbonyl compounds. These pyridines can also be obtained via a one-pot reaction from metalated phosphonates and sequential addition of nitriles and unsaturated caibonyl compounds <96TL(37)4577>. 

The reaction of the anion ICHXY with 75 shows a marked solvent dependence60. Addition of nitriles, e.g. CH3CN, suppresses the addition at C1 — sometimes observed as a side reaction (77) — in favor of addition at C3 resulting in triafulvene formation... 

DFT studies of the intramolecular ene-like (or the so-called 1,3-dipolar ene) reaction between nitrile oxides and alkenes show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular [3 + 2] cycloaddition between nitrile oxides and alkenes or the intermolecular dimerization of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reaction if the tether joining the nitrile oxide and alkene is elongated, or if substituents such as trimethylsilyl are absent (425). 

Iridium hydride complexes effectively catalyze addition of nitriles or 1,3-dicarbonyl compounds (pronucleophiles) to the C=N triple bonds of nitriles to afford enamines.42S,42Sa Highly chemoselective activation of both the a-C-H bonds and the C=N triple bonds of nitriles has been observed (Equation (72)). To activate simple alkane dinitriles, IrHs(P1Pr3)2 has proved to be more effective (Equation (73)). The reaction likely proceeds through oxidative addition of the a-C-H bonds of pronucleophiles to iridium followed by selective insertion of the CN triple bonds to the Ir-C bond. 

Formally related reactions are observed when anthracene [210] or arylole-fines [211-213] are reduced in the presence of carboxylic acid derivatives such as anhydrides, esters, amides, or nitriles. Under these conditions, mono- or diacylated compounds are obtained. It is interesting to note that the yield of acylated products largely depends on the counterion of the reduced hydrocarbon species. It is especially high when lithium is used, which is supposed to prevent hydrodimerization of the carboxylic acid by ion-pair formation. In contrast to alkylation, acylation is assumed to prefer an Sn2 mechanism. However, it is not clear if the radical anion or the dianion are the reactive species. The addition of nitriles is usually followed by hydrolysis of the resulting ketimines [211-213]. 

Cyclodextrines, modified with 2-cyanoethyl and with bis(2-cyanoethyl)amino groups were used as ligands in the [PdCy + [CuCU]-catalyzed Wacker-oxidation of 1-octene. Without the modified cyclodextrins the yield of 2-octanone was less than 1 %, which could be raised to 73 % by the addition of nitrile-modified P-cyclodextrin ligands (60 °C, 2 h). 

Substituted 1,2,4-oxadiazoles were prepared by addition of nitrile oxides to imines or hydrazones. It has been reported that interaction of hydroximoyl chlorides 262 with chiral hydrazones 263 in the presence of EtsN leads to intermediates 264 with diastereoselectivity up to 97%. A subsequent N-N bond cleavage to remove chiral auxiliary by formic acid leads to 1,2,4-oxadiazolines 265 with ee up to 91% (equation 113). ... 

The synthesis of quinazoline derivatives by the addition of N(3)-C(4) fragment units has not previously been a major synthetic route, but 2,4-dialkyl, alkyl/aryl, and diaryl quinazolines 865 are now readily available by a new procedure that involves activation of A -arylamides 864 with trifluoromethanesulfonic anhydride and 2-chloropyridine, and subsequent addition of nitriles <2006JA14254>. Either normal or microwave heating can be used to perform the final ring-closure step. 

In the first addition of nitrile ylides to a,()-unsaturated lactones (92), it was found that the reaction of benzonitrilio 4-nitrobenzylide with the lactones 178-180 were strongly regioselective. Compounds 178 and 179 reacted to give [e.g., 181 from 178 (51%)] and its methyl analogue from 179 (54%). The exocyclic double bond in 180 was, however, the most reactive and gave 182 (69%). The six-membered analogue of 178 was less reactive (34%) and the seven-membered analogue failed to react. 

Arylation of malononitriles 5-17 Addition of nitriles to unsaturated nitriles (Michael)... 

Reaction between aldehydes and ketones, zinc, and halo nitriles 6-41 Addition of nitriles to ketones 6-49 Addition of HCN to aldehydes or ketones... 

The kinetics of the oxidative addition of nitriles to Ni(P—P)2 have been studied. The organocyano nickel(II) complexes presumably have a dinuclear structure with trans planar coordination for the nickel atom.270 Some of the [Ni(CN)(R)(PR3)2] compounds (R = alkyl, aryl) are unstable and therefore cannot be isolated in the solid state. Their decomposition in solution promotes the formation of alkanes, alkenes, diphenyl, etc.217... 

Most of the approaches outlined in Figure 15.10 have been successfully realized on insoluble supports, either with the alkene or alkyne linked to the support, or with support-bound 1,3-dipoles (Table 15.16). Nitrile oxides are highly reactive 1,3-dipoles and react smoothly with both electron-poor and electron-rich alkenes, including enol ethers [200]. The addition of resin-bound nitrile oxides to alkenes (Entries 5 and 6, Table 15.16) has also been accomplished enantioselectively under catalysis by diisopropyl tartrate and EtMgBr [201], The diastereoselectivity of the addition of nitrile oxides and nitrones to resin-bound chiral acrylates has been investigated [202], Intramolecular 1,3-dipolar cycloadditions of nitrile oxides and nitrones to alkenes have been used to prepare polycyclic isoxazolidines on solid phase (Entries 7 and 9, Table 15.16). 

A variety of ligands other than phosphites are of course also important in hydrocyanation. The isolation of the 16-electron complex Ni[P(0-o-tolyl)3]3 (17) provided a remarkable opportunity for the study of how various components of the catalytic system interact with nickel. The addition of nitriles to this complex led to the observation of the first nitrile complex of zero-valent nickel (25). When the phosphite ligands are very bulky, as in the case of P(0-o-tolyl)3, a nitrile complex of formula (RCN)NiL3 is formed nearly quantitatively even in the presence of excess L, and is identified easily... 

Regio- and enantio-selective additions of nitrile amines (R1-C=N+-N--R2, from the hydrazonyl bromide) to enones allows access to dihydropyrazoles close to enantiop- urity, via a 3 + 2-cycloaddition.65... 

Addition of Nitriles to Carbon-Carbon (Michael Addition) and Carbon-Nitrogen Multiple Bonds... 

Addition of nitriles to acetylenic compounds proceeds with chemoselectivity in contrast with the corresponding base-promoted reactions, where the products derived from acetylides are contaminants. The RuH2(PPh3)4-catalyzed reaction of ethyl 2-cyanopropionate (12) with methyl propiolate (14) at room temperature gave 15 in 90 % yield. 

The principle can be also applied to the addition of nitriles to imines. The reaction of 2-methylmalononitrile (16) with 4-methoxycarbonyl-N-(4-methylbenzylide-ne)aniline(17) in the presence of 1 [8] or RhH(CO)(PPh3)3 (15) [16] gave the corresponding cyano amine 18 in 91 % yield. 

Scheme 5. Catalytic Michael Addition of nitrile and addition of nitriles to acetylenes and imines.

Catalytic Thorpe-Ziegler reaction (Addition of Nitriles to Nitriles)... 

Scheme 2. Selected examples for Pd-catalyzed addition of nitriles to C-C multiple bonds dba = dibenzylideneacetone dppb = 1,4-bis(diphenylphosphino) butane dppf= l,l -bis(diphenylphosphino)-ferrocene.

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