Alkylation of Activated Nitriles

CeHjCHjCN + C2H5CI+ NaOH sCH2N(C2Hs)3Cl CgHy-CH-CN + NaCl 

Alkaline hydrolysis of the alkylated product gives isoquinoline derivatives which are starting materials for the synthesis of alkaloids. 

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The percent ring substitution (% RS) of the polymer with active sites affects catalytic activity. Polystyrenes with < 25 % RS with lipophilic quarternary onium ions are swollen in triphase mixtures almost entirely by the organic phase. Water reduces the activity of anions by hydrogen bonding. In most triphase nucleophilic displacement reactions onium ion catalysts with <25% RS are highly active, and those with >40% RS, such as most commercial ion exchange resins, are much less active. However, low % RS is not critical for the reactions of hydroxide ion with active methylene compounds, as commericial ion exchange resins work well in alkylation of active nitriles. 

Sawamura, M., Sudoh, M., and Ito, Y., An enantioselective two-component catalyst system. Rh-Pd-catalyzed allylic alkylation of activated nitriles, 7. Am. Chem. Soc., 118, 3309, 1996. 

Nucleophilic displacement reactions and alkylations of active nitriles and carbonyl compounds comprise the two most important classes of phase transfer catalyzed reactions. Balakrishnan l> 2 has carried out a detailed kinetic study of alkylation reactions using polystyrene-supported benzyltrimethylammonium ion catalysts. 

Sawamura M, Sudoh M, Ito Y (1996) An enantioselective two-component catalyst system Rh-Pd-catalyzed allyhc alkylation of activated nitriles. J Am Chem Soc 118 3309-3310... 

The alkylation of activated halogen compounds is one of several reactions of trialkylboranes developed by Brown (see also 15-16,15-25,18-31-18-40, etc.). These compounds are extremely versatile and can be used for the preparation of many types of compounds. In this reaction, for example, an alkene (through the BR3 prepared from it) can be coupled to a ketone, a nitrile, a carboxylic ester, or a sulfonyl derivative. Note that this is still another indirect way to alkylate a ketone (see 10-105) or a carboxylic acid (see 10-106), and provides an additional alternative to the malonic ester and acetoacetic ester syntheses (10-104). 

Although ethers have been used less frequently than alcohols, it has recently been reported that tetrahydrofuran (THF) is photocatalytically activated by TBADT, and the alkylation of unsaturated nitriles is obtained in good yield [15]. As an alternative, the C—Br bond in various glycosyl bromides has been homolytically cleaved, and the resulting radical trapped by acrylonitrile to form the corresponding C-glycosides. The halogen abstraction step is initiated by a photolabile iron-based dimeric metal complex [16]. 

Usually, the aqueous salt could be too hydrophilic to allow the quaternary salt to dissolve in the organic phase, and resided exclusively in the aqueous phase anion exchange occured at or near the interface. The mechanism is applied to carbanion reactions, carbene reactions, condensation of polymerization, and C-alkylation of active methylene compounds such as activated benzylic nitriles, activated hydrocarbons, and activated ketones under PTC/OH. In most cases, the reaction involves the Q OH complex because QOH is highly hydrophilic and has extremely low solubility in the organic phase. 

Alkylation of nitriles. An example (equation I) of a general method for alkylation of active methylene groups by phase-transfer catalysis has been 4Ncribed in detail. ... 

The C-alkyl derivatives of activated nitriles are useful intermediates for the manufacture of various pharmaceuticals and are commonly used in industry. Similarly, N-benzoyl-l,2-dihydroisoquinaldenitrile can be alkylated (Scheme M) " in presence of NaOH (aq.) and TEBA. 

The association of RuH2(CO)(PPh3)3 (0.5 mol%) with Xantphos hgand (0.5 mol%) led to the formation of the RuH2(CO)(diphosphine)(PPh3) complex, which had a positive effect on the reactivity of the ruthenium catalyst for alkylation of activated methylene substrates including malonates, ketonitriles and ester nitriles [40]. 

Omission of the side chain methyl group also leads to an active analgesic, the potency of which is somewhat less than half that of the parent. Alkylation of the familiar nitrile with N (2-chioroethyl)dimethylamine gives the amine, 126. Reaction with... 

Replacement of one of the phenyl groups by an alkyl group of similar bulk, on the other hand, alters the biologic activity in this series. Alkylation of phenylacetonitrile with isopropyl bromide affords the substituted nitrile, 136. Treatment of the anion prepared from 136 with strong base with 2-dimethylamino-l-chloropropane gives isoaminile (137). It is of note that alkylation of this halide, isomeric with that used in the early methadone synthesis, is apparently unaccompanied by isomer formation. Isoaminile is an agent with antitussive activity. 

ANILINES, BENZYL AMINES, AND ANALOGUES An orally active local anesthetic agent that can be used as an (intiarrhythmic agent is meobenti ne (57). Its patented synthesis starts with -hydroxyphenyl nitrile and proceeds by dimethyl sulfate etherification and Raney nickel reduction to Alkylation of -methyl-dimethylthiourea with completes l.he synthesis of meobenti ne (57). ... 

The reductive capability of CgK has been a subject of interest (LA). Uses for CgK include the reductive cleavage of carbon-sulfur bonds (S5), the reductive alkylation of nitriles and esters (S6), and the reductive alkylation of aldehydes and ketones (S7). The activity of CgK has... 

Another important click reaction is the cycloaddition of azides. The addition of sodium azide to nitriles to give l//-tetrazoles is shown to proceed readily in water with zinc salts as catalysts (Eq. 11.71).122 The scope of the reaction is quite broad a variety of aromatic nitriles, activated and nonactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. The reaction of an arylacetylene with an azide in hot water gave 1,4-disubstituted 1,2,3-triazoles in high yields,123 while a similar reaction between a terminal aliphatic alkyne and an azide (except 111 - nitroazidobenzcnc) afforded a mixture of regioisomers with... 

A more highly substituted pyrrolidone, doxapram, shows activity as a respiratory stimulant. Preparation of this agent involves an interesting rearrangement, which in effect results in a ring exchange reaction. Alkylation of the anion from diphenylacetonitrile with the chloropyrrolidine 14 affords 15. Hydrolysis of the nitrile function leads to the... 

Interposition of an oxygen atom between the aromatic ring and the imidazoline-bearing side chain leads to a compound reported to show antidepressant activity. Its preparation begins with alkylation of phenol 125 with chloroacetonitrile to afford intermediate 126. Condensation of that nitrile with the... 

Rapid monoalkylations are achieved in good yield compared with classical methods. Of particular interest is the synthesis of ot-amino acids by alkylation of aldimines with microwave activation. Subsequent acidic hydrolysis of the alkylated imine provides leucine, serine, or phenylalanine in preparatively useful yields within 1-5 min [50], Alkylation of phenylacetonitrile was performed by solid-liquid PTC in 1-3 min under microwave irradiation (Eq. 36 and Tab. 5.14). The nitriles obtained can subsequently be quickly hydrolyzed in a microwave oven to yield the corresponding amides or acids [56]. 

Typical liquickliquid alkylation of methylene groups activated by a carbonyl or nitrile group... 

The addition of sodium azide to nitriles to give IH-tetrazoles is shown to proceed readily in water with zinc salts as catalysts. The scope of the reaction is quite broad a variety of aromatic nitriles, activated and unactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction. 

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