Lithium diisopropylamide nitriles

Alpha hydrogen atoms of carbonyl compounds are weakly acidic and can be removed by strong bases, such as lithium diisopropylamide (LDA), to yield nucleophilic enolate ions. The most important reaction of enolate ions is their Sn2 alkylation with alkyl halides. The malonic ester synthesis converts an alkyl halide into a carboxylic acid with the addition of two carbon atoms. Similarly, the acetoacetic ester synthesis converts an alkyl halide into a methyl ketone. In addition, many carbonyl compounds, including ketones, esters, and nitriles, can be directly alkylated by treatment with LDA and an alkyl halide. 

The conversion of the polystyrene-supported selenyl bromide 289 into the corresponding acid 290 allowed dicyclohexylcarbodiimide (DCC)-mediated coupling with an amidoxime to give the 1,2,4-oxadiazolyl-substituted selenium resin 291 (Scheme 48). Reaction with lithium diisopropylamide (LDA) and allylation gave the a-sub-stituted selenium resin 292, which was then used as an alkene substrate for 1,3-dipolar cycloaddition with nitrile oxides. Cleavage of heterocycles 293 from the resin was executed in an elegant manner via selenoxide syn-elimination from the resin <2005JC0726>. 

Lithium salts of resonance-stabilized organic anions have also found a role in carbon-phosphorus bond formation by displacement at phosphorus. The generation of the lithium salt derived from acetonitrile (or other aliphatic nitriles by reaction with butyl lithium or lithium diisopropylamide) provides for carbon-phosphorus bond formation by displacement of halide from phosphorus (Equation 4.24).68... 

The third synthetic route reported by Husson and co-workers 140) is as follows Amino nitrile 472 obtained from the ketal (471) was converted to the 2,6-dialkylpiperidine (473) by catalytic hydrogenation followed by alkylation with lithium diisopropylamide and pentyl bromide. Refluxing a solution of 473 in methanol containing hydrochloric acid led to the formation of 9-benzyladaline (475) in 90% yield. Debenzylation of 475 gave d/-adaline (107) in nearly quantitative yield (Scheme 59) 140). 

Metalation of 2 with lithium diisopropylamide (LDA) generates diazo(trimethyl-silyl)methyl hthium (3), which reacts with a,p-unsaturated nitrile 36 and phenyl-sulfones (37) to form 3(or 5)-trimethylsilyl-l//-substituted pyrazole 4 that can be desilylated to furnish pyrazoles 5 (Scheme 8.3). 

A somewhat different approach to this series of compounds involves the reaction between a carbanion and an aromatic nitrile. Thus, a series of methylpyrazines 253 is first treated with lithium diisopropylamide (LDA) to generate an anion at the methyl group. Addition of an aromatic nitrile produces 254 (Equation 89) <2003JME222, 2004EUP1388541>. Many other examples have been reported <2003JME222>, including some with substituents at the open position in structure 254. 

Preparation of 7-arylmethyl-17/-pyrrolo[3,4-r-]pyridine-l,3-(27/)-diones 128 from 5-bromonicotinamide, arylaceto-nitriles, and lithium diisopropylamide (LDA) occurs via a pyridyne mechanism (Scheme 21). Under similar conditions, 5-chloro-3-pyridinol and arylacetonitriles afford the C-5 substitution products (Equation 49) <1998T3391>. 

The use of 6-methyl-2,3,4,5-tetrahydropyridine 163 has been widely reported in the synthesis of heterocycles due to its ability to be deprotonated selectively on the o -methyl group using lithium diisopropylamide (LDA). Deprotonation of tetrahydropyridine 163 with LDA followed by addition of a nitrile and propargyl bromide give tetrahydroindolizines 164 in moderate to high yields (Equation 12) <1996JOC2185>. 

Alkyl and arylmagnesium halides react with 2-methylquinoxaline by addition of one mole of reactant to the 3,4-bond. After hydrolysis the 2-alkyl- or 2-aryl-l,2-dihydro-3-methylquinoxalines (52) are obtained. When ethylmagnesium bromide is used a dimeric by-product (53) is also isolatedReaction of 2,3-dimethylquinoxaline with benzonitrile and lithium amide gives l-amino-l-phenyl-2-(3-methyl-2-quinoxalinyl)-ethylene (54). The mono- and dilithium salts of 2,3-dimethylquinoxaline have been generated from the quinoxaline by reaction with one or two equivalents of lithium diisopropylamide (LiNPr, respectively. These salts have been reacted with a variety of electrophilic reagents such as alkyl halides, aryl ketones, esters, and nitriles. " ... 

Oxidative decyanation. Selikson and Watt have converted secondary nitriles, for example (1), into ketones (4) by the following sequence. The anion (a) is generated with lithium diisopropylamide in THF at -78° and then oxygen is bubbled into the solution of (a). A lithium a-cyanohydroperoxide (b) is formed. Quenching with aqueous acid or acetyl chloride provides the isolable a-hydroperoxynitrile (2) or the corresponding acetate. Reduction of (2) leads... 

Lithium diisopropylamide 1-Aminoisoquinolines from 2 nitrile molecules... 

Lithium diisopropylamide j sulfuric acid 6,7,8,8a-Tetrahydropyrrolo[l,2-alpyrimidines from Y>(alkylideneamino)acetals and nitriles... 

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. 

DITHIANES (SCHEME I). The dithiane benzamides were synthesized from the commercially available (Aldrich Chemical Co.) ethyl 1,3-dithiane-2-carboxylate. Treatment (2-4) with a base (e.g. lithium diisopropylamide) followed by methyl iodide or ethyl iodide gave the substituted dithiane esters 1. For the synthesis of isoxazoles, the esters were treated with acetonitrile and base to give the keto nitrile 2. Treatment with hydroxylamine gave the desired amino-isoxazolyldithiane 3. Condensation with 2,6-dimethoxybenzoyl chloride yielded dithianes 4a-c. Overall yields for these compounds were good. 

The chemical operations described in the literature to introduce or into citric acid molecule are based essentially on the Grimaux and Adam synthesis. Labeled citric acid was prepared by Wilcox et al. [35] in the reaction of Na CN with 3-chloro-2-carboxy-2-hydroxybutyric acid and the formed nitrile was hydrolyzed directly with hydrochloric acid. From this solution, citric acid was isolated in the form of calcium citrate and finally converted to the acid. An alternative procedme was proposed by Rothchild and Fields [36] to obtain trimethyl citrate from labeled sodium cyanide and di-chloromethyl glycolate. A more complex synthesis of C labeled citric acid is described by Winkel et al. [39]. They used labeled methyl acetate and acetyl chloride (in the presence of hthium 1,1,1,3,3,3,-hexamethyldisilazide, [(CH3)2Si]2NLi which was dissolved in tetrahydiofuran) to obtain methyl acetoac-etate. It reacts in the presence of lithium diisopropylamide, [(CH3)2CH]2NLi, also dissolved in tetrahydrofuran, with dimethyl carbonate to give dimethyl 1,3-ace-tonedicaiboxylate. It is dicarboxylated by the action of bisulfite and potassium cyanide is converted to 3-cyano-3-hydroxy-l,5 pentanedioate and finally hydrolyzed by hydrochloric acid to citric acid. 

Recently, a new synthetic route (Figure 10.5) to symmetric alkyl branched dienes has been presented and utilized in the synthesis of a whole family of precision alkyl-branched polyolefins (Rojas et al, 2007). This general route, which can be used to create dienes with virtually any branch, involves only two steps with quantitative yields. The first step is the dialkylation of a primary nitrile using freshly prepared lithium diisopropylamide (LDA). Alkylation in this fashion affords a symmetric diene premonomer with the desired alkyl branch and a nitrile group on the central carbon. In the next step, this nitrile is removed by reductive elimination in the presence of potassium metal, HMPA, and r-butanol. 

A variety of carbanionic species derived from carboxylic acids, esters, amides, and nitriles have been prepared and added to aldehydes and ketones. Usually, strong bases such as lithium diisopropylamide are used owing to the low level of... 

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