Cyanation of tertiary amines

The photooxidation of tertiary methylamines sensitized by electron acceptors such as 9,10-dicyanoanthracene in the presence of lithium perchlorate results in demethylation thus tropinone yields nortropinone257. Photoinduced cyanation of tertiary amines with oxygen, a sensitizer and trimethylsilyl cyanide results in a-cyano nitriles (equation 88)258. 

There is a primary alcohol-to-aldehyde step in the synthesis of (+)-batzelladine A, and it was suggested that the oxidation of the primary alcohol (1) with TRAP/ NMO/PMS/CH Cl proceeds through an iminium-Ru alkoxide complex (2), rearranging as in (3)-(4) to give the aldehyde (5) (Fig. 1.13) [101] (a similar mechanism was proposed for the Ru-catalysed oxidative cyanation of tertiary amines [403] cf. 5.1.3.4, Fig. 5.3). 

Cyanation of tertiary amines RNMe to the corresponding a-aminonitriles RNCH(CN) Me was catalysed by RuCl3/Na(CN)/CH3OH-AcOH/60°C (R=Ph, m-MeC H, p-MeC y, p-BrCgH or p-PhOC y). Thus A,A-dimethylaniline gave A-methyl-A-phenylaminoacetonitrile in 93% yield after 2 h (Fig. 5.3 cf mech. Ch. 1) [39]. 

Scheme 12 Anodic cyanation reaction 4.3.1 Cyanation of Tertiary Amines...

Recently, a new type of reaction - that is, aerobic oxidative cyanation of tertiary amines - was discovered. In this reaction, oxidation with molecular oxygen in place of peroxides, in addition to direct carbon-carbon bond formation by trapping of the iminium ion intermediates with a carbon nucleophile under oxidative conditions, is accomplished simultaneously. The ruthenium-catalyzed oxidation of tertiary amines with molecular oxygen (1 atom) in the presence of sodium cyanide gives the corresponding a-aminonitriles (Eq. 3.74) [132], which are useful for synthesis of a-amino acids and 1,2-diamines. 

Scheme 3 Ruthenium-catalyzed oxidative cyanation of tertiary amines with sodium cyanide...

Santamaria et al [42] for synthesizing a-amino nitriles in the alkaloid field and also for preparing 6-cyano-l,2,3,6-tetrahydropyridine from corresponding pyridine nucleus. A similar approach has also been used by Sundberg et al. [43a,43b] for the cyanation of Catharanthine alkaloids. In situ trapping of the iminium cation (37) by allyltrimethylsilanes or silyl enol ethers is also shown [44] recently as a direct —C-C— bond formation methodology at the a-posi-tion of tertiary amines (Scheme 8). The success of this reaction is based on the comparative correlation of ion-pair yield with the AGg, values from amines and enol ethers. 

Anodic cyanation of tertiary aliphatic and heterocyclic amines in sodium cyanide-aqueous methanol solutions using platinum electrodes takes place a-to the nitrogen atom to form the a-cyano-amines in reasonable yields. ... 

Murahashi et al. [1] reported Ru(III)-catalyzed aerobic oxidative cyanation of N,N-dimethylanilines with NaCN in 2003, and the next year Li and co-workers developed an efficient Cu(I)-catalyzed alkynylation of tertiary amines with TBHP... 

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

The anodic cyanation of A-alkyl tertiary cyclic amines can give a mixture of regioisomers as observed in Scheme 109. 

Photo-oxidation of l,l-dialkyl-2-arylhydrazines by single-electron transfer with trimethylsilyl cyanide (TMSCN) as cyanide ion source leads to regio- and stereoselective a-hydrazino nitriles. This stereoselective cyanation of hydrazines takes place on the more substituted carbon atom compared with the results obtained with tertiary amines (Scheme 5). 

Aromatic cyanates are synthesized by the condensation of phenols with C1CN and a tertiary amine [1], The most important dicyanate is 2,2-bis(4-cyanatopbenyl) propane or Bisphenol A dicyanate [2] (Scheme 1). 

Cyanate esters (CEs) are formed in excellent yields by the reaction of the corresponding phenols with cyanogen halide [34]. The reaction scheme is shown in Scheme la. The reaction is usually carried out in solution, in the presence of a tertiary amine as the acid scavenger at very low temperatures. Since the trimer-ization reactions of cyanate esters are highly prone to catalysis by spurious impurities, the most difficult aspect of cyanate ester synthesis is their scrupulous purification. Low molar mass esters are purified by distillation or recrystallization. Polymeric cyanates are purified by repeated precipitation in non-solvents such as water, isopropanol, etc. While distillation and recrystallization lead to pure materials, the precipitation method for polymeric cyanates is not always conducive to obtaining pure materials. A recent patent application claims a purification method for polymeric cyanates based on treatment with cation and anion exchangers [35]. 

When either of these two procedures was applied to tertiary amines, cyanation occurred at an a. position ... 

One of the most interesting cyanate esters is derived from Bisphenoi A. Blsphenol A Is widely used as a starting material for epoxy resins, poly- carbonate resins, polysulphones, polyetherimldes and polyarylates. Bisphenoi A dicyanate can be commercially produced by reacting bisphenoi A with cyanogen chloride in the presence of a tertiary amine such as triethyl andne. 

Oxidation of (-amines in the presence of NaCN affords a-cyanoamines in 53-83% yield. Tertiary a-cyanoamines are known to afford iminum salts by loss of cyanide ion and this oxidative cyanation is used in a synthesis of the indolizidine... 

Martin et al report investigations on the kinetics and the mechanism of aryl cyanate formation frx>m cyanogen bromide and phenols in the presence of different tertiary aliphatic amines. According to Vo-winkel," the use of diethyl ether as the solvent at -10 C raises the yields and various patents describe how the amines can be replaced by sodium hydroxide. There are even reports on work in aqueous solution under phase transfer conditions. With all synthetic variants it is crucial to avoid a surplus of the phenolate as only under these conditions can the often quite fast formation of imino carbonates be prevented (equation 28). 

---