1-oxide Reissert-Henze reaction

Heterocyclic N-oxides such as pyridine, quinoline, or isoquinoline N-oxides can be converted into a mixture of 2- and some 4-cyanopyridines, 2- or 4-cyanoquino-lines, or 1-cyanoisoquinolines, in 40-70% yield, in a Reissert-Henze reaction, by activation of the N-oxide function by O-acylation [1] or O-alkylation [2, 3] followed by treatment with aqueous alkali metal cyanide in H2O or dioxane. 

Benzoylation constitutes the first step of the Reissert and Reissert-Henze reactions of quinoline and quinoline 1-oxides respectively, but as the benzoyl intermediates are rarely isolated this topic will be dealt with in Section 2.05.4.7. Pyridine and quinoline N-oxides react easily with p-toluenesulfonyl chloride in pyridine solution to give a variety of products which closely resemble those from the last two reactions discussed (equations 22 and 23). These belong to a family of reactions that have considerable synthetic potential and much mechanistic interest (B-67MI20501) which will be discussed collectively in Section 2.05.4.5. 

The Reissert-Henze and the Feely-Beavers-Tani reactions are considered together in this section because of their similarity. The former involves cyanation of acyloxy (formed in situ) (Scheme 113), and the latter alkoxy (Scheme 114), quaternary salts. The Reissert-Henze reaction is a facile, fairly general reaction for quinoline and isoquinoline AT-oxides (Table 19) with cyanation occurring a to the ring nitrogen. Certain substituents inhibit reaction, for example a 1-methyl group (equation 125), and others undergo replacement (Scheme 130) (81H(15)98l). Reaction of 1-methylisoquinoline 2-oxide with benzoyl chloride... 

Table 19 Reaction of Af-Oxides with Cyanide Ions Reissert-Henze Reactions... 

In the Reissert-Henze reaction, quinoline 1-oxide reacts with benzoyl chloride and potassium cyanide to give 2-cyanoquinoline in good yield (Scheme 30). Pyridine 1-oxides undergo the Reissert-Henze reaction readily when the reaction is carried out in non-aqueous medium using PhCOCl-Me3SiCN (Scheme 31). Pyrimidine /V-oxides and pyrazine /V-oxides also undergo Reissert-Henze reactions. 

Reissert compounds have been prepared from compounds (21) and (23) using either trimethylsilyl cyanide or potassium cyanide as the cyanating agents. Yields ranged from 57% to 71 % <84JHCl 119, 86JHC545). The N-oxides of some thieno[2,3-6]pyridine derivatives, as shown in Equation (8), have been used in the Reissert-Henze reaction to produce cyano-substituted products <83JHC213>. 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

When the iV-alkoxypyridinyl compound is subjected to cyanide, it imdergoes the Reissert-Henze reaction to afford the 2-cyano-derivative with loss of the alkoxy group. Ethylation of W-oxide 311 with diethylsulfate afforded intermediate 312, which was treated with cyanide to afford the corresponding cyano-pyridine 313, an intermediate used in the synthesis of 5-adenosylmethionine decarboxylase inhibitor 314. ... 

Later on, trimethylsilylcyanide and diethyl phosphorocyanidate (DEPC) were also found to activate the A -oxide in the above the Reissert-Henze reaction. In addition, lithium diethylphosphite was used as the nucleophile other than cyanide as shown in the transformation of N-methoxy pyridine 315 into the diethylphosphonate 316. ... 

Another class of useful terpy synthons are carbonitrile-substituted terpyridines. Incorporation of a carbonitrile group at the 6- and 6 -positions of terpy can be achieved from the pyridine di-N-oxide, using a modified Reissert-Henze reaction with Me3Si(CN) and an acyl-chloride to provide the 6,6 -di(carbonitrile)terpyridine (4) [31, 32],... 

A -Activation in quinolines (through acylation) and pyridines (through etherification of the respective A-oxides) allows the nucleophilic addition of [ CJcyanide to the position alpha to nitrogen, resulting in the formation of 2-[ C]cyanoquinolines and [2- C]-cyanopyridines (Reissert-Henze reaction). This has been exploited for the preparation of the 2-[ C]cyano derivative 21 in good yield ". ... 

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