Phthalazine Reissert reactions

Sydnonimimes are prepared in a similar way to sydnones (Section 5.03.9.2) but rely on the availability of the appropriate aminonitrile (Scheme 8) <2002CRV1091>. Substituted dihydro- and tetrahydrophthalazine 122 and 124, formed from phthalazine by modification of the Reissert reaction, were converted to the novel sydnonimines 123 and 125 (Equation 22) <1995JHC643>. 

Among examples of reactions of (benzo)pyridazines with activated CH reagents reviewed in CHEC-I <84CHEC-l(3B)i> are the methylation and ethylation of 3(27/)-pyridazinones, substituted with, for example, 4-carboxy, by the corresponding nitroalkanes in DMSO, and the application of the Reissert reaction to phthalazines. More recent examples, including those utilising an acylated intermediate similar to the Reissert reaction, are discussed in Section 6.01.5.4.5.iii. 

Reissert type reactions of pyridazine 1-A -oxides to give 6-cyanopyridazines in poor yield, and the alkylation of a phthalazine Reissert compound to give 1 -methylphthalazine after hydrolysis, were discussed in CHEC-I <84CHEC-1(3B)1). Examples of the use of Reissert type chemistry and an unusual reaction with cyanide ion are described below. 

Note. The classical Reissert reaction may be considered as the addition of benzoyl cyanide (supplied as benzoyl chloride and potassium cyanide) across a —HC=N— portion of an appropriate heteroaromatic substrate to afford an A -benzoyl-C-cyanodihydro derivative. It was applied first to phthalazine circa 1967 ( 333) and subsequently improved and extended greatly, as illustrated in the examples that follow. 

Note. Phthalazine undergoes several two-synthon additions, clearly akin to the Reissert reaction but affording 2-acylphthalazines with a 1-substituent other than cyano. 

The main routes to such nitriles have been covered already by primary synthesis (Chapter 8), by the Reissert reaction (Section 9.1.3), by cyanalysis of halogen-ophthalazines (Section 10.3.5), from phthalazine N-oxides (Section 11.6), by cyanolysis of alkylsulfonylphthalazines (Section 12.3), and by dehydration of phthalazinecarboxamides (Section 14.4.2). Other preparative methods are exemplified here. 

Polyhydro-azine preparation with carbanionic species is well known, and many variants using enamines, Michael acceptors, etc. have been described in the past. This year s selection includes work on Reissert reactions of phthalazines (Scheme 43) various enamine annelations leading to alkaloid skeletons [for example... 

Reissert type reaction, 3, 25 Phthalazine, tetrahydro-synthesis, 3, 44 Phthalazinediones in synthesis of (3S,5S)-5-... 

Reissert compounds (>70%), derived from benzimidazole, phthalazine, quinoline and isoquinoline, have been prepared by a simple catalysed one-pot N-acylation of the appropriate heterocycle, followed by reaction with cyanide ion [e.g. 101-103],... 

Koizumi et al.266 have reported the synthesis of Reissert compounds under PT conditions. Ulf and Budrham267 report the same reaction with phthalazines (171). 

The acid-catalyzed hydrolysis continues to be used as a highly satisfactory method for the synthesis of quinaldic acids. The reaction of Reissert compound (7) with hydrobromic acid in acetic acid gave near quantitative yields of quinaldic acid hydrobromide with no contamination from other acid derivatives and would appear to be the method of choice for this conversion. This method has subsequently been used to produce high yields of benzo(/)quinoline-3-carboxylic acid and phthalazine-1-carboxylic acid. ... 

Most activity in this area has centered around the isolation of so-called pseudo-bases (82) in which the cyano group is replaced by a hydroxy group. Thus the pseudo-base is obtained, in addition to the normal Reissert compound, from S-nitroisoquinoline, " 3-methyl-5-nitroisoquinoline, 6-nitroquinoline, and phthalazine. Heating the pseudo-bases in alcohol gives rise to the ethers 83. A discussion of some of the chemistry and properties of the pseudo-bases has appeared. The formation of the pseudo-bases can be suppressed and that of the Reissert compounds increased by the use of a phase-transfer catalyst. Pseudo-bases have also been obtained in attempts to form Reissert compounds from 1,6-naphthyridine and 4,6-phenanthroline. 2-Phenyl-1,2,3-thiadiazole and benzoyl chloride in the presence of cyanide gave 84 and imidazo[l,5-a]pyrazines with acid chloride gave 85 in reactions analogous to the pseudo-base formation. 

The paper reporting the reaction of isoquinoline and potassium cyanide with dialkyl chlorophosphates and dialkyl chlorothiophosphates to give products of the type 114 has now appeared. These compounds can be alkylated in the same manner as a normal Reissert compound, and hydrolysis of the alkylation product gives 1-methylisoquinoline. A phthalazine analog (115) has also been prepared. ... 

Dimethylphosphoryl Reissert type adducts are prepared by the reaction of phthalazine with acid and sulfonyl chlorides in the presence of trimethyl phosphite and sodium iodide (Equation (8)). Phthalazine is not very reactive under these conditions, especially with the acid chlorides the structure of the methylsulfonyl derivative was confirmed by x-ray analysis <90CPB1504>. 

Modified conditions have been developed for the preparation of cyanoheteroarenes from hetero-arene Woxides by the Reissert-Henze reaction, using TMSCN and DBU (Equation (9)). DBU as base is much more productive than triethylamine, which gave only 37% yield in 180 minutes compared to 76% in 40 minutes for the example shown <92H(33)2l l >. The use of tri- -butyltin cyanide with benzoyl chloride for the preparation of Reissert compounds when applied to phthalazine gave... 

Reactions of phthalazinecarbonitriles already covered include conversion of Reissert nitriles into extracyclic hydroxyphthalazines (Section 11.2.1), hydrolysis to phthalazinecarboxylic acids (Section 14.1.1), controlled hydrolysis to phthalazine-carboxamides (Section 14.4.1), and thiolysis to phthalazinecarbothioamides (Section 14.4.1). A variety of other reactions are illustrated in the following examples. 

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