Reissert-type reactions

A very useful procedure for introducing a cyano group into a pyridazine ring is the Reissert-type reaction of the A/-oxide with cyanide ion in the presence of an acyl halide or dimethyl sulfate. The cyano group is introduced into the a-position with respect to the A-oxide function of the starting compound. The yields are, however, generally poor. In this way, 6-cyanopyridazines (111) can be obtained from the corresponding pyridazine 1-oxides (Scheme 33). 

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

Rawal and Kozmin have utilized a Reissert type reaction in the total synthesis of tabersonine. The requisite nitro ketone is prepared by SNAr reaction of o-nitrophenylphenyliodonium fluoride with ketone silyl enol ether (Scheme 10.10).96... 

Additions to quinoline derivatives also continued to be reported last year. Chiral dihydroquinoline-2-nitriles 55 were prepared in up to 91% ee via a catalytic, asymmetric Reissert-type reaction promoted by a Lewis acid-Lewis base bifunctional catalyst. The dihydroquinoline-2-nitrile derivatives can be converted to tetrahydroquinoline-2-carboxylates without any loss of enantiomeric purity <00JA6327>. In addition the cyanomethyl group was introduced selectively at the C2-position of quinoline derivatives by reaction of trimethylsilylacetonitrile with quinolinium methiodides in the presence of CsF <00JOC907>. The reaction of quinolylmethyl and l-(quinolyl)ethylacetates with dimethylmalonate anion in the presence of Pd(0) was reported. Products of nucleophilic substitution and elimination and reduction products were obtained . Pyridoquinolines were prepared in one step from quinolines and 6-substituted quinolines under Friedel-Crafts conditions <00JCS(P1)2898>. 

The polymer-bound catalyst was recyclable by filtration and showed just slightly decreased activity when reused. Catalyst (33) also promotes asymmetric Reissert-type reactions [106]. 

Including Reissert-type reaction of quinolines and isoquinolines... 

When first reported in 1905, the Reissert reaction demonstrated the addition of KCN to quinoline in the presence of benzoyl chloride, but many new modifications since then have employed other nucleophiles and catalytic promotion by a Lewis acid. Shibasaki reported in 2001 the first catalytic enantioselective Reissert-type reaction. Optimized reaction conditions involving an electron-rich aromatic acid chloride in a low-polarity solvent, and use of catalyst 14, were found to suppress the racemic pathway and resulted in good enantioselectivity (Scheme 2) <2001JA6801>. 

Range of Activating Agents in Reissert-Type Reactions. 132... 

Scheme 9 Range of nucleophiles used in Reissert-type reactions...

Zhu and coworkers implemented a family of Ugi-type MCRs, based on intramolecular trapping of the intermediate nitrilium ion by a carboxamido group, to prepare diversely substituted oxazoles as versatile synthetic intermediates [192-194], They later reported an interesting example of the Ugi-Reissert process using this feature (237, Scheme 34a) [195], This strategy enabled the direct addition of isocyanides to the Ai-alkyl nicotinamide salts 239. However, the different substitution pattern of the carboxamido group, led to a different outcome isomerization of the putative bis-iminofurane intermediate to the cyano-carbamoyl derivative 240. Remarkably, the process is also efficient in a Reissert-type reaction (Scheme 34b, c) [196]. 

Alternative reaction pathways exploring different synthetic possibilities have been studied. For instance, electron-rich dihydroazines also react with isocyanides in the presence of an electrophile, generating reactive iminium species that can then be trapped by the isocyanide. In this case, coordination of the electrophile with the isocyanide must be kinetically bypassed or reversible, to enable productive processes. Examples of this chemistry include the hydro-, halo- and seleno-carba-moylation of the DHPs 270, as well as analogous reactions of cyclic enol ethers (Scheme 42a) [223, 224]. p-Toluenesulfonic acid (as proton source), bromine and phenylselenyl chloride have reacted as electrophilic inputs, with DHPs and isocyanides to prepare the corresponding a-carbamoyl-(3-substituted tetrahydro-pyridines 272-274 (Scheme 42b). Wanner has recently, implemented a related and useful process that exploits M-silyl DHPs (275) to promote interesting MCRs. These substrates are reacted with a carboxylic acid and an isocyanide in an Ugi-Reissert-type reaction, that forms the polysubstituted tetrahydropyridines 276 with good diasteroselectivity (Scheme 42c) [225]. The mechanism involves initial protiodesilylation to form the dihydropyridinum salt S, which is then attacked by the isocyanide, en route to the final adducts. 

Asymmetric two-center catalytic Reissert-type reactions 02CC1989. 

Asymmetric acylcyanation of quinolines (Reissert-type reaction) with 2-furoyl chloride and TMSCN is successfully performed by using the chiral catalyst 168 (Scheme 10.243) [658]. In this reaction the sterically more demanding complex 168b exceeds 168a in enantioselectivity. 

The Reissert-type reaction is considered to proceed via two steps (i) the generation of an acyl quinolinium intermediate by a nucleophilic attack of quinoline to an acid chloride and (ii) the addition of cyanide [150]. Shibasaki has developed an... 

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. 

Makosza et al. recently reported two-step procedure for selective introduction of CF3 or (CF3)2CF group into heteroaromatic ring, using Reissert type reaction between A -acylated heterocycles and the corresponding perfluoroalkyl anions. 

One routine method for the functionalization of quinolines is the addition of substituents to the 2-position. Further advances in the catalytic, enantioselcctive Reissert-type reaction were reported. Quinoline 63 was treated with 2-furoyl chloride and TMSCN in the presence of Lewis acid-Lewis base bifunctional catalyst 64 followed by reduction of the corresponding enamine to afford quinoline 65 in 93% ee. Quinoline 65 was subsequently converted to (-)-L-689,560, a potent NMDA receptor antagonist <01JA6801>. Additions of ally.silanes to quinolines acylated with chloroformate esters and catalyzed by various triflate salts were reported <01T109>. 

Elaboration of isoquinoline derivatives in asymmetric fashion was examined as well in 2001. In a manner similar to that described in section 6.1.3.2, an enantioselective Reissert-type reaction was utilized to construct a chiral, quaternary center at the Cl position of isoquinoline derivatives. For example, treatment of isoquinoline 85 with vinyl chloroformate and TMSCN in the presence of bifunctional catalyst 86 afforded isoquinoline derivatives such as 87 in up to 95% ee. The effect of the R group at the 1-position and the catalyst counterion were detailed. 

The first example of a catalytic enantioselective Reissert-type reaction with electronically tuned bifunctional catalyst 43 as the catalyst was accomplished by the Shibasaki group in 2001 (Scheme 19.52). A broad range of 1-substituted isoquinolines underwent the Reissert-type reaction well, giving the corresponding adducts with chiral quaternary stereocentre in 73-95% enantiomeric excess. 

Scheme 19.52 Asymmetric Reissert-type reactions of isoquinolines catalysed by a bifunctional Al-BINOL derivative.

Scheme 19.53 Asymmetric Reissert-type reactions of pyridine derivatives catalysed by Al-BINOL derivatives.

Shibasaki and coworkers developed a bifunctional chiral catalyst possessing the Lewis acid (aluminum metal) and the Lewis base (phosphine oxide), which was successfully applied to asymmetric Reissert-type reaction of trimethylsilylcyanide (TMSCN) [45]. The reaction of quinoline (92) with TMSCN and 2-furoyl chloride in the presence of Lewis acid Lewis base catalyst (91) occurred to give the Reisser product in 91% yield and 85% ee. The chiral catalyst was connected to JandaJRL... 

Addition to Carbonyls, Imines (Strecker-type Reactions), and Heteroaromatic Rings (Reissert-type Reactions). Cyanohydrin trimethylsilyl ethers are of significant synthetic interest as they can be transformed into a variety of multifunctional intermediates. Aldehydes and ketones can be enantioselectively converted to cyanohydrin trimethylsilyl ethers when treated with cyanotrimethylsilane in the presence of a Lewis acid and a chiral ligand. Enantioselective and/or diastereoselective formation of cyanohydrins and their derivatives has been reported and most of these reactions involve chiral ligands and metal catalysts containing Ti (eq 24), Sm (eq 25), and A1 (eq 26). ... 

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