The Use of Reissert Compounds

A series of bisbenzylisoquinolines has been prepared through alkylation of 6,7-disubstituted isoquinoline Reissert compounds with diaryl ethers such as 8, 9, and 10.  

The sequence involving diaryl ether 9 and the Reissert derivative from 6,7-methylenedioxyisoquinoline is represented here. 

Potassium permanganate in acetone oxidation of a bisbenzylisoquinoline results in selective cleavage at the C-1 to C-a benzylic bond of the isoquinoline moiety which is unsubstituted at C-8. Relative stereochemistry does not affect the site of the oxidation. The product is an aldehydo lactam showing 1640-1645 cm and 1690-1720 cm (5.82-5.92 and 6.08-6.17/a) which can be used for characterization purposes. The C-8 hydrogen peri to the new lactam carbonyl appears in the NMR spectrum as a singlet between 87.20 and 7.42. To exemplify, in the case of the oxidation of (H-)-hernandezine, the C-8 peri proton singlet is found at 87.23. The yields range from 5 to 35% and it is preferable to protect phenolic functions by acetylation prior to oxidation.  

This oxidation has been utilized in the determination of the location of the phenolic function in ( + )-tiliacorine, which had been formulated as either 11 or 12. Permanganate in acetone oxidation of its (9-acetyl derivative, followed by ester hydrolysis, yielded secotiliacorine aldehydo lactam, 212, 282, and 310 sh (4.10, 3.44, and 2.94). This product showed a strong bathochromic shift in base, 230, 292, and 340 nm (4.00, 3.27, and 3.21), indicative of a 

Hernandezine has been prepared from tetrandrine through the sequence of selective monobromination, metal-bromine exchange, and oxygenation of the organometallic intermediate with nitrobenzene followed by 0-methylation. Oxidations of this type have also been extended to the tetrahydrobenzyliso-quinoline and the aporphine series. 

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The chemistry of Reissert compounds has been the subject of numerous general reviews (3-10). In 1973 Popp gave a summary on the use of Reissert compounds in the synthesis of isoquinoline alkaloids and related compounds (7). We now wish to summarize new results that have appeared from 1973 to the end of 1985 for the application of Reissert compounds in the synthesis of isoquinoline as well as indole alkaloids. 

Photocyclization of an enamide (review [2S9S]) containing a methoxy group leads to the formation of a pyridinone ring of an intermediate in the synthesis of (— )-sincitine. Reviews of numerous syntheses of isoquinoline alkaloids [2487] and of the use of Reissert compounds in such syntheses [2488] are available. 

The partial ether cleavage of methoxy- and methylenedioxy-substituted isoquinoline alkaloids has been reviewed in a new journal. Additional reviews concerning the use of Reissert compounds in the total synthesis of isoquinoline alkaloids and related compounds, electro-oxidation and isoquinoline alkaloid biosynthesis, and the synthesis of isoquinoline alkaloids by a systematic design have appeared in early issues of the same journal. The chemotaxonomy of alkaloids, together with distribution within plants, biosynthesis, structural classification, and physiological activity, has been treated in a monograph. ... 

Still a method of choice for the alkylation or acylation of isoquinolines at C-1 is the use of Reissert compounds. These reactions, carefully studied over a number of years by Popp and others, have been thoroughly reviewed. " To cite an example, reaction of the anion of the Reissert compound 8 with formaldehyde furnished the benzoyl ester 9. Hydrolysis followed by catalytic hydrogenation then supplied calycotomine in excellent yield. (A number of Reissert compounds are commercially available from the Parish Chemical Co., Provo, Utah 84601.)... 

Using the original conditions for the formation of Reissert compounds the triazolopyrimidine (91 R = H) undergoes ring fission producing the triazole (92) and the amide (93) (Scheme 6). Under... 

The previous review noted the formation of Reissert compounds from less than half the quinolines investigated and stated that ... the ease of formation of Reissert compounds is dependent upon steric as well as electronic factors, since the presence of substituents in the 2- and 8-positions of quinoline inhibits the formation of. .. Reissert compounds. That a steric factor does indeed exist is evidenced by the fact that from a total of seven 2-substituted and nine 8-substituted quinolines subjected to the reaction none has yielded a Reissert compound. Using the methylene chloride-water solvent system, however, Reissert compounds have been prepared from 3-, 4-, 5-, 6-, and 7-substituted quinolines and from disubstituted quinolines. Quinolines having various substituents in these positions, including all those previously reported as not giving Reissert compounds, gave positive results in this solvent system. In addition to Reissert compound formation, hydroxyquinolines were esterified and aminoquinolines were converted to the amides. 

The acid bromide or acid anhydride may be used in place of the acid chloride but the yields of Reissert compounds are generally not as satisfactory with these reagents. "... 

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. ... 

The major application of the alkylation of Reissert compounds (2) via 26 to 27 and then hydrolysis to 28 has been in the field of alkaloid synthesis. Thus, the Reissert alkylation scheme has been used in the synthesis of amurensine and isoamurensine, caseadine methyl ether, cularine, - ... 

In addition to the conventional sodium hydride method of anion generation, organolithium compounds 50% aqueous sodium hydroxide in acetonitrile and 50% sodium hydroxide with a phase transfer catalyst have been used to generate the anion of Reissert compounds for condensation with aldehydes. A variety of substituted benzaldehydes have been allowed to react with anions of type 26 to give45. ° - ... 

The anion of the Reissert compound (62.1) reacts at or below room temperature with an aldimine or an isothiocyanate by cycloaddition, and then displacement of the nitrile to form a tricyclic isoquinoline. The chemistry of Reissert compounds has been reviewed [2488, 2959a], as have the synthetic uses of isothiocyanates [3990]. 

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. 

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... 

Reissert reaction. The alkylation of Reissert compounds with bcnzylic halides was originally conducted with NaH as base in DMF. Skiles and Cava have examined three more modern systems LDA and HMPT in THF, KOH and a crown ether, and phase-transfer conditions. Of these, the two last systems are clearly superior to the first the phase-transfer system is somewhat superior to the crown ether system, both in yields and economic use of reagents. Cetyltrimethyl-ammonium bromide served as catalyst. 

Sonication [130, 131] aids the standard phase-transfer catalysed [e.g. 132, 133] C-alkylation of Reissert compounds. As much as twofold increases in yield are observed with shortened reaction times. No alkylation is observed when sonication is used alone. 

The most frequently used method for the preparation of isoquinoline Reissert compounds is treatment of an isoquinoline with acyl chloride and potassium cyanide in water or in a dichloromethane-water solvent system. Though this method could be successfully applied in a great number of syntheses, it has also some disadvantages. First, the starting isoquinoline and the Reissert compound formed in the reaction are usually insoluble in water. Second, in the case of reactive acyl halides the hydrolysis of this reaction partner may became dominant. Third, the hydroxide ion present could compete with the cyanide ion as a nucleophile to produce a pseudobase instead of Reissert compound. To decrease the pseudobase formation phase-transfer catalysts have been used successfully in the case of the dichloromethane-water solvent system, resulting in considerably increased yields of the Reissert compound. To avoid the hydrolysis of reactive acid halides in some cases nonaqueous media have been applied, e.g., acetonitrile, acetone, dioxane, benzene, while utilizing hydrogen cyanide or trimethylsilyl cyanide as reactants instead of potassium cyanide. 

The previously described Reissert compounds (94) can be converted back to the original heterocycles (91) by sodium hydroxide or, more usefully, by sodium hydride to the nitrile substituted heterocycles (100) <92CPB5137>. Under acidic conditions fission of the dihydropyrimidine ring occurs to give the triazole (101). V-Nitration of the tetrahydro[ 1,2,5]oxadiazolo[3,4-6]pyrazine (102) gives the explosive dinitro compound (67) (Scheme 7) <85J0C5123>. 

Although solvents such as dimethylformamide have been tried, the use of anhydrous benzene and anhydrous hydrogen cyanide appears to remain as the most general nonaqueous solvent system and several new Reissert compounds have been prepared by this method. " With the use of anhydrous hydrogen cyanide this method suffers from an obvious disadvantage. 

An extremely convenient and general " " method of Reissert compound formation has been developed. This involves the addition of the acid halide (or less frequently anhydride) neat or in methylene chloride to a mixture of the heterocyclic base in methylene chloride and potassium cyanide in a minimum of water. Although the methylene chloride-water system is heterogeneous it has the advantage over the aqueous system that all the reactants and products are soluble in one phase or the other. Also water is slightly soluble in methylene chloride. The amount of water present is not sufficient to prevent the use of even reactive acid chlorides. This system appears to be the method of choice for Reissert compound formation. 

In addition to the use of a dialdehyde to react with 2 moles of Reissert compound in the synthesis of 25, terephthalaldehyde has been reacted with 19 and 20 to give the meso form and racemate of the bis diol esters.3 In the quinoline series the product has been converted to a compound having curariform activity. 

Reaction of quinazoline, benzoyl chloride, and trimethylsilyl cyanide in a 2 2 1 molar ratio in anhydrous dichloromethane affords l,3-dibenzoyl-2,4-dicyano-l,2,3,4-tetrahydroquinazoline in 25% yield. When the reaction of quinazoline with trimethylsilyl cyanide and benzoyl chloride or a,/ -unsaturated acid chlorides [molar ratio (1 2.2 2.2)] is carried out in the presence of a catalytic amount of anhydrous aluminum trichloride, a more vigorous reaction takes place and the quinazoline di-Reissert compounds 22 are obtained in higher yield. Attempted Reissert compound formation with benzoyl chloride and potassium cyanide using a dichloromethane/water solvent system leads to ring opening (cf. pp 84, 149). 

Blocking of the 4-position of quinazoline by use of 4-methylquinazoline, 4-phenylquinazoline, or 4-ethoxyquinazolinc in the Reissert reaction permits access to the alternative mono-Reissert compounds 24 by selective addition across the 1,2-double bond. ... 

Two new methods of Reissert compound formation have appeared. Silver cyanide and benzoyl chloride in chloroform is eifective in the 1,6-naphthy-ridine series. Reissert compounds have been prepared from quinoline or isoquinoline and an acid chloride, using trimethylsilyl cyanide and a catalytic amount of aluminum chloride in methylene chloride. The Reissert compound of 6,7-dimethoxyphthalazine has also been prepared using this latter method. ... 

Most work has been in the isoquinoline area, principally because of the usefulness of isoquinoline Reissert compounds in the synthesis of isoquinoline alkaloids. Aside from 5-chloro- and 3-acetylaminomethylquinoline and a few halo, methyl, and carbomethoxyisoquinolines, all the substituted quinoline or isoquinoline Reissert compounds have involved oxygen-type functions in one or more of positions 4-, 5-, 6-, 7-, and 8- of the isoquinoline... 

Except for a demonstration that the phthalazine Reissert compound (3 R = Ph) behaves normally in giving benzaldehyde on acid-catalyzed hydrolysis, no new reports have appeared of Reissert compounds being used in aldehyde synthesis. Acid-catalyzed hydrolysis has been used, however, in some cases to prepare heterocyclic carboxylic acids. Thus in addition to the preparation of isoquinaldic acid, phthalazine-1-carboxyIic acid and 15 have been prepared from 3(R = Ph) and 11, respectively. Acid-catalyzed hydrolysis of 16 occurs with cyclization to give 17. A series of Reissert compounds derived from substituted 3-aminoquinolines have been converted to the corresponding quinaldic acids by acid-catalyzed hydrolysis. ... 

The cation isolated from treatment of Reissert compounds with acid has generally been written as 18. A detailed study using a combination ... 

The anion (26) derived from the isoquinoline Reissert compound (2) and the related anions derived from other Reissert compounds have most generally been generated by the use of sodium hydride in dimethylformamide. ... 

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