Alkylation of Reisserts Compound

Reissert s compound (l-cyano-l,2-dihydroquinolinyl benzamide) is apparently de-protonated under phase transfer conditions at the one-carbon as expected. The condensation of the carbanion with an aldehyde or ketone leads to an N-benzoyl alk-oxide in which oxygen acylation (N - 0 acyl transfer) results in five-membered ring formation. The intermediate oxazolidine decomposes with loss of cyanide to give the benzoate ester of an isoquinolinoylcarbinol as shown in equation 10.26 [36]. 

In order to facilitate the use of the tables in this chapter, they have been organized as follows The substrates are listed in order of increasing (total) number of carbons. The list of substances used as alkylating agents is likewise in order of increasing carbon number and in order of increasing complexity within a set of isomers or closely related compounds. 

Number Substrate Electrophile Product % Yield Catalyst Refer- 

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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. 

Several additional examples of the alkylation of Reissert compounds appeared before the development of this new system and these are noted below. In addition to the previously reported l-(j9-dimethyl-aminoethyl)isoquinoline the alkylation of 20 with jS-chloroethyl-dimethylamine also gave rise to l,2-di-(l -isoquinolyl)ethane. ... 

Ring cbsures through intramolecular alkylation of Reissert compounds have been described. The sequential dialkylation of dimethylaminoacetonitrile (44) first with methallyl chloride and then isopentenyl bromide, followed by hydrolysis and isomerization, affords artemesia ketone in 77% overdl yield (Scheme 20). ... 

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, - ... 

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. 

Exanqrle 4, Asymmetric organocatalytic allylic alkylation of Reissert compounds ... 

Excellent yields of the former product are also obtained with quinoline N-oxide. Improved yields of Reissert compounds are found under phase-transfer conditions (29). The regiochemistry of the method changes dramatically with /V-alkyl quin olinium salts, eg, /V-methy1quino1inium iodide [3947-76-0] (12), which form 4-cyanoquinoline [23395-72-4] (13) (30), through the intermediary in this example of A[-methyl-4-cyano-l,4-dihydroquinoline... 

The synthesis of the basic skeleton of 1-benzylisoquinoline alkaloids has been reported by Uff et al. 15) starting from isoquinoline and benzyl chloride (Scheme 5). The preparation of Reissert compound iV-benzyl-l-cyano-l,2-di-hydroisoquinoline (4) was performed in a dichloromethane-water two-phase system with potassium cyanide and benzoyl chloride in about 64-69% yield. The deprotonation of 4 with sodium hydride in dimethylformamide solution, the subsequent alkylation with benzyl chloride, and the final alkaline hydrolysis could be performed as a one-pot reaction sequence to supply 1-benzylisoquinoline (25) in an overall yield of 75-84%. 

Sodium borohydride reduction of alkylated isoquinoline Reissert compounds (27) gives rise to 1-alkylisoquinolines (28) and provides an alternative to base hydrolysis for this conversion." Sodium borohydride reduction of the perchlorate salts of Reissert compounds (19 R = Ar, X- CIO4) leads to the iV-benzyl-l,2,3,4-tetrahydroisoquinaldamides70. ... 

Treatment of the compounds 78 with various alkyl halides in the presence of sodium hydride results in 1-alkylation as with normal Reissert com-pounds. ° Acylation has also been reported under these conditions. Under a variety of conditions, however, 78 does not react with benzaldehyde. Acid hydrolysis of 80 gave tetrahydroquinaldic acid, while acid hydrolysis of the alkylated dihydroisoquinoline-Reissert compounds gave the amino acids 81. By first complexing the alkylated dihydroisoquinoline-Reissert compound with zinc chloride in ether and then hydrolyzing the complex, the nitrile was hydrolyzed to an acid, but the amide group was left intact. The perchlorate salts of dihydroisoquinoline-Reissert compounds have also been prepared, and sodium borohydride reduction proceeds in the same manner as reduction of the Reissert salt to... 

Carbanion formation. Makosza1 has used the combination of benzyltriethylammonium chloride and sodium hydroxide as the base for alkylation of phenyl-acetonitrile with alkyl halides and with halonitrobenzenes. The same combination was found to be superior to phenyllithium (used previously2) for alkylation of Reissert s compound (N-benzoyl-1,2-dihydroisoquinaldonitrile).3... 

Phosphonate analogues of Reissert compounds (76) have been prepared and converted into 1-alkyl-isoquinolines (Scheme 49). Treatment of a number of A -methylisocarbostyrils with mercuric acetate gave rise to 4-mercuri-ated derivatives, which underwent insertion reactions with methyl acrylate and with styrenes in the presence of palladium chloride (Heck reaction). 

An alternative synthesis has been used by Jackson and co-workers to synthesize ( )-cularine (11) (62, 6J). Remarkable improvement in the synthesis of the required ( )-crassifoline (75) is obtained by alkylating the Reissert compound 74, easily prepared from 0-vanillin by a small modification of the Pomerantz-Fritsch cyclization. 

Carbon Acids. Active methylene compounds, such as mal-onates and 8-keto esters, can be deprotonated with sodium hydride and alkylated on carbon (eqs 12 and 13). Alkylation of Reissert anions is also facile with sodium hydride (eq 14). ... 

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.)... 

Qu tern iy S Its. The ring nitrogen of quinoline reacts with a wide variety of alkylating and acylating agents to produce useful intermediates like A/-benzoylquinolinium chloride [4903-36-0] (8). The quinoline 1,2-adducts, eg, A/-benzyl-2-cyano-l,2-dihydroquinoline [13721 -17-0] (9), or Reissert compounds (28), formed with potassium cyanide can produce 2-carboxyquinoline [93-10-7] (10) or 2-cyanoquinoline [11436-43-7] (11). 

Heterocyclic structures analogous to the intermediate complex result from azinium derivatives and amines, hydroxide or alkoxides, or Grignard reagents from quinazoline and orgahometallics, cyanide, bisulfite, etc. from various heterocycles with amide ion, metal hydrides,or lithium alkyls from A-acylazinium compounds and cyanide ion (Reissert compounds) many other examples are known. Factors favorable to nucleophilic addition rather than substitution reactions have been discussed by Albert, who has studied examples of easy covalent hydration of heterocycles. 

The Reissert method15—conversion of an isoquinoline to a 2-benzoyl-1,2-dihydroisoquinaldonitrile (Reissert compound), alkylation, and hydrolysis—has enjoyed wide success in the synthesis of benzyliso-quinoline and related alkaloids.16,17 In particular, aporphines are prepared conveniently by converting isoquinolines to I-(o-nitrobcnzyl)-isoquinolines via a Reissert sequence, followed by A7-alkylation, reduction, and Pschorr cyclization.17... 

This reaction is illustrative of a general procedure for the alkylation of active methylene functions in the presence of concentrated aqueous alkali catalyzed by tetraalkylammonium salts. This catalytic method has been used to alkylate arylacetonitriles with monohaloalkanes,2 dihaloalkanes,3 a-chloroethers,4 chloronitriles,.5 haloacetic acid esters,6 and halonitro aromatic compounds.7 It has also been used to alkylate ketones,8 lf/ indene,9 9i/-fluorene,ll) and the Reissert compound.11 The reaction is inhibited by alcohols and by iodide ion.2... 

Method B (with sonication) Sonication of the Reissert compound (4.6 mmol), haloalkane (6.6 mmol), and TEBA-C1 (34 mg, 0.15 mmol) in CH,C1, (2.5 ml) and aqueous NaOH (50%, 1.8 ml) is conducted for 20 min. Work-up at this stage, as described in 6.2.30.A, yields the alkylated Reissert compound. Addition of EtOH (6 ml) and sonication for a further 30 min with subsequent work-up by addition of the mixture to 11,0 (20 ml) and extraction with CH,C1, (3 x 10 ml) produces the C-alkylated heteroarene, which is isolated as the hydrochloride salt (70-90%) by saturation of the dried organic extracts with HC1 gas. 

The formation of a Reissert anion (intermediate of type 16) is usually the introductory step in a great number of synthetic routes leading to isoquinoline as well as indole alkaloids and related compounds. On the one hand, the alkylation of a Reissert anion with alkyl halide followed by alkaline hydrolysis is the most frequently used method for the synthesis of 1-alkyl- or 1-arylalkylisoquinolines (20) (Scheme 4). On the other hand, Reissert anions react with aldehydes to form... 

Skiles and Cava have investigated the alkylation method of isoquinoline Reissert compounds (76), performing a comparative study on the alkylation of... 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

Jackson et al. (22) reported the biomimetic total synthesis of ( )-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3-benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-... 

Treatment of 4-chlorobutanoyl Reissert compounds 219 and 220 with sodium hydride in dimethylformamide afforded indolo[2,3-a]quinolizine derivatives 221 and 222, respectively, in an intramolecular alkylation process (Scheme 28). 

AICI3 gave 5-cyanopyridopyrazine 93. Reaction of H-5 in 91 (R = R = Ph) with NaH in the presence of iodo-methane or benzyl bromide gave the Reissert compound 92 or the alkylated pyridopyrazine derivative 94 depending upon the nature of R when R = Ph, the product was 94, whereas R = OEt gave 92 <1994JHC819>. 

Makosza118 has also shown that Reissert compounds, A-benzoyl-1,2-dihydroisoquinaldenitrile (67), can be alkylated in the presence of NaOH and TEBA. Alkaline hydrolysis of alkylated 68 will give isoquinoline derivatives, which are starting materials for the synthesis of alkaloids. 

Reissert compounds (l-acyl-l,2-dihydro-2-quinolinecarbonitriles) have been prepared on cross-linked polystyrene and C-alkylated in the presence of strong bases (Entry 8, Table 15.25). Treatment of polystyrene-bound C-alkylated Reissert compounds with KOH leads to the release of isoquinolines into solution (Entry 9, Table 15.25). The reaction of support-bound quinoline- and isoquinoline /Y-oxides with acy-lating agents followed by treatment with electron-rich heteroarenes and enamines has been used to prepare alkylated and arylated derivatives of these heterocycles (Entry 10, Table 15.25 see also Table 15.26). 

Rozwadowska and coworkers carried out the asymmetric alkylation of isoquino-line Reissert compounds under phase-transfer conditions using cinchonine-derived quaternary ammonium salts as catalysts. The best enantioselectivity was achieved in the benzylation and allylation of 1 -cyano-2-phenoxy carbonyl-1,2-dihydroisoquinoline (17) catalyzed by 2a (Scheme 2.14) [34]. 

Only one example of an attachment of heteroarenes by addition/elimination strategy has been devised [77, 111]. Although arenes are more or less resistant toward addition, heteroaromatic systems such as isoquinolines 118 are prone to addition of nucleophiles. Subsequent reaction with addition of electrophiles furnishes the so-called Reissert compounds 120. These are stable compounds which can, for example, be alkylated. In solid-phase synthesis the electrophile chosen was a polymer-based acid chloride. Detachment can be achieved by simple addition of hydroxide ions (Scheme 6.1.30). 

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