Reissert Intermediates

Reissert compounds are useful in the preparation of the benzylisoquino-lines required for aporphine synthesis, and the field has been reviewed. Reissert intermediates have also been used in the preparation of 7-hydroxylated aporphines by the oxazolinone method. 

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The total synthesis of pavinane alkaloid platycerine (89) (Scheme 14) has been accomplished successfully (26) via 1-benzylisoquinoline derivative 91 obtained from Reissert intermediate 90. Quatemarization of 91 with methyl iodide followed by lithium aluminum hydride reduction supplied 1,2-dihydroisoquinoline 92, which on treatment with a 7 5 mixture of formic acid and phosphorous acid gave ( )-platycerine (89) in 60-70% yield. 

Cyanoisoquinolines and 2-cyanoquinolines were recently prepared via the reaction of isoquinolines and quinolines with p-TsCl/KCN.119 The reaction proceeds in two steps, as shown in the example of Scheme 13, and involves Reissert intermediates, which upon treatment with base give the cyano aromatic products in good overall yields.119... 

A traceless solid-phase synthetic strategy has been developed. For example, a solid-phase Suzuki coupling of the Reissert intermediate 30 to 31 has been reported. The process consists of three steps (a) Solid-phase Reissert formation by the reaction of polymer-supported benzoic acid chloride resin with an isoquinoline, followed by reaction with TMSCN to afford the aryl bromide of Reissert 30, (b) Suzuki coupling of the solid-phase Reissert 30 with phenylboronic acid to provide the coupling product, and (c) subsequent treatment of the coupling product with aqueous KOH to produce 31 (86 % overall yield based on the starting bromide) (Eq. (62)) [99]. 

A synthesis of homomoschatoline (1,2,3-trimethoxyoxoaporphine) via a Reissert intermediate and Pschorr cyclization has been described/ and a photolytic synthesis of atheroline (l,2,10-trimethoxy-9-hydroxyoxoaporphine) is now available/ The u.v. spectra of oxoaporphines are strongly dependent on the solvent used. ... 

A model (276) of ochrobirine (274) has been prepared.248 Condensation of 3,4-methylenedioxy-/ -phenethylamine with ninhydrin under conditions which may be difficult to reproduce (abs. EtOH, 0 °C, 25 minutes, dry HC1 gas passed over the surface at —78 °C until a clear solution was obtained) gave (275), which in two steps yielded (276) as an inseparable mixture of stereoisomers. A different attempt to prepare a spirobenzylisoquinoline skeleton by intramolecular Friedel-Crafts acylation of (277) and derivatives of (278) failed.249 Compound (278) was prepared from the dihydro Reissert intermediate (277) by modification of the N-benzoyl and the cyano-functions, showing that the stability of such systems may be greater than intuitively expected. 

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). 

In 1897, Reissert reported the synthesis of a variety of substituted indoles from o-nitrotoluene derivatives. Condensation of o-nitrotoluene (5) with diethyl oxalate (2) in the presense of sodium ethoxide afforded ethyl o-nitrophenylpyruvate (6). After hydrolysis of the ester, the free acid, o-nitrophenylpyruvic acid (7), was reduced with zinc in acetic acid to the intermediate, o-aminophenylpyruvic acid (8), which underwent cyclization with loss of water under the conditions of reduction to furnish the indole-2-carboxylic acid (9). When the indole-2-carboxylic acid (9) was heated above its melting point, carbon dioxide was evolved with concomitant formation of the indole (10). 

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. 

Cyclic Reissert equivalent compound 265 yields, by transformation into intermediate 266 followed by sulfuryl chloride-mediated ring-opening rearrangement, L-type homoberbine enamide 267 (05T5037). 

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... 

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-... 

A reinvestigation of the experiments on the UV irradiation of l-acetyl-l,2-dihydroquinoline-2-carbonitriles (Reissert compounds) 561 unequivocally demonstrated that the rearrangement via the diradical intermediate 562 gave 4//-3,l-benzoxazines 563 and 565 rather than the benzazete derivatives described earlier. The yields and the type of products were strongly influenced by the substituent R at position 4 while irradiation of the unsubstituted quinoline 561 (R=H) gave 3,1-benzoxazine 563 in nearly quantitative yield, the amount of the corresponding methyl-substituted analog 565 that could be isolated was considerable lower, due to its irreversible isomerization via 562 to the stable cycloprop[/ ]indole derivative 564 (Scheme 107) <199811(49)121 >. 

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. 

In the early days, greatest interest was focused on the acid-catalyzed hydrolysis (by hydrochloric acid in the presence of 2,4-dinitrophenylhydrazine) of Reissert compounds to aldehydes and the corresponding heterocyclic carboxylic acid derivatives. This reaction is fairly general for compounds of quinoline (178) and isoquinoline (179) (Table 18), but it is not applicable to pyridines as they rarely form Reissert compounds. The 3-hydroxyquino-line Reissert compound does not yield benzaldehyde, probably because acylation of the 3-hydroxy group prevents formation of the required cyclic intermediate (180). Some nitroquinolines and isoquinolines give low yields of benzaldehyde. Rather curiously, disub-stituted quinoline Reissert compounds yield less of the aldehyde than of the corresponding... 

Reissert compounds (cf Section 3.2.1.6.8.iv) can be deprotonated (NaH/HCONMe2) to give anions (e.g. 507) which react with electrophiles to give intermediates (508) which can be hydrolyzed to substituted heterocycles (509). Electrophiles utilized include alkyl and reactive aryl halides and carbonyl compounds. 

The Reissert reaction would now require a base-catalysed acylation of the methyl group with dimethyl oxalate to give 42. They say All attempts. .. in the presence of various bases to produce intermediate [42] failed. So they used the radical bromination of 43 with NBS (chapter 24) to give 51, alkylated with the anion of methyl acetoacetate to give 52. 

Note 1,6-Naphthyridine appears to undergo Reissert-type additions only at its 5-and 6-positions the products are useful intermediates for further elaboration. 

Reissert compounds have been prepared from derivatives of 3,4-dihydro-/ -carboline. Some of the compounds derived from these intermediates, such as the derivative (66), are of interest as potential intermediates in the preparation of indole alkaloid systems (Scheme 18) <81H(15)481, 81JHC909). 

Azine approach. Reissert compounds such as (222) on treatment with acid form transient cyclic intermediates containing the 3,4-fused oxazole ring. When the acid is tetrafluoroboric acid, the Reissert salt (223) can be isolated (73JA2392). 

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