2- Methyl-l,2-dihydroisoquinoline

By acylation of 2-methyl-l,2-dihydroisoquinoline (127) with 3,4-dimeth-oxyphenacylchloride a C-4 alkylated product 128 is formed (208). 

When l-allyl-2-methyl-l,2-dihydroisoquinoline [(149) R = H] is treated with dilute mineral acids under the conditions of the benzyl... 

Methyl-l,2-dihydroisoquinoline has been reacted8,66 with a variety of acid chlorides (Table III) the expected vinylogous amides (64) were isolated in most cases. 2-Benzyl-l,2-dihydroisoquinoline behaves similarly. The acylation reaction fails with simple aliphatic acid chlorides. Sometimes, the reaction of the enamine with the acid in the presence of dicyclohexylcarbodimide succeeds. The 1,2-dihydro-isoquinoline (65) also reacts with ethoxalyl chloride to yield 66.86... 

Isoquinoline methiodide reacted with LiAlH4 in abs. ether, cooling occasionally with ice water —2-methyl-l,2-dihydroisoquinoline. Y ca. 70%. (F. e. s. H. Schmid and P. Karrer, Helv. 32, 960 (1949).)... 

When l-allyl-2-methyl-l,2-dihydroisoquinoline is heated with dilute mineral acid, a rearrangement occurs rapidly and in high yield to the 2-methyl-3-allyl-3,4-dihydroisoquinoline salt (14). This is an intramolecular suprafacial sigma-tropic [3,3] shift analogous to the Claisen and Cope rearrangements, with a transition state as denoted below. " ... 

An efficient synthesis of 2-methyl-l-(2-oxoalkyl)-1,2-dihydroisoquinolines 86 via addition of ketone enolates to isoquinolinium methiodide has been reported < 6JCK (61)483Q>. 

Additionally, the photolysis of an isoquinoline salt resulted in the formation of 2-methyl-l-(2,3,4,5,6-pentafluorophenyl)-l,2-dihydroisoquinoline via photoinduced transfer of CeFs... 

When isoquinoline is refluxed with acetic anhydride, iV-acetyl-l-carboxy-methyl-l,2-dihydroisoquinoline is obtained in analogy with the Reissert reaction. If acetone is also present during the refluxing, 7V-acetyl-l-acetony 1-1,2-dihydro-isoquinoline is formed in addition. ... 

Methyl-1,2-dihydropapaverine (175, R = OMe) rearranges to the 2-methyl-3-(3,4-dimethoxybenzyl)-6,7-dimethoxy-3,4-dihydroisoquinolin-ium salt (176, R = OMe) under very mild conditions (treatment with 2% hydrochloric acid). A similar rearrangement of l-(3,4-methyl-enedioxybenzyl) - 2 - methyl - 6,7 - dimethoxyisoquinoline (175, R, R = —O—CHj—O—) affords 3-(3,4-methylenedioxybenzyl)-2-methyl-6,7-di-methoxy-3,4-dihydroisoquinolinium chloride (176, R, R = O—CHj—O—) (256). The reaction was shown to be an allylic rearrangement with internal return (275,275). 

Alkyl-3-ethoxy-4-[(mesyloxy)methyl]-l,4-dihydroisoquinolines 27 on treatment with potassium /Vrt-butoxide in dimethyl sulfoxide undergo ring expansion to 1/7-2-benzazepines.24 0 (For related ring expansions of acridines, see Section 3.2.1.4.1.5.) The 4-methyl and 4-methyl-l-phenyl derivatives 27a and 27b, respectively, yield mixtures of the 3-ethoxy-5-methyl- 28 and 3-ethoxy-4-methyl- 29 l//-2-benzazcpines cyclopropaquinolines are thought to be involved as intermediates (see Section 3.2.1.4.1.6.). In contrast, the 4-[l-(mesyloxy)ethyl] derivatives 27e and 27d yield only the 4,5-dimethyl-li/-2-benzazepines 29c and 29d. 

Treatment of 2-(3-bromopropyl)-l,2-dihydroisoquinoline with methyl-amine in ethanol afforded 1-me thy 1-1,3,4,6,1 l,lla-hexahydro-2//-pyrimido [1,2-b]isoquinoline (73JOC437). 

Reaction of methyl isocyanoacetate with methyl 2-formylbenzoate in the presence of sodium hydride in DMF at 30-40°C gives methyl 1-oxo-l,2-dihydroisoquinoline-3-carboxylate in 42% yield. 

Similar methodology was used in the synthesis of 3-methyl derivatives of the alkaloids thalactamine, doryanine, and 6,7-dimethoxy-A-methyl-l(2//)-isoquinolone652. The S l reaction between 0rr/20-halogenobenzylamines and enolates derived from a series of ketones and aldehydes affords 1,2-dihydroisoquinolines, from which the isoquinoline derivatives can be obtained by dehydrogenation and the 1,2,3,4-tetrahydroisoquinolines by reduction653. The products of the S l reactions of (2-halo-4,5-dimethoxyphenyl)acetic... 

The reactions of l-[(6-methyl-5-methylthio-4-oxo-4//-l,3-oxazin-2-yl)-methylene]l,2-dihydroisoquinoline with secondary amines or with ethanolic... 

Pseudocyanides. 6,7-Dimethoxy-2-methyl-l-allyl-l,2-dihydroisoquinoline dissolved in N H(5i, heated 0.5 hr. at 80° bath temp., cooled, made alkaline with NaHCOj, and treated with coned. NaCN-soln. pseudocyanide. Y 92%. F. rearrangements s. J. Knabe and H.-D. Holtje, Ardi. Pharm. 303, 404 (1970) Pharmazie 25, 313 (1970). 

Phase-transfer catalysts improve substantially the yields of the Reissert reactionFor example, isoquinoline, benzoyl chloride, and aqueous potassium cyanide, in the presence of benzyltriethylammonium chloride, give iV-benzoyl-1-cyano-l,2-dihydroisoquinoline in 82% yield (previous yield 38%). n.m.r. studies on the adducts of quinolines and isoquinolines with acetylene-dicarboxylates have necessitated revision of the structures of many of these adducts. For example, the so-called azepine adduct from 1-methyl-isoquinoline has been re-formulated as the cyclobutapyrrole (133). 

By a modified Bischler-Napieralsky reaction, 6 -nitrophenylaceto-jS-3 4-methylenedioxyphenylethylamide, resulting from the condensation of -3 4-methylenedioxyphenylethylamine with 2-nitrophenylacetyl chloride, was converted into 6 nitro-l-benzyl-6 7-methylenedioxy-3 4-dihydroisoquinoline. The methiodide of the latter was reduced with zinc and hydrochloric acid to 6 -amino-l-benzyl-2-methyl-6 7-methylenedioxy-1 2 3 4-tetrahydro/soquinoline dihydrochloride, which by the Pschorr ring-closure reaction, produced dZ-roemerine (IV, p. 317), m.p. 85-7°. By treatment in succession with d- and Z-tartaric acids, the dZ-base was resolved into Z- and tZ-forms. Synthetic Z-roemerine is dimorphic, m.p. 85-7° and 102°, and has [aju — 79-9° (EtOH), these constants being in good agreement with those of the natural base. 

A methylene base formed from quinaldine ethiodide, l-ethyl-2-methyl-ene-1,2-dihydroisoquinoline (129), exhibits a number of reactions characteristic of enamines (207,209). On treatment with benzoylchloride a dialkylated product (130) is produced by C and subsequent O benzoylation (210). 

The submitters, working on a kilogram scale without purification of reagent or solvent and with no precaution against moisture, obtained 6,7-dimethoxy-l-methyl-3,4-dihydroisoquinoline hydrochloride,2 m.p. 202-203°, instead of the dichlorophosphate at this stage. The checkers obtained this hydrochloride by either treating the free base with... 

Several 1-benzylisoquinoline alkaloids have been synthesized utilizing the above reaction sequence. For example, takatonine (34) has been obtained from Reissert compound 27 via alkylation with p-methoxybenzyl chloride and subsequent hydrolysis and quatemarization with methyl iodide 17). Similarly, es-cholamine (37) has been prepared from A-benzoyl-l-cyano-6,7-meth-ylenedioxy-1,2-dihydroisoquinoline (28) and 3,4-methylenedioxybenzyl chloride (77) as shown in Scheme 6. 

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