1,2-Dihydroisoquinolines, 1-benzyl

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. 

Knabe et al. (271-274) later observed that 6,7-dimethoxy-2-methyl-1,2-dihydroisoquinolines (175), possessing either a free or a substituted benzyl group in position 1, readily rearrange to 3,4-dihydroisoquinoline salts (176) on treatment with dilute acids. 

A mixture of isomers was, however, obtained if the a,a -dibromoxylene was not symmetrical. This difficulty was overcome by using a reductive coupling of a substituted 3,4-dihydroisoquinoline (71) as its salt with an o-methoxycarbonyl-substituted benzyl bromide (73)129 [Eq. (60)]. 

Benzyl-l-cyano-l,2-dihydroisoquinoline behaves quite differently to the isomeric quinoline (Section V,G,6) and through cycloaddition and dehydrogenation yields 399.861 Isoquinolinediones (400 R = H and Me)... 

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]. 

This powerful quaternization method enabled the catalytic asymmetric synthesis of quaternary isoquinoline derivatives with 42 (R1 = Me) as a substrate. When 42 (R1 = Me) was treated with a,a -dibromo-o-xylene, CsOHH20 and (S,S)-le (1 mol%) in toluene at 0 °C, the transient monoalkylation product was rapidly produced, and subsequently transformed into the desired 44 (64%, 88% ee) during the work-up procedure. Catalytic asymmetric alkylation of 42 (R1 = Me) with functionalized benzyl bromide 45, followed by the sequential treatment with 1 M HC1 and then excess NaHC03, furnished the corresponding dihydroisoquinoline derivative 46 in 87% with 94% ee (Scheme 5.23) [25]. 

Agbalyan et al 9 recently employed this reaction in the synthesis of several 3,4-dihydroisoquinoline derivatives with unsaturated substituents in the 1-position. The Madrid group50 has shown that (with the exception of benzyl thiocyanate) aliphatic and aromatic thiocyanates yield 1-alkylthio- and l-arvlthio-3,4-dihydroisoquinolines as expected (cf. Table V). 

The relative stabilities of some 1,2-dihydroisoquinolines may be related to their ease of protonation at C-4. Thus, introduction of a C-3 methyl group,12,41 a C-4 methyl group,53 a C-4 benzyl group,18, 65... 

Methyl-1,2-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... 

In 1964 Grewe et al.bb reported that when a mixture of isoquinoline methiodide and benzaldehyde is hydrogenated in the presence of alkali, a 64% yield of 4-benzyl-2-methyl-1,2,3,4-tetrahydroiso-quinoline can be isolated. It was postulated that reduction of isoquinoline methiodide occurs to form the 1,2-dihydroisoquinoline, which then condenses with the benzaldehyde to form 81 and this is immediately further reduced. With isoquinoline itself and a variety... 

In an effort to define the scope of the benzyl migration reaction, and to elucidate its mechanism, Knabe et al.1 have treated a series of 1-substituted 1,2-dihydroisoquinolines with acids. The following reactions have been observed (a) rearrangement, (b) elimination of the C-l substituent, (c) disproportionation without rearrangement, (d) disproportionation after rearrangement, and (e) recovery of starting material (Scheme VIII). The results are summarized in... 

The l-benzyl-l,2-dihydroisoquinoline [(138) R = OH, R = OMe] has been rearranged,116 and the structure of the product (140) proved by synthesis.147 The threshold for pavine formation versus migration... 

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

To a solution of 460 mg (1.5 mmol) spiro-cyclopropene in 50 ml of dry ether an equimolar amount (32.2 mg =1.5 mmol) of l-benzyl-3,4-dihydroisoquinoline was slowly added at room temperature. After 24 h of stirring in the dark, the precipitate was filtered off. Column chromatography in Si02 with CH2CI2 and recrystallisation from ether afforded the tetrahydroindolizine. Yield 420 mg (53.2%) mp 238°C. 

Intermediacy of a zwitterionic peroxide was postulated also for the oxidation of 1-benzyl-3,4-dihydroisoquinolines to the corresponding 1-benzoyl derivatives6 (Scheme 6). 

Acylation of the well-known Bischler-Napieralski product, 1-benzyl-3,4-dihydroisoquinoline, with ethyl chloroformate gave a mixture of two carbamates, E isomer 118 and Z isomer 119 in the ratio of 1 2, which were readily assigned from their UV and NMR spectra and underwent cycliza-tion on irradiation under either nonoxidative or oxidative conditions to afford the 8-oxoberbine 120 or aporphine skeleton 121 (104,105). Irradiation of either the E or Z enamide, (118 or 119) or their mixture quickly... 

Reaetion between the benzyl-3,4-dihydroisoquinoline hydrochloride 43 with the carbamates 52a and 52b in the presence of NaHCOs afforded the pyrrole carbamates 54a and 54b in 91 and 81% yields, respectively. The carbonates 51a and 51b were also coupled with 43 under similar conditions to give the pyrrole carbonates 53a and 53b in 72 and 60% overall yields. 

It is of interest that a dihydroisoquinoline like 3,4-dihydropapaverine is more easily reducible than the parent compound [268] the electrode reaction is saturation of the azomethine bond. 3,4-Dihydro-2-alkylisoquinolinium salts may be reductively benzylated at C-1 [17] in aprotic media. 

A further reaction of 1,2-dihydroisoquinolines with acids is the elimination of the C-1 substituent. An isoquinolinium salt (29) and a toluene derivative (30) are formed from (28) (70AP255). The reaction can occur if the C-1 substituent is a benzyl or a heteroanalogous benzyl group. In 1,2-dihydroisoquinolines that are able to rearrange, the elimination reaction only is... 

The dihydroisoquinoline 83 gave with 2 N HCl the isoquinolinium salt 85, which was formed under the reaction conditions from 84 by dehydration, followed by aromatization (73AP648). Compound 86, having benzyl groups in... 

In order to study the stereochemical course of the rearrangement of 1-benzyl-l,2-dihydroisoquinolines, the optically active acetal (-f-)-106 was synthesized, starting with the amine (-i-)-105. Compound (-f-)-106 is a precursor of an optically active l-benzyl-l,2-dihydroisoquinoline possessing an asymmetric center in the 1 position. The ring closure of the acetal (-f- )-106, performed with 6 N HCl, leads to 1,2-dihydroisoquinolines or, in compounds that can be rearranged under acidic conditions, via 107 to the 3-substituted... 

In order to demonstrate the transfer of a benzyl group to an acceptor under the rearrangement conditions, a mixture of the l-benzyl-3-ethyl-l,2-dihyd-roisoquinoline 110, a 3-substituted 1,2-dihydroisoquinoline that does not rearrange, and the l-ethyl-l,2-dihydroisoquinoline 111, which normally gives disproportionation, was treated with dilute acid. The 3,4-dihydroisoquino-linium salt 112 was obtained in 5% yield. This experiment demonstrated that the transfer of a benzyl group from a 1,2-dihydroisoquinoline (110), existing as a 1,4-dihydroisoquinolinium salt in acidic solution, to form the 3,4-dihydroisoquinolinium salt 112 is possible. The low yield of 112 can be... 

In Section III,C it was shown that various 1-substituted 1,2-dihydroiso-quinolines can be cyclized intramolecularly to give pavinanes, isopavinanes, homopavinanes, and homoisopavinanes. Section III,D deals with the formation of 3-substituted isoquinoline derivatives from 1-allyl-, 1-benzyl-1,2-dihydroisoquinolines, and related compounds. In this section some synthetic reactions of 1,2-dihydroisoquinolines are reported. 

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