1.2- Dihydroisoquinolines disproportionation

Dihydroisoquinolines, e.g. (484), are basic and form quaternary salts, e.g. (521). With alkali these salts form carbinolamine pseudo-bases, e.g. cotamine (522 Y = OH), which can be oxidized to lactams or which disproportionate on standing. The quaternary ions can also react with other nucleophilic reagents, e.g. (521) + RMgBr — (522 Y = R) (521) + MeCOMe — (522 Y = CH2COMe) (521) + CN — (522 Y = CN) (521) + RNH2 —+ (522 Y = NHR). The pseudo-bases are in equilibrium with open-chain compounds since aldehyde derivatives can be prepared. 

Treatment of a quaternary salt (14) with concentrated alkali causes disproportionation to occur to yield an isocarbostyril (13) and a 1,2-dihydroisoquinoline (6).25 The reaction, which probably proceeds via the pseudobase (15), has been used26 in a modified berbine ring... 

Exposure of some 1,2-dihydroisoquinolines to air results in rapid polymerization or in oxidation to isocarbostyrils. In the presence of acids, 1,2-dihydroisoquinolines may undergo disproportionation, dimerization, or polymerization (see Section V,D, l,a). 

There is a discrepancy in the literature concerning 1,2-dihydro-isoquinoline itself. Thus, Huckel and Graner54 report its trimerization to 31 (m.p. 138°, the same melting point that Packham and Jackman11 ascribe to the monomer). It is thought63 that in a nonpolar solvent, 1,2-dihydroisoquinoline is relatively stable, but in methanol, protonation and trimerization occur certainly the mass spectrum of the compound (m.p. 138°) described by Packham and Jackman indicates that it is trimeric.63 The series of 1,2-dialkyl-1,2-dihydroisoquinolines described by Bradley and Jeffry30 was purified by distillation under reduced pressure. The stability of these compounds is quite remarkable in view of the known tendency for 1,2-dihydroisoquinolines to undergo disproportionation. Some other 1,2-dialkyl-1,2-dihydroisoquinolines have been described,7 as well as 1-aryl derivatives.7 The derivative (32) when heated with triethyl phosphite is transformed by an unknown mechanism, in 37% yield, into 33.64... 

Disproportionation to an equimolecular mixture of the 1,2,3,4-tetrahydroisoquinoline and the fully aromatic derivative is a common consequence of the interaction of 1,2-dihydroisoquinolines with acids. It is possible that protonation at C-4 occurs first (Scheme II), but with... 

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... 

AP831). Product 74 was obtained in only 10% yield, and a considerable part of the starting material (22a) was found to be resinified under the acidic conditions. The iminium salts 75 and 76 form in 23 and 49% yields, respectively. In both cases, disproportionation products could be isolated from 23a the compounds 77 and 78 in low yields and from 24a the compounds 79 and 80 in yields of about 15%. These findings demonstrate that the furo-(22a) and thienodihydropyridines (23a and 24a) under the rearrangement conditions behave similarly to the corresponding l-allyl-1,2-dihydroisoquinolines. 

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... 

Lithium in liquid ammonia conditions can produce l,4-dihydroquinoline" and 3,4-dihydroisoquinoline." Conversely, lithium aluminium hydride reduces generating l,2-dihydroquinoline" and 1,2-dihydroisoquinoline. These dihydro-heterocycles can be easily oxidised back to the fully aromatic systems, or disproportionate, especially in acid solution, to give a mixture of tetrahydro and re-aromatised compounds. Stable dihydro-derivatives (see also 9.13) can be obtained by trapping following reduction, as a urethane, by reaction with a chloroformate. Quaternary salts of quinoline and isoquinoline are particularly easily reduced, either catalyticaUy or with a borohydride in protic solution, giving... 

An important discovery which promises to improve the yields of most of the above syntheses has been recently described. "" Since side reactions such as disproportionation and rearrangement [e.g. (74)— (75)] observed in the crucial cyclization [e.g. (76)— (73)] are bimolecular processes, it was reasoned that high-dilution conditions should favour the desired reaction. In the event, treatment of the appropriate dihydroisoquinolines with perchloric acid gave the corresponding pavinane derivatives (79 R = Me, CH2Ph, P-NO2C6H4CH2, or 2,6-Cl2C6H3CH2) in 50—95% yield. 

The 1,2-dihydroisoquinoline 11 undergoes hydrolysis in acid medium to give aldehydes and isoquinoline-1-carboxylic acid. This disproportionation reaction, which is used for an aldehyde synthesis, probably involves formation of an aminooxazolium ion 13, followed by ring-opening to the amide 14 ... 

The cyclopropylcarbinyl isoquinoline (882) does not rearrange on treatment with acid, excluding a cationic mechanism for the dihydroisoquinoline rearrangement, but disproportionates to (883) and (884). 

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