1.4- substituted isoquinolines, synthesis

Several modified forms of this synthesis are available. For example, treatment of either isocyanate (28) or urethane (29) derivatives with phosphoryl chloride followed by stannic chloride has been reported to give the substituted isoquinoline [80388-01-8] (158). 

Pomeranz-Fntsch Synthesis, Isoquinolines aie available fiom the cycUzation of benzalamiaoacetals undei acidic conditions (165). The cyclization is preceded by the formation of the Schiff base (33). Although the yields ate modest, polyphosphoric acid produces product in all cases, and is especially useful for 8-substituted isoquinolines (166). 

A variation involves the reaction of benzylamines with glyoxal hemiacetal (168). Cyclization of the intermediate (35) with sulfuric acid produces the same isoquinoline as that obtained from the Schiff base derived from an aromatic aldehyde and aminoacetal. This method has proved especially useful for the synthesis of 1-substituted isoquinolines. 

As exemplified in the present procedure, the reaction has been optimized and extended in scope it affords functionalized benzocyclobutenes as well as substituted isoquinolines in high yields. Benzocyclobutenes have been used as intermediates in the synthesis of many naturally occurring alkaloids, - steroids,polycyclic terpenoids,and anthracycline antibiotics. The traditional routes leading to the preparation of benzocyclobutenes have been... 

Substituted 4-aryl-1 -oxo-1,2-dihydropyrazino[l, 2-i]isoquinolinium salts 402 were obtained when 3-substituted isoquinolines 401 were cleaved from a polymer by treatment 25% TFA (00MIP5). c/i-3,lla-H-3-Phenyl-1,2,3,4,11,11 fl-hexahydropyrazino[l, 2-i]isoquinoline-1,4-dione (404) formed when isoquinoline derivative 403 was cleaved from a resin with 25% TFA during an automated solid-phase synthesis (98BMCL2369). 

Kobayashi and co-workers have also reported an alternate synthesis of 1,4-disubstituted isoquinolines and a new synthesis of 1,3,4-dihydroisoquinoline derivatives <06BCJ 1126 06S2934>. The 1,4-disubstituted isoquinolines 121 are synthesized in good yields by reacting a variety of organolithiums 122 with different benzonitriles 123. In addition, a variety of lithium dialkylamides 124 were also reacted with different benzonitriles 123 to form 1 -amino-4-substituted isoquinolines 121 in moderate yields. 

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. 

Typical irradiation reactions have been utilized in the synthesis of isoquinolines for example, the phenylalanine derivative 21 yields the substituted isoquinoline as the major product (Equation 41) <1996TL5917>. 

Guastavino, J.F., Barolo, S.M. and Rossi, R.A. (2006) One-pot synthesis of 3-substituted isoquinolin-l-(2H)-ones and fused isoquinolin-l-(2H)-ones... 

Various cyclizations of alkynylbenzaldimines (e.g., 174) are particularly useful in the synthesis of isoquinolines as summarized in Scheme 101 . The use of electrophiles and base yields 3,4-disubstituted isoquinolines 175 <2002JOC3437> whereas the palladium-catalyzed carbonylation affords 4-aroylquinolines 173 <2002JOC7042>. Cyclization followed by Heck reaction gives rise to 4-alkenyl substituted isoquinolines 176 (Scheme 101) <2002TL3557>. 

The Pomeranz-Fritsch synthesis [Eqs. (1) and (2)]1 is the only isoquinoline synthesis involving a simple two-step sequence from common starting materials. Furthermore, it is one of the few methods which can be used to prepare isoquinolines substituted in the 7- and 8-positions. The first step, Schiff base formation [Eq. (1)], takes place readily, but the ring closure [Eq. (2)] is difficult. The yields vary markedly with the concentration of H2S04 and are generally low. Frequently the reaction fails completely. Most of the work described in this chapter was undertaken to circumvent these problems and to realize the potential promise of the synthesis. 

Although the number and variety of isoquinolines investigated does not approach that of the quinoline series, it would appear that the synthesis of isoquinoline Reissert compounds is general when the methylene chloride-water solvent system is used. A possible exception is 1-substituted isoquinolines where a steric effect, similar to that... 

Another useful variation is the Pictet-Spengler isoquinoline synthesis, also known as the Pictet-Spengler reaction. The reactive intermediate is an iminium ion 49 rather than an oxygen-stabilized cation, but attack at the electrophilic carbon of the C=N unit (see 16-31) leads to an isoquinoline derivative. When a p-aryla-mine reacts with an aldehyde, the product is an iminium salt, which cyclizes with an aromatic ring to complete the reaction and generate a tetrahydroisoquinoline." ° A variety of aldehydes can be used, and substitution on the aromatic ring leads to many derivatives. When the reaction is done in the presence of a chiral thiourea catalyst, good enantioselectivity was observed." ... 

A new synthesis for 2-substituted Isoquinolines starts with o-toluo-nltrlle. Base catalyzed acylation followed by ketalizatlon gives the key intermediate. Reduction of the amine followed by acid cycllzation and dehydrogenation (I2) gives the heterocycle. 

The major use of these anions has been in the synthesis of 1-substituted isoquinolines. 

In an alternative synthesis of ( )-64 by MacLean s group 120), the pyridone 145 was treated with MeLi in tetrahydrofuran at -78°C to afford, after reduction with NaBH, a mixture of ( )-142 and ( )-143. Debenzyl-ation of the mixture by catalytic hydrogenolysis furnished ( )-64 and ( )-144 in 20 and 40% yields, respectively. In yet another synthesis of ( )-64, Reimann and Renz 122) obtained the 8-methylisoquino[2,l-6][2,7]naph-thyridinium salt 149 by alkylation of the Reissert compound 146 with the 4-chloromethylpyridine derivative 147 in N,N-dimethylformamide in the presence of NaH and subsequent treatment of the resulting 1-substituted isoquinoline (148) with hydrochloric acid in EtOH. Reduction of 149 with NaBH, in MeOH gave ( )-142 and ( )-143 in 9 and 34% yields, respectively. Separate debenzylations of ( )-142 and ( )-143 with hydrochloric acid in EtOH furnished ( )-64 and ( )-144, respectively, in good yields. 

Gitto R, De Luca L, Pagano B et al (2008) Synthesis and anticonvulsant evaluation of N-substituted isoquinoline AMPA receptor antagonists. Bioorg Med Chem 16 2379-2384... 

The partial ether cleavage of methoxy- and methylenedioxy-substituted isoquinoline alkaloids has been reviewed in a new journal. Additional reviews concerning the use of Reissert compounds in the total synthesis of isoquinoline alkaloids and related compounds, electro-oxidation and isoquinoline alkaloid biosynthesis, and the synthesis of isoquinoline alkaloids by a systematic design have appeared in early issues of the same journal. The chemotaxonomy of alkaloids, together with distribution within plants, biosynthesis, structural classification, and physiological activity, has been treated in a monograph. ... 

An alternative synthesis to the Pomeranz-Fritsch method has been developed for 7- and 5,7-substituted isoquinolines. As an extension to the photolysis of... 

An interesting isoquinoline synthesis uses an intramolecular aza-WiTTiG reaction to establish the C=N bond in o-acylstyryl ylides 72, producing 1-substituted isoquinoline-3-carboxylic esters 73 [117] ... 

Oxidation of codamine ethyl ether (LXVI) cleaved the benzylisoquinoline system to 4-methoxy-5-ethoxyphthalic acid (LXVH) and veratric acid (VT). While the formation of these two acids precluded the location of the phenolic hydroxyl in the benzyl residue, LXVTI could have arisen from either a 6- or 7-ethoxy-substituted isoquinoline system. This question was settled by repeating the potassium permanganate oxidation of 0.0085 g. of codamine ethyl ether (LXVI) under gentle conditions. This time, 1-ke-to-2-methyl-6-methoxy-7-ethoxy-l, 2,3,4-tetrahydroisoquinoline (LXVIII) was isolated its structure was confirmed by synthesis, and therefore codamine is XXII. 

This reaction has general application in synthesis of 1-, 4- and A -substituted 1,2,3,4-tetrahydroisoquinolines and 1 and 4-substituted isoquinolines. In addition, this reaction has been applied to the synthesis of some alkaloids such as salsoline, salsolidine, carnegine, and lophocerine. ... 

A new method for the synthesis of highly substituted isoquinolines (78) has been developed, based on the addition of azides (76) to acetylenes (77), involving activation of the C-H bond in the ortho-position. A mechanistic study showed that the rhodium and copper cooperate synergistically in a multistep sequence. " ... 

---