1- Alkoxy isoquinolines

Substituted 1-halo and 1-alkoxy isoquinolines are formed from A/-methoxy benzimidoyl halides and alkynes with a ruthenium catalyst (Scheme 59) (13CC3703). The reaction with an unsymmetrical alkyne, 1-phenyl-l-propyne, occurs regioselectively, with the phenyl adding adjacent to the nitrogen. The reaction occurs with both imidoyl chlorides and... 

One important variation of the Bischler-Napieralski reaction is the Pictet-Gams modification, in which p-hydroxy or -alkoxy phenethylamides 38 are converted to isoquinolines 39. This transformation is covered in detail in section 9.12 of this text. 

Alkoxy-3-(4-biphenyl)perhydropyrido[], 2-c][], 4]oxazines were obtained from 3-hydroxy derivative with PrOH and Br(CH2)30H in a boiling acidified medium (00JMC609, 00MIP13). Spontaneous dehydration of b-hydroxy-1,3,4,6,7,1 lZ -hexahydro[l,4]oxazino[3,4-n]isoquinolin-4-one 258 in CHCI3 gave 3,4,6,7-tetrahydro derivative 259 (97JOC2080). 

The Reissert-Henze and the Feely-Beavers-Tani reactions are considered together in this section because of their similarity. The former involves cyanation of acyloxy (formed in situ) (Scheme 113), and the latter alkoxy (Scheme 114), quaternary salts. The Reissert-Henze reaction is a facile, fairly general reaction for quinoline and isoquinoline AT-oxides (Table 19) with cyanation occurring a to the ring nitrogen. Certain substituents inhibit reaction, for example a 1-methyl group (equation 125), and others undergo replacement (Scheme 130) (81H(15)98l). Reaction of 1-methylisoquinoline 2-oxide with benzoyl chloride... 

Irradiation of compound 357 (R = Me) in methanol and ethanol at 300 nm gave ethyl 2-methyl-4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-car-boxylate (371) and 3-alkoxy-2-methyl 4//-pyrimido[2,l-a]isoquinoline-4-ones (369, R = Me, R1 = Me, Et) along with two imidazo[2,l-a]isoquino-lines (368, R = Me and 372) and a ring-opened product (92AJC1811). At 254 nm the yields of 4//-pyrimido[2,l-a]isoquinolin-4-ones (369, R = Me and 371) and 368, (R = Me) were lower no formation or trace of them was observed in acetonitrile, acetone, acetic acid, and ethyl acetate. Irradition of compound 357 (R = Me) at 300 nm in acetonitrile containing 36% hydrochloric acid afforded 3-chloro-2-methyl-4//-pyrimido[2,l-a]isoquinolin-4-one (373) in 31-81% yields and other products. 

Hanna and Shutt (146) studied the relationship between the chemical structure and the coronary dilator action of papaverine analogs on anesthetized dogs. The 6-alkoxy-, 5,6-dialkoxy-, and 6,7-dialkoxy-isoquinoline derivatives acted as dilators. The 6,7-dialkoxyisoquinoline derivatives were most effective. Optimum results were obtained when the isoquinoline nucleus was aromatic, but the 3,4-dihydro- and 1,2,3,4-... 

Rather complex fragmentation is often observed with alkoxy-substituted azines, especially with quinolines and isoquinolines, and intramolecular transfer of a hydrogen atom from the ether alkyl group to a ring carbon atom appears... 

In Tables I and II, the known types of 4-acetoxy-, 4-alkoxy-, and 4-hydroxy-l,2,3,4-tetrahydroisoquinolines are indicated. Table III summarizes the known 4-keto-l,2,3,4-tetrahydroisoquinolines. In Tables IV and V, the various classes of 1,2,3,4-tetrahydroisoquinolines and aromatic isoquinolines which have been made by the methods discussed in this article are given. In Tables VI and VII, the 4-phenyl-l,2,3,4-tetrahydroisoquinolines and bicyclic compounds made by nucleophilic displacement of the 4-hydroxy group are summarized. Twenty-four compounds e.g., (31-40) prepared from 30 with active CH,78 NH, and SH77 compounds have been reported details may be found in the references cited. 

Several inhibitors of lipases have been described (for a review see Patkar et al. [45]). HSL was first described in 1964, but it was not until 2000 that the first inhibitors were reported. Several companies have recently investigated HSL inhibitors to treat diabetes and lipid disorders. In 2000 Alteon [46] published a patent on eu-desmannolides, a natural product isolated from Ivoa microcephala nut. One year later Aventis [47] reported a series of natural products from Streptomyces called cy-clipostines. In the same year Aventis [48] and Novo Nordisk [49] published the first synthetic HSL inhibitors (3,4-dihydro-lH-isoquinolin-2-yl)carbamates, Novo Nordisk, and 3-phenyl-5-alkoxy-l,3,4-oxadiazol-2-ones, Aventis. In 2003, Ontogene [50] described pyrrolopyrazinediones and Novo Nordisk [51] reported another class... 

Firstly, (benzylidenamino)acetaldehyde acetals 58 are formed they are cyclized to give 4-alkoxy>3,4-dihydroisoquinolines 59, which are converted into isoquinolines by loss of ROH. The electrophilic cyclization is favoured by meta- and or /zo-electron-releasing substituents in the arylaldehyde. Electron-withdrawing substituents (especially NO2 groups) favour an alternative ring closure leading to oxazoles 61 with dehydrogenation. 

In all of the syntheses discussed, alkoxy derivatives of a-aminoaceto-phenone or of /3-phenethylamine were employed to supply the main structural outline of the isoquinoline system. Some of these amines are hard to obtain, especially if the resistant aromatic methoxyl groups are replaced by more sensitive substituents which may serve in the preparation of partly demethylated derivatives of papaverine or laudanosine. A significant innovation (60) which avoids the preparation of such unstable amines is the degradation of j3-phenylpropionic acid azides (hydrocinnamic acid azides) to the corresponding isocyanates, which add to the required phenylacetic acids probably with the intermediate formation of four-membered cyclic hemiacetals. The latter are transformed to A-carboxylic acids, which lose carbon dioxide and yield amides needed in the isoquinoline syntheses. In practice, the azide is heated with the phenylacetic acid in benzene solution for several hours, and the amide is isolated from the reaction mixture without difficulty. 

Nucleophilic-substitution reactions of 4-bromoisoquinoline (382) with thiolate and alkoxy ions were completed within 35 00 s under MWI to give the corresponding 4-substituted isoquinoline 383 in 53 98% yields (Scheme 77) (02T1125). 

Quinolines react with arynes and aldehydes in a diastereoselective manner to form benzoxazino quinolines in good yields (Scheme 71) (13OL4620). Halides and alkoxy groups were tolerated on the aromatic aldehydes. Heteroaromatic aldehydes also reacted smoothly (2 examples, 57—69%). The aldehydes can be replaced with ketones without a loss in yield. Various functional groups are also tolerated on the quinoline or aryne. Finally, the reaction proceeds in an analogous fashion with isoquinolines but with less diastereoselectivity (8 examples, 62-92%, 3 1). 

Alkynylbenzaldehyde 0-alkyl oximes were also used as precursors of isoquinolines (Scheme 16, route c). After intramolecular electrophilic cyclization, Af-alkoxy groups were eliminated to form aldehydes (for example benzaldehyde). Shin et al. synthesized 5-fluoro-3-phenylisoquinoline using a AgOTf/TfOH catalytic system (Scheme 19), [55] while Wu achieved Cu-catalyzed synthesis of several 7-fluoroisoquinoUne derivatives [56]. 

---