1- Methylene-isoquinolines

The aporphinoid alkaloid PO-3 (129) was also prepared by intermolecular benzyne cycloaddition between 1-methylene isoquinolines 148 and arynes derived from 147 (Scheme 53). The alkaloid was finally isolated by means of preparative thin layer chromatography (91JOC2984). 

OH) (T. Ohta et at, j. Amer.chem.Soc., 1980, 102, 6385). Another potentially useful synthesis involves the Diels-Alder condensation of benzynes with 1-methylene-isoquinolines -acetyldehydronornuciferine (154) has been prepared in this way from 2-acetyl-6,7-dimethoxy-1-methylenetetrahydroisoquinoline (Castedo et al. Tetrahedron Letters, 1982, 23, 457). 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

In the case of the 2-dimethylamino- (or 2-amino-)methylene derivatives, the products were at first thought to be pyrimido[4,5-c]isoquinolines (267), but later work with 6-(N-substituted amino)uracils assigned the structures of the products (268) as belonging to the isomeric pyrimido[4,5-f>]quinoline system (74CB2537), in agreement with the regioselection rules above. 

Formally analogous to the foregoing Grignard additions are the intramolecular condensations of amides with aromatic systems, found in the Bischler-Napieralski reaction 101), which is of particular interest in isoquinoline and indole alkaloid syntheses (102). Condensations of amidines with reactive methylene compounds also led to enamines (103-106). 

Fluorination. Attention has been focused on the direct fluorination of isoquinolines activated by conversion into 2-methylisocarbostyril (80). With gaseous fluorine (diluted to 10% with argon) in acetic acid a 54% yield of the 4-fluoro derivative was obtained. (Scheme 40). With methylene chloride as the solvent, only the 4-chloro analogue was formed [82H( 17)429]. Fluoroisoquinolines have also been made by displacement of nitro groups, and from diazonium fluoroborates (87JHC181). Hepta-chloroisoquinoline was converted into a perfluoro derivative by heating it in an autoclave with anhydrous potassium fluoride [66JCS(C)2328]. 

B. 2-Acetyl-6,l-dimethoxy-l-methylene-l,2,3,4-tetrahydroisoquinoline [Isoquinoline, 2-acetyl-l,2, A,4-tetrahydro-6,7-dimethoxy-l-methylene-]. A 1-1., three-necked, round-bottomed flask equipped with a mechanical stirrer, a reflux condenser topped with a calcium chloride drying tube, and a thermometer is charged with 110 ml. of acetic anhydride, 110 ml. of pyridine, and 45.0 g. (0.22 mole) of the dihydroisoquinoline prepared in Part A. The reaction mixture is stirred and heated at 90-95° for 30 minutes, stored at room temperature overnight, and concentrated by distillation at 50° using a rotary evaporator. The residue is diluted with 20 ml. of ethyl acetate, and another evaporation under reduced pressure gives material that can be crystallized from 75 ml. of ethyl acetate to yield 38.5 41.0 g. (72-77%) of product, m.p. 106-107° (Note 11). 

Catalysis by organopalladium complexes has also been used to effect cyclization of appropriately substituted bromarylamines into indoles (cf. Scheme 44 in Section IV,A,3).73 By extending the side chain by one methylene unit, the method can be applied to the synthesis of isoquinolines (Scheme 147) but the preparative scope has not been evaluated.73... 

N-Substituted 4-methylene-3,4-dihydro-l-(2H)-isoquinolin-l-ones are synthesized by means of a palladium-catalyzed three-component process (Scheme 16.5) [9]. 

Contrary to the normal Michael reaction of the chloro ester 1-Me with (di-phenylmethylene)amine (DPMA-H) in methanol (Scheme 29), reaction of DMPA-H with 1-Me in methylene chloride or tetrachloromethane containing sodium hydride proceeded much more slowly and gave the isoquinoline 126 in 26 and 39% yield, respectively (Scheme 42) [60 a]. The structure of 126 was ascertained by X-ray crystallography [60a]. Taking into consideration the stability of the Michael adducts 94 in refluxing CCI4, the reaction mechanism with intermediacy of a formal [4-1-2] cycloadduct 125 which may be formed in either a concerted or, more probably, a two-step domino Michael reaction, has been postulated [60a]. 

Sainsbury et al. (88) utilized the intramolecular 1,3-dipolar cycloaddition of tetrahydroquinolines 166 to construct 1 l-acetoxycarbonyl-1,2,3,4,5,10-hexahy-droindeno[2,3-fl]isoquinoline (167). The presence of an ester functionality on the alkyne is essential for the cycloaddition to occur. With one less methylene group in the tether, the yield of the corresponding pentaleno[2,3-a]isoquinoline is 37%. 

The reaction of o-nitrobenzaldehydes with some benzene derivatives in the presence of strong acid (H2S04, PPA) is a classical synthesis of acridinol N-oxides (373) (37BSF240) The synthesis works for benzyl alcohol, benzene, toluene and halobenzenes, but not for benzoic acid, benzonitrile, dimethylaniline, or nitrobenzene. Isoquinoline N-oxides (374) have been obtained from o-bromobenzaldoxime or the acetophenone derivative, and active methylene compounds with copper bromide and sodium hydride (77S760). The azobenzene cobalt tricarbonyl (375) reacts with hexafluorobut-2-yne to give a quinol-2-one (72CC1228), and the 3,4,5-tricyanopyridine (376) is formed when tetracyanoethylene reacts with an enaminonitrile (80S471). 

Isoquinoline, 2-acetyl-l,2,3,4-tetrahydro-6,7-dimethoxy-1-methylene-, 56, 4 Isoquinohne, 2 benzoyl 1-benzyl 1 cyano 1,2-drhydro-, 56, 23 Isoquinohne, 2-benzoyl-l-cyano-l, 2-di-hydro-, 56, 20... 

Hydrogenation of 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-nitrile in tetrahydrofuran in the presence of ammonia over Raney nickel under 60 psi for 5 h yielded 3-aminomethyl-4//-pyrimido[2,l-a]isoquinolin-4-one (86EUP166439). Reduction of ethyl 4-oxo-4//-pyrimido[2,l-a]isoquino-line-3-carboxylate with diisobutylaluminum hydride in methylene chloride... 

Oxidation of ethyl 7-allyl-10-methoxy-4-oxo-6,7-dihydro-4//-pyrimido-[2,l-a]isoquinoline-3-carboxylate (99) by ozone in methylene chloride at -70°C, then treatment of the mixture with dimethyl sulfide at ambient temperature for 1 h gave either 7-(2-oxoethyl)- or 7-(2,2-dimethoxyethyl) derivatives (105 and 106), depending upon whether methanol was used during the workup (78USP4127720). 

The 1-benzoyl derivative of l,2,3,4-tetrahydro-6//-pyrimido[l,2-b]-isoquinolin-6-one was prepared from l,2,3,4-tetrahydro-6//-pyrimido-[l,2-h]isoquinolin-6-one by benzoylation [69LA(729)83]. Reaction of l,3,4,6,ll,lla-hexahydro-2//-pyrimido[l,2-b]isoquinolines and methyl iodide in methylene chloride at 0°C afforded 5-methyl-l, 3,4,6,11,1 la-hexahy-dro-2//-pyrimido[l,2-h]isoquinolinium iodides (43) (73JOC437). 

C-Alkylation of 1-methyl-1,2,3,4-tetrahydro-6//-pyrimido[l,2-b]isoquino-lin-6-one with benzyl bromide in boiling methylene chloride overnight in the presence of potassium carbonate, and with excess methyl iodide gave 11-substituted derivatives (113 and 114) (88HCA77). The treatment of hydrobromide salt of 11-benzyl derivative 113 with a base yielded 11-benzyl-1 -methyl-1,2,3,4-tetrahydro-6//-pyrimido[l, 2-6]isoquinolin-6-one (115). 

The hydroxyl group of ethyl 2-hydroxy-4-oxo-4//-pyrimido[2,l-a]-isoquinoline-3-carboxylate (20) was methylated with methyl iodide in dry boiling acetone for 5 h in the presence of potassium carbonate, with dimethyl sulfate in methylene chloride in methanol in the presence of Triton B at 20°C for 18 h, with methyl fluorosulfonate in 2.5 M sodium hydroxide at 20°C for 5 h, and with diazomethane in a mixture of diethyl ether and methylene chloride at 20°C for 3 h to give the 2-methoxy derivative (89AJC2161). The hydroxy group of 3-hydroxymethyl-4//-pyrimido[2,l-b]-isoquinolin-4-one was alkylated and acylated with 2-(diethylamino)ethyl chloride in dimethylformamide in the presence of sodium hydroxide, and with acetic anhydride in boiling chloroform in the presence of triethylamine and a few drops of 4-dimethylaminopyridine, respectively (86EUP 166439). 

The carboxyl group of 4-oxo-4//-pyrimido[2,l-a]isoquinoline-3-carboxylic acids was esterified with various alcohols [84JAP(K)84/172490] and was converted into N-substituted 3-carboxamides by treatment with ethyl chloroformate in the presence of triethylamine in methylene chloride, followed by amines and hydroxylamine at 0°C [84JAP(K)84/172490 85EUP143001]. 

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