Symmetrical and Unsymmetrical Bis-1,1′-(3,4-dihydroisoquinolines)

Abstract

Shklyaev3,3,-Dialkyl-1-cyano-3,4-dihydroisoquinolines were prepared by Beckmann defragmentation of ethyl α-(3,3-dialkyl-3,4-dihydroisoquinol-1-yl)-α-hydroximinoacetates and they take part in a Ritter reaction to form substituted bis-1,1'-(3,4-dihydroisoquinolines).As heterocyclic analogs of 1,1'-binaphthyl systems, bis-1,1'-isoquinolines are promising ligands for the preparation of metallocomplex catalysts since coordination with a metal is possible at the nitrogen atoms [1]. A method is known for the Ullman preparation [2] of bis-1,1'-isoquinolines while 3,4-dihydro derivatives are not formed under these conditions and they are rather inaccessible compounds. Bis-1,1'-(3,4-dihydroisoquinolines) unsubstituted in position 3 have been previously obtained using a Bischler-Napieralski reaction by the action of POCl 3 in acetonitrile [3] or Tf 2 O in the presence of 4-N,N-dimethylaminopyridine [4] on the corresponding oxamide. In the current work we propose a route to bis-1,1'-(3,4-dihydroisoquinolines) which is based on the Ritter reaction [5,6].A second order Beckmann rearrangement [7,8] of ethyl α-(3,3-dialkyl-3,4-dihydroisoquinol-1-yl)-αhydroximinoacetates 1a-c using the method [9, 10] gave the nitriles 2a-c. Despite the simplicity it should be noted that the indicated method is poorly reproducible in our hands, the yields of the products 2 differing markedly from one experiment to another.The nitrile 2a was also prepared by the dehydration of 3,3-dimethyl-3,4-dihydroisoquinolylaldoxime 3 [11] in refluxing xylene using a known method [12] (see Experimental section. The hydrochloride 3.HCl has been reported before [13]).The Ritter reaction of nitriles 2a-c and carbinols 4a-c (stirring the reagents in a mixture of toluene and conc. H 2 SO 4 at 20°C) gave 42-71% yields of compounds 5a-e (Tables 1 and 2). According to this scheme another combination of nitrile and carbinol is possible which leads to both symmetrical and unsymmetrical bis-1,1'-(3,4-dihydroisoquinolines) 5. Compound 5c was also prepared in somewhat lower yield (37%) by the condensation of nitrile 2b with veratrole and isobutylene oxide using method [14] (Scheme 1).A feature of the 1 H NMR spectrum of compound 5b is the small shift of the H-8 signal of the 6,7-dimethoxy-substituted ring to high field by about 0.2 ppm when compared with the H-8 signal of 6,7-dimethoxy-1,3,3-trimethyl-3,4-dihydroisoquinoline [14] and this is due to the anistropic effect of the neighboring 3,4-dihydroisoquinoline fragment. A similar high field shift caused by a benzene ring has previously been observed by us in the case of 6,7-dimethoxy-3,3-dimethyl-1-phenyl-3,4-dihydroisoquinoline [14].0009-3122/05/4104-0475©2005 Springer Science+Business Media, Inc. nitrile 2b (0.3 g, 1.23 mmol) and carbinol 4a (0.2 ml, 1.25 mmol) in toluene (20 ml) was added to conc. H 2 SO 4 (10 ml) and the mixture obtained was stirred for 2 h at 20°C and poured into water (100 ml).The aqueous layer was separated, washed with toluene (15 ml) and NH 4 OH (25%) was then added to pH ~ 8. The product was ext...

Thiocarbamoylation of 1,2,3,4-tetrahydroisoquinoline enamines with phenyl isothiocyanate

“…The initial enamines [10] and compounds I, Va, III [16], Vb, Vc [3], IXa-IXc [17], Xa [12], and XII [11] were reported previously. All compounds were recrystallized from propan-2-ol.…”

“…Cyano group is a stronger electron acceptor than ester or amide; in addition, no intramolecular H-bond is possible in enamino nitrile molecules. Initial nitriles Xa-Xc were synthesized according to the procedure described in [12], by replacement of the chlorine atom in chloromethyl derivatives IXa-IXc by the action of potassium cyanide in propan-2-ol. The acylation of enamino nitriles Xa-Xc with phenyl isothiocyanate was complete in 5-10 min (TLC), which reflected the stability of intermediate carbanion due to electron- withdrawing effect of the cyano group.…”

Glycosyl Triazole Based Pyridinamide/CuI-Catalyzed Coupling of 2-Halobenzamides with Active Methylene Compounds

“…The effective existence of this scaffold in natural products and synthetic pharmaceuticals has led to the need for new efficient protocols to practically assemble these biologically significant molecules. 14 15 16 17 Many synthetic approaches have been devised for the classical synthesis of isoquinolinone derivatives; for example, Gabriel and Coleman initially reported a classical method to develop isoquinolinone motifs. 18 Further selected examples include the synthesis of isoquinolinones from a base-assisted condensation reaction of homophthalic anhydride and 2-(bromomethyl)benzonitrile, 19 an intramolecular coupling of amides and ketones in the presence of base in DMF, 20 palladium-catalyzed carbonylation–decarboxylation reactions introduced by Zheng and Alper, 21 a tandem reaction between 2-halobenzamides and β-keto esters reported by F. Wang et al, 22 a CuBr-catalyzed aerobic protocol to assemble isoquinolinone using 2-alkynylbenzaldehydes and primary amines, 23 a nucleophilic aromatic substitution reaction to assemble these derivative reported by the X. J. Wang group, 24 a Pd-catalyzed tandem Heck/C–H activation and decarboxylation route to the isoquinolinone skeleton introduced by the Yang group, 25 and a Cu 2 O-catalyzed tandem cyclization of o -halobenzoate with enaminones reported recently by Liang and Wang.…”