Reactions of isoquinolines

A variety of metal mediated or catalyzed reactions involving isoquinoline derivatives were reported in the literature over the past year. An efficient method for the reductive amination of tetrahydroisoquinoline was performed in the presence of Ti(Oi-Pr)4 and NaBH4 to make a variety 

Additionally, the photolysis of an isoquinoline salt resulted in the formation of 2-methyl-l-(2,3,4,5,6-pentafluorophenyl)-l,2-dihydroisoquinoline via photoinduced transfer of CeFs 

The asymmetric addition of different types of nucleophiles at the C-l position of 3,4-dihydroisoquinolines were highlighted in a number of publications. Schreiber et al. described an enantioselective addition of terminal alkynes 136 to 3,4-dihydroisoquinolinium bromide 137 in the presence of triethylamine, catalytic copper bromide, and QUINAP 06OL143 . The resulting 1-substituted tetrahydroquinolines 138 were isolated in high yield and high enantiomeric excess in most cases. 

Kundu et al. developed a mild and efficient one-pot protocol for the synthesis of dihydroindazoloisoquinolines 142 via an unprecedented SnCl2-mediated intramolecular cyclization of nitro-aryl substrates 143 06OL1525 . As illustrated below, the cyclization occurs via the hydroxylamines 144 and leads to the formation of dihydroindazoloisoquinolines 142 in high yield and purity. 

Using an efficient IBX-mediated Ugi-type reaction, Zhu and co-workers reported the synthesis of a series of 1,2-disubstituted tetrahydroisoquinolines 143 in moderate to high yields 07AG(I)5775 . To the best of the author s knowledge, this is the first example of dual acylation at the Cl position and at the N-H group of tetrahydroisoquinoline. 

Shaabani et al. described a novel water-promoted one-pot three-component reaction of aldehydes, 2-aminobenzothiazole and 6-hydroxyquinoline to synthesize a series of 5-(2  

In an additional report, Shaabani el al. described a novel environmentally friendly three-component reaction of isoquinoline and isocyanides in the presence of activated CH-acids in water to provide 1,2-dihydroisoquinoline derivatives 145 07TL4743 . The desired products were synthesized in good to high yields without the need for a catalyst. 

---

Chlorination. When 75 was treated with chlorine in the presence of aluminium chloride, initial chlorination took place at the 5-position, but the reaction was rather unselective 5,8-di-, 5,7,8-tri-, and 5,6,7,8-tetra-chloroisoquinolines were also formed (64JOC329). Perchlorination has been achieved by initial reaction of the isoquinoline-aluminium chloride complex with chlorine, as above, followed by treatment with phosphorus pentachloride at 270°C in an autoclave [66JCS(C)2328]. Treatment of 1,8-dimethylisoquinoline with NCS gave the 5-chloro derivative (91NKK-1193). Meisenheimer reaction of isoquinoline 2-oxides with phosphoryl chloride gave 1-chloroisoquinoline (84MI2). 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

The situation with isoquinoline in many respects is similar to that seen with quinoline, although as yet there are no reports of the directed lithiation of substituted derivatives. l,l -Diisoquinolyl was obtained from the reaction of isoquinoline with LDA, showing that deprotonation occurred at the 1-position (74TL2373), whereas with LDA/f-BuOK and dimethyldisul-fide the 4-derivative 111 was obtained (84CC257). Again, as with quinoline,... 

The mixed trimerization of heterocyclic compounds is another potentially valuable route to fused systems. The reaction of isoquinoline and 2-chloro-4,5-dihydroimidazole is a recent example of this approach (equation 104) (81S154). 

Cyanoisoquinolines and 2-cyanoquinolines were recently prepared via the reaction of isoquinolines and quinolines with p-TsCl/KCN.119 The reaction proceeds in two steps, as shown in the example of Scheme 13, and involves Reissert intermediates, which upon treatment with base give the cyano aromatic products in good overall yields.119... 

The reaction of quinoline with [( 5-Cp )Rh(AN)3]2+ gives the rjl(N)-coordinated complex 121 (88OM2250). If this reaction occurs in acetone or acetonitrile containing traces of water, the product is [( 75-Cp )Rh (quinoline)(/x-OH)]2(BF4)2. The reaction of isoquinoline with [( 5-Cp ) Rh(AN)3]2+ or [( 5-Cp )Rh(/ -xylene)]2+ gives complex 122. 2-Methyl quinoline gives a mixture of products 123 and 124. In 124 coordination is fulfilled via the benzene ring. 

Another nice example of SRR is depicted in Scheme 8. The original reaction was developed by Diels and Harms in 1936 [61]. Reaction of isoquinoline 71 with dimethyl acetylenedicarboxylate (DMAD, 72) initially forms zwitterionic intermediate 73, which is reacted with a second equivalent of DMAD to form benzoqui-nolizine 74. This is, however, not a true 3CR reaction, since two components are identical. In 1967, Huisgen reported three variations of this reaction in which... 

In a different context, chiral reagents have been implemented in this chemistry. For instance, Liebscher and Itho developed the use of chiral acylating agents such as amino acid-fluorides 158 and -chlorides 156, respectively, (Scheme 21). The outcome of the reaction of isoquinoline (6), TMS-CN (14) and A -protected a-amino acid fluorides is dictated by the nature of the protecting group whereas Cbz- and... 

Reaction of isoquinoline, potassium cyanide, and N,iV-diphenyl-carbamoyl chloride gave 67. A similar compound was also obtained through the use of A,iV-diethylcarbamoyl chloride. Again the infrared... 

Reaction of isoquinoline and potassium cyanide with dialkyl ehlorothiophosphates - and dialkyl chlorophosphates gives rise to compounds of the type 72a (X = S or O). 

The ring-closure reactions of isoquinoline derivatives (21) with phenylphos-phonyl chloride afforded a new ring system (see 1,3,2-diazaphosphorinano [6,1-a] isoquinolines (22) and (23) in Scheme 2). Their conformational analysis was performed by H, P-NMR. ... 

The transformation of isoquinolinium salts into naphthalene derivatives described in connection with berberine (c/. Section 11) may have general applicability since similar reaction of isoquinoline methiodide gave -naphthyl acetate, albeit in small yield (see ref. 362). 

Reaction of isoquinoline with allylzinc bromide in THP gave the dizinc complex 99 which on heating at 65 C for 30 minutes furnished the dizinc complex of the isoquinuclidine ring system (101). Work up with MeOH and base yielded a 7 3 mixture of the ISQ isomers, endo-X l and exo-102 (Scheme 13) [98]. Transformation of 99 to the tricyclic compound 101 appears to proceed by the addition of the benzylzinc fragment to the double bond of the 1-allyl group. The predominant formation of endo-102 is most likely caused by the electronic effect of the benzene ring on the orientation of the double bond and the 4-ZnBr group in the transition state [98]. 

Seubert et al. [25] have reported the first synthesis of praziquantel from the intermediate 37 obtained by the Reissert reaction of isoquinoline and followed by high pressure hydrogenation of the cyano compound 36 [36], Acylation of 37 followed by base catalysed cyclisation of the diacylated product affords praziquantel [25,37,38] (Scheme 2). 

The unpublished results in this area that were noted in the earlier review have now been published. Reaction of isoquinolines,quino-... 

The paper reporting the reaction of isoquinoline and potassium cyanide with dialkyl chlorophosphates and dialkyl chlorothiophosphates to give products of the type 114 has now appeared. These compounds can be alkylated in the same manner as a normal Reissert compound, and hydrolysis of the alkylation product gives 1-methylisoquinoline. A phthalazine analog (115) has also been prepared. ... 

A number of other miscellaneous systems that bear some relationship to Reissert compounds have also been reported but will not be covered in depth here. Thus, for example, the reaction of isoquinoline, potassium cyanide, and alkyl chloromethyl ethers give 116. A similar compound was also prepared from quinoline. Compounds of type 117 have been reported to undergo rearrangements similar to Reissert compounds. A... 

In some cases nonaromatized adducts are isolated. The reaction of isoquinoline IV-imine17,190 and phenanthridine iV-imine17,33 with dimethyl acetylenedicarboxylate gives tautomeric isomers of the primary adducts, e.g., 61. These IV-imines also react with iV-phenylmaleimide to give the primary 1 1 cycloadducts, e.g., 62.33,190 Of particular interest is the reaction of isoquinoline IV-imine with mesityl oxide which produces 63. This reaction involves disproportionation and elimination of methane from the primary adduct.17... 

Reactions of electron-r/cA acetylenes with heteroaromatic compounds are rare. Such (2 + 2>cycloadditions have been proposed as the first step in the boron-trifluoride-catalyzed reaction of isoquinoline with l-dimethylamino-2-phenylacetyleneM and in the reaction of 1,2,4-triazines with 1-diethylamino-l-propyne, 1 but no experimental... 

New reactions of isoquinoline derivatives include the following 3,4-di-hydroisoquinoline N-oxide with 2-acetylcycloalkane-l,3-diones, Reissert compounds with stilbene and tolan derivatives, isoquinoline with pyrrole derivatives and with 2-methylfuran " (both in the presence of benzyl chloride), and the chromium trioxide oxidation of the benzo[a]quinolizidine (49) to give (50). Compound (49) was prepared by the condensation of 3,4-dihydroiso-quinoline with the 5-lactone (51). Further examples of a classical benzo[a]-... 

The reactions of isoquinoline closely parallel those of quinoline and pyridine. Protonation, alkylation, acylation and oxidation with peroxy acids occur on nitrogen. SeAt and SNAr reactions take place on the ring C-atoms. As in quinoline, the fused benzene ring influences the reaction site and reactivity. 

---