3,4-Substituted isoquinolin-1 -ones

The acid catalyzed cyclization of 2-acylphenylacetonitriles 94 was investigated using strong acidic conditions. It was found that the use of Amberlyst ion exchange resins, such as A-15 and A-XNlOlO In place of sulfuric or methanesulfonic acid provided 1-substituted 2//-isoquinolin-3-ones 95 (Scheme 42) in improved yields <04JHC979>. 

The second illustration above is a phthalide THIQ, and these phenethylamines are sometimes referred to as secophthalide-isoquinolines. Here, the oxygen atom of the original isofuranone ring is substituted on the newly formed double bond. This structure can easily open up to the corresponding ketonic carboxylic acid. These seco-modifications of the attacked isoquinoline (first example, illustrated with an aporphine) and the simpler 1-substituted isoquinolines (second example, as illustrated by the isobenzofuranone) are the only ones included in this book. The standard phenethylamines that are commonly found in cacti, compounds which are not from these seco-mecha-nisms, have been tabulated in TIHKAL and will not be repeated here. 

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... 

The fully-unsaturated 1,3-benzodiazepine 310 is formed by a photoreaction of the 1-substituted isoquinoline 7V-imide 309 (Scheme 169) <1980CPB2602>. The same principle has been applied to prepare thieno-, furo-, and pyrrolo-fused 1,3-diazepines <1980CC454, 1981CPB1539>. The imidazolo-fused l,3-benzodiazepin-2-ones 313 can be prepared by the reaction of 5-amino-4-(cyanoformimidoyl)imidazoles 311 with tosyl isocyanate. The mechanism of this reaction includes a 1-exo-dig cyclization of intermediates 312 followed by a Dimroth rearrangement to give the thermodynamic products 313 (Scheme 170) <1996JHC855, CHEC-III(13.05.9.2.2)174>. 

Dialkyl phosphites such as 49 (Scheme 9) have been reacted as nucleophiles with activated pyridines [69, 70]. The first examples of this chemistry involved either 77-alkyl-pyridinium salts in the presence of DDQ, or pyridine and terminal alkynes as activating agents in a one-step protocol. The reaction proceeds under mild conditions that include AI2O3 catalysis. Quinolines 1 and chloroformates afford the expected adducts 68. The latter structures can be easily oxidized with O3 to provide the substituted indoles 69 (Scheme 12a). Isoquinolinephosphonates obtained this way have been used in Wittig-Homer chemistry. The whole sequence offers ready access to alkyl substituted isoquinolines [71]. Analogously, sUyl substituents have been introduced into A-acylated pyridines by using silylcuprates [72]. 

Cu(l)-mediated cychzations to substituted isoquinolines (34), or their monocyclic pyridyl analogs, take place in one pot following a Pd/Cn catalyzed Sonogashira conphng see Sonogashira Coupling) between an aryl halide (32) and... 

The reaction of dialkylquinolylboranes (34) with organic halides (35) furnishes substituted quinolines (36) in moderate to fair yield, as in the case of pyridines (85H2375) (Scheme 13). Similarly, 4-substituted isoquinolines (38), one of the common structural units of isoquinoline alkaloids, have been prepared from diethyl-(4-isoquinolyl)borane (37) (87H1603) (Scheme 14). 

Following exactly the same logic, quinoline and isoquinoline N-oxides can be easily transformed to the corresponding quinolinones or isoquinolin-ones in reaction with acetic anhydride or halogen-substituted... 

Reaction of papaverinol with glacial acetic acid produces papaverine and papaveraldine through hydride transfer. However, treatment of papaverinol with 90% sulfuric acid results in some 0-demethylation of one of the methoxyl groups in ring C, together with some cleavage of the C-a to C-1 bond to form a substituted isoquinoline-1-carboxaldehyde. ... 

A rhodium-catalyzed one-pot synthesis of substituted pyridine derivatives from a,(3-unsaturated ketoximes and alkynes was developed in 2008 by Cheng and coworkers [99], Good yields of the desired pyri-dines can be obtained (Scheme 3.48). The reaction was proposed to proceed via rhodium-catalyzed chelation-assisted activation of the (3—C—H bond of a,(3-unsaturated ketoximes and subsequent reaction with alkynes followed by reductive elimination, intramolecular electro-cyclization, and aromatization to give highly substituted pyridine derivatives finally [100]. Later on, in their further studies, substituted isoquinolines and tetrahydroquinoline derivatives can be prepared by this catalyst system as well [101]. Their reaction mechanism was supported by isolation of the ort/jo-alkenylation products. Here, only asymmetric internal alkynes can be applied. 

The photocyclization of a series of suitably substituted enamides [e.g. (197)] has been used to create spiro-substituted isoquinolin-l-ones (198) a ring system present in a range of natural products. Although a great variety of products is available by this route, compounds lacking CHjPh do not cyclize. 

SCHEME 18 One-pot three-component reaction of variously substituted isoquinolines, 2-bromoacetophenone, and N-arylmaleimide derivatives to form tetrahydropyrrolo-[3, 4 3.4]pyrrolo[2.1-fl]isoquinoline-9,ll-diones. 

Monsal and coworkers have achieved the construction of pyrrolidine nucleus in the synthesis of tetrahy-dropyrrolo[3, 4 3.4]pyrrolo[2.1-fl]isoquinoline-9,ll-diones 57 derivatives in an aqueous micellar medium [53]. The S5mthesis involves a one-pot three-component reaction of variously substituted isoquinolines 54, 2-bromoacetophenone 55, and N-arylmaleimide derivatives 56 in the presence of triethylamine as a base (Scheme 18). The preliminary investigation indicated that the presence of surfactant was essential for the success of reaction. Accordingly, the reactions were carried out in cationic, anionic, and nonionic surfactants well above their critical micelle concentrations (CMC). The maximum yields were obtained in cetyltrimethylammonium bromide (CTAB) (CTABiCMC value 0.29 mM at 80mM concentration). The mechanism of formation involves an in situ generation of isoquinolinium ylides followed by [2 -h3] cycloaddition of N-aryl maleimides. 

Almost simultaneously, Hua and co-workers developed a versatile and straightforward route to construct multisubstituted isoquinolines and relative fused pyridine heterocycles (60) by using readily availableketones (59) and alkynes (Scheme 7.41) [110]. The reaction involves condensation of aryl ketones and hydroxylamine, rhodium(III)-catalyzed C-H bond activation of the in situ generated aryl ketone oximes, and cycUzation with internal alkynes. This reaction proceeds under external-oxidant-free and moderately mild conditions. Later, a similar one-pot multi-component process promoted by a Rh(III) catalyst that generates substituted isoquinolines under microwave irradiation conditions was uncovered by Jun [111]. 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

As shown in Scheme 26, Papaverine hydrochloride yields a separable mixture of Protopapaverine (67) and the salt norpapaverinium chloride (68) when heated slightly beyond its melting point for several minutes. Molecule 67 can exist as conjugated mesomeric betaine 67A (7-hydroxy form) or as 2-substituted-2//-isoquinolin-6-one 67B (6-hydroxy form) (66TL1177). Similar structures were described as zwitterionic pentacyclic... 

The mass spectral fragmentations of 9,10-dimethoxy-2,3,4,6,7,ll/)-hexa-hydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140 and -2,4-diones 141, under electron ionization (at 70 eV) were examined by metastable ion analysis, a collosion-induced dissociation technique and exact mass measurement (97RCM1879). Methyl substituent on N(3) in 140 (R = Me) had a larger effect on both the fragmentation and on the peak intensities, than a methyl substituent on C(6) (R = Me). The ionized molecules of 140 (R = H) were rather stable, whereas 4-phenyl substitution on C(4) of 140 (R = Ph) promoted the fragmentations of the molecular ions. The hexahydro-1//-pyrimido[6,l-n]isoquinoline-2,4-diones 141 were more stable, than the hexahydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140, and the molecular ions formed base peaks. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

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