Ketone substituted isoquinolines

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. 

Cyclization of oximes and diazo compounds via Rh(III)-catalyzed C-H activation provided substituted isoquinoline and pyridine Af-oxides (Scheme 63) (13JA12204). A number of ketones (including those with some steric hindrance) were transformed into oximes that would undergo cyclization. Also, structural diversity, including both electron-donating and... 

Scheme 8.27 Synthesis of substituted isoquinolines utilizing palladium-catalyzed a-arylatlon of ketones, as described by Donohoe s group [59].

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]. 

Isoquinolinylpalladium(II) intermediates of type 27 (Scheme 19.7) are useful precursors of 4-substituted isoquinolines. For example, when the reaction was carried out under a CO atmosphere in the presence of R X (aryl iodides/acyl chlorides) [8] or ROH [9], the corresponding ketones 29 or esters 31 were produced through carbony-lation (Scheme 19.8). Additionally, palladium(II)-catalyzed isoquinoline formation followed by a Heck reaction under oxidative conditions (CUCI2/O2) effectively produces 4-alkenylisoquinolines 33 [10]. 

For the synthesis of quinolines and isoquinolines the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid medium has been reported to be accelerated under microwave irradiation to give differently substituted quinolines and dihydro quinolines [137]. Although the yields are much better and the conditions are milder than under conventional heating, the acidity of the medium may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

An appropriately functionalized isoquinoline (38) bearing a benzyl group is prepared from an aromatic aldehyde (37). The benzyl position is metalated with LDA and the resulting carbanion is reacted with a highly substituted methyl benzoate to produce a ketone (39). The isoquinoline nitrogen is alkylated with ethyl a-bromoacetate and the resulting quaternary salt is cyclized... 

The isoquinoline system is conveniently prepared from treatment of o-iodobenzylamines with the enolate ions derived from symmetrical ketones (or ketones with one a-position blocked), aldehydes, or the dimethyl acetal of pyruvaldehyde, to give aminocarbonyl compounds which condensed in situ to give 2- and/or 3-substituted 1,2-dihydroisoquinolines. Catalytic dehydrogenation or borohydride reduction of these products then led to the corresponding isoquinolines or tetrahydroisoquinolines in moderate to high... 

A typical reaction is the photostimulated substitution of aryl halides by ketone [121-131] (and much less efficiently aldehyde [124]) enolate anions (Scheme 5), both inter- [121-128] and intramolecularly [129-131]. The SRN1 reaction with o-bromoacetophenones is a useful method for the construction of an aromatic ring (Scheme 24) [132-133], with o-halophenylalkyl ketones for macrocycles (Scheme 25) [134], with o-haloanilines for indoles [123], with o-halobenzylamines for isoquinolines [135], and several other heterocyclic syntheses are possible [136]. 

A synthesis of 4-hydroxy-substituted TIQ has been developed in connection with plant isoquinolines (169,170), and the glycine ester route used for a similar purpose (171) is shown in Fig. 23. Reaction of the benzyl bromide 85 with N-methylglycine ester gave 86 the ketoester 87 was obtained on Dieckmann condensation. Alkaline hydrolysis of ester 87 followed by treatment with mineral acid gave ketone 88 alcohol 89 was obtained on reduction of 88 with sodium borohydride. 

An efficient single-step synthesis of isoquinolines was achieved by a three-component reaction of aromatic ketone with benzylamine and alkyne. Rhodium (I) is used as the catalyst and o-functionalization of the aromatic rings is not necessary, indicating an extended scope for this method <03OL2759>. The reaction is complicated by a sizable amount of phenethyl-substituted side product. 

At the time of the last review it was noted that the condensation of ketones with the Reissert anion was a relatively unsatisfactory reaction. It has now been shown that acetone, acetophenone, cyclohexanone, and several N-substituted 4-piperidones ° react with the isoquinoline Reissert compound in the presence of 50% aqueous sodium hydroxide-acetonitrile containing TEB A chloride. Isatin, A(-benzyl-3-piperidone, ° and a variety of N-substituted 4-piperidones ° "° also react with isoquinoline or... 

Acylation of 3-substituted indoles is more difficult, however 2-acetylation can be effected with the aid of boron trifluoride catalysis." " Indoles, with a carboxyl-containing side-chain acid at C-3, undergo intramolecular acylation forming cyclic 2-acylindoles." Intramolecular Vilsmeier processes, using tryptamine amides, have been used extensively for the synthesis of 3,4-dihydro-p-carbolines, a sub-structure found in many indole alkaloids (P-carboline is the widely used, trivial name for pyrido[3,4-fc]indole). Note that it is the imine, rather than a ketone, that is the final product the cyclic nature of the imine favours its retention rather than hydrolysis to amine plus ketone as in the standard Vilsmeier sequence " this ring closure is analogous to the Bischler-Napieralski synthesis of 3,4-dihydro-isoquinolines (9.15.1.7). 

Isoquinolines substituted at C-1 are not easily formed by the standard Pomeranz-Fritsch procedure. The first step would require formation of a ketimine from aminoacetal and a aromatic ketone, which would proceed much less well than for an aryl aldehyde. A variation, which overcomes this difficulty, has a benzylamine condensing with glyoxal diethyl acetal the resulting, isomeric imine, can be cyclised with acid. ... 

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