Isoquinolines reaction with activated alkynes

Methods that rely on alkynes and alkenes for the synthesis of isoquinoline core are based on two basic modes for their cyclization. The first uses electrophilic reagents as activators of alkynes or alkenes for the cyclization process, while the second method uses a nucleophilic atom usually nitrogen in reaction with the alkyne or alkene moiety. 

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]. 

The attacks of heterocyclic A -oxides, e.g. of pyridine, quinoline, isoquinoline, phenanthridine, etc., on activated alkynes (RC CR R = R = COOMe R = Ph, R = COOEt R = Ph, R = CN) pose similar problems . An acyclic intermediate has been postulated but is rarely detected. Some of the possibilities are illustrated in equation (126) . If the open intermediate is formed, then the paths to the ylid and the 2-substituted quinoline in equation (126) seem simple enough, but several possible mechanisms can lead to the 3-substituted products . Other workers regard the reaction of the nitrone (or azomethine oxide) with alkyne as simple cycloadditions - which yield 2,3-dihydro-l,2-oxazoles since these are often unstable, only decomposition products may be found (equation 127). The construction of the indolizine skeleton initiated by a similar process has been reviewed (equation 128). ... 

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. 

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]. 

The enantioselective intramolecular formal 2+4-cycloaddition of acrylates and a, -unsaturated imines (99) catalysed by chiral phosphines (100), derived from amino acids, produced A-heterocycles (101) (Scheme 31). Chiral dirhodium(II) carboxamidates (102) catalysed the hetero-Diels-Alder reactions between 2-aza-3-silyloxy-l,3-butadienes and aldehydes to yield all cw-substituted l,3-oxazinan-4-ones in high yields and high enantioselectivity (98% ee)P The nickel-catalysed 4 + 2-cycloaddition of a, -unsaturated oximes with alkynes yielded 2,3,4,6-tetrasubstituted pyridine derivatives. The reaction of isoquinoline, an activated alkyne, and 4-oxo-4//-l-benzopyran-3-carboxaldehyde (103), in ionic solvents, produced 9a//,15//-benzo[a][l]benzopyrano[2,3-/t]quinolizine derivatives (105) via the zwitterion (104) selectively and in good yields (Scheme 32).The Diels-Alder cycloaddition of ethyl 3-(tetrazol-5-yl)-l,2-diaza-l,3-butadiene-l-carboxylates with -rich heterocycles, nucleophilic olefins, and cumulenes formed 3-tetrazolyl-l,4,5,6-tetrahydropyridazines regioselectively. The silver-catalysed formal inverse-electron-demand Diels-Alder... 

Even poor nucleophiles such as the amides 46 can react with azines in the presence of alkynes as activating agents [59, 60]. Various nucleophiles (including alkoxides, thiols, amines and nitrogen heterocycles) were recently employed in a related process with Ai-oxide azaindoles (Reissert-Henze reaction. Scheme 10). In the process, the oxygen is alkylated with dimethyl sulfate and, after the nucleophilic attack, methanol is released to aromatize the initial adduct [61,62]. Following similar mechanistic trends, V-heteroatom-activated azines afford the corresponding substituted adducts. Likewise, W-tosylated isoquinoline [63, 64] and W-fluoropyridinium salts [65] are also reactive substrates in Reissert-Henze type processes. 

In a similar context Amdtsen developed a new pyrrole synthesis from alkynes, acid chlorides either imines or isoquinolines, based on the reactivity of isocyanides (Scheme 35a) [197]. Although all atoms from the isocyanide are excluded from the final structure, its role in the reaction mechanism is crucial. The process takes place through the activation of the imine (isoquinoline) by the acid chloride to generate the reactive M-acyliminium salt, which is then attacked by the isocyanide to furnish a nitrilium ion. This cationic intermediate coordinates with the neighboring carbonyl group to form a miinchnone derivative, which undergoes a [3+2] cycloaddition followed by subsequent cycloelimination of the isocyanate unit, to afford the pentasubstituted pyrrole adducts 243 and 244 (Scheme 35a, b). 

Very recently, Jun et al. [179] have described the synthesis of isoquinoUnes 181 and pyridines 182 by the [Cp RhCy2-catalyzed Al-annulation reaction between aryl or a,p-unsaturated ketones 179-180, alkynes 178, and NH OAc, employing stoichiometric amounts of Cu(OAc)j as the oxidant and microwave irradiation. The reaction is successful with a wide family of arylketones 179 and enones 180 to afford the desired isoquinolines 181 and pyridines 182 in good to excellent yields (Scheme 3.69). A four-component reaction could be developed by in situ generation of enones by aldol reaction between an enolizable ketone and formaldehyde, affording the desired products in moderate yields. The proposed mechanism involves the Rh" -promoted consecutive N—H and p-C—H bond activation of imine XXXVII, generated from ketone/enone and NH, ... 

Nitrogen heterocycles can also b e prepared by silver(I)-catalyzed cyclization reaction. Asao, Yamamoto, and their colleagues have shown synthesis of 1,2-dihydro-isoquinoline derivatives by addition of pronucleophiles to ortho-alkynylaryl ald-imines employing AgOTf as a catalyst [29]. For example, treatment of imine (19) with 2 equiv of nitromethane (20) in the presence of 3 mol% of the catalyst at 80 °C, 1,2-dihydroisoquinoline derivative (21) is produced in 85% yield (Scheme 18.7). Terminal alkynes and carbonyl compounds possessing activated methylene groups are also usable as the pronucleophiles [29]. 2-Alkoxyazetidines are efficiently synthesized by Ag(fod)-catalyzed [2-F2] cycloadditions of imines to (alkoxymethylene)... 

The aerobic dehydrogenative annulation of 2-aryl-substituted pyrroles and indoles for a variety of alkynes, using the system ruthenium(Il) catalyst with oxidant Cu(0Ac)2.H20, was then reported. The reaction was now performed under ambient air as the ideal sacrificial oxidant, thus only 10 mol% of Cu (0Ac)2.H20 could be used for efficient transformations of indoles [(Eq. 89)] [178]. This method could also be applied to synthesize pyrrolo[2,l-a]isoquinolines from 2-arylpyrroles with dialkyl-, diaryl-, or alkylarylacetylenes with an excellent regioselectivity. The competition experiments showed that an electron-deficient alkyne favours this reaction and that the more acidic C-H bond activation is favoured [(Eq. 89)] [178]. 

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