Heterocyclic synthesis in PEG

Similar reaction conditions as those by Bose were used for a range of other applications, for example, the synthesis of heterocycles. A combination of a microwave-assisted Paal-Knorr reaction15 with a transfer hydrogenation takes place in the preparation of 2,5-di- and 1,2,5-trisubstituted pyrroles from -l,4-diaryl-2-butene-l,4-diones in a one-pot operation. Hydrogenation was achieved with ammonium formates and 10% Pd/C as catalyst in PEG-200. Yields of up to 92% were obtained within 0.5-2 min (Scheme 4.2)16. 

Formation of the imine and subsequent reduction can often be achieved in one pot . Thus, a microwave-assisted reductive amination-cyclisation domino reaction was used as the key step in the synthesis of perhydrocyclo-penta[ij]quinolizines from 1,5,9-triketones. This type of heterocycle is an important structural element in a series of alkaloids. The reaction of the triketone with ammonium formate in PEG-200 was performed within 1 min using microwave irradiation of370 W in a domestic microwave oven. Amixture oftwo ofthree possible stereoisomers was obtained in 87% overall yield (Scheme 4.29)52. 

The utilization of solid-support pyridinium salts in the synthesis of bicyclic pyridines has been reported. Yue et al. synthesized 1,2,3,7-tetrasubstituted indolizines using poly(ethyleneglycol)bound pyridinium salts <06JHC781>. The PEG-bound pyridinium salts 53 were reacted with alkenes or alkynes in the presence of Et3N, via 1,3-dipolar cycloaddition, to give polymer-bound indolizines 54 and 55, respectively. Liberation of the heterocycle with KCN/MeOH afforded 1,2,3,7-tetrasubstituted indolizines 56 and 57 in good to excellent yield. 

The Suzuki coupling of soluble polyethylene glycol (PEG)-bound bromothiophene 71 and p-formylphenylboronic acid provided biaryl 72 [56]. Due to the high solubilizing power of PEG, the reaction was conducted as a liquid-phase synthesis. Treatment of 72 with o-pyridinediaminc resulted in a two-step-one-pot heterocyclization through an imine intermediate. Nitrobenzene served as an oxidant in the ring closure step. Finally, transesterification with NaOMe in MeOH resulted in l//-imidazole[4,5-e]pyridine 73. 

Environmentally benign solvents (supercritical fluids, ionic liquids, low melting polymers (especially PEG), perfluorinated solvents and water) in organic synthesis, particularly, that of heterocycles 05COC195. 

An efficient method for the synthesis of dihydrothiophene ureidoformamides 149 from commercially available materials in a four-component domino process was reported by Cai et al. [82] (Scheme 12.58). The reaction efficiently assembled aromatic aldehydes 69, malodinitrile 71a, 1,3-thiazolidinedione 148, and anitines 102 with high yields by conducting the reaction in a cosolvent mixture of polyethylene glycol (PEG) 400/H2O (1 1) at 80 °C. Under optimized conditions, a wide range of aldehydes and amines were converted into the desired heterocycles with yields ranging from 27% to 90%. 

In an effort to develop new synthetic methodologies for liquid-phase synthesis of small organic molecules, we have explored the scope of liquid-phase synthesis for generating heterocyclic molecules using MeO-PEG-OH. For our study we chose MeO-PEG-OH as a carrier because it is inexpensive, commercially available with a wide range of molecular weights, and easily functionalized with different spacers and linkers. 

We next explored the applications of liquid-phase synthesis of benzofused heterocycles from a common building block PEG-bound nitro-activated aryl fluoride (Fig. 8). In these synthetic strategies, we created multiple accesses to the structurally diverse core molecules based on a fundamental scaffold 10. We focused on the construction of a variety of benzimidazole libraries starting from a versatile synthon 4-fluoro-3-nitrobenzoic acid via liquid-phase nucleo-... 

It is well known that 2,6-diheteroaryl-containing pyridines display important biological properties such as antitumor and cyclin-dependent kinase inhibitory activities. Also, the introduction of ferf-butyl group into some heterocycles can greatly enhance their biological activity. Recently, Vang et al. [99] described a facile ultrasound-assisted synthesis of new 2,6-bis(5-fcrf-butyl-benzo[fc]furan-2-ylcarbonyl)pyridines from 2,6-bis(bromoacetyl)pyridine with f-butyl-substituted salicylaldehydes in acetonitrile in the presence of nontoxic and inexpensive catalyst as PEG-400. The new heterocyclic compounds were synthesized in short reaction times under mild reaction conditions with satisfactory yields. 

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