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Organic Chemistry Highlights

Microwave Chemistry

Sunday, April 15, 2007
Doris Dallinger, C. Oliver Kappe
Karl-Franzens-University Graz

Synthesis of Pyrido[2,3-d]pyrimidine-dione Derivatives

The group of Shujiang Tu from Xuzhou Normal University, China, has reported on the synthesis of a series of pyrido[2,3-d]pyrimidine-4,7-diones (Org. Biomol. Chem. 2007, 7, ASAP. DOI: 10.1039/b617201f). By reacting isoxazoles 1 with 2,6-diaminopyridinone 2 or naphthalene-2-amine, pyridopyrimidines 3 and 4 with a hydroxyiminoethyl substituent at the 6-position are obtained, whereas 6-benzamide functionalized products 6 are generated by the reaction of oxazolones 5 with 2,6-diaminopyridinone. The authors propose a Michael addition, cyclization and ring-opening reaction sequence, where the acetic acid acts as both solvent and catalyst.

Synthesis of 2,6,9-Substituted Purines

Hong Liu and co-workers from the Chinese Academy of Sciences have developed a simple procedure for the synthesis of 2,6,9-substituted purines 2 (J. Comb. Chem. 2007, 9, 197. DOI: 10.1021/cc060155o). 2-Chloro-6,9-substituted purines 1 are obtained via an one-pot two-step reaction of 2,6-chloropurine with anilines or amines in the first step, followed by N-alkylation or N-arylation at the 9-position with alkyl halides or phenyl boronic acid, respectively. In a subsequent reaction sequence the generated 2-chloro-6,9-substituted purines 1 are further reacted with various amines and anilines under NaBF4 catalysis to finally provide the 2,6,9-funtionalized purines 2 in low to excellent yields (13-99%).

Synthesis of Pyridines via a Cycloisomerization-6π-Cyclization Sequence

A protocol for the synthesis of substituted pyridines was disclosed by Barry Trost and Alicia Gutierrez from Stanford University (Org. Lett. 2007, 9, 1473. DOI: 10.1021/ol070163t). Ruthenium-catalyzed cycloisomerization of primary and secondary propargyl diynols 1 at room temperature afforded unsaturated ketones and aldehydes 2, respectively. The α,β,γ,δ-unsaturated aldehydes and ketones 2 are subsequently reacted with hydroxylamine hydrochloride to the corresponding pyridines via 1-azatriene intermediates which undergo an electrocyclization-dehydration sequence. This last step can be either performed in a one-pot format for aryl- or unsubstituted aldehydes or ketones (2, R2 = H, Ph) applying microwave irradiation, or in a two-step protocol for isopropyl-substituted aldehydes and ketones (addition of NH2OH•HCl, NaOAc, MeOH, reflux for 1-6 h then extraction, removal of solvent and subsequent microwave irradiation of the oxime at 220-230 C for 40 min-4.25 h.

Reformatsky Conjugate Additions

A re-examination of the reactivity of Reformatsky reagents in conjugate additions was performed by Mark Moloney and co-workers from the University of Oxford (Synlett 2007, 733, DOI: 10.1055/s-2007-970756). t-Butyl 2-bromopropionate (1a) and 2-bromopropionitrile (1b) were used as Reformatsky reagent precursors in the reaction with α,β-unsaturated malonate esters under both microwave and conventional conditions. Compared to thermal heating, the protocol could be simplified when microwave irradiation is applied: the Reformatsky reagents are formed in situ when activated Zn, iodine, precursers 1a and 1b, respectively, and malonates in THF are microwave heated. Bromopropionitrile 1b showed increased reactivity compared to the thermal approach, whereas bromopropionate 1a gave higher yields only when being activated (R1 = p-ClPh).

D. Dallinger, C. O. Kappe Org. Chem. Highlights 2007, April 15.