Michihiko Noguchi

A facile and regio- and stereo-selective preparation of bicyclic guanidines by iodocyclization of 3-(alk-2-enyl)-2-(substituted amino)-1-imidazolin-4-ones

Abstract The iodocyclization of 3-(alk-2-enyl)-2-(substituted amino)-1-imidazolin-4-ones proceeded in regio- and stereo-selective manners to give bicyclic guanidines, imidazo[1,2- a ]imidazole and/or imidazo[1,2- a ]pyrimidine, in good yields. The regiochemistry of the cyclization depended mainly on the kind of substituents of the alkenyl moieties and was interpretable by the PM3 MO calculations of the iodonium ion intermediates.

Metal ion-mediated diastereoface-selective 1,3-dipolar cycloaddition of nitrile oxides with dipolarophiles bearing an oxazolidinone chiral auxiliary

Abstract Magnesium ion-mediated cycloaddition reactions of nitrile oxides to chiral 3-acryloyl-2-oxazolidinones lead to highly diastereoselective formation of 2-isoxazolines. The magnesium ion serves to fix the α,β-unsaturated moiety through chelation to effect chiral shielding. These asymmetric reactions provide the first successful examples of Lewis acid-mediated stereocontrol of nitrile oxide cycloaddition reactions to electron-deficient dipolarophiles.

Generation of NH-azomethine imine intermediates through the 1,2-hydrogen shift of hydrazones and their intermolecular cycloaddition reaction with olefinic dipolarophiles

The thermal 1,2-hydrogen shift of the hydrazone generates the NH-azomethine imine intermediate in the 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde system under mild conditions. Therein, the resulting NH-azomethine imine should be stabilized by forming an internal hydrogen bond with the carbonyl oxygen at the 4-position. Its smooth stereoselective intermolecular cycloaddition reaction with olefinic dipolarophiles giving pyrazolidine derivatives is discussed.

Reaction of 2-substituted-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde oximes with electron-deficient olefins and acetylenes

Abstract A facile oxime–nitrone isomerization through the 1,2-hydrogen shift in 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbaldehyde oximes is discussed. The resultant NH-nitrones are trapped by maleimides to afford intermolecular cycloadducts. The reaction of the oximes with electron-deficient acetylenes undergoes via another path initiated by a nucleophilic attack of the oxime to acetylene moiety.

Intramolecular 1,3-dipolar cycloaddition at the periphery of heterocyclic systems. Part 3. A facile hydrazone-azomethine imine isomerization at the periphery of pyridine and pyrido[1,2-a]pyrimidine systems☆

Abstract The phenylhydrazones of 2-(alk-2-enylamino)-4-oxo-4 H -pyrido[1,2- a ]pyrimidine-3-carbaldehydes and 4-(alk-2-enylamino)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbaldehydes underwent the thermally induced 1,3-dipolar cycloaddition leading to a mixture of the fused pyrazolidine and pyrazoline derivatives under extremely mild conditions. For the observed facile hydrazone-azomethine imine isomerization, we proposed an intramolecularlly assisted process similar to that for the facile oxime-nitrone isomerization in these systems; the intramolecular proton transfer from the the protonated alkenylamino and/or carbonyl moieties to the imine nitrogen facilitated the generation of the azomethine imine intermediates.

Mechanistic considerations on the azepine-ring formation through the ene reactions at the periphery of heterocyclic systems

Abstract A mechanistic proposal for the azepine-ring formation at the periphery of heterocyclic systems is described. Intramolecular thermal ene reactions of O-alkyl oximes 5 and 6, N′,N′-disubstituted hydrazone 11, and N-tosyl imines, obtained from aldehydes of pyrido[1,2-a]pyrimidine1, pyridine 2, and pyrimidine system 3, have been developed. These reactions reveal to be a fruitful and stereoselective approach to the azepine derivatives fused by heterocycles. The mechanistic discussions on the azepine-ring formation through the imine and carbonyl ene reactions have been accomplished by the kinetic studies as well as the molecular orbital calculations (PM3 method) of the model reactions. These results demonstrate that both ene reactions proceed in a concerted manner.

A facile and stereoselective azepine-ring formation at the periphery of pyridone and pyrido[1,2-a]pyrimidone systems via intramolecular imine and carbonyl ene reactions

Abstract Thermal reaction of the N-alkyl and N-aryl imines of 2-(alk-2-enylamino)-4-oxo-4H-pyrido[1,2-a]pyrimidine 3-carboxaldehyde (9) gave pyrido[1′,2′:1,2]pyrimido[4,5-b]azepines11–14 in good to excellent yields. Similarly, the imines of 4-(alk-2-enylamino)-1,6-dimethyl-2-oxo-1H-pyridine 3-carboxaldehyde (15) afforded pyrido[4,3-b]azepines 16 and 2,4-ethanopyrido[4,3-d]pyrimidines17 depending on the reaction conditions, the latter of which were secondary products from azepines 16. Heating aldehyde 15 in appropriate solvents also gave 2,4-ethanopyrido[4,3-d][1,3]oxazine 18. On the other hand, the thermal reaction of aldehyde 9 gave pyridopyrimidoazepine 20 and 12,13-ethanopyrido[1′,2′:1,2]pyrimido[5,4-b]azepine 21 in good total yields. These azepine-ring formation could be regarded as the intramolecular imine and carbonyl ene reactions at the periphery of the heterocyclic systems. Therein, the reactions proceeded in a highly stereoselective manner to give 4,5-cis azepines. The details and limitations of these ene reactions will be described.

Intramolecular 1,3-dipolar cycloaddition at the periphery of heterocyclic systems. Part 2. A mechanistic proposal for the facile oxime-nitrone isomerization at the periphery of pyridine and pyrido[1,2-a]pyrimidine systems☆

Abstract The oximes of 4-(alk-2-enylamino)-1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbaldehydes and 2-(alk-2-enylamino)-4-oxo-4 H -pyrido[1,2- a ]pyrimidine-3-carbaldehydes underwent the thermally induced 1,3-dipolar cycloadditions leading to fused isoxazolidine derivatives under very mild conditions. For the facile oxime-nitrone isomerization, we proposed a mechanistic feature that the alkenylamino nitrogen and/or carbonyl groups in the oximes could play a role as intramolecular catalyst for the consecutive proton transfers on the basis of the thermal behaviors as well as kinetic studies of the oximes isolated.

Thermal ene reaction of 4-(2-alkenylamino)-3-formyl-2(2H)-chromenones

Abstract Intramolecular ene reaction of 4-(2-alkenylamino)-3-formyl-2(2 H )-chromenones 7 involving carbonyl enophile proceeded stereoselectively to afford 5-hydroxychromen[3,4- b l-azepines 14 . The intramolecular nucleophilic attack of hydroxy group to the enemine moiety in 14 gave 1,2-dihydro-2,4-ethanochromen[4.3- d ][1,3]oxazin-5(4 H ,5 H )-one derivatives 13 as final products. PM3MO calculations of the process reveal that this ene reaction proceeds with two steps through an intermediate.

An asymmetry induced azepine-ring formation through the ene reactions at the periphery of heterocyclic systems

Abstract The azepine-ring formation through the ene reactions proceeds in a concerted manner although the PM3 molecular orbital calculations of the model reactions suggests that the azepinering formation is constituted of two consecutive orbital-allowed reactions. Both imine and carbonyl ene reactions using the aldehydes bearing a chiral center at the alkenylamino moiety have performed a self-immolating chirality transfer to the azepine ring.