Utilization of Nitrilimines and Nitrile oxides in the synthesis of Triazoles and Oxadiazoles Review Molecules, 2005, 10(3) Adel Mohamed Awadallah (A. R. S. Ferwanah) Chemistry Department, Faculty of Science, Islamic University of Gaza, P. O. Box-108 Gaza, Palestine

Nitrilimines and nitrile oxides Nitrilimines 2, also called nitrile imides, are transient intermediates in solutions. The most common method for their generation is dehydrohalogenation of hydrazonoyl halides 1 in presence of triethylamine

Nitrile oxides 4 are generated and usually trapped in situ; The most common method for their generation is also dehydrohalogenation of α- chloro-oximes 3 on reaction with a base (usually triethylamine). * 1,3-Dipolar Cycloaddition, Padwa, A. ed.; Wiley-Interscience, New York, * Shawali, A. S.; Heterocycles, 1983, 20, 2239; Shawali, A. S.; Chem Rev.; 1993, 93, 2731.

Reactions of Nitrilimines and Nitrile Oxides i) Replacement reaction with nucleophiles (Nu) leading to acyclic adducts:.

ii) cycloaddition reaction with multiple bonds leading to five- membered heterocycles. The reaction proceeds with: almost complete stereochemical control and a remarkable regiochemical control in many cases

iii) Cyclocondensation reactions with nucleophiles incorporating suitably located electrophilic centers 1-Ethoxycarbonyl-1-methylhydrazine readily reacts with the nitrile oxide yielding the acyclic adducts. The latter cyclizes almost quantitatively to the corresponding novel 4,5-dihydro-,1,2,4,5- oxatriazin-6-one 5 by stirring with excess sodium hydride in dry tetrahydrofuran for 30 min. at room temperature. Ferwanah, A. R. S.; Awadallah, A. M.; Asian J. Chem.; 1998, 10, 180.

On the other hand Completely different modes of reaction were observed with nitrilimines by M. El-Haddad and H. Dalloul

Reaction of Nitrilimines and Nitrile Oxides with Hydrazines Reaction with simple, phenyl-, acetyl- and benzoyl-hydrazines Nitrilimines undergo 1,3-electrophilic addition with simple, phenyl-, acetyl- and benzoyl-hydrazines leading to the acyclic adducts 6.

On the other hand Reaction with methylhydrazine The reaction with methylhydrazine occurs at the N-Me group rather than the NH 2 group leading to the acyclic adducts 7.

On the other hand Reaction of nitrilimines with 1-ethoxycarbonyl-2-phenylhydrazine This reaction gave the acyclic adducts 8. El-Haddad, M.; Ferwanah, A. R. S.; Awadallah, A. M.; J. Prakt. Chem. 1998, 340, 623.

Reaction with ethylhydrazinoacetate Reaction of C-methoxycarbonyl nitrilimines with ethylhydrazino acetate under smooth conditions gave 4-amino-1-aryl-3- methoxycarbonyl-6-oxo-1,4,5,6-tetrahydro-1,2,4-triazine 9. * El-Abadelah, M. M.; Nazer, M.; El-Abadlah, N. S.; Meier, H.; J. Prackt. Chem. 1997, 339, 90.

On the other hand The reaction of nitrile oxides with ethyl hydrazine acetate gave the acyclic adducts 11 which resulted from electrophilic addition at the terminal NH 2 followed by oxidation. * Awadallah, A. M.; unpublished data.

Reaction of nitrile oxides with hydrazones Aryl nitrile oxides undergo 1,3-dipolar cycloaddition with alkanone hydrazones 33 to give the cycloaddition product 4-amino-3-aryl-5,5- dialkyl-4,5-dihydro-1,2,4-oxadiazole 11. The reaction with alkanal hydrazones gave, however, a complex mixture of intractable products, from which the oxadiazole 12 was the major product El-Abadelah, M. M.; Hussein, A. Q.; Awadallah, A. M.; Heterocycles 1989, 29, 1957.

On the other hand Reaction of hydrazones of aryl aldehydes and ketones with nitrile oxides gave the corresponding acyclic adducts 13 obtained by way of electrophilic addition. 1,3-Dipolar cycloaddition across azomethine л- bond of the hydrazones was not observed here. El-Abadelah, M. M., Nazer, M. Z.; Hussein, A. Q.; Awadallah, A. M.; Rademacher, P.; Woydt; M.; J. Heterocycl. Chem. 1991, 28, 1229.

Ring Transformation of 1,2,4-oxadiazolines into 1,3,4- oxadiazoles Acylation of the 4-amino-4,5-oxadiazoles in refluxing toluene or treatment of the acyl derivatives of these compounds 14 with trifluoroacetic anhydride brings up ring transformation to the aromatic 1,3,4-oxadiazoles 15.

Similarly, 4-amino-4,5-dihydro-1,2,4-oxadiazole are transformed into the corresponding 2-arylamino-1,3,4-oxadiazoles (16, X = O) or thiadiazoles (17, X = S) via reaction with phenylisocyanate or phenylisothiocyanate, followed by brief treatment of the resulting adducts 15 with trifluoroacetic anhydride at ambient temperature. Hussein, A. Q.; El-Abadelah, M. M.; Nazer, M. Z.; Awadallah, A. M.; Rademacher, P.; Bandman, H.; Heterocycles, 1994, 38, 981.

Reaction of Nitrile oxides with methyl hydrazones The reaction of nitrile oxides with methylhydrazones in chloroform was found to constitute a convenient synthetic route to the novel 4,5- dihydro-6H-1,2,4,5-oxatriazines 18.

On the other hand Risitano and coworkers obtained the triazoles 19 directly from the appropriate monomethylhydrazones of aryl aldehydes in refluxing ether for 2 hours.

Ring Transformation of Oxatriazines into Triazoles 1,2,3,4- tetrahydro-1,2,4,5-oxatrazines 18 derived from methylhydrazones of aryl aldehydes underwent ring contaction, via elimination of H 2 O, to yield the respective 1H-1,2,4-triazoles 19. El-Abadelah, M.M.; Hussein, A. Q.; Nazer, M. Z.; Musa, O. M.; Rademacher, P.; Bandmann, H; Heterocycles, 1993, 36, 455.

The reaction of nitrile oxides with 1,1-dimethylhydrazones yields the cycloaddition N,N-dimethylamino-oxadiazolines 20.

Reaction of nitrilimines with hydrazones carrying electron withdrawing groups

*El-Sawi, E. A.; Awadallah, A. M.; Ferwanah, A. R. S.; Dalloul, H. M.; Asian J. Chem. 2002, 14, * Awad, B. M.; Ferwanah, A. R. S.; Awadallah, A. M.; El-Halabi, N. M.; Asian J. Chem. 2002, 14, 1235

Ferwanah also reported the synthesis of another series of these triazoles 23 from the reaction C-Acetyl-N-arylnitrilimines with acetaldehyde, alkanone and cycloalkanone benzoylhydrazones. Intersting spiro compounds containing heteroatoms were prepared from this reaction. Ferwanah, A. R. S. Synth. Commun. 2003, 33, 243.

Synthesis of Triazole derivatives

C-methoxycarbonyl Hydrazonoyl halides were also found to react with substituted hydrazones of alkanone, cycloalkanone and heterocyclic ketones to give the cycloaddition products 3- methoxycarbonyl-4,5-dihydro-1,2,4-triazoles 24 [26]. Adel M. Awadallah, Abdel-Rahman S. Ferwanah, Mehtab R. El- Haddad, W. Schrader, Synthesis of Substituted 1,2,4-Triazoles from Reaction of Nitrilimines with Substituted Hydrazones, Asian J. Chem, 2004, 16, 1691.

Reaction with Oximes Acetone oxime readily react with nitrilimines yielding the unexpected 3-acetyl-4,5-dihydro-5,5-dimethyl-1H-triazoles 25 in moderate yields. An evidence was obtained from 15 N-NMR spectra, which displays a doublet for the NH at ppm relative to nitromethane ( 1 J N-H = 85Hz; 3 J N-CH3 = 2.5Hz).

15 NMR of the compound

Nitrilimines reacted similarly with acetophenone oxime to afford the corresponding triazaoles 25. Similarly, the reaction with 1-methyl-4- piperidone oxime yields the respective spiro triazoles 27. Ferwanah, A. R. S.; Asian J. Chem. 1999, 11, 480. Ferwanah, A. R. S.; Awadallah, A. M.; Khafaja, N. A.; Asian J. Chem. 2001, 13, 1203.

The reaction with cycloalkanone oximes gave the heterocyclic spiro triazoles 28 in moderate yields. Ferwanah, A. R. S.; Kandile, N. G.; Awadallah, A. M.; Miqdad, O. A. Synth. Commun. 2002, 32, 2017.

On the other hand The reaction of nitrile oxides with oximes was reported to give the 4- hydoxy-4,5-dihydro-1,2,4-oxadiazolines 29 [30]. Morrocchi, S.; Ricca, A.; Chim Ind. (Milan), 1967, 49, 629.

Ring Transformation of Triazolines into Triazoles Reaction of triazoles with acetyl chloride or acetic anhydride gave the ring transformation product 1-Aryl-3-acetyl-5-methyl-1H-1,2,4- triazole 32 instead of the expected N-acetyl derivative 31.

A. M. Awadallah, "Ring Transformation of Heterocycles, Transformation of 4,5-Dihydro-5,5-Dimethyl-1H-1,2,4- Triazoles into 5-Methyl-1H-1,2,4-Triazoles" Abhath Al- Yarmouk Journal (Series of naural studies) 2001, 10 (2A), (Jordan). * Ferwanah, A. R. S.; Kandile, N. G.; Awadallah, A. M.; Miqdad, O. A. Synth. Commun. 2002, 32, 2017.

Ring Transformation of 1,2,4-triazoles into 1,2,3,5-oxatriazine

Complexes of 1,2,4-Triazole oximes

Complexes of 1,2,4-triazole hydrazones

Current Work Reaction of Nitrilimines with Cyanomethylbenzimidazoles

. Reaction of Nitrilimines with Acetone Aryledenehydrazone

ACKNOWLEDGEMENT Dr. Adel Awadallah Dr. A. R. S. Ferwana Thank * Prof. Dr. Imtithal Al-Sawi, Prof. Dr. Boshra Awad Ain Shams University * Prof. Dr. M. El-Abadelah Dr. Jalal Ahmed Jordan University for doing the NMr Spectra * Dr. L. Goossen Dr. W. Schrader Max-Planck Institut fuer Kohlenforschung, Muelheim, Germany * Our Students and Colleagues Mrs. Mehtab El-Haddad Dr. Hany Dalloul Dr. Nabil El-Halabi Mr. Omar Miqdad Mrs. Niveen Khafaja