SYNTHESIS OF 5-METHYL-3-PHENYL-1,3,4-OXADIAZOL-2(3H)-ONE DERIVATIVES BY ELECTROPHILIC AROMATIC SUBSTITUTION A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By AMANDA SOLIS CONDE B.S., Central State University, 2013 2018 Wright State University WRIGHT STATE UNIVERSITY GRADUATE SCHOOL December 13th, 2018 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Amanda Solis Conde ENTITLED Synthesis of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)- one derivatives by electrophilic aromatic substitution BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF Master of Science. __________________________ Kenneth Turnbull, Ph.D. Thesis Director __________________________ David Grossie, Ph.D. Chair, Chemistry Committee on Final Examination: ________________________________ Kenneth Turnbull, Ph.D. ________________________________ Eric Fossum, Ph.D. ________________________________ Daniel Ketcha, Ph.D. ________________________________ Barry Milligan, Ph.D. Interim Dean of the Graduate School Abstract Conde, Amanda Solis. M.S. Department of Chemistry, Wright State University, 2018. Synthesis of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one derivatives by electrophilic aromatic substitution An important research element in the Turnbull laboratory has been the one-pot synthesis of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one from sydnone. The present study reexamined the reaction of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one with electrophiles and optimized methods for synthesis of oxadiazolinone derivatives. Further the oxadiazolinone derivatives were reacted with electrophiles to better comprehend the donating ability of the oxadiazolinone ring system in general with the expectation that the oxadiazolinone ring system is a slightly donating system. Additionally, when the structure assignment of the oxadiazolinone derivative was ambiguous, the corresponding oxadiazolinone or it’s isomer was synthesized from the appropriate sydnone to validate or refute the suggested structure. The results of the present study showed the reproducibility of experiments done by previous interns in the Turnbull laboratory. The procedure for nitration of 5-methyl-3-phenyl- 1,3,4-oxadiazol-2(3H)-one could be optimized. Extension of nitration to para substituted oxadiazolinones resulted in di-substituted derivatives. Through these nitration studies, the oxadiazolinone ring system is shown to be a moderate donor. iii Table of Contents Page I.Sydnones introduction ...................................................................................................... 1 i. Historical ...................................................................................................................................... 1 ii. Chemical and physical properties of sydnones .......................................................................... 3 iii. Synthesis of sydnones ............................................................................................................... 4 iv. Reactions of sydnones ............................................................................................................... 5 II. Oxadiazolinones introduction ......................................................................................... 7 i. Background ............................................................................................................................... 7 ii. Synthesis of 5-methyl-3-aryl-1,3,4-oxadiazol-2(3H)-ones from sydnones ............................... 13 iii. Chemical and physical properties of oxadiazolinones ............................................................ 19 iv. Reactions of oxadiazolinones .................................................................................................. 21 v. Aims ......................................................................................................................................... 26 III. Results and discussion ................................................................................................. 29 i. Preparation of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) ........................................ 29 ii. Reaction of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with electrophiles ............. 36 a. Bromination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) .............................. 36 b. Bromination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with potassium bromate ........................................................................................................................... 37 c. Bromination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with bromine in ethyl acetate ............................................................................................................................. 40 d. Bromination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with N- bromosuccinimide ........................................................................................................... 41 iii. Chlorination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) ..................................... 44 a. Synthesis of 5-methyl-3 (4-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one (50) from 4-chloro- 3-phenylsydnone (52) ................................................................................................... 44 b. Chlorination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with potassium chlorate in ~19% HCl ....................................................................................................... 47 c. Chlorination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with N- chlorosuccinimide (NCS).................................................................................................. 49 iv Table of Contents (Continued) d. Attempted chlorination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with ICl in DCM ................................................................................................................................. 50 iv. Iodination of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with N-iodosuccinimide ... 52 v. Nitration of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) with potassium nitrate and sulfuric acid .................................................................................................................................... 56 vi. Dinitration of 3-phenyl-5-methyl-1,3,4-oxadiazol-2(3H)-one (17) .......................................... 65 vii. Nitration of 5-methyl-3-(4-bromophenyl)-1,3,4-oxadiazol-2(3H)-one (49) ........................... 72 viii. Nitration of 5-methyl-3-(4-chlorophenyl)-1,3,4-oxadiazol-2(3H)-one (50) .......................... 77 ix. Synthesis of 3-(4-chloro-3-nitrophenyl)-5-methyl-1,3,4 -oxadiazol-2(3H)-one (68) ............. 82 x. Nitration of 3-(4-iodophenyl)-5-methyl-1,3,4-oxadiazol-2(3H)-one (53) ..................... 91 xi. Nitration of 3-(4-methoxyphenyl)-5-methyl-1,3,4-oxadiazol-2(3H)-one (73) ....................... 94 IV. Conclusion............................................................................................................................... 100 V. Experimental .............................................................................................................. 104 VI. References ................................................................................................................. 109 VII. Appendix A ............................................................................................................... 113 v List of schemes Page Scheme 1: Synthesis of 3-phenylsydnone ......................................................................... 1 Scheme 2: Reaction of 3-phenylsydnone with acid or base .............................................. 2 Scheme 3: Classical synthesis of sydnones ........................................................................ 5 Scheme 4: Common reactions of 3-arylsydnones ............................................................. 6 Scheme 5: Schestakoff's reaction of benzoylurea with sodium hypochlorite ................... 7 Scheme 6: First synthesis of 1,3,4-oxadiazol-2(3H)-one (10) ........................................... 8 Scheme 7: Reaction of hydrazides and phosgene ............................................................. 8 Scheme 8: Synthesis of 5-(4-pyridyl)-1,3,4-oxadiazol-2(3H)-one (15) ............................... 9 Scheme 9: Stansfield synthesis of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) .. 10 Scheme 10: Synthesis of oxadiazolinones 19 using CO and a Pd catalyst ....................... 11 Scheme 11: Synthesis of N-substituted 1,3,4-oxadiazolinones 21 ................................... 11 Scheme 12: 1,3-Dipolar cycloaddition using carbon dioxide to yield oxadiazolinones 23 ........................................................................................................................................... 12 Scheme 13: Baker et al. bromination of 3-phenylsydnone (16) ...................................... 14 Scheme 9: Stansfield synthesis of 5-methyl-3-phenyl-1,3,4-oxadiazol-2(3H)-one (17) ... 14 Scheme 14: Badami's synthesis of oxadiazolinones 26 from arylsydnones .................... 15 Scheme 15: Badami's proposed mechanism for sydnone to oxadiazolinone conversion ........................................................................................................................................... 16 Scheme 16: Badami's reaction of 4-bromo-3-phenylsydnone (24) with HBr or Ac2O ..... 16 Scheme 17: Yeh et al.