PREPARATEON AND REACTIONS OF SOME TEIRACYANOCYCLOPROPANES Thai: for “as Degree of pl‘l. D. MICHIGAN STATE UNIVERSETY Fillmore Freeman 1962 3 5-1 E3132 :1 ”'1 _-I k- LIBRARY l ‘3 Michigan 31‘3““ 33-- Univcrbi‘ir' f - -I,m-ur 4"."ka \ill\l IMCWGMJ SMTE UNl‘JERSW $111813?!" w ACPILUPHP: Am AWN.“ mmce‘ ' DEPAT«’T.‘.1E'\JT OF CHEr/nsmv EA81 LANSING, MICHaGAN D"- an“ ABS TRACT PREPARATION AND REACTIONS OF SOME TETRACYANOCYCLOPROPANES by Fillmore Fre eman ketone, methyl isopropyl ketone, methyl n-propylketone and methyl cyclopropyl ketone. However, no crystalline products were obtained from glycidaldehyde, di'cycl'opropyl ketone, diiSOpropyl ketone, methyl t-butyl ketone, ethyl butyl ketone and di-n-amyl ketone. The reaction appeared to be subject to steric, inductive and electronic effects. The Wideqvist reaction was used to prepare spiro systems from cyclobutanone, cyclopentanone, cycloheptanone, cyclooctanone and Cyclononanone. The reaction failed with cyclodecanone, cyclododecanone and cyclopentadecanone. The structure of the imido-acid proposed by Ramberg and Wideqvist (3) for the initial hydrolysis product of 3, 3-dirnethyl-l, l, 2, Z-tetracyano- 'Cyclopropane was confirmed by microanalysis, neutralization equivalent, CN CH3 CN _ . CH3 OH CH3 CN CH3 . § CN' CONHZ o Chemical reactions and infrared and n. m. r. data. Fillmore Freeman CN OH H CN \ ‘1’ CN 0H E 4> N-HZO N . o COZH CN ' COZH)2 A similar reaction sequence was also demonstrated with l, l, 2, Z-tetra- Cyanospiro[2, 4]heptane. During the thermal decarboxylation of the imido-acids the cyclo- Propane ring was ruptured to give derivatives of isopropylidene- and CYCIOPentylidenesuccinimide. A new rearrangement was discovered during the alkaline hydrolysis (in methanol) of methyl 2, 4-dioxo-5-carboxamido-3, 6, 6-trimethyl-3- azabicyclo[3. l. O]hexane-l-carboxylate which gave 2, 4-dioxo-5-(N-methy1)- carboxamido-6, 6-dimethy1-3-azabicyclo[3. 1. O]hexane- l -carboxy1ic acid. Fillmore Freeman 3 i : O l—_——éo CONHZ COECHB This remarkable rearrangement was also observed in 3, 3-dimethy1-3, 5- dicyanocyclopropane- 1, 2-(N-methyl)-dicarboximide, 4, 4-tetramethy1ene- 3, 5-dicyanocyclopropane-l, 2.-(N-methyl)-dicarboximide and methyl Z-carboxamido- l , Z— (N-methyl) -dicarboximidospiro[2, 4]heptane- l -carboxylate. The cyclopropyl hydrogens in tetracyanocyclopropanes derived from aldehydes appeared at unusually low fields (6.47-6. 537 when R: alkyl and 4-8-5. 1 7 when R = aryl) in the n.m. r. spectrum. 4 An explanation in terms of the diamagnetic anisotropy of the nitrile group is suggested. During the n.m. r. examination of the bismalononitriles a new Michael-type equilibrium involving the dicyanomethyl anion was observed with 2-methy1- and Z-ethyl-l, l, 3, 3-tetracyanopropane. R - - H ace One" 6 RCH = C(CN)z + CHZ(CN)Z H(CN)Z ‘-—— (R = CH3. Csz) This dissociation did not occur with 1, l, 3, 3-tetracyanopropane. FillInore Freeman REFERENCES l.. L. Ramberg and S- Wideqvist, Arkiv- Kemi, Mineral. Geol., 12A, No. 25, 12 pp. (1937). 2. L.. Ramberg and S. Wideqvist, Arkiv. Kemi, Mineral. Geol., 14B, No. _3_7_, 13 pp. (1941). Fillmore Freeman A THESIS Submitted to Michigan State University a1 fulfillment of the requirements for the degree of in parti DOCTOR OF PHILOSOPHY Department of Chemistry 1962 ACKNOWLEDGMENT The author wishes to express his sincere appreciation and gratitude to Professor Harold Hart for his inspiration, guidance and understanding during the course of this investigation. Grateful acknowledgment is extended to Mr. J- S. Fleming for determining some of the proton magnetic resonance spectra. Grateful acknowledgment is also extended to the Office of Ordnance Research and the Petroleum Research Fund of the American Chemical Society who provided personal financial assistance from September 1959 through June 1960 and June 1960 through June 1962, respectively. 3:: >1: 9,: >:< >:< >:< >:< >§< >:< >:< >:: >:< >:< >1: >:< ii TABLE OF CONTENTS INTRODUCTION . . . . ............. RESULTS AND DISCUSSION . . . . A. Scope and Nature of the Reaction ........ B. Hydrolysis of 3, 3-Dimethy1-1, 1,2, 2—tetracyanocyclo- propane ..... . ................... C. Extension of Hydrolysis Studies to Tetracyanocyclo- propanes from Other Ketones . . ........... . D. Hydrolysis of Tetracyanocyclopropanes Prepared from Aldehydes ....................... .. 1. From Benz‘aldehyde ................ 2. From p— ~Chlorobenza1dehyde ........... 3. From Several Aliphatic Aldehydes ....... E- N. M. R- Spectra of Some Tetracyanocyclopropanes and Alkylidene Bismalononitriles ............. EXPERIMENTAL ........................ A. General Procedures ................... 1. Apparatus ..................... 2.. Purification of Acetone .............. 3. Purification of Aldehydes and Ketones ...... 4. Melting Points ................... 5. Microanalyses ................... B. Preparation of Tetracyanocyclopropanes ........ 1.. Preparation of 1, 1, 2, Z-Tetracyanocyclopropane . 2. Preparation of 3-Methyl-1, 1, 2, Z-tetracyano- cyclopropane. . . . . ............... 3. Preparation of 3-Ethy1-1, 1, Z, Z-tetracyanocyclo- propane ................. . . . 4. Preparation of 3-n-Propy1-1, 1, 2, Z-tetracyano- cyclopropane . . . . ................ 5. Preparation of 3—iso-Propy1-1, l, 2, Z-tetracyano- cyclopropane .................... 6. Preparation of 3-Cyclopropyl-1, 1, 2, Z-tetra- cyanocyclopropane ................. iii Page 11 33 44 44 52 56 58 72 73 73 73 73 74 74 74 74 74 75 75 75 76 TABLE OF CONTENTS - Continued Page 7. Preparation of 3-Pheny1-1, 1, 2, 2-tetracyano- cyclopropane. ............. . 76 8. Preparation of 3-p-Chlorophenyl-1,1,2,2-tetra- cyanocyclopropane ............ . 76 9. Preparation of 3-m-Nitrophenyl-1, 1, 2, 2-tetra- cyanocyclopropane. ................ 76 10.. Preparation of 3- -Cyclopropy1-3-,-met.hy1-l, l, 2, 2- tetracyanocyclopropane . . . . . ...... 76 11. Preparation of 3, 3-Dimethyl-1,1,2,2-tetracyano- cyclopropane .................... 78 12. Preparation ofl, 1,2, 2-Tetracyanospiro[2,3]- hexane ....................... 79 13. Preparation ofl, 1, 2, 2- Tetracyanospiro[2, 4]- heptane. . ..................... 79 14. Preparation ofl, 1, 2, 2- Tetracyanospiro[2,5]- octane .............. . . . 79 15. Preparation of1,1,2,2-Tetracyanospiro[2,7]- decane ....................... 79 16. Preparation of 1, 1, 2, 2-Tetracyanospiro[2, 8]- undecane ...................... 81 17. Preparation of 1, l, 2, 2-Tetracyanospiro[2, 6]- nonane ................ . ...... 81 18. Preparation of Tetracyanocyclopropanes from Certain Ketones .................. 81 C. Preparation of f3, {3- -Dialkyl- a, a.‘-dicyanoglutarimides . 82 1. Preparation of 4, 4- Dimethyl- 3 .5 -dicyano- glutarimide ..................... 83 2.. Preparation of 4, 4-Tetramethy1ene-3, 5-dicyano- glutarimide ..... . ....... . ....... 83 3. Preparation of 4, 4-Pentamethy1ene-3, 5-dicyano- glutarimide ..................... 83 D. Preparation of Cyanosubstituted Cyclopropanedi- carboximides ................ . 83 1. Preparation of 3, 3— Dimethyl- 1, 2- -dicyanocyclo- propane- 1, 2- dicarboximide ........... . 83 2. Preparation of 3, 3-Tetramethylene-1, Z-dicyano- cyclopropane- 1, 2-dicarboximide ......... 84 3. Preparation of 3, 3-Pentamethy1ene- 1, 2-dicyano- cyclopropane- l , 2-dicarboximide ......... 84 4. Preparation of 3, 3-Dimethy1- 1, 2-dicyanocyclo- propane-1, 2- (N-methyl)-dicarboximide ..... 84 iv TABLE OF CONTENTS - Continued Page 5. Preparation of 3., 3-Tetramethy1ene-l, 2-dicyano- cyclopropane-1,2-(N-methyl)-dicarboximide. . . 84 E. Preparation of Imido- acids. . . ....... . . . . . 85 a. From Tetracyanocyclopropanes. .. . . . . 85 1. Preparation of 2, 4- Dioxo- 5- carboxamido- 6, 6- dimethy1-3-azabicyclo[3.1.0]hexane- l-carboxylic acid ......................... 85 2. Preparation of 2-Carboxamido-1, 2-dicarboximido- spiro[2, 3]hexane- l-carboxylic acid ........ 85 3. Preparation of 2- Carboxamido-l, 2- dicarboximido- spiro[2,4]heptane-1-carboxylic acid. . . . . 87 4. Preparation of 2- Carboxamido- 1, 2- dicarboximido- spiro{2, 5]octane-1-carboxylic acid ....... . 87 b. From Dicyanocyc’lopropanedicarboXimides . . . . . 87 F. Hydrolysis of 3, 3-DimethyI-l, 1, 2, 2-tetracyanocyclo- propane ...................... . . . . 89 1.. Preparation of Methyl 2, 4-dioxo-5-carboxamido- 3, 6, 6-trimethy1- 3-azabicyclo[3.1.0]hexane-l- carboxylate .......... . . 89 2. Preparation of 2, 4- Dioxo- 5- (N- methy1)- carbox- amido- 6,6- ~dimethy1- 3- azabicyclo[3. 1. O]hexane- 1-carboxylic acid .................. 89 3. Preparation of Methyl 2, 4-dioxo-5-(N-methyl)- carboxamido-3, 6, 6-trimethyl-3-azabicyclo- [3. l. O]hexane- l-carboxylate ............ 91 4. Preparation of 3, 3-Dimethy1cyclopr0pane-1, 1,2, 2- -tetracarboxy1ic acid ............ . 91 5. Preparation of Methyl 3, 3- -dimethylcyclopropane- 1, 1, 2, 2- -tetracarboxylate ............. 92 6. Preparation of 2,4-Dioxo-6, 6-dimethy1-3- azabicyclo[3.1.0]hexane-1, 5-dicarboxylic acid. . 92 7. Preparation of Methyl 2, 4-dioxo-3, 3-dimethy1- 3-azabicyclo[3. 1. O]hexane-l, 5-dicarboxy1ate . . 9'3 8. Preparation of 3-Isopropylidene-4-carboxamido- succinimide ..................... 9'3 9. Preparation of 4- Carboxamido- 3-isopropylidene- 1- -methylsuccinimide ..... . 94 10. Hydrolysis of 4- Carboxamido- 3- isopropylidene- 1- -methylsuccinimide ................ 94 TABLE OF CONTENTS - Continued 11. 12. 13. 14. 15. Page Preparation of 4- (N- Methyl)-carboxamido-3-iso- propylidenesuccinimide. . . . . 96 Preparation of4- (N-Methy1)- carboxamido- 3- -iso- propylidene- 1- -methylsuccinimide . . . 96 Hydrolysis of 4- (N- Methyl)- carboxamido- 3- -iso- propylidene- 1-methy15uccinimide . . . . . . . . 96 Preparation of Isopropylidenesuccinimide . . . . 98 Isolation of Potassium 2,4-dioxo-5-carboxamido- 6, 6-dimethy1- 3- azabicyclo[3. 1. O]hexane-l- carboxylate ............... . 98 G. Hydrolysis of 1, 1, 2, 2- Tetracyanospiro[2, 4]heptane . 99 1. Preparation of Methyl 2- carboxamido- 1, 2- (N-methy1)- dicarboximidospiro[2, 4]heptane-1- carboxylate. ............... 99 . Preparation of 2- (N- Methy1)- carboxamido- 1, 2- dicarboximidospiro[2,4]heptane- 1- -carboxylic acid ......................... .99 . Preparation of Methyl 2-(N-methyl)-carboxamido- l, 2-(N-methyl)-dicarboximidospiro[2, 4]heptane- 1-carboxy1ate ................... , 99 4. Preparation of Spiro[2, 4]heptane-1, 1, 2, 2-tetra- carboxylic acid .................. 101 5. Preparation of l, 2-Dicarboximidospiro[2, 4]- heptane- 1, 2-dicarboxylic acid and Methyl 1, 2- . dicarboximidospiro[2, 4]heptane- 1, 2-dicarboxy- late ......................... 101 6.. Preparation of 4-Carboxamido-3-cyclopentyli- denesuccinimide .................. 101 7. Preparation of 4-Carboxamido-3-cyclopentyli- denesuccinimide ................. 102 8. Preparation of 4- (N- Methy1)- carboxoamido-3- cyclopentylidenesuccinimide ....... . . 102 9.. Preparation of 4- (N-Methy1)- carboxamido- 3- clopentylidene- 1- methylsuccinimide ....... 102 H. Hydrolysis of Tetranitriles from Aliphatic and Aro- matic Aldehydes ..................... 10:7 1. Hydrolysis of 3-Methy1-1, 1, 2, 2-tetracyano- cyclopropane .................. 107 2. Hydrolysis of 3-Ethy1- and 3-iso-Propy1-1, 1,2,2- tetracyanocyclopropane .............. 10*? vi TABLE OF CONTENTS - Continued Page 3. Preparation of 2, 4- Dioxo- 6- --pheny1 3- -azabicyclo- [3. 1. O]hexane- l, 5- dicarboxylic acid. . . . . 107 4. Preparation of 5- --Hydroxy 4- -phenylpyridone- 3, 5- dicarboxylic acid hydrate. . . . . . 1.08 5. Preparation of Methyl 2, 4- dioxo- 3-methy1-6- phenyl- 3- azabicyclo[3. 1.0]hexane- 1,5- dicar- boxylate. . ................ . . . 108 6.. Preparation of Methyl 6- --hydroxy 4- -phenyl- pyridone-3, 5- -dicarboxylate ........... . 109 7. Preparation of 2,4-Dioxo-6-p-chloropheny1-3- azabicyclo[3. 1. O]hexane- 1, 5-dicarboxylic acid and 3-Carboxamido-4-p-chlorophenyl-6-hydroxy- pyridone-S-carboxylic acid hydrate ........ 109 8. Preparation of Methyl 6-p-chlorophenyl-2, 4- dioxo-3-methy1-3-azabicyclo[3. 1. O]hexane- 1, 5- dicarboxylate ....... , ............. 110 I. Miscellaneous Experiments .............. . 1'10 1. Preparation of Bromomalonitrile ........ . 110 2. Attempted Preparation of 2-[2'2'3'3'-tetracyano- cyclopropyl]oxirane ............... . 1110 3. Attempted Preparation of 3, 3-Dicyclopropyl- 1, l, 2, 2-tetracyanocyclopropane ........ . 114 4.. Attempted Condensations with Cyclodecanone, Cyclododecanone and Cyclopentadecanone . . . . . 111 5. Preparation of Isopropylidenesuccinic acid . . . . 111 6. Preparation of Isopropylidenesuccinic anhydride . 113 7. Preparation of Cyclopropanecarboxaldehyde. . . . 113 8.. Preparation of Benzylidenemalononitrile . . . . . 113 9. Preparation of Z-Methyl-l, l, 3, B-tetracyano- propane .................. . . . . 114 10. Preparation of 2-Ethy1-1, 1, 3, 3-tetracyano- propane ...................... . 115 11- Preparation of 1, 1, 3, 3-Tetracyanopropane . . . . 115 12. Preparation of Cyclododecanone ......... . 115 13. Preparation of Methyl Z-carboxamido-l, 2-(N- methyl) -dicarboximidospiro[2, 5]octane-1-carboxy- late ........................ . 116 14. Attempted Preparation of 1, 5-Dicarboxamido-2, 4- dioxo- 3, 6, 6-trimethy1-3-azabicyclo[3. 1. O]hexane 116 15. Attempted Preparation of 2, 4-Dioxo-6, 6-di- methyl- 3-azabicyclo[3 . 1 . O]hexane- 1, 5-dicar- boxylic with Nitrous Acid .............. 116 vii TABLE OF CON'l ENTS - Continued Page 16. Attempted Preparation of 2, 4-Dioxo-3, 3-di- methyl-3-azabicyclo[3. 1. O]hexane- l , 5-dicar- boxylic acid with Isoamyl Nitrite ......... 118 17. Attempted Preparation of l-Carbomethoxy-Z, 4- dioxo-3, 6, 6-trimethy1-2-azabicyclo[3. 1. 0]- hexane- l -carboxylic acid ............. 118 18. Attempted Preparation of 4-Isopropy1idene-l- methylsuccinimide-3-.carboxylic acid with ’ Nitrosyl Chloride ................. 119 19. Attempted Hydrolysis of 2, 4-Dioxo-5-(N-methy1)- carboxamido-6, 6-dimethyl-3-azabicyclo[3. l. 0]- hexane- l-carboxylic acid ............. 120 SUMMARY ............................. 121 LITERATURE CITED ....................... 124 viii TABLE II. III . IV. VI. VII. VIII. LIST OF TA BLES Yields of Some Tetracyanocyclopropanes from Aldehydes ......................... Yields of Some Tetracyanocyclopropanes from Ketones Yields of Some Tetracyanocyclopropanes from Cyclic and Long-chain Ketones .......... . . ..... NMR Positions of Cyclopropyl Hydrogens in Some Tetracyanocyclopropanes ....... . . . . . Yields and Physical Properties of Some Tetracyano- cyclopropanes from Aldehydes .......... Tetracyanocyclopropanes from Certain Ketones Yields and Physical Properties of Various Irnido-acids Physical Properties and Yields of Products from Re- action of the Imido-acids with Diazomethane . . . . . . ix Page 12 60 77 82 88 90 ““M‘F—‘F LIST OF FIGURES FIGURE ' Page I. Infrared spectrum of 2, 4-dioxo-5-carboxamido-6, 6-di- methyl-3-azabicyclo[3.1.0]hexane-1-carboxylic acid. . 14 II. NMR spectra of 2, 4-dioxo-5-carboxamido-6, 6-dimethy1- 3-azabicyclo[3. 1. O]hexane-l-carboxylic acid. . . . . . 15 III. Infrared spectrum of potassium 2,4-dioxo-5-carbox- amido-6, 6-dimethy1-3-azabicyclo[3. l. O]hexane- 1- carboxylate ...................... . . 17 IV. Infrared spectrum of methyl 2, 4-dioxo-3, 6, 6-trimethy1- 3-azabicyclo[3. 1. O]hexane-l, 5-dicarboxylate. . . . . . 19 V. Infrared spectrum of methyl 2,4-dioxo-5-carboxamido- 3, 6, 6-trimethy1-3-azabicyclo[3. 1. O]hexane-l-carboxy- late ....................... . . . . . 22 VI. NMR spectra of 2, 4-dioxo-6, 6-dimethy1-3-azabicyclo- [3. 1. O]hexane-l, 5-dicarboxylic acid and 2, 4-dioxo-5- (N-methy1)-carboxamido-6, 6-dimethy1-3-azabicyclo- [3. 1 . O]hexane- 1-carboxylic acid ............. 24 VII. Infrared spectrum of methyl 2, 4-dioxo-5-(N-methy1)- 3, 6, 6-trimethy1- 3-azabicyclo[3. 1. O]hexane- l-carboxy- late ...... . . . .................... 26 VIII, NMR spectrum of methyl 2, 4-dioxo-5-(N-methyl)- carboxamido-3, 6, 6-trimethy1-3-azabicyclo[3. 1. 0]- hexane- 1 -carboxylate ................. . 27 IX. Infrared spectrum of methyl 3, 3-dimethylcyclopropane- 1, 1, 2, 2-tetracarboxylate ................ 28 X. NMR spectra of methyl 3, 3-dimethylcyclopropane-l, l, n 2, 2-tetracarboxylate and 4-carboxamido-3-isopropy1- idenesuccinimide. . .................. . 30 XI. Infrared spectrum of 4-carboxamido-3-isopropy1idene- succinimide. . ...................... ,31 LIST OF FIGURES - Continued Page XII-Infrared spectrum of 4-(N-methy1)-carboxamido-3- isopropylidenesuccinimide ......... . ...... . 34 XIII. Infrared spectrum of methyl 1, 2-(N-methy11-dicarbox- amidospiro[2, 4]heptane- 1, 2-dicarboxy1ate ....... 36 XIV.. NMR spectra of 2-carboxamido-1, 2-dicarboximido- Spiro[2, 4]heptane-1-carboxylic acid and methyl 2- carboxamido- 1, 2- (N-methyl)-dicarboximidospiro[2, 4]- heptane- 1 -carboxy1ate . . ................ 39 XV. Infrared spectrum of methyl Spiro[2, 4]heptane- l, l, 2, 2- tetracarboxylate ..................... 40 XVI. NMR spectra of 2-carboxamido-1, 2-dicarboximidospiro- [2, 5]octane- l-carboxylic acid and 3, 3-dimethy1-l, 2- dicyanocyclopropane-l, 2-(N-methy1)-carboximide. . .. 43 XVII- Infrared spectrum of methyl 2, 4-dioxo-3-methy1-6- pheny1-3-azabicyclo[3. l. O]hexane- l, S-dicarboxylate . 45 XVIII. NMR spectra of methyl 2, 4-dioxo-3-methy1-6-phenyl- 3-azabicyclo[3. 1 . O]hexane-l, 5-dicarboxy1ate and 2, 4- dioxo-6-phenyl-3-azabicyclo[3. l. O]hexane- 1, 5-di- carboxylic acid ...................... 46 XIX. NMR spectra of 6-hydroxy-4-pheny1pyridone-3, 5-di- carboxylic acid hydrate ................. 48 XX. Infrared spectrum of methyl 6-hydroxy-4-pheny1- pyridone-3, S-dicarboxylate ........ . ...... 50 XXI. NMR spectrum of methyl 6-hydroxy-4-phenylpyridone- 3, 5-dicarboxy1ate .................... 51 XXII. NMR spectra of 3-carboxamido-4-p-chlorophenyl-6- hydroxypyridone-5-carboxylic acid hydrate and methyl 6-hydroxy-4-pheny1pyridone- 3, 5-dicarboxy1ate ..... 54 XXIII. Infrared spectrum of methyl 6-p-chlorophenyl-2, 4- dioxo-3-methy1- 3-azabicyclo[3. 1. O]hexane- 1 , 5-di- carboxylate ........................ 55 xi '—;—r ‘. - i LIST OF FIGURES - Continued Page XXIV- NMR spectrum of methyl 6-p-chloropheny1-2, 4-dioxo-3- methyl-3-azabicyclo[3. l. O]hexane- 1, 5-dicarboxylate and 2, 4-dioxo-6-p-chloropheny1-3-azabicyclo[3. l. O]- hexane-l, S-dicarboxylic acid ............... 57 XXV. NMR spectra of 3-methyl, 3-ethy1-, 3-n-propy1-l, l, 2, 2- tetracyanocyclopropane. . . ............... 61 XXVI- NMR spectra of 3-cyclopropyl- and 3-isopropy1-1, l, 2, 2- tetracyanocyclopropane and benzylidenemalononitrile. . 62 XXVII. NMR spectra of 3'-pheny1-,. 3-p-chloropheny1- and 3-m- nitrophenyl- 1, 1, 2, 2-tetracyanocyclopropane ....... 63 XXVIII.. NMR spectrum of 1, 1, 3, 3-tetracyanopropane ..... . 66 XXIX. Comparison of the ultraviolet spectra of 3-pheny1-l, 1, 2, 2-tetracyanocyclopropane and benzylidenemalononitrile . 67 XXX- NMR spectra (vs. time) of Z-ethyl-l, 1, 3, 3-tetracyano- propane ............. . ............. 68 XXXI. NMR spectra (vs. time) of Z-methyl-l, l, 3, 3-tetracyano- propane ........................... 7O XXXII- NMR spectra of 3-cyclopropy1-3-methy1-1, 1, 2, 2-tetra- cyanocyclopropane and l, 1, 2, 2-tetracyanospiro[2, 3]- hexane ................... . ....... 80 XXXIII. Infrared spectrum of 3, 3-tetramethy1ene-1, 2-dicyano- cyclopropane- 1 , 2- (N-methy1)dicarboximide ....... 86 XXXIV. Infrared spectrum of 4-carboxamido-3-isopropylidene- 1 -methyl suc cinimide ............. . ..... 9 5 XXXV. Infrared spectrum of 4-(N-methyl)-carboxamido-3-iso- propylidene- 1 -methyl succinimide ............ . 9.7 XXXVI- Infrared spectrum of methyl 2-(N-methyl)-carboxamido- 1, 2- (N-methyl) -dicarboximido Spiro[2, 4]heptane-1- carboxylate ....................... . 100 xii LISTOF FIGURES -- Continued Page XXXVII- Infrared spectrum of 4-(N-methyl)-carboxamido-3- cyclopentylidenesuccinimide ............... 103 XXXVIII. Infrared spectrum of 4-(N-methyl)-carboxamido—3- 104 cyclopentylidene- 1 -methyl suc cinimide ......... XXXIX. Infrared spectrum of 4-carboxamido-3-cyclopentylidene- 1 -methyl suc cinimide ........ . .......... 105 XL. Infrared spectrumof isopropylidenesuccinimide . . . . 106 XLI. Infrared spectrum of methyl 2-carboxamido-1, 2- (N—methyl)-dicarboximidospiro[2, 5]octane-1-carboxylate 117 xiii INTRODUCTION —4 —4.—)— l IN TRODUC TION In 1937. Ramberg and Wideqvist (1) observed that addition of aqueous potassium iodide at room temperature to a solution of bromomalononitrile and acetone resulted in an immediate red color and deposition of color— less, halogen-free crystals, m.p. 208-2090, to which the structure 3, 3-dimethy1-1, 1., 2,2-tetracyanocyclopropane (I) was assigned. The reaction was formulated as CN :1: CH3 CN C/H3 CH3 CN CN I u. 1 Air—M GIF— This reaction constitutes a remarkably simple synthesis of cyclopropanes which, if general, might be rather versatile, provided suitable conversion of the four cyano groups to other useful functions might be found. The hydrolytic reactions of I were used by Ramberg and Wideqvist (2) to establish its structure. The scope of the reaction was shown by Wideqvist (3) to include methyl ethyl ketone, phenylacetone, cyclohexanone, methyl hexyl ketone, acetophenone, benzaldehyde, acetaldehyde, and furfural. . No crystalline products were obtained from benzophenone, mesityl oxide, methyl o-naphthyl ketone, formaldehyde, acetol, benzoyl- carbinol and benzoquinone. By using tetrahydrofuran as the solvent, Scribner (4) and co-workers obtained 1, l, 2, 2-tetracyanocyclopropane from formaldehyde by the Wideqvist reaction; these workers also synthesized the same compound by three alternate routes. The hydrolytic and synthetic experiments (2) used to prove the structure of I are summarized in Scheme 1 . Alkaline hydrolysis - Scheme I CN COZH 0 CN . ' 1. 2N KOH, 15 min. reflux 2 H‘“ T) NH CN ‘ 16 CN 45. 5% O I 1.. KOH, KOBr H+ fum. HCl CN 0 100°, 1 hr. 111 81% HOAc, 100% fum. HCl 100°, 1 hr. 77% co H 2 O CN r 0 Br; éNCH>E NH -—-———> NH C Br was reported to rapidly liberate one-half of the theoretical nitrogen as ammonia, acidification gave a solid, m.p. 196-1970 with decompos1tion (carbon dioxide evolution), to which the imido-acid structure 11(2 4 dioxo- 5 carboxamido-6, 6-dimethy1-3-azabicyclo[3. 1.0]hexane 1 carboxyhc ac1d) was as s1gned. The same product was obtained from the prev1ously H 0 CN 002 (30111 fl: 0311 . CONHz N 11 Ila known (5, 6) 3, 3-dimethy1-1, 2-dicyanocyc10propane-l, 2-dicarboximide (III). The alternate structure Ila was discarded mainly on the basis of titration data (> one but < two equivalents of base required for neutrali- zation) and synthesis from III. Attempts (2) to degrade I to a caronic acid were unsuccessful. Hydrolysis with concentrated ammonia contain— ing potassium hydroxide, followed by treatment with concentrated hydro- chloric acid, gave a solid dibasic acid, .m.p. 1650, originally thought (2) to be impure cis-caronic acid, but in fact probably (7) 'y, y-dimethylitaconic acid. Mariella and Roth (7) showed that prolonged hydrolysis of 3-alkyl- 1, l, 2, 2-tetracyanocyclopropanes with concentrated hydrochloric acid leads to ‘y-alkylitaconic acids in 20-40% yields. Mariella and Roth (7) prepared several alkylidene bismalononitriles, in 70-80% yield, by reaction of acetaldehyde, propionaldehyde or butyr- aldehyde with malononitrile in the presence of a piperidine-dioxane catalyst. . Reaction of the alkylidene bismalononitriles with bromine caused instant discoloration of the bromine, but the products did not con- tain halogen. It was concluded (7) that cyclopropane derivatives were produced, this conclusion being supported by molecular weight determin- ations, microanalyses and infrared studies. The probable mechanism suggested was H Br r N ‘3 R_ Céé-(cm Br, R'Céé-(CN)z+R-C{S - (amt? H on \0 -(CN). . \li-(CNh \C - (6N). R cm CN H H Wideqvist (3) prepared tetracyanocyclopropanes from four methyl ketones, one cyclic ketone and three aldehydes. One purpose of the present investigation was to explore the scope of the Wideqvist reaction, particularly with regard to the use of cyclanones, as a method for pre- Paring spiro systems. In addition, reinvestigation of the structure of the imido-acid II with modern instrumental methods not available at the time I—‘m- it vir— ' of the original work seemed desirable. The structure of this substance was confirmed. . Subsequent reactions in the hydrolysis sequence, and a study of the chemistry of the various intermediates led to the discovery of several interesting rearrangements. It was ultimately possible to convert the tetranitrile I to the corres- ponding tetracarboxylic acid(IV) in a reaction sequence requiring five steps and the isolation, purification and identification of five intermediates. COZH C0311 C0211 02H IV Extension of the hydrolytic studies to the tetracyanocyclopropane derived from cyclopentanone indicated a similar sequence. But study of those tetracyanocyclopropanes prepared from aliphatic or aromatic aldehydes showed that the hydrolysis path depends on the nature of the alkyl or aryl groups. The unusual course of these reactions is described in this thesis. Finally, routine examination of the nuclear magnetic resonance (n.m. r.) spectra of many of the large number of new compounds led to the discovery that certain cyclopropane hydrogens may occur at unusually low fields; it also led to the discovery of a new Michael-type equilibrium involving the dicyanomethyl anion. RESULTS AND DISCUSSION RESULTS AND DISCUSSION A. Scope and Nature of the Reaction Malononitrile possesses a highly reactive methylene group which readily condenses with a variety of carbonyl compounds to give deriva- tives of o-cyanoac rylonitriles (8, 9). The deshielding effect of the cyano CN OH > = o + CH2(CN)Z ——> 1132-9- \c = c< '(CN12 / CN groups in malononitrile is evident from its n.m. r. spectrum which shows a singlet at 5. 907 . Bromomalononitrile, which is readily obtained from malononitrile and bromine (1), has an even more acidic hydrogen, as indicated by its n. m. r. spectrum which showed a singlet at still lower field (4. 957 ). The reaction of bromomalononitrile with carbonyl compounds in the presence of potassium iodide affords a novel route to tetracyanocyclo- Propanes (2). A plausible mechanism is + OH H / BrCH(CN)z Ii 3 : 4 >‘ I f 0+ BrCH(CN)z /C\ —C-(CN)7_ C9(CN) ,1, . /\ 1'3... r “C(CNh r CN Br CN 1 \ ) -(CN).zq e 0 CN / \c -(CN)z CN (rim I The mechanistic details of the condensation are not known. Reaction of the initial adduct with the second mole of bromomalononitrile may involve protonation of the oxygen and displacement of water. All steps except the last are probably reversible equilibria, and the whole reaction is driven to completion by the final 1, 3-elimination which leads to the insoluble tetracyanocyclopropane. . The Wideqvist reaction can be used to prepare a variety of tetra- cyanocyc10propanes. The reaction appears to be general for most alde- hydes, but there are limitations to the type of ketone which may be used. Table I shows the yields of some tetracyanocyc10propanes derived from certain aldehydes. In general, the yields were good, varying from 50% to 93%. Aldehydes reacted faster than ketones, the reaction being complete in a matter of minutes at room temperature. The yields of tetracyanocyc10propanes from a number of aliphatic and aromatic ketones are given in Table II. When one R-group of the ketone is kept constant (methyl) and the other varied in the series methyl, ethyl, n-propyl, iSOpropyl, t-butyl, the yield decreases from 58. 2% to 0%. This may be a result of increased size or of an inductive effect, since both would operate in the same direction. Groups which make the carbonyl carbon less positive would be expected to decrease the rate of attack by the bromodicyanomethyl anion, and might decrease the overall yield (admittedly it is not good to argue about yields on the basis of rates, but this is perhaps allowable in the present case because all the reactions involve similar reactants and were carried out under identical reaction conditions). The sharp decrease in yield as one proceeds from acetone to methyl cyclopropyl ketone and dicyclopropyl ketone may be a result of distribution 0f the positive charge on the carbonyl carbon to the cyclopropane rings (10, 11). In the same series, Brown (12) found the rates of borohydride reduction to decrease, with relative values of 1:0. 015:0. 000167. Phenyl groups also retard the reaction (cf. , acetophenone, benzophenone). Table I. Yields of Some TetracyanocycloPropanes from Aldehydes N H CN R' CN CN Compound Yield Reaction Time Reference R ,7 % (minutes) Hydrogen 68 few 4 Methyl 70 few 3 Phenyl 80 few 3 Furyl 50 few 3 Ethyl 72.4 20 this work n-Propyl 75. 9 20 this work Cyclopropyl 9'3. 4 20 this work p-Chlorophenyl 84 20 this work m-Nitrophenyl 77. 2 20 this work .10 Table II. Yields of Some Tetracyanocyclopropanes from Ketones CN CN R1 CN CN r—L Compound Yield Reaction Time R R1 % . (hours) Reference Methyl Methyl 58. 2 12 this work Methyl Ethyl 46. 2 12 this work Methyl n-Propyl 39 12 this work Methyl iso-Propyl 18. 3 12 this work Methyl t-Butyl 0 12 this work Methyl Cyc10pr0pyl 2. 5 12 this work Ethyl Ethyl 21. 2 12 this work Ethyl Butyl 0 12 this work CyclOpropyl Cyclopropyl 0 24 this work Isopropyl Isopropyl 0 24 this work Methyl Benzyl 39 Z 3 Methyl Phenyl l4 overnight 3 Methyl a-Naphthyl 0 - overnight 3 Phenyl Phenyl 0 overnight 3 _._ 11 The yields of tetracyanocyclopropanes from certain cyclic ketones are given in Table III. Despite the expected strain in the Spiro[2, 3]hexane ring, the yield from cyclobutanone was reasonably good. Perhaps this may be because one would expect a decrease in the internal strain in the cyclobutane ring when one of the carbon atoms is converted from Sp2 to SP3 hybridization. In accord with this, Brown and Ichikawa (13) found that cyclobutanone is reduced particularly rapidly by sodium borohydride. The very low yields with rings larger than cyclohexanone is note- worthy. The available evidence indicates that the medium rings (8- to 12- members) are highly strained (14). These strains are believed to arise from both bond opposition forces and compression of van der Waals radii. Consequently, these rings should favor reactions in which bonds to a ring atom are broken and resist reactions in which additional bonds are made. From Table III it can be seen that cycloheptanone (25%), cycloocta- none (4%) and cyclononanone (7%) gave the tetracyanocyclOpropanes in low yields. The low yields of these ketones and lack reactivity of the other medium rings may be due to internal strain (13). One notes that cyclo- octanone forms no bisulfite addition product and cyclodecanone does not add hydrogen cyanide. Large rings should behave like high molecular weight open-chain derivatives. Neither cyclopentadecanone nor di-n-amyl ketone formed the tetracyanocycloprOpane; neither does the latter form a bisulfite addition compound. B. Hydrolysis of 3, 3-Dimet1‘il- 1, l, 2, 2-tetracyanocyclgropane(I) Ramberg and Wideqvist (2) obtained an imido-acid, m.p. l96--197O (dec. ), in 45. 5% yield from the hydrolysis of I with 2N potassium hydroxide for fifteen minutes. We obtained the same product in 80. 7% yield by the basic hydrolysis of I in methanol. . Structure II was assigned to this 12 Table III. Yields of Some Tetracyanocyclopropanes from chlic and Long-chain Ketones Compound Yield Reaction Time Reference R R1 % (hours) - (CH2); - 60.4 0. 5 this work - (CH2)4 - 76. 3 0. 5 this work " (CH215 - 92 --- 3 - (CI-~12)6 - 25 24 this work - (CH2)7 - 4 24 this work - (CHZ)8 - 7 24 this work - (CI-12)., - o 24 this work - (CI-12)” - 0 24 this work - (CH2)14 - 0 24 this work n-Amyl, n-Amyl 0 24 this work Methyl, n-Hexyl 30 24 3 13 cozH o 8.74 NH - 1.14 8.76 § CONHz o 2.39 11* substance by the previous workers (2) and the evidence presented below indicates that the assignment was correct. II, neutralization equivalent 112. 3 (theory 113. l), titrated as a dibasic acid and the titration curve showed a strong acid (pKa 2. 45) and a weak acid (pKa 8. 35) to be present. Microanalysis indicated that the empirical formula was CngoNzOs. The infrared spectrum (Figure I) showed absorption bands at 2. 85 and 2. 95 u (primary amide), 5. 50 and 5. 70 H (imide carbonyl) and 5.85 p. (acid carbonyl). The absence of nitrile was indicated by the lack of absorption in the 4.40 to 4.45 11 region (15). The n.m. r. spectrum of II in D30 (containing NaOD) (Figure 11) showed two singlets with equal areas at 8. 74 and 8. 76 ’1’ (methyls). 'In dimethyl sulfoxide (DMSO) the n.m. r. spectrum (Figure II) showed singlets at -1. 14’7’ (imide hydrogen) and 2. 39 1’ (amide) with relative areas 1:2. The assignment of the -1.14 ’1’ position to the imide hydrogen is supported by the observation that succinimide and phthalimide, in the same solvent, showed singlets at -1.0 ’T and -1.13 ’1’ , respectively. The microanalytical, titration, infrared and n.m. r. data are con- sistent only with structure 11 for the initial hydrolysis product of I. The same compound was obtained independently by the sequence of reactions shown at thetop of page 16. >l ”Numbers adjacent to this and other formulas in this thesis refer to n. m. r. Tvalues. 14 40.32 E a: pace ofl>xonnwouauocdxo£o .H .mmoaocnofimumum13:38:qu .o noEmeon-Hmonmnoxofifluv .N mo 8.3.30on pounds“: .H chew-h 15 1A) 7/ I H 5°34 8.74 8.76 (B) l l - -1.14 2.39 10.00 Figure II. NMR Spectra of 2, 4-Dioxo-5-carboxamido-6, 6-dimethy1-3- azabicyclo[3. l. O]hexane- 1-carboxylic acid (II). (A) In D30 containing NaOD (H30 Reference). (B) In DMSO. l6 EN CN 0 CH3 Hz-COzEt 64 1,7 ‘ . CHz-COzEt CH3 N , OLXIv C B172 CN N i 0 OH‘ AflCOIi B +-—-, NH ‘ 3 r H ‘40 99 0 Br CN 111 (:11 The initial hydrolysis of I, if followed by analyzing the amount of ammonia produced, seems to come to a halt after fifteen minutes, two moles of ammonia being obtained. . Isolation of II on acidification followed by further alkaline hydrolysis of II gave additional ammonia. It seemed, therefore, that an intermediate might be obtained if the initial hydrolysis were worked up without acidification. Later it was found that the pro- longed hydrolysis of I does continue to evolve ammonia, but at a greatly reduced rate. ' When the original hydrolysis was worked up without acidification the dipotassium salt (V) of II was isolated in 82. 7% yield. The same GEES—QC >H ondmflh 20 caronimide(IX) which on hydrolysis would provide a route to the caronic acids(X). Elemental analysis of the decarboxylation product, obtained 0 - 02H .. 93-i— >< NH ——->-CH-’-NZ -CH3 —-—>OH H \ . 0 -NHZ Po -NH ‘0 F'NHZ (I) II: I I 0 CH3 0 II XII X111 0 H O . COZCH3 6.42 C 2 II 6.22 OZCH3 COZH - C-OCH //C7).05 8. 56 CH N OH 8. 42 \ PM (—— -CH3 COzCHs COZH 8. 75 \ \ COZCH3 COZH f-l‘llH O 3 CH, 7. 13 XVI IV Hydrolysis of XII with methanolic sodium hydroxide gave an acidic material which microanalysis indicated had the empirical formula CIOHIZNZOS (hYdI‘OIysis of one of the methyl groups). Of the two plausible structures 22 Home 5 Eva 6810138973328 .2 .2 uoHorwofimNdum sinuocfinuuo .o .mnopflgdxoofimmUum noxofipnw .N Tnfiuoz mo 93.30on ponHwGH .> 0.22th 23 (XIII, XIIIa), the latter can be eliminated because the compound titrated O O H l C-OH .-0H 8.84 NH N-CH LA M 3 ’ -NH 0 -NH2 0 1 1.. 1 XIII XIIIa as a dibasic acid (pKa 2. 65 and pKa 8. 38). The n.m. r. spectrum (Figure VI) ,was consistent with structure XIII. In DZO containing NaOD, it showed N-CH3 (7. 367) and C-CH3 (8.84 T) with relative areas 1:2. The same product (2, 4-dioxo-5-(N-methyl)-carboxamido-6, 6-di- methyl-3-azabicyclo[3. 1. O]hexane-l-carboxylic acid) was obtained from III by the sequence 00211 N 0 CN 0 _ 0 NH EELN-L’ N.CH3 931-;- N_H o 0 0 CN CN CONHCH, 111 XIV x111 Product XIII presumably arises by Opening of the imide ring to produce an acid and N-methylamide group, while on the opposite side of the cyclo- propane ring, the ester and amide functions close to an imide. This type CONHCH, of rearrangement is unprecedented and the details of its mechanism are not known. 24 (A) 11 , l/ L 11 5.34 8.62 8.68 (B) 1 .JL 11 . 1 1,) 7/ f 1' J l 5.34 7.36 8.84 Figure VI. NMR Spectra (H30 Reference) (A) Z, 4-Dioxo-6, 6-dimethy1-3-azabicyclo[3. 1 . O]hexane- l, 5-dicarboxylic acid (VI) inlDzO containing NaOD. (B) 2, 4-Dioxo- 5- (N-methy1)- carboxamido-6, 6-dimethy1- 3-azabicyclo- [3. 1. O]hexane- l-carboxylic acid (XIII) in DzO containing NaOD. 25 Recently House and co-workers (20) reported a similar formation of an imide by reaction of an amide-ester with sodium methylate in methanol. H MeO- ' MeOH 3 H3 1 COZCH3 l CONHZ . H Reaction of XIII with diazomethane gave methyl 2, 4-dioxo-5-(N-methy1)- carboxamido-3, 6, 6-trimethy1-3-azabicyclo[3. 1. O]hexane- 1 -carboxy1ate (XV) in 93. 3% yield. Its infrared spectrum (Figure VII) had absorption bands at 2. 95 u (secondary amide), 5. 70' u (ester carbonyl), 5.88 ,1 (imide carbonyl) and a shoulder at 5. 95 p. (amide carbonyl). The n.m. r. spectrum (Figure VIII) in chloroform showed singlets at 6. 22 'T ('-.OCH3), 7.057 '7’ (-NCH3), 8.42 7(C-CH3) and 8. 75 7’ (C-CH3) and a doublet at 7. 137 (-NCH3) with equal areas. An attempt to convert XIII to the tetraacid by refluxing (3 hours) with 10% sodium hydroxide was unsuccessful; however, hydrolysis of XV in methanolic sodium hydroxide gave the crude tetraacid IV which could not (be purified. It was identified by conversion to its tetramethyl ester XVI by reaction with diazomethane. The infrared spectrum of XVI (Figure IX) had an absorption band at 5. 75 p. (ester carbonyl). The n.m. r. spectrum (Figure X) showed two singlets at 6.42 T (-OCH3) and 8. 56 ’T (gem-dimethyl) with relative areas 2:1. . In another attempt to find a convenient route to the caronic acids(X) the imido-acid(II) was decarboxylated by heating to its melting point. After decarboxylation (gas evolution) was complete, an oil remained which solidified on cooling. Elemental analysis indicated loss of one mole of carbon dioxide, the empirical formula of the product being C8H10N203. 26 2 2 o .JDU aw C53 oudaxoapmouauocmxnfifio .H .mHoHorwoMQMNm -mésfimfifluno .o .méenfimxonumogifimfiiv-m noxoflouv .N Tnauoz .«o €530on UoHNMHGH .HH> oudwfim 27 -3 .2 .Sofisofifimé-1fiu6fl7e.o.mAifiofiiTmévaé.N 1332 mo EB 00;: min meg m>.w Nvé homo E :63 poo QdXQS mumgxonuaona to admfih mm 5,2, 42> 0 MN .0 _ WIT 1 _ # 28 u>xonumUduuouum .N .H Jam gumam Atwfiuozmo 5:50on poumuwcm .Joo 5 :33 82 ammoumofiornofnfiocu .5 £ng 29 This is consistent with either structure XVII or XVIII. The infrared spectrum (Figure XI) has in addition to the expected bands for amide X . __ O 703% .__ j_,,o NH 8T4 NH-IJB . O 2. 27 ONHZ O i . CONH, 2.80 XVII XVIII N-H(2. 95 and 3.15 p), imide (5. 70 and 5. 85 p.) and amide (5. 96 p.) carbonyls, a shoulder at 6. 05 p. which is indicative of a carbon-carbon double bond. The product gave a positive Baeyer test indicating the presence of the double bond. The n.m. r. spectrum (Figure X) showed singlets at -1. 037’ (imide hydrogen) 2. 27 and 2. 80 T (amide) with relative areas 1:1:1. The fact that the amide resonance is split into two positions indicates that one of the amide hydrogens is hydrogen-bonded to an imide oxygen. The n.m. r. spectrum in 10% sodium hydroxide (Figure X) showed singlets at 7.72 ’7’ \ /o / fin is m /c\ ~H,-’o o/ '15 and 8. l4 7 (isopropylidene group) with equal areas. »Reaction of XVIII with diazomethane gave 4-carboxamido-3-iso- Propylidene-l-methylsuccinimide (XIX) in 86.4% yield. Hydrolysis of XIX with 10% sodium hydr0xide gave approximately 2 moles of nitrogen bases and isopropylidenesuccinic acid(XX) was isolated in 38. 2% yield. Comparison with an authentic sample, prepared by the procedure of Overberger and Roberts (21), showed that the two materials were identical. 30 UH 6.42 8.56 10.00 (B) WU WM -l.03 2.27 2.80 10.00 7.72 8.14 10 00 Figure X. .NMR Spectra (A) Methyl 3, 3-dimethy1cyc10propane-l, l, 2, 2-tetracarboxy1ate (XVI) in CHC13. (B) 4-Carboxamido-3-isopropy1idenesuccinimide (XVIII) in DMSO. (C) 4-Carboxamido-3-isopropy1idenesuccinimide (XVIII) in 10% NaOH (TMS in capillary reference). 31 M“ 40.32 8 SEE . xonumouv mo Edy 6383335ocmpfiaaoumog woomm vamAmcH .va oudmfih 32 O \ ,L‘ o \ 40 /--- .. OH \ / N'CH3 1 L——-——(”:-OH CONHZ 0 o o XIX XX XXI Each was converted to the known isopropylidene succinic anhydride(XXI) on heating. This provides another example (see VI) of decarboxylation which leads to opening of the three-membered ring. In both cases, decomposition via an enol would lead to impossible structures which are avoided by the ring opening. If a five-membered ring is not fused to the cyclopropane ring, 0 O R H R ll C-O C = O K}: \\ (i=9 % Ci - OH ,C‘N C‘N 0’ 1'4 6’ H normal de carboxylation oc cu r s . o \\ . \\ fl c=o 02H H —/'o —+ W-OH —‘~'> H H Still another example is seen in the decarboxylation of XIII which gave 4-(N-methyl)-carboxamido-3-isopropylidene(XXII) in 89% yield. /— Y CHzNz/— Y NH —-—->- NH ——> N-CH3 _ H 0 ‘—_—§o CONHCH3 LONHCH3 CONHCH3 XIII XXII XXIII, l..' uv- but. 23“.. 'H" .A'v‘ o... “s7 A“ E 33 The infrared spectrum (Figure XII) is consistent with the structure assigned. XXII gave a positive Baeyer test indicating the presence of unsaturation. . Reaction of XXII with diazomethane gave 4-(N-methy1)-—carbox— amido-3-isopropy1idene-1-methylsuccinimide(XXIII) in 85. 7% yield. Additional support for the structure of XXIII was obtained from alkaline hydrolysis. . After reflux with 10% sodium hydroxide for six hours almost two moles (95. 4%) of methylamine were isolated as the hydrochloride. The other hydrolysis product was isopropylidenesuccinic acid(XX) obtained in 33. 6% yield. . C. Extension of Hydrolysis Studies to Tetracyanocyclopropanes From Other Ketones In order to show that the hydrolytic reaction sequences just described were general it was decided to investigate one other case in detail and the tetracyanocyclopropane from cyclopentanone was selected. Some of the hydrolytic products obtained from 1, 1, 2, 2-tetracyano- Spiro[2, 3]hexane(XXIV) and its derivatives are outlined in Scheme 3. Hydrolysis of XXIV in the same manner as described for I gave XXV, m.p. 187-1880 (dec.), in 76. 9% yield. Microanalysis indicated the empirical formula CnleNzOS. The neutralization equivalent, 124. 62 (theory 126. 12) showed that the compound was dibasic. The presence of the imide and amide groups were demonstrated in the n.m. r. spectrum (Figure XIV) in DMSO which showed singlets at -1. 12 T (imide) and 2.447 (amide) with relative areas 1:2. The same compound was obtained by alkaline hydrolysis of the dicyanoimide (XXVIII). Hydrolysis of XXV with 10% sodium hydroxide for 3. 5 hours gave 1, 2-dicarboximidospiro[2, 4]heptane-1, 2-dicarboxy1ic, acid (XXVI) which could not be obtained pure. It was identified via its methyl ester XXVII, obtained by reaction with diazomethane. The infrared spectrum of the ester (Figure XIII) is consistent with the structure. 34 MA Ha 40.92 fi 3.803 opwgfifioosmonopflamosmomfiom-ovwemxonudo nficwzuozozvsv Mo 8530on ponHwGH .HUA 6.5;me 35 Scheme 3 CN COZH 0 CN _ L___¢ OH ' —-—-—-—+ NH -1. 12 .‘ MeOH ~ g CN 0 CN CONHz 2.44 XXIV XXV 10H" OzCH3 ‘ COZH 0 Ho .‘ N-,-C.H3 (£11211; NH 0 So COZCH3 COZH XXVII XXVI ZN N o Hz-COzEt 0 + + NH: -—-> NH in-COZEI o N N LXV 1. Br; 2. HCOZH, .. N O XXV ei— NH CN 0 XXVIII 36 MM 3 o .300 E 5303 BmExonsafieé 4 nosdumofimv . NH—ouamopwgwxonumowpn Sensuoauziv .. N . A 3862 m0 Espuoomm pondsmcu .HHUA one—warm 37 The reactions used to further elucidate the structure of the imido- acid XXV are outlined in Scheme 4. Diazomethane reacted with XXV to give methyl 2-carboxamido- 1, 2-(N-methyl)-dicarboximidospiro[2, 4]heptane- l-carboxylate (XXIX) in quantitative yield. The n.m. r. spectrum (Figure XIV) showed singlets at 6. 307' (~OCH3), 7. 14 ’7' (—NCH3) and 8. 32 ’7’ (broad, cyclopentane) with relative areas 3:3:8. Hydrolysis of XXIX with methanolic sodium hydroxide gave XXX in 80.6% yield, m.p. 180-1810 (dec.). This material was identical to the product obtained from the basic hydrolysis of the dicyanoimide (XXXI). The neutralization equivalent, 133. 3 (theory 133. 13) showed that XXX was dibasic. The presence of the carboxyl and the imide groups was demon- strated by their methylation with diazomethane to methyl 2-(N-methyl)- carboxamido— 1, 2- (N—methyl)-dicarboximidospiro[2, 4]heptane-l-carboxy1ate (XXXII) in 93. 1%yield. . When XXXII was hydrolyzed with methanolic base Spiro[2, 4]heptane- 1, 1, 2, Z-tetracarboxylic acid (XXXIII) was obtained. The tetraacid was not isolated pure but was identified by conversion to its tetramethyl ester (XXXIV). The infrared spectrum (Figure XV) had an ester carbonyl absorption band at 5. 75 p. The decarboxylation products from XXV and some of its derivatives are shown in Scheme 5. . When XXV was heated at 180° for one minute carbon dioxide was evolved and 4-carboxamido-3-cyclopentylidene- succinimide (XXXV) was obtained in 88.9% yield. The empirical formula, C10H12N203, was consistent with loss of one mole of carbon dioxide. Unsaturation was indicated by a positive Baeyer test. The imide was con- verted by methylation with diazomethane to 4-carboxamido-3~cyclopenty1idene— 1 -methyl suc cinimide (XXXVI). In a similar manner XXX was decarboxylated at its melting point to 4 “(N-methy1)- carboxamido- 3 - cyclopentylidene succinimide (XXXVII) in 92. 4% yield. The imide group was methylated with diazomethane to 4 -(N-methy1) - carboxamido- 3 - cyclopentylidene— l -methylsuc cinimide (XXXVIII) in 71. 5% yield. 38 Scheme 4 COZCI'I3 O XXV ELLE-2.). "CH3”7 J14 . go . Y1 8.30 CONHZ XXIX _ XXX OH CHZNZ CN 0 002.0113 :0 XXVIII ———>.‘ N-CH3 |:>< N-CH3 CN 0 f-l‘lII-l O CH, XXXI XXXH OH' COZCH3 COzH COZCH3 COzI-l CHN .4 ,___.__. .4 ,COZCH3 COzH COZCH3 COZH XXXIV XXXIII 39 (A) ew -1.12 2.44 10.00 (B) v T 6.30 7.14 8.32 10.00 Figure XIV. NMR Spectra (A) 2- Carboxamido— 1 , Z-dicarboximido spiro[2, 4]heptane- 1 -carboxy1ic acid (XXV) in DMSO. (B) Methyl 2- carboxamido¢ 1 , 2-(N-methy1) -dicarboximidospiro[2 , 4]heptane- l-carboxylate (XXIX) in CHCl3 . 40 MA HA 0 N. .480 E AZxxxv oomfwxoorumomupooum .N .H .Hnocmuaoflaw .NHOHEm 1:332 mo 55.30on possum“: .>N oudwfim 41 Scheme 5 _._ 0 -o A . — ‘V XXV ——>- NH (341% N-CH3 o 1—4 CONHz CONHZ O XXXV XXXVI ,o - so XXX “7 N-H ——> N.CH3 ' o (fi-NH C- H l H3 0 CH3 XXXVII XXXVIII The same criteria as used earlier (elemental analysis, infrared spectra, Baeyer test) established the structures of these compounds. It is seen that the entire sequence of hydrolysis and decarboxylation reactions established for the acetone derivatives is also followed for the cyclopentanone compounds. The first stage in the hydrolysis was also .shown to be general for the tetranitrile derived from cyclobutanone and cyclohexanone . . Hydrolysis of 1, 1, 2, 2-tetracyanospiro[2, 3]hexane(XXXIX) gave Z-carboxamido-l, 2-dicarboximidospiro[2, 3]hexane-1-carboxy1ic acid (XL) in 44. 9% yield. When 1, 1, 2, 2-tetracyanospiro[2, 5]octane(XLI) CN - ‘4 £1, 04 NH O CNCN CONHZ XL XXXIX 42 was similarly hydrolyzed (2) 2-carboxamido- l, 2-dicarboximidospiro[2, 5]- octane(XLII)) was obtained in 92. 4% yield. The n. m. r. spectrum of XLII LCONHZ 2. 47 OH' OH XLII 87.2% 92.4% LXVI (Figure XVI) showed two singlets at -1. 14 'T (imide) and 2. 47 7(amide) with relative areas 1:2. The same product was obtained by alkaline hydrolysis of the dicyanoimide XLIII. The erroneous structure XLIV had previously (5) been assigned to this hydrolysis product. CN COZH . I COZH CN X LIV 43 (A) I J .1.14 2.47 10.00 (B) QLJ MAL 7.16 8.43 , . 10. oo ' Figure XVI. . NMR Spectra (A12- Carboxamido-l, 2-dicarboximidospiro[2, 5]octane-1-carboxy1ic acid (XLII) in DMSO. (B) 3, 3-Dimethy1- 1, Z-dicyanocyclopropane-1, 2-(N-methy1)-carboximide in CH3CN. 44 D- Hydrolysis of Tetracyanocyclopropanes Prepared from Aldehydes. Although the hydrolysis of the tetranitriles derived from aliphatic and cyclic ketones gave imido-acids, tetranitriles from aliphatic and aromatic aldehydes gave different hydrolysis products whose nature de- pended on the alkyl or aryl group. 1) From Benzaldehyde Hydrolysis of 3-pheny1—l, 1, 2, 2-tetracyanocyclopropane (XLV) with 2N potassium hydroxide (2) did not give the expected imido-acid. The product, an acidic material, m.p. 238-2390 (dec. ), had an empirical formula C13H9N06. Reaction with diazomethane gave an ester, C16H15NO6, to which the structure methyl 2, 4-dioxo—3-methy1-6-pheny1-3-azabicyclo- [3.1.0]hexane-1, 5-dicarboxy1ate(XLVI) was assigned. This structure was supported by infrared and n.m. r. data. The infrared spectrum (Figure XVII) had absorption bands at 5. 59 and 5.82 n (imide carbonyl) and 5. 73 p. (ester carbonyl). The n.m. r. spectrum (Figure XVIII) showed singlets at 2.74’T (Ar-H), 5.67’T (pH), 6.13 ’T (-OCH3) and 7.55 7’ (-NCH3) with relative areas 5:1:6:3. On this evidence, the original acid presumably was 2, 4-dioxo-6- pheny1-3-azabicyclo[3. 1. O]hexane-l, S-dicarboxylic acid (XLVII), 6.13- N 5.67 cozcm3 o ,cozH o H CN H —-——Q 7.55 H . RV N-CHa NH -1. 11 4) CN c) 2 74 ' Eo C) $0 CN COZCH3 COzH 2.17 2.87 XLV XLVI XLVII which is consistent with its microanalysis. The n.m. r. spectrum (Figure XVIII) of this acid showed the types of hydrogens to be expected 45 MA um.~:®dd%®£~ _ A 2.60 5 555 38188366 o .2 .2363336;-inenaedafiefié noonowpuwd 193mg mo Eguuomm possum”: .HH>N ondmfm 46 (A) 2.74 5.67 6.13 7.55 10.00 (B) -1.11 . . 5.87 10.00 Figure XVIII. NMR Spectra (A) Methyl 2, 4-dioxo-3-methy1-6-pheny1-3-azabicyclo[3. 1. O]hexane- l , 5- dicarboxylate (XLVI) in CDC13. . . . (B) 2, 4-Dioxo-6-pheny1-3-azabicyclo[3. 1. O]hexane- 1, 5-dlcarboxy11c ac1d (XLVII) in DMSO. 47 (-NH, -l.ll ’T ), Ar-H, 2.17 and 2.87 7’; cyc10propyl—H 5.77 7" ). But the areas on integration showed twice as many aromatic hydrogens as predicted. This enigma has not been resolved, primarily because attempts to repeat the hydrolysis were unsuccessful. Indeed, such attempts lead to a different product. 7 This material was also acidic, contained nitrogen and melted at 228-2290 (dec.). Elemental analysis indicated the empirical formula C13H11NO7. The n.m. r. spectrum (Figure XIX) of this substance in acetone-d6 showed singlets at 2.63 ’7’ (Ar-H), 3. 72 ’1’ (broad, -OH) and 5. 777' (C-H) with relative areas 5:3:1. The n.m. r. spectrum (Figure XIX) was altered when it was obtained in DMSO, but bands were observed at -1. 11 7’ (singlet, NH), 2.70’7’ (broad singlet, Ar-H) and 5.87’)’ (singlet, C-H) with relative areas 1:5:1. On the basis of these data the substance was assigned the structure 6-hydroxy-4-pheny1pyridone-3, 5-dicarboxylic acid hydrate (XLVIII). The alternate structure XLVIIIa is unlikely due H . COZH OH .N.HZO 3.27 >< -Hio .. z , (l A.) 2.63 ' COZH O COZH XLVIII XLVIIIa to the unfavorable double bond in the 5-membered ring imide. It is possible that the water of hydration is doubly hydrogen bound to the imide nitrogen and carbonyl oxygen (XLVIIIb). Presumably DMSO acts as a drying agent; in it one does not see the water protons, and the compound itself appears to be in the keto (imide) form XLVIIIc, hence the NH band in the n.m. r. spectrum. 48 1(3) 2.63 3.72 5.77 10.00 (B) I 10.00 70 5.87 I - 1. ll 2. Figure XIX, , NMR Spectra of 6-Hydroxy-4-phenylpyridone-3, 5-dicarboxylic acid hydrate (XLVIII). (A) In Acetone-d6. (B) In DMSO. 49 COZH o / NH - 1. ll COZH O XLVIIIb XLVIIlc This may ‘be due to the increased polarity of the solvent. Further support for structure XLVIII was obtained by its reaction with diazomethane (only two moles consumed) to give methyl 6-hydroxy- 4-pheny1pyridone-3, 5-dicarboxylate (XLIX) in 88. 5% yield. Its infrared spectrum (Figure XX) had absorption bands at 2. 97 (I (-OH), 5. 58 (p. (imide carbonyl) and 5. 73 I-L (ester carbonyl) and was consistent with the structure assigned. The n.m. r. spectrum (Figure XXI) showed singlets at 2.42 ’1’ (-OH), 2. 75 ’T (Ar-H), 5.72’)’ (C-H) and 6. 207(-OCH3) with relative areas 1:5:lz6. The n.m. r. spectrum was different when it was obtained in DMSO (Figure XXII ). The methoxyl's are not observable in this solvent, but bands were found at -1.13 T(sing1et, ~NH). 5. 74 [r (singlet, C-H) and 2. 65 T (multiplet, Ar-H) with relative areas 1:1:5. Again, it appears that DMSO causes a shift to the keto form. . It is well-known that pyridones and hydroxypyridines are tautomers. It is noteworthy that XLVIII was not N-methylated with diazomethane. XLIX Ramirez and Paul (22) N-methylated 6-(4'-carboxy)))buty1-2-hydroxy-5- oxo-6, 7-dihydro-l, 5H-pyrindine with diazomethane in ether—methanol. 50 2 HA 0 h M m m . m .JUIU ca 03133 oumfwuaasmawcum .Maocogfwmacofim u¢i>xosc>£to T2302 mo 55.30on consume: .XN ondwwh . 51 52 H C 02H This example of N-alkylation of an a-pyridone with diazomethane is interesting because treatment of 2-hydroxypyridine with diazomethane yields only 2-methoxypyridine (23). The product (XLVIII) obtained from the alkaline hydrolysis of XLV is surprising. This type of rearrangement could not occur in the ketone derivatives because of the absence of an acidic hydrogen. Presumably, it should occur easier in the aromatic tetranitriles than in those from aliphatic aldehydes since the rearrangement probably proceeds via an anion which would be stabilized by the phenyl ring. The mechanism of the reaction is not known but one plausible path is COZH XLV ——————§ It is not knOwn whether the ring cleavage occurs with the nitrile or one or more of its acid derivatives. The reaction is of interest from a synthetic and a mechanistic viewPoint. A more detailed study of these hydrolyses should provide additional information on the mechanism or mechanisms involved . 2) From E-Chlorobenzaldehyde When 3-p-chlorophenyl- l, 1, 2,, 2-tetracyanocyclopropane(L) was hydrolyzed with 2N potassium hydroxide (2) as described for XLV, cooled and acidified a crystalline acid, m.’p. 248-2490 (dec. ), was obtained. 53 Elemental analysis indicated the empirical formula C13HHC1N206. The n.m. r. spectrum (Figure XXII) in acetone-d6 showed singlets at 2. 74 T (Ar-H), 4.42/1’ (-OH) and 5.897 (C-H) with relative areas 4:3:1. On the basis of these data the acid was assigned the structure 3-carboxamido- 4-p-chlorophenyl-6-hydroxypyridone-5-carboxy1ic acid hydrate (Lla) or one of the three other possible structures (le, LIc,. LId). Of these, LIa and LIb are preferredbecause of the greater conjugation in their structures. The filtrate from the above reaction was extracted continuously with CN ONHZ H CN ‘ H / \OH p_C1_ ‘ N~HZO p_c1_¢ , N-HZO -c .. p “P CN 0 0 CN CONHZ 02H L LIa LIb LIc LId ether to give another acidic material, m. p. 235-236. 50 (dec. ), different from L1. Reaction with diazomethane gave an ester, C16H14C1NO6, to which the structure methyl 2, 4-dioxo-6-p-chloropheny1-3-azabicyclo[3. 1. O]hexane- l, 5-dicarboxylate (LIII) was assigned. This structure was supported by microanalysis, and infrared and n.m. r. data. The infrared spectrum is shown in Figure XXIII. The n.m. r. spectrum (Figure XXIV ) showed a multiplet at 2.84 T (Ar-H) and singlets at 5. 79T (C-H), 6.17T(-OCH3) and 7. 52 ’Y(-NCH3) with relative areas 4:1:6:3. 54 » 1 44M 2.74 4.42 . 10 00 l l L l -o.93 2.30 2.75 10.00 (C) W , ,. i. 256 5.74 10.00 -1. 13 Figure XXII. NMR Spectra (A) 3-Carboxamido—4-p-chloropheny1—6—hydroxypyridone-5-ca.rboxy1ic acid (LI) in Acetone-d6. (B) L1 in DMSO. (C) Methyl 6-hydroxy-4-pheny1pyridone-3, 5-dicarboxy1ate (XLIX) in DMSO, 55 2 2 o a fi _ .326 S and eemaxoneeeeee .Teeexeflog .2 :oHotwoBdNMumtaksuofiamsoxoflutw .Nuaewcmzmonogonmno Twnuoz mo 8.9.30on poumhqu 7 .HHUCA 0.2:th 56 From these data it appears that its acidicprecursor, m. p. 235—236. 50 (dec. ), has the structure 2., 4-dioxo-6 -p-chloropheny1—3oazabicyclo[3. 1. 0]- hexane-l, 5-dicarboxylic acid (LII). Although LII was not analyzed, its . 6.17 qOZH ’ (€03CH3 . . ’ H -———<9 #0 "c— 01¢ NH H N-CH3 7.52 P‘ " .._._____< -Cl- A 2.67 p (‘3 \O COZH cozcn3 LII LIII n.m. r. spectrum in acetone-d6 (Figure XXIV ) showed a doublet at Z. 67 hr (Ar-H) and a singlet at 5. 84 7 (C-H) with relative areas with 8:1. The anomalously large area for the aromatic protons is not explicable at present. The n.m. r. spectrum of LI in DMSO (Figure XXII) is noteworthy in that it showed a singlet at -0. 93 IT (-NH). a quartet at 2- 75 (T (Ar-H) and a doublet at 2. 30 ’T (amide) with relative areas 1:4:2. In the imide tautomer which is obviously present in DMSO, the number of possible isomers is reduced to two. The doublet for the amide may be due to hydrogen bonding of one amide hydrogen with the imide carbonyl, or it may be due to the presence of both possible isomers. 3) From Several Aliphatic Aldehydes Hydrolysis (2) of 3-methyl-1, 1, 2, Z-tetracyanocyclopropane (LIV) gave an acidic substance, m.p. 214-2170 (dec.), which did not contain nitrogen. . Only preliminary information regarding its structure is as yet available. Microanalysis indicated the empirical formula C6H907. The n. m. r. spectrum .(NaOD in D30) showed two quartets at 6. 75 and 7. 37 (hydrogens split by different methyls 7) and two doublets near 8. 50 (methyls split by different hydrogens ?) with relative areas 121:3:3. 57 (A) 2.84 5.79 6.17 7.52 10.00 (B) /,~ 2.67 5.84 10.00 4,—- Figure XXIV. NMR Spectra. (A) Methyl 6-p-chloropheny1-2, 4-dioxo-3-methy1-3-azabicyclo[3. 1. O]hexane- 1, 5-dicarboxy1ate (LIII) in CDCl3. (B) Z, 4-Dioxo-6-p-chlorophenyl-3-azabicyclo[3. 1. O]hexane- l , 5-dicarboxylic acid (LII) in Acetone-d6. 58 When the n. m. r. spectrum was obtained in acetone~d6 a strong resonance was observed at l. 75 T (~OH?). Although this material was not identified it may be a mixture of hydrated polybasic acids and/or their derivatives. When 3-ethy1-1, 1, 2, 2-tetracyanocyclopropane (LV) and 3-isopropyl— 1, 1, 2, Z-tetracyanocyclopropane (LVI) were hydrolyzed (2) under the . N CN H CN H CN H ‘ HZ ‘ H: , _ CH3 CN N , CN H3 CN ( H“ LIV LV LVI CN CN CN same conditions the imido—acids were not obtained. The hydrolysis products from these reactions were extremely soluble in ether and in water. Their decomposition during recrystallization made it impossible to obtain them pure. It appears that the rate of hydrolysis of tetracyano- cyclopropanes depends on their source, increasing in the order ketones < aromatic aldehydes < aliphatic aldehydes. E- N.M. R. Spectra of Some Tetracyanocyclopropanes and Alkylidene Bismalononitriles In aliphatic compounds methyl groups usually show resonance in the region 9. 05 to 9. 15,1] . . Acyclic methylene groups are less shielded than methyl groups and usually fall near 8. 75M], ; there appears to be a further small shift to lower field on passing to the methine type of proton (N 8. 5 Ir) (24). The shielding of protons in the alicyclic series depends on the ring size. This effect is most pronounced in cyclopropane, where the protons are more shielded than methyl groups. For example (25), cyclopropane hydrogens appear at 9. 78 ”r , norcarane has its cycloprOpyl methylene band at 9. 98 Ihr and bicyclo[3. l . O]hexane has its corresponding band at 9. 91 IT . 59 With a number of tetracyanocyclopropanes available, it was decided to examine their n.m. r. spectra. The cyclopropyl hydrogen in these compounds appeared at unusually low fields (6. 47-6. 53/T when R = alkyl, 4.8-5.1 7’ when R = aryl, see Table IV). . An alternative structure for the tetracyanocyclopropanes from aldehydes is H \C/CN / \CN R - C \ /CN C, EN which might arise by a tautomeric isomerization. This structure can be excluded on two grounds. The multiplicity of the H-band in question and the observed J—values vary with R as one would predict for the cyclopropane structure (quartet when R = methyl, triplet when R = ethyl or n-propyl, doublet when R = isopropyl). Secondly, the T-values of H are too high 7 for a hydrogen on a carbon containing two cyano groups (6. 5 vs 5. 10 The proton in these cyclopropanes would be expected to occur at lower field than normal because of the electronegativity of the nitrile groups. Similar shifts have been reported by Meyer and Gutowsky (26) in the case of halogen substitution. However, this simple explanation did not seem sufficient for the large downfield shift (N 37 ). The GEN bond has four pi electrons capable of undergoing dia- magnetic precession (27) around the c_=_N axis. This diamagnetic anisotrOpy (depicted below) may deshield the cyc10propyl hydrogens and hence shift their resonance to lower field. (I ‘\ 4 N‘ . m . C ,' 1 Ho * / 60 Table IV. N.M. R. Positions (31) of Cyclopropyl Hydrogens in Some Tetracyanocyclopropanes CN CN CN CN Compound Position Figure ‘ R (1) H 6.53 (S) ‘- Methyl 6.49 (Q) XXV Ethyl 6.47 (T) XXV n-Propyl 6.45 (T) XXV iso-Propyl 6.50 (D) XXVI CyCIOpropyl 6.75 (M) XXVI Phenyl 5.07 (S) XXVII p-Chlorophenyl 5. 10 (S) XXVII m—Nitrophenyl 4.77 (S) XXVII 61 (A) 6.49 8.38 10.00 6.47 7.97 8.7 10.00 (C) I 1 J l 6.45 8.47 8.90 10.00 Figure XXV. NMR Spectra in Acetone-d6. (A) 3-Methyl- 1, 1, 2, 2-tetracyanocyclopropane (LIV). (B) 3-Ethyl- l, 1, 2, Z-tetracyanocyclopropane (LV). (C) 3-n-Propy1— 1, l, 2, 2-tetracyanocyclopropane. 62‘. (A) 6.75 9.03 10.00 (a) A: A MW...) (a... 1 J. .L 6.50 8.03 8.63 10.00 (C) we) . 1.87 2.12 2.50 10.00 Figure XXVI. . NMR Spectra. . (A) 3-Cyc10propy1-l, 1, Z, 2-tetracyanocyclopropane inAcetone-d6, (B) 3-iso-Propy1-1, 1, 2, 2-tetracyanocyc10propane (LVI) in Acetone-d6. (C) Benzylidenemalononitrile (LXI) inAcetone. 63 (A) ,_———_a/q*_ A__J 1....4/%*__ “’ ‘_1 l l v7 2.17 2.42 5.07 10.00 (B) (wLee 2.32 5.10 10.00 (C) WM I J 1.03 1.53 2.13 4.77 10.00 fi— fi~" Figure XXVII. . NMR Spectra in Acetone. (A) 3-Pheny1-l, 1, 2, 2-tetracyanocyclopropane (XLV). (B) 3-p-Chloropheny1-1, l, 2, 2-tetracyanocyclopropane (L). (C) 3-m-Nitropheny1-l, l, 2, 2-tetracyanocyclopropane1. 64 The importance of the diamagnetic anisotropy of the cyano group has been stressed by Goldstein and co-workers (28), who analyzed the n.m. r. spectrum of acrylonitrile and found that the a-proton came at higher field than the B-protons; this was unexpected since the a-proton, because of the electronegativity of the cyano group, should be less shielded and occur at lower field. The shift was explained (28) by esti- mating the diamagnetic anisotropic shielding due to the GEN group on the protons. The corrected position of the a-proton was at lower field than that of the B—protons. . In order to determine whether the low position of the proton was due to the rigid geometry of the tetracyanocyclopropanes, several open- chain analogs were prepared. The n.m. r. spectrum (Figure XXVIII) of 1, l, 3, 3-tetracyanopropane (LVII) showed resonance for the methylene group at 6. 907 . The n.m. r. spectra (Figures XXXI and XXX) of 2-methy1- and Z-ethyl-homologs (LVIII and ’LIX)} showed multiplets for their 5. 10 5.14 H\C/CN H\c/CN ‘5-07 H\:/CN \CN / \CN CN 8.40 8.77 7.99 ' 6.90 HZ H CH3-C-\H 6.67 , CH3-CHZ- -H 6.87 CI R- H CN + H \ /CN 5 C/ \— |\ CN CN H H CN (b c\ n-m/ C” ——>, R-CH=C(CN)2 + 'CH(CN)2 CN / C\ | CN H 'cmcm, + H + ——> CH;(CN)2 V'— 70 00;: 0%. 2 x N 63:38.5 needs—ME om 933w Amv moudcflb o 73 ASE/1: mammoumocmcnomfiootm .m J .Htagumzum mo mhuommm fizz .HXXX mudwwh .m es.s 88.8.. mw.m on ggiiul. 1T3... Am: L gingiimdi 71:3.) :3 71 The dissociation was not observed with LVII in acetone-d6 at room temperature, but Ardis and co-workers (29) prepared 1, l-dicyanoethylene by its pyrolysis at 150-2000. (CN)2 ' ) 150-2oo° /CN CH; \. CH3=C + CH2(CN)Z H H -\ \ )2 (CM. CN EXPERIMENTAL 72 US EXPERIMENTAL A . General Procedure 8 1 . Apparatus All infrared spectra were obtained on a Perkin-Elmer Model 21 recording infrared spectrophotometer, using sodium chloride cells. The band positions were recorded in microns. The ultraviolet spectra were determined in l-cm. ground stoppered quartz cells using a Beckman DK-Z spectrophotometer. . All neutralization equivalents were determined using a Beckman Model H-Z Glass Electrode pH Meter. Proton magnetic resonance spectra were obtained on a Varian Model A-60 or a Varian Model HR-60 instrument. All spectra were obtained at 60 Mc. using tetramethylsilane as an internal standard. The band positions were recorded in Tunits as prescribed by Tiers (30). The relative peak areas were obtained by electronic integration. Unless specified otherwise all solvent evaporations were performed using a Rinco type rotary evaporator. 2.. Purification of Acetone Reagent grade acetone was purified using the modified Shipsey- Werner method as described by Livingston (31). . Acetone, in an Erlenmeyer flask, was saturated with sodium iodide at room temperature. The solution was decanted from the excess solid, cooled to -100 and filtered. The cold salt was transferred to an Erlenmeyer flask, warmed to 30°, decanted ' into a distilling flask and distilled through a 23x0. 5 cm. glass helix packed column. The distillate boiling at 560 was collected. 3. Purification of Aldehydes and Ketones All aldehydes and ketones were purified by recrystallization or distillation before use . 73 La’: DWI. 7'4 4 . Melting, Points All melting points are uncorrected. 5. Microanalyses All microanalyses were performed by the Spang Microanalytical Laboratory, Ann Arbor, Michigan. W“ . B. Preparation of Tetraganochlolropanes 1. Preparation of 1, 1, 2., 2-Tetracyanocyclopropane The method of Scribner (4) was employed to make this compound. *- To a solution of 5. 8 g. (0. 04 mole) of bromomalononitrile in 20 ml. of tetrahydrofuran (freshly distilled from lithium aluminium hydride) diluted with 1 m1. of water was added 1. 6 g. (0.02 mole) of 37-38% formalin ' followed by 6. 6 g- (0. 04 mole) of potassium iodide in 8 m1. of water. When the exothermic reaction had subsided, the mixture was diluted with a little water and filtered. The precipitate so obtained was washed with dilute potassium iodide solution and then with water. - Recrystallization from methyl alcohol gave 1.67 g. (60%) of white needles, m.p. 223-2240 (dec.), (lit. value (4), m.p. 223-2240 (dec.). The n.m.r. spectrum showed a single peak at 6. 53 T. 2.. Preparation of 3-Methyl-l, 1, 2, Z-tetracyanocyclopropane (LIV) The method of Wideqvist (3) was used to prepare this compound. To a 50-ml. Erlenmeyer flask containing 3. 0 g. (0. 02 mole) of bromoé malononitrile dissolved in 10 ml. of acetaldehyde was added a solution of 7.0 g. (0. 043 mole) of potassium iodide in 20 m1. of water with stirring. After 20 minutes the solid was filtered and washed with cold water. Recrystallization from 95% ethanol gave 2. 2 g. (70. 7%) of the tetranitrile, m.p. 190° dec. (lit. value (3),m.p. 190o dec.). The infrared spectrum (Nujol) showed a nitrile band at 4.41 pt. The n.m. r. spectrum is shown in Figure XXV. 75 Anal. Calcd. for C3H4N4; C, 61.53; H, 2.58; N, 35.85. Found: C, 61.34; H, 2.74; N, 35.75. 3. Preparation of 3-Ethy1-l, 1, 2, 2-tetragyanocyclopropane (LV) A modification of the procedure of Wideqvist (3) was used to prepare LV. To a 50-ml. beaker containing 1.16 g. (0. 02 mole) of propionaldehyde, 2. 9 g. (0. 04 mole) of bromomalononitrile and 5 m1. of ethanol was added a solution of 7 g. of potassium iodide in 20 m1. of water with stirring. The reaction mixture darkened and crystals separated after a few minutes. After 20 minutes the solid was removed by filtration and washed thoroughly with cold water. Recrystallization from 95% ethanol gave 1. 2 g. (70. 6%) of white needles, m.p. 186-1870 (lit. value (7), m.p. 1970). .Numerous attempts to raise the melting point of LV proved to be unsuccessful. The n.m. r. spectrum is shown in Figure XXV. £221.. Calcd. for C9HqN4: C, 63.52; H, 3.55; N, 32.93. Found: C, 63.34; H, 3.61; N, 32.80. 4. Preparation of 3-n-Propy1-1, l, 2, 2-tetracyanocyclopropane The procedure was completely analogous to that described above for LV, with the use .of butyraldehyde in the place of propionaldehyde. The product was purified by recrystallization from 95% ethanol and was obtained in 75.9% yield, m.p. .130-131° (lit. value (7). m.p. 131°). The n.m. r. spectrum is shown in Figure XXV. 5. Prgparation of 3-Isopropyl-l, 1., 2, Z-tetracyanocyclopropane (LVI) The procedure was completely analogoUs to that described above for LV with the use of isobutyraldehyde in the place of propionaldehyde. The product was purified by recrystallization from 95% ethanol and was obtained in 73.2% yield, m.p. 17.2.1-172.8°. The n.m.r. spectrum is Shown in Figure XXVI. M. Calcd. for C10H7N4: C, 65.56; H, 3.85; N, 30.59.) Found: C, 65.48; H, 3.99; N, 30.70. 76 6. Prgparation of 3-Cyc10propy1- 1, 1, 2, Z-tetracyanocyclopropane The procedure of Wideqvist (3) was used to prepare this compound and those listed in Table V. In a typical preparation, cyclopropane- carboxaldehyde (1.49 g. , 0. 02 mole), and 20 m1. of ethanol in a lOO-ml. beaker was treated with a solution of 7. 0 g. of potassium iodide in 20 ml. of water with stirring. The reaction mixture darkened and the crystals began to separate after a few minutes. After 20 minutes the solid was filtered and washed thoroughly with cold water. Recrystallization from 95% ethanol gave 1.7 g. (93.4%) of glistening needles, m.p. 234-2350 dec. The infrared spectrum (Nujol) showed an absorption band a 4. 39 u for nitrile. The n.m. r. spectrum is shown in Figure XXVI. £1231. Calcd. for C10H6N4: C, 65.93; H, 3.32; N, 30.76. Found: C, 65.79; H, 3. 38; N, 30.87. 7. Preparation of 3-Pheny1—l, l, 2, 2-tetracyanocycloprppane (XLV) See Table V. The infrared spectrum (Nujol) showed a nitrile band at 4.45 (I. The n.m. r. spectrum is shown in Figure XXVII. 8. Preparation of 3-p-Chlor0phenyl-l, 1, 2, Z-tetracyanocyclopropane (L) See Table V. The n.m. r. spectrum is shown in Figure XXVII. 9.. Preparation of 3-m-Nitropheny1-l, l, 2, Z-tetraganocyclopropane See Table V for physical properties. The n.m. r. spectrum is shown in Figure XXVII. 10. Preparation of 3-Cyclopropylimethyl-l, 1, 2, 2-tetracyano- cyc10propane A modification of the procedure described by Scribner (4) was used to prepare this compound. To a 100 ml. beaker containing 5. 8 g. (0.04 mole) of bromomalononitrile in 20 ml. of ethyl alcohol was added 1. 68 g. (0. 02 mole) of methyl cyclopropyl ketone followed by a solution of potassium iodide in 8 ml. of water. The reaction mixture darkened and was stirred '(n 77 Table V. Yields and) Physical Properties of Some Tetracyanocyglopropanes £19m Aldehydes Analyses Yield Calculated Found Compound % M. p. (dec.) C H N C H N CN H N o 93.4 234-235 65.93 3.82 30.76 65.79 3.38 30.87 N CN CN H CN 0 83.0 232-233 71.55 2.77 25.67 71.56 2.87 25.50 CN CN CN CN 0 84.0 240-241 61.80 1.99 22.17 61.87 2.04 22.00 -c1- p (b or: CN CN H CN 77.2 245-246O 59.32 1.91 26.61 59.43 2.04 26.70 I!) N ,n_ Ch (:N 78 for 12 hours. It was then diluted with a little water and filtered. The precipitate so obtained was washed with dilute potassium iodide solution and cold water. . Recrystallization from ethyl acetate gave 0. 55 g. (14%) of prisms, m.p. 194-195°. The n.m. r. spectrum (Figure XXXII) showed a singlet at 8. 55 7 (-CH3) and a multiplet at 8. 99 T (D-H), with relative areas 3:5. $1211.. Calcd. for C11H8N4: C, 67.33; H, 4.10; N, 28.55. Found: C, 67.48; H, 4.06; N, 28.38. 11. Preparation of 3, 3-Dimethyl-l, 1, 2, 2-tetraganocyclc3propane (I) The method of Wideqvist '(l) was used to prepare this compound. To 17 g. (0. 117 mole) of bromomalononitrile in 50 m1. of acetone in a 250—ml. beaker was added a solution of 41 g. (0. 24 mole) of potassium iodide in 100 ml. of water with stirring. The reaction mixture darkened and after a few minutes crystals began to separate. The mixture was stirred for 1 hour, filtered, washed with cold water, cold dilute sodium thiosulfate solution and again with cold water. . Recrystallization from 95% ethanol gave 7.1 g. (71%) of white needles, m.p. 207-208O (lit. value (1), m. p- 209. 5-2100). The infrared spectrum (Nujol) showed a nitrile band at 4.40 it. There was no absorption in the ultraviolet region. The n.m. r. spectrum showed a singlet at 8. 25 T . ‘flfil‘ .Calcd. for C9I-19N4: C, 63.53; H, 3.55; N, 32.91. Found: C, 63.57; H, 3.41; N, 33.02. 12. Preparation of 1, 1., 2, 2-Tetracyanospiro[2, 3]hexane (XXIX) A modification of the procedure -of Wideqvist (3) was used to prepare this tetranitrile. To a lOO-ml. Erlenmeyer flask containing 2. 9 g. (0. 02 mole) of bromomalononitrile, l. 4 g. (0.02 mole) of cyclobutanone and 20 ml. of 95% ethanol was added a solution of 7. 0 g. of potassium iodide in 20 ml. of water with stirring. Themixture darkened and crystals began to separate after a few minutes. After 30 minutes the solid was removed 2 out“ 1.9- 11' “3 ban- CY . . a; V. we ‘79 by filtration and washed thoroughly with cold water. Recrystallization from aqueous acetone gave 1.1 g- (60.4%) of white crystals, m.p. 221- 221.50 (dec.). The infrared spectrum showed a nitrile band at 4.42 p. The n.m. r. spectrum is shown in Figure XXXII). fl. Calcd. for C10H6N4: C, 65.92; H, 3.32; N, 30.75. , Found: C, 65.78; H, 3. 30; N, 30.68. 13. Preparation of 1, 1, 2, Z-Tetracyanospiroiz, 4]heptane (XXIV) A modification of the method of Wideqvist (3) was used to prepare this compound. To a lOO-ml. beaker containing 1.68 g. (0.02 mole) of cyclopentanone, 2. 90 g. (0. 02 mole) of bromomalononitrile (and 20 ml. of ethanol was added a solution of 7. 0 g. of potassium iodide in 20 ml. of water with stirring. After a few minutes crystals began to separate. After 30 minutes the solid was removed by filtration and washed with cold water. Recrystallization from ethyl acetate gave 1.49 g. (76. 3%) of XXIV, m.p. 239-2100 (dec.). Anal. Calcd. for C11H8N4: C, 67.33; H, 4.10; N, 28. 55. Found: C, 67.19; H, 3.98; N, 28.62. 14. Preparation of 1, 1, 2, 2-Tetracyanospiro[2, 5]octane (XLI) The method of Wideqvist (3) was used to prepare XLI. To a 100-ml. beaker containing 2. 9 g. (0.02 mole) of bromomalononitrile 2. 0 g. (0. 02 mole) of cyclohexanone and 20 m1. of ethanol was added a solution of 7. 0 g. of potassium iodide in 20 ml. of water with stirring. . After 20 minutes the solid was removed by filtration and washed with cold water. Recrystallization from 95% ethanol gave 1. 95 g. (92. 9%) of white crystals, mp. 180-1810 (lit. value (3), m.p. 180°). 15. Preparation of 1, 1, 2, 2-Tetracyano_spiro[2, 71decane A modification of the method of Wideqvist (3) was used to prepare this compound. To a beaker containing 1. 52 g. (0.011 mole) of cyclooctanone, 8O (A) 8.55 8.99 10.00 (B) I l 7.59 10.00 Figure XXXII. .NMR Spectra. (A) 3-Cyclopropy1-3-methy1-1, l, 2, 2-tetracyanocyclopropane in Acetone-d6. (B) l, 1, 2, 2-Tetracyanospiro[2, 3]hexane (XXXIX) in Acetone-d6. 81 2. 9 g. (0. 02 mole) of bromomalononitrile and 10 m1. of ethanol was added a solution of 7. 0 g. of potassium iodide in 10 ml. of water. The reaction was stirred for 24 hours and filtered to give 0. 096 g. (4%) of the tetra- nitrile. . Recrystallization from ethanol gave white needles, m.p. 172. 5- 173°. _£_\_n_a.l. Calcd. for C14H14N4: C, 70.56; H, 5.92; N, 23.51. Found: C, 70.68; H, 6.16; N, 23.65. 16.. Preparation of l, 1, 2, 2-Tetracyanospiro[2, 8]undecane The procedure used was analogous to the preceding one. The product was purified by recrystallization from 95% ethanol and was obtained in 7% yield, m.p. 205-2060. _A_na_._1. .Calcd. for C15H16N4: C, 71.40; H, 6.39; N, 22.21. Found: C, 71.47; H, 6.42; N, 22.25. 17. Preparation of 1, l, 2, 2-TetracyanospiroL2, 6]nonane The procedure used was analogous to the one used for the preparation of 1, 1, 2, 2-tetracyanospiro[2, 7]decane with the use of cycloheptanone in the place of cyclooctanone. The product was purified by recrystallization from 95% ethanol and was obtained in 25% yield, m.p. 168-1690. £341. .Calcd. for C13I-112N4: C, 69.62; H, 5.40; N, 24.98. Found: C, 69.42; H, 5.48; N, 25.00. 18.. Preparation of TetracyanocxcloPropanes from Certain Ketones To acquire information concerning the yields of various ketones some were converted to the tetranitrile under identical conditions (see Table II). In a typical preparation 0. 02 mole of the ketone, 0.02 mole Of bromomalononitrile in 20 ml. of ethanol was treated with a solution of 7 g. of potassium iodide in 20 ml. of water. The reaction mixture was stirred for 12 hours and filtered. The tetranitrile was recrystallized from 95 % ethanol. 82 However, no crystalline products were obtained from dicyclopropyl ketone, di-n-amyl ketone, diisopropyl ketone, methyl t-butyl ketone and ethyl butyl ketone. The physical properties of the new tetranitriles prepared in this manner are summarized in Table VI. Table VI. Tetraganogclopropanes from Certain Ketones CN R N R; CN CN =—===== — _——_ Analyses Compound Calculated. Found R R, M.p. °C. 0 H .N c H ~ N Methyl n-Propyl 167.5-168 66.65 5.091 28.27 66.64 5.11 28.40 Ethyl Ethyl 167-168 66.65 5.09 28.27 66.56 5.03 28.25 ¥ C. Preparation 'of (3, (S-Dialkyl-o, a' -dicyanog1utarimides_ 1.. Preparation of 4, 4-Dimethy1-3, 5-dicyanog1utarimide (LXIV) The method of Kon (32) was used to prepare this compound. . To 90 m1. of 15% ammonia in absolute ethanol in a 500-ml. Erlenmeyer flask im- mersed in an ice bath was added 50 ml. (0.44 mole) of ethyl cyanoacetate and 17. 5 g. (0. 3 mole) of acetone. ‘ The flask was allowed to stand in the ice bath until the ice melted and then at room temperature for 36 hours, during which time the ammonium salt of the imide deposited. The salt was filtered, washed with ether to remove any oily impurities and dissolved in 500 ml. of hot water. Acidification (to Congo Red) of the aqueous 83 solution with dilute hydrochloric acid and cooling gave on filtration 26. 9 g. (64.1%) of white crystals, m.p. 216-2170 (lit. value (6), m.p. 216-2170). The n.m. r. spectrum (NaOD in D20) showed a singlet at 9. ZZT (gem- dimethyl). 2. Preparation of 4, 4—Tetramethylene-3, 5-digyanog1utarimide (LXV) The procedure was analogous to that described above for LXIV, with the use of cyclopentanone in place of acetone. The product was purified by recrystallization from 95% ethanol and was obtained in 62. 7% yield, m.p. 181-1820 (lit. value (33), m.p. 179-1800). 3. Preparation of 4, 4-Pentamethylener3, 5-dicyanog1utarimide (LXVI) The procedure was analogous to that used to prepare LXIV, with the use of cyclohexanone in the place of acetone. The product was purified by recrystallization from 95% ethanol and was obtained in 81. 2% yield, m. p. 206-2070 (lit. value (34), m.p. 206-2070). D. Preparation of Cyanosubstituted Cyclopropanecarboximides 1. Preiaration of 3, 3-Dimethyl- 1, 2-dicyanocyclomopane-1, 2- carboximide (III) The procedure described by Kon and co-workers (5) was used to prepare this compound. To a 2-1. three-necked round-bottomed flask equipped with a stirrer, reflux condenser and dr0pping funnel were added 19. 1 g. (0. 01 mole) of finely powdered LXIV and 160 ml. of water. 7 The suspension was stirred vigorously and 10. 9 m1. (0. 2 mole) of bromine was added dropwise. Hydrogen bromide was evolved and the liquid acquired a permanent yellow tinge due to the excess bromine. The mixture was stirred for 15 minutes, treated with 160 m1. of 80% formic acid and heated gently to boiling with constant stirring to preclude frothing. The solution was boiled 30 minutes and cooled. Removal of the solid; by filtration gave 18.8 g. (99.4%) of white needles, m.p. 242o dec. (lit. 'value (5), m.p. 84 2420 dec.). The n.m. r. spectrum (in CH3CN) showed two singlets at 8. 50 T and 8. 57 ’T (C-CH3) of equal areas. 2. Preparation of 3, 3-Tetramethylene-1, 2-digranocyclppropane- 1, 2-carboximide (XXVIII) The procedure was analogous to that used to prepare III, with the use of LXV in place of LXIV. The product was purified by recrystallization from 95% ethanol and was obtained in 50. 2% yield, m. p. 202-2030 (lit. value (35), m.p. 202-203°). 3. Prgaaration of 3, 3—Pentamethy1ene-1, Z-dicyanocyclopr’opane- 1, 2-carboximide (LX111) The procedure was the same used to prepare 111. The product was purified by recrystallization from 95% ethanol and was obtained in 98% yield, m.p. 232-2330 (lit. value (5), m.p. 3330)- 4. Preparation of 3, 3-Dimethyl- 1, 2-dicyanocyclqiropane-1, 2- (N-methy1)-carboximide (XIV) An ether solution of diazomethane was added to 1. 9 g. (0.01 mole) of 111 dissolved in 10 m1. of absolute methanol, cooled to 0-50, until excess diazomethane was present. The solution was allowed to stand at room temperature for 15 minutes. The excess reagent and ether were evaporated. After standing in the refrigerator overnight the solid was removed by filtration. . Recrystallization from methanol gave 2. 0 g. (98. 8%) of white needles, m.p. 235-236° dec. (lit. value (36), m.p. 241.50). The n,\m.r. spectrum is shown in Figure XVI. M' Calcd. for C10H9N3Oz: C, 59.10; H, 4.46; N, 20.68. Found: ‘c, 59.23; H, 4.54; N, 20.61. 5. Preparation of 3, 3-Tetramethy1ene-1, 2-dicyanocyclopropane- 1, 2-(N-methy1)-carboximide (XXXI) The same procedure described above was used to prepare this com- pound. The product was purified by recrystallization from methyl alcohol 85 and was obtained in 97. 9% yield, m. p. 247-»248O (dec. ). The infrared spectrum is shown in Figure .XXXIII. 'fl‘il' Calcd. for C12H11N3Oz: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.81; H, 4.90; N, 18.28. . E- Preparation of Imido-acids a. From the Tetracyanochlopropanes 1. Preparation of 2, 4-Dioxo-5-carboxamido-6, 6-dimethjl-3-azabi- cyclo[3. 1 . O]hexane- 1 -carboxylic acid (11) To a lOO-ml. roundabottomed flask equipped with a reflux condenser wer.e_added 2. 8 g. (0.016 mole) of I, 30 m1. of 25% potassium hydroxide and' 40 ml. of methyl alcohol. The solution was refluxed for 3 hours, the alcohol removed and the remaining liquid extracted continuously with ether for_4 hours in order to remove any non-acidic materials. The aqueous solution was made acid to Congo Red with dilute hydrochloric acid and extracted continuously with ether for 24 hours. Removal of the solid from the extract by filtration and recrystallization from water gave 2.81 g. (80.1%) of white crystals, m.p. 196-1970 dec. (lit. value (2), m.p. 196-1970 dec.), neutralization equivalent 112.. 3 (theory 113.1). The infrared spectrum is shown in Figure 1. The n.m. r. spectra are shown in Figure 11. M. Calcd. for C9H10N205: C, 47.79; H, 4.46; N, 12.39. Found: C, 47.68; H, 4.49; N, 12. 33. 2. Preparation of 2-Carboxamido-l, 2-dicarboximidospiro[2, 3]- hexane-l-carboxylic acid (XL) The method of Wideqvist (2) was used to prepare this. compound. To a 50-ml. round-bottomed flask fitted with a reflux condenser were added 1. 82 g. (0. 01 mole) of the tetranitrile (XXXIX), and 40 m1. of 2N potassium hydroxide. The solution was refluxed for 25 minutes, cooled and made acid to Congo Red with 4N hydrochloric acid. The solution was allowed to stand in the refrigerator for two days during which time it deposited a 86 3 Z a e .n HUEU aw «503$ 363238 you Agatha: .. . .. . . a “U 7: N H ocmmosmofiounoocmtwomptm.dtocogauog umsuofitm :6. mo 5:30on pososwsH .HHUCAX ousmah 87 white solid. Removal of the solid by filtration and recrystallization from methanol gave 1.14 g. (44.9%) of white crystals, m.p. 218-2190 (dec.). .M- Calcd. for C10H10N205: C, 50.42; H, 4.23; N, 11.76. . Found: C, 50.55; H, 4.34; N, 11.62. - 3. Preparation of 2-Carboxamido-1, 2-dicarboximid63piroi2, 4]- . heptane-l-carboxylic acid (XXV). Using the procedure described for the preparation of II, 3. 14 g. (0. 016 mole) of XXIV, 30 ml. of methanol and 30 m1. of 25% potassium hydroxide were placed in a 100-ml. round-bottomed flask equipped with a reflux condenser. The solution was refluxed for 3 hours and the product isolated as previously described. . Recrystallization from water gave 3.1 g. (76.9%) of white crystals, m.p. 187-1880 (dec.), N. E. 124.62 (theory 126. 12). The n.m. r. spectrum is shown in Figure XIV. £52. Calcd. for CnleNzOs: C, 52. 37; H, 4.80; N, 11.11. Found: C, 52.17; H, 4.88; N, 11.08. 4. Preparation of 2-Carboxamido-1, 2-dicarboximidospiro[2, 5]- octane-l-carboxylic acid (LXII) . The procedure for the preparation of II was utilized. The product was purified by recrystallization from water and was obtained in 92. 4% - yield, m.p. 202. 5-203O (dec.). The n.m. r. spectrum is shown in Figure XVI. Ala—1. .CaICd. for C12H19N205: C, 54.13, H, 5. 30; N, 10.52. Found: C, 54.24; H, 5.20; N, 10.50. b. From Dicyanocyclopropanecarboximides The imido-acids were also prepared from the dicyanocyclopropane- carboximides. In a typical preparation, 1. 9 g. (0.01 111018) Of 111 and 15 m1. of 10% sodium hydroxide in a 25-ml. round-bottomed flask fitted with a reflux condenser were refluxed for 30 minutes. The solution was cooled, 88‘ made strongly acid with dilute hydrochloric acid and placed in the refrig- erator for 2 days. . Removal of the solid by filtration gave 1.62 g. (71. 7%) of II, m.p. 196-1970 (dec. ). The properties of the imido-acids prepared by this procedure are summarized in Table VII. Table VII. Yields and Physical Properties of Various Imido-acids i .- _—_.m ,-_M Analyses Calculated Found Yields Compound M. p. (dec.) C H N C H N , % CCXIH 196.1970 47.79 4.46 12.39 47.68 4.49 12.33 71.7 >< NH CONH2 COOH 0 --—§ 187.1880 52.37 4.80 11.11 52.17 4.88 11.08 64.2 NH CONHZO ZOLS-HBO 54J3 s30 MLSZ 5424 520 HLSO 872 89 F. Hydrolysis of 3, 3-Dimethy1-l, 1, 2, 2-tetracyanocyclopropane (I) 1.. Preparation of Methyl 2, 4-dioxo-5-carboxamido-3, 6,6-trimethy1- ' 3-azabigcloi3. 1. O]hexane- 1-carboxylate (XII) Treatment of the imido-acids with diazomethane gave the methyl esters in excellent yields. A typical preparation is described. To a 100-ml- Erlenmeyer flask cooled in an ice bath and containing 2. 26 g. (0. 01 mole) of II dissolved in 50 ml. of absolute methyl alcohol was added an ethereal solution of diazomethane in small portions until gas evolution ceased and the solution acquired a pale yellow color. A glass rod moistened with glacial acetic acid was introduced into a test tube containing a few drops of the yellow solution with immediate evolution of gas indicating an excess of diazomethane. The solvent and excess reagent were evaporated and the residue recrystallized from methanol to give 2.4 g. (98.1%) of white crystals, m.p. 195-195. 50. The infrared spectrum is shown in Figure 1V. 532.1; Calcd. for C11H14N2053 C, 51.96; H, 5.55; N, 11.02. Found: C, 51.93;. H, 5.58; N, 11.16. The physical properties of the methyl esters prepared by this pro- cedure are summarized in Table VIII. 2 . Preparation of 2, 4-Dioxo-5-(N-methyl)-carboxamido-6, 6-dimethyl- 3-azabicyclo[3. 1. O]hexane- 1-carboxy1ic acid (XIII) To a 100-ml. round-bottomed flask equipped with a reflux condenser there was added 2. 54 g- (0. 01 mole) of XII, 35 ml. of methanol and 25 ml. of 10% sodium hydroxide. After 30 minutes reflux the solution was cooled and the methanol removed by evaporation. . After the solution was made strongly acidic with dilute hydrochloric acid it was placed in the refrigerator overnight. . Removal of the white solid by filtration gave 2. 15 g.. (90%) of x111, m.p. 204-205° (dec.), N.E. 118.03 (theory 120.11). The n.m. r. spectrum is shown in Figure VI. 90 Table VIII. Physical Properties and Yields of Products from Reaction of the Innido- acids with Diazomethane. 1 . Analyses Calculated Found Yields Compound M. p. C H N C H N % COZCI-I3 >< N-CH3195-195.50 51.96 5.55 11.06 51.93 5.58 11.16 “’ l f) CONHz COZCH3 ”—‘QO N-CH3133-134O 55.70 5.75 10.00 55.61 5.77 10.06 “0 CONHZ COZCH3 O< N-CH,147-148° 57.13 6.16 9.52 57.21 5.96 9.50 ___—1 ‘o CONHZ £131. Calcd. for ClofllzNzOs: C, 49.99; H. 5.04; N, 11.66. Found: C, 49.98; H, 5.04; N, 11.66. XIII could also be prepared from XIV. To a 25-ml. round-bottomed flask fitted with a reflux condenser was added 2.03 g. (0.01 mole) of XIV and 15 m1. of 10% sodium hydroxide. The resulting solution was re- fluxed for 30 minutes, cooled, made strongly acid with dilute hydrochloric acid and placed in the refrigerator overnight. . Removal of the solid by filtration gave 1. 99 g. (83. 1%) of white crystals, m.p. 204-2050 (dec.). This compound was identical to XIII described above. 98.1 100.0 96.6 91 3. Preparation of Methyl 2, 4-dioxo-5-(N-methyl)-carboamido-3, 6, 6- trimethyl-B-aza-bicycloD. 1. Olhexane- 1 -carboxy1ate (XV) To a 100-ml. Erlenmeyer flask immersed in an ice bath and contain- ing 1. 2 g. (0.005 mole) of the acid (XIII) dissolved in 20 m1. of absolute methyl alcohol was added a cold ether solution of diazomethane. The diazomethane solution was added until an excess was indicated by the pale yellow color. The solution was allowed to stand at room temperature for 15 minutes. The excess reagent and ether were evaporated. After cooling in the refrigerator overnight the solid was filtered. . Recrystallization from methanol gave 1.25 g. (93. 3%) of the ester, m.p. 154-1550. The infrared spectrum is shown in Figure VII. The n.m. r. spectrum is shown in Figure VIII. ing-1. .Calcd. for CquszOs: C, 53.72; H, 6.01; N, 10.44. Found: C, 53.82; H, 6.15; N, 10. 31. 4. Preparation of 3, 3-Dimethy1gclopropane- 1, 1, 2, 2-tetracarboxylic acid (1V) T To a 50-ml. round-bottomed flask fitted with a reflux condenser was added 1. 34 g. (0.005 mole) of XV, 13 ml. of 10% sodium hydroxide and 20 ml. of methyl alcohol. The solution was refluxed for 30 minutes and cooled. The alcohol was removed and the remaining solution extracted continuously with ether for 6 hours. The aqueous solution was acidified with dilute hydrochloric acid solution and again extracted continuously , (36 hours) with ether. The ether extract was dried over anhydrous sodium sulfate and the solvent partially evaporated. 7 To the remaining solution was added 10 m1. of ethyl acetate and some Norite. After filtration the product was obtained from boiling ethyl acetate-pentane. . Recrystalli- zation from ethyl acetate-pentane gave 0. 87 g. of the acid, m.p. 166-1690 (dec. ). 7 Further attempts at purification resulted in decomposition of the acid. The acid was not analyzed, but was converted to its tetramethyl ester (below) for analysis . 92 5. Preparation of Methyl 3, 3-dimethy1cyclopr0pane-1, 1, 2, 2-tetra— carboxylate (XVI) To a 50-ml. Erlenmeyer flask containing 0. 98 g. (0.004 mole) of the crude tetraacid (IV) dissolved in ether and cooled to 00 was added an excess of an ethereal solution of diazomethane. The excess reagent and solvent were removed on the steam bath. On cooling there was obtained 0. 96 g. of the tetramethyl ester, m.p. 154. 5-1550. The infrared spectrum is shown in Figure IX. The n.m.r. spectrum is shown in Figure X. 165.1%" Calcd. for C13H1808: C, 51.65; H, 6.00. Found: C, 51.81; H, 6.12. 6.. Preparation of 2, 4-Dioxo-3, 3-dimethy1-3-azabicyclofl 1. (fl- hexane-l, 5-dicarboxylic acid (VI) To a 50-ml. round-bottomed flask fitted with a gas inlet sidearm and reflux condenser with gaseous outlet were placed 1.13 g. (0.005 mole) of II and 30 m1. of 10% sodium hydroxide solution. The solution was refluxed for 3. 25 hours. During the reflux period the ammonia evolved was swept via a stream of dry nitrogen into a standard hydrochloric acid solution. After heating, the solution was cooled, acidified with dilute hydrochloric acid and extracted continuously with ether for 36 hours. The ether extract was dried over anhydrous sodium sulfate and reduced in volume. Ethyl acetate (5 m1.), was added to the remaining solution. After treatment with Norite, the product was obtained from boiling ethyl acetate-pentane mixture. . Recrystallization from ethyl acetate-pentane gave 0.92 g. (80.7%) of the acid, m.p. 168-169° (dec.), N.E. 75.1 (theory 75. 7). The n.m. r. spectrum is shown in Figure V1. Titration of the excess standard hydrochloric acid with standard sodium hydroxide indicated that almost one mole of base was liberated dur- ing the hydrolysis. fl. Calcd. for C9H9N06: C, 47.58; H, 3.99; N, 6.16. Found: C, 47.36; H, 4.22; N, 6.05. 93 VI could also be prepared in good yield by the alkaline hydrolysis of the tetranitrile I. To a 100-ml. round-bottomed flask fitted with a reflux condenser was added 1.7 g. (0.01 mole) of I and 40 ml. of 2N potassium hydroxide. The resulting solution was refluxed for 9 hours, made acid to Congo Red with dilute hydrochloric acid and extracted continuously with ether for 36 hours. The extracted mixture was filtered to give 0. 39 g. of II, m.p. 196-1970 (dec.) after recrystallization from water. The filtrate was dried over anhydrous sodium sulfate, filtered, treated with Norite, filtered and the solvent evaporated. Recrystalli- zation of the crude residue, 1. 92 g. , several times from ethyl acetate- pentane gave white crystals (VI), m.p. 167-1680 (dec.), which did not depress the melting point on admixture with an authentic sample. 7. Preparation of Methyl 2, 4-dioxo-3, 6, 6-trimethj1-3-azabicyclo- L3. 1. thexane-l, 5-dicarb03glate (V11) The procedure used was the same as described for the preparation of XII using V1 in the place of II. The product was purified by recrystal- lization from methyl alcohol and was obtained in 91.1% yield, m. p. 106- 1070. The infrared spectrum is shown in Figure V. £11131. Calcd. for C12H15N06: C, 53.52; H, 5.62; N, 5.20. Found: C, 53.47; H, 5.70; N, 5.16. 8. Preparation of 3-150propylidene-4-carboxamidosuccinimide (XVIII) To a 50-ml. round-bottomed flask equipped with a side-arm for nitrogen inlet and a take-off (packed with glass wool) for gaseous outlet, there was placed 2. 26 g. (0.01 mole) of finely powdered 11. .A stream of dry nitrogen was passed into the system to sweep out any gaseous products formed by the reaction. The reaction flask was immersed in an oil bath and the temperature raised slowly to 1979. The solid melted and bubbles of gas were evolved. After one minute the flask was removed from the oil bath and allowed to cool to room temperature. The light yellow 94 residue was dissolved in methanol, treated with Norite and filtered. The solvent was evaporated and the residue triturated thoroughly with cold water. Removal of the solid by filtration gave 1. 58 g. (87. 1%) of a white solid. Recrystallization from water gave white needles, m.p. 240-2410 (dec. ). This compound gave a positive Baeyer test for unsatur- ation. The infrared spectrum is shown inFigure XI. The n.m. r. spectra are shown in Figure X. £1321. -Calcd. for C8H10N203: ' C, 52.74; H, 5. 53; N, 15. 37. Found: C, 53.06; H, 5.56; N, 15.27. 9. Preparation of 4-Carboxamido-3-isopropylidene-1-methy1- succinimide (XIX) The procedure used was the same as described previously for the preparation of XII. The product was purified by recrystallization from methanol and was obtained 86.4% yield, m.p. 229-230. The infrared spectrum is shown in Figuret.XXX1V. £131. Calcd. for C9H13N203: C, 55.09; H, 6.17; N, 14.28. Found: C, 55.29; H, 6.26; N, 14.19. 10. Hydrolysis of XIX To a 50-ml. round-bottomed flask fitted with a gas inlet side-arm and condenser with a gas outlet was placed 0. 70 g. (0.0035 mole) of XIX and 30 ml. of sodium hydroxide. The flask was heated at reflux for 5 hours. During the heating the volatile basic materials were swept via a stream of dry nitrogen into a standard solution of hydrochloric acid. After heating the flask was cooled, the contents acidified with dilute hydrochloric acid and placed in the refrigerator overnight. . Removal of the solid by filtration and recrystallization from water gave 0. 21 g. (38. 2%) of isopropylidenesuccinic acid (XX), m.p. 164-165O (lit. value (21), m.p. 16l.5-162°), N.E. 79.15 (theory 79.07). final. .Calcd. for C7H1004: C, 53.16; H, 6. 37. Found: C, 53.41; H, 6.55. 95 40...: X Z a“ A US opwgficfloosmgawogtdtosop >9 . 2 OHQOmT . m 1035me t nst 4 mo 83.30on posmsmcH .> COCA osdwa .rm 96' Titration of the excess hydrochloric acid solution with standard solution of potassium hydroxide indicated that almost two moles of base had been liberated . 11. Preparation of 4-(N-methy1)-carboxamido-3-isopropylidene- succinimide (XXII) The procedure used was completely analogous to that described above for the preparation of XVIII, with the use of XIII in place of II. The product was purified by recrystallization from water and was obtained in 89% yield, m.p. 131-1320. This material gave a positive Baeyer test for unsaturation. The infrared spectrum is shown in Figure XII. £231. .Calcd. for C9H12N204: C, 55.09; H, 6.17; N, 14.28. Found: C, 55.18; H, 6.25; N, 14. 31. 12. Preparation of 4-(N-Methyl)-carboxamido-3-isopropylidene- 1-methylsuccinimide (XXIII) XXII was treated with diazomethane in the same manner as described for the preparation of XIX. The product was purified by recrystallization from methanol and was obtained in 85. 7% yield, m.p. 69-700. The infra- red spectrum is shown in Figure XXXV. _A_n_a_l. Calcd. for C10H14NZO3: C, 57.12; H, 6.71; N, 13.33. Found: C, 57.19; H, 6.87; N, 13.09. 13. Hydrciysis of XXIII To a 50-ml. round-botthmed flask equipped with a side-arm'for nitrogen inlet and condenser with gaseous outlet was placed 0. 26 g. (0. 00125 mole) of XXIII and 15 ml. of 10% sodium hydroxide. After connect- ing the gas outlet to a trap containing a standard solution of hydrochloric acid, a stream of dry nitrogen was passed into the system to sweep out any gaseous products formed. The flask was heated to reflux. After 6 hours, the standard hydrochloric acid was evaporated to dryness and the white residue dissolved in 10 m1. of refluxing dry absolute ethyl alcohol. 97 Z a e _ m _ 1.50 E 2503 opflawafioosmanpogt A tocopflkmoumoflt m 13:83.83st 412302129 iv mo 6.9.30on ponHmEH (COCA oudmfm 98 On cooling, there was deposited 0. 162 g. (95.4%) of white crystals, m. p. 226-2270. This material in a mixture melting point with authentic methylamine hydrochloride showed no depression. The solution, from refluxing, was extracted continuously (4 hours) with ether, acidified with dilute hydrochloric acid and again extracted continuously (24 hours) with ether. The ether was evaporated and the residue recrystallized from water to give 0. 066 g. (33. 6%) of isopropyl- idenesuccinic acid (XX), m.p. 164-165o (lit. value (21), 161. 5-1620). 14. Preparation of Isopropylidinesuccinimide (XI) The method of decarboxylation was the same as described previously for the preparation of XVII. From 2. 27 g. (0. 01 mole) of V1, when heated to 1680 for one minute, there was obtained 0. 59 g. (42.. 2%) of XI, m.p. 166-1670. The product was purified by recrystallization from water and gave a positive Baeyer test for unsaturation. A_nal. .Calcd. for C7H9NOZ: C, 60.42; H, 6.52; N, 10.07. “ Found: c, 60.40; H, 6.60; N, 10.00. 15. Isolation of Potassium 2,4-dioxo-6fi-dimethy1-3-azabicyclo- i3. 1. O]hexane-l, 5-dicarboxy1ate (V). To a 100-ml. round-bottomed flask fitted with a reflux condenser Was added 1. 7 g. (0. 01 mole) of I and 40 m1. of 2N potassium hydroxide. The resulting solution was refluxed for 20 minutes, cooled and evaporated to dryness in a stream of air. The residue was transferred to a Soxhlet and extracted with anhydrous methanol for 30 hours. The insoluble material V. 2. 5 g. (82. 7%), was obtained. The same material was prepared in an analogous manner by treating H with a 2N potassium hydroxide solution. Acidification of the salt, prepared either way, gave 11. The infrared Spectrum is shown invFigure III. 99 G. Hydrobrsis of 1, l, 2, 2-TetracyanoppiroL2, 4B16ptane (XXIV) 1. Preppration of Methyl 2-carboxamido-1, 2-(N-methyl)-dicarbox- imidoppiroj}, 41heptane-1-carboyy1ate (XXIX) The procedure used for the preparation of X11 was used in the preparation of XXIX. The physical properties of XXIX are summarized in Table V. . Its n.m. r. spectrum is shown in Figure XIV. 2.. Preparation of 2-(N-Methyl)-carboxamido-1, 2-dicarboximidospiro- L2, flheptane-l-carboxylic acid (XXX) The procedure used was analogous to the one used for the preparation cfXIII. The product was purified by recrystallization from methanol and was obtained in 80.6%yield, m.p. 180-181° (dec.), N.E. 133.3 (theory 133. 12). A_na_1_. Calcd. for C12H16N205: C, 54.13; H, 5.30; N, 10.52. Found: C, 54.43; H, 5.10; N, 10.54. XXX could also be prepared from the cyanosubstituted cyclopropane- carboximide (XXXI). The procedure used was the same as the one described for the preparation of XIII. The product was purified by re- crystallization from water and was obtained in 62% yield, m. p. 180-1810 (dec.). This material did not depress the melting point on admixture with an authentic sample . 3. Preparation of Methyl 2-(N-methyl)-carboxamido-1, 2-(N-methjl)- dicarboximidospiroLZ, 41pentane—1-carboxylate (XXXII) When 0. 26 g. (0. 001 mole) ofXXX dissolved in 5 m1. of absolute methyl alcohol was treated with an excess of ethereal diazomethane in the same manner as described for the preparation of XII, there was obtained 0.27 g. (93.1%) of XXXII, m.p. 118-119°. . Its infrared spectrum is shown in Figure XXXVI. £111. Calcd. for C14H1§N205: C, 57. 13; H, 6.16; N, 9.52. ' Found: c, 57.25; H, 6.02; N, 9.48. 100 S o m H ._ _ .Too 8.. Exxon ouwH>xonudo t d tocmumoflv . Naosamopfigfixonsmofip u Aggpoatzv 1N . H topwgmxonud01 Agguogtzv 1N TEN—o2 mo 8330on posdnmfi .CCCCm onsmwh 101 4. Preparation of Spiro[2, 4jheptane-1, 1, 2, 2-tetracarboxylic acid (XXXIII) and Methyl spircLZ, 4]heptane- 1, 1, 2, 2-tetracarb<)}_ylate (XXXIV) When XXXII was hydrolyzed with 10% sodium hydroxide as described in the hydrolysis of XV, the tetraacid (XXXIII) obtained was not analyzed but was converted to its tetramethyl ester (below) for analysis. After the volume of solvent (ether extract) had been reduced the solution was treated with an excess of ethereal diazomethane as previously described. The product was purified by recrystallization from methanol and was obtained in 63. 1% yield (based on XXXII), m.p. 103-104°. The infrared spectrum is shown in Figure XV. inil. . Calcd. for C15H2003: C, 54.87; H, 6.14. Found: C, 55.01; H, 6.23. 5.. Preparation of 1, 2-dicarboximidospiro[2, 4]heptane-1, 2-dicar- boxylic acid (XXVI) and Methyl 1, 2-(N-methyl)-dicarboximido- Spiro[2, 41heptane- 1, 2-dicarboxylate (XXVII) When 1. 26 g. (0. 005 mole) of XXV was hydrolyzed in the same manner as 11, there was obtained 0. 99 g. of product, m.p. 135-136. 50 (dec.). Numerous recrystallizations from ethyl acetate-pentane did not alter the melting point. Upon treatment with an excess of ethereal diazo- methane, as described previously, the methyl ester XXVII was obtained in 83. 5% yield (based on crude acid), m.p. 101-1020. Its infrared spectrum is shown in Figure XIII. £2.11. . Calcd. for C14H17N06: C, 56.94; H, 5.80; N, 4. 74. Found: C, 56.73; H, 5.85; N, 4.78. 6. Preparation of 4-Carboxamido-3-cyclopenpylidenesuccinimide (XXXV) The decarboxylation of XXV was carried out in the same manner as described for 11. The product was purified by recrystallization from water and was obtained in 88.9% yield, m.p. 137-1380. This material gave a positive Baeyer test for unsaturation. 102 Anal. -Calcd. for C10H12N203: C, 57.68; H, 5.81; N, 13.46. Found: C, 57.79; H, 5.68; N, 13.38. 7. Preparation of 4-Carboxamido-3-cyclppentylidene-1-methy1- succinimide (XXXVI) When 0. 21 g. (0. 001 mole) of XXXV in 5 m1. of absolute methyl alcohol was treated with an excess of ethereal diazomethane, as described previously, there was obtained 0.16 g. (72.3%) of XXXVI, m.p. 148.5-1490. Its infrared spectrum is shown in Figure XXXIX. £1111. Calcd. for C11H14NZO3: C, 59.44; H, 6.35; N, 12.61. Found: C, 59.51; H, 6.26; N, 12.77. 8. Preparation of 4-(N-Methyl)-carboxamido-3-cyclopentylidene- succinimide (XXXVII) The procedure used for the preparation of XXXVII was analogous to that described for the preparation of XXII. The product was purified by recrystallization from water and was obtained in 92.4% yield, m. p. 0 . . . . . 131-132 . This material gave a p051t1ve Baeyer test for unsaturation. The infrared spectrum is shown in Figure XXXVH Anal. Calcd. for C11H14NZO3: C, 59.44; H, 6.35; N, 12.61. Found: C, 59.30; H, 6.28; N, 12.70. 9. Preparation of 4-(N-Methyl)-carboxamido-3-cyc10penty1idene- l-methyl succinimide (XXXVIII) The method used for the preparation of this compound was the same as described for the preparation of XXIII. The product was purified by recrystallization from methanol and was obtained in 71. 5% yield, in. p. 93. 3-940. The infrared spectrum is shown in Figure XXXVIII. -_A_na_1_. Calcd. for c,,H,6N,o3; C, 61.08; H, 6.82; N, 11.68. Found: C, 60.80; H, 6.80; N, 11.79. 1’0 3 Ma .azomo 5 Sac/XXXV opMEwswooDmonopflrwucomoaouwo1mtopwgmxooflamv Lassogtzvtv mo 83300an poussmfl .H>XXN onsmmh 104 MA HA 0 N. Ln 1.80 E figxxfi opflgfifioodm 1:38.. A .. ocopflcficomofioumot m topflEMXOQsmo 13>£uozazve¢ mo 55:0on posmuwcH JEN/XXX oudwfim m 105 _ d _ 1 .azomo 8.1 £3033 63888683568;-odoonfidoa toHorwothoEmeonsmUtc Ho 8330on pounds: .XHNXX ondwfim 106 .azomo on 53 83838:... nonopflcwmofimofl mo Edsuuomm “60.33de .AN oudmfim j 107 H. Hydrolysis of Tetranitriles from Aliphatic andyéfiromatiychldEhydes 1. Hydrolysis of 3-Methy_l-1, 1, 2, 2-tetrapyanocyclopropane (LIV) When a solution of 2. 5 g. (0.016 mole) of LIV in 30 m1. of 25% potassium hydroxide and 40 m1. of methanol was refluxed for 3 hours and worked up in the same manner as described for the preparation of 11 an acidic material (2.80 g.) was obtained. This material was extremely soluble in ether and in water. .After several recrystallizations from water the material melted 214-2170 (dec.) and gave a negative test for nitrogen. The n.m. r. spectrum (DMSO) showed the absence of the imide or the amide group. {2131. .Calcd. for C611907: C, 37.30; H, 4.67. Found: C, 36. 12, 36.03; H, 4.51, 4.56. The same product was obtained when the tetranitrile (LIV) was hydrolyzed according to the procedure of Wideqvist (2). In either case additional rec rystallizations did not elevate the melting point. 2. Hydroylysis of 3-n-Ethyl- and 3-isp—Propy1-1, l, 2, 2—tetra- cyanocyc10prppane (LV and LVI) When (LV) and (LVI) were hydrolyzed in methanol or according to the procedure of Wideqvist (2) as described for (LIV) nitrogen-free acidic materials were obtained. The product(s), in each instance, was extremely soluble in water and in ether and could not be obtained pure after several rec rystallizations from water . 3. Preparation of 2, 4-Dioxo-6-phglyl-3-azabicycloj3. 1. O]hexane- 1, 5-dicarboxylic acid (XLVII) To a 50-ml. round-bottomed flask was added 2. 16 g.. (0. 01 mole) of (LXV) and 40 m1. of 2N potassium hydroxide. The resulting solution was refluxed for 20 minutes, cooled, acidified to Congo Red with dilute hydrochloric acid solution and again cooled. Removal of the solid by filtration gave 1. 37 g. (50%) of XLVII, m.p. 238-2390 (dec.). The n.m. r. spectrum is shown in Figure XVIII. 108 Anal. Calcd. for C13H9N06: c, 56.73; H, 3.30; N, 5.09. * Found: C, 56.77; H, 3.29; N, 5.12. 4. Preparation of 6-Hydroxy-4joheny1pyridone-3, 5-dicarboxylic acid hydrate (XLVIII) To a 50-ml. round-bottomed flask was added 2. 16 g. (0. 01 mole) of QXLV, and 40 ml. of 2N potassium hydroxide. The reaction mixture darkened on warming and after refluxing 20 minutes it was cooled and acidified to Congo Red with dilute hydrochloric acid. During the addition of the acid a dark precipitate began to separate. After cooling the mixture was filtered and the filtrate extracted continuously with ether for 24 hours. The yellow ether extract was treated with Norite and evaporated to dry- ness. The residue was dissolved in dilute hydrochloric acid, cooled and filtered to give 1.95 g. (66.5%) of XLVIII, m.p. 223-225° (dec.). Several recrystallizations from dilute hydrochloric acid gave pure crystals, m.p. 228-2290 (dec.). The n.m. r. spectrum is shown in Figure XIX. '_A_n_a_._l_. Calcd. for C13H11N07: C, 53.25; H, 3.78; N, 4.77. Found: c, 53.40;H, 3.84; N, 4.94. 5. Preparation of Methyl 2, 4-dioxo-3-methy1-6-pheny1-3-azabigclo- Q 1. O]hexane-l, 5-dicarboxy1ate (XLVI) The procedure was similar to the one previously described. To 0. 59 g.. (0. 0021 mole) of XLVII: dissolved in 5 ml. of anhydrous methyl alcohol and cooled to 0 to 50 was added an excess of ethereal diazomethane. The excess solvent and reagent were removed on a steam bath. Recrystal- lization from methyl alcohol gave 0. 58 g. (80%) of .XLVI, m.p. 141—141. 5°. The infrared spectrum is shown in Figure XVII. The n.m. r. spectrum‘is shown in Figure XVIII. fin_a__l_. .Calcd. for cmH15N06; C, 60.56; H, 4.76; N, 4.41. Found: C, 60.30; H, 4.75; N, 4.46. 10.9 6.. Preparation of Methgrl 6-hydroxy-4-phepylpyridone-3, 5-di- carboxylate (XLIV) The procedure was analogous to that described above for LXVI. The product was recrystallized from methanol and was obtained in 88. 5% yield, m.p. 155-1560. The infrared spectrum is shown in Figure XX. Thein.m. r. spectrum is shown in Figure XXI. i121. .Calcd. for C15H13N06: C, 59.40; H, 4. 32; N, 4. 62. Found: C, 59.46; H, 4.27; N, 4.60. 7. Premration of 2, 4-Dioxo-6-Echloropheny1-3-azabicyclo[3. 1. 0L- hexane-l, 5-dicarboxylic acid (LII) and 3-Carboxamido-4-p-chloro- phenyl-6-hydroxypyridone-5-carb0fl1ic acid hydrate (LI) To a 50-ml. round-bottomed flask fitted with a reflux condenser was added 2. 52 g. (0. 01 mole) of L and 40 ml. of 2N potassium hydroxide. The solution was refluxed for 20 minutes, cooled and made acid to Congo Red with dilute hydrochloric acid. After cooling several hours the crystals were filtered to give, after washing and drying, 1. 13 g. of. tan crystals. The crystals were dissolved in acetone and treated with Norite. Removal of the acetone by evaporation and recrystallization from dilute hydrochloric acid gave pure crystals of LI, m.p. 248-2490 (dec.). The n.m. r. spectrum is shown in Figure.XXII. én_al. Calcd. for C13H11C1N06: C, 47.79; H, 3.39; N, 8.58. Found: C, 48.01; H, 3.41; N, 8.42. The filtrate from above was extracted continuously with ether for 24 hours. The ether extract was treated with Norite, filtered and the solvent evaporated. . Recrystallization of the residue from ether-benzene gave 1. 64 g. of brown crystals, m.p. 235-236. 50 (dec.). This material (LII) was not analyzed, but was converted to its ester (below) for analysis. The n.m. r. spectrum is shown in Figure XXIV. 110 8.. Preparation of Methyl 6-p-chlorophenyl-2, 4-dioxo-3-methy1- 3-azabicyclo[3. 1. O]hexane- 1, 5-dicarboxy1ate (LIII) The procedure was analogous to that used to prepare XLVI. The product was purified by recrystallization from methanol and was obtained in 82.8% yield (based on crude acid), m.p. 167. 5-168°. The infrared spectrum is shown in Figure XXIII. . The n.m. r. spectrum is shown_ in Figure XXIV. fl. .Calcd. for C16H14C1N06: C, 54.63; H, 4.01; N, 3.98. Found: C, 54.68; H, 4.03; N, 4.07. 1. Miscellaneous Experiments 1. Preparation of Bromomalononitrile A modification of the method of Ramberg and Wideqvist (1) was em- ployed in this preparation. During a 15 minute period, bromine (10. 2 ml. , 0. 2 mole) was added dropwise to a solution of malononitrile (6. 6 g. , 0. 1 mole) and 50 m1. of water in a 250-ml. round-bottomed flask. The reaction mixture was stirred during addition and then for an additional 10 minutes. Malononitrile (6. 6 g. , 0. 1 mole) was added and the mixture was stirred for 2 hours. .After 12 hours in the refrigerator the solid was filtered, to give, after washing with a little cold water and drying, 20. 7 g. (72. 3%) of white crystals, m.p; 64-65o (lit. value (1), m.p. 64. 5-65.1O). The n. m. r. spectrum (CHC13) showed a singlet at 4. 95 7. 2.. Attempted prgparation of 2-[2'2'3'3'-tetracyanocyclopropy1]oxirane The methods of Wideqvist (3) and Scribner (4) were tried in this preparation. To a 50-ml. Erlenmeyer flask containing 1.45 g.. (0. 01 mole) of bromomalononitrile, 10 ml. of ethanol and 1. 2 g. (0.016 mole) of glycidaldehyde was added a solution of 3. 5 g. of potassium iodide in 10 m1. of water with stirring. The reaction mixture darkened but after 2 hours no solid material was observed. After 24 hours the mixture was filtered and a dark gummy material was obtained. . Attempts to purify this material proved fruitless . The same results were obtained when 10 m1. of freshly distilled tetrahydrofuran diluted with 1 m1. of water was used in the place of ethanol. 3. Attempted Preparation of 3, 3-Dicyc10propyl-1, 1, 2, 2-tetracyano- cycloEopane The methods of Wideqvist (3) and Scribner (4) were used in attempts to prepare this compound. To a 100-ml. beaker containing 5.8 g. (0.04 mole) of bromomalonitrile, 20 m1. of ethanol and 2. 5 g. (0. 023 mole) of dicyclopropyl ketone was added a solution of 6.6 g. (0.04 mole) of potassium iodide in 8 m1. of water with stirring. .After the dark solution had been stirred for 24 hours p0 crystalline product was obtained. The above procedure was repeated using 10 m1. of freshly distilled tetrahydrofuran diluted with 1 m1. of water, 2. 9 g. (0. 02 mole) of bromo- malononitrile, 2. 5 g (0.023 mole) of ketone and a solution of 3. 3 g. (0.02 mole) of potassium iodide in 4 m1. of water. Again, no solid material was isolated. 4. Attempted Condensations with Cyclodecanone, Cyclododecanone and Cyclopentadecanone The condensation was unsuccessful with-cyclodecanone, cyclododeca- none and cyclopentadecanone. , In a typical procedure 0. 01 mole of the ketone, 0. 02 mole of bromomalononitrile in 10 m1. of ethanol was treated with a solution of 7 g. of potassium iodide in 10 m1. of water. The reaction mixture was stirred at room temperature for 24 hours and filtered. In each instance no product was isolated from the ketones above. 5. Preparation of Isopropylidenesuccinic Acid (XX) The method described by Overberger and Roberts (21) was used to prepare this compound. A mixture of 5. 8 g.. (0. 1 mole) of acetone and 21. 75 g.. (0. 125 moles) of diethyl succinate was added over 15 minutes to a refluxing solution of 4. 29 g. (0. 11 mole) of potassium in 100 m1. of 112 anhydrous t-butyl alcohol. The stirred reaction mixture was heated under reflux for 30 minutes. The solvent was removed from the reaction mixture under reduced pressure, the residue made slightly acidic to litmus with dilute hydrochloric acid and the remainder of the solvent was removed. The organic layer was dissolved in 25 m1. of ether and the aqueous layer was separated and extracted with three 25-ml. portions of ether. The combined ether solutions were washed with water and then extracted com- pletely with 10% aqueous sodium carbonate. The alkaline solution was made strongly acidic with concentrated hydrochloric acid and chilled. The organic layer was separated and the aqueous layer extracted with four 20-m1. portions of ether. The ether layers were combined with the separated organic layer, washed with water, and dried over anhydrous magnesium sulfate. After removal of the ether from the “half-acid, " a chilled solution of the residue in 10 volumes of anhydrous ethanol was treated with dry hydrogen chloride to give a 5% solution by weight. After 24 hours at room temperature, the alcohol was removed under reduced pressure. The residue was poured into an ice-water mixture and the ester layer was then extracted with four 25-ml. portions of ether and the extracts after combining with the original separation, were neutralized by washing with aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The residual diester was fractionated through a 23 x 0. 5 cm. helix packed column to give 9. 1 g. (85.1%) of product, b. p. 770 at O. 6 mm. Five grams of the pure diethyl compound were saponified in 50 m1. of refluxing 10% aqueous sodium hydroxide. .Acidification of the decolorized and filtered reaction mixture with concentrated hydrochloric acid gave the crystalline acid. Recrystallization from water gave the pure acid, m.p. 164-1650 (lit. value (21), m.p. 161.5-1620). 113 6. Preparation of IsoPropylidene succinic anhydride To a SO-ml. round-bottomed flask equipped with a side-arm for nitrogen inlet and a take-off (packed with glass wool) for gaseous outlet, there was placed 1.58 g. (0. 01 mole) of finely powdered teraconic acid (XX). The reaction flask was immersed in a mineral oil bath and the temperature raised slowly to 1800. After 10 minutes the flask was removed from the oil bath and permitted to cool to room temperature. The residue was recrystallized from carbon disulfide several times to give leaflets, m.p. 44° (lit. value (37), m.p. 44°). £3._a1.Calcd. for C7HgO3: C, 59.99; H, 5.75. Found: C, 59.89; H, 5.81. 7. Preparation of Cyclopropanecarboxaldehyde The method of Smith and Rogier (38) was used to prepare this com- pound. A solution of lithium aluminum hydride (0. 098 mole) in dry ether (125 ml.) was added slowly (30 minutes) and with stirring to cyclopropyl cyanide (25 g. , 0. 375 mole) in dry ether (110 ml.) in an apparatus cooled in a bath of dry ice-acetone and provided with a calcium chloride guard tube. Stirring was continued for 15 minutes; the cooling bath was removed and shortly (20-30 minutes) a vigorous reaction began. The cooling bath was immediately replaced; after the reaction subsided, the bath was re- moved and the mixture was stirred for 30 minutes. A small amount of hydroquinone was added, followed by cautious addition of dilute 10% sulfuric acid, with cooling, until the mixture was faintly acidic. The ether layer was removed, and the aqueous layer was extracted twice with ether. The combined ether solutions were dried over anhydrous magnesium sulfate and the product (7.9 g., 30.4%), b.p. 97—99°. n25 1.4264,, (lit. value (28), D b.p. 97.-101°) was isolated. 8. Preparation of Benzylidenemalononitrile The procedure of Corson (8) was used to prepare this compound. To a 50--ml. beaker containing 1.06 g. (0.01 mole) of benzaldehyde, 114 0. 79 g.. (0. 012 mole) of malononitrile and 13ml. of t-amyl alcohol were added two drops of piperidine. The solution became warm and red after several minutes. After 15 minutes the beaker was cooled to room temperature, the solid removed by filtration and washed with water containing a small amount of acetic acid. Recrystallization from n-propyl alcohol gave 1.48 g. (93.6%) of white needles, m.p. 83-840. (lit. value EtOH (8), m.p. 83.5-840), , )‘max 306 mu, 5 = 22,000. The n.m.r. spectrum is shown in Figure XXVI. 9. Preparation of Z-Methyl-l, 1, 3, 3-tetracyanppropane (LVIII) The procedure of Diels (39) was used to prepare this compound. To a 504ml. Erlenmeyer flask containing 3. 0 g. (0. 045 mole) of malononitrile in 30 m1. of 95% ethanol and 1. 20 g. (0.027 mole) of acetaldehyde cooled to 00 was added 6 drops of piperidine. The flask was maintained at 0 to -50 and after 8 hours the crystals were filtered, washed with ethanol and dried. Recrystallization from benzene gave 1.50 g. of LVIII, m.p. 99- 1000 (lit. value (39), m.p. 1130; (7), m.p. 92-930). .Numerous recrystal- lizations from benzene and also from ethanol failed to elevate the melting point. The n.m. r. spectrum (Figure XXXI ) showed this material to be a mixture of LVIII, malononitrile and ethylidenemalononitrile. . Ethylidenebismalononitrile (LVIII) was also prepared by a modifi- cation of the procedure described by Mariella (7). To a chilled solution of 3. 3 g. (0. 05 mole) of malononitrile and 2. 25 g. (0.05 mole) of acetaldehyde was added one drop of modified catalyst (1/3 piperidine and 2/3 dioxane). The reaction mixture was kept at 50 overnight. After 12 hours the viscous material was dissolved in 10 m1. of ethanol and kept at 0 to -50 for 12 hours. The crystals were filtered and washed with cold 95% ethanol. . Recrystallization from benzene gave 1.06 g. (27%) of white crystals, m.p. 99-1000. Again, this product was impure as indicated by its n.m. r. spectrum in ac etone- d6 . 115 10. Preparation of 2-Ethy1- 1, 1, 3, 3-tetracyan0J3_ropane (LXIX) Using the modification of the procedure described by Mariella (7), as above, LXIX was prepared in 64. 4% yield from propionaldehyde. The product was purified by recrystallization from benzene and melted 91-920 (lit. value (7), m.p. 650). The n.m. r. spectrum (Figure XXX) showed that this material was pure. £131. Calcd. for C9H3N4: C, 62.78; H, 4.68; N, 32.54. Found: C, 62.87; H, 4.59; N, 32.48. 11. Preparation of 1, 1, 3, 3-Tetracyangropane (LVII) A modification of the procedure of Diels (39) was used to prepare this compound. To a 100-m1.. Erlenmeyer flask containing 4. 0 g. (0. 06 mole) of malononitrile in 60 ml. of ethanol, 2.45 g. (0. 03 mole) of 37% formalin solution and cooled to 00 was added 2 drops of piperidine. . After standing at 0 to -50 for two days the crystals were filtered, washed with cold 95% ethanol and dried to give 1. 97 g.. (45. 6%) of white crystals, m.p. 136-1370. . Recrystallization from benzene-acetonitrile gave needles, m.p. 136.5-137° (lit. value (29), m.p. 137°). The n.m.r. spectrum is shown in Figure XXVIII. 12. Prpparation of Cyclododecanone The method of Brown (40) was used to prepare this compound. . Ethyl ether, 125 ml., and 2. 3 g. (0. 0125 mole) of cyclododecanol were placed in a 50-ml. round-bottomed flask fitted with a condenser and addition funnel. . Chromic acid solution, prepared from 1. 25 g.. (0.0042 mole) of sodium dichromate dihydrate and 0. 94 m1. (0.017 mole) of 96% sulfuric acid diluted to 7 m1. , was added to the magnetically stirred solu- tion over 15 minutes, maintaining the temperature at 25-280. . After 2 hours, the upper ether layer was separated, and the aqueous phase extracted with two 5-m1. portions of ether. The combined extracts were washed with saturated sodium bicarbonate, water, and dried over anhydrous sodium 116 sulfate. . Evaporation of the solvent yielded 1. 87 g. (87.2%) of nearly pure ketone. The ketone was recrystallized from pentane by cooling in dry ice, m.p. 61-62O (lit. value (13), m.p. 61-620). 13. Preparation of Methyl 2-carboxamido-1, 2-(N-methll)-dicar- boximidospiroié 5]octane- l -carboxylate ’ The procedure used was analogous to the one used for the prepara- tion of XII with the use of XLII in the place Of 11. .See Table V for the physical properties. The infrared spectrum is shown in Figure XLI. 14. Attempted Preparation of l, 5-dicarboxamido-2, 4-dioxo-3, 6, 6- trimethyl- 3-azabicyclo[3. 1. O]hexane To a 300-ml. Erlenmeyer flask immersed in an ice bath containing 200 m1. of anhydrous methanol was added 2. 54 g. (0.01 mole) of XII. Anhydrous ammonia gas was passed through the solution for one hour. The flask was allowed to stand in the ice bath overnight and then gradually permitted to warm to room temperature. Removal of the solid by filtration and recrystallization from methanol gave 2. 37 g. of starting material (X11), m.p. 195-1960. Another attempt was made to prepare this compound by a different procedure. . To a 125-ml- Erlenmeyer flask immersed in a salt-ice bath and containing 20 m1. of liquid ammonia was added 1. 27 g.. (0. 005 mole) of XII. The mixture was stirred magnetically overnight and the ammonia was allowed to evaporate slowly. The tan residue was recrystallized twice from methanol and melted 195-1960. This proved to be starting material. 15. Attempted Preparation of 2,4-Dioxo-6, 6-dimethy1-3-azabicyclo— i3. 1. O]hexane- 1, 5-dicarboxylic acid (V1) with Nitrous Acid To a beaker containing 1.13 g. (0.005 mole) of II and 20 ml. of 10% hydrochloric acid cooled to 0-50 in an ice bath, was added (dropwise) a . solution of 1. 5 g. of sodium nitrite in 2 ml. of water. During the addition the reaction mixture was stirred vigorously. After addition the reaction mixture was allowed to stand in the ice bath for one hour and then filtered. 117 ME Ha -—()-o‘ .3030 a: oumaswunonrhmuta techno“ . t .. to was Am .Naouamopdfiflnonpmgpt23308-2” N um osflmfm . xonhmoam {$302 mo guuuomm poumuflm HA —)r~ l—i) 118 The white‘ solid, 0.97 g. , m.p. 196-1970 (dec.), proved to be unreacted starting material (11). , An alternative method also proved fruitless. To a beaker containing 1. 13 g. (0. 005 mole) of II dissolved in 4 ml. of 10% potassium‘ hydroxide was added a solution of 0. 5 g. of sodium nitrite in 3. 5 ml. of water. To the resulting solution was. added, dropwise and with stirring, an ice cold solution of one ml. of water and 2 ml. of concentrated hydrochloric acid. After addition, 7. 0 ml. of water was added and the solution placed in the refrigerator overnight. Removal of the solid by filtration gave 0. 98 g. of starting material, m.p. 196-1970 (dec.). 16. Attempted Preparation of 2, 4-Dioxo-3, 3-dimethyl-3-azabic1clo— fl. 1. thexane- l, 5-dicarboxylic acid (V1) with Isoamyl Nitrite To a solution of 1. 13 g. (0.005 mole) of II in 50 ml. of 95% ethanol, cooled below 50, was added 3 ml. of concentrated sulfuric acid. Isoamyl nitrite (freshly distilled), 3. 5 g. , was added dropwise with stirring. . After addition the reaction mixture was stirred 30 minutes and placed in the refrigerator for 12 hours. Removal of the solid by filtration gave 0. 85 g. of starting material (11), m.p. 196-1970 (dec.). 17 . Attempted Preparation of l-Carbomethoxy-Z, 4-dioxo-3, 6, 6—tri- methyl- 3-azabigyclo[3. l .flhexane- l-carboxylic acid The method of Sperber (41) was used in this procedure. In a 3— necked flask fitted with a gas inlet tube, dropping funnel, reflux condenser and stirrer was placed a solution of Z. 54 g. (0.01 mole) of XII in 50 ml. ofiglacial acetic acid. .Anhydrous hydrogen chloride was bubbled into the solution for 7 minutes and 2. 34 g.. (0.02 mole) of freshly distilled amyl nitrite was added dropwise to the stirred solution over a period of 10 minutes. . After the addition of the amyl nitrite the solution was stirred at room temperature for 2 hours and then on the steam bath for an additional 2 hours, during which time the solution acquired a yellow color. 119 The solution was evaporated to dryness in a stream of dry air. The residue was triturated thoroughly with 10% sodium hydroxide and filtered. . The solid, 0. 6 g. , was recrystallized from methanol and melted 195-1960. This proved to be starting material. , The filtrate was made strongly acidic with dilute hydrochloric acid and extracted continuously with ether for 24 hours. The extracted mixture was filtered to give 0.98 g. of white crystals, m.p. 203-2040 (dec.). This material was identical to XIII. The filtrate was dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue, a yellow viscous oil, could not be obtained crystalline. 18. Attempted Preparation of 4-Isepropylidene:l-methyl-succinirlide- jig-carboxylic addiflithN/itrosyl Chloride The method described by Sperber (41) was used in this procedure. In a 3-necked flask fitted with a gas inlet tube, dropping funnel, reflux condenser and stirrer was placed a solution of 2.0 g.. (0. 01 mole) of XVIII in 40 ml. of glacial acetic acid. Anhydrous hydrogen chloride was slowly bubbled into the solution for 7 minutes and 2. 34 g. (0. 02 mole) of freshly distilled amyl nitrite was added drOpwise to the stirred solution over a period of 15 minutes. The solution assumed a deep red color and within 10 minutes evolution of gas was observed. .After the addition of the amyl nitrite was complete, the solution was stirred at room temperature for 2 hours and then on the steam bath for an additional 2 hours. The solvent was evaporated and the residue dissolved in 10% potassium hydroxide, decolorized with Norite, filtered and acidified with dilute hydrochloric acid. After 12 hours in the refrigerator no solid was observed. The solution was extracted continuously with ether for 24 hours. . The extract was dried over anhydrous sodium sulfate and the solvent evaporated. . No crystalline material could be obtained from the viscous yellow oil. 120 19. Attempted Iiydrolysis of 2, 4-Dioxo-5-(N-methyl)-carboxamido- 6, 6-dimethyl-3-azabicyclo[3. l. O]hexane- l-carboxylic acid (XIII). In, a 50-ml. round-bottomed flask equipped with a reflux condenser was placed 2.0 g. (0.0083 mole) of XIII and 30 m1. of 10% sodium hydroxide. The solution was refluxed for 3 hours, cooled, made acid to Congo Red with dilute hydrochloric acid and extracted continuously with ether for 24 hours. The extracted mixture was filtered to give 1. 53 g. of tan crystals, m.p. 201-2030 (dec.). Recrystallization from methanol gave white crystals of XIII, m. p. 205-2060 (dec. ). A mixture melting point with an authentic sample showed no depression. No crystalline material could be obtained from the filtrate. . SUMMARY 1. The Wideqvist reaction, which consists of the condensation of a carbonyl compound with bromomalononitrile in the presence of iodide ion to produce a tetracyanocyclopropane, was extended to cyclopropanecarbox- aldehyde, p-chlorobenzaldehyde, m-nitrobenzaldehyde, diethyl ketone, methyl n—propyl ketone, methyl isopropyl ketone and methyl cyclopropyl ketone. . However, no crystalline products were obtained from glycid- aldehyde, dicyclopropyl ketone, diisopropyl ketone, methyl t-butyl ketone, ethyl butyl ketone and di-n-amyl ketone. The reaction appeared to be subject to steric, inductive and electronic effects. 2. The Wideqvist reaction was used to prepare spiro systems from cyclobutanone, cyc10pentanone, cycloheptanone, cyclooctanone and cyclo- nonanone. The reaction failed with cyclodecanone, cyclododecanone and cyclopentadecanone. 3. The structure of the imido-acid proposed by Ramberg and Wideqvist for the initial hydrolysis product of 3, 3-dimethyl-l, 1, Z, Z-tetracyanocyclo- propane was confirmed by microanalysis, neutralization equivalent, CN COZH .CN - ~ 0 0H h f NH CN CN coNHz chemical reactions and infrared and n.m. r. data. 4. The alkaline hydrolysis of the dialkyl tetracyanocyclopropanes to imido-acids was shown to be general, whereas hydrolysis of the (mono- alkyl) tetracyanocyc10propanes derived from aldehydes showed that the path depended on the nature of the aryl or alkyl group. For example, 121 122 6s-hydroxy-4-phenylpyridone- 3», S—dicar'boxylic acid hydrate was obtained from the hydrolysis of 3-phenyl—1, l, 2, Z-tetracyanocyclo- propane. CN COZH H CN ’Lfl: ‘ 0H“ \ H20 4) ON ON COZH 5. 3, 3-Dimethyl-1, 1, 2, Z-tetracyanocyclopropane was converted to 3, 3-dimethy1cyclopropane- l, l, 2, Z-tetracarboxylic acid in a reaction sequence requiring 5 steps. N CN (cozH)2 5 steps\ >4: 7 CN (COZH)Z N A similar reaction sequence was also demonstrated with 1, 1, 2, Z-tetra- cyanospiro[2, 3]heptane. 6.. During the thermal decarboxylation of the imido-acids the cyclo- propane ring was ruptured to give derivatives of iSOpropylidene- and cyclopropylidenesuccinimide. 7. A new rearrangement was discovered during the alkaline hydrolysis (in methanol) of methyl 2, 4-dioxo-5-carboxamido-3, 6, 6-trimethyl-3- azabicyclo[3. 1. O]hexane- 1-carboxylate which gave 2, 4-dioxo-5—(N-methyl)- carboxamido-6, 6-dimethyl-3-azabicyclo[3. 1. O]hexane- l-carboxylic acid. . COZCH3 ' (3021-! o N CH3 i» "'"'—” ~40 CONHZ CONCH3 H 123 The remarkable rearrangement was also observed with 3, 3-dimethy1-3, 5- dicyanocyclopropane- 1, 2-(N-methyl)-‘-carboximide, 4, 4-tetramethylene-3, 5- dicyanocyclopropane- l, 2-(N-methy1)-carboximide and methyl Z-carbox- amido- 1 , 2- (N-methyl)-dicarboximidospiro[2, 4]heptane- 1 -carboxylate. ’ 8. The cyclopropyl hydrogens in the tetracyanocyclopropanes derived from aldehydes appeared at unusually low fields (6. 47-6. 53 Twhen R 2 alkyl and 4. 8-5. 1 ’T when R = aryl) in the n.m. r. Spectrum. CN CN ON ON An explanation in terms of the diamagnetic anisotropy of the nitrile group is suggested. During the n.m. r. examination of the bismalononitriles a new Michael-type equilibrium involving the dicyanomethyl anion was observed with Z-methyl— and Z-ethyl-l, 1, 2., Z-tetracyanopropane. H(CN)2 acetone - d6 \ i R- -H CH(CN)2, (R=CH3. Csz) This dissociation did not occur with 1, l, 2., Z—tetracyanopropane. 10. 11. 12. 13. 14. 15. 16. LITERATURE CITED . L. Ramberg and S..Wideqvist, Arkiv. Kemi, Mineral. Geol., 12A, No. £2, 12pp. (1937). . L. Ramberg and S.. Wideqvist, Arkiv.. Kemi,. Mineral. Geol. , 14B, No-3, l3pp. (1941). ..S. Wideqvist, Arkiv..Kemi, Mineral. Geol., 20B, No. 4, 8pp. (1945). R.M..Scribner, G..N. Sausen and W. W. Prichard, J. Org. Chem., Q, 1440 (1960). S. F. Birch, W. H. Cough and G. A. R..Kon, J. Chem. Soc., 119, 1315 (1921). I. Guareschi and E. Grande, Atti R. Accad. Torino, 3_3, II, 544 (1898); Chem.. Zentr. II, 439 (1899). R. P. Mariella and A. J. Roth, III, J. Org.. Chem., §_2_, 1130 (1957). B. B. Corson and R. W. Stoughton, J. Am. 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Zentr. .I, 578 (1901). R. F. Fittig and H.. Krafft, Ann., E4, 196 (1899). L. 1.. Smith and W. R. Rogier, J._Am. Chem. Soc., __3, 4047 (1951). O. Diels, H. Gartner and R..Kaack, Ber., g, 3445 (1922). H. C. Brown and C. P. Gray, J. Am. Chem. Soc., _8_3, 2952 (1961). N.. Sperber, D. Papa and E. Schwenk, J. Am. Chem. Soc., 12, 3091 (1948). 1w 7'“: .e .u CHEMISTRY LIBRARY 4". M11111) 111111 111111111111111 ”111111153 3 1293 03056 6669