a-Chloro-N-arylisobutyrimidyl chloride (I) reacted with ethyl sodiomalonate to afford N-aryl-2,2-dimethyl-3 carbethoxysuccinimide. This reaction seems to proceed in a different mechanism from that of the synthesis of tetronic acids(2) and is supposed to involve a primary attack of the carbanion at the a-carbon atom of the chloride followed by the cyclization

Ohmura, Yutaka

Takeda, Akira

Wada, Satosi

Okayama University Digital Information Repository

Reaction of α-Chloro-N-arylisobutyrimidyl Chloride with Ethyl Malonate(1)

Okayama University Scientific Achievement Repository

MEMOIRS OF THE SCHOOL OF ENGINEERING, QUYAMA UNIVERSITY, Vol. 1, No.1, MARCH, 1966Reaction of a-Chloro-N-arylisobutyrimidyl Chloridewith Ethyl Malonate!)Akira TAKEDA, Satosi WADA, and Yutaka OHMURA*Department of Industrial Chemistry(Received November 20, 1965)a-Chloro-N-arylisobutyrimidyl chloride (I) reacted with ethyl sodiomalonateto afford N-aryl-2,2-dimethyl-3-carbethoxysuccinimide. This reaction seems toproceed in a different mechanism from that of the synthesis of tetronic acids2)and is supposed to involve a primary attack of the carbanion at the a-carbonatom of the chloride followed by the cyclization.It has been known that a-chloroacetyl chloridereacts with ethyl sodiomalonate to give a-car-bethoxytetronic acid.2) The reaction probablyinvolves the nucleophilic attack of carbanionderived from malonate upon the carbonyl carbonof a-chloroacetyl chloride followed by the ringclosure of the condensation product.Based on the fact that the treatment of a-chloro-N-arylisobutyrimidyl chloride with waterleads to the formation of a-chloro-N-arylisobutyr-amide and hydrochloric acid,3) it might beassumed that the carbonyl carbon of I should beenough reactive to undergo nucleophilic attackof malonic ester anion. The reaction of I (R =CaH5, P-CI-CaH4, P-CH3-CaH4) with ethyl sodio-malonate was attempted by the authors in orderto prepare imino derivatives (VI) related totetronic acid, however, the sole product isolatedand identified in this reaction was a succinimidederivative, which was not expected from theabove assumption. The present report describesand discusses the result of the reaction, exem-plified by the reaction sequence of a-chloro-N-(p.chlorophenyl) isobutyrimidyl chloride (Ia) asshown in Scheme I.CHaR-N=C-C/ I (Ia: R=P-CI-CsH4-)I , "-Cl Cl CHaThe reaction of Ia with ethyl sodiomalonatein the excess of ethyl malonate at 120-1300afforded colorless crystals (II) of m. p. 80-81 0 ,whose analytical values correspond to the molec-ular formula of CI5Hla04CIN. The infraredspectrum of II exhibits three carbonyl bands at1785, 1740, and 1710 cm- t • When treated with* Kurasiki Rayon Co., Ltd., Kurasiki, Japan47concentrated hydrochloric acid at 1000 , II wasreadily hydrolyzed to give the correspondingcarboxylic acid (III). When heated above itsmelting point, III was easily decarboxylated togive colorless crystals (IV) of m. p. 69-71 0 •The infrared spectrum of IV shows absorptionbands at 1770 and 1705 cm- I for the cyclic imidecarbonyl group.4) Principal features of the n. m.r. spectrum of IV taken in chloroform were aC-methyl singlet ('t' 8.85) and a carbonyl-meth-ylene singlet ('t' 7.40).From these data together with the correctanalysis the structure of N-arylsuccinimide de-rivatives rather than the lactones has now beenassigned to IV. The identity of both infraredspectrum and melting point of IV with those ofauthentic sample prepared from a, a-dimethyl-succinic anhydride and p.chloroaniline sub-stantiates the structure.The reaction of Ia with methyl sodiomalonate,carried out in the same manner as with ethyIester, gave colorless crystals (V), m. p. 101-1030 • which was shown identical with meth·ylation product of III, by means of infraredspectra (1735 em-I for ester carbonyl group;1780 and 1710 cm-I for cyclic imide carbonylgroup). All these data and the reaction sequencesupport the structure of N-(p-chlorophenyl)-2,2-dimethyl.3-carbethoxysuccinimide for the prod-uct II. N-ArYI-2, 2 -dimethyl- 3 -carbethoxysuc-cinimides obtained similarly are listed in TableI.The mechanism of the reaction is postulatedin Scheme II to fit the formation of II whichsuggests the primary attack of ethyl malonateanion on a-carbon atom of I, followed by thecyc1ization to an intermediary lactone and theinternal rearrangement to II.48 A. TAKEDA, S. WADA and Y. OHMURASCHEME I(Vol. 1,ClbCI-O~N=C-C/ ----+-=! I I" NaCH(COlC2H5)2Cl CI ClbIa~ /ClbC-C"CI-Q-~N/ I Clb- "C - CHCOlC2H5IIoIIHCIo ClbII /C-CCI-Q-N~ I"CH3C-CHC02ClbIIov4-o Clb\I /C-C"CI-Q-N( I Clb- C-CHC02HIIoIIIIVCH3CI-Q-'\N=C-C/- I I"HC 0 CH3/,,/C2H5OC C11 IIo 0VI TABLE IN.Aryl.2,2-dimethyl.3-carbethoxysuceinimidet>o ClbII /C-CR-N~ I"CH3C-CHCOAH5\IoIYield,IAnalyses, %IIR absorption em- lR B. p. (m. p. ), °c.I I I% C H N (C=O)0;& 178-180/3.5mm. 37.2 Calcd. 65.44 6.22 5.09 1785 (w), 1710 (5),Found 65.46 6.68 4.94 1740 (shoulder)P-CHa-O;H4 187-190/3.5mm. 38.6 Calcd. 66.42 6.62 4.84 1785 (w), 1710 (s),Found 66.43 6.82 4.75 1740 (shoulder)p-Cl-O;H4 (80-81) 38.8 Caled. 58.11 5.28 4.52 1785 (w), 1710 (s),Found 58.30 5.27 4.56 1740 (shoulder)a All the compounds listed here are new.1966) ReacJioll of a-Chloro-N-ary/isobutyrimidyl ChlorideSCHEME IIExperimental**The following experiments illustrate themanner in which the reaction was carried out.Starting Materials. - N-(p-Chlorophenyl)-isobutyramide*** was prepared by the reactionof isobutyryl chloride and p-chloroaniline inbenzene (Yield 88.8%, m. p. 150-151°. Anal.Calcd. for CloH1ZCINO: C, 60.76; H, 6.12;N. 7.09. Found: C, 61.01; H, 6.22; N, 7.14.).a-Chloro-N-(p-chlorophenyl)isobutyrimidyl chlo-ride*** (B. p. 158° /18 mm. Anal. Calcd. forCloHloClaN: C, 47. 93; H,4.02; N,5.60. Found:C,48.52; H, 4.Z0; N, 5.71.) and a-chloro-N-(P-tolyl) isobutyrimidyl chloride*** (B. p. 147°/17mm. Anal. Calcd. for ClIHlaClzN: C, 57.41;H, 5.69; N, 6.09. Found: C, 57.25; H, 5.77;N, 6.39.) were obtained by the procedure de-scribed for the preparation of the phenyl deriva-tive,a) in good yields (80-90 %).Reaction of a-Chloro-N-(p-chlorophenyl)isobutyrimidyl Chloride (Ia) with Ethyl Ma-lonate - To a stirred solution of 3.4 g. (0.148mole) of sodium dissolved in 71 g. (0.444 mole)of ethyl malonate was added 18.8g. (0.074 mole)of a -chloro -N-(p -chloropheny1) isobutyrimidylchloride at 120-130°. The mixture was stirredat room temperature for 5 hr. and was allowedto stand for overnight. The reaction mixture,after the addition of water, was extracted withether. The ether extract was washed with waterand dried over anhydrous sodium sulfate. Afterthe removal of solvent under reduced pressure, athick oil remained. This was fractionally distilled,collecting 8.9 g. (38.8 %) of heavy oil boiling at188-190° (1. 5 mm.). After a while this oil (II)** All melting points are uncorrected.*** New compound.solidified and was recrystallized from n-hexane,m. p. 80-81 0.Anal. Calcd. for CI5H1SCIN04: C, 58.11; H,5.28; N, 4.52. Found: C, 58.30; H, 5.27; N,4.56.Hydrolysis and Decarboxylation of 11.-A mixture of 1.2 g. (0.004 mole) of II and 10 m!.of concentrated hydrochloric acid was vigorouslystirred under reflux for 5 hr. Upon cooling toroom temperature, the mixture solidified to give1.0 g. (88.5 %) of III. III dissolved in aqueoussodium hydrogen carbonate.A mixture of 0.5 g. (0.0018 mo~e) of III and0.05g. of potassium hydrogen sulfate was heatedfor 10 min. at above its melting point and therewas obtained as neutral substance, 0.2 g. of a,a-dimethyl-N-(p-chlorophenyl)succinimide (IV),m. p. 69-71 0 •Anal. Calcd. for ClzH1ZClNOz: C, 60.63;H, 5.09; N, 5.89. Found: C, 60.69; H, 5.05;N,6.05.Esterification of N-(p-chlorophenyl) -2,2-di-methyl-3-carboxysuccinimide (III) with Di-azomethane. - A solution of 0.5g. (0.0018mole) of III in 10 m!. of ether was treated withan excess of diazomethane in 30 m!. of ether andallowed to stand at room temperature for over-night. The ether solution was extracted withfaturated sodium hydrogen carbonate, washedwith water and dried over anhydrous sodiumsulfate. After the removal of solvent, an oilremained, which, on standing, solidified andwas recrystallized from n-hexane to give methylester of III (V), m. p. 99-101 0 •Anal. Calcd. for C14H14ClN04: C, 56.86; H,4.77; N, 4.74. Found: C, S7.09; H, 4.84; N,4.47.50 A. TAKEDA, S. WADA and Y. OHMURAReaction of a-ChIoro-N-(p-chloropheny1)-isobutyrirnidyl Chloride (Ia) with MethylMalonate. - This reaction was carried out inthe same manner as with ethyl malonate, usinglAg. (0.06 mole) of sodium, 23.8g. (0.18 mole)of methyl malonate and 7.5 g. (0.03 mole) of I,yield 2.2 g. (24.8 %), b. p. 195-203° (2.5 mm.).On standing it solidified and was recrystallizedfrom n-hexane, m. p. 101-103°.Anal. Calcd. for C14H14CIN04: C, 56.86; H,4.77; N, 4.74. Found: C, 56.96; H,4.76;N,4.58.References1) Presented at the 18th Annual Meeting of the Chemi-cal Society of Japan, Osaka, April 3, 1965.2) E. Benary: Ber. 40, (1907) 1079.3) J. v. Braun, F. Jostes and W. Munch: Ann. 453,(1927) 127.4) K. Nakanishi: .. IR Absorption Spectroscopy-Practical", Nankodo, Tokyo, 1960, pp. 52.

Reaction of α-Chloro-N-arylisobutyrimidyl Chloride with Ethyl Malonate(1)

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