Q-Der

cf. CA 55, 9299i. 1,1,2,2-Tetrasubstituted cyclopropanes were formed by the reaction of α-halo esters, nitriles, or ketones with Me methacrylate (I) or methacrylonitrile (II) in the presence of NaH.In all cases, the predominant or exclusive product isomer was that in which the activating groups, ester, nitrile, or carbonyl, were cis to each other.The effects of several variables on the yields and cis-trans isomer ratios were determinedThe previously described method of preparing 1,2-cyclopropanedicarboxylic acids by use of NaH-oil was applied.Temperature control procedures used were: (A) the flask immersed in a cooling bath (usually kept at 20-30°) and maintained at a min. temperature which allowed a slow evolution of H; (B) the mixtures kept at gentle reflux and the reaction controlled by the rate of addition of I or II; (C) the reaction allowed to warm without external heating.With the exception of the runs using Me α-bromo- and α-iodopropionates, gas phase chromatography of the products showed only one or 2 peaks corresponding to the cis and(or) trans isomers.The reaction mixtures of runs 15 and 16 and the ester or nitrile mixtures of several other runs were hydrolyzed to the acids and the isomers separatedNo attempt was made to find the best conditions.In the specific experiments, the reactants were dried over NaH and the amounts of NaH used referred to the weights dispersions 51.1% NaH-oil (run, Y of CH₂:CYMe, Z, R, X of RCHZX, procedure, % yield of RZC.CMeY.CH₂, % cis, % trans, % cis acids, and % trans acids given): 1, CO₂Me, CO₂Me, Me, Cl, A, 71, 93, 7, 72, 3; 2, CO₂Me, CO₂Me, Me, Cl, B, 69, 85, 15, -, -; 3, CO₂Me, CO₂Me, Me, Br, B, 32, 68, 32, -, -; 4, CO₂Me, CO₂Me, Me, I, B, 21, 50, 50, -, -; 5, CN, CO₂Me, Me, Cl, A, 59, 75, 25, -, -; 6, CN, CO₂Me, Me, Cl, B, 61, 73, 27, 32, 15; 7, CN, CO₂Me, Me, Br, B, 33, 53, 47, -, -; 8, CO₂Me, CN, Me, Cl, B, 0, -, -, -, -; 9, CN, CN, Me, Cl, B, 2, -, -, -, -; 10, CO₂Me, CO₂Me, Cl, Cl, C, 74, 100, 0, 90, 0; 11, CN, CO₂Me, Cl, Cl, C, 64, 80, 20, 48, 4; 12, CO₂Me, CN, Cl, Cl, C, 0, -, -, -, -; 13, CN, CN, Cl, Cl, C, 0, -, -, -, -; 14, CO₂Me, CO₂Me, Ph, Cl, C, -, -, -, 38, 0; 15, CO₂Me, Bz, Me, Cl, C, -, -, -, 35, 0.The following special cases were described.Run 1.I(10 g.), 12.3 g. Me α-chloropropionate (IV), 4.7 g. NaH, and 10 ml. PhMe left at 20-30° gave di-Me 1,2-dimethyl-1,2-cyclopropanedicarboxylate (III), b₂₂ 110-14°, n²⁶_D 1.4465.In run 2 the mixture was refluxed.In run 3 Me α-bromopropionate (V) replaced the Cl compoundIn run 4 Me α-iodopropionate (VI) was used in place of the Cl compound and the mixture refluxed.By gas chromatography about 1/3 of the distillate was unchanged iodo compoundIII was obtained in all 4 runs.Run 5.I (6.7 g.), 12.3 g. IV, 4.7 g. NaH, and 10 ml. PhMe left at 20-30° gave Me 1,2-dimethyl-2-cyanocyclopropanecarboxylate (VII), b₂₂ 88-120°, n³¹_D 1.4489.Run 6.The reaction repeated under reflux gave VII of wide distillation range, fractionated to 2 fractions.Hydrolysis of the 2 fractions gave 15% trans-diacid, and 32% cis-diacid, and showed that the low boiling fractions were almost all trans-, and the high boiling fractions cis-diacid.Run 7.V (16.7 g.) was used.Run 8.I (10 g.), 8.9 g. α-chloropropionitrile (VIII), 4.7 g. NaH, and 10 ml. PhMe refluxed gave negligible gas evolution and no product was isolated.Run 9.II (6.7 g.), 8.9 g. VIII, 4.7 g. NaH, and 10 ml. PhMe refluxed 5 hrs. evolved some gas and gave 0.5 g. distillate.1,2-Dimethyl-1,2-dicyanocyclopropane (0.2 g.) was obtained, m. 46-8° (by sublimation).Run 10.I (20 g.), 28.6 g. Me dichloroacetate (IX), 9.4 g. NaH, and 60 ml. C₆H₆ gave 30.5 g. di-Me 1-chloro-2-methyl-1,2-cyclopropanedicarboxylate, b₁₂ 106-9°, n²⁶_D 1.4581, saponified to diacid, m. 131-3.35°, converted into the anhydride and sublimed, m. 55-6.5°.Run 11.II(13.4 g.), 28.6 g. IX, 9.4 g. NaH, and 60 ml. C₆H₆ gave 22.3 g. Me 1-chloro-2-cyano-2-methylcyclopropanecarboxylate, b₁₄ 110-12°, n²⁶_D 1.4680, hydrolyzed to a mixture of diacids.Treating the mixture with Ac₂O removed the cis-diacid as anhydride and recrystallization then gave trans-diacid, m. 246-7°.Recrystallization of the crude mixture of diacids gave 48% crude cis-diacid, m. 123-34°; anhydride m. 53-5°.Run 12.I(10 g.), 11 g. Cl₂CHCN (XI), 4.7 g. NaH, and 30 ml. C₆H₆ gave tarry product.Run 13. II (6.1 g.), 11 g. XI, 4.3 g. NaH, and 30 ml. C₆H₆ failed to give 1-chloro-2-methyl-1,2-dicyanocyclopropane.Run 14. I (20 g.), 36.9 g. Me α-chlorophenylacetate, 9.4 g. NaH, and 50 ml. PhMe gave crude oily 1-methyl-2-phenyl-1,2-cyclopropanedicarboxylate, saponified to diacid.Crystallization afforded the cis-diacid, m. 157-8° (decomposition).The diacid was converted to anhydride, m. 92-3°.Run 15.I (7.5 g.), 13.8 g. α-chloropropiophenone, 3.5 g. NaH, and 7.5 ml. PhMe gave red oily ester of 1,2-dimethyl-2-benzoylcyclopropanecarboxylic acid.Saponification and extraction with Et₂O removed some neutral material.The aqueous portion acidified and extracted with Et₂O gave free acid, m. 108-10° and 129.5-31.0°.On heating the material to about 115° it melted then crystallized, m. 129-30.5°.Recrystallization from CCl₄ gave the material with the double m.p.Apparently the two substances were isomeric lactol and oxo acid.

L-Histidyl-D-phenylalanyl-L-arginyl-L-tryptophylglycine (I) was synthesized and assayed for its melanocyte-stimulating activity by three different methods.Carbobenzyloxy-L-arginine (II) (12.5 g.) in 40 cc. 4N NaOH and 320 cc. Me₂CO treated dropwise with stirring at 0° with 19 g. p-MeC₆H₄SO₂Cl in 60 cc. Me₂CO, the mixture stirred 2 hrs. at 0°, acidified to pH 5, and worked up yielded 13.5 g. N-carbobenzyloxy-G-tosyl-L-arginine (III), amorphous solid, m. 75-85°, [α]²⁵_D -1.3° (c 2, MeOH), R_f 0.40 (85:15 EtMeCHOH-10% NH₄OH, solvent A), 0.90 (4:1:1 BuOH-AcOH-H₂O, solvent B).III (1 g.) in 50 cc. MeOH and 2 cc. glacial AcOH hydrogenated catalytically, the MeOH and AcOH evaporated, the aqueous solution treated with CuCO₃ and NaHCO₃, and the product crystallized from aqueous MeOH and aqueous Me₂CO yielded 0.45 g. Cu complex of G-tosyl-L-arginine-H₂O, blue needles, m. 182-5°, decomposed at 315°, R_f 0.26-0.30 (B); the Cu salt dissolved in 5% aqueous KCN, acidified with AcOH, evaporated, and the residue carbobenzyloxylated at pH 9 gave III.II (10.4 g.) in aqueous NaOH and Me₂CO treated with dry ice to pH 8.2 and then at -10° in the usual manner with p-MeC₆H₄SO₂Cl, stirred 3 hrs. at room temperature, adjusted to pH 5 with 6N HCl, and worked up yielded 5.2 g. anhydride of III, plates, m. 156-7° (Me₂CO and EtOAc), [α]²⁴_D -10.5° (c 2, Me₂CO), R_f 0.9 (A), 0.9 (B); the mother liquors gave 2.5 g. III.III (4.62 g. and 3.1 g. L-tryptophylglycine Me ester in 100 cc. MeCN treated at 0° with 2.2 g. dicyclohexylcarbodiimide (IV) and refrigerated overnight yielded 5.75 g. α-carbobenzyloxy-G-tosyl-L-arginyl-L-tryptophylglycine (V), amorphous, [α]²⁵_D -21.8° (c 2, MeOH), R_f 0.85 (B).V (1.9 g.) in 40 cc. MeOH and 0.5 cc. glacial AcOH hydrogenated 5 days while adding fresh catalyst every 24 hrs., filtered, evaporated, the residue digested with EtOAc, dissolved in 20 cc. H₂O, stirred at 0° 10 min. with 0.5 cc. Et₃N, and filtered gave 1.07 g. G-tosyl-L-arginyl-L-tryptophylglycine Me ester (VI), R_f 0.58 (B).Carbobenzyloxy-im-benzyl-L-histidyl-D-phenylalanine (870 mg.) and 1070 mg. VI in 200 cc. Me₂CN treated 0° with 370 mg. IV and refrigerated 48 hrs. gave 340 mg. dicyclohexylurea; the filtrate yielded 1.1 g. amorphous Me ester (VII) of carbobenzyloxy-imbenzyl-L-histidyl-D-phenylalanyl-G-tosyl-L-arginyl-L-tryptophylglycine (VIII), m. 115-19° with sintering at 110°, [α]²⁶_D -26.5° (c 2, MeOH).VII (660 mg.) in 20 cc. MeOH and 1.5 cc. N NaOH kept 2.5 hrs. at room temperature, treated with 1 equivalent N HCl, evaporated, and the residue reprecipitated from MeOH with H₂O yielded 620 mg. VIII, m. 148-50° with sintering at 145°, [α]²⁶_D -23.5° (c 2, MeOH), R_f 0.45 (A), 0.84 (B).VIII (570 mg.) in 100 cc. liquid NH₃ treated with stirring with small pieces of Na until the blue color persisted, the mixture worked up, and the crude product chromatographed on Amberlite XE-64 yielded 280 mg. I, [α]²⁷_D -20° (c 1, 0.1N NH₄OH).The melanocyte-stimulating activity by the in vitro frog skin method was determined for the following compounds: I, 3.3 × 10₅; L-phenylalanyl isomer (IX) of I, 3.1 × 10⁴; L-histidyl-D-phenylalanyl-L-ornithyl-L-tryptophylglycine (X), 2.6 × 10⁴; L-phenylalanyl isomer (XI) of X, 2.9 × 10⁴.The minimal effective dose causing color change in the skin of A nolis carolinensis in vitro was determined: I 0.02, IX 0.2, X 1.2, XI 8.5.The activity in vivo in hypophysectomized Rana pipiens was determined: I 2, IX 10, X 20, XI 50.