+++Helv. chim. Acta. thanks suprachemister

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Dear colleagues,

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FYI, this article is not indexed in Web of Knowledge, but this issue is.

[suprachemister]

Novel, mild procedure for the preparation of reactive carboxylic acid esters and their use as acylating agents
By Glatthard, R.; Matter, M.
From Helvetica Chimica Acta (1963), 46, 795-804. Language: German
[cut]Reactive esters of carboxylic acids were prepd. from the carboxylate ions with carbonic acid esters or hemiester chlorides of acidic phenols. The resulting esters, particularly the 2,4-dinitrophenyl esters of carbobenzyloxyamino acids, are well suited for peptide syntheses since their aminolysis proceeds very rapidly under mild conditions and since the liberated 2,4-(O2N)2C6H3OH can be removed readily; optically active carbobenzyloxyamino acids are not racemized in this reaction sequence. p-O2NC6H4OH (120 g.) in 480 cc. C6H6 and 96 g. C5H5N treated dropwise with stirring during 2 hrs. with 200 g. 20% COCl2-MePh, stirred 4 hrs., kept overnight, dild. with 3 l. CHCl3, washed with 150 cc. concd. HCl, 200 g. ice, 2N aq. NaOH, and 50 cc. concd. HCl, and evapd. yielded 86.0 g. (p-O2NC6H4O)2CO (I), prisms, m. 118-22° with the loss of C6H6, remelting at 142-3°. 2,4-Cl2C6H3OH (71.7 g.) gave similarly 30.2 g. (2,4-Cl2C6H3O)2CO (II), needles, m. 97-8° (EtOH). (PhO)2CO (97 g.) added during 3 hrs. with stirring to 500 g. H2SO4.H2O and 500 g. 98% HNO3 below 5°, stirred several hrs., kept 2 days at room temp., poured onto 3 kg. ice, and filtered yielded 160 g. [2,4-(O2N)2C6H3O]2CO (III), m. 148° (C6H6). BzOH (2.44 g.) in 25 cc. C5H5N treated with 2 g. p-O2NC6H4O2CCl (CO2 evolution) and then 5 hrs. with a stream of N, dild. with 100 cc. CHCl3 and ice, and worked up in the usual manner yielded 2.1 g. p-O2NC6H4OBz (IV), m. 142°. BzOH (2.44 g.) in 25 cc. HCONMe2, 2.78 cc. Et3N, and 3.8 g. I treated 2 hrs. at room temp. with a stream of N and worked up gave 2.4 g. IV, m. 142-3° (EtOH); a similar run in 30 cc. C5H5N (instead of HCONMe2 and Et3N) heated 2 hrs. at 60-70° also gave IV. Hippuric acid (V) (1.97 g.) in 15 cc. C5H5N treated with N and 1.9 g. I and heated 1.25 hrs. at 75° yielded 1.1 g. p-nitrophenyl hippurate, m. 170-3° (EtOH). PhCH2O2CNHCH2CO2H (1.05 g.) in 10 cc. C5H5N treated under N with 0.95 g. I and heated 2 hrs. at 80° yielded 0.8 g. p-O2NC6H4O2CCH2NHCO2CH2Ph, m. 125-6° (EtOH). BzOH (2.14 g.) and 2.9 g. II in 20 cc. C5H5N heated 2 hrs. at 90° under N gave 1.9 g. 2,4-Cl2C6H3OBz, needles, m. 93.5-94° (EtOH). BzOH (1.2 g.) and 1.5 g. III in 20 cc. C5H5N yielded during 0.5 hr. at 20° 1.1 g. 2,4-(O2N)2C6H3OBz, m. 131° (EtOH), which was also obtained in 94% during 0.5 hr. from equimol, amts. BzOH and III. Et3N.BzOH in HCONMe2 during 15 min. or in tetrahydrofuran during 4 hrs. also gave 2,4-(O2N)2C6H3OBz. BzCH2CO2Et (48 g.), 18 g. (CH2OH)2 and 150 cc. C6H6 refluxed 15 hrs. with a catalytic amt. of p-MeC6H4SO3H with the azeotropic removal of H2O, washed, evapd., and distd. gave 34.4 g. ethylene ketal (VI), b0.02 106-8°. VI (25.7 g.) in 120 cc. MeOH refluxed 1 hr. with 6.73 g. KOH in 30 cc. H2O, concd., dild. with 70 cc. H2O, washed with 100 cc. Et2O, acidified weakly with stirring with 2N HCl under 200 cc. Et2O, the aq. phase extd. with Et2O, and the combined Et2O solns. evapd. below 400 yielded 18.8 g. henzoylacetic acid ethylene ketal (VII), m. 92-3° (Et2O-petr. ether). VII (2.08 g.) in 20 cc. C5H5N treated at 20° with 3.74 g. III, kept 2 hrs. at room temp., dild. with 50 cc. CHCl3 and ice, and worked up in the usual manner yielded 1.9 g. 2,4-dinitrophenyl ester of VII, needles, m. 112-13° (1:1 C6H6-petr. ether). 1,2-(m-HO2CC6H4N:N)C10H6OH (VIII) (1.8 g.), m. 243-5°, in 10 cc. C5H5N treated at room temp. with 2 g. III and filtered after 2 hrs. gave 1.7 g. 2,4-dinitrophenyl ester of VIII, m. 219-22° (C5H5N and HCONMe2). V (2.07 g.) in 30 cc. H2O and 1.37 cc. Et3N shaken 0.5 hr. with 3.9 g. III and 30 cc. CHCl3, dild. with 20 cc. CHCl3, and worked up gave 1.5 g. 2,4-dinitrophenyl ester of V, m. 116° (EtOAc or C6H6. PhCH2O2CNHCH2CO2H (IX) (2.3 g.) in 25 cc. H2O and 1.5 cc. Et3N shaken 4 hrs. with 3.94 g. III, and the CHCl3 phase worked up gave 3.0 g. 2,4dinitrophenyl ester (X) of IX, m. 94° (1:1 EtOAc-petr. ether), which was also obtained in about the same yield in HCONMe2 during 15 min. at 25° or 14 hrs. at 0°. Carbobenzyloxy-DL-phenylalanine (XI) (3.3 g.) in 30 cc. CHCl3 and 1.5 cc. Et3N treated with stirring with 3.94 g. III, shaken after 1 hr. with K phosphate buffer'(pH 8.5) until the yellow color disappeared, and worked up yielded 4.3 g. 2,4-dinitrophenyl ester (XII) of XI, m. 115° (4:1 C6H6-ligroine). L-XI (0.825 g.), m. 85-7°, and 0.262 g. Et3N in 8 cc. CHCl3 treated with cooling with N and slowly with 0.985 g. III, kept 1 hr. at 20°, and worked up yielded 1.1 g. 2,4-dinitrophenyl ester (XIII) of L-XI, m. 108-9° (1:1 EtOAc-petr. ether), [α]26D -42.6 ± 1.5° (c 1.4895, EtOH). 2,4-(O2N)2C6H3OBz (XIV) (2.9 g.) and 1.6 g. 2-C10H7OH in 20 cc. C5H5N kept overnight at room temp. with 3.7 g. Bu3N, treated with 3 cc. Et2NCH2CH2NH2, poured after 15 min. onto 40 g. crushed ice and 20 cc. concd. HCl, and extd. with Et2O yielded 2.38 g. 2-C10H7OBz, m. 106° (EtOH). p-HOC6H4N:NPh (2.0 g.) in 20 cc. CHCl3 and 2 g. Et3N treated dropwise with stirring with 2.9 g. XIV, 1 cc. HCONMe2, and 10 cc. CHCl3, kept 0.5 hr., dild. with 50 cc. CHCl3, and worked up yielded 2.5 g. p-PhN:NC6H4OBz, orange crystals, m. 138° (EtOH and ligroine). X (1.13 g.) and 0.417 g. H2NCH2CO2Et.HCl (XV) in 20 cc. CHCl3 treated dropwise with stirring during 0.5 hr. with 0.83 cc. Et3N in 20 cc. CHCl3, kept 2 hrs. at room temp., and worked up gave 0.8 g. PhCH2O2CNHCH2CONHCH2CO2Et (XVI), leaflets, m. 80-1° (C6H6-ligroine). IX (1.15 g.) in 10 cc. HCONMe2 and 0.74 cc. Et3N treated with 2 g. III in small portions and the mixt. treated with cooling with 0.7 g. XV and then dropwise with 1.4 cc. Et3N gave 1.25 g. XVI, m. 78-80° (MeOH). Acetyl-L-leucine (1.9 g.) and 3.94 g. III in 20 cc. HCONMe2 treated with N and during 0.5 hr. with 1.45 cc. Et3N, kept 15 min., treated with 2.1 g. XV and then during 15 min. with 4.14 cc. Et3N, dild. with 50 cc. CHCl3, and worked up yielded 1.7 g. Ac-DL-Leu-Gly-OEt, m. 120-20.5°; complete racemization had occurred. Carbobenzyloxy-L-leucine (XVII) (2.91 g.) and 0.87 g. C5H5N in 30 cc. CHCl3 treated with 3.94 g. III at 0° kept 2 hrs. at room temp. with occasional shaking, and worked up, the resulting oily 2,4-dinitrophenyl ester (4.2 g.) of XVII in CHCl3 added at 0° to 2.1 g. XV, 3.03 g. Et3N, and 20 cc. CHCl3, and the mixt. dild. after 15 min. with CHCl3 and worked up yielded 3.1 g. Et carbobenzyloxy-L-leucylglycinate, m. 103° (EtOH), [α]26D -25.5 ± 1.5° (c 1.5687, EtOH). XII (230 mg.), 70 mg. XV, and 10 cc. CHCl3 stirred 3 hrs. with 100 mg. Et3N in 10 cc. CHCl3, dild. with CHCl3, and worked up gave 180 mg. carbobenzyloxy-DL-Phe-Gly-OEt (XVIII), m. 100° (EtOAc-petr. ether). XV (290 mg.), 303 mg. Et3N, and 4 cc. CHCl3 treated at 0° with 465 mg. XIII, kept 0.5 hr. at room temp. with occasional shaking, dild. with CHCl3, and worked up yielded 382 mg. L-isomer of XVIII, m. 111-13° (EtOAc-petr. ether), [α]25D -16.7 ± 1.5° (c 1.4954, EtOH). Carbobenzyloxy-Gly-L-Phe-OH in 5 cc. HCONMe2 and 95 mg. C5H5N treated with cooling with N and 390 mg. III, kept 0.5 hr. without cooling, cooled to 0°, treated with 143 mg. XV and then 174 mg. C5H5N, treated 0.5 hr. at room temp. with N, dild. with 30 cc. CHCl3, and worked up gave 200 mg. carbobenzyloxy-Gly-DL-Phe-Gly-OEt, m. 132° (abs. EtOH), and addnl. crops, m. 130-2° 129-30°, and 128-30°.[/cut]