Ruthenium Tetroxide Oxidation of N-Acylated Alkylamines: A New General Synthesis of Imides1)

Transcription

1 Ruthenium Tetroxide Oxidation of N-Acylated Alkylamines: A New General Synthesis of Imides1) KEN-ICHI TANAKA,* SHIGEYUKI YOSHIFUJI, and YOSHIHIRO NITTA School of Pharmacy, Hokuriku University, Kanagawa-machi, Kanazawa , Japan (Received September 1, 1986) Oxidation of various N-acylalkylamines with ruthenium tetroxide (RuO4) was systematically investigated. N-Acylalkylamines having an electron-donating group at the ƒ - or ƒà-position with respect to amide nitrogen or an electron-donating alkyl function in the acyl group were smoothly oxidized to the corresponding imides in excellent yields. On the other hand, N-acylalkylamines having an electron-withdrawing group were not oxidized at all, and most of the starting material was recovered. It appears that the reactivity of N-acylalkylamines is closely correlated with the acidity of the carboxylic acid from which the N-acyl group is derived, and also with the electron density at the methylene moiety adjacent to the amide nitrogen atom. Keywords oxidation; ruthenium tetroxide oxidation; imide synthesis; acyclic imide; amide; ruthenium tetroxide; substituent effect Ruthenium tetroxide (RuO4) is well known as an effective multipurpose oxidant2) and has recently been used for the oxidation of some N-acylated cyclic amines to lactams and imides.3) In contrast, only one example of RuO4 oxidation of an N-acylated acyclic amine, i.e., the conversion of N-hexylheptanamide into N-hexanoylheptanamide, has been reported.4) The oxidation was carried out in a one-phase system of carbon tetrachloride (CCl4) solution containing a stoichiometric amount of RuO4 oxidant to afford the imide in a low yield. To date, no detailed and systematic study on RuO, oxidation of N-acylated alkylamines has been done, and the above procedure seems not to represent a generally applicable synthetic method for acyclic imides in terms of yield. Chart 1

2 In connection with our program aimed at developing a strategy for the oxidative transformation5) of L-ƒ,ƒÖ-diamino acids into the corresponding L-ƒÖ-carbamoyl-ƒ -amino acids by employing RuO4 oxidation, we decided to investigate the oxidation of N-acylated alkylamines, as outlined in Chart 1. We report in the present paper the RuO4 oxidation of N- acylated alkylamines in detail. As the first model of alkylamines for the present study, we selected a propylamine, which was acylated with various acyl chlorides under the Schotten-Baumann reaction conditions. Initially, we investigated the relationship between the N-acyl group and reactivity. In our recent studies on RuO4 oxidation, we developed an improved oxidation method3e) employing ethyl acetate (AcOEt) as an organic solvent in a two-phase system instead of the traditional halogenated solvents (CCl4 and CHCl3). In our system, the oxidation time was significantly shortened and products were obtained in high yields in comparison with those by employing the traditional solvent systems. This was also confirmed by the present results (Table I, entries 7-9) obtained in the oxidation of N-acetylPropylamine 1g under various conditions. Thus, the RuO4 oxidation of a variety of N-acylated propylamines was carried out using a small amount of RuO2 hydrate and excess 10% aqueous sodium metaperiodate in a two-phase system of AcOEt-water at room temperature according to our procedure3e) reported previously. The consumption of the starting materials was checked by thin layer chromatography (TLC). The corresponding N-acylated amides (imides) were obtained and their structures were assigned on the basis of the spectral data (proton nuclear magnetic resonance (1H-NMR) spectra, infrared (IR) spectra, and mass spectra (MS)). The individual results are summarized in Table I. As shown in Table I, the N-acylamines (1a-g) were oxidized to give the corresponding imides (2a-g) in 67-96% yields. However, in the case of N-trichloroacetylpropylamine 1h, the reaction did not occur at all even after 120 h and most of the starting material was recovered unchanged. Among the results obtained above, the shortest reaction time was observed with the pivaloyl group, as shown in entry 1. It was found that the reaction rate of the N-acylamines is dependent on the N-acyl group. Thus, the relative oxidation rates of these compounds are approximately parallel to the acidity of the carboxylic acids from which the N- TABLE I. Oxidation of N-Acylpropylamines

3 Chart 2 TABLE II. 7 8 acyl groups were derived. Namely, the reactivity of RuO4, oxidation is dependent on the electron density at the nitrogen atom. This is consistent with an earlier suggestion3a) by Sheehan and Tulis, who investigated the oxidation of N-acylated cyclic amines with RuO4. It has been shown that the product yields are little affected by the bulkiness or acidity of the N- acyl group. Next, we examined the oxidation of various amines having an acyl group (Chart 2 and Table II). An N-acylated secondary amine 3 was smoothly oxidized to the corresponding imide 4 in 96% yield. This observation can be explained in terms of the increase of electron density at the nitrogen atom. An arylalkylamide 5 of benzylamine type was oxidized to N- benzoylalkylamide 6 in moderate yield, as in the case of N-benzoylpropylamine 1c (Table I), due to oxidative degradation of the aromatic ring.7 When the reaction was carried out at 0 Ž, the yield of 6 was found to increase to 84%. This suggests that the oxidative degradation of the aromatic ring is prevented at the lower reaction temperature. N-Butyrylamines (7a and 7b) having an alkyl or halogen group at the ƒà-position with respect to the nitrogen atom were smoothly oxidized to the corresponding imides (8a and 8b) in 92% and 82% yields, respectively. However, with the N-butyrylamines (7c-e) bearing an electron-withdrawing group at the ƒ - or ƒà-position from the nitrogen atom, the reaction did not progress even after 120 h. These results show that the electron density at the methylene moiety adjacent to the nitrogen atom significantly affects the reactivity. In conclusion, RuO4 oxidation should be a useful method for the synthesis of simple symmetrical and unsymmetrical acyclic imides, which have generally been prepared under drastic reaction conditions which have resulted in low yields.8) Experimental All melting points were measured on a Yanagimoto micro melting point apparatus and are uncorrected. IR

4 spectra were recorded on a JASCO IRA-2 or Hitachi spectrometer. MS were measured on a JEOL JMS D-300 spectrometer. NMR spectra were obtained at 23 Ž using tetramethylsilane as an internal standard with a JEOL JNM-MH-100 spectrometer. Column chromatography was performed on Merck silica gel ( mesh). Starting Materials for the RuO4 Oxidation All the starting N-acylamines (1a-h, 3, 5, and 7a-e) were prepared from commercially available amines and amino acid esters by acylation with the corresponding acid chlorides under the Shotten-Baumann reaction conditions (benzene- or EtOH-aqueous Na2CO3, 0-5 Ž) and purified by distillation or recrystallization. The samples for the RuO4 oxidation were characterized as described below. N-Propylpivalamide (1a): by Ž (1 mmhg), colorless solid. Anal. Calcd for C8H17NO: C, 67.09; H, 11.96; N, Found: C, 67.14; H, 11.82; N, N-Propylcyclohexanecarboxamide (1b): mp Ž, colorless solid. Anal. Calcd for C10H19NO: C, 70.96; H, 11.32; N, Found: C, 70.88; H, 11.21; N N-Propylbenzamide (1c): mp Ž (lit.9) mp 84.5 Ž), colorless plates (from hexane). N-Propyldodecanamide (1d): mp Ž, colorless scales. Anal. Calcd for C15H31NO: C, 74.63; H, 12.94; N, Found: C, 74.54; H, 12.87; N, N-Propyl-isobutyramide (1e): by Ž (1 mmhg), colorless solid. Anal. Calcd for C7H15NO: C, 65.07; H, 11.70; N, Found: C ; H, 11.73; N, N-Propylbutyramide (10: by Ž (1 mmhg) (lit.10) by 93 Ž (0.3 mmhg)), colorless solid. N-Propylacetamide (1g): bp Ž (8 mmhg) (lit.10) by Ž (10 mmhg)), colorless oil. N-Propyltrichloroacetamide (1h): by Ž (1 mmhg), colorless solid. Anal. Calcd for C5H8Cl3NO: C, 29.37; H. 3.94; N, Found: C, 29.20; H, 3.88; N, N,N-Diethylbutyramide (3): by Ž (4 mmhg) (lit.11) by 89 Ž (12 mmhg)), colorless oil. N-Benzylacetamide (5): mp Ž mp Ž), colorless needles (from hexane). N-Isobutylbutyramide (7a): by 110 Ž (5 mmhg) (lit.13) by 137 Ž (17 mmhg)), colorless oil. N-2-Chloroethylbutyramide (7b): by 111 C (5 mmhg), colorless solid. Anal. Calcd for C6H12ClNO: C, 48.17; H, 8.09; N, Found: C, 48.10; H, 8.21; N, TABLE III. MS and IR Spectral Data and Elemental Analyses for the Imides

5 TABLE IV. 1H-NMR Spectral Data for the Imides Ethyl N-Butyryl-fl-alaninate (7c): by Ž (7 mmhg), colorless oil. Anal. Calcd for C91-17NO3: C, 57.73; H, 9.15; N, Found: C, 57.65; H, 9.00; N, N-Cyanomethylbutyramide (7d): by 154 Ž (5 mmhg) (lit.14) by Ž (3 mmhg)), colorless oil. Ethyl N-Butyrylglycinate (7e): by Ž (8 mmhg) (lit15) by 124 Ž (3 mmhg)), colorless oil. General Procedure for the RuO4 Oxidation of N-Acylamines (1a-h, 3, 5, and 7a-e) in a Two-Phase System Using AcOEt \A solution of substrates (6 mmol) to be oxidized in AcOEt (20 ml) was added to a mixture of RuO2 E H2O (100 mg) and 10% aqueous NaIO4 (30 ml). The mixture was vigorously stirred in a sealed flask at room temperature. After the starting material had disappeared as determined by TLC, the layers were separated. The aqueous layer was extracted with three 20-ml portions of AcOEt. The combined AcOEt solution was treated with isopropyl alcohol (2 ml) for 2-3 h to destroy the RuO4 oxidant. Black-colored RuO2 which precipitated from the solution was filtered of and the filtrate was washed with saturated NaCl solution, then dried over anhydrous Na2SO4. The solution was concentrated in vacuo to leave a residue, which was purified by recrystallization for the solid products or by vacuum distillation for the oily products. The results are summarized in Tables I and II, and Chart 2. Analytical and spectral (MS, IR, and 1H-NMR) data for the oxidation products (2a \g, 4, 6, 8a, and 8b) are listed in Tables III and IV. N-Propionylpivalamide (2a): mp Ž, colorless prisms (from H2O). N-Propionylcyclohexanecarboxamide(2b): mp Ž, colorless prisms (from 70% EtOH). N-Propionylbenzamide (2c): mp Ž mp 98 Ž), colorless prisms (from hexane). N-Propionyl-isobutyramide (2e): mp Ž, colorless needles (from hexane). N-Propionylbutyramide (2f): mp Ž, colorless needless (from hexane). N-Acetylpropionamide (2g): mp Ž mp Ž), colorless needles (from hexane). N-Acetyl-N-ethylbutyramide (4): The oxidation of 3 was carried out under the general conditions for 3 h to give 4 (96%) as a colorless oil, by 1l0-115 Ž (bath temp.)/6 mmhg. N-Acetylbenzamide (6): 1) The oxidation of 5 was carried out under the general conditions for 2 h to give 6 as a colorless solid (64%), which was recrystallized from 70% EtOH as colorless needles, mp Ž (lit.18) mp Ž). 2) A similar oxidation of 5 was carried out at 0 Ž for 7 h to give 6 (84%). N-Isobutyrylbutyramide (8a): mp C, colorless needles (from hexane). N-Chloroacetylbutyramide (8b): mp C, colorless prisms (from hexane). RuO4 Oxidation of 1g in a One-Phase System The substrate (1g) (607 mg, 6 mmol) was added to a mixture of

6 RuO2 E xh2o (100 mg) and 10% aqueous NaIO4 solution (30 ml), and the mixture was vigorously stirred at room temperature in a sealed flask. After disappearance of the substrate, the reaction mixture was extracted with three 20- ml portions of AcOEt. The aqueous layer was concentrated in vacuo to leave a white solid, which was triturated with two 20-ml portions of AcOEt. The AcOEt extracts were combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give crude 2g, which was purified by column chromatography on SiO2 with AcOEt hexane (1 : 2, v/v) as an eluent to give 2g (310 mg, 45%). RuO4 Oxidation of 1g in a Two-Phase System Using CCl4 \Oxidation of 1g was carried out under the general conditions in CCl4 as an organic solvent for 120 h, then the-reaction mixture was worked up in a manner similar to that described above. The crude oxidation products were purified by column chromatography on SiO2 with AcOEthexane (1 : 2, v/v) as an eluent. From the earlier part of the eluate, 2g (25%) was obtained. From the later part, 1g (65%) was recovered. Oxidation of 1h, Ethyl N-Butyl-ƒÀ-alaninate (7c), N-Cyanomethylbutyramide (7d), and Ethyl N-Butylglycinate (7e) \The oxidation of these compounds (1h, 7c, 7d, and 7e) did not progress under the general conditions for 120 h. The recovery of each starting material was 86-92%. References 1) A part of this work was presented at the 11th Symposium on Progress in Organic Reactions and Syntheses, Nagasaki, Japan, Nov. 1984, p ) D. G. Lee and M. van den Engl, "Oxidation in Organic Chemistry," Part B, ed. by W. S. Trahanovsky, Academic Press, New York, 1973, Chapter 4. 3) a) J. C. Sheehan and R. W. Tulis, J. Org. Chem., 39, 2264 (1974); b) N. Tangari and V. Tortorella, J. Chem. Soc., Chem. Commun., 1975, 71; c) R. Perrone, G. Bettoni, and V. Tortorella, Synthesis, 1976, 598; d) G. Bettoni, G. Carbonara, C. Franchini, and V. Tortorella, Tetrahedron, 37, 4159 (1981); e) S. Yoshifuji, K. Tanaka, T. Kawai, and Y. Nitta, Chem. Pharm. Bull., 33, 5515 (1985). 4) L. M. Berkowitz and P. N. Rylander, J. Am. Chem. Soc., 80, 6682 (1958). 5) S. Yoshifuji, K. Tanaka, and Y. Nitta, Chem. Pharm. Bull., 33, 1749 (1985). 6) Z. Rappoport, "Handbook of Tables for Organic Compound Identification," 3rd ed., CRC Press, Inc., Cleveland, 1967, p ) D. C. Ayres, J. Chem. Soc., Chem. Commun., 1975, ) R. B. Bates, F. A. Fletcher, K. D. Janda, and W. A. Miller, J. Org. Chem., 49, 3038 (1984) and references cited therein. 9) A. W. Titherly, J. Chem. Soc., 79, 405 (1901). 10) G. M. Burnett and K. M. Riclies, J. Chem. Soc. (B), 1966, ) C. R. Hauser and H. G. Walker, Jr., J. Am. Chem. Soc., 69, 295 (1947). 12) H. Amsel and A. W. Hofmann, Ber., 19, 1286 (1886). 13) S. I. Gertler and A. P. Yerington, U. S. Dep. Ag. Research Service, Entomol. Research Branch ARS-33-31, 1956, p. 10 [Chem. Abstr., 50, 17297h (1956)]. 14) A. Kotelko, Acta Polon. Pharm., 19, 109 (1962) [Chem. Abstr., 59, 1482f (1963)]. 15) G. Ya. Kondrateva and C.-H. Hung, Zh. Obshch. Kim., 32, 2348 (1962) [Chem. Abstr., 58, 7919h (1963)]. 16) J. B. Polya and T. M. Spotwood, Recl. Tray. Chim. Pays-Bas, 67, 927 (1948) [Chem. Abstr., 43, 4221b (1949)]. 17) Q. E. Thompson, J. Am. Chem. Soc., 73, 5841 (1951). 18) A. W. Titherley and T. H. Holden, J. Chem. Soc., 101, 1871 (1912).