Ruthenium Tetroxide (Ruo4) Oxidation of N-Alkyllactams Proceeded Regioselectively Depend- Ing on the Size of Lactam Ring, Except for the Seven-Membered Ring

No. 1 357

Chem. Pharm. Bull. 35(1) 357-363 (1987)

Ruthenium Tetroxide Oxidation of N-Alkyllactams

SHIGEYUKIYOSHIFUJI,* YUKIMI ARAKAWA, and YOSHIHIRONITTA

Schoolof Pharmacy,Hokuriku University,Kanagawa-machi, Kanazawa920-11, Japan

(ReceivedJuly 31, 1986)

Ruthenium tetroxide (RuO4) oxidation of N-alkyllactams proceeded regioselectively depending on the size of lactam ring, except for the seven-membered ring. Four- and eight-membered N- methyl- and N-ethyllactams were oxidized at the exocyclic ƒ¿-carbon adjacent to nitrogen to produce the N-acyllactams and NH-lactams, while five- and six-membered lactams underwent endocyclic oxidation to yield the cyclic imides. Oxidation of seven-membered lactams yielded a mixture of

products arising from both exocyclic and endocyclic oxidations. These regioselectivities were confirmed in the oxidation of substrates having a tertiary carbon at the oxidation position.

Keywords•\oxidation; ruthenium tetroxide oxidation; regioselective oxidation; hydroxyl- ation; imide synthesis; N-alkyllactam; N-acyllactam; imide; ruthenium tetroxide; two-phase method

Ruthenium tetroxide (RuO4) is a good reagent for the conversion of N-acylated cyclic amines to the corresponding lactams,1) by oxidation of one of two carbons adjacent to nitrogen. As a common feature of the RuO4 oxidation in this conversion (la to 2 in Chart 1) and in the transformation of cyclic ethers into the corresponding lactones,2) it has been considered that RuO4 predominantly oxidizes a secondary carbon rather than a tertiary one. However, as reported previously,3) we obtained an opposite result in the RuO4 oxidation of some 1-azabicycloalkan-2-ones, such as quinolizidin-4-one (1b), which gave the hydroxylated products, such as 3, resulting from the oxidation of the tertiary carbon. At that time, we predicted that the 1-azabicycloalkan-2-ones might belong not to the category of N-acyl cyclic amines but to that of N-alkyllactams, in terms of RuO4 oxidation. However, to date, there has been no report on the latter category. Here we wish to describe a systematic study on the RuO4 oxidation of N-alkyllactams. As model compounds, simple N-methyl- and N-ethyllactams ranging in size from four- to eight-membered rings were selected for the present work. The RuO4 oxidation of these substrates was carried out at room temperature under catalytic conditions using a catalytic amount of ruthenium dioxide (RuO2) in combination with an excess of 10% aqueous sodium metaperiodate (NaIO4). In the catalytic procedure of RuO4 oxidation, a two-phase system of organic solvent-water is usually employed as a reaction medium and the organic phase is a chlorinated methane such as carbon tetrachloride (CCl4)4) or the combination of CCl4 and

Chart 1 358 Vol. 35 (1987)

TABLE I. RuO4 Oxidation of N-Alkyllactams

I II III IV

acetonitrile developed by Sharpless et al.5) Recently we developed a new solvent system of ethyl acetate (AcOEt)-water which gave short reaction times and high yields of the products in the transformation of N-acylated L-proline esters into the corresponding L-pyroglutamic acid derivatives.1c) Therefore, our new system was applied to the present work. However, in the oxidation of the four-membered lactams, the organic phase (AcOEt) was omitted due to the ready solubility of these compounds in water. The oxidation reaction was monitored by observing the disappearance of the starting lactams on thin layer chromatographic (TLC) plates; it proceeded slowly, with a yellow color which indicated the existence of active RuO4 generated in situ from RuO2 under the above conditions. The results are summarized in Table I. A highly regioselective oxidation depending on the ring size of the lactams, except for seven-membered lactams, was observed. Four- and eight-membered lactams were oxidized at the exocyclic ƒ¿-carbon to nitrogen. N-Methyl-ƒÀ-lactam afforded a low yield of the de- methylated NH-lactam. Eight-membered N-methyllactam also gave predominantly the NH- lactam together with a small amount of the N-formyllactam. N-Ethyllactams were transform- ed into the N-acetyllactams (and the NH-lactam in the case of the eight-membered lactam). Formation of the NH-lactams must be based on the elimination of aldehyde (formaldehyde or acetaldehyde) from the intermediates leading to the N-formyl or N-acetyl lactams and/or on the hydrolytic deacylation of the N-acyllactams. Five- and six-membered lactams were oxidized at the endocyclic ƒ¿-carbon to provide the corresponding cyclic imides in high yields. The precursors of these imides are the corresponding ƒ¿-hydroxylactams which could be detectable in the early stage of the oxidation on TLC analysis. In an incomplete run with 1-methylpyrrolidin-2-one (5a) using a traditional two- phase system of CCl4—H2O, 2-hydroxy-1-methylpyrrolidine-5-one was isolated from the aqueous phase in 16% yield. When the hydroxy compound was oxidized with RuO4 according to our standard procedure, N-methylsuccinimide (5c) was obtained in 97% yield. Alternatively, treatment of seven-membered lactams with RuO4 provided a mixture of products arising from endocyclic and exocyclic oxidations. Next, in order to confirm the above mentioned regioselectivity depending on the size of the lactam ring, further RuO4 oxidation was done under the same conditions with some N- No. 1 359

alkyllactams bearing a tertiary carbon at the oxidation position. These compounds were chosen because a tertiary carbon is less susceptible to RuO, than a primary or secondary carbon.1,2,4) The results are shown in Chart 2. N-Isopropyl-ƒÀ-lactam (9) was oxidized with

Chart 2 360 Vol. 35 (1987)

long reaction times to afford two products, an NH-lactam (4c) and a N-acetyllactam (4d), in 35% and 42% yields, respectively. Apparently, this oxidation occurred at the exocyclic tertiary carbon and these products (4c, d) were formed from a common intermediate, the hydroxylactam (10), which could not be isolated. Presumably 10 was decomposed directly to 4c by the loss of acetone and indirectly to the acetyl derivative (4d) via dehydration to the N- isopropenyllactam (11) and oxidative cleavage of the double bond of 11. RuO4 oxidation of the eight-membered N-isopropyllactam (12) proceeded very sluggishly and was not completed within 30d; a little of the starting lactam (7%) was recovered. This must be due to the difficulty of access of RuO4 to the exocyclic ƒ¿-position. Only a low yield of the exocyclic oxidized product (8c, 25%) was obtained together with the cyclic imide (13, 25%) generated in the kinetically controlled reaction. In this regard, the analogous oxidation of the seven- membered lactams gave reasonable results. N-Isopropylcaprolactam (14) was oxidized exclusively at the endocyclic ƒ¿-position to produce the cyclic imide (15) in 89% yield. On the other hand, the reaction of 1,2-dimethylcaprolactam (16) with RuO4 provided a mixture of products resulting from the exocyclic and endocyclic oxidations: four compounds, 17 (41%), 18 (18%), 19 (19%), and 20 (9%), were obtained on chromatographic separation of the mixture. Although regioselective endocyclic oxidation in the five- and six-membered lactams having a tertiary carbon at the oxidation position has already been observed with 1- azabicycloalkan-2-ones such as 1b (Chart 1),3) 1,2-diethylpiperidin-6-one (21) was examined as a model compound. Thus, treatment of 21 with RuO4 as described above using the CCl4-H2O system gave a 94% yeild of the ring-opened product (23), which is equivalent to the hydroxylactam (22). When the AcOEt-H2O system was used in the above oxidation of 21, the major product was the ring-opened imide (24) as a result of further oxidation of the initially formed amide (23).6) On the basis of the results described above, it is possible to conclude that the RuO4 oxidation of N-alkyllactams proceeds regioselectively depending on the size of the lactam ring, except for the seven-membered ring, even when a saturated tertiary carbon (which has not previously been reported to be oxidized by RuO4) occupies the oxidation position in the four-, five-, and six-membered N-alkyllactams. Recently, a similar type of reaction has been reported in the direct or indirect anodic oxidation of N-alkyllactams.7) Our RuO4 oxidation can be regarded as superior to these oxidations in respect of the high regioselectivity of the reaction and the high yield of the products.

Experimental

Melting points were taken on a Yanagimoto melting point apparatus. All melting points and boiling points are uncorrected. Infrared (IR) spectra were recorded on a JASCO IRA-2 or a Hitachi 270-30 spectrophotometer. Mass spectra (MS) were measured on a JEOL JMS D-100 or a JEOL JMS D-300 spectrometer. Nuclear magnetic resonance (1H-NMR) spectra were obtained at 23•Ž on a JEOL JNM-MH-100 or a JEOL FX-100 spectrometer with tetramethylsilane as an internal standard. Starting Materials All starting materials were obtained from commercial suppliers (5a, 5b, 6a) or prepared according to the established methods.8). New compounds were characterized as described below. 1-Isopropylazetidin-2-one (9)•\A colorless oil, by 83-85•Ž (17mmHg). MS m/z: 113 (M+). IRcm-1: 1737 (C=O). 1H-NMR (CDCl3) ƒÂ: 1.18 (6H, d, J=7Hz, 2•~CH3), 2.81 (2H, t, J=4Hz, C3-H2), 3.16 (2H, t, J= 4 Hz, C4-H2), 3.75-4.05 (1H, m, CH). 1-Isopropyloctahydroazocin-2-one (12) A colorless oil, by 76•Ž (2 mmHg). MS m/z: 169 (M+). IR v film maxcm-1: 1610 (C=O). 1H-NMR (CDCl3) ƒÂ: 1.14 (6H, d, J= 7 Hz, 2•~CH3), 1.35-1.93 (8H, m, C4-H2, C5-H2, H6- H2, and C7-H2), 2.4-2.61 (2H, m, C3-H2), 3.32-3.47 (2H, m, C8-H2), 4.44-4.92 (1H, m, CH). Standard Procedure for RuO4 Oxidation of N-Alkyllactams A solution of a substrate (12mmol) to be oxidized in an organic solvent (AcOEt, 40ml) was added to a mixture of RuO2 hydrate [Aldrich Chemical Co.]

(120mg) and 10% aqueous NaIO4 (120ml). The mixture was vigorously stirred using a mechanical stirrer with a No. 1 361

glass blade at room temperature. The reaction was monitored by TLC. In the case of the four-membered lactams, the organic solvent (AcOEt) was omitted. Work-up (A) [Isolation of the Product from the Organic Phase]: After the starting material had disappeared as determined by TLC, the layers were separated. The aqueous layer was extracted with AcOEt (3•~40ml). The combined organic solution was treated with isopropyl alcohol (2ml) for 3h to decompose RuO4, and then filtered. The filtrate was washed with 10% aqueous Na2S2O3 (10ml) and dried over anhydrous Na2SO4. The solution was evaporated in vacuo to leave a residue, which was purified by column chromatography on silica-gel or alumina using a solvent system of AcOEt-hexane as the eluent, and/or by recrystallization for solid products or by vacuum distillation for oily substances. Work-up (B) [Isolation of the Product from the Aqueous Phase]: The aqueous layer, which had been extracted with AcOEt as described above, was concentrated under reduced pressure to dryness and the resulting white solid was extracted with hot AcOEt (3•~40ml). The combined extracts were dried over anhydrous Na2SO4 and evaporated in vacuo to leave a residue, which was purified. Work-up (C) [For the Four-Membered Lactams]: The reaction solution was washed withCCl4 (3•~40ml) and concentrated under reduced pressure to dryness, leaving a white solid, which was extracted with hot AcOEt

(3•~40ml). The combined AcOEt extract was dried over anhydrous Na2SO4 and evaporated in vacuo to afford the crude product. The results (reaction time and yield) of all oxidations are summarized in Table I and Chart 2. The identification of the oxidation products was done by comparison of their physical and spectral data with those of authentic samples, whenever they were known (4c,9) 5c,10) 5d,11) 6c,10) 6(1,12) 7c,13) 7e,10 7f,14) 8c,13) 18,15)).New compounds were characterized as described below. 1-Acetylazetidin-2-one (4d)•\A colorless oil, by 102-105•Ž (17mmHg, bath temp.). MSm/z: 113 (M+). IR vfilm maxcm-1: 1784, 1696 (C=O). 1H-NMR (CDCl3) 5: 2.35 (3H, s, COCH3), 3.05 (2H, t, J=5Hz, C3-H2), 3.58 (2H, t, J=5 Hz, C4-H2). Isolation of 2-Hydroxy-1-methylpyrrolidin-5-one in the Oxidation of 1-Methylpyrrolidin-2-one (5a)•\Oxidation of 5a was carried out under the standard conditions, but CCl4 was used instead of AcOEt. After 10d, the reaction mixture was treated as follows: work-up (A) gave 1-methylsuccinimide (Sc, 78%) and work-up (B) gave 2-hydroxy-1- methylpyrrolidin-5-one (16%), which was identical with an authentic sample)prepared from 1-methylsuccinimide on NaBH4 reduction. 2-Hydroxy-1-methylpyrrolidin-5-one was oxidized with RuO4 under the standard conditions (AcOEt-H2O system, 28h) to afford 5c in 97% yield. Oxidation of Hexahydro-1-methyl-2H-azepin-2-one (7a)•\A mixture of two products, 1-formylhexahydro-2H- azepin-2-one (7d) and hexahydro-1-methyl-2H-azepin-2,7-dione (7e), was obtained on work-up (A) and separated by column chromatography. Hexahydro-2H-azepin-2-one (7c) was obtained on work-up (B). 7d: A colorless oil, by 148•Ž (16mmHg, bath temp.). IR v film maxcm-1: 1720, 1682(C=O). 1H-NMR (CDCl3) ƒÂ: 1.50-2.0 (6H, m, C4-H2, C5-H2, and C6-H2), 2.6-2.8 (2H, m, C3-H2), 3.8-3.9 (2H, m, C7-H2), 9.34 (1H, s, CHO). Oxidation of 1-Ethylhexahydro-2H-azepin-2-one (7b) A mixture of two products, .1-acetylhexahydro-2H- azepin-2-one (7f) and 1-ethylhexahydro-2H-azepin-2,7-dione (7g), was obtained on work-up (A) and separated by column chromatography. 7g: A colorless oil, by 103•Ž (3 mmHg, bath temp.). IR v film maxcm-1: 1710, 1660(C=O). 1H-NMR (CDCl3) ƒÂ: 1.11 (3H, t, J=7Hz, CH3), 1.8-2.0 (4H, m, C3-H2 and C6-H2), 2.7-2.9 (4H, m, C4-H2 and C5-H2), 3.77 (2H, q, J= 7Hz, CH2-CH3). Oxidation of 1-Methyloctahydroazocin-2-one (8a)•\Work-up (A) gave 1-formyloctahydroazocin-2-one (8d) and work-up (B) gave octahydroazocin-2-one (8c). 8d: A colorless oil. IR v film maxcm-1: 1710, 1690 (C=O). 1H-NMR (CDCl3) ƒÂ:1.3-2.0 (8H, m, C4-H2, C5-H2, C6- H2, and C7-H2), 2.5-2.7 (2H, m, C3-H2), 3.7-3.9 (2H, m, C8-H2), 9.32 (1H, s, CHO). Oxidation of 1-Ethyloctahydroazocin-2-one (8b) Work-up (A) gave 1-acetyloctahydroazocin-2-one (8e) and work-up (B) gave octahydroazocin-2-one (8c). 8e: A colorless oil, by 105•Ž (4mmHg). MSm/z 169 (M+). IR v film maxcm-1: 1688 (b, C=O). 1H-NMR (CDCl3) ƒÂ: 1.27-2.0 (8H, m, C4-H2, C5-H2, C6-H2, and C7-H2), 2.49 (3H, s, COCH3), 2.54-2.74 (2H, m, C3-H2), 3.74-4.0

(2H, m, C8-H2). Oxidation of 1-Isopropyloctahydroazocin-2-one (12)•\On work-up (A), a mixture of two products, octahydroazocin-2-one (Sc) and 1-isopropyloctahydroazocin-2,8-dione (13) was obtained together with the starting lactam (12). NH-Lactam (8c) was also obtained on work-up (B). 13: A colorless oil, by 90•Ž (1mmHg, bath temp.). MSm/z: 183(M+). IR v film maxcm-1: 1698, 1655 (C=O). 1H- NMR (CDCl3) ƒÂ : 1.30 (6H, d, J=7Hz, 2•~CH3), 1.47-2.0 (6H, m, C4-H2, C5-H2, and C6-H2), 2.7-2.9 (4H, m, C3- H2 and C7-H2), 4.6-5.0 (1H, m, N-CH).

Oxidation of 1-Isopropylhexahydro-2H-azepin-2-one (14)•\1-Isopropylhexahydro-2H-azepin-2,7-dione (15) was obtained on work-up (A). 15: A colorless oil, by 84•Ž (2mmHg, bath temp.). MS m/z: 169 (M+). IR v film maxcm-1: 1710, 1660 (C=O). 1H- 362 Vol. 35 (1987)

NMR (CDCl3) ƒÂ: 1.31 (6H, d, J=7Hz, 2•~CH3), 1.8-2.0 (4H, m, C4-H2 and C5-H2), 2.6-2.8 (4H, m, C3-H2 and C6-H2), 4.5-5.0 (1H, m, N-CH). Oxidation of 1,2-Dimethylhexahydro-2H-azepin-7-one (16)•\After the oxidation under the standard conditions was completed, the two layers were separated and the aqueous layer (aq-1) was extracted with AcOEt (2•~30ml). The

extracts were combined with the original AcOEt solution and treated with isopropyl alcohol (3ml). The solution was filtered and the filtrate was concentrated under reduced pressure to leave a residue, which was dissolved in a mixture of H2O (20ml) and hexane (40ml). After vigorous shaking, the two layers were separated and the aqueous layer was extracted with hexane (2•~40ml). This aqueous layer was combined with the above aqueous layer (aq-1) and subjected to work-up (B) to give a mixture of products. Chromatography on alumina using CHCl3-hexane (1:1, v/v) as the eluent gave three products (18, 19, and 20). The hexane solution was dried over anhydrous Na2SO4 and evaporated in vacuo to give 1-formyl-hexahydro-2-methyl-2H-azepin-7-one (17). 17: A colorless oil, by 135•Ž (13mmHg, bath temp.). IRv film max cm-1: 1712, 1686 (C=O), 1H-NMR (CDCl3) 6: 1.34 (3H, d, J= 7Hz, CH3), 1.49-2.1 (6H, m, C4-H2, and C5-H2), 2.63-2.87 (2H, m, C6-H2), 4.75-5.2 (1H, m, C2-H), 9.36 (1H, s, CHO). Hexahydro-2-methyl-2H-azepin-7-one (18): Colorless needles, mp 91-92•Ž. MS m/z: 127 (M+). IR v KBr maxcm-1: 3200, 3100 (NH), 1663 (C=O). 1H-NMR (CDCl3) ƒÂ: 1.23 (3H, d, J= 7Hz, N-CH3), 1.3-2.10 (6H, m, C4-H2 and C5-H2), 2.36-2.55 (2H, m, C6-H2), 3.36-3.68 (1H, m, C2-H), 5.8-6.3 (1H, b, NH). N-Methyl-6-oxoheptanamide (19): Colorless scales, mp 60-61•Ž. MS m/z: 157 (M+). IR v KBr maxcm-1: 3300

(NH), 1710, 1703, 1642 (C=O). 1H-NMR (CDCl3) ƒÂ: 1.52-1.72 (4H, m, C3-H2 and C4-H2), 2.15 (3H, s, COCH3), 2.1-2.3 (2H, m, C5-H2), 2.38-2.60 (2H, m, C2-H2), 2.78 (3H, d, J= 5Hz, N-CH3), 5.64-6.12 (1H, b, NH). Anal. Calcd for C8H15NO2: C, 61.12; H, 9.62; N, 8.91. Found: C, 61.22; H, 9.58; N, 8.89. 6-Oxoheptanamide (20): Colorless needles, mp 80•Ž. MSm/z: 143 (M+). IR vKBr maxcm-1: 3400, 3210 (NH2), 1700, 1663, 1614 (C=O). 1H-NMR (CDCl3) ƒÂ: 1.55-1.76 (4H, m, C3-H2 and C4-H2), 2.13 (3H, s, COCH3), 2.1-2.4 (2H, m, C5-H2), 2.4-2.6 (2H, m, C2-H2), 6.00 (2H, brs, NH2). Oxidation of 1,2-Diethylpiperidin-6-one (21)•\Oxidation of 21 was carried out under the standard conditions, but with CCl4 as the organic phase, giving N-ethyl-5-oxoheptanamide (23) on work-up (A). When AcOEt was used as the organic phase, the further oxidized product, N-acetyl-5-oxoheptanamide (24), was obtained after 130h. 23: Colorless scales, mp 63-64•Ž. MSm/z: 171 (M+). IR v KBr maxcm-1: 3310 (NH), 1715, 1635 (C=O). 1H-NMR

(CDCl3) 6: 1.05 (3H, t, J=7Hz, C7-H3), 1.13 (3H, t, J=7Hz, NCH2CH3), 1.78-2.06 (2H, m, C3-H2), 2.1-2.3 (2H, m, C4-H2), 2.39 (2H, q, J=7Hz, C6-H2), 2.49 (2H, t, J=6.5Hz, C2-H2), 3.1-3.44 (2H, m, N-CH2CH3, added D2O, q, J= 7Hz), 5.76 (1H, brs, NH, added D2O, disappeared). 24: Colorless needles, mp 90-92•Ž. MS m/z: 185 (M+). IR v KBr maxcm-1: 3268, 3180 (NH), 1730, 1704, 1654

(C=O). 1NMR (CDCl3) ƒÂ: 1.05 (3H, t, J=7Hz, C7-H3), 1.73-2.08 (2H, m, C3-H2), 2.32 (3H, s, NCOCH3), 2.3- 2.65 (6H, m, C2-H2, C4-H2, and C6-H2), 9.18 (1H, s, NH).

Acknowledgement The authors are greatly indebted to Professor Tozo Fujii of Kanazawa University and ex- Professor Yoshio Arata of Hokuriku University for their kind encouragement.

References and Notes

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6) RuO4 oxidation of N-acylated alkylamines to the corresponding imides is a new method for the general synthesis of imides. K. Tanaka, S. Yoshifuji, and Y. Nitta, Chem. Pharm. Bull., 35, 364 (1987). 7) a) M. Okita, T. Wakamatsu, and Y. Ban, J. Chem. Soc., Chem. Commun., 1979, 749; b) M. Okita, T. Wakamatsu, M. Mori, and Y. Ban, Heterocycles, 14, 1089 (1980); c) M. Masui, S. Hara, and S. Ozaki, Chem. Pharm. Bull., 34, 975 (1986). 8) a) H. Takahata, T. Hashizume, and T. Yamazaki, Heterocycles, 12, 1449 (1979); b) H. Takahata, Y. Ohnishi, and T. Yamazaki, ibid., 14, 467 (1980).

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