Preparation and benzoylation of 3-hydroxy-2,3,5,5-tetramethyl-1-pyrroline 1-oxide (3-hydroxy-2,3,5,5-tetramethyl-4,5-dihydro-3H-pyrrole 1-oxide)

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1995 Preparation and Benzoylation of 3-Hydroxy-2,3,5,5-tetramethyl-l -pyrroline 1-Oxide (3-Hydroxy-2,3,5,5 -tetramethyI-4,5-dihydro-3H-pyrroIe 1-Oxide)t,' Neil J. Gibson,8 Alexander R. Forrester"raand Charles Brownb a Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB9 2UE, UK'Smith-Kline Beecham Ltd., The Frythe, Welwyn, Herts A16 SAR. UK ~~ ~ ~ ~ ~ ~ ~ Treatment of 2,3,5,5-tetramethyl-3-hydroxy-l -pyrroline 1-oxide 6, prepared from butanone in six steps, with benzoyl chloride under Schotten-Baumann conditions leads to an unprecedented dimerisation to give a spiro, tricyclic N-benzoyloxypyrrolidirie in good yield. The acylation of nitrones has been widely studied.'-' Nitrones lacking a proton p to the nitronyl carbon usually undergo 0-iii,iv MMe e d o acylation followed by a 1,2 migration of the acyloxy group to L-4f-give an 1-acyloxy imine which undergoes acidolysis resulting in NO2 Me the formation of an amide.2 In the case of nitrones with a proton, 0 acylation is usually followed by the 1,3 hetero-Cope 1 migration of the acyloxy group to give (3-acyloxy imine~.~-~ Aldo I-pyrroline 1-oxides give 3-acyloxy 1-pyrrolines when treated with acid anhydride^,^ acid chlorides4 and chloro-formates,' During our studies' of the preparation of l-pyrro-line I-oxides bearing an electrophilic substituent at C-3, suit-able to act as spin traps for the superoxide radical anion, we prepared the 3-hydroxy-1-pyrroline 1-oxide 6 which was treated with benzoyl chloride and pyridine in order to effect esterification.The desired putative ester, 3-benzoyloxy-2,3,5,5-tetramethyl-I-pyrroline I-oxide 7 was not expected to be a useful spin trap for superoxide since it lacks a proton Q to the nitronyl carbon and all spin adducts would give ESR spectra which were simple triplets as is observed for TMPO 16.6 However, it was intended to establish the principle that a 1-pyrroline 1 -oxide with an electrophilic group at C-3 such as 7 could spin trap superoxide and subsequently 'cap' the hydroperoxy functionality of the resulting adduct via an intramolecular transesterification. 3-Hydroxy-2,3,5,5-tetramethyl-l-pyrrolineResults and Discussion 1-oxide was pre-pared from butanone according to Scheme 1. Butanone was treated with aqueous, basic paraformaldehyde to give the hydroxymethyl aldol adduct which, although not isolated, was then dehydrated with polyphosphoric acidmethod of Cook and3-methylbut-3-en-2-one 1 according to the and copper to give Waring.' The z,P-unsaturated ketone 1underwent the Michael addition of 2-nitropropane to give the y-nitro ketone 2.When 2 was treated with concentrated perchloric acid and acetic anhydride the enol acetate 3 was formed slowly. The extent of reaction was readily monitored by observing the diminution of the absorbance of the carbonyl stretch of the ketone at 1720cm with the simultaneous increase in the carbonyl stretch of the enol acetate at 1750 cm-'. The enol acetate 3 was treated with m-chloroperbenzoic acid (m-CPBA) in dichloromethane to afford the acetoxy epoxide 4, treatment ofwhich with mineral acid in refluxing ethanol afforded the 3-hydroxyhexan-2-one 5.Reduction of the y-nitro ketone with zinc dust and aqueous ammonium chloride afforded the 3-hydroxy-1-pyrroline 1-oxide 6 in good yield. t Although in the earlier sections of this paper the compounds are, for convenience, described as 1-pyrrolines, the IUPAC-approved names are given in the Experimental section. /* Me-.,,+,, Me A O A Me NO:, Me NO:, Me 3 Meo Me NO2 Me 5 viii Me : Me y0-y6Me OH Me: I 0-N Me ';Jtea+$ =Me Me 0-8 7 Scheme 1 i, (CH,O),, NaOH,,; ii, H,PO,, Cu, reflux; iii. Me,CHNO,, Triton BO, THF; iv, HCI,; v, Ac,O, CCI,, HClO,(conc.); vi, m-CPBA; vii, 2 rnol dm? HCI.EtOH, reflux; viii, Zn, NHbCI. THF. H,O; ix, Py, PhCoC' equiv,). The IR spectrum of the hydroxy nitrone 6 shows strong absorptions at 3129 (hydroxy) and 1617 cm-' (C=N).The lH NMR spectrum shows four methyl groups including one with a chemical shift of 1.97 ppm which is consistent with a 2-methyl- I-pyrroline I-oxide.' The 4-CH2 protons give an AB quartet (JI2 Hz) and there is a broad, exchangeable signal arising from the hydroxy proton. The I3C NMR spectrum shows only seven signals due to equivalence of two of the methyl groups. C-2 has a chemical shift of 147.4 ppm which is characteristic of a 2- methyl-I-pyrroline I-oxide' while C-3 has a chemical shift of 72.34ppm which is consistent with a quaternary carbon bonded to a hydroxy group.Treatment of the 3-hydroxy-1-pyrroline 1-oxide 6 with benzoyl chloride (1 equiv.) and pyridine in dichloromethane failed to induce simple esterification of the hydroxy func- tionality to give the ester 7, but, instead, the spiro tricyclic N- benzoyloxyamine 8 was isolated in good yield. The latter shows strong absorption in the IR region at 3397 (hydroxy) and 1746 and 1738 cm-' ((24). Apart from a weak band at 1601 cm-' arising from the 'ring breathing' stretch of the phenyl C==C bonds there is no absorbance in the range 1500-1700 cm-' which demonstrates the absence of C=N bonds. The 'H NMR spectrum of 8 shows seven methyl reson- ances, signals from six other aliphatic protons comprising three AB spin systems and also signals arising from ten aromatic protons. There is a broad signal which integrates for one proton which is assigned to an OH group.The 13C and 3/4 n NMR spectra reveal the following: (a) There are 26 non-equivalent carbons including 7 methyls, 3 methylenes, 6 aliphatic quaternaries, 8 aromatics and 2 carbonyls. (b) There are no signals which may be assigned to a I-pyrrolinyl carbon (16 175)**' or to a keto I-pyrroline I-oxide (140-150 ppm).' (c) Of the 6 aliphatic quaternary carbons. one has a chemical shift of 106.1 ppm and therefore must be bonded to two electronegative atoms. There is only one singlet arising from a carbon bonded to a benzoyloxy group (87.72 ppm) and, consequently, only one of the hydroxy groups is esterified and the remaining benzoyl group must be present as an acyloxyamine.The unesterified tertiary alcohol gives rise to a signal at 75.48 ppm. A suggested mechanism for the formation of 8 is shown in 0-002 6 9 Me 0-6 10 6 Me c-~i'Me 12 11 Scheme 2 i, PhCOCl(0.5 equiv.) J. CHEM. SOC. PERKlN TRANS. I 1995 Scheme 2. It has been shown that the nitronyl oxygen of 1-pyrroline I-oxides is a good electrophile' and it would be expected that treating the nitrone 6 with benzoyl chloride would lead initially to the formation of the N-benzoyloxy- iminium cation 9. It is proposed that the cation 9 undergoes deprotonation at the 2-methyl group to give the N-benzoyloxy- 2,2'-exo-methylenepyrrolidine10 which does not undergo the expected hetero-Cope rearrangement to 2-benzoyloxymethyl- 3,5,5-trimethyl-3-hydroxy-I-pyrrolinebut adds nucleophilic- ally to a molecule of unchanged nitrone 6 with the tandem ring closure of the intermediate bridged N-benzoyloxyiminium-N'- hydroxonium species 11 to give the spiro tricyclic dialcohol 12.This dialcohol undergoes selective benzoylation of one of the hydroxy groups. It was not possible to determine the site of benzoylation spectrometrically. Molecular modelling of the dialcohol 12 suggests that the hydroxy groups are in practically identical environments since the fused bicyclic rings attached at the pyrrolidinyl 2'-position do not give rise to increased steric crowding of the 3'-OH.In structure 8 the 6-OH has been arbitrarily indicated as the site of benzoylation in preference to 3'-OH, however this is conjectural. When Alazard and co-workers lo treated the fused pentacyclic 2-methyl-1 -pyrroline 1-oxide 13 with benzoyl ww 13 14 15 Scheme 3 chloride, 0-benzoylation was followed by deprotonation of the 2-methyl group to give the exocyclic 2,2'-exo-methylene-N- benzoyloxypyrrolidine 14 which underwent a hetero-Cope rearrangement to give the 2-benzoyloxymethylpyrrolidine 15. There is no report of the nucleophilic attack of the intermediate 14 upon unchanged 1-pyrroline 1-oxide, probably due to the large steric bulk of these steroid-based nitrones. Also no B-deprotonation at C-3 was observed since this would necessitate forming a bridgehead double bond at the junction of two fused five-membered rings which would not be favoured. When Black and Strauch I ' treated 2,5,5-trimethyl- 1 -pyrro-line 1-oxide 16 with benzoyl chloride in pyridine, of the two possible P-benzoyloxy-I-pyrrolines only the 3-benzoyloxy adduct 20 was formed.Initial benzoylation is followed by j3 deprotonation to give an z,P unsaturated N-benzoyloxypyr- rolidine prior to the Hetero-Cope rearrangement to the product P-benzoyloxy-1 -pyrroline. It is unclear whether the non-formation of the 2-benzoyloxymethyl- 1-pyrroline 18 is due to the relative rate of j3-deprotonation at C-3 being greater than at 2-Me so that the formation of the 2,2'-exo-methylene-N- benzoyloxypyrrolidine 17 is disfavoured or whether both the a,j3 unsaturated N-benzoyloxypyrrolidines17 and 19 exist in equilibrium but the latter undergoes rearrangement to the j3- J.CHEM. SOC. PERKIN TRANS. I 1995 Me OBZ Q-19 16 MeQCHp IMe OBZ 20 17 f 18 Scheme 4 benzoyloxy-1-pyrroline at a much faster rate than does the former. The benzoylation of the 3,3-disubstituted- I -pyrroline I-oxide 6 presents an intermediate case. As with the fused bicyclic nitrone 13, 0-benzoylation can only be followed by p-deprotonation of the 2-methyl group to give the N-benzoyloxy- 2-em-methylenepyrrolidine 10. In this case nucleophilic attack by 10 on unchanged nitrone is more rapid than rearrangement to the corresponding 2-benzoyloxymethyl- I -pyrroline.This observation suggests that such rearrangements are slow and are probably only feasible when, for structural reasons, both p-deprotonation at C-3 is prevented and when nucleophilic reactions of the intermediate N-benzoyloxy-2-e,xo-methyl-enepyrrolidine are sterically hindered. Experimental For instrumentation details see previous paper in series. 3-Methylbut-3-enone 1.-The ketone 1 was prepared from butanone according to the method of Cook and Waring;7 b.p. 98-100 "C 98-100 "C), m.p. of 2,4-dinitrophenylhydra- zone 186-187 OC (lit.,' 189.5-191.5 "C). 3.5-Dimethyl-5-nitrohexan-2-one 2.-3-Methylbut-3-enone (1 1.47 g, 0. I36 mol) in dried tetrahydrofuran (THF) (30 cm3) was added over 2 h to a solution of freshly distilled 2- nitropropane (18.25 g.0.205 mol) and Triton B* (1 cm3) in dried THF (20 cm3) at 5 "C with vigorous stirring. The reaction mixture was quenched by acidification with hydrogen chloride gas and concentrated to afford an oil which was distilled to give the title nitro ketone (19.3 g, 82) as an oil, b.p. 80-85 "C at 0.1 mmHg 118-120"C at 2 mmHg); v,,,/cm-' 1718 and 3-Hyiiroxy-3,5-dimeth,vl-5-nitrohexan-2-one5.-Asolution of the hexanone 2 (3.92 g, 0.022 rnol) in carbon tetrachloride (20 cm3) was treated with acetic anhydride (8.13 g, 0.080 mol) and perchloric acid (70; 0.5 cm3) with stirring. After 24 h the FTIR spectrum of the solution revealed that the carbonyl stretch of * Triton B' Benzyltrimethylammonium hydroxide, 40 wt.solution in methanol. Aldrich Chemical Company Ltd. the ketone at 1718 cm-' was absent and had been replaced by a band at 1750 cm-' arising from the enol acetate 3. Water (50 cm3) and ether (70 cm3) were added to the dark brown solution followed by potassium hydrogen carbonate, added in portions until all effervescence ceased. The aqueous phase was separated and extracted with ether (50 cm3) and the combined ether fractions were washed with water (30 cm3), dried (CaCI,) and concentrated to afford an oil. This was taken up in di- chloromethane (DCM) (20 cm3) and m-CPBA (50 active peracid; 7.80 g, 0.022 mol) was added slowly to the solution with stirring. After 48 h the precipitated m-chlorobenzoic acid was collected and the filtrate was concentrated under reduced pressure to 15 cm3.After 2 h a further crop of rn-chlorobenzoic acid was collected and the filtrate was reduced to a colourless solid. This was taken up in ethanol (100 cm3) and treated with hydrochloric acid (2 mol drn-,; 20 cm3) for 2 h under reflux. The cooled solution was concentrated to 30 cm3 and extracted with chloroform (2 x 40 an3). The combined extracts were washed successively with sat. aqueous sodium hydrogen carbonate (2 x 30 cm3) and water (2 x 30 cm') and then dried (MgSO,) and evaporated to give the title hydroxy ketone (1.77 g, 45 based on ketone 2) which was recrystallised from DCM to give largeoff-whiteprisms,m.p.72-73 "C(Found: C, 51.2; H, 8.1;N, 7.3. C,Hl,N06 requires C, 50.8; H, 8.0;N, 7.4); v,,x/cm-l 3451,1700,154l,1455,1406,l352,1l92,1169and l151;6,1.31 (3 H, s, 3-CH,), 1.50, 1.55 (both 3 H, s, gem-CH,), 2.26 (3 H, s, COCH,), 2.48 (1 H, d, J 15.5, 4-H), 2.67 (1 H, d, J 15.5, 4'-H) and3.56(1 H, brs,0H);Sc23.52,25.26,27.76,28.32(4CH,),x 46.51 (C-4), 77.69 (C-3), 86.07 (C-5) and 21 1.6 (C=O).3-Hydroxy-2,3,5,5-tetramethyl-4,5-dihydro-3H-pyrrole1-0x-ide 6.-A mixture of the hexanone 5 (0.918 g, 4.85 mmol), THF (30 cm3), water (30 cm3) and ammonium chloride (1.35 g, 25.2 mmol) was cooled to 0-5 "C. Zinc dust (3.12 g, 47.7 mmol) was added slowly to the mixture over 2 h with vigorous stirring after which stirring was continued for a further 2 h. The zinc salts were then collected and washed with THF (2 x 20 cm3) and the combined filtrate and washings were reduced to 20 cm3 and extracted with chloroform (2 x 30 cm3).The combined extracts were dried (MgSO,) and concentrated under reduced pressure and the residue was recrystallised from ether-acetone (1 : 1) to give the title nitrone 6 (0.549 g, 72) as large plates, m.p. 109-1 10 "C (Found: M+, 157.1 103. C,H,,N02 requires M', 157.1103); v,,,/cm-' 3219, 1617, 1474, 1458, 1437, 1375, 1319, 1310, 1242, 1227 and 1184; 6, 1.6 (3 H, s, 3-CH3), 1.44, 1.45(both 3 H, s,gem-CH,), 1.97 (3 H, s, 2-CH,), 2.1 1 (1 H, d, J 12.0,4-H), 2.22 (1 H, d, J 12.0,4'-H) and 4.66 (I H, br s, OH); 9.05, 26.48, 26.90 (4 x CH3). 49.32 (C-4), 72.34 (C-3), 75.64 (C-5) and 147.4 (C-2); m/z (El) 157 (M', 573, 142 (10) and 43 (100);mlz (NH, chemical ionisation) I58 (M' + I, loo), 142 (10) and I40 (21).1,6-Dzben~oyloxy-3',5',5',5,6,8,8-heptarneth,v~-3'-hydro.uy-spiro2-oxa-l-azabicyclo3.3.0octnne-3,2'-pyrrolzdine8.-A stirred solution of the I-pyrroline I-oxide 6 (98 mg, 0.62 mmol) and pyridine (49 mg, 0.62 mmol) in DCM (5 em3) was treated with benzoyl chloride (87 mg, 0.62 mmol) over 16 h. It was then diluted with DCM (20 cm3), and washed with sat. aqueous potassium hydrogen carbonate (2 x 10 cm3), dried (MgSO,) and evaporated to provide a foam, m.p. 69-70 "C (Found: M+ +I, 523.2808. C,,,H,,N,O6 requires M + 1, 523,2808); v,,,/ cm~'3397,1746,1738,1601,1453,1408,1381,1314and1246;JH l.ll,1.19,1.20,1.21,1.30,1.37,1.55(each3H,s.7x CH,),1.60 (1 H,d,J15.1), 1.81 (1 H,d,J12.0), 1.85(1 H,d.J13.8),2.21(1 H, d, J 12.0), 2.45 (1 H, d, J 13.8), 2.48 (1 H, d, J 15.1), 5.14 (1 H, br s, OH) and 7.38-8.04 (10 H, m, 2 x ArH); 6, 17.30q, 25.45q, 25.55q, 26.80q, 29.10q, 29.24q, 29.55q (7 x CH,), 41.60t (C-4), 50.36t (C-4'), 51.16t (C-2), 62.22s (C-8), 65.16s (C- 5'),74.00~ (C-5), 75.48s (C-3'), 87.27s (C-6), 106.1 (C-3), 128.5d, 128.64, 129.ld, 129.3d, 129.64, 129.7d, 133.2d, 133.64 (2 x ArH), 166.3s and 166.9s (2 x GO); m/z (EI) 523 (M+ +I, 279,401 (71), 343 (lo), 302 (12), 281 (39,279 (34), 262 (38), 244 (18), 221 (26), 264(23), 140(18), 124(25), 122(32), 105 (loo), 77 (36) and 43 (33); m/z (NH, chemical ionisation) 523 (M' + 1, lo), 401 (49,281 (loo), 279 (50), 262 (45) and 105 (18).Acknowledgements This work was supported by SmithKline Beecham plc.The mass spectra were determined by the SERC Mass Spectrometry Service at the University College of Swansea. 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Waring, J. Chem. Soc., Perkin Trans. I, 1973, 529. 8 N. J. Gibson, Ph.D. Thesis, University of Aberdeen, 1991. 9 W. Kemp, Qualitative Organic Analysis, Spectrochemical Tech- niques, McGraw-Hill, Maidenhead, 2nd edn., p. 155. 10 J. P. Alazard, B. Khemis and L. Lusinchi, Tetrahedron, 1975, 31, 1427. 11 D. St. C. Black and R. J. Strauch, Aust. J. Chem., 1989,42, 71. Paper 4104555F Received 25th July 1994 Accepted 24th October 1994