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Electrochemical reductive cleavage of 1,3=dioxanes containing nitro or halo groups was studied in aprotic medium. The voltammetric behavior of these compounds showed the formation of a radical anion which is relatively stable on the time scale of cyclic voltammetry.
Electrochemical reductive cleavage of 1,3=dioxanes containing nitro or halo groups was studied in aprotic medium. The voltammetric behavior of these compounds showed the formation of a radical anion which is relatively stable on the time scale of cyclic voltammetry.
Electrochemical reductive cleavage of 1,3=dioxanes containing nitro or halo groups was studied in aprotic medium. The voltammetric behavior of these compounds showed the formation of a radical anion which is relatively stable on the time scale of cyclic voltammetry.
Hertrochimica Arm, Vol. 42. Nos. 13-14. 2089-2099. pp. 1997
0 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain PII: !30013-4686(96)004864 0013-4686/97 $17.00 + 0.00 Electrolabile protecting groups for ketones: the electrochemical reductive cleavage of 1,3=dioxolanes and 1,3=dioxanes containing nitro or halo groups R. Labrecque, J. Mailhot, B. Daoust, J. M. Chapuzet and J. Lessard* Centre de Recherche en filectrochimie et filectrocatalyse, Dtpartement de Chimie, Sherbrooke, Sherbrooke, Quebec J 1 K 2R1, Canada Universitt de (Received 6 November 1996) Abstract-The electroreductive cleavage of 4-(4-nitrophenyl)-1,3-dioxolanes 1, 7-nitro-1,3benzodioxane 2 and 5-nitro-1,3-benzodioxanes 3 was studied in aprotic medium (DMF/Et.+NClO, (0.1 M)). The voltammetric behavior of these compounds showed the formation of a radical anion which is relatively stable on the time scale of cyclic voltammetry. When the electroreduction of these compounds was carried out at cu. - 1.5 V vs Ag/Ag+ (0.01 M), at the potential of the formation of the radical anion, its cleavage did occur with the formation of the corresponding ketone. We also investigated the electroreduction of the 4-halomethyl- and 4,5-dihalomethyl-1,3-dioxolanes (4 and 5). 0 1997 Elsevier Science Ltd. Key words: 4-(4-nitrophenyl)-1,3-dioxolanes, 7-nitro-1,3-benzodioxane, cyclic voltammetry, polarography, electroreduction, electrolabile protecting groups, INTRODUCTION Thioketals and ketals are useful protecting groups of ketones and aldehydes [l]. In the literature, the electrochemical deprotection of 1,3-dithiolanes and 1,3-dithianes [2,3], diethyl dithioacetal [4], and of 4-phenyl-1,3-dioxolanes [5] was accomplished by oxidation at relatively low potentials (f0.8 V to + 1.3 V vs see) with good to excellent yields. On the other hand, the cathodic cleavage of 4-nitrobenzyl- carbamates to the corresponding amines has been successfully carried out in aprotic media [6]. Ketals of I-bromopropane-2,3-diol have been used as protect- ing groups and removed by reductive cleavage with zinc [7]. However, to our knowledge, no example of electrochemical reductive cleavage of 1,3-dioxolanes has been reported. In this paper, we report the results of a study of the cathodic cleavage of 4-(4-nitro- phenyl)-1,3-dioxolanes 1,7-nitro-1,3benzodioxane 2, 5-nitro-1,3benzodioxanes 3, halomethyl-1,3-diox- olanes 4 and 4,5-dihalomethyl- 1,3-dioxolanes 5 in an aprotic medium. The nitro group being easily reduced to the radical anion, it should be possible to cleave *Author to whom correspondence should be addressed. dioxolane 1 and dioxanes 2 and 3 selectively by electroreduction in the presence of a variety of functional groups. EXPERIMENTAL General Solutions for all voltammetric analyses and preparative electrolyses were deoxygenated by bub- bling with dry argon and an argon atmosphere was maintained throughout the experiments. The cyclic voltammetry experiments were performed using a Princeton Applied Research (PAR) 173 potentiostat in a single compartment cell with 7 ml of electrolyte solution containing 2 or 5 x 10m3 M of substrate. No correction was applied to compensate for the solution resistance. The voltammograms were recorded and processed using the EG&G software M270. The hanging mercury electrode was prepared by elec- trodeposing a mercury drop at the tip of a platinum wire 1 mm in diameter. A platinum wire (2 mm in diameter) or a glassy carbon rod (3 mm in diameter) were used as the counter electrode and a Ag/Ag+ electrode (0.01 M) served as the reference. The & RI=CH3 R2= /&JJ polarography experiments were performed in the same cell and with the same counter electrode and reference electrode as the cyclic voltammograms, the characteristics of the dropping mercury electrode being m = 3mg/s, t = 7s, height = 650mm and using a PAR 174 polarographic analyzer and a PAR RE0089 X-Y recorder and a scan rate of 2 mV/s. The controlled potential electrolyses were carried out at a mercury electrode in a vertical glass cell with two compartments separated with a glass frit, using an Electrosynthesis Company (ESC) 410 potentiostat with an ESC 640 coulometer and an ammeter connected in series within the auxiliary circuit. The volume of the cathodic compartment was 40 ml, that of the anodic compartment 10 ml. The substrate concentration in the catholyte was 5 mM. The same reference electrode as above was used and the counter electrode was a platinized platinum grid (1.5 cm x 1.5 cm). The mercury was washed in he usual way and distilled [8]. Dimethylformamide (DMF) was dried and distilled under argon [9]. Tetraethylammonium perchlorate (EbNClOd) was prepared and dried at 69C for 12 h [lo]. After the current dropped to zero, the catholyte was poured into ether (or ethyl acetate) and the solution was washed with brine. The organic phase was dried (MgS04) and the solvent evaporated. The residue was dissolved in 100 ml of ethyl acetate for determining the yield of ketone by vapor phase chromatography (VPC) using a Hewlett Packard (HP) 5710A chromatograph with a FID detector, a HP 339014 integrator and a DB-5 fused silica capilary column (30 m). The other products formed were isolated by thick layer chromatography on silica gel (Merck F254) using mixtures of hexane and ether as eluent. Infrared spectra were recorded in chloroform on a Perkin Elmer 1600 FTIR spectrometer and nuclear magnetic resonance spectra were recorded on deuterochloroform or deuteroacetone on a Bruker AC-300 spectrometer using the signal from chloroform or acetone as reference (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet). Substrate synthesis and characterization The synthesis of compounds la, lb, lc, 2a, 3a, and 3b will be reported elsewhere. Halomethyl and dihalomethyl-dioxolanes 4 and 5. The bromomethyl and dibromomethyl-dioxolanes 4b (X = Br) and Sb (X = Br) were prepared by reaction of 1 -bromopropane-2,3-diol and dl- 1,4-di- bromobutane-2,3-diol and I-phenylpropan-2-one ac- cording to a published procedure [ 111. dl-Dibromobutane-2,3-diol was obtained from Aldrich. I-Bromopropane-2,3-diol was prepared as described [12]. The iodomethyl and diiodomethyl dioxolanes 4b (X = I) and 5b (X = I) were prepared from the corresponding bromomethyl and dibro- momethyldioxolanes (4b, X = Br and 5b, X = Br) by heating to reflux a solution of the bromodioxolane and sodium iodide in excess (4 to 8 equivalents) in acetone. Bromomethyldioxolane 4b (X = Br): oil, l/l mixture of isomers (69% yield); MS (m/e): 255 (M+ = CH3) and 179 (M+ = CrHr); HRMS: 255.0019 (calcd for C~~H~~B~OZ-CHJ: 255.0021); ir (CHCIr): 1600 (C=C arom.), 1220 and 1050 (C--o--c) cm-; H-NMR (CDCh): 6 = 1.33, 1.39 (3H, s, CHr), 2.97 (2H, s, CHzPh), 3.78-4.18 (4.5H, m, CHzBr, CH20 of isomers A and B and CH-CHr of isomer B), 4.24-4.31 (0.5H, m, CH-CH2 of isomer A), 7.22-7.34 (5H, m, CH arom.) ppm; W-NMR (CDClr): 6 = 24.4, 25.7 (CH3), 32.2, 32.7 (CHzPh), 45.2, 45.9 (CHzBr), 68.5, 68.7 (CHzO), 75.4, 75.6 (CH), 111.3, 111.6 (C-CHJ), 126.5, 131.7 (CH arom.), 136.5, 137.2 (CH arom.) ppm. Dibromomethyidioxolane Sb (X = Br): oil (85% yield), MS (m/e): 273 (M+ = CrH,); H-NMR (CDCL): 6 = 1.44 (3H, s, CH3), 2.96 (2H, d, J = 2.0 Hz, CHzPh), 3.15-3.29 (2H, m, CHzBr), 3.40-3.65 (2H, d, CHzBr), 4.12 (lH, m, 0-CH), 7.25-7.30 (5H, m, CH arom.) ppm. I odomethyldioxolane 4b (X = I): oil, l/l mixture of isomers (95% yield); MS (m/e): 303 (M+ = CH,), 227 (M+ = CHsPh); HRMS: 302.9896 (calcd for C~~HI~IO~-CH~: 302.9884); ir Electrolabile protecting groups for ketones 2091 (CHCb): 1600 (C=C arom.), 1220 and 1030 (CW) cm-; H-NMR (CDCh): fourteen signals corresponding to seven different protons of each diastereoisomer: 6 = 1.31 (3H, s, CHr of one isomer), 1.40 (3H, s, CH3 of one isomer), 2.71 (lH, dd, J = 7.8 Hz, J = 10.0 Hz, Hi of one isomer), 2.89 (2H, s, CHrPh of one isomer), 2.98 (2H, s, CHzPh of one isomer), 2.99 (lH, dd, J = 4.8 Hz, J = 10.0 Hz, HI on one isomer), 3.12 (lH, dd, J = 7.5 Hz, J= 10.0 Hz, HI of one isomer), 3.23 (lH, dd, J = 5.0 Hz, J = 10.0 Hz, Hz of one isomer), 3.52 (lH, dd, J= 5.0 Hz, J = 8.8 Hz, Hj of one isomer), 3.934.05 (two overlapping signals, lH, dd, J = 5.5 Hz, J = 8.8 Hz, Hr of one isomer), 4.2334.34 (lH, m, H2 of one isomer) ppm. Diiodomefhyfdixofune 5b (X = I): oil (86% yield); MS: 459 (M+), 443 (M+ = CH3); HRMS: 458.9337 (calcd for Ci3H&02: 458.9221); ir (CHClj): 1600 (C==C arom.), 1240 and 1020 (C-O-C) cm-; H-NMR (CDClj): d = 1.44 (3H, s, CHj), 3.04 (2H, d, J = 5.8 Hz, CHlI ), 3.31 (3H, m, CHCHrI and CHzI), 3.86 (lH, m, CHCHzI), 7.24-7.30 (5H, m, CH arom.) ppm. Characterization of secondary products from electrolyses Amide 11: oil (17-26% yield); MS (m/e): 382 (M+); HRMS: 382.1521 (calcd for Czi HzzN205: 382.1529); ir (CHClj): 1678 (C==O), 1602 (C==C arom.), 1527 and 1348 (NOz), 1104 (C-O-C) cm-l; H-NMR (CDCIx): 6 = 1.39-1.85 (lOH, m, CH2), 3.68 (lH, dd, JAM = 8.0 HZ, JAX = 8.1 HZ), 4.30 (lH, dd, JXM = 6.1 Hz, JXA = 8.1 Hz), 5.07 (lH, dd, J MX = 6.1 HZ, J MA = 8.0 HZ), 7.40 (2H, d, J = 8.5 Hz, CH ortho to NH), 7.62 (2H, d, J = 8.5 Hz, CH meta to NH), 7.94 (lH, s, NH), 8.03 (2H, d, J = 8.8 Hz, CH meta to NOz), 8.33 (2H, d, J = 8.8 Hz, CH ortho to NO2) ppm; 13C-NMR (CDC13): 6 = 23.7, 23.9, 25.0, 35.3, 36.1 (CH2), 71.2 (CH2-0) 77.0 (CH-O), 110.3 (C quaternary aliph.), 120.7, 123.7, 126.9 and 128.3 (CH arom.), 136.4, 136.9, 140.2 and 149.5 (C quaternary), 164.0 (C=O) ppm; identical to an authentic sample prepared by an independent synthesis. Formamide derivative 12: oil (5-8% yield); MS (m/e): 262 (M+ = C3HhNO); CI (isobutane): 335 (MH+); HRMS: 335.1618 (calcd for CirHrrN205: 335.1607); ir (CHCl3): 1671 and 1640 (amide), 1603 (C=C arom.), 1524 and 1350 (Nor), 1226 (C-O-C) cm-; H-NMR (CDC13): 6 = 1.40-1.85 (lOH, m, CHz), 2.89 and 2.96 (6H, s, CH3), 3.71 (lH, d, J = 8.6 HZ, CHAHB), 5.22 (lH, d, J = 8.6 HZ, CHAH~), 7.66 (2H, d, J = 8.9 HZ, CH meta to NO?), 8.21 (2H, d, J = 8.9 Hz, CH ortho to Nor); 13C-NMR (CDC13): 6 = 23.9, 25.0, 35.4, 35.8 (CHr), 37.1 and 37.7 (CHr), 74.0 (CHz-O), 112.8 (C quatemary aliph.), 124.0 and 125.4 (CH arom.), 147.2 and 170.2 (C-Nor, C=O) ppm. Aminodioxolane 19b: oil (12% yield); MS (m/e): 269 (M+); HRMS: 269.1416 (calcd for CirHi9NOr: 269.1415); ir (CHCl3): 1639 (NH), 1605 (C=C arom.), 1214 (C-N) cm-; H-NMR, (CDCI3): 6 = 1.47 (3H, s, CH3), 3.00 (2H, s, CHlPh), 3.64 (IH, dd, J AM = 8.3Hz, J AX = 8.5Hz), 4.12 (lH, dd, J XM = 5.9 Hz, J XA = 8.3 HZ), 4.59 (lH, dd, J MX = 5.9 HZ, J MA = 8.3 HZ), 6.65 (2H, d, J = 8.5 Hz, CH ortho to NH& 7.10 (2H, d, J = 8.5 Hz, CHmeta to NH?), 7.21-7.38 (5H, m, CH arom.) ppm. Azoxy compound 2Qa: oil (65% yield); MS (m/e): 478 (M+); HRMS: 478.2456 (calcd for CzsH34N205: 478.2468); ir (CHCl3): 1606 (C=C arom.), 1464 (N=N-O), 1279 (N=N--O), 1103 (C-O-C) cm-; H-NMR (CDCl3): 6 = 1.4G1.90 (20H, m, CH2), 3.67-3.74 (2H, m, CHAHB), 4.314.39 (2H, m, CHAHB), 5.11-5.19 (2H, m, CH-O), 7.48 (2H, d, J = 6.3 Hz, CH ortho to N), 7.51 (2H, d, J = 6.3 Hz, CH meta to N), 8.22 (2H, d, J = 8.6 Hz, CH meta to N-O), 8.29 (2H, d, J = 8.6 Hz, CH ortho to N-O) ppm; 13C-NMR (CDC13): 6 = 23.9, 24.0, 25.2, 35.5, 36.1 (CH2), 71.2 (CHT-O), 76.8 and 77.3 (CH-O), 110.6 and 110.9 (C quaternary aliph.), 122.6, 125.8, 126.4 (CH arom.), 141.2, 143.7 and 147.8 (C quaternary) ppm. Lactone 24: oil (15-23% yield): MS (m/e): 263 (M+); HRMS: 263.0794 (calcd for Cr~HirN05: 263.0794); ir (CHCl3): 1743 (c--O), 1619 (C==C arom.), 1538 and 1350 (NO& 1263 (Ar-0) cm-; H-NMR (CDCI,: 6 = 1.45-2.10 (lOH, m, CHz), 7.85 (lH, d, J = 2.1 Hz, CH arom. ortho to NOz), 7.93 (lH, dd, J = 2.1 Hz, J = 8.5 Hz, CH arom. ortho to NOz and meta to C=O), 8.14 (lH, dd, J = 8.5 Hz, CH arom. ortho to 0) ppm; C-NMR (CDCl3): 22.1, 24.3, 33.4 (CHz), 108.3 (C-O), 113.0, 117.0, 131.1 (CH arom.), 152.5, 156.1, 159.2 (C arom. quaternary) ppm. 2-Hydroxy-4-nitrobenzaldehyde (25): oil (2&28% yield); MS (m/e): 167 (M+) HRMS: 167.0219 (calcd for C,HsNOd: 167.0219); ir (CHC4): 1674 (C=O), 1604 (C==C arom.), 1533 and 1352 (NO& 1190 (Ar-0) cm-; H-NMR (CDC13): 6 = 7.75-7.87 (3H, m, CH arom.), 10.05 (lH, s, HC=O), 11.1-l 1.2 (lH, m, OH) ppm; i3C-NMR (CDCl3): 6 = 113.5, 114.3, 134.7 (CH arom.), 152.5, 161.9 (C arom. quaternary), 195.9 (C=O) ppm. Lactone 34: oil (23-26% yield) MS (m/e): 263 (MC); HRMS: 263.0788 (caked for CrrHuN05: 263.0794); ir (CHCI3): 1743 (C=O), 1619 (W arom.), 1538 and 1350 (NOz), 1263 (Ar-0) cm-, H-NMR (CDCl3): 6 = 1.45-2.12 (lOH, m, CH2), 7.18-7.28 (2H, m, CH arom.), 7.63 (lH, t, J = 7.24 Hz, CH arom.) ppm; 2092 -17 t R. Labrecque et al. I , I I I I I , -I -1.5 -2 -2.5 -3 V Fig. 1. Cyclic voltammogram of la (2 mM) at Hg cathode Fig. 2. Polarogram of la (2 mM) in DMF/EtsNClOd in DMF/EbNClOd (0.1 M); reference electrode: Ag/Ag+ (0.1 M); reference electrode: Ag/Ag+ (0.01 M); counter (0.01 M); counter electrode: vitreous carbon; scan rate: electrode: vitreous carbon; 7 = 0. 5 s; scan rate: 2 mV s-r; 100 mV s-l; room temperature. h = 38 cm; m = 0.8 mg s-l; room temperature. )C-NMR (CDCl3): 6 = 22.1, 24.3, 34.2 (CHr), 107.9 (C-O), 117.0, 120.5, 136.0 (CH arom.), 155.9 and 156.4 (C arom. quaternary) ppm. 2-Hydroxy-64trobenzaldehyde (35): oil (28-31% yield); MS (m/e): 167 (M+); HRMS: 167.0215 (calcd for CrHsN04: 167.0219); ir (CHCb): 1659 (c--O), 1600 (C=C arom.), 1532 and 1356 (NO& 1177 (Ar-0) cm-; H-NMR (CDCl3): 7.267.66 (3H, m, CH arom.), 10.32 (lH, s, HC=O), 12.1 (lH, s, OH) ppm; 13C-NMR (CDCl3): 116.1, 124.2, 135.9 (CH arom.), 151.2, 163.3 (C arom. quaternary), 193.8 (C=O) ppm. RESULTS AND DISCUSSION Electrochemical behavior of nitro l&dioxolanes Cyclic voltammetry and polarography The voltammetric study of 2-cyclohexyl-4-(4-ni- trophenyl)-1,3-dioxolane la has been carried out at a mercury cathode in DMF/EbNClOb (0.1 M) at room temperature. The cyclic voltammogram of la shown in Fig. 1 is typical of the voltammogram of 4-(4 nitrophenyl)-1,3-dioxolanes lb and lc. The cyclic voltammetric data are given in Table 1. By comparison with the electrochemical behavior of nitrobenzene [8] under the same conditions, the cathodic peak Ic and the anodic peak Ia were attributed to the reversible reduction of la to its radical anion 6 which has some kinetic stability on the voltammetric time scale (Scheme 1). The third cathodic peak III corresponds to the classical three-electron reduction of the radical anion to hydroxylamine 10 via the dianion 7 (Scheme 1). This has been confirmed by polarography. Again the polarogram of la shown in Fig. 2 is typical of the polarograms of the other 1,3-dioxolanes studied. Wave I (El/z = - 1.50 V) and wave III (El/ 2 = -2.47 V) correspond respectively to peaks Ic and III of Fig. 1, the ratio of diffusion currents of wave III and wave Ic (&a/&) being 2.7 as observed by Huang [8] in the polarogram of nitrobenzene. Evidence of cleavage of the radical region 6 (see Scheme 1) was proved by the decrease of ratio of the cathodic peak current to the anodic peak current (i&la) upon increasing the scan rate. In the case of dioxolane la, this ratio decreased from 1.4 at 50 mV s-i to 1.1 at 600 mV s-l. That cleavage to the ketone did occur was confirmed by preparative electroreduction at potentials of which the radical anion 6 is formed (see below). The assignment of the irreversible cathodic peak II (see Table 1 and Fig. 1) to which corresponds wave II (E1,2 = -2.19 V (ill/i, = 2.1)) of Fig. 2 proved much more difficult. The intensity of this peak relative to that of peak Ic (or to peak III) decreased with increasing scan rate. For instance i~+~c decreased froml.5at50mVs-tol.2at600mVs-.Again,a similar behavior was observed with the other 4-nitrophenyl-1,3-dioxolanes. Such a decrease of irl/il, Table 1. Cyclic voltammetric data for dioxolanes la, lb and 1~9 Peak potential in Vb (and current ratios) Dioxolane Ic Ia (L/h) II (hrihe) III (h/ik) la - 1.57 -1.42 (1.3) -2.32 (1.5) -2.60 (2.5) lb - 1.50 - 1.38 (1.4) -2.17 (1.5) -2.48 (2.5) IC - 1.58 -1.42 (1.3) -2.32 (1.6) -2.54 (2.3) Conditions: DMF/EtNClOd (0.1 M); cathode: Hg; counter electrode: vitreous carbon; scan rate: 100 mV s-r; substrate concentration: 2 mM; room temperature. bReference electrode: Ag/Ag+ (0.01 M). Electrolabile protecting groups for ketones 2093 Scheme 1. with increasing scan rate strongly suggests that this peak corresponds to the reduction of species formed by the cleavage of radical anion 6 to the corresponding ketone. As the scan rate increases, the rate of cleavage of 6 being constant the proportion of cleavage of 6 occurring during the voltammetric sweep decreases and hence the i& ratio decreases. Peak (wave) II was therefore tentatively assigned to further reduction of the distonic radical anion 8 (Scheme 2) (see [13] for the origin of the term distonic). As will be seen below, a product (see 11) resulting from 8 has been isolated from the preparative electroreduction of la. According to literature data, peak (wave) IV was assigned to the reduction of the superoxide anion (OF, EtN+) [14]. _Oy=Jd_ s I-e ? 0 +4 Ar- N,f\ Preparative electrolyses Controlled-potential electrolyses were carried out under the same conditions as those used for cyclic voltammetry and polarography. The substrate con- centration was 5 mM. The electrolyses were stopped when the current dropped to zero and the results are reported in Table 2. At the working potential of entries 1 to 6 (reduction of 1 to the radical anion 6), cleavage to the ketone occurred. The yield of ketone increased from 30% to 45-55% as the temperature was decreased from 0 to - 15C (entries 1 to 6) as a result of a decrease of the rate of side reactions consuming the substrate. Amide 11 and dioxolane 12 (structures y=y-_ Aa !I!! 3j or 16 (ekmtrode) k Q z +=+H!~NC& u Scheme 2. 2094 Table 2. R. Labrecque et al. Preparative electroreduction of dioxolanes la, lb and lc: effect of working potential and temperature& Yield of other products Yieldd of Potential ketone 12 Entry Dioxolane (Vb) n(e) (%) (!) (i) (%) I lb -1.5 0 1.8 30 n.d. - 2 lb -1.5 -15 2.1 49 n.d. 3 la -1.5 0 2.0 34 - 26 8 4 la -1.5 -15 1.5 55 - 18 5 5 la -1.5 -20 2.1 41 - 17 5 6 lc -1.5 -15 2.5 45 - 7 lb -2.2 0 5.2 30 n.d. - 8 lb -2.5 0 4.7 I7 12 - Electrolysis conditions: DMF/Et.+NClOd (0.1 M); cathode: Hg; counter electrode: Pt; concentration: 5 mM. bReference electrode: Ag/Ag+ (0.01 M). The electrolysis was stopped when the current dropped to zero. dYield determined by vapor phase chromatography (VPC): I-phenylpropan-2-one from lb and cyclohexanone from la (the yield of isolated ketone was lower by about 2 to 5%). Yield of product isolated by thick layer chromatography. shown in Schemes 2 and 3) resulting from such side The formation of dioxolane 12 clearly involves the reactions were isolated and their yield was indeed benzylic position of dioxolane la and DMF (Scheme lower at - 15C than at 0C (compare entries 3 and 3). That the mechanism illustrated in Scheme 3 is 4). Lowering the temperature further to -20C did plausible was shown by the isolation of dioxolane 12 not cause any further increase of the yield of from the reaction of dioxolane la with sodium cyclohexanone and any further decrease of the yields hydride (5 eq.) in DMF/EtNClOd (0.1 M) (the of amide 11 and dioxolane 12 (entry 5). In amide hydride acceptor is most probably the nitro group of 11, the amine fragment clearly comes from the the dioxolane la). In effect, at OC, after a reaction reduction of the nitro group of dioxolane la and the time (5 h) corresponding to the duration of the carbonyl fragment must come from the distonic preparative electrolyses, extensive decomposition of radical anion 8 formed in the cleavage of the radical dioxolane la occurred since only 11% of la was anion 6a (Scheme 1). A possible mechanism for recovered. Dioxolane 12 was isolated in a 10% yield the formation of amide 11 is shown in Scheme 2 and 6% of cyclohexanone was formed. In order to where the nitro group of dioxolane la would oxidize verify that, during preparative electrolyses, cyclohex- the anion 14 to the nitrone 16 which would anone was not formed by cleavage of the benzylic then be hydrolyzed to the amide 11 during the anion 17 (Scheme 3) (deprotonation of la by work up (such hydrolysis has literature precedent electrogenerated bases), the stability of dioxolane la PSI). was examined in basic medium. At 0C. in Scheme 3. Electrolabile protecting groups for ketones 2095 DMF/Et4NC104 (0.1 M), in the presence of one equivalent of sodium hydride and after 5 h, dioxolane la was stable since 92% of the starting substrate was recovered together with 4% of cyclohexanone. When the reaction was performed at - 15C no cyclohex- anone was formed and the starting dioxolane la was quantitatively recovered. As a result, yields of deprotection reported in Table 2 are due to the cleavage of the radical anion 6. Carrying out the electroreduction of dioxolane lb at a potential (- 2.2 V) at which the distonic radical anion 8 would be reduced (entry 7 of Table 2) had no effect on the yield of 1 -phenylpropan-2-one (compare with entry 1) in agreement with the mechanism proposed in Scheme 2 for the formation of amide 11. When the reduction of dioxolane lb was carried out at the potential (-2.5 V) of the reduction of the radical anion 6b to the dianion 7b (see Scheme I), the yield of I-phenylpropan-Zone was significantly lower (17%, entry 8 of Table 2) most probably because protonation of dianion 7b, a stronger base than the radical anion 6b, competes more effectively with its cleavage to 9 and 1 -phenylpropan-2-one {Scheme 1). The hydroxylamine lob (Scheme 1) was not detected (an authentic sample was prepared by electroreduc- tion) but the amine 19b was isolated in 12% yield from the electrolysis carried out at 0C (entry 8). Thus, as reported by Huang [8] for the electroreduc- tion of nitrobenzene in the same medium, the dioxolane lb was reduced to amine 19b at the potential of the reduction of the radical anion to the dianion. We have studied the influence of adding relatively strong proton donors on the yield of cyclohexanone in the reductive cleavage of dioxolane la carried out at 0C at - 1.5 V in DMF/EbNClOa (0.1 M). The results are reported in Table 3. The presence of an acid caused a decrease of the yield of cyclohexanone (compare entries 2 to 4 with entry 1). The yield of ketone was lower in the presence of acetic acid (entry 2) than in the presence of phenol (entry 3), a weaker acid than acetic acid. Increasing the concentration of phenol carried a decrease in the yield of ketone (entry 4). The decrease in the yield of ketone in the presence of such proton donors can be readily explained by the fact that protonation of the radical anion 6a does compete with its cleavage to the ketone. Hence, the stronger or more concentrated is the acid, the faster is the protonation and the lower the yield of ketone as observed. That protonation of the radical anion 6a did occur was confirmed by the isolation of the azoxy EA 42/13-l - Table 3. Preparative electrolysis of 2-cyclohexyl-4-(4.nitrophenyl)- 1,3-dioxolane la at 0C: effect of acid on the yield of cyciohexanonea Entry Acid n(e) Yield of ketone (%) lb None 2.0 34 2 CHKOOH (2 eq.)b 2.3 12 3 Phenol (2 eq.) 2.9 25 4 Phenol (6 eq.) 3.0 10 5 Li+(LiC104 (2 ea.))d 3.0 25 Conditions: DMF/Et4NC104 (0.1 M); cathode: Hg; counter electrode: Pt; reference electrode: Ag/Ag+ (0.01 M); substrate concentration: 5 mM; working potential: - 1.5 V. bTaken from Table 2, entry 3. CThe axoxy compound 2Oa was isolated in a 65% yield. dLi+ is a Lewis acid. compound 20a in 65% yield in the electrolysis of entry 2. Huang [8] has reported that the presence of a proton donor does favor the formation of azoxyben- zene in the electrochemical reduction of nitrobenzene in DMF/Et4NC104 (0.1 M). The azoxy compound is formed by the reaction between the nitroso derivative resulting from reduction of the protonated radical anion with the hydroxylamine formed by reduction of the nitroso derivative (a well known mechanism) [16]. The presence of LiC104 in the electrolysis medium also led to a decrease in the yield of cyclohexanone (entry 5). Strong ion pairing or complexation between the radical anion 6a and the lithium cation (a Lewis acid) most probably lowers the rate of cleavage of 6a. Electrochemical behavior of nitro 1,3dioxanes The cieavage of the radical anion derived from the reduction of nitrodioxanes such as 2 and 3 would give the corresponding ketone and a radical anion 21 as illustrated in Scheme 4. We wanted to verify if such a radical anion and species derived from it could be less reactive than the distonic radical anion 8 formed in the cleavage of dioxolanes 1 and species derived from it (see I4 in Scheme 2) and if, as a consequence, the yield of cleavage to ketone could be higher with the dioxanes than with the dioxolanes. The yield of cleavage was found to be higher with the dioxanes will as be seen below. 2096 R. Labrecque et al. Scheme 4. Voltammetric behavior The cyclic voltammetric data of 1,3-dioxanes 2a, 3a and 3b are recorded in Table 4 and the voltam- mogram of 2a shown in Fig. 3 is representative of the voltammogram of the other dioxanes. The conditions are the same as those used for the voltammetric study of the 1,3-dioxolanes above. Peaks Ic and Ia correspond to the nitrodioxane/radical anion reversible redox couple. The ratio iic/Zia larger than one shows that cleavage of the radical anion does occur on the voltammetric time scale and this ratio approaches 1 when the scan rate is increased as in the case of the dioxolanes 1. Peak II is assigned to three-electron reduction of the radical anion to the hydroxylamine (or its conjugate base) via the dianion as in the cyclic voltammogram of nitro- benzene under the same conditions [8]. In polarogra- phy, the ratio iii/ii, is 2.6, a value very close to the value of 2.7 observed in the polarogram of nitrobenzene [8]. Peak III could result from the reduction of a specie formed in the cleavage of the radical anion to the ketone, since the ratio ill,/& decreases upon increasing the scan rate (the ratio of the diffusion current of wave III and wave I, illl/il, in the polarogram of 2a is 0.5). This specie is not the ketone. Likely candidates would be a radical anion such as 22 (Scheme 4), the reduction of which could be more difficult than the reduction of the distonic radical anion 8 produced in the cleavage of 1,3-dioxolanes 1 (ca. -2.2 V) to a distonic dianion, or a specie derived from 22 such as the anion 23, resulting from protonation and reduction of 22 Table 4. Cyclic voltammetric data for dioxanes (Scheme 4). However, as in the case of dioxolanes (peak IV in Fig. l), peak III in Fig. 3 could also be attributed to the reduction of the superoxide anion (O;, EbN+) [14]. Peak IV on the reverse scan can be attributed to the oxidation of hydroxylamines (or their conjugate base) generated at the potential of peaks II and III. Huang [8] has observed an oxidation peak at - 1.34 V in the cyclic voltammogram of nitrobenzene under the same conditions and this peak was attributed to the oxidation of conjugate base of phenylhydroxylamine. Preparative electrolyses The controlled-preparative electrolysis of dioxanes 2a, 3a and 3b in aprotic medium was carried out at - 1.5 V, a potential at which the dioxane is reduced to its radical anion (see 21, Scheme 4), under the same conditions as those used in the electrolysis of dioxolanes 1. The results are recorded in Table 5. As in the case of dioxolanes 1, cleavage of radical anion 21 to the ketone did occur (Scheme 4). The yield of ketone was found to increase upon lowering the temperature from 0 to - 15C and the yield of cleavage to cyclohexanone was higher than that of cleavage to 1 -phenylpropan-2-one. However, the yield of ketone at 0C and at - 15C was higher than in the case of the dioxolanes 1 as already mentioned. This means that secondary reactions consuming the starting nitrodioxanes 2 and 3 compete less effectively with the formation and cleavage of radical anion 21 than in the electrolyses of dioxolanes 1 as hypothesized above. That Peak potential in Vb (and current ratios) Dioxane IC la (h/h) II (ill/ilJ III (in&) IV 2a -1.57 -1.46 (1.4) -2.40 (2.5) -2.84 (0.9) -1.28 3n - 1.56 -1.44 (1.5) -2.37 (2.4) -2.78 (0.3) -1.18 3b -1.53 -1.41 (1.5) -2.34 (2.4) -2.76 (0.4) - 1.20 Conditions: DMF/Et4NC104 (0.1 M); cathode: Hg; counter electrode: vitreous carbon; Scan rate: 100 mV s-i; substrate concentration: 2 mM; room temperature. bReference electrode: Ag/Ag+ (0.01 M). Electrolabile protecting groups for ketones 2097 -17 UA t n m -12 - -7 - -1 - 3 I) 4.2 -1.2 -1.1 -3.1 v Fig. 3. Cyclic voltammogram of 2a (2 mM) at Hg cathode in DMF/EtaNClOd (0.1 M); reference electrode: Ag/Ag+ (0.01 M); counter electrode: vitreous carbon; scan rate: 100 mV s-; room temperature. such secondary reactions do not interfere was shown by the isolation of lactone 24 and aldehyde 25 from the electrolysis of dioxane 2a. In fact, the yield of these products were lower at - 15C (15% for 24 and 20% for 25) than at 0C (23% and 28% respectively). The lactone 24 must result from the oxidation of the benzylic position of dioxane 2a whereas aldehyde 25 must come from the radical anion 22 formed in the cleavage of the radical anion 21, the benzylic position having been oxidized also. During the electrolysis, the most likely oxidizing species is the unreacted nitrodioxane 2a. Mechanisms for the formation of 24 and 25 are proposed in Schemes 5 and 6, respectively, in which the oxidation step involves the reaction of a carbanion with the nitro group to form a nitrone which is hydrolyzed during the work up. These mechanisms are similar to that suggested for the formation of amide 11 isolated from the electrolysis of dioxolane la (Scheme 2). It is interesting that the intermediate 33 of Scheme 6 apparently prefers Table 5. Preparative electrolyses of dioxanes to cleave to give aldehyde 25 and the hydroxylamine 29 (not detected) rather than eliminate water (as in Scheme 2) to give the corresponding amide which was not detected. This could be attributed to the intramolecular protonation of the hydroxylamine moiety as shown in Scheme 6 (intramolecular hydrogen bonding). Lactone 34 and aldehyde 35 were isolated also from the electrolysis of dioxane 3a at 0C and - 15C in yields (Table 5 entries 3 and 4) comparable to those of lactone 24 and aldehyde 25 obtained from 2a (entries 1 and 2). Like dioxolane la, the stability of dioxanes 2a and 3a in the presence of one equivalent of sodium hydride was examined in DMF/EbNClOd (0.1 M). At 0C dioxanes 2a and 3a led to 4% and 13% of cyclohexanone, respectively. In both cases, the mass balance consisted of the starting nitrodioxane. At - 15C no cyclohexanone was formed and the starting nitro compounds were quantitatively recovered. Electrochemical behavior of halomethyl 1Jdioxolanes The investigation on 4-halomethyl- and 4,5-di- halomethyl- 1,3-dioxolanes 4 and 5, as electrolabile protecting groups, seemed very interesting because the electroreductive cleavage of dioxolane 5, for example, would give an intermediate such as 36 (see Scheme 7) which should be unreactive towards the starting dioxolane as well as towards the ketone formed. We have studied their voltammetric behavior in aprotic medium (DMF/EbNClOd (0.1 M)) at a mercury cathode and at room temperature. We have observed only one peak of reduction for each of the dioxolanes 4b and 5b (see Table 6) when the bromine atom(s) is (are) replaced by iodine, the potential of reduction of dioxolane 4b increases from - 2.52 V to - 1.90 V (entries 1 and 2) and that of dioxolane 56 increases from - 2.46 to - 1.75 V (entries 3 and 4). Entry Dioxane Mediumb 1 2n DMF 2 2a DMF 3 3a DMF 4 3a DMF 5 3b DMF 0 -15 0 -15 -15 n(e) 2.0 1.5 2.2 1.3 2.1 Yield of ketone W) 59 65 54 66 42 Yieldd of other products Lactonec AIdehyde W) W) 23 28 15 20 26 31 23 28 - - Conditions: substrate concentration: 5 mM; cathode: Hg; counter electrode: Pt; reference electrode: Ag/Ag+ (0.01 M); working potential - 1.5 V in DMF. bDMF: DMF/Et4NC104 (0.1 M). (Determined by VPC. Cyclohexanone from 2a and 3a. I-phenylpropan-2-one from 3b. dYield of isolated product. Lactone 24 from 2a and 34 from 3a. AIdehyde 25 from 2a and 35 from 3a. 2098 R. Labrecque er al. HCMN-Ar + - 29 24 Scheme 5. Scheme 6 Rl R2 ox0 ii x x a 4 -0 Scheme 7. Electrolabile protecting groups for ketones 2099 Table 6. Cyclic voltammetric data and preparative electroreduction of dioxolanes 4b and 5b Yield of (7) Edr ketone Entry Dioxolane Xb (V) n(e) (%) 1 4b Br -2.52 -2.5 3.3 59 2 4b I -1.90 -1.9 3.1 74 3 5b Br -2.46 -2.5 5.0 95 4 5b I -1.75 -1.8 5.7 92 Conditions: DMF/Et4NCI04 (0.1 M) cathode: Hg, counter electrode; Pt, room temperature. bFunctional group on protecting group. Reference electrode: Ag/Ag+ (0.01 M); peak potential on cyclic voltammetry; substrate concentration: 1 mM. dReference electrode: Ag/Ag+ (0.01 M); working potential during electroreduction. Determined by vapor phase chromatography (vpc). Substrate concentration for preparative electrolyses: entry 1: 25 mM; entry 2: 20 mM; entry 3: 18 mM; entry 4: 9 mM. Then, the preparative electrochemical cleavage of the iododioxolanes can be performed at a less negative potential than that of the bromodioxolanes. In addition, the yield of ketone is higher with the iododioxolane 4b (X = I) than with the bromodiox- olane 4b (X = Br) (compare entries 2 and 1). It is noteworthy that the yield of ketone is almost quantitative (92-95%) with the dihalomethyl diox- olanes 5b (entries 3 and 4). From a synthetic point of view, the latters have a further advantage over the monohalomethyldioxolanes 4b in having a two-fold axis of symmetry (they were prepared from the dl- 1,4-dihalopropane-2,3-dials) (see Experimental). As a consequence, the dihalomethyldioxolanes 5b do not consist of a mixture of diastereoisomers as in the case of the monohalomethyldioxolanes 4b. CONCLUSION The introduction of a nitro group suitably positioned on the aromatic ring of 4-(nitrophenyl)- 1,3-dioxolanes (1) and of nitro-1,3-benzodioxanes (2 and 3) allows cleavage of the ketal to the ketone (removal of the protecting group) at the potential of the formation of the radical anion (as shown by the cyclic voltammetric and polarographic studies) in aprotic (- 1.5 V vs Ag/Ag+ (0.01 M)) medium. The yields could be substantially increased by carrying out the electrolysis at - 1 YC, that is by slowing down side reactions consuming the starting ketal. The yields of cleavage were higher in the case of the nitrodioxanes 2 and 3 than with the nitro-1,3-diox- olanes 1 because side reactions were less important. Furthermore, the former do not consist of a mixture of diastereoisomers since there is no asymmetric center in the nitro-2-hydroxybenzylic alcohols used to prepare the dioxanes whereas there is one asymmetric center in the I-(nitrophenyl)-ethane 1,2-diols used to prepare the dioxolanes. This is an advantage from the synthetic point of view. The dihalomethyl-1,3-diox- olanes sb, also not consisting of a mixture of diastereoisomers, were cleaved to the ketone in an almost quantitative yield but at a more negative potential (-2.5 V for X = Br, - 1.8 V for X = I) than the dioxolanes 1 and the benzodioxanes 2 and 3. ACKNOWLEDGEMENTS Financial support from the National Research Council of Canada (fellowships to R.L. and J.M. and operating grants to J.L.) and the Fonds FCAR du QuCbec is gratefully acknowledged. 1. 2. 3. 4. 5. 6. I. 8. 9. 10. II. 12. 13. 14. 15. 16 REFERENCES T. W. Green, Protective Groups in Organic Chemistry, chap. 4. John Wiley and Sons Inc., New York, (1991). M. 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