Electroquímica- Desprotección de Cetonas

8/12/2019 Electroqumica- Desproteccin de Cetonas

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PergamonHertrochimica Arm, Vol. 42. Nos. 13-14. 2089-2099.p. 19970 1997 Elsevier Science Ltd. All rights reservedPrinted in Great BritainPII: 30013-4686(96)004864 0013-4686/97 $17.00 + 0.00

Electrolabile protecting groups for ketones:the electrochemical reductive cleavageof 1,3=dioxolanes and 1,3=dioxanescontaining nitro or halo groupsR. 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 1K 2R1, CanadaUniversitt de

(Received 6 November 1996)Abstract-The electroreductive cleavage of 4-(4-nitrophenyl)-1,3-dioxolanes 1, 7-nitro-1,3benzodioxane 2and 5-nitro-1,3-benzodioxanes 3 was studied in aprotic medium (DMF/Et.+NClO, (0.1 M)). The voltammetricbehavior of these compounds showed the formation of a radical anion which is relatively stable on the timescale of cyclic voltammetry. When the electroreduction of these compounds was carried out at cu. - 1.5 Vvs Ag/Ag+ (0.01 M), at the potential of the formation of the radical anion, its cleavage did occur with theformation of the corresponding ketone. We also investigated the electroreduction of the 4-halomethyl- and4,5-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,

INTRODUCTIONThioketals and ketals are useful protecting groups ofketones and aldehydes [l]. In the literature, theelectrochemical deprotection of 1,3-dithiolanes and1,3-dithianes [2,3], diethyl dithioacetal [4], and of4-phenyl-1,3-dioxolanes [5] was accomplished byoxidation at relatively low potentials (f0.8 V to+ 1.3 V vs see) with good to excellent yields. On theother hand, the cathodic cleavage of 4-nitrobenzyl-carbamates to the corresponding amines has beensuccessfully carried out in aprotic media [6]. Ketals ofI-bromopropane-2,3-diol have been used as protect-ing groups and removed by reductive cleavage withzinc [7]. However, to our knowledge, no example ofelectrochemical reductive cleavage of 1,3-dioxolaneshas been reported. In this paper, we report the resultsof 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 anaprotic medium. The nitro group being easily reducedto the radical anion, it should be possible to cleave*Author to whom correspondence should be addressed.

dioxolane 1 and dioxanes 2 and 3 selectively byelectroreduction in the presence of a variety offunctional groups.

EXPERIMENTALGeneral

Solutions for all voltammetric analyses andpreparative electrolyses were deoxygenated by bub-bling with dry argon and an argon atmosphere wasmaintained throughout the experiments. The cyclicvoltammetry experiments were performed using aPrinceton Applied Research (PAR) 173 potentiostatin a single compartment cell with 7 ml of electrolytesolution containing 2 or 5 x 10m3M of substrate. Nocorrection was applied to compensate for the solutionresistance. The voltammograms were recorded andprocessed using the EG&G software M270. Thehanging mercury electrode was prepared by elec-trodeposing a mercury drop at the tip of a platinumwire 1 mm in diameter. A platinum wire (2 mm indiameter) 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


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& RI=CH3 R2= /&JJ

polarography experiments were performed in thesame cell and with the same counter electrode andreference electrode as the cyclic voltammograms, thecharacteristics of the dropping mercury electrodebeing m = 3mg/s, t = 7s, height = 650mm andusing a PAR 174 polarographic analyzer and a PARRE0089 X-Y recorder and a scan rate of 2 mV/s. Thecontrolled potential electrolyses were carried out at amercury electrode in a vertical glass cell with twocompartments separated with a glass frit, using anElectrosynthesis Company (ESC) 410 potentiostatwith an ESC 640 coulometer and an ammeterconnected in series within the auxiliary circuit. Thevolume of the cathodic compartment was 40 ml,that of the anodic compartment 10 ml. The substrateconcentration in the catholyte was 5 mM. The samereference electrode as above was used and the counterelectrode was a platinized platinum grid(1.5 cm x 1.5 cm). The mercury was washed in heusual way and distilled [8]. Dimethylformamide(DMF) was dried and distilled under argon [9].Tetraethylammonium perchlorate (EbNClOd) wasprepared and dried at 69C for 12 h [lo]. After thecurrent dropped to zero, the catholyte was pouredinto ether (or ethyl acetate) and the solution waswashed with brine. The organic phase was dried(MgS04) and the solvent evaporated. The residuewas dissolved in 100 ml of ethyl acetate fordetermining the yield of ketone by vapor phasechromatography (VPC) using a Hewlett Packard(HP) 5710A chromatograph with a FID detector,a HP 339014 integrator and a DB-5 fused silicacapilary column (30 m). The other products formedwere isolated by thick layer chromatography onsilica gel (Merck F254) using mixtures of hexaneand ether as eluent. Infrared spectra were recordedin chloroform on a Perkin Elmer 1600 FTIRspectrometer and nuclear magnetic resonancespectra were recorded on deuterochloroform ordeuteroacetone on a Bruker AC-300 spectrometerusing the signal from chloroform or acetone asreference (s = singlet, d = doublet, t = triplet,q = quartet, dd = doublet of doublets, m =multiplet).

Substrate synthesis and characterizationThe synthesis of compounds la, lb, lc, 2a, 3a, and

3b will be reported elsewhere.Hal omethy l and dihal omethy l-di oxolanes 4 and 5.The bromomethyl and dibromomethyl-dioxolanes

4b X = Br) and Sb X = Br) were prepared byreaction 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 fromAldrich. I-Bromopropane-2,3-diol was prepared asdescribed [12]. The iodomethyl and diiodomethyldioxolanes 4b X = I) and 5b (X = I) were preparedfrom the corresponding bromomethyl and dibro-momethyldioxolanes 4b, X = Br and 5b, X = Br) byheating to reflux a solution of the bromodioxolaneand sodium iodide in excess (4 to 8 equivalents) inacetone.

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); i r(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-CHrof isomer B), 4.24-4.31 (0.5H, m, CH-CH2 of isomerA), 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 (CHarom.), 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.

Iodomethyldioxolane 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); i r


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Electrolabile protecting groups for ketones 2091(CHCb): 1600 (C=C arom.), 1220 and 1030(CW) cm-; H-NMR (CDCh): fourteensignals corresponding to seven different protons ofeach diastereoisomer: 6 = 1.31 (3H, s, CHr of oneisomer), 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 ofone 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); i r(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 fromelectrolyses

Amide 11: oil (17-26% yield); MS (m/e): 382 (M+);HRMS: 382.1521 (calcd for Czi HzzN205: 382.1529);i r (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,JM X = 6.1 HZ, JM A = 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 quaternaryaliph.), 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 sampleprepared by an independent synthesis.

Formami de deriv at iv e 12:oil (5-8% yield); MS (m/e): 262 (M+ = C3HhNO);

CI (isobutane): 335 (MH+); HRMS: 335.1618 (calcdfor CirHrrN205: 335.1607); i r (CHCl3): 1671 and1640 (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, CHmeta to NO?), 8.21 (2H, d, J = 8.9 Hz, CH ortho toNor); 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 (Cquatemary 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); i r(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, JAM = 8.3Hz, JAX = 8.5Hz), 4.12 (lH, dd,JXM = 5.9 Hz, JXA = 8.3 HZ), 4.59 (lH, dd,JM X = 5.9 HZ, JM A = 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, CHarom.) ppm.

Azoxy compound 2Qa:oil (65% yield); MS (m/e): 478 (M+); HRMS:

478.2456 (calcd for CzsH34N205: 478.2468); i r(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 metato 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), 110.6and 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); i r(CHCl3): 1743 (c--O), 1619 (C==C arom.), 1538 and1350 (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 andmeta 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 (CHarom.), 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); i r (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); i r(CHCI3): 1743 (C=O), 1619 (W arom.), 1538 and1350 (NOz), 1263 (Ar-0) cm-, H-NMR (CDCl3):6 = 1.45-2.12 (lOH, m, CH2), 7.18-7.28 (2H, m, CHarom.), 7.63 (lH, t, J = 7.24 Hz, CH arom.) ppm;


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2092-17 t

R. Labrecque et al.

I , I I I I I ,-I -1.5 -2 -2.5 -3V

Fig. 1. Cyclic voltammogram of la 2mM) at Hg cathode Fig. 2. Polarogram of la (2 mM) in DMF/EtsNClOdin 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 ; can rate: 2 mV s-r;100mV 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 and156.4 (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); i r (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 DISCUSSIONElectrochemical behavior of nitro l&dioxolanes

Cyclic voltammetry and polarographyThe 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 roomtemperature. The cyclic voltammogram of la shownin Fig. 1 is typical of the voltammogram of 4-(4nitrophenyl)-1,3-dioxolanes lb and lc. The cyclicvoltammetric data are given in Table 1.

By comparison with the electrochemical behaviorof nitrobenzene [8] under the same conditions, thecathodic peak Ic and the anodic peak Ia wereattributed to the reversible reduction of la to itsradical anion 6 which has some kinetic stability on

the voltammetric time scale (Scheme 1). The thirdcathodic peak III corresponds to the classicalthree-electron reduction of the radical anion tohydroxylamine 10 v ia the dianion 7 (Scheme 1). Thishas been confirmed by polarography. Again thepolarogram of la shown in Fig. 2 is typical of thepolarograms 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 Icand III of Fig. 1, the ratio of diffusion currents ofwave III and wave Ic (&a/&)being 2.7 as observed byHuang [8] in the polarogram of nitrobenzene.Evidence of cleavage of the radical region 6 (seeScheme 1) was proved by the decrease of ratio of thecathodic peak current to the anodic peak current( i& la) upon increasing the scan rate. In the case ofdioxolane la, this ratio decreased from 1.4 at50 mV s-i to 1.1 at 600 mV s-l. That cleavage to theketone did occur was confirmed by preparativeelectroreduction at potentials of which the radicalanion 6 is formed (see below).

The assignment of the irreversible cathodic peak II(see Table 1 and Fig. 1) to which corresponds waveII (E1,2= -2.19 V (il l/i , = 2.1)) of Fig. 2 provedmuch more difficult. The intensity of this peakrelative to that of peak Ic (or to peak III) decreasedwith increasing scan rate. For instance i~+~cecreasedfroml.5at50mVs-tol.2at600mVs-.Again,asimilar behavior was observed with the other4-nitrophenyl-1,3-dioxolanes. Such a decrease of i r l / i l ,

Table 1.Cyclic voltammetric data for dioxolanes la, lb and 1~9Peak 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).


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Electrolabile protecting groups for ketones 2093

Scheme 1.with increasing scan rate strongly suggests that thispeak corresponds to the reduction of species formedby the cleavage of radical anion 6 to thecorresponding ketone. As the scan rate increases, therate of cleavage of 6 being constant the proportion ofcleavage of 6 occurring during the voltammetricsweep decreases and hence the i ratio decreases.Peak (wave) II was therefore tentatively assigned tofurther reduction of the distonic radical anion 8(Scheme 2) (see [13] for the origin of the termdistonic). As will be seen below, a product (see 11)resulting from 8 has been isolated from thepreparative electroreduction of la. According toliterature data, peak (wave) IV was assigned to thereduction of the superoxide anion (OF, EtN+) [14].

_Oy=Jd_s

I-e

? 0+4Ar- N,f\

Preparative electrolysesControlled-potential electrolyses were carried out

under the same conditions as those used for cyclicvoltammetry and polarography. The substrate con-centration was 5 mM. The electrolyses were stoppedwhen the current dropped to zero and the results arereported in Table 2.At the working potential of entries 1 to 6(reduction of 1to the radical anion 6), cleavage to theketone occurred. The yield of ketone increased from30% to 45-55% as the temperature was decreasedfrom 0 to - 15C (entries 1 to 6) as a result of adecrease of the rate of side reactions consuming thesubstrate. Amide 11 and dioxolane 12 (structures

y=y-_AaI 3jr 16 ekmtrode)k

Qz +=+H ~NC&u

Scheme 2.


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2094Table 2.

R. Labrecque et al

Preparative electroreduction of dioxolanes la, lb and lc: effect of working potential and temperature&Yield of other productsYieldd of

Potential ketone 12Entry 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 84 la -1.5 -15 1.5 55 - 18 55 la -1.5 -20 2.1 41 - 17 56 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 (theyield 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 thereactions were isolated and their yield was indeed benzylic position of dioxolane la and DMF (Schemelower at - 15C than at 0C (compare entries 3 and 3). That the mechanism illustrated in Scheme 3 is4). Lowering the temperature further to -20C did plausible was shown by the isolation of dioxolane 12not cause any further increase of the yield of from the reaction of dioxolane la with sodiumcyclohexanone and any further decrease of the yields hydride (5 eq.) in DMF/EtNClOd (0.1 M) (theof amide 11 and dioxolane 12 (entry 5). In amide hydride acceptor is most probably the nitro group of11 the amine fragment clearly comes from the the dioxolane la). In effect, at OC, after a reactionreduction of the nitro group of dioxolane la and the time (5 h) corresponding to the duration of thecarbonyl fragment must come from the distonic preparative electrolyses, extensive decomposition ofradical anion 8 formed in the cleavage of the radical dioxolane la occurred since only 11% of la wasanion 6a (Scheme 1). A possible mechanism for recovered. Dioxolane 12 was isolated in a 10% yieldthe formation of amide 11 is shown in Scheme 2 and 6% of cyclohexanone was formed. In order towhere 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 benzylicthen be hydrolyzed to the amide 11 during the anion 17 (Scheme 3) (deprotonation of la bywork up (such hydrolysis has literature precedent electrogenerated bases), the stability of dioxolane laPSI). was examined in basic medium. At 0C. in

Scheme 3.


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Electrolabile protecting groups for ketones 2095DMF/Et4NC104 (0.1 M), in the presence of oneequivalent of sodium hydride and after 5 h, dioxolanela was stable since 92% of the starting substrate wasrecovered together with 4% of cyclohexanone. Whenthe reaction was performed at - 15C no cyclohex-anone was formed and the starting dioxolane la wasquantitatively recovered. As a result, yields ofdeprotection reported in Table 2 are due to thecleavage of the radical anion 6.

Carrying out the electroreduction of dioxolane lbat a potential (- 2.2 V) at which the distonic radicalanion 8 would be reduced (entry 7 of Table 2) had noeffect on the yield of 1 phenylpropan-2-one (comparewith entry 1) in agreement with the mechanismproposed in Scheme 2 for the formation of amide 11.When the reduction of dioxolane lb was carried outat the potential (-2.5 V) of the reduction of theradical anion 6b to the dianion 7b (see Scheme I), theyield of I-phenylpropan-Zone was significantly lower(17%, entry 8 of Table 2) most probably becauseprotonation of dianion 7b, a stronger base than theradical anion 6b, competes more effectively with itscleavage 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% yieldfrom the electrolysis carried out at 0C (entry 8).Thus, as reported by Huang [8] for the electroreduc-tion of nitrobenzene in the same medium, thedioxolane lb was reduced to amine 19b atthe potential of the reduction of the radical anion tothe dianion.

We have studied the influence of adding relativelystrong proton donors on the yield of cyclohexanonein the reductive cleavage of dioxolane la carried outat 0C at - 1.5 V in DMF/EbNClOa (0.1 M). Theresults are reported in Table 3. The presence of anacid caused a decrease of the yield of cyclohexanone(compare entries 2 to 4 with entry 1). The yield ofketone was lower in the presence of acetic acid (entry2) than in the presence of phenol (entry 3), a weakeracid than acetic acid. Increasing the concentration ofphenol carried a decrease in the yield of ketone (entry4). The decrease in the yield of ketone in the presenceof such proton donors can be readily explained by thefact that protonation of the radical anion 6a doescompete with its cleavage to the ketone. Hence, thestronger or more concentrated is the acid, the fasteris the protonation and the lower the yield of ketoneas observed. That protonation of the radical anion 6adid occur was confirmed by the isolation of the azoxyEA 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 ofcyciohexanonea

Entry Acid n(e)Yield

of ketone(%)lb None 2.0 342 CHKOOH (2 eq.)b 2.3 123 Phenol (2 eq.) 2.9 254 Phenol (6 eq.) 3.0 105 Li+(LiC104 (2 ea.))d 3.0 25Conditions: DMF/Et4NC104 (0.1 M); cathode: Hg; counterelectrode: 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 ofentry 2. Huang [8] has reported that the presence of aproton donor does favor the formation of azoxyben-zene in the electrochemical reduction of nitrobenzenein DMF/Et4NC104 (0.1 M). The azoxy compound isformed by the reaction between the nitroso derivativeresulting from reduction of the protonated radicalanion with the hydroxylamine formed by reduction ofthe nitroso derivative (a well known mechanism) [16].

The presence of LiC104 in the electrolysis mediumalso led to a decrease in the yield of cyclohexanone

(entry 5). Strong ion pairing or complexation betweenthe radical anion 6a and the lithium cation (aLewis acid) most probably lowers the rate of cleavageof 6a.

Electrochemical behavior of nitro 1,3dioxanesThe cieavage of the radical anion derived from

the reduction of nitrodioxanes such as 2 and3 would give the corresponding ketone and a radicalanion 21 as illustrated in Scheme 4. We wantedto verify if such a radical anion and species derivedfrom it could be less reactive than the distonic radicalanion 8 formed in the cleavage of dioxolanes 1and species derived from it (see I4 in Scheme 2)and if, as a consequence, the yield of cleavageto ketone could be higher with the dioxanes thanwith the dioxolanes. The yield of cleavage wasfound to be higher with the dioxanes will as be seenbelow.


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2096 R. Labrecque et al.

Scheme 4.

Voltammetric behaviorThe cyclic voltammetric data of 1,3-dioxanes2a, 3a

and 3b are recorded in Table 4 and the voltam-mogram of 2a shown in Fig. 3 is representative of thevoltammogram of the other dioxanes. The conditionsare the same as those used for the voltammetric studyof the 1,3-dioxolanes above. Peaks Ic and Iacorrespond to the nitrodioxane/radical anionreversible redox couple. The ratio iic/Zia larger thanone shows that cleavage of the radical anion doesoccur on the voltammetric time scale and this ratioapproaches 1when the scan rate is increased as in thecase of the dioxolanes 1. Peak II is assigned tothree-electron reduction of the radical anion tothe hydroxylamine (or its conjugate base) via thedianion 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 thevalue of 2.7 observed in the polarogram ofnitrobenzene [8]. Peak III could result from thereduction of a specie formed in the cleavage of theradical anion to the ketone, since the ratio ill,/decreases upon increasing the scan rate (the ratio ofthe diffusion current of wave III and wave I, illl/il, inthe polarogram of 2a is 0.5). This specie is not theketone. Likely candidates would be a radical anionsuch as 22 (Scheme 4), the reduction of which couldbe more difficult than the reduction of the distonicradical anion 8 produced in the cleavage of1,3-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 beattributed to the reduction of the superoxide anion(O;, EbN+) [14]. Peak IV on the reverse scan can beattributed to the oxidation of hydroxylamines (ortheir conjugate base) generated at the potential ofpeaks II and III. Huang [8] has observed an oxidationpeak at - 1.34 V in the cyclic voltammogram ofnitrobenzene under the same conditions and this peakwas attributed to the oxidation of conjugate base ofphenylhydroxylamine.

Preparative electrolysesThe controlled-preparative electrolysis of dioxanes2a, 3a and 3b in aprotic medium was carried outat - 1.5 V, a potential at which the dioxane isreduced to its radical anion (see 21, Scheme 4), underthe same conditions as those used in the electrolysisof dioxolanes 1. The results are recorded in Table 5.As in the case of dioxolanes 1, cleavage of radicalanion 21 to the ketone did occur (Scheme 4). Theyield of ketone was found to increase upon loweringthe temperature from 0 to - 15C and the yield ofcleavage to cyclohexanone was higher than that ofcleavage to 1 phenylpropan-2-one. However, theyield of ketone at 0C and at - 15C was higherthan in the case of the dioxolanes 1 as alreadymentioned. This means that secondary reactionsconsuming the starting nitrodioxanes 2 and 3compete less effectively with the formation andcleavage of radical anion 21 than in the electrolysesof dioxolanes 1 as hypothesized above. That

Peak potential in Vb (and current ratios)Dioxane IC la h/h) II (ill/ilJ III (in&) IV2a -1.57 -1.46 (1.4) -2.40 (2.5) -2.84 (0.9) -1.283n - 1.56 -1.44 (1.5) -2.37 (2.4) -2.78 (0.3) -1.183b -1.53 -1.41 (1.5) -2.34 (2.4) -2.76 (0.4) - 1.20Conditions: DMF/Et4NC104 (0.1 M); cathode: Hg; counter electrode: vitreous carbon; Scan rate:100mV s-i; substrate concentration: 2 mM; room temperature.bReference electrode: Ag/Ag+ (0.01 M).


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Electrolabile protecting groups for ketones 2097-17UA

t n m-12 -

-7 -

-1 -

3 I)4.2 -1.2 -1.1 -3.1v

Fig. 3. Cyclic voltammogram of 2a (2 mM) at Hg cathodein 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 shownby the isolation of lactone 24 and aldehyde 25 fromthe electrolysis of dioxane 2a. In fact, the yield ofthese products were lower at - 15C (15% for 24and 20% for 25) than at 0C (23% and 28%respectively).

The lactone 24 must result from the oxidation ofthe benzylic position of dioxane 2a whereas aldehyde25 must come from the radical anion 22 formed in thecleavage of the radical anion 21, the benzylic positionhaving been oxidized also. During the electrolysis, themost likely oxidizing species is the unreactednitrodioxane 2a. Mechanisms for the formation of 24and 25 are proposed in Schemes 5 and 6, respectively,in which the oxidation step involves the reaction ofa carbanion with the nitro group to form a nitronewhich is hydrolyzed during the work up. Thesemechanisms are similar to that suggested for theformation of amide isolated from the electrolysisof dioxolane la (Scheme 2). It is interesting thatthe intermediate 33 of Scheme 6 apparently prefers

Table 5.Preparative electrolyses of dioxanes

to cleave to give aldehyde 25 and the hydroxylamine29 (not detected) rather than eliminate water (asin Scheme 2) to give the corresponding amide whichwas not detected. This could be attributed to theintramolecular protonation of the hydroxylaminemoiety as shown in Scheme 6 (intramolecularhydrogen bonding). Lactone 34 and aldehyde 35were isolated also from the electrolysis of dioxane3a at 0C and - 15C in yields (Table 5 entries 3and 4) comparable to those of lactone 24 andaldehyde 25 obtained from 2a (entries 1 and 2). Likedioxolane la, the stability of dioxanes 2a and 3a inthe presence of one equivalent of sodium hydride wasexamined in DMF/EbNClOd (0.1 M). At 0Cdioxanes 2a and 3a led to 4% and 13% ofcyclohexanone, respectively. In both cases, the massbalance consisted of the starting nitrodioxane. At- 15C no cyclohexanone was formed and thestarting nitro compounds were quantitativelyrecovered.

Electrochemical behavior of halomethyl1Jdioxolanes

The investigation on 4-halomethyl- and 4,5-di-halomethyl- 1,3-dioxolanes 4 and 5, as electrolabileprotecting groups, seemed very interesting becausethe electroreductive cleavage of dioxolane 5, forexample, would give an intermediate such as 36 (seeScheme 7) which should be unreactive towards thestarting dioxolane as well as towards the ketoneformed. We have studied their voltammetric behaviorin aprotic medium (DMF/EbNClOd (0.1 M)) at amercury cathode and at room temperature. We haveobserved only one peak of reduction for each of thedioxolanes 4b and 5b (see Table 6) when the bromineatom(s) is (are) replaced by iodine, the potential ofreduction of dioxolane 4b increases from - 2.52 V to- 1.90 V (entries 1 and 2) and that of dioxolane 56increases from - 2.46 to - 1.75 V (entries 3 and 4).

Entry Dioxane Mediumb1 2n DMF2 2a DMF3 3a DMF4 3a DMF5 3b DMF

0-15

0-15-15

n(e)2.01.52.21.32.1

Yield ofketone

W)5965546642

Yieldd of other productsLactonec AIdehyde

W) W)23 2815 2026 3123 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.


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2098 R. Labrecque er al.

HCMN-Ar + -29 24

Scheme 5.

Scheme 6

Rl R2ox0iix xa

4

-0

Scheme 7.


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Electrolabile protecting groups for ketones 2099Table 6.Cyclic voltammetric data and preparative electroreduction of dioxolanes 4b and 5b

Yield of(7) Edr ketoneEntry Dioxolane Xb (V) n(e) (%)

1 4b Br -2.52 -2.5 3.3 592 4b I -1.90 -1.9 3.1 743 5b Br -2.46 -2.5 5.0 954 5b I -1.75 -1.8 5.7 92Conditions: DMF/Et4NCI04 (0.1 M) cathode: Hg, counter electrode; Pt, roomtemperature.bFunctional group on protecting group.Reference electrode: Ag/Ag+ (0.01 M); peak potential on cyclic voltammetry; substrateconcentration: 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 theiododioxolanes can be performed at a less negativepotential than that of the bromodioxolanes. Inaddition, the yield of ketone is higher with theiododioxolane 4b X = I) than with the bromodiox-olane 4b X = Br) (compare entries 2 and 1). It isnoteworthy that the yield of ketone is almostquantitative (92-95%) with the dihalomethyl diox-olanes 5b (entries 3 and 4). From a synthetic point ofview, the latters have a further advantage over themonohalomethyldioxolanes 4b in having a two-foldaxis of symmetry (they were prepared from thedl- 1,4-dihalopropane-2,3-dials) (see Experimental).As a consequence, the dihalomethyldioxolanes 5b donot consist of a mixture of diastereoisomers as in thecase of the monohalomethyldioxolanes 4b.

CONCLUSIONThe introduction of a nitro group suitably

positioned on the aromatic ring of 4-(nitrophenyl)-1,3-dioxolanes (1) and of nitro-1,3-benzodioxanes (2and 3) allows cleavage of the ketal to the ketone(removal of the protecting group) at the potential ofthe formation of the radical anion (as shown by thecyclic voltammetric and polarographic studies) inaprotic (- 1.5 V vs Ag/Ag+ (0.01 M)) medium. Theyields could be substantially increased by carryingout the electrolysis at - 1YC, that is by slowing downside reactions consuming the starting ketal. Theyields of cleavage were higher in the case of thenitrodioxanes 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 mixtureof diastereoisomers since there is no asymmetriccenter in the nitro-2-hydroxybenzylic alcohols used toprepare the dioxanes whereas there is one asymmetriccenter in the I-(nitrophenyl)-ethane 1,2-diols used toprepare the dioxolanes. This is an advantage from thesynthetic point of view. The dihalomethyl-1,3-diox-olanes sb, also not consisting of a mixture of

diastereoisomers, were cleaved to the ketone in analmost quantitative yield but at a more negativepotential (-2.5 V for X = Br, - 1.8 V for X = I)than the dioxolanes 1and the benzodioxanes 2 and 3.

ACKNOWLEDGEMENTSFinancial support from the National Research

Council of Canada (fellowships to R.L. and J.M. andoperating grants to J.L.) and the Fonds FCAR duQuCbec is gratefully acknowledged.

1.2.3.4.5.6.I.8.9.

10.II.12.13.14.15.

16

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Electroquímica- Desprotección de Cetonas

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