Pergamon

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
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