Mild electrochemical deprotection of N-phenylsulfonyl N-substituted amines derived from (R)-phenylglycinol

Article abstract of DOI:10.1002/ejoc.200700709

The electrochemical reduction of N-phenylsulfonyl N-substituted amines in a protic medium under constant cathodic potential was found to be a mild desulfonylation method, which is able to challenge the chemical ones. The influence of the nature of the N-substituents was considered in order to clarify the mechanistic aspects and to evaluate the scope of the method. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700709

FULL PAPER
DOI: 10.1002/ejoc.200700709
Mild Electrochemical Deprotection of N-Phenylsulfonyl N-Substituted Amines
Derived from (R)-Phenylglycinol
Vincent Coeffard,[a] Christine Thobie-Gautier,[b] Isabelle Beaudet,[a] Erwan Le Grognec,*[a]
and Jean-Paul Quintard*[a]
Keywords: Sulfonamides / Protecting groups / Cleavage reactions / Electrolyses / Cyclic voltammetry
The electrochemical reduction of N-phenylsulfonyl N-substi-
tuted amines in a protic medium under constant cathodic po-
tential was found to be a mild desulfonylation method, which
is able to challenge the chemical ones. The influence of the
ify the mechanistic aspects and to evaluate the scope of the
method.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
nature of the N-substituents was considered in order to clar- Germany, 2008)
fective. More recently, milder experimental conditions in-
Introduction
volving electron transfers were disclosed for desulfonylation
such as magnesium in methanol under sonication,[9] SmI2
in THF/DMPU[10] or in THF/HMPA.[11]
Since its use by Fischer in 1915 for the protection of the
amino functionality of α-amino acids,[1] arenesulfonyl
groups (SO2Ar) have emerged amongst the most useful in
the activation and protection of alcohol and amine func-
tional groups.[2,3] In particular, the toluenesulfonyl group
(tosyl or Ts) has been widely used as an efficient protecting
group for nitrogen because of its easy introduction and its
propensity to lower the basicity of the nitrogen atom. In
addition, the obtained sulfonamides, which are often crys-
talline, provide a strong chromophore and are stable to a
wide variety of reaction conditions.
In parallel, to circumvent these harsh conditions, a
number of sulfonyl protecting groups that are amenable to
mild deprotection have been developed.[2,3] For instance,
Fukuyama recently reviewed the versatility of p- and o-
nitrobenzenesulfonyl group (nosyl or Ns) into both acti-
vation and protection of the amino group.[12] However, the
nitrobenzenesulfonyl group strongly lowers the basicity of
the nitrogen atom and presents the drawback of a possible
displacement of the nitro group during the sulfonamide
cleavage with thiolate.[13] Similarly, the pyridylsulfonyl
group was described as a versatile protecting group.[14] Pyr-
idylsulfonyl chloride is, however, still not commercially
available and its preparation is not straightforward.[15]
Other sulfonyl protecting groups that have also been re-
ported are the (β-trimethylsilyl)ethanesulfonyl (SES)[16,17]
and the 2-(1,3-dioxan-2-yl)ethylsulfonyl (Dios)[18] or hetero-
arenesulfonyl groups;[19,20] they are, however, not commer-
cially available. Recently, a new sulfonamide analogue of
the Boc group, the tert-butylsulfonyl group (Bus), which is
stable to strong metallation conditions, was introduced.[21]
However, the tert-butylsulfonyl moiety is not readily intro-
duced because it requires two steps from the tert-butylsulf-
inyl chloride. Several other sulfonyl protecting groups have
also been described, such as the methanesulfonyl (Ms)[22] or
trifluoromethanesulfonyl (Tf) groups,[23] but they are often
unable to satisfy the requirements for the synthesis of poly-
functional molecules owing to their harsh cleavage condi-
tions.[2]
However, sulfonyl protection of amines involves prob-
lematic removal in the case of highly functionalized, sensi-
tive substrates. Indeed, the early deprotection protocols for
N-SO2Ar derivatives involved reduction with Na/NH3, par-
ent reactions with anthracene or naphthalene–sodium or re-
fluxing in CH3CO2H/HBr, conditions which often detract
with their initial synthetic appeal.[2] Several other deprotec-
tion protocols including reduction by LiEt3BH in THF,[4]
photolysis in the presence of NaBH4,[5] reduction by
[7]
Bu3SnH/AIBN,[6] treatment with KF supported on Al2O3
or with NaI/TMSCl[8] were also shown to be sometimes ef-
[a] Université de Nantes, Nantes Atlantique Universités, CNRS,
Faculté des Sciences et des Techniques, Laboratoire de Synthèse
Organique (LSO), UMR 6513,
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
Fax: +33-2-51125402
E-mail: erwan.legrognec@univ-nantes.fr
jean-paul.quintard@univ-nantes.fr
[b] Université de Nantes, Nantes Atlantique Universités, CNRS,
Faculté des Sciences et des Techniques, Laboratoire d’Analyse
Isotopique et Electrochimique des Métabolismes (LAIEM),
UMR 6006,
Besides the chemical removal of N-arenesulfonyl groups,
several electrochemical studies related to the cathodic cleav-
age of protecting groups and notably sulfonamides have
2 rue de la Houssinière, B. P. 92208, 44322 Nantes Cedex 3,
France
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V. Coeffard, C. Thobie-Gautier, I. Beaudet, E. Le Grognec, J.-P. Quintard
FULL PAPER
been reported in the last decades.[24] In a pioneering work,
Horner and Neumann showed that the electrochemical re-
duction of simple sulfonamides at a mercury cathode in
MeOH containing Me4NCl as a supporting electrolyte led
to the corresponding amines and sulfinic acid in good
yields.[25] Later, the mechanism of the electrochemical cleav-
age of sulfonamides was rationalized according to Equa-
tion (1).[24,26,27] Moreover, further electrochemical investi-
gations have underlined the milder reduction potential re-
quired for the cleavage of more labile sulfonamides like N-
SO2Pyr,[14] or N-Ns[28] relative to N-Ts[29–31] as a result of
their lower LUMO.
Scheme 1.
RRЈNSO2Ar + 2e– + 2H+ Ǟ RRЈNH + ArSO2H
(1)
led to β-amino alcohol 4 in 70% yield (Scheme 2). The
spectroscopic data obtained for 4 were in complete agree-
ment with those previously described in the literature.[39]
Gratifyingly, treatment of 3a with Mg (10 equiv.) in dry
methanol under sonication was effective. Compound 3a was
sonicated at 50 °C until consumption of the starting mate-
rial was complete, and after workup, desulfonylated com-
pound 4a was isolated in 82% yield (Scheme 2). Unfortu-
nately, we found that this procedure was hardly reproduc-
ible on 3a and that several decomposition products were
observed when the conditions were applied to secondary
amine 2a.
Nevertheless, to the best of our knowledge these studies
were mostly limited to unfunctionalized sulfonamides,[24]
even if desulfonylation by electrochemical reduction was
used in some multistep syntheses.[32,33] In connection with
some ongoing projects, we were interested in the smooth
and selective removal of the arenesulfonyl group on β-
amino alcohols that was compatible with functionalities,
stereogenic centres and nitrogen substitution.[34] Because
the usual chemical methods of N-SO2Ph removal were not
efficient to solve our problem, we then considered that such
a cleavage could be performed electrochemically. Herein, we
describe the electrochemical cleavage of the N-SO2Ph bond
of N-substituted β-amino alcohols as a simple, selective, re-
producible and efficient method.
Results and Discussion
We first considered (R)-phenylglycinol derivative 3a as a
model compound in order to find a smooth and efficient
method for removing the benzenesulfonyl group. This β-
amino alcohol, commercially available as both (R) and (S)
enantiomers, is widely used as a chiral auxiliary in organic
synthesis, as we have recently reported in a study devoted
to the preparation of enantioenriched α-aminoorganostan-
Scheme 2.
Therefore, we concluded after numerous attempts that
nanes.[35,36] In addition, phenylglycinol contains an epi- this method could not be considered as a versatile and gene-
merizable hydrogen at the benzylic position, which was an ral one. As SmI2 in association with DMPU (or HMPA)
additional criterion for our study. Treatment of (R)-phenyl- was reported to be an efficient removal method for the N-
glycinol with benzenesulfonyl chloride in the presence of SO2Ph group, we then applied the described procedure to
triethylamine in dichloromethane afforded benzenesulfon- 3a.[40] However, when 3a was heated at reflux in THF in
amide 1 in 96% yield (Scheme 1). Subsequent protection of the presence of SmI2 (6 equiv.) and DMPU (0.4 mL) no
the alcohol with tert-butyldimethylsilyl chloride in dichloro- color change was observed and the characteristic purple
1
methane gave 2a in 95% yield, which was in turn treated color remained after 15 h. Finally, H NMR spectroscopic
with benzyl bromide and an excess amount of K2CO3 to and HPLC analyses of the crude material revealed that no
afford 3a in 94% yield.
cleavage of the sulfonamide group had occurred. The latter
We then considered the usual methods used for chemical attempt revealed to us that the reducing power of SmI2
deprotection of the N-SO2Ph group of derivative 3a (vide when associated to DMPU was not sufficient to cleave the
supra).[2,3] Treatment of 3a with metallic sodium in liquid N-SO2Ph bond. In order to determine the appropriate po-
ammonia induced complete degradation of the starting ma- tential required to promote N–S bond cleavage, we em-
terial. Similarly, heating of 3a at 70 °C in an acetic acid barked upon electrochemical studies. First, a cyclic voltam-
solution containing HBr for 8 h resulted in complete de- metry study of compound 3a was performed to evaluate its
composition of 3a.[37] When 3a was treated with LiAlH4 in reduction potential and to examine the feasibility of the
THF (reflux, 8 h),[38] N–S bond cleavage occurred, but the selective removal of the N-benzenesulfonyl group of 3a
alkoxysilane functionality was also totally unmasked, which (Figure 1).
384
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Electrochemical Deprotection of Amines Derived from (R)-Phenylglycinol
tions previously established. The electrolysis was conducted
at –2.3 V and the number of electrons consumed was deter-
mined to be 2.05 Fmol–1 (Table 1, Entry 2), which is a value
that is in good agreement with the mechanism. At the end
1
of the electrolysis, the analysis of the crude material by H
NMR spectroscopy indicated that the SO2Ph moiety was
completely removed. The amine was isolated in 85% yield
after chromatography on silica gel. Similarly, extension of
the electrolysis to sulfonamide 2a resulted in complete re-
moval of the protecting group to give desired β-amino
alcohol 2b in 96% yield, whereas chemical methods failed
(vide supra). At this stage we checked by 1H NMR spectro-
scopic analysis that no epimerization occurred during the
electrolysis.[43]
Table 1. Electrochemical data for the removal of N-benzenesulfonyl
group.
Figure 1. Cyclic voltammograms at a glassy carbon electrode in
MeCN and Bu4NHSO4 (0.1 molL–1) (---) and in the presence of
3a (Ϫ), c = 3.3.10–3 molL–1, v = 100 mVs–1.
By considering the literature and after extensive investi-
gation of solvents and supporting electrolytes, we found
that the electrochemical experiments should be performed
in MeCN by using Bu4NHSO4 as the supporting electrolyte
at a glassy working electrode. Whereas no oxidation peak
was observed for 3a in the potential range from 0 to 1.5 V
(vs. SCE), it displayed an irreversible reduction wave at
–2.31 V (vs. SCE). This potential explains the lack of repro-
ducibility of the deprotection method for 3a by using Mg/
MeOH, as this value is close to the normal potential of
magnesium (–2.3 V vs. SCE).[41] By using a rotating elec-
trode, we determined this reduction to be a two-electron
process with respect to ferrocene. The observed reduction
corresponds to the formation of a radical anion, which al-
lows cleavage of the N–S bond into a sulfinate anion and a
nitrogen-centred radical able to trap a second electron to
give the corresponding amine after protonation by
Bu4NHSO4 as proposed by Simonet (Scheme 3).[27] These
results are in good agreement with previous work reporting
the electrochemical reduction of arenesulfonamides.[26,42]
[a] Determined by cyclic voltammetry. [b] Isolated yields obtained
after electrolysis, extraction with diethyl ether and chromatography
on silica gel. [c] A Hg pool was used as cathode for the electrolysis.
[d] A vitreous carbon electrode was used as cathode for the electrol-
ysis. [e] In this case, we also observed 2b in the crude (4d/2b, 71:29
by 1H NMR spectroscopy). [f] In this case, we also observed 3e
and 4g in the crude (3e/4e/4g, 17:65:18 by 1H NMR spectroscopy).
Scheme 3.
We then decided to evaluate the scope of this electro-
chemical removal procedure with N-substituted sulfon-
We then performed electrolysis of benzenesulfonamide 3a amides. Indeed, we anticipated that aminyl radical A could
at a controlled potential in order to assess the feasibility of be prone to give rise to imine B by β-fragmentation
preparative cathodic cleavage under the experimental condi- (Scheme 4) as already reported.[44–46]
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V. Coeffard, C. Thobie-Gautier, I. Beaudet, E. Le Grognec, J.-P. Quintard
FULL PAPER
of 2b was observed in those cases, although β-scissions ex-
pelling a benzyl radical have already been reported.[49] For
3d, this radical decomposition, which releases PhS·, consti-
tutes a competitive reaction to the formation of expected
unmasked amine 4d. This result is in good agreement with
the easier β-elimination of the thiophenoxy radical from the
intermediate aminyl radical.[50]
Scheme 4.
To evaluate the limits of the methodology and to support
In this context, N-substituted benzenesulfonamides 3b–d
were conveniently prepared from 2a according to Scheme 5.
Tertiary amines 3b (R = Bn) and 3c (R = allyl) were ef-
ficiently obtained by using the corresponding p-nitroben-
zenesulfonyl derivative according to a reported pro-
cedure.[47] In contrast, the preparation of phenylthiomethyl
derivative 3d required an aqueous/dichloromethane bi-
phasic reaction and the use of Bu4NBr as a phase-transfer
agent. This procedure afforded 3d in 40% yield from 2a
after purification by flash chromatography. The cyclic vol-
tammetry of these benzenesulfonamides was investigated
and indicated similar behaviour relative to that of 3a. An
irreversible reduction peak in the range of –2.2 to –2.3 V
(vs. SCE) corresponding to a two-electron process was ob-
served (Table 1). As with 3a, no oxidation peak was ob-
served for these derivatives in the potential range from 0 to
1.5 V (vs. SCE).
the above interpretation, we then turned our attention to
the study of cyclopropyl derivative 3e, as the cyclopropyl
ring opening is highly favoured in the presence of radi-
cals.[51–53] The preparation of 3e was achieved through N-
SO2Ph protection of cyclopropylamine (87% yield), fol-
lowed by benzylation with benzyl bromide under usual con-
ditions that proceeded in 82% yield (Scheme 6).
Scheme 6.
The cyclic voltammetry of 3e exhibits an irreversible re-
duction peak at –2.27 V. In this case, as a result of adsorp-
tion of 3e on the vitreous carbon electrode, the preparative
electrolysis was carried out on a Hg pool. Surprisingly, we
observed a significantly larger amount of electrons con-
sumed (2.8 Fmol–1) relative to those of compounds 3a–d
(Table 1). The reaction resulted in the production of N-ben-
zylcyclopropylamine 4e (56%) by path A along with N-ben-
1
zylpropylamine 4g (4e/4g, 78:22 from the H NMR spec-
trum of the crude) by path B (Scheme 7).
Scheme 5.
Whatever the nature of the substitution on nitrogen in
3a–d, the cathodic potentials present low differences, which
indicates the poor influence of the substituents. The elec-
trolysis of sulfonamides 3b–d was performed under similar
conditions to those used for 3a by using either a vitreous
carbon or a Hg pool as the cathodic electrode.[48] Under
these conditions, desired deprotected β-amino alcohols 4b,c
were isolated in good yields (85 and 89% yield, respec-
tively). In contrast, the electrolysis conducted on 3d af-
forded amine 4d in moderate yield (57%) along with pri-
mary amine 2b (4d/2b, 71:29 on the basis of 1H NMR spec-
tra recorded of the crude material). The formation of the
latter compound could be explained by the hydrolysis of
Scheme 7.
The formation of 4g can be explained by ring opening of
corresponding imine B during the workup procedure the cyclopropyl aminyl radical, which leads to the imine
(Scheme 4). Within the detection limits of the NMR spec- intermediate that is subsequently reduced with two elec-
trometer, N-methylamine, which might be expected through trons. It is noteworthy that both electrochemical processes
reduction of the imine moiety, was not observed in the (paths A and B) are fortuitously overlapped. Indeed, the
crude reaction mixture. For 3b,c, β-fragmentation produc- observed cyclic voltammogram of 3e encompassed the for-
·
·
ing PhCH2 or CH2=CH–CH2 did not occur, as no trace mation of amine 4e (path A) and the reduction of imine 4f
386
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Electrochemical Deprotection of Amines Derived from (R)-Phenylglycinol
performed by using a potentiostat-galvanostat E66 PARC Model
(path B) (see Figure 2). This interpretation was confirmed
by carrying out separate cyclic voltammetry on 4f, prepared
by condensation of benzylamine and propionaldehyde.
These results confirmed that N-substituted amines are
prone to give homolytic β-scission, which can seriously
challenge the formation of the expected deprotected amine,
such as 4d and 4e. In spite of these possible side reactions,
it is noteworthy that the electrochemical reduction of sul-
fonamides is able to afford the corresponding deprotected
amines in good yields and in a preparative fashion at the
laboratory scale.
273 controlled by the Echem software. CH3CN and CH2Cl2 were
dried with CaH2 prior to use and THF was distilled from sodium–
benzophenone. MeOH was dried with magnesium methoxide and
distilled before use. DMF was dried with 4 Å molecular sieves prior
to distillation. TLC analyses were achieved on silica-coated plates
(Merck Kieselgel 60F254).
N-[(1R)-2-Hydroxy-1-phenylethyl]benzenesulfonamide (1): To
a
solution of (R)-phenylglycinol (5 g, 36.45 mmol) and Et3N (5.6 mL,
40.09 mmol) in CH2Cl2 (50 mL) was added dropwise benzenesulfo-
nyl chloride (4.65 mL, 36.45 mmol) diluted in CH2Cl2 (50 mL) at
0 °C. The reaction mixture was stirred at room temperature over-
night, and then quenched by the addition of aqueous H2SO4 (2 n,
50 mL). The organic layer was further washed with aqueous H2SO4
(2 n, 2ϫ50 mL) and dried with MgSO4. Concentration of the fil-
tered organics under reduced pressure gave 1 as a white solid (9.7 g,
96%), which was used without further purification.[54] M.p. 117–
120 °C. 1H NMR (300 MHz, CDCl3): δ = 7.75–7.65 (br. d, J =
7.4 Hz, 2 H), 7.50–7.41 (tt, J = 7.4, 1.4 Hz, 1 H), 7.40–7.30 (br. t,
J = 7.4 Hz, 2 H), 7.21–7.13 (m, 3 H), 7.11–7.03 (m, 2 H), 5.77 (d,
J = 7.2 Hz, 1 H, NH), 4.37 (ddd, J = 7.2, 6.3, 4.6 Hz, 1 H, CHPh),
3.71 (dd, J = 11.4, 4.6 Hz, 1 H, CH2O), 3.67 (dd, J = 11.4, 6.3 Hz,
1 H, CH2O), 2.20 (br. s, 1 H, OH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 140.2, 137.4, 132.4, 128.8 (2 C), 128.5 (2 C), 127.8,
127.0 (2 C), 126.9 (2 C), 66.1 (CH2O), 59.8 (CHPh) ppm. IR (KBr):
ν = 3543, 3497, 3324, 1603, 1495, 1452, 1309, 1162, 1149, 1074,
˜
753, 692, 594, 554 cm–1. MS (EI): m/z (%) = 246 (33), 141 (30), 91
(8), 77 (100), 51 (18). MS (CI): m/z = 295 [M + NH4]+.
N-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenylethyl]benzenesul-
fonamide (2a): To a solution of 1 (3 g, 10.82 mmol) in CH2Cl2
(125 mL) were added imidazole (4.42 g, 64.92 mmol) and
TBDMSCl (4.89 g, 32.46 mmol). The mixture was stirred overnight
and then hydrolyzed with water (100 mL). The aqueous layer was
extracted with CH2Cl2 (2ϫ100 mL), dried with MgSO4, filtered
and concentrated under reduced pressure. Purification by flash
chromatography (hexanes/Et2O, 70:30) afforded 2a as a white solid
Figure 2. Cyclic voltammograms of 3e (Ϫ), c = 6.10–3 molL–1, in
MeCN and Bu4NHSO4 (0.1 molL–1), v = 100 mVs–1 and 4f (---),
c = 2.3.10–3 molL–1.
1
(4.03 g, 95%). Rf = 0.25 (hexanes/Et2O, 75:25). M.p. 60–62 °C. H
NMR (300 MHz, CDCl3): δ = 7.69 (br. d, J = 8.3 Hz, 2 H), 7.5–
Conclusions
The above results complete previous reports on the 7.1 (m, 8 H), 5.33 (d, J = 4.7 Hz, 1 H, NH), 4.33 (ddd, J = 6.6,
4.7, 4.5 Hz, 1 H, CHPh), 3.69 (dd, J = 10.2, 4.5 Hz, 1 H, CH2O),
3.58 (dd, J = 10.2, 6.6 Hz, 1 H, CH2O), 0.81 (s, 9 H), 0.08 (s, 3 H,
CH3Si), –0.09 (s, 3 H, CH3Si) ppm. 13C NMR (75 MHz, CDCl3):
δ = 140.3, 138.0, 132.4, 128.7 (2 C), 128.2 (2 C), 127.9, 127.2 (4 C),
66.6 (CH2O), 59.3 (CHPh), 25.7 (3 C), 18.2, –5.6 (2 C) ppm. IR
mechanism of deprotection of N-arenesulfonylamines. The
mechanism previously proposed is firmly established on the
basis of the observed β-elimination of a thiophenoxy radi-
cal or on the basis of the rearrangement of a cyclopro-
pylaminyl radical. This study points out the efficiency of
the electrochemical method to deprotect N-phenylsulfonyl
N-substituted amines under mild experimental conditions
without alteration of the stereochemistry of the benzylic po-
sition of the phenylglycinol moiety.
(KBr): ν = 3224, 2957, 2857, 1469, 1461, 1327, 1161, 1116, 1076,
˜
837, 778, 546 cm–1. MS (EI): m/z (%) = 334 (6), 246 (36), 214 (100),
141 (17), 77 (52), 51 (6). MS (CI): m/z = 409 [M + NH4]+, 392 [M
+ H]+. HRMS (CI): calcd. for C20H30NO3SSi [M + Na]+ 392.1716;
found 392.1717.
N-Benzyl-N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]-
benzenesulfonamide (3a): To a solution of 2a (500 mg, 1.28 mmol)
in DMF (12 mL) were added K2CO3 (885 mg, 6.40 mmol) and
BnBr (230 μL, 1.92 mmol) in sequence. The reaction mixture was
stirred until complete consumption of the starting material as mon-
itored by TLC analysis. Then, the mixture was diluted with H2O
and extracted with Et2O. The combined organic layer was washed
with brine, dried with MgSO4, filtered and concentrated under re-
duced pressure. Column chromatography on silica gel (hexanes/
Et2O, 95:5) gave rise to pure 3a (578 mg, 94%) as a viscous oil. Rf
= 0.54 (hexanes/Et2O, 75:25). 1H NMR (300 MHz, CDCl3): δ =
7.8 (br. d, J = 8.3 Hz, 2 H), 7.6–6.85 (m, 13 H), 5.02 (dd, J = 8.3,
6.0 Hz, 1 H, NCHPh), 4.57 (d, J = 16 Hz, 1 H, CH2Ph), 3.98 (d,
Experimental Section
General Method: 1H and 13C NMR spectra were recorded with
Bruker Avance 300 or Bruker ARX 400 spectrometers. Chemical
shifts are given in ppm as δ values relative to tetramethylsilane (1H,
13C) and coupling constants are given in Hz. Mass spectra were
obtained in EI (70 eV) and CI modes with a HP apparatus (Engine
5989A) in direct introduction mode. HRMS were recorded at the
CRMPO in Rennes (Centre Régional de Mesures Physiques de
l’Ouest) or at the Université Claude Bernard Lyon 1. IR spectra
were recorded with a Bruker IFS Vector 22 apparatus. Cyclic vol-
tammetry experiments and controlled potential electrolyses were
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V. Coeffard, C. Thobie-Gautier, I. Beaudet, E. Le Grognec, J.-P. Quintard
J = 16 Hz, 1 H, CH2Ph), 3.91 (dd, J = 10.4, 6.0 Hz, 1 H, CH2O), MgSO4, filtered off and concentrated under vacuum to give a solu-
FULL PAPER
3.78 (dd, J = 10.4, 8.3 Hz, 1 H, CH2O), 0.75 (s, 9 H), –0.06 (s, 6 tion of starting sulfonamide 3a in DMPU.
H, CH3Si) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.1, 137.6,
136.1, 132.2, 128.8–127.1 (14 C), 63.3 (CH2O), 62.5 (NCHPh), 48.8
N-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenylethyl]-N-(2-phe-
nylethyl)benzenesulfonamide (3b): 2-Phenethyl-4-nitrobenzenesulfo-
nate[56] (785 mg, 2.55 mmol) was added to a stirred mixture of sul-
fonamide 2a (1 g, 2.55 mmol) and K2CO3 (530 mg, 3.83 mmol) in
dry acetonitrile (10 mL), and the reaction mixture was heated at
reflux whilst the reaction progress was evaluated by TLC. After the
reaction was complete, the mixture was diluted with ethyl acetate
(25 mL) and washed with water (2 ϫ 20 mL) followed by brine
(20 mL) solution. After drying over MgSO4, evaporation of the sol-
vent under reduced pressure afforded the crude compound, which
was purified on column chromatography (hexanes/AcOEt, 95:5) to
afford product 3b (1.09 g, 86%) as a viscous oil that crystallized on
(CH Ph), 25.7 (3 C), 18.0, –5.5, –5.6 ppm. IR (neat): ν = 3064,
˜
2
3031, 2928, 2856, 1680, 1496, 1471, 1447, 1343, 1258, 1164, 1092,
861, 814, 729, 599 cm–1. MS (EI): m/z (%) = 424 (3), 336 (7), 177
(7), 91 (100), 77 (6). MS (CI): m/z = 499 [M + NH4]+, 482 [M +
H]+. HRMS (ESI): calcd. for C27H35NNaO3SSi [M + Na]+
504.2004; found 504.1995.
Reaction of 3a with Na/NH3: In a three-necked flask equipped with
a dry acetone cooled Dewar condenser, small pieces of sodium were
added to liquid ammonia (ca. 35 mL) until a permanent dark blue
colour was obtained. Substrate 3a (200 mg, 0.42 mmol) in freshly
distilled THF was added, and the resulting solution was left to stir
at –78 °C for 1 h under an atmosphere of argon before quenching
with 2-propanol, then water and warming to room temperature.
Once the ammonia had evaporated, the mixture was extracted twice
with CH2Cl2, and the combined organic phase was washed with
brine, dried with MgSO4 and concentrated under vacuum to pro-
vide decomposition products.
1
long standing. Rf = 0.35 (hexanes/Et2O, 90:10). M.p. 49–50 °C. H
NMR (300 MHz, CDCl3): δ = 7.91–7.80 (m, 2 H), 7.60–7.42 (m, 3
H), 7.30–7.10 (m, 8 H), 7.00–6.93 (m, 2 H), 5.07 (dd, J = 7.4,
5.8 Hz, 1 H, NCHPh), 4.07 (dd, J = 10.7, 7.4 Hz, 1 H CH2O), 3.96
(dd, J = 10.7, 5.8 Hz, 1 H, CH2O), 3.37 (ddd, J = 15.0, 11.9, 5.3 Hz,
1 H, CH2N), 3.25 (ddd, J = 15.0, 11.9, 5.7 Hz, 1 H, CH2N), 2.83
(dt, J = 11.9, 5.7 Hz, 1 H, CH2Ph), 2.47 (dt, J = 11.9, 5.3 Hz, 1 H,
CH2Ph), 0.80 (s, 9 H), 0.01 (s, 6 H, CH3Si) ppm. 13C NMR
(75 MHz, CDCl3): δ = 141.1, 138.8, 137.1, 132.3, 128.9–126.3 (14
C), 63.2 (CH2O), 61.7 (NCHPh), 47.4 (CH2N), 37.5 (CH2Ph), 25.7
Reaction of 3a with HBr/AcOH and Phenol: To sulfonamide 3a
(150 mg, 0.31 mmol) in a sealed tube was added phenol (105 mg,
1.12 mmol) and hydrogen bromide (33% in acetic acid, 5 mL), and
the resulting mixture was stirred and heated at 70 °C for 8 h. After
cooling to 0 °C, saturated aqueous NaHCO3 solution was added
until pH was ca. 7. Then, the mixture was extracted with Et2O
(2ϫ25 mL), and the combined organic extract was washed with
water, dried with MgSO4 and the solvent removed to provide de-
composition products.
(3 C), 18.1, –5.5 (2 C) ppm. IR (KBr): ν = 3063, 3029, 2954, 2929,
˜
2857, 1603, 1585, 1497, 1447, 1344, 1257, 1163, 1094, 837, 778,
751, 698, 581 cm–1. MS (EI): m/z (%) = 438 (2), 362 (17), 274 (100),
242 (40), 177 (29), 141 (38), 105 (39), 91 (27), 77 (87), 73 (86), 59
(26). MS (CI): m/z = 513 [M + NH4]+, 496 [M + H]+. HRMS (ESI):
calcd. for C28H37NNaO3SSi [M + Na]+ 518.2161; found 518.2165.
N-(But-3-en-1-yl)-N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phe-
nylethyl]benzenesulfonamide (3c): Compound 3c was prepared from
2a and homoallyl nosylate[47] according to the procedure outlined
for 3b. Yield: 75 %. Rf = 0.34 (hexanes/Et2O, 90:10). 1H NMR
(300 MHz, CDCl3): δ = 7.88–7.80 (m, 2 H), 7.59–7.42 (m, 3 H),
7.28–7.15 (m, 5 H), 5.55 (ddt, J = 17, 10.2, 6.8 Hz, 1 H, =CH),
5.03 (dd, J = 7.2, 5.8 Hz, 1 H, NCHPh), 4.93 (br. d, J = 10.2 Hz,
1 H, =CH2), 4.88 (dq, J = 17.0, 1.5 Hz, 1 H, =CH2), 4.10 (dd, J =
10.6, 7.2 Hz, 1 H, CH2O), 3.98 (dd, J = 10.6, 5.8 Hz, 1 H, CH2O),
3.26 (ddd, J = 14.7, 10.6, 5.5 Hz, 1 H, NCH2), 3.13 (ddd, J = 14.7,
10.6, 5.5 Hz, 1 H, NCH2), 2.35–2.15 (m, 1 H, CH2CH=), 2.10–1.92
(m, 1 H, CH2CH=), 0.81 (s, 9 H), 0.01 (s, 3 H, CH3Si), 0 (s, 3 H,
CH3Si) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.1, 137.1, 134.7
(=CH), 132.1, 128.7 (2 C), 128.2 (2 C), 128.1 (2 C), 127.5, 127.0 (2
C), 116.4 (=CH2), 63.2 (CH2O), 61.8 (NCHPh), 45.0 (CH2N), 35.0
Reaction of 3a with LiAlH4: To a solution of sulfonamide 3a
(153 mg, 0.32 mmol) in THF (2 mL) was added a solution of Li-
AlH4 (0.5 m in DME, 1.3 mL, 0.64 mmol), and the reaction mix-
ture was heated at reflux for 8 h. After cooling, the mixture was
quenched with H2O (10 mL) and extracted with Et2O (3ϫ10 mL).
The combined organic layer was washed with brine (20 mL), dried
with MgSO4, filtered and concentrated under reduced pressure.
Column chromatography on silica gel (hexanes/Et2O, 30:70) gave
pure 4 (50 mg, 70%) as white crystals.[39]
General Procedure for Mg/MeOH Reduction Under Sonication: In
a Schlenk flask, anhydrous methanol (3.5 mL) was added to sulfon-
amides 3a or 2a (0.20 mmol) and Mg (48 mg, 2 mmol) under an
atmosphere of argon. The resulting suspension was degassed (three
freeze–pump–thaw cycles), placed under an argon atmosphere and
sonicated at 50 °C until complete consumption of the starting ma-
terial. The reaction was then diluted with brine (10 mL) and filtered
through a pad of Celite by using Et2O as eluent. The phases were
separated, and the aqueous phase was extracted with Et2O
(2ϫ10 mL). The combined organic layer was dried with MgSO4
and concentrated in vacuo to afford 4a as an oil (67 mg, 82%),
which was not purified. No reduction occurred with 2a.
(CH CH=), 25.7 (3 C), 18.0, –5.6 (2 C) ppm. IR (neat): ν = 3065,
˜
2
3031, 2953, 2928, 2856, 1641, 1603, 1548, 1447, 1344, 1255, 1164,
1090, 918, 836, 777, 751, 690, 587 cm–1. MS (EI): m/z (%) = 388
(14), 300 (20), 268 (20), 235 (16), 177 (25), 131 (100), 77 (89), 59
(32). MS (CI): m/z = 463 [M + NH4]+, 446 [M + H]+. HRMS (ESI):
calcd. for C24H35NNaO3SSi [M + Na]+ 468.2004; found 468.2007.
N-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenylethyl]-N-[(phe-
nylthio)methyl]benzenesulfonamide (3d): Sulfonamide 2a (600 mg,
1.53 mmol) dissolved in CH2Cl2 (5 mL) was treated with chlo-
romethyl phenyl sulfide (592 μL, 4.59 mmol), KI (252 mg,
1.53 mmol) and then with tetrabutylammonium bromide (35 mg,
0.17 mmol). To the resulting mixture was added aqueous NaOH
(50%, 1.0 mL) at 0 °C. After stirring at room temperature for 12 h,
the mixture was poured into saturated aqueous NH4Cl solution
and extracted with ethyl acetate. The organic phase was washed
with water, dried with MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
Reaction of 3a with SmI2/DMPU: In a Schlenk flask, THF (1 mL)
and DMPU (0.4 mL) were added to sulfonamide 3a (50 mg,
0.10 mmol), and the solution was degassed (three freeze–pump–
thaw cycles) and placed under an atmosphere of argon. SmI2
(0.60 mmol, 6 mL of a 0.1 m solution in THF prepared from 1,2-
diiodoethane and metallic Sm)[55] was added by syringe, and the
dark-purple solution was heated at reflux until all the SmI2 was
consumed (as judged by the solution colour, which turned yellow).
The mixture was hydrolyzed with brine and extracted three times
with CH2Cl2. The combined organic extract was dried with
388
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 383–391

Electrochemical Deprotection of Amines Derived from (R)-Phenylglycinol
(hexanes/AcOEt, 95:5) to afford 3d (315 mg, 40%) as a colourless
tween Et2O (100 mL) and water (100 mL). After neutralization
oil. Rf = 0.41 (hexanes/Et2O, 90:10). 1H NMR (300 MHz, CDCl3): with saturated aqueous NaHCO3 solution to pH ca. 7 and extrac-
δ = 7.69 (br. d, J = 7.8 Hz, 2 H), 7.51–7.02 (m, 13 H), 5.03 (d, J = tion with Et2O (2 ϫ 100 mL), the combined organic phase was
14.5 Hz, 1 H, CH2S), 4.88 (dd, J = 7.9, 5.2 Hz, 1 H, NCHPh), 4.39
(d, J = 14.5 Hz, 1 H, CH2S), 4.14 (dd, J = 10.3, 7.9 Hz, 1 H,
CH2O), 3.91 (dd, J = 10.3, 5.2 Hz, 1 H, CH2O), 0.71 (s, 9 H), –0.09
(s, 6 H, CH3Si) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.7, 135.8,
134.6, 132.6–127.5 (15 C), 63.4 (CH2O), 62.2 (NCHPh), 52.3
dried with MgSO4, filtered and concentrated under vacuum.
(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenylethanamine (2b):
Amine 2b was obtained from 2a (279 mg, 0.71 mmol) as a white
solid in pure form in a 96% yield (171 mg) without further purifica-
tion. All the physical and spectroscopic data were in complete
agreement with the reported ones.[57]
(CH S), 25.8 (3 C), 18.1, –5.5 (2 C) ppm. IR (neat): ν = 3061, 3032,
˜
2
2954, 2928, 2856, 1584, 1480, 1471, 1463, 1447, 1347, 1258, 1163,
1090, 837, 776, 689, 612, 586 cm–1. MS (EI): m/z (%) = 404 (2),
235 (40), 179 (23), 115 (11), 91 (12), 77 (12), 73 (100), 59 (24). MS
(CI): m/z = 531 [M + NH4 ]+ . HRMS (ESI): calcd. for
C27H35NNaO3S2Si [M + Na]+ 536.1725; found 536.1724.
(1R)-N-Benzyl-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethan-
amine (4a): Amine 4a was obtained from 3a (310 mg, 0.64 mmol)
and purified by flash chromatography (hexanes/Et2O, 95:5) to pro-
vide 4a as an oil (186 mg, 85%). Rf = 0.83 (hexanes/Et2O, 70:30).
1H NMR (300 MHz, CDCl3): δ = 7.4–7.1 (m, 10 H), 3.77–3.50 (m,
5 H), 2.39 (br. s, 1 H, NH), 0.88 (s, 9 H), 0.01 (s, 3 H, CH3Si),
–0.01 (s, 3 H, CH3Si) ppm. 13C NMR (75 MHz, CDCl3): δ = 140.8,
128.9–125.6 (11 C), 68.5 (CH2O), 64.1 (NCHPh), 51.3 (CH2Ph),
N-Cyclopropylbenzenesulfonamide (2e): This compound was pre-
pared from cyclopropylamine according to the procedure outlined
for 1. Sulfonamide 2e was obtained as a white solid after purifica-
tion by chromatography on silica gel (hexanes/Et2O, 50:50). Yield:
87%. Rf = 0.18 (hexanes/Et2O, 70:30). M.p. 54–57 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.95–7.87 (m, 2 H), 7.64–7.48 (m, 3 H),
5.11 (br. s, 1 H, NH), 2.27–2.20 (m, 1 H), 0.64–0.54 (m, 4 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 139.6, 132.8, 129.1 (2 C), 127.4
25.9 (3 C), 18.3, –5.3, –5.4 ppm. IR (neat): ν = 3333, 3063, 3027,
˜
2954, 2928, 2856, 1604, 1495, 1453, 1257, 1085, 836, 777, 700,
616 cm–1. MS (EI): m/z (%) = 284 (2), 196 (87), 91 (100), 73 (10),
65 (9). MS (CI): m/z = 342 [M + H]+. HRMS (ESI): calcd. for
C21H32NOSi [M + H]+ 342.2253; found 342.2246.
(2 C), 24.3 (CHN), 6.1 (2 C) ppm. IR (KBr): ν = 3236, 3014, 1447,
˜
(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenyl-N-(2-phenylethyl)-
ethanamine (4b): Electrolysis of 3b (305 mg, 0.62 mmol) afforded
4b as an oil in pure form (186 mg, 85%) without further purifica-
tion. Rf = 0.34 (hexanes/Et2O, 90:10). 1H NMR (300 MHz,
CDCl3): δ = 7.37–7.10 (m, 10 H), 3.76 (dd, J = 9.0, 3.8 Hz, 1 H,
NCHPh), 3.63 (dd, J = 9.6, 3.8 Hz, 1 H, CH2O), 3.50 (dd, J = 9.6,
9.0 Hz, 1 H, CH2O), 2.85–2.67 (m, 5 H, NCH2CH2Ph + NH), 0.82
(s, 9 H), –0.03 (s, 3 H, CH3Si), –0.04 (s, 3 H, CH3Si) ppm. 13C
NMR (75 MHz, CDCl3): δ = 141.0, 140.2, 128.8 (2 C), 128.5 (2 C),
128.4 (2 C), 127.8 (2 C), 127.4, 126.1, 68.5 (CH2O), 65.2 (NCHPh),
48.8 (CH2N), 36.5 (CH2Ph), 26.0 (3 C), 18.3, –3.4 (2 C) ppm. IR
1478, 1324, 1167, 1161, 1094, 734, 687, 575 cm–1. MS (EI): m/z (%)
= 141 (9), 77 (100), 56 (61), 51 (47), 39 (8).
N-Benzyl-N-cyclopropylbenzenesulfonamide (3e): This compound
was prepared from 2e according to the procedure outlined for 3a.
N-Benzyl sulfonamide 3e was obtained as a white solid after purifi-
cation by chromatography on silica gel (hexanes/Et2O, 70:30).
1
Yield: 82%. Rf = 0.37 (hexanes/Et2O, 70:30). M.p. 100–102 °C. H
NMR (300 MHz, CDCl3): δ = 7.90–7.80 (m, 2 H), 7.64–7.47 (m, 3
H), 7.37–7.21 (m, 5 H), 4.36 (s, 2 H), 2.06–1.97 (m, 1 H), 0.69–0.52
(m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 138.6, 136.9,
132.6, 128.9–127.8 (9 C), 54.7 (CH2N), 30.8 (CHN), 7.1 (2 C) ppm.
(neat): ν = 3326, 3085, 3063, 3027, 2954, 2927, 2856, 1603, 1494,
˜
1471, 1453, 1257, 1129, 1087, 837, 777, 700 cm–1. MS (EI): m/z (%)
= 298 (2), 264 (4), 210 (100), 179 (7), 105 (44), 91 (10), 73 (37). MS
(CI): m/z = 356 [M + H]+. HRMS (ESI): calcd. for C22H34NOSi
[M + H]+ 356.2409; found 356.2409.
IR (KBr): ν = 3067, 2966, 1485, 1446, 1356, 1349, 1173, 1168, 730,
˜
576 cm–1. MS (EI): m/z (%) = 146 (72), 91 (100), 77 (13), 65 (13),
51 (7). MS (CI): m/z = 305 [M + NH4]+, 288 [M + H]+. HRMS
(ESI): calcd. for C16H17NNaO2S [M + Na]+ 310.0877; found
310.0880.
N-[(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenylethyl]but-3-en-1-
amine (4c): Electrolysis of 3c (356 mg, 0.80 mmol) afforded 4c as
an oil in pure form (218 mg, 89%) without further purification. Rf
= 0.35 (hexanes/Et2O, 90:10). 1H NMR (300 MHz, CDCl3): δ =
7.40–7.20 (m, 5 H), 5.55 (ddt, J = 17.1, 10.4, 6.8 Hz, 1 H, =CH),
5.09 (dq, J = 17.1, 1.7 Hz, 1 H, =CH2), 5.02 (ddt, J = 10.4, 1.7,
1.1 Hz, 1 H, =CH2), 3.76 (dd, J = 9.0, 4.0 Hz, 1 H, NCHPh), 3.65
(dd, J = 9.8, 4.0 Hz, 1 H, CH2O), 3.53 (dd, J = 9.8, 9.0 Hz, 1 H,
CH2O), 2.63–2.43 (m, 2 H, NCH2), 2.30–2.15 (m, 2 H, CH2CH=),
1.95 (br. s, 1 H, NH), 0.89 (s, 9 H), 0.02 (s, 6 H, CH3Si) ppm. 13C
NMR (75 MHz, CDCl3): δ = 141.2, 136.8 (=CH), 128.4 (2 C),
127.9 (2 C), 127.4, 116.4 (=CH2), 68.6 (CH2O), 65.3 (NCHPh),
46.7 (CH2N), 34.4 (CH2CH=), 26.0 (3 C), 18.4, –5.3 (2 C) ppm.
General Procedure for Cyclic Voltammetry Studies: Cyclic voltam-
metry experiments were performed with 2.10–3 to 6.10–3 molL–1
of sample in MeCN and Bu4NHSO4 (0.1 molL–1). A conventional
three-electrode system was used with a glassy carbon working elec-
trode (diameter 2 mm), saturated calomel reference electrode (SCE)
and a platinum wire counter electrode.
General Procedure for the Preparative Electrochemical Deprotection
of N-Benzenesulfonyl Derivatives: Bulk electrolyses were carried out
under constant cathodic potential in a concentric cylindrical cell
with two compartments separated by a glass frit diaphragm. A mer-
cury pool electrode (diameter 4.7 cm) or reticulated vitreous carbon
electrode (HF 2077-BAS) was used as the cathode, calomel satu-
rated electrode as reference and a platinum plate as the anode.
Bu4NHSO4 (100 mL) in acetonitrile (0.1 molL–1) was added into
the anode and the cathode compartments. The solution was stirred,
purged of oxygen by bubbling argon through the solution for
10 min, and then, pre-electrolysis was carried out at the appropriate
potential for 10 min (Table 1). Sample (0.4–0.8 mmol) was added
to the cathode compartment and electrolysis was performed at the
appropriate potential. The reaction was monitored by cyclic vol-
tammetry analysis and by TLC. When all starting material had
disappeared, the content of the cathodic compartment was concen-
trated under reduced pressure and the residue was partitioned be-
IR (neat): ν = 3330, 3063, 3026, 2955, 2929, 2857, 1640, 1603, 1493,
˜
1457, 1257, 1087, 837, 778, 701 cm–1. MS (EI): m/z (%) = 248 (2),
160 (100), 131 (37), 91 (11), 73 (33), 55 (11), 41 (5). HRMS (ESI):
calcd. for C18H32NOSi [M + H]+ 306.2253; found 306.2272.
(1R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-1-phenyl-N-[(phenylthio)-
methyl]ethanamine (4d): Electrolysis of 3d (240 mg, 0.47 mmol) pro-
vided 4d as an oil (100 mg, 57%) after careful column chromatog-
raphy on silica gel (hexanes/Et2O, 95:5). Rf = 0.70 (hexanes/Et2O,
90:10). 1H NMR (300 MHz, CDCl3): δ = 7.44–7.11 (m, 10 H), 4.40
(d, J = 13.4 Hz, 1 H, CH2S), 4.30 (dd, J = 9.8, 4.0 Hz, 1 H,
NCHPh), 3.82 (d, J = 13.4 Hz, 1 H, CH2S), 3.57 (dd, J = 9.8,
Eur. J. Org. Chem. 2008, 383–391
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
389

V. Coeffard, C. Thobie-Gautier, I. Beaudet, E. Le Grognec, J.-P. Quintard
FULL PAPER
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1 H, NH), 0.75 (s, 9 H), –0.84 (s, 6 H, CH3Si) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.2, 137.0, 132.1, 129.0–125.5 (9 C), 68.1
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118, 9796–9797.
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N-Benzylpropylamine (4g): All the physical and spectroscopic data
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7.40–7.20 (m, 5 H), 4.57 (s, 2 H, CH2Ph), 2.29 (dq, J = 7.5, 4.7 Hz,
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We are grateful to CNRS and to MENRT for financial support
and for a doctoral fellowship (V. C.).
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