Anodic oxidation of chiral sulfinylamines: A new route to highly diastereoselective α-alkylation of piperidine

Article abstract of DOI:10.1016/j.tetlet.2005.05.123

The anodic oxidation of some chiral non-racemic N-arylsulfinyl piperidines was investigated and for the first time α methoxylated sulfinyl piperidines were obtained. The so-formed compounds are equivalent of chiral N-sulfinyliminiums and used as new inter

Full text of DOI:10.1016/j.tetlet.2005.05.123

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5131–5134
Anodic oxidation of chiral sulfinylamines: a new route to highly
diastereoselective a-alkylation of piperidine
*
´
Serge Turcaud, Thierry Martens, Emma Sierecki, Joe¨lle Perard-Viret and Jacques Royer
` ´ ´ ˆ
Synthese et structure de molecules d’interet pharmacologique, UMR 8638 CNRS-University Paris 5, Faculty of Pharmacy,
4 avenue de l’Observatoire, 75270 Paris cedex 6, France
Received 15 April 2005; revised 30 May 2005; accepted 31 May 2005
Available online 16 June 2005
Abstract—The anodic oxidation of some chiral non-racemic N-arylsulfinyl piperidines was investigated and for the first time a meth-
oxylated sulfinyl piperidines were obtained. The so-formed compounds are equivalent of chiral N-sulfinyliminiums and used as new
intermediates for the preparation of chiral a-substituted piperidine derivatives in good yield and diastereoselectivity.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Stereoselective substitution at the a position of second-
ary amines offers opportunities for convenient and effi-
cient syntheses of nitrogen containing derivatives.
Nevertheless, this sequence remains challenging and,
despite several attempts, very few reactions permitting
this substitution have been described so far.
Z
N
Z
N
H
N
OMe
1
2
3
Lewis
acid
Both anionic and cationic routes were reported. Depro-
tonation a to the nitrogen was investigated1 with some
success and asymmetric versions1–3 exist whilst confined
to the alkylation of allylamines2b and pyrrolidines.2a,3
The cationic pathway has been extensively studied
(Scheme 1). A secondary amine 1 is transformed to a-
methoxy derivative 3 (Z = COOR) via carbamate 2
(Z = COOR) using the ShonoÕs anodic oxidation.4 The
methoxy compound 3 reacts with a nucleophile in the
presence of a Lewis acid to give the substituted deriva-
tive 5 via acyliminium 4.5 This anodic oxidation–amido-
alkylation sequence is a very powerful method allowing
the introduction of various nucleophiles.6 Moreover this
process is very easy to perform and does not need any
special technical knowledge.7 Surprisingly, few asym-
metric developments of this efficient methodology ap-
peared in the literature. Use of chiral carbamates led
to disappointing diastereoselectivities8 (except if a chiral
center is already present on the starting amine 1).9 A re-
cent example using a chiral Lewis acid and providing an
Z
N
Z
N
H
N
Nu
R
6
5
4
Scheme 1.
encouraging 56% ee was also reported.10 It thus ap-
peared that improvement of the diastereoselectivity
would call for the choice of another type of chiral acti-
vating Z group besides carbamates.
Several reports from the literature showed that diastereo-
selectivities for addition of nucleophiles to chiral sulfin-
ylimines are consistently good to excellent.11 Thus, we
planned to study the use of sulfoxide as chiral auxiliary
in the oxidation/alkylation sequence described in
Scheme 1 (Z = S*(O)R).
To the best of our knowledge there is no report in the
literature neither concerning the generation of N,O-ace-
tal equivalent of N-sulfinyliminium by direct oxidation
of sulfinylamine, nor their use in the alkylation step.
Keywords: Sulfinylamine; Anodic oxidation; Diastereoselective alkyl-
ation; Pelletierine.
*
Corresponding author. Tel.: +33 153739749; fax: +33 143291403;
e-mail: jacques.royer@univ-paris5.fr
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.123

5132
S. Turcaud et al. / Tetrahedron Letters 46 (2005) 5131–5134
oxidation is known to generate protons, which can be a
R
O
serious drawback for the integrity of N–S bond.11a The
first very simple idea was to perform the anodic oxida-
tion in the presence of added base. Furthermore, it
can help in the kinetic of deprotonation of the expect-
edly formed nitrogen centered cation-radical. After
some trials, it was found that anodic oxidation,18 at con-
stant current with graphite plate electrodes, of sulfinyl-
amine 7a (R = p-tolyl) in MeOH and in the presence
of KHCO3 occurred cleanly to furnish the desired a-
methoxylated derivative 8a in a good 69% yield as a
mixture (75:25) of two diastereoisomers. The enantio-
meric purity of each diastereoisomer was checked by
chiral HPLC and no racemization was observed. The
formation of methylsulfinate 11a corresponding to the
N–S bond cleavage reported by DÕOca et al.19 (Scheme
2) could not be completely avoided. Under more basic
conditions, the formation of 11a was minimized and
8a was formed in a nice 77% yield but each diastereoiso-
mer of 8a was proved to be only 80% ee. This partial
racemization under these specific conditions is not
clearly understood.
S
N
R
OMe
O
S
N
H
N
i)
iii)
8a-d
or ii)
R
7a-f
O
+ piperidine
S
OMe
11a-f
Scheme 2. Reagents and conditions: (i) MeMgBr, THF, 0 ꢁC, then
menthyl arylsulfinate, 1 equiv; (ii) for 7f: BuLi, THF, ꢀ78 ꢁC, then
t-BuSS(O)t-Bu; (iii) anodic oxidation.18
Only one example of N-sulfinyliminium was described
(as the expected intermediate in the Pictet–Spengler
reaction of (R)-N-p-toluenesulfinyltryptamine).12
We now report on the first successful electrochemical
oxidation of chiral N-sulfinylamine to a-alkoxy-N-sulfin-
ylamine and the diastereoselective addition of a nucleo-
phile onto this potential sulfinyliminium. In this
preliminary study, we investigated some chiral sulfoxide
groups as N-activating group (Z, Scheme 1) of the piper-
idine ring chosen as a model substrate (Scheme 2). The
sequence was applied to the asymmetric synthesis of pel-
letierine (10).
As it can be seen in Table 1, compounds 7a–d gave the
expected a-methoxylated sulfinylamines 8a–d13 in
acceptable to good yields. The N–S bond cleavage is still
present in a small amount (about 15%) in all cases
regardless of the structure. It is noteworthy that com-
pound 11 were found to be racemic products.
In contrast to the oxidation of 7a–d, N-sulfinyl piper-
idines 7e (R = mesityl) and 7f (R = t-Bu) containing
bulky groups led exclusively to cleavage products under
several experimental conditions. This can be linked to
their lower oxidation potential (Ep = 1.3 and 1.5 V sce
for, respectively, 7f and 7e compared to 1.7–1.9 V sce
for 7a–d).
N-Sulfinyl piperidines 7 were prepared13 according to
the literature14 with some modifications. The enantio-
enriched N-arylsulfinyl piperidines 7a–d were obtained
in high yields and ee (Table 1) by addition of piperidine
magnesium bromide to the diastereomerically pure men-
thyl sulfinates.15 Compound 7e was prepared in only
30% ee from unseparated mesityl menthyl sulfinate dia-
stereoisomers and 7f was prepared in racemic form from
t-BuSS(O)t-Bu16 and piperidine lithium.17
The possibility to regenerate the sulfinyliminium
from the a-methoxylated product 8 and the diastereo-
selectivity of the addition of a nucleophile were then
investigated. When 8a was treated with trimethyl-
silyloxypropene at ꢀ78 ꢁC in the presence of 0.4 equiv
of TMSOTf, the N-sulfinyl amino ketone 9a was ob-
tained in a fair 64 % yield and a nice 90:10 diastereoiso-
meric ratio (Scheme 3). This ratio was determined by
HPLC and NMR analyses on the crude reaction mix-
ture. The absence of racemization at sulfur atom was
once again checked by chiral HPLC on each diastereo-
isomer. The methoxylated derivatives 8b–d proceeded
as well with de ranging from 64% to 84% (Table 2). A
by-product was systematically observed and identified
as the S-alkylated derivative 12.22 In each case the major
isomer of 913 is obtained pure after simple flash
chromatography.
The oxidation step was particularly challenging and
hypothetic since both nitrogen and sulfur atoms can
be oxidized. Indeed, the anodic oxidation of sulfinylam-
ines was reported by DÕOca et al.19 to give sulfur oxida-
tion or N–S bond cleavage.20 However, fragmentary
data from the literature suggested that the regioselective
nitrogen oxidation is possible.21
We reasoned that this electrochemical procedure should
be quite sensitive to the reaction conditions. The anodic
Table 1. Preparation and anodic oxidation of N-sulfinyl piperidines 7
R
7
8
11
Yield (%) ee (%) Yield (%) dr
Brief treatment (10 min) with 0.5 equiv of a 0.5 M aque-
ous H2SO4 solution in MeOH gave quantitatively the
(S)-enantiomer of pelletierine sulfate (10): ([a]D +28.9
(c 0.9, H2O))23 without epimerization. This very simple
cleavage of the N-sulfoxide bond contrasts with the
tedious cleavage of carbamates. The alkylation of a-meth-
oxylated sulfinylamines 8a–d possessing a (S)-sulfoxide
a
b
c
d
e
f
p-Tol
o-Tol
Ph
84
82
88
98
94
98
99
30
0
69
48
67
71
0
75/25 13
82/18 26
73/27 15
90/10 17
o-CF3–C6H4 87
Mesityl
t-Bu
73
61
—
—
66
—
0

S. Turcaud et al. / Tetrahedron Letters 46 (2005) 5131–5134
5133
References and notes
R
O
S
N
1. (a) Gawley, R. E.; Rein, C. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 3, pp 65–83; (b) Beak, P.; Basu, A.;
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Soc. 1994, 116, 3231–3239; (b) N-allylamines are easily
deprotonated giving mainly c-subtituted products, see for
example: Whisler, M.; Beak, P. J. Org. Chem. 2002, 68,
1207–1215.
CH3
R
O
O
OTMS
H3C
S
N
OMe
9a-d
R
TMSOTf (0.4 equiv.)
CH2Cl2, -78 °C
O
S
CH3
8a-d
3. (a) Beak, P.; Lee, W. K. J. Org. Chem. 1993, 58, 1109–
1117; (b) Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S.;
Wiberg, K. B. J. Am. Chem. Soc. 2002, 124, 1889–1896.
4. (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem.
Soc. 1981, 103, 1172–1176; (b) Shono, T. Tetrahedron
1984, 40, 811–850; (c) Shono, T. In Topics in Current
Chemistry; Streckham, E., Ed.; Springer: Berlin, 1988;
Vol. 148, p 131.
O
12a-d
H
N
H2SO4 0.5M
CH3
9a-d
0.5 equiv., 10 min.
O
5. A variant was proposed allowing the direct substitution
without isolation of methoxy derivative, for recent papers
see: (a) Suga, S.; Nishida, T.; Yamada, D.; Nagaki, A.;
Yoshida, J. J. Am. Chem. Soc. 2004, 126, 14338–14339; (b)
Suga, S.; Susuki, S.; Yoshida, J. J. Am. Chem. Soc. 2002,
124, 30–31.
6. Overman, L. E.; Ricca, D. J. In Comprehensive Organic
Synthesis; Trost, B. M., Flemming, I., Heathcock, C. H.,
Eds.; Pergamon: Oxford, 1991; Vol. 2, p 1007.
7. Moeller, K. D. Tetrahedron 2000, 56, 9527–9554.
8. (a) DÕOca, M. G.; Pilli, R. A.; Vencato, I. Tetrahedron
Lett. 2000, 41, 9709–9712; (b) Gawley, R. E.; Barolli, G.;
Madan, S.; Saverin, M.; OÕConnor, S. Tetrahedron Lett.
2004, 45, 1759–1761.
9. For more recent examples see: (a) Aggarwal, V. K.; Astle,
C. J.; Rogers-Evans, M. Org. Lett. 2004, 6, 1469–1471; (b)
Hanessian, S.; Claridge, S.; Johnstone, S. J. Org. Chem.
2002, 67, 4261–4274; (c) Ma, D.; Yang, J. J. Am. Chem.
Soc. 2001, 123, 9706–9707; (d) Halab, L.; Belec, L.; Lubell,
W. D. Tetrahedron 2001, 57, 6439–6446.
10
Scheme 3.
Table 2. Diastereoselective alkylation of methoxylated N-sulfinyl
piperidines 8
R
9
9:12 ratio
Isolated yield (%)
de
a
b
c
p-Tol
o-Tol
64
55
60
62
80
84
80
64
92:8
83:17
82:18
82:18
Ph
o-CF3–C6H4
d
moiety gave 10 with the (S) configuration. The same
configuration was reported upon alkylation of (S)-p-
toluenesulfinyl imine with several nucleophiles,11c sug-
gesting analogue diastereocontrol with chiral
sulfinyliminium.
10. Braun, M.; Kotter, W. Angew. Chem., Int. Ed. 2004, 43,
514–517.
11. For reviews see: (a) Davis, F. A.; Zhou, P.; Chen, B.-C.
Chem. Soc. Rev. 1998, 27, 13–18; (b) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984–995; (c)
Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60,
8003–8030.
In conclusion, we showed for the first time that N-sulfin-
ylamines can be transformed to the corresponding a-
methoxy N-sulfinylamines through anodic oxidation.
This allowed us to prepare chiral non-racemic equiva-
lent of sulfinyliminium on 0.5 g scale. The so-formed
a-methoxylated N-sulfinylamines can react as potential
sulfinyliminium allowing highly diastereoselective alkyl-
ation. The R group beared at the sulfoxide is important
to the success of the anodic oxidation, while several sub-
stituents allow the alkylation reaction to occur in good
yield and diastereoselectivity.
12. Gremmen, C.; Wanner, M. J.; Koomen, G.-J. Tetrahedron
Lett. 2001, 42, 8885–8888.
13. The structures of all new compounds are supported by 1H,
13C NMR spectra and HRMS data.
22
Compound 7a: white solid; mp: 66 ꢁC; ½aꢁD +110 (c 1.4,
MeOH); 1H NMR (300 MHz, CDCl3) d (ppm): 7.48 (d,
J = 8.1 Hz, 2H); 7.24 (d, J = 8.1 Hz, 2H); 3.01 (m, 2H);
2.90 (m, 2H); 2.35 (s, 3H); 1.51 (m, 6H). 13C NMR
(75 MHz, CDCl3) d (ppm): 140.9; 140.2; 129.4; 126.1; 46.8;
26.1; 23.9; 21.2. IR (Nujol): 2922, 2852, 1598, 1457, 1377,
1241 cmꢀ1
.
HRMS: m/z calcd for C12H17NOSNa
The overall sequence is a short (four steps) procedure to
diastereomerically a-alkylate secondary amines. The
generalization of this procedure to other amines and
nucleophiles is under investigation.
(M+Na): 246.0929. Found: 246.0917.
Compound 8a: 1H NMR (300 MHz, CDCl3) d (ppm): 7.49
(m, 2H); 7.25 (m, 2H); 4.70 (br s, 1H, major); 4.60 (br s, 1H,
minor); 3.38 (s, 3H, major); 3.33 (s, 3H, minor); 2.94 (m,
1H); 2.76 (m, 1H); 2.37 (s, 3H); 1.90 (m, 1H); 1.71 (m, 2H),
1.49 (m, 2H); 1.21 (m, 1H). 13C NMR (75 MHz, CDCl3) d
(ppm): 141.1; 129.6 (minor)/129.4 (major); 126.2 (major)/
126.1 (minor); 89.2 (major)/88.9 (minor); 55.5 (major)/55.2
(minor); 40.4; 37.7; 31.7 (major)/31.2 (minor); 26.4 (minor)/
26.3 (major); 21.3; 18.3. IR (neat): 2941, 2827, 1594, 1443,
1091. HRMS: m/z calcd for C13H20NSO2Na: 276.1034.
Acknowledgements
The authors thank the CNRS and the French Ministry
of Education and Research for funding.

5134
S. Turcaud et al. / Tetrahedron Letters 46 (2005) 5131–5134
Found: 276.1040. Compound 9a: white solid; mp: 50 ꢁC;
(35 · 20 mm) and at a constant current (15 mA), under
nitrogen on a 0.05 M methanolic solution of 7 containing
Et4NBF4 (0.5 equiv) and KHCO3 (0.5 equiv). The course
of the electrolysis was checked by HPLC, the terminal
voltage was 4.5 V.
22
1
½aꢁD +99 (c 1.08, MeOH); H NMR (300 MHz, CDCl3) d
(ppm): 7.49 (d, J = 8.1 Hz, 2H); 7.28 (d, J = 8.1 Hz, 2H);
4.13 (m, 1H); 3.10 (m, 2H); 2.86 (m, 2H); 2.35 (s, 3H); 2.40
(s, 3H); 2.15 (s, 3H); 1.81 (m, 1H); 1.60 (m, 4H); 1.40 (m,
1H). 13C NMR (75 MHz, CDCl3) d (ppm): 206.1; 141.0;
140.2; 129.5; 126.2; 54.0; 45.4; 42.0; 31.0; 30.5; 26.0; 21.3;
20.5. IR (Nujol): 2937, 2859, 1713, 1595, 1359, 1095, 1064.
MS: m/z 302 (M+Na). HRMS: m/z calcd for
C15H21NO2SNa (M+Na): 302.1191. Found: 302.1195.
19. DÕOca, M. G.; Russowsky, D.; Canto, K.; Gressler, T.;
Gonc¸alves, R. S. Org. Lett. 2002, 4, 1763–1766.
20. N–S cleavage was also observed in N-sulfinyl anilines:
Carreno, M. C.; Ribagorda, M. J. Org. Chem. 2000, 65,
1231–1234.
14. Garcia-Ruano, J.; Alonso, R.; Zarzuelo, M. M.; Noheda,
P. Tetrahedron: Asymmetry 1995, 6, 1133–1142.
15. (a) Andersen, K. K. Tetrahedron Lett. 1962, 3, 93–95; (b)
Klunder, J. M.; Sharpless, K. B. J. Org. Chem. 1987, 52,
2598–2602.
16. Netscher, T.; Prinzbach, H. Synthesis 1987, 683–688.
17. Cogan, D. A.; Liu, G.; Kim, K.; Backes, B. J.; Ellman, J.
A. J. Am. Chem. Soc. 1998, 120, 8011–8019.
21. (a) Hartung, C.; Illgen, K.; Sieler, J.; Schneider, B.;
Schulze, B. Helv. Chim. Acta 1999, 82, 685–695; (b)
Taubert, K.; Sieler, J.; Hennig, L.; Findeisen, M.; Schulze,
B. Helv. Chim. Acta 2002, 85, 183–195; (c) Siegemund, A.;
Hartung, C.; Baumann, S.; Schulze, B. Helv. Chim. Acta
2004, 87, 376–381.
22. The enantiomeric purity of 12 was not checked.
23. Reported values for the natural (R) isomer: [a]D ꢀ29.5 (c
1.09, H2O): Gilman, R. E.; Marion, L. Bull. Soc. Chim. Fr.
1961, 1993–1995.
18. The electrolysis was conducted at 0 ꢁC in an undivided
glass cell equipped with two graphite plate electrodes