One-pot synthesis of new chiral sulfides and selenides containing oxazolidines: Catalyst in the enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1055/s-2002-35225

A new easily accessible class of chiral sulfides 1 and selenides 2 containing oxazolidine was prepared from amino acids. They were used as chiral ligands in the catalytic asymmetric addition of diethylzinc to benzaldehyde to give the corresponding seconda

Full text of DOI:10.1055/s-2002-35225

2338
SHORT PAPER
One-Pot Synthesis of New Chiral Sulfides and Selenides Containing
Oxazolidines: Catalyst in the Enantioselective Addition of Diethylzinc to
Benzaldehyde
S
ynthesis of Chira
n
l
S
ulfides and
t
Selen
o
ides Contain
n
ing
O
xazolid
i
ines o L. Braga,*a Oscar E. D. Rodrigues,a Marcio W. Paixão,a Helmoz R. Appelt,b Claudio C. Silveira,a
Diana P. Bottegaa
a
Departamento de Química, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil
E-mail: albraga@quimica.ufsm.br
b
Centro Universitário Franciscano, Rua dos Andradas, 1614 – Centro 97010-032, Santa Maria, RS, Brazil
Received 15 July 2002
were reduced with NaBH4/I2 or LiAlH4 to give the desired
Abstract: A new easily accessible class of chiral sulfides 1 and se-
lenides 2 containing oxazolidine was prepared from amino acids.
They were used as chiral ligands in the catalytic asymmetric addi-
tion of diethylzinc to benzaldehyde to give the corresponding sec-
ondary alcohols in up to 80% ee with an R-configuration.
amino alcohols. The reaction of amino alcohols with
paraformaldehyde and the respective organochalcogenol
furnished the desired chiral chalcogenides 1 or 2 in satis-
factory yields (Table 1). Our ligands are stable for a long
period when stored in the refrigerator.
Key words: sulfur, selenium, stereoselective synthesis, asymmet-
ric catalysis, zinc
Table 1 Preparation of Compounds 1 or 2 from Amino Alcohols
Catalyst
1a
R
n
0
1
1
0
1
1
Yield (%)
Oxazolidines, usually obtained from amino acids, have
found widespread use as chiral nonracemic ligands in
asymmetric catalysis.1 Recently, we developed oxazoli-
dine disulfides as a new class of ligands containing a soft
donor center.2 They proved to be highly effective catalysts
for the enantioselective addition of diethylzinc to alde-
hydes.
PhCH2
PhCH2
Me2CH
PhCH2
PhCH2
Me2CH
59
61
65
57
55
41
1b
1c
2a
2b
These findings together with the potential of chiral orga-
nochalcogen compounds as catalysts for a number of tran-
sition metal mediated carbon-carbon bond forming
reactions in asymmetric synthesis,3,4 ensure the continued
importance for the development of improved catalysts de-
rived from non-toxic and inexpensive starting materials.
With this aim, together with our interest in obtaining sul-
fur and selenium catalysts,2,5b we report now the prepara-
tion of new sulfides 1 and selenides 2 containing
oxazolidines (Scheme 1) for catalytic enantioselective re-
actions.
2c
With these ligands in hand, we chose one classical catalyt-
ic enantioselective reaction to test their behavior. Thus,
ligands 1 and 2 were tested as catalysts for the diethylzinc
addition to benzaldehyde (Scheme 2).
Scheme 2
With sulfide 1a containing the SPh moiety (Table 2, entry
1), we obtained a good yield but a low enantiomeric ex-
cess. A similar result was obtained with the analogous Se
compound 2a (Table 2, entry 4). The change of the SPh-
moiety into a SBn-moiety 1b had a negative effect on the
enantiomeric excess (Table 2, entry 2). The contrary was
observed in the case of the Se-moiety 2b (Table 2, entry
5). By using 10 mol% of selenide 2b at room temperature,
we obtained the desired (R)-1-phenylpropanol in 80% ee.
At 0 °C, both the chemical yield and ee decreased. A dra-
matic decrease of the ee was observed when we changed
the benzyl-substituent of the oxazolidine ring to an iso-
Scheme 1
The chiral sulfides 1 and selenides 2 containing oxazol-
idines were readily prepared from amino acids in a two
step synthesis (Scheme 1). In the first step, amino acids
Synthesis 2002, No. 16, Print: 14 11 2002.
Art Id.1437-210X,E;2002,0,16,2338,2340,ftx,en;m03202SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

SHORT PAPER
Synthesis of Chiral Sulfides and Selenides Containing Oxazolidines
2339
propyl (Table 2, entries 5 and 6). This result is difficult to In summary, we have reported a new class of chiral chal-
rationalize and we do not yet understand the reasons.
cogenides ligands prepared in an easy synthesis from
commercial and inexpensive amino acids. Preliminary re-
sults from their behavior as ligands to enantioselective ad-
dition of diethylzinc to benzaldehyde, showed a great
catalytic potential. Further studies dealing with their ap-
plication in asymmetric catalysis are in progress.
Although the actual catalytic active species are not deter-
mined for these ligands, the transition state model shown
in Figure 1 is suggested for the enantioselective catalysts,
assuming the dinuclear Zn complexes.6
Reagents were used as received unless otherwise stated. All manip-
ulations were carried out under N2. The glassware was flame dried
prior to use for the alkylation reactions. Optical rotations were mea-
1
sured on a Perkin-Elmer 341 polarimeter. The H and 13C NMR
spectra were recorded on Bruker DPX 200 and DPX 400 spectrom-
eters using TMS as an internal standard. Elemental analyses (C, H,
N) were performed on a Vario El and Perkin-Elmer CHN 2400 an-
alyzer. GC was performed using a Varian 3800 gas chromatograph
with (2,6-Me-3-Pe)- -cyclodextrin column as chiral stationary
phase for ee determinations of the secondary alcohols obtained. The
purity of the ligands was determined by HPLC analyses using a DA-
Figure 1 Possible model to account for the observed stereochemi-
stry
ICEL CHIRALCEL OD-H column (0.46 cm
hexane–propan-2-ol (99:1), 0.5 mL/min as the mobile phase, and
detection with a UV-monitor (254).
25 cm), degassed
Table 2 Enantioselective Addition of Diethylzinc to Benzaldehyde
According to Scheme 2
Catalyst
Temp. Time
Yield
(%)
ee (%)a,b
(Config.)
Chalcogenides 1 and 2; General Procedure
(°C)
(h)
In a 50 mL round-bottomed flask fitted with a Dean–Stark appara-
tus was added benzene (30 mL), the respective amino alcohol (2.19
mmol), paraformaldehyde (3.3 mmol) and p-toluenesulfonic acid
(catalytic amount). The mixture was refluxed for 3 h. Additional
amounts of paraformaldehyde (3.3 mmol) and the respective chal-
cogenol (3 mmol) were then added and the mixture was refluxed for
an additional 3 h. The benzene was removed under vacuum and the
residue was dissolved in CH2Cl2 (30 mL). The CH2Cl2 solution was
washed with aq 0.5 N NaOH, dried (MgSO4), filtered and the sol-
vent was removed under vacuum. The product was purified by flash
chromatography (silica gel) by eluting with EtOAc–hexane (1:9) to
afford the respective compound 1 or 2.
1
2
r.t.
20
97
51
30 [R-(+)]
35[R-(+)]
0
60
r.t.
0
20
60
95
30
13 [R-(+)]
14 [R-(+)]
3
r.t.
0
20
60
75
42
37 [R-(+)]
35 [R-(+)]
1a
[ ]D20 +11.0 (c = 1.0, CH2Cl2).
1H NMR (200 MHz, CDCl3): = 7.50–7.01 (m, 10 H), 4.50 (d, 1 H,
J = 4.44 Hz), 4.46 (d, 1 H, J = 4.44 Hz), 4.37 (d, 1 H, J = 13.04 Hz),
4.28 (d, 1 H, J = 13.04 Hz) 3.97–3.88 (m, 1 H), 3.55–3.40 (m, 2 H),
2.81 (dd, 1 H, J = 6.54, 13.34 Hz), 2.56 (dd, 1 H, J = 6.54, 13.34
Hz).
13C NMR (50 MHz): = 138.42, 136.50, 131.30, 129.03, 128.99,
128.40, 126.71, 126.34, 84.43, 71.19, 61.58, 60.17, 39.33.
4
5
r.t.
0
20
60
99
52
31 [R-(+)]
30 [R-(+)]
r.t.
0
20
60
61
25
80 [R-(+)]
45 [R-(+)]
Anal. Calcd for C17H19NOS: C, 71.54; H, 6.71; N, 4.91. Found: C,
71.57; H, 6.73; N, 4.94.
1b
[ ]D20 +13.0 (c = 1.0, CH2Cl2).
6
r.t.
0
20
60
83
48
33 [R-(+)]
32 [R-(+)]
1H NMR (200 MHz, CDCl3): = 7.28–7.13 (m, 10 H) 4.48 (d, 1 H,
J = 5.72 Hz), 4.45 (d, 1 H, J = 5.72 Hz), 3.91 (m, 1 H), 3.67–3.55
(m, 4 H), 3.50–3.36 (m, 2 H), 2.84 (dd, 1 H, J = 7.32, 13.57 Hz),
2.62 (dd, 1 H, J = 7.32, 13.57 Hz).
13C NMR (50 MHz, CDCl3): = 138.91, 129.76, 129.43, 128.88,
127.34, 126.87, 85.35, 70.36, 63.76, 56.64, 40.39, 34.75.
a The ee’s were determined by GC using a (2,6-Me,3-Pe)- -CD-Col-
umn.
b Assigned by comparison of the sign of optical rotation reported.4
Anal. Calcd for C18H21NOS. C, 72.20; H, 7.07; N, 4.68;. Found: C,
72.22; H, 7.10; N, 4.70.
1c
[ ]D20 +51.0 (c = 1.0, CH2Cl2).
Synthesis 2002, No. 16, 2338–2340 ISSN 0039-7881 © Thieme Stuttgart · New York

2340
A. L. Braga et al.
SHORT PAPER
1H NMR (200 MHz, CDCl3): = 7.33–7.20 (m, 5 H), 4.47 (d, 1 H,
J = 5.86 Hz), 4.25 (d, 1 H, J = 5.86 Hz), 3.93 (t, 1 H, J = 8.05 Hz),
3.81 (s, 2 H), 3.76–3.71 (m, 2 H), 3.44 (dd, 1 H, J = 5.86, 8.05 Hz),
2.77 (dd, 1 H, J = 8.05, 13.53 Hz), 1.57 (m, 1 H), 0.97 (d, 3 H,
J = 6.60 Hz), 0.84 (d, 3 H, J = 6.60 Hz).
Acknowledgements
The authors thank the following agencies for support: CNPq, FA-
PERGS, CAPES and DAAD (German Academic Exchange Ser-
vice) for travel grants as part of PROBRAL project.
13C NMR (50 MHz, CDCl3): = 134.46, 128.88, 128.39, 126.87,
85.23, 68.23, 57.95, 34.81, 31.15, 19.97, 18.48.
References
Anal. Calcd for C14H21NOS: C, 66.89; H, 8.42; N, 5.57. Found: C,
66.92; H, 8.46; N, 5.60.
(1) (a) Okuyama, Y.; Nakano, H.; Hongo, H. Tetrahedron:
Asymmetry 2000, 11, 1193. (b) Falorni, M.; Collu, C.;
Conti, S.; Giacomelli, G. Tetrahedron: Asymmetry 1996, 7,
293. (c) Joshi, N. N.; Prasad, P. R. K. J. Org. Chem. 1997,
62, 3770.
(2) (a) Braga, A. L.; Appelt, H. R.; Schneider, P. H.; Silveira, C.
C.; Wessjohann, L. A. Tetrahedron: Asymmetry 1999, 10,
1733. (b) Braga, A. L.; Appelt, H. R.; Schneider, P. H.;
Rodrigues, O. E. D.; Silveira, C. C.; Wessjohann, L. A.
Tetrahedron 2001, 57, 3291.
2a
[ ]D20 +10.0 (c = 1.0, CH2Cl2).
1H NMR (200 MHz, CDCl3): = 7.57–6.96 (m, 10 H), 4.65 (d, 1 H,
J = 11.77 Hz), 4.51 (d, 1 H, J = 11.77 Hz), 4.44 (d, 1 H, J = 3.70
Hz), 4.34 (d, 1 H, J = 3.70 Hz), 3.93 (m, 1 H), 3.58–3.29 (m, 2 H),
2.78 (dd, 1 H, J = 6.50, 13.35 Hz), 2.53 (dd, 1 H, J = 7.66, 13.35
Hz).
(3) For chiral sulfur ligands, see: (a) Holf, R. P.; Poelert, M. A.;
Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron:
Asymmetry 1994, 5, 31. (b) Fitzpatrick, K.; Hulst, R.;
Kellogg, R. M. Tetrahedron: Asymmetry 1995, 6, 1861.
(c) Kang, J.; Lee, D. J. W.; Kim, J. L. J. Chem. Soc., Chem.
Commun. 1994, 2009. (d) Kang, J.; Kim, D. S.; Kim, J. L.
Synlett 1994, 842. (e) Kang, J.; Kim, J. B.; Kim, J. W.; Lee,
D. J. Chem. Soc., Perkin Trans. 2 1997, 189. (f) Nakano,
H.; Kumagai, N.; Matsuzaki, H.; Kabuto, C.; Hongo, H.
Tetrahedron: Asymmetry 1997, 8, 1391. (g) Iwasa, K.;
Hongo, H. Heterocycles 1997, 46, 267. (h) Chelucci, G.;
Berta, D.; Fabbri, D.; Pinna, G. A.; Saba, A.; Ulgheri, F.
Tetrahedron: Asymmetry 1998, 9, 1933. (i) Gibson, C. L. J.
Chem. Soc., Chem. Commun. 1996, 645. (j) Gibson, C. L.
Tetrahedron: Asymmetry 1996, 7, 3357. (k) Cran, G. A.;
Gibson, C. L.; Handa, S.; Kennedy, A. R. Tetrahedron:
Asymmetry 1996, 7, 2511. (l) Fulton, D. A.; Gibson, C. L.
Tetrahedron Lett. 1997, 38, 2019. (m) Cran, G. A.; Gibson,
C. L.; Handa, S. Tetrahedron: Asymmetry 1995, 6, 1553.
(n) Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen, M. D.;
Boersma, J.; van Koten, G. Tetrahedron Lett. 1994, 35,
6521. (o) Satoh, Y.; Makihara, T.; Shi, M. Chem. Pharm.
Bull. 1996, 44, 454. (p) Hulst, R.; Heres, H.; Fitzpatrick, K.;
Peper, N. C. M. W.; Kellogg, R. M. Tetrahedron:
Asymmetry 1996, 7, 2755. (q) Jin, M.-J.; Ahm, S.-J.; Lee,
K.-S. Tetrahedron Lett. 1996, 37, 8767. (r) Rijnberg, E.;
Hovestad, N. J.; Kleij, A. W.; Jastrzebski, J. T. B. H.;
Boersma, J.; Janssen, M. D.; Spek, A. L.; van Koten, G.
Organometallics 1997, 16, 2847. (s) Anderson, J. C.;
Cubbon, R.; Harding, M.; James, D. S. Tetrahedron:
Asymmetry 1998, 9, 3461. (t) Mehler, T.; Martens, J.
Tetrahedron: Asymmetry 1993, 4, 2299. (u) Trentmann, W.;
Mehler, T.; Martens, J. Tetrahedron: Asymmetry 1997, 8,
2033. (v) Kossenjans, M.; Martens, J. Tetrahedron:
Asymmetry 1998, 9, 1409. (w) Juanes, O.; Rodriguez-Ubis,
J. C.; Brune, E.; Pennemann, H.; Kossenjans, M.; Martens,
J. Eur. J. Org. Chem. 1999, 3323.
13C NMR (50 MHz, CDCl3): = 138.17, 134.23, 131.52, 129.14,
128.95, 128.39, 127.07, 126.36, 85.07, 71.74, 61.27, 56.89, 38.79.
Anal. Calcd for C17H19NOSe: C, 61.45; H, 5.76; N, 4.22. Found: C,
61.41; H, 5.73; N, 4.20
2b
[ ]D20 +23.0 (c = 1.0, CH2Cl2).
1H NMR (200 MHz, CDCl3): = 7.32–7.15 (m, 10 H), 4.40 (d, 1 H,
J = 4.38 Hz), 4.25 (d, 1 H, J = 4.38 Hz), 4.15 (d, 1 H, J = 11.75 Hz),
4.01 (d, 1 H, J = 11.75 Hz), 3.92 (dd, 1 H, J = 7.08, 8.04 Hz), 3.73
(s, 2 H), 3.50 (dd, 1 H, J = 5.88, 8.04 Hz), 3.28 (m, 1 H), 2.81 (dd,
1 H, J = 6.96, 13.53 Hz), 2.59 (dd, J = 7.34, 13.53 Hz).
13C NMR (50 MHz, CDCl3): = 139.63, 138.43, 128.97, 128.78,
128.47, 128.42, 126.65, 126.38, 85.33, 71.08, 62.41, 51.17, 39.21,
26.97.
Anal. Calcd for C18H21NOSe: C, 62.43; H, 6.11; N, 4.04. Found: C,
62.46; H, 6.13; N, 4.06
2c
[ ]D20 +53.0 (c = 1.0, CH2Cl2).
1H NMR (200 MHz, CDCl3): = 7.33–7.20 (m, 5 H), 4.29 (d, 1 H,
J = 11.60 Hz), 4.10 (d, 1 H, J = 11.60 Hz), 3.95–3.87 (m, 1 H), 3.81
(s, 2 H), 3.76–3.71 (m, 2 H), 3.44 (dd, 1 H, J = 6.00, 8.20 Hz), 2.77
(dd, 1 H, J = 6.00, 13.40 Hz), 1.57 (m, 1 H), 0.97 (d, 3 H, J = 6.60
Hz), 0.84 (d, 3 H, J = 6.60 Hz).
13C NMR (50 MHz, CDCl3): = 134.46, 128.88, 128.39, 126.87,
85.23, 68.23, 57.95, 34.81, 31.15, 19.97, 18.48.
Anal. Calcd for C14H21NOSe: C, 56.37; H, 7.10; N, 4.70. Found: C,
56.39; H, 7.13; N, 4.72.
Asymmetric Addition of Diethylzinc to Benzaldehyde; General
Procedure
In a 25 mL flask containing toluene (7 mL), benzaldehyde (3 mmol,
0.32 g) and the catalyst (10 mol%) was slowly injected a 1 M solu-
tion of diethylzinc in hexane (5 mmol, 5 mL) with constant stirring.
The stirring was continued for the time and the temperature indicat-
ed in Table 2. Finally, the temperature was adjusted to 0 °C (ice-
bath) and aq 1 N HCl (5 mL) was slowly added (10 min) with con-
tinuous stirring. The organic layer was separated and washed with
of aq 1 N HCl (2 8 mL). After drying (Na2SO4), and filtration, the
toluene was removed under reduced pressure. The crude alcohol
was purified by bulb-to-bulb distillation under reduced pressure (ca.
0.1 mbar).
(4) For chiral selenium ligands, see: (a) Wirth, T. Tetrahedron
1999, 55, 1. (b) Wirth, T. Angew. Chem., Int. Ed. 2000, 39,
3740. (c) Wirth, T. Tetrahedron Lett. 1995, 36, 7849.
(d) Wirth, T.; Kulicke, K. J.; Fragale, G. Helv. Chim. Acta
1996, 1957. (e) Santi, C.; Wirth, T. Tetrahedron: Asymmetry
1999, 10, 1019. (f) Wirth, T. Tetrahedron 1999, 55, 7849.
(5) (a) Cho, B. T.; Chun, Y. S. Tetrahedron: Asymmetry 1998,
9, 1489. (b) Braga, A. L.; Vargas, F.; Silveira, C. C.;
Andrade, L. H. Tetrahedron Lett. 2002, 43, 2335.
(6) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl.
1991, 30, 49.
Synthesis 2002, No. 16, 2338–2340 ISSN 0039-7881 © Thieme Stuttgart · New York