Catalytic asymmetric hydrosilylation of acetophenone with new chiral thiourea ligands containing the (S)-α-phenylethyl group

Article abstract of DOI:10.1016/j.tetasy.2009.11.027

New chiral thioureas 1-8 containing 1,2-ethylendiamine or trans-1,2-diaminocyclohexane as the carbon skeleton, and containing an (S)-α-phenylethyl group have been prepared (79-98% yield). Thioureas 1-8 were used as ligands for the zinc-based catalyzed asy

Full text of DOI:10.1016/j.tetasy.2009.11.027

Tetrahedron: Asymmetry 20 (2009) 2788–2794
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric hydrosilylation of acetophenone with new chiral
thiourea ligands containing the (S)-a-phenylethyl group
Ericka Santacruz a, Gabriela Huelgas a, Sandra K. Angulo a, Virginia M. Mastranzo a,b
,
d
Simón Hernández-Ortega b, Judit A. Aviña c, Eusebio Juaristi c, Cecilia Anaya de Parrodi a, , Patrick J. Walsh
*
a Departamento de Ciencias Químico-Biológicas, Universidad de las Américas-Puebla, Sta. Catarina Mártir, 72820 Cholula, Mexico
b Instituto de Química, Universidad Nacional Autónoma de Mexico, 04510 D.F., Mexico
c Departamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07000 D.F., Mexico
d Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
New chiral thioureas 1–8 containing 1,2-ethylendiamine or trans-1,2-diaminocyclohexane as the carbon
skeleton, and containing an (S)- -phenylethyl group have been prepared (79–98% yield). Thioureas 1–8
were used as ligands for the zinc-based catalyzed asymmetric hydrosilylation of acetophenone with poly-
methylhydrosiloxane (PMHS). The best result was achieved with monothiourea 1 (up to 75% ee), in tol-
uene and a catalyst load of 5 mol %.
Received 23 September 2009
Accepted 27 November 2009
Available online 6 January 2010
a
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Our goal is the design of new ligands using the a-phenylethyl-
amino group as an economic chiral moiety.26 Herein we report the
preparation of new thioureas 1–8 (Chart 1) containing 1,2-ethylen-
diamine or trans-1,2-diaminocyclohexane as the backbone, and
The search for more economical and environmentally friendly
methods for the enantioselective reduction of prochiral ketones
is a rewarding goal. Asymmetric hydrosilylation of arylketones cat-
alyzed by transition metals with chiral nitrogen and sulfur-con-
taining ligands is a useful synthetic route to optically active
alcohols.1–5
(S)-a-phenylethyl groups as chiral appendages. We also report
the use of ligands 1–8 in the catalytic asymmetric hydrosilylation
of acetophenone with PMHS and diethylzinc.
Polymethylhydrosiloxane (PMHS), a polymer coproduct of the
silicone industry, is a safe and inexpensive hydrosilylating agent,
which can transfer its hydride to a variety of inexpensive and
non-toxic metal catalysts (Ti, Zn, and Cu).2,3 The enantioselective
hydrosilylation of prochiral ketones and imines in the presence
of PMHS as a reducing reagent with zinc-based catalysts in the
presence of bidentate N,N-ligands6–12 and N,S-ligands13,14 had been
reported by several groups.
Considerable attention has been focused on the development of
chiral thioureas, which are air and moisture stable and have been
used as ligands in asymmetric catalysis.15–25 Chiral thiourea A
has been employed in the asymmetric reduction of acetophenone
by ruthenium- and rhodium-catalyzed hydride transfer with 87%
and 63% ee, respectively, in 98% yield.17,18,21 Additionally, the
hydrosilylation of acetophenone using thiourea B with iridium-
based catalysts and diphenylsilane has been reported. Enantiose-
lectivities as high as 74% were achieved, although only 30% conver-
sion was reported (Scheme 1).21
2. Results and discussion
2.1. Preparation of chiral thioureas 1–8
Thioureas 1–8 were prepared in dichloromethane at 25 °C with
1.0 equiv of 1,2-diamines 9–1110 and 2 equiv of isothiocyanates
12–16.27,28 Diamine 9 afforded monothioureas 1–4 in 79–80% yield
after purification by column chromatography on silica gel [hex-
anes/EtOAc; 12:1] (Scheme 2, Eq. 1). Thioureas 1–4 did not react
with the second equivalent of isothiocyanate. The dithioureas were
obtained with 1,2-diamines 10 and 11 affording 5 in 98% yield, and
6–8 in 79–80% yield (Scheme 2, Eqs. 2 and 3), respectively.
We observed dynamic phenomena in the NMR spectra of chiral
thioureas 1–8 in CDCl3 at 25 °C, and so we recorded the spectra in
DMSO-d6 at 50–110 °C. Monothioureas 1–3 formed suitable crys-
tals for X-ray diffraction analysis. ORTEP diagrams are shown in
Figures 1–3. The structures of 1–3 show that the secondary amines
are sterically crowded. The congested environment about the sec-
ondary amines might explain the formation of the monothioureas
1–4 as the major product, instead of the corresponding dithioureas
as in the case of 6–8, even though an excess of isothiocyanate was
used in all reactions.
* Corresponding author. Fax: +52 222 229 2419.
E-mail address: cecilia.anaya@udlap.mx (Cecilia Anaya de Parrodi).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.11.027

E. Santacruz et al. / Tetrahedron: Asymmetry 20 (2009) 2788–2794
2789
Ph
MeN
Ph
NMe
S
S
Ph
Ph
A
OH
O
OH
O
(eq 1)
A (10 mol%), (RuCl2C6H6)2 (5 mol%)
+
CH3
+
CH3
tBuOK, 82 ºC, 9 h
98% conversion, 87% ee (S)
S
S
NH HN
Ph
Ph
B
OH
O
(eq 2)
1. B, Ph2SiH2, [Ir(COD)Cl]2 (1 mol%)
50 ºC, toluene, 21 h
CH3
CH3
2. K2CO3, MeOH, r. t.
ee (R), % yield, %
B, mol%
conversion, %
−
3
55
74
50
−
10
30
Scheme 1.
2.2. Enantioselective reduction of acetophenone
the 1,2-ethylendiamine backbone (Table 1). The highest enantiose-
lectivities were observed with a catalyst formed from thiourea 1,
affording 1-phenylethanol with 75% ee. In all cases, the yields were
low (Table 1) and no side reaction was observed. Higher loadings
of the catalysts or long reaction times led to a higher conversion with
areductionintheenantioselectivity. Unfortunately, theuseof differ-
ent solvents did not afford better results (Table 2).
Compounds 1–4 are bifunctional ligands that presumably bind
through the amine and thiourea groups. The basic nitrogen of the
amine is normally a good ligand for zinc.6,9,10 We surmise that
With a series of new ligands in hand, we optimized the asymmet-
ric reduction of acetophenone with diethylzinc, PMHS, and the sub-
strate. We observed the best yields and enantioselection in the
hydrosilylation of 1 equiv of acetophenone with 1.2 equiv of PMHS
in the presence of toluene as a solvent, 5 mol % thiourea ligand and
5 mol % Et2Zn for 48 h at room temperature.10 Thioureas 1–4, con-
taining the trans-1,2-diaminocyclohexane backbone, afforded high-
er yields and enantioselectivities compared with thiourea 5–8 with
Ph
Ph
Ph
Ph
Ph
NH
Ph
N
Ph
NH
Ph
N
Ph
NH
N
Ph
NH
N
N
H
N
H
N
H
N
H
S
S
S
S
Ph
Ph
4
1
3
2
Ph
S
S
H
H
H
N
Ph
N
N
N
Ph
N
N
N
H
Ph
N
H
N
Ph
H
S
S
S
Ph
5
6
Ph
Ph
S
S
H
N
H
Ph
Ph
N
N
Ph
N
N
H
N
N
Ph
H
S
Ph
Ph
8
7
Chart 1.

2790
E. Santacruz et al. / Tetrahedron: Asymmetry 20 (2009) 2788–2794
(1)
CH2Cl2
+
2 S C N
Ph
Ph
25 ºC, 12 h
R
N
Ph
NH
NH HN
N
H
−
79 80% yield
Ph
S
R
9
12 − 15
1 − 4
1, 12; R = (S)-CHCH3Ph
2, 13; R = (S)-CHCH3-1-Naphthyl
3, 14; R = CH2Ph
4 15
,
; R = CHPh2
S
H
N
H
N
CH2Cl2
(2)
(3)
Ph
S C N
H2N
NH2
+
2
N
N
H
Ph
25 ºC, 12 h
H
Ph
S
98% yield
10
12
5
Ph
S
CH2Cl2
Ph
H
N
+
2 S C N
N
R
NH HN
25 ºC, 12 h
R
N
N
H
R
Ph
−
79 80% yield
S
Ph
−
8
11
12, 14, 16
6
6 12
,
; R = (S)-CHCH3Ph
; R = CH2Ph
7 14
,
8, 16; R = Ph
Scheme 2.
Ph
N
Ph
NH
N
H
S
Ph
N
Ph
NH
N
H
S
Ph
2
1
Figure 1. Solid-state structure of (1S,2S)-N,N0,N00-tris[(S)-
inocyclohexylthiourea 1.
a-phenylethyl]-1,2-diam-
´
0
´
Figure 2. Solid-state structure of (1S,2S)-N,N -bis[(S)-1-phenylethyl]-N-[(S)-1-
naphthylethyl)-1,2-diaminocyclohexylthiourea 2.
the low conversion and moderate enantioselectivities observed
with compounds 1–4 are due to the congestion around the basic
nitrogen atoms (Fig. 4). On the other hand, the poor results with li-
gands 5–8, which are dithiourea ligands, might be caused by two
factors: (a) the presence of only weakly coordinating nitrogen
atoms and (b) coordination of the sulfur atoms with zinc would re-
sult in the formation of a nine-membered metallocycle with very
conformationally flexible rings.
shown in Table 3. A shorter N–Hꢀ ꢀ ꢀS hydrogen bond is observed in
compound 1 in comparison with compounds 2 and 3. Furthermore,
we found a weak intermolecular interaction involving C–Hꢀ ꢀ ꢀS along
the c axis in 1 and 2 and along the b axis in compound 3 (Table 3).
3. Conclusion
In conclusion, new chiral thiourea ligands 1–8 have been pre-
pared in good yields (79–98%). They have been used as zinc-based
We also observed the presence of intramolecular interactions
N–Hꢀ ꢀ ꢀS in the structures of thioureas 1–3 (Figs. 1–3), which are

E. Santacruz et al. / Tetrahedron: Asymmetry 20 (2009) 2788–2794
2791
Ph
Ph
NH
N
N
H
S
Ph
3
Figure 3. Solid-state structure of (1S,2S)-N,N0-bis[(S)- -phenylethyl]-N00-(benzyl)-1,2-diaminocyclohexylthiourea 3.
a
Table 1
Enantioselective reduction of acetophenone in the presence of diethylzinc and thioureas 1–8
a
1 8
−
(5 mol%)
OH
CH3
O
ZnEt2 (5 mol%,
1.6 M in hexanes)
Toluene, 2d, 25 ºC
+
PMHS
CH3
1.2 equiv
1.0 equiv
Entry
Thiourea
Yieldb (%)
ee (config.)c (%)
1
2
3
4
1
2
3
4
33
38
54
31
75 (R)
46 (R)
38 (R)
57 (R)
a
b
c
Thioureas 5–8 gave low enantioselectivities (1–39%) and low yields (20–53%).
Yields were measured after column chromatography on silica gel (hexanes/EtOAc; 12:1 as eluent).
The enantiomeric excesses were determined by HPLC with a Chiralcel OD column.
Table 2
Enantioselective reduction of acetophenone in the presence of diethylzinc and thiourea 1 under different reaction conditions
O
OH
CH3
Thiourea 1, ZnEt2 (1.6 M hexanes), 25 ºC
PMHS
+
CH3
Entry
PMHS (equiv)
ZnEt2 (mol %)
Thiourea 1 (mol %)
Solvent
Time (d)
Yielda (%)
ee (config.)b (%)
1
2
3
5
5
5.0
1.2
1.2
1.2
1.2
5
10
10
10
5
5
10
10
5
Toluene
Toluene
Hexanes
Hexanes
Solvent-free
4
2
2
2
2
50
60
87
62
36
70 (R)
59 (R)
52 (R)
65 (R)
58 (R)
5
a
Yields were measured after column chromatography on silica gel (hexanes/EtOAc; 12:1 as eluent).
The enantiomeric excesses were determined by HPLC with a Chiralcel OD column.
b
catalysts in the hydrosilylation of acetophenone with polymethyl-
hydrosiloxane (PMHS) as the hydride source with enantioselectiv-
ities reaching 75%. Based on these results, we are currently
working on the design of new chiral thiourea-based catalyst for
the asymmetric hydrosilylations of prochiral ketones.
Table 3
Hydrogen bonds for thioureas 1–3 (Å and °)
Ph
Thiourea D–Hꢀ ꢀ ꢀA
d(D–H)
d(Hꢀ ꢀ ꢀA) d(Dꢀ ꢀ ꢀA) \(DHA)
N
Ph
NH
Zn
1
2
3
1
2
3
N(26)–H(26)ꢀ ꢀ ꢀS(17) 0.889(9) 2.80(2)
3.496(2) 136.1(17)
3.672(2) 127(2)
3.881(2) 133.8(2)
N(31)–H(31)ꢀ ꢀ ꢀS(17) 0.88(1)
N(26)–H(26)ꢀ ꢀ ꢀS(17) 0.90(1)
3.07(2)
3.20(1)
2.95
NH
H
S
H
C(4)–H(4)ꢀ ꢀ ꢀS(17)
C(23)–H(23)ꢀ ꢀ ꢀS(17)
C(23)–H(23)ꢀ ꢀ ꢀS(17)
0.97
0.93
0.93
3.82
3.78
3.80
150.6
171.6
164.4
Ph
2.86
2.86
Figure 4.

2792
E. Santacruz et al. / Tetrahedron: Asymmetry 20 (2009) 2788–2794
180.3. IR-FT (KBr): 3379, 3302, 3053, 3027, 2969, 2928, 2856,
4. Experimental
4.1. General methods
1599, 1519, 1449, 1410, 1347, 1297, 1263, 1227, 1118, 1083,
1036, 999, 961, 913, 863, 804, 781, 751, 732, 701, 650, 622, 538,
498, 442 cmꢂ1. Recrystallized from hexanes/CH2Cl2 (5:1), color-
less prism 0.34 ꢃ 0.18 ꢃ 0.08 mm; C35H41N3S. Monoclinic, P21, a =
7.672(2) Å, b = 19.080 (5) Å, c = 10.763 (3) Å, b = 95.022(4)°, Z = 2,
All manipulations involving diethylzinc were carried out under
an argon atmosphere. Benzaldehyde was distilled prior to use.
NMR spectra were obtained on a Varian 200 and 400 MHz Fourier
transform spectrometer. 1H NMR spectra were referenced to tetra-
methylsilane; 13C{1H} NMR spectra were referenced to the solvent
resonances.
dcalcd = 1.134 mg/m3, V = 1569.5(7)Å3,
l
= 0.130 mmꢂ1. A set of
12930 reflections was collected at T = 298(2) K, 5760 independent
reflections [Rint = 0.0369]. (Brucker Smart diffractometer, APEX AXS
CCD area detector, omega scans). The structure was solved by di-
rect methods (SHELXTL-2008) and was refined with all data by full
matrix least squares using SHELXTL-2008.30b All non-hydrogen atoms
were localized from the difference electron density map and re-
fined anisotropically. H atoms were placed in geometrically ideal-
ized positions [0.97 Å (CH2) and 0.96 Å (CH3)] tied to the parent
atom with Uiso(H) = 1.2 UeqC(sp2) and 1.5 UeqC(sp2) and were re-
fined using the riding model. The absolute configuration was
established by stereogenic centers C1(S) and C6(S), as reference
and was confirmed by anomalous dispersion effects in diffraction
measurements on the crystal. The other stereogenic centers were
assigned as C8(S), C19(S), and C28(S). Flack parameter ꢂ0.11(7).
Final R indices: R1 = 0.0478 and wR2 = 0.0922 for all data CCDC
deposition number: 747612. Structure factors and raw files are
available on request to the authors. FAB-MS: m/z [M+H]+ calcd
536.3099 for C35H42N3S; found 536.3109.
4.2. General procedure for the preparation of chiral thioureas
1–8
1,2-Diamines (2.0 mmol) 9–11 and isothiocyanates 12–16
(4.0 mmol) were dissolved in CH2Cl2 (10 mL). The mixture was stir-
red for 12 h at 25 °C. The reaction mixture was concentrated in va-
cuo and the residue was purified by column chromatography on
silica gel [hexanes/EtOAc/CH2Cl2, (2:1:1)].
4.2.1. (1S,2S)-N,N0,N00-Tris[(S)-
a-phenylethyl]-1,2-diaminocy
clohexylthiourea 1
Affording colorless crystals (1.8 g, 90% yield); mp 105.0–107.0 °C;
½
a 2D0
ꢁ
¼ þ18 (c 1.0, CHCl3). 1H NMR (200 MHz, DMSO-d6, 105 °C) d:
1.05 (m, 6H), 1.26 (d, 6H, J = 6.6 Hz), 1.58 (m, 7H), 2.26 (m, 2H), 3.81
(q, 2H, J = 6.2 Hz), 5.18 (q, 1H, J = 7.0 Hz), 7.17–7.39 (m, 14H), 7.80
(d, 1H, J = 6.0 Hz). 13C NMR (50 MHz, CDCl3) d: 19.2, 21.8, 23.2, 25.4,
26.5, 32.2, 33.4, 53.6, 54.3, 55.3, 56.3, 65.2, 125.8, 126.1, 126.2,
126.6, 126.8, 127.2, 127.4, 127.9, 128.4, 140.1, 142.7, 147.0, 180.4.
IR-FT (KBr): 3394, 3295, 3059, 3027, 2968, 2929, 2857, 1602, 1584,
1519, 1448, 1413, 1347, 1229, 1204, 1142, 1083, 1044, 1030, 999,
963, 913, 871, 855, 804, 761, 699 cmꢂ1. Recrystallized from hexanes/
CH2Cl2 (3:1), colorless prism 0.30 ꢃ 0.17 ꢃ 0.16 mm; C31H39N3S.
Orthorhombic, P212121, a = 12.486 (1) Å, b = 13.984 (1) Å, c = 16.422
4.2.3. (1S,2S)-N,N0-Bis[(S)-1-phenylethyl]-N00-(benzyl)-1,2-
diaminocyclohexylthiourea 3
Affording colorless crystals (0.60 g, 85% yield); mp 104–106 °C;
[a]
D = +13 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d (ppm): 1.05
(m, 1H), 1.16 (d, 3H, J = 6.4 Hz), 1.36 (m, 1H), 1.47–1.69 (m, 5H),
1.73 (d, 3H, J = 6.9 Hz), 2.05 (d, 1H, J = 12.0 Hz), 2.15 (d, 1H,
J = 10.8 Hz), 2.84 (dt, 1H, J = 10.2 Hz, J = 3.6 Hz), 3.94 (q, 1H,
J = 6.4 Hz), 4.54 (dd, 1H, J = 14.6 Hz, J = 4.2 Hz), 4.78 (dd, 1H,
J = 14.6 Hz, J = 4.6 Hz), 5.15 (m, 1H), 5.69 (m, 1H), 5.92 (br, 1H), 6.85
(m, 2H), 7.16–7.37 (m, 11H), 7.88 (d, 2H, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): 18.4, 22.7, 24.7, 25.7, 31.4, 33.0, 50.3, 53.4, 54.3,
56.2, 65.5, 126.3, 126.5, 126.9, 127.2, 127.3, 127.5, 128.1, 128.2,
128.6, 137.5, 140.4, 147.2, 182.8; IR-FT (KBr): 3397, 3297, 3060,
3027, 2930, 2857, 1602, 1584, 1518, 1495, 1449, 1415, 1369, 1320,
1273, 1230, 1203, 1160, 1142, 1075, 1029, 1000, 962, 913, 872, 857,
804, 761, 741, 699 cmꢂ1. Recrystallized from hexanes/CH2Cl2 (7:1),
colorless irregular, 0.78 ꢃ 0.61 ꢃ 0.44 mm3, C30H37N3S. Orthorhom-
bic, P212121, a = 7.549(2) Å, b = 10.857(2) Å, c = 33.203(7) Å, Z = 4,
(2) Å, Z = 4, dcalcd = 1.125 mg/m3, V = 2867.4(5)Å3
l ,
= 0.136 mmꢂ1
F(0 0 0) = 1048 A set of 31776 reflections was collected at T = 298(2)
K, 5329 independent reflections [Rint = 0.0688]. (Brucker Smart dif-
fractometer,APEXAXSCCDareadetector, omegascans).Thestructure
was solved by direct methods (SHELXTL-2008) and refined with all data
by full matrix least squares using SHELXTL-2008.30b All non-hydrogen
atomswerelocalizedfromthedifferenceelectrondensitymapandre-
fined anisotropically. H atoms were placed in geometrically idealized
positions [0.97 Å(CH2) and 0.96 Å (CH3)] tied to the parent atom with
Uiso(H) = 1.2 UeqC(sp2) and 1.5 UeqC(sp2) and were refined using
the riding model. The absolute configuration was established by ste-
reogenic centers C1(S) and C6(S), as a reference and was confirmed by
anomalous dispersion effects in diffraction measurements on the
crystal. The other stereogenic centers were assigned as C8(S),
C19(S), and C28(S). Flack parameter ꢂ0.02(7). A phenyl ring fragment
was disordered and was refined anisotropically in two major contrib-
utors. Final R indices: R1 = 0.0413 and wR2 = 0.0611 for all data. CCDC
deposition number: 747611. Structure factors and raw files are avail-
ableonrequest to theauthors. Elemental Anal. Calcd for C31H39N3S: C,
76.65; H, 8.09; N, 8.65. Found: C, 76.81; H, 7.98; N, 8.68.
q
calcd = 1.151 g cmꢂ3. A set of 6080 reflections was collected at
T = 293(2) K using Mo K radiation (k = 0.71073 Å, Enraf-Nonius
a
CAD4 diffractometer), corresponding to 2hmax = 52.40°. 5382 inde-
pendent reflections (Rint = 0.0738) were used for the refinement of
308 parameters (SHELXL-86).30a H atoms were placed in idealized posi-
tions and were refined using a standard riding model. The absolute
configuration of the chiral centers was assigned as S-C8, S-C27, and
confirmed by refinement of a Flack parameter, x = ꢂ0.11(15), based
on non-merged Friedel pairs. Final R indices: R1 = 0.0530 for 2864
reflections with I > 2a(I) and wR2 = 0.1448 for all data. CCDC deposi-
tion number: 748359. Structure factors and raw files are available
on request to the authors. Elemental Anal. Calcd for C30H37N3S: C,
76.39; H, 7.91; N, 8.91. Found: C, 76.44; H, 7.90; N, 8.91.
4.2.2. (1S,2S)-N,N0-Bis[(S)-1-phenylethyl]-N00-(1-naphthylethyl)-
1,2-diaminocyclohexyl-thiourea 2
Affording colorless crystals (0.300 g, 70% yield); mp 164–
165 °C; [a]
D = +12 (c 1.0, CHCl3); 1H NMR (200 MHz, DMSO-d6,
4.2.4. (1S,2S)-N,N0-Bis[(S)-1-phenylethyl]-N00-
105 °C) d: 1.04 (m, 6H), 1.30 (d, 6H, J = 6.6 Hz), 1.53 (m, 3H), 1.81
(m, 4H), 2.33 (m, 2H), 3.86 (q, 2H, J = 6.6 Hz), 5.83 (q, 1H,
J = 6.6 Hz), 7.12–8.08 (m, 17H). 13C NMR (50 MHz, CDCl3) d: 19.1,
20.1, 23.3, 25.5, 26.6, 32.2, 33.5, 51.3, 53.8, 54.4, 56.5, 65.3,
122.3, 124.0, 124.8, 125.4, 126.1, 126.3, 126.4, 127.4, 127.5,
127.8, 128.0, 128.2, 128.4, 130.9, 133.4, 138.0, 140.2, 147.2,
[di(phenyl)methylene]-1,2-diaminocyclo-hexylthiourea 4
Affording a pale white solid (0.500 g, 80% yield); mp 150–
155 °C; [a]
D = +19 (c 1.0, CHCl3); 1H NMR (200 MHz, DMSO-d6,
105 °C) d: 1.06 (m, 6H), 1.26 (d, 6H, J = 6.2 Hz), 1.61 (m, 3H), 2.26
(m, 2H), 3.81 (q, 2H, J = 6.6 Hz), 5.66 (d, 1H, J = 0.8 Hz), 6.41 (s,
1H), 6.82 (m, 1H), 7.03–7.45 (m, 18H), 7.79 (m, 1H). 13C NMR

E. Santacruz et al. / Tetrahedron: Asymmetry 20 (2009) 2788–2794
2793
(50 MHz, CDCl3) d: 18.1, 23.3, 25.4, 26.5, 31.0, 33.4, 53.9, 54.2,
4.2.10. (1S,2S)-N,N0-Bis[(S)-
a-phenylethyl]-1,2-
56.1, 63.5, 65.5, 126.1, 126.2, 126.6, 126.8, 127.2, 127.4, 127.6,
127.7, 128.0, 128.1, 128.6, 140.0, 141.0, 141.6, 147.1, 181.1. IR-
FT (KBr): 3401, 3301, 3055, 3027, 2996, 2926, 2857, 1598,
1519, 1493, 1449, 1412, 1343, 1291, 1222, 1145, 1078, 1030,
cyclohexanodiamine 11
1,2-Diamine 11 was prepared from cyclohexene oxide and (S)-
1-phenylethylamine, according to the literature procedure.10
962, 911, 859, 838, 806, 748, 698, 649, 637, 611, 536, 467 cmꢂ1
.
4.3. Enantioselective reduction of acetophenone
FAB-MS: m/z [M+H]+; calcd 548.3099 for C36H42N3; found
548.3094.
In a Schlenk flask Et2Zn (0.05 mL, 1 M in hexanes, 0.05 mmol)
and the chiral ligand (0.05 mmol) were dissolved in 1 mL of hexane
and stirred under
a nitrogen atmosphere for 10 min. Then
4.2.5. N,N0-Bis[(S)-
a-phenylethyl]-1,2-diaminoethylendithiourea 5
1.0 mmol of acetophenone was added, and PMHS (0.78 g,
1.2 mmol) was added slowly to the mixture. The reaction was kept
at rt for two days. The reaction mixture was poured on to 15%
aqueous KOH solution (5 mL) and extracted three times with
EtOAc (3 mL). The organic layer was washed with water (3 mL),
dried over MgSO4, and concentrated in vacuo. The product was
purified by column chromatography on silica gel, with hexanes/
EtOAc, 10:1, as eluent.
Affording a white solid (0.76 g, 98% yield), mp 75.0–77.0 °C;
½
a 2D0
ꢁ
¼ þ37 (c 1.0, CHCl3). 1H NMR (200 MHz, DMSO-d6, 50 °C) d:
1.40 (d, 6H, J = 7.0 Hz), 3.24 (s, 2H), 3.51 (m, 4H), 5.41 (m, 2H,
J = 7.0 Hz), 7.17–7.38 (m, 10H), 7.81 (d, 2H, J = 8.0 Hz). 13C NMR
(50 MHz, DMSO-d6, 50 °C) d: 22.3, 42.7, 52.2, 125.1, 125.7, 127.2,
143.0, 180.3. IR-FT (KBr): 3228, 3060, 2972, 2871, 2820, 1545,
1494, 1448, 1355, 1249, 1217, 1140, 1084, 1019, 913, 761, 736,
699 cmꢂ1. Elemental Anal. Calcd for C20H26N4S2: C, 62.14; H,
6.78. Found: C, 61.90; H, 6.93.
4.4. Conditions for the determination of the enantiomeric
excess
4.2.6. N,N0,N00,N000-Tetraquis-[(S)-
a-phenylethyl]-1,2-diaminoethy
lendithiourea 6
Chiral HPLC: Chiralcel OD column, 254 nm UV detector, 97:3
hexanes/IPA, flow rate 5 mL/min, retention time (R): 15 min, reten-
tion time (S): 18 min. Specific rotations of the secondary alcohols
were measured and compared with those reported on the litera-
ture to assign configuration.29 rac-1-Phenyl-1-ethanol was ob-
tained by the addition of NaBH4 to acetophenone in MeOH.
Affording a white solid (0.70 g, 80% yield); mp 76.0–78.0 °C;
½
a 2D0
ꢁ
¼ ꢂ0:7 (c 1.0, CHCl3). 1H NMR (200 MHz, DMSO-d6,
100 °C) d: 1.28 (d, 6H, J = 7.0 Hz), 1.46 (d, 6H, J = 7.0 Hz), 3.00
(s, 2H), 3.35 (s, 4H), 5.78 (m, 2H), 6.22 (q, 2H, J = 7.0 Hz),
7.09–7.38 (m, 18H), 8.00 (d, 2H, J = 7.6 Hz). 13C NMR (50 MHz,
DMSO-d6, 100 °C) d: 16.4, 21.3, 43.7, 54.3, 55.3, 124.9, 125.1,
125.3, 126.0, 126.7, 127.1, 139.1, 142.6, 179.8. IR-FT (KBr):
3228, 3029, 2974, 2936, 1603, 1541, 1494, 1449, 1356, 1263,
Acknowledgments
1240, 1205, 1156, 1126, 1084, 1027, 986, 788, 758, 698 cmꢂ1
.
This work was supported by ACS-Petroleum Research Fund (PRF
# 46222-B) and CONACYT, Consejo Nacional de Ciencia y Tec-
nología (Project No. 55802. G.H. and S.K.A. thank CONACYT for
postdoctoral scholarships. We also acknowledge Instituto de Quí-
mica of the Universidad Nacional Autónoma de México for mass
spectra. P.J.W. also thanks the U.S. NSF for support (CHE 0848460).
HRMS-FAB+: m/z [M+H]+ calcd for C36H43N4S2: 595.2929; found:
595.2924.
4.2.7. N,N0-Bis[(S)- -phenylethyl]-N00,N000-bis(benzyl)-1,2-
a
diaminoethylendithiourea 7
Affording a pale yellow solid (0.31 g, 79% yield); mp 67.0–
69.0 °C; ½a 2D0
ꢁ
¼ ꢂ68 (c 1.0, CHCl3). 1H NMR (200 MHz, DMSO-d6,
References
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138.9, 180.8. IR-FT (KBr): 3216, 3030, 2976, 2940, 2906, 1603,
1551, 1526, 1495, 1452, 1380, 1340, 1224, 1152, 1094, 1028,
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