Reaction of nitroorganic compounds using thiourea catalysts anchored to polymer support

Article abstract of DOI:10.1055/s-2006-950196

Immobilization of chiral thiourea catalyst was studied. The PEG-bound thiourea showed better catalytic activity than those of the carboxypolystyrene HL resin-bound and TentaGel carboxy resin-bound thioureas. In the presence of PEG-bound thiourea, Michael and tandem Michael reactions of trans-β- nitrostyrene proceeded enantioselectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950196

SPECIAL TOPIC
3295
Reaction of Nitroorganic Compounds Using Thiourea Catalysts Anchored to
Polymer Support
P
olymer-Supporte
i
d Chir
a
d
l
T
hiourea
C
e
atalyst to Miyabe,a Sayo Tuchida,a Masashige Yamauchi,b Yoshiji Takemoto*a
a
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
b
Faculty of Pharmaceutical sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295, Japan
Received 20 April 2006
CF3
CF3
1) (COCl)2, EtOH,
74%
Abstract: Immobilization of chiral thiourea catalyst was studied.
The PEG-bound thiourea showed better catalytic activity than those
of the carboxypolystyrene HL resin-bound and TentaGel carboxy
resin-bound thioureas. In the presence of PEG-bound thiourea,
Michael and tandem Michael reactions of trans-b-nitrostyrene pro-
ceeded enantioselectively.
HO
EtO
NO2
NH2
2) H2, Pd/C
98%
O
O
3
4
1) 1,1-thiocarbonyldiimidazole, 83%
2
Key words: organocatalyst, thiourea, enantioselective, polymer
2)
support, PEG
H2N
82%
N
Me
Me
Scheme 1
The use of organocatalyst in organic synthesis has gener-
ated considerable interest from both economical and envi-
ronmental points of view. Recent progress in this area has
resulted in the development of various chiral organocata-
lysts which do not require the strictly controlled reaction
conditions compared to the metal-containing catalysts.1
To test the activity of catalyst 2, the catalytic enantioselec-
tive Michael and aza-Henry reactions of nitroorganic
compounds were investigated, since these reactions pro-
ceeded well by using original thiourea 1 (Scheme 2).7 In
the presence of 2 (10 mol%), the reaction of trans-b-ni-
trostyrene (5) with diethyl malonate in toluene afforded
the Michael adduct (S)-6 in 88% yield with 91% ee. In our
previous study on reaction of 5 using original thiourea 1,
the Michael adduct (S)-6 was obtained in 86% yield with
93% ee, after stirring at room temperature for 24 h.7b Next,
we tried the aza-Henry reaction of N-phosphinoylimine 7.
In the presence of 2 (10 mol%), nitromethane was reacted
with 7 to give the adduct 8 in 66% ee, comparable to that
obtained by the reaction using catalyst 1.10 These observa-
tions suggest that thiourea 2 acts as a chiral catalyst with
slightly less catalytic activity.
Several groups have begun to explore the potential of
ureas and thioureas to serve as Brønsted acid catalysts.2–7
We have recently developed the chiral thiourea 1 as a bi-
functional organocatalyst (Figure 1).7 During our studies
on thiourea catalysts, we found that thiourea 1 accelerates
the aza-Henry reaction and the Michael reaction of nitro
olefins or a,b-unsaturated imides as a result of dual acti-
vation of electrophile and nucleophile. However, these re-
actions suffered from the difficulty of recovering thiourea
1. Immobilization of such catalyst is a challenging goal in
advanced organic synthesis.8 Immobilization facilitates
the recovery and reuse of catalyst from the reaction mix-
ture. Hence, we planned to develop a new and effective
thiourea catalyst anchored to polymer support.
O
O
O
O
EtO
OEt
EtO
OEt
We planned to attach the thiourea to several polymer sup-
ports by using ester moiety. Prior to exploring issues of
immobilization, we first investigated the catalytic activity
of thiourea 2 having an ester group. Preparation of thio-
urea 2 is summarized in Scheme 1.9
NO2
Ph
Ph
NO2
catalyst 2 (10 mol%)
Ph
5
toluene, r.t., 2 d
6 (88%, 91% ee)
P(O)Ph2
HN
P(O)Ph2
MeNO2
N
NO2
Ph
catalyst 2 (10 mol%)
CH2Cl2, r.t., 2 d
CF3
7
8 (82%, 66% ee)
S
Scheme 2
R
N
N
1: R = CF3
2: R = CO2Et
H
H
N
Me
Me
On the basis of these results, we next explored the immo-
bilization of catalyst. At first, the cross-linked polystyrene
was used as a support for immobilizing the thiourea 2
(Figure 2). To enhance the catalytic activity of resin-
bound thioureas, we introduced a spacer generated from
pentane-1,5-diol. Preparation of resin-bound catalysts 9
Figure 1 Chiral thiourea catalysts
SYNTHESIS 2006, No. 19, pp 3295–3300
Advanced online publication: 15.08.2006
DOI: 10.1055/s-2006-950196; Art ID: C04006SS
x
x.
x
x
.
2
0
0
6
© Georg Thieme Verlag Stuttgart · New York

3296
H. Miyabe et al.
SPECIAL TOPIC
and 10 is shown in Scheme 3.9 We used carboxypolysty-
rene HL resin and TentaGel carboxy resin purchased from
Novabiochem. The thiourea 13 having the spacer moiety
was attached to these resins by treatment with EDC in the
presence of DMAP to give the resin-bound catalysts 9 and
10 in ca. 0.79 mmol/g and ca. 0.19 mmol/g loading levels,
respectively. The loading levels of catalyst were deter-
mined by quantification of fluoride by elemental analysis.
Table 1 Michael and Aza-Henry Reactions Using Catalysts 9 and
10a
Entry
Substrate Catalyst
Product
ee (%)c
(yield, %)b
1
2
3
4
5
6
5
5
5
7
7
7
9
6 (37)
6 (25)
6 (4)
87
85
88
67
68
67
9 (recovered)
10
CF3
9
8 (19)
8 (13)
8 (3)
S
9 (recovered)
O
O
N
N
H
H
O
O
N
10
Me
Me
9: carboxypolystyrene HL resin
10: TentaGel carboxy resin
a Reactions were carried out in CH2Cl2 in the presence of catalyst 9 or
10 (10 mol%) at room temperature for 6 days.
b Isolated yields.
Figure 2 Resin-bound thiourea catalysts
c Enantioselectivity was determined by HPLC analysis.
CF3
(COCl)2
TBSO
OH
and 10 was attributed to the difference in their loading lev-
els. However, we were pleased to find that good enantio-
selectivities were observed in both Michael and aza-
Henry reactions.
3
TBSO
O
NO2
83%
11
O
CF3
1) H2, Pd/C, quant.
To overcome these drawbacks, we focused on a non-
crosslinked polymer as a support for immobilizing the
thiourea 2. Particularly, soluble non-crosslinked polymer
supports offer certain advantages over insoluble polymers
in terms of ease of analysis and the establishment of ho-
mogeneous conditions.11 Since poly(ethylene glycol)
(PEG) has been wildly used as a soluble polymer support
in combinatorial and general organic syntheses, we next
prepared PEG-bound thiourea 15 as a homogeneous cata-
lyst (Scheme 4).12 The purity of catalyst 15 was deter-
mined to be ca. 80% by 1H NMR analysis.
TBSO
O
2) 1,1-thiocarbonyl
diimidazole, 93%
N
C
S
12
O
1)
CF3
H2N
S
73%
N
HO
O
Me
Me
N
H
N
H
2) TBAF, 54%
O
N
13
Me
Me
CO2H
9: carboxypolystyrene HL resin
10: TentaGel carboxy resin
EDC, DMAP
Scheme 3
To survey the potency of PEG-bound thiourea 15 as a cat-
alyst, we applied thiourea 15 to Michael and tandem
Michael reactions of trans-b-nitrostyrene (5) (Scheme 5).
As expected, the catalytic activity of 15 was enhanced un-
der homogeneous conditions using CH2Cl2 as solvent.
The Michael reaction of 5 with diethyl malonate afforded
the Michael adduct (S)-6 in 71% yield with 86% ee, after
stirring at room temperature for six days. Furthermore,
catalyst 15 was recoverable and reusable. The catalyst 15
was precipitated by the addition of diethyl ether and re-
The viability of resin-bound thioureas 9 and 10 as cata-
lysts was the next focus of our efforts (Table 1). The te-
dious workup to recover the catalyst was eliminated from
the polymer-support methodology by washing the resin
with solvents. Unfortunately, these catalysts showed low-
er catalytic activities as compared to the soluble catalyst
2, leading to the low yields of the desired products 6 and
8. It is assumed that the difference of activity between 9
CF3
CF3
PEG 8000
2) H2, Pd/C, AcOEt
1) (COCl)2,HO
OH
3
PEG 8000
O
O
H2N
NH2
CF3
O
O
14
1) 1,1-thiocarbonyldiimidazole
2)
CF3
S
S
H2N
N
PEG 8000
15 (ca. 80% purity)
O
O
N
H
Me
N
N
N
H
H
H
Me
Me
N
O
O
N
Me
Me
Me
Scheme 4
Synthesis 2006, No. 19, 3295–3300 © Thieme Stuttgart · New York

SPECIAL TOPIC
Polymer-Supported Chiral Thiourea Catalyst
3297
13C NMR (125 MHz, CDCl3): d = 163.2, 148.5, 133.6, 132.8 (q,
J = 34 Hz), 131.9, 127.5, 124.3, 122.5 (q, J = 271 Hz), 62.6, 14.1.
tained in 74% yield with 90% ee. Tandem Michael reac- MS (EI+): m/z (%) = 263 (19, M+), 218 (100).
used without further treatment after recovery by filtration.
In the repeated use of the recovered catalyst, (S)-6 was ob-
tion of 5 also proceeded smoothly to give the cyclic
product 16 in 63% yield with 76% ee.7e,7g The catalyst 15
was reused for the second and third reactions, affording 16
in 64% yield with 76% ee and in 63% yield with 79% ee,
respectively.
Anal. Calcd for C10H8F3NO4: C, 45.64; H, 3.06; N, 5.32. Found: C,
45.38; H, 2.97; N, 5.25.
Ethyl 3-Amino-5-(trifluoromethyl)benzoate (4)
To a solution of ethyl 5-(trifluoromethyl)-3-nitrobenzoate (1.0 g,
3.8 mmol) in anhyd EtOH (30 mL) was added 10% Pd/C (300 mg)
at r.t. After stirring for 2 h under a H2 atmosphere at r.t., the mixture
was filtered through Celite pad and concentrated under reduced
pressure. The crude solid was recrystallized from hexane–EtOAc
providing amine 4 (870 mg, 98%) as colorless crystals; mp 72–
74 °C (hexane–EtOAc).
O
O
O
O
EtO
Ph
OEt
EtO
OEt
NO2
NO2
Ph
Ph
catalyst 15 (10 mol%)
5
5
6 (First run: 71%, 86% ee)
(Second run: 74%, 90% ee)
CH2Cl2, r.t., 6 d
IR (CHCl3): 1717 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.62 (1 H, s), 7.48 (1 H, s), 7.03
(1 H, s), 4.35 (2 H, q, J = 7.0 Hz), 4.08 (2 H, br s), 1.37 (3 H, t,
J = 7.0 Hz).
13C NMR (125 MHz, CDCl3): d = 165.7, 147.2, 132.2, 131.8 (q,
J = 33 Hz), 123.7 (q, J = 273 Hz), 118.5, 115.7, 115.0, 61.3, 14.0.
OH
O
O
O
OEt
Me
OEt
NO2
Me
Ph
catalyst 15 (10 mol%)
NO2
CH2Cl2, r.t., 6 d
16 (first run: 63%, 76% ee)
(second run: 64%, 76% ee)
(third run: 63%, 79% ee)
MS (EI+): m/z (%) = 233 (68, M+), 188 (100).
Anal. Calcd for C10H10F3NO2: C, 51.51; H, 4.32; N, 6.01. Found: C,
51.38; H, 4.24; N, 5.97.
Scheme 5
Ethyl 3-Isothiocyanato-5-(trifluoromethyl)benzoate
To a solution of amine 4 (870 mg, 3.7 mmol) in anhyd MeCN (15
mL) were added imidazole (76 mg, 1.1 mmol) and 1,1-thiocarbon-
yldiimidazole (1.0 g, 5.6 mmol) under argon at 0 °C. After stirring
for 1.5 h at r.t., the mixture was concentrated under reduced pres-
sure. Purification of the residue by flash chromatography (hexane–
EtOAc, 5:1) afforded ethyl 3-isothiocyanato-5-(trifluorometh-
yl)benzoate (850 mg, 83%) as a colorless oil.
IR (CHCl3): 1726 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.13 (1 H, s), 8.00 (1 H, s), 7.57
(1 H, s), 4.40 (2 H, q, J = 7.4 Hz), 1.39 (3 H, t, J = 7.4 Hz).
In summary, we have demonstrated the utility of PEG-
bound thiourea as a homogeneous catalyst. To test the ac-
tivity of the catalyst, the catalytic enantioselective reac-
tions of nitroorganic compounds were investigated.
Although the reaction rate was somewhat decreased with
PEG-bound thiourea 15, immobilization to a PEG support
was proved to facilitate the recovery and reuse of thiourea
catalyst without affecting the chemical yield and enantio-
selectivity.
13C NMR (125 MHz, CDCl3): d = 163.9, 139.6, 133.3, 133.2, 132.6
(q, J = 33 Hz), 129.7, 126.1, 124.5, 122.8 (q, J = 273 Hz), 62.0,
14.1.
MS (EI+): m/z (%) = 275 (37, M+), 230 (100).
HRMS (EI+): m/z calcd for C11H8F3NO2S (M+): 275.0228; found:
Melting points were taken on a YANAGIMOTO micro melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded in CDCl3 at 500 MHz, and at 125 MHz, respectively; TMS
was used as an internal standard. IR spectra were recorded on a
JASCO FT/IR-410 Fourier-transfer infrared spectrometer. Low-
and high-resolution mass spectra were obtained by EI or FAB meth-
od. Optical rotations were recorded on a JASCO DIP-360 polar-
imeter. Enantiomeric excess was determined by HPLC analysis.
275.0232.
Thiourea Catalyst 2
To a solution of ethyl 3-isothiocyanato-5-(trifluoromethyl)benzoate
(85 mg, 0.31 mmol) in anhyd benzene (1.2 mL) was added (1R,2R)-
N,N-dimethylcyclohexanediamine (88 mg, 0.62 mmol) under argon
at 0 °C. After stirring for 3 h at r.t., the mixture was concentrated un-
der reduced pressure. Purification of the residue by flash chroma-
tography (CHCl3–MeOH, 7:1) afforded thiourea 2 (106 mg, 82%)
as colorless crystals; mp 118–120 °C (hexane–EtOAc); [a]D27 –43.8
(c = 2.0, CHCl3).
Ethyl 5-(Trifluoromethyl)-3-nitrobenzoate
To a solution of 5-(trifluoromethyl)-3-nitrobenzoic acid (1.0 g, 4.3
mmol) in anhyd CH2Cl2 (50 mL) were added oxalyl chloride (1.61
mL, 18.8 mmol) and anhyd DMF (2 drops) under argon at 0 °C. Af-
ter stirring for 18 h at room temperature, the mixture was concen-
trated under reduced pressure. The resulting oil was dissolved in
anhyd THF (20 mL) under argon. To this solution was added anhyd
EtOH (5 mL) under argon at 0 °C. After stirring for 3 h at r.t., the
mixture was concentrated under reduced pressure. The residue was
dissolved in EtOAc, and then the organic layer was washed with
H2O and brine, dried (MgSO4), and concentrated under reduced
pressure. The crude solid was recrystallized from hexane–EtOAc to
afford ethyl 5-(trifluoromethyl)-3-nitrobenzoate (832 mg, 74%) as
colorless crystals; mp 53–55 °C (hexane–EtOAc).
IR (CHCl3): 1723 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.12 (1 H, s), 8.06 (1 H, s), 7.89
(1 H, s), 4.40 (2 H, q, J = 7.0 Hz), 3.89 (1 H, br s), 2.61 (1 H, br s),
2.45 (1 H, dt, J = 11.0, 3.4 Hz), 2.27 (6 H, s), 1.94–1.67 (3 H, br m),
1.40 (3 H, t, J = 7.0 Hz), 1.40–1.05 (6 H, br m).
13C NMR (125 MHz, CDCl3): d = 179.6, 164.4, 139.3, 132.1, 131.3
(q, J = 32 Hz), 127.8, 124.4, 123.0 (q, J = 272 Hz), 122.4, 66.2,
61.3, 55.6, 39.5, 32.4, 24.5, 24.2, 21.1, 13.8.
IR (CHCl3): 1729 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.05 (1 H, s), 8.68 (1 H, s), 8.63
(1 H, s), 4.49 (2 H, q, J = 7.4 Hz), 1.46 (3 H, t, J = 7.4 Hz).
MS (FAB+): m/z (%) = 418 (100, M + H+).
Synthesis 2006, No. 19, 3295–3300 © Thieme Stuttgart · New York

3298
H. Miyabe et al.
SPECIAL TOPIC
Anal. Calcd for C19H26F3N3O2S: C, 54.66; H, 6.28; N, 10.06.
Found: C, 54.87; H, 6.41; N, 9.81.
13C NMR (125 MHz, CDCl3): d = 163.9, 139.6, 133.3, 133.2, 132.6
(q, J = 33 Hz), 129.6, 126.2, 124.5, 122.7 (q, J = 273 Hz), 66.1,
62.7, 32.2, 28.3, 25.8, 22.3, 18.2, –5.5.
5-(tert-Butyldimethylsilyloxy)pent-1-yl 5-(Trifluoromethyl)-3-
nitrobenzoate (11)
MS (FAB+): m/z (%) = 448 (8, M + H+), 73 (100).
HRMS (FAB+): m/z calcd for C20H29F3NO3SSi (M + H+): 448.1590;
To a solution of 5-(trifluoromethyl)-3-nitrobenzoic acid (3; 2.0 g,
8.6 mmol) in anhyd CH2Cl2 (50 mL) were added oxalyl chloride
(3.3 mL, 38 mmol) and anhyd DMF (4 drops) under argon at 0 °C.
After stirring for 18 h at r.t., the mixture was concentrated under re-
duced pressure. The resulting oil was dissolved in anhyd THF (30
mL) under argon. To this solution were added 5-(tert-butyldimeth-
ylsilyloxy)pentan-1-ol (2.3 g, 11 mmol) and Et3N (6 mL) under ar-
gon at 0 °C. After stirring for 12 h at r.t., the mixture was
concentrated under reduced pressure. The residue was dissolved in
EtOAc, and then the organic layer was washed with H2O and brine,
dried (MgSO4), and concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography (hexane–EtOAc, 12:1)
afforded ester 11 (3.1 g, 83%) as a colorless oil.
found: 448.1585.
Thiourea 13
To a solution of isothiocyanate 12 (12.9 g, 28.9 mmol) in anhyd
benzene (110 mL) was added (1R,2R)-N,N-dimethylcyclohexanedi-
amine (6.1 g, 43.0 mmol) under argon at 0 °C. After stirring for 3 h
at r.t., the mixture was concentrated under reduced pressure. Purifi-
cation of the residue by flash chromatography (CHCl3–
MeOH, 20:1) afforded the silylated thiourea (12.3 g, 73%) as a col-
orless oil; [a]D27 –9.2 (c = 1.0, CHCl3).
IR (CHCl3): 1721 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.09 (1 H, s), 7.80 (1 H, s), 7.86
(1 H, s), 4.29 (2 H, t, J = 6.7 Hz), 3.90 (1 H, br s), 3.59 (2 H, t,
J = 6.4 Hz), 2.57 (1 H, br s), 2.42 (1 H, dt, J = 11.0, 3.1 Hz), 2.22 (6
H, s), 1.88–1.05 (15 H, m), 0.84 (9 H, s), 0.00 (6 H, s).
13C NMR (125 MHz, CDCl3): d = 179.7, 164.5, 139.3, 132.2, 131.4
(q, J = 33 Hz), 127.8, 124.5, 123.1 (q, J = 273 Hz), 122.5, 66.5,
65.5, 62.5, 55.8, 39.6, 32.5, 32.0, 28.1, 25.6, 24.6, 24.3, 22.0, 21.1,
17.9, –5.7.
IR (CHCl3): 1729 cm–1.
1H NMR (500 MHz, CDCl3): d = 9.03 (1 H, s), 8.68 (1 H, s), 8.61
(1 H, s), 4.44 (2 H, t, J = 6.7 Hz), 3.65 (2 H, t, J = 6.7 Hz), 1.85 (2
H, m), 1.60 (2 H, m), 1.54 (2 H, m), 0.88 (9 H, s), 0.05 (6 H, s).
13C NMR (125 MHz, CDCl3): d = 163.2, 148.6, 133.6, 132.8 (q,
J = 34 Hz), 131.8, 127.4, 124.3, 122.4 (q, J = 273 Hz), 66.6, 62.7,
32.2, 28.3, 25.8, 22.3, 18.2, –5.5.
MS (FAB+): m/z (%) = 436 (21, M + H+), 69 (100).
HRMS (FAB+): m/z calcd for C19H29F3NO5Si (M + H+): 436.1776;
MS (FAB+): m/z (%) = 590 (100, M + H+).
HRMS (FAB+): m/z calcd for C28H47F3N3O3SSi (M + H+):
590.3060; found: 590.3063.
found: 436.1767.
To a solution of the above silylated thiourea (3.2 g, 5.4 mmol) in
THF (16 mL) was added Bu4NF (1 mol/L in THF, 11 mL, 11 mmol)
under argon at r.t. After stirring for 12 h at r.t., the mixture was con-
centrated under reduced pressure. The residue was dissolved in
EtOAc, and then the organic layer was washed with H2O and brine,
dried (MgSO4), and concentrated under reduced pressure. Purifica-
tion of the residue by flash chromatography (CHCl3–MeOH, 7:1)
afforded the desilylated thiourea 13 (1.4 g, 54%); white solid; [a]D
–0.2 (c = 0.1, CHCl3).
IR (CHCl3): 1721 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.15 (1 H, s), 8.04 (1 H, s), 7.89
(1 H, s), 4.34 (2 H, t, J = 6.7 Hz), 3.94 (1 H, br s), 3.67 (2 H, t,
J = 6.4 Hz), 2.58 (1 H, br s), 2.46 (1 H, dt, J = 10.9, 3.0 Hz), 2.28 (6
H, s), 1.95–1.00 (16 H, m).
13C NMR (125 MHz, CDCl3): d = 179.5, 164.6, 139.5, 131.9, 131.2
(q, J = 32 Hz), 127.4, 124.1, 123.1 (q, J = 273 Hz), 122.2, 66.3,
65.4, 61.9, 55.6, 39.6, 32.4, 31.9, 28.0, 24.5, 24.2, 21.9, 20.9.
5-(tert-Butyldimethylsilyloxy)pent-1-yl 3-Amino-5-(trifluoro-
methyl)benzoate
To a solution of ester 11 (4.0 g, 9.2 mmol) in EtOAc (200 mL) was
added 10% Pd/C (500 mg) at r.t. After stirring for 5 h under a H2 at-
mosphere at r.t., the mixture was filtered through a Celite pad and
concentrated under reduced pressure. Purification of the residue by
flash chromatography (hexane–EtOAc, 1:1) afforded 5-(tert-butyl-
dimethylsilyloxy)pent-1-yl 3-amino-5-(trifluoromethyl)benzoate
(3.7 g, quant) as a colorless oil.
26
IR (CHCl3): 1717 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.60 (1 H, s), 7.46 (1 H, s), 7.02
(1 H, s), 4.30 (2 H, t, J = 6.7 Hz), 4.05 (2 H, br s), 3.61 (2 H, t,
J = 6.4 Hz), 1.76 (2 H, m), 1.56 (2 H, m), 1.46 (2 H, m), 0.86 (9 H,
s), 0.02 (6 H, s).
13C NMR (125 MHz, CDCl3): d = 165.7, 147.2, 132.3, 131.9 (q,
J = 32 Hz), 123.7 (q, J = 272 Hz), 118.5, 115.8, 115.0, 65.4, 62.8,
32.3, 28.4, 25.8, 22.3, 18.2, –5.5.
MS (FAB+): m/z (%) = 476 (58, M + H+), 125 (100).
HRMS (FAB+): m/z calcd for C22H33F3N3O3S (M + H+): 476.2195;
MS (FAB+): m/z (%) = 406 (30, M + H+), 73 (100).
HRMS (FAB+): m/z calcd for C19H31F3NO3Si (M + H+): 406.2026;
found: 476.2202.
found: 406.2016.
Attachment of Thiourea 13 to Resin
5-(tert-Butyldimethylsilyloxy)pent-1-yl 3-Isothiocyanato-5-(tri-
fluoromethyl)benzoate (12)
To a suspension of carboxypolystyrene HL resin (1.10 mmol/g, 1.0
g, 1.10 mmol) in CH2Cl2 (20 mL) were added thiourea 13 (1.36 g,
2.9 mmol), EDC (0.56 g, 2.9 mmol) and DMAP (0.21 mg, 1.7
mmol) under argon at r.t. After stirring for 1 h at r.t. for 1 h, the mix-
ture was kept for 11 h. The resin was then filtered, washed well with
CH2Cl2, EtOAc followed by MeOH and then dried in vacuo to give
the catalyst 9. Following the same procedure as for 9, catalyst 10
was obtained from TentaGel carboxy resin (0.26 mmol/g). Loading
level of catalyst 9: ca. 0.79 mmol/g (Anal. Calcd: F, 4.17. Found: F,
3.00). Loading level of catalyst 10: ca. 0.19 mmol/g (Anal. Calcd:
F, 1.33. Found: F, 0.97).
To a solution of 5-(tert-butyldimethylsilyloxy)pent-1-yl 3-amino-5-
(trifluoromethyl)benzoate (7.8 g, 19 mmol) in anhyd MeCN (74
mL) were added imidazole (375 mg, 5.5 mmol) and 1,1-thiocarbo-
nyldiimidazole (4.9 g, 28 mmol) under argon at 0 °C. After stirring
for 2 h at r.t. for 2 h, the mixture was concentrated under reduced
pressure. Purification of the residue by flash chromatography (hex-
ane–EtOAc, 10:1) afforded isothiocyanate 12 (8.0 g, 93%) as a col-
orless oil. IR (CHCl3): 1724 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.16 (1 H, s), 8.03 (1 H, s), 7.63
(1 H, s), 4.38 (2 H, t, J = 6.7 Hz), 3.64 (2 H, t, J = 6.1 Hz), 1.81 (2
H, m), 1.58 (2 H, m), 1.51 (2 H, m), 0.88 (9 H, s), 0.05 (6 H, s).
Synthesis 2006, No. 19, 3295–3300 © Thieme Stuttgart · New York

SPECIAL TOPIC
Polymer-Supported Chiral Thiourea Catalyst
3299
PEG-Bound Ester
Michael Reaction of 5; General Procedure
To a solution of 5-(trifluoromethyl)-3-nitrobenzoic acid (3; 1.0 g,
4.3 mmol) in anhyd CH2Cl2 (25 mL) were added oxalyl chloride
(1.61 mL, 18.8 mmol) and anhyd DMF (2 drops) under argon at
0 °C. After stirring for 18 h at r.t., the mixture was concentrated un-
der reduced pressure. The resulting oil was dissolved in anhyd
CH2Cl2 (10 mL) under argon. To this solution was added, a solution
of poly(ethylene glycol) (typical Mn 8000, 20 g, 2.5 mmol) and Et3N
(3 mL) in CH2Cl2 (100 mL) under argon at 0 °C. After stirring for 3
h at r.t., the mixture was concentrated under reduced pressure. The
residue was dissolved in a minimum amount of H2O and extracted
with CH2Cl2. The organic layers were combined, and 95% of the re-
sulting volume was removed under reduced pressure. A tenfold of
Et2O was slowly added to the residue with stirring. The crystalline
polymer was collected by filtration and washed with ice-cold EtOH.
The polymer was dissolved in CH2Cl2 and precipitated as above.
This procedure was repeated twice. The PEG-bound ether was dried
in vacuo; white solid.
To a solution of trans-b-nitrostyrene (5; 29.8 mg, 0.20 mmol) and
diethyl malonate or a g,d-unsaturated b-keto ester (0.40 mmol) in
anhyd CH2Cl2 (5 mL) was added thiourea catalyst 9, 10, or 15 (0.02
mmol) under argon at r.t. The mixture was slowly stirred at r.t. In
the case of 9 or 10, the resin was filtered and washed well with
CH2Cl2, and EtOAc followed by EtOH, and then the filtrate was
concentrated under reduced pressure. In the case of 15, 95% of the
volume of the mixture was removed under reduced pressure, and
then a tenfold of Et2O was slowly added to the residue. The crystal-
line polymer was filtered and washed well with Et2O, and then fil-
trate was concentrated under reduced pressure. Purification of the
residue by preparative TLC (hexane–Et2O, 3:1) afforded Michael
adduct 6 or 16.13
Aza-Henry Reaction of 7; General Procedure
To a solution of N-phosphinoylimine 7 (61 mg, 0.20 mmol) and ni-
tromethane (0.11 mL, 2.0 mmol) in anhyd CH2Cl2 (5 mL) was add-
ed thiourea catalyst 9 or 10 (0.02 mmol) under argon at r.t. After
stirring slowly at r.t., the resin was filtered and washed well with
CH2Cl2, and EtOAc followed by EtOH, and then the filtrate was
concentrated under reduced pressure. Purification of the residue by
preparative TLC (hexane–EtOAc, 1:1) afford the adduct 8.13,14
1H NMR (500 MHz, CDCl3): d = 9.06 (2 H, s), 8.69 (2 H, s), 8.64
(2 H, s).
Anal. Calcd for C380H736F6N2O189: C, 53.87; H, 8.76; N, 0.33.
Found: C, 53.51; H, 8.45; N, 0.53.
PEG-bound amine 14
To a solution of the above PEG-bound ester (10 g, 1.1 mmol) in
EtOAc–CH2Cl2 (10:3, 300 mL) was added 10% Pd/C (1.0 g) at r.t.
After stirring for 5 h under a H2 atmosphere at r.t. for 5 h, the mix-
ture was filtered through Celite pad and concentrated under reduced
pressure. After the residue was dissolved in a minimum amount of
CH2Cl2, a tenfold of Et2O was slowly added with stirring. The crys-
talline polymer was collected by filtration and washed with ice-cold
EtOH. The polymer was dissolved in CH2Cl2 and precipitated as
above. This procedure was repeated twice. The PEG-bound amine
14 was dried in vacuo; white solid.
Acknowledgment
This work was supported in part by Grant-in-Aid for Young Scien-
tists (B) (H.M.) and Scientific Research on Priority Areas 17035043
(Y.T. and H.M.) from the Ministry of Education, Culture, Sports,
Science and Technology of Japan, 21st Century COE Program
‘Knowledge Information Infrastructure for Genome Science’.
References
1H NMR (500 MHz, CDCl3): d = 7.62 (2 H, s), 7.50 (2 H, s), 7.06
(1) For recent reviews on the organocatalyst chemistry, see:
(a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40,
3726. (b) Pihko, P. M. Angew. Chem. Int. Ed. 2004, 43,
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2004, 43, 5138. (d) Special Issue on Asymmetric
Organocatalysis Acc. Chem. Res. 2004, 37, 487. (e) Bolm,
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(i) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed.
2006, 45, 1520.
(2 H, s).
PEG-Bound Isothiocyanate
To a solution of PEG-bound amine 14 (1.4 g, 0.16 mmol) in anhyd
MeCN (20 mL) were added imidazole (6.8 mg, 0.1 mmol) and 1,1-
thiocarbonyldiimidazole (200 mg, 1.1 mmol) under argon at 0 °C.
After stirring for 2 h at r.t., 95% of the volume of the mixture was
removed under reduced pressure. A tenfold of anhyd Et2O was
slowly added with stirring under argon and then solvent was re-
moved by syringe. The crystalline polymer was washed with anhyd
Et2O as above to give PEG-bound isothiocyanate. Unstable isothio-
cyanate was immediately subjected to the next reaction; white solid.
(2) (a) Curran, D. P.; Kuo, L. H. J. Org. Chem. 1994, 59, 3259.
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Curran, D. P. Tetrahedron 1995, 51, 621.
1H NMR (500 MHz, CDCl3): d = 8.19 (2 H, s), 8.07 (2 H, s), 7.64
(2 H, s).
(3) (a) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
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PEG-Bound Thiourea 15
To a solution of PEG-bound isothiocyanate (1.3 g, 0.15 mmol) in
anhyd benzene–CH2Cl2 (1:1, 30 mL) was added (1R,2R)-N,N-di-
methylcyclohexanediamine (0.14 g, 1.0 mmol) under argon at r.t.
After stirring for 3 h at r.t., 95% of the volume of the mixture was
removed under reduced pressure. A tenfold of Et2O was slowly add-
ed to the residue with stirring. The crystalline polymer was collect-
ed by filtration and washed with ice-cold EtOH. The polymer was
dissolved in CH2Cl2 and precipitated as above. This procedure was
repeated twice. The PEG-bound thiourea 15 was dried in vacuo;
white solid.
(4) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 4901. (b) Vachal, P.; Jacobsen, E. N. J. Am. Chem. Soc.
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1H NMR (500 MHz, CDCl3): d = 8.13 (2 H, s), 8.10 (2 H, s), 8.03
(2 H, s).
Anal. Calcd for C398H772F6N6O185S2: N, 0.96; F, 1.30. Found: N,
0.77; F, 1.23.
Synthesis 2006, No. 19, 3295–3300 © Thieme Stuttgart · New York

3300
H. Miyabe et al.
SPECIAL TOPIC
(5) For urea catatyst anchored to resin, see: (a) Sigman, M. S.;
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(b) Kobayashi, S. Curr. Opin. Chem. Biol. 2000, 4, 338.
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(9) Details are provided in the experimental section.
(10) In a previous study on the reaction of 7 using original
thiourea 1, the adduct 8 was obtained in 87% yield with
67% ee, after being stirred in CH2Cl2 at room temperature
for 24 h.7c
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(12) Poly(ethylene glycol) (Mn 8000) was purchased from
Sigma-Aldrich.
(13) Characterization data for compounds 6,14 7c and 167g have
8
(r) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J.
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Synthesis 2006, No. 19, 3295–3300 © Thieme Stuttgart · New York