Enantiopure trans-1-amino-2-(arylsulfanyl)cyclohexanes: Novel chiral motifs for ligands and organocatalysts

Article abstract of DOI:10.1016/j.tetasy.2011.09.015

In order to obtain the title compounds (1R,2R)-cyclohexane-1,2-diol was stereoselectively converted into cis-(1R,2S)-2-(arylsulfanyl)cyclohexanols and these products were submitted to the nucleophilic substitution via the Mitsunobu reaction (HN₃

Full text of DOI:10.1016/j.tetasy.2011.09.015

Tetrahedron: Asymmetry 22 (2011) 1687–1691
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Tetrahedron: Asymmetry
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Enantiopure trans-1-amino-2-(arylsulfanyl)cyclohexanes: novel chiral
motifs for ligands and organocatalysts
⇑
_
_
´
Anna E. Nowak, Elzbieta Wojaczynska, Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to obtain the title compounds (1R,2R)-cyclohexane-1,2-diol was stereoselectively converted into
cis-(1R,2S)-2-(arylsulfanyl)cyclohexanols and these products were submitted to the nucleophilic
substitution via the Mitsunobu reaction (HN3, DEAD). Reduction of the isolated azides gave the
desired trans-(1S,2S)-1-amino-2-(arylsulfanyl)cyclohexanes. The (1S,2S)-1-amino-2-(2-aminophenylsulfa-
nyl)cyclohexanes thus prepared were reacted with 3,5-bis(trifluoromethyl)phenyl isothiocyanate to
furnish the respective bis-thiourea compounds. An application of a derivative of this type as an organocat-
alyst (20 mol %) in the Baylis–Hillman reaction gave the respective product in up to 93% ee.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 18 August 2011
Accepted 28 September 2011
Available online 5 November 2011
1. Introduction
Recently, we have developed a stepwise enantiospecific substi-
tution of chiral vic-diols into their respective vic-bis(sulfides).5
Over the last few decades, many studies have been devoted to
the search of chiral ligands for metal-catalyzed enantioselective
reactions. These studies have led to the identification of the most
successful molecular motifs of various catalysts (privileged
catalysts).1 However, the often encountered ligand–substrate spec-
ificity poses serious limitations in their application to asymmetric
transformations. Thus, there is still much interest in the develop-
ment of new ligands. Recently, stereoselective organocatalytic pro-
cedures using chiral bifunctional thiourea catalysts have gained
much attention.2 In spite of being successfully applied in various
enantioselective transformations, these catalysts also suffer from
limitations, similarly to other ligands.
Most of the chiral ligands and organocatalysts used in asym-
metric reactions are phosphorus-, nitrogen-, oxygen-, and sulfur-
containing compounds.1 In particular, C2-symmetric derivatives
with a relatively rigid cyclic structure, such as a trans-1,2-disubsti-
tuted cyclohexane framework, are regarded as catalysts belonging
to the aforementioned privileged class.1b On the other hand, in a
number of reactions chiral ligands and organocatalysts without
C2-symmetry perform better.3 However, there is a limited number
of readily available chiral C1 derivatives of the trans-1,2-disubsti-
tuted cyclohexane type. Since the respective chiral vic-diols and
vic-diamines4 are easily accessible, we were interested in their
transformation into the desired C1 compounds. A direct approach
via double nucleophilic substitution of a vic-diol is often hampered
by neighboring group participation effects.4e
Herein, we report the successful enantiospecific introduction of
the corresponding sulfur- and nitrogen-containing vic-functionality
to the cyclohexane backbone. We also report the preparation of
novel chiral amino-compounds and their transformations into the
respective thioureas. The results of our preliminary trials demon-
strate their usefulness in catalytic asymmetric reactions.
2. Results and discussion
We reacted commercially available enantiopure (1R,2R)-cyclo-
hexane-1,2-diol 1 with 3 equiv of (PhS)2/Bu3P (the Hata reaction
conditions),5,6 and the nucleophilic substitution of one of the hy-
droxy groups stereoselectively gave cis-(1R,2S)-2-(phenylsulfa-
nyl)cyclohexanol 3a in 34% yield and with over 95% ee.5
Extending this observation we undertook the synthesis of enantio-
merically pure cis-(1R,2S)-2-(2-aminophenylsulfanyl)cyclohexanol
3b, which has not been previously prepared. This compound was
synthesized directly from (1R,2R)-1 and the disulfide 2b via the
Hata reaction (Scheme 1). Similarly, we carried out the reaction
of chiral diol 1 with disulfides 2c and 2d. Only 2-(2-quinolylsulfa-
nyl)cyclohexanol 3c was obtained in 35% yield and 84% de, while
the reaction of 2d led to the isolation of the C2-symmetric bis-
substituted product 4 only.
The monofunctionalized alcohols 3a5 and 3b were used as start-
ing materials for further transformations involving the alcohol
fragment. Since an attempted hydroxyl substitution with DPPA
and DBU did not lead to the desired product, we carried out this
transformation using the Mitsunobu reaction with azidoic acid.7
This reaction worked well and we obtained the expected azides 5
as single diastereomers (Scheme 2). The reduction to amines 6
⇑
Corresponding author.
E-mail address: jacek.skarzewski@pwr.wroc.pl (J. Skarzewski).
_
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.09.015

1688
A. E. Nowak et al. / Tetrahedron: Asymmetry 22 (2011) 1687–1691
OH
OH
Ar
S
S
S
Bu3P
Ar
Ar
Ar
S
S
or
Ar
toluene
OH
(1R,2R)-1
2a-d
(1S,2S)-4
(1R,2S)-3a-c
NH2
N
N
2b, 3b:
Ar =
2c, 3c:
Ar =
2a, 3a:Ar =
2d, 4: Ar =
Scheme 1.
X
X
X
S
S
S
Ph3P/MeOH
or HS(CH2)3SH
HN3
DEAD, Ph3P
OH
N3
NH2
6a, b
3a, b
(1R,2S)-
a:
b:
X=H; X=NH2
(1S,2S)-
(1S,2S)-5a, b
Scheme 2.
was carried out using 1,3-propanedithiol as a reductant8 for 5a and
the Staudinger reaction conditions9 for 5b.
comparison with 8, we obtained compound 11 (p-toluenesulfon-
amide of 3b), which was also tested in the organocatalytic
Baylis–Hillman reaction.
Thus for the preliminary screening, we tested the catalytic prop-
erties of 8a,b, 9a,b, and 10 in the model Baylis–Hillman reaction11h
(Scheme 4). The reaction of p-fluorbenzaldehyde with 2-cyclohexe-
none in the presence of 20 mol % of DMAP and the chiral catalyst
was examined first (Table 1, entries 1–5). In most cases, the ob-
tained product 12a was nearly racemic, but for 9b the chemical
yield was considerable. For 8a the yield was poor, but moderate
Since many successful organocatalysts are thiourea derivatives
forming specific hydrogen bonds,2 we decided to prepare com-
pounds 8 and 9 (Scheme 3). Both 8b and 9b, which contain the
strongly electron withdrawing 3,5-bis(trifluoromethyl)phenyl
group10 were regarded as particularly promising structures. This
type of organocatalyst has already been applied in the Baylis–
Hillman reaction.11,12 However, there are relatively few examples
of the successful asymmetric version of this reaction. For a
R
R
N
C
S
R
HN
S
3b
(1R,2S)-
HN
CH2Cl2
R
S
7
7a, 8a
7b, 8b
R = H
R = CF3
OH
(1R,2S)-8a, b
R
R
NH
NH
S
S
S
NH
7a, b
7b
CH2Cl2
(1S,2S)-6b
6a
(1S,2S)-
CH2Cl2
HN
S
NH
HN
S
R
(1S,2S)-10
CF3
F3C
(1S,2S)-9a, b
7a, 9a R = H
7b, 9b R = CF3
R
Scheme 3.

A. E. Nowak et al. / Tetrahedron: Asymmetry 22 (2011) 1687–1691
1689
utilizing electrospray ionization mode. Chromatographic separa-
tions were performed on Silica Gel 60 (70–230 mesh) purchased
from Merck. Thin layer chromatography analyses were performed
using Silica Gel 60 precoated plates (Fluka). Enantiomeric excess
was determined by 1H NMR using a chiral shift reagent Eu(hfc)3
and chiral HPLC using Chiracel OB-H, Chralpak AS-H, and Chiracel
OD-H columns.
O
OH
O
DMAP (20 mol%)
cat* (20 mol%)
RCHO
R
R: p-FC6H4 (a), c-C6H11 (b), n-C6H13 (c)
(S)-12a, b, c
Scheme 4.
4.2. Preparation of sulfides
Table 1
Results of the catalyzed Baylis–Hillman reactiona
Tributylphosphine (0.99 mL, 4 mmol, 4 equiv) was added via
syringe to a solution of diol 1 (116 mg, 1 mmol) and diaryldisulfide
2a–2d (3 equiv) in 8 mL of dry toluene in an ampoule, which was
filled with argon and sealed. This reaction mixture was kept at
80 °C for 3–4 days. The solvent was evaporated and products 3a,
3b, 3c and 4 were purified by column chromatography (hex-
ane ? hexane/ethyl acetate 5:1).
Entry
Catalyst
Yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
8a
8b
9a
9b
11
9b
9b
8a
8a
25 (19)b
40
31
44 (41)b
5
8
77
32
5
4
88c
30d
10c
25d
75c
93d
24c
>5d
4.2.1. (ꢀ)-(1R,2S)-2-(2-Aminophenylsulfanyl)cyclohexanol 3b
Yield 82%; ½a 2D0
ꢁ
¼ ꢀ52:1 (c 0.86, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 1.34–1.41 (m, 3H, cyclohexane ring), 1.53–1.84 (m,
5H, cyclohexane ring), 2.9 (br s, 1H, OH), 3.01–3.07 (m, 1H, CH),
3.58–3.61 (m, 1H, CH), 4.34 (br s, 2H, NH2), 6.61–6.70 (m, 2H,
ArH), 7.05–7.11 (m, 1H, ArH), 7.20–7.35 (m, 1H, ArH); 13C NMR
(CDCl3), d = 19.2, 24.2, 26.7, 30.8, 52.7 (CH), 66.3 (CH), 114.4,
116.0, 118.0, 129.3, 136.2, 147.5; IR (film): 3447, 3345, 1607,
1254, 751 cmꢀ1; HRMS (ESI, [M+H]+): calcd for [C12H17NOS+H]+
224.1104, found 224.1111. Rf = 0.78 (hexane/ethyl acetate 1:1).
a
The catalytic reaction was run using 2-cyclohexenone (2 equiv), 4-fluorobenz-
aldehyde (1 equiv), DMAP (0.2 equiv) and the catalyst (0.2 equiv), in the absence of
solvent, for 7 days at room temperature; for further details, see Section 4.
b
DABCO was used instead DMAP.
Cyclohexanecarboxaldehyde was used instead of 4-fluorobenzaldehyde.
Heptanal was used instead of 4-fluorobenzaldehyde.
c
d
enantioselectivity was observed, namely 44% and 41% ee of (S)-11a
with DMAP and DABCO, respectively. These two catalysts 8a and 9b
were tested in a reaction with cyclohexanecarboxaldehyde (entries
6 and 8) and n-heptanal (entries 7 and 9). Catalyst 9b performed
well in these two reactions giving 75% and 93% ee of (S)-12b and
(S)-12c, respectively. As it was already noted,11,12 the enantioselec-
tivity in the Baylis–Hillman reaction is strongly substrate-
dependent. In spite of the limited results, bis-thiourea 9b seems
to outperform the corresponding C2 symmetric bis-thiourea
derived from 1,2-cyclohexanediamine.11h
Compound 3b and bis-pyridyl derivative 4 were also examined
as ligands in the palladium-catalyzed Tsuji–Trost allylic alkylation
of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate,13 but
the results obtained were disappointing (for 3b: 92% yield, 8% ee,
for 4: 29% yield, 4% ee).
4.2.2. (ꢀ)-(1R,2S)-2-(2-Quinolylsulfanyl)cyclohexanol 3c
Yield 35%; ½a 2D0
ꢁ
¼ ꢀ52:1 (c 0.92, CH2Cl2, 84% de); 1H NMR
(300 MHz, CDCl3): d = 1.05–1.98 (m, 8H, cyclohexane ring), 3.43–
3.48 (m, 1H, CH), 3.62–3.66 (m, 1H, CH), 4.80 (br s, 1H, OH),
7.37–7.45 (m, 2H, ArH), 7.67–7.71 (m, 1H, ArH), 7.86–7.89 (m,
1H, ArH), 8.11–8.16 (m, 1H, ArH), 8.91–8.95 (m, 1H, ArH); 13C
NMR (CDCl3): d = 21.7, 23.8, 28.6, 30.8, 47.7 (CH), 47.8 (CH);
120.3, 125.2, 125.5, 128.3, 128.7, 129.5, 129.7, 136.6, 149.5; IR
(film): 3375, 3060, 2932, 2856, 1593, 1493, 1456, 1069, 789,
;
757 cmꢀ1 HRMS (ESI, [M+H]+): calcd for [C15H17NOS+H]+
260.1104, found 260.1109. Rf = 0.72 (hexane/ethyl acetate 1:1).
4.2.3. (ꢀ)-(1S,2S)-1,2-Bis(2-pirydylsulfanyl)cyclohexane 4
Yield 62%; ½a 2D0
ꢁ
¼ ꢀ40:0 (c 1.046, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 1.47–1.58 (m, 2H, cyclohexane ring), 1.71–1.80 (m,
4H, cyclohexane ring), 2.28–2.37 (m, 2H, cyclohexane ring), 4.22–
4.23 (m, 2H, CH), 6.83–6.95 (m, 2H, ArH), 7.09–7.21 (m, 2H, ArH),
7.42–7.45 (m, 2H, ArH), 8.37–8.38 (m, 2H, ArH); 13C NMR (CDCl3):
d = 24.6, 31.9, 47.1 (CH), 119.8, 123.4, 136.3, 149.8, 159.4; IR (film):
3043, 2931, 2854, 1578, 1452, 1413, 757, 724 cmꢀ1; HRMS (ESI,
[M+H]+): calcd for [C16H18N2S2+H]+ 303.0984, found 303.0958.
Rf = 0.56 (hexane/ethyl acetate 3:1).
3. Conclusions
In conclusion, the sequential displacement of the hydroxy
groups in trans-1,2-cyclohexanediol can be carried out enantiose-
lectively. Reactions leading to the corresponding cis-2-(phen-
ylsulfanyl)cyclohexanol followed by the Mitsunobu reaction with
azidoic acid and the reduction of the resulting azides allowed for
the easy preparation of the respective thioureas, which are prom-
ising organocatalysts for the Baylis–Hillman reaction.
4.3. Synthesis of azide 5 and its reduction to amine 6
4. Experimental
4.1. General
Compound 3b (0.16 g, 0.72 mmol) and Ph3P (0.246 g,
0.94 mmol, 1.3 equiv) were dissolved in dry toluene (8 mL). Next,
HN3 (0.94 mL, 0.937 mmol, 1.3 equiv in benzene) was added drop-
wise under an argon atmosphere followed by a solution of DEAD
(0.17 mL, 1.082 mmol, 1.5 equiv, 40% solution in toluene). After
stirring for 24 h, the solvent was evaporated and the crude product
5a was purified by column chromatography using hexane/ethyl
acetate (6:1 v/v) as an eluent. The analogous procedure was ap-
plied for the synthesis of compounds 5b, using alcohol 3a.
Melting points were measured using the open capillary tube
method. IR spectra were recorded on a Perkin Elmer System 2000
FTIR spectrophotometer. 1H and 13C NMR spectra were measured
on a Bruker DRX 300 Avance spectrometer (1H, 300 MHz; 13C,
75.5 MHz) using a residual CHCl3 signal as a lock and the internal
standard. Optical rotations were measured using an Optical Activ-
ity Ltd, Model AA-5 automatic polarimeter. High resolution mass
spectra were recorded using a LCT Premier (Waters) instrument
Triphenylphosphine (0.161 g, 0.615 mmol, 1.5 equiv) was
added to a solution of azide 5 (0.102 g, 0.41 mmol) in methanol
(5 mL). After refluxing for 2 h, the solvent was evaporated and

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A. E. Nowak et al. / Tetrahedron: Asymmetry 22 (2011) 1687–1691
the product 6 was purified on a silica column. Elution with
CHCl3 containing CH3OH (5–10%) yielded a fraction containing
amine 6.
4.4.1. (+)-3-(2-{[(1S,2R)-2-Hydroxycyclohexyl]sulfanyl}phenyl)-
1-phenylthiourea 8a
Yield 82%; ½a 2D0
ꢁ
¼ þ18:4 (c 3.16, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 1.16–1.67 (m, 8H, cyclohexane ring), 2.07 (s, 1H, OH),
2.95–2.98 (m, 1H, CH), 3.57 (s, 1H, CH), 7.10–7.13 (td, J1 = 7.2 Hz,
J2 = 1.2 Hz, 1H, ArH), 7.24–7.49 (m, 7H, ArH), 8.20 (d, J = 8.0 Hz,
1H, ArH), 8.45 (s, 1H, NH), 8.74 (s, 1H, NH); 13C NMR (CDCl3): d
20.4, 24.6, 27.9, 31.9, 54.5 (CH), 67.8 (CH), 125.3, 126.0, 126.2,
127.6, 127.7, 128.9, 130.0, 135.4, 136.6, 140.1, 179.5 (C@S); IR
4.3.1. (+)-(1S,2S)-trans-2-(Phenylsulfanyl)cyclohexylazide 5a
Yield = 76%; ½a 2D0
ꢁ
¼ þ46:4 (c 0.47, CH2Cl2), (ee >95%), 1HNMR
(300 MHz, CDCl3): d = 1.21–1.30 (m, 2H, cyklohexyl), 1.39–1.45
(m, 2H, cyklohexyl), 1.66–2.72 (m, 2H, cyklohexyl), 2.05–2.33 (m,
2H, cyklohexyl), 2.93 (td, 1H, J1 = 9.8, Hz J2 = 4 Hz, CH), 3.20–3.25
(td, 1H, J1 = 9.7, Hz J2 = 4 Hz), 7.24–7.31 (m, 3H, ArH), 7.46–7.47
(m, 2H, ArH); 13CNMR (CDCl3): d = 24.2, 25.3, 31.8, 32.7, 52.1,
64.4, 127.9, 129.3, 130.5, 133.7; IR (film): 2936, 2858, 2096,
(film): 3243, 1581, 1539, 1520, 1442, 1293, 1254, 758, 695 cmꢀ1
.
HRMS (ESI): calcd for [C19H22N2OS2+Na]+ 381.1066, found
381.1068. Rf = 0.4 (hexane/ethyl acetate 5:1).
1474, 1448, 1439, 1259, 753, 739, 692 cmꢀ1
.
4.4.2. (+)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-(2-{[(1S,2R)-2-
4.3.2. (+)-(1S,2S)-trans-2-(2-Aminophenylsulfanyl)
hydroxycyclohexyl]sulfanyl}phenyl)thiourea 8b
cyclohexylazide 5b
Yield 73%; ½a 2D0
ꢁ
¼ þ90:9 (c 0.66, CH2Cl2); 1H NMR (300 MHz,
Yield 64%, de >95%; ½a D20
ꢁ
¼ þ118 (c 0.39, CH2Cl2); 1H NMR
CDCl3): d = 1.36–1.79 (m, 8H, cyclohexane ring), 2.75 (s, 1H, OH),
3.21–3.23 (m, 1H, CH), 3.78–3.80 (m, 1H, CH), 7.21 (td,
J1 = 7.8 Hz, J2 = 1.5 Hz, 1H, ArH), 7.37 (td, J1 = 7.5 Hz, J2 = 1.5 Hz,
1H, ArH), 7.60 (dd, J1 = 7.8 Hz, J2 = 1.5 Hz, 1H, ArH), 7.67 (s, 1H,
ArH), 7.94 (dd, J1 = 7.8 Hz, J2 = 1.0 Hz, 1H, ArH), 8.00 (s, 2H, ArH),
8.41 (s, 1H, NH), 9.23 (s, 1H, NH); 13C NMR (CDCl3): d = 21.2,
23.6, 28.7, 31.9, 54.8 (CH), 69.3 (CH), 119. 2 (br r), 123.0
(JCF = 277.5 Hz), 124.4 (br r), 125.1, 127.0, 129.3, 132.2 (JCF = 30 Hz),
135.8, 137.2, 139, 139.8, 179.6 (C@S); IR (film): 3252, 1574, 1538,
1471, 1276, 744, 701, 682 cmꢀ1. HRMS (ESI, [M+H]+) calcd for
[C21H20F6N2OS2+H]+ 495.0994, found 495.1000. Rf = 0.38 (hexane/
ethyl acetate 3:1). Column chromatography, eluent: hexane/ethyl
acetate 5:1.
(300 MHz, CDCl3): d = 1.10–1.51 (m, 4H, cyclohexane ring), 1.65–
1.78 (m, 2H, cyclohexane ring), 1.99–2.06 (m, 1H, cyclohexane
ring), 2.14–2.21 (m, 1H, CH), 2.74 (td, J1 = 11.1 Hz, J2 = 4.2 Hz, 1H,
CH), 3.22 (td, J1 = 10.2 Hz, J2 = 3.9 Hz, 1H, CH), 4.51 (s, 2H, NH2),
6.65–6.75 (m, 2H, ArH), 7.13–7.19 (m, 1H, ArH), 7.40 (dd,
J1 = 7.2 Hz, J2 = 1.5 Hz, 1H, ArH); 13C NMR (CDCl3): d = 24.1, 25.2,
31.6, 32.7, 51.2, 64.0, 115.0, 118.2, 130.6 (two signals overlapped),
138.1, 149.6; IR (film): 3463, 3357, 2935, 2858, 2095, 1607, 1478,
1308, 1256, 752 cmꢀ1
;
HRMS (ESI, [M+H]+): calcd for
[C12H16N4S+H]+ 249.1168, found 249.1146. Rf = 0.6 (hexane/ethyl
acetate 6:1).
4.3.3. (+)-(1S,2S)-trans-2-(Phenylsulfanyl)cyclohexylamine 6a
Yield = 91%; ½a 2D0
ꢁ
¼ þ84:2 (c 0.38, CH2Cl2), (ee >95%); 1H NMR
4.4.3. (+)-1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-
(300 MHz, CDCl3): d = 1.22–1.30 (m, 4H, cyclohexsyl), 1.68–1.80
(m, 4H, cyclohexyl), 2.00–2.13 (m, 2H, CH), 2.57–2.74 (m, 2H,
NH2), 7.22–7.35 (m, 3H, ArH), 7.46–7.49 (m, 2H, ArH); IR (film):
3401, 3063, 2927, 2855, 2098, 1621, 1578, 1474, 1445, 1376,
1336, 1089, 839, 746, 695 cmꢀ1 This compound has already been
obtained and described as a racemate4c and its 1H NMR spectrum
is in agreement with the given above.
(phenylsulfanyl)cyclohexyl]thiourea 10
Yield 98%; ½a 2D0
ꢁ
¼ þ110:5 (c 0.19, CH2Cl2). Mp = 156–157 °C. 1H
NMR (300 MHz, CDCl)3: d = 1.21–1.45 (m, 4H, cyclohexyl), 1.66–
1.75 (m, 2H, cyclohexyl), 1.66–1.76 (m, 1H, cyclohexyl), 2.42–
2.53 (m, 1H, cyclohexyl), 3.00 (td, 1H, J1 = 12 Hz, J2 = 6 Hz, CH),
4.18–4.31 (m, 1H, CH), 6.46 (d, J = 6 Hz, NH), 7.24–7.29 (m, 3H,
ArH), 7.41–7.44 (m, 2H, ArH), 7.67 (s, 1H, ArH), 7.83 (s, 1H, ArH),
8.50 (s, 1H, NH) ppm; 13C NMR (CDCl3): d = 24.3, 25.7, 33.1 (two
signals overlapped), 52.1 (CH), 58.3 (CH), 119.3 (br r), 122.8
(JCF = 271.3 Hz), 123.7 (br r), 128.0, 129.2, 132.2, 133.0
(JCF = 33.8 Hz), 133.6, 138.9, 179.5 (C@S); IR (KBr): 3236, 3139,
3063, 2946, 2863, 1587, 1557, 1473, 1459, 1387, 1343, 1315,
1279, 1176, 1130, 1107, 982, 884, 705, 681 cmꢀ1; HRMS (ESI,
[M+H]+): calcd for [C21H20F6N2S2+H]+ 479.1045, found 479.1050.
Rf = 0.5 (hexane/ethyl acetate 5:1). Column chromatography, elu-
ent: hexane/ethyl acetate 6:1.
4.3.4. (+)-(1S,2S)-2-(2-Aminophenylsulfanyl)cyclohexylamine
6b
Yield 90%; ½a 2D0
ꢁ
¼ þ54:2 (c 0.24, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 1.14–1.42 (m, 4H, cyclohexane ring), 1.64–1.68 (m,
2H, cyclohexane ring), 1.94–2.03 (m, 2H, cyclohexane ring), 2.50–
2.61 (m, 2H, CH), 3.20 (s, 4H, NH2), 6.63–6.73 (m, 2H, ArH), 7.09–
7.15 (m, 1H, ArH), 7.60–7.80 (m, 1H, ArH); 13C NMR (CDCl3):
d = 24.6, 26.4, 33.3, 35.8, 54.2, 57.0, 115.0, 118.2, 128.6, 132.1,
137.8, 149.4; IR (film): 3441, 3348, 3177, 2930, 1607, 1479,
1446, 1309, 1158, 750 cmꢀ1; HRMS (ESI, [M+H]+): calcd for
[C12H18N2S+H]+ 223.1263, found 223.1260. Rf = 0.3 (CHCl3/MeOH,
10:1).
4.4.4. (+)-1-Phenyl-3-[(1S,2S)-2-({2-[(phenylcarbamothioyl)
amino]phenyl}sulfanyl)cyclohexyl]thiourea 9a
Yield 50%, Mp = 113–114 °C. ½a D20
ꢁ
¼ þ46:3 (c 0.8, CH2Cl2) 1H
NMR (300 MHz, CDCl3): d = 1.03–1.22 (m, 2H, cyclohexane ring),
1.23–1.43 (m, 2H, cyclohexane ring), 1.56–1.71 (m, 2H, cyclohex-
ane ring), 1.72–1.89 (m, 1H, cyclohexane ring), 2.19–2.30 (m, 1H,
cyclohexane ring), 2.82–2.94 (m, 1H, CH), 4.34–4.49 (m, 1H, CH),
6.25 (d, J = 9 Hz, 1H, NH), 7.10–7.14 (m, 3H, ArH), 7.15–7.23 (m,
1H, ArH), 7.29–7.34 (m, 4H, ArH), 7.38–7.43 (m, 4H, ArH), 7.53
(d, J = 9 Hz, 1H, ArH) 8.07–8.11 (m, 2H, NH+ArH), 8.52 (s, 1H,
NH), 8.63 (s, 1H, NH) ppm; 13C NMR (CDCl3): d = 24.3, 25.6, 32.7,
33.2, 53.1, 58.7, 124.6, 125.3, 125.7, 126.5, 126.6, 127.5, 127.7,
129.1, 129.8, 135.8, 136.5, 136.8, 140.0, (one aromatic signal over-
lapped), 179.4, 179.5; HRMS (ESI, [M+H]+): calcd for
[C26H28N4S3+H]+ 493.1543, found 493.1562. Rf = 0.79 (chloro-
form/acetone 98:2).
4.4. Preparation of thiourea derivatives
A solution of compound 3b (0.144 g, 0.64 mmol) and phenyl
isothiocyanate 7a (0.08 mL, 0.64 mmol, 1 equiv) in CH2Cl2 (4–
5 mL) was stirred for 5 days at room temperature. The solvent
was then evaporated, and the product 8a was purified by column
chromatography. For the synthesis of compound 8b, 3,5-bis(tri-
fluoromethyl)phenyl isothiocyanate 7b (1.2 equiv) was used in
place of 7a, and the reaction was carried out under an argon atmo-
sphere. An analogous procedure was applied for the synthesis of
compounds 9 and 10, using amines 6 and 2 equiv of isothiocyanate
7a or 7b.

A. E. Nowak et al. / Tetrahedron: Asymmetry 22 (2011) 1687–1691
1691
4.4.5. 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-{[2-({[3,
5-bis(trifluoromethyl)phenyl]carbamothioyl}amino)phenyl]sul-
fanyl}cyclohexyl]thiourea 9b
(S)-12a: Chiralcel OB-H, hexane/2-propanol 95:5, 1.0 mL/min,
k = 254 nm, (S)-major: 30.9 min, (R)-minor: 44.4 min. Spectro-
scopic data are in agreement with the literature.14
(S)-12b: Chiralpak AS-H, hexane/2-propanol 90:10, 1.0 mL/min,
k = 254 nm, (S)-major: 10.24 min, (R)-minor: 13.92. Spectroscopic
data are in agreement with the literature.15
(S)-12c: Chiralpak AS-H, hexane/2-propanol 90:10, 1.0 mL/min,
k = 254 nm, (S)-major: 7.78 min, (R)-minor: 10.35 min. Spectro-
scopic data are in agreement with the literature.15
Yield 95%; ½a 2D
ꢁ
¼ þ3:6 (c 0.41, CH2Cl2). Mp = 107–108 °C. 1H
NMR (300 MHz, CDCl3): d = 0.86 (m, 1H, cyclohexane ring), 1.23–
1.25 (m, 2H, cyclohexane ring), 1.61–1.90 (m, 4H, cyclohexane
ring), 2.05 (m, 1H, cyclohexane ring), 2.37 (m, 1H, CH), 2.75 (m,
1H, CH), 4.50 (br s, 1H, NH), 6.77–6.80 (d, 1H, ArH), 7.30 (td, 1H,
ArH), 7.45 (m, 1H, ArH), 7.58 (s, 1H, ArH), 7.69–7.70 (m, 2H,
ArH), 7.88 (s, 2H, ArH), 7.95 (s, 2H, ArH), 8.40 (br s, 2H, NH), 8.51
(br s, 1H, NH); 13C NMR (CDCl3): d = 14.0, 24.4, 25.8, 33.5, 54.6,
57.7, 118.4 (br r), 120.5 (br r), 122.8 (JCF = 272.7 Hz), 123.0
(JCF = 272.3 Hz), 123.1 (br r), 125.2 (br r), 126.4, 128.4, 130.0,
130.2, 131.5 (JCF = 28.1 Hz), 132.5 (JCF = 29.2 Hz), 137.6, 138.1,
139.0, 139.7, 179.5 (C@S), 179.9 (C@S); IR (KBr): 3421, 2940,
1536, 1471, 1383, 1279, 1179, 1134, 982, 888, 681 cmꢀ1; HRMS
(ESI, [M+H]+) calcd for [C30H24S3N4F12+H]+ 765.1038 found
765.1005. Rf = 0.24 (hexane/ethyl acetate 4:1).
Acknowledgement
This work was supported by grant no. 344151/20305 from
Wroclaw University of Technology.
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fanyl}phenyl)-4-methylbenzene-1-sulfonamide 11
Method A: Compound 3b (0.1 g, 0.45 mmol) and p-toluenesulfo-
nyl chloride (0.147 g, 0.77 mmol, 1.7 equiv) were dissolved in 3 mL
of CH2Cl2. To the stirred mixture, aqueous KOH (3%, 0.046 g,
0.82 mmol, 1.8 equiv) and DMAP (15 mg, 0.12 mmol) were added.
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separated and extracted with CH2Cl2 (3 ꢂ 5 mL). The combined or-
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with hexane/ethyl acetate 5:1.
Method B: Alternatively, 11 could be prepared by the reaction of
compound 3b with p-toluenesulfonyl chloride in pyridine with
DMAP as a catalyst. A mixture of compound 3b (0.1 g, 0.45 mmol),
p-toluenesulfonyl chloride (0.09 g, 0.47 mmol, 1.05 equiv), pyri-
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11 was purified by column chromatography using hexane/ethyl
}
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_
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acetate 5:1. Yield 68% (method A)/60% (method B). ½a D20
¼ þ10:6
ꢁ
(c 1.64, CH2Cl2). 1H NMR (300 MHz, CDCl3): d 1.18–1.63 (m, 8H,
cyclohexane ring), 2.28 (s, 3H, CH3), 2.42 (s, 1H, OH), 2.65–2.71
(m, 1H, CH), 3.63 (d, J = 3.05 Hz, 1H, CH), 6.90–6.91 (m, 1H, ArH),
7.13–7.20 (m, 1H, ArH), 7.35–7.39 (m, 1H, ArH), 7.55–7.58 (m,
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119.7, 124.4, 127.3, 129.7, 130.3, 137.2, 139.8, 143.9, (two aromatic
signals hidden); IR (film): 3508, 3243, 1334, 1598, 1587, 1393,
1334, 1185, 1156, 914, 814, 666 cmꢀ1; HRMS (ESI, [M+H]+): calcd
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ane/ethyl acetate 1:1).
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4.6. Procedure for the catalytic Baylis–Hillman reaction
To a preweighed sample of 0.1 mmol of catalysts 8a, 8b, 9a, 9b
or 11 and DMAP (12.2 mg, 0.1 mmol) was added 0.5 mmol of suit-
able aldehyde: p-fluorobenzaldehyde (53.7
oxaldehyde (60.6 L) or heptanal (72.5 l) and 2-cyclohexenone
(96.5 L, 1.0 mmol). The resulting mixture was magnetically stir-
lL), cyclohexanecarb-
l
l
´
´
13. For the experimental details, see: Wojaczynska, E.; Zielinska-Błajet, M.;
l
_
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red at room temperature for 7 days. The crude products 12a–c
were purified by column chromatography (hexane/ethyl acetate
8:1 ? 2:1) and analyzed by chiral HPLC.
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