Synthesis and evaluation of N,S-compounds as chiral ligands for transfer hydrogenation of acetophenone

Article abstract of DOI:10.1039/b208907f

New nitrogen- and sulfur-containing compounds, bicyclic and monocyclic, were prepared and evaluated as ligands in the transfer hydrogenation of acetophenone. Utilising [Ir(COD)Cl]₂ as metal precursor the best result, 80% ee, was obtained using

Full text of DOI:10.1039/b208907f

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Synthesis and evaluation of N,S-compounds as chiral ligands for
transfer hydrogenation of acetophenone†
Jenny K. Ekegren, Peter Roth, Klas Källström, Tibor Tarnai‡ and Pher G. Andersson*
Department of Organic Chemistry, Uppsala University, Box 531, SE-751 21 Uppsala, Sweden.
E-mail: phera@kemi.uu.se
Received 11th September 2002, Accepted 5th November 2002
First published as an Advance Article on the web 9th December 2002
New nitrogen- and sulfur-containing compounds, bicyclic and monocyclic, were prepared and evaluated as ligands in
the transfer hydrogenation of acetophenone. Utilising [Ir(COD)Cl]2 as metal precursor the best result, 80% ee, was
obtained using a bicyclic sulfoxide ligand.
Introduction
Sulfur-containing ligands have been studied in a variety of
applications in asymmetric catalysis.1 The different electronic
properties of sulfur compared to oxygen2 as the chelating atom
and the fact that sulfur can become chiral when coordinated
to a metal have challenged many scientists.3–6 Utilisation of
nitrogen and sulfur as chelating atoms in ligands have afforded
moderate to excellent results in e.g. allylic alkylation,1,3,7 hydro-
genation,1,8 diethylzinc addition,9–11 conjugate addition to
enones,1,12 metal-catalysed cross-coupling1 and hydrosilylation
of imines and ketones.1
Prior to work done by the groups of Lemaire13–16 and van
Leeuwen17,18 very little has been reported regarding sulfur-
containing ligands for the transfer hydrogenation reaction.1
Enantioselective transfer hydrogenation of ketones is a well
explored reaction in asymmetric catalysis.19,20 The attractive
feature of this reaction lies primarily in the use of isopropyl alco-
hol or formic acid as the hydrogen source instead of molecular
hydrogen. We have previously reported that 2-azanorbornan-
3-ylmethanol is an efficient ligand in Ru(arene)-catalysed
asymmetric transfer hydrogenation.21–24
Scheme 2 (i) Boc2O, Et3N, THF, rt, overnight; (ii) LAH, THF, 0 ЊC
Here we report the synthesis and evaluation of two new
classes of N,S-ligands for transfer hydrogenation. With the
results of the 2-azanorbornyl amino alcohols in mind, we
prepared the corresponding amino sulfides bearing this bicyclic
backbone. Aiming for access to active ligands that can be easily
prepared and modified, we also developed a class of cyclohexyl-
based amino sulfides. A short synthetic protocol afforded these
compounds as racemic mixtures easily separated by chiral
HPLC. The influence of different backbones and substituents
in the amino sulfides was investigated by subjecting them to the
transfer hydrogenation conditions using [Ir(COD)Cl]2 as the
metal precursor and i-PrOH as the hydrogen donor (Scheme 1).
2 h; (iii) TsCl, pyridine, CH2Cl2, 0 ЊC, rt 5 h; (iv) BnSH, n-BuLi, THF,
0 ЊC 1 h, rt overnight; (v) TFA, CH2Cl2, rt, 2 h.
gave alcohol 2, which was subjected to tosylation to give 3.
Nucleophilic substitution of the tosylate with deprotonated
toluene-α-thiol and subsequent deprotection yielded com-
pound 5.
In earlier reports17,26 on N,S-ligands in asymmetric transfer
hydrogenation, it has been revealed that [Ir(COD)Cl]2 is the
most active pre-catalyst. Amino sulfide 5 was therefore evalu-
ated in the transfer hydrogenation of acetophenone in i-PrOH
using this iridium salt and i-PrOK as the base (entry 1,
Table 1). Under these conditions acetophenone was reduced to
the corresponding alcohol with high rate but low selectivity
(95% conversion after 1 h, 63% ee).
Monooxidation of the sulfur atom introduces new centre of
chirality into the ligand. This was performed with Boc-
protected 4 using sodium periodate in a MeOH–H2O solution
(Scheme 3). The product was formed as a 3:2 mixture of
diastereomers that were separated by preparative chiral HPLC.
Boc-deprotection yielded sulfoxides major-7 and minor-7.
Major-7 and minor-7 were evaluated in the transfer hydro-
genation reaction and the results are shown in Table 1, entries 2
and 3. Both were found to yield less active catalysts compared
to 5, (respectively, 10 and 52% conversion after 1 h), but a
higher enantiomeric excess was recorded for minor-7: 80% ee of
(R)-1-phenylethanol. In addition, ligands 5, and minor- and
major-7 were evaluated in the asymmetric transfer hydrogen-
Scheme 1 Asymmetric transfer hydrogenation of acetophenone.
Results and discussion
Amino sulfide 5 was synthesised in five steps from amino ester
1, prepared according to literature procedures (Scheme 2).21,25
Boc-protection of 1 and reduction of the ester with LiAlH4
† Electronic supplementary information (ESI) available: NMR spectra.
See http://www.rsc.org/suppdata/ob/b2/b208907f/
‡ Biovitrum AB, Rapsgatan 7, UF4B-1, SE-751 82 Uppsala, Sweden.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
358

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Table 1 Transfer hydrogenation of acetophenone using ligands 5 and 7a
Entry
Ligandb
Time (t/h)
Conv. (%)c
Ee (%)c
Config. of product
1
2
3
5
1
1
1
95
10
52
63
55
80
R
S
R
Major-7
Minor-7
a See the Experimental section for procedure. b Substrate:metal:ligand:base = 200:1:2.5:6.25. c Determined by chiral GC.
Table 2 Transfer hydrogenation of acetophenone using formic acid as the hydrogen donora
Entry
Ligandb
Temp. (T /ЊC)
Time (t/h)
Conv. (%)c
Ee (%)c
Config. of product
1
2
3
4
5
60
Rt
6
96
100
30
15
28
R
S
5
Major-7
Minor-7
No reaction
No reaction
a See the Experimental section for procedure. b Substrate:metal:ligand = 200:1:2.5. c Determined by chiral GC.
Attempts to ring open 8 with 2-methylpropane-2-thiol were not
successful, probably due to the large degree of steric hindrance
in the thiol. However, we found that with the activated Cbz-
protected aziridine 12 in combination with BF2ؒOEt2, ring
opening was possible with 2-methylpropane-2-thiol (Scheme 4).
The resulting amino sulfide 10d was resolved into the pure
enantiomers by chiral HPLC and thereafter deprotected
yielding 11d.
Racemic 9a and 9c was benzylated via reductive amination
yielding compounds with a secondary amine functionality
(Scheme 5). The two enantiomers of the resulting compounds
14 and 15 were separated by chiral HPLC. Alkylation with an
isopropyl group was done using enantiomerically pure 11a since
the enantiomers of product 13 did not separate on chiral HPLC
(Scheme 5). Attempts to monooxidise sulfide 14 in the same
manner as for the bicyclic compound were also made but it was
not possible to purify or characterise satisfactorily the oxidised
product.
Faster access to N-benzylamino sulfides such as 14 and 15
was obtained using aziridine 16, derived from cyclohexene
oxide and benzylamine (Scheme 6).30–32 This aziridine was ring
opened with four different substituted phenyl thiols resulting
in compounds 17a–d. These ligands enabled us to study sub-
stituent effects in the aryl ring.
A third chiral center in the ligand structure was introduced
via ring opening of chiral aziridine 18, derived from (S)-1-
phenylethylamine and cyclohexene oxide (Scheme 7).30,31 A 3:1
mixture of diastereomers was obtained when 18 was ring
opened with toluene-α-thiol (major-19 and minor-19, ratio
determined by NMR analysis), which could be separated by
flash chromatography.
The effect of a smaller ring in the ligand backbone was
studied using compound 22 (Scheme 8). Aziridine 20, syn-
thesised according to a literature procedure,29 was ring opened
with toluene-α-thiol, N-benzylated and separated into the pure
enantiomers in the same manner as for 14.
Compounds 11a,b,d,13, 14, 15, 17a–d, major-19, minor-19
and 22 were evaluated in the transfer hydrogenation reaction
and the results are shown in Table 3. Primary amine 11a gave
Scheme 3 (i) NaIO4, MeOH–H2O, 0 ЊC to rt; (ii) TFA, CH2Cl2, rt, 2 h.
ation of acetophenone using formic acid as the hydrogen donor
(Table 2).
Using ligand 5, full conversion was reached after 6 h at 60 ЊC
and the enantiomeric excess of the (R)-product was 15%. At
room temperature the reaction was very slow, 30% conversion
after 96 h, but interestingly this led to a reversal of the stereo-
selectivity and the (S)-product was obtained in 28% ee. With
ligands minor- and major-7 there was no reaction at all.
To obtain ligands prepared according to a shorter synthetic
protocol with more possibilities to change substituents on
nitrogen and sulfur, a class of cyclohexylamino sulfides was
prepared. Aziridine 8, derived from cyclohexene oxide served as
the starting point for these new ligands (Scheme 4).27–29
Ring opening of 8 with sulfur nucleophiles yielded racemic
9a–c. After Cbz-protection of these primary amines, the
enantiomers could be separated by chiral HPLC. Deprotection
of the Cbz-group using 6 M HCl was performed in clean reac-
tions yielding enantiomerically pure amino sulfides 11a,b.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
359

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Scheme 4 (i) RSH, MeOH, reflux, 7 h; (ii) CbzCl, Et3N, Et2O, 0 ЊC, 2 h and then separation on chiral HPLC; (iii) 6 M HCl, reflux, over night; (iv)
CbzCl, Et3N, Et2O, 0 ЊC, 1.5 h; (v) t-BuSH, BF3ؒOEt2, CH2Cl2, 0 ЊC 3 h, rt overnight and then separation on chiral HPLC; (vi) Pd–C, NH4ϩCOOϪ,
MeOH, rt 1 h.
Scheme 8 (i) BnSH, MeOH, reflux, 6 h; (ii) benzaldehyde, MgSO4,
EtOH, rt, 4 h and then NaBH4, EtOH, rt, overnight, separation on
chiral HPLC.
sulfur, 11b and d, showed a decrease in both activity and selec-
tivity of the catalyst (entries 2 and 3). Amino sulfides 13 and 14,
with a secondary amine, both gave a higher enantiomeric excess
than the corresponding primary amine 11a, 63 and 70% ee,
respectively (entries 4 and 5). For 14 the same rate as for the
primary amine 11a was recorded (approximately full conversion
Scheme
5
(i) Acetone, NaCNBH3, MeOH, rt overnight; (ii)
in 0.5 h, entry 5). Ligand 15 afforded a low ee (33%, entry 6)
probably due to too much steric bulk around the sulfur. The
results obtained with the aryl substituted analogues 17a–d,
(entries 7–10) showed that electron-donating aryl substituents
gives a slight increase in the enantiomeric excess (cf. entries 6–9)
whilst an electron-withdrawing group lowered the enantiomeric
excess (cf. entries 6 and 10). The introduction of steric bulk into
the aryl ring close to the metal centre did not effect the selec-
tivity much (cf. entries 6 and 7). Ligands major- and minor-19
(entries 11 and 12), differed significantly in rate, 94 and 20%
conversion, respectively, in 1 h, even though both of them gave
very low enantiomeric excesses. A one-carbon decrease in ring
size (ligand 22, entry 13) was not beneficial either (38% ee); one
reason might be the change in dihedral angle between the
heteroatoms.
benzaldehyde, NaCNBH3, MeOH, rt overnight and then separation on
chiral HPLC; (iii) benzaldehyde, MgSO4, EtOH, rt 4 h and then
NaBH4, rt overnight and then separation on chiral HPLC.
Conclusions
Scheme 6 (i) RSH, MeOH, reflux overnight and then separation on
chiral HPLC.
Two new classes of nitrogen and sulfur containing ligands have
been synthesised and evaluated in the asymmetric transfer
hydrogenation of acetophenone. Bicyclic sulfoxide minor-7
gave rise to a catalyst of good selectivity, 80% ee. A synthetic
protocol for rapid access to a number of monocyclic ligands,
open to different structural modifications, was also developed.
Dibenzyl ligand 14 afforded the most efficient catalyst in this
study, 98% conversion in 0.5 h using a substrate:catalyst ratio of
200:1.
Experimental
Scheme 7 (i) BnSH, MeOH, reflux 7 h.
General
rise to a more efficient catalyst than the bicyclic ligands 5 and
minor-7 (97% conversion in 0.5 h), but which was less selective,
59% ee. The primary amines with more bulky substituents on
All reactions were run under argon or nitrogen using dry glass-
ware and magnetic stirring. THF and Et2O were freshly distilled
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
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Table 3 Transfer hydrogenation of acetophenone using ligands 11a,b,d, 13, 14, 15, 17a–d, major-19, minor-19 and 22a
Entry
Ligandb, c
Time (t/h)
Conv. (%)d
Ee (%)d
Config. of product
1
2
3
4
5
6
7
8
9
10
11
12
13
11a
0.5
2.5
1
97
100
41
96
98
79
80
91
92
59
94
20
89
59
16
28
63
70
33
35
35
44
29
24
32
38
S
S
S
S
S
S
S
S
S
S
R
S
S
11b
11d
13
1
14
0.5
0.5
1
1
1
1
1
1
1
15
17a
17b
17c
17d
Major-19
Minor-19
22
a See the Experimental section for procedure. b Substrate:metal:ligand:base = 200:1:2.5:6.25. c For ligands prepared as racemates and then separated
into pure enantiomers by chiral HPLC, the enantiomer first eluted from the column was used. d Determined by chiral GC.
under nitrogen from a deep-blue solution of sodium–benzo-
phenone ketyl just prior to use. CH2Cl2 and i-PrOH were
freshly distilled under nitrogen from powdered CaH2 just
prior to use. Flash chromatography was performed using
Matrex silica gel 60 Å (37–70 µm). Analytical TLC was carried
out utilising 0.25 mm precoated plates from Merck, silica gel
60 UV254, and spots were visualised by use of UV light and
mixture (3 ml) was added and the reaction was stirred at the
indicated temperature and time in an open-air vessel. The
reaction was quenched by the addition of water (10 ml) and
extracted with diethyl ether (3 × 4 ml). The combined organic
fractions were dried (MgSO4) and evaporated in vacuo. The
resulting red oil was analysed as described above.
1
(1S,3R,4R)-2-Azabicyclo[2.2.1]heptane-3-carboxylic acid
methyl ester 1
ethanolic phosphomolybdic acid followed by heating. H and
13C NMR spectra were recorded on a Varian Gemini 200 or a
Varian Unity 400 spectrometer at ambient temperature for
CDCl3 solutions. Chemical shifts for protons are reported
using the residual CHCl3 as internal reference (δ 7.26). Carbon
signals are referenced to the shift from the 13C signal of CDCl3
(δ 77.0). Infrared spectra were recorded on a Perkin-Elmer 1760
FT-IR spectrometer. Optical rotations were measured using a
Perkin-Elmer 241 polarimeter. Mass spectra were recorded using
a Finnigan MAT GCQ PLUS system (EI; 70 eV) or a Varian
Saturn 2100T GC/MS (EI). GC analysis was performed using a
Varian 3400 instrument equipped with a CP-Chirasil-Dex CB
column with N2 as the carrier gas at 15 psi and a FID detector.
Preparative separations were performed using a Gilson HPLC
with a Chiralcel OD column (25 cm/2 cm id) and UV detector.
Elementary analysis was performed by Mikro Kemi AB and
Analytiche Laboratorien AG. For some of the compounds it
This compound was prepared according to literature pro-
cedures via an aza-Diels–Alder reaction25 followed by hydro-
genation and hydrogenolysis of the resulting adduct.21 Amino
ester 1 was used without further purification.
(1S,3R,4R)-3-Hydroxymethyl-2-azabicyclo[2.2.1]heptane-2-
carboxylic acid tert-butyl ester 2
To a stirred solution of (Boc)2O (9.70 g, 44.4 mmol) and Et3N
(10.9 ml, 78.2 mmol) in THF (60 ml), amino ester 1 (5.70 g, 36.7
mmol) as a solution in THF (60 ml) was added slowly over a 20
min period. The reaction mixture was stirred at rt overnight.
After evaporation of the solvent the residue was dissolved in
Et2O (50 ml) and extracted with 1 M HCl (2 × 50 ml), NaHCO3
(sat., 50 ml) and brine (50 ml). Drying (MgSO4) and evapor-
ation afforded Boc-protected 1 as a colourless oil that was
reduced without further purification. To a stirred suspension of
LAH (2.1 g, 55.1 mmol) in THF (70 ml) Boc-protected 1 (10.8
g, 36.7 mmol) as a solution in THF (45 ml) was added dropwise
at 0 ЊC. The reaction mixture was stirred at 0 ЊC for 2 h and
thereafter quenched with water (2.1 ml), 1 M NaOH (2.1 ml)
and water (6.3 ml). Filtration followed by drying (MgSO4)
gave 2 (8.04 g, 96%) as a colourless oil. [In the case of impure
product, flash chromatography could be performed (pentane–
EtOAc, 95:5 to 40:60)]. Rf 0.57 (EtOAc–pentane, 60:40);[α]2D4
ϩ71.6 (c 0.87 in CHCl3); (Found: C, 62.9; H, 9.7; N, 6.2. Calc.
for C12H21NO3: C, 63.4; H, 9.3; N, 6.2%); νmax(film)/cmϪ1 3420,
1697, 1670, 1397, 1165; δH(200 MHz) 1.24 (m, 2H), 1.45 (s, 9H),
1.65 (m, 4H), 2.28 (s, 1H), 3.45 (m, 1H), 3.56 (m, 2H), 4.08
(s, 1H), 4.46 (m, 1H); δC(50.2 MHz) 27.9, 28.4, 29.7, 35.7, 39.7,
57.9, 66.6, 67.3, 80.2, 157.4; m/z (EI) 227 (Mϩ, 1%), 68 (42), 96
(15), 112 (18), 140 (100), 196 (26).
was not possible to obtain satisfactory analysis data. 1H and 13
C
NMR spectra are included in the supplementary data.†
General procedure for transfer hydrogenation of acetophenone
To a dry 50 ml Schlenk flask under argon was added [IrCl-
(COD)]2 (0.00335 g, 0.005 mmol), ligand (0.025 mmol) and
i-PrOH (2 ml). The solution was stirred for 30 minutes at 80 ЊC
and then cooled to rt. i-PrOH (18 ml) was added, followed by
acetophenone (235 µl, 2.0 mmol) and i-PrOK (63 µl, 0.063
mmol, 1.0 M solution in i-PrOH). The reaction was stirred at
room temperature until completion and quenched by addition
of 2 drops of 1 M hydrochloric acid. Evaporation of the solvent
in vacuo and flash chromatography (Et2O–pentane) gave the
pure 1-phenylethanol. The enantiomeric excess was determined
by chiral GC analysis.
General procedure for transfer hydrogenation of acetophenone
with formic acid–triethylamine as reductant
(1S,3R,4R)-3-(4-Tolylsulfonyloxymethyl)-2-aza-
bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester 3
To a dry round-bottomed flask was added [IrCl(COD)]2
(0.00335 g, 0.005 mmol) and ligand (0.025 mmol). Aceto-
phenone (235 µl, 2 mmol) was added and the mixture was
stirred for 30 min at 60 ЊC. A 5:2 HCOOH–Et3N azeotropic
Compound 2 (8.04 g, 35.4 mmol) was dissolved in pyridine
(72 ml) and cooled to 0 ЊC. TsCl (8.82 g, 46.0 mmol) was added
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
361

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at 0 ЊC and then the reaction mixture was stirred at rt for 5 h.
CH2Cl2 (300 ml) was added and the solution was extracted
with1MHCl(4×100ml), NaHCO3 (sat., 100ml)andwater(100
ml). Purification by flash chromatography (EtOAc–pentane,
1:10 to 1:4) afforded 3 (9.94 g, 74%) as a colourless oil. Rf 0.82
(EtOAc–pentane, 60:40); [α]2D4 ϩ65.5 (c 1.11 in CHCl3); (Found:
C, 59.1; H, 7.2; N, 3.6. Calc. for C19H27NO5S: C, 59.8; H, 7.1;
N, 3.7%); νmax(film)/cmϪ1 1698, 1366, 1177; δH(200 MHz, 1:1
mixture of rotamers) 1.22 (m, 2H), 1.32 (s, 9H), 1.39 (s, 9H),
1.65 (m, 8H), 2.43 (s, 6H), 2.51 (m, 2H), 3.30 (m, 1H), 3.44 (m,
1H), 3.64 (m, 1H), 3.77 (m, 1H), 4.10 (m, 6H), 7.33 (m, 4H),
7.77 (m, 4H); δC(50.2 MHz, 1:1 mixture of rotamers) 21.6, 27.2,
28.3, 28.4, 29.6, 30.1, 33.8, 34.6, 38.6, 39.2, 56.7, 57.6, 61.5,
61.7, 68.4, 68.6, 79.8, 127.9, 129.8, 133.0, 145.2; m/z (EI) 281
(Mϩ – Boc, <1%), 53 (17), 54 (30), 65 (28), 66 (32), 67 (100), 68
(74), 77 (11), 78 (10), 79 (14), 80 (68), 81 (17), 82 (12), 94 (72),
108 (54), 112 (29), 138 (17), 153 (66).
(1S,3R,4R)-3-Benzylsulfinylmethyl-2-azabicyclo[2.2.1]heptane-
2-carboxylic acid tert-butyl ester 6
Compound 4 (0.300 g, 0.9 mmol) was dissolved in MeOH (10
ml) and cooled to 0 ЊC. NaIO4 (0.222 g, 1.04 mmol) was dis-
solved in H2O (5 ml) and added dropwise. The reaction was
stirred for one hour at 0 ЊC then the ice bath was removed and
the reaction was stirred at rt for 3.5 h. The solvent was removed
in vacuo and the residue was extracted with CH2Cl2 (3 × 5 ml).
The combined organic phases were dried (MgSO4) and the sol-
vent was evaporated. Purification of the residue by flash chro-
matography (EtOAc–MeOH, 20:0.3) afforded 6 (0.200 g, 64%)
as a 3:2 mixture of diastereomers, as pale yellow crystals. The
diastereomers were separated on an OD column [hexane–i-
PrOH, 85:15, 6 ml minϪ1, retention times 24 min (major), 33
min (minor)].
Major-6: [α]2D4 ϩ46.2 (c 1.01 in CHCl3); νmax(CDCl3)/cmϪ1
3063, 2973, 2875, 1690, 1392, 1033;δH(400 MHz, mixture of
rotamers) 1.30 (s, 9H), 1.26–1.32 (m, 1H), 1.45 (s, 9H), 1.54–
1.74 (m, 5H), 2.46–2.55 (m, 1H), 2.69–2.74 (m, 1H), 2.79–2.85
(m, 1H), 3.04–3.11 (m, 1H), 3.49–3.54 (m, 1H), 3.62–3.68 (m,
1H), 3.86–3.93 (m, 1H), 4.02–4.08 (m, 1H), 4.11–4.18 (m, 1H),
7.26–7.40 (m, 5H); δC(100.6 MHz, mixture of rotamers) 27.4
28.3, 28.5, 29.8, 30.3, 34.2, 34.9, 41.2, 42.1, 55.2, 56.6, 57.6,
58.9, 60.2, 60.6, 60.7, 128.2, 128.5, 128.7, 129.1, 129.9, 130.3;
m/z (EI) 350 (Mϩ ϩ 1, 20%), 334 (26), 294 (16), 278 (19), 250
(27), 232 (11) 202 (36), 186 (7), 154 (16), 140 (45), 91 (100),
68 (20).
(1S,3R,4R)-3-Benzylsulfanylmethyl-2-azabicyclo[2.2.1]heptane-
2-carboxylic acid tert-butyl ester 4
Toluene-α-thiol (0.882 g, 7.08 mmol) was dissolved in THF (20
ml). The solution was cooled to 0 ЊC and n-BuLi (4.42 ml, 7.08
mmol, 1.6 M in hexanes) was added dropwise via syringe. The
reaction was stirred for 10 min then more n-BuLi was added
until the solution turned deep red. The reaction was stirred for
an additional 40 min. The mixture was added to an ice-cooled
solution of 3 (1.80 g, 4.72 mmol) as a solution in THF (20 ml).
The mixture was stirred at rt overnight. The solvent was evap-
orated and the mixture was extracted with water (30 ml) and
Et2O (30 ml). The water phase was then extracted with Et2O
(2 × 30 ml) and the combined organic phases were dried
(MgSO4) and filtrated. The crude product was purified by
column chromatography (pentane–EtOAc, 10:1) to give 4 (1.00 g,
64%) as a colourless oil. [α]2D4 Ϫ67.0 (c 0.941 in CHCl3); (Found:
C, 68.6; H, 8.3; N, 4.35. Calc. for C19H27NO2S: C, 68.4; H, 8.2;
N, 4.2%); νmax(CDCl3)/cmϪ1 2973, 2873, 1693, 1391, 1175;
δH(400 MHz, 1:1 mixture of rotamers) 1.17 (m, 1H), 1.20 (m,
1H), 1.25–1.76 (m, 15H), 2.17–2.31 (m, 1H), 2.51–2.57 (m, 1H),
2.86 (dd, 1H, J = 13.4, 3.1 Hz), 2.94 (dd, 1H, J = 13.4, 3.1 Hz),
3.18–3.24 (m, 1H), 3.39–3.43 (m, 1H), 3.76 (s, 1H), 3.80 (s, 1H),
4.00–4.04 (m, 1H), 4.11–4.15 (m, 1H), 7.38–7.17 (m, 10H);
δC(100.6 MHz, 1:1 mixture of rotamers) 27.8, 28.7, 28.8, 29.9,
30.5, 34.1, 34.4, 34.8, 35.0, 37.6, 38.5, 39.9, 40.6, 57.3, 58.2,
63.8, 64.1, 79.1, 79.4, 126.8, 127.0, 128.3, 128.5, 128.7, 128.9,
138.3, 138.7, 154.9; m/z (EI) 334 (Mϩ ϩ 1, 100%), 278 (14), 234
(20), 196 (9), 140 (33), 96 (40), 91 (18), 68 (30).
Minor-6: [α]2D4 ϩ91.7 (c 0.86 in CHCl3); νmax(CDCl3)/cmϪ1
2975, 2873, 1691, 1393, 1026; δH(400 MHz, mixture of rotam-
ers) 1.23–1.32 (m, 1H), 1.37 (s, 9H), 1.46 (s, 9H), 1.54–1.64 (m,
1H), 2.32–2.38 (m, 1H), 2.53–2.57 (m, 1H), 2.68–2.74 (m, 1H),
2.89–2.98 (m, 1H), 3.62–3.66 (m, 1H), 3.68–3.73 (m, 1H), 3.98–
4.05 (m, 1H), 4.08 (m, 1H), 4.16 (m, 1H), 4.29–4.33 (m, 1H),
7.25–7.41 (m, 5H); δC(100.6 MHz, mixture of rotamers) 27.4,
28.4, 28.5, 29.6, 30.1, 34.1, 35.0, 40.8, 41.5, 54.1, 54.7, 56.8,
57.8, 57.8, 57.9, 58.6, 128.1, 128.4, 128.7, 128.9, 130.1, 130.3;
m/z (EI) 350 (Mϩ ϩ 1, 20%), 334 (26), 294 (16), 278 (19), 250
(27), 232 (11) 202 (36), 186 (7), 154 (16), 140 (45), 91 (100), 68
(20).
(1S,3R,4R)-3-Benzylsulfinylmethyl-2-azabicyclo[2.2.1]heptane:
major-7
Use of the same procedure as reported for 5 using major-6
(0.120 g, 0.36 mmol) and TFA (1.25 ml), afforded major-7
(0.0801 g, 94%) as white crystals. [α]2D4 Ϫ163.2 (c 0.95 in CHCl3);
νmax(CDCl3)/cmϪ1 3435, 2960, 2897, 1640, 1023; δH(400 MHz)
1.20–1.24 (m, 1H), 1.30–1.49 (m, 2H), 1.53–1.71 (m, 3H), 1.83
(br s, 1H), 2.24 (m, 1H), 2.43 (dd, 1H, J = 12.2, 10. 1 Hz), 2.57
(dd, 1H, J= 12.2, 3.6 Hz), 3.49 (m, 1H), 3.95 (d, 1H, J = 13.1
Hz), 3.97 (d, 1H, J = 13.1 Hz), 7.27–7.38 (m, 5H); δC(100.6
MHz) 28.7, 32.9, 34.3, 41.4, 54.9, 56.4, 58.7, 59.4, 128.2, 128.8,
130.0, 130.1; m/z (EI) 250 (Mϩ ϩ 1, 59%), 232 (15), 197 (25),
185 (15), 140 (19), 109 (74), 91 (100), 68 (94).
(1S,3R,4R)-3-Benzylsulfanylmethyl-2-azabicyclo[2.2.1]heptane
5
Compound 4 (0.820 g, 0.36 mmol) was dissolved in CH2Cl2
(16 ml) and cooled to 0 ЊC after which TFA (8.2 ml) was added
dropwise. The ice bath was removed and the reaction mixture
was stirred at rt for 2 h. The solvent and TFA were then evapor-
ated off in vacuo. The residue was dissolved in CH2Cl2 (5 ml)
and K2CO3 was added until no evolution of CO2 (g) could be
seen. The solution was filtred through Celite and extracted with
2 M HCl (10 ml), and the water phase was made basic (pH 9–
10) by addition of 2 M NaOH, and extracted with CH2Cl2
(3 × 10 ml). The combined organic phases were dried (MgSO4),
filtered through Celite and evaporated. Purification by flash
chromatography (CH2Cl2–MeOH, 100:0 to 80:20) yielded 5
(0.399 g, 70%) as a pale yellow oil. [α]2D4 Ϫ32.6 (c 0.276 in
CHCl3); νmax(CDCl3)/cmϪ1 3392, 2944, 2861, 1600, 1412; δH(400
MHz) 1.12–1.16 (m, 1H), 1.30 (m, 1H), 1.47–1.51 (m, 1H),
1.52–1.68 (m, 1H), 2.28 (m, 1H), 2.38–2.22 (m, 3H), 2.73
(m, 1H), 3.42 (m, 1H), 3.72 (s, 2H), 7.35–7.15 (m 5H); δC(100.6
MHz) 28.8, 32.6, 34.3, 36.6, 38.3, 40.5, 56.2, 60.7, 126.9, 128.4,
128.8, 138.6; m/z (EI) 234 (Mϩ ϩ 1, 15%), 223 (9), 123 12), 96
(61), 91 (51), 68 (100).
(1S,3R,4R)-3-Benzylsulfinylmethyl-2-azabicyclo[2.2.1]heptane:
minor-7
Use of the same procedure as reported for 5 using minor-6
(0.130 g, 0.39 mmol) and TFA (1.25 ml) yielded minor-7
(0.0534 g, 58%) as white crystals. [α]2D4 ϩ57.4 (c 0.35 in CHCl3);
νmax(CDCl3)/cmϪ1 3400, 3031, 2960, 2873, 1685, 1201, 1026;
δH(400 MHz) 1.27 (m, 1H), 1.47 (m, 2H), 1.49 (m, 1H), 1.63 (m,
3H), 1.8 (br s), 2.35 (m, 1H), 2.54 (dd, 1H, J = 13.1, 8.0 Hz),
2.79 (dd, 1H, J = 13.1, 6.1 Hz), 3.25–3.62 (m, 3H), 4.08 (s, 2H),
7.20–7.42 (m, 5H); δC(100.6 MHz) 28.7, 32.9, 34.3, 41.4, 54.9,
56.4, 58.7, 59.4, 128.2, 128.8, 130.0, 130.1; m/z (EI) 250 (Mϩ ϩ
1, 58%), 232 (10), 197 (25), 185 (15), 140 (19), 109 (33), 91 (100),
68 (69).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
362

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7-Azabicyclo[4.1.0]heptane 8
trans-2-Cyclohexylsulfanylcyclohexylcarbamic acid benzyl ester
10b
This compound was prepared according to literature pro-
cedures, namely, ring opening of cyclohexene oxide with
sodium azide27 and ring closure using PPh3 in MeCN.28 All
spectroscopic and physical data for 8 were in complete
agreement with those published.29
Use of the same procedure as reported for 10a using 9b (0.127
g, 0.595 mmol), benzyl chloroformate (0.089 ml, 0.625 mmol)
and Et3N (0.087 ml, 0.625 mmol) afforded 10b (0.202 g, 98%)
as white crystals. The enantiomers were separated with a pre-
parative OD column (HPLC) with hexane–i-PrOH as the
eluent (90:10, 5 ml minϪ1, retention times, respectively, 21 and
27 min.). [α]2D4 Ϫ40.0 (first peak eluted from HPLC, c 0.80 in
CHCl3); (Found: C, 69.2; H, 8.4; N, 3.8. Calc for C20H29N02S:
C, 69.1; H, 8.4; N, 4.0%); νmax(CH2Cl2)/cmϪ1 3438, 2936, 2361,
1717, 1508; δH(400 MHz) 1.14–1.44 (8H, m), 1.48–1.80 (6H, m),
1.91 (2H, m), 2.08 (1H, m), 2.22 (1H, m), 2.61 (1H, m), 2.68
(1H, m), 3.43 (1H, m), 4.92 (1H, br s), 5.11 (2H, s), 7.28–7.41
(5H, m); δC(100.6 MHz) 23.9, 25.2, 25.7, 26.1, 26.2, 32.5, 33.4,
34.3, 34.5, 42.7, 47.0, 53.9, 66.6, 128.1, 128.5, 136.7, 155.8,
128.0; m/z (EI) 347 (Mϩ, 1%), 196 (100), 115 (96), 91 (77), 81
(59).
trans-2-Benzylsulfanylcyclohexylamine 9a
To a solution of 8 (1.5 g, 15.4 mmol) in MeOH (20 ml) was
added toluene-α-thiol (2.76 ml, 2.92 g, 23.5 mmol) via syringe at
rt, and the mixture was refluxed for 7 h. The solvent was then
evaporated in vacuo and flash chromatography of the residue
(CH2Cl2–MeOH, 90:10) yielded 9a (3.30 g, 97%) as a colourless
oil. νmax(film)/cmϪ1 3360, 3027, 2928, 2360, 1601 and 1447;
δH(400 MHz) 1.02–1.35 (m, 3H), 1.38–1.52 (m, 1H), 1.58 (br s,
2H), 1.64–1.74 (m, 2H), 1.90–2.09 (m, 2H), 2.15–2.25 (m, 1 H),
2.47–2.55 (m, 1H), 3.76 (s, 1H), 3.77 (s, 1H) and 7.22–7.39 (m,
5H); δC(100.6 MHz) 24.9, 26.4, 33.4, 34.6, 35.5, 53.7, 53.8,
126.8, 128.3, 128.6 and 138.7; m/z (EI) 221 (Mϩ, <1%), 204 (30),
123 (40), 113 (65), 91 (74) and 79 (100).
trans-(2-tert-Butylsulfanyl)cyclohexylcarbamic acid benzyl ester
10d
To 12 (2.4 g, 10.3 mmol) in CH2Cl2 under N2 at 0 ЊC was added
2-methylpropane-2-thiol (1.22 ml, 10.8 mmol) followed by the
dropwise addition of boron trifluoride–diethyl ether (1.37 ml,
10.8 mmol) in CH2Cl2 (5 ml) via syringe. The reaction was
stirred at 0 ЊC for 3 h and was then allowed to reach rt and
stirred at this temperature overnight. The mixture was extracted
with NaHCO3 (sat.) and brine, and the organic phase was dried
(MgSO4) and evaporated in vacuo. This crude product was
purified by flash chromatography (EtOAc–pentane, 1:9) to
yield 10d (2.25 g, 68%) as a white solid. The enantiomers were
separated with a preparative OD column (HPLC) with hexane–
i-PrOH as the eluent (85:15, 6 ml minϪ1, retention times,
respectively, 15 and 22 min). [α]2D0 Ϫ16.8 (first peak eluted from
HPLC, c 3.2 in CH2Cl2); (Found: C, 67.1; H, 8.5; N, 4.4. Calc.
for C18H27NO5S: C, 67.3; H, 8.5; N, 4.4%); νmax(KBr)/cmϪ1
3345, 2935, 1691, 1545; δH(400 MHz) 1.32 (s, 9H), 1.33–1.44
(m, 3H), 1.51–1.63 (m, 3H), 2.04–2.17 (m, 2H), 2.62–2.66
(m, 1H), 3.44–3.50 (m, 1H), 4.92 (br s, 1H), 5.11 (s, 2H),
7.28–7.34 (m, 5H); δC(100.6 MHz) 23.1, 24.4, 31.0, 31.4, 34.0,
43.4, 45.0, 53.6, 66.6, 128.0, 128.1, 128.5, 136.6, and 155.9;
m/z (EI) 321 (Mϩ, <1%), 170 (56), 114 (100), 91 (85).
trans-2-Cyclohexylsulfanylcyclohexylamine 9b
Use of the same procedure as reported for 9a using 8 (0.250 g,
2.57 mmol) and cyclohexanethiol (0.47 ml, 3.86 mmol) yielded
9b in quantitative yield as a colourless oil. (Found: C, 67.35;
H, 11.0; N, 6.7. Calc. for C12H23NS: C, 67.5; H, 10.9; N, 6.6%);
νmax(Et2O)/cmϪ1 2977, 2932, 2861, 1383, 1124; δH(400 MHz)
2.71 (m, 1H), 2.48 (dt, 1H, J = 4.0, 10.5 Hz), 2.27 (ddd, 1H,
J = 4.0, 10.1, 11.9 Hz), 2.07 (m, 1H), 1.97 (m, 3H), 1.81–1.52
(m, 8H), 1.45–1.06 (m, 8H); δC(100.6 MHz) 54.4, 52.6, 43.2,
35.6, 35.1, 34.8, 34.5, 26.7, 26.2, 26.2, 25.7, 25.1; m/z (EI) 214
(Mϩ ϩ 1, 14%), 197 (16), 131 (50), 114 (27), 82 (100).
trans-2-Phenylsulfanylcyclohexylamine 9c
Use of the same procedure as reported for 9a using 8 (0.490 g,
5.04 mmol) and thiophenol (0.62 ml, 6.05 mmol) yielded 9c in
quantitative yield as a colourless oil. (Found: C, 69.0; H, 8.2; N,
6.4. Calc. for C12H17NS: C, 69.5; H, 8.3; N, 6.8%); νmax(film)/
cmϪ1 3365, 3056, 2931, 2854; δH(400 MHz) 1.12–1.43 (m, 4H),
1.60–1.79 (m, 4H), 1.93–2.18 (m, 2H), 2.57 (dt, 1H, J = 4.05,
10.1 Hz), 2.64 (m, 1H), 7.18–7.34 (m, 3H), 7.38–7.56 (m, 2H);
δC(100.6 MHz) 24.9, 26.4, 33.5, 35.6, 54.0, 57.1, 127.2, 128.8,
133.1, 134.0; m/z (EI) 207 (Mϩ, 44%), 135 (26), 109 (28), 98
(100), 56 (70).
trans-2-Benzylsulfanylcyclohexylamine 11a
To enantiomerically pure 10a (0.200 g, 0.564 mmol) was added
HCl (aq., 6 M, 10 ml) and the solution was refluxed overnight.
The reaction was cooled to 0 ЊC, after which CH2Cl2 (10 ml)
was added, the organic phase was made basic by addition of
NaOH (aq., 2 M) and the phases were separated. The aqueous
phase was extracted with CH2Cl2 (10 ml) and the combined
organic phases were washed with brine (10 ml). Drying
(MgSO4), evaporation of the solvent and flash chromatography
(CH2Cl2–MeOH, 100:0 to 70:30) afforded 11a (0.115 g, 92%) as
a colourless oil. [α]2D0 Ϫ70.8 (first peak eluted from HPLC, c 2.2
in CH2Cl2). For full characterisation see 9a.
trans-2-Benzylsulfanylcyclohexylcarbamic acid benzyl ester 10a
To 9a (0.615 g, 2.76 mmol) and Et3N (0.41 ml, 2.93 mmol) in
Et2O (7 ml) was added dropwise benzyl chloroformate (0.37 ml,
2.47 mmol) in Et2O (1.5 ml) at 0 ЊC. The reaction mixture was
stirred for 1.5 h, after which it was extracted with saturated
NaHCO3 (aq.) and brine. The organic phase was dried
(MgSO4) and evaporated in vacuo and the crude product
obtained was purified by flash chromatography (pentane–
EtOAc, 4:1) to give racemic 10a (0.405 g, 65%) as a white solid.
The enantiomers were separated with a preparative OD column
trans-2-Cyclohexylsulfanylcyclohexylamine 11b
(HPLC) with hexane–i-PrOH as the eluent (85:15, 6 ml minϪ1
,
By following the same procedure as reported for 11a compound
11b was obtained as a colourless oil in 90% yield. [α]2D0 Ϫ76.7
(first peak eluted from HPLC, c 2.1 in CH2Cl2). For full
characterisation see 9b.
retention times, respectively, 15 and 23 min). [α]2D0 Ϫ63.4 (first
peak eluted from HPLC, c 3.5 in CH2Cl2); νmax(KBr)/cmϪ1 3321,
2931, 2359, 1683 and 1539; δH(400 MHz) 1.16–1.21 (m, 2H),
1.22–1.38 (m, 1H), 1.51–1.55 (m, 1H), 1.63–1.72 (m, 2H),
2.08–2.20 (m, 2H), 2.37–2.43 (ddd, J = 10.4, 10.4, 4.0 Hz, 1H),
3.47–3.73 (m, 1H), 3.72 (s, 1H), 3.73 (s, 1H), 4.73 (br s, 1H),
5.11 (s, 2H) and 7.19–7.39 (m, 10H); δC(100.6 mHz) 24.3, 25.4,
32.8, 33.1, 34.4, 48.4, 53.3, 66.5, 126.9, 127.9, 128.0, 128.4,
128.8, 136.6, 138.3 and 155.8; m/z (EI) 354 (Mϩ, <1%), 310
(100), 197 (54), 196, (57), 186 (38) and 106 (75).
trans-2-(tert-Butylsulfanyl)cyclohexylamine 11d
To a suspension of Pd–C (10%, 0.100 g) in MeOH (2 ml) was
added ammonium formate (0.155 g, 2.46 mmol) and 10d (0.250
g, 0.778 mmol) in MeOH (2 ml) via syringe. The mixture was
stirred at rt for 1 h and then filtered through Celite. The product
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
363

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was extracted using CH2Cl2–brine and the organic phase was
the dried (MgSO4) and evaporated to give 11d (0.134 g, 92%) as
a colourless oil. [α]2D0 Ϫ66.8 (c 1.87 in CH2Cl2); νmax(film)/cmϪ1
3364, 2926, 1579, 1447;δH(400 MHz) 1.11–1.24 (m, 1H),
1.24–1.31 (m, 4H), 1.34 (s, 9H), 1.39–1.67 (m, 1H), 1.66 (br s,
2H), 1.65–1.73 (m, 2H), 1.97–2.03 (m, 1H), 2.07–2.13 (m, 1H),
2.16–2.26 (m, 1H), 2.35.2.42 (m, 1H); δC(100.6 MHz) 25.1, 26.9,
31.8, 35.5, 37.1, 43.2, 51.2, 54.0; m/z (EI) 187 (Mϩ, 50%), 130
(100), 113 (51), 79 (56).
2.21 (m, 1H), 2.45 (m, 1H), 2.88 (br s, 1H), 2.96 (ddd, 1H, J =
4.0, 10.0, 11.3 Hz), 3.74 (d, 1H, J = 13.1 Hz), 3.94 (d, 1H, J =
13.1 Hz), 7.22–7.30 (m, 4H), 7.31–7.40 (m, 6H); δC(100.6 MHz)
24.3, 26.2, 32.0, 33.4, 50.8, 53.5, 59.0, 126.9, 127.2, 128.1, 128.4,
128.7, 133.2, 133.6, 140.2; m/z (EI) 298 (Mϩ ϩ 1, 4%), 188 (9),
146 (25), 106 (100), 91 (84).
7-Benzyl-7-azabicyclo[4.1.0]heptane 16
Ring opening of cyclohexene oxide with benzylamine was per-
formed according to a literature procedure30 and ring closure of
the resulting amino alcohol yielding 16 was done according to a
slightly modified literature procedure31 where DEAD replaced
DIAD, which was used in the reference. All spectroscopic and
physical data for 16 were in complete agreement with those
published.32
7-Azabicyclo[4.1.0]heptane-7-carboxylic acid benzyl ester 12
To 8 (0.200 g, 2.06 mmol) and Et3N (0.35 ml, 2.47 mmol) in
Et2O (7 ml) was added dropwise benzyl chloroformate (0.37 ml,
2.47 mmol) in Et2O (1.5 ml) at 0 ЊC. After being stirred for 1.5 h,
the reaction mixture was extracted with saturated NaHCO3
(aq.) and brine. The organic phase was dried (MgSO4) and
evaporated in vacuo and the crude product obtained was
purified by flash chromatography (pentane–EtOAc, 4:1) to give
12 (0.405 g, 85%) as a colourless oil. νmax(film)/cmϪ1 3032,
2937, 1718, 1440, 1219; δH(400 MHz) 1.21–1.25 (m, 2H),
1.37–1.41(m, 2H), 1.78–1.81 (m, 2H), 1.90–1.97 (m, 2H), 2.65
(dd, J = 3.2, 1.6 Hz, 2H), 5.11 (s, 2H), 7.31–7.39 (m, 5H);
δC(100.6 MHz) 19.7, 23.6, 37.0, 67.7, 128.0, 128.1, 128.3, 128.5,
163.2; m/z (EI) 231 (Mϩ, 1%), 91 (100), 69 (9) and 65 (18).
trans-N-Benzyl-2-(2-methylphenylsulfanyl)cyclohexylamine 17a
Compound 16 (0.100 g, 0.53 mmol) was dissolved in MeOH
(5 ml) and o-thiocresol (0.073 g, 0.58 mmol) was added. The
solution was refluxed overnight and then cooled to rt after
which the solvent was evaporated off. Purification of the
residue by flash chromatography (silica, Et2O–pentane 10:90)
afforded 17a (0.080 g, 49%) as a colourless oil. The enantiomers
were separated on a chiral OD columm (HPLC) using hexane–
i-PrOH as the eluent (90:10, 6 ml minϪ1, retention times 15 and
19 min, respectively). [α]3D0 ϩ65.5 (second peak eluted from
HPLC, c 1.00 in CHCl3); νmax(CDCl3)/cmϪ1 3436, 3061, 2931,
2855, 1642, 1455; δH(400 MHz) 1.25 (m, 3H), 1.42 (m, 1H), 1.70
(m, 2H), 2.06 (m, 1H), 2.20 (m, 1H), 2.41 (s, 3H), 2.54 (m, 1H),
3.02 (m, 1H), 3.74 (d, 1H, J = 13.4 Hz), 3.92 (d, 1H, J = 13.4
Hz), 7.07–7.19 (m, 3H), 7.25 (m, 1H), 7.33 (m, 5H); δC(100.6
MHz) 21.1, 24.3, 26.1, 32.1, 33.3, 51.0, 53.2, 59.6, 126.3, 126.8,
126.9, 128.1, 128.4, 130.3, 132.4, 140.0, 140.5; m/z (EI) 313
(Mϩ ϩ 1, 9%), 312 (36), 204 (21), 188 (26), 187(17), 147 (14),
146 (33), 107 (87), 106 (100), 92 (90), 91 (69), 79 (16).
trans-N-Isopropyl-2-benzylsulfanylcyclohexylamine 13
To a suspension of NaCNBH3 (0.034 g) in MeOH (0.5 ml) was
added via syringe acetone (0.071 g, 1.08 mmol) followed by 11a
(0.119 g, 0.54 mmol), in MeOH (0.5 ml) at rt and the mixture
was stirred overnight. The reaction was quenched by the addi-
tion of water (0.6 ml) and 10% NaOH (aq., 0.6 ml). Extraction
with CH2Cl2 (3 × 1 ml), drying (MgSO4) and evaporation in
vacuo yielded 13 (0.102 g, 72%) as a colourless oil that was
purified by flash chromatography (CH2Cl2–MeOH, 90:10). [α]2D0
Ϫ81.3 (c 2.6 in CH2Cl2); νmax(film)/cmϪ1 3028, 2854, 2360, 1452,
1170; δH(400 MHz) 1.01 (d, 3H, J = 6 Hz), 1.05 (d, 3H, J = 6
Hz), 1.02–1.14 (m, 1H), 1.20–1.29 (m, 2H), 1.48–1.53 (m, 1H),
1.65–1.71 (m, 2H), 1.77 (s, 1H), 2.03–2.11 (m, 2H), 2.38–2.49
(m, 2H), 2.81–2.87 (m, 1H), 3.74 (s, 1H), 3.75 (s, 1H), 7.20–7.34
(m, 5H); δC(100.6 MHz) 22.4, 24.4, 24.6, 26.12, 33.2, 33.5,
34.6, 45.7, 50.7, 57.1, 126.9, 128.4, 128.7, 138.6; m/z (EI) 263
(Mϩ, 92%), 172 (54), 113 (43), 91 (17), 79 (32), 58 (100).
trans-N-Benzyl-2-(4-methylphenylsulfanyl)cyclohexylamine 17b
The same procedure as reported for 17a was followed, using 16
(0.100 g, 0.53 mmol) and 4-methylbenzenethiol (0.073 g, 0.58
mmol), to afford 17b (0.073 g, 44%) as a colourless oil. The
enantiomers were separated on a chiral OD column (HPLC)
using hexane–i-PrOH as the eluent (90:10, 6 ml minϪ1, retention
times 15 and 20 min). [α]3D0 ϩ154.2 (second peak eluted from
HPLC, c 0.54 in CHCl3); νmax(CDCl3)/cmϪ13412, 3025, 2931,
2855, 1601, 1493, 1452; δH(400 MHz) 1.11–1.40 (m, 4 H), 1.69
(m, 2H), 2.05 (m, 1H), 2.20 (m, 1H), 2.32 (s, 3H), 2.40 (m, 1H)
2.84 (m 1H), 3.72 (d, 1H, J = 13.3 Hz), 3.94 (d, 1H, J = 13.3 Hz),
7.06 (m, 2H), 7.26 (m, 3H), 7.34 (m, 4H); δC(100.6 MHz) 21.1,
24.4, 26.3, 32.1, 33.4, 50.9, 53.9, 58.9, 126.8, 128.2, 128.4, 129.5,
134.0, 137.5, 138.3, 140.5; m/z (EI) 313 (Mϩ ϩ 1, 5%), 312 (18),
205 (7), 188 (24), 187 (11), 146 (25), 107 (83), 106 (100), 91 (75),
79 (17).
trans-N-Benzyl-2-benzylsulfanylcyclohexylamine 14
By following the same procedure as reported for 13 compound
14 (76%) was obtained as a colourless oil. [α]2D0 Ϫ82.2 (first peak
eluted from HPLC, c 3.1 in CH2Cl2); νmax(film)/cmϪ1 3026, 2929,
2360, 1453; δH(400 MHz) 1.16–1.27 (m, 3H), 1.45–1.51 (m, 1H),
1.67–1.74 (m, 2H), 2.03 (s, 1H), 2.02–2.07 (m, 1H), 2.10–2.18
(m, 1H), 2.33–2.40 (m, 1H), 2.50–2.58 (ddd, 1H, J = 11.6, 11.6,
4.0 Hz), 3.59 (d, 1H, J = 13.2 Hz), 3.67 (s, 2H), 3.86 (d, 1H,
J = 13.2 Hz), 7.20–7.35 (m, 10H); δC(100.6 MHz) 24.4, 26.2,
31.5, 33.5, 34.3, 50.0, 50.3, 58.4, 126.9, 127.0, 128.0, 128.8,
129.0, 138.6, 139.7; m/z (EI) 312 (Mϩ, 13%), 220 (22), 106 (100),
91 (54).
trans-N-Benzyl-2-(4-methoxyphenylsulfanyl)cyclohexylamine
17c
The same procedure as reported for 17a was followed, using 16
(0.100 g, 0.53 mmol) and 4-methoxybenzenethiol (0.081 g, 0.58
mmol) to afford 17c (0.075 g, 43%) as a colourless oil. The
enantiomers were separated on a chiral OD column (HPLC)
using hexane–i-PrOH as the eluent (90:10, 6 ml minϪ1, retention
times 24 and 25 min). [α]3D0 ϩ116.1 (second peak eluted from
HPLC, c 1.00 in CHCl3,); νmax(CDCl3)/cmϪ1 3420, 3026, 2931,
2855, 1592, 1494, 1461, 1285; δH(400 MHz) 1.10–1.41 (m, 4H),
1.69 (m, 2H), 2.04 (m, 1H), 2.20 (m, 1H), 2.36 (m, 1H), 2.64
(br s, 1H), 2.74 (m, 1H), 3.75 (d, 1H, J = 13.0 Hz), 3.78 (s, 3H),
2.93 (d, 1H, J = 13.0 Hz), 6.78 (m, 2H), 7.28 (m, 3H), 7.36
(m, 4H); δC(100.6 MHz) 24.4, 26.3, 32.0, 33.2, 50.8, 54.2, 55.2,
trans-N-Benzyl-2-phenylsulfanylcyclohexylamine 15
The same procedure as reported for 22 (below) was followed
using 9c (1.05 g, 5.06 mmol), benzaldehyde (0.51 ml, 5.06
mmol) and NaBH4 (0.37 g, 9.88 mmol) to afford 15 (0.827 g,
55%) as a colourless oil. The enantiomers were separated with a
preparative OD column (HPLC) with hexane–i-PrOH as the
eluent (90:10, 5 ml minϪ1, retention times 19 and 35 min). [α]2D7
Ϫ111 (first peak eluted from HPLC, c 0.98 in CHCl3); (Found:
C, 76.4; H, 7.8; N, 4.5. Calc. for C19H23NS: C, 76.7; H, 7.8; N,
4.7%); νmax(CDCl3)/cmϪ1 3292, 3065, 3022, 2934, 2858, 2246;
δH(400 MHz) 1.17–1.48 (m, 4H), 1.71 (m, 2H), 2.09 (m, 1H),
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
364

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58.5, 114.2, 122.9, 126.8, 128.2, 128.4, 136.5, 140.5, 159.6; m/z
(EI) 329 (Mϩ ϩ 1, 7%), 328 (31), 327 (17), 221 (14), 188 (33),
187 (9), 147 (13), 146 (21), 107 (100), 106 (87), 92 (83), 91 (53),
79 (12).
Purification of the residue by flash chromatography (CH2Cl2–
MeOH 100:0 to 90:10) afforded racemic 21 (0.530 g, 24%) as a
yellow oil. νmax(CDCl3)/cmϪ1 3359, 3061, 3027, 2953, 2865,
2344, 2359, 1601, 1495, 1453; δH(400 MHz) 1.33 (m, 1H), 1.45
(br s, 2H), 1.62 (m, 3H), 2.25 (m, 2H), 2.53 (ddd, 1H, J = 7.6,
6.7, 0.4 Hz), 3.04 (ddd, 1H, J = 7.4, 6.9, 0.4 Hz), 3.72–3.76
(d, 1H, J = 13.4 Hz), 3.77–3.82 (d, 1H, J = 13.4 Hz), 7.20–7.36
(m, 5H); δC(100.6 MHz) 21.8, 32.5, 34.1, 36.0, 53.1, 58.8, 126.9,
128.4, 128.7, 138.7; m/z (EI) 208 (Mϩ ϩ 1, 100%), 191 (8), 150
(12), 115 (37).
trans-N-Benzyl-2-(4-nitrophenylsulfanyl)cyclohexylamine 17d
The same procedure as reported for 17a was followed, using 16
(0.100 g, 0.53 mmol) and 4-nitrobenzenethiol (0.081 g, 0.58
mmol) to afford 17d (0.080 g, 46%) as yellow crystals. The
enantiomers were separated on a chiral OD column (HPLC)
using hexane–i-PrOH as the eluent (70:30, 6 ml minϪ1, retention
times 30 and 35 min). [α]3D0 Ϫ2.6 (first peak eluted from HPLC,
c 1.00 in CHCl3); νmax(CDCl3)/cmϪ1 3436, 2929, 2847, 1640;
δH(400 MHz) 1.10–1.60 (m, 5H), 1.65–1.82 (m, 2H), 2.12–2.29
(m, 3H), 2.57 (m, 1H), 3.25 (m, 1H), 3.78 (d, 1H, J = 13.1 Hz),
3.95 (d, 1H, J = 13.1 Hz), 7.20–7.50 (m, 7H), 8.05 (m, 2H);
δC(100.6 MHz) 24.1, 25.9, 31.9, 33.0, 50.9, 52.5, 59.0, 123.8,
125.8, 127.1, 128.0, 128.5, 128.7, 129.0, 146.1; m/z (EI) 343
(Mϩ ϩ 1, 17%), 239 (51), 149 (25), 146 (16), 106 (100), 91 (77).
trans-N-Benzyl-2-benzylsulfanylcyclopentylamine 22
Compound 21 (0.300 g, 1.40 mmol) was dissolved in EtOH (10
ml), MgSO4 was added and the mixture was cooled to 0 ЊC.
Benzaldehyde (0.153 g, 1.40 mmol) was added via syringe and
the reaction mixture was stirred at rt for 4 h. NaBH4 (0.106,
2.80 mmol) was added and the reaction mixture was stirred at
rt overnight. The solvent was evaporated off and the crude
product was extracted with CH2Cl2 and brine (3 × 10 ml). The
combined organic phases were dried (MgSO4) and evaporation
of the solvent afforded 22 (0.300 g, 72%) as a yellow oil. The
enantiomers were separated on a chiral OD (HPLC) column
using hexane–i-PrOH as the eluent (90:10, 6 ml minϪ1, retention
times 15 and 17 min). [α]2D3 Ϫ44.6 (first peak eluted from HPLC,
c 0.87 in CHCl3); νmax(CDCl3)/cmϪ1 3401, 3084, 3061, 3027,
2952, 1495, 1453; δH(400 MHz) 1.36–1.46 (m, 1H)1.54–1.73
(m, 3H), 1.75 (br s, 1H), 1.95–2.13 (m, 2H), 2.78 (ddd, 1H,
J = 0.4, 6.7, 7.9 Hz), 2.93 (ddd, 1H, J = 0.4, 6.5, 6.8 Hz), 3.67
(d, 1H, J = 13.2 Hz), 3.74 (d, 1H, J = 2.7 Hz), 3.75–3.80 (d, 1H,
J = 13.2 Hz), 7.19–7.39 (m, 10H); δC(100.6 MHz) 22.5, 32.0,
32.6, 36.0, 49.9, 52.5, 64.3, 124.4,33 126.4, 128.1, 128.3, 128.4,
128.7, 138.7, 140.2; m/z (EI) 298 (Mϩ ϩ 1, 100%), 207 (45), 191
(10), 174 (20), 146 (12), 106 (30), 91 (70), 65 (9).
7-[(S )-1-Phenylethyl]-7-azabicyclo[4.1.0]heptane 18
Ring opening of cyclohexene oxide with (S)-1-phenylethyl-
amine was performed according to a literature procedure30 and
ring closure of the resulting amino alcohol yielding 18 was done
according to a slightly modified literature procedure31 where
DEAD replaced DIAD, which was used in the reference.
Spectroscopic and physical data for 18 were in complete agree-
ment with those published.30
trans-N-[(S )-1-Phenylethyl]-2-benzylsulfanylcyclohexylamine
19
Compound 18 (0.480 g, 2.38 mmol) was dissolved in MeOH (20
ml) and BnSH (0.340 ml, 2.86 mmol) was added. The reaction
mixture was refluxed for 7 h and then cooled to rt, after which
the solvent was evaporated off. Purification of the residue by
flash chromatography (Et2O–pentane, 30:70 to 40:60) afforded
19 as a colourless oil (0.123 g of the minor isomer, 0.248 g of
the major isomer, 48%).
Acknowledgements
We would like to thank Solvias AG, Ciba Specialty Chemicals
AG, the Swedish Natural Science Research Council (NFR), the
Swedish Research Council for Engineering Science (TFR) and
the Wenner-Gren Foundation for generous financial support.
Major-19: [α]2D6 ϩ38.9 (c 1.03 in CHCl3); (Found: C, 77.3; H,
8.3; N, 4.1. Calc. for C21H27NS: C, 77.5; H, 8.4; N, 4.3%); νmax
-
(film)/cmϪ1 3308, 3061, 3027, 2928, 1494, 1451; δH(400 MHz)
0.97 (1H, m), 1.19 (2H, m), 1.33 (3H, d, J = 6.6 Hz), 1.54 (2H,
m), 1.66 (1H, m), 1.75 (1H, m), 2.08 (2H, m), 2.43 (dt, 1H, J =
4.0, 9.5 Hz), 2.52 (1H, m), 3.79 (3H, m), 7.19–7.39 (10H, m);
δC(100.6 MHz) 24.2, 24.3, 25.8, 33.1, 33.6, 34.7, 50.4, 56.9, 58.9,
126.57, 126.58, 126.9, 128.2, 128.5, 128.8, 138.8, 147.1; m/z (EI)
325 (16), 234 (95), 203 (45), 105 (100), 91 (55).
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8.4; N, 4.3. Calc. for C21H27NS: C, 77.5; H, 8.4; N, 4.3%); νmax
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(film)/cmϪ1 3308, 3061, 3027, 2928, 1494, 1451; δH(400 MHz)
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128.73, 128.74, 129.1, 138.7, 140.9; m/z (EI) 325 (13), 234 (92),
203 (44), 105 (100), 91 (54).
6-Azabicyclo[3.1.0]hexane 20
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trans-2-Benzylsulfanylcyclopentylamine 21
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
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O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 5 8 – 3 6 6
366