Novel (+)-3-carene derivatives and their application in asymmetric synthesis

Article abstract of DOI:10.1055/s-0034-1378942

A simple synthetic procedure for the preparation of mono-N-tosylated-1,2-diamines derived from (+)-3-carene is described. (+)-3-Carene is transformed into the corresponding N-tosylaziridine derivative using chloramine-T trihydrate. Subsequent ring opening with sodium azide followed by reduction of the azide function gives the optically pure mono-N-tosylated-1,2-diamine. This ligand is effective in asymmetric transfer hydrogenations of aromatic ketones. It can also be transformed into other chiral ligands by alkylation of the amino group for application in the addition of diethylzinc to benzaldehydes.

Full text of DOI:10.1055/s-0034-1378942

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 569–574
paper
569
P. Roszkowski et al.
Paper
Synthesis
Novel (+)-3-Carene Derivatives and Their Application in Asym-
metric Synthesis
Piotr Roszkowski*a
Paweł Małeckia
Jan K. Maurinb,c
H2
N
Ru
Zbigniew Czarnockia
Cl
N
NH2
3 steps
Ts
a Faculty of Chemistry, University of Warsaw, Pasteura 1,
02-093 Warsaw, Poland
NH
Ts
n
roszkowski@chem.uw.edu.pl
N
b National Medicines Institute, Chełmska 30/34,
00-725 Warsaw, Poland
n = 1, 2
NH
Ts
c National Centre for Nuclear Research, Andrzeja Sołtana 7,
05-400 Otwock-Świerk, Poland
Received: 05.08.2014
Accepted after revision: 06.11.2014
Published online: 03.12.2014
ration of amino diols5a from (+)-3-carene, and sulfonated
diamines5b from (–)-apopinene, with these terpenes serv-
ing as chiral catalysts in the addition of diethylzinc to alde-
hydes. In the same type of reaction Wills successfully used
monotosylated 1,2-diphenylethylene diamine derivatives.6
Suisse and co-workers synthesized β-amino alcohol ligands
based on α-pinene and used them in asymmetric transfer
hydrogenations of acetophenones.7 Recently, we described
a simple procedure for the transformation of limonene into
trans-1,2-diamine derivatives and demonstrated their ef-
fectiveness as ligands in asymmetric transfer hydrogena-
tions of aromatic ketones and imines.8
DOI: 10.1055/s-0034-1378942; Art ID: ss-2014-n0492-op
Abstract A simple synthetic procedure for the preparation of mono-
N-tosylated-1,2-diamines derived from (+)-3-carene is described. (+)-3-
Carene is transformed into the corresponding N-tosylaziridine deriva-
tive using chloramine-T trihydrate. Subsequent ring opening with sodi-
um azide followed by reduction of the azide function gives the optically
pure mono-N-tosylated-1,2-diamine. This ligand is effective in asym-
metric transfer hydrogenations of aromatic ketones. It can also be
transformed into other chiral ligands by alkylation of the amino group
for application in the addition of diethylzinc to benzaldehydes.
Key words asymmetric catalysis, chiral auxiliaries, hydrogen transfer,
ligands, natural products
In continuation of our interest in monoterpenes as a
source of chiral ligands, herein we present the synthesis of
new (+)-3-carene-based monotosylated diamines and their
application in asymmetric hydrogenations of acetophe-
nones and enantioselective additions of diethylzinc to
benzaldehydes.
Naturally occurring terpenes such as (+)-3-carene, (–)-
α- and (–)-β-pinene and (R)-(+)-limonene are readily avail-
able chiral reagents that are widely used in organic synthe-
sis. They may serve as the chiral core of auxiliaries or li-
gands in different stereoselective catalytic transforma-
tions,1 and as substrates for the construction of complex
chiral molecules.2 Several amino alcohols and diamines, the
structures of which are based on monoterpenes, have been
developed and employed as chiral ligands for asymmetric
transfer hydrogenations to ketones and for the enantiose-
lective addition of dialkylzinc reagents to aldehydes. Singa-
ram et al. have prepared several β-amino alcohols from lim-
onene oxide and have evaluated them as efficient catalysts
for the asymmetric addition of organometallic reagents to
aldehydes,3a,b and for the asymmetric hydrogenation of ke-
tones.3 Moreover, Palmieri et al. have developed convenient
methods for the synthesis of new diamines and amino alco-
hols based on limonene and (+)-3-carene epoxides.4 The
procedures reported by Fülöp et al. have enabled the prepa-
The synthetic route to obtain mono-N-tosylated trans-
1,2-diamine 4 is shown in Scheme 1. The starting material,
(+)-3-carene (1) was converted into cis-aziridine 2 via a di-
rect N-tosylaziridination reaction.9 Thus, treatment of
carene 1 with chloramine-T trihydrate in the presence of
phenyltrimethylammonium tribromide (PTAB) at 25 °C re-
sulted in the formation of cis-aziridine 2 in 34% yield (Table
1, entry 2). Additionally, the bromine-containing by-prod-
uct 5 was isolated in 12% yield. Increasing the reaction tem-
perature to 45 °C gave a higher 48% yield of product 2 (Table
1, entry 3), but the yield was still lower than that reported
by Sureshkumar9a (64%). Under these conditions, the bro-
mine derivative 5 was not detected. When the reaction was
carried out at 0 °C, the brominated compound 5 was isolat-
ed as the major product in 23% yield, and the aziridine was
formed in only 20% yield (Table 1, entry 1).
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P. Roszkowski et al.
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Synthesis
Ts
N
chloramine-T·3H2O
PTAB, MeCN, 45 °C
NaN3
DMF, r.t.
48%
94%
1
2
Ts
Ts
N3
NH2
NH
NH
H2, Pd/C
95%
3
4
Ts
NH
Ts
N
chloramine-T·3H2O
PTAB, MeCN
Br
+
1
2
5
Scheme 1 Synthetic pathway toward monotosylated diamine 4
Table 1 Investigation of the N-Tosylaziridination Reaction
Figure 1 The X-ray crystal structure (ORTEP) of compound 5
Entry
Temp (°C)
Time (h)
2 (%)
5 (%)
room temperature (24–25 °C), a solution of the catalyst and
a mixture of formic acid and triethylamine were added to
the ketone.
1
2
3
0
4
4
4
20
34
48
23
12
0
25
45
The absolute stereochemistry of compound 5 was deter-
mined on the basis of X-ray crystal analysis, as shown in
Figure 1.
The subsequent nucleophilic ring opening of carene N-
tosylaziridine 2 by the azide anion is a regio- and diastereo-
selective process. The reaction of 2 with sodium azide
(NaN3) occurred at the more sterically hindered tertiary
carbon atom and led to formation of the azido amine 3 (94%
yield), with inversion of the configuration at this stereogen-
ic center. The absolute configuration of compound 3 was
determined by single crystal X-ray analysis, as shown in
Figure 2. Finally, compound 3 was hydrogenated over 10%
palladium on charcoal to afford the desired monotosylated
diamine 4, almost quantitatively.
In order to evaluate diamine 4 as a potential ligand, we
chose to study a ruthenium-catalyzed asymmetric hydro-
gen transfer (ATH) protocol on a series of ketones. Two typi-
cal reduction procedures were examined. In the first meth-
od, the catalyst 6 was prepared in situ by mixing ben-
zeneruthenium(II) chloride dimer {[RuCl2(benzene)]2}with
amine 4 and triethylamine (Ru:4:Et3N molar ratio = 1:2.5:2)
in acetonitrile under argon. After stirring for 20 minutes at
Figure 2 The crystal structure (ORTEP) of compound 3
The reduction of the acetophenones was carried out at
24–25 °C and the reaction progress was monitored by TLC
(Scheme 2). Unfortunately, hydrogenation of ketones under
these conditions gave the corresponding products in low
yields and low optical purities.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 569–574

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Synthesis
OH
*
Table 2 The Asymmetric Transfer Hydrogenation of Acetophenones
Using Catalyst 6
O
Ru catalyst 6
A: HCOOH, Et3N, r.t.
B: KOH, propan-2-ol, r.t.
X
X
Y
Y
Entry
X
Y
Time
Yield (%) ee (%)c,d
see Table 2
1a
H
H
Me
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
6 d
22
5
32 (S)
36 (S)
12 (R)
23 (S)
9 (R)
H2
N
2a
H
6 d
3a
o-Cl
p-Cl
o-Br
p-Br
p-Me
p-MeO
H
6 d
9
Ru
N
4a
6 d
16
25
27
32
29
62
77
83
75
62
85
76
75
65
60
68
74
Cl
Ts
6
5a
6 d
6a
6 d
16 (S)
36 (S)
34 (S)
64 (S)
56 (S)
22 (R)
48 (S)
42 (S)
20 (R)
45 (S)
36 (S)
24 (R)
73 (S)
52 (S)
71 (S)
Scheme 2 Asymmetric transfer hydrogenation of acetophenones us-
ing catalyst 6
7a
6 d
8a
6 d
9b
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
Taking into account the unsatisfactory results, we next
conducted the reductions under alkaline conditions. In this
version, the catalyst was prepared in situ by heating
[RuCl2(benzene)]2 in the presence of amine 4 and KOH
(Ru:4:KOH molar ratio = 1:2.5:8), at 70 °C, in propan-2-ol
under argon. After stirring for 20 minutes, the catalyst solu-
tion was cooled to room temperature (24–25 °C) and the
ketone was added to the mixture. The reduction of the ace-
tophenones was carried out 24–25 °C and once again, the
reaction progress was monitored by TLC. Under these con-
ditions the reduction was much faster and gave the expect-
ed alcohols in high yields after 24 hours, however, the opti-
cal purities remained at moderate levels (Table 2). The best
results for the asymmetric hydrogenation with 6 were ob-
tained with meta-substituted acetophenones, with the
yields and enantiomeric excesses ranging from 60–76% and
45–73%, respectively. The lowest enantioselectivities were
observed for ketones containing ortho-substituents, but the
yields were higher in these cases (see Scheme 2 and Table
2).
It has already been shown that derivatives containing a
combination of a monosulfonylated amine and a tertiary
amine group can be used as efficient ligands in diethylzinc
addition reactions.5b,6 Therefore, we transformed amine 4
into compounds 7 and 8. Ligands 7 and 8 were prepared ac-
cording to the procedure described by Wills.6 As shown in
Scheme 3, reactions of amine 4 with the appropriate diio-
doalkanes gave new chiral N-alkylated derivatives in good
yields.
10b
11b
12b
13b
14b
15b
16b
17b
18b
19b
20b
H
o-Cl
m-Cl
p-Cl
o-Br
m-Br
p-Br
o-Me
m-Me
p-Me
p-MeO
a The reaction was carried out at room temperature using the ketone (2.40
mmol) in MeCN (1 mL) and a formic acid/triethylamine mixture (5:2, 1 mL);
S/C = 100.
b The reaction was carried out at room temperature using the ketone (2.40
mmol) in propan-2-ol (1 mL) and 0.1 M KOH solution in propan-2-ol (1
mL); S/C = 100.
c Determined by GC analysis using a Supelco cyclodextrin β-DEX 120 capil-
lary column (20 × 0.25 mm I.D., 0.25 μm film thickness).
d Configuration determined by the sign of the specific rotation of the isolat-
ed product.
NH2
H
N
Ts
4
1,5-diiodopentane
82%
1,4-diiodobutane
77%
K2CO3
MeCN
reflux, 15 h
Amines 7 and 8 were subsequently used as catalysts in
ethylation reactions with substituted benzaldehydes
(Scheme 4). These ligands containing tertiary amino groups
gave the expected products in high yields but with moder-
ate enantiomeric excesses. Slightly better enantioselectivi-
ties were obtained using derivative 8, which contained a
piperidine ring (Table 3).
N
H
N
H
N
N
Ts
Ts
7
8
Scheme 3 Synthesis of N-alkylated catalysts 7 and 8
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 569–574

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P. Roszkowski et al.
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Synthesis
OH
H2O (60 mL), and after separation of the layers, the aq layer was ex-
tracted with EtOAc (60 mL). The combined organic layers were
washed with brine (60 mL), dried over MgSO4 and evaporated. The
residue was purified by column chromatography on silica gel
(hexane–EtOAc, 0–4% of EtOAc) to afford aziridine 2 (48%, 4.65 g) as a
colorless oil.
[α]D23 +4.4 (c 1.0, CHCl3); the optical purity (>98% ee) was determined
by HPLC (Chiralcel OD-H, hexane–i-PrOH, 95:5, 1 mL/min); tR = 7.2
min.
O
ligand 7 or 8 (5 mol%)
X
X
20 h
H
+ Et2Zn
see Table 3
Scheme 4 The ethylation reaction of substituted benzaldehydes with
catalysts 7 and 8
Table 3 Ethylation Reactions of Benzaldehydes with Catalysts 7 and 8
IR (CH2Cl2): 3373, 3276, 2967, 2868, 1646, 1599, 1447, 1337, 1160,
Entry
Cat.
X
Yield (%)
ee (%)a,b
1093, 912, 815 cm–1
.
1
2
3
4
5
6
7
8
7
8
7
8
H
82
93
85
92
87
90
38 (R)
56 (R)
27 (R)
48 (R)
41 (R)
54 (R)
1H NMR (200 MHz, CDCl3): δ = 0.56–0.67 (m, 2 H), 0.77 (s, 3 H), 0.84–
0.87 (m, 1 H), 0.98 (s, 3 H), 1.12–1.23 (m, 1 H), 1.76 (s, 3 H), 2.04–2.32
(m, 2 H), 2.42 (s, 3 H), 3.02 (dd, J = 7.8, 3.8 Hz, 1 H), 7.29 (d, J = 8.2 Hz,
2 H), 7.77 (d, J = 8.4 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 14.8, 19.07, 19.09, 19.3, 19.4, 20.8, 21.8,
27.9, 28.6, 47.2, 51.5, 127.2, 129.6, 138.6, 143.6.
H
p-Cl
p-Cl
p-MeO
p-MeO
HRMS: m/z [M + Na]+ calcd for C17H23NO2SNa: 328.1347; found:
a Determined by GC analysis using a Supelco cyclodextrin β-DEX 120 capil-
lary column (20 m × 0.25 mm I.D., 0.25 μm film thickness).
b Configuration determined by the sign of the specific rotation of the isolat-
ed product.
328.1363.
(1R,3S,4S,6S)-N-(4-Azido-4,7,7-trimethylbicyclo[4.1.0]heptan-3-
yl)-4-methylbenzenesulfonamide (3)
To a stirred solution of aziridine 2 (3.1 g, 10.15 mmol) in DMF (150
mL) was added NaN3 (2.52 g, 40.60 mmol). The resulting suspension
was stirred at 24–25 °C for 20 h and then the solvent was evaporated
in vacuo. To the residue were added Et2O (50 mL) and H2O (25 mL),
the layers were separated and the aq layer was extracted with Et2O
(2 × 40 mL). The combined organic layers were washed with brine (20
mL), dried over MgSO4 and the solvent was evaporated in vacuo. The
oily residue was purified by column chromatography on silica gel
(hexane–EtOAc, 0–20% of EtOAc) to afford azide 3 (94%, 3.32 g) as col-
orless crystals.
In summary, we have presented a simple synthesis of
new monotosylated diamine derivatives 4, 7 and 8 starting
from the inexpensive, enantiomerically pure natural prod-
uct, (+)-3-carene. We have shown that these diamines can
be used as ligands for the asymmetric reduction of aromatic
ketones and addition reactions of diethylzinc to benzalde-
hydes.
All solvents used in the reactions were anhydrous. TLC analyses were
performed on silica gel plates (Merck Kieselgel GF254) and were made
visual using UV light or iodine vapor. Column chromatography was
carried out at atmospheric pressure using Silica Gel 60 (Merck, 230–
400 mesh) and mixtures of CHCl3–MeOH or hexane–EtOAc as eluents.
Melting points were determined on a Boetius hot-plate microscope
and are uncorrected. Optical rotations were measured on a Perkin-
Elmer 247 MC polarimeter. IR spectra were recorded using a Shimadzu
FTIR-8400S spectrometer. Optical purities were determined by HPLC
analysis using a Chiralcel OD-H column or by GC analysis using a β-
DEX 120 capillary column. NMR spectra were obtained on Varian
Unity Plus spectrometers operating at 500 MHz or 200 MHz (1H NMR)
and at 125 MHz or 50 MHz (13C NMR). The spectra were recorded in
CDCl3 and the chemical shifts are given as δ values (in ppm) relative to
TMS. Mass spectrometry was performed on Quatro LC Micromass and
LCT Micromass TOF HiRes apparatus. Single crystal X-ray measure-
ments were run on an Oxford Diffraction Excalibur R CCD κ-axis dif-
fractometer using monochromatic CuKα radiation. After initial cor-
rections and data reduction, intensities of reflections were used to
solve and consecutively refine the structures using the SHELXS97 and
SHELXL97 programs.10
23
Mp 111–113 °C; [α]D +11.9 (c 1.0, CHCl3); the optical purity (>98%
ee) was determined by HPLC (Chiralcel OD-H, hexane–i-PrOH, 90:10,
1 mL/min); tR = 12.9 min.
IR (CH2Cl2): 3377, 3283, 3064, 2948, 2867, 2106, 1652, 1340, 1163,
1083, 914, 815 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.60–0.67 (m, 2 H), 0.77–0.84 (m, 1 H),
0.90 (s, 3 H), 0.97 (m, 3 H), 1.02–1.07 (m, 1 H), 1.17 (s, 3 H), 1.78–1.83
(m, 1 H), 1.99–2.04 (m, 1 H), 2.44 (s, 3 H), 3.21–3.26 (m, 1 H), 4.85 (d,
J = 9.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.78 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 15.0, 17.5, 18.4, 21.1, 21.6, 22.6, 25.6,
28.0, 31.1, 56.7, 63.6, 127.1, 129.7, 137.4, 143.6.
HRMS: m/z [M + Na]+ calcd for C17H24N4O2SNa: 371.1518; found:
371.1506.
Monocrystals of 3 suitable for crystallographic measurements were
obtained by slow evaporation from hexane–EtOAc solution. The abso-
lute structure of the studied crystal, and hence the absolute configu-
ration of the compound was determined based on the value of the
Flack parameter.11 Since its value for the structure shown in Figure 2
was approximately 0, the molecular structure has the depicted con-
figuration. These data have been deposited with the Cambridge Crys-
tallographic Data Centre, CCDC 990398.
(1S,3R,5S,7R)-3,8,8-Trimethyl-4-(toluene-4-sulfonyl)-4-azatricyc-
lo[5.1.0.03,5]octane (2)
(1S,3R,4R,6R)-N-(4-Bromo-3,7,7-trimethylbicyclo[4.1.0]heptan-3-
yl)-4-methylbenzenesulfonamide (5)
To a stirred suspension of (+)-3-carene (4.32 g, 31.71 mmol) and chlo-
ramine-T trihydrate (TsNClNa·3H2O) (9.82 g, 34.88 mmol) in MeCN
(120 mL) was added phenyltrimethylammonium tribromide (PTAB)
(1.19 g, 3.17 mmol). After 4 h of vigorous stirring at 45 °C, the mixture
was concentrated. To the oily residue were added EtOAc (150 mL) and
To a stirred suspension of (+)-3-carene (3.16 g, 23.20 mmol) and chlo-
ramine-T trihydrate (TsNClNa·3H2O) (4.91 g, 25.52 mmol) in MeCN
(90 mL) was added phenyltrimethylammonium tribromide (PTAB)
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P. Roszkowski et al.
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Synthesis
(0.87 g, 2.32 mmol). After 4 h of vigorous stirring at 0 °C, the mixture
was concentrated. To the oily residue were added EtOAc (115 mL) and
H2O (45 mL), and after separation of the layers, the aq layer was ex-
tracted with EtOAc (45 mL). The combined organic layers were
washed with brine (45 mL), dried over MgSO4 and evaporated. The
residue was purified by column chromatography on silica gel
(hexane–EtOAc, 0–10% of EtOAc) to afford brominated amide 5 (23%,
2.06 g) as colorless crystals.
uo. To the residue were added CH2Cl2 (50 mL) and H2O (50 mL). The
organic phase was separated, washed with brine (15 mL) and dried
over MgSO4. After evaporation of the solvent, the oily residue was pu-
rified by column chromatography on silica gel (CHCl3–MeOH, 0–2% of
MeOH) to give compound 7 (77%, 0.36 g) as a colorless oil.
[α]D23 +55.7 (c 1.0, CHCl3); the enantiomeric purity (>98% ee) was de-
termined by HPLC (Chiralcel OD-H, hexane–i-PrOH, 80:20,
mL/min); tR = 7.1 min.
1
23
Mp 161.5–162.5 °C; [α]D –94.0 (c 1.0, CHCl3); the optical purity
IR (CH2Cl2): 3361, 3254, 2949, 1652, 1599, 1340, 1162, 1093, 815 cm–1
.
(>98% ee) was determined by HPLC (Chiralcel OD-H, hexane–i-PrOH,
95:5, 1 mL/min); tR = 10.1 min.
1H NMR (500 MHz, CDCl3): δ = 0.39–0.44 (m, 1 H), 0.66–0.71 (m, 1 H),
0.75–0.85 (m, 2 H), 0.88 (s, 3 H), 0.94 (s, 3 H), 1.03 (s, 3 H), 1.61 (br s, 4
H), 2.05 (br s, 2 H), 2.35 (br s, 2 H), 2.43 (s, 3 H), 2.53 (br s, 2 H), 3.22
(dd, J = 10.0, 2.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2
H).
13C NMR (125 MHz, CDCl3): δ = 15.1, 18.4, 18.7, 21.5, 22.4, 23.0, 23.6,
25.0, 25.8, 28.1, 45.6, 55.6, 127.2, 129.5, 137.4, 143.2.
IR (CH2Cl2): 3356, 2944, 2867, 1652, 1316, 1155, 1091, 990, 815 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 0.63–0.72 (m, 2 H), 0.89 (s, 3 H), 0.93
(s, 3 H), 1.31 (s, 3 H), 1.54–1.62 (m, 2 H), 2.33–2.39 (m, 2 H), 2.43 (s, 3
H), 4.10 (t, J = 9.2 Hz, 1 H), 4.98 (s, 1 H), 7.29 (d, J = 9.0 Hz, 2 H), 7.79
(d, J = 8.2 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 15.7, 18.1, 18.6, 20.4, 21.7, 21.9, 28.5,
30.6, 31.1, 59.0, 63.2, 127.2, 129.8, 140.5, 143.4.
HRMS: m/z [M + Na]+ calcd for C17H2479BrNO2SNa: 408.0609; found:
408.0619; m/z [M + Na]+ calcd for C17H2481BrNO2SNa: 410.0588;
found: 410.0597.
HRMS: m/z [M + Na]+ calcd for C21H32N2O2SNa: 399.2082; found:
399.2098.
(1R,3S,4S,6S)-4-Methyl-N-{4,7,7-trimethyl-4-(piperidin-1-yl)bicyc-
lo[4.1.0]heptan-3-yl}-benzenesulfonamide (8)
Monocrystals of 5 suitable for crystallographic measurements were
obtained by slow evaporation from dichloromethane solution. The
absolute structure of the studied crystal, and hence the absolute con-
figuration of the compound was determined based on the value of the
Flack parameter.11 Since its value for the structure shown in Figure 1
was approximately 0, the molecular structure has the depicted con-
figuration. These data have been deposited with the Cambridge Crys-
tallographic Data Centre, CCDC 990399.
To a vigorously stirred suspension of amine 4 (0.70 g, 2.17 mmol) and
K2CO3 (0.75 g, 5.43 mmol) in MeCN (15 mL) was added 1,5-diiodopen-
tane (0.84 g, 2.60 mmol). The resulting mixture was stirred at reflux
temperature for 15 h, after which the solvent was evaporated under
reduced pressure. To the residue were added CH2Cl2 (100 mL) and H2O
(100 mL). The organic phase was separated, washed with brine (30
mL) and dried over MgSO4. After evaporation of the solvent, the oily
residue was purified by column chromatography on silica gel (CHCl3–
MeOH, 0–1.5% of MeOH) to give compound 8 (82%, 1.06 g) as a color-
less oil.
(1R,3S,4S,6S)-N-(4-Amino-4,7,7-trimethylbicyclo[4.1.0]heptan-3-
[α]D23 +43.0 (c 1.0, CHCl3); the enantiomeric purity (>98% ee) was de-
yl)-4-methylbenzenesulfonamide (4)
To a stirred solution of azide 3 (2.51 g, 7.20 mmol) in anhydrous EtOH
(120 mL) was added 10% Pd/C (500 mg), and the resulting suspension
was shaken for 4 h at 24–25 °C under an atm of H2 (balloon). The eth-
anolic solution was filtered through Celite® and the solvent was evap-
orated in vacuo. The oily residue was purified by column chromatog-
raphy on silica gel (CHCl3–MeOH, 0–3% of MeOH) to afford compound
4 (95%, 2.21 g) as a colorless oil.
termined by HPLC (Chiralcel OD-H, hexane–i-PrOH, 80:20,
mL/min); tR = 5.0 min.
1
IR (CH2Cl2): 3386, 3264, 2938, 1652, 1599, 1457, 1340, 1167, 1092,
902, 815 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.34–0.39 (m, 1 H), 0.64–0.73 (m, 2 H),
0.77–0.83 (m, 1 H), 0.89 (s, 3 H), 0.91 (s, 3 H), 0.94 (s, 3 H), 1.33 (br s, 6
H), 2.03 (dd, J = 16.5, 9.0 Hz, 1 H), 2.14–2.19 (m, 1 H), 2.22–2.36 (m, 4
H), 2.43 (s, 3 H), 3.22 (dd, J = 12.0, 4.0 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 2 H),
7.79 (d, J = 8.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 15.1, 18.4, 19.0, 21.5, 22.2, 22.9, 23.4,
24.9, 25.4, 26.7, 28.2, 46.7, 54.3, 127.3, 129.5, 137.2, 143.1.
23
[α]D –22.1 (c 1.0, CHCl3); the optical purity (>98% ee) was deter-
mined by HPLC (Chiralcel OD-H, hexane–i-PrOH, 80:20, 1 mL/min);
tR = 6.9 min.
IR (CH2Cl2): 3373, 2946, 1652, 1340, 1161, 1092, 815 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.57 (q, J = 8.0 Hz, 1 H), 0.66 (q, J = 8.0
Hz, 1 H), 0.82–0.88 (m, 1 H), 0.90 (s, 3 H), 0.94 (s, 3 H), 1.06 (s, 3 H),
1.06–1.10 (m, 1 H), 1.56–1.62 (m, 1 H), 1.83 (dd, J = 15.0, 8.5 Hz, 1 H),
2.43 (s, 3 H), 3.06 (dd, J = 15.0, 5.0 Hz, 1 H), 7.31 (d, J = 8.5 Hz, 2 H),
7.79 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 15.1, 17.4, 18.3, 21.5, 21.8, 24.9, 26.6,
28.1, 32.9, 52.2, 59.8, 127.1, 129.7, 137.5, 143.4.
HRMS: m/z [M + Na]+ calcd for C22H34N2O2SNa: 413.2239; found:
413.2251.
Preparation of Catalyst 6 for the Reductions with HCOOH–Et3N as
the Hydrogen Source
A mixture of [RuCl2(benzene)]2 (6 mg, 12 μmol), ligand 4 (9.7 mg, 30
μmol) and Et3N (24 μmol) in MeCN (1 mL) was stirred at 24–25 °C for
30 min. After this time, the resulting pale brown solution of the cata-
lyst was used immediately for the reduction of the ketones.
HRMS: m/z [M
+
H]+ calcd for C17H27N2O2S: 323.1793; found:
323.1780.
(1R,3S,4S,6S)-4-Methyl-N-{4,7,7-trimethyl-4-(pyrrolidin-1-yl)bicy-
clo[4.1.0]heptan-3-yl}-benzenesulfonamide (7)
Reductions of Ketones Using Catalyst 6 and HCOOH–Et3N; General
Procedure
To a vigorously stirred suspension of amine 4 (0.40 g, 1.24 mmol) and
K2CO3 (0.45 g, 3.23 mmol) in MeCN (8 mL) was added 1,4-diiodobu-
tane (0.44 g, 1.43 mmol). The resulting mixture was stirred at reflux
temperature for 15 h, after which the solvent was evaporated in vac-
A solution of the preformed ruthenium catalyst 6 in MeCN (1 mL, 24
μmol) and an azeotropic mixture of HCOOH–Et3N (1 mL) were added
to a vial containing the ketone (2.4 mmol). The mixture was stirred at
24–25 °C for 6 d (monitored by TLC). After evaporation of the sol-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 569–574

574
P. Roszkowski et al.
Paper
Synthesis
vents, CH2Cl2 (4 mL) and 10% aq HCl (1.5 mL) were added to the resi-
due. The layers were separated and the aq layer was extracted with
CH2Cl2 (2 × 2 mL). The combined organic layers were dried over
Na2SO4 and concentrated under reduced pressure. The product12,13
was isolated by filtration through a short-path silica gel column using
CHCl3 (dried over CaCl2) as the eluent. The enantiomeric excess was
determined by GC analysis using a Supelco cyclodextrin β-DEX 120
capillary column (20 m × 0.25 mm I.D., 0.25 μm film thickness). The
results obtained from the reduction reactions are summarized in Ta-
ble 2.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378942.
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References
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Preparation of Catalyst 6 for the Reductions with Propan-2-ol as
the Hydrogen Source
A mixture of [RuCl2(benzene)]2 (6 mg, 12 μmol), ligand 4 (9.7 mg, 30
μmol) and propan-2-ol (2 mL) was heated at 80 °C for 20 min under
an Ar atm. After cooling to room temperature (24–25 °C), the result-
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Reductions of Ketones Using Catalyst 6 and Propan-2-ol; General
Procedure
A solution of preformed ruthenium catalyst 6 (24 μmol) in propan-2-
ol (2 mL) and 0.1 M KOH solution (1 mL) was added to a vial contain-
ing a solution of the ketone (2.4 mmol) in propan-2-ol (1 mL). The
mixture was stirred at 24–25 °C for 24 h (monitored by TLC). The re-
action mixture was neutralized with dilute HCl and then concentrat-
ed in vacuo. The residue was diluted with CH2Cl2 (8 mL), washed with
brine (2 mL), dried over Na2SO4 and concentrated under reduced pres-
sure. The product12,13 was isolated by filtration through a short-path
silica gel column using CHCl3 (dried over CaCl2) as the eluent. The en-
antiomeric excess was determined by GC analysis using a Supelco cy-
clodextrin β-DEX 120 capillary column (20 m × 0.25 mm I.D., 0.25 μm
film thickness). The results obtained from the reduction reactions are
summarized in Table 2.
Catalytic Asymmetric Addition of Diethylzinc to Aldehydes; Gen-
eral Procedure
To a stirred solution of ligand 7 (9 mg, 0.024 mmol) in anhydrous hex-
ane (2 mL) under an Ar atm was added dropwise a solution of Et2Zn
(1.0 mL, 1.0 M in hexane) at 0 °C. After being stirred for an additional
1 h, freshly distilled aldehyde (53 mg, 0.5 mmol) was added via a sy-
ringe. The resulting mixture was stirred at 0 °C for another 20 h and
then quenched with aq HCl (2 M). The aq phase was extracted with
EtOAc (3 × 5 mL) and the combined organic phase dried over anhy-
drous Na2SO4. The solvent was removed under reduced pressure and
the product12,14 was isolated by filtration through a short-path silica
gel column using CHCl3 (dried over CaCl2) as the eluent. The enantio-
meric excess was determined by GC analysis using a Supelco cyclo-
dextrin β-DEX 120 capillary column (20 m x 0.25 mm I.D. and 0.25
μm film thickness). The results obtained from the reduction reactions
are summarized in Table 3.
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dron: Asymmetry 2010, 21, 2258.
Acknowledgment
(13) Li, Y.; Zhou, Y.; Shi, Q.; Ding, K.; Noyori, R.; Sandoval, C. A. Adv.
Synth. Catal. 2011, 353, 495.
(14) Prasad, K. R.; Revu, O. Tetrahedron 2013, 69, 8422.
We acknowledge the financial support from the Polish Ministry of
Science and Higher Education in the form of grant N N204 117939.
We cordially thank Dr. Dariusz Błachut (Internal Security Agency) for
the determination of ee values by GC and Dr Stefan Czarnocki for
valuable experimental assistance.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 569–574