573
P. Roszkowski et al.
Paper
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