H
Z. J. Garlets, J. P. Wolfe
Special Topic
Synthesis
The enantiopurity was determined to be 97:3 er by chiral HPLC analy-
sis (Chiralcel ADH, 15 cm × 4.6 mm, 4% i-PrOH/hexanes, 1.0 mL/min,
λ = 210 nm, tR = 26.2 and 28.6 min).
(S)-(–)-1,3-Dibenzyl-4-[3-(trifluoromethyl)benzyl]-2-thia-1,3-di-
azaspiro[5.5]undecane 2,2-Dioxide (6j)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(1-allylcyclohexyl)sulfamide (5b) (80.0 mg, 0.20 mmol) and
3-bromobenzotrifluoride (56 μL, 0.40 mmol) using a catalyst com-
posed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg,
0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction temperature
of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O
(7 μL). This procedure afforded the title compound (98 mg, 90%) as a
colorless solid; mp 119–121 °C; [α]D23 –70 (c 1.6, CH2Cl2).
(S)-(–)-2,6-Dibenzyl-3,3-dimethyl-5-(2-methylbenzyl)-1,2,6-thia-
diazinane 1,1-Dioxide (6h)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(2-methylpent-4-en-2-yl)sulfamide (5a) (72.0 mg, 0.20
mmol) and 1-bromo-2-methylbenzene (48 μL, 0.4 mmol) using a cat-
alyst composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE
(5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.60 mmol), a reaction tem-
perature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and
H2O (7 μL). This procedure afforded the title compound (26 mg, 29%)
as a colorless solid; mp 118–124 °C; [α]D23 –44.2 (c 2.0, CH2Cl2).
IR (neat): 1495, 1453, 1327, 1154, 1116, 1074 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.46–7.39 (m, 3 H), 7.38–7.20 (m, 11
H), 4.68 (d, J = 2.5 Hz, 1 H), 4.65 (d, J = 4.7 Hz, 1 H), 4.37–4.25 (m, 3 H),
2.95 (dd, J = 14.0, 5.7 Hz, 1 H), 2.69 (dd, J = 14.0, 9.2 Hz, 1 H), 2.17 (d,
J = 11.7 Hz, 1 H), 2.06 (dd, J = 14.6, 3.0 Hz, 1 H), 1.83 (t, J = 13.2 Hz,
1 H), 1.65–1.42 (m, 6 H), 1.18 (q, J = 13.0 Hz, 1 H), 1.00 (q, J = 13.0 Hz,
1 H), 0.83 (q, J = 12.8 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 140.5, 138.5, 137.8, 132.3, 131.0 (q,
JC–F = 32.5 Hz), 129.2, 128.6, 128.5, 128.1, 127.7, 127.1, 125.8 (q, JC–F
3.75 Hz), 124.1 (q, JC–F = 270 Hz), 123.7 (q, JC–F = 3.75 Hz), 63.9, 56.6,
50.7, 44.9, 40.5, 38.1, 31.1, 29.8, 25.3, 22.9, 22.6; 1 carbon signal is
missing.
19F NMR (471 MHz, CDCl3): δ = –62.65 (s).
IR (neat): 1604, 1494, 1452, 1320, 1138 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.47–7.41 (m, 4 H), 7.32 (q, J = 7.5 Hz, 4
H), 7.28–7.22 (m, 2 H), 7.13–7.02 (m, 4 H), 4.74 (d, J = 15.9 Hz, 1 H),
4.65 (d, J = 16.8 Hz, 1 H), 4.42 (tdd, J = 9.9, 4.7, 2.3 Hz, 1 H), 4.30 (d,
J = 15.9 Hz, 1 H), 4.14 (d, J = 16.8 Hz, 1 H), 2.85 (dd, J = 13.9, 4.6 Hz, 1
H), 2.62 (dd, J = 13.9, 10.0 Hz, 1 H), 2.19 (s, 3 H), 2.09 (t, J = 14.3 Hz, 1
H), 1.40 (dd, J = 14.3, 2.9 Hz, 1 H), 1.27 (s, 3 H), 1.13 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 140.4, 138.5, 136.5, 135.7, 130.7,
129.7, 128.6, 128.5, 128.0, 127.5, 127.4, 127.2, 126.9, 126.2, 60.4, 56.2,
50.1, 45.8, 38.83, 37.99, 31.0, 22.8, 19.7.
=
HRMS (ESI+): m/z [M + H]+ calcd for C30H34F3N2O2S: 543.2288; found:
543.2292.
HRMS (ESI+): m/z [M + H]+ calcd for C27H33N2O2S: 449.2257; found:
449.2258.
The enantiopurity was determined to be 96.5:3.5 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 6% i-PrOH/hexanes, 1.0
mL/min, λ = 210 nm, tR = 15.4 and 18.9 min).
The enantiopurity was determined to be 85:15 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 4% i-PrOH/hexanes, 1.0
mL/min, λ = 210 nm, tR = 13.9 and 23.3 min).
(S)-(–)-1,3-Dibenzyl-4-(3-methoxybenzyl)-2-thia-1,3-di-
azaspiro[5.5]undecane 2,2-Dioxide (6k)
(S)-(–)-1,3-Dibenzyl-4-[3-(4-fluorophenoxy)benzyl]-2-thia-1,3-di-
azaspiro[5.5]undecane 2,2-Dioxide (6i)
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(1-allylcyclohexyl)sulfamide (5b) (80.0 mg, 0.20 mmol) and
3-bromoanisole (51 μL, 0.40 mmol) using a catalyst composed of
Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-PE (5.1 mg, 0.010
mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction temperature of
120 °C, and a reaction time of 18 h in xylenes (1.6 mL) and H2O (7 μL).
This procedure afforded the title compound (89 mg, 88%) as a color-
less solid; mp 141–144 °C; [α]D23 –52 (c 1.9, CH2Cl2).
General procedure 3 was employed for the coupling of N-benzyl-N′-
benzyl-N-(1-allylcyclohexyl)sulfamide (5b) (80.0 mg, 0.20 mmol) and
1-bromo-3-(4-fluorophenoxy)benzene (107 mg, 0.40 mmol) using a
catalyst composed of Pd2(dba)3 (1.8 mg, 0.002 mmol) and (S)-Siphos-
PE (5.1 mg, 0.010 mmol), t-BuONa (38.0 mg, 0.40 mmol), a reaction
temperature of 120 °C, and a reaction time of 18 h in xylenes (1.6 mL)
and H2O (7 μL). This procedure afforded the title compound (98 mg,
84%) as a colorless solid; mp 122–125 °C; [α]D23 –65 (c 1.6, CH2Cl2).
IR (neat): 1584, 1496, 1452, 1327, 1150, 1111 cm–1
.
IR (neat): 1497, 1441, 1330, 1198, 1157, 1110 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.5 Hz, 4 H), 7.32 (t, J = 7.6
Hz, 4 H), 7.24 (q, J = 7.1 Hz, 2 H), 7.17 (t, J = 7.9 Hz, 1 H), 6.74 (dd,
J = 8.2, 2.5 Hz, 1 H), 6.70–6.66 (m, 1 H), 6.60 (t, J = 2.0 Hz, 1 H), 4.68
(dd, J = 16.4, 13.1 Hz, 2 H), 4.29 (dd, J = 30.4, 16.6 Hz, 3 H), 3.76 (s, 3
H), 2.89 (dd, J = 13.5, 4.6 Hz, 1 H), 2.58 (dd, J = 13.5, 10.3 Hz, 1 H), 2.18
(d, J = 12.2 Hz, 1 H), 2.09 (dd, J = 14.6, 2.6 Hz, 1 H), 1.74 (t, J = 12.0 Hz
1 H), 1.65–1.36 (m, 6 H), 1.24–1.08 (m, 1 H), 1.07–0.91 (m, 1 H), 0.90–
0.73 (m, 1 H).
1H NMR (700 MHz, CDCl3): δ = 7.43–7.38 (m, 4 H), 7.34–7.28 (m, 4 H),
7.26–7.20 (m, 3 H), 7.04–6.99 (m, 2 H), 6.92–6.88 (m, 2 H), 6.85–6.81
(m, 2 H), 6.67 (t, J = 2.0 Hz, 1 H), 4.67 (dd, J = 16.5, 11.7 Hz, 2 H), 4.31
(d, J = 15.7 Hz, 1 H), 4.28–4.21 (m, 2 H), 2.86 (dd, J = 13.6, 4.9 Hz, 1 H),
2.57 (dd, J = 13.6, 10.0 Hz, 1 H), 2.20–2.14 (m, 1 H), 2.07 (dd, J = 14.6,
2.9 Hz, 1 H), 1.74 (t, J = 14.1 Hz, 1 H), 1.63–1.47 (m, 5 H), 1.41 (d,
J = 13.1 Hz, 1 H), 1.17 (qt, J = 13.4, 3.7 Hz, 1 H), 1.02 (qt, J = 13.8, 4.0
Hz, 1 H), 0.84 (qt, J = 13.4, 4.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 159.9, 140.7, 139.1, 138.4, 129.7,
128.6, 128.5, 128.1, 127.5, 127.1, 127.0, 121.4, 114.6, 112.5, 63.9, 56.9,
55.4, 50.4, 44.9, 41.0, 38.2, 31.1, 29.5, 25.3, 22.9, 22.6.
13C NMR (176 MHz, CDCl3): δ = 158.9 (d, JC–F = 242.9 Hz), 157.9, 153.1
(d, JC–F = 3.5 Hz), 140.6, 139.6, 138.2, 130.1, 128.6, 128.5, 128.1, 127.5,
127.1, 127.0, 124.0, 120.5 (d, JC–F = 8.8 Hz), 119.1, 117.0, 116.5 (d, JC–F
22.9 Hz), 63.8, 56.8, 50.4, 44.9, 40.7, 38.2, 31.0, 29.5, 25.3, 23.0, 22.6.
19F NMR (471 MHz, CDCl3): δ = –120.00 to –120.07 (m).
HRMS (ESI+): m/z [M + H]+ calcd for C35H38FN2O3S: 585.2582; found:
=
HRMS (ESI+): m/z [M + H]+ calcd for C30H37N2O3S: 505.2519; found:
505.2523.
The enantiopurity was determined to be 97:3 er by chiral HPLC analy-
sis (Chiralcel ADH, 25 cm × 4.6 mm, 6% i-PrOH/hexanes, 1.0 mL/min,
λ = 210 nm, tR = 32.5 and 35.2 min).
585.2582.
The enantiopurity was determined to be 95.5:4.5 er by chiral HPLC
analysis (Chiralcel ADH, 25 cm × 4.6 mm, 6% i-PrOH/hexanes, 1.0
mL/min, λ = 210 nm, tR = 24.6 and 33.5 min).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I