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Supporting Information
© Copyright Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, 2006
S 1
Syntheses of Substituted 1, 3-Diene Synthons by a Ru-Catalyzed Diyne Hydrative Cyclization
Barry M. Trost* and Xiaojun Huang
Department of Chemistry, Stanford University, Stanford, CA 94305
S 2
General Experimental Conditions: All reactions were carried out in a flame-dried flask
under dry nitrogen or argon. Dry acetone was distilled over drierite. Dry tetrahydrofuran
(THF) was distilled over sodium benzophenone ketyl or purified on an alumina column
purification system. All other solvents were purified on an alumina column purification
system. All solvents were HPLC grade or analytical pure. Flash chromatography
employed ICN silica gel (Kieselgel 60, 230 ± 400 mesh), analytical TLC was performed
with 0.2 mm silica-coated glass plates (E. Merck, DC-Platten Kieselgel 60 F254).
Infrared (IR) data were recorded on sodium chloride plates on a Perkin Elmer Paragon
500 FT-IR spectrometer. Proton and broadband decoupled 13C nuclear magnetic
resonance (NMR) data were acquired at room temperature on Varian GEM 300, Inova
Unity 400, or Inova Unity 500 spectrometer as indicated. Chemical shifts are reported in
ppm relative to CDCl3, or C6D6. Elemental analyses were performed by M-H-W
Laboratories (USA). HRMS (EI) m/z spectra were recorded by the Mass Spectrometer
Facility of the School of Pharmacy, University of California, San Francisco (USA).
EtS
Et
O
O2a
1-(Pent-2-yne-1-sulfonyl)-pent-2-yne (2a): (a) 1-Pent-2-ynylsulfanylpent-2-yne (6a): 1-
Bromopent-2-yne 5a (1 mL, 9.78 mmol) was added to a solution of Na2S (385 mg, 4.93
mmol) in methanol (10 mL) and the resulting mixture was stirred at room temperature for
5 h. The reaction mixture was quenched with H2O and the solvent was evaporated in
vacuo. The aqueous phase was extracted with Et2O and the extract was washed with H2O
and brine, dried (Na2SO4), filtered through a pad of silica gel and evaporated in vacuo to
give the crude sulfide 6a (750 mg, 92%) which was used directly into the next step. Rf =
0.72 (EtOAc/pet. ether 1:4); IR (thin film): ν = 2975, 2916, 2878, 2232, 1454, 1412,
1319, 1228, 1062, 742 cm−1; 1H NMR (300 MHz, CDCl3): δ = 3.36 (t, J = 2.4 Hz, 4H),
2.18 (qt, J = 7.5, 2.4 Hz, 4H), 1.10 (t, J = 7.5 Hz, 6H); 13C NMR (75.4 MHz, CDCl3): δ =
84.9, 74.4, 19.5, 13.9, 12.5.
(b) 1-(Pent-2-yne-1-sulfonyl)-pent-2-yne (2a): mCPBA (3.43 g, 13.5 mmol) was added in
one portion to a stirred solution of the crude propargylic sulfide 6a (750 mg, 4.51 mmol)
S 3
in CH2Cl2 (80 mL). Stirring was continued for 2 h. The mixture was diluted with
CH2Cl2 and washed successively with saturated aqueous Na2S2O3 (2×), saturated aqueous
NaHCO3 (2×) and H2O, dried (Na2SO4) and evaporated in vacuo. Flash chromatography
of the residue over silica gel, using 1:4 EtOAc/pet. ether, gave sulfone 2a (760 mg, 85%).
Rf = 0.4 (EtOAc/pet. ether 1:4); m.p. 46 oC; IR (thin film): ν = 2979, 2915, 2242, 1458,
1396, 1332, 1244, 1177, 1126, 1063, 869, 781 cm−1; 1H NMR (400 MHz, CDCl3): δ =
3.96 (t, J = 2.4 Hz, 4H), 2.23 (tq, J = 2.4, 7.2 Hz, 4H), 1.14 (t, J = 7.2 Hz, 6H); 13C NMR
(100.6 MHz, CDCl3): δ = 90.2, 66.3, 43.5, 13.3, 12.5; elemental analysis calcd (%) for
C10H14O2S: C 60.57, H 7.12; found: C 60.71, H 6.98.
SO
O
2b 1-(But-2-yne-1-sulfonyl)-but-2-yne (2b): (a) 1-But-2-ynylsulfanylbut-2-yne (6b): The
procedure for the preparation of 6a was followed, using 5b (0.9 mL, 10.3 mmol), Na2S
(406 mg, 5.20 mmol) and MeOH (10 mL), and a reaction time of 6 h. The crude sulfide
6b (720 mg, 100%) was used immediately for next step. Rf = 0.64 (EtOAc/pet. ether
1:4); IR (thin film): ν = 2918, 2855, 2230, 1437, 1413, 1230, 1030, 902, 677 cm−1; 1H
NMR (500 MHz, CDCl3): δ = 3.33 (q, J = 2.5 Hz, 4H), 1.80 (t, J = 2.5 Hz, 6H); 13C
NMR (125.7 MHz, CDCl3): δ = 79.9, 74.2, 19.5, 3.6.
(b) 1-(But-2-yne-1-sulfonyl)-but-2-yne (2b): The procedure for the preparation of 2a was
followed, using 6b (720 mg, 5.2 mmol), mCPBA (3.96 g, 15.6 mmol) and CH2Cl2 (80
mL), and a reaction time of 2 h. Flash chromatography of the crude product over silica
gel, using CH2Cl2, gave sulfone 2b (710 mg, 80%). Rf = 0.65 (EtOAc/pet. ether 1:1);
m.p. 93 oC; IR (thin film): ν = 2956, 2913, 2244, 1402, 1324, 1282, 1254, 1184, 1124,
876 cm−1; 1H NMR (500 MHz, CDCl3): δ = 3.94 (q, J = 2.5 Hz, 4H), 1.87 (t, J = 2.5 Hz,
6H); 13C NMR (125.7 MHz, CDCl3): δ = 84.6, 66.0, 43.5, 3.8; elemental analysis calcd
(%) for C8H10O2S: C 56.44, H 5.92; found: C 56.62, H 6.00.
SPh
O
O2c
S 4
[3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-benzene (2c): (3-But-2-ynylsulfanylprop-1-
ynyl)-benzene (6c): Thioacetic acid S-but-2-ynyl ester 7 (0.655 g, 5.11 mmol) was added
to a solution of KOH (287 mg, 5.11 mmol) and Na2S2O3 (10 mg, 0.063 mmol) in
methanol (10 mL) under nitrogen at 0 oC. After stirred at 0 oC for 30 min, (3-
Bromoprop-1-ynyl)-benzene 5c (997 mg, 5.11 mmol) was added dropwise to the reaction
mixture. Ice bath was removed and the mixture was stirred for 2 h. The reaction mixture
was quenched with H2O and the solvent was evaporated in vacuo. The aqueous phase
was extracted with Et2O and the extract was washed with H2O and brine, dried (Na2SO4),
filtered through a pad of silica gel and evaporated in vacuo to give the crude sulfide 6c
(920 mg) which was used directly into the next step. Rf = 0.72 (EtOAc/pet. ether 1:10).
[3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-benzene (2c): The procedure for the preparation
of 2a was followed, using 6c (920 mg, 4.59 mmol), mCPBA (3.0 g, 11.8 mmol) and
CH2Cl2 (50 mL), and a reaction time of 3 h. Flash chromatography of the crude product
over silica gel, using 2:7 EtOAc/pet. ether, gave sulfone 2c (570 mg, 53% over two
steps). Rf = 0.30 (EtOAc/pet. ether 1:4); m.p. 57 oC; IR (thin film): ν = 2958, 2912,
2243, 1491, 1444, 1395, 1331, 1260, 1229, 1174, 1126, 869, 759, 692 cm−1; 1H NMR
(500 MHz, CDCl3): δ = 7.42-7.50 (m, 2H), 7.28-7.38 (m, 3H), 4.24 (s, 2H), 4.20 (q, J =
2.5 Hz, 2H), 1.89 (t, J = 2.5 Hz, 3H); 13C NMR (125.7 MHz, CDCl3): δ = 132.0, 129.2,
128.4, 121.4, 87.7, 84.9, 76.0, 66.0, 44.0, 43.9, 3.9; elemental analysis calcd (%) for
C13H12O2S: C 67.21, H 5.21; found: C 66.97, H 5.05.
SO
O
2dOH
6-(But-2-yne-1-sulfonyl)-hex-4-yn-2-ol (2d): (a) 2-hexyne-1,5-diol: BuLi (2.5 M in
THF, 17 mL, 42.5 mmol) was added to a stirred and cooled (-78 oC) solution of 4-
pentyne-2-ol (2.0 mL, 21.2 mmol) in Et2O (40 mL) and THF (20 mL). After 30 min,
formaldehyde (636 mg, 22.3 mmol) was added all at once. The bath was removed and
stirring was continued for 6 h. The mixture was then poured into ice-water and extracted
with EtOAc (8×100 mL), dried and evaporated. Flash chromatography of the residue
over silica gel, using 2:1 EtOAc/pet. ether, gave 2-hexyne-1,5-diol (1.5 g, 62%). Rf =
0.24 (EtOAc/pet. ether 1:1); IR (thin film): ν = 3354, 2972, 2930, 2226, 1422, 1377,
S 5
1116, 1012, 940, 733 cm−1; 1H NMR (300 MHz, CDCl3): δ = 4.2 (t, J = 2.1 Hz, 2H),
3.87-3.99 (m, 1H), 3.61 (s, 2H), 2.22-2.45 (m, 2H), 1.21 (d, J = 6.3 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3): δ = 82.6, 80.7, 66.3, 50.7, 29.0, 22.2.
(b) 6-bromohex-4-yn-2-ol (5d): CBr4 (1.51 g, 4.55 mmol) and Ph3P (1.19 g, 4.54 mmol)
were added successively to a stirred and cooled (0 oC) solution of 2-hexyn-1,5-diol (519
mg, 4.55 mmol) in CH2Cl2 (10 mL). The mixture was stirred for 10 h and the solvent
was evaporated. Flash chromatography of the crude mixture over silica gel, using 1:2
EtOAc/pet. ether, gave 6-bromohex-4-yn-2-ol 5d (725 mg, 90%). Rf = 0.58 (EtOAc/pet.
ether 1:1); IR (thin film): ν = 3374, 2972, 2909, 2233, 1420, 1211, 1115, 1085, 939, 609
cm−1; 1H NMR (300 MHz, CDCl3): δ = 3.80-4.00 (m, 3H), 2.20-2.50 (m, 3H), 1.21 (d, J
= 6.3 Hz, 3H); 13C NMR (75.4 MHz, CDCl3): δ = 84.2, 77.6, 66.2, 29.3, 22.3, 15.1.
(c) 6-But-2-ynylsulfanyl-hex-4-yn-2-ol (6d): The procedure for the preparation of 6c was
followed, using thioacetic acid S-but-2-ynyl ester 7 (0.506 g, 3.95 mmol), 5d (700 mg,
3.95 mmol), Na2S2O3 (8 mg, 0.05 mmol), KOH (222 mg, 3.96 mmol) and MeOH (5 mL),
and a reaction time of 4 h. Product 6d (800 mg) was used as crude.
(d) 6-(But-2-yne-1-sulfonyl)-hex-4-yn-2-ol (2d): The procedure for the preparation of 2a
was followed, using 6d (800 mg, ca. 3.95 mmol), mCPBA (2.9 g, 11.8 mmol) and
CH2Cl2 (40 mL), and a reaction time of 5 h. Flash chromatography of the crude product
over silica gel, using 1:1 EtOAc/pet. ether, gave sulfone 2d (700 mg, 83% over two
steps). Rf = 0.47 (EtOAc/pet. ether 1:1); IR (thin film): ν = 3520, 2968, 2913, 2242,
1631, 1398, 1325, 1247, 1124, 940, 872 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.93-
4.02 (m, 5H), 2.32-2.48 (m, 2H), 2.12 (s, 1H), 1.87 (t, J = 2.4 Hz, 3H), 1.25 (d, J = 6.0
Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ = 85.8, 84.8, 69.5, 66.2, 66.0, 43.7, 43.5,
29.2, 22.4, 3.8; HRMS (EI): m/z: calcd for C10H15O3S: 215.0742 [M + H]+; found:
215.0744.
SO
O2e
OTBDPS
tert-Butyl-[5-(but-2-yne-1-sulfonyl)-1-methylpent-3-ynyloxy]-diphenylsilane (2e):
TBDPSCl (1.9 mL, 7.3 mmol) and imidazole (502 mg, 7.37 mmol) was added
successively to a stirred solution of 2d (518 mg, 2.417 mmol) in CH2Cl2 (50 mL), and the
S 6
mixture was stirred for 18 h. After quenched by saturated aqueous NH4Cl, the mixture
was extracted with Et2O, washed with brine, dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel, using 1:5 EtOAc/pet. ether, gave 2e (1.08
g, 99%) as colorless oil. Rf = 0.48 (EtOAc/pet. ether 1:4); IR (thin film): ν = 2960, 2243,
1589, 1428, 1334, 1126, 996, 870, 704 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.63-7.68
(m, 4H), 7.33-7.45 (m, 6H), 3.97 (sextet, J = 6.0 Hz, 1H), 3.89-3.93 (m, 4H), 2.32-2.37
(m, 2H), 1.86 (t, J = 2.4 Hz, 3H), 1.19 (d, J = 6.0 Hz, 3H), 1.04 (s, 9H); 13C NMR (100.6
MHz, CDCl3): δ = 135.77, 135.76, 133.92, 133.91, 129.7, 127.61, 127.59, 86.1, 84.6,
68.8, 67.8, 66.1, 43.5, 43.4, 29.3, 26.9, 22.9, 19.1, 3.8; elemental analysis calcd (%) for
C26H32O3SSi: C 68.98, H 7.13; found: C 69.12, H 6.91.
STMS
O
O
2f [3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-trimethylsilane (2f): (a) (3-Bromoprop-1-
ynyl)-trimethylsilane (5f): Propargylic bromide (80% in PhMe, 1.78 mL, 16 mmol) was
added to a stirred and cooled (-78 oC) solution of LDA (16 mmol) in Et2O (32 mL).
After 1 h, TMSCl (2.05 mL, 16 mmol) was added, and stirring was continued overnight
(-78 oC → room temperature). The mixture was quenched with saturated aqueous
NH4Cl, extracted with Et2O. The organic layer was washed with brine, dried (Na2SO4)
and evaporated. Flash chromatography of the residue over silica gel, using 1:50 Et2O/pet.
ether, gave 5f (1.45 g, 47%) as colorless oil. Rf = 0.77 (EtOAc/pet. ether 1:10); IR (thin
film): ν = 2961, 2900, 2181, 1422, 1252, 1206, 1042, 845, 761, 619 cm−1; 1H NMR (300
MHz, CDCl3): δ = 3.89 (s, 2H), 0.16 (s, 9H); 13C NMR (75.4 MHz, CDCl3): δ = 99.9,
92.3, 14.7, -0.4.
(b) 3-But-2-ynylsulfanylprop-1-ynyl)-trimethylsilane (6f): The procedure for the
preparation of 6c was followed, using thioacetic acid S-but-2-ynyl ester 7 (0.641 g, 5.00
mmol), 5f (956 mg, 5.0 mmol), Na2S2O3 (10 mg, 0.06 mmol), KOH (281 mg, 5.00 mmol)
and MeOH (10 mL), and a reaction time of 3 h. Product 6f (1 g) was used as crude.
(c) [3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-trimethylsilane (2f): The procedure for the
preparation of 2a was followed, using 6f (1 g, ca. 5.0 mmol), mCPBA (3.6 g, 14.6 mmol)
and CH2Cl2 (50 mL), and a reaction time of 15 h. Flash chromatography of the crude
S 7
product over silica gel, using 1:5 EtOAc/pet. ether, gave sulfone 2f (1.05 g, 92% over two
steps). Rf = 0.41 (EtOAc/pet. ether 1:4); IR (thin film): ν = 2961, 2913, 2244, 2184,
1395, 1335, 1252, 1128, 848, 762 cm−1; 1H NMR (400 MHz, CDCl3): δ = 4.00 (s, 2H),
3.94 (s, 2H), 1.86 (s, 3H), 0.16 (s, 9H); 13C NMR (100.6 MHz, CDCl3): δ = 94.1, 91.8,
84.7, 65.8, 44.2, 43.5, 3.8, -0.6; elemental analysis calcd (%) for C10H16O2SSi: C 52.59,
H 7.06; found: C 52.70, H 7.22.
SSiMe2Ph
O
O
2g [3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-dimethylphenylsilane (2g): (a) (3-Bromoprop-
1-ynyl)-dimethylphenylsilane (5g): The procedure for the preparation of 5f was followed,
using propargylic bromide (80% in PhMe, 0.89 mL, 10 mmol), LDA (10 mmol), Et2O
(20 mL) and PhMe2SiCl (1.7 mL, 10 mmol). Flash chromatography of the crude product
over silica gel, using 1:40 EtOAc/pet. ether, gave 5g (2.15 g, 85%) as colorless oil. Rf =
0.63 (EtOAc/pet. ether 1:10); 1H NMR (300 MHz, CDCl3): δ = 7.55-7.70 (m, 2H), 7.35-
7.45 (m, 3H), 3.95 (s, 2H), 0.46 (s, 6H); 13C NMR (75.4 MHz, CDCl3): δ = 136.2, 133.6,
129.6, 127.9, 101.6, 90,3, 14.5, -1.2.
(b) (3-But-2-ynylsulfanylprop-1-ynyl)-dimethylphenylsilane (6g): The procedure for the
preparation of 6c was followed, using thioacetic acid S-but-2-ynyl ester 7 (0.641 g, 5.00
mmol), 5g (1.27 g, 5.0 mmol), Na2S2O3 (10 mg, 0.06 mmol), KOH (281 mg, 5.00 mmol)
and MeOH (10 mL), and a reaction time of 3 h. Product 6f (1.35 g) was used as crude.
(c) [3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-dimethylphenylsilane (2g): The procedure for
the preparation of 2a was followed, using 6g (1.35 g, ca. 5.0 mmol), mCPBA (3.6 g, 14.6
mmol) and CH2Cl2 (50 mL), and a reaction time of 15 h. Flash chromatography of the
crude product over silica gel, using 1:5 EtOAc/pet. ether, gave sulfone 2g (1.4 g, 96%
over two steps). Rf = 0.37 (EtOAc/pet. ether 1:4): 0.37; IR (thin film): ν = 2960, 2911,
2244, 2185, 1429, 1335, 1251, 1127, 1043, 819, 734 cm−1; 1H NMR (500 MHz, CDCl3):
δ = 7.58-7.63 (m, 2H), 7.34-7.42 (m, 3H), 4.08 (s, 2H), 3.96 (q, J = 2.5 Hz, 2H), 1.88 (t, J
= 2.5 Hz, 3H), 0.44 (s, 6H); 13C NMR (125.7 MHz, CDCl3): δ = 135.7, 133.6, 129.7,
S 8
128.0, 93.5, 92.4, 84.8, 65.8, 44.3, 43.7, 3.8, -1.4; elemental analysis calcd (%) for
C15H18O2SSi: C 62.03, H 6.25; found: C 62.23, H 6.40.
SO
O
2h [3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-cyclopropane (2h): (a) (3-Bromoprop-1-ynyl)-
cyclopropane (5h): The procedure for the preparation of 5d was followed, using 3-
cyclopropylprop-2-yn-1-ol (768 mg, 7.99 mmol), CBr4 (2.65 g, 7.99 mmol), Ph3P (2.096
g, 7.99 mmol), and CH2Cl2 (16 mL), and a reaction time of 3 h. Bromide 5h (1.515 g,
mixed with CHBr3) was used as crude. 1H NMR (400 MHz, CDCl3): δ = 3.87-3.90 (m,
2H), 1.18-1.35 (m, 1H), 0.65-0.82 (m, 4H); 13C NMR (100.6 MHz, CDCl3): δ = 91.3,
70.5, 16.0, 8.4, -0.3.
(b) (3-But-2-ynylsulfanylprop-1-ynyl)-cyclopropane (6h): The procedure for the
preparation of 6c was followed, using thioacetic acid S-but-2-ynyl ester 7 (0.61 g, 4.76
mmol), 5h (1.515 g, mixed with CHBr3, ca. 3.95 mmol), Na2S2O3 (10 mg, 0.06 mmol),
KOH (270 mg, 4.81 mmol) and MeOH (7 mL), and a reaction time of 2 h. Sulfide 6h
(905 mg) was used as crude in the next step.
(c) [3-(But-2-yne-1-sulfonyl)-prop-1-ynyl]-cyclopropane (2h): The procedure for the
preparation of 2a was followed, using 6h (0.905 g), mCPBA (4.07 g, 16.5 mmol) and
CH2Cl2 (50 mL), and a reaction time of 20 h. Flash chromatography of the crude product
over silica gel, using 1:3 EtOAc/pet. ether, gave sulfone 2h (532 mg, 34% over three
steps). Rf = 0.27 (EtOAc/pet. ether 1:4); IR (thin film): ν = 2958, 2913, 2241, 1396,
1329, 1246, 1176, 1126, 868 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.88-3.95 (m, 4H),
1.84 (t, J = 2.6 Hz, 3H), 1.18-1.30 (m, 1H), 0.62-0.80 (m, 4H); 13C NMR (100.6 MHz,
CDCl3): δ = 91.9, 84.5, 66.0, 61.9, 43.6, 43.3, 8.2, 3.7, -0.5; elemental analysis calcd (%)
for C10H12O2S: C 61.20, H 6.16; found: C 61.38, H 6.16.
SO
O
2i' OH 7-(But-2-yne-1-sulfonyl)-hept-5-yn-2-ol (2i’): (a) Hept-2-yne-1,6-diol: 5% Aqueous
NaHCO3 (90 mL), TEMPO (64 mg, 0.41 mmol), KBr (488 mg, 4.10 mmol) and bleach
S 9
(73 ml, ca. 60 mmol NaClO2) were added successively to a stirred and cooled (0 oC)
solution of 4-pentyne-1-ol (3.8 mL, 40 mmol) in CH2Cl2 (160 mL). Ice bath was
removed and stirring was continued for 1 h. The resulting two layers were separated, and
the CH2Cl2 layer was dried and concentrated to ca. 100 mL.
MeMgBr (3.0 M in Et2O, 13.5 mL, 40.5 mmol) was added to a stirred and cooled (-78 oC) aldehyde solution from above. Stirring was continued for 2h at -78 oC. The mixture
was quenched by saturated aqueous NH4Cl and separated. The organic phase was dried
(Na2SO4), and solvent was distilled (55 oC oil bath, 1 atm) to gave the crude 5-hexyne-2-
ol (3.45 g).
BuLi (2.5 M in THF, 29 mL, 72.5 mmol) was added to a stirred and cooled (-78 oC)
solution of 5-hexyne-2-ol (crude, 3.45 g, ca. 35 mmol) in THF (70 mL). After 30 min,
formaldehyde (1.10 g, 36.7 mmol) was added all at once. The bath was removed and
stirring was continued overnight. The mixture was quenched with saturated aqueous
NH4Cl (4 mL), dried (Na2SO4), filtered through a pad of silica gel (using EtOAc), and
evaporated. Flash chromatography of the residue over silica gel, using 2:1 EtOAc/pet.
ether, gave 2-heptyne-1,6-diol (2.1g, 41%, three steps). Rf = 0.26 (EtOAc/pet. ether 1:1); 13C NMR (125.7 MHz, CDCl3): δ = 85.7, 79.0, 67.0, 51.2, 37.3, 23.3, 15.3.
(b) 7-Bromo-hept-5-yn-2-ol (5i): The procedure for the preparation of 5d was followed,
using 2-Heptyne-1,6-diol (2.1 g, 16.4 mmol), CBr4 (5.44 g, 16.4 mmol), Ph3P (4.30 g,
16.4 mmol) and CH2Cl2 (36 mL), and a reaction time of 10 h. Flash chromatography of
the crude mixture over silica gel, using 1:2 EtOAc/pet. ether, gave 7-bromo-hept-5-yn-2-
ol 5i (2.62 g, 84%). Rf = 0.58 (EtOAc/pet. ether 1:1); IR (thin film): ν = 3360, 2967,
2232, 1428, 1215, 1128, 1078, 609 cm−1; 1H NMR (500 MHz, CDCl3): δ = 3.83-3.91 (m,
3H), 2.29-2.35 (m, 2H), 1.95 (s, 1H), 1.54-1.64 (m, 2H). 1.17 (d, J = 6.0 Hz, 3H); 13C
NMR (125.7 MHz, CDCl3): δ = 87.5, 75.7, 66.7, 37.2, 23.3, 15.50, 15.46.
(c) 7-But-2-ynylsulfanyl-hept-5-yn-2-ol (6i): The procedure for the preparation of 6c was
followed, using thioacetic acid S-but-2-ynyl ester 7 (1.75 g, 13.6 mmol), 5i (2.60 g, 13.6
mmol), Na2S2O3 (27 mg, 0.17 mmol), KOH (764 mg, 13.6 mmol) and MeOH (18 mL),
and a reaction time of 5 h. Flash chromatography of the residue over silica gel, using 1:3
EtOAc/pet. ether, gave sulfide 6i (2.6 g, 97%). Rf = 0.28 (EtOAc/pet. ether 1:4); IR (thin
film): ν = 3374, 2918, 2229, 1413, 1230, 1127, 1078, 907, 733 cm−1; 1H NMR (500
S 10
MHz, CDCl3): δ = 3.88 (s, 1H), 3.22-3.42 (m, 4H), 2.28 (s, 2H), 1.48-2.00 (m, 6H), 1.05-
1.30 (m, 3H); 13C NMR (125.7 MHz, CDCl3): δ = 82.9, 79.0, 75.7, 74.1, 67.0, 37.6, 23.3,
19.50, 19.46, 15.4, 3.6.
(d) 7-(But-2-yne-1-sulfonyl)-hept-5-yn-2-ol (2i’): The procedure for the preparation of 2a
was followed, using 6i (2.60 g, 13.2 mmol), mCPBA (9.8 g, 40 mmol) and CH2Cl2 (130
mL), and a reaction time of 5 h. Flash chromatography of the crude product over silica
gel, using 1:1 EtOAc/pet. ether, gave sulfone 2i’ (2.56 g, 85%). Rf = 0.53 (EtOAc/pet.
ether 1:1); IR (thin film): ν = 3531, 2964, 2919, 2241, 1631, 1397, 1325, 1246, 1124, 871
cm−1; 1H NMR (500 MHz, CDCl3): δ = 3.96 (t, J = 2.5 Hz, 2H), 3.94 (q, J = 2.5 Hz, 2H),
3.85-3.93 (m, 1H), 2.28-2.42 (m, 2H), 1.87 (t, J = 2.5 Hz, 3H), 1.77 (s, 1H), 1.57-1.69
(m, 2H), 1.08 (d, J = 6.5 Hz, 3H); 13C NMR (125.7 MHz, CDCl3): δ = 88.6, 84.7, 67.3,
66.7, 66.0, 43.51, 43.48, 37.0, 23.5, 15.4, 3.8; elemental analysis calcd (%) for
C11H16O3S: C 57.87, H 7.06; found: C 57.96, H 6.95.
SO
O
2i Cl 1-(But-2-yne-1-sulfonyl)-6-chlorohept-2-yne (2i): CCl4 (0.34 mL, 3.5 mmol) and Ph3P
(0.918 g, 3.5 mmol) were added successively to a stirred and cooled (0 oC) solution of
alcohol 2i’ (526 mg, 2.3 mmol) in CH3CN (23 mL). The mixture was stirred for 10 h and
the solvent was evaporated. Flash chromatography of the residue over silica gel, using
1:4 EtOAc/pet. ether, gave 2i (495 mg, 87%). Rf = 0.33 (EtOAc/pet. ether 1:4); IR (thin
film): ν = 2959, 2917, 2242, 1445, 1330, 1246, 1177, 1125, 870 cm−1; 1H NMR (400
MHz, CDCl3): δ = 4.07-4.17 (m, 1H), 3.95 (t, J = 2.0 Hz, 2H), 3.93 (q, J = 2.4 Hz, 2H),
2.39-2.46 (m, 2H), 1.77-1.96 (m, 2H), 1.86 (t, J = 2.4 Hz, 3H), 1.50 (d, J = 6.8 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ = 87.3, 84.6, 67.8, 65.9, 57.0, 43.5, 43.4, 38.2, 25.1,
16.4, 3.8; elemental analysis calcd (%) for C11H15ClO2S: C 53.54, H 6.13; found: C
53.70, H 5.91.
SO
O
2j Br
S 11
6-Bromo-1-(but-2-yne-1-sulfonyl)-hept-2-yne (2j): The procedure for the preparation
of 5d was followed, using alcohol 2i’ (424 mg, 1.86 mmol), CBr4 (924 mg, 2.79 mmol),
Ph3P (731 mg, 2.79 mmol) and CH3CN (19 mL), and a reaction time of 3 h. Flash
chromatography of the crude mixture over silica gel, using 1:4 EtOAc/pet. ether, gave
bromide 2j (440 mg, 81%). Rf = 0.35 (EtOAc/pet. ether 1:4); IR (thin film): ν = 2958,
2918, 2242, 1443, 1330, 1245, 1176, 1125, 870 cm−1; 1H NMR (500 MHz, CDCl3): δ =
4.22 (sextet, J = 7.0 Hz, 1H), 3.97 (t, J = 2.5 Hz, 2H), 3.95 (q, J = 2.5 Hz, 2H), 2.46 (tt, J
= 7.0, 2.5 Hz, 2H), 1.96 (q, J = 7.0 Hz, 2H), 1.88 (t, J = 2.5 Hz, 3H), 1.72 (d, J = 7.0 Hz,
3H); 13C NMR (125.7 MHz, CDCl3): δ = 87.2, 84.7, 68.1, 66.0, 49.7, 43.6, 43.4, 39.0,
26.3, 17.7, 3.8; elemental analysis calcd (%) for C11H15BrO2S: C 45.37, H 5.19; found: C
45.57, H 5.09.
SO
O
2k OTBDPS tert-Butyl-[6-(but-2-yne-1-sulfonyl)-1-methylhex-4-ynyloxy]-diphenylsilane (2k):
TBDPSCl (0.9 mL, 3.46 mmol) and imidazole (242 mg, 3.55 mmol) was added
successively to a stirred solution of 2i’ (267 mg, 1.17 mmol) in CH2Cl2 (24 mL), and the
mixture was stirred for 12 h. After quenched by saturated aqueous NH4Cl, the mixture
was extracted with Et2O, washed with brine, dried (Na2SO4) and evaporated. Flash
chromatography of the residue over silica gel, using 1:5 EtOAc/pet. ether, gave 2k (531
mg, 97%) as colorless oil. Rf = 0.44 (EtOAc/pet. ether 1:4); IR (thin film): ν = 2961,
2858, 2243, 1589, 1428, 1334, 1126, 1025, 704 cm−1; 1H NMR (500 MHz, CDCl3): δ =
7.63-7.69 (m, 4H), 7.33-7.44 (m, 6H), 3.91 (sextet, J = 6.0 Hz, 1H), 3.90 (t, J = 2.5 Hz,
2H), 3.88 (q, J = 2.5 Hz, 2H), 2.30 (tt, J = 7.5, 2.5 Hz, 2H), 1.87 (t, J = 2.5 Hz, 3H), 1.57-
1.76 (m, 2H), 1.03 (d, J = 6.0 Hz, 3H), 1.03 (s, 9H); 13C NMR (125.7 MHz, CDCl3): δ =
135.83, 135.81, 134.5, 134.0, 129.6, 129.5, 127.6, 127.4, 88.9, 84.5, 68.3, 66.8, 66.0,
43.5, 43.3, 37.7, 27.0, 23.1, 19.2, 15.0, 3.8.
SO
O
2l O
S 12
7-(But-2-yne-1-sulfonyl)-hept-5-yn-2-one (2l): Dess-Martin reagent (2.33 g, 5.5 mmol)
was added to a stirred solution of 2i’ (628 mg, 2.75 mmol) in CH2Cl2 (27.5 mL). After
90 min, the mixture was diluted with Et2O, washed with a 1:1 mixture of saturated
aqueous NaHCO3 and 10% aqueous Na2S2O3, and brine, dried (Na2SO4) and evaporated.
Flash chromatography of the residue over silica gel, using 1:1 EtOAc/pet. ether, gave 2l
(614 mg, 99%) as a white solid. Rf = 0.55 (EtOAc/pet. ether 1:1); m.p. 65 oC; IR (thin
film): ν = 2958, 2914, 2242, 1713, 1400, 1369, 1326, 1246, 1168, 1124, 872, 735 cm−1; 1H NMR (500 MHz, CDCl3): δ = 3.85-3.95 (m, 4H), 2.63 (t, J = 7.0 Hz, 2H), 2.42 (tt, J =
7.0, 2.5 Hz, 2H), 2.10 (s, 3H), 1.82 (t, J = 2.5 Hz, 3H); 13C NMR (125.7 MHz, CDCl3): δ
= 206.1, 87.4, 84.4, 67.3, 65.9, 43.35, 43.26, 41.5, 29.7, 13.1, 3.7; elemental analysis
calcd (%) for C11H14O3S: C 58.38, H 6.24; found: C 58.28, H 5.93.
SO
O
2m' OH 8-(But-2-yne-1-sulfonyl)-oct-6-yn-2-ol (2m’): (a) 2-Octyne-1,7-diol: The procedure for
the preparation of hept-2-yne-1,6-diol was followed, using 5-hexyn-1-ol (5.6 mL, 50
mmol), CH2Cl2 (200 mL), 5% Aqueous NaHCO3 (110 mL), TEMPO (80 mg, 0.51
mmol), KBr (610 mg, 5.1 mmol), bleach (90 mL, ca. 75 mmol NaClO2); MeMgBr (17
mL, 3.0 M in Et2O, 51 mmol); BuLi (29 mL, 2.5 M in THF, 72.5 mmol), THF (70 mL),
formaldehyde (1.10 g, 36.7 mmol). Flash chromatography of the residue over silica gel,
using 3:2 EtOAc/pet. ether, gave 2-octyne-1,7-diol (2.15 g, 30% over three steps). Rf =
0.28 (EtOAc/pet. ether 1:1); IR (thin film): ν = 3355, 2932, 2867, 2225, 1643, 1457,
1375, 1133, 1013 cm−1; 1H NMR (400 MHz, CDCl3): δ = 4.12-4.22 (m, 2H), 3.71-3.83
(m, 1H), 3.25 (s, 1H), 2.50-2.60 (m, 1H), 2.13-2.24 (m, 2H), 1.41-1.65 (m, 4H), 1.40 (d, J
= 6.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ = 85.7, 78.9, 67.5, 50.8, 38.0, 24.6,
23.3, 18.6.
(b) 8-Bromooct-6-yn-2-ol (5m): The procedure for the preparation of 5d was followed,
using 2-octyne-1,7-diol (1.76 g, 12.4 mmol), CBr4 (4.11 g, 12.4 mmol), Ph3P (3.25 g,
12.4 mmol), and CH2Cl2 (28 mL), and a reaction time of 12 h. Flash chromatography of
the residue over silica gel, using 1:2 EtOAc/pet. ether, gave bromide 5m (1.8 g, 71%). Rf
S 13
= 0.54 (EtOAc/pet. ether 1:1); IR (thin film): ν = 3364, 2965, 2232, 1634, 1456, 1374,
1216, 1129, 1086, 608 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.87 (t, J = 2.4 Hz, 2H),
3.75 (sextet, J = 6.0 Hz, 1H), 2.22 (tt, J = 6.4, 2.4 Hz, 2H), 1.84 (s, 1H), 1.42-1.65 (m,
4H), 1.40 (d, J = 6.0 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ = 87.8, 75.5, 67.4, 38.1,
24.5, 23.5, 18.8, 15.6; elemental analysis calcd (%) for C8H13BrO: C 46.85, H 6.39;
found: C 46.66, H 6.17.
(c) 8-But-2-ynylsulfanyl-oct-6-yn-2-ol (6m): The procedure for the preparation of 6c was
followed, using thioacetic acid S-but-2-ynyl ester 7 (1.13 g, 8.82 mmol), 5m (1.8 g, 8.78
mmol), Na2S2O3 (18 mg, 0.11 mmol), KOH (495 mg, 8.82 mmol) and MeOH (12 mL),
and a reaction time of 5 h. Product 6m (2.7 g) was used as crude in the next step. Rf =
0.19 (EtOAc/pet. ether 1:4).
(d) 8-(But-2-yne-1-sulfonyl)-oct-6-yn-2-ol (2m’): The procedure for the preparation of 2a
was followed, using 6m (2.70 g, ca. 8.78 mmol), mCPBA (6.5 g, 26.4 mmol) and CH2Cl2
(85 mL), and a reaction time of 5 h. Flash chromatography of the crude product over
silica gel, using 1:1 EtOAc/pet. ether, gave sulfone 2m’ (1.62 g, 76% over two steps). Rf
= 0.49 (EtOAc/pet. ether 1:1); IR (thin film): ν = 3535, 3404, 2962, 2914, 2241, 1631,
1327, 1125, 871 cm−1; 1H NMR (500 MHz, CDCl3): δ = 3.97 (t, J = 2.5 Hz, 2H), 3.95 (q,
J = 2.5 Hz, 2H), 3.81 (sextet, J = 6.0 Hz, 1H), 2.27 (tt, J = 7.0, 2.5 Hz, 2H), 1.88 (t, J =
2.5 Hz, 3H), 1.50-1.71 (m, 4H), 1.49 (br s, 1H), 1.18 (d, J = 6.0 Hz, 3H); 13C NMR
(125.7 MHz, CDCl3): δ = 88.8, 84.6, 67.3, 67.2, 66.0, 43.5, 43.4, 38.1, 24.3, 23.5, 18.7,
3.8; elemental analysis calcd (%) for C12H18O3S: C 59.47, H 7.49; found: C 59.60, H
7.52.
SO
O
2m O 8-(But-2-yne-1-sulfonyl)-oct-6-yn-2-one (2m): Dess-Martin reagent (1.99 g, 4.69
mmol) was added to a stirred solution of 2m’ (568 mg, 2.34 mmol) in CH2Cl2 (23 mL).
After 3 h, the mixture was diluted with Et2O, washed with a 1:1 mixture of saturated
aqueous NaHCO3 and 10% aqueous Na2S2O3, and brine, dried (Na2SO4) and evaporated.
Flash chromatography of the residue over silica gel, using 1:1 EtOAc/pet. ether, gave 2m
S 14
(555 mg, 99%). Rf = 0.54 (EtOAc/pet. ether 1:1). IR (thin film): ν = 2957, 2913, 2241,
1712, 1372, 1328, 1177, 1125, 871 cm−1; 1H NMR (500 MHz, CDCl3): δ = 3.95 (t, J =2.5
Hz, 2H), 3.92 (q, J = 2.5 Hz, 2H), 2.54 (t, J = 7.0 Hz, 2H), 2.26 (tt, J = 7.0, 2.5 Hz, 2H),
2.11 (s, 3H), 1.85 (t, J = 2.5 Hz, 3H), 1.75 (quintet, J = 7.0 Hz, 2H); 13C NMR (125.7
MHz, CDCl3): δ = 208.0, 88.0, 84.7, 67.8, 66.0, 43.5, 43.4, 41.8, 30.0, 21.9, 18.1, 3.8;
elemental analysis calcd (%) for C12H16O3S: C 59.97, H 6.71; found: C 59.74, H 6.86.
2n O
EtO2C
EtO2C
2-But-2-ynyl-2-(6-oxo-hept-2-ynyl)-malonic acid diethyl ester (2n): (a) 2-But-2-ynyl-
2-(6-hydroxyhept-2-ynyl)-malonic acid diethyl ester (2n’): 2-(2-butynyl)malonic acid
diethyl ester (608 mg, 2.86 mmol) in THF (2.8 mL) was added to a stirred and cooled (0 oC) solution of NaH (114 mg, 2.85 mmol) in THF (2.8 mL). After 30 min, bromide 5i
(365 mg, 1.91 mmol) in THF (2 mL) was added, and stirring was continued at 0 oC for 2
h. The mixture was quenched with saturated aqueous NH4Cl, extracted with Et2O, dried
(Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, using 1:2
EtOAc/pet. ether, gave 2n’ (591 mg, 96%). Rf = 0.59 (EtOAc/pet. ether 1:1); IR (thin
film): ν = 3428, 2979, 2925, 2237, 1739, 1430, 1295, 1210, 1072, 1053, 861 cm−1; 1H
NMR (500 MHz, CDCl3): δ = 4.15 (q, J = 7.0 Hz, 4H), 3.83 (sextet, J = 6.5 Hz, 1H), 2.84
(t, J = 2.5 Hz, 2H), 2.82 (t, J = 2.5 Hz, 2H), 2.11-2.26 (m, 2H), 1.92 (s, 1H), 1.69 (t, J =
2.5 Hz, 3H), 1.52 (q, J = 6.5 Hz, 2H), 1.19 (t, J = 7.0 Hz, 6H), 1.13 (d, J = 6.5 Hz, 3H); 13C NMR (125.7 MHz, CDCl3): δ = 169.2, 82.9, 78.8, 74.8, 73.1, 66.8, 61.6, 56.9, 37.6,
23.2, 22.78, 22.76, 15.2, 13.9, 3.4.
(b) 2-But-2-ynyl-2-(6-oxo-hept-2-ynyl)-malonic acid diethyl ester (2n): Dess-Martin
reagent (1.08 g, 2.55 mmol) was added to a stirred solution of 2n’ (411.5 mg, 1.276
mmol) in CH2Cl2 (13 mL). After 90 min, the mixture was diluted with Et2O, washed
with a 1:1 mixture of saturated aqueous NaHCO3 and 10% aqueous Na2S2O3, and brine,
dried (Na2SO4) and evaporated. Flash chromatography of the residue over silica gel,
using 1:3 EtOAc/pet. ether, gave 2n (408 mg, 100%). Rf = 0.59 (EtOAc/pet. ether 1:1);
IR (thin film): ν = 2983, 2924, 2237, 1736, 1430, 1367, 1291, 1209, 1053, 861 cm−1; 1H
S 15
NMR (400 MHz, CDCl3): δ = 4.15 (q, J = 7.2 Hz, 4H), 2.84 (t, J = 2.4 Hz, 2H), 2.81 (q, J
= 2.4 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H), 2.32 (tt, J = 7.2, 2.4 Hz, 2H), 2.11 (s, 3H), 1.69 (t,
J = 2.4 Hz, 3H), 1.20 (t, J = 7.2 Hz, 6H); 13C NMR (100.6 MHz, CDCl3): δ = 206.7,
169.1, 81.9, 78.8, 74.9, 73.1, 61.6, 56.8, 42.6, 29.8, 22.73, 22.67, 14.0, 13.2, 3.4;
elemental analysis calcd (%) for C18H24O5: C 67.48, H 7.55; found: C 67.60, H 7.36.
TsN
O2o N-But-2-ynyl-4-methyl-N-(6-oxohept-2-ynyl)-benzenesulfonamide (2o): N-But-2-
ynyl-N-(6-hydroxyhept-2-ynyl)-4-methylbenzene-sulfonamide (2o’): Ph3P (525 mg, 2
mmol) and DIAD (0.4 mL, 2 mmol) was added successively to a stirred and cooled (0 oC)
solution of N-but-2-ynyl-4-methylbenzenesulfonamide (446 mg, 2 mmol) and 2-heptyne-
1,6-diol (256 mg, 2 mmol) in THF (20 mL). The cooling bath was removed and stirring
was continued overnight. The solvent was evaporated in vacuo. Flash chromatography
of the residue over silica gel, using 1:2 EtOAc/pet. ether, gave 2o’ (400 mg, 60%) as
colorless oil. Rf = 0.40 (EtOAc/pet. ether 1:1); 1H NMR (400 MHz, CDCl3): δ = 7.67 (d,
J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 4.06 (t, J = 2.0 Hz, 2H), 4.02 (q, J = 2.0 Hz,
2H), 3.76 (sextet, J = 6.4 Hz, 1H), 2.38 (s, 3H), 2.10 (tt, J = 6.4, 2.0 Hz, 2H), 1.66 (s,
1H), 1.61 (t, J = 2.0 Hz, 3H), 1.44 (q, J = 6.4 Hz, 2H), 1.13 (d, J = 6.4 Hz, 3H); 13C NMR
(100.6 MHz, CDCl3): δ = 143.5, 135.4, 129.2, 127.9, 85.6, 81.6, 72.8, 71.5, 66.8, 37.3,
36.58, 36.57, 23.3, 21.5, 15.1, 3.4.
(b) N-But-2-ynyl-4-methyl-N-(6-oxohept-2-ynyl)-benzenesulfon-amide (2o): Dess-Martin
reagent (656 mg, 1.55 mmol) was added to a stirred solution of 2o’ (258 mg, 0.774
mmol) in CH2Cl2 (8 mL). After 1h, the mixture was diluted with Et2O, washed with a 1:1
mixture of saturated aqueous NaHCO3 and 10% aqueous Na2S2O3, and brine, dried
(Na2SO4) and evaporated. Flash chromatography of the residue over silica gel, using 2:5
EtOAc/pet. ether, gave 2o (230 mg, 90%). Rf = 0.55 (EtOAc/pet. ether 1:1); IR (thin
film): ν = 2921, 2236, 1718, 1598, 1433, 1350, 1163, 1094, 904, 748, 659 cm−1; 1H NMR
(400 MHz, CDCl3): δ = 7.64 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 4.01 (t, J = 2.0
Hz, 2H), 4.00 (q, J = 2.4 Hz, 2H), 2.45 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.21 (tt, J = 7.2,
2.0 Hz, 2H), 2.07 (s, 3H), 1.58 (t, J = 2.4 Hz, 3H); 13C NMR (100.6 MHz, CDCl3): δ =
S 16
206.2, 143.4, 135.3, 129.2, 127.9, 84.5, 81.6, 72.8, 71.3, 41.9, 36.5, 36.4, 29.7, 21.4, 12.9,
3.3; elemental analysis calcd (%) for C18H21NO3S: C 65.23, H 6.39; found: C 65.03, H
6.21.
S 17
Compound 2d (13C NMR)
S 18
Compound 2d (1H NMR)
S 19
Compound 2k (13C NMR)
S 20
Compound 2k (1H NMR)
S 21
Compound 3h (13C NMR)
S 22
Compound 3h (1H NMR)
S 23
Compound 3j (13C NMR)
S 24
Compound 3j (1H NMR)
S 25
Compound 3j’ (13C NMR)
S 26
Compound 3j’ (1H NMR)
S 27
Compound 3k’ (13C NMR)
S 28
Compound 3k’ (1H NMR)
S 29
Compound 3n’ (13C NMR)
S 30
Compound 3n’ (1H NMR)
S 31
Compound 4c (13C NMR)
S 32
Compound 4c (1H NMR)
S 33
Compound 4k (13C NMR)
S 34
Compound 4k (1H NMR)
S 35
Compound 7 (13C NMR)
S 36
Compound 7 (1H NMR)
S 37
Compound 13 (13C NMR)
S 38
Compound 13 (1H NMR)
S 39
Compound 14 (13C NMR)
S 40
Compound 14 (1H NMR)
S 41
Compound 15 (13C NMR)
S 42
Compound 15 (1H NMR)
S 43
Compound 16 (13C NMR)
S 44
Compound 16 (1H NMR)