Convenient access to bicyclic and tricyclic diazenes

Article abstract of DOI:10.1021/jo8017704

(Chemical Equation Presented) Heating the tosylhydrazone of an ω-alkenyl ketone or aldehyde to reflux in toluene in the presence of K₂CO₃ delivered the bicyclic diazene. Irradiation of the diazene converted it to the cyclopropane. Th

Full text of DOI:10.1021/jo8017704

Convenient Access to Bicyclic and Tricyclic Diazenes
Douglass F. Taber and Pengfei Guo
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716
taberdf@udel.edu
Supporting Information
Contents
General experimental……………………………………………………………S2
Experimental procedures……………………………………………………….. S3 – S26
X-ray of Diazene 2a……………………………………………………………...S26
References.............................................................................................................S27
1
13
H NMR and C NMR spectra …………………………………..…….…...…..S28 – S64
S1

General:
1
13
H NMR and C NMR spectra were recorded, as solutions in deuteriochloroform
1
3
(
3
CDCl ) unless otherwise indicated, at 400 MHz and 100 MHz, respectively. C
multiplicities were determined with the aid of a JVERT pulse sequence, differentiating
the signals for methyl and methine carbons as "d" from methylene and quaternary
carbons as "u". The infrared (IR) spectra were determined as neat oils. Rf values
indicated refer to thin layer chromatography (TLC) on 2.5 x 10 cm, 250 µm analytical
plates coated with silica gel GF, unless otherwise noted, and developed in the solvent
system indicated. All glassware was oven dried and rinsed with dry solvent before use.
THF and diethyl ether were distilled from sodium metal/benzophenone ketyl under dry
nitrogen. MTBE is methyl tert-butyl ether and PE is petroleum ether. All reactions were
2
conducted under N and stirred magnetically.
S2

O
MgCl
mCPBA,
CH Cl
Cl
O
THF
2
2
O
O
O
BrMg
CuI, THF
6
7%
HO
7
1
-(4-Methoxyphenyl)oct-7-en-3-ol (7). To a stirred solution of p-methoxy benzyl
chloride (3.28 g, 20.9 mmol) in dry THF (20 mL), was dropwise added allylmagnesium
chloride (40 mmol) in THF over 5 min at 0℃. After stirring for 5 h at 60℃, the reaction
mixture was quenched with methanol (3 mL). The mixture was partitioned between
CH
Na
To a stirred solution of the above crude alkene in dry CH
mCPBA (6.27g, 27.9 mmol) at rt. After stirring overnight at rt, the reaction mixture was
diluted with CH Cl (100 mL), washed with saturated aqueous NaHSO and then with 1
) and concentrated to afford crude
2
Cl
2
and, sequentially, water and brine. The combined organic extracts were dried
(
2
SO
4
) and concentrated to give crude alkene (3.45 g).
2
2
Cl (50 mL) was added
2
2
3
M NaOH. The organic extracts were dried (Na
2 4
SO
epoxide (3.41 g).
To a stirred solution of 4-butenyl magnesium bromide {freshly prepared with Mg (2.1 g,
7.5 mmol), 4-bromo-1-butene (7.15 g, 53.0 mmol) and I in dry THF (30 mL)} in dry
8
2
THF was added CuI (672 mg, 3.53 mmol) at 0℃. It was stirred for 5 min at 0℃ and then
the solution of the above crude epoxide in THF (5 mL) was added. After stirring
4
overnight at rt, the reaction mixture was quenched with saturated aqueous NH Cl (10
S3

mL) and then partitioned between CH
combined organic extracts were dried (Na
chromatographed to yield alcohol 7 (3.31 g, 67% yield from p-methoxy benzyl chloride)
2
Cl
2
and, sequentially, water and brine. The
2
SO ) and concentrated. The residue was
4
-1
f
as a colorless oil: TLC R (20% MTBE/PE) = 0.33; IR (cm ) 3380, 2929, 1510, 1240,
1
1
4
1
3
034; H NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.75-5.85 (m 1H),
.90-5.05 (q, 2H), 3.75 (s, 3H), 3.60 (s, 1H), 2.70 (m, 1H), 2.60 (m, 1H), 2.05 (m, 2H),
13
.70 (m, 2H), 1.40-1.60 (m, 5H); C NMR δ u 157.8, 134.2, 114.7, 39.4, 37.0, 33.7,
+
1.2, 24.9; d 138.7, 129.3, 113.9, 71.2, 55.3; HRMS calcd for C15
H
22
O
2
(M ) 234.1620,
obsd 234.1618.
O
O
DM, CH Cl2
2
80%
HO
O
7
1b
1
-(4-Methoxyphenyl)oct-7-en-3-one (1b). To a stirred solution of the alcohol 7 (360
mg, 1.54 mmol) in dry CH Cl (5 mL), was added Dess-Martin periodinane reagent (748
2
2
mg, 1.69 mmol) at 0℃. The reaction mixture was stirred for 15 min at 0℃ and then
concentrated. The residue was chromatographed to yield ketone 1b (286 mg, 80% yield)
-1
1
f
as a colorless oil: TLC R (20% MTBE/PE) = 0.53; IR (cm ) 1707, 1510, 1245; H NMR
δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.75 (m, 1H), 5.00 (q, 2H), 3.75 (s,
1
3
3
H), 2.80 (m, 2H), 2.65 (m, 2H), 2.35 (t, J = 7.4 Hz, 2H), 2.00 (m, 2H), 1.65 (m, 2H); C
NMR δ u 210.2, 157.9, 133.2, 115.2, 44.6, 42.2, 33.1, 28.9, 22.7; d 138.0, 129.3, 113.9,
+
5
5.3; HRMS calcd for C15
H
21
O
2
(MH ) 233.1541, obsd 233.1551.
S4

O
O
H
O
N
N
1
b
2
b
6
1
a-(4-Methoxyphenethyl)-3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole (2b). Ketone
b (263 mg, 1.13 mmol) and tosylhydrazine (1.05 equiv, 223 mg, 1.20 mmol) were
stirred in MeOH (4 mL) at rt overnight. The MeOH was removed under reduced pressure,
the crude hydrazone was redissolved in toluene (3 mL), K CO (6 equiv, 950 mg, 6.9
mmol) was added and the reaction mixture was heated in a sealed vial at 120℃ (oil bath)
for 16 h. After cooling to rt, the reaction mixture was partitioned between CH Cl and,
sequentially, water and brine. The combined organic extracts were dried (Na SO ) and
concentrated. The residue was chromatographed to yield 2b (211 mg, 76% yield) as a
2
3
2
2
2
4
-1
f 2 2
pale yellow oil: TLC R (5% MTBE/ CH Cl ) = 0.40; IR (cm ) 2939, 1609, 1506, 1241;
1
H NMR δ 7.05 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 4.60 (dd, J = 9.2, 18.4 Hz,
H), 4.35 (dd, J = 3.2, 18.4 Hz, 1H), 3.75 (s, 3H), 2.40-2.55 (m, 2H), 2.30 (m, 2H), 2.10
1
1
3
(
m, 1H), 1.90 (m, 1H), 1.70 (m, 2H), 1.55 (m, 1H), 1.35 (m, 1H), 1.00 (m, 1H); C NMR
δ u 157.9, 133.8, 104.7, 85.8, 39.4, 36.3, 34.5, 30.4, 23.6; d 129.7, 113.9, 55.3, 37.8;
+
HRMS calcd for C15
H
21
N
2
O (MH ) 245.1654, obsd 245.1663.
O
O
H
H
N
N
2b
3b
1
-(4-Methoxyphenethyl)bicyclo[3.1.0]hexane (3b). A solution of diazene 2b (40 mg,
S5

0
.16 mmol) in dry toluene (6 mL) was photolyzed for 16 h at rt in a Rayonet apparatus
350 nm). The reaction mixture was concentrated and chromatographed to yield
cyclopropane 3b (26 mg, 72% yield) as a colorless oil: TLC R (CH Cl ) = 0.80; IR (cm
(
-
f
2
2
1
1
)
2919, 1609, 1510, 1240; H NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H),
3
.70 (s, 3H), 2.60 (t, J = 8.2 Hz, 2H), 2.30 (m, 1H), 1.50-1.90 (m, 6H), 1.20 (m, 1H), 0.95
1
3
(
m, 1H), 0.30 (m, 1H), 0.20 (m, 1H); C NMR δ u 157.6, 135.2, 38.6, 33.6, 31.3, 27.7,
+
2
4.2, 21.4, 12.2; d 129.2, 113.6, 55.3, 23.3; HRMS calcd for C15
H
20O (M ) 216.1514,
obsd 216.1518.
O
O
1) O , CH Cl , MeOH;
3 2 2
2
) PPh , NaHCO
3
3
HO
HO
O
9
1%
7
8
6
-(4-Methoxyphenethyl)-tetrahydro-2H-pyran-2-ol (8). Ozone was passed through a
stirred solution of alkene 7 (1.67 g, 7.13 mmol) in dry CH Cl (5 mL) and MeOH (15
mL) at -78℃. After stirring at -78℃ for 10 min, the color of the reaction mixture changed
to pale blue. N was then passed through to remove the excess ozone. PPh (3.2 g) and
NaHCO (3.2 g) were added at -78℃. The reaction mixture was warmed to rt and stirred
for an additional hour. Then the mixture was partitioned between CH Cl and,
sequentially, water and brine. The combined organic extracts were dried (Na SO
concentrated. The residue was chromatographed to yield lactol 8 (1.52 g, 91% yield, a 3:2
mixture of two isomers) as a white solid: mp 85℃; TLC R (20% MTBE/PE) = 0.59; IR
2
2
2
3
3
2
2
2
4
) and
f
-
1
1
(
cm ) 3400, 2929, 1609, 1506; H NMR δ 7.10 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz,
S6

2
H), 5.60 (m, 0.4H), 4.70 (m, 0.6H), 3.95 (m, 0.4H), 3.80 (s, 3H), 3.40 (m, 0.6H), 3.00
(
d, J = 6.3 Hz, 0.6H), 2.70 (m, 1H), 2.60 (m, 1H), 2.45 (m, 0.4H), 1.75 (m, 2H), 1.45-
1
3
1
3
.70 (m, 4H), 1.15-1.35 (m, 2H); C NMR δ u 157.7, 134.3, 38.1, 37.8, 32.9, 31.2, 30.8,
0.4, 29.8, 22.1, 17.4; d 129.3, 113.8, 96.5, 91.2, 75.4, 68.0, 55.3.
O
O
CH CH PPh Br,
3
2
3
KH(P), THF
HO
O
HO
95%
8
9
(
Z)-1-(4-Methoxyphenyl)non-7-en-3-ol (9). To the mixture of ethyl
triphenylphosphonium bromide (757 mg, 2.04 mmol) and KH (125 mg, 50% in paraffin,
.56 mmol) was added dry THF (5 mL) at rt. After stirring at rt for 5 min, a solution of
1
lactol 8 (241 mg, 1.02 mmol) in dry THF (1 ml) was added and the reaction mixture was
3
stirred for another 30 min at rt. The reaction mixture was quenched with saturated
aqueous NH
4
Cl (5 mL) and then partitioned between CH
2
4
Cl
2
and, sequentially, water and
brine. The combined organic extracts were dried (Na
2
SO
) and concentrated. The residue
was chromatographed to yield alcohol 9 (240 mg, 95% yield, a ~ 5 : 1 Z/E mixture) as a
-
1
1
colorless oil: TLC R
f
(20% MTBE/PE) = 0.24; IR (cm ) 3371, 2929, 1609, 1510; H
NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.30-5.50 (m, 2H), 3.75 (s,
3
6
3
H), 3.60 (bs, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 2.05 (m, 2H), 1.70 (m, 2H), 1.55 (d, J =
1
3
.6 Hz, 3H), 1.30-1.50 (m, 5H); C NMR (major isomer) δ u 157.8, 134.2, 39.3, 37.1,
24 2
1.1, 26.8, 25.5; d 129.3, 128.5, 124.2, 113.9, 71.3, 55.3, 12.8; HRMS calcd for C16H O
+
(
M ) 248.1776, obsd 248.1775.
S7

O
O
DM, CH Cl2
2
HO
O
8
4%
1
c
9
(
Z)-1-(4-Methoxyphenyl)non-7-en-3-one (1c). To a solution of the alcohol 9 (203.8 mg,
0
0
.82 mmol) in dry CH
2 2
Cl (3 mL), was added Dess-Martin periodinane reagent (398 mg,
.90 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min and then
concentrated. The residue was chromatographed to yield ketone 1c (169 mg, 84% yield, a
-1
~
f
5 : 1 Z/E mixture) as a colorless oil: TLC R (20%MTBE/PE) = 0.59; IR (cm ) 2929,
1
1
1
708, 1609, 1510; H NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.45 (m,
H), 5.30 (m, 1H), 3.75 (s, 3H), 2.80 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.35 (t,
1
3
J = 7.5 Hz, 2H), 2.00 (q, 2H), 1.65 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H); C NMR (major
isomer) δ u 210.3, 157.9, 133.2, 44.6, 42.3, 28.9, 26.1, 23.5; d 129.6, 129.3, 124.8, 113.9,
+
5
5.2, 12.8; HRMS calcd for C16
H
22
O
2
(M ) 246.1620, obsd 246.1618.
O
O
H
O
N
N
1
c
2
c
6
a-(4-Methoxyphenethyl)-3-methyl-3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole
(
2c). Ketone 1c (78.5 mg, 0.32 mmol) and tosylhydrazine (1.05 equiv, 63 mg, 0.34
mmol) were stirred in MeOH (2 mL) at rt overnight. The MeOH was removed under
reduced pressure, the crude hydrazone was redissolved in toluene (3 mL), K CO (6
2
3
equiv, 263 mg, 1.9 mmol) was added and the reaction mixture was heated in a sealed vial
S8

at 120℃ (oil bath) for 16 h. After cooling to rt, the reaction mixture was partitioned
between CH Cl and, sequentially, water and brine. The combined organic extracts were
dried (Na SO ) and concentrated. The residue was chromatographed to yield diazene 2c
58 mg, 70% yield, a ~ 5:1 mixture of diastereomers) as a pale yellow oil: TLC R (5%
MTBE/PE) = 0.41; IR (cm ) 2939, 1609, 1510, 1240; H NMR δ 7.10 (d, J = 8.6 Hz,
H), 6.80 (d, J = 8.6 Hz, 2H), 4.25-4.40 (m, 1H), 3.30 (s, 3H), 2.35-2.70 (m, 3H), 2.25
m, 1H), 2.10 (m, 1H), 1.95 (m, 1H), 1.75 (m, 1H), 1.55-1.60 (m, 2H), 1.50 (d, J = 7.6
2
2
2
4
(
f
-
1
1
2
(
1
3
Hz, 3H), 1.40- 1.45 (m, 1H), 0.95 (m, 1H); C NMR (major isomer) δ u 157.9, 134.0,
1
05.7, 40.7, 36.5, 30.4, 27.8, 23.7; d 129.1, 113.9, 86.2, 55.3, 41.7, 13.8; HRMS calcd for
+
C
16
H
23
N
2
O (MH ) 259.1810, obsd 259.1814.
O
O
H
H
N
N
2
c
3c
1
-(4-Methoxyphenethyl)-6-methylbicyclo[3.1.0]hexane (3c). A solution of diazene 2c
(
45 mg, 0.17 mmol) in dry toluene (6 mL) was photolyzed for 24 h at rt in a Rayonet
apparatus (350 nm). The reaction mixture was concentrated and chromatographed to
yield cyclopropane 3c (29 mg, 71% yield, a 1:1 mixture of diastereomers) as a colorless
-
1
1
oil: TLC R
f
(CH
2 2
Cl ) = 0.75; IR (cm ) 2918, 1643, 1510, 1245; H NMR δ 7.10 (m, 2H),
6
1
3
.80 (m, 2H), 3.70 (s, 3H), 2.60 (m, 2H), 2.30 (m, 1H), 1.45-2.00 (m, 7H), 1.10-1.35 (m,
1
3
H), 0.80-1.00 (m, 3H), 0.60 (m, 1H); C NMR δ u 157.6, 135.4, 135.2, 40.7, 33.9, 33.7,
3.6, 33.5, 32.7, 32.1, 29.1, 28.0, 26.9, 25.0, 22.0; d 129.2, 113.7, 113.6, 55.3, 31.1, 28.2,
S9

+
2
1.2, 16.8, 13.2, 8.1; HRMS calcd for C16H23O (MH ) 231.1749, obsd 231.1750.
O
O
(
CH ) CHPPh I,
3 2 3
KH(P), THF
HO
O
HO
10
72%
8
1
-(4-Methoxyphenyl)-8-methylnon-7-en-3-ol (10). To the mixture of isopropyl
triphenylphosphonium iodide (846 mg, 1.96 mmol) and KH (121 mg, 50% in paraffin,
.51 mmol) was added dry THF (5 mL) at rt. After stirring at rt for 5 min, a solution of
lactol 8 (220 mg, 0.93 mmol) in dry THF (1 ml) was added and the reaction mixture was
1
stirred at reflux for 2 h. Then the mixture was quenched with saturated aqueous NH
mL) and then partitioned between CH Cl and, sequentially, water and brine. The
combined organic extracts were dried (Na SO ) and concentrated. The residue was
chromatographed to yield alcohol 10 (177 mg, 72% yield) as a colorless oil: TLC R
4
Cl (5
2
2
2
4
f
(5%
-
1
1
MTBE/ CH
2
Cl
.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.10 (m, 1H), 3.75 (s, 3H), 3.60 (bs, 1H), 2.70 (m,
H), 2.60 (m, 1H), 1.95 (m, 2H), 1.70-1.80 (m, 2H), 1.65 (s, 3H), 1.55 (s, 3H), 1.30-1.50
2
) = 0.52; IR (cm ) 3351, 2918, 1609, 1506, 1240; H NMR δ 7.10 (d, J =
8
1
1
3
(
m, 5H); C NMR δ u 157.7 134.3, 131.7, 39.3, 37.2, 31.2, 28.0, 25.9; d 128.3, 124.4,
+
1
13.8, 71.3, 55.3, 25.8, 17.7; HRMS calcd for C17
C
26
O
2
(M ) 262.1933, obsd 262.1925.
O
O
DM, CH Cl2
2
85%
HO
O
10
1d
1
-(4-Methoxyphenyl)-8-methylnon-7-en-3-one (1d). To a solution of the alcohol 10
S10

(
(
162 mg, 0.62 mmol) in dry CH
2 2
Cl (3 mL), was added Dess-Martin periodinane reagent
302 mg, 0.68 mmol) at 0℃. The reaction mixture was stirred at 0℃ for 30 min and then
concentrated. The residue was chromatographed to yield ketone 1d (136 mg, 85% yield)
-1
1
as a colorless oil: TLC R
f 2 2
(CH Cl ) = 0.40; IR (cm ) 2929, 1708, 1511, 1447, 1245; H
NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 5.05 (t, 1H), 3.75 (s, 3H), 2.80
(
t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 1.95 (q, 2H), 1.65 (s,
1
3
3
2
2
H), 1.55-1.60 (m, 2H), 1.55 (s, 3H); C NMR δ u 210.5, 157.9, 133.2, 132.4, 44.6, 42.4,
+
8.9, 27.4, 23.9; d 129.3, 123.8, 113.9, 55.2, 25.7, 17.7; HRMS calcd for C17
60.1776, obsd 260.1771.
H
24
O
2
(M )
O
O
H
O
N
N
1d
2d
6
a-(4-Methoxyphenethyl)-3,3-dimethyl-3,3a,4,5,6,6a-
hexahydrocyclopenta[c]pyrazole (2d). Ketone 1d (75 mg, 0.29 mmol) and
tosylhydrazine (1.05 equiv, 58 mg, 0.31 mmol) were stirred in MeOH (2 mL) at rt
overnight. The MeOH was removed under reduced pressure, the crude hydrazone was
redissolved in toluene (3 mL), K CO (6 equiv, 245 mg, 1.77 mmol) was added and the
reaction mixture was heated in a sealed vial at 120℃ (oil bath) for 16 h. After cooling to
rt, the reaction mixture was partitioned between CH Cl (30 mL) and, sequentially, water
10 mL) and brine. The combined organic extracts were dried (Na SO ) and concentrated.
2
3
2
2
(
2
4
The residue was chromatographed to yield diazene 2d (53 mg, 68% yield) as a pale
S11

-
1
1
yellow oil: TLC R
f 2 2
(5% MTBE/ CH Cl ) = 0.40; IR (cm ) 2939, 1511, 1457, 1241; H
NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 3.75 (s, 3H), 2.90 (m, 1H),
2
1
3
.70 (m, 1H), 2.35 (m, 1H), 2.00 (m, 2H), 1.60-1.80 (m, 3H), 1.55 (m, 1H), 1.50 (m, 1H),
1
3
.35 (s, 3H), 1.30 (s, 3H), 0.90 (m, 1H); C NMR δ u 157.9, 134.1, 105.9, 91.1, 41.2,
25 2
5.9, 31.0, 29.6, 24.7; d 129.1, 113.9, 55.3, 48.4, 29.2, 21.9; HRMS calcd for C17H N O
+
(
MH ) 273.1967, obsd 273.1968.
O
O
H
H
N
N
2
d
3d
1
2
-(4-Methoxyphenethyl)-6,6-dimethylbicyclo[3.1.0]hexane (3d). A solution of diazene
d (43 mg, 0.16 mmol) in dry toluene (6 mL) was photolyzed for 24 h at rt in a Rayonet
apparatus (350 nm). The reaction mixture was concentrated and chromatographed to
yield cyclopropane 3d (29 mg, 74% yield) as a colorless oil: TLC R (2% MTBE/PE) =
f
-
1
1
0
8
.47; IR (cm ) 2929, 1732, 1511, 1246; H NMR δ 7.10 (d, J = 8.6 Hz, 2H), 6.80 (d, J =
.6 Hz, 2H), 3.75 (s, 3H), 2.55 (m, 2H), 1.85 (m, 3H), 1.70 (m, 3H), 1.55 (m, 1H), 1.40
13
(
m, 1H), 0.95 (s, 3H), 0.90 (s, 3H), 0.70 (d, J = 5.4 Hz, 1H); C NMR δ u 157.6, 135.4,
3
8.3, 36.2, 34.3, 31.6, 27.6, 25.9, 23.4; d 129.2, 113.7, 55.3, 36.1, 23.9, 16.6; HRMS
+
calcd for C17
H
25O (MH ) 245.1905, obsd 245.1905.
O
S
Cl
Ph
PhS
O
n-BuLi, DABCO, THF
5
9%
1
1
2
-(2-(Phenylthio)ethyl)oxirane (11). To a stirred solution of DABCO (1.22 g, 10.9
S12

mmol) and thioanisole (13.2 g, 106 mmol) in dry THF (100 mL) was added n-BuLi (106
4
mmol, 43 mL, 2.46 M in Et
2
O) at 0℃. After stirring at room temperature for 2 h, the
reaction mixture was cooled to -78℃. Then epichlorohydrin (19.6 g, 212 mmol) was
added at -78℃ and the reaction mixture was slowly warmed to rt in 2 h. The reaction
mixture was quenched with saturated aqueous NH
between CH Cl and, sequentially, water and brine. The combined organic extracts were
dried (Na SO ) and concentrated. The residue was chromatographed to yield the epoxide
1 (11.3 g, 59% yield) as a colorless oil: TLC R
4
Cl (50 mL) and then partitioned
2
2
2
4
-
1
1
f
(20% MTBE/PE) = 0.57; IR (cm )
1
2
989, 2923, 1581, 1479; H NMR δ 7.10-7.40 (m, 5H), 3.05 (m, 3H), 2.75 (m, 1H), 2.50
1
3
(
m, 1H), 1.90 (m, 1H), 1.80 (m, 1H); C NMR δ u 136.0, 47.2, 32.3, 30.2; d 129.4,
+
1
29.0, 126.2, 51.1; HRMS calcd for C10
H
12OS (M ) 180.0609, obsd 180.0607.
PhS
MgCl
PhS
O
THF, 98%
OH
11
12
1
-(Phenylthio)hept-6-en-3-ol (12). To a solution of epoxide 11 (9.1 g, 50.3 mmol ) in
dry THF (50 mL) was added allyl magnesium chloride (100 mmol, 50 mL, 2 M in THF)
5
at 0℃. The reaction mixture was stirred at 0℃ for 1 h and at rt for another 3 h. The
4
reaction mixture was quenched with saturated aqueous NH Cl (50 mL) and then
partitioned between CH
2
Cl
2
and, sequentially, water and brine. The combined organic
extracts were dried (Na
2
SO
4
) and concentrated. The residue was chromatographed to
f
yield the alcohol 12 (11.2 g, 98% yield) as a colorless oil: TLC R (20% MTBE/PE) =
S13

-
1
1
0
.32; IR (cm ) 3417, 2930, 2360, 1641; H NMR δ 7.10-7.40 (m, 5H), 5.80 (m, 1H), 5.00
1
3
(
q, 2H), 3.75 (bs, 1H), 3.00 (m, 2H), 2.10 (m, 3H), 1.75 (m, 2H), 1.50 (m, 2H); C NMR
δ u 136.4, 115.0, 36.5, 36.4, 30.1, 30.0; d 138.3, 129.1, 129.0, 126.0, 70.4; HRMS calcd
+
for C13
H
18OS (M ) 222.1078, obsd 222.1072.
PhS
PhS
PhS
MsCl, Et N,
NaI, acetone
5%
3
8
CH Cl
2
2
OMS
I
OH
12
13
(
3-Iodohept-6-enyl)(phenyl)sulfane (13). To a stirred solution of alcohol 12 (11.0 g, 50
mmol) in dry CH Cl (50 mL) were sequentially added Et N (10.5 g, 103 mmol) and
mesyl chloride (8.7 g, 76 mmol) at 0℃. After stirring at rt for 1 h, the reaction mixture
was quenched with saturated aqueous NH Cl (30 mL) and then partitioned between
CH Cl and, sequentially, water and brine. The combined organic extracts were dried
Na SO ) and concentrated to give the crude mesylate.
To a stirred solution of the above crude mesylate in acetone (100 mL) was added NaI
22.3 g, 149 mmol) at rt. The reaction mixture was stirred at reflux overnight. After
cooling to rt, the reaction mixture was quenched with saturated aqueous Na (40 mL)
and then partitioned between CH Cl and, sequentially, water and brine. The combined
organic extracts were dried (Na SO ) and concentrated. The residue was
chromatographed to yield the iodide 13 (14.3 g, 85% yield) as a colorless oil: TLC R
2
2
3
4
2
2
(
2
4
(
2 2 3
S O
2
2
2
4
f
-
1
1
(
(
2 2
CH Cl ) = 0.82; IR (cm ) 3072, 2923, 1581, 1437; H NMR δ 7.05-7.30 (m, 5H), 5.65
m, 1H), 4.95 (q, 2H), 4.10 (m, 1H), 3.10 (m, 1H), 2.90 (m, 1H), 2.15 (m, 1H), 2.05 (m,
S14

1
3
2
1
3
H), 1.85 (m, 2H), 1.65 (m, 1H); C NMR δ u 134.7, 114.9, 38.5, 38.4, 32.7, 32.4; d
35.5, 128.8, 127.9, 125.2, 35.4; HRMS calcd for C13
32.0081.
H17SI (M+) 332.0096, obsd
PhS
PhS
NaCN, DMSO,
71%
I
CN
13
14
2
-(2-(Phenylthio)ethyl)hex-5-enenitrile (14). To a solution of iodide 13 (2.4 g, 7.1
6
mmol) in DMSO (30 mL) was added NaCN (3.6 g, 73.5 mmol) at rt. After stirring at rt
overnight, the reaction mixture was partitioned between CH
and brine. The combined organic extracts were dried (Na SO
residue was chromatographed to yield nitrile 14 (1.2 g, 71% yield) as a colorless oil: TLC
2
Cl
2
and, sequentially, water
2
4
) and concentrated. The
-
1
1
R
f
(20% MTBE/PE) = 0.55; IR (cm ) 3074, 2931, 2238, 1641; H NMR δ 7.20-7.50 (m,
5
2
1
H), 5.85 (m, 1H), 5.05 (m, 2H), 3.20 (m, 1H), 3.00 (m, 1H), 2.85 (m, 1H), 2.15-2.45 (m,
1
3
H), 1.55-2.00 (m, 4H); C NMR δ u 134.6, 121.0, 116.2, 31.2, 30.9, 30.7, 29.4; d 135.8,
29.6, 128.8, 126.3, 27.7.
PhS
PhS
DIBAL-H,
Toluene
CN
81%
O
H
14
1e
2
-(2-(Phenylthio)ethyl)hex-5-enal (1e). To a stirred solution of nitrile 14 (1.0 g, 4.3
mmol) in dry toluene (25 mL) was added DIBAL-H (13 mmol, 13 mL, 1 M in pentane) at
7
-
78℃. After stirring at -78℃ for 1 h, the reaction mixture was quenched with saturated
aqueous NH
4
2 2
Cl (20 mL) and then partitioned between CH Cl and, sequentially, water
S15

2 4
and brine. The combined organic extracts were dried (Na SO ) and concentrated. The
residue was chromatographed to give aldehyde 1e (817 mg, 81% yield) as a colorless oil:
-
1
1
TLC R
f
(CH
2 2
Cl ) = 0.62; IR (cm ) 3580, 2090, 1642; H NMR δ 9.65 (s, 1H), 7.15-7.45
(
m, 5H), 5.75 (m, 1H), 5.05 (q, 2H), 2.90 (m, 2H), 2.50 (m, 1H), 2.05 (m, 3H), 1.80 (m,
1
3
2
1
H), 1.55 (m, 1H); C NMR δ u 135.4, 115.4, 30.8, 30.6, 27.8, 27.6; d 203.6, 137.0,
+
29.5, 120.0, 125.8, 49.7; HRMS calcd for C14
H
18OS (M ) 234.1078, obsd 234.1078.
PhS
PhS
H
H
O
H
N
N
1
e
2e
6
1
-(2-(Phenylthio)ethyl)-3,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrazole (2e). Aldehyde
e (110 mg, 0.47 mmol) and tosylhydrazine (1.07 equiv, 95 mg, 0.51 mmol) were stirred
in MeOH (3 mL) at rt overnight. The MeOH was removed under reduced pressure, the
crude hydrazone was redissolved in toluene (3 mL), K CO (6 equiv, 395 mg, 2.9 mmol)
2
3
was added and the reaction mixture was heated in a sealed vial at 120℃ (oil bath) for 13
h. After cooling to room temperature, the reaction mixture was partitioned between
CH
2
Cl
2
and, sequentially, water and brine. The combined organic extracts were dried
(
Na
2
SO
4
) and concentrated. The residue was chromatographed to yield diazene 2e (105
1
mg, 91% yield, 6:1 mixture of two isomers based on H NMR) as a pale yellow oil: TLC
-
1
1
R
f
(5% MTBE/ CH
2 2
Cl ) = 0.41; IR (cm ) 3056, 2947, 2863, 1582, 1478; H NMR δ
7
3
.10-7.50 (m, 5H), 4.20-5.00 (m, 3H), 3.05-3.40 (m, 2H), 2.40 (m, 2H), 1.60-2.05 (m,
13
H), 1.50 (m, 1H), 1.30 (m, 1H), 1.05 (m, 1H); C NMR(major isomer) δ u 136.5, 83.7,
S16

3
3.9, 32.3, 32.2, 30.2; d 129.3, 129.0, 126.0, 100.2, 42.8, 34.0; HRMS calcd for
+
C
14
H
19
N
2
S (MH ) 247.1269, obsd 247.1269.
O
O
CH I , MeLi,
2
2
H
THF, 48%
1
5
2
-(2,6-Dimethylhept-5-enyl)oxirane (15). To a stirred solution of aldehyde (6.18 g, 40
mmol) and diiodomethane (17.7 g, 66 mmol) in THF(150 mL) was added dropwise
methyl lithium (80 mmol) over 30 min at 0℃. The reaction mixture was stirred at 0℃ for
1
h and at rt for 3 h. Then resulting mixture was quenched with ice water and partitioned
between CH Cl and, sequentially, water and brine. The combined organic extracts were
dried (Na SO ) and concentrated. The residue was chromatographed to yield epoxide 15
3.22 g, 48% yield) as a colorless oil: TLC R
2
2
2
4
-
1
(
f
(10% MTBE/PE) = 0.60; IR (cm ) 2957,
1
2
2
091, 1643, 1457; H NMR δ 5.05 (m, 1H), 2.90 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H),
13
.00 (m, 2H), 1.70 (s, 3H), 1.60 (s, 3H), 1.10-1.55 (m, 4H), 0.90-1.05 (m, 4H); C NMR
δ u 131.3, 50.5, 47.5, 46.9, 39.8, 37.3, 36.9, 25.5, 25.4; d 124.5, 51.1, 51.0, 31.1, 30.6,
2
5.8, 20.1, 19.5, 17.8.
MgBr
OH
O
O
O
1
5
16
1
-(4-Methoxyphenyl)-4,8-dimethylnon-7-en-2-ol (16). To a stirred solution of (p-
methoxyphenyl)magnesium bromide {freshly prepared with Mg (2.42 g, 101 mmol), p-
bromo anisole (10.7 g, 57.5 mmol) and I
2
in dry THF (30 mL)} in dry THF was added
S17

CuI (730 mg, 3.83 mmol) at 0℃. The mixture was stirred for 5 min at 0℃ and then the
solution of epoxide 15 (3.2 g, 19 mmol) in dry THF (5 mL) was added dropwise over 5
min. After stirring overnight at rt, the reaction mixture was quenched with saturated
aqueous NH
and brine. The combined organic extracts were dried (Na
residue was chromatographed to yield alkene 16 (2.84 g, 54% yield, a 1:1 mixture of
4
Cl (10 mL) and then partitioned between CH
2
Cl
2
and, sequentially, water
2
SO
4
) and concentrated. The
-
1
f
diastereomers) as a colorless oil: TLC R (20%MTBE/PE) = 0.42; IR (cm ) 3417, 2920,
1
1
3
512, 1247; H NMR δ 7.10 (m, 2H), 6.85 (m, 2H), 5.10 (m, 1H), 3.85 (bs, 1H), 3.75 (s,
H), 2.50-2.80 (m, 2H), 1.95 (m, 2H), 1.65 (s, 3H), 1.60 (s, 3H), 1.10-1.55 (m, 6H), 0.90
1
3
(
d, J = 6.7 Hz, 3H); C NMR δ u 158.3, 131.3, 131.2, 130.6, 130.5, 44.3, 44.2, 43.9,
4
2
3.4, 37.9, 36.7, 25.5, 25.4; d 130.6, 130.4, 124.8,114.0, 70.8, 70.4, 55.3, 29.4, 29.0,
+
5.7, 20.3, 19.1, 17.8; HRMS calcd for C18
H
28
O
2
(M ) 276.2089, obsd 276.2084.
OH
OH
OH
CH PPh Br,
1
2
) O , CH Cl
3
3
3
2
2
KOtBu, THF,
MeOH;
H
7
0%
) PPh , NaHCO3
3
O
92%
1
6
O
O
17
O
1
-(4-Methoxyphenyl)-4-methyloct-7-en-2-ol (17). Ozone was passed through a stirred
Cl (5 mL) and MeOH (15 mL) at -
8℃. After stirring at -78℃ for 8 min, the color of the reaction mixture changed to pale
solution of alkene 16 (1.90 g, 6.88 mmol) in dry CH
2
2
7
2 3 3
blue. N was then passed through to remove the excess ozone. PPh (3.8 g) and NaHCO
(
3.8 g) were added at -78℃. The reaction mixture was warmed to rt and stirred for an
2 2
additional hour. Then the mixture was partitioned between CH Cl and, sequentially,
S18

2 4
water and brine. The combined organic extracts were dried (Na SO ) and concentrated.
The residue was chromatographed to yield aldehyde (1.58 g, 92% yield) as a colorless
oil.
To the mixture of methyl triphenylphosphonium bromide (4.3 g, 12 mmol) and KOtBu
(
1.0 g, 8.9 mmol) was added dry THF (15 mL) at rt. After stirring at rt for 30 min, a
solution of aldehyde (758 mg, 3.03 mmol) in dry THF (2 ml) was added and the reaction
mixture was stirred for another 3 h at rt. The reaction mixture was quenched with
saturated aqueous NH
sequentially, water and brine. The combined organic extracts were dried (Na
concentrated. The residue was chromatographed to yield alkene 17 (525 mg, 70% yield)
4 2 2
Cl (10 mL) and then partitioned between CH Cl and,
2
4
SO ) and
-1
1
as a colorless oil: TLC R
f
(20% MTBE/PE) = 0.44; IR (cm ) 2924, 1640, 1512, 1460; H
NMR δ 7.10 (m, 2H), 6.85 (m, 2H), 5.80 (m, 1H), 4.95 (q, 2H), 3.85 (bs, 1H), 3.80 (s,
3
1
4
5
H), 2.75 (m, 1H), 2.55 (m, 1H), 2.05 (m, 2H), 1.65 (m, 1H), 1.35-1.55 (m, 3H), 1.10-
1
3
.25 (m, 2H), 0.90 (d, J = 6.7 Hz, 3H); C NMR δ u 158.3, 130.5, 130.4, 114.3, 114.2,
4.3, 44.1, 43.9, 43.4, 37.0, 35.7, 31.3, 31.2; d 139.2, 139.1, 130.4, 114.0, 70.7, 70.4,
5.3, 29.2, 28.9, 20.2, 19.1; HRMS calcd for C16H24O2 (M+) 248.1776, obsd 248.1775.
OH
O
2 2
PCC,NaOAC, CH Cl , 82%
O
O
1f
1
7
1
-(4-Methoxyphenyl)-4-methyloct-7-en-2-one (1f). PCC (1.32 g, 6.12 mmol) and
NaOAc (1.31 g) were suspended in dry CH
2
Cl
2
(10 mL) at rt. After stirring for 5 min at
S19

room temperature, alcohol 17 (505 mg, 2.04 mmol) was added in one portion. The
reaction mixture was stirred at rt for 6 h. Et O (25 mL) was added and the mixture was
2
stirred vigorously for 1 h at rt. The mixture was filtered with celite, the filtrate was
concentrated and the residue was chromatographed to yield ketone 1f (409 mg, 82%
-
1
1
yield) as a colorless oil: TLC R
NMR δ 7.10 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz, 2H), 5.75 (m, 1H), 4.95 (q, 2H),
.80 (s, 3H), 3.60 (s, 2H), 2.40 (m, 1H), 2.25 (m, 1H), 2.00 (m, 3H), 1.30 (m 1H), 1.20
f 2 2
(CH Cl ) = 0.46; IR (cm ) 2927, 1709, 1609, 1512; H
3
1
3
(
m, 1H), 0.85 (d, J = 6.6 Hz, 3H); C NMR δ u 208.5, 158.6, 126.3, 114.1, 49.7, 49.1,
3
2
5.9, 31.2; d 138.7, 130.5, 113.7, 55.2, 28.6, 19.6; HRMS calcd for C16
46.1620, obsd 246.1623.
22 2
H O (M+)
O
O
H
N
N
1
f
2f
O
7
a-(4-Methoxybenzyl)-6-methyl-3a,4,5,6,7,7a-hexahydro-3H-indazole (2f). Ketone 1f
(
98 mg, 0.40 mmol) and tosylhydrazine (1.02 equiv, 77 mg, 0.41 mmol) were stirred in
MeOH (2 mL) at rt overnight. The MeOH was removed under reduced pressure, the
crude hydrazone was redissolved in dry toluene (2 mL), K CO (6 equiv, 345 mg, 2.5
mmol) was added and the reaction mixture was heated in a sealed vial at 120℃ (oil bath)
for 24 h. After cooling to rt, the reaction mixture was partitioned between CH Cl and,
sequentially, water and brine. The combined organic extracts were dried (Na SO ) and
2
3
2
2
2
4
concentrated. The residue was chromatographed to yield the diastereomeric mixture of
S20

diazenes 2f (74 mg, 72% yield) as a pale yellow oil: TLC R
f
2 2
(5% MTBE/ CH Cl ) = 0.41;
-
1
1
IR (cm ) 2923, 2862, 1611, 1511, 1455; H NMR δ 6.95-7.10 (m, 2H), 6.80 (m, 2H),
4
3
4
3
2
.25-4.40 (m, 1H), 3.50-3.80 (m, 4H), 2.50-3.00 (m, 2H), 1.20-2.00 (m, 6H), 0.90 (m,
1
3
H), 0.45-0.80 (m, 1H); C NMR δ u 158.4, 158.3, 129.4, 128.5, 92.4, 89.6, 82.8, 78.0,
3.3, 41.1, 40.0, 38.9, 30.3, 29.1, 28.7, 22.0; d 131.4, 131.3, 113.7, 113.6, 55.2, 33.5,
+
3.4, 27.2, 27.0, 22.6, 22.4; HRMS calcd for C16
H
23
N
2
O (MH ) 259.1810, obsd
59.1804.
O
O
H
H
N
N
3
f
2
f
1
-(4-Methoxybenzyl)-3-methylbicyclo[4.1.0]heptane (3f). A solution of diazenes 2f (53
mg, 0.21 mmol) in toluene was photolyzed for 24 h at rt in a Rayonet apparatus (350 nm).
The reaction mixture was concentrated and chromatographed to yield the diastereomeric
mixture of cyclopropanes 3f (38 mg, 80% yield) as a colorless oil: TLC R
f
2 2
(CH Cl ) =
-
1
1
0
2
4
1
.75; IR (cm ) 2913, 2849, 1611,1512, 1457; H NMR δ 7.05-7.20 (m, 2H), 3.85 (s, 3H),
13
.40-3.30 (m, 2H), 0.50-2.20 (m, 12H), 0.25 (m, 1H); C NMR δ u 157.8, 133.0, 132.7,
6.3, 46.1, 38.3, 37.1, 31.7, 28.2, 24.5, 24.2, 17.3, 16.6; d 130.1, 130.0, 129.8, 129.3,
13.6, 113.5.113.4, 55.3, 55.2, 29.5, 29.3, 27.0, 26.7, 22.5, 22.4, 21.8, 18.4, 16.5; HRMS
+
calcd for C16
H
22O (M ) 230.1671, obsd 230.1673.
S21

O
O
KOtBu, DMSO,
Br
CO Et
2
OEt
4
6%
O
18
Ethyl 1-(but-3-enyl)-2-oxocyclohexanecarboxylate (18). Theβ-ketoester (5.16 g, 30.3
mmol) was added, over a period of 10 min, to a stirred solution of t-BuOK (3.04 g, 30.5
8
mmol) in dry DMSO (100 mL). After 1.5 h, 4-bromo-1-butene (1.5 equiv, 6.03 g, 44.5
mmol) was added over a period of 5 min. After 20 h at rt, the reaction mixture was
partitioned between Et
2
O and, sequentially, water and brine. The combined organic
SO ) and concentrated. The residue was chromatographed to
extracts were dried (Na
2
4
f
yield alkene 18 (3.12 g, 46% yield) as a colorless oil: TLC R (20% MTBE/PE) = 0.56;
1
H NMR δ 5.75 (m, 1H), 4.95 (q, 2H), 4.15 (m, 2H), 2.35-2.55 (m, 3H), 1.85-2.05 (m,
1
3
4
1
H), 1.55-1.80 (m, 4H), 1.45-1.50 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H); C NMR δ u 207.7,
71.8, 114.6, 61.1, 60.5, 41.0, 36.1, 33.8, 28.5, 27.6, 22.5; d 138.0, 14.1.
ethylene glycol,
PTSA, benzene,
CO Et
CO Et
2
2
O
7
8%
O
O
1
8
19
Ethyl 2-(but-3-enyl)-1,7-dioxospiro[5, 4]decan-2-carboxylate (19). A solution of
ketone 18 (3.12 g, 13.9 mmol), ethylene glycol (4.45 g, 71.8 mmol), and p-
toluenesulfonic acid (173 mg, 1.1 mmol) in benzene (150 mL) was heated under reflux
for 12 h, using a Dean-Stark trap. Most of the solvent was then distilled off and the
reaction mixture was partitioned between Et
2
O (300 mL) and, sequentially, NaHCO
3
(100
mL) and brine. The combined organic extracts were dried (Na SO ) and concentrated.
2 4
S22

The residue was chromatographed to yield ketal 19 (2.91g, 78% yield) as a colorless oil:
-1
1
TLC R
f
(5% MTBE/CH
2 2
Cl ) = 0.61; IR (cm ) 1722, 1451, 1201, 1093; H NMR δ 5.70
(
m, 1H), 4.85 (q, 2H), 4.10 (m, 2H), 3.85 (m, 4H), 2.05 (m, 1H), 1.95 (m, 2H), 1.60-1.80
(
m, 2H), 1.55 (m, 3H), 1.35-1.50 (m, 3H), 1.20—1.30 (m, 1H), 1.15 (t, J = 7.2 Hz, 3H);
1
3
C NMR δ u 173.9, 114.4, 111.1, 64.8, 64.6, 60.3, 54.2, 32.1, 30.4, 29.6, 28.9, 23.1,
+
2
0.7; d 138.5, 14.3; HRMS calcd for C15
H
24
O
4
Na (MNa ) 291.1572, obsd 291.1570.
OH
CO Et
2
LAH, THF,
0%
8
O
O
O
O
1
9
20
2
-(Hydroxymethyl)-2-(but-3-enyl)-1,7-dioxospiro[5, 4]decane (20). LiAlH
4
(2.0 equiv,
4
22.6 mg, 11.1 mmol) was added in five portions, over a period of 5 min, to a solution of
ester 19 (1.52 g, 5.65 mmol) in dry THF (20 mL) at 0℃ and the mixture was stirred at
this temperature for 0.5 h and at rt for 7 h. Excess LiAlH was destroyed with saturated
aqueous NH Cl (30 mL) and the reaction mixture was partitioned between Et O and,
sequentially, water and brine. The combined organic extracts were dried (Na SO ) and
concentrated. The residue was chromatographed to yield alcohol 20 (1.02 g, 80% yield)
4
4
2
2
4
-1
f 2 2
as a colorless oil: TLC R (5% MTBE/CH Cl ) = 0.46; IR (cm ) 3538, 1702, 1451, 1083;
1
H NMR δ 5.75 (m, 1H), 5.00 (q, 2H), 3.90 (m, 4H), 3.75 (d, J = 10 Hz, 1H), 3.35 (d, J =
0 Hz, 1H), 2.70 (bs, 1H), 1.85-2.10 (m, 2H), 1.55-1.70 (m, 3H), 1.45-1.55 (m, 4H),
1
1
3
1
2
.30-1.45 (m, 3H); C NMR δ u 114.1,114.0, 65.0, 64.5, 64.1, 44.1, 30.1, 29.4, 28.7,
+
7.3, 23.2, 20.2; d 139.5; HRMS calcd for C13
H O
23 3
(MH ) 227.1647, obsd 227.1650.
S23

OH
OBn
NaH, TBAI,
benzyl bromide,
O
O
THF, 72%
O
O
21
2
0
2
-(Benzyloxymethyl)-2-(but-3-enyl)-1,7-dioxospiro[5, 4]decane (21). To a suspension
of NaH (60%, 185 mg, 4.62 mmol) and TBAI (136 mg, 0.37 mmol) in THF (8 mL) was
added a solution of alcohol 20 (805 mg, 3.56 mmol) in THF (1 mL) at 0℃. To this
reaction mixture was added a solution of benzyl bromide (715 mg, 4.18 mmol) in DMF
(
1 mL) at 0℃, and the reaction mixture was stirred at rt for 12 h. The reaction was
quenched with MeOH (0.1 mL). Then the reaction mixture was partitioned between
EtOAc (90 mL) and, sequentially, saturated aqueous NH Cl (20 mL) and brine. The
combined organic extracts were dried (Na SO ) and concentrated. The residue was
chromatographed to yield benzyl ether 21 (806 mg, 72% yield) as a colorless oil: TLC R
4
2
4
f
-
1
1
(
20% MTBE/PE) = 0.63; IR (cm ) 1717, 1638, 1451, 1088; H NMR δ 7.10-7.35 (m,
5
3
H), 5.75 (m, 1H), 4.85 (q, 2H), 4.40 (m, 2H), 3.80 (m, 4H), 3.45 (d, J = 9.2 Hz, 1H),
1
3
.30 (d, J = 9.2 Hz, 1H), 1.90-2.10 (m, 2H), 1.70 (m, 1H), 1.25-1.65 (m, 9H); C NMR δ
u 138.9, 113.5, 112.3, 73.4, 71.8, 64.5, 44.9, 31.3, 31.2, 30.7, 28.6, 23.4, 20.4; d 140.3,
+
1
28.3, 127.8, 127.6; HRMS calcd for C20
H
28
O
3
Na(MNa ) 339.1936, obsd 339.1932.
BnO
OBn
PTSA, acetone,
H2O, 74%
O
O
O
21
1g
2
-(Benzyloxymethyl)-2-(but-3-enyl)cyclohexanone (1g). A solution of ketal 21 (1.42 g,
.49 mmol) and p-toluenesulfonic acid (74 mg, 0.47 mmol) in acetone/H O 2:1 (15 mL)
4
2
S24

was heated under reflux for 4 h. After cooling to rt, the reaction mixture was partitioned
between Et O and, sequentially, water and brine. The combined organic extracts were
dried (Na SO ) and concentrated. The residue was chromatographed to yield ketone 1g
908 mg, 74% yield) as a colorless oil: TLC R
2
2
4
-
1
(
f
(20% MTBE/PE) = 0.57; IR (cm ) 1702,
1
1
447, 1098; H NMR δ 7.10-7.35 (m, 5H), 5.70 (m, 1H), 4.85 (q, 2H), 4.45 (m, 2H), 3.50
(
d, J = 9.8 Hz, 1H), 3.35 (d, J = 9.8 Hz, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 1.80-1.95 (m,
1
3
3
3
3
H), 1.50-1.80 (m, 7H); C NMR δ u 214.2, 138.4, 114.6, 73.3, 72.7, 52.6, 39.5, 35.2,
+
2.4, 28.1, 27.1, 20.8; d 138.5, 128.3, 127.5; HRMS calcd for C18
27.1572, obsd 327.1586.
H
24
O
4
Na(MNa )
OBn
BnO
N
O
N
1g
2g
5
a-(Benzyloxymethyl)-3a,4,5,5a,6,7,8,9-octahydro-3H-indeno[1-c]pyrazole (2g).
Ketone 1g (73 mg, 0.27 mmol) and tosylhydrazine (1.03 equiv, 55 mg, 0.29 mmol) were
stirred in MeOH (2 mL) at rt overnight. The MeOH was removed under reduced pressure,
the crude hydrazone was redissolved in toluene (2 mL), K
mmol) was added and the reaction mixture was heated in a sealed vial at 120℃ (oil bath)
for 24 h. After cooling to rt, the reaction mixture was partitioned between CH Cl and,
sequentially, water and brine. The combined organic extracts were dried (Na SO ) and
concentrated. The residue was chromatographed to yield (52 mg, 68% yield) as a pale
2 3
CO (6 equiv, 232 mg, 1.68
2
2
2
4
-
1
1
yellow oil: TLC R
f
(5%MTBE/ CH
2
Cl
2
) = 0.50; IR (cm ) 2935, 2859, 1642, 1452; H
S25

NMR δ 7.20-7.40 (m, 5H), 4.45-4.65 (m, 3H), 4.35 (dd, J = 7.5, 17.9 Hz, 1H), 4.25 (d, J
9.4 Hz, 1H), 3.75 (d, J = 9.4 Hz, 1H), 2.25 (t, J = 8.2 Hz, 1H), 2.10 (d, J = 12.4 Hz,
H), 1.90-2.05 (m, 2H), 1.80 (m, 1H), 1.55 (m, 3H), 1.15-1.35 (m, 2H), 1.05 (m, 2H),
=
1
0
2
1
3
.95 (m, 1H); C NMR δ u 139.1, 105.6, 84.5, 73.7, 73.4, 48.1, 36.3, 30.9, 29.2, 26.8,
+
3.5, 21.4; d 128.3, 127.3, 127.0, 37.0; HRMS calcd for C18
H
25
N
2
O (MH ) 285.1967,
obsd 285.1957.
X-ray of 2a
S26

References
1
2
. List, B.; Lerner, R.A.; Barbas Ⅲ, C.F. Org. Lett. 1999, 1, 59
. Exner, K.; Heizmann, M.; Yang, F.; Kegel, M.; Keller, M.; Knothe, L.; Heinze, J.; Prinzbach, H.
Eur. J. Org. Chem. 2005, 1311
3
4
5
6
7
8
. Taber, D.F.; Nelson, C.G. J. Org. Chem. 2006, 71, 8973
. Hanessian, S; Cooke, N.G.; DeHoff, B.; Sakito, Y. J. Am. Chem. Soc. 1990, 112, 5276
. Cheng, W.; Kurth, M.J. J. Org. Chem. 2002, 13, 4387
. Boyer, F.; Hanna, I. Eur. J. Org. Chem. 2006, 471
. Ooi, T.; Ohmatsu, K.; Maruoka, K. J. Am. Chem. Soc. 2007, 129, 2410
. Belotti, D.; Cossy, J.; Pete, J.P.; Portella, C. J. Org. Chem. 1986, 51, 4196
S27

Ph
O
CDCl , 400MHz
3
1
a
S28

Ph
H
N
N
CDCl , 400MHz
3
2
a
S29

Ph
H
CDCl , 400MHz
3
3
a
S30