Synthesis of 2-azaspiro[4.6]undec-7-enes from N -tosyl- N -(3-arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ols

Article abstract of DOI:10.1021/jo301764g

The FeCl₃-promoted synthesis of 2-azaspiro[4.6]undec-7-ene rings proceeds via ring expansion/cyclization/chlorination of N-tosyl-N-(3- arylpropargyl)-tethered 6-methylbicyclo[4.1.0]heptan-2-ols. This azaspirocyclic ring skeleton can also be obtained in one pot from the tert-butyldimethylsilyl- protected N-tosyl-N-(3-arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ols and diethylzinc/diiodomethane.

Full text of DOI:10.1021/jo301764g

Article
pubs.acs.org/joc
Synthesis of 2‑Azaspiro[4.6]undec-7-enes from N‑Tosyl‑N‑(3-
arylpropargyl)-Tethered 3‑Methylcyclohex-2-en-1-ols
Ming-Chang P. Yeh,* Chia-Jung Liang, Chern-Wei Fan, Wei-Hang Chiu, and Jun-Yuan Lo
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan, Republic of
China
S
* Supporting Information
ABSTRACT: The FeCl3-promoted synthesis of 2-azaspiro[4.6]-
undec-7-ene rings proceeds via ring expansion/cyclization/chlori-
nation of N-tosyl-N-(3-arylpropargyl)-tethered 6-
methylbicyclo[4.1.0]heptan-2-ols. This azaspirocyclic ring skeleton
can also be obtained in one pot from the tert-butyldimethylsilyl-
protected N-tosyl-N-(3-arylpropargyl)-tethered 3-methylcyclohex-2-
en-1-ols and diethylzinc/diiodomethane.
propargyl-tethered 3-methylcyclohex-2-en-1-ols with diethyl-
zinc/diiodomethane.
INTRODUCTION
■
The development of facile and practical synthetic strategies for
the construction of azaspirocyclic building blocks is of great
importance because such ring skeletons are present in
numerous natural products with a range of biological interest.1
Therefore, many studies have been devoted to construct these
structural motifs, including the ruthenium-catalyzed ring-
closing metathesis reaction of nitrogen heterocycles possessing
geminal olefinic side chains,2a−d the rhodium-catalyzed cyclo-
addition of N-tosyl-linked 1,6-dien-10-ynes followed by
oxidative cleavage of the carbon−carbon double bond of the
resulting azatricycles,3 the thermolysis of N-unsaturated alkyl-
N-alkyl-β-ketoamides,4 the platinum(II)-catalyzed reaction of
cyclic N-sulfonyl enamines with the terminal alkyne,5 the
cationic palladium-catalyzed ene-type cyclization of N-tosyl-
linked cyclic 1,7-enynes,6 the thiourea-catalyzed Michael
addition of β-ketoamides to methyl vinyl ketone followed by
spirolactamization,7 the cationic gold(I)-catalyzed addition of
silyl enol ethers to the terminal alkyne,8 and the gold-catalyzed
addition of five-membered-ring β-ketoamides to the tethered
unactivated alkene.9 While most of these approaches focused
on synthesis of azaspiro[4.4]nonane and -[4.5]decane ring
skeletons, methods for the construction of the azaspiro[4.6]-
undecene scaffold were limited.2b,6b Herein, we report a simple
and mild synthesis of (Z)-4-(arylchloromethylene)-substituted
azaspiro[4.6]undec-7-enes from (3-arylpropargyl)tosylamide-
tethered 6-methylbicyclo[4.1.0]heptan-2-ols and FeCl3. In this
reaction, the iron salt acts as the Lewis acid to remove the
hydroxyl group of the bicyclic ynols, affording a bicyclo[4.1.0]-
hept-2-yl cationic intermediate. anti-Addition of the cyclo-
propylcarbinyl cation and a chloride ion across the alkyne
provides the azaspiro[4.6]undec-7-ene derivatives. Moreover,
this azaspirocyclic skeleton can also be constructed in one pot
by reaction of tert-butyldimethylsilyl-protected N-tosyl-N-
RESULTS AND DISCUSSION
■
The starting N-tosyl-N-(3-arylpropargyl)-tethered 6-
methylbicyclo[4.1.0]heptan-2-ols 1 were prepared from cyclo-
propanation of the known N-tosyl-N-propargyl-tethered 3-
methylcyclohex-2-en-1-ols10 with the Furukawa-modified Sim-
mons−Smith reagent derived in situ from diethylzinc and
diiodomethane11 in CH2Cl2 and ether at 0 °C in 68−90%
yields. Compound 1a was used as the model substrate to search
optimal reaction conditions for the ring expansion/cyclization/
chlorination reaction, as revealed in Table 1. A moderate yield
(66%) of the desired (Z)-4-(chlorophenylmethylene)-2-tosyl-2-
azaspiro[4.6]undec-7-ene (2a) was obtained when 1a was
mixed with 1.2 equiv of FeCl3 in CH2Cl2 at 30 °C under
nitrogen for 1 min (Table 1, entry 1). The Z-configuration of
2a was confirmed by NMR spectroscopies and was further
secured by X-ray diffraction analysis (Figure 1). A comparable
yield (63%) of 2a was achieved when the reaction was run in
open air for 1 min at 30 °C (Table 1, entry 1). Therefore, the
following optimization experiments were carried out under an
ambient atmosphere. At 0 °C, 1a gave 2a in 73% yield upon
treatment with 1.2 molar equiv of FeCl3 for 3 min (Table 1,
entry 2). Lowering the reaction temperature to −15 °C for 3
min and −78 °C for 4 h provided 2a in 82% and 75% yields,
respectively (Table 1, entries 3 and 4). The use of 1.2 equiv of
FeBr3 in CH2Cl2 at −15 °C resulted in the formation of the
brominated azaspiro[4.6]undecene derivative 312 (Figure 2) in
81% yield, whereas the use of FeCl3·6H2O was less effective
and gave 2a in 70% yield after 50 min at 30 °C (Table 1, entry
Received: August 24, 2012
Published: October 17, 2012
© 2012 American Chemical Society
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(Table 1, entry 9), and the use of a catalytic amount of
Fe(OTf)3 at 30 °C for 24 h with an external source of
nucleophile (MeOH, 2.0 molar equiv) did not give any cyclized
products (Table 1, entry 10). Moreover, treatment of 1a with
an excess amount of concentrated HCl(aq) at −15 °C for 10
min in CH2Cl2 produced only a 10% yield of 2a (Table 1, entry
11), while HBr(aq) caused the decomposition of 1a under the
same reaction conditions.
Table 1. Optimization of the Ring Expansion/Cyclization/
Chlorination of 1a to 2a
a
entry
acid
FeCl3
solvent
temp (°C)
time
yield (%)
The investigation of various reaction media showed that the
use of 1,2-dichloroethane (DCE) and 1,2-dibromoethane
(DBE) decreased the isolated yields of 2a to 35% and 52%
(Table 1, entries 12 and 13), respectively, whereas the use of
dibromomethane (DBM) required an extended reaction time
(1.5 h) at −15 °C and the desired 2a was isolated in 80% yield
(Table 1, entry 14). In contrast, no reaction took place in
CH3CN even after prolonged reaction at 30 °C for 24 h (Table
1, entry 15). Thus, the optimal reaction procedure follows: a
mixture of 1a and FeCl3 (1.2 molar equiv) was stirred in
CH2Cl2 at −15 °C in the air (Table 1, entry 3) until no starting
substrate 1a was detected by TLC (3 min). Although
ruthenium2b and palladium6b were used to construct the
azaspiro[4.6]undecane ring scaffold from unsaturated N-
containing compounds, these protocols required complex
catalyst systems and higher reaction temperatures (40−100
°C). Furthermore, the palladium-catalyzed cycloisomerization
of 1,6-enynes produced the azaspiro[4.6]undecane ring
skeleton needing seven-membered-ring starting substrates.6b
The present method to the synthesis of the azaspiro[4.6]-
undecenes is operated without removal of air and moisture,
requiring only N-tosyl-linked six-membered cyclic 8-aryl-2-en-
7-yn-1-ols, Et2Zn/CH2I2, and FeCl3 at −15 °C in the air for 3−
15 min.
1
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
CH2Cl2
DCE
30
0
1 min
3 min
3 min
4 h
63
73
82
75
70
67
54
49
0
FeCl3
3
FeCl3
−15
−78
30
4
FeCl3
5
FeCl3·6H2O
TiCl4
50 min
1 min
25 min
1 h
6
−15
30
7
InCl3
8
ZnCl2
30
9
(TMS)Cl
30
24 h
b
10
11
12
13
14
15
Fe(OTf)3
30
24 h
0
c
HCl(aq)
−15
−15
30
10 min
1 min
1 min
1.5 h
24 h
10
35
52
80
0
FeCl3
FeCl3
FeCl3
FeCl3
DBE
DBM
−15
30
CH3CN
a
All reactions were conducted using 0.1 M 1a and 1.2 molar equiv of
acids in the air, and yields were obtained by flash column
b
chromatography. A catalytic amount (10 mol %) of Fe(OTf)3 was
c
used. An excess amount of HCl(aq) was used.
With a satisfactory protocol we next examined the substrate
scope of this reaction. Results of the ring expansion/
cyclization/chlorination of substrates 1a−h to produce
azaspiro[4.6]undecenes 2a−h are listed in Scheme 1. It was
Scheme 1. Iron Trichloride-Promoted Synthesis of
Azaspiro[4.6]undecene Derivatives 2
Figure 1. X-ray crystallographic structure of 2a.
observed that the reaction was quite general with a phenyl or
tolyl group at the alkyne terminus, for example, 1a−d, as the
yields of desired products 2a−d ranged from 58% to 82%. Only
the Z-isomers of the chloro-containing azacycles 2a−d were
Figure 2. Compounds 3, 1i, and 4.
1
noticed in 400 MHz H NMR spectra of crude mixtures (vide
infra). It was found that a bromine atom at the C-4 position of
the phenyl ring, for example, 1e and 1f, had little influence on
product yields, as azaspirocycles 2e12 and 2f were isolated in
77% and 70% yields, respectively. However, substrate 1g,
bearing a carbethoxy group at the C-3 position of the phenyl
ring, reacted less efficiently with FeCl3 to produce the desired
product 2g12 in 46% yield. The electron-donating methoxy
5). The reaction of 1a with 1.2 equiv of TiCl4 in CH2Cl2 at −15
°C took place instantaneously and afforded 2a in 67% yield
(Table 1, entry 6), while other Lewis acids, such as InCl3 and
ZnCl2, were much less reactive and generated 2a in 54% and
49% yields (Table 1, entries 7 and 8), respectively. On the
other hand, (TMS)Cl did not give any desired product 2a
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group at the C-3 position of the phenyl ring, for example, 1h,
did not affect the activity of FeCl3 and afforded the
corresponding azaspirocycle 2h in 77% isolated yield.
Unfortunately, the reaction of the substrate with the stronger
electron-withdrawing nitro group at the C-4 position of the
phenyl ring, for example, 1i (Figure 2), failed to give any
cyclized products. The homoallylic chloride 412 was isolated in
64% yield (Figure 2). It must be mentioned that compounds
bearing a methyl substituent at the alkynyl terminus or with a
terminal alkyne led to decomposition of starting substrates
upon treatment with FeCl3.
Scheme 3. Plausible Mechanism for the Formation of
Compound 7
A reaction pathway is speculated in Scheme 2. Detachment
of the hydroxyl group of 1 by FeCl3 led to the bicyclo[4.1.0]-
Scheme 2. Plausible Mechanism for Formation of 2 and 4
hept-2-yl cation 5a, which may rearrange to the seven-
membered tertiary cation 5b and the bicyclic tertiary cation
6.13 A subsequent anti-addition of the cyclopropylcarbinyl
cation and a chloride ion across the alkyne of 5a gave the
azaspiro[4.6]undecene derivative 2 with Z-selectivity. Alter-
natively, anti-addition of the tertiary cation and a chloride ion
across the alkyne of 5b also led to the formation of 2. A similar
reaction path involving a bicyclo[4.1.0]hept-2-yl cation for the
synthesis of bicyclo[5.3.0]decane derivatives was reported in
the literature.14 However, cyclization/chlorination of 1i, with a
p-nitrophenyl group at the alkyne, did not occur, but instead
attack of a chloride ion at the cyclopropyl ring of intermediate 6
took place, generating the homoallylic chloride 4 (Scheme 2).
Interestingly, compound 1j with the electron-releasing
methoxy group at the C-4 position of the phenyl ring gave
the azatricyclic compound 712 as the only stereoisomer isolated
in 57% yield (Scheme 3). It is worth noting that three
stereogenic centers of azatricycle 7 are created in a single step
and only one diastereomer is isolated. The formation of 7 is
suggested in Scheme 3. The initial formed bicyclo[4.1.0]hept-2-
yl cation 8 was attacked by the electron-rich (p-
methoxyphenyl)alkynyl group to give the allenyl intermediate
9. anti-Addition of a chloride anion and the sp-hybridized
carbon center of the allenyl moiety across the double bond led
to azatricycle 7 as a single diastereomer. The stereochemistry of
7 was confirmed by a single-crystal X-ray analysis (Figure 3). A
similar azatricyclic ring obtained by the platinum-catalyzed
cycloisomerization of the propargyltosylamide-tethered cyclo-
heptatriene in toluene at 90 °C for 10 h was reported in the
literature.15
Figure 3. X-ray crystallographic structure of 7.
Unfortunately, treatment of 5-phenyl-4-pentynyl-tethered
bicyclo[4.1.0]heptan-1-ol 11, readily accessible by cyclopropa-
nation of the known cyclic enynol 10,16 gave a complex mixture
of products when treated with 1.2 molar equiv of FeCl3 in
CH2Cl2 at 25 °C in the air for 3 min (Scheme 4). Much to our
Scheme 4. Reaction of Compound 11 with Iron Trichloride
delight, bicyclo[4.1.0]heptan-2-one 12a afforded, upon reaction
with 1.5 molar equiv of FeCl3 in DBE at 50 °C for 1 h, a 50%
yield of (E)-1-(chlorophenylmethylene)spiro[4.6]undecan-8-
one (13a).12 Several examples of the FeCl3-promoted ring
expansion/cyclization/chlorination of the bicyclic phenyl-
alkynones 12a−f to afford the C-4-substituted spiro[4.6]-
undecan-8-ones 13a−f are summarized in Scheme 5. The
structure elucidation of 13 was achieved by X-ray diffraction
analysis of 13a and 13c. In general, the FeCl3-promoted
synthesis of the spiro[4.6]undecan-8-one derivatives required
longer reaction times (1−6 h) at 50 °C in DBE and in
moderate yields (45−62%).
Surprisingly, when the cyclopropanation was performed
through treatment of the tert-butyldimethylsilyl-protected (3-
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containing azatricycle 1612 as the only diastereomer in 31%
yield (Scheme 6).
Scheme 5. Iron Trichloride-Promoted Synthesis of
Spiro[4.6]undecan-8-ones 13
Scheme 6. Diethylzinc/Diiodomethane-Promoted Synthesis
of Azatricycle 16
arylpropargyl)sulfonamide-tethered 3-methylcyclohex-2-en-1-ol
with diethylzinc and diiodomethane in DCE, the azaspiro[4.6]-
undecene ring skeleton was afforded directly. Thus, the reaction
of the TBS-protected N-tosyl-linked six-membered 8-phenyl-2-
en-7-yn-1-ol 14a with Et2Zn and CH2I2 in DCE at 50 °C under
1 atm of nitrogen for 9 h resulted in the direct formation of the
iodine-incorporated 2-azaspiro[4.6]undec-7-ene derivative
15a12 in 43% isolated yield (Table 2, entry 1). The
In conclusion, this work showed simple and mild methods
for the construction of (Z)-4-(arylchloromethylene)-substi-
tuted azaspiro[4.6]undecene ring skeletons from N-tosyl-N-(3-
arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ol, diethyl-
zinc/diiodomethane, and the economic and environmentally
friendly iron trichloride. This azaspirocyclic ring skeleton can
be obtained directly from treatment of TBS-protected N-tosyl-
N-(3-arylpropargyl)-tethered 3-methylcyclohex-2-en-1-ol with
diethylzinc/diiodomethane. Further studies on the one-pot
synthesis of other heterocycles using the Furukawa reagent are
currently under way in our laboratory.
Table 2. One-Pot Process for the Construction of
a
Azaspiro[4.6]undecene Derivatives 15
EXPERIMENTAL SECTION
■
General Considerations. All Lewis acids, dichloromethane
(DCM), and dibromoethane (DBE) were purchased from commercial
sources and were used without further purification. Dichloroethane
(DCE) used for general procedure V was dried by passage through
Al2O3. Flash column chromatography was carried out with silica gel
(230−400 mesh) using the indicated solvents. All melting points were
determined in open capillaries and are uncorrected. 1H nuclear
magnetic resonance (NMR) spectra were obtained with 400 and 500
MHz spectrometers. The chemical shifts are reported in parts per
million with either tetramethylsilane (0.00 ppm) or CDCl3 (7.26 ppm)
as the internal standard. 13C NMR spectra were recorded with 100 and
125 MHz spectrometers with CDCl3 (77.0 ppm) as the internal
standard. Infrared (IR) spectra were recorded as neat solutions. High-
resolution mass spectra were obtained with a double-focusing mass
spectrometer.
entry substrate
R
Ar
time (h)
yield (%)
1
2
3
4
5
6
7
8
14a
14b
14c
14d
14e
14f
H
phenyl
9
25
20
12
11
12
9
43 (15a)
46 (15b)
56 (15c)
73 (15d)
48 (15e)
57 (15f)
59 (15g)
47 (15h)
H
4-methylphenyl
4-bromophenyl
phenyl
H
CH3
CH3
CH3
CH3
CH3
4-methylphenyl
4-bromophenyl
3-methoxyphenyl
4-phenylphenyl
14g
14h
9
a
All reactions were run in dried DCE under nitrogen, and yields were
obtained after flash column chromatography.
advantageous feature of this procedure is that it is a one-pot
process in which the cyclopropanation of the olefin, the ring
expansion of the resulting bicyclo[4.1.0]heptane ring, and
cyclization/iodination of the newly formed N-propargyl-
tethered cyclopropylcarbinyl cation proceeded successively to
provide azaspirocycle 15a. It was suggested that the initial
formed ZnI2, generated from Et2Zn and CH2I2, may trigger the
desiloxylation of 14a to form a bicyclo[4.1.0]hept-2-yl cation
which then undergoes the same ring expansion/cyclization/
halogenation as that found for intermediate 5, affording 15a as
a single stereoisomer. Several examples of (Z)-4-(iodoaryl-
methylene)-2-tosyl-2-azaspiro[4.6]undec-7-enes in a multistep,
one-pot synthesis from TBS-protected N-tosyl-linked six-
membered cyclic 8-aryl-2-en-7-yn-1-ols 14 and Et2Zn/CH2I2
are listed in Table 2. In general, the one-pot process required a
higher reaction temperature (50 °C) and longer reaction times
(9−25 h) in DCE under nitrogen. As illustrated in Table 2,
substrate 14d with two methyl groups at the C-5 position of the
six-membered ring obtained the best result (73%, Table 2, entry
4). Moreover, substrate 14i with the C-4 methoxyphenyl group
at the alkyne terminus underwent a reaction with Et2Zn/CH2I2
analogous to that observed for 1j, generating the iodine-
General Procedure I for the Synthesis of Starting Substrates
1. To a solution of 1,3-cyclohexanedione (3.360 g, 30 mmol) and
isobutanol (10 mL, 108 mol) in toluene (20 mL) was added p-
toluenesulfonic acid (0.260 g, 1.50 mmol). The reaction mixture was
heated to reflux to remove water using a Dean−Stark apparatus. After
10 h, the mixture was cooled to room temperature followed by
addition of triethylamine (0.50 mL, 3.73 mmol), and the mixture was
concentrated under reduced pressure. The crude mixture was purified
via flash chromatography (silica gel, 50% ethyl acetate/hexanes) to
give 3-isobutoxycyclohex-2-en-1-one (4.45 g, 26.4 mmol, 88%). To a
stirred solution of tetramethylethylenediamine (9.06 mL, 60 mmol) at
0 °C was added n-BuLi (1.6 M, 37.5 mL, 60 mmol) dropwise, and the
mixture was stirred at 0 °C for 0.5 h followed by addition of dimethyl
sulfide (4.43 mL, 60 mmol). The resulting mixture was stirred at room
temperature for 4 h. The mixture was cooled to −78 °C, and then 3-
isobutoxy-2-cyclohexen-1-one (5.040 g, 30 mmol) in THF (30 mL)
was added. The reaction mixture was further stirred for 2 h at room
temperature followed by addition of 2.5 N HCl(aq) (40 mL) at 0 °C.
The reaction mixture was extracted with ether (30 mL × 4). The
mixture was concentrated under reduced pressure. The crude mixture
was purified via flash chromatography (silica gel, 10% ethyl acetate/
hexanes) to give 3-((methylthio)methyl)cyclohex-2-en-1-one (3.840 g,
24.6 mmol, 82%). To a stirred solution of 3-((methylthio)methyl)-
cyclohex-2-en-1-one (3.50 g, 22.4 mmol) in 25 mL of CH2Cl2 was
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added methyl iodide (12.710 g, 89.6 mmol) at room temperature. The
mixture was heated at 45 °C for 3 days in a sealed tube. The reaction
mixture was poured into Na2S2O3(aq) (20 mL) and extracted with
CH2Cl2 (20 mL × 3). The combined organic extracts were dried to
give the crude 3-(iodomethyl)cyclohex-2-en-1-one. The crude product
was used for the following step without further purification. To the
crude 3-(iodomethyl)cyclohex-2-en-1-one (0.98 g, 4.15 mmol) and
K2CO3 in 6 mL of acetone was added 4-methyl-N-(3-phenylprop-2-
yn-1-yl)benzenesulfonamide (0.91g, 3.190 mmol) in 6.0 mL of
acetone via syringe. The mixture was reacted at room temperature
for 10 h. The reaction mixture was concentrated, poured into saturated
NH4Cl(aq), and extracted with CH2Cl2 (10 mL × 3). The combined
organic extracts were dried. The crude mixture was purified via flash
chromatography (silica gel, 30% ethyl acetate/hexanes) to give of the
crude 4-methyl-N-((3-oxocyclohex-1-en-1-yl)methyl)-N-(3-phenyl-
prop-2-yn-1-yl)benzenesulfonamide (1.01 g, 2.57 mmol, 81%). To a
solution of the crude 4-methyl-N-((3-oxocyclohex-1-en-1-yl)methyl)-
N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (2.10 g, 5.34 mmol)
and CeCl3·7H2O (1.99 g, 5.34 mol) in MeOH (25 mL) at 0 °C was
added NaBH4 (0.240 g, 6.41 mmol), and the mixture was stirred for 1
h. The mixture was concentrated under reduced pressure, poured into
saturated NH4Cl(aq), and extracted with CH2Cl2 (10 mL × 3). The
combined organic extracts were dried to give N-((3-hydroxycyclohex-
1-en-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)-
benzenesulfonamide. To the above crude enynol was added Et2Zn (1.5
M, 10.68 mL, 16.02 mmol) in ether/CH2Cl2 (20 mL/5 mL) followed
by slow addition of CH2I2 (5.72 g, 21.36 mmol) at 0 °C, and the
reaction mixture was allowed to stir at 30 °C for 10 h. The reaction
mixture was poured into saturated NH4Cl(aq) (10 mL) and extracted
with CH2Cl2 (10 mL × 3). The crude mixture was purified via flash
chromatography (silica gel, 30% ethyl acetate/hexanes) to give 1a.
Data for ( )-N-(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]heptan-1-yl)-
methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide
(1a): yield 1.99 g (4.59 mmol, 86%); white solid; mp 131−132 °C; IR
MHz, CDCl3) δ 143.4, 136.0, 131.4, 129.4, 128.4, 128.1, 127.7, 122.0,
86.2, 81.4, 65.3, 55.3, 41.8, 39.3, 36.9, 32.0, 31.5, 25.6, 22.0, 21.3, 20.6,
14.4; HRMS (ESI) m/e 460.1913, calcd for C26H31NO3SNa [M +
Na]+ 460.1913.
Data for ( )-N-(((1R,5R,6S)-5-hydroxy-3,3-dimethylbicyclo[4.1.0]-
heptan-1-yl)methyl)-4-methyl-N-(3-p-tolylprop-2-yn-1-yl)-
benzenesulfonamide (1d). yield 0.31 g (0.65 mmol, 65%) from the
corresponding enone (0.44 g, 1.00 mmol); white solid; mp 134−135
°C; IR (CH2Cl2) 3379, 2952, 1449, 1347, 1161, 1094 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2 H), 7.26−7.22 (m, 2 H),
7.02 (d, J = 7.9 Hz, 2 H), 6.89 (d, J = 8.0 Hz, 2 H), 4.57 (d, J = 18.4
Hz, 1 H), 4.35 (d, J = 18.4 Hz, 1 H) 4.37−4.29 (m, 1 H), 3.44 (d, J =
13.0 Hz, 1 H), 2.72 (d, J = 13.0 Hz, 1 H), 2.34 (s, 3 H), 2.31 (s, 3 H),
1.88 (d, J = 14.2 Hz, 1 H), 1.56−1.49 (m, 1 H), 1.20−1.14 (m, 2 H),
1.41 (s, 1 H), 0.91 (s, 3 H), 0.89 (s, 3 H), 0.82−0.70 (m, 1 H), 0.44 (t,
J = 5.3 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 143.3, 138.6, 136.1,
131.4, 129.5, 128.9, 127.8, 119.0, 86.3, 80.7, 65.4, 55.3, 41.8, 39.3, 37.0,
32.0, 31.5, 25.6, 22.0, 21.4, 20.6, 14.4; HRMS (ESI) m/e 474.2072,
calcd for C27H33NO3SNa [M + Na]+ 474.2079.
Data for
( )-N-(3-(4-bromophenyl)prop-2-yn-1-yl)-N-
(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]heptan-1-yl)methyl)-4-methyl-
benzenesulfonamide (1e): yield 0.67 g (1.32 mmol, 88%) from the
corresponding enone (0.71 g, 1.50 mmol); white solid; mp 130−132
°C; IR (CH2Cl2) 3393, 2928, 1598, 1346, 1161, 1115, 1092 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8 Hz, 2 H), 7.37 (d, J = 8.4
Hz, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.86 (d, J = 8.4 Hz, 2 H), 4.49 (d, J
= 18.7 Hz, 1 H), 4.38 (d, J = 18.7 Hz, 1 H), 4.23 (br s, 1 H), 3.14 (d, J
= 13.0 Hz, 1 H), 3.04 (d, J = 13.0 Hz, 1 H), 2.35 (s, 3 H), 2.10−1.98
(m, 1 H), 1.73−1.62 (m, 1 H), 1.57−1.44 (m, 2 H), 1.42−1.34 (m, 1
H), 1.30−1.16 (m, 2 H), 1.11−1.00 (m, 1 H), 0.67−0.61 (m, 1 H),
0.61−0.52 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 143.1, 135.5,
132.6, 131.0, 129.2, 127.4, 122.3, 120.6, 84.7, 82.5, 65.9, 54.6, 36.3,
29.3, 24.8, 23.3, 21.1, 19.9, 12.0; HRMS (ESI) m/e 510.0718, calcd for
C24H26BrNO3NaS [M + Na]+ 510.0714.
Data for
( )-N-(3-(4-bromophenyl)prop-2-yn-1-yl)-N-
1
(CH2Cl2) 3383, 2935, 1599, 1443, 1347, 1162, 1116, 1092 cm−1; H
(((1R,5R,6S)-5-hydroxy-3,3-dimethylbicyclo[4.1.0]heptan-1-yl)-
methyl)-4-methylbenzenesulfonamide (1f): yield 0.37 g (0.68 mmol,
68%) from the corresponding enone (0.50 g, 1.00 mmol); white solid;
mp 121−122 °C; IR (CH2Cl2) 3394, 2952, 1485, 1347, 1161, 1094
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1 H), 7.39−
7.34 (m, 1 H), 7.27−7.22 (m, 1 H), 6.90−6.82 (m, 1 H), 4.56 (d, J =
18.4 Hz, 1 H), 4.41−4.30 (m, 2 H) 3.45 (d, J = 13.1 Hz, 1 H), 2.71 (d,
J = 13.1 Hz, 1 H), 2.34 (s, 3 H), 1.89−1.83 (m, 1 H), 1.57−1.50 (m, 1
H), 1.37−1.28 (m, 1 H), 1.22−1.13 (m, 1 H), 0.92 (s, 3 H), 0.90 (s, 3
H), 0.83−0.75 (m, 1 H), 0.73−0.67 (m, 1 H), 0.46 (t, J = 5.3 Hz, 1
H); 13C NMR (100 MHz, CDCl3) δ 143.1, 135.5, 132.6, 131.0, 129.2,
127.4, 122.3, 120.6, 84.7, 82.5, 65.9, 54.6, 36.3, 29.3, 24.8, 23.3, 21.1,
19.9, 12.0; HRMS (ESI) m/e 538.1027, calcd for C26H30BrNO3SNa
[M + Na]+ 538.1036.
NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.4 Hz, 2 H), 7.31−7.17 (m, 5
H), 7.04−6.95 (m, 2 H), 4.50 (d, J = 18.6 Hz, 1 H), 4.39 (d, J = 18.6
Hz, 1 H), 4.28−4.17 (m, 1 H), 3.14 (d, J = 13.0 Hz, 1 H), 3.04 (d, J =
13.0 Hz, 1 H), 2.32 (s, 3 H), 2.09−2.00 (m, 1 H), 1.68−1.63 (m, 1 H),
1.55−1.37 (m, 3 H), 1.29−1.15 (m, 2 H), 1.11−0.97 (m, 1 H), 0.66−
0.60 (m, 1 H), 0.60−0.53 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ
143.4, 135.9, 131.4, 129.5, 128.4, 128.1, 127.7, 122.0, 86.2, 81.4, 66.5,
54.8, 36.7, 29.8, 25.1, 23.6, 21.4, 20.4, 20.1, 12.1; HRMS (ESI) m/e
432.1603, calcd for C24H27NO3NaS [M + Na]+ 432.1603.
Data for ( )-N-(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]heptan-1-yl)-
methyl)-4-methyl-N-(3-p-tolylprop-2-yn-1-yl)benzenesulfonamide
(1b): yield 0.60 g (1.35 mmol, 90%) from the corresponding enone
(0.61 g, 1.50 mmol); white solid; mp 130−131 °C; IR (CH2Cl2) 3375,
1
2935, 1598, 1347, 1161, 1092 cm−1; H NMR (400 MHz, CDCl3) δ
Data for ( )-ethyl 3-(3-(N-(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]-
heptan-1-yl)methyl)-4-methylbenzenesulfonamido)prop-1-yn-1-yl)-
benzoate (1g): yield 0.51 g (1.02 mmol, 68%) from the corresponding
enone (0.70 g, 1.50 mmol); colorless oil; IR (CH2Cl2) 3412, 2937,
1719, 1599, 1347, 1229, 1161, 1093 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.96−7.90 (m, 1 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.70−7.68
(m, 1 H), 7.30 (t, J = 8.0 Hz, 1 H), 7.24 (d, J = 8.0 Hz, 2 H), 7.20−
7.16 (m, 1 H), 4.50 (d, J = 18.7 Hz, 1 H), 4.43−4.35 (m, 3 H), 4.26−
4.18 (m, 1 H), 3.14 (d, J = 13.0 Hz, 1 H), 3.05 (d, J = 13.0 Hz, 1 H),
2.29 (s, 3 H), 2.07−1.97 (m, 1 H), 1.70−1.57 (m, 2 H), 1.56−1.44
(m, 2 H), 1.41(t, J = 7.1 Hz, 3 H), 1.28−1.17 (m, 2 H), 1.11−1.01 (m,
1 H), 0.67−0.61 (m, 1 H), 0.60−0.53 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ 165.6, 143.6, 135.7, 135.4, 132.4, 130.6, 129.4, 129.3, 128.2,
127.7, 122.3, 85.1, 82.4, 66.4, 61.2, 54.8, 36.5, 29.7, 25.1, 23.6, 21.3,
20.4, 20.1, 14.3, 12.1; HRMS (ESI) m/z = 504.1812, calcd for
C27H31NO5NaS [M + Na]+ 504.1821.
7.73 (d, J = 8 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2 H), 7.04 (d, J = 8.0 Hz, 2
H), 6.90 (d, J = 8.4 Hz, 2 H), 4.49 (d, J = 18.6 Hz, 1 H), 4.38 (d, J =
18.6 Hz, 1H), 4.28−4.20 (m, 1 H), 3.14 (d, J = 13.0 Hz, 1 H), 3.03 (d,
J = 13.0 Hz, 1 H), 2.33 (s, 3H), 2.32 (s, 3 H), 2.09−1.99 (m, 1 H),
1.69−1.60 (m, 1 H), 1.57−1.43 (m, 1 H), 1.43−1.38 (br, 1 H), 1.30−
1.16 (m, 2 H), 1.11−0.98 (m, 1 H), 0.68−0.60 (m, 1 H), 0.60−0.54
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 143.1, 138.4, 135.7, 131.1,
129.3, 128.6, 127.5, 118.7, 86.1, 80.5, 66.1, 54.6, 36.5, 29.5, 25.0, 23.4,
21.2, 20.1, 20.0, 12.0; HRMS (ESI) m/e 446.1761, calcd for
C25H29NO3NaS [M + Na]+ 446.1766.
Data for ( )-N-(((1R,5R,6S)-5-hydroxy-3,3-dimethylbicyclo[4.1.0]-
heptan-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)-
benzenesulfonamide (1c): yield 0.30 g (0.64 mmol, 64%) from the
corresponding enone (0.42 g, 1.00 mmol); white solid; mp 143−144
°C; IR (CH2Cl2) 3380, 2953, 1490, 1347, 1162, 1094 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2 H), 7.29−7.20 (m, 5 H),
7.00 (d, J = 7.2 Hz, 2 H), 4.59 (d, J = 18.7 Hz, 1 H), 4.39 (d, J = 18.6
Hz, 1 H), 4.39−4.31 (m, 2 H), 3.47 (d, J = 13.0 Hz, 1 H), 2.73 (d, J =
13.0 Hz, 1 H), 2.33 (s, 3 H), 1.89 (d, J = 14.4 Hz, 1 H), 1.57−1.50 (m,
1 H), 1.33 (br s, 1 H), 1.23−1.15 (m, 2 H), 0.93 (s, 3 H), 0.90 (s, 3
H), 0.83−0.71 (m, 2 H), 0.46 (t, J = 5.2 Hz, 1 H); 13C NMR (100
Data for ( )-N-(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]heptan-1-yl)-
methyl)-N-(3-(3-methoxyphenyl)prop-2-yn-1-yl)-4-methylbenzene-
sulfonamide (1h): yield 0.41 g (0.89 mmol, 82%) from the
corresponding enone (0.46 g, 1.08 mmol); white solid; mp 122−
123 °C; IR (CH2Cl2) 3403, 2936, 1598, 1347, 1290, 1162, 1116, 1092,
1041 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2 H),
9711
dx.doi.org/10.1021/jo301764g | J. Org. Chem. 2012, 77, 9707−9717

The Journal of Organic Chemistry
Article
7.24 (d, J = 8.0 Hz, 2 H), 7.13 (t, J = 8.0 Hz, 1 H), 6.85−6.79 (m, 2
H), 6.58 (d, J = 7.6 Hz, 1 H), 6.53 (s, 1 H), 4.49 (d, J = 18.6 Hz, 1 H),
4.39 (d, J = 18.8 Hz, 1 H), 3.77 (s, 3 H), 3.13 (d, J = 13.0 Hz, 1 H),
3.03 (d, J = 13.0 Hz, 1 H), 2.33 (s, 3 H), 2.08−1.98 (m, 1 H), 1.72−
1.60 (m, 1 H), 1.54−1.42 (m, 3 H), 1.28−1.17 (m, 2 H), 1.11−0.99
(m, 1 H), 0.63 (t, J = 5.4 Hz, 1 H), 0.60−0.53 (m, 1 H)); 13C NMR
(100 MHz, CDCl3) δ 146.8, 143.4, 135.5, 132.0, 129.3, 128.5, 127.5,
123.1, 87.0, 84.0, 66.0, 54.9, 36.3, 29.3, 24.9, 23.3, 21.1, 20.0, 19.9,
12.6; HRMS (ESI) m/e 462.1719, calcd for C25H29NO4SNa [M +
Na]+ 462.1715.
0.25 mmol) was purified by flash column chromatography (silica gel,
5% ethyl acetate/hexanes) to give 2b (0.064 g, 0.15 mmol, 58%) as a
white solid: mp 191−192 °C; IR (CH2Cl2) 2925, 1598, 1350, 1162,
1094 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.2 Hz, 2 H),
7.37 (d, J = 8.1 Hz, 2 H), 7.13 (s, 4 H), 5.81−5.72 (m, 1 H), 5.53−
5.44 (m, 1 H), 4.07 (d, J = 15.4 Hz, 1 H), 4.01 (d, J = 15.4 Hz, 1 H),
3.18 (d, J = 9.5 Hz, 1 H), 3.09 (d, J = 9.6 Hz, 1 H), 2.46 (s, 3 H), 2.35
(s, 3 H), 2.08−1.98 (m, 1 H), 1.98−1.88 (m, 2 H), 1.88−1.79 (m, 1
H), 1.79−1.68 (m, 1 H), 1.50−1.36 (m, 2 H), 1.24−1.11 (m, 1 H);
13C NMR (100 MHz, CDCl3) δ 143.7, 143.1, 138.8, 133.9, 132.4,
Data for ( )-N-(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]heptan-1-yl)-
methyl)-4-methyl-N-(3-(4-nitrophenyl)prop-2-yn-1-yl)-
benzenesulfonamide (1i): yield 0.36 g (0.79 mmol, 38%) from the
corresponding enone (0.91 g, 2.08 mmol); white solid; mp 101−103
°C; IR (CH2Cl2) 3393, 2937, 1594, 1519, 1344, 1161, 1092, 854 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.10 (dt, J = 8.8, 2.0 Hz, 2 H), 7.74 (d,
J = 8.0 Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.14 (dt, J = 8.8, 2.0 Hz, 2
H), 4.52 (d, J = 18.8 Hz, 1 H), 4.43 (d, J = 18.8 Hz, 1 H), 4.26−4.18
(m, 1 H), 3.14 (d, J = 13.1 Hz, 1 H), 3.06 (d, J = 13.1 Hz, 1 H), 2.34
(s, 3 H), 2.06−1.97 (m, 1 H), 1.70−1.59 (m, 1 H), 1.55−1.40 (m, 3
H), 1.29−1.15 (m, 2 H), 1.12−1.00 (m, 1 H), 0.66 (t, J = 5.4 Hz, 1
H), 0.58−0.52 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 146.8,
134.4, 135.5, 132.0, 129.3, 128.5, 127.5, 123.1, 87.0, 84.0, 66.0, 54.9,
36.3, 29.3, 24.9, 23.3, 21.1, 20.0, 19.9, 12.1; HRMS (ESI−) m/e
453.1476, calcd for C24H25N2O5S [M + H]− 453.1484.
Data for ( )-N-(((1S,5R,6S)-5-hydroxybicyclo[4.1.0]heptan-1-yl)-
methyl)-N-(3-(4-methoxyphenyl)prop-2-yn-1-yl)-4-methylbenzene-
sulfonamide (1j): yield 0.47 g (1.02 mmol, 79%) from the
corresponding enone (0.55 g, 1.29 mmol); white solid; mp 124−
125 °C; IR (CH2Cl2) 3386, 2936, 1606, 1346, 1249, 1161,1092, 1032
cm−1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 8 Hz, 2 H), 7.24 (d,
J = 8.0 Hz, 2 H), 6.95 (d, J = 8.4 Hz, 2 H), 6.75 (d, J = 8.4 Hz, 2 H),
4.50 (d, J = 18.6 Hz, 1 H), 4.38 (d, J = 18.6 Hz, 1 H), 4.27−4.18 (m, 1
H), 3.79 (s, 3 H), 3.14 (d, J = 13.2 Hz, 1 H), 3.03 (d, J = 13.2 Hz, 1
H), 2.35 (s, 3 H), 2.10−1.98 (m, 1 H), 1.72−1.60 (m, 1 H), 1.51−1.41
(m, 3 H), 1.30−1.15 (m, 2 H), 1.12−0.98 (m, 1 H), 0.62−0.57 (m, 2
H); 13C NMR (100 MHz, CDCl3) δ 146.8, 143.3, 135.5, 132.0, 129.3,
128.5, 127.5, 123.1, 87.0, 84.0, 66.0, 54.9, 36.3, 29.3, 24.9, 23.3, 21.1,
20.0, 19.9, 12.0; HRMS (ESI) m/e 462.1706, calcd for C25H29NO4NaS
[M + Na]+ 462.1715.
129.7, 129.1, 128.9, 127.9, 127.6, 125.5, 56.9, 53.7, 48.4, 39.7, 36.2,
28.3, 22.7, 21.5, 21.3; HRMS (ESI) m/e 442.1611, calcd for
C25H29ClNO2S [M + H]+ 442.1608.
(Z)-4-(Chlorophenylmethylene)-10,10-dimethyl-2-tosyl-2-
azaspiro[4.6]-undec-7-ene (2c). The crude mixture from general
procedure II (1c, 0.12 g, 0.25 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 2c
(0.091 g, 0.20 mmol, 80%) as a white solid: mp 134−135 °C; IR
1
(CH2Cl2) 2953, 1482, 1350, 1162, 1095 cm−1; H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 8 Hz, 2 H), 7.39 (d, J = 8 Hz, 2 H), 7.32−7.22
(m, 3 H), 7.17 (d, J = 8.0 Hz, 2 H), 5.73−5.58 (m, 2 H), 4.01 (d, J =
15.2 Hz, 1 H), 3.75 (d, J = 15.2 Hz, 1 H), 3.50 (d, J = 9.2 Hz, 1 H),
3.09 (d, J = 9.2 Hz, 1 H), 2.48 (s, 3 H), 2.11 (d, J = 7.6 Hz, 2 H),
1.74−1.68 (m, 2 H), 1.37 (s, 2 H), 0.80 (s, 3 H), 0.59 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 151.0, 143.7, 132.3, 132.2, 129.7, 128.5,
128.2, 128.0, 92.8, 61.1, 58.8, 51.6, 51.1, 40.0, 35.3, 34.6, 33.3, 26.4,
21.6. HRMS (ESI) m/e C26H31ClNO2S [M + H]+ calcd 456.1764,
found 456.1760.
(Z)-4-(Chloro-p-tolylmethylene)-10,10-dimethyl-2-tosyl-2-
azaspiro[4.6]undec-7-ene (2d). The crude mixture from general
procedure II (1d, 0.11 g, 0.25 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 2d
(0.074 g, 0.16 mmol, 63%) as a white solid: mp 138−139 °C; IR
1
(CH2Cl2) 2952, 1482, 1351, 1162, 1094 cm−1; H NMR (500 MHz,
CDCl3) δ 7.74 (d, J = 16 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.16−
7.08 (m, 4 H), 5.54−5.72 (m, 2 H), 3.96 (d, J = 15 Hz, 1 H), 3.75 (d, J
= 15 Hz, 1 H), 3.44 (d, J = 9.5 Hz, 1 H), 3.12 (d, J = 9.5 Hz, 1 H),
2.48 (s, 3 H), 2.33 (s, 3 H), 2.14−2.04 (m, 2 H), 1.77−1.66 (m, 2 H),
1.77−1.66 (m, 2 H), 0.82 (s, 3 H), 0.62 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 150.9, 143.7, 141.0, 138.2, 132.3, 129.8, 128.7, 128.6,
128.1, 128.0, 93.3, 61.2, 58.8, 51.6, 51.1, 40.1, 35.4, 34.7, 33.4, 26.5,
21.6, 21.3. HRMS (ESI) m/e C27H33ClNO2S [M + H]+ calcd
470.1921, found 470.1924.
General Procedure II for Formation of Compounds 2a−h, 3,
4, and 7. To a 25 mL oven-dried round-bottom flask equipped with a
stir bar were added compound 1a (0.10 g, 0.25 mmol), CH2Cl2 (2.5
mL), and FeCl3 (0.049 g, 0.30 mmol) at −15 °C under air. The
reaction mixture was stirred at −15 °C for 3 min. The solvent was
concentrated, and the residue was added to 10 mL of water. The
resulting mixture was extracted with diethyl ether (10 × 3 mL). The
combined organic layer was washed with brine, dried over MgSO4,
filtered through a bed of Celite, and concentrated to give the crude
mixture. The crude mixture was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 2a.
(Z)-4-(Chlorophenylmethylene)-2-tosyl-2-azaspiro[4.6]-undec-7-
ene (2a). The crude mixture from general procedure II (1a, 0.11 g,
0.25 mmol) was purified by flash column chromatography (silica gel,
5% ethyl acetate/hexanes) to give 2a (0.088 g, 0.21 mmol, 82%) as a
pale yellow solid: mp 191−193 °C; IR (CH2Cl2) 2930, 1598, 1450,
(Z)-4-((4-Bromophenyl)chloromethylene)-2-tosyl-2-azaspiro[4.6]-
undec-7-ene (2e). The crude mixture from general procedure II (1e,
0.12 g, 0.24 mmol) was purified by flash column chromatography
(silica gel, 5% ethyl acetate/hexanes) to give 2e (0.10 g, 0.20 mmol,
82%) as a white solid: mp 205−206 °C; IR (CH2Cl2) 2930, 1598,
1
1351, 1159, 1093 cm−1; H NMR (400 MHz, CDCl3) δ 7.74 (d, J =
8.2 Hz, 2 H), 7.49 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 8 Hz, 2 H), 7.13
(d, J = 8.4 Hz, 2 H), 5.84−5.75 (m, 1 H), 5.54−5.44 (m, 1 H), 4.07
(d, J = 15.8 Hz, 1 H), 4.00 (d, J = 15.5 Hz, 1 H), 3.18 (d, J = 9.6 Hz, 1
H), 3.10 (d, J = 9.6 Hz, 1H), 2.47 (s, 3 H), 2.12−2.00 (m, 1 H), 1.94
(d, J = 6.8 Hz, 2 H), 1.89−1.80 (m, 1 H), 1.80−1.70 (m, 1 H), 1.51−
1.43 (m, 1 H), 1.42−1.30 (m, 1 H), 1.25−1.12 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ 144.2, 143.8, 137.0, 134.1, 132.3, 131.6, 130.9,
129.7, 127.9, 127.3, 123.9, 123.2, 56.8, 53.7, 48.5, 39.9, 36.3, 28.3, 22.7,
21.6; HRMS (FAB+) m/e 506.0547, calcd for C24H26BrClNO2S [M +
H]+ 506.0556. Crystals suitable for X-ray diffraction analysis were
grown from CH2Cl2 and hexanes.
1
1349, 1162, 1094 cm−1; H NMR (500 MHz, CDCl3) δ 7.75 (d, J =
8.5 Hz, 2 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.34−7.33 (m, 3 H), 7.26−
7.24 (m, 2 H), 5.79−5.74 (m, 1 H), 5.51−5.45 (m, 1 H), 4.08 (d, J =
15.5 Hz, 1 H), 4.03 (d, J = 15.5 Hz, 1 H), 3.17 (d, J = 9.5 Hz, 1 H),
3.11 (d, J = 9.5 Hz, 1 H), 2.47 (s, 3 H), 2.05−2.00 (m, 1 H), 1.95 (d, J
= 6.6 Hz, 2 H), 1.85−1.81 (m, 1 H), 1.74−1.68 (m, 1 H), 1.46−1.36
(m, 2 H), 1.20−1.13 (m, 1 H); 13C NMR (125 MHz, CDCl3) δ 143.7,
143.4, 138.1, 134.0, 132.4, 129.8, 129.3, 128.9, 128.3, 128.0, 127.6,
125.3, 57.0, 53.7, 48.5, 39.8, 36.2, 28.4, 22.8, 21.6; HRMS (ESI) m/e
calcd for C24H27ClNO2S (M + H)+ 428.1451, found 428.1446.
Crystals suitable for X-ray diffraction analysis were grown from
CH2Cl2 and hexanes.
(Z)-4-((4-Bromophenyl)chloromethylene)-10,10-dimethyl-2-tosyl-
2-azaspiro[4.6]undec-7-ene (2f). The crude mixture from general
procedure II (1f, 0.14 g, 0.25 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 2f
(0.093 g, 0.18 mmol, 70%) as a white solid: mp 140−143 °C; IR
1
(CH2Cl2) 2954, 1598, 1482, 1349, 1162, 1095 cm−1; H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 9.5 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H),
7.41 (d, J = 8.0 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 5.75−5.67 (m, 1
H), 5.66−5.62 (m, 1 H), 3.97 (d, J = 15.0 Hz, 1 H), 3.87 (d, J = 15.0
Hz, 1 H), 3.46 (d, J = 9.0 Hz, 1 H), 3.16 (d, J = 9.0 Hz, 1 H), 2.50 (s, 3
(Z)-4-(Chloro-p-tolylmethylene)-2-tosyl-2-azaspiro[4.6]-undec-7-
ene (2b). The crude mixture from general procedure II (1b, 0.11 g,
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H), 2.10 (d, J = 6.5 Hz, 2 H), 1.81−1.72 (m, 2 H), 1.45 (d, J = 14.5
Hz, 1 H), 1.39 (d, J = 14.5 Hz, 1 H), 0.85 (s, 3 H), 0.68 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 152.1, 143.9, 142.7, 132.5, 131.3, 129.9,
129.8, 128.3, 128.0, 122.3, 90.9, 61.2, 58.7, 51.9, 51.3, 40.1, 35.5, 34.7,
33.5, 26.4, 21.6. HRMS (FAB) m/e C26H30BrClNO2S [M + H]+ calcd
534.0869, found 534.0864.
36.3, 26.4, 26.2, 21.5, 20.9; HRMS (ESI) m/e 495.1120, calcd for
C24H25ClN2O4NaS [M + Na]+ 495.1121. Crystals suitable for X-ray
diffraction analysis were grown from diethyl ether.
(
)-(1S,7S,8R)-8-Chloro-6-(4-methoxyphenyl)-3-tosyl-3-
azatricyclo[5.4.1.01,5]dodec-5-ene (7). The crude mixture from
general procedure II (1j, 0.11 g, 0.25 mmol) was purified by flash
column chromatography (silica gel, 5% ethyl acetate/hexanes) to give
7 (0.065 g, 0.14 mmol, 57%) as a pale yellow solid: mp 212−213 °C;
(Z)-Ethyl 3-(chloro(2-tosyl-2-azaspiro[4.6]undec-7-en-4-ylidene)-
methyl)benzoate (2g). The crude mixture from general procedure II
(1g, 0.13 g, 0.25 mmol) was purified by flash column chromatography
(silica gel, 5% ethyl acetate/hexanes) to give 2g (0.058 g, 0.12 mmol,
46%) as a pale yellow solid: mp 213-214 °C; IR (CH2Cl2) 2933, 1721,
IR (CH2Cl2) 2930, 1606, 1341, 1252, 1158, 1097 cm−1; H NMR
1
(400 MHz, CDCl3) δ 7.71 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8 Hz, 2
H), 7.14 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 4.23 (d, J =
14.8 Hz, 1 H), 4.20−4.13 (m, 1 H), 3.88−3.77 (m, 5 H), 3.51 (d, J =
8.8 Hz, 1 H), 2.76 (d, J = 8.8 Hz, 1 H), 2.40 (s, 3 H), 2.34 (d, J = 12.7
Hz, 1 H), 2.23−2.11 (m, 1 H), 1.93−1.75 (m, 4 H), 1.69−1.60 (m, 1
H), 1.47−1.35 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 159.3,
143.4, 141.5, 134.0, 133.6, 129.7, 128.5, 127.4, 125.5, 114.5, 61.6, 59.0,
58.7, 58.3, 55.3, 46.2, 36.6, 35.2, 35.2, 21.5, 21.4; HRMS (FAB+) m/e
458.1548, calcd for C25H29ClNO3S [M + H]+ 458.1557. Crystals
suitable for X-ray diffraction analysis were grown from CH2Cl2 and
hexanes.
1
1599, 1350, 1214, 1162 cm−1; H NMR (400 MHz, CDCl3) δ 8.07−
8.01 (m, 1 H), 7.94 (s, 1 H), 7.75 (d, J = 8.0 Hz, 2 H), 7.45−7.40 (m,
2 H), 7.39 (d, J = 8.0 Hz, 2 H), 5.82−5.74 (m, 1 H), 5.46−5.48 (m, 1
H), 4.38 (q, J = 14.4, J = 7.2 Hz, 2 H), 4.10 (d, J = 15.6 Hz, 1 H), 4.03
(d, J = 15.6 Hz, 1 H), 3.19 (d, J = 9.6 Hz, 1 H), 3.10 (d, J = 9.6 Hz, 1
H), 2.48 (s, 3 H), 2.10−1.98 (m, 1 H), 1.98−1.84 (m, 3 H), 1.77−1.65
(m, 1 H), 1.51−1.32 (m, 5 H), 1.25−1.15 (m, 1 H); 13C NMR (100
MHz, CDCl3) δ 165.8, 144.3, 143.8, 138.3, 134.0, 133.5, 132.3, 130.7,
130.4, 130.0, 129.8, 128.4, 128.0, 127.3, 124.1, 61.3, 56.9, 53.7, 48.5,
39.9, 36.2, 28.3, 22.7, 21.6, 14.3; HRMS (ESI) m/e 500.1657, calcd for
C27H31ClNO4S [M + H]+ 500.1662. Crystals suitable for X-ray
diffraction analysis were grown from CH2Cl2 and hexanes.
Typical Experimental Procedure for Synthesis of Starting
Substrates 12a−c. To a stirred solution of t-BuLi (1.6 M, 12.6 mL,
20.2 mmol) at −78 °C was added 1-phenyl-5-iodo-1-pentyne (4.0 g,
14.8 mmol) in ether (10 mL) dropwise over 0.5 h, and the mixture
was stirred at −78 °C for 0.5 h followed by addition of 3-
methoxycyclohex-2-en-1-one (1.5 g, 11.9 mmol) in 10 mL of ether.
The resulting mixture was stirred at room temperature for 12 h
followed by addition of 2.5 N HCl(aq) (15 mL) at 0 °C. The reaction
mixture was extracted with ether (50 mL × 3). The mixture was
concentrated, and the residue was purified via flash chromatography
(silica gel, 5% ethyl acetate/hexanes) to give 3-(5-phenylpent-4-yn-1-
yl)cyclohex-2-en-1-one (2.83 g, 8.6 mmol, 82%). To an oven-dried
100 mL round-bottom flask equipped with a stir bar was added NaH
(0.67 g, 16.8 mmol). The apparatus was evacuated (oil pump) and
filled with nitrogen three times, and then Me3SOI (3.69 g, 16.78
mmol) and via syringe DMSO (16 mL) were added. The reaction
mixture was stirred at room temperature for 0.5 h followed by addition
of 3-(5-phenylpent-4-yn-1-yl)cyclohex-2-en-1-one in DMSO (2 mL),
and the mixture was stirred at room temperature for 16 h. The
reaction mixture was poured into water (30 mL) and extracted with
ether (50 mL × 3). The crude mixture was purified via flash
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 12a.
Data for 6-(5-phenylpent-4-yn-1-yl)bicyclo[4.1.0]heptan-2-one
(12a): yield 1.164 g (4.61 mmol, 55%); pale yellow oil; IR
(CH2Cl2) 3019, 2938, 2860, 2229, 1686, 1598, 1490, 1442, 1324,
(Z)-4-(Chloro(3-methoxyphenyl)methylene)-2-tosyl-2-azaspiro-
[4.6]undec-7-ene (2h). The crude mixture from general procedure II
(1h, 0.11 g, 0.25 mmol) was purified by flash column chromatography
(silica gel, 5% ethyl acetate/hexanes) to give 2h (0.087 g, 0.19 mmol,
77%) as a pale yellow solid: mp 212−213 °C; IR (CH2Cl2) 2931,
1597, 1450, 1348, 1162, 1094, 1038 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.75 (d, J = 8 Hz, 2 H), 7.38 (d, J = 8 Hz, 2 H), 7.25 (t, J = 8
Hz, 1 H), 6.89−6.83 (m, 2 H), 6.78 (t, J = 2 Hz, 1 H), 5.83−5.72 (m,
1 H), 5.55−5.43 (m, 1 H), 4.07 (d, J = 14.6 Hz, 1 H), 4.01 (d, J = 14.9
Hz, 1 H), 3.79 (s, 3 H), 3.18 (d, J = 9.5 Hz, 1 H), 3.11 (d, J = 9.5 Hz, 1
H), 2.47 (s, 3 H), 2.10−1.91 (m, 3 H), 1.90−1.81 (m, 1 H), 1.81−1.68
(m, 1 H), 1.52−1.39 (m, 2 H), 1.27−1.14 (m, 1 H); 13C NMR (100
MHz, CDCl3) δ 159.2, 143.7, 143.2, 139.2, 134.0, 132.4, 129.7, 129.3,
128.0, 127.6, 125.0, 121.7, 114.9, 114.5, 57.0, 55.3, 53.6, 48.5, 39.7,
36.1, 28.4, 22.7, 21.6. HRMS (ESI) m/e 458.1558, calcd for
C25H29ClNO3S [M + H]+ 458.1557.
(Z)-4-(Bromophenylmethylene)-2-tosyl-2-azaspiro[4.6]-undec-7-
ene (3). The crude mixture from general procedure II (1a, 0.11 g, 0.25
mmol, and FeBr3, 0.089 g, 0.30 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 3 (0.097
g, 0.21 mmol, 82%) as a white solid: mp 214.0−214.5 °C; IR
1
(CH2Cl2) 2931, 1605, 1444, 1349, 1161, 1094 cm−1; H NMR (400
1
1246, 758, 693, 523 cm−1; H NMR (400 MHz, CDCl3) δ 7.26−7.28
MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2 H), 7.40 (d, J = 8 Hz, 2 H),
7.35−7.30 (m, 3 H), 7.25−7.21 (m, 2 H), 5.80−5.71 (m, 1 H), 5.52−
5.44 (m, 1 H), 4.04 (d, J = 15.4 Hz, 1 H), 3.97 (d, J = 15.4 Hz, 1 H),
3.21 (d, J = 9.5 Hz, 1 H), 3.13 (d, J = 9.5 Hz, 1 H), 2.47 (s, 3 H),
2.07−1.97 (m, 1 H), 1.97−1.91 (m, 2 H), 1.90−1.81 (m, 1 H), 1.75−
1.64 (m, 1 H), 1.49−1.33 (m, 2 H), 1.23−1.13 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ 145.9, 143.7, 139.9, 134.0, 132.4, 129.8, 129.1,
128.8, 128.2, 128.0, 127.5, 116.0, 57.1, 56.3, 49.4, 39.7, 36.2, 28.3, 22.7,
21.6; HRMS (ESI) m/e 472.0947, calcd for C24H27BrNO2S [M + H]+
472.0946. Crystals suitable for X-ray diffraction analysis were grown
from CH2Cl2 and hexanes.
N-((3-(Chloromethyl)cyclohex-1-enyl)methyl)-4-methyl-N-(3-(4-
nitrophenyl)prop-2-yn-1-yl)benzenesulfonamide (4). The crude
mixture from general procedure II (1i, 0.11 g, 0.25 mmol) was
purified by flash column chromatography (silica gel, 5% ethyl acetate/
hexanes) to give 4 (0.079 g, 0.16 mmol, 64%) as a pale yellow solid:
mp 123−125 °C; IR (CH2Cl2) 2923, 1594, 1519, 1343, 1162 cm−1;
1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.8 Hz, 2 H), 7.77 (d, J =
(m, 3 H), 7.36−7.38 (m, 2 H), 2.39−2.43 (t, J = 6.8 Hz, 2 H), 2.25−
2.31 (m, 1 H), 1.95−2.06 (m, 2 H), 1.47−1.79 (m, 8 H), 1.39−1.42 (t,
J = 4.8 Hz, 1 H), 0.96−1.00 (dd, J = 10.0, 5.2 Hz, 1 H); 13C NMR
(100 MHz, CDCl3) δ 209.1, 131.4, 128.2, 127.6, 123.7, 89.5, 81.1,
38.0, 36.1, 33.5, 27.8, 25.6, 25.5, 19.3, 18.2, 17.1; HRMS (ESI) [M +
Na]+ m/e 275.1416, calcd for C18H20ONa 275.1412.
Data for ( )-(1S,6R)-6-(5-p-tolylpent-4-yn-1-yl)bicyclo[4.1.0]-
heptan-2-one (12b): yield 1.05 g (4.0 mmol, 46%) from the
corresponding enone (2.17 g, 8.6 mmol); pale yellow oil; IR
(CH2Cl2) 3026, 2938, 2861, 2200, 1686, 1510, 1444, 1326, 1247,
1
819, 526 cm−1; H NMR (400 MHz, CDCl3) δ 7.26−7.28 (d, J = 8.0
Hz, 2 H), 7.07−7.09 (d, J = 8.0 Hz, 2 H), 2.39−2.42 (t, J = 6.8 Hz, 2
H), 2.26−2.33 (m, 4 H), 1.96−2.06 (m, 2 H), 1.58−1.79 (m, 7 H),
1.48−1.53 (m, 1 H), 1.39−1.41 (t, J = 4.8 Hz, 1 H), 0.96−1.00 (dd, J
= 10.0, 5.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 209.1, 137.6,
131.3, 128.9, 120.7, 88.7, 81.1, 38.1, 36.2, 33.5, 27.8, 25.7, 25.6, 21.3,
19.3, 18.3, 17.1; HRMS (ESI) [M + Na]+ m/e 289.1568, calcd for
C19H22ONa 289.1571.
8.4 Hz, 2 H), 7.28−7.25 (m, 2 H), 7.19 (d, J = 8.8 Hz, 2 H), 5.66 (s, 1
H), 4.29 (d, J = 18.6 Hz, 1 H), 4.23 (d, J = 18.6 Hz, 1 H), 3.80 (d, J =
13.3 Hz, 1 H), 3.75 (d, J = 13.4 Hz, 1 H), 3.45 (dq, J = 25.5, J = 6.3
Hz, 2 H), 2.58−2.48 (m, 1 H), 2.36 (s, 3 H), 2.16−1.96 (m, 2 H),
1.88−1.77 (m, 2 H), 1.47−1.36 (m, 1 H), 1.35−1.21 (m, 1 H), 0.92−
0.80 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 143.6, 136.1, 134.7,
132.3, 129.5, 129.0, 128.1, 127.9, 123.4, 87.6, 83.8, 53.1, 49.1, 38.1,
Data for ( )-(1S,6R)-6-(5-(3-methoxyphenyl)pent-4-yn-1-yl)-
bicyclo[4.1.0]heptan-2-one (12c): yield 0.53 g (1.88 mmol, 43%)
from the corresponding enone (1.17 g, 4.36 mmol); pale yellow oil; IR
(CH2Cl2) 3008, 2940, 2232, 1686, 1604, 1575, 1288, 1205, 1045, 785,
1
689, 479 cm−1; H NMR (400 MHz, CDCl3) δ 7.17−7.21 (t, J = 8.0
Hz, 1 H), 6.96−6.98 (d, J = 7.6 Hz, 1 H), 6.91−6.92 (d, J = 2.0 Hz, 1
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H), 6.82−6.85 (dd, J = 8.3, 2.5 Hz, 1 H), 3.79 (s, 3 H), 2.40−2.43 (t, J
= 7.0 Hz, 2 H), 2.26−2.32 (m, 1 H), 1.97−2.04 (m, 2 H), 1.58−1.80
(m, 7 H), 1.48−1.54 (m, 1 H), 1.40−1.42 (t, J = 4.8 Hz, 1 H), 0.97−
1.01 (dd, J = 10.1, 5.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
209.0, 159.3, 129.2, 124.8, 124.0, 116.4, 114.1, 89.4, 81.0, 55.2, 38.1,
36.2, 33.5, 27.8, 25.6, 25.5, 19.3, 18.3, 17.1; HRMS (ESI) [M + Na]+
m/e = 305.1518, calcd for C19H22O2Na 305.1517.
δ 7.30−7.32 (d, J = 8.8 Hz, 2 H), 6.80−6.82 (d, J = 8.8 Hz, 2 H), 3.79
(s, 3H), 2.37−2.41 (t, J = 6.9 Hz, 2 H), 2.03−2.06 (d, J = 14.3 Hz, 1
H), 1.79−1.83 (d, J = 14.3 Hz, 1 H), 1.65−1.74 (m, 4 H), 1.50−1.61
(m, 2 H), 1.34−1.42 (m, 1 H), 1.19−1.23 (dd, J = 9.7, 4.6 Hz, 1 H),
1.01−1.03 (t, J = 4.7 Hz, 1 H), 0.97 (s, 3 H), 0.94 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 210.0, 159.0, 132.7, 115.8, 113.7, 87.8, 80.8,
55.1, 48.7, 42.2, 39.8, 37.0, 32.6, 30.8, 29.3, 26.4, 26.3, 26.0, 19.3;
HRMS (ESI) [M + Na]+ m/e 333.1822, calcd for C21H26O2Na
333.1831.
Typical Experimental Procedure for Synthesis of Starting
Substrates 12d−f. To a stirred solution of t-BuLi (1.6 M, 6.52 mL,
10.4 mmol) at −78 °C was added 1-phenyl-5-iodo-1-pentyne (2.06 g,
7.64 mmol) in ether (10 mL) dropwise over 0.5 h, and the mixture
was stirred at −78 °C for 0.5 h followed by addition of 3-methoxy-5,5-
dimethylcyclohex-2-en-1-one (0.94 g, 6.1 mmol) in 10 mL of ether.
The resulting mixture was stirred at room temperature for 12 h
followed by addition of 2.5 N HCl(aq) (15 mL) at 0 °C. The reaction
mixture was extracted with ether (50 mL × 3). The mixture was
concentrated under reduced pressure and purified via flash
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 5,5-
dimethyl-3-(5-phenylpent-4-yn-1-yl)cyclohex-2-en-1-one (1.26 g, 4.73
mmol, 68%). To an oven-dried 100 mL round-bottom flask equipped
with a stir bar at 0 °C were added the crude enone (1.25 g, 4.7 mmol),
NaBH4 (0.23 g, 6.11 mmol), and CeCl3·7H2O (1.75 g, 4.7 mmol) in
10 mL of methanol at 0 °C for 20 min. The reaction mixture was
poured into 50 mL of water and extracted with CH2Cl2 (3 × 30 mL).
The combined orgainc solution was dried and concentrated to give the
crude 5,5-dimethyl-3-(5-phenylpent-4-yn-1-yl)cyclohex-2-en-1-ol
(1.24 g, 4.6 mmol, 98%). The crude enynol was used in the next
step without further purification. To the above crude enynol in 10 mL
of ether at 0 °C was added Et2Zn (1.5 M, 9.4 mL, 14.1 mmol)
followed by slow addition of CH2I2 (5.03 g, 18.8 mmol) at 0 °C, and
the mixture was then stirred at 30 °C for 10 h. The reaction mixture
was poured into saturated NH4Cl(aq) (10 mL) and extracted with
CH2Cl2 (10 mL × 3). The crude mixture was purified via flash
chromatography (silica gel, 10% ethyl acetate/hexanes) to give the
crude 4,4-dimethyl-6-(5-phenylpent-4-yn-1-yl)bicyclo[4.1.0]heptan-2-
ol (0.64 g, 2.3 mmol, 58%). To the above crude ynol in 20 mL of
acetone was added 2-iodoxybenzoic acid (1.27 g, 4.54 mmol). The
reaction mixture was heated at reflux for 3 h. The solvent was
concentrated under reduced pressure and purified via flash
chromatography (silica gel, 10% ethyl acetate/hexanes) to give 12d.
Data for ( )-(1S,6R)-4,4-dimethyl-6-(5-phenylpent-4-yn-1-yl)-
bicyclo[4.1.0]heptan-2-one (12d): yield 0.38 g (1.35 mmol, 60%);
pale yellow oil; IR (CH2Cl2) 3064, 2957, 2868, 2203, 1686, 1599,
1443, 1282, 1253, 758, 693, 525 cm−1; 1H NMR (400 MHz, CDCl3) δ
7.36−7.38 (m, 2 H), 7.26−7.28 (m, 3 H), 2.40−2.43 (t, J = 6.5 Hz, 2
H), 2.02−2.06 (d, J = 14.3 Hz, 1 H), 1.80−1.83 (d, J = 14.3 Hz, 1 H),
1.67−1.74 (m, 4 H), 1.51−1.61 (m, 2 H), 1.35−1.42 (m, 1 H), 1.19−
1.23 (dd, J = 9.6, 4.5 Hz, 1 H), 1.01−1.03 (t, J = 4.6 Hz, 1 H), 0.97 (s,
3 H), 0.94 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 210.0, 131.5,
128.2, 127.6, 123.8, 89.5, 81.1, 48.7, 42.4, 39.9, 37.0, 32.7, 30.8, 29.3,
26.5, 26.3, 26.0, 19.3; HRMS (ESI) [M + Na]+ m/e 303.1723, calcd for
C20H24ONa 303.1725.
General Procedure III for Formation of Spiro[4.6]undecan-8-
ones 13. To a stirred solution of 12a (0.13 g, 0.5 mmol) in DBE (5
mL) was added FeCl3 (0.12 g, 0.75 mmol), and the mixture was stirred
at 50 °C for 1 h. The solvent was concentrated under reduced
pressure, and the crude mixture was poured into water (30 mL) and
extracted with ether (30 mL × 3). The combined organic layer was
washed with brine, dried over MgSO4, filtered through a bed of Celite,
and concentrated to give the crude mixture.
(E)-1-(Chlorophenylmethylene)spiro[4.6]undecan-8-one (13a).
The crude mixture from general procedure III (12a, 0.14 g, 0.50
mmol) was purified by flash column chromatography (silica gel, 3%
ethyl acetate/hexanes) to give 13a (0.078 g, 0.25 mmol, 50%) as a
colorless solid: mp 85−87 °C; IR (CH2Cl2) 3057, 2949, 2868, 1704,
1454, 1444, 1342, 881, 834, 771, 732, 701 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.26−7.35 (m, 5 H), 2.70−2.72 (m, 2 H), 2.34−2.43 (m, 1
H), 2.27−2.32 (dd, 12.0, 6.0 Hz, 1 H), 2.17−2.23 (m, 1 H), 2.05−2.12
(m, 1 H), 1.60−1.72 (m, 7 H), 1.42−1.50 (m, 2 H), 1.30−1.37 (m, 1
H); 13C NMR (100 MHz, CDCl3) δ 214.3, 149.7, 139.5, 129.6, 128.4,
128.1, 124.8, 50.6, 43.6, 39.7, 39.1, 36.2, 35.2, 32.9, 21.2, 20.7; HRMS
(ESI) [M + Na]+ m/e = 311.1185, calcd for C18H21OClNa 311.1179.
Crystals suitable for X-ray diffraction analysis were grown from
CH2Cl2.
(E)-1-(Chloro-p-tolylmethylene)spiro[4.6]undecan-8-one (13b).
The crude mixture from general procedure III (12b, 0.15 g, 0.50
mmol) was purified by flash column chromatography (silica gel, 3%
ethyl acetate/hexanes) to give 13b (0.075 g, 0.23 mmol, 46%) as a pale
yellow oil: IR (CH2Cl2) 3026, 2947, 2869, 1702, 1607, 1453, 885, 810,
744 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.13−7.19 (m, 4 H), 2.68−
2.70 (m, 2 H), 2.28−2.41 (m, 5 H), 2.09−2.24 (m, 2 H), 1.31−1.74
(m, 10 H); 13C NMR (100 MHz, CDCl3) δ 214.5, 149.6, 138.3, 136.7,
129.5, 128.9, 125.1, 50.6, 43.6, 39.8, 39.0, 36.2, 35.3, 32.8, 21.3, 21.2,
20.8; HRMS (ESI) [M + Na]+ m/e 325.1332, calcd for C19H23OClNa
325.1335.
(E)-1-(Chloro(3-methoxyphenyl)methylene)spiro[4.6]undecan-8-
one (13c). The crude mixture from general procedure III (12c, 0.15 g,
0.50 mmol) was purified by flash column chromatography (silica gel,
3% ethyl acetate/hexanes) to give 13c (0.077 g, 0.23 mmol, 45%) as a
colorless solid: mp 137−140 °C; IR (CH2Cl2) 3026, 2950, 2863, 1700,
1
1593, 1457, 1317, 1262, 1165, 1042, 784, 742 cm−1; H NMR (400
MHz, CDCl3) δ 7.24−7.26 (m, 1 H), 6.86−6.89 (m, 2 H), 6.83−6.84
(m, 1 H), 3.82 (s, 3 H), 2.67−2.70 (m, 2 H), 2.29−2.42 (m, 2 H),
2.10−2.26 (m, 2 H), 1.62−1.75 (m, 6 H), 1.37−1.59 (m, 4 H); 13C
NMR (100 MHz, CDCl3) δ 214.4, 159.2, 149.6, 140.7, 129.2, 124.5,
122.0, 115.4, 113.8, 55.3, 50.7, 43.6, 39.8, 39.0, 36.2, 35.2, 32.7, 21.2,
20.8; HRMS (EI) [M + Na]+ m/e 341.1293, calcd for C19H23O2ClNa
341.1284. Crystals suitable for X-ray diffraction analysis were grown
from CH2Cl2 and hexanes.
Data for ( )-(1S,6R)-4,4-dimethyl-6-(5-p-tolylpent-4-yn-1-yl)-
bicyclo[4.1.0]heptan-2-one (12e): yield 0.14 g (0.48 mmol, 72%)
from the corresponding bicyclic ynol (0.22 g, 0.75 mmol); yellow oil;
IR (CH2Cl2) 3028, 2954, 2868, 2214, 1689, 1510, 1458, 1282, 818,
526 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.25−7.27 (d, J = 8.0 Hz, 2
H), 7.07−7.09 (d, J = 8.0 Hz, 2 H), 2.38−2.42 (t, J = 6.9 Hz, 2 H),
2.32 (s, 3 H), 2.02−2.06 (d, J = 14.3 Hz, 1 H), 1.80−1.83 (d, J = 14.3
Hz, 1 H), 1.66−1.73 (m, 4 H), 1.51−1.61 (m, 2 H), 1.34−1.41 (m, 1
H), 1.19−1.22 (dd, J = 9.7, 4.7 Hz, 1 H), 1.00−1.02 (t, J = 4.8 Hz, 1
H), 0.97 (s, 3 H), 0.94 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
210.0, 137.5, 131.3, 128.9, 120.6, 88.6, 81.1, 48.7, 42.3, 39.8, 37.0, 32.7,
30.8, 29.3, 26.5, 26.3, 26.0, 21.3, 19.3; HRMS (ESI) m/e 317.1888,
calcd for C21H26ONa [M + Na]+ 317.1881.
(E)-1-(Chlorophenylmethylene)-10,10-dimethylspiro[4.6]-
undecan-8-one (13d). The crude mixture from general procedure III
(12d, 0.15 g, 0.50 mmol) was purified by flash column
chromatography (silica gel, 3% ethyl acetate/hexanes) to give 13d
(0.098 g, 0.31 mmol, 62%) as a pale yellow oil: IR (CH2Cl2) 3048,
1
2958, 1698, 1594, 1450, 1238, 734, 702 cm−1; H NMR (400 MHz,
CDCl3) δ 7.33−7.37 (m, 3 H), 7.27−7.31 (m, 2 H), 2.63−2.69 (m, 2
H), 2.24−2.38 (m, 3 H), 1.96−2.21 (d, J = 12.0 Hz, 1 H), 1.61−1.76
(m, 6 H), 1.45 (s, 2 H), 0.91 (s, 3 H), 0.76 (s, 3 H); 13C NMR (100
MHz, CDCl3) δ 212.6, 150.7, 139.7, 129.6, 128.3, 128.1, 124.5, 54.9,
51.9, 51.1, 40.2, 37.3, 35.8, 34.6, 33.7, 32.3, 26.6, 21.6; HRMS (EI)
[M]+ m/e 316.1591, calcd for C20H25OCl 316.1594.
Data for 6-(5-(4-methoxyphenyl)pent-4-yn-1-yl)-4,4-
dimethylbicyclo[4.1.0]heptan-2-one (12f): yield 1.01 g (3.25 mmol,
91%) from the corresponding bicyclic ynol (1.12 g, 3.59 mmol);
yellow oil; IR (CH2Cl2) 3000, 2953, 2867, 2049, 1688, 1607, 1509,
1289, 1247, 1173, 1034, 833, 536 cm−1; 1H NMR (400 MHz, CDCl3)
(E)-1-(Chloro-p-tolylmethylene)-10,10-dimethylspiro[4.6]-
undecan-8-one (13e). The crude mixture from general procedure III
9714
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Article
(12e, 0.16 g, 0.5 mmol) was purified by flash column chromatography
(silica gel, 2% ethyl acetate/hexanes) to give 13f (0.10 g, 0.29 mmol,
55%) as a pale yellow oil: IR (CH2Cl2) 3026, 2957, 1701, 1606, 1458,
1237, 816, 783, 748, 526 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.15−
7.20 (m, 4 H), 2.63−2.68 (m, 2 H), 2.20−2.40 (m, 6 H), 1.97−2.00
(d, J = 12.0 Hz, 1 H), 1.58−1.78 (m, 6 H), 1.51−1.54 (d, J = 14.6 Hz,
1 H), 1.45−1.48 (d, J = 14.6 Hz, 1 H), 0.92 (s, 3 H), 0.79 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 212.9, 150.6, 138.2, 136.9, 129.6, 128.8,
124.8, 55.0, 51.8, 51.2, 40.3, 37.4, 36.0, 34.7, 33.8, 32.5, 26.7, 21.7,
21.3; HRMS (EI) [M]+ m/e 330.1748, calcd for C21H27OCl 330.1750.
(E)-1-(Chloro(3-methoxyphenyl)methylene)-10,10-dimethylspiro-
[4.6]undecan-8-one (13f). The crude mixture from general procedure
III (12f, 0.16 g, 0.5 mmol) was purified by flash column
chromatography (silica gel, 2% ethyl acetate/hexanes) to give 13f
(0.10 g, 0.29 mmol, 55%) as a white solid: mp 119−120 °C; IR
(CH2Cl2) 3055, 2955, 1701, 1596, 1457, 1428, 1286, 1261, 1043, 782,
nesulfonamide (14c). The crude mixture was purified by flash column
chromatography (silica gel, 10% ethyl acetate/hexanes) to give 14c
(0.31 g, 0.50 mmol, 32%) from the corresponding enol (0.74 g, 1.56
mmol) as a colorless oil: IR (CH2Cl2) 2930, 2857, 1634, 1486, 1351,
1255, 1164, 1071, 755 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J
= 8.4 Hz, 2 H), 7.38−7.32 (m, 2 H), 7.24 (d, J = 8.0 Hz, 2 H), 6.9−
6.88 (m, 2 H), 5.63 (m, 1 H), 4.26 (d, J = 18.5 Hz, 2 H), 4.22 (br s, 1
H) 4.14 (d, J = 18.4 Hz, 1 H), 3.79 (d, J = 13.2 Hz, 1 H), 3.68 (d, J =
13.2 Hz, 1 H), 2.33 (s, 3 H), 2.06−1.97 (m, 2 H), 1.85−1.74 (m, 2 H),
1.59−1.45 (m, 2 H), 0.86 (s, 9 H), 0.04 (s, 3 H), 0.04 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ 143.3, 136.0, 134.0, 132.8, 131.3, 129.4,
127.8, 122.5, 121.1, 84.5, 83.0, 66.7, 52.5, 36.3, 32.2, 25.9, 25.8, 21.4,
19.5, 18.1, −4.6, −4.7; HRMS (ESI+) m/z 610.1430,
C29H38BrNO3SSiNa [M + Na]+ calcd 610.1423.
N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-
y l ) m e t h y l ) - 4 - m e t h y l - N - ( 3 - p h e n y l p r o p - 2 - y n - 1 - y l ) -
benzenesulfonamide (14d). The crude mixture was purified by flash
column chromatography (silica gel, 10% ethyl acetate/hexanes) to give
14d (0.93 g, 1.66 mmol, 75%) from the corresponding enol (0.94 g,
2.21 mmol) as a white solid: mp 99−100 °C; IR (CH2Cl2) 2954, 2929,
1
748, 700 cm−1; H NMR (400 MHz, CDCl3) δ 7.25−7.29 (m, 1 H),
6.87−6.90 (m, 2 H), 6.84 (s, 1 H), 3.81 (s, 3 H), 2.62−2.67 (m, 2 H),
2.38−2.41 (d, J = 12.0 Hz, 1 H), 2.30−2.34 (dd, J = 12.2, 4.6 Hz, 1 H),
2.21−2.28 (dt, J = 18.6, 4.4 Hz, 1 H), 1.97−2.00 (d, J = 12.0 Hz, 1 H),
1.61−1.79 (m, 6 H), 1.53−1.57 (d, J = 14.4 Hz, 1 H), 1.45−1.49 (d, J
= 14.4 Hz, 1 H), 0.92 (s, 3 H), 0.79 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 212.6, 159.1, 150.5, 140.7, 129.0, 124.1, 122.0, 115.2, 114.0,
55.2, 54.8, 51.7, 51.1, 40.2, 37.2, 35.9, 34.5, 34.5, 33.7, 32.2, 26.5, 21.5;
HRMS (ESI) [M + Na]+ m/e 369.1595, calcd for C21H27O2ClNa
369.1597.
General Procedure IV for Synthesis of Starting Compounds
14a−f. To a stirred solution of N-((3-hydroxycyclohex-1-en-1-
yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulf-onamide
(1.05 g, 2.65 mmol) in 5.0 mL of CH2Cl2 was added 0.032 g (0.27
mmol) of (dimethylamino)pyridine, 0.60 g (3.98 mmol) of tert-
butyldimethylsilyl chloride, and 1.18 g (2.31 mmol) of triethylamine.
The reaction mixture was stirred at 30 °C for 12 h. The reaction
mixture was added to 10 mL of water and extracted with CH2Cl2 (10
× 3 mL). The combined organic layer was washed with brine, dried
over MgSO4, filtered through a bed of Celite, and concentrated to give
the crude mixture.
N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-
methyl-N-(3-phenylprop-2-yn-1-yl)benzenesulfonamide (14a). The
crude mixture was purified by flash column chromatography (silica gel,
10% ethyl acetate/hexanes) to give 14a (1.33 g, 2.60 mmol, 98%) as a
white solid: mp 66−67 °C; IR (CH2Cl2) 3057, 2930, 1598, 1491,
1349, 1163, 1092, 661 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J
= 8.2 Hz, 2 H), 7.28−7.18 (m, 5 H), 7.06−7.01 (m, 2 H), 5.67 (s, 1
H), 4.30 (d, J = 18.4 Hz, 1 H), 4.24 (br s, 1 H), 4.17 (d, J = 18.4 Hz, 1
H), 3.82 (d, J = 13.4 Hz, 1 H), 3.70 (d, J = 13.4 Hz, 1 H), 2.32 (s, 3
H), 2.08−2.00 (m, 2 H), 1.78−1.75 (m, 2 H), 1.58−1.49 (m, 2 H),
0.87 (s, 9 H), 0.07−0.03 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ
143.3, 136.0, 134.0, 131.4, 131.1, 129.4, 129.3, 128.2, 128.0, 127.7,
122.2, 85.6, 81.6, 66.7, 52.4, 36.3, 32.2, 25.9, 25.8, 21.3, 19.4, 18.1,
−4.7; HRMS (ESI+) m/z 532.2325, C29H39NO3SSiNa [M + Na]+
calcd 532.2318.
1
1459, 1351, 1165, 1071, 661 cm−1; H NMR (400 MHz, CDCl3) δ
7.76 (d, J = 8.0 Hz, 2 H), 7.27−7.20 (m, 5 H), 7.03 (d, J = 6.8 Hz, 2
H), 5.64 (s, 1 H), 4.35 (d, J = 18.4 Hz, 1 H), 4.29 (br s, 1 H), 4.11 (d,
J = 18.4 Hz, 1 H), 3.84 (d, J = 13.2 Hz, 1 H), 3.67 (d, J = 13.2 Hz, 1
H), 2.32 (s, 3 H), 1.89−1.87 (m, 2 H), 1.68−1.63 (m, 1 H), 1.39−1.34
(m, 1 H), 1.01 (s, 3 H), 0.90 (s, 3 H), 0.87 (s, 9 H), 0.05 (s, 6 H); 13C
NMR (100 MHz, CDCl3) δ 143.3, 136.0, 132.2, 131.4, 131.4, 130.2,
129.4, 129.4, 128.2, 128.0, 127.7, 122.1, 85.8, 81.3, 66.9, 52.4, 45.1,
39.6, 36.2, 31.0, 30.8, 26.3, 25.8, 21.3, 18.1, −4.6, −4.8; HRMS (ESI+)
m/e 560.2632, C31H43NO3SSiNa [M + Na]+ calcd 560.2631.
N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-
y l ) m e t h y l ) - 4 - m e t h y l - N - ( 3 - p - t o l y l p r o p - 2 - y n - 1 - y l ) -
benzenesulfonamide (14e). The crude mixture was purified by flash
column chromatography (silica gel, 10% ethyl acetate/hexanes) to give
14e (0.94 g, 1.63 mmol, 71%) from the corresponding enol (1.00 g,
2.30 mmol) as a yellow oil: IR (CH2Cl2) 2952, 1669, 1510, 1348,
1093, 905, 671 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.0
Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 6.98 (d, J = 8.0 Hz, 2 H), 6.89 (d, J
= 8.0 Hz, 2 H), 5.62 (m, 1 H), 4.32−4.28 (m, 2 H), 4.07 (d, J = 18.4
Hz, 1 H), 3.80 (d, J = 13.2 Hz, 1 H), 3.66 (d, J = 13.2 Hz, 1 H), 2.28
(s, 3 H), 2.26 (s, 3 H), 1.90−1.79 (m, 2 H), 1.64−1.60 (m, 1 H),
1.36−1.31 (m, 1 H), 0.97 (s, 3 H), 0.87 (s, 3 H), 0.84 (s, 9 H), 0.02 (s,
6 H); 13C NMR (100 MHz, CDCl3) δ 143.1, 138.2, 135.8, 132.1,
131.2, 130.0, 129.3, 128.6, 127.6, 119.0, 85.8, 80.5, 66.8, 52.1, 45.0,
39.5, 36.2, 30.9, 30.7, 26.3, 25.7, 21.2, 18.0, − 4.7, −4.8; HRMS (ESI+)
m/e 574.2783, C32H45NO3SSiNa [M + Na]+ calcd 574.2787.
N-(3-(4-Bromophenyl)prop-2-yn-1-yl)-N-((3-((tert-
butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-yl)methyl)-4-
methylbenzenesulfonamide (14f). The crude mixture was purified by
flash column chromatography (silica gel, 10% ethyl acetate/hexanes)
to give 14f (0.32 g, 0.50 mmol, 17%) from the corresponding enol
(1.51 g, 3.00 mmol) as a yellow solid: mp 84−85 °C; IR (CH2Cl2)
1
2956, 1665, 1486, 1347, 1162, 905, 662 cm−1; H NMR (400 MHz,
N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-
methyl-N-(3-p-tolylprop-2-yn-1-yl)benzenesulfonamide (14b). The
crude mixture was purified by flash column chromatography (silica gel,
10% ethyl acetate/hexanes) to give 14b (0.52 g, 0.96 mmol, 66%)
from the corresponding enol (0.60 g, 1.45 mmol) as a yellow oil: IR
CDCl3) δ 7.75 (d, J = 8.2 Hz, 2 H), 7.37−7.35 (m, 2 H), 7.27−7.23
(m, 2 H), 6.90−6.88 (m, 2 H), 5.62 (m, 1 H), 4.34−4.29 (m, 2H),
4.10 (d, J = 18.5 Hz, 1H), 3.82 (d, J = 13.2 Hz, 1 H), 3.68 (d, J = 13.2
Hz, 1 H), 2.34 (s, 3 H), 1.88−1.86 (m, 2 H), 1.67−1.63 (m, 1 H),
1.38−1.33 (m, 1 H), 1.01 (s, 3 H), 0.91 (s, 3 H), 0.87 (s, 9 H), 0.05 (s,
6 H); 13C NMR (100 MHz, CDCl3) δ 143.3, 135.8, 132.8, 132.2,
131.3, 130.3, 129.4, 127.8, 122.5, 121.1, 84.6, 82.7, 66.9, 52.4, 45.1,
39.6, 36.2, 31.0, 30.8, 26.4, 25.8, 21.3, 18.1, −4.6, −4.8; HRMS (ESI+)
m/e 638.1735, C31H42BrNO3SSiNa [M + Na]+ calcd 638.1736.
N-((3-((tert-Butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-
yl)methyl)-N-(3-(3-methoxyphenyl)prop-2-yn-1-yl)-4-methylbenze-
nesulfonamide (14g). The crude mixture was purified by flash column
chromatography (silica gel, 10% ethyl acetate/hexanes) to give 14g
(0.73 g, 1.23 mmol, 71%) from the corresponding enol (0.78 g, 1.73
mmol) as a white solid: mp 90−91 °C; IR (CH2Cl2) 2952, 1424, 1164,
1071, 877 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.2 Hz, 2
H), 7.28 (d, J = 8.1 Hz, 2 H), 7.16 (t, J = 8.0 Hz, 1 H), 6.86−6.83 (m,
1 H), 6.65 (d, J = 7.6 Hz, 1 H), 6.59−6.58 (m, 1 H), 5.65 (m, 1 H),
1
(CH2Cl2) 2929, 2857, 1661, 1447, 1349, 1163, 1092, 671 cm−1; H
NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.2 Hz, 2 H), 7.24 (d, J = 8.2
Hz, 2 H), 7.03 (d, J = 8.0 Hz, 2 H), 6.93 (d, J = 8.0 Hz, 2 H), 5.66 (s, 1
H), 4.29 (d, J = 18.4 Hz, 1 H), 4.24 (br s, 1 H), 4.15 (d, J = 18.4 Hz, 1
H), 3.81 (d, J = 13.4 Hz, 1 H), 3.69 (d, J = 13.4 Hz, 1 H), 2.34 (s, 3
H), 2.32 (s, 3 H), 2.09−1.98 (m, 2 H), 1.87−1.74 (m, 2 H), 1.61−1.46
(m, 2 H), 0.87 (s, 9 H), 0.07−0.03 (m, 2 H); 13C NMR (100 MHz,
CDCl3) δ 143.2, 138.4, 136.0, 134.1, 131.3, 131.1, 129.4, 128.8, 127.7,
119.1, 85.8, 80.9, 66.7, 52.4, 36.4, 32.3, 25.9, 25.8, 21.3, 19.5, 18.1,
−4.6, −4.7; HRMS (ESI+) m/e 546.2477, C30H41NO3SSiNa [M +
Na]+ calcd 546.2474.
N-(3-(4-Bromophenyl)prop-2-yn-1-yl)-N-((3-((tert-
butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-methylbenze-
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4.39−4.31 (m, 2 H), 4.12 (d, J = 18.5 Hz, 1 H), 3.86 (d, J = 13.2 Hz, 1
H), 3.79 (s, 3H), 3.69 (d, J = 13.2 Hz, 1 H), 2.36 (s, 3 H), 1.90−1.89
(m, 2 H), 1.70−1.65 (m, 1 H), 1.40−1.35 (m, 1 H), 1.03 (s, 3 H), 0.91
(s, 3 H), 0.86 (s, 9 H), 0.04 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ
159.1, 143.5, 135.9, 132.3, 130.2, 129.5, 129.1, 127.8, 124.0, 123.2,
116.9, 114.3, 85.7, 81.3, 66.9, 55.2, 52.3, 45.2, 39.6, 36.2, 31.0, 30.9,
26.4, 25.8, 21.3, 18.1, −4.6, −4.7; HRMS (ESI) m/e 590.2740,
C32H45NO4SSiNa [M + Na]+ calcd 590.2736.
5% ethyl acetate/hexanes) to give 15b (0.12 g, 0.23 mmol, 46%) as a
yellow solid: mp 163−164 °C; IR (CH2Cl2) 2915, 1640, 1349, 1160
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2 H), 7.40
(d, J = 8.0 Hz, 2 H), 7.09 (s, 4 H), 5.77−5.75 (m, 1 H), 5.50−5.47 (m,
1 H), 3.98 (d, J = 14.8 Hz, 1 H), 3.88 (d, J = 14.8 Hz, 1 H), 3.31 (d, J
= 9.5 Hz, 1 H), 3.16 (d, J = 9.5 Hz, 1 H), 2.49 (s, 3 H), 2.34 (s, 3 H),
2.05−2.01 (m,1 H), 1.95 (d, J = 6.6 Hz, 2 H), 1.87−1.85 (m, 1 H),
1.75−1.69 (m, 1 H), 1.48−1.19 (m, 2 H), 1.17 (q, J = 12.4 Hz,1 H);
13C NMR (100 MHz, CDCl3) δ 151.0, 143.7, 143.4, 133.9, 132.3,
129.7, 128.2, 128.0, 127.9, 127.4, 92.4, 61.5, 57.5, 50.0, 39.7, 36.1, 28.2,
22.6, 21.6; HRMS (ESI) m/e 534.0966, C25H29INO2S [M + H]+ calcd
534.0964.
(Z)-4-((4-Bromophenyl)iodomethylene)-2-tosyl-2-azaspiro[4.6]-
undec-7-ene (15c). The crude mixture from general procedure V
(14c, 0.31 g, 0.50 mmol) was purified by flash column chromatog-
raphy (silica gel, 5% ethyl acetate/hexanes) to give 15c (0.17 g, 0.28
mmol, 56%) as a white solid: mp 212−214 °C; IR (CH2Cl2) 2934,
1482, 1346, 1158, 1092 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.75 (d,
J = 8.0 Hz, 2 H), 7.44 (d, J = 8.8 Hz, 2 H), 7.39 (d, J = 8.4 Hz, 2 H),
7.06 (d, J = 8.4 Hz, 2 H), 5.78−5.75 (m, 1 H), 5.48−5.46 (m, 1 H),
3.96 (d, J = 15.2 Hz, 1 H), 3.87 (d, J = 15.2 Hz, 1 H), 3.29 (d, J = 9.6
Hz, 1 H), 3.17 (d, J = 9.5 Hz, 1 H), 2.48 (s, 3 H), 2.08−2.02 (m, 1 H),
1.96−1.92 (m, 2 H), 1.88−1.84 (m, 1 H), 1.77−1.70 (m, 1 H), 1.45−
1.34 (m, 2 H), 1.25−1.15 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ
152.1, 143.8, 142.4, 134.1, 132.3, 131.4,129.9, 129.8, 128.0, 127.2,
122.3, 90.5, 61.6, 57.5, 50.2, 39.9, 36.3, 28.3, 22.7, 21.6; HRMS (FAB+)
m/e 597.9902, C24H26BrINO2S [M + H]+ calcd 597.9912.
N-(3-([1,1′-Biphenyl]-4-yl)prop-2-yn-1-yl)-N-((3-((tert-
butyldimethylsilyl)oxy)-5,5-dimethylcyclohex-1-en-1-yl)methyl)-4-
methylbenzenesulfonamide (14h). The crude mixture was purified
by flash column chromatography (silica gel, 10% ethyl acetate/
hexanes) to give 14h (0.72 g, 1.14 mmol, 71%) from the
corresponding enol (0.80 g, 1.60 mmol) as a white oil: IR (CH2Cl2)
1
2953, 2928, 1486, 1349, 1162, 1071, 840 cm−1; H NMR (500 MHz,
CDCl3) δ 7.78 (d, J = 8.5 Hz, 2 H), 7.55 (d, J = 7.5 Hz, 2 H), 7.46 (d,
J = 8.5 Hz, 2 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.35 (t, J = 7.3 Hz, 1 H),
7.26 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.2 Hz, 2 H), 5.66 (m, 1 H), 4.37
(d, J = 18.5 Hz, 1 H), 4.34−4.26 (m, 1 H), 4.13 (d, J = 18.5 Hz, 1 H),
3.86 (d, J = 13.2 Hz, 1 H), 3.70 (d, J = 13.2 Hz, 1 H), 2.33 (s, 3 H),
1.95−1.83 (m, 2 H), 1.70−1.62 (m, 1 H), 1.41−1.33 (m, 1 H), 1.02
(s, 3 H), 0.91 (s, 3 H), 0.88 (s, 9 H), 0.07 (s, 6 H); 13C NMR (125
MHz, CDCl3) δ 143.3, 141.1, 140.0, 135.8, 132.3, 131.8, 130.2, 129.4,
128.8, 127.8, 127.7, 126.9, 126.6, 121.0, 85.6, 82.0, 66.9, 52.3, 45.1,
39.5, 36.3, 31.0, 30.9, 26.3, 25.8, 21.4, 18.1, −4.6, −4.7; HRMS (ESI+)
m/e 636.2942, C37H47NO3SSiNa [M + Na]+ calcd 636.2944.
N-((3-((tert-Butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-N-
(3-(4-methoxyphenyl)prop-2-yn-1-yl)-4-methylbenzenesulfonamide
(14i). The crude mixture was purified by flash column chromatography
(silica gel, 10% ethyl acetate/hexanes) to give 14i (0.95 g, 1.70 mmol,
95%) from the corresponding enol (0.76 g, 1.79 mmol) as a yellow oil:
IR (CH2Cl2) 2931, 2858, 1607, 1463, 1350, 1250, 1163, 1075, 755
(Z)-4-(Iodophenylmethylene)-10,10-dimethyl-2-tosyl-2-azaspiro-
[4.6]undec-7-ene (15d). The crude mixture from general procedure V
(14d, 0.28 g, 0.50 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 15d
(0.21 g, 0.37 mmol, 73%) as a white solid: mp 124−126 °C; IR
(CH2Cl2) 2952, 1635, 1347, 1162 cm−1; 1H NMR (400 MHz, CDCl3)
δ 7.75 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.33−7.26 (m,
3H), 7.17 (d, J = 8.0 Hz, 2 H), 5.71−5.59 (m, 2 H), 4.01 (d, J = 15.2
Hz, 1H), 3.75 (d, J = 15.2 Hz, 1 H), 3.50 (d, J = 9.2 Hz, 1 H), 3.09 (d,
J = 9.2 Hz, 1 H), 2.48 (s, 3 H), 2.12−2.10 (m, 2 H), 1.71−1.68 (m, 2
H), 1.37 (s, 2 H), 0.80 (s, 3 H), 0.59 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 151.0, 143.8, 143.7, 132.3, 132.2, 129.7, 128.5, 128.2, 128.0,
92.8, 61.1, 58.8, 51.6, 51.1, 40.0, 35.3, 34.6, 33.3, 26.4, 21.6; HRMS
(ESI+) m/e 570.0946, C26H30INO2SNa [M + Na]+ calcd 570.0940.
(Z)-4-(Iodo-p-tolylmethylene)-10,10-dimethyl-2-tosyl-2-azaspiro-
[4.6]undec-7-ene (15e). The crude mixture from general procedure V
(14e, 0.29 g, 0.50 mmol) was purified by flash column chromatog-
raphy (silica gel, 5% ethyl acetate/hexanes) to give 15e (0.14 g, 0.24
mmol, 48%) as a white solid: mp 157−158 °C; IR (CH2Cl2) 2949,
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 2 H), 7.25
(d, J = 8.8 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 2 H), 6.75 (d, J = 8.8 Hz, 2
H), 5.65 (s, 1 H), 4.28 (d, J = 18.4 Hz, 1 H), 4.24 (br s, 1 H), 4.14 (d,
J = 18.4 Hz, 1 H), 3.82−3.79 (m, 4 H), 3.68 (d, J = 13.4 Hz, 1 H),
2.35 (s, 3 H), 2.03 (m, 2 H), 1.82−1.80 (m, 2 H), 1.55−1.53 (m, 2 H),
0.87 (s, 9 H), 0.05 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 159.6,
143.2, 136.2, 134.2, 132.9, 131.1, 129.4, 127.8, 114.2, 113.7, 85.6, 80.2,
66.8, 55.3, 52.4, 36.5, 32.3, 26.0, 25.9, 21.4, 19.6, 18.2, −4.6; HRMS
(ESI+) m/e 562.2428, C30H41NO4SSiNa [M + Na]+ calcd 562.2423.
General Procedure V for Formation of Compounds 15a−f
and 16. To a dried DCE solution (5.0 mL) of compound 14a (0.27 g,
0.50 mmol) were added Et2Zn (0.66 mL, 1.0 mmol) and CH2I2 (0.54
g, 2.0 mmol) at 0 °C under 1 atm of nitrogen for 1 h. The resulting
mixture was then stirred at 50 °C until no starting compound 14a was
detected on TLC (ca. 9−12 h). The reaction mixture was added to 10
mL of water and extracted with diethyl ether (10 × 3 mL). The
combined organic layer was washed with brine, dried over MgSO4,
filtered through a bed of Celite, and concentrated to give the crude
mixture.
(Z)-4-(Iodophenylmethylene)-2-tosyl-2-azaspiro[4.6]undec-7-ene
(15a). The crude mixture from general procedure V (14a, 0.27 g, 0.50
mmol) was purified by flash column chromatography (silica gel, 5%
ethyl acetate/hexanes) to give 15a (0.12 g, 0.22 mmol, 43%) as a
colorless solid: mp 101−102 °C; IR (CH2Cl2) 2922, 2841, 1638, 1347,
1159 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.0 Hz, 2 H),
7.38 (d, J = 7.9 Hz, 2 H), 7.30−7.17 (m, 5 H), 5.74 (m, 1 H), 5.47−
5.45 (m, 1 H), 3.98 (d, J = 15.2 Hz, 1 H), 3.90 (d, J = 15.2 Hz, 1 H),
3.28 (d, J = 9.4 Hz, 1 H), 3.17 (d, J = 9.5 Hz, 1 H), 2.47 (s, 3 H),
2.03−1.83 (m, 4 H), 1.71−1.67 (m, 1 H), 1.43−1.37 (m, 2 H), 1.19−
1.13 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 151.0, 143.7, 143.4,
133.9, 132.3, 129.7, 128.2, 128.0, 127.9, 127.4, 92.4, 61.5, 57.5, 50.0,
39.7, 36.1, 28.2, 22.6, 21.6; HRMS (ESI) m/z calcd for
C24H26INO2SNa (M + Na)+ 542.0627, found 542.0632. Crystals
suitable for X-ray diffraction analysis were grown from CH2Cl2 and
hexanes.
1
1349, 1160, 1093 cm−1; H NMR (500 MHz, CDCl3) δ 7.74 (d, J =
8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.10 (d, J = 8.1 Hz, 2 H), 7.06
(d, J = 8.0 Hz, 2 H), 5.71−5.59 (m, 2 H), 3.96 (d, J = 15.0 Hz, 1 H),
3.75 (d, J = 15.0 Hz, 1 H), 3.44 (d, J = 9.5 Hz, 1 H), 3.12 (d, J = 9.5
Hz, 1 H), 2.48 (s, 3 H), 2.33 (s, 3 H), 2.14−2.04 (m, 2 H), 1.78−1.66
(m, 2 H), 1.44 (d, J = 14.3 Hz, 1 H), 1.40 (d, J = 14.5 Hz, 1 H), 0.81
(s, 3 H), 0.62 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 150.9, 143.7,
141.0, 138.2, 132.3, 129.8, 128.7, 128.6, 128.1, 128.0, 93.3, 61.2, 58.8,
51.6, 51.1, 40.1, 35.4, 34.7, 33.4, 26.5, 21.6, 21.3; HRMS (ESI+) m/e
562.1286, C27H33INO2S [M + H]+ calcd 562.1277.
(Z)-4-((4-Bromophenyl)iodomethylene)-10,10-dimethyl-2-tosyl-
2-azaspiro[4.6]undec-7-ene (15f). The crude mixture from general
procedure V (14f, 0.32 g, 0.50 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 15f
(0.18 g, 0.29 mmol, 57%) as a yellow solid: mp 176−178 °C; IR
1
(CH2Cl2) 2923, 1598, 1348, 1159, 1012 cm−1; H NMR (500 MHz,
CDCl3) δ 7.63 (d, J = 8.0 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.41 (d,
J = 8.0 Hz, 2 H), 7.08 (d, J = 8.0 Hz, 2 H), 5.75−5.70 (m, 1 H), 5.67−
5.62 (m, 1 H), 3.98 (d, J = 15.0 Hz, 1 H), 3.78 (d, J = 15.0 Hz, 1 H),
3.46 (d, J = 9.0 Hz, 1 H), 3.16 (d, J = 9.0 Hz, 1 H), 2.50 (s, 3 H), 2.10
(d, J = 6.5 Hz, 2 H), 1.81−1.72 (m, 2 H), 1.46 (d, J = 14.5 Hz, 1 H),
1.39 (d, J = 14.5 Hz, 1 H), 0.85 (s, 3 H), 0.67 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 152.1, 143.9, 142.7, 132.5, 131.3, 130.0, 129.9, 128.3,
128.0, 128.0, 122.3, 90.9, 61.2, 58.7, 51.9, 51.3, 40.1, 35.5, 34.7, 33.5,
(Z)-4-(Iodo-p-tolylmethylene)-2-tosyl-2-azaspiro[4.6]undec-7-
ene (15b). The crude mixture from general procedure V (14b, 0.27 g,
0.50 mmol) was purified by flash column chromatography (silica gel,
9716
dx.doi.org/10.1021/jo301764g | J. Org. Chem. 2012, 77, 9707−9717

The Journal of Organic Chemistry
Article
26.4, 21.6; HRMS (ESI+) m/e 626.0217, C26H30BrINO2S [M + H]+
calcd 626.0225.
ACKNOWLEDGMENTS
■
This work has been supported by the National Science Council
(Grants NSC 98-2119-M-003-004-MY3 and NSC 98-2119-M-
003-001-MY2) and National Taiwan Normal University.
(Z)-4-(Iodo(3-methoxyphenyl)methylene)-10,10-dimethyl-2-
tosyl-2-azaspiro[4.6]undec-7-ene (15g). The crude mixture from
general procedure V (14g, 0.30 g, 0.50 mmol) was purified by flash
column chromatography (silica gel, 5% ethyl acetate/hexanes) to give
15g (0.17 g, 0.30 mmol, 59%) as a yellow solid: mp 157−158 °C; IR
REFERENCES
■
1
(CH2Cl2) 2952, 1595, 1348, 1160, 1093 cm−1; H NMR (400 MHz,
(1) (a) Fujimoto, R. A.; Boxer, J.; Jackson, R. H.; Simke, J. P.; Neale,
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CDCl3) δ 7.75 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.20 (t, J
= 8.0 Hz, 1 H), 6.81−6.76 (m, 2 H), 6.71 (s, 1 H), 5.69−5.62 (m, 2
H), 3.98 (d, J = 14.8 Hz, 1 H), 3.78−3.74 (m, 4 H), 3.46 (d, J = 9.2
Hz, 1 H), 3.12 (d, J = 9.2 Hz, 1 H), 2.47 (s, 3 H), 2.16−2.09 (m, 2 H),
1.76−1.70 (m, 2 H), 1.47 (d, J = 14.3 Hz, 1 H), 1.40 (d, J = 14.5 Hz, 1
H), 0.82 (s, 3 H), 0.63 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
158.9, 150.9, 144.7, 143.8, 132.3, 132.2, 129.7, 129.0, 128.5, 128.0,
120.7, 92.4, 61.0, 58.8, 55.3, 51.6, 51.1, 40.0, 35.2, 34.6, 33.3, 26.4,
21.6; HRMS (ESI+) m/e 578.1230, C27H33INO3S [M + H]+ calcd
578.1226.
(Z)-4-([1,1′-Biphenyl]-4-yliodomethylene)-10,10-dimethyl-2-
tosyl-2-azaspiro[4.6]undec-7-ene (15h). The crude mixture from
general procedure V (14h, 0.32 g, 0.50 mmol) was purified by flash
column chromatography (silica gel, 5% ethyl acetate/hexanes) to give
15h (0.15 g, 0.24 mmol, 47%) as a white solid: mp 201−202 °C; IR
(CH2Cl2) 2937, 1348, 1160, 1086 cm−1; 1H NMR (500 MHz, CDCl3)
δ 7.76 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 8.0
Hz, 2 H), 7.48−7.38 (m, 4 H), 7.38−7.34 (m, 1 H), 7.25 (d, J = 8.0
Hz, 2H), 5.69−5.63 (m, 2 H), 4.02 (d, J = 15.2 Hz, 1 H), 3.78 (d, J =
15.0 Hz, 1 H), 3.51 (d, J = 9.0 Hz, 1 H), 3.11 (d, J = 9.5 Hz, 1 H), 2.48
(s, 3 H), 2.21−2.11 (m, 2 H), 1.76−1.66 (m, 2 H), 1.47 (d, J = 14.4
Hz, 1 H), 1.40 (d, J = 14.3 Hz, 1 H), 0.81 (s, 3 H), 0.60 (s, 3 H); 13C
NMR (125 MHz, CDCl3) δ 151.4, 143.8, 142.7, 141.1, 140.2, 132.4,
132.3, 129.8, 128.9, 128.8, 128.5, 128.1, 127.7, 127.1, 126.7, 92.5, 61.2,
58.9, 51.8, 51.2, 40.1, 35.5, 34.7, 33.4, 26.4, 21.6; HRMS (ESI+) m/e
624.1431, C32H35INO2S [M + H]+ calcd 624.1433.
(2) (a) Suga, S.; Watanabe, M.; Yoshida, J. I. J. Am. Chem. Soc. 2002,
124, 14824. (b) Bittermann, H.; Bockler, F.; Einsiedel, J.; Gmeiner, P.
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( )-(1S,7S,8R)-8-Iodo-6-(4-methoxyphenyl)-3-tosyl-3-azatricyclo-
[5.4.1.01,5]dodec-5-ene (16). The crude mixture from general
procedure V (14i, 0.27 g, 0.50 mmol) was purified by flash column
chromatography (silica gel, 5% ethyl acetate/hexanes) to give 16 (0.09
g, 0.16 mmol, 31%) as a white solid: mp 196−198 °C; IR (CH2Cl2)
1
2915, 1513, 1336, 1247, 1098 cm−1; H NMR (500 MHz, CDCl3) δ
7.69 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 8.5 Hz, 2 H), 7.11 (d, J = 8.5 Hz,
2 H), 6.92 (d, J = 8.5 Hz, 2 H), 4.49−4.47 (m, 1 H), 4.18 (d, J = 15.0
Hz, 1 H), 4.05 (d, J = 6.5 Hz, 1 H), 3.83 (s, 3 H), 3.75 (d, J = 15.0 Hz,
1 H), 3.51 (d, J = 8.5 Hz, 1 H), 2.75 (d, J = 8.5 Hz, 1 H), 2.40 (s, 3 H),
2.34 (d, J = 12.5 Hz, 1 H), 2.24−2.17 (m, 1 H), 2.14−2.05 (m, 1 H),
1.89−1.81 (m, 2 H), 1.69−1.65 (m, 2 H), 1.41−1.38 (m, 1 H); 13C
NMR (125 MHz, CDCl3) δ 159.4, 143.5, 141.3, 134.5, 134.1, 129.8
128.5, 127.4, 125.4, 114.5, 60.7, 59.0, 58.4, 55.4, 46.3, 38.2, 36.5, 36.3,
35.5, 24.9, 21.5; HRMS (ESI+) m/e 550.0905, C25H29INO3S [M + H]+
calcd 550.0913.
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ASSOCIATED CONTENT
■
S
* Supporting Information
NMR spectra for compounds 1a−j, 2a−d, 2f−h, 3, 4, 7, 12a−f,
13a−f, 14a−i, 15a,b,d−h, and 16 and X-ray structure data and
crystallographic information files for compounds 2a,c−e,g, 3, 4,
7, 13a,c, 15a, and 16. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cheyeh@ntnu.edu.tw.
Notes
The authors declare no competing financial interest.
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dx.doi.org/10.1021/jo301764g | J. Org. Chem. 2012, 77, 9707−9717