Transition-metal-free carbofluorination of TBS-protected nitrogen-containing cyclic enynols: Synthesis of fluorinated azabicycles

Article abstract of DOI:10.1021/jo400634c

The synthesis of fluorinated azabicycles from tert-butyldimethylsilyl- protected N-containing cyclic enynols using inexpensive BF₃· OEt₂ is described. In this reaction, BF₃ reacts as both the Lewis acid and the fluoride source for cyclization/fluorination of the TBS-protected cyclic N-containing enynols. The method provides an easy access to fluorinated azabicycles where a new C(sp²)-F bond and a new bicyclic skeleton are generated at ambient temperature within 1-13 min under metal-free reaction conditions.

Full text of DOI:10.1021/jo400634c

Article
pubs.acs.org/joc
Transition-Metal-Free Carbofluorination of TBS-Protected Nitrogen-
Containing Cyclic Enynols: Synthesis of Fluorinated Azabicycles
Ming-Chang P. Yeh,* Chia-Jung Liang, Tzu-Lin Huang, Hsiao-Ju Hsu, and Yu-Shuo Tsau
Department of Chemistry, National Taiwan Normal University, 88 Ding-Jou Road, Section 4, Taipei 11677, Taiwan, Republic of
China
S
* Supporting Information
ABSTRACT: The synthesis of fluorinated azabicycles from tert-butyldime-
thylsilyl-protected N-containing cyclic enynols using inexpensive BF3·OEt2 is
described. In this reaction, BF3 reacts as both the Lewis acid and the fluoride
source for cyclization/fluorination of the TBS-protected cyclic N-containing
enynols. The method provides an easy access to fluorinated azabicycles
where a new C(sp2)−F bond and a new bicyclic skeleton are generated at
ambient temperature within 1−13 min under metal-free reaction conditions.
simple, inexpensive Lewis acid to generate C(sp2)−F bonds has
INTRODUCTION
■
yet to be developed. Inspired by our recent results on the
Fluorine-containing molecules play an important role in
FeCl3-promoted carbochlorination of N-containing 2-en-7-yn-
agrochemicals, pharmaceuticals, biomedical imaging agents,
1-ols to give arylchloromethylene-substituted azaspirocycles13
and chemical-resistant materials due to their unique physical
and the literature reports on the BF3·OEt2-promoted Prins
and chemical properties.1 Among them, monofluoroalkenes are
fluorination reactions of unsaturated alcohols and aldehydes to
of particular interest since they have potential applications in
produce fluorinated heterocycles,14 we envision an easy
material sciences,2 medicinal chemistry,3 and synthetic organic
available fluorine-containing reagent that may act as both the
chemistry4 where they can be metalated and elaborated to other
Lewis acid and the nucleophilic fluorine source would greatly
functionalities. Therefore, many synthetic methods have been
assist the synthesis of potential biologically active fluorinated
developed for the efficient synthesis of these moieties, including
azabicycles from tert-butyldimethylsilyl (TBS)-protected N-
Wittig-type olefination reactions via fluorine-containing diphe-
containing cyclic enynols. In this paper, we report a simple
nylphosphane oxides and aldehydes,5 fluorination reactions of
reaction that forms arylfluoromethylene-substituted azabicycles
vinylstannanes and -silanes with electrophilic fluorine reagents,6
in a regio- and stereoselective fashion by the BF3·OEt2-
the nucleophilic 1,4-addition of fluoride to ethyl prop-2-
promoted carbofluorination of 3-arylpropagyltosylaminometh-
ynoate,7 and the reaction of alkenylboronic acid with 1-
yl-tethered cyclohex-2-en-1-ols. In this transformation, detach-
chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-
ment of the siloxy group of the enynol by BF3·OEt2 generated
(tetrafluoroborate) (Selectfluor).8 Recently, transition-metal-
an allylic carbonium ion. A subsequently anti-addition of the
catalyzed fluorination of alkynes employing nucleophilic or
transient allylic carbonium ion and a fluoride ion across the
electrophilic fluorinating reagents to generate alkenyl fluorides
alkyne led to the stereoselective formation of fluorinated-
have been studied extensively, including attack of nucleophiles
octahydroisoquinolines and 2-azaspiro[4.5]decenes. Further-
onto the gold-activated C−C triple bond followed by
more, this process can be applied to the synthesis of fluorinated
treatments of the resulting vinylgold intermediates with
spirocarbocyclic analogous from 3-(5-arylpent-4-yn-1-yl)-
electrophilic fluorinating reagents,9 the silver-catalyzed intra-
molecular oxidative aminofluorination of alkynes or allenes
cyclohex-2-en-1-ols.
using N-fluorobenzenesulfonimide (NFSI) as an electrophilic
RESULTS AND DISCUSSION
fluorinating reagent,10 the palladium-catalyzed carbofluorina-
■
The required TBS-protected 3-phenylpropagyltosylamine-teth-
tion of nitrogen-containing 1,6-enynes using NFSI as the
fluorinating source,11 and the (NHC)gold-catalyzed trans-
ered 2-methylcyclohex-2-en-1-ol 1a was prepared, according to
the literature procedure, starting from treatments of cyclohex-2-
en-1-one with formaldehyde under Baylis−Hillman reaction
hydrofluorination of alkynes using Et3N·3HF as the nucleo-
philic fluorination reagent.12 Despite the above-mentioned
metal-catalyzed fluorination of alkynes affording alkenyl
fluorides using various fluorine sources, a direct regio- and
stereoselective fluorination of unactivated alkynes employing a
Received: March 27, 2013
© XXXX American Chemical Society
A
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conditions.15 Compound 1a was used as the parent substrate
for the survey of the optimal combination of solvent,
concentration and fluorine-containing Lewis acids as revealed
in Table 1. When BF3·OEt2 (1.0 molar equiv) was subjected to
silica gel (Scheme 1). The relative configuration within 3a was
assigned as depicted on the basis of NOESY experiments and
Scheme 1. Synthesis of Ketones 3a−d
Table 1. Optimizing of Reaction Conditions in the
Carbofluorination of 1a with BF3·OEt2
a
loading
(equiv)
yield
(%)
entry Lewis acid
solvent
time
1
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
Ph3CBF4
Ph3CBF4
BF3·OEt2
n-Bu4NF
BF3·OEt2
BF3·OEt2
BF3·OEt2
1
2
0.1 M CH2Cl2
0.1 M CH2Cl2
0.1 M DBE
1 min
1 min
1 min
1 min
1 min
1 min
15 min
25
48
34
33
34
6
was further characterized by X-ray diffraction analysis of 3b and
3d. Moreover, the use of unprotected enynol 1a′ (Figure 1)
and 1.0 equiv of BF3·OEt2 significantly increased the yield of
ketone 3a. The desired 2a and ketone 3a was isolated in a ratio
of 2:1 and in 20% overall yield. It was speculated that HOBF2,
detached by BF3 from 1a′ may attack at the acetylene to
produce ketone 3a while TBSOBF2 from 1a does not add at the
acetylene in the case of 1a.
2
3
2
4
2
0.1 M DCE
5
2
0.1 M CHCl3
0.1 M toluene
0.01 M toluene
6
2
7
2
11
25
8
2
2.5 mM toluene 35 min
b
9
2
0.1 M CH3CN
0.1 M CH2Cl2
0.1 M CH2Cl2
0.1 M CH2Cl2
0.1 M THF
1 min
1 min
1 min
1 min
10 h
0
In order to eliminate the formation of the undesired ketone
3, the following screening of the cyclization/fluorination
reaction conditions was conducted using the TBS-protected
substrate 1a. Delightfully, the yield of 2a increased up to 48%
when 1a (0.1 M in CH2Cl2) was treated with 2.0 equiv of
BF3·OEt2 at room temperature for 1 min (Table 1, entry 2).
The use of dibromoethane (DBE), dichloroethane (DCE),
chloroform, or toluene as solvents (substrates concentration 0.1
M) and 2.0 molar equiv of BF3·OEt2 did not improve the yield
of 2a (Table 1, entries 3−6). Moreover, lowering concentration
of 1a in toluene to 0.01 M or 2.5 mM slightly increased the
yield of 2a to 11% and 25%, respectively (Table 1, entries 7 and
8). Changing the solvent to CH3CN, a cyclization/amidation
reaction occurred rapidly and generated the acetamido-
(phenyl)methylene-substituted hexahydroisoquinoline 4 (Fig-
ure 1) as the major product in 79% yield, and no fluorinated
compound was isolated (Table 1, entry 9). Moreover,
increasing BF3·OEt2 loading to 10 molar equiv did not
improvement the yield of 2a (Table 1, entry 10). The other
fluoride source such as triphenylcarbenium tetrafluoroborate
(Ph3CBF4) was also tested for the cyclization reaction. Reaction
of Ph3CBF4 (2 or 5 equiv) with 1a in CH2Cl2 at room
temperature within 1 min produced 2a, albeit in 26% and 27%
yields, respectively (Table 1, entries 11 and 12). On the other
hand, treatment of 1a with 2.0 equiv of BF3·OEt2 (0.1 M) or
tetra-n-butylammonium fluoride (0.1 M) in THF at room
temperature gave desilylation product 1a′ in good yields, and
no fluorination reaction took place (Table 1, entries 13 and
14). When treated with BF3·OEt2 in THF at lower
concentration (0.01 M), 1a was recovered quantitatively
(Table 1, entry 15). Lowering concentration of 1a in CH2Cl2
to 0.01 M gave 2a in 51% yield (Table 1, entry 16). Finally, an
increasing yield (56%) of 2a was observed with decreasing
concentration of 1a to 2.5 mM in CH2Cl2 (Table 1, entry 17).
Therefore, the use of BF3·OEt2 (2.0 equiv) and 1a in diluted
CH2Cl2 (2.5 mM) at room temperature under nitrogen was
found to be the most effective method and was selected as the
standard reaction conditions. It is noteworthy that carbofluori-
nation of 1a under the optimal reaction conditions exclusively
generated the fluorinated isoquinoline derivatives with the (Z)-
10
11
12
13
14
15
16
17
10
2
50
26
27
5
c
2
0
c
2
0.1 M THF
0.5 h
36 h
0
d
2
0.01 M THF
0.01 M CH2Cl2
0
2
1 min
51
56
2
2.5 mM CH2Cl2 1 min
a
b
Isolated yields by column chromatography. Compound 4 was
isolated in 79% yield. Deprotection product 1a′ was isolated in good
c
d
yields. Compound 1a was recovered quantitatively.
compound 1a in 0.1 M of CH2Cl2 (DCM) at room
temperature under an atmosphere of nitrogen, the reaction
proceeded instantaneously to afford the phenyl(fluoro)-
methylene-substituted octahydroisoquinolines 2a with (Z)-
configuration in 25% isolated yield (Table 1, entry 1), together
with a trace amount of 4-benzoyloctahydroisoquinolines 3a
(Figure 1). None of the regioisomer resulting from addition of
Figure 1. Structures of 1a′, 4, and 5.
fluoride at the alkynyl carbon distal to the phenyl was
detectable in the H NMR spectrum of the crude mixture.
1
The structure of 2a was confirmed by X-ray diffraction analysis.
Ketone 3a may derive from BF3·OEt2-assisted addition of
water, presumably presenting in CH2Cl2, and the allylic moiety
across the acetylene. To further clarify the structure of 3a,
compounds 1a−d were treated with 0.1 molar equiv of TfOH
at room temperature for 0.5−4.5 h,16 ketones 3a−d were
obtained as the only diastereomer in each case, in 51−93%
yields after aqueous workup and column chromatography on
B
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configuration. However, most transition-metal-catalyzed fluori-
nation of alkynes required complex reaction conditions,
elevated reaction temperatures or prolonged reaction times to
give fluorinated olefins as a mixture of regio- or stereo-
isomers.9,12b
accomplished without employing transition metal catalysts or
complex reaction conditions, only requiring 2.0 equiv of
BF3·OEt2 in diluted CH2Cl2 at room temperature for 1−5 min.
A concerted reaction path for the formation of 2 and 3 is
suggested in Scheme 2. Detachment of the siloxy group of 1a
With these optimized reaction conditions, we next turned
our effort to the scope of the substituent at the terminal
position of the acetylene in this C(sp2)−F-forming reaction
using BF3 ·OEt2 in diluted CH2Cl2 at room temperature (Table
2). Substrates 1a−d bearing electron-neutral aryl groups, within
Scheme 2. Postulated Reaction Paths for Formation of 1a
and 3a
Table 2. Substrate Scope
a
entry
enynol
R
product
yield (%)
c
1
1a
1b
1c
1d
1e
1f
phenyl
2a
56
40
50
56
74
71
72
56
c
2
4-methylphenyl
3-methylphenyl
1-naphthyl
2b
c
3
2c
4
2d
c
5
4-nitrophenyl
2e
c
6
3-nitrophenyl
2f
c
7
1g
1h
1i
4-carbethoxyphenyl
3-carbethoxyphenyl
4-methoxyphenyl
4-bromophenyl
hydrogen
2g
c
8
2h
b
9
2i
0
c
10
11
12
1j
2j
52
0
by BF3·OEt2 generated the allylic carbonium ion 6 and released
a fluoride ion.17 The acetylene was then simultaneously
attacked by the allylic carbonium ion and an external fluoride
(from the less congested side) in a trans manner to generate 2a
with (Z)-configuration. Addition of H2O or TfOH to the allylic
carbonium ion 6 afforded ketone 3a after aqueous workup. This
suggestion agreed with better yields obtained from substrates
bearing an electron-withdrawing nitro- or ester groups on the
phenyl ring (Table 2, entries 5−8). A similar cation-π
cyclization of alkynes terminated by fluoride to give fluorinated
bicyclo[4.4.0]decanes was observed when cyclodec-5-yn-1-ol
was treated with BF3·OEt2 in CH2Cl2.18
1k
1l
2k
2l
methyl
83
a
b
Yields of isolated products. Dienone 5 was isolated in 50% yield.
c
Structures were confirmed by X-ray diffraction analysis.
1−13 min, produced the corresponding fluorinated octahy-
droisoquinolines 2a−d in 40−56% yields (Table 2, entries 1−
4). The presence of electron-withdrawing nitro or ester groups
on the phenyl ring, for example, 1e−h, has been shown to be
more efficient as evidenced by good yields (56−74%) of 2e−h
(Table 1, entries 5−8). Furthermore, treatment of the p-
nitrophenyl alkyne 1e with Ph3CBF4 in CH2Cl2 (2.5 mM) at
room temperature for 1 min and triphenylcarbenium
hexafluorophosphate (Ph3CPF6) in CH2Cl2 (2.5 mM) at
room temperature for 1 h also produced 2e in 60% and 59%
yields, respectively. Compound 1i with an electron-donating
methoxy group at the C-4 position of the phenyl ring (Table 2,
entry 9) did not afford any fluorinated isoquinoline derivatives.
Instead, the dienone 5 (Figure 1) was obtained in 50% isolated
yield. A bromine at the C-4 position of the phenyl ring, for
example, 1j, did not interfere with the activity of BF3·OEt2 and
gave the corresponding fluorinated isoquinoline derivative 2j in
52% yield (Table 2, entry 10). Unfortunately, the reaction of
BF3·OEt2 with the terminal alkyne 1k (Table 2, entry 11)
resulted in decomposition of starting substrates. Finally, we
were glad to find that the methyl terminal alkyne 1l reacted
efficiently with 2.0 molar equiv of BF3·OEt2 at room
temperature for 5 min, leading to the desired fluorinated
octahydroisoquinoline derivative 2l in 83% isolated yield
(Table 2, entry 12). It is important to mention that the
palladium-catalyzed carbofluorination of nitrogen-containing
1,6-enynes with the p-nitrophenyl- or the methyl terminal-
alkynes was inefficient and only produced trace amounts of the
desired fluorinated lactams.9d The current approach to the
synthesis of fluorinated octahydroisoquinolines 2e and 2l is
However, given that 2.0 molar equiv of BF3 was required for
−
the carbofluorination, we suspect that tetrafluoroborate (BF4 ),
generated from fluoride and BF3, may be the nucleophilic
fluorine source. This suggestion is consistent with the success
of Ph3CBF4 (Table 1, entries 11 and 12) acting as both the
Lewis acid and the fluoride source in the cyclization/
fluorination reactions. Examples of fluoride abstraction from
tetrafluoroborates have been reported in the AgBF4-assisted
vinylation of aromatic compounds19a and photochemical
decomposition of vinyl iodonium tetrafluoroborates.19b The
formation of the dienone 5 is postulated in Scheme 3. The
transient allylic carbonium ion 7 was attacked by the electron-
rich (p-methoxyphenyl)alkynyl group to give the allenyl cation
8. Upon aqueous quenching, attack of H2O at the sp-hybridized
carbon center of the allenyl moiety afforded 9, which after the
proton shuffle followed by the six-membered ring fragmenta-
tion gave dienone 5.
This chemistry can be extended to the synthesis of (Z)-4-
(arylfluoromethylene)-substituted azaspirocycles. As revealed in
Scheme 4, the carbofluorination reaction of TBS-protected N-
tosyl-3-arylpropagylamine-tethered 3-methylcyclohex-2-en-1-ol
derivatives 10a−d13 proceeded within 1−2 min at room
temperature to generate fluorinated azaspiro[4.5]dec-6-enes
11a−d with (Z)-configuration in 45−77% yields. The structure
C
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19F NMR spectra were recorded with a 376 MHz spectrometer. Mass
Scheme 3. Postulated Reaction Path Led to the Formation of
Dienone 5 from 1i
spectra were acquired on a spectrometer at an ionization potential of
70 eV and were reported as mass/charge (m/e) with percent relative
abundance. High-resolution mass spectra were obtained with a double-
focusing mass spectrometer.
Representative Procedure for Synthesis of Starting Com-
pound 1. To a solution of cyclohex-2-en-1-one (7.69 g, 80.0 mmol)
in MeOH (26.67 mL) and H2O (133.33 mL) under nitrogen were
added formaldehyde (37 wt % solution in water, 3.00 g, 100 mmol),
Ba(OH)2 (0.206 g, 1.2 mmol), and N-methyl-2-pyrrolidone (NMP,
0.34 g, 4.00 mmol). The reaction mixture was stirred at 29 °C for 4 h.
The reaction mixture was extracted with CH2Cl2 (100 mL × 3). The
combined extracts were washed with water (300 mL × 3) and brine
(300 mL × 3), dried over anhydrous MgSO4 (20 g), and concentrated
to give a crude oil. The crude mixture was purified by flash column
chromatography (silica gel, 1:3 ethyl acetate/hexanes) to afford 2-
(hydroxymethyl)cyclohex-2-enol (4.33 g, 34.32 mmol, 43%). To the
solution of 2-(hydroxymethyl)cyclohex-2-enol (4.33 g, 34.32 mmol) in
CH2Cl2 (171.6 mL) were added triethylamine (4.55 g, 44.61 mmol)
and acetic anhydride (4.20 g, 41.18 mmol). The reaction mixture was
stirred at 30 °C for 6 h before quenching with 100 mL of saturated
ammonium chloride solution. The solution was washed with water
(300 mL × 3) and brine (300 mL × 3), dried over anhydrous MgSO4
(15 g), and concentrated to give a crude oil. The crude mixture was
purified by flash column chromatography (silica gel, 1:5 ethyl acetate/
hexanes) to afford the corresponding acetate (3.23 g, 19.20 mmol,
56%). To the solution of the above acetate in 171 mL of CH2Cl2 was
added CeCl3·7H2O (7.90 g, 21.12 mmol) followed by addition of
NaBH4 (0.73 g, 19.2 mmol) at 0 °C under nitrogen. The reaction was
stirred at 0 °C for 30 min before quenching with 100 mL of saturated
ammonium chloride solution. The resulting mixture was extracted with
CH2Cl2 (200 mL × 3), and the combined extracts were washed with
water and brine and dried over MgSO4 (10 g). The filtrate was
concentrated in vacuo to give (6-hydroxycyclohex-1-en-1-yl)methyl
acetate (3.23 g, 19.01 mmol, 99%). To the above enol in 19.0 mL of
CH2Cl2 were added triethylamine (3.88 g, 38.0 mmol), 4-
dimethylaminopyridine (DMAP, 0.23 g, 1.90 mmol), and tert-
butyldimethylsilyl chloride (4.30 g, 41.18 mmol). The reaction
mixture was heated at reflux for 12 h, after which time the reaction
mixture was filtered through a bed of Celite. The resulting solution
was concentrated, and the residue was separated by flash column
chromatography (silica gel, 1:20 ethyl acetate/hexanes) to afford (6-
tert-butyldimethylsiloxycyclohex-1-en-1-yl)methyl acetate (3.95 g,
13.88 mmol, 73%). To the above crude mixture in MeOH (65.40
mL) in a 200 mL round-bottom flask was added K2CO3 (1.93 g, 13.88
mmol). The reaction was stirred at 30 °C for 1 h followed by
quenching with 200 mL of saturated ammonium chloride. The
resulting mixture was washed with water (200 mL × 3) and brine (200
mL × 3) and dried over MgSO4 (10 g) to give (3-((tert-
butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methanol (3.30 g, 13.6
mmol, 98%). To the above crude product in 68 mL of THF at 0
°C under nitrogen were added diisopropyl azodicarboxylate (DIAD,
3.30 g, 16.3 mmol), triphenylphosphine (4.28 g, 16.3 mmol), and N-
tosylprop-2-yn-1-amine (2.85 g, 13.6 mmol). The reaction was stirred
at 0 °C for 2 h before quenching with 100 mL of water. The resulting
mixture was extracted with CH2Cl2 (200 mL × 3), and the combined
extracts were washed with water (200 mL × 3) and brine (200 mL ×
3) and dried over MgSO4 (10 g). The filtrate was concentrated in
vacuo to give a crude oil. The crude mixture was purified by flash
column chromatography (silica gel, ethyl acetate/hexanes 1:20) to give
N-((6-((tert-butyldimethylsilyl)oxy)cyclohex-1-en-1-yl)methyl)-4-
methyl-N-(prop-2-yn-1-yl)-p-toluenesulfonamide (4.77 g, 11.0 mmol,
78%). To the above product in Et3N (22.0 mL) were added
Pd(PPh3)4 (25.40 mg, 0.022 mmol), CuI (0.084 g, 0.44 mmol), and
iodobenzene (2.69 g, 13.2 mmol). The reaction mixture was stirred at
40 °C for 12 h before quenching with 100 mL of saturated aqueous
ammonium chloride. The resulting solution was extracted with
CH2Cl2 (100 mL × 3). The combined organic solution was washed
with water (200 mL × 3) and brine (200 mL × 3) and dried over
MgSO4 (10 g). The filtrate was concentrated in vacuo to give a crude
Scheme 4. Synthesis of (Z)-4-(Arylfluoromethylene)-
Substituted Aza- and Carbospirocycles
elucidation of 11a was accomplished by X-ray diffraction
analysis.20 Moreover, this method can be applied to the
synthesis of fluorinated carbospirocycles. Cyclic TBS-protected
enynols 10e−h21 also underwent carbofluorination smoothly
with 2.0 equiv of BF3·OEt2 under the standard reaction
conditions for 1−2 min to afford fluorinated carbospirocycles
11e−h in 52−88% yields (Scheme 4).
In conclusion, we have developed a mild but highly efficient
BF3·OEt2-mediated carbofluorination of TBS-protected N-
containing cyclic enynols. This reaction is operationally simple
and proceeds to completion within 13 min at ambient
temperature, providing a highly practical and economical
method to the stereodefined fluorinated azabicycles.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were performed in oven-
dried glassware under a nitrogen atmosphere unless otherwise
indicated. Anhydrous solvents or reaction mixtures were transferred
via an oven-dried syringe or cannula. Solvents were predried by
1
molecular sieves and then by passing through an Al2O3 column. H
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 internal standard. 13C NMR spectra were recorded with a 100
MHz spectrometer with CDCl3 (77.0 ppm) as the internal standard.
D
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Article
oil. The crude mixture was purified by flash column chromatography
(silica gel, ethyl acetate/hexanes 1:20) to produce N-((6-((tert-
butyldimethylsilyl)oxy)cyclohex-1-en-1- yl)methyl)-4-methyl-N-(3-
phenylprop-2-yn-1-yl)-p-toluenesulfonamide (1a) (2.7 g, 5.30 mmol,
mixture was purified by flash column chromatography (silica gel, 1:20
ethyl acetate/hexanes) to give 2b (0.046 g, 0.11 mmol, 40%) as
colorless crystals: mp 133−134 °C; H NMR (400 MHz, CDCl3) δ
1
7.76 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.9 Hz,
2H), 6.97 (d, J = 7.9 Hz, 2H), 5.69 (s, 1H), 4.74 (d, J = 14.0 Hz, 1H),
3.93 (d, J = 11.9 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 3.44 (dd, J = 14.1,
4.8 Hz, 1H), 2.83 (s, 1H), 2.38 (s, 3H), 2.35 (s, 3H), 2.00−1.93 (m,
2H), 1.67−1.58 (m, 1H), 1.58−1.51 (m, 1H), 1.34−1.15 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 154.2 (d, J = 246 Hz), 143.1, 139.4, 134.9,
131.4, 129.4, 129.0, 128.6, 128.5, 128.1, 127.8, 114.6 (d, J = 18 Hz),
50.8 (d, J = 9 Hz), 36.2 (d, J = 4 Hz), 28.3 (d, J = 3 Hz), 25.0, 21.5,
21.4, 21.3; 19F NMR (CDCl3, 376 MHz) δ −95.9; IR (CH2Cl2) 2924,
1
48%) as colorless crystals: mp 114−115 °C; H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.27−7.18 (m, 5H), 6.99 (d, J = 6.8
Hz, 2H), 5.84 (s, 1H), 4.41 (d, J = 18.5 Hz, 1H), 4.22 (s, 1H), 4.09 (d,
J = 18.6 Hz, 1H), 4.04 (d, J = 15.7 Hz, 1H), 3.62 (d, J = 14 Hz, 1H),
2.30 (s, 3H), 2.12−1.97 (m, 2H), 1.78−1.74 (m, 2H), 1.67−1.52 (m,
2H), 0.89 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.3, 135.9, 133.5, 131.4, 129.4, 129.3, 128.2, 128.0, 127.9,
122.3, 85.8, 81.9, 65.4, 49.5, 36.8, 32.3, 25.9, 25.4, 21.4, 18.1, 17.6,
−4.4, −4.6; IR (CH2Cl2) 2929, 2851, 2356, 1351, 1165 cm−1; HRMS
(ESI) calcd for C29H39NO3NaSSi [M + Na]+ 532.2318, found
532.2310.
2860, 2358, 1347, 1162 cm−1
; HRMS (ESI) calcd for
C24H26FNO2NaS [M + Na]+ 434.1566, found 434.1570. Crystals
suitable for X-ray diffraction analysis were grown from CH2Cl2 and
hexanes.
To the solution of 1a (0.62 g, 1.21 mmol) in 2.42 mL of THF was
added tetra-n-butylammonium fluoride (TBAF, 0.379 g, 1.45 mmol) at
0 °C. The reaction was stirred at 0 °C for 30 min before filtering
through a bed of Celite. The resulting solution was concentrated in
vacuo to give a crude oil. The oil was purified by flash column
chromatography (silica gel, ethyl acetate/hexanes 1:10) to give N-((6-
hydroxycyclohex-1-en-1-yl)methyl)-4-methyl-N-(3-phenylprop-2-yn-
1-yl)-p-toluenesulfonamide (1a′) (0.44 g, 1.12 mmol, 93%) as
Data for (Z)-4-(Fluoro(m-tolyl)methylene)-2-tosyl-
1,2,3,4,4a,5,6,7-octahydroisoquinoline (2c). In the typical procedure,
to a solution of 1c (0.1 g, 0.19 mmol) in 74.0 mL of CH2Cl2 at room
temperature under an atmosphere of nitrogen was added BF3·OEt2
(0.046 mL, 0.37 mmol). The reaction mixture was stirred for 10 min,
and the crude mixture was purified by flash column chromatography
(silica gel, 1:20 ethyl acetate/hexanes) to give 2c (0.048 g, 0.093
1
1
mmol, 50%) as colorless crystals: mp 144−145 °C; H NMR (400
colorless crystals: mp 106−107 °C; H NMR (400 MHz, CDCl3) δ
MHz, CDCl3) δ 7.77 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H),
7.24−7.14 (m, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.70 (s, 1H), 4.74 (d, J =
14.0 Hz, 1H), 3.94 (d, J = 11.9 Hz, 1H), 3.49 (d, J = 13.3 Hz, 1H),
3.45 (dd, J = 14.1, 5 Hz, 1H), 2.81 (s, 1H), 2.38 (s, 3H), 2.33 (s, 3H),
2.00−1.94 (m, 2H), 1.67−1.60 (m, 1H), 1.55−1.50 (m, 1H), 1.33−
1.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 154.3 (d, J = 246 Hz),
143.1, 138.0, 134.9, 131.8, 131.5, 131.3, 130.1, 129.4, 128.6, 128.2,
127.9, 125.1 (d, J = 4 Hz), 114.8 (d, J = 18 Hz), 50.8, 40.5 (d, J = 8
Hz), 36.2 (d, J = 3 Hz), 28.4 (d, J = 3 Hz), 25.0, 21.4; 19F NMR
(CDCl3, 376 MHz) δ −95.5; IR (CH2Cl2) 2925, 2863, 2362, 1348,
1161 cm−1; HRMS (ESI) calcd for C24H26FNO2NaS [M + Na]+
434.1566, found 434.1558. Crystals suitable for X-ray diffraction
analysis were grown from CH2Cl2 and hexanes.
Data for (Z)-4-(Fluoro(naphthalen-1-yl)methylene)-2-tosyl-
1,2,3,4,4a,5,6,7-octahydroisoquinoline (2d). In the typical procedure,
to a solution of 1d (0.1 g, 0.18 mmol) in 72.0 mL of CH2Cl2 at room
temperature under an atmosphere of nitrogen was added BF3·OEt2
(0.044 mL, 0.36 mmol). The reaction mixture was stirred for 1 min
and the crude mixture was purified by flash column chromatography
(silica gel, 1:10 ethyl acetate/hexanes) to give 2d (0.045 g, 0.10 mmol,
56%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.2
Hz, 3H), 7.84 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.40 (t, J =
7.5 Hz, 1H), 7.36−7.31 (m, 3H), 7.19 (s, 1H), 7.07 (d, J = 4.9 Hz,
1H), 5.73 (s, 1H), 4.90 (d, J = 14.2 Hz, 1H), 4.00 (d, J = 11.4 Hz, 1H),
3.61 (dd, J = 14.2, 4.8 Hz, 1H), 3.49 (d, J = 11.4 Hz, 1H), 2.47 (s, 1H),
2.38 (s, 3H), 1.94−1.87 (m, 2H), 1.50−1.42 (m, 1H), 1.27−1.12 (m,
2H), 1.09−0.97 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 153.3 (d, J
= 251 Hz), 143.4, 134.8, 133.5, 131.1 (d, J = 6 Hz), 130.4 (d, J = 3
Hz), 129.6, 129.3, 128.6, 128.5, 128.3, 128.0, 127.0, 126.3, 124.9,
124.7, 117.2 (d, J = 16 Hz), 50.7, 40.1 (d, J = 6 Hz), 36.4 (d, J = 3 Hz),
29.7, 28.2 (d, J = 3 Hz), 24.9, 21.5, 21.3; 19F NMR (CDCl3, 376 MHz)
δ −89.8; IR (CH2Cl2) 2926, 2858, 1459, 1345, 1161 cm−1; HRMS
(ESI) calcd for C27H26FNO2NaS [M + Na]+ 470.1566, found
470.1574.
7.80 (d, J = 8.2 Hz, 2H), 7.32−7.22 (m, 5H), 7.09−7.05 (m, 2H), 5.81
(t, J = 3.4 Hz, 1H), 4.54 (d, J = 18.5 Hz, 1H), 4.37−4.28 (m, 2H), 4.04
(d, J = 18.4 Hz, 1H), 3.45 (d, J = 14 Hz, 1H), 2.94 (d, J = 4.6 Hz, 1H),
2.34 (s, 3H), 2.14−1.95 (m, 2H), 1.94−1.84 (m, 1H), 1.80−1.71 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 143.6, 135.7, 134.1, 131.5,
130.8, 129.5, 128.4, 128.1, 127.8, 122.1, 85.7, 81.7, 64.3, 49.9, 36.4,
31.0, 25.5, 21.4, 19.0; IR (CH2Cl2) 3527, 2930, 1598, 1444, 1346,
1161 cm−1; HRMS (ESI) calcd for C23H25NO3NaS [M + Na]+
418.1453, found 418.1451.
General Experimental Procedure for BF3-Mediated Carbo-
fluorination of TBS-Protected 3-Phenylpropagyltosylamine-
Tethered 2-Methylcyclohex-2-en-1-ol 1a. To a solution of 1a (0.1
g, 0.2 mmol) in 80.0 mL of CH2Cl2 at room temperature under an
atmosphere of nitrogen was added BF3·OEt2 (0.048 mL, 0.39 mmol).
The reaction mixture was stirred at room temperature for 1 min, after
which time no substrate 1a was detected, as monitored by TLC. The
reaction mixture was quenched with saturated aqueous sodium
bicarbonate. The organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were washed with brine (100 mL × 3), dried over anhydrous
MgSO4 (10 g), and concentrated to give the crude mixture.
Data for (Z)-4-(Fluoro(phenyl)methylene)-2-tosyl-
1,2,3,4,4a,5,6,7-octahydroisoquinoline (2a). In the typical procedure,
to a solution of 1a (0.1 g, 0.2 mmol) in 80.0 mL of CH2Cl2 at room
temperature under an atmosphere of nitrogen was added BF3·OEt2
(0.048 mL, 0.39 mmol). The reaction mixture was stirred for 1 min,
and the crude mixture was purified by flash column chromatography
(silica gel, 1:20 ethyl acetate/hexanes) to give 2a (0.044 g, 0.11 mmol,
1
56%) as colorless crystals: mp 143−144 °C; H NMR (400 MHz,
CDCl3) δ 7.77 (d, J = 8.1 Hz, 2H), 7.37−7.30 (m, 3H), 7.28−7.26 (m,
2H), 7.09−7.07 (m, 2H), 5.70 (s, 1H), 4.75 (d, J = 14.0 Hz, 1H), 3.94
(d, J = 11.9 Hz, 1H), 3.52−3.43 (m, 2H), 2.84 (s, 1H), 2.37 (s, 3H),
2.00−1.94 (m, 2H), 1.64−1.60 (m, 1H), 1.56−1.52 (m, 1H), 1.32−
1.20 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 154.1 (d, J = 246 Hz),
143.2, 134.8, 131.2, 129.4, 129.3, 128.3, 128.2, 127.9, 127.8, 115.1 (d, J
= 17 Hz), 50.8, 40.5 (d, J = 9 Hz), 36.1 (d, J = 3 Hz), 28.3 (d, J = 3
Hz), 24.9, 21.4; 19F NMR (CDCl3, 376 MHz) δ −96.2; IR (CH2Cl2)
2923, 1676, 1598, 1447, 1344, 1159 cm−1; HRMS (ESI) calcd for
Data for (Z)-4-(Fluoro(4-nitrophenyl)methylene)-2-tosyl-
1,2,3,4,4a,5,6,7-octahydroisoquinoline (2e). In the typical procedure,
to a solution of 1e (0.1 g, 0.18 mmol) in 72.0 mL of CH2Cl2 at room
temperature under an atmosphere of nitrogen was added BF3·OEt2
(0.045 mL, 0.36 mmol). The reaction mixture was stirred for 1 min,
and the crude mixture was purified by flash column chromatography
(silica gel, 1:15 ethyl acetate/hexanes) to give 2e (0.059 g, 0.133
+
C23H24FNO2NaS [M + Na] 420.1409, found 420.1399. Crystals
suitable for X-ray diffraction analysis were grown from CH2Cl2 and
hexanes.
Data for (Z)-4-(Fluoro(p-tolyl)methylene)-2-tosyl-1,2,3,4,4a,5,6,7-
octahydroisoquinoline (2b). In the typical procedure, to a solution of
1b (0.15 g, 0.28 mmol) in 111.0 mL of CH2Cl2 at room temperature
under an atmosphere of nitrogen was added BF3·OEt2 (0.069 mL, 0.56
mmol). The reaction mixture was stirred for 13 min, and the crude
1
mmol, 74%) as colorless crystals: mp 142−143 °C; H NMR (400
MHz, CDCl3) δ 8.20 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H),
7.32 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 5.74 (s, 1H), 4.77
(d, J = 14.0 Hz, 1H), 3.97 (d, J = 12.1 Hz, 1H), 3.55 (d, J = 12.1 Hz,
1H), 3.47 (dd, J = 14.1, 5.0 Hz, 1H), 2.91 (s, 1H), 2.37 (s, 3H), 2.03−
E
dx.doi.org/10.1021/jo400634c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.96 (m, 2H), 1.71−1.63 (m, 1H), 1.56−1.49 (m, 1H), 1.37−1.23 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 151.5 (d, J = 244 Hz), 147.9,
143.4, 137.9, 137.6, 134.8, 130.3, 129.4, 128.8, 128.6, 128.5, 127.8,
123.7, 118.9 (d, J = 16 Hz), 50.7, 40.5 (d, J = 9 Hz), 36.1 (d, J = 3 Hz),
28.4, 24.8, 21.5, 21.3; 19F NMR (CDCl3, 376 MHz) δ −99.7; IR
(CH2Cl2) 2930, 1599, 1520, 1347, 1161 cm−1; HRMS (ESI) calcd for
C23H22FN2O4S [M − H]− 441.1284, found 441.1290. Crystals suitable
for X-ray diffraction analysis were grown from CH2Cl2 and hexanes.
Data for (Z)-4-(Fluoro(3-nitrophenyl)methylene)-2-tosyl-
1,2,3,4,4a,5,6,7-octahydroisoquinoline (2f). In the typical procedure,
to a solution of 1f (0.1 g, 0.18 mmol) in 72.0 mL of CH2Cl2 at room
temperature under an atmosphere of nitrogen was added BF3·OEt2
(0.045 mL, 0.36 mmol). The reaction mixture was stirred for 1 min,
and the crude mixture was purified by flash column chromatography
(silica gel, 1:15 ethyl acetate/hexanes) to give 2f (0.057 g, 0.128 mmol,
14.3; 19F NMR (CDCl3, 376 MHz) δ −97.6; IR (CH2Cl2) 2934, 2867,
1721, 1255, 1161 cm−1; HRMS (ESI) calcd for C26H28FNO4NaS [M +
Na]+ 492.1612, found 492.1621. Crystals suitable for X-ray diffraction
analysis were grown from CH2Cl2 and hexanes.
Data for (Z)-4-((4-Bromophenyl)fluoromethylene)-2-tosyl-
1,2,3,4,4a,5,6,7- octahydroisoquinoline (2j). In the typical procedure,
to a solution of 1j (0.12 g, 0.204 mmol) in 82.0 mL of CH2Cl2 at room
temperature under an atmosphere of nitrogen was added BF3·OEt2
(0.051 mL, 0.41 mmol). The reaction mixture was stirred for 12 min
and the crude mixture was purified by flash column chromatography
(silica gel, 1:20 ethyl acetate/hexanes) to give 2j (0.051 g, 0.11 mmol,
1
52%) as colorless crystals: mp 164−165 °C; H NMR (400 MHz,
CDCl3) δ 7.76 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.26 (d, J
= 7.8 Hz, 2H), 6.96 (d, J = 8.3 Hz, 2H), 5.71 (s, 1H), 4.73 (d, J = 14.0
Hz, 1H), 3.94 (d, J = 12.0 Hz, 1H), 3.51 (d, J = 11.9 Hz, 1H), 3.44
(dd, J = 14.0, 4.8 Hz, 1H), 2.80 (s, 1H), 2.38 (s, 3H), 2.01−1.94 (m,
2H), 1.68−1.60 (m, 1H), 1.54−1.47 (m, 1H), 1.35−1.18 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 152.9 (d, J = 245 Hz), 143.2, 134.8, 131.7,
130.9, 130.5 (d, J = 30 Hz), 129.5, 129.4, 128.5, 127.8, 123.6, 116.0 (d,
J = 17 Hz), 50.8, 40.4 (d, J = 8 Hz), 36.1, 28.3, 24.9, 21.5, 21.4; 19F
NMR (CDCl3, 376 MHz) δ −97.2; IR (CH2Cl2) 2925, 2361, 1685,
1347, 1161 cm−1; HRMS (ESI) calcd for C23H23BrFNO2NaS [M +
Na]+ 500.0494, found 500.0497. Crystals suitable for X-ray diffraction
analysis were grown from CH2Cl2 and hexanes.
1
71%) as colorless crystals: mp 133−134 °C; H NMR (400 MHz,
CDCl3) δ 8.22 (d, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.78 (d, J = 8.0 Hz,
2H), 7.56 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.0
Hz, 2H), 5.76 (s, 1H), 4.77 (d, J = 14.2 Hz, 1H), 3.98 (d, J = 12.0 Hz,
1H), 3.55 (d, J = 12.1 Hz, 1H), 3.47 (dd, J = 14.2, 5.0 Hz, 1H), 2.83 (s,
1H), 2.37 (s, 3H), 2.04−1.97 (m, 2H), 1.71−1.63 (m, 1H), 1.55−1.49
(m, 1H), 1.37−1.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 151.3
(d, J = 245 Hz), 148.1, 143.6, 134.8, 133.6 (d, J = 4 Hz), 133.2 (d, J =
31 Hz), 130.4, 129.6, 129.5, 128.9, 127.8, 124.1, 122.9 (d, J = 4 Hz),
118.0 (d, J = 16 Hz), 50.8, 40.4 (d, J = 9 Hz), 36.1 (d, J = 3 Hz), 28.4
(d, J = 3 Hz), 24.9, 21.4, 21.3; 19F NMR (CDCl3, 376 MHz) δ −98.4;
IR (CH2Cl2) 2932, 1694, 1533, 1351, 1160 cm−1; HRMS (ESI) calcd
for C23H22FN2O4S [M − H]− 441.1284, found 441.1291. Crystals
suitable for X-ray diffraction analysis were grown from CH2Cl2 and
hexanes.
Data for (Z)-4-(1-Fluoroethylidene)-2-tosyl-1,2,3,4,4a,5,6,7-octa-
hydroisoquinoline (2l). Compound 1l was prepared from N-(but-2-
yn-1-yl)-4-methylbenzenesulfonamide and (3-((tert-
butyldimethylsilyl)oxy)cyclo-hex-1-en-1-yl)methanol under the Mitsu-
nobu reaction condition. In the typical procedure, to a solution of 1l
(0.1 g, 0.224 mmol) in 89.0 mL of CH2Cl2 at room temperature under
an atmosphere of nitrogen was added BF3·OEt2 (0.055 mL, 0.45
mmol). The reaction mixture was stirred for 5 min, and the crude
mixture was purified by flash column chromatography (silica gel, 1:20
ethyl acetate/hexanes) to give 2l (0.063 g, 0.186 mmol, 83%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H),
7.28 (d, J = 7.8 Hz, 2H), 5.66 (s, 1H), 4.58 (d, J = 13.8 Hz, 1H), 3.88
(d, J = 11.9 Hz, 1H), 3.39 (d, J = 11.9 Hz, 1H), 3.23 (dd, J = 13.7, 1.9
Hz, 1H), 2.65 (d, J = 9.7 Hz, 1H), 2.42 (s, 3H), 2.03−1.95 (m, 2H),
1.79−1.69 (m, 5H), 1.51−1.38 (m, 1H), 1.281.16 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 153.6 (d, J = 249 Hz), 143.0, 134.9, 131.4, 129.2,
128.0, 127.7, 112.0 (d, J = 14 Hz), 50.4, 39.6 (d, J = 9 Hz), 36.3 (d, J =
5 Hz), 28.1 (d, J = 3 Hz), 24.9, 21.5, 14.3 (d, J = 31 Hz); 19F NMR
(CDCl3, 376 MHz) δ −98.2; IR (CH2Cl2) 2925, 2849, 2361, 1715,
1347, 1161 cm−1; HRMS (ESI) calcd for C18H22FNO2NaS [M + Na]+
358.1253, found 358.1260.
Data for (Z)-Ethyl 4-(Fluoro(2-tosyl-2,3,4a,5,6,7-hexahydroiso-
quinolin-4(1H)- ylidene)methyl)benzoate (2g). In the typical
procedure, to a solution of 1g (0.1 g, 0.17 mmol) in 68.0 mL of
CH2Cl2 at room temperature under an atmosphere of nitrogen was
added BF3·OEt2 (0.042 mL, 0.34 mmol). The reaction mixture was
stirred for 3 min, and the crude mixture was purified by flash column
chromatography (silica gel, 1:15 ethyl acetate/hexanes) to give 2g
1
(0.058 g, 0.12 mmol, 72%) as colorless crystals: mp 139−140 °C; H
NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 8.2
Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.72 (s,
1H), 4.76 (d, J = 14.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 3.96 (d, J =
12.0 Hz, 1H), 3.53 (d, J = 12.0 Hz, 1H), 3.46 (dd, J = 14.2, 5.0 Hz,
1H), 2.87 (s, 1H), 2.37 (s, 3H), 2.01−1.95 (m, 2H), 1.67−1.60 (m,
1H), 1.55−1.48 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.34−1.16 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 165.8, 152.9 (d, J = 246 Hz), 143.3,
135.8 (d, J = 30 Hz), 134.8, 131.2, 130.8, 129.5, 129.4, 128.5, 127.8,
127.7, 117.0 (d, J = 17 Hz), 61.3, 50.8, 40.5 (d, J = 9 Hz), 36.1 (d, J =
3 Hz), 28.3 (d, J = 3 Hz), 24.9, 21.5, 21.4, 14.3; 19F NMR (CDCl3, 376
MHz) δ −98.4; IR (CH2Cl2) 2923, 2856, 1716, 1277, 1159 cm−1;
HRMS (ESI) calcd for C26H29FNO4S [M + H]+ 470.1801, found
470.1796. Crystals suitable for X-ray diffraction analysis were grown
from CH2Cl2 and hexanes.
Data for Phenyl(2-tosyl-1,2,3,4,4a,5,6,7-octahydroisoquinolin-4-
yl)methanone (3a). In the typical procedure, to a solution of 1a (0.2
g, 0.39 mmol) in 3.9 mL of CH2Cl2 at room temperature under open
system was added TfOH (0.0036 mL, 0.04 mmol). The reaction
mixture was stirred for 4.5 h, and the crude mixture was purified by
flash column chromatography (silica gel, 1:15 ethyl acetate/hexanes)
to give 3a (0.113 g, 0.282 mmol, 72%) as colorless crystals: mp 167−
1
168 °C; H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 7.4 Hz, 2H),
Data for (Z)-Ethyl 3-(Fluoro(2-tosyl-2,3,4a,5,6,7- hexahydroiso-
quinolin-4(1H)-ylidene)methyl)benzoate (2h). In the typical proce-
dure, to a solution of 1h (0.155 g, 0.27 mmol) in 106.0 mL of CH2Cl2
at room temperature under an atmosphere of nitrogen was added
BF3·OEt2 (0.066 mL, 0.53 mmol). The reaction mixture was stirred for
1 min, and the crude mixture was purified by flash column
chromatography (silica gel, 1:15 ethyl acetate/hexanes) to give 2h
(0.070 g, 0.150 mmol, 56%) as colorless crystals: mp 164−165 °C; 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.9 Hz, 1H), 7.80−7.76 (m,
3H), 7.42 (t, J = 7.8 Hz, 1H), 7.31−7.26 (m, 3H), 5.71 (s, 1H), 4.75
(d, J = 14.1 Hz, 1H), 4.39 (quart, J = 7.1 Hz, 2H), 3.96 (d, J = 12.0 Hz,
1H), 3.53 (d, J = 12.0 Hz, 1H), 3.47 (dd, J = 14.1, 5.0 Hz, 1H), 2.85 (s,
1H), 2.35 (s, 3H), 2.01−1.95 (m, 2H), 1.67−1.61 (m, 1H), 1.57−1.51
(m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 1.33−1.18 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 165.8, 152.9 (d, J = 246 Hz), 143.4, 134.7, 132.0,
131.9, 131.9 (d, J = 30 Hz), 130.9, 130.8, 130.3, 129.4, 128.9 (d, J = 4
Hz), 128.5, 128.4, 127.7, 116.1 (d, J = 17 Hz), 61.3, 50.8, 40.5, (d, J =
9 Hz), 36.1 (d, J = 3 Hz), 28.3 (d, J = 3 Hz), 24.9, 21.4 (d, J = 3 Hz),
7.64−7.60 (m, 3H), 7.50 (t, J = 7.6 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
5.80 (s, 1H), 4.17 (dd, J = 12.6, 1.44 Hz, 1H), 3.91 (ddd, J = 11.8, 3.3,
2.0 Hz, 1H), 3.50 (td, J = 11.1, 3.7 Hz, 1H), 2.94 (d, J = 12.5 Hz, 1H),
2.48−2.42 (m, 5H), 2.00 (m, 2H), 1.72−1.60 (m, 2H), 1.40−1.29 (m,
1H), 1.12−1.02 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 200.8,
143.8, 136.7, 133.9, 133.1, 131.4, 129.7, 128.9, 128.4, 127.8, 126.1,
52.8, 49.2, 38.1, 28.0, 25.2, 21.5, 21.2; IR (CH2Cl2) 2926, 1677, 1597,
1587, 1348, 1167 cm−1; (ESI) calcd for C23H25NO3NaS [M + Na]+
418.1453, found 418.1451.
Data for p-Tolyl(2-tosyl-1,2,3,4,4a,5,6,7-octahydroisoquinolin-4-
yl)methanone (3b). In the typical procedure, to a solution of 1b (0.15
g, 0.28 mmol) in 2.8 mL of CH2Cl2 at room temperature under open
system was added TfOH (0.0026 mL, 0.028 mmol). The reaction
mixture was stirred for 18 min, and the crude mixture was purified by
flash column chromatography (silica gel, 1:10 ethyl acetate/hexanes)
to give 3b (0.058 g, 0.14 mmol, 51%) as colorless crystals: mp 99−100
°C; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.1 Hz, 2H), 7.62 (d, J
F
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The Journal of Organic Chemistry
Article
= 8.2 Hz, 2H), 7.35−7.27 (m, 4H), 5.80 (s, 1H), 4.16 (d, J = 12.5 Hz,
1H), 3.89 (dd, J = 11.6, 1.8 Hz, 1H), 3.47 (td, J = 11.1, 3.7 Hz, 1H),
2.93 (d, J = 12.5 Hz, 1H), 2.49−2.41 (m, 8H), 2.05−1.96 (s, 2H),
1.73−1.65 (m, 1H), 1.64−1.57 (m, 1H), 1.40−1.27 (m, 1H), 1.11−
1.00 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 200.3, 144.9, 143.7,
134.2, 133.1, 131.5, 129.7, 129.6, 128.5, 127.8, 126.1, 52.8, 49.3, 49.0,
38.1, 28.0, 25.2, 21.7, 21.5, 21.2; IR (CH2Cl2) 2925, 2360, 1673, 1348,
1161 cm−1; HRMS (ESI) calcd for C24H27NO3NaS [M + Na]+
432.1609, found 432.1600. Crystals suitable for X-ray diffraction
analysis were grown from CH2Cl2 and hexanes.
Data for m-Tolyl(2-tosyl-1,2,3,4,4a,5,6,7-octahydroisoquinolin-4-
yl)methanone (3c). In the typical procedure, to a solution of 1c (0.1 g,
0.19 mmol) in 1.9 mL of CH2Cl2 at room temperature under open
system was added TfOH (0.0017 mL, 0.019 mmol). The reaction
mixture was stirred for 3.5 h, and the crude mixture was purified by
flash column chromatography (silica gel, 1:10 ethyl acetate/hexanes)
to give 3c (0.067 g, 0.16 mmol, 88%) as colorless crystals: mp 144−
145 °C; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.2 Hz, 2H), 7.62
(d, J = 8.2 Hz, 2H), 7.45−7.36 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 5.80
(s, 1H), 4.17 (d, J = 12.5 Hz, 1H), 3.90 (d, J = 11.8 Hz, 1H), 3.49 (td,
J = 11.1, 3.7 Hz, 1H), 2.94 (d, J = 12.5 Hz, 1H), 2.48−2.41 (m, 8H),
2.05−1.97 (s, 2H), 1.73−1.66 (m, 1H), 1.65−1.58 (m, 1H), 1.41−
1.28 (m, 1H), 1.12−1.01 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
200.9, 143.7, 138.7, 136.7, 134.6, 133.0, 131.4, 129.7, 128.8, 127.8,
126.1, 125.6, 52.7, 49.2, 38.0, 27.9, 25.1, 21.5, 21.3, 21.1; IR (CH2Cl2)
2926, 2360, 1676, 1349, 1162 cm−1; HRMS (ESI) calcd for
C24H27NO3NaS [M + Na]+ 432.1609, found 432.1614.
Data for Naphthalen-1-yl(2-tosyl-1,2,3,4,4a,5,6,7-octahydroiso-
quinolin-4-yl)methanone (3d). In the typical procedure, to a solution
of 1d (0.1 g, 0.18 mmol) in 1.8 mL of CH2Cl2 at room temperature
under open system was added TfOH (0.0016 mL, 0.018 mmol). The
reaction mixture was stirred for 35 min, and the crude mixture was
purified by flash column chromatography (silica gel, 1:10 ethyl
acetate/hexanes) to give 3d (0.074 g, 0.17 mmol, 93%) as colorless
crystals: mp 187−188 °C; 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J =
8.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.90
(d, J = 8.9 Hz, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.61−7.51 (m, 3H), 7.32
(d, J = 8 Hz, 2H), 5.79 (s, 1H), 4.18 (d, J = 12.6 Hz, 1H), 4.02 (dt, J =
11.8, 1.6 Hz, 1H), 3.48 (td, J = 11, 3.7 Hz, 1H), 2.99 (d, J = 12.5 Hz,
1H), 2.62 (t, J = 11.6 Hz, 1H), 2.56 (s, 1H), 2.44 (s, 3H), 2.02−1.95
(m, 2H), 1.83−1.75 (m, 1H), 1.62−1.55 (m, 1H), 1.42−1.30 (m, 1H),
1.16−1.03(m, 1H); 13C NMR (100 MHz, CDCl3) δ 204.1, 143.7,
135.5, 134.0, 133.7, 133.2, 131.3, 130.0, 129.7, 128.6, 128.3, 127.8,
126.6, 126.1, 125.5, 124.4, 53.0, 52.7, 49.3, 38.6, 28.0, 25.1, 21.5, 21.2;
IR (CH2Cl2) 2927, 2358, 1670, 1591, 1347, 1159 cm−1; HRMS (ESI)
calcd for C27H27NO3NaS [M + Na]+ 468.1609, found 468.1604.
Crystals suitable for X-ray diffraction analysis were grown from
CH2Cl2 and hexanes.
was added BF3·OEt2 (0.046 mL, 0.37 mmol). The reaction mixture
was stirred for 1 min and the crude mixture was purified by flash
column chromatography (silica gel, 1:5 ethyl acetate/hexanes) to give
1
5 (0.039 g, 0.093 mmol, 50%) as a pale-yellow oil: H NMR (400
MHz, CDCl3) δ 7.78 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H),
7.25 (d, J = 8.2 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.84 (s, 1H), 5.53
(d, J = 17.1 Hz, 2H), 5.16 (t, J = 6.2 Hz, 1H), 3.88 (s, 3H), 3.58−3.44
(m, 2H), 3.28 (s, 1H), 2.38 (s, 3H), 2.08−1.99 (m, 1H), 1.95−1.84
(m, 1H), 1.53−1.45 (m, 3H), 1.42−1.35 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 197.5, 163.5, 149.3, 143.0, 137.6, 133.0, 132.2, 129.9,
129.4, 128.5, 127.2, 124.4, 113.6, 55.5, 47.6, 37.6, 27.8, 24.8, 21.4, 17.8;
IR (CH2Cl2) 3278, 2931, 1945, 1599, 1160 cm−1; HRMS (ESI) calcd
for C24H27NO4NaS [M + Na]+ 448.1559, found 448.1555.
Data for (Z)-4-(Fluoro(phenyl)methylene)-2-tosyl-2-azaspiro-
[4.5]dec-6-ene (11a). In the typical procedure, to a solution of 10a
(0.13 g, 0.25 mmol) in 101 mL of CH2Cl2 at room temperature under
an atmosphere of nitrogen was added BF3·OEt2 (0.062 mL, 0.51
mmol). The reaction mixture was stirred for 1 min and the crude
mixture was purified by flash column chromatography (silica gel, 1:30
ethyl acetate/hexanes) to give 11a (0.073 g, 0.18 mmol, 73%) as
1
colorless crystals: mp 146−147 °C; H NMR (500 MHz, CDCl3) δ
7.74 (d, J = 8.2 Hz, 2H), 7.37−7.33 (m, 4H), 7.31 (d, J = 6.7 Hz, 1H),
7.28 (d, J = 7.6 Hz, 2H), 5.50−5.47 (m, 1H), 5.03 (d, J = 11.1 Hz,
1H), 4.28 (dd, J = 14.7, 3.4 Hz, 1H), 3.96 (dd, J = 14.7, 3.4 Hz, 1H),
3.40 (dd, J = 9.4, 2.5 Hz, 1H), 2.78 (d, J = 9.4 Hz, 1H), 2.46 (s, 3H),
1.99−1.91 (m, 1H), 1.83−1.75 (m, 1H), 1.70 (dd, J = 13.5, 2.9 Hz,
1H), 1.61 (dd, J = 12.0, 1.3 Hz, 1H), 1.53−1.43 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 151.9 (d, J = 242 Hz), 143.7, 132.3, 131.3 (d, J =
27 Hz), 129.7, 129.4, 129.3, 129.2, 128.8, 128.0, 127.5, 123.2 (d, J = 19
Hz), 59.4, 49.7 (d, J = 10 Hz), 44.6 (d, J = 5 Hz), 32.3 (d, J = 3 Hz),
24.4, 21.6, 20.0; 19F NMR (CDCl3, 376 MHz) δ −90.4; IR (CH2Cl2)
2935, 1713, 1598, 1446, 1351, 1163 cm−1; HRMS (ESI) calcd for
C23H24FNO2S [M − H]− 396.1434, found 396.1439. Crystals suitable
for X-ray diffraction analysis were grown from CH2Cl2 and hexanes.
Data for (Z)-4-(Fluoro(p-tolyl)methylene)-2-tosyl-2-azaspiro[4.5]-
dec-6-ene (11b). In the typical procedure, to a solution of 10b (0.13 g,
0.25 mmol) in 101 mL of CH2Cl2 at room temperature under an
atmosphere of nitrogen was added BF3·OEt2 (0.062 mL, 0.51 mmol).
The reaction mixture was stirred for 1 min and the crude mixture was
purified by flash column chromatography (silica gel, 1:30 ethyl
acetate/hexanes) to give 11b (0.08 g, 0.20 mmol, 77%) as colorless
crystals: mp 133−134 °C; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J =
8.2 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.08
(d, J = 7.9 Hz, 2H), 5.52−5.49 (m, 1H), 5.05 (dd, J = 10.0, 1.0, Hz,
1H), 4.26 (dd, J = 14.6, 2.8 Hz, 1H), 3.95 (dd, J = 14.7, 3.3 Hz, 1H),
3.39 (dd, J = 9.3, 2.44 Hz, 1H), 2.78 (d, J = 9.3 Hz, 1H), 2.45 (s, 3H),
2.33 (s, 3H), 1.98−1.92 (m, 2H), 1.86−1.77 (m, 1H), 1.73−1.63 (m,
2H), 1.54−1.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 152.0 (d, J
= 242 Hz), 143.7, 139.3, 132.2, 129.7, 129.3, 128.6, 128.5, 128.2,
128.1, 128.0, 122.5 (d, J = 20 Hz), 59.4, 49.8 (d, J = 11 Hz), 44.5 (d, J
= 5 Hz), 32.1 (d, J = 2 Hz), 24.4, 21.4 (d, J = 22 Hz), 20.0; 19F NMR
(CDCl3, 376 MHz) δ −90.4; IR (CH2Cl2) 3027, 2935, 2865, 2361,
1712, 1598, 1451, 1350 cm−1; HRMS (ESI) calcd for C24H26FNO2S
[M − H]− 410.1590, found 410.1599.
Data for (Z)-N-(Phenyl(2-tosyl-2,3,4a,5,6,7-hexahydroisoquino-
lin-4(1H)ylid- ene)methyl)acetamide (4). In the typical procedure, to
a solution of 1a (0.1 g, 0.2 mmol) in 2.0 mL of CH3CN at room
temperature under open system was added BF3·OEt2 (0.048 mL, 0.39
mmol). The reaction mixture was stirred for 1 min, and the crude
mixture was purified by flash column chromatography (silica gel, 1:1
ethyl acetate/hexanes) to give 4 (0.068 g, 0.155 mmol, 79%) as
Data for (Z)-4-(Fluoro(naphthalen-1-yl)methylene)-2-tosyl-2-
azaspiro[4.5]dec-6-ene (11c). In the typical procedure, to a solution
of 10c (0.11 g, 0.25 mmol) in 101 mL of CH2Cl2 at room temperature
under an atmosphere of nitrogen was added BF3·OEt2 (0.062 mL, 0.51
mmol). The reaction mixture was stirred for 1 min and the crude
mixture was purified by flash column chromatography (silica gel, 1:30
ethyl acetate/hexanes) to give 11c (0.068 g, 0.15 mmol, 60%) as
1
colorless crystals: mp 204−205 °C; H NMR (400 MHz, CDCl3) δ
7.75 (d, J = 8.2 Hz, 2H), 7.33−7.30 (m, 5H), 7.10−7.08 (m, 2H), 6.75
(s, 1H), 5.59 (s, 1H), 4.21 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 12.1 Hz,
1H), 3.75 (d, J = 12.1 Hz, 1H), 3.35 (d, J = 13.9 Hz, 1H), 2.98 (s, 1H),
2.42 (s, 3H), 2.09 (s, 3H), 1.90−1.88 (m, 2H), 1.56−1.48 (m, 2H),
1.26−1.13 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.3, 143.4,
137.1, 135.5, 131.6, 131.1, 131.0, 129.5, 128.7, 128.3, 128.2, 127.8,
127.5, 50.8, 43.7, 38.0, 28.3, 24.9, 23.5, 21.5; IR (CH2Cl2) 3247, 2929,
1669, 1507, 1158 cm−1; HRMS (ESI) calcd for C25H28N2O3NaS [M +
Na]+ 459.1718, found 459.1715. Crystals suitable for X-ray diffraction
analysis were grown from CH2Cl2 and hexanes.
1
colorless crystals: mp 193−194 °C; H NMR (400 MHz, CD2Cl2) δ
7.87−7.77 (m, 5H), 7.51−7.47 (m, 2H), 7.44−7.33 (m, 4H), 5.07 (dd,
J = 9.8, 5.6 Hz, 1H), 4.85 (d, J = 9.6 Hz, 1H), 4.44 (dd, J = 14.5, 2.9
Hz, 1H), 4.09 (dd, J = 14.5, 3.3 Hz, 1H), 3.39 (dd, J = 9.4, 2.6 Hz,
1H), 2.79 (d, J = 9.4 Hz, 1H), 2.49 (s, 3H), 1.90−1.87 (m, 1H), 1.67
(dd, J = 12.2, 4.3 Hz, 1H), 1.49−1.29 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 151.2 (d, J = 247 Hz), 143.7, 133.2, 132.7, 132.0, 130.4 (d, J
= 2 Hz), 129.8, 129.6, 129.5 (d, J = 4 Hz), 128.8, 128.6, 128.2, 128.0,
126.7, 126.1, 125.3 (d, J = 18 Hz), 125.3, 124.2, 59.1, 49.2 (d, J = 7
Data for N-((6-(3-(4-Methoxyphenyl)-3-oxoprop-1-en-2-yl)-
cyclohex-1-en-1-yl)methyl)-4-methylbenzenesulfonamide (5). In
the typical procedure, to a solution of 1i (0.1 g, 0.19 mmol) in 74.0
mL of CH2Cl2 at room temperature under an atmosphere of nitrogen
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Article
Hz), 44.8 (d, J = 4 Hz), 32.8, 24.3, 21.6, 20.0; 19F NMR (CDCl3, 376
MHz) δ −84.2; IR (CH2Cl2) 2934, 2341, 1717, 1597, 1447, 1348,
1163 cm−1; HRMS (ESI) calcd for C27H26FNO2S [M − H]−
446.1590, found 446.1594.
2866, 1701, 1613, 1512, 1450, 1260 cm−1; HRMS (FAB+) calcd for
C18H21F [M]+ 256.1627, found 256.1634.
Data for (E)-4-(Fluoro(spiro[4.5]dec-6-en-1-ylidene)methyl)-1,1′-
biphenyl (11h). In the typical procedure, to a solution of 10h (0.177 g,
0.41 mmol) in 164 mL of CH2Cl2 at room temperature under an
atmosphere of nitrogen was added BF3·OEt2 (0.104 mL, 0.82 mmol).
The reaction mixture was stirred for 1 min, and the crude mixture was
purified by flash column chromatography (silica gel, hexanes) to give
Data for (Z)-4-((4-Bromophenyl)fluoromethylene)-2-tosyl-2-
azaspiro[4.5]dec-6- ene (11d). In the typical procedure, to a solution
of 10d (0.15 g, 0.25 mmol) in 101 mL of CH2Cl2 at room temperature
under an atmosphere of nitrogen was added BF3·OEt2 (0.062 mL, 0.51
mmol). The reaction mixture was stirred for 1 min, and the crude
mixture was purified by flash column chromatography (silica gel, 1:30
ethyl acetate/hexanes) to give 11d (0.054 g, 0.11 mmol, 45%) as
1
11h (0.099 g, 0.31 mmol, 76%) as colorless oil: H NMR (400 MHz,
CDCl3) δ 7.62−7.60 (m, 2H), 7.57−7.51 (m, 4H), 7.45−7.41 (m,
2H), 7.36−7.32 (m, 1H), 5.47−5.40 (m, 2H), 2.78−2.64 (m, 2H),
1.95−1.89 (m, 1H), 1.83−1.67 (m, 5H), 1.66−1.51 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 151.4 (d, J = 235 Hz), 140.7 (d, J = 30
Hz), 135.0, 132.2 (d, J = 30 Hz), 130.3 (d, J = 19 Hz), 129.3 (d, J = 5
Hz), 128.8, 127.4, 126.0, 125.2, 45.4 (d, J = 5 Hz), 42.6, 32.5 (d, J = 2
Hz), 30.1 (d, J = 6 Hz), 24.7, 22.2, 20.3; 19F NMR (CDCl3, 376 MHz)
δ −92.0; IR (CH2Cl2) 3029, 2936, 2863, 1698, 1582, 1487, 1434, 1272
cm−1; HRMS (FAB+) calcd for C23H23F [M]+ 318.1784, found
318.1790.
1
colorless crystals: mp 147−148 °C; H NMR (400 MHz, CD2Cl2) δ
7.74 (d, J = 8.1 Hz, 2H), 7.39 (dd, J = 20.2, 8.1 Hz, 4H), 7.22 (d, J =
8.3 Hz, 2H), 5.57−5.54 (m, 1H), 5.01 (d, J = 10.1 Hz, 1H), 4.27 (dd, J
= 14.9, 2.6 Hz, 1H), 3.92 (dd, J = 14.9, 3.3 Hz, 1H), 3.41 (dd, J = 9.3,
2.2 Hz, 1H), 2.77 (d, J = 2.2 Hz, 1H), 2.46 (s, 3H), 2.02−1.97 (m,
2H), 1.84−1.78 (m, 1H), 1.75−1.71 (m, 1H), 1.58−1.52 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 150.6 (d, J = 242 Hz), 143.8, 132.2, 130.7,
130.2, 130.1, 130.0, 129.7, 128.9, 128.0, 124.1 (d, J = 19 Hz), 123.6 (d,
J = 2 Hz), 59.3, 49.8 (d, J = 10 Hz), 44.6 (d, J = 5 Hz), 32.1 (d, J = 2
Hz), 24.4, 21.5, 19.9; 19F NMR (CDCl3, 376 MHz) δ −92.0; IR
(CH2Cl2) 3024, 2936, 2864, 2257, 1916, 1711, 1595, 1488, 1394,
1350, 1163 cm−1; HRMS (ESI) calcd for C23H23BrFNO2S [M + H]+
476.0695, found 476.0692.
ASSOCIATED CONTENT
* Supporting Information
■
S
NMR spectra for compounds 1a−l, 2a−h,j,l, 3a−d, 4, 5, 10a−
h, and 11a−h and X-ray crystallographic information files for
compounds 2a−c,e−h,j, 3b,d, 4, and 11a. This material is
available free of charge via the Internet at http://pubs.acs.org.
Data for (E)-1-(Fluoro(phenyl)methylene)spiro[4.5]dec-6-ene
(11e). In the typical procedure, to a solution of 10e (0.177 g, 0.5
mmol) in 200 mL of CH2Cl2 at room temperature under an
atmosphere of nitrogen was added BF3·OEt2 (0.127 mL, 1.0 mmol).
The reaction mixture was stirred for 1 min and the crude mixture was
purified by flash column chromatography (silica gel, hexanes) to give
AUTHOR INFORMATION
Corresponding Author
*E-mail: cheyeh@ntnu.edu.tw.
■
1
11e (0.092 g, 0.38 mmol, 76%) as colorless oil: H NMR (400 MHz,
CDCl3) δ 7.47−7.44 (m, 2H), 7.29−7.27 (m, 3H), 5.40−5.33 (m,
2H), 2.76−2.63 (m, 2H), 1.91−1.85 (m, 1H), 1.76−1.65 (m, 5H),
1.63−1.47 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 151.7 (d, J = 236
Hz), 135.0, 133.3 (d, J = 30 Hz), 129.9 (d, J = 19 Hz), 129.1 (d, J = 4
Hz), 128.3 (d, J = 2 Hz), 127.3, 125.0, 45.3 (d, J = 5 Hz), 42.5, 32.6 (d,
J = 2 Hz), 29.9 (d, J = 6 Hz), 24.6, 22.2, 20.3; 19F NMR (CDCl3, 376
MHz) δ −90.8; IR (CH2Cl2) 3059, 3020, 2936, 2862, 1700, 1602,
1492, 1446, 1435, 1292, 1261 cm−1; HRMS (FAB+) calcd for C17H19F
[M]+ 242.1471, found 242.1477.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by the National Science Council
(NSC 98-2119-M-003-004-MY3 and NSC 101-2113-M-003-
002-MY3) and National Taiwan Normal University.
Data for (E)-1-((4-Bromophenyl)fluoromethylene)spiro[4.5]dec-
6-ene (11f). In the typical procedure, to a solution of 10f (0.217 g, 0.5
mmol) in 200 mL of CH2Cl2 at room temperature under an
atmosphere of nitrogen was added BF3·OEt2 (0.127 mL, 1.0 mmol).
The reaction mixture was stirred for 1 min, and the crude mixture was
purified by flash column chromatography (silica gel, hexanes) to give
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1
11f (0.141 g, 0.44 mmol, 88%) as colorless oil: H NMR (400 MHz,
CDCl3) δ 7.41 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.6 Hz, 2H), 5.43 (ddd,
J = 9.8, 5.3, 2.0 Hz, 1H), 5.34 (dd, J = 2.5, 1.3 Hz, 1H), 2.78−2.59 (m,
2H), 1.94−1.89 (m, 1H), 1.77−1.65 (m, 5H),1.56−1.51 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 150.5 (d, J = 235 Hz), 134.7, 132.1 (d, J =
31 Hz), 130.9 (d, J = 19 Hz), 130.5 (d, J = 5 Hz), 127.9, 125.5, 122.5
(d, J = 24 Hz), 45.3 (d, J = 5 Hz), 42.5, 32.4, 30.0 (d, J = 6 Hz), 24.6,
22.1, 20.2; 19F NMR (CDCl3, 376 MHz) δ −92.4; IR (CH2Cl2) 3018,
2936, 2862, 1699, 1590, 1487, 1393, 1258 cm−1; HRMS (FAB+) calcd
for C17H18BrF [M]+ 320.0576, found 320.0574.
Data for (E)-1-(Fluoro(p-tolyl)methylene)spiro[4.5]dec-6-ene
(11g). In the typical procedure, to a solution of 10g (0.184 g, 0.5
mmol) in 200 mL of CH2Cl2 at room temperature under an
atmosphere of nitrogen was added BF3·OEt2 (0.127 mL, 1.0 mmol).
The reaction mixture was stirred for 1 min and the crude mixture was
purified by flash column chromatography (silica gel, hexanes) to give
1
11g (0.066 g, 0.26 mmol, 52%) as colorless oil: H NMR (400 MHz,
CDCl3) δ 7.35 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 5.43−5.36
(m, 2H), 2.74−2.60 (m, 2H), 2.34 (s, 3H), 1.93−1.87 (m, 1H), 1.78−
1.63 (m, 5H), 1.62−1.48 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
151.9 (d, J = 236 Hz), 138.2 (d, J = 21 Hz), 135.1, 130.5 (d, J = 30
Hz), 129.3 (d, J = 20 Hz), 128.9 (d, J = 5 Hz), 128.1, 124.9, 45.2 (d, J
= 5 Hz), 42.6, 32.5 (d, J = 2 Hz), 29.9 (d, J = 6 Hz), 24.6, 22.2, 21.3,
20.3; 19F NMR (CDCl3, 376 MHz) δ −90.6; IR (CH2Cl2) 3020, 2936,
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dx.doi.org/10.1021/jo400634c | J. Org. Chem. XXXX, XXX, XXX−XXX

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