Synthesis of Ketones and Esters from Heteroatom-Functionalized Alkenes by Cobalt-Mediated Hydrogen Atom Transfer

Article abstract of DOI:10.1021/acs.joc.6b01709

Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates and provides a mild and practical alternative to the Tamao-Fleming oxidation of vinylsilanes and the Arndt-Eistert homologation.

Full text of DOI:10.1021/acs.joc.6b01709

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Featured Article
Synthesis of Ketones and Esters from Heteroatom-Functionalized
Alkenes by Cobalt-Mediated Hydrogen Atom Transfer
Xiaoshen Ma, and Seth B Herzon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01709 • Publication Date (Web): 06 Sep 2016
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The Journal of Organic Chemistry
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Synthesis of Ketones and Esters from Heteroatom-Functionalized
Alkenes by Cobalt-Mediated Hydrogen Atom Transfer
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Xiaoshen Ma1 and Seth B. Herzon1,2,*
1Department of Chemistry, Yale University, New Haven, Connecticut 06520, United States. Department of Phar-
macology, Yale School of Medicine, New Haven, Connecticut 06520, United States.
2
KEYWORDS: functionalized alkene • hydrolysis • hydrogen atom transfer
ABSTRACT: Cobalt bis(acetylacetonate) is shown to mediate hydrogen atom transfer to a broad range of functionalized
alkenes; in situ oxidation of the resulting alkylradical intermediates, followed by hydrolysis, provides expedient access to
ketones and esters. By modification of the alcohol solvent, different alkyl ester products may be obtained. The method is
compatible with a number of functional groups including alkenyl halides, sulfides, triflates, and phosphonates, and pro-
vides a mild and practical alternative to the Tamao–Fleming oxidation of vinylsilanes and the Arndt–Eistert homologation.
in 62% yield.5f Surprisingly, when DHB was omitted from
the reaction mixture, the formal hydrolysis product 3a
INTRODUCTION
Ketones and esters are among the central functional
groups in organic chemistry.1 They are most frequently
accessed by oxidation of the corresponding alcohols.2 Alt-
hough heteroatom-substituted alkenes are at the carbonyl
or carboxylic acid oxidation state, their application as
synthetic equivalents of ketones or esters is limited.3 Clas-
sical methods to convert heteroatom-substituted alkenes
to carbonyl compounds typically employ Lewis acids or
bases, or late transition metals (Scheme 1).4
was obtained in 47% yield. None of the reduction prod-
uct 2 was observed (1H NMR analysis). Given the facility
of hydrogen atom transfer to functionalized alkenes,5e, 5f, 6
this result suggested a potentially general method. As
shown below, this formal hydrolysis proceeds under near
neutral conditions and is amenable to a range of func-
tionalized alkenes. Trimethylsilylalkenes undergo a novel
oxidative desilylation to the corresponding ketone deriva-
tives, thereby establishing a useful and mild alternative to
the Tamao–Fleming oxidation.7 When used in conjunc-
tion with the Ramirez alkenylation,8 the oxydehalogena-
tion of gem-dihaloalkenes provides a useful alternative to
the Arndt–Eistert homologation.9
Scheme 1. Classical methods for the conversion of func-
tionalized alkenes to ketones typically employ strong ac-
ids or bases, or late transition metal complexes.
RESULTS AND DISCUSSION
Synthesis of ketones by the formal hydrolysis of
heteroatom-functionalized alkenes. We optimized the
conversion of 2-bromoallyl 4-methoxybenzoate (1b) to 2-
oxopropyl 4-methoxybenzoate (3a, Table 1). In the pres-
ence of 1 equiv Co(acac)2, 1 equiv TBHP, and 5 equiv of
Et3SiH in n-propanol under 1 atm of air, a 68% isolated
yield of the desired product 3a and an 8% yield (by NMR)
of 2,2-dibromopropyl 4-methoxybenzoate (4) were ob-
tained. Use of N,N-dimethylformamide (DMF) as solvent
increased the yield of 3a to 76% (entry 2). Attempts to
decrease the catalyst loading to 25 mol% resulted in lower
conversion (52%, entry 3). We attributed this reduction
in conversion to the hydrobromic acid generated in the
reaction. Attempts to neutralize the acid with isoamylene
(entry 4) or lithium acetylacetonate [Li(acac)] (entry 5) in
DMF were not successful. After some experimentation,
an 81% isolated yield of 3a was obtained when methanol
was used as solvent under 1 atm of dioxygen and in the
We have previously reported the reduction of 2-
chloroallyl 4-methoxybenzoate (1a) by a hydrogen atom
transfer pathway (Scheme 2).5 Under optimized condi-
tions, treatment of 1a with the hydrogen atom donors
triethylsilane (Et3SiH) and 1,4-dihydrobenzene (DHB) in
the presence of cobalt acetylacetonate [Co(acac)2] and
tert-butyl hydroperoxide (TBHP) formed the reduction
product 2
Scheme 2. Hydrogenation (left) and oxydechlorination
(right) of 1a.
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Table 1. Optimization of the Co(acac)2–mediated formal
Table 2. Preliminary scope of the formal hydrolysis reac-
hydrolysis of 1b.a
tion.a
1
2
3
4
5
6
7
8
9
en-
try
substrate
conv.b
product
yieldc
conv. yield yield yield
x
entry
1
additive solvent atm.
mol%
1b
3a
4
5
A:>95%
B:>95%
A:99%
B:99%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
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1
n-
PrOH
100
–
air >95%(68%)b 8% <1%
1c
1a
1b
3a
3a
3a
3a
3b
2
3
100
25
–
–
DMF
DMF
air >95% (76%) 3% (10%)
air 52% 46% <1% <1%
air 55% 41% <1% <1%
air 16% 15% <1% <1%
A:>95%
B:>95%
A:92%
B:89%
2
3
4
5
4
5
25 isoamylene DMF
25 Li(acac) DMF
6
25 Li(acac) CH3OH O2 >95% (81%) <1% <1%
A:>95%
B:>95%
A:81%
B:85%
7
8c
100
10
–
–
CH3OH O2 >95% (85%) <1% 5%
THF O2 62% (20%) (39%) <1%
aReactions employed 250 μmol of 1b. Conversions and yields were
determined by 1H NMR spectroscopy using mesitylene as an internal
standard. bYields in parentheses are isolated yields after purification
by flash-column chromatography. cPhSiH3 was employed instead of
Et3SiH.
A:85%
B:45%
A:63%
B:40%
1d
1e
1f
presence of 1.5 equivalents of Li(acac) as the acid scaven-
ger (entry 6). Consistent with our analysis, stoichiometric
quantities of Co(acac)2 afforded an 85% yield of 3a in the
absence of added Li(acac) (entry 7). As the conditions of
entry 6 enabled transformation with a substoichiometric
amount of Co(acac)2 and those of entry 7 afforded the
highest yield, both were employed in our investigation of
the scope. Mukaiyama hydration conditions were also
applied to the hydrolysis of 3a (entry 8);6b however, the
conversion was low and the major product was the gem-
dibromide 4 (39%); the ketone 3a was obtained in 20%
yield.
A:>95%
B:>95%
A:88%
B:78%
A:>95%
B:>95%
A:0%
B:50%
6
7
3c
A:>95%
B:>95%
A:80%
B:91%
1g
3d
A:>95%
B:>95%
A:61%
B:73%
In its present form, the scope of the reaction encom-
passes a wide range of heteroatom-functionalized alkenes
(Table 2). The alkenyl fluoride 1c, chloride 1a, and bro-
mide 1b all underwent smooth conversion to the ketone
3a in 81–99% yield (entries 1–3). The alkenyl iodide 1d
was also converted to 3a, but the conversion was incom-
plete (45% or 85% conversion, 40% or 63% yield, entry 4).
We have previously observed that styrene derivatives un-
8
3d
3e
1h
1i
A:29%
B:95%
A:0%
B:47%
9
A:–
A:–
dergo decomposition in the hydrogen atom transfer re-
10
B:>95%
B:90%
duction,5f,
but the styryl bromide 1e was efficiently
5g
1j
3f
transformed in 88% yield under these conditions (entry 5).
The trisubstituted alkenyl bromide 1f was also converted
to the ketone 3c in 50% yield, with concomitant oxidation
of the C–Si bond (entry 6). The cyclic alkenyl bromide 1g
was transformed to α-benzoyloxyl cyclohexanone (3d) in
91% yield (entry 7). The alkenyl alkyl ether 1h was con-
verted to 3d in 73% yield (entry 8). The alkenyl phenyl
ether 1i provided the ketone 3e in 47% yield (entry 9).
A:>95%
B:>95%
A:78%
B:64%
11
1k
3g
A:19%
B:>95%
A:0%
B:50%
12
3h
1l
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experiment demonstrated that the ester was stable in the
Table 2. Preliminary scope of the formal hydrolysis reac-
tion (continued).a
1
2
3
4
absence of cobalt and in the absence of both cobalt and
Li(acac) (Table S1), and under the more neutral stoichio-
metric conditions, 1j was converted to the ketone 1f in 90%
yield (entry 10). The alkenyl triflate 1k was cleanly con-
verted to the corresponding ketone 3g in 78% yield (entry
11). Reaction of the alkenyl phosphonate 1l proceeded in
50% yield under stoichiometric conditions; catalytic con-
ditions led to an 81% recovery of starting material (entry
12). The enoxysilane 1m was also cleaved under the neu-
tral stoichiometric conditions to provide the ketone 3i in
74% yield (entry 13).
en-
substrate
try
conv.b
product
yieldc
5
6
A:9%
B:>95%
A:0%
B:74%
7
13
8
9
1m
3i
3a
3d
10
11
12
13
14
15
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A:>95%
B:>95%
A:41%
B:82%
14
Classical methods for the hydrolysis of alkenyl sulfides
usually require stoichiometric quantities of mercury
salts.4c, 10 Cobalt-mediated hydrolysis of the alkenyl sul-
fides 1n, 1o, and 1p proceeded smoothly to provide the
ketones 3a and 3d in 41–93% yield (entries 14–16). The
alkenyl sulfone 1q was also converted cleanly to the ke-
tone 3d in 89% yield (entry 17). The stoichiometric condi-
tions allowed efficient transformation of the alkenyl sele-
nide 1r to the ketone 3d (66%), but low conversion (22%)
of 1r was observed when catalytic conditions were applied
(entry 18). Although the hydrolysis of enamides typically
require strong Brønsted acids,4h, 11 the enamide 1s under-
went cobalt-mediated hydrolysis in 79% yield (entry 19).
The alkenyl boronic ester 1t was transformed to 2'-
chloroacetophenone (3k) in 79% yield under stoichio-
metric conditions (entry 20), and control experiments
1n
A:>95%
B:>95%
A:80%
B:92%
15
1o
A:>95%
B:>95%
A:93%
B:87%
16
3d
3d
3d
3j
1p
A:>95%
B:>95%
A:83%
B:89%
17
1q
A:22%
B:>85%
A:18%
B:66%
18
1r
A:>95%
B:>95%
A:64%
B:79%
19
1s
A:–
B:>95%
A:–
B:79%
20
1t
3k
Scheme 3. Synthesis and reaction of the alkyl hydroper-
oxide 6.
A:66%
B:>95%
A:63%
B:89%
21
1u
3a
3e
A:10%
B:>95%
A:7%
B:88%
22
1v
A:12%
B:>95%
A:0%
B:32%
23
1w
3a
aCondition A: Co(acac)2 (25 mol%), Li(acac) (1.50 equiv), TBHP (1.00
equiv), Et3SiH (5.00 equiv), CH3OH (0.3 M), O2, 24 °C; condition B:
Co(acac)2 (1 equiv), TBHP (1 equiv), Et3SiH (5 equiv), CH3OH (0.3 M),
Scheme 4. Proposed mechanism.
O2, 24 °C. bConversions determined by H NMR spectroscopy using
1
mesitylene as an internal standard. cIsolated yield after purification
by flash-column chromatography.
The addition of Li(acac) renders the reaction condi-
tions slightly basic, and control experiments (Table S1)
demonstrated that the alkenyl ester 1j underwent formal
hydrolysis without Co(acac)2, presumably by base-
catalyzed methanolysis of the ester. However, a separate
Scheme 5. Allylic stereocenter can be preserved during formal
hydrolysis process.
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equiv), Et3SiH (5.00 equiv), CH3OH (0.3 M), O2, 24 °C. cConditions:
Table 3. Preliminary scope of gem-dihalides.
Co(acac)2 (1 equiv), TBHP (1 equiv), Et3SiH (5 equiv), CH3OH (0.3 M),
1
2
O2, 24 °C. d46% of 1c was recovered. e59% of 1c was recovered.
demonstrated that the cobalt reagent was required for
this transformation (Table S1). The stoichiometric condi-
tions allowed efficient conversion of the alkenyl silanes 1u
and 1v to the ketones 3a (89%) and 3e (88%). Although
the mechanism of this reaction is not known, it provides a
useful and mild alternative to the Tamao–Fleming oxida-
tion, which typically requires installation of a heteroatom
substituent at silicon.7 Interestingly, when propargyl 4-
methoxybenzoate (1w) was used as substrate, 88% of the
starting material was recovered using substoichiometric
quantities of cobalt. When stoichiometric conditions
were applied, significant decomposition was observed and
the ketone 3a was obtained in only 32% yield (entry 23).
3
4
5
6
7
8
9
entry
substrate
Product
yielda
A:92%b
B:98%c
1
2
11a
11b
11c
11d
11e
11f
12a
12a
12a
12b
12c
12d
12e
12f
10
11
12
13
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A:87%b
B:88%c
A:47%b,d
B:38%c,e
3
To gain insight into the mechanism of the reaction, the
conversion of the alkenyl chloride 1a in n-propanol was
terminated after 4 h (Scheme 3). Purification of the mix-
ture by flash-column chromatography provided a 42%
yield of the ketone 3a and 57% of the alkyl hydroperoxide
6. Resubjection of the alkyl hydroperoxide 6 to the reac-
tion conditions afforded 74% of the desired ketone 3a.
A:61%b
B:85%c
4
5
A:86%b
B:92%c
Based on these results and literature precedent, we
A:91%b
B:98%c
propose that hydrogen atom transfer from
a co-
6
7
balt(III)hydride intermediate occurs to generate the more
stable α-heteroatom-substituted radical 7 (Scheme 4).5d, 5f,
6q
A:91%b
B:70%c
Addition of dioxygen may form a peroxycobalt (III)
intermediate 8, which undergoes exchange with methanol
to form the acetal 9. Silylation of the cobalt peroxide in-
termediate to provide 10, followed by hydrolysis on silica
gel or reduction in situ, may then generate the observed
product. The mechanism of oxidation of the vinyl boro-
nate 1t and the vinylsilanes 1u and 1v is likely to be dis-
tinct.
11g
11h
11i
A:89%b
B:96%c
8
9
10
A:0%b
B:51%c
12g
12h
As further evidence of the near-neutral hydrolysis con-
ditions, we prepared the enantiomerically enriched (R)-1g
(94:6 e.r., Scheme 5). The yields of both conditions are
comparable to those obtained with racemic 3d, and no
racemization of the allylic stereocenter was observed.
A:81%b
B:86%c
11j
A:0%b
Synthesis of esters from gem-dibromoalkenes. We
then applied the optimized conditions to the transfor-
mation of gem-dihaloalkenes to esters (Table 3).12 These
substrates are readily-accessible by Ramirez alkenylation
of the corresponding aldehydes or ketones.8b The gem-
dichloride 11a and gem-dibromide 11b both underwent
formal hydrolysis to the methyl ester 12a in 87–98% yield
(entries 1 and 2). The gem-diiodide 11c was also converted
to 12a, but the conversion was incomplete (41 or 54% con-
version, 38 or 47% yield, entry 3). Though the gem-
dichloroalkene 11a transformed more efficiently than
gem-dibromoalkene 11b, the latter was preferred due to
its ease of preparation. The formal hydrolysis conditions
are compatible with a broad range of functional groups
including methyl aryl ethers (entry 4, 85%), methyl ben-
zoates (entry 5, 92%), aryl bromides (entry 6, 98%), nitrile
substituents (entry 7, 91%), nitro substituents (entry 8,
96%), aryl boronic esters (entry 9, 51%), and trifluomethyl
11
12
13
B:49%c
11k
11l
12i
12j
A:0%b
B:77%c
A:0%b
B:31%c
11m
11n
11o
12k
8l
A:0%b
14
15
B:82%c
A:83%b
B:89%c
8m
aIsolated yield after purification by flash-column chromatography.
bConditions: Co(acac)2 (25 mol%), Li(acac) (1.50 equiv), TBHP (1.00
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General Experimental Procedures. All reactions
Table 4. Variation of the nucleophilic component.
1
were performed in single-neck, flame-dried, round-
bottomed flasks fitted with rubber septa under a positive
pressure of argon, unless otherwise noted. Air- and mois-
ture-sensitive liquids were transferred via syringe or stain-
less steel cannula, or were handled in a nitrogen-filled
drybox (working oxygen level <5 ppm). Organic solutions
were concentrated by rotary evaporation at 30–33 °C.
Intermediates were purified using a Biotage Isolera sys-
tem, employing polypropylene cartridges preloaded with
silica gel (60 Å , 40–63 µm particle size, purchased from
Silicycle, Quebec City, Canada) or neutral aluminium
oxide (60 Å , 50–200 µm particle size, purchased from
Acros Organics, New Jersey, USA). Alternatively, inter-
mediates were purified using a Teledyne ISCO system,
employing RediSep Rf High Performance Gold cartridges
(RediSep Rf Gold Silica, 20–40 um spherical, purchased
from Teledyne ISCO, Dallas, Texas). Samples were eluted
using a flow rate of 12–50 mL/min, with detection by UV
(254 nm). Analytical thin-layered chromatography (TLC)
was performed using glass plates pre-coated with silica
gel (0.25 mm, 60 Å pore size) impregnated with a fluores-
cent indicator (254 nm). TLC plates were visualized by
exposure to ultraviolet light (UV) and/or submersion in
aqueous ceric ammonium molybdate solution (CAM),
acidic p-anisaldehyde solution (PAA), or aqueous potassi-
um permanganate solution (KMnO4), followed by brief
heating on a hot plate (120 °C, 10–15 s).
2
3
4
5
6
7
8
9
entry
1
product
yielda
A:41%b
B:79%c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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46
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60
12n
12o
12p
A:49%b
B:68%c
2
3
A:32%b,d
B:71%c,d
aIsolated yield after purification by flash-column chromatography.
bConditions: Co(acac)2 (25 mol%), Li(acac) (1.50 equiv), TBHP (1.00
equiv), Et3SiH (5.00 equiv), PrOH or tBuOH (0.3 M), O2, 24 °C.
i
cConditions: Co(acac)2 (1 equiv), TBHP (1 equiv), Et3SiH (5 equiv),
iPrOH or BuOH (0.3 M), O2, 24 °C. reaction conducted in THF (0.3
t
d
M) with H2O (10 equiv).
groups (entry 10, 86%). The stoichiometric conditions
appeared to be less sensitive to steric hindrance than the
substoichiometric conditions (entry 11–13). The α-amino
acid derivative 11n can be transformed to the β-amino
acid derivative 12l in 82% yield (entry 14). The tetrasub-
stituted gem-dibromoalkene 11i derived from the corre-
sponding ketone was transformed to the ester 12m in 89%
yield (entry 15).
Materials. Commercial solvents and reagents were
used as received with the following exceptions. Acetoni-
trile, dichloromethane, ether, and toluene were purified
according to the method of Pangborn et al.14 Pyridine was
distilled from calcium hydride under an atmosphere of
nitrogen immediately before use. Commercial anhydrous
N,N-dimethylformamide was degassed by three freeze–
pump–thaw cycles and stored over activated 4 Å MS un-
der an atmosphere of nitrogen before use. Tetrahydrofu-
ran was distilled from sodium–benzophenone under an
atmosphere of nitrogen immediately before use. Tri-
ethylamine was distilled from calcium hydride under an
atmosphere of nitrogen immediately before use. Metha-
nol was distilled from magnesium under an atmosphere
of nitrogen immediately before use. n-Propanol was dried
over calcium hydride for 12 h at 24 °C, degassed by three
freeze–pump–thaw cycles, vacuum transferred, and stored
under an atmosphere of argon before use. Triethylsilane
was degassed by three freeze–pump–thaw cycles and
stored under an atmosphere of argon before use. 1,4-
Dihydrobenzene was degassed by three freeze-pump-
thaw cycles, vacuum transferred, and stored under an
atmosphere of argon at –10 °C before use. Cobalt
bis(acetylacetonate) was dried by heating overnight in
vacuo (70 °C, 200 mTorr), and stored under an atmos-
phere of argon before use. Benzyl 4-oxopiperidine-1-
carboxylate,15 2-fluoro-2-propen-1-ol alcohol,5f 2-iodo-2-
propen-1-ol alcohol,16 3-(4-methoxyphenyl)propanal,17 2-
Interestingly, gem-dibromoalkenes 11d–m derived from
arylaldehydes can also be converted to the corresponding
methyl esters 12b–12k under optimized conditions despite
the fact that benzylic radical has been reported to be
more stable than gem-dibromoalkyl radical.13 We attrib-
ute this result to the steric hindrance created by the gem-
dibromo group, which biases the first hydrogen atom
transfer to the less-hindered benzylic position.
When conducted in different alcoholic solvents, the
iso-propyl ester 12h and tert-butyl ester 12i can both be
accessed in 41–79% yield (Table 4, entry 1 and 2). The
gem-dibromoalkene 11d could also be transformed to the
carboxylic acid 12i with 71% yield when using tetrahydro-
furan (THF) containing 10 equiv of water as the solvent.
CONCLUSION
In summary, we have shown that in situ oxidation of
alkylradical intermediates derived from heteroatom-
functionalized alkenes provides access to ketones or es-
ters from a broad range of starting materials. The meth-
odology provides a simple alternative to the Tamao–
Fleming oxidation of alkenyl silanes and the Arndt-Eistert
homologation. This reaction constitutes a useful addition
to the burgeoning area of alkene functionalization by hy-
drogen atom transfer.
bromocyclohex-2-en-1-ol,18
2-((2-
4-(tert-
bromobenzyl)oxy)cyclohex-2-en-1-ol,19
EXPERIMENTAL SECTION
butyl)cyclohex-1-en-1-yl trifluoromethanesulfonate,20 4-
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oxocyclohexyl benzoate,21 2-(phenylthio)prop-2-en-1-ol,22
2-(phenylthio)cyclohex-2-en-1-ol,23
2-
dine (22 mL) at 0 C. The reaction mixture was stirred for
30 min at 0 C, and then the ice bath was removed. The
1
2
3
4
5
6
7
8
(phenylselanyl)cyclohex-2-en-1-one,24 and 4-(tert-butyl)-1-
chlorocyclohex-1-ene25 were prepared according to pub-
lished procedures. The concentration of tert-butyllithium
in hexanes was determined by titration against a standard
solution of diphenylacetic acid (average of three determi-
nations).26
reaction mixture was stirred for 24 h at 24 C. The prod-
uct mixture was transferred to a separatory funnel that
had been charged with ethyl acetate (20 mL). The diluted
product mixture was washed with saturated aqueous so-
dium bicarbonate solution (20 mL). The aqueous layer
was isolated and the isolated aqueous layer was extracted
with ethyl acetate (3  20 mL). The organic layers were
combined and the combined organic layers were dried
over sodium sulfate. The dried solution was filtered and
the filtrate was concentrated. The residue obtained was
purified by automated flash-column chromatography
(eluting with 5% ethyl acetate–hexanes initially, grading
to 10% ethyl acetate–hexanes, linear gradient) to afford 2-
chloroallyl 4-methoxybenzoate (1a) as a colorless oil (1.20
Instrumentation. Proton nuclear magnetic resonance
spectra (1H NMR) were recorded at 400, 500, or 600 MHz
at 24 °C, unless otherwise noted. Chemical shifts are ex-
pressed in parts per million (ppm, δ scale) downfield from
tetramethylsilane and are referenced to residual protium
in the NMR solvent (CHCl3, δ 7.26; CHDCl2, δ 5.32; C6HD5,
δ 7.16). Data are represented as follows: chemical shift,
multiplicity (s = singlet, d = doublet, t = triplet, q = quar-
tet, m = multiplet and/or multiple resonances, br = broad),
integration, coupling constant in Hertz, and assignment.
Proton-decoupled carbon nuclear magnetic resonance
spectra (13C NMR) were recorded at 100, 125, or 150 MHz
at 24 °C, unless otherwise noted. Chemical shifts are ex-
pressed in parts per million (ppm, δ scale) downfield from
tetramethylsilane and are referenced to the carbon reso-
nances of the solvent (CDCl3, δ 77.0; CD2Cl2, δ 54.0; C6D6,
δ 128.1). Distortionless enhancement by polarization
transfer spectra [DEPT (135)] were recorded at 100, 125, or
150 MHz at 24 °C, unless otherwise noted. 13C NMR and
DEPT (135) data are combined and represented as follows:
chemical shift, carbon type [obtained from DEPT (135)
experiments]. Proton-decoupled fluorine nuclear mag-
netic resonance spectra (19F NMR) were recorded at 375
MHz or 470 MHz at 24 °C, unless otherwise noted.
Chemical shifts are expressed in parts per million (ppm, δ
scale) downfield from fluorotrichloromethane. Proton-
decoupled phosphine nuclear magnetic resonance spectra
(31P NMR) were recorded at 200 MHz at 24 °C, unless oth-
erwise noted. Chemical shifts are expressed in parts per
million (ppm, δ scale) downfield from trimethyl phos-
phate. Attenuated total reflectance Fourier transform
infrared spectra (ATR-FTIR) were obtained using an FTIR
spectrometer referenced to a polystyrene standard. Data
are represented as follows: frequency of absorption (cm–1),
intensity of absorption (s = strong, m = medium, w =
weak, br = broad). High-resolution mass spectrometry
(HRMS) were obtained on a UPLC/HRMS instrument
equipped with a photodiode array detector, a dual
API/ESI ionizer and quadrupole time-of-flight (Q-TOF)
mass detector. Unless otherwise noted, samples were
eluted over a reverse-phase C18 column (1.7 μm particle
size, 2.1 × 50 mm) with a linear gradient of 5% acetoni-
trile–water containing 0.1% formic acid95% acetoni-
trile–water containing 0.1% formic acid over 1.6 min, fol-
lowed by 100% acetonitrile containing 0.1% formic acid
for 1 min, at a flow rate of 600 μL/min.
9
10
11
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13
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15
16
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18
19
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21
22
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24
25
26
27
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55
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59
60
g, 98%).
Rf = 0.52 (10% ethyl acetate–hexanes; UV,
1
KMnO4). H NMR (500 MHz, CDCl3) δ 8.04 (d, 2H, J = 9.0
Hz), 6.94 (d, 2H, J = 9.0 Hz), 5.55–5.53 (m, 1H), 5.45–5.42
(m, 1H), 4.87 (br s, 2H), 3.87 (s, 3H). 13C NMR (150 MHz,
CDCl3) δ 165.0 (C), 163.4 (C), 135.9 (C), 131.6 (CH), 121.5 (C),
114.4 (CH2), 113.5 (CH), 65.8 (CH2), 55.2 (CH3). 1H and C
13
NMR data for 2-chloroallyl 4-methoxybenzoate (1a) pre-
pared in this way were in agreement with those previously
described.5f
Preparation of 2-bromoallyl 4-methoxybenzoate
(1b). 4-Methoxybenzoyl chloride (938 mg, 5.50 mmol, 1.10
equiv) was added dropwise via syringe to a solution of 2-
bromo-2-propen-1-ol (685 mg, 5.00 mmol, 1 equiv) in pyr-
idine (20 mL) at 0 C. The reaction mixture was stirred
for 30 min at 0 C, and then the ice bath was removed.
The reaction mixture was stirred for 24 h at 24 C. The
product mixture was transferred to a separatory funnel
that had been charged with ethyl acetate (20 mL). The
diluted product mixture was washed with saturated aque-
ous sodium bicarbonate solution (20 mL). The aqueous
layer was isolated and the isolated aqueous layer was ex-
tracted with ethyl acetate (3  20 mL). The organic layers
were combined and the combined organic layers were
dried over sodium sulfate. The dried solution was filtered
and the filtrate was concentrated. The residue obtained
was purified by automated flash-column chromatography
(eluting with 5% ethyl acetate–hexanes initially, grading
to 10% ethyl acetate–hexanes, linear gradient) to afford 2-
bromoallyl 4-methoxybenzoate (1b) as a colorless oil (1.26
g, 93%). Rf = 0.51 (20% ethyl acetate–hexanes; UV,
KMnO4). 1H NMR (400 MHz, CD2Cl2) δ 8.03 (d, 2H, J =
8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.00 (br s, 1H), 5.70 (br s,
1H), 4.92 (s, 2H), 3.86 (s, 3H). 13C NMR (100 MHz, CD2Cl2)
δ 165.6 (C), 164.3 (C), 132.2 (CH), 127.2 (C), 122.4 (C), 119.3
(CH2), 114.3 (CH), 68.1 (CH2), 56.0 (CH3). IR (ATR-FTIR),
cm–1: 1714 (s), 1604 (s), 1510 (m), 1249 (s), 1165 (s). HRMS-
ESI (m/z): [M
+
H]+ calcd for C11H1279/81BrO3,
270.9970/272.9949; found, 270.9975/272.9943.
Synthetic Procedures.
Preparation of 2-fluoroallyl 4-methoxybenzoate
(1c). 4-Methoxybenzoyl chloride (1.24 g, 7.24 mmol, 1.10
equiv) was added dropwise via syringe to a solution of 2-
fluoro-2-propen-1-ol (500 mg, 6.58 mmol, 1 equiv) in pyri-
dine (26 mL) at 0 C. The reaction mixture was stirred for
Preparation of 2-chloroallyl 4-methoxybenzoate
(1a). 4-Methoxybenzoyl chloride (1.02 g, 5.96 mmol, 1.10
equiv) was added dropwise via syringe to a solution of 2-
chloro-2-propen-1-ol (500 mg, 5.41 mmol, 1 equiv) in pyri-
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The Journal of Organic Chemistry
syringe to 4-ethynylanisol (736 mg, 5.57 mmol, 1 equiv) at
30 min at 0 C, and then the ice bath was removed. The
1
0 C. The reaction mixture was stirred for 30 min at 0 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with dichloromethane (100
mL). The diluted product mixture was washed with water
(20 mL). The aqueous layer was isolated and the isolated
aqueous layer was extracted with dichloromethane (3  20
mL). The organic layers were combined and the com-
bined organic layers were dried over sodium sulfate. The
dried solution was filtered and the filtrate was concen-
trated. The residue obtained was purified by automated
flash-column chromatography (eluting with 1% ether–
hexanes initially, grading to 10% ether–hexanes, linear
gradient) to afford 1-(1-bromovinyl)-4-methoxybenzene
(1e) as a white solid (1.14 g, 96%). Rf = 0.15 (hexanes; UV,
reaction mixture was stirred for 24 h at 24 C. The prod-
uct mixture was transferred to a separatory funnel that
had been charged with ethyl acetate (20 mL). The diluted
product mixture was washed with saturated aqueous so-
dium bicarbonate solution (20 mL). The aqueous layer
was isolated and the isolated aqueous layer was extracted
with ethyl acetate (3  20 mL). The organic layers were
combined and the combined organic layers were dried
over sodium sulfate. The dried solution was filtered and
the filtrate was concentrated. The residue obtained was
purified by automated flash-column chromatography
(eluting with 5% ethyl acetate–hexanes initially, grading
to 10% ethyl acetate–hexanes, linear gradient) to afford 2-
fluoroallyl 4-methoxybenzoate (1c) as a colorless oil (1.20
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
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58
59
60
1
KMnO4). mp 34−37 °C. H NMR (500 MHz, CD2Cl2) δ 7.55
g, 86%).
Rf = 0.52 (20% ethyl acetate–hexanes; UV,
1
(d, 2H, J = 8.5 Hz), 6.89 (d, 2H, J = 8.5 Hz), 6.04 (br s, 1H),
5.69 (br s, 1H), 3.82 (s, 3H). 13C NMR (125 MHz, CD2Cl2) δ
160.4 (C), 131.0 (C), 130.6 (C), 128.6 (CH), 115.7 (CH2), 113.5
KMnO4). H NMR (400 MHz, CDCl3) δ 8.02 (d, 2H, J = 8.8
Hz), 6.92 (d, 2H, J = 8.8 Hz), 4.87–4.63 (m, 4H), 3.85 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 164.5 (d, C, J = 188 Hz),
161.8 (C), 159.2 (C), 131.8 (CH), 121.8 (C), 113.7 (CH), 94.2 (d,
CH2, J = 170 Hz), 61.4 (d, CH2, J = 340 Hz), 55.4 (CH3). 19F
NMR (375 MHz, CDCl3) δ –105.4. IR (ATR-FTIR), cm–1:
1715 (s), 1605 (s), 1511 (m), 1250 (s), 1166 (s). HRMS-ESI
(m/z): [M + H]+ calcd for C11H12FO3, 211.0770; found,
211.0776.
(CH), 55.3 (CH3).
1H and 13C NMR data for 1-(1-
bromovinyl)-4-methoxybenzene (1e) prepared in this way
were in agreement with those previously described.27
Preparation
of
1-(4,4-dibromobut-3-en-1-yl)-4-
methoxybenzene (11b). Carbon tetrabromide (9.95 g,
30.0 mmol, 4.00 equiv) and zinc dust (1.96 g, 30.0 mmol,
4.00 equiv) were added sequentially to a solution of 3-(4-
methoxyphenyl)propanal (1.23 g, 7.50 mmol, 1 equiv) in
dichloromethane (90 mL) at 24 C. Triphenylphosphine
(7.87 g, 60.0 mmol, 4.00 equiv) was added portionwise to
the reaction mixture over 1 h at 24 C. The reaction mix-
ture was stirred for 1 h at 24 C. The product mixture was
diluted sequentially with ether (200 mL) and pentane
(200 mL). The diluted product mixture was filtered
through a pad of silica gel and the pad was rinsed with
50% ether–pentane (500 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography (eluting with hexanes initially, grading
to 10% ether–hexanes, linear gradient) to afford 1-(4,4-
dibromobut-3-en-1-yl)-4-methoxybenzene (11b) as a white
solid (2.19 g, 91%). Rf = 0.56 (5% ether–hexanes; UV,
Preparation of 2-iodoallyl 4-methoxybenzoate (1d).
4-Methoxybenzoyl chloride (1.29 g, 7.58 mmol, 1.10 equiv)
was added dropwise via syringe to a solution of freshly
purified 2-iodo-2-propen-1-ol (1.27 g, 6.89 mmol, 1 equiv)
in pyridine (28 mL) at 0 C. The reaction vessel was cov-
ered with foil to exclude light. The reaction mixture was
stirred for 30 min at 0 C, and then the ice bath was re-
moved. The reaction mixture was stirred for 24 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 5% ethyl acetate–hexanes ini-
tially, grading to 10% ethyl acetate–hexanes, linear gradi-
ent) to afford 2-iodoallyl 4-methoxybenzoate (1d) as a
colorless oil (2.18 g, 98%). Rf = 0.53 (20% ethyl acetate–
1
CAM). mp 33−36 °C. H NMR (400 MHz, CDCl3) δ 7.12 (d,
2H, J = 8.4 Hz), 6.85 (d, 2H, J = 8.4 Hz), 6.42 (t, 1H, J = 7.2
Hz), 3.81 (s, 3H), 2.70 (t, 2H, J = 7.2 Hz), 2.43–2.37 (m, 2H).
13C NMR (125 MHz, CDCl3) δ 156.2 (C), 137.7 (CH), 132.6
(C), 129.3 (CH), 114.0 (CH), 89.3 (C), 55.3 (CH3), 34.9 (CH2),
33.0 (CH2). IR (ATR-FTIR), cm–1: 2953 (w), 1511 (s), 1244 (s),
801 (m), 729 (s). HRMS-EI (m/z): [M + H]+ calcd for
C11H1379Br81BrO, 320.9313; found, 320.9323.
1
hexanes; UV, KMnO4). H NMR (400 MHz, CD2Cl2) δ 8.03
(d, 2H, J = 8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz), 6.43 (br s, 1H),
5.98 (br s, 1H), 4.88 (br s, 2H), 3.86 (s, 3H). 13C NMR (100
MHz, CD2Cl2) δ 164.9 (C), 163.7 (C), 131.7 (CH), 127.0 (CH2),
121.9 (C), 113.7 (CH), 102.8 (C), 70.8 (CH2), 55.5 (CH3). IR
(ATR-FTIR), cm–1: 1713 (s), 1604 (s), 1510 (m), 1248 (s), 1165
(s). HRMS-ESI (m/z): [M + Na]+ calcd for C11H11INaO3,
340.9651; found, 340.9659.
Preparation
of
(Z)-(2-bromo-5-(4-
methoxyphenyl)pent-2-en-1-yl)trimethylsilane (1f).
This experiment was adapted from the work of Uenishi
and Ohmi.28 A 50-mL round-bottomed flask that had
been fused to a Teflon-coated valve was charged sequen-
tially
with
1-(4,4-dibromobut-3-en-1-yl)-4-
methoxybenzene (7b, 368 mg, 1.15 mmol, 1 equiv) and
dichloro(1,3-bis(diphenylphosphino)propane)nickel (62.3
mg, 115 μmol, 0.100 equiv). The reaction vessel was evac-
uated and refilled using a balloon of argon. This process
Preparation of 1-(1-bromovinyl)-4-methoxybenzene
(1e). This experiment was adapted from the work of
Rovis and co-workers.27 A solution of hydrobromic acid
in acetic acid (33%, w/w, 1.00 mL) was added dropwise via
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was repeated two times. Ether (20 mL) was added the
C13H1379/81BrNaO2,
303.0001/304.9993.
302.9997/304.9976;
found,
1H and 13C NMR data for 2-
1
2
3
4
5
6
7
8
reaction vessel and the resulting mixture was degassed by
three freeze–pump–thaw cycles. A solution of (trime-
thylsilyl)methylmagnesium chloride in ether (1.00 M, 4.60
mL, 4.60 mmol, 4.00 equiv) was added dropwise via sy-
ringe to the reaction mixture. The reaction vessel was
sealed and reaction mixture was stirred for 72 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous ammonium chloride solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 1% ether–hexanes initially,
grading to 7% ether–hexanes, linear gradient) to afford
(Z)-(2-bromo-5-(4-methoxyphenyl)pent-2-en-1-
yl)trimethylsilane (1f) as a colorless oil (334 mg, 88%). Rf
= 0.75 (10% ether–hexanes; UV, CAM). 1H NMR (400
MHz, CD2Cl2) δ 7.12 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4
Hz), 5.43 (t, 1H, J = 6.8 Hz), 3.77 (s, 3H), 2.64 (t, 2H, J = 7.8
Hz), 2.44–2.38 (m, 2H), 2.09 (br s, 2H), 0.07 (s, 9H). 13C
NMR (100 MHz, CD2Cl2) δ 157.9 (C), 133.7 (C), 129.2 (CH),
125.1 (C), 125.0 (CH), 113.6 (CH), 55.1 (CH3), 33.9 (CH2), 33.6
(CH2), 32.6 (CH2), –1.2 (CH3). IR (ATR-FTIR), cm–1: 2952
(w), 1511 (s), 1244 (s), 839 (s). HRMS-EI (m/z): [M + H]+
calcd for C15H2479BrOSi, 327.0780; found, 327.0779.
bromocyclohex-2-en-1-yl benzoate (1g) prepared in this
way were in agreement with those previously described.5f
Preparation of (R)-2-bromocyclohex-2-en-1-yl ben-
zoate [(R)-1g]. A 100-mL round-bottomed flask that had
been fused to a Teflon-coated valve was charged with a
solution of the (S)-Corey-Bakshi-Shibata catalyst in tolu-
ene (1.0 M, 0.297 mL, 297 μmol, 0.100 equiv). The solu-
tion was concentrated to dryness in vacuo. The residue
obtained was dissolved in tetrahydrofuran (15 mL) and
the resulting solution was cooled to –20 C. A solution of
borane dimethylsulfide complex (5.0 M, 1.19 mL, 5.94
mmol, 2.00 equiv) was added to the cooled solution and
the resulting clear, colorless mixture was stirred for 10
min at –20 C. A solution of 2-bromocyclohex-2-en-1-one
[520 mg, 2.97 mmol, 1 equiv; dried by azeotropic distilla-
tion with benzene (6.0 mL)] in tetrahydrofuran (12 mL)
was then added dropwise via cannula to the cold catalyst
solution. The flask containing 2-bromocyclohex-2-en-1-
one was rinsed three times with tetrahydrofuran (1.0 mL)
and the rinses were transferred to the reaction mixture
via cannula. The reaction mixture was stirred for 12 h at –
20 C. Methanol (15 mL) was added slowly to the product
mixture at –20 C. The diluted product mixture was
washed with saturated aqueous sodium chloride solution
(20 mL). The aqueous layer was isolated and the isolated
aqueous layer was extracted with ethyl acetate (3  20
mL). The organic layers were combined and the com-
bined organic layers were dried over sodium sulfate. The
dried solution was filtered and the filtrate was concen-
trated. The residue obtained was suspended in dichloro-
methane (100 mL) and the product mixture was filtered
through a pad of celite. The pad was rinsed with di-
chloromethane (3  20 mL). The filtrates were combined
and the combined filtrate was concentrated to dryness.
The (R)-2-bromocyclohex-2-en-1-ol prepared in this way
was immediately used in the following step without fur-
ther purification.
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20
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24
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60
Preparation of 2-bromocyclohex-2-en-1-yl benzoate
(1g). Benzoyl chloride (310 mg, 2.20 mmol, 1.10 equiv) was
added dropwise via syringe to
a solution of 2-
bromocyclohex-2-en-1-ol (354 mg, 2.00 mmol, 1 equiv) in
pyridine (8.0 mL) at 0 C. The resulting mixture was
stirred for 30 min at 0 C, and then the ice bath was re-
moved. The reaction mixture was stirred for 5 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 5% ethyl acetate–hexanes ini-
tially, grading to 20% ethyl acetate–hexanes, linear gradi-
ent) to afford 2-bromocyclohex-2-en-1-yl benzoate (1g) as
a colorless oil (515 mg, 92%). Rf = 0.63 (20% ethyl ace-
tate–hexanes; UV). 1H NMR (400 MHz, CDCl3) δ 8.10 (d,
2H, J = 7.6 Hz), 7.57 (t, 1H, J = 7.4 Hz), 7.45 (t, 2H, J = 7.6
Hz), 6.41 (br s, 1H), 5.66 (br s, 1H), 2.29–2.19 (m, 1H), 2.17–
2.01 (m, 3H), 1.83–1.68 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ 165.8 (C), 135.4 (CH), 133.0 (CH), 130.1 (C), 129.7 (CH),
128.3 (CH), 119.9 (C), 71.8 (CH), 30.1 (CH2), 27.6 (CH2), 17.4
(CH2). IR (ATR-FTIR), cm–1: 2948 (w), 1715 (s), 1264 (s),
1106 (m), 709 (s). HRMS-ESI (m/z): [M + Na]+ calcd for
Benzoyl chloride (447 mg, 3.17 mmol, 1.10 equiv) was
added dropwise via syringe to a solution of (R)-2-
bromocyclohex-2-en-1-ol (nominally 2.88 mmol, 1 equiv)
in pyridine (12 mL) at 0 C. The resulting mixture was
stirred for 30 min at 0 C, and then the ice bath was re-
moved. The reaction mixture was stirred for 5 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 5% ethyl acetate–hexanes ini-
tially, grading to 20% ethyl acetate–hexanes, linear gradi-
ent) to afford (R)-2-bromocyclohex-2-en-1-yl benzoate
[(R)-1g] as a colorless oil (661 mg, 79%, 2 steps). The en-
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The Journal of Organic Chemistry
antiomeric ratio of (R)-1g was determined to be 94:6 by The reaction vessel was sealed and the sealed reaction
1
2
3
4
5
6
7
8
chiral stationary phase HPLC analysis (Chiralpak AD-H: 1%
ethanol–hexanes, 24 C, 1.0 mL/min, λ = 254 nm, tR(major)
= 15.5 min, tR(minor) = 17.3 min).
vessel was placed in an oil bath that had been preheated
to 100 C. The reaction mixture was stirred and heated
for 24 h at 100 C. The product mixture was allowed to
cool over 20 min to 24 C. The cooled product mixture
was filtered through a pad of celite and the pad was
rinsed with hexanes (100 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography on neutral aluminum oxide (eluting with
3% ether–hexanes, isocratic gradient) to afford ((4-(tert-
butyl)cyclohex-1-en-1-yl)oxy)benzene (1i) as a light yellow
13
1H and C NMR data for (R)-2-bromocyclohex-2-en-1-yl
benzoate [(R)-1g] prepared in this way were in agreement
with the racemic form.
Preparation of 2-((2-bromobenzyl)oxy)cyclohex-2-
en-1-yl benzoate (1h). Benzoyl chloride (122 mg, 866
μmol, 1.05 equiv) was added dropwise via syringe to a so-
lution of 2-((2-bromobenzyl)oxy)cyclohex-2-en-1-ol (182
mg, 825 μmol, 1 equiv) in pyridine (3.3 mL) at 0 C. The
resulting mixture was stirred for 30 min at 0 C, and then
the ice bath was removed. The reaction mixture was
stirred overnight at 24 C. The product mixture was
transferred to a separatory funnel that had been charged
with ethyl acetate (20 mL). The diluted product mixture
was washed with saturated aqueous sodium bicarbonate
solution (20 mL). The aqueous layer was isolated and the
isolated aqueous layer was extracted with ethyl acetate (3
 20 mL). The organic layers were combined and the
combined organic layers were dried over sodium sulfate.
The dried solution was filtered and the filtrate was con-
centrated. The residue obtained was purified by auto-
mated flash-column chromatography (eluting with 1%
ether–hexanes initially, grading to 15% ether–hexanes,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
oil (235 mg, 73%). Rf = 0.23 (3% ether–hexanes; CAM). H
NMR (400 MHz, CDCl3) δ 7.31 (t, 2H, J = 8.0 Hz), 7.04 (t,
1H, J = 7.4 Hz), 7.00–6.97 (m, 2H), 5.07–5.04 (m, 1H), 2.26–
2.08 (m, 3H), 1.96–1.89 (m, 2H), 1.40–1.34 (m, 2H), 0.92 (s,
9H). 13C NMR (100 MHz, CDCl3) δ 155.9 (C), 152.2 (C),
128.7 (CH), 121.7 (CH), 117.8 (CH), 106.7 (CH), 43.4 (CH),
1
31.4 (C), 26.9 (CH2) 26.4 (CH3), 24.3 (CH2), 23.5 (CH2). H
and 13C NMR data for ((4-(tert-butyl)cyclohex-1-en-1-
yl)oxy)benzene (1i) prepared in this way were in agree-
ment with those previously described.29
Preparation of methyl 4-(1-acetoxyvinyl)benzoate
(1j). This experiment was adapted from the work of
Wangelin and co-workers.30 A solution of methyl 4-
acetylbenzoate (891 mg, 5.00 mmol, 1 equiv) in tetrahy-
drofuran (5 mL) was added dropwise via syringe over 30
min via syringe to a solution of lithium hexamethyldisi-
lazide (920 mg, 5.50 mmol, 1.10 equiv) in tetrahydrofuran
(10 mL) at –78 C. The resulting mixture was stirred for
30 min at –78 C. A solution of acetic anhydride (562 mg,
5.50 mmol, 1.10 equiv) in tetrahydrofuran (6 mL) was add-
ed dropwise via syringe over 15 min to the reaction mix-
ture at –78 C. The reaction mixture was stirred for 30
min at –78 C, and then the cold bath was removed. The
reaction was stirred overnight at 24 C. The product mix-
ture was transferred to a separatory funnel that had been
charged with ethyl acetate (20 mL). The diluted product
mixture was washed with saturated aqueous ammonium
chloride solution (20 mL). The aqueous layer was isolated
and the isolated aqueous layer was extracted with ethyl
acetate (3  20 mL). The organic layers were combined
and the combined organic layers were dried over sodium
sulfate. The dried solution was filtered and the filtrate
was concentrated. The residue obtained was purified by
automated flash-column chromatography (eluting with
20% ethyl acetate–hexanes, isocratic gradient) to afford
methyl 4-(1-acetoxyvinyl)benzoate (1j) as a white solid
(978 mg, 89%). Rf = 0.31 (20% ethyl acetate–hexanes; UV,
linear
gradient)
to
afford
2-((2-
bromobenzyl)oxy)cyclohex-2-en-1-yl benzoate (1h) as a
colorless oil (315 mg, 98%). Rf = 0.33 (20% ether–hexanes;
1
UV, CAM). H NMR (400 MHz, CD2Cl2) δ 8.05 (d, 2H, J =
8.4 Hz), 7.56 (t, 1H, J = 7.4 Hz), 7.50 (d, 1H, J = 8.0 Hz),
7.46–7.41 (m, 3H), 7.24 (t, 1H, J = 7.6 Hz), 7.14–7.10 (m, 1H),
5.86 (t, 1H, J = 4.0 Hz), 5.09 (dd, 1H, J = 5.2, 3.2 Hz), 4.83 (s,
2H), 2.28–2.20 (m, 1H), 2.16–2.10 (m, 1H), 2.09–2.01 (m, 1H),
1.94–1.86 (m, 1H), 1.80–1.72 (m, 1H), 1.71–1.63 (m, 1H). 13C
NMR (100 MHz, CD2Cl2) δ 165.9 (C), 151.1 (C), 136.5 (C),
132.7 (CH), 132.3 (CH), 130.8 (C), 129.5 (CH), 128.9 (CH),
128.6 (CH), 128.3 (CH), 127.4 (CH), 122.0 (C), 101.4 (CH),
68.6 (CH), 68.1 (CH2), 29.3 (CH2), 23.6 (CH2), 18.2 (CH2).
IR (ATR-FTIR), cm–1: 2938 (w), 1714 (s), 1269 (s), 1109 (m),
710 (s).
HRMS-ESI (m/z): [M
+
Na]+ calcd for
409.0415/411.0395; found,
C20H1979/81BrNaO3,
409.0429/411.0388.
Preparation
of
((4-(tert-butyl)cyclohex-1-en-1-
yl)oxy)benzene (1i). This experiment was adapted from
the work of Willis and co-workers.29 A 25-mL round-
bottomed flask that had been fused to a Teflon-coated
valve was charged sequentially with phenol (197 mg, 2.10
mmol, 1.50 equiv), tris(dibenzylideneacetone)dipalladium
(38.4 mg, 42.0 μmol, 0.03 equiv), JohnPhos (37.5 mg,
126μmol, 0.09 equiv), and sodium tert-butoxide (235 mg,
2.45 mg, 1.75 equiv). The reaction vessel was evacuated
and refilled using a balloon of argon. This process was
repeated two times. Toluene (10 mL) was added to the
reaction vessel and the resulting mixture was degassed by
three freeze–pump–thaw cycles. 4-(tert-Butyl)cyclohex-1-
en-1-yl trifluoromethanesulfonate (400 mg, 1.40 mmol, 1
equiv) was added dropwise to the reaction vessel at 24 C.
1
CAM). mp 69−73 °C. H NMR (400 MHz, CDCl3) δ 8.01 (d,
2H, J = 7.2 Hz), 7.52 (d, 2H, J = 7.2 Hz), 5.58 (br s, 1H), 5.14
(br s, 1H), 3.91 (s, 3H), 2.28 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 168.9 (C), 166.5 (C), 152.0 (C), 138.5 (C), 130.3 (C),
129.8 (CH), 124.8 (CH), 104.3 (CH2), 52.2 (CH3), 20.9 (CH3).
1H and 13C NMR data for 4-(1-acetoxyvinyl)benzoate (1j)
prepared in this way were in agreement with those previ-
ously described.30
Preparation
of
benzyl
4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-
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Page 10 of 32
dihydropyridine-1(2H)-carboxylate (1k). This experi-
ment was adapted from the work of Patel and co-
workers.31
solution of benzyl 4-oxopiperidine-1-
carboxylate (1.17 g, 5.00 mmol, 1 equiv) in tetrahydrofuran
(11 mL) was added dropwise via syringe over 10 min via
syringe to a solution of lithium hexamethyldisilazide (920
mg, 5.50 mmol, 1.10 equiv) in tetrahydrofuran (22 mL) at –
78 C. The reaction mixture was stirred for 30 min at –78
grading to 30% ether–hexanes, linear gradient) to afford
tert-butyl 4-((diphenoxyphosphoryl)oxy)-3,6-
1
2
3
4
5
6
7
8
A
dihydropyridine-1(2H)-carboxylate (1l) as a colorless oil
(2.04 g, 82%). Rf = 0.24 (15% ether–hexanes; UV, KMnO4).
1H NMR (400 MHz, CDCl3) δ 7.39–7.36 (m, 4H), 7.25–7.22
(m, 6H), 5.56 (br s, 1H), 3.94 (br s, 2H), 3.55 (br s, 2H), 2.31
(br s, 2H), 1.44 (s, 9H). 31P NMR (200 MHz, CDCl3) δ –17.6.
1H
and
31P
NMR
data
for
tert-butyl
4-
((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-
carboxylate (1l) prepared in this way were in agreement
with those previously described.32
C.
A
solution
of
N-phenyl-
9
bis(trifluoromethanesulfonimide) (1.96 g, 5.50 mmol, 1.10
equiv) in tetrahydrofuran (11 mL) was added dropwise via
syringe over 10 min to the reaction mixture at –78 C. The
reaction mixture was stirred for 2 h at –78 C, and then
the cold bath was removed. The reaction was stirred for 2
h at 24 C. The product mixture was transferred to a sep-
aratory funnel that had been charged with ethyl acetate
(20 mL). The diluted product mixture was washed with
saturated aqueous ammonium chloride solution (20 mL).
The aqueous layer was isolated and the isolated aqueous
layer was extracted with ethyl acetate (3  20 mL). The
organic layers were combined and the combined organic
layers were dried over sodium sulfate. The dried solution
was filtered and the filtrate was concentrated. The resi-
due obtained was purified by automated flash-column
chromatography (eluting with 20% ether–hexanes, iso-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of 4-((triisopropylsilyl)oxy)cyclohex-3-
en-1-yl benzoate (1m). This experiment was adapted
from the work of Corey and co-workers.33 Triisopropylsi-
lyl trifluoromethanesulfonate (434 μL, 2.40 mmol, 1.20
equiv) was added dropwise via syringe to a solution of 4-
oxocyclohexyl benzoate (437 mg, 2.00 mmol, 1 equiv) and
trimethylamine (502 μL, 3.60 mmol, 1.80 equiv) in di-
chloromethane (6.0 mL) at 24 C. The reaction mixture
was stirred for 2 h at 24 C. The product mixture was
transferred to a separatory funnel that had been charged
with ether (50 mL) and pentane (50 mL). The diluted
product mixture was washed with saturated aqueous
ammonium chloride solution (20 mL). The aqueous layer
was isolated and the isolated aqueous layer was extracted
with ether (3  20 mL). The organic layers were com-
bined and the combined organic layers were dried over
sodium sulfate. The dried solution was filtered and the
filtrate was concentrated. The residue obtained was puri-
fied by automated flash-column chromatography (eluting
with 5% ether hexane, isocratic gradient) to afford 4-
((triisopropylsilyl)oxy)cyclohex-3-en-1-yl benzoate (1m) as
a colorless oil (749 mg, 98%). Rf = 0.83 (20% ether–
cratic
gradient)
to
afford
benzyl
4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1k) as a colorless oil (1.50 g, 95%). Rf =
0.24 (33% ether–hexanes; UV, KMnO4). 1H NMR (400
MHz, CDCl3) δ 7.40–7.31 (m, 5H), 5.77 (br s, 1H), 5.16 (s,
2H), 4.12 (br s, 2H), 3.71 (br s, 2H), 2.46 (br s, 2H). 19F
1
NMR (375 MHz, CDCl3) δ –73.8. H and 19F NMR data for
benzyl
4-(((trifluoromethyl)sulfonyl)oxy)-3,6-
1
dihydropyridine-1(2H)-carboxylate (1k) prepared in this
hexanes; UV, CAM). H NMR (400 MHz, CDCl3) δ 8.04 (d,
way were in agreement with those previously described.31
2H, J = 6.8 Hz), 7.54 (t, 1H, J = 7.0 Hz), 7.42 (t, 2H, J = 7.6
Hz), 5.30–5.24 (m, 1H), 4.81–4.79 (m, 1H), 2.52–2.45 (m,
1H), 2.32–2.26 (m, 3H), 2.06–1.98 (m, 2H), 1.26–1.05 (m,
21H). 13C NMR (100 MHz, CDCl3) δ 166.1 (C), 150.1 (C),
132.8 (CH), 130.7 (C), 129.6 (CH), 128.2 (CH), 99.6 (CH),
69.5 (CH), 29.4 (CH2), 27.6 (CH2), 27.1 (CH2), 18.0 (CH3),
12.6 (CH). IR (ATR-FTIR), cm–1: 2944 (w), 2866 (w), 1718
(s), 1274 (s), 1114 (m), 711 (m). HRMS-ESI (m/z): [M + Na]+
calcd for C22H34NaO3Si, 397.2175; found, 397.2163.
Preparation
of
tert-butyl
4-
((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1l). This experiment was adapted
from the work of Begtrup and co-workers.32 A solution of
potassium hexamethyldisilazide (1.21 g, 6.06 mmol, 1.27
equiv) in toluene (12 mL) was added dropwise via syringe
over 15 min to a solution of tert-butyl 4-oxopiperidine-1-
carboxylate (1.17 g, 5.00 mmol, 1 equiv), diphenyl chloro-
phosphate (1.21 mL, 5.82 mmol, 1.22 equiv), and hexa-
methylphosphoramide (1.18 mL, 6.77 mmol, 1.42 equiv) in
tetrahydrofuran (20 mL) at –78 C. The reaction mixture
was stirred for 2 h at –78 C, and then the cold bath was
removed. The reaction was stirred for another 2 h at 24
C. The product mixture was transferred to a separatory
funnel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous ammonium chloride solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 10% ether–hexanes initially,
Preparation
of
2-(phenylthio)allyl
4-
methoxybenzoate (1n). 4-Methoxybenzoyl chloride (210
mg, 1.23 mmol, 1.10 equiv) was added dropwise via syringe
to a solution of 2-(phenylthio)prop-2-en-1-ol (186 mg, 1.12
mmol, 1 equiv) in pyridine (4.5 mL) at 0 C. The reaction
mixture was stirred for 30 min at 0 C, and then the ice
bath was removed. The reaction mixture was stirred for
24 h at 24 C. The product mixture was transferred to a
separatory funnel that had been charged with ethyl ace-
tate (20 mL). The diluted product mixture was washed
with saturated aqueous sodium bicarbonate solution (20
mL). The aqueous layer was isolated and the isolated
aqueous layer was extracted with ethyl acetate (3  20
mL). The organic layers were combined and the com-
bined organic layers were dried over sodium sulfate. The
dried solution was filtered and the filtrate was concen-
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The Journal of Organic Chemistry
trated. The residue obtained was purified by automated The diluted product mixture was washed with saturated
1
2
3
4
5
6
7
8
flash-column chromatography (eluting with 7.5% ethyl
acetate–hexanes, isocratic gradient) to afford 2-
(phenylthio)allyl 4-methoxybenzoate (1n) as a colorless
oil (322 mg, 96%). Rf = 0.80 (30% ethyl acetate–hexanes;
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with hexanes initially, grading to 5%
ethyl acetate–hexanes, linear gradient) to afford 2-((4-
chlorophenyl)thio)cyclohex-2-en-1-yl benzoate (1o) as a
colorless oil (388 mg, 57%, 3 steps). Rf = 0.71 (20% ethyl
1
UV, CAM). H NMR (400 MHz, CD2Cl2) δ 8.00 (d, 2H, J =
8.0 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.38–7.20 (m, 3H), 6.95 (d,
2H, J = 8.0 Hz), 5.64 (br s, 1H), 5.36 (br s, 1H), 4.84 (br s,
2H), 3.86 (s, 3H). 13C NMR (100 MHz, CD2Cl2) δ 165.9 (C),
164.2 (C), 140.2 (C), 133.0 (C), 132.8 (CH), 132.2 (CH), 129.8
(CH), 128.4 (CH), 122.8 (C), 118.1 (CH2), 114.2 (CH), 66.2
(CH2), 56.0 (CH3). IR (ATR-FTIR), cm–1: 2936 (w), 1714 (s),
1605 (s), 1510 (m), 1254 (s), 1167 (s), 1098 (s). HRMS-ESI
(m/z): [M + Na]+ calcd for C17H16NaO3S, 323.0729; found,
323.0718.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
acetate–hexanes; UV, CAM). H NMR (400 MHz, CD2Cl2)
δ 7.87 (d, 2H, J = 8.4 Hz), 7.58–7.53 (m, 1H), 7.41 (t, 2H, J =
7.6 Hz), 7.28–7.19 (m, 4H), 6.52 (t, 1H, J = 4.0 Hz), 5.53–
5.51 (m, 1H), 2.41–2.30 (m, 1H), 2.29–2.21 (m, 1H), 2.06–1.99
(m, 1H), 1.96–1.88 (m, 1H), 1.85–1.69 (m, 2H). 13C NMR
(100 MHz, CD2Cl2) δ 165.5 (C), 141.9 (CH), 134.1 (C), 132.8
(CH), 132.4 (C), 131.4 (CH), 130.4 (C), 130.1 (C), 129.4 (CH),
128.9 (CH), 128.2 (CH), 69.5 (CH), 29.6 (CH2), 27.1 (CH2),
17.4 (CH2). IR (ATR-FTIR), cm–1: 2945 (w), 1715 (s), 1475
(s), 1266 (s), 1108 (m), 817 (m), 710 (s). HRMS-ESI (m/z):
[M + Na]+ calcd for C19H1735/37ClNaO2S, 367.0535/369.0506;
found, 367.0539/369.0531.
Preparation of 2-((4-chlorophenyl)thio)cyclohex-2-
en-1-yl benzoate (1o). This experiment was adapted
from the work of Fringuelli and co-workers.34 An aqueous
solution of sodium hydroxide (0.100 M, 0.600 mL, 60.0
μmol, 0.03 equiv) was added dropwise to a suspension of
4-chlorothiophenol (224 mg, 2.00 mmol, 1.00 equiv) in
water (3.4 mL) at 30 C. The resulting mixture was stirred
for 5 min at 30 C. 7-Oxabicyclo[4.1.0]heptan-2-one (198
μL, 2.00 mmol, 1 equiv) was added dropwise to the reac-
tion mixture. The resulting mixture was stirred for 2 h at
30 C. The product mixture was transferred to a separato-
ry funnel that had been charged with ethyl acetate (20
mL). The diluted product mixture was washed with 15%
aqueous sodium hydroxide solution (6  20 mL). The
organic layer was dried over sodium sulfate. The dried
solution was filtered and the filtrate was concentrated.
The 2-((4-chlorophenyl)thio)cyclohex-2-en-1-one pre-
pared in this way was immediately used in the following
step without further purification.
Preparation of 2-(benzylthio)cyclohex-2-en-1-yl
benzoate (1p). This experiment was adapted from the
work of Fringuelli and co-workers.34 An aqueous solution
of sodium hydroxide (0.100 M, 0.600 mL, 60.0 μmol, 0.03
equiv) was added dropwise to a suspension of benzyl
mercaptan (235 μL, 2.00 mmol, 1.00 equiv) in water (3.4
mL) at 30 C. The reaction mixture was stirred for 5 min
at 30 C. 7-Oxabicyclo[4.1.0]heptan-2-one (198 μL, 2.00
mmol, 1 equiv) was added dropwise. The resulting mix-
ture was stirred for 2 h at 30 C. The product mixture was
transferred to a separatory funnel that had been charged
with ethyl acetate (20 mL). The diluted product mixture
was washed with 15% aqueous sodium hydroxide solution
(6  20 mL). The organic layer was dried over sodium
sulfate. The dried solution was filtered and the filtrate
was concentrated. The 2-(benzylthio)cyclohex-2-en-1-one
prepared in this way was immediately used in the follow-
ing step without further purification.
Cerium (III) chloride heptahydrate (553 mg, 1.49 mmol,
1.10 equiv) was added to
a
solution of 2-((4-
chlorophenyl)thio)cyclohex-2-en-1-one (nominally, 1.35
mmol) in methanol (6.8 mL) at 0 C. Sodium borohy-
dride (51.1 mg, 1.35 mmol, 1.00 equiv) was added to the
reaction mixture portionwise over 30 min at 0 C. The
resulting mixture was stirred for 1 h at 0 C. Acetone (5
mL) was added dropwise via syringe and the resulting
mixture was stirred for 10 min at 0 C. The product mix-
ture was concentrated and the residue obtained was fil-
tered through a pad of silica gel and the pad was rinsed
with ether (100 mL). The filtrates were combined and the
Cerium (III) chloride heptahydrate (693 mg, 1.86 mmol,
1.10 equiv) was added to
a
solution of 2-
(benzylthio)cyclohex-2-en-1-one (nominally, 1.69 mmol)
in methanol (8.5 mL) at 0 C. Sodium borohydride (63.9
mg, 1.69 mmol, 1.00 equiv) was added to the reaction mix-
ture portionwise over 30 min at 0 C. The resulting mix-
ture was stirred for 1 h at 0 C. Acetone (10 mL) was add-
ed dropwise via syringe and the resulting mixture was
stirred for 10 min at 0 C. The product mixture was con-
centrated and the residue obtained was filtered through a
pad of silica gel and the pad was rinsed with ether (200
mL). The filtrates were combined and the combined fil-
trates were concentrated. The 2-(benzylthio)cyclohex-2-
en-1-ol prepared in this way was immediately used in the
following step without further purification.
combined filtrates were concentrated.
The 2-((4-
chlorophenyl)thio)cyclohex-2-en-1-ol prepared in this way
was immediately used in the following step without fur-
ther purification.
Benzoyl chloride (197 mg, 1.40 mmol, 1.05 equiv) was
added dropwise via syringe to a solution of 2-((4-
chlorophenyl)thio)cyclohex-2-en-1-ol (nominally 1.33
mmol) in pyridine (5.3 mL) at 0 C. The reaction mixture
was stirred for 30 min at 0 C, and then the ice bath was
removed. The reaction mixture was stirred for 24 h at 24
C. The product mixture was transferred to a separatory
funnel that had been charged with ethyl acetate (20 mL).
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Benzoyl chloride (213 mg, 1.51 mmol, 1.05 equiv) was
added dropwise via syringe to solution of 2-
mL). The diluted product mixture was washed with satu-
rated aqueous sodium bicarbonate solution (20 mL). The
1
2
3
4
5
6
7
8
a
(benzylthio)cyclohex-2-en-1-ol (nominally 1.44 mmol) in
pyridine (5.8 mL) at 0 C. The reaction mixture was
stirred for 30 min at 0 C, and then the ice bath was re-
moved. The reaction mixture was stirred for 24 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 2% ethyl acetate–hexanes ini-
tially, grading to 15% ethyl acetate–hexanes, linear gradi-
ent) to afford 2-(benzylthio)cyclohex-2-en-1-yl benzoate
(1p) as a colorless oil (450 mg, 73%, 3 steps). Rf = 0.47
(15% ethyl acetate–hexanes; UV, CAM). 1H NMR (400
MHz, CD2Cl2) δ 8.05 (d, 2H, J = 8.4 Hz), 7.59–7.55 (m, 1H),
7.44 (t, 2H, J = 7.6 Hz), 7.28–7.20 (m, 5H), 6.04 (t, 1H, J =
4.2 Hz), 5.63–5.61 (m, 1H), 3.89 (q, 2H, J = 12.7 Hz), 2.24–
2.06 (m, 1H), 2.03–2.01 (m, 1H), 2.00–1.97 (m, 1H), 1.92–1.87
(m, 1H), 1.85–1.61 (m, 2H). 13C NMR (100 MHz, CD2Cl2) δ
165.8 (C), 137.8 (C), 134.7 (CH), 132.8 (CH), 130.8 (C), 130.6
(C), 129.5 (CH), 128.9 (CH), 128.3 (CH), 128.3 (CH), 126.9
(CH), 69.6 (CH), 37.2 (CH2), 29.4 (CH2), 26.7 (CH2), 17.6
(CH2). IR (ATR-FTIR), cm–1: 2942 (w), 1712 (s), 1452 (w),
1266 (s), 1108 (m), 710 (s). HRMS-ESI (m/z): [M + Na]+
calcd for C20H20NaO2S, 347.1082; found, 347.1079.
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 30% ethyl acetate–hexanes,
isocratic gradient) to afford 2-(phenylsulfonyl)cyclohex-2-
en-1-yl benzoate (1q) as a white solid (296 mg, 89%, 2
steps). Rf = 0.54 (40% ethyl acetate–hexanes; UV, CAM).
9
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1
mp 135−136 °C. H NMR (400 MHz, CD2Cl2) δ 7.74 (d, 2H,
J = 8.0 Hz), 7.56 (t, 2H, J = 8.4 Hz), 7.52–7.48 (m, 2H),
7.35–7.27 (m, 5H), 5.95 (br s, 1H), 2.58–2.51 (m, 1H), 2.34–
2.29 (m, 1H), 2.09–2.00 (m, 1H), 1.76–1.65 (m, 3H). 13C
NMR (100 MHz, CD2Cl2) δ 164.8 (C), 145.9 (CH), 140.5 (C),
138.3 (C), 132.9 (CH), 132.9 (CH), 129.7 (C), 129.4 (CH),
129.0 (CH), 128.0 (CH), 127.7 (CH), 63.7 (CH), 28.4 (CH2),
26.0 (CH2), 15.9 (CH2). IR (ATR-FTIR), cm–1: 2951 (w), 1714
(s), 1447 (w), 1263 (s), 1148 (s), 1095 (m), 710 (s). HRMS-
ESI (m/z): [M + K]+ calcd for C19H18KO4S, 381.0563; found,
381.0559.
Preparation of 2-(phenylselanyl)cyclohex-2-en-1-yl
benzoatee (1r). Cerium (III) chloride heptahydrate (553
mg, 1.49 mmol, 1.10 equiv) was added to a solution of 2-
(phenylselanyl)cyclohex-2-en-1-one (339 mg, 1.35 mmol, 1
equiv) in methanol (13.5 mL) at 0 C. Sodium borohy-
dride (51.1 mg, 1.35 mmol, 1.00 equiv) was added to the
reaction mixture portionwise over 30 min at 0 C. The
resulting mixture was stirred for 1 h at 0 C. Acetone (5
mL) was added dropwise via syringe and the resulting
mixture was stirred for 10 min at 0 C. The product mix-
ture was concentrated and the residue obtained was fil-
tered through a pad of silica gel and the pad was rinsed
with ether (150 mL). The filtrates were combined and the
Preparation of 2-(phenylsulfonyl)cyclohex-2-en-1-yl
benzoate (1q). Benzoyl chloride (144 mg, 1.02 mmol, 1.05
equiv) was added dropwise via syringe to a solution of 2-
(phenylthio)cyclohex-2-en-1-ol (200 mg, 969 μmol, 1 equiv)
in pyridine (3.9 mL) at 0 C. The reaction mixture was
stirred for 30 min at 0 C, and then the ice bath was re-
moved. The reaction mixture was stirred for 24 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
combined filtrates were concentrated.
The 2-
(phenylselanyl)cyclohex-2-en-1-ol prepared in this way
was immediately used in the following step without fur-
ther purification.
Benzoyl chloride (185 mg, 1.31 mmol, 1.05 equiv) was
added dropwise via syringe to
a solution of 2-
(phenylselanyl)cyclohex-2-en-1-ol (nominally 1.25 mmol)
in pyridine (5.0 mL) at 0 C. The reaction mixture was
stirred for 30 min at 0 C, and then the ice bath was re-
moved. The reaction mixture was stirred for 24 h at 24 C.
The product mixture was transferred to a separatory fun-
nel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with saturated
aqueous sodium bicarbonate solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layers were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 5% ether–hexanes, isocratic
gradient) to afford 2-(phenylselanyl)cyclohex-2-en-1-yl
benzoate (1r) as a colorless oil (421 mg, 87%, 2 steps). Rf =
filtered and the filtrate was concentrated.
The 2-
(phenylthio)cyclohex-2-en-1-yl benzoate prepared in this
way was immediately used in the following step without
further purification.
3-Chloroperoxybenzoic acid (70% purity, 567 mg, 2.30
mmol, 2.50 equiv) was added to a solution of 2-
(phenylthio)cyclohex-2-en-1-yl benzoate (nominally 918
μmol) in dichloromethane (9.7 mL) at 0 C. The reaction
mixture was stirred for 1 h at 0 C, and then the ice bath
was removed. The reaction mixture was stirred for 2 h at
24 C. The product mixture was transferred to a separato-
ry funnel that had been charged with ethyl acetate (20
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1
0.65 (20% ether–hexanes; UV, CAM). H NMR (400 MHz,
CD2Cl2) δ 7.90 (d, 2H, J = 8.0 Hz), 7.58–7.53 (m, 1H), 7.48–
7.44 (m, 2H), 7.41 (t, 2H, J = 7.6 Hz), 7.27–7.22 (m, 3H),
6.52 (t, 1H, J = 4.0 Hz), 5.58–5.55 (m, 1H), 2.37–2.19 (m,
2H), 2.05–1.93 (m, 2H), 1.85–1.69 (m, 2H). 13C NMR (100
MHz, CD2Cl2) δ 165.6 (C), 141.4 (CH), 132.7 (CH), 132.6
(CH), 130.5 (C), 130.3 (C), 129.5 (CH), 129.1 (CH), 128.2
(CH), 127.6 (C), 127.0 (CH), 70.9 (CH), 29.8 (CH2), 27.6
(CH2), 17.6 (CH2). IR (ATR-FTIR), cm–1: 2943 (w), 1714 (s),
1451 (w), 1266 (s), 1108 (m), 710 (w). HRMS-ESI (m/z): [M
+ Na]+ calcd for C19H18NaO2Se, 381.0370; found, 381.0373.
added dropwise via syringe over 15 min to a solution of (1-
bromovinyl)trimethylsilane (501 mg, 2.80 mmol, 1 equiv)
in ether (10 mL) at –78 C. The resulting mixture was
stirred for 2.5 h at –78 C. The cold mixture was trans-
ferred over 15 min via cannula to a suspention of para-
formaldehyde (83.9 mg, 2.80 mmol, 1.00 equiv) in ether (5
mL) at –78C. The resulting mixture was allowed to warm
up to 24 C over 15 min. The reaction mixture was stirred
for 2.5 h at 24 C. The product mixture was cooled to 0 C
and water (5 mL) was added to quench the reaction. The
resulting mixture was transferred to a separatory funnel
that had been charged with pentane (10 mL). The diluted
product mixture was washed with water (50 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ether (3  20 mL). The organic layers
were combined and the combined organic layers were
dried over sodium sulfate. The dried solution was filtered
and the filtrate was concentrated (150 Torr, 0 C). The 2-
(trimethylsilyl)prop-2-en-1-ol prepared in this way was
immediately used in the following step.
1
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5
6
7
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10
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15
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Preparation of N-(4-phenylbut-1-en-2-yl)acetamide
(1s). This experiment was adapted from the work of
Reeves and co-workers.35 A solution of ammonia in
methanol (7.00 M, 2.14 mL, 15.0 mmol, 1.50 equiv) and
titanium (IV) isopropoxide (5.92 mL, 20.0 mmol, 2.00
equiv) were added sequentially to a solution of 4-phenyl-
2-butanone (1.50 mL, 10.0 mmol, 1 equiv) in toluene (6.0
mL) at 0 C. The reaction mixture was stirred for 30 min
at 0 C, and then the ice bath was removed. The reaction
mixture was stirred for 24 h at 24 C. The resulted mix-
ture was cooled again to 0 C. Triethylamine (5.58 mL,
40.0 mmol, 4.00 equiv) and acetic anhydride (1.89 mL,
20.0 mmol, 2.00 equiv) were added sequentially to the
cooled reaction mixture. The reaction mixture was stirred
for 30 min at 0 C, and then the ice bath was removed.
The reaction mixture was stirred for 6 h at 24 C.
N,N,N',N'-Tetrakis(2-hydroxyethyl)ethylenediamine (4.51
mL, 21.0 mmol, 2.10 equiv) was added dropwise to the
product mixture. The resulted mixtue was placed in an
oil bath that bad been preheated to 55C. The product
mixture was stirred and heated for 15 min at 55 C. The
product mixture was allowed to cool over 20 min to 24 C.
The cooled product mixture was transferred to a separa-
tory funnel that had been charged with ethyl acetate (20
mL). The diluted product mixture was washed with 10%
aqueous ammonium hydroxide solution (20 mL). The
aqueous layer was isolated and the isolated aqueous layer
was extracted with ethyl acetate (3  20 mL). The organic
layer were combined and the combined organic layers
were dried over sodium sulfate. The dried solution was
filtered and the filtrate was concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with 10% ethyl acetate–hexanes ini-
tially, grading to 50% ethyl acetate–hexanes, linear gradi-
ent) to afford N-(4-phenylbut-1-en-2-yl)acetamide (1s) as
a white solid (110 mg, 12%). Rf = 0.52 (40% ether–hexanes;
UV, PAA). mp 86−90 °C. 1H NMR (400 MHz, CD2Cl2) δ
7.32–7.26 (m, 2H), 7.23–7.19 (m, 3H), 6.84 (br s, 1H), 5.46
(s, 1H), 4.48 (s, 1H), 2.82 (t, 2H, J = 7.8 Hz), 2.46 (t, 2H, J =
7.8 Hz), 1.95 (s, 3H). 13C NMR (100 MHz, CD2Cl2) δ 168.6
(C), 141.4 (C), 141.2 (C), 128.4 (CH), 128.3 (CH), 126.1 (CH),
4-Methoxybenzoyl chloride (525 mg, 3.08 mmol, 1.10
equiv) was added dropwise via syringe to a solution of
freshly prepared 2-(trimethylsilyl)prop-2-en-1-ol (nomi-
nally 2.80 mmol) in pyridine (9 mL) at 0 C. The reaction
mixture was stirred for 30 min at 0 C, and then the ice
bath was removed. The reaction mixture was stirred for
24 h at 24 C. The product mixture was transferred to a
separatory funnel that had been charged with ethyl ace-
tate (20 mL). The diluted product mixture was washed
with saturated aqueous sodium bicarbonate solution (20
mL). The aqueous layer was isolated and the isolated
aqueous layer was extracted with ethyl acetate (3  20
mL). The organic layers were combined and the com-
bined organic layers were dried over sodium sulfate. The
dried solution was filtered and the filtrate was concen-
trated. The residue obtained was purified by automated
flash-column chromatography (eluting with hexanes ini-
tially, grading to 20% ether–hexanes, linear gradient) to
afford 2-(trimethylsilyl)allyl 4-methoxybenzoate (1u) as a
colorless oil (491 mg, 66%, 2 steps). Rf = 0.52 (10% ether–
1
hexanes; UV, KMnO4). H NMR (400 MHz, CDCl3) δ 8.02
(d, 2H, J = 7.6 Hz), 6.92 (d, 2H, J = 7.6 Hz), 5.87 (br s, 1H),
5.50 (br s, 1H), 4.92 (br s, 2H), 3.86 (s, 3H), 0.16 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 166.0 (C), 163.3 (C), 146.7 (C),
131.6 (CH), 125.6 (CH2), 122.7 (C), 113.6 (CH), 68.2 (CH2),
55.4 (CH3), –1.6 (CH3). IR (ATR-FTIR), cm–1: 2955(w), 1711
(m), 1606 (m), 1251 (s), 1166 (s), 1098 (m), 837 (s). HRMS-
ESI (m/z): [M + H]+ calcd for C14H21O3Si, 265.1260; found,
265.1273.
Preparation
of
(4-(tert-butyl)cyclohex-1-en-1-
yl)trimethylsilane (1v). This experiment was adapted
from the work of Adam and Richter.25 Chlorotrime-
thylsilane (3.43 mL, 27.0 mmol, 1.50 equiv) was added
dropwise to a suspension of sodium (1.03 g, 45 mmol, 2.5
equiv) in toluene (36 mL) at 24 C. The resulting mixture
98.2 (CH2), 37.4 (CH2). 34.4 (CH2), 24.3 (CH3). 1H and C
NMR data for N-(4-phenylbut-1-en-2-yl)acetamide (1s)
prepared in this way were in agreement with those previ-
ously described.35
13
was stirred at 24 C for 15 min.
4-(tert-butyl)-1-
Preparation
of
2-(trimethylsilyl)allyl
methoxybenzoate (1u). A solution of tert-butyllithium
in pentane (1.63 M, 3.42 mL, 5.59 mmol, 2.00 equiv) was
4-
chlorocyclohex-1-ene (3.12 mL, 18.0 mmol, 1 equiv) was
added dropwise to the reaction mixture. The reaction
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Page 14 of 32
equiv) was added dropwise at 0 C and the reaction mix-
vessel was placed in an oil bath that had been preheated
1
to 115 C. The reaction mixture was stirred and heated for
10 min at 115 C. The reaction mixture was allowed to cool
over 2 h to 24 C. The cooled product mixture was fil-
tered through a pad of silica gel and the pad was rinsed
with pentane (5 mL). The filtrates were combined and
the combined filtrates were concentrated. The residue
obtained was purified by reduced pressure distillation
(~50 C, ~300 mTorr) to afford (4-(tert-butyl)cyclohex-1-
en-1-yl)trimethylsilane (1v) as colorless oil that solidifies
at room temperature (757 mg, 20%). Rf = 0.81 (hexanes;
KMnO4). 1H NMR (400 MHz, CDCl3) δ 6.00 (br s, 1H),
2.21–2.16 (m, 1H), 2.11–2.01 (m, 2H), 1.87–1.79 (m, 2H), 1.29–
1.22 (m, 1H), 1.14–1.06 (m, 1H), 0.86 (s, 9H), 0.03 (s, 9H).
13C NMR (100 MHz, CDCl3) δ 138.2 (C), 135.9 (CH), 44.0
(CH), 32.2 (C), 28.6 (CH2), 28.4 (CH2), 27.1 (CH3), 24.3
(CH2), –2.2 (CH3). 1H and 13C NMR data for (4-(tert-
butyl)cyclohex-1-en-1-yl)trimethylsilane (1v) prepared in
this way were in agreement with those previously de-
scribed.25
ture was slowly warmed to 24 C over 4 h. Acetic acid
(5.0 mL) and zinc powder (497 mg, 7.60 mmol, 2.00 equiv)
were added to the reaction mixture at 24 C. The reaction
vessel was placed in an oil bath that had been preheated
to 60 C. The reaction mixture was stirred and heated for
2 h at 60 C. The product mixture was allowed to cool
over 20 min to 24 C. The cooled product mixture was
filtered through a pad of celite and the pad was rinsed
with hexanes (100 mL). The filtrates were combined and
the combined filtrates were concentrated. The residue
obtained was purified by automated flash-column chro-
matography (eluting with hexanes initially, grading to 5%
ether–hexanes, linear gradient) to afford 1-(4,4-
dichlorobut-3-en-1-yl)-4-methoxybenzene (11a) as a light
yellow oil (480 mg, 55%). Rf = 0.56 (5% ether–hexanes;
UV, CAM). 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H, J =
8.4 Hz), 6.84 (d, 2H, J = 8.4 Hz), 5.86 (t, 1H, J = 7.2 Hz),
3.80 (s, 3H), 2.67 (t, 2H, J = 7.8 Hz), 2.48–2.43 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 158.0 (C), 132.7 (C), 129.3 (CH),
129.0 (CH), 120.4 (C), 113.9 (CH), 55.3 (CH3), 33.3 (CH2),
31.5 (CH2). IR (ATR-FTIR), cm–1: 2933 (w), 1613 (w), 1511 (s),
1245 (s), 1037 (m), 878 (m), 818 (m). HRMS-EI (m/z): [M +
Na]+ calcd for C11H12Na35Cl2O, 253.0163; found, 253.0154.
2
3
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6
7
8
9
10
11
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37
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60
Preparation of propargyl 4-methoxybenzoate (1w).
4-Methoxybenzoyl chloride (938 mg, 5.50 mmol, 1.10
equiv) was added dropwise via syringe to a solution of
propargyl alcohol (280 mg, 5.00 mmol, 1 equiv) in pyri-
dine (20 mL) at 0 C. The reaction mixture was stirred for
30 min at 0 C, and then the ice bath was removed. The
reaction mixture was stirred for 24 h at 24 C. The prod-
uct mixture was transferred to a separatory funnel that
had been charged with ethyl acetate (20 mL). The diluted
product mixture was washed with saturated aqueous so-
dium bicarbonate solution (20 mL). The aqueous layer
was isolated and the isolated aqueous layer was extracted
with ethyl acetate (3  20 mL). The organic layers were
combined and the combined organic layers were dried
over sodium sulfate. The dried solution was filtered and
the filtrate was concentrated. The residue obtained was
purified by automated flash-column chromatography
(eluting with 5% ethyl acetate–hexanes, isocratic gradient)
to afford propargyl 4-methoxybenzoate (1w) as a white
Preparation
of
1-(4,4-diiodobut-3-en-1-yl)-4-
methoxybenzene (11c). This experiment was adapted
from the work of Charette and Cloarec.38 Potassium tert-
butoxide (525 mg, 4.68 mmol, 2.00 equiv) was added por-
tionwise to a solution of iodoform (1.84 mg, 4.68 mmol,
2.00 equiv) and triphenylphosphine (1.23 g, 4.68 mmol,
2.00 equiv) in toluene (12 mL) over 30 min at –20 C. The
reaction mixture was stirred for 30 min at –20 C. 3-(4-
Methoxyphenyl)propanal (384 mg, 2.34 mmol, 1 equiv)
was added dropwise at –20 C and the reaction mixture
was stirred for 30 min at –20 C. The product mixture
was filtered through a pad of celite and the pad was
rinsed with hexanes (100 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography (eluting with hexanes initially, grading
to 5% ether–hexanes, linear gradient) to afford 1-(4,4-
diiodobut-3-en-1-yl)-4-methoxybenzene (11c) as a white
solid (91.0 mg, 9%). Rf = 0.55 (5% ether–hexanes; UV,
solid (955 mg, 96%).
Rf = 0.49 (20% ethyl acetate–
1
hexanes; UV, KMnO4). mp 34−38 °C. H NMR (400 MHz,
CDCl3) δ 8.02 (d, 2H, J = 9.0 Hz), 6.92 (d, 2H, J = 9.0 Hz),
4.89 (br s, 2H), 3.87 (s, 3H), 2.51 (br s, 1H). 13C NMR (100
MHz, CDCl3) δ 165.5 (C), 163.6 (C), 131.9 (CH), 121.7 (C),
113.7 (CH), 78.0 (C), 74.8 (CH), 55.4 (CH3), 52.1 (CH2). 1H
and 13C NMR data for propargyl 4-methoxybenzoate (1w)
prepared in this way were in agreement with those previ-
ously described.36
1
CAM). mp 52−56 °C. H NMR (500 MHz, CD2Cl2) δ 7.11 (d,
2H, J = 8.0 Hz), 6.99 (t, 1H, J = 7.0 Hz), 6.84 (d, 2H, J = 8.0
Hz), 3.78 (s, 3H), 2.68 (t, 2H, J = 8.5 Hz), 2.24–2.19 (m, 2H).
13C NMR (100 MHz, CDCl3) δ 158.7 (C), 153.0 (CH), 133.1
(C), 129.8 (CH), 114.3 (CH), 55.7 (CH3), 42.0 (CH2), 33.0
(CH2), 12.8 (C). IR (ATR-FTIR), cm–1: 2931 (w), 1611 (w),
1511 (s), 1246 (s), 1177 (m), 1035 (m), 828 (m). HRMS-EI
(m/z): [M + Na]+ calcd for C11H12I2NaO, 436.8875; found,
436.8862.
Preparation
of
1-(4,4-dichlorobut-3-en-1-yl)-4-
methoxybenzene (11a). This experiment was adapted
from the work of Ichikawa and co-workers.37 Sodium tri-
chloroacetate (1.06 g, 5.70 mmol, 1.50 equiv) was added
portionwise to a solution of trichloroacetic acid (931 mg,
5.70 mmol, 1.50 equiv) and 3-(4-methoxyphenyl)propanal
(624 mg, 3.80 mmol, 1 equiv) in N,N-dimethylformamide
(5.5 mL) over 30 min at 24 C. The reaction mixture was
stirred for 4 h at 24 C and the resulting mixture was
cooled to 0 C. Acetic anhydride (718 μL, 7.60 mmol, 2.00
Preparation
of
1-(2,2-dibromovinyl)-4-
methoxybenzene (11d). Carbon tetrabromide (3.32 g,
10.0 mmol, 2.00 equiv) was added to a solution of p-
anisaldehyde (681 mg, 5.00 mmol, 1 equiv) in dichloro-
methane (12 mL) at 0 C. Triphenylphosphine (5.25 g,
20.0 mmol, 4.00 equiv) was added portionwise to the re-
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ford 1-bromo-4-(2,2-dibromovinyl)benzene (11f) as an off-
action mixture over 1 h at 0 C. The reaction mixture was
1
white solid (1.21 g, 95%). Rf = 0.76 (10% ether–hexanes;
stirred for 3 h at 0 C. The product mixture was diluted
sequentially with ether (200 mL) and pentane (200 mL).
The diluted product mixture was filtered through a pad of
silica gel and the pad was rinsed with 50% ether–pentane
(500 mL). The filtrates were combined and the combined
filtrates were concentrated. The residue obtained was
purified by automated flash-column chromatography
(eluting with hexanes initially, grading to 5% ether–
hexanes, linear gradient) to afford 1-(2,2-dibromovinyl)-4-
methoxybenzene (11d) as an off-white solid (1.37 g, 94%).
Rf = 0.57 (10% ether–hexanes; UV, CAM). mp 36−38 °C.
1H NMR (400 MHz, CDCl3) δ 7.51 (d, 2H, J = 8.8 Hz), 7.41
(s, 1H), 6.89 (d, 2H, J = 8.8 Hz), 3.82 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 159.7 (C), 136.3 (CH), 129.9 (CH), 127.8 (C),
1
2
3
4
5
6
7
8
9
UV). mp 28−30 °C. H NMR (400 MHz, CDCl3) δ 7.49 (d,
2H, J = 8.4 Hz), 7.41–7.39 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ 135.7 (CH), 134.1 (C), 131.6 (CH), 129.9 (CH), 122.6
(C), 90.5 (C). 1H and 13C NMR data for 1-bromo-4-(2,2-
dibromovinyl)benzene (11f) prepared in this way were in
agreement with those previously described.41
Preparation
of
1-cyano-4-(2,2-
dibromovinyl)benzene (11g).
Carbon tetrabromide
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2.32 g, 7.00 mmol, 2.00 equiv) was added to a solution of
4-cyanobenzaldehyde (459 mg, 3.50 mmol, 1 equiv) in
dichloromethane (10 mL) at 0 C. Triphenylphosphine
(3.67 g, 14.0 mmol, 4.00 equiv) was added portionwise to
the reaction mixture over 1 h at 0 C. The reaction mix-
ture was stirred for 3 h at 0 C. The product mixture was
diluted sequentially with ether (200 mL) and pentane
(200 mL). The diluted product mixture was filtered
through a pad of silica gel and the pad was rinsed with
50% ether–pentane (500 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography (eluting with hexanes, isocratic gradient)
to afford 1-cyano-4-(2,2-dibromovinyl)benzene (11g) as an
off-white solid (594 mg, 59%). Rf = 0.76 (10% ether–
hexanes; UV). mp 82−86 °C. 1H NMR (400 MHz, CDCl3)
δ 7.67–7.62 (m, 4H), 7.50 (s, 1H). 13C NMR (100 MHz,
CDCl3) δ 139.6 (C), 135.2 (CH), 132.2 (CH), 128.9 (CH), 118.5
113.8 (CH), 87.3 (C), 55.3 (CH3). H and 13C NMR data for 1-
1
(2,2-dibromovinyl)-4-methoxybenzene (11d) prepared in
this way were in agreement with those previously de-
scribed.39
Preparation
of
methyl
4-(2,2-
dibromovinyl)benzoate (11e). Carbon tetrabromide
(3.32 g, 10.0 mmol, 2.00 equiv) was added to a solution of
methyl 4-formylbenzoate (821 mg, 5.00 mmol, 1 equiv) in
dichloromethane (12 mL) at 0 C. Triphenylphosphine
(5.25 g, 20.0 mmol, 4.00 equiv) was added portionwise to
the reaction mixture over 1 h at 0 C. The reaction mix-
ture was stirred for 3 h at 0 C. The product mixture was
diluted sequentially with ether (200 mL) and pentane
(200 mL). The diluted product mixture was filtered
through a pad of silica gel and the pad was rinsed with
50% ether–pentane (500 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography (eluting with 2.5% ether–hexanes, iso-
13
(C), 112.0 (C), 93.4 (C). 1H and C NMR data for 1-cyano-
4-(2,2-dibromovinyl)benzene (11g) prepared in this way
were in agreement with those previously described.41
Preparation
of
1-nitro-4-(2,2-
dibromovinyl)benzene (11h).
Carbon tetrabromide
(2.32 g, 7.00 mmol, 2.00 equiv) was added to a solution of
4-nitrobenzaldehyde (529 mg, 3.50 mmol, 1 equiv) in di-
chloromethane (10 mL) at 0 C. Triphenylphosphine (3.67
g, 14.0 mmol, 4.00 equiv) was added portionwise to the
reaction mixture over 1 h at 0 C. The reaction mixture
was stirred for 3 h at 0 C. The product mixture was di-
luted sequentially with ether (200 mL) and pentane (200
mL). The diluted product mixture was filtered through a
pad of silica gel and the pad was rinsed with 50% ether–
pentane (500 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 10% ether–hexanes, isocratic gra-
dient) to afford 1-nitro-4-(2,2-dibromovinyl)benzene (11h)
as a light yellow solid (563 mg, 58%). Rf = 0.70 (10%
ether–hexanes; UV). mp 87−90 °C. 1H NMR (400 MHz,
CDCl3) δ 8.22 (d, 2H, J = 8.8 Hz), 7.69 (d, 2H, J = 8.8 Hz),
7.55 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 147.2 (C), 141.4
cratic
gradient)
to
afford
methyl
4-(2,2-
dibromovinyl)benzoate (11e) as a white solid (1.37 g, 86%).
Rf = 0.35 (10% ether–hexanes; UV). mp 67−70 °C. 1H
NMR (400 MHz, CDCl3) δ 8.02 (d, 2H, J = 8.4 Hz), 7.59 (d,
2H, J = 8.4 Hz), 7.51 (s, 1H), 3.92 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 166.5 (C), 139.6 (C), 136.0 (CH), 129.8 (C),
129.6 (CH), 128.3 (CH), 91.9 (C), 52.2 (CH3). 1H and 13C
NMR data for methyl 4-(2,2-dibromovinyl)benzoate (11e)
prepared in this way were in agreement with those previ-
ously described.40
Preparation
of
1-bromo-4-(2,2-
dibromovinyl)benzene (11f). Carbon tetrabromide (2.32
g, 7.00 mmol, 2.00 equiv) was added to a solution of 4-
bromobenzaldehyde (648 mg, 3.50 mmol, 1 equiv) in di-
chloromethane (10 mL) at 0 C. Triphenylphosphine (3.67
g, 14.0 mmol, 4.00 equiv) was added portionwise to the
reaction mixture over 1 h at 0 C. The reaction mixture
was stirred for 3 h at 0 C. The product mixture was di-
luted sequentially with ether (200 mL) and pentane (200
mL). The diluted product mixture was filtered through a
pad of silica gel and the pad was rinsed with 50% ether–
pentane (500 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with hexanes, isocratic gradient) to af-
1
(C), 134.9 (CH), 129.2 (CH), 123.7 (CH), 94.1 (C). H and 13C
NMR data for 1-nitro-4-(2,2-dibromovinyl)benzene (11h)
prepared in this way were in agreement with those previ-
ously described.41
Preparation of 2-(4-(2,2-dibromovinyl)phenyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11i). Carbon
tetrabromide (1.16 g, 3.50 mmol, 2.00 equiv) was added to
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Page 16 of 32
a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
flash-column chromatography (eluting with 10% ether–
hexanes, isocratic gradient) to afford 1-(2,2-
1
2
3
4
5
6
7
8
yl)benzaldehyde (406 mg, 1.75 mmol, 1 equiv) in di-
chloromethane (10 mL) at 0 C. Triphenylphosphine (1.84
g, 7.00 mmol, 4.00 equiv) was added portionwise to the
reaction mixture over 1 h at 0 C. The reaction mixture
was stirred for 3 h at 0 C. The product mixture was di-
luted sequentially with ether (200 mL) and pentane (200
mL). The diluted product mixture was filtered through a
pad of silica gel and the pad was rinsed with 50% ether–
pentane (500 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 2.5% ether–hexanes, isocratic gra-
dient) to afford 2-(4-(2,2-dibromovinyl)phenyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (11i) as an off-white solid
(583 mg, 86%). Rf = 0.76 (10% ether–hexanes; UV). mp
dibromovinyl)naphthalene (11k) as a light yellow solid
(815 mg, 75%). Rf = 0.70 (10% ether–hexanes; UV). mp
1
45−47 °C. H NMR (400 MHz, CDCl3) δ 7.93–7.87 (m, 4H),
7.63–7.49 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 135.9
(CH), 133.5 (C), 133.2 (C), 130.7 (C), 128.9 (CH), 128.6 (CH),
126.8 (CH), 126.6 (CH), 126.2 (CH), 125.3 (CH), 124.2 (CH),
92.9 (C).
1H and 13C NMR data for 1-(2,2-
9
dibromovinyl)naphthalene (11k) prepared in this way
were in agreement with those previously described.41
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Preparation of 1-(2,2-dibromovinyl)-2-iodobenzene
(11l). Carbon tetrabromide (2.32 g, 7.00 mmol, 2.00 equiv)
was added to a solution of 1-naphthaldehyde (547 mg,
3.50 mmol, 1 equiv) in dichloromethane (10 mL) at 0 C.
Triphenylphosphine (3.67 g, 14.0 mmol, 4.00 equiv) was
added portionwise to the reaction mixture over 1 h at 0 C.
The reaction mixture was stirred for 3 h at 0 C. The
product mixture was diluted sequentially with ether (200
mL) and pentane (200 mL). The diluted product mixture
was filtered through a pad of silica gel and the pad was
rinsed with 50% ether–pentane (500 mL). The filtrates
were combined and the combined filtrates were concen-
trated. The residue obtained was purified by automated
flash-column chromatography (eluting with 10% ether–
1
34−35 °C. H NMR (400 MHz, CDCl3) δ 7.81 (d, 2H, J = 8.8
Hz), 7.53–7.50 (m, 3H), 1.35 (s, 12H). 13C NMR (100 MHz,
CDCl3) 137.9 (C), 136.9 (CH), 134.8 (CH), 127.6 (C, CH),
90.4 (C), 83.9 (C), 24.9 (CH3). IR (ATR-FTIR), cm–1: 2978
(w), 1608 (w), 1356 (s), 1142 (s), 1089 (s), 857 (m), 654 (m).
HRMS-EI (m/z): [M + Na]+ calcd for C14H17B79Br2NaO2,
408.9586; found, 408.9584.
Preparation
of
1-(2,2-dibromovinyl)-4-
(trifluoromethyl)benzene (11j). Carbon tetrabromide
(2.32 g, 7.00 mmol, 2.00 equiv) was added to a solution of
4-nitrobenzaldehyde (529 mg, 3.50 mmol, 1 equiv) in di-
chloromethane (10 mL) at 0 C. Triphenylphosphine (3.67
g, 14.0 mmol, 4.00 equiv) was added portionwise to the
reaction mixture over 1 h at 0 C. The reaction mixture
was stirred for 3 h at 0 C. The product mixture was di-
luted sequentially with ether (200 mL) and pentane (200
mL). The diluted product mixture was filtered through a
pad of silica gel and the pad was rinsed with 50% ether–
pentane (500 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 10% ether–hexanes, isocratic gra-
hexanes,
isocratic
gradient)
to
afford
1-(2,2-
dibromovinyl)-2-iodobenzene (11l) as a light yellow oil
(626 mg, 81%). Rf = 0.70 (10% ether–hexanes; UV). 1H
NMR (400 MHz, CDCl3) δ 7.87 (d, 1H, J = 8.0 Hz), 7.60 (d,
1H, J = 7.8 Hz), 7.41 (s, 1H), 7.37 (t, 1H, J = 7.8 Hz), 7.04 (t,
1H, J = 7.8 Hz). 13C NMR (100 MHz, CDCl3) δ 140.8 (CH),
139.9 (C), 139.0 (CH), 130.0 (CH), 129.9 (CH), 128.0 (CH),
98.4 (C), 93.3 (C). 1H and 13C NMR data for 1-(2,2-
dibromovinyl)-2-iodobenzene (11l) prepared in this way
were in agreement with those previously described.42
Preparation
of
2-(2,2-dibromovinyl)-1,3,5-
trimethylbenzene (11m). Carbon tetrabromide (2.32 g,
7.00 mmol, 2.00 equiv) was added to a solution of me-
sitaldehyde (516 μL, 3.50 mmol, 1 equiv) in dichloro-
methane (10 mL) at 0 C. Triphenylphosphine (3.67 g,
14.0 mmol, 4.00 equiv) was added portionwise to the reac-
tion mixture over 1 h at 0 C. The reaction mixture was
stirred for 3 h at 0 C. The product mixture was diluted
sequentially with ether (200 mL) and pentane (200 mL).
The diluted product mixture was filtered through a pad of
silica gel and the pad was rinsed with 50% ether–pentane
(500 mL). The filtrates were combined and the combined
filtrates were concentrated. The residue obtained was
purified by automated flash-column chromatography
(eluting with 10% ether–hexanes, isocratic gradient) to
afford 2-(2,2-dibromovinyl)-1,3,5-trimethylbenzene (11m)
as a white solid (740 mg, 69%). Rf = 0.70 (10% ether–
dient)
to
afford
1-(2,2-dibromovinyl)-4-
(trifluoromethyl)benzene (11j) as a light yellow solid (869
mg, 75%). Rf = 0.73 (10% ether–hexanes; UV). 1H NMR
(400 MHz, CDCl3) δ 7.63 (s, 4H), 7.51 (s, 1H). 19F NMR
1
(375 MHz, CDCl3) δ –62.8. H and 19F NMR data for 1-(2,2-
dibromovinyl)-4-(trifluoromethyl)benzene (11j) prepared
in this way were in agreement with those previously de-
scribed.39
Preparation of 1-(2,2-dibromovinyl)naphthalene
(11k). Carbon tetrabromide (2.32 g, 7.00 mmol, 2.00 equiv)
was added to a solution of 1-naphthaldehyde (547 mg,
3.50 mmol, 1 equiv) in dichloromethane (10 mL) at 0 C.
Triphenylphosphine (3.67 g, 14.0 mmol, 4.00 equiv) was
added portionwise to the reaction mixture over 1 h at 0 C.
The reaction mixture was stirred for 3 h at 0 C. The
product mixture was diluted sequentially with ether (200
mL) and pentane (200 mL). The diluted product mixture
was filtered through a pad of silica gel and the pad was
rinsed with 50% ether–pentane (500 mL). The filtrates
were combined and the combined filtrates were concen-
trated. The residue obtained was purified by automated
1
hexanes; UV). mp 53−54 °C. H NMR (400 MHz, CDCl3) δ
7.39 (s, 1H), 6.90 (s, 2H), 2.30 (s, 3H), 2.23 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ 137.8 (C), 137.5 (CH), 135.6 (C),
132.9 (C), 128.2 (CH), 92.7 (C), 21.1 (CH3), 19.9 (CH3). 1H
and 13C NMR data for 2-(2,2-dibromovinyl)-1,3,5-
trimethylbenzene (11m) prepared in this way were in
agreement with those previously described.43
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The Journal of Organic Chemistry
Preparation of benzyl (4,4-dibromo-1-phenylbut-3-
light yellow oil (941 mg, 97%). Rf = 0.23 (10% ether–
hexanes; UV). H NMR (400 MHz, CDCl3) δ 7.39–7.31 (m,
1
1
2
3
4
5
6
7
8
en-2-yl)carbamate (11n). Triphenylphosphine (2.62 g,
10.0 mmol, 4.00 equiv) was added portionwise to a solu-
tion of carbon tetrabromide (1.66 g, 5.00 mol, 2.00 equiv)
in dichloromethane (15 mL) over 1 h at 0 C. The ice bath
was removed and the resulting mixture was stirred for 1 h
at 24 C. The ylide solution was cooled to –78 C and a
solution of benzyl (1-oxo-3-phenylpropan-2-yl)carbamate
(708 mg, 2.50 mmol, 1 equiv) in dichloromethane (5.0 mL)
was added dropwise via syringe over 15 min at –78 C.
The reaction mixture was stirred for 30 min at –78 C and
the resulting mixture was allowed to warm up 24 C over
2 h. The product mixture was transferred to a separatory
funnel that had been charged with ethyl acetate (20 mL).
The diluted product mixture was washed with water (20
mL). The aqueous layer was isolated and the isolated
aqueous layer was extracted with ethyl acetate (3  20
mL). The organic layers were combined and the com-
bined organic layers were dried over sodium sulfate. The
dried solution was filtered and the filtrate was concen-
trated. The residue obtained was purified by automated
flash-column chromatography (eluting with 30% ether–
hexanes, isocratic gradient) to afford benzyl (4,4-
dibromo-1-phenylbut-3-en-2-yl)carbamate (11n) as an off-
white solid (599 mg, 64%). Rf = 0.23 (30% ether–hexanes;
UV). mp 102−107 °C. 1H NMR (400 MHz, CDCl3) δ 7.39–
7.16 (m, 10H), 6.41 (br s, 1H), 5.08 (s, 2H), 4.91 (br s, 1H),
4.59–4.56 (m, 1H), 2.92–2.87 (m, 2H). 13C NMR (100 MHz,
CDCl3) 155.4 (C), 138.0 (CH), 136.2 (C), 136.1 (C), 129.5 (CH),
128.7 (CH), 128.5 (CH), 128.2 (CH), 128.1 (CH), 127.0 (CH),
91.6 (C), 66.9 (CH2), 54.9 (CH), 39.6 (CH2). IR (ATR-
FTIR), cm–1: 3363 (w), 1689 (s), 1523 (m), 1236 (m), 1021 (m),
5H), 5.15 (s, 2H), 3.53 (t, 4H, J = 5.8 Hz), 2.50 (t, 4H, J = 5.8
Hz). 13C NMR (100 MHz, CDCl3) 155.1 (C), 140.1 (CH), 136.6
(C), 133.8 (C), 128.5 (CH), 127.9 (CH), 85.3 (C), 67.3 (CH2),
43.3 (CH2), 33.9 (CH2). IR (ATR-FTIR), cm–1: 2903 (w),
1695 (s), 1422 (m), 1279 (m), 1213 (s), 1110 (m), 990 (m).
HRMS-EI (m/z): [M + Na]+ calcd for C14H1579Br2NNaO2,
409.9367; found, 409.9368.
9
Hydrogenation
of
2-Chloroallyl
4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methoxybenzoate (1a, Scheme 2). A 10-mL round-
bottomed flask fitted with a rubber septum was charged
sequentially with 2-chloroallyl 4-methoxybenzoate (1a,
56.7 mg, 250 μmol, 1 equiv) and cobalt bis(acetylacetonate)
(64.3 mg, 250 μmol, 1 equiv). A 16-gauge needle was pene-
trated through the septum to maintain the reaction mix-
ture under air (atmospheric pressure). n-Propanol (830
μL), 1,4-cyclohexadiene (119 μL, 1.25 mmol, 5.00 equiv), a
solution of tert-butyl hydroperoxide in nonane (~5.5 M,
45.5 μL, 250 μmol, 1.00 equiv), and triethylsilane (200 μL,
1.25 mmol, 5.00 equiv) were then added sequentially to
the reaction vessel via syringe. The reaction mixture was
stirred at 24 C until the consumption of 1a was complete
(as determined by TLC analysis, 40 min for 1a). The
product mixture was concentrated to dryness and the
residue obtained was purified by automated flash-column
chromatography (eluting with 5% ethyl acetate–hexanes
initially, grading to 10% ethyl acetate–hexanes, linear gra-
dient) to afford 2-chloropropyl 4-methoxybenzoate (2,
colorless oil, 35.5 mg, 62%). Rf = 0.52 (20% ethyl acetate–
1
hexanes; UV). H NMR (500 MHz, CDCl3) δ 8.02 (d, 2H, J
= 9.0 Hz), 6.93 (d, 2H, J = 9.0 Hz), 4.42–4.38 (m, 2H),
4.34–4.27 (m, 1H), 3.87 (s, 3H), 1.60 (d, 3H, J = 6.5 Hz). 13C
NMR (150 MHz, CDCl3) δ 165.6 (C), 163.4 (C), 131.7 (CH),
121.9 (C), 113.6 (CH), 68.6 (CH2), 55.3 (CH3), 54.1 (CH), 21.5
(CH3). IR (ATR-FTIR), cm–1: 2936 (w), 1712 (m), 1605 (m),
1252 (s), 1167 (s). HRMS-ESI (m/z): [M+H]+ calcd for
C11H1435/37ClO3, 229.0631/231.0602; found, 229.0638/231.0614.
706 (m).
C18H1779Br2NNaO2, 459.9524; found, 459.9557.
Preparation of benzyl 4-(1-bromo-2,2-
HRMS-EI (m/z): [M +
Na]+ calcd for
dimethylpropylidene)piperidine-1-carboxylate (11o).
Triphenylphosphine (2.62 g, 10.0 mmol, 4.00 equiv) was
added portionwise to a solution of carbon tetrabromide
(1.66 g, 5.00 mol, 2.00 equiv) in dichloromethane (15 mL)
over 1h at 0 C. The ice bath was removed and the result-
ing mixture was stirred for 1 h at 24 C. The ylide solution
was cooled to –78 C and a solution of benzyl 4-
oxopiperidine-1-carboxylate (583 mg, 2.50 mmol, 1 equiv)
in dichloromethane (5.0 mL) was added dropwise via sy-
ringe over 15 min at –78 C. The reaction mixture was
stirred for 30 min at –78 C and the resulting mixture was
allowed to warm up 24 C over 2 h. The product mixture
was transferred to a separatory funnel that had been
charged with ethyl acetate (20 mL). The diluted product
mixture was washed with water (20 mL). The aqueous
layer was isolated and the isolated aqueous layer was ex-
tracted with ethyl acetate (3  20 mL). The organic layers
were combined and the combined organic layers were
dried over sodium sulfate. The dried solution was filtered
and the filtrate was concentrated. The residue obtained
was purified by automated flash-column chromatography
(eluting with 10% ether–hexanes, isocratic gradient) to
Hydrogenation
of
2-Chloroallyl
4-
Methoxybenzoate (1a) in n-Propanol (Scheme 2).
A
10-mL round-bottomed flask fitted with a rubber septum
was charged sequentially with 2-chloroallyl 4-
methoxybenzoate (1a, 56.7 mg, 250 μmol, 1 equiv) and
cobalt bis(acetylacetonate) (64.3 mg, 250 μmol, 1 equiv).
A 16-gauge needle was penetrated through the septum to
maintain the reaction mixture under air (atmospheric
pressure). n-Propanol (830 μL), a solution of tert-butyl
hydroperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv), and triethylsilane (200 μL, 1.25 mmol, 5.00 equiv)
were then added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred at 24 C until
the consumption of 1a was complete (as determined by
TLC analysis, 40 min for 1a). The product mixture was
concentrated to dryness and the residue obtained was
purified by automated flash-column chromatography
(eluting with 5% ethyl acetate–hexanes initially, grading
to 10% ethyl acetate–hexanes, linear gradient) to afford 2-
oxopropyl 4-methoxybenzoate (3a, colorless oil, 24.6 mg,
47%).
afford
benzyl
4-(1-bromo-2,2-
dimethylpropylidene)piperidine-1-carboxylate (11o) as a
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Condition Optimization for the Hydrolysis (Table 1,
separately 2-oxopropyl 4-methoxybenzoate (3a, colorless
oil, 39.5 mg, 76%) and 2-bromopropyl 4-methoxybenzoate
(5, cleaer oil, 6.8 mg, 10%). 2-Bromopropyl 4-
1
2
3
4
5
6
7
8
Entry 1). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv) and cobalt bis(acetylacetonate) (64.3 mg, 250 μmol,
1.00 equiv). A 16-gauge needle was penetrated through
the septum. n-Propanol (830 μL), triethylsilane (199 μL,
1.25 mmol, 5.00 equiv), and a solution of tert-butyl hy-
droperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred at 24 C until
the consumption of 1b was complete (as determined by
TLC analysis, 3.5 h for 1b). The product mixture was con-
centrated to dryness and the residue obtained was filtered
through a short column of silica gel and the short column
was rinsed with 50% ethyl acetate–hexanes (100 mL). The
filtrates were combined and the combined filtrates were
methoxybenzoate (5): Rf = 0.45 (20% ethyl acetate–
1
hexanes; UV). H NMR (500 MHz, CD2Cl2) δ 8.01 (d, 2H, J
= 9.0 Hz), 6.95 (d, 2H, J = 9.0 Hz), 4.49–4.35 (m, 3H), 3.86
(s, 3H), 1.77 (d, 3H, J = 6.5 Hz). 13C NMR (125 MHz, CD2Cl2)
δ 166.0 (C), 164.3 (C), 132.2 (CH), 122.7 (C), 114.3 (CH), 69.5
(CH2), 56.1 (CH3), 46.1 (CH), 23.0 (CH3). IR (ATR-FTIR),
cm–1: 2931 (w), 1714 (m), 1605 (m), 1254 (s), 1167 (s).
HRMS-ESI (m/z): [M + Na]+ calcd for C11H1379/81BrNaO3,
294.9946/296.9925; found, 294.9944/296.9909.
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Condition Optimization for the Hydrolysis (Table 1,
Entry 3). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv) and cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol,
0.25 equiv). A 16-gauge needle was penetrated through
the septum. N,N-Dimethylformamide (830 μL), tri-
ethylsilane (199 μL, 1.25 mmol, 5.00 equiv), and a solution
of tert-butyl hydroperoxide in nonane (~5.5 M, 45.5 μL,
250 μmol, 1.00 equiv) were added sequentially to the reac-
tion vessel via syringe. The reaction mixture was stirred
for 24 h at 24 C. The product mixture was concentrated
to dryness and the residue obtained was filtered through
a short column of silica gel and the short column was
rinsed with 50% ethyl acetate–hexanes (100 mL). The
filtrates were combined and the combined filtrates were
1
concentrated. H NMR analysis of the unpurified product
mixture using mesitylene as an internal standard revealed
an 8% yield of 2,2-dibromopropyl 4-methoxybenzoate (4).
The NMR sample was concentrated to dryness and the
residue obtained was purified by automated flash-column
chromatography (eluting with 2% ethyl acetate–hexanes
initially, grading to 40% ethyl acetate–hexanes, linear
gradient) to afford 2-oxopropyl 4-methoxybenzoate (3a,
colorless oil, 35.4 mg, 68%).
2-Oxopropyl 4-
methoxybenzoate (3a): Rf = 0.27 (20% ethyl acetate–
1
hexanes; UV). H NMR (400 MHz, CD2Cl2) δ 8.03 (d, 2H, J
= 8.8 Hz), 6.96 (d, 2H, J = 8.8 Hz), 4.83 (s, 2H), 3.86 (s,
3H), 2.19 (s, 3H). 13C NMR (100 MHz, CD2Cl2) δ 202.2 (C),
165.9 (C), 164.4 (C), 132.3 (CH), 122.2 (C), 114.3 (CH), 69.1
(CH2), 56.1 (CH3), 26.5 (CH3). IR (ATR-FTIR), cm–1: 2937
(w), 1714 (s), 1606 (m), 1256 (s), 1167 (m). HRMS-ESI (m/z):
[M+Na]+ calcd for C11H12NaO4, 231.0633; found, 231.0632.
1
concentrated. H NMR analysis of the unpurified product
mixture using mesitylene as an internal standard revealed
a 48% yield of 2-bromoallyl 4-methoxybenzoate (1b) and
a 46% yield of 2-oxopropyl 4-methoxybenzoate (3a).
Condition Optimization for the Hydrolysis (Table 1,
Entry 4). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv) and cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol,
0.25 equiv). A 16-gauge needle was penetrated through
the septum. N,N-Dimethylformamide (830 μL), isoamyl-
ene (132 μL, 1.25 mmol, 5.00 equiv), triethylsilane (199 μL,
1.25 mmol, 5.00 equiv), and a solution of tert-butyl hy-
droperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred for 24 h at 24 C.
The product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. 1H NMR
analysis of the unpurified product mixture using mesity-
lene as an internal standard revealed a 45% yield of 2-
bromoallyl 4-methoxybenzoate (1b) and a 41% yield of 2-
oxopropyl 4-methoxybenzoate (3a).
Condition Optimization for the Hydrolysis (Table 1,
Entry 2). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv) and cobalt bis(acetylacetonate) (64.3 mg, 250 μmol,
1.00 equiv). A 16-gauge needle was penetrated through
the septum. N,N-Dimethylformamide (830 μL), tri-
ethylsilane (199 μL, 1.25 mmol, 5.00 equiv), and a solution
of tert-butyl hydroperoxide in nonane (~5.5 M, 45.5 μL,
250 μmol, 1.00 equiv) were added sequentially to the reac-
tion vessel via syringe. The reaction mixture was stirred
at 24 C until the consumption of 1b was complete (as
determined by TLC analysis, 3 h for 1b). The product
mixture was concentrated to dryness and the residue ob-
tained was filtered through a short column of silica gel
and the short column was rinsed with 50% ethyl acetate–
hexanes (100 mL). The filtrates were combined and the
combined filtrates were concentrated. 1H NMR analysis
of the unpurified product mixture using mesitylene as an
internal standard revealed
a
3% yield of 2,2-
Condition Optimization for the Hydrolysis (Table 1,
Entry 5). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv), lithium acetylacetoante (39.8 mg, 375 μmol, 1.50
equiv), and cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol,
dibromopropyl 4-methoxybenzoate (4). The NMR sample
was concentrated to dryness and the residue obtained was
purified by automated flash-column chromatography
(eluting with 2% ethyl acetate–hexanes initially, grading
to 40% ethyl acetate–hexanes, linear gradient) to afford
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The Journal of Organic Chemistry
0.25 equiv). A 16-gauge needle was penetrated through ethyl acetate–hexane initially, grading to 40% ethyl ace-
1
2
3
4
5
6
7
8
the septum. N,N-Dimethylformamide (830 μL), tri-
ethylsilane (199 μL, 1.25 mmol, 5.00 equiv), and a solution
of tert-butyl hydroperoxide in nonane (~5.5 M, 45.5 μL,
250 μmol, 1.00 equiv) were added sequentially to the reac-
tion vessel via syringe. The reaction mixture was stirred
for 24 h at 24 C. The product mixture was concentrated
to dryness and the residue obtained was filtered through
a short column of silica gel and the short column was
rinsed with 50% ethyl acetate–hexanes (100 mL). The
filtrates were combined and the combined filtrates were
tate–hexanes, linear gradient) to afford 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 44.3 mg, 85%).
Condition Optimization for the Hydrolysis (Table 1,
Entry 8). This experiment was adapted from the work of
Mukaiyama and co-workers.44 A 10-mL round-bottomed
flask fitted with a rubber septum was charged sequential-
ly with 2-bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250
μmol, 1 equiv) and cobalt bis(acetylacetonate) (6.4 mg, 25
μmol, 0.100 equiv). The reaction vessel was evacuated
and refilled using a balloon of dioxygen. This process was
repeated two times. Tetrahydrofuran (1.25 mL) and
phenylsilane (154 μL, 1.25 mmol, 5.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 24 h at 24 C. The product
mixture was concentrated to dryness and the residue ob-
tained was filtered through a short column of silica gel
and the short column was rinsed with 50% ethyl acetate–
hexanes (100 mL). The filtrates were combined and the
combined filtrates were concentrated. 1H NMR analysis
of the unpurified product mixture using mesitylene as an
internal standard revealed a 38% yield of 2-bromoallyl 4-
methoxybenzoate (1b). The residue obtained was purified
by automated flash-column chromatography (eluting
with 5% ethyl acetate–hexane initially, grading to 40%
ethyl acetate–hexanes, linear gradient) to afford separate-
ly 2-oxopropyl 4-methoxybenzoate (3a, colorless oil, 10.4
mg, 20%) and 2,2-dibromopropyl 4-methoxybenzoate (4,
colorless oil, 34.4 mg, 39%). 2,2-Dibromopropyl 4-
methoxybenzoate (4): Rf = 0.43 (20% ethyl acetate–
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1
concentrated. H NMR analysis of the unpurified product
mixture using mesitylene as an internal standard revealed
an 84% yield of 2-bromoallyl 4-methoxybenzoate (1b) and
a 15% yield of 2-oxopropyl 4-methoxybenzoate (3a).
Condition Optimization for the Hydrolysis (Table 1,
Entry 6). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv), lithium acetylacetoante (39.8 mg, 375 μmol, 1.50
equiv), and cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol,
0.25 equiv). The reaction vessel was evacuated and re-
filled using a balloon of dioxygen. This process was re-
peated two times. Methanol (830 μL), triethylsilane (199
μL, 1.25 mmol, 5.00 equiv), and a solution of tert-butyl
hydroperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred at 24 C until
the consumption of 1b was complete (as determined by
TLC analysis, 24 h for 1b). The product mixture was con-
centrated to dryness and the residue obtained was filtered
through a short column of silica gel and the short column
was rinsed with 50% ethyl acetate–hexanes (100 mL). The
filtrates were combined and the combined filtrates were
concentrated. The residue obtained was purified by au-
tomated flash-column chromatography (eluting with 5%
ethyl acetate–hexane initially, grading to 40% ethyl ace-
tate–hexanes, linear gradient) to afford 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 42.2 mg, 81%).
1
hexanes; UV). H NMR (500 MHz, CD2Cl2) δ 8.05 (d, 2H, J
= 8.5 Hz), 6.97 (d, 2H, J = 8.5 Hz), 4.75 (s, 2H), 3.87 (s, 3H),
2.56 (s, 3H). 13C NMR (125 MHz, CD2Cl2) δ 165.3 (C), 164.5
(C), 132.4 (CH), 122.1 (C), 114.4 (CH), 74.7 (CH2), 61.7 (C),
56.1 (CH3), 37.8 (CH3). IR (ATR-FTIR), cm–1: 2933 (w), 1719
(m), 1605 (m), 1254 (m), 1091 (m). HRMS-ESI (m/z): [M +
H]+ calcd for C11H1379/81Br2O3, 350.9231/352.9211/354.9191;
found, 350.9240/352.9212/354.9185.
Representative Formal Hydrolysis Procedure A
(Table 2, 3, and 4). A 10-mL round-bottomed flask fitted
with a rubber septum was charged sequentially with the
substrate (250 μmol, 1 equiv), lithium acetylacetoante
(39.8 mg, 375 μmol, 1.50 equiv), and cobalt
bis(acetylacetonate) (16.1 mg, 62.5 μmol, 0.25 equiv). The
reaction vessel was evacuated and refilled using a balloon
of dioxygen. This process was repeated two times. Meth-
anol (830 μL), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred at 24 C until the consumption of
substrate was complete (as determined by TLC analysis).
The product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. Conver-
sions were judged based on 1H NMR analyses of the unpu-
rified product mixtures using mesitylene as an internal
Condition Optimization for the Hydrolysis (Table 1,
Entry 7). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 2-
bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1
equiv) and cobalt bis(acetylacetonate) (64.3 mg, 250 μmol,
1.00 equiv). The reaction vessel was evacuated and re-
filled using a balloon of dioxygen. This process was re-
peated two times. Methanol (830 μL), triethylsilane (199
μL, 1.25 mmol, 5.00 equiv), and a solution of tert-butyl
hydroperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred at 24 C until
the consumption of 1b was complete (as determined by
TLC analysis, 12 h for 1b). The product mixture was con-
centrated to dryness and the residue obtained was filtered
through a short column of silica gel and the short column
was rinsed with 50% ethyl acetate–hexanes (100 mL). The
filtrates were combined and the combined filtrates were
concentrated. The residue obtained was purified by au-
tomated flash-column chromatography (eluting with 5%
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The Journal of Organic Chemistry
Page 20 of 32
standard. The NMR sample was concentrated to dryness. using 2-bromoallyl 4-methoxybenzoate (1b, 67.8 mg, 250
1
2
3
4
5
6
7
8
The residue obtained was purified by automated flash-
column chromatography to afford the hydrolysis product.
μmol, 1 equiv). Reaction time was 24 h. Purification by
automated flash-column chromatography (eluting with 5%
ethyl acetate–hexanes initially, grading to 40% ethyl ace-
tate–hexanes, linear gradient) afforded 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 42.2 mg, 81%).
Representative Formal Hydrolysis Procedure B
(Table 2, 3, and 4). A 10-mL round-bottomed flask fitted
with a rubber septum was charged sequentially with the
substrate
(250
μmol,
1
equiv)
and
cobalt
Following the general procedure B using 2-bromoallyl
4-methoxybenzoate (1b, 67.8 mg, 250 μmol, 1 equiv). Re-
action time was 12 h. Purification by automated flash-
column chromatography (eluting with 5% ethyl acetate–
hexanes initially, grading to 40% ethyl acetate–hexanes,
linear gradient) afforded 2-oxopropyl 4-methoxybenzoate
(3a, colorless oil, 44.3 mg, 85%).
bis(acetylacetonate) (64.3 mg, 250 μmol, 1.00 equiv). The
reaction vessel was evacuated and refilled using a balloon
of dioxygen. This process was repeated two times. Meth-
anol (830 μL), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred at 24 C until the consumption of
substrate was complete (as determined by TLC analysis).
The product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. Conver-
sions were judged based on 1H NMR analyses of the unpu-
rified product mixtures using mesitylene as an internal
standard. The NMR sample was concentrated to dryness.
The residue obtained was purified by automated flash-
column chromatography to afford the hydrolysis product.
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Hydrolysis of 2-iodoallyl 4-methoxybenzoate (1d;
Table 2, entry 4). Following the general procedure A
using 2-iodoallyl 4-methoxybenzoate (1d, 79.5 mg, 250
μmol, 1 equiv). The reaction vessel was covered with foil
to exclude light. Reaction time was 60 h. Purification by
automated flash-column chromatography (eluting with 5%
ethyl acetate–hexanes initially, grading to 33% ethyl ace-
tate–hexanes, linear gradient) afforded separately 2-
iodoallyl 4-methoxybenzoate (1d, colorless oil, 12.0 mg,
15%) and 2-oxopropyl 4-methoxybenzoate (3a, colorless
oil, 32.8 mg, 63%).
Following the general procedure B using 2-iodoallyl 4-
methoxybenzoate (1d, 79.5 mg, 250 μmol, 1 equiv). The
reaction vessel was covered with foil to exclude light.
Reaction time was 60 h. Purification by automated flash-
column chromatography (eluting with 5% ethyl acetate–
hexanes initially, grading to 33% ethyl acetate–hexanes,
linear gradient) afforded separately 2-iodoallyl 4-
methoxybenzoate (1d, colorless oil, 43.7 mg, 55%) and 2-
oxopropyl 4-methoxybenzoate (3a, colorless oil, 20.9 mg,
40%).
Hydrolysis of 2-fluoroallyl 4-methoxybenzoate (1c;
Table 2, entry 1). Following the general procedure A
using 2-fluoroallyl 4-methoxybenzoate (1c, 52.6 mg, 250
μmol, 1 equiv). Reaction time was 24 h. Purification by
automated flash-column chromatography (eluting with 5%
ethyl acetate–hexanes initially, grading to 33% ethyl ace-
tate–hexanes, linear gradient) afforded 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 51.5 mg, 99%).
Following the general procedure B using 2-fluoroallyl 4-
methoxybenzoate (1c, 52.6 mg, 250 μmol, 1 equiv). Reac-
tion time was 36 h. Purification by automated flash-
column chromatography (eluting with 10% ethyl acetate–
hexanes initially, grading to 40% ethyl acetate–hexanes,
linear gradient) afforded 2-oxopropyl 4-methoxybenzoate
(3a, colorless oil, 51.6 mg, 99%).
Hydrolysis of 1-(1-bromovinyl)-4-methoxybenzene
(1e; Table 2, entry 5). Following the general procedure A
using 1-(1-bromovinyl)-4-methoxybenzene (1e, 53.3 mg,
250 μmol, 1 equiv). The reaction vessel was covered with
foil to exclude light. Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with 15% ether–hexanes, isocratic gradient) afforded 1-(4-
methoxyphenyl)ethan-1-one (3b, white solid, 33.0 mg,
88%).
Hydrolysis of 2-chloroallyl 4-methoxybenzoate (1a;
Table 2, entry 2). Following the general procedure A
using 2-chloroallyl 4-methoxybenzoate (1a, 56.7 mg, 250
μmol, 1 equiv). Reaction time was 24 h. Purification by
automated flash-column chromatography (eluting with 5%
ethyl acetate–hexanes initially, grading to 33% ethyl ace-
tate–hexanes, linear gradient) afforded 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 47.7 mg, 92%).
Following the general procedure
B
using 1-(1-
bromovinyl)-4-methoxybenzene (1e, 53.3 mg, 250 μmol, 1
equiv). The reaction vessel was covered with foil to ex-
clude light. Reaction time was 12 h. Purification by au-
tomated flash-column chromatography (eluting with 15%
ether–hexanes, isocratic gradient) afforded 1-(4-
methoxyphenyl)ethan-1-one (3b, white solid, 29.1 mg,
78%). Rf = 0.31 (20% ether–hexanes; UV, PAA). mp
Following the general procedure B using 2-chloroallyl
4-methoxybenzoate (1a, 56.7 mg, 250 μmol, 1 equiv). Re-
action time was 48 h. Purification by automated flash-
column chromatography (eluting with 5% ethyl acetate–
hexanes initially, grading to 33% ethyl acetate–hexanes,
linear gradient) afforded 2-oxopropyl 4-methoxybenzoate
(3a, colorless oil, 47.1 mg, 89%).
1
37−38 °C. H NMR (400 MHz, CDCl3) δ 7.88 (d, 2H, J = 8.8
Hz), 6.87 (d, 2H, J = 8.8 Hz), 3.81 (s, 3H), 2.50 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 196.7 (C), 163.4 (C), 130.5 (CH),
130.3 (C), 113.6 (CH), 55.4 (CH3), 26.3 (CH3). 1H and 13C
NMR data for 1-(4-methoxyphenyl)ethan-1-one (3b) pre-
pared in this way were in agreement with those previously
described.45
Hydrolysis of 2-bromoallyl 4-methoxybenzoate (1b;
Table 2, entry 3). Following the general procedure A
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The Journal of Organic Chemistry
Hydrolysis
methoxyphenyl)pent-2-en-1-yl)trimethylsilane
Table 2, entry 6). Following the general procedure A
using (Z)-(2-bromo-5-(4-methoxyphenyl)pent-2-en-1-
yl)trimethylsilane (1f, 81.8 mg, 250 μmol, 1 equiv). Reac-
tion time was 12 h. 1H NMR analysis of the unpurified
product mixture revealed a complex mixture of unidenti-
fied decomposition products.
of
(Z)-(2-bromo-5-(4-
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 33.3 mg, 61%).
1
2
3
4
5
6
7
8
(1f;
Following the general procedure
B using 2-((2-
bromobenzyl)oxy)cyclohex-2-en-1-yl benzoate (1h, 96.8
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 40.1 mg, 73%).
Following the general procedure B using (Z)-(2-bromo-
9
5-(4-methoxyphenyl)pent-2-en-1-yl)trimethylsilane
(1f,
Hydrolysis
of
((4-(tert-butyl)cyclohex-1-en-1-
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15
16
17
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22
23
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81.8 mg, 250 μmol, 1 equiv). Reaction time was 12 h. Puri-
fication by automated flash-column chromatography
(eluting with 15% ether–hexanes, isocratic gradient) af-
forded 1-hydroxy-5-(4-methoxyphenyl)pentan-2-one (3c,
colorless oil, 26.3 mg, 50%). Rf = 0.10 (20% ethyl acetate–
yl)oxy)benzene (1i; Table 2, entry 9). Following the
general procedure A using ((4-(tert-butyl)cyclohex-1-en-1-
yl)oxy)benzene (1i, 57.6 mg, 250 μmol, 1 equiv). Reaction
time was 48 h. Purification by automated flash-column
chromatography on neutral aluminum oxide (eluting with
5% ether–hexanes, isocratic gradient) recovered ((4-(tert-
butyl)cyclohex-1-en-1-yl)oxy)benzene (1i, colorless oil,
40.8 mg, 71%).
1
hexanes; UV, CAM). H NMR (400 MHz, CD2Cl2) δ 7.10 (d,
2H, J = 8.8 Hz), 6.83 (d, 2H, J = 8.4 Hz), 4.18 (d, 2H, J = 4.4
Hz), 3.77 (s, 3H), 3.01 (t, 1H, J = 4.8 Hz), 2.58 (t, 2H, J = 7.6
Hz), 2.40 (t, 2H, J = 7.6 Hz), 1.95–1.87 (m, 2H). 13C NMR
(100 MHz, CD2Cl2) δ 209.7 (C), 158.0 (C), 133.3 (C), 129.3
(CH), 113.7 (CH), 68.0 (CH2), 55.1 (CH3), 37.4 (CH2), 34.0
(CH2), 25.3 (CH2). IR (ATR-FTIR), cm–1: 3483 (w), 2929
(m), 1721 (s), 1513 (s), 1246 (s), 1123 (m), 1073 (m). HRMS-
ESI (m/z): [M + Na]+ calcd for C12H16NaO3, 231.0997; found,
231.0989.
Following the general procedure B using ((4-(tert-
butyl)cyclohex-1-en-1-yl)oxy)benzene (1i, 57.6 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
15% ethyl acetate–hexanes, isocratic gradient) afforded 4-
(tert-butyl)cyclohexan-1-one (3e, white solid, 18.2 mg,
47%). Rf = 0.59 (20% ethyl acetate–hexanes; UV, I2). mp
Hydrolysis of 2-bromocyclohex-2-en-1-yl benzoate
(1g; Table 2, entry 7). Following the general procedure A
using 2-bromocyclohex-2-en-1-yl benzoate (1g, 70.3 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 43.8 mg, 80%).
1
38−41 °C. H NMR (400 MHz, CDCl3) δ 2.38–2.23 (m, 4H),
2.08–2.02 (m, 2H), 1.46–1.38 (m, 3H), 0.88 (s, 9H). 13C
NMR (100 MHz, CDCl3) δ 212.5 (C), 46.7 (CH), 41.3 (CH2),
1
32.4 (C), 27.6 (CH2, CH3). H and 13C NMR data for 4-(tert-
butyl)cyclohexan-1-one (3e) prepared in this way were in
agreement with those previously described.47
Hydrolysis of methyl 4-(1-acetoxyvinyl)benzoate (1j;
Table 2, entry 10). Following the general procedure B
using methyl 4-(1-acetoxyvinyl)benzoate (1j, 55.1 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
12% ethyl acetate–10% dichloromethane–hexanes, isocrat-
ic gradient) afforded methyl 4-acetylbenzoate (3f, white
solid, 40.3 mg, 90%). Rf = 0.45 (20% ethyl acetate–
hexanes; UV). mp 82−84 °C. 1H NMR (400 MHz, CDCl3)
δ 8.11 (d, 2H, J = 8.0 Hz), 7.90 (d, 2H, J = 8.0 Hz), 3.93 (s,
3H), 2.63 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 197.5 (C),
166.2 (C), 140.2 (C), 133.9 (C), 129.8 (CH), 128.2 (CH), 52.4
(CH3), 26.9 (CH3). 1H and 13C NMR data for methyl 4-
acetylbenzoate (3f) prepared in this way were in agree-
ment with those previously described.48
Following the general procedure
B
using 2-
bromocyclohex-2-en-1-yl benzoate (1g, 70.3 mg, 250 μmol,
1 equiv). Reaction time was 12 h. Purification by auto-
mated flash-column chromatography (eluting with 7.5%
ethyl acetate–10% dichloromethane–hexanes, isocratic
gradient) afforded 2-oxocyclohexyl benzoate (3d, white
solid, 49.5 mg, 91%).
Rf = 0.41 (20% ethyl acetate–
hexanes; UV, CAM). mp 67−72 °C. 1H NMR (500 MHz,
CDCl3) δ 8.09 (d, 2H, J = 7.5 Hz), 7.57 (t, 1H, J = 7.5 Hz),
7.45 (t, 2H, J = 8.0 Hz), 5.41 (dd, 1H, J = 12.3, 6.2 Hz), 2.59–
2.55 (m, 1H), 2.50–2.41 (m, 2H), 2.15–2.11 (m, 1H), 2.05–2.03
(m, 1H), 1.96–1.90 (m, 1H), 1.88–1.80 (m, 1H), 1.74–1.65 (m,
1H). 13C NMR (100 MHz, CDCl3) δ 204.2 (C), 165.5 (C),
133.1 (CH), 129.8 (CH), 129.6 (C), 128.3 (CH), 76.9 (CH),
Hydrolysis
of
benzyl
4-
13
40.7 (CH2), 33.1 (CH2), 27.1 (CH2), 23.7 (CH2). 1H and C
(((trifluoromethyl)sulfonyl)oxy)-3,6-
NMR data for 2-oxocyclohexyl benzoate (3d) prepared in
this way were in agreement with those previously de-
scribed.46
dihydropyridine-1(2H)-carboxylate (1k; Table 2, entry
11). Following the general procedure A using benzyl 4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1k, 91.3 mg, 250 μmol, 1 equiv). Reac-
tion time was 60 h. Purification by automated flash-
column chromatography on neutral aluminum oxide
(eluting with 20% ethyl acetate–hexanes, isocratic gradi-
ent) afforded benzyl 4-oxopiperidine-1-carboxylate (3g,
colorless oil, 46.0 mg, 78%).
Hydrolysis of 2-((2-bromobenzyl)oxy)cyclohex-2-
en-1-yl benzoate (1h; Table 2, entry 8). Following the
general
procedure
A
using
2-((2-
bromobenzyl)oxy)cyclohex-2-en-1-yl benzoate (1h, 96.8
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
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Following the general procedure B using benzyl 4-
7.8 Hz), 5.43–5.38 (m, 1H), 2.66–2.59 (m, 2H), 2.44–2.38
(m, 2H), 2.26–2.12 (m, 4H). 13C NMR (100 MHz, CDCl3) δ
1
2
3
4
5
6
7
8
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1k, 91.3 mg, 250 μmol, 1 equiv). Reac-
tion time was 12 h. Purification by automated flash-
column chromatography (eluting with 20% ethyl acetate–
hexanes, isocratic gradient) afforded benzyl 4-
oxopiperidine-1-carboxylate (3g, colorless oil, 37.3 mg,
64%). Rf = 0.59 (20% ethyl acetate–hexanes; UV, CAM).
1H NMR (400 MHz, CDCl3) δ 7.36–7.30 (m, 5H), 5.16 (br s,
2H), 3.77 (t, 4H, J = 6.4 Hz), 2.43 (br s, 4H). 13C NMR (100
MHz, CDCl3) δ 207.1 (C), 155.1 (C), 136.3 (C), 128.6 (CH),
128.2 (CH), 128.0 (CH), 67.6 (CH2), 43.1 (CH2), 41.0 (CH2).
1H and 13C NMR data for benzyl 4-oxopiperidine-1-
carboxylate (3g) prepared in this way were in agreement
with those previously described.49
209.7 (C), 165.7 (C), 133.2 (CH), 130.2 (C), 129.5 (CH), 128.4
13
(CH), 69.0 (CH), 37.3 (CH2), 30.5 (CH2). 1H and C NMR
data for 4-oxocyclohexyl benzoate (3i) prepared in this
way were in agreement with those previously described.21
Hydrolysis
of
2-(phenylthio)allyl
4-
methoxybenzoate (1n; Table 2, entry 14). Following
the general procedure A using 2-(phenylthio)allyl 4-
methoxybenzoate (1n, 75.0 mg, 250 μmol, 1 equiv). Reac-
tion time was 12 h. Purification by automated flash-
column chromatography (eluting with 5% ethyl acetate–
hexanes initially, grading to 33% ethyl acetate–hexanes,
linear gradient) afforded 2-oxopropyl 4-methoxybenzoate
(3a, colorless oil, 21.3 mg, 41%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hydrolysis
((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1l; Table 2, entry 12). Following the
general procedure using tert-butyl 4-
of
benzyl
tert-butyl
4-
Following the general procedure
B
using 2-
(phenylthio)allyl 4-methoxybenzoate (1n, 75.0 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
5% ethyl acetate–hexanes initially, grading to 33% ethyl
acetate–hexanes, linear gradient) afforded 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 42.6 mg, 82%).
A
((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-
carboxylate (1l, 107 mg, 250 μmol, 1 equiv). Reaction time
was 60 h. Purification by automated flash-column chro-
matography (eluting with 20% ether–hexanes, isocratic
Hydrolysis of 2-((4-chlorophenyl)thio)cyclohex-2-
en-1-yl benzoate (1o; Table 2, entry 15). Following the
gradient)
recovered
tert-butyl
4-
((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-
carboxylate (1l, colorless oil, 87.8 mg, 81%).
general
procedure
A
using
2-((4-
chlorophenyl)thio)cyclohex-2-en-1-yl benzoate (1o, 86.2
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 43.8 mg, 80%).
Following the general procedure B using tert-butyl 4-
((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-
carboxylate (1l, 107 mg, 250 μmol, 1 equiv). Reaction time
was 36 h. Purification by automated flash-column chro-
matography (eluting with hexanes initially, grading to
33% ether–hexanes, linear gradient) afforded tert-butyl 4-
oxopiperidine-1-carboxylate (3h, white solid, 24.9 mg,
50%). Rf = 0.24 (20% ethyl acetate–hexanes; UV, CAM).
mp 64−68 °C. 1H NMR (400 MHz, CDCl3) δ 3.69 (t, 4H, J
= 6.2 Hz), 2.40 (t, 4H, J = 6.2 Hz), 1.45 (s, 9H1). 13C NMR
(100 MHz, CDCl3) δ 207.7 (C), 154.4 (C), 80.3 (CH2), 43.0
Following the general procedure
B using 2-((4-
chlorophenyl)thio)cyclohex-2-en-1-yl benzoate (1o, 86.2
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 50.4 mg, 92%).
13
(C), 41.1 (CH2), 28.3 (CH3). 1H and C NMR data for tert-
butyl 4-oxopiperidine-1-carboxylate (3h) prepared in this
way were in agreement with those previously described.50
Hydrolysis of 2-(benzylthio)cyclohex-2-en-1-yl ben-
zoate (1p; Table 2, entry 16). Following the general pro-
cedure A using 2-(benzylthio)cyclohex-2-en-1-yl benzoate
(1p, 81.1 mg, 250 μmol, 1 equiv). Reaction time was 12 h.
Purification by automated flash-column chromatography
(eluting with 7.5% ethyl acetate–10% dichloromethane–
hexanes, isocratic gradient) afforded 2-oxocyclohexyl
benzoate (3d, white solid, 50.7 mg, 93%).
Hydrolysis of 4-((triisopropylsilyl)oxy)cyclohex-3-
en-1-yl benzoate (1m; Table 2, entry 13). Following the
general
procedure
A
using
4-
((triisopropylsilyl)oxy)cyclohex-3-en-1-yl benzoate (1m,
93.7 mg, 250 μmol, 1 equiv). Reaction time was 60 h. Pu-
rification by automated flash-column chromatography
(eluting with 5% ether–hexanes, isocratic gradient) recov-
ered 4-((triisopropylsilyl)oxy)cyclohex-3-en-1-yl benzoate
(1m, colorless oil, 85.2 mg, 91%).
Following the general procedure
B
using 2-
(benzylthio)cyclohex-2-en-1-yl benzoate (1p, 81.1 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
7.5% ethyl acetate–10% dichloromethane–hexanes, iso-
cratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 47.7 mg, 87%).
Following the general procedure
B
using 4-
((triisopropylsilyl)oxy)cyclohex-3-en-1-yl benzoate (1m,
93.7 mg, 250 μmol, 1 equiv). Reaction time was 24 h. Pu-
rification by automated flash-column chromatography
(eluting with 20% ethyl acetate–hexanes, isocratic gradi-
ent) afforded 4-oxocyclohexyl benzoate (3i, white solid,
40.4 mg, 74%). Rf = 0.31 (20% ethyl acetate–hexanes; UV,
CAM). mp 45−49 °C. 1H NMR (400 MHz, CDCl3) δ 8.04
(d, 2H, J = 7.6 Hz), 7.56 (t, 1H, J = 7.4 Hz), 7.44 (t, 2H, J =
Hydrolysis of 2-(phenylsulfonyl)cyclohex-2-en-1-yl
benzoate (1q; Table 2, entry 17). Following the general
procedure A using 2-(phenylsulfonyl)cyclohex-2-en-1-yl
benzoate (1q, 85.6 mg, 250 μmol, 1 equiv). Reaction time
was 12 h. Purification by automated flash-column chro-
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The Journal of Organic Chemistry
matography (eluting with 7.5% ethyl acetate–10% di- (400 MHz, CDCl3) δ 7.53–7.51 (m, 1H), 7.40–7.25 (m, 3H),
2.62 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 200.4 (C), 139.1
(C), 132.0 (CH), 131.2 (C), 130.6 (CH), 129.4 (CH), 126.9
(CH), 30.7 (CH3). 1H and 13C NMR data for 1-(2-
chlorophenyl)ethan-1-one (3k) prepared in this way were
in agreement with those previously described.52
1
2
3
4
5
6
7
8
chloromethane–hexanes, isocratic gradient) afforded 2-
oxocyclohexyl benzoate (3d, white solid, 45.4 mg, 83%).
Following the general procedure
B
using 2-
(phenylsulfonyl)cyclohex-2-en-1-yl benzoate (1q, 85.6 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 48.7 mg, 89%).
Hydrolysis
of
2-(trimethylsilyl)allyl
4-
methoxybenzoate (1u; Table 2, entry 21). Following
the general procedure A using 2-(trimethylsilyl)allyl 4-
methoxybenzoate (1u, 66.1 mg, 250 μmol, 1 equiv). Reac-
tion time was 12 h. Purification by automated flash-
column chromatography (eluting with 2% ethyl acetate–
hexanes initially, grading to 40% ethyl acetate–hexanes,
linear gradient) afforded separately 2-(trimethylsilyl)allyl
4-methoxybenzoate (1u, colorless oil, 22.7 mg, 34%) and
2-oxopropyl 4-methoxybenzoate (3a, colorless oil, 33.2 mg,
63%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hydrolysis of 2-(phenylselanyl)cyclohex-2-en-1-yl
benzoate (1r; Table 2, entry 18). Following the general
procedure A using 2-(phenylselenyl)cyclohex-2-en-1-yl
benzoate (1r, 86.2 mg, 250 μmol, 1 equiv). Reaction time
was 12 h. Purification by automated flash-column chro-
matography (eluting with 2% ethyl acetate–hexanes ini-
tially, grading to 35% ethyl acetate–hexanes, linear gradi-
ent) afforded separately 2-(phenylselanyl)cyclohex-2-en-1-
yl benzoate (1r, colorless oil, 69.9 mg, 78%) and 2-
oxocyclohexyl benzoate (3d, white solid, 9.8 mg, 18%).
Following the general procedure
B
using 2-
(trimethylsilyl)allyl 4-methoxybenzoate (1u, 66.1 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
2% ethyl acetate–hexanes initially, grading to 40% ethyl
acetate–hexanes, linear gradient) afforded 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 46.5 mg, 89%).
Following the general procedure
B
using 2-
(phenylselenyl)cyclohex-2-en-1-yl benzoate (1r, 86.2 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with 7.5% ethyl acetate–10% dichloromethane–hexanes,
isocratic gradient) afforded 2-oxocyclohexyl benzoate (3d,
white solid, 36.1 mg, 66%).
Hydrolysis
of
(4-(tert-butyl)cyclohex-1-en-1-
yl)trimethylsilane (1v; Table 2, entry 22). Following
the general procedure A using (4-(tert-butyl)cyclohex-1-
en-1-yl)trimethylsilane (1v, 52.6 mg, 250 μmol, 1 equiv).
Reaction time was 12 h. 1H NMR study of the unpurified
product mixture using mesitylene as an internal standard
revealed a 90% yield of 1v. Purification by automated
flash-column chromatography (eluting with hexanes ini-
tially, grading to 33% ether–hexanes, linear gradient) af-
forded 4-(tert-butyl)cyclohexan-1-one (3e, white solid, 2.8
mg, 7%). The mixture containing starting material was
repurified by flash-column chromatography (silver nitrate
impregnated silica gel; eluting with hexanes initially,
grading to 5% ether–hexanes, linear gradient) afforded (4-
(tert-butyl)cyclohex-1-en-1-yl)trimethylsilane(1v, clear oil,
46.5 mg, 88%).
Hydrolysis of N-(4-phenylbut-1-en-2-yl)acetamide
(1s; Table 2, entry 19). Following the general procedure
A using N-(4-phenylbut-1-en-2-yl)acetamide (1s, 47.3 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with 10% ether–hexanes, isocratic gradient) afforded 4-
phenylbutan-2-one (3j, colorless oil, 23.8 mg, 64%).
Following the general procedure
B using N-(4-
phenylbut-1-en-2-yl)acetamide (1s, 47.3 mg, 250 μmol, 1
equiv). Reaction time was 12 h. Purification by automat-
ed flash-column chromatography (eluting with 10%
ether–hexanes,
isocratic
gradient)
afforded
4-
phenylbutan-2-one (3j, colorless oil, 29.3 mg, 79%). Rf =
1
Following the general procedure B using(4-(tert-
0.55 (20% ethyl acetate–hexanes; UV, PAA). H NMR (400
butyl)cyclohex-1-en-1-yl)trimethylsilane (1v, 52.6 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
hexanes initially, grading to 33% ether–hexanes, linear
gradient) afforded 4-(tert-butyl)cyclohexan-1-one (3e,
white solid, 34.1 mg, 88%).
MHz, CDCl3) δ 7.30–7.26 (m, 2H), 7.21–7.17 (m, 3H), 2.90
(t, 2H, J = 7.6 Hz), 2.76 (t, 2H, J = 7.8 Hz), 2.13 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 207.9 (C), 141.0 (C), 128.5 (CH),
128.3 (CH), 126.1 (CH), 45.1 (CH2), 30.1 (CH3), 29.7 (CH2).
1H and 13C NMR data for 4-phenylbutan-2-one (3j) pre-
pared in this way were in agreement with those previously
described.51
Hydration of propargyl 4-methoxybenzoate (1w;
Table 2, entry 23). Following the general procedure A
using propargyl 4-methoxybenzoate (1w, 47.6 mg, 250
μmol, 1 equiv). Reaction time was 60 h. Purification by
automated flash-column chromatography (eluting with
2% ethyl acetate–hexanes initially, grading to 15% ethyl
acetate–hexanes, linear gradient) recovered propargyl 4-
methoxybenzoate (1w, white solid, 41.6 mg, 88%).
Hydrolysis of 2-(1-(2-chlorophenyl)vinyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1t; Table 2, entry 20).
Following the general procedure
B using 2-(1-(2-
chlorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (1t, 66.1 mg, 250 μmol, 1 equiv). Reaction
time was 12 h. Purification by automated flash-column
chromatography (eluting with hexanes initially, grading
to 30% ether–hexanes, linear gradient) afforded 1-(2-
chlorophenyl)ethan-1-one (3k, colorless oil, 30.5 mg, 79%).
Rf = 0.6 (20% ethyl acetate–hexanes; UV, PAA). 1H NMR
Following the general procedure B using propargyl 4-
methoxybenzoate (1w, 47.6 mg, 250 μmol, 1 equiv). Reac-
tion time was 24 h. Purification by automated flash-
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column chromatography (eluting with 5% ethyl acetate–
isocratic
methoxybenzoate (3a, colorless oil, 5.4 mg, 74%).
Hydrolysis of 1-(4,4-dichlorobut-3-en-1-yl)-4-
methoxybenzene (11a; Table 3, entry 1). Following the
general procedure A using 1-(4,4-dichlorobut-3-en-1-yl)-4-
methoxybenzene (11a, 57.8 mg, 250 μmol, 1 equiv). Reac-
tion time was 12 h. Purification by automated flash-
column chromatography (eluting with hexanes initially,
grading to 25% ether–hexanes, linear gradient) afforded
methyl 4-(4-methoxyphenyl)butanoate (12a, colorless oil,
48.0 mg, 92%).
gradient)
to
afford
2-oxopropyl
4-
1
2
3
4
5
6
7
8
hexanes initially, grading to 33% ethyl acetate–hexanes,
linear gradient) afforded 2-oxopropyl 4-methoxybenzoate
(3a, colorless oil, 16.4 mg, 32%).
Mechanistic Studies (Scheme 3). A 10-mL round-
bottomed flask fitted with a rubber septum was charged
sequentially with 2-chloroallyl 4-methoxybenzoate (1a,
56.7 mg, 250 μmol, 1 equiv) and cobalt bis(acetylacetonate)
(16.1 mg, 62.5 μmol, 0.250 equiv). The reaction vessel was
evacuated and refilled using a balloon of dioxygen. This
process was repeated two times. n-Propanol (830 μL),
triethylsilane (199 μL, 1.25 mmol, 5.00 equiv), and a solu-
tion of tert-butyl hydroperoxide in nonane (~5.5 M, 45.5
μL, 250 μmol, 1.00 equiv) were added sequentially to the
reaction vessel via syringe. The reaction mixture was
stirred for 4 h at 24 C. The product mixture was concen-
trated to dryness and the residue obtained was filtered
through a short column of silica gel and the short column
was rinsed with 50% ethyl acetate–hexanes (100 mL). The
filtrates were combined and the combined filtrates were
concentrated. The residue obtained was purified by au-
tomated flash-column chromatography (eluting with hex-
anes initially, grading to 50% ethyl acetate–hexanes, line-
ar gradient) to afford separately 2-oxopropyl 4-
methoxybenzoate (3a, colorless oil, 25.1 mg, 42%) and 2-
hydroperoxy-2-propoxypropyl 4-methoxybenzoate (6,
clear oil, 40.2 mg, 57%). 2-Hydroperoxy-2-propoxypropyl
4-methoxybenzoate (6): Rf = 0.36 (20% ethyl acetate–
hexanes; UV). 1H NMR (500 MHz, CDCl3) δ 9.56 (s, 1H),
8.01 (d, 2H, J = 8.5 Hz), 6.92 (d, 2H, J = 8.5 Hz), 4.92 (d, 1H,
J = 12.0 Hz), 3.93 (d, 1H, J = 12.0 Hz), 3.91 (s, 3H), 3.68–3.63
(m, 1H), 3.52–3.47 (m, 1H), 1.67–1.60 (m, 2H), 1.37 (s, 3H),
0.95 (t, 3H, J = 7.5 Hz). 13C NMR (100 MHz, CDCl3) δ 167.4
(C), 163.9 (C), 132.0 (CH), 121.7 (C), 113.8 (CH), 104.5 (C),
64.2 (CH2), 63.0 (CH2), 55.5 (CH3), 23.0 (CH2), 17.5 (CH3),
10.6 (CH3). IR (ATR-FTIR), cm–1: 3357 (br), 2963 (w), 1716
(m), 1605 (s), 1258 (s), 1167 (s), 1105 (m), 848 (m), 770 (m).
HRMS-ESI (m/z): [M+Na]+ calcd for C14H20NaO6, 307.1158;
found, 307.1153.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Following the general procedure
B using 1-(4,4-
dichlorobut-3-en-1-yl)-4-methoxybenzene (11a, 57.8 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with hexanes initially, grading to 25% ether–hexanes, lin-
ear
gradient)
afforded
methyl
4-(4-
methoxyphenyl)butanoate (12a, colorless oil, 50.8 mg,
1
98%). Rf = 0.30 (20% ether–hexanes; UV). H NMR (500
MHz, CDCl3) δ 7.09 (d, 2H, J = 8.0 Hz), 6.83 (d, 2H, J = 8.0
Hz), 3.79 (s, 3H), 3.66 (s, 3H), 2.65 (t, 2H, J = 7.8 Hz), 2.32
(t, 2H, J = 7.5 Hz), 1.95–1.89 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 174.0 (C), 157.9 (C), 113.4 (C), 129.3 (CH), 113.8
(CH), 55.2 (CH3), 51.5 (CH3), 34.2 (CH2), 33.3 (CH2), 26.7
(CH2). IR (ATR-FTIR), cm–1: 2951 (w), 1734 (s), 1152 (s),
1243 (s), 1175 (s), 1034 (s), 811 (m). HRMS-ESI (m/z): [M +
H]+ calcd for C12H17O3, 209.1178; found, 209.1185.
Hydrolysis
of
1-(4,4-dibromobut-3-en-1-yl)-4-
methoxybenzene (11b; Table 3, entry 2). Following the
general procedure A using 1-(4,4-dibromobut-3-en-1-yl)-4-
methoxybenzene (11b, 80.0 mg, 250 μmol, 1 equiv). Reac-
tion time was 7 h. Purification by automated flash-
column chromatography (eluting with hexanes initially,
grading to 25% ether–hexanes, linear gradient) afforded
methyl 4-(4-methoxyphenyl)butanoate (12a, colorless oil,
45.5 mg, 87%).
Following the general procedure
B using 1-(4,4-
dibromobut-3-en-1-yl)-4-methoxybenzene (11b, 80.0 mg,
250 μmol, 1 equiv). Reaction time was 8 h. Purification
by automated flash-column chromatography (eluting
with hexanes initially, grading to 25% ether–hexanes, lin-
Mechanistic Studies (Scheme 3). A 10-mL round-
bottomed flask fitted with a rubber septum was charged
sequentially with 2-hydroperoxy-2-propoxypropyl 4-
methoxybenzoate (6, 10.0 mg, 35.0 μmol, 1 equiv) and
cobalt bis(acetylacetonate) (2.2 mg, 8.75 μmol, 0.250
equiv). The reaction vessel was evacuated and refilled
using a balloon of dioxygen. This process was repeated
two times. n-Propanol (117 μL), triethylsilane (28.0 μL, 175
μmol, 5.00 equiv), and a solution of tert-butyl hydroper-
oxide in nonane (~5.5 M, 6.4 μL, 35.0 μmol, 1.00 equiv)
were added sequentially to the reaction vessel via syringe.
The reaction mixture was stirred for 12 h at 24 C. The
product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. The resi-
due obtained was purified by automated flash-column
chromatography (eluting with 15% ethyl acetate–hexanes,
ear
gradient)
afforded
methyl
4-(4-
methoxyphenyl)butanoate (12a, colorless oil, 45.9 mg,
88%).
Hydrolysis
of
1-(4,4-diiodobut-3-en-1-yl)-4-
methoxybenzene (11c; Table 3, entry 3). Following the
general procedure A using 1-(4,4-dichlorobut-3-en-1-yl)-4-
methoxybenzene (11c, 45.5 mg, 110 μmol, 1 equiv). Reac-
tion time was 60 h. Purification by automated flash-
column chromatography (eluting with hexanes initially,
grading to 25% ether–hexanes, linear gradient) afforded
separately
1-(4,4-dichlorobut-3-en-1-yl)-4-
methoxybenzene (11c, white solid, 20.9 mg, 46%) and
methyl 4-(4-methoxyphenyl)butanoate (12a, colorless oil,
10.8 mg, 47%).
Following the general procedure B using 1-(4,4-
dichlorobut-3-en-1-yl)-4-methoxybenzene (11c, 45.5 mg,
110 μmol, 1 equiv). Reaction time was 60 h. Purification
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The Journal of Organic Chemistry
by automated flash-column chromatography (eluting methyl 2-(4-bromophenyl)acetate (12d, colorless oil, 52.3
1
2
3
4
5
6
7
8
with hexanes initially, grading to 25% ether–hexanes, lin-
ear gradient) afforded separately 1-(4,4-dichlorobut-3-en-
1-yl)-4-methoxybenzene (11c, white solid, 26.8 mg, 59%)
and methyl 4-(4-methoxyphenyl)butanoate (12a, colorless
oil, 8.7 mg, 38%).
mg, 91%).
Following the general procedure B using 1-bromo-4-
(2,2-dibromovinyl)benzene (11f, 85.2 mg, 250 μmol, 1
equiv). Reaction time was 12 h. Purification by automat-
ed flash-column chromatography (eluting with hexanes
initially, grading to 25% ether–hexanes, linear gradient)
afforded methyl 2-(4-bromophenyl)acetate (12d, colorless
oil, 56.9 mg, 98%). Rf = 0.72 (20% ether–hexanes; UV,
CAM). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H, J = 8.0
Hz), 7.15 (d, 2H, J = 8.0 Hz), 3.66 (s, 3H), 3.57 (s, 2H). 13C
NMR (100 MHz, CDCl3) δ 171.4 (C), 132.9 (C), 131.6 (CH),
131.0 (CH), 121.1 (C), 52.1 (CH3), 40.5 (CH2). 1H and 13C
NMR data for methyl 2-(4-bromophenyl)acetate (12d)
prepared in this way were in agreement with those previ-
ously described.54
Hydrolysis
methoxybenzene (11d; Table 3, entry 4). Following the
general procedure using 1-(2,2-dibromovinyl)-4-
of
1-(2,2-dibromovinyl)-4-
A
9
methoxybenzene (11d, 73.0 mg, 250 μmol, 1 equiv). Reac-
tion time was 12 h. Purification by automated flash-
column chromatography (eluting with hexanes initially,
grading to 25% ether–hexanes, linear gradient) afforded
methyl 2-(4-methoxyphenyl)acetate (12b, colorless oil,
27.6 mg, 61%).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Following the general procedure
B using 1-(2,2-
dibromovinyl)-4-methoxybenzene (11d, 80.0 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
hexanes initially, grading to 25% ether–hexanes, linear
gradient) afforded methyl 2-(4-methoxyphenyl)acetate
(12b, colorless oil, 38.2 mg, 85%). Rf = 0.51 (20% ether–
Hydrolysis of 4-(2,2-dibromovinyl)benzonitrile (11g;
Table 3, entry 7). Following the general procedure A
using 4-(2,2-dibromovinyl)benzonitrile (11g, 71.7 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
hexanes initially, grading to 33% ether–hexanes, linear
gradient) afforded methyl 2-(4-cyanophenyl)acetate (12e,
colorless oil, 39.8 mg, 91%).
1
hexanes; UV, CAM). H NMR (400 MHz, CDCl3) δ 7.20 (d,
2H, J = 8.8 Hz), 6.86 (d, 2H, J = 8.8 Hz), 3.79 (s, 3H), 3.68
(s, 3H), 3.57 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 172.3
(C), 158.6 (C), 130.2 (CH), 126.0 (C), 113.9 (CH), 55.2 (CH3),
51.9 (CH3), 40.2 (CH2). 1H and 13C NMR data for methyl 2-
(4-methoxyphenyl)acetate (12b) prepared in this way
were in agreement with those previously described.53
Following the general procedure
B using 4-(2,2-
dibromovinyl)benzonitrile (11g, 71.7 mg, 250 μmol, 1
equiv). Reaction time was 12 h. Purification by automat-
ed flash-column chromatography (eluting with hexanes
initially, grading to 33% ether–hexanes, linear gradient)
afforded methyl 2-(4-cyanophenyl)acetate (12e, colorless
oil, 30.6 mg, 70%). Rf = 0.59 (33% ether–hexanes; UV,
CAM). 1H NMR (400 MHz, CDCl3) δ 7.60 (d, 2H, J = 8.0
Hz, H1), 7.38 (d, 2H, J = 8.0 Hz, H2), 3.69 (s, 3H, H4), 3.68
(s, 2H, H3). 13C NMR (100 MHz, CDCl3) δ 170.7 (C), 139.3
(C), 132.3 (CH), 130.2 (CH), 118.8 (C), 111.1 (C), 52.3 (CH3),
41.0 (CH2). 1H and 13C NMR data for methyl 2-(4-
cyanophenyl)acetate (12e) prepared in this way were in
agreement with those previously described.55
Hydrolysis of methyl 4-(2,2-dibromovinyl)benzoate
(11e; Table 3, entry 5). Following the general procedure
A using methyl 4-(2,2-dibromovinyl)benzoate (11e, 80.0
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with hexanes initially, grading to 40% ether–hexanes,
linear gradient) afforded methyl 4-(2-methoxy-2-
oxoethyl)benzoate (12c, colorless oil, 44.7 mg, 86%).
Following the general procedure B using methyl 4-(2,2-
dibromovinyl)benzoate (11e, 80.0 mg, 250 μmol, 1 equiv).
Reaction time was 12 h. Purification by automated flash-
column chromatography (eluting with hexanes initially,
grading to 40% ether–hexanes, linear gradient) afforded
m methyl 4-(2-methoxy-2-oxoethyl)benzoate (12c, color-
less oil, 47.8 mg, 92%). Rf = 0.31 (33% ether–hexanes; UV,
CAM). 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 2H, J = 8.0
Hz), 7.35 (d, 2H, J = 8.0 Hz), 3.91 (s, 3H), 3.71 (s, 3H), 3.69
(s, 2H). 13C NMR (100 MHz, CDCl3) δ 171.1 (C), 166.7 (C),
139.0 (C), 129.7 (CH), 129.2(CH), 129.0 (C), 52.1 (CH3), 52.0
Hydrolysis of 1-(2,2-dibromovinyl)-4-nitrobenzene
(11h; Table 3, entry 8). Following the general procedure
A using 1-(2,2-dibromovinyl)-4-nitrobenzene (11h, 76.7
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with hexanes initially, grading to 33% ether–hexanes, lin-
ear gradient) afforded methyl 2-(4-nitrophenyl)acetate
(12f, light yellow oil, 43.4 mg, 89%).
Following the general procedure
B using 1-(2,2-
dibromovinyl)-4-nitrobenzene (11h, 76.7 mg, 250 μmol, 1
equiv). Reaction time was 12 h. Purification by automat-
ed flash-column chromatography (eluting with hexanes
initially, grading to 33% ether–hexanes, linear gradient)
afforded methyl 2-(4-nitrophenyl)acetate (12f, light yellow
oil, 46.7 mg, 96%). Rf = 0.47 (33% ether–hexanes; UV,
CAM). 1H NMR (400 MHz, CDCl3) δ 8.17 (d, 2H, J = 8.4
Hz), 7.45 (d, 2H, J = 8.4 Hz), 3.73 (s, 2H), 3.71 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 170.6 (C), 147.2 (C), 141.2 (C),
13
(CH3), 41.0 (CH2). 1H and C NMR data for methyl 2-(4-
methoxyphenyl)acetate (12c) prepared in this way were in
agreement with those previously described.54
Hydrolysis
dibromovinyl)benzene (11f; Table 3, entry 6). Follow-
ing the general procedure using 1-bromo-4-(2,2-
of
1-bromo-4-(2,2-
A
dibromovinyl)benzene (11f, 85.2 mg, 250 μmol, 1 equiv).
Reaction time was 12 h. Purification by automated flash-
column chromatography (eluting with hexanes initially,
grading to 25% ether–hexanes, linear gradient) afforded
1
130.28 (CH), 123.7 (CH), 52.4 (CH3), 40.7 (CH2). H and 13C
NMR data for methyl 2-(4-nitrophenyl)acetate (12f) pre-
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Page 26 of 32
pared in this way were in agreement with those previously
equiv). Reaction time was 12 h. Purification by automat-
described.56
ed flash-column chromatography (eluting with hexanes
initially, grading to 15% ether–hexanes, linear gradient)
afforded methyl 2-(naphthalen-1-yl)acetate (12i, colorless
oil, 24.4 mg, 49%). Rf = 0.63 (20% ether–hexanes; UV,
CAM). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 1H, J = 8.8
Hz), 7.89 (d, 1H, J = 8.8 Hz), 7.82 (d, 1H, J = 7.6 Hz), 7.59–
7.43 (m, 4H), 4.11 (s, 2H), 3.70 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 172.0 (C), 133.8 (C), 132.1 (C), 130.5 (C), 128.8 (CH),
128.1 (CH), 128.0 (CH), 126.4 (CH), 125.8 (CH), 125.5 (CH),
123.8 (CH), 52.2 (CH3), 39.1 (CH2). 1H and 13C NMR data
for methyl 2-(naphthalen-1-yl)acetate (12i) prepared in
this way were in agreement with those previously de-
scribed.59
1
2
3
4
5
6
7
8
Hydrolysis
of
2-(4-(2,2-dibromovinyl)phenyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11i; Table 3,
entry 9). Following the general procedure A using 2-(4-
(2,2-dibromovinyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (11i, 97.0 mg, 250 μmol, 1 equiv). Reaction
time was 12 h. 1H NMR analysis of the unpurified sample
showed complicated decomposition of unidentified prod-
ucts.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Following the general procedure B using 2-(4-(2,2-
dibromovinyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (11i, 97.0 mg, 250 μmol, 1 equiv). Reaction
time was 12 h. Purification by automated flash-column
chromatography (eluting with hexanes initially, grading
to 15% ether–hexanes, linear gradient) afforded methyl 2-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
Hydrolysis of 1-(2,2-dibromovinyl)-2-iodobenzene
(11l; Table 3, entry 12). Following the general procedure
A using 1-(2,2-dibromovinyl)-2-iodobenzene (11l, 97.0 mg,
1
250 μmol, 1 equiv). Reaction time was 12 h. H NMR anal-
yl)phenyl)acetate (12g, white solid, 35.5 mg, 51%). Rf =
0.52 (20% ether–hexanes; UV, CAM). mp 42−45 °C. 1H
NMR (400 MHz, CDCl3) δ 7.77 (d, 2H, J = 8.0 Hz), 7.29 (d,
2H, J = 8.0 Hz), 3.67 (s, 3H), 3.64 (s, 2H), 1.33 (s, 12H). 13C
NMR (100 MHz, CDCl3) δ 171.7 (C), 137.1 (C), 135.0 (CH),
ysis of the unpurified sample showed complicated de-
composition of unidentified products.
Following the general procedure
B using 1-(2,2-
dibromovinyl)-2-iodobenzene (11l, 97.0 mg, 250 μmol, 1
equiv). Reaction time was 12 h. Purification by automat-
ed flash-column chromatography (eluting with hexanes
initially, grading to 20% ether–hexanes, linear gradient)
afforded methyl 2-(2-iodophenyl)acetate (12j, colorless oil,
53.2 mg, 77%). Rf = 0.57 (20% ether–hexanes; UV, CAM).
1H NMR (400 MHz, CDCl3) δ 7.85 (d, 1H, J = 8.0 Hz), 7.34–
7.27 (m, 2H), 6.98–6.94 (m, 1H), 3.81 (s, 2H), 3.72 (s, 3H).
13C NMR (100 MHz, CDCl3) δ 170.9 (C), 139.5 (CH), 137.7
(C), 130.6 (CH), 128.9 (CH), 128.4 (CH), 101.0 (C), 52.2
(CH3), 46.1 (CH2). 1H and 13C NMR data for methyl 2-(2-
iodophenyl)acetate (12j) prepared in this way were in
agreement with those previously described.60
1
128.6 (CH), 83.7 (C), 52.0 (CH3), 41.4 (CH2), 24.8 (CH3). H
and 13C NMR data for methyl 2-(4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)acetate (12g) prepared in
this way were in agreement with those previously de-
scribed.57
Hydrolysis
(trifluoromethyl)benzene (11j; Table 3, entry 10). Fol-
lowing the general procedure using 1-(2,2-
of
1-(2,2-dibromovinyl)-4-
A
dibromovinyl)-4-(trifluoromethyl)benzene (11j, 82.5 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with hexanes initially, grading to 15% ether–hexanes, line-
ar
gradient)
afforded
methyl
2-(4-
Hydrolysis
of
2-(2,2-dibromovinyl)-1,3,5-
(trifluoromethyl)phenyl)acetate (12h, colorless oil, 44.1
trimethylbenzene (11m; Table 3, entry 13). Following
the general procedure A using 2-(2,2-dibromovinyl)-1,3,5-
trimethylbenzene (11m, 76.0 mg, 250 μmol, 1 equiv). Re-
action time was 12 h. 1H NMR analysis of the unpurified
sample showed complicated decomposition of unidenti-
fied products.
mg, 81%).
Following the general procedure
B using 1-(2,2-
dibromovinyl)-4-(trifluoromethyl)benzene (11j, 82.5 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with hexanes initially, grading to 15% ether–hexanes, line-
Following the general procedure
B using 2-(2,2-
ar
gradient)
afforded
methyl
2-(4-
dibromovinyl)-1,3,5-trimethylbenzene (11m, 76.0 mg, 250
μmol, 1 equiv). Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
hexanes initially, grading to 15% ether–hexanes, linear
gradient) afforded methyl 2-mesitylacetate (12k, colorless
oil, 14.9 mg, 31%). Rf = 0.59 (20% ether–hexanes; UV,
(trifluoromethyl)phenyl)acetate (12h, colorless oil, 47.1
mg, 86%). Rf = 0.54 (20% ether–hexanes; UV, CAM). 1H
NMR (400 MHz, CDCl3) δ 7.58 (d, 2H, J = 8.0 Hz), 7.40 (d,
2H, J = 8.0 Hz), 3.71 (s, 3H), 3.69 (s, 2H). 19F NMR (375
MHz, CDCl3) δ –62.6. H and C NMR data for methyl 2-
(4-(trifluoromethyl)phenyl)acetate (12h) prepared in this
way were in agreement with those previously described.58
1
13
1
CAM). H NMR (400 MHz, CDCl3) δ 6.90 (s, 2H), 3.70 (s,
3H), 3.69 (s, 2H), 2.32 (s, 6H), 2.29 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 172.0 (C), 137.0 (C), 136.5 (C), 128.9 (CH),
128.5 (C), 51.9 (CH3), 34.9 (CH2), 20.9 (CH3), 20.2 (CH3).
1H and 13C NMR data for methyl 2-mesitylacetate (12k)
prepared in this way were in agreement with those previ-
ously described.61
Hydrolysis of 1-(2,2-dibromovinyl)naphthalene (11k;
Table 3, entry 11). Following the general procedure A
using 1-(2,2-dibromovinyl)naphthalene (11k, 78.0 mg, 250
μmol, 1 equiv). Reaction time was 12 h. 1H NMR analysis
of the unpurified sample showed complicated decomposi-
tion of unidentified products.
Hydrolysis of benzyl (4,4-dibromo-1-phenylbut-3-
en-2-yl)carbamate (11n; Table 3, entry 14). Following
the general procedure A using benzyl (4,4-dibromo-1-
Following the general procedure
B using 1-(2,2-
dibromovinyl)naphthalene (11k, 78.0 mg, 250 μmol, 1
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The Journal of Organic Chemistry
peated two times. iso-Propanol (830 μL), triethylsilane
phenylbut-3-en-2-yl)carbamate (11n, 110 mg, 250 μmol, 1
equiv). Reaction time was 12 h. 1H NMR analysis of the
unpurified sample showed complicated decomposition of
unidentified products.
(199 μL, 1.25 mmol, 5.00 equiv), and a solution of tert-
butyl hydroperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol,
1.00 equiv) were added sequentially to the reaction vessel
via syringe. The reaction mixture was stirred for 12 h at 24
C. The product mixture was concentrated to dryness
and the residue obtained was filtered through a short col-
umn of silica gel and the short column was rinsed with 50%
ethyl acetate–hexanes (100 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography (eluting with hexane initially, grading to
20% ether–hexanes, linear gradient) to afford iso-propyl
2-(4-methoxyphenyl)acetate (12n, colorless oil, 21.2 mg,
41%).
1
2
3
4
5
6
7
8
Following the general procedure B using benzyl (4,4-
dibromo-1-phenylbut-3-en-2-yl)carbamate (11n, 110 mg,
250 μmol, 1 equiv). Reaction time was 12 h. Purification
by automated flash-column chromatography (eluting
with hexanes initially, grading to 20% ethyl acetate–
9
hexanes,
linear
gradient)
afforded
methyl
3-
(12l,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(((benzyloxy)carbonyl)amino)-4-phenylbutanoate
colorless oil, 67.2 mg, 82%). Rf = 0.47 (20% ethyl acetate–
hexanes; UV, CAM). 1H NMR (400 MHz, CD2Cl2) δ 7.41–
7.22 (m, 10H), 5.38 (d, 1H, J = 9.2 Hz), 5.08 (s, 2H), 4.29–
4.20 (m, 1H), 3.68 (s, 3H), 2.98–2.85 (m, 2H), 2.60–2.47 (m,
2H). 13C NMR (100 MHz, CD2Cl2) δ 171.8 (C), 155.5 (C),
137.8 (C), 136.9 (C), 129.3 (CH), 127.5 (CH), 128.4 (CH),
127.9 (CH), 127.8 (CH), 126.6 (CH), 66.3 (CH2), 51.6 (CH3),
49.5 (CH), 40.3 (CH2), 37.8 (CH2). IR (ATR-FTIR), cm–1:
3334 (br), 2952 (w), 1720 (s), 1527 (m), 1249 (m), 1046 (m),
743 (m), 699 (m). HRMS-EI (m/z): [M + H]+ calcd for
C19H22NO4, 328.1549; found, 328.1544.
A 10-mL round-bottomed flask fitted with a rubber sep-
tum was charged sequentially with 1-(2,2-dibromovinyl)-
4-methoxybenzene (11d, 73.0 mg, 250 μmol, 1 equiv) and
cobalt bis(acetylacetonate) (64.3 mg, 250 μmol, 1.00
equiv). The reaction vessel was evacuated and refilled
using a balloon of dioxygen. This process was repeated
two times. iso-Propanol (830 μL), triethylsilane (199 μL,
1.25 mmol, 5.00 equiv), and a solution of tert-butyl hy-
droperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred for 12 h at 24 C.
The product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. The resi-
due obtained was purified by automated flash-column
chromatography (eluting with hexane initially, grading to
20% ether–hexanes, linear gradient) to afford iso-propyl
2-(4-methoxyphenyl)acetate (12n, colorless oil, 41.0 mg,
Hydrolysis
of
benzyl
4-
(11o;
(dibromomethylene)piperidine-1-carboxylate
Table 3, entry 15). Following the general procedure A
using benzyl 4-(dibromomethylene)piperidine-1-
carboxylate (11o, 97.3 mg, 250 μmol, 1 equiv). Reaction
time was 12 h. Purification by automated flash-column
chromatography (eluting with hexanes initially, grading
to 15% ethyl acetate–hexanes, linear gradient) afforded 1-
benzyl 4-methyl piperidine-1,4-dicarboxylate (12m, color-
less oil, 57.4 mg, 83%).
Following the general procedure B using benzyl 4-
(dibromomethylene)piperidine-1-carboxylate (11o, 97.3
mg, 250 μmol, 1 equiv). Reaction time was 12 h. Purifica-
tion by automated flash-column chromatography (eluting
with hexanes initially, grading to 15% ethyl acetate–
hexanes, linear gradient) afforded 1-benzyl 4-methyl pi-
peridine-1,4-dicarboxylate (12m, colorless oil, 61.9 mg,
89%). Rf = 0.45 (20% ethyl acetate–hexanes; UV, CAM).
1H NMR (400 MHz, CDCl3) δ 7.38–7.29 (m, 5H), 5.12 (s,
2H), 4.11 (br s), 3.69 (s, 3H), 2.93 (t, 2H, J = 12.6 Hz), 2.50–
2.45 (m, 1H), 1.91–1.88 (m, 2H), 1.70–1.60 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 174.8 (C), 155.2 (C), 136.7 (C),
128.5 (CH), 128.0 (CH), 127.8 (CH), 67.1 (CH2), 51.8 (CH3),
43.2 (CH2), 40.8 (CH), 27.9 (CH2). 1H and 13C NMR data
for 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (12m)
prepared in this way were in agreement with those previ-
ously described.62
1
79%). Rf = 0.55 (20% ether–hexanes; UV, CAM). H NMR
(500 MHz, CDCl3) δ 7.20 (d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J
= 8.5 Hz), 5.02–4.99 (m, 1H), 3.79 (s, 3H), 3.52 (s, 2H), 1.22
(d, 6H, J = 6.5 Hz). 13C NMR (100 MHz, CDCl3) δ 171.4 (C),
158.6 (C), 130.2 (CH), 126.4 (C), 113.9 (CH), 68.0 (CH), 55.3
(CH3), 40.8 (CH2), 21.8 (CH3). 1H and 13C NMR data for
iso-propyl 2-(4-methoxyphenyl)acetate (12n) prepared in
this way were in agreement with those previously de-
scribed.53
Hydrolysis
of
1-(2,2-dibromovinyl)-4-
methoxybenzene (11d) with tert-butanol (Table 4,
entry 2). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 1-(2,2-
dibromovinyl)-4-methoxybenzene (11d, 73.0 mg, 250 μmol,
1 equiv), lithium acetylacetoante (39.8 mg, 375 μmol, 1.50
equiv), and cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol,
0.25 equiv). The reaction vessel was evacuated and re-
filled using a balloon of dioxygen. This process was re-
peated two times. tert-Butanol (830 μL), triethylsilane
(199 μL, 1.25 mmol, 5.00 equiv), and a solution of tert-
butyl hydroperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol,
1.00 equiv) were added sequentially to the reaction vessel
via syringe. The reaction mixture was stirred for 12 h at 24
C. The product mixture was concentrated to dryness
Hydrolysis
of
1-(2,2-dibromovinyl)-4-
methoxybenzene (11d) with iso-propanol (Table 4,
entry 1). A 10-mL round-bottomed flask fitted with a
rubber septum was charged sequentially with 1-(2,2-
dibromovinyl)-4-methoxybenzene (11d, 73.0 mg, 250 μmol,
1 equiv), lithium acetylacetoante (39.8 mg, 375 μmol, 1.50
equiv), and cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol,
0.25 equiv). The reaction vessel was evacuated and re-
filled using a balloon of dioxygen. This process was re-
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The Journal of Organic Chemistry
Page 28 of 32
and the residue obtained was filtered through a short col- sulfate. The dried solution was filtered and the filtrate
1
2
3
4
5
6
7
8
umn of silica gel and the short column was rinsed with 50%
ethyl acetate–hexanes (100 mL). The filtrates were com-
bined and the combined filtrates were concentrated. The
residue obtained was purified by automated flash-column
chromatography (eluting with hexane initially, grading to
20% ether–hexanes, linear gradient) to afford tert-butyl 2-
(4-methoxyphenyl)acetate (12o, colorless oil, 27.6 mg,
49%).
was concentrated. The residue obtained was purified by
automated flash-column chromatography (eluting with
20% ether–1% acetic acid–hexanes, isocratic gradient) to
afford 2-(4-methoxyphenyl)acetic acid (12p, off-white
solid, 13.3 mg, 32%).
A 10-mL round-bottomed flask fitted with a rubber sep-
tum was charged sequentially with 1-(2,2-dibromovinyl)-
4-methoxybenzene (11d, 73.0 mg, 250 μmol, 1 equiv) and
cobalt bis(acetylacetonate) (64.3 mg, 250 μmol, 1.00
equiv). The reaction vessel was evacuated and refilled
using a balloon of dioxygen. This process was repeated
two times. Tetrahydrofuran (830 μL), water (45.0 μL, 2.50
mmol, 10.0 equiv), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 12 h at 24 C. The product
mixture was transferred to a separatory funnel that had
been charged with ethyl acetate (20 mL). The diluted
product mixture was washed with 1 N aqueous hydrochlo-
ric acid solution (20 mL). The aqueous layer was isolated
and the isolated aqueous layer was extracted with ethyl
acetate (3  20 mL). The organic layers were combined
and the combined organic layers were dried over sodium
sulfate. The dried solution was filtered and the filtrate
was concentrated. The residue obtained was purified by
automated flash-column chromatography (eluting with
20% ether–1% acetic acid–hexanes, isocratic gradient) to
afford 2-(4-methoxyphenyl)acetic acid (12p, off-white
solid, 29.5 mg, 71%). Rf = 0.19 (20% ethyl acetate–1% ace-
9
A 10-mL round-bottomed flask fitted with a rubber sep-
tum was charged sequentially with 1-(2,2-dibromovinyl)-
4-methoxybenzene (11d, 73.0 mg, 250 μmol, 1 equiv) and
cobalt bis(acetylacetonate) (64.3 mg, 250 μmol, 1.00
equiv). The reaction vessel was evacuated and refilled
using a balloon of dioxygen. This process was repeated
two times. tert-Butanol (830 μL), triethylsilane (199 μL,
1.25 mmol, 5.00 equiv), and a solution of tert-butyl hy-
droperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred for 12 h at 24 C.
The product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. The resi-
due obtained was purified by automated flash-column
chromatography (eluting with hexane initially, grading to
20% ether–hexanes, linear gradient) to afford tert-butyl 2-
(4-methoxyphenyl)acetate (12o, colorless oil, 37.7 mg,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
68%). Rf = 0.55 (20% ether–hexanes; UV, CAM). H NMR
(500 MHz, CDCl3) δ 7.19 (d, 2H, J = 8.5 Hz), 6.86 (d, 2H, J
= 8.5 Hz), 3.80 (s, 3H), 3.46 (s, 2H), 1.44 (s, 9H). 13C NMR
(125 MHz, CDCl3) δ 171.0 (C), 158.5 (C), 130.2 (CH), 127.0
(C), 113.7 (CH), 80.4 (C), 55.1 (CH3), 41.5 (CH2), 27.7 (CH3).
1H and 13C NMR data for tert-butyl 2-(4-
methoxyphenyl)acetate (12o) prepared in this way were in
agreement with those previously described.63
1
tic acid–hexanes; UV, CAM). mp 66−68 °C. H NMR (500
MHz, CDCl3) δ 11.8 (br s, 1H), 7.21 (d, 2H, J = 8.4 Hz), 6.88
(d, 2H, J = 8.4 Hz), 3.80 (s, 3H), 3.59 (s, 2H). 13C NMR (125
MHz, CDCl3) δ 178.4 (C), 158.9 (C), 130.4 (CH), 125.3 (C),
114.1 (CH), 55.3 (CH3), 40.2 (CH2). 1H and 13C NMR data
for 2-(4-methoxyphenyl)acetic acid (12p) prepared in this
way were in agreement with those previously described.64
Hydrolysis
of
1-(2,2-dibromovinyl)-4-
methoxybenzene (11d) with water (Table 4, entry 3).
A 10-mL round-bottomed flask fitted with a rubber sep-
tum was charged sequentially with 1-(2,2-dibromovinyl)-
4-methoxybenzene (11d, 73.0 mg, 250 μmol, 1 equiv), lith-
ium acetylacetoante (39.8 mg, 375 μmol, 1.50 equiv), and
cobalt bis(acetylacetonate) (16.1 mg, 62.5 μmol, 0.25
equiv). The reaction vessel was evacuated and refilled
using a balloon of dioxygen. This process was repeated
two times. Tetrahydrofuran (830 μL), water (45.0 μL, 2.50
mmol, 10.0 equiv), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 12 h at 24 C. The product
mixture was transferred to a separatory funnel that had
been charged with ethyl acetate (20 mL). The diluted
product mixture was washed with 1 N aqueous hydrochlo-
ric acid solution (20 mL). The aqueous layer was isolated
and the isolated aqueous layer was extracted with ethyl
acetate (3  20 mL). The organic layers were combined
and the combined organic layers were dried over sodium
Hydrolysis of (R)-2-bromocyclohex-2-en-1-yl ben-
zoate [(R)-1g; Scheme 5]. Following the general proce-
dure A using (R)-2-bromocyclohex-2-en-1-yl benzoate
[(R)-1g, 70.3 mg, 250 μmol, 1 equiv]. Reaction time was 12
h. Purification by automated flash-column chromatog-
raphy (eluting with 7.5% ethyl acetate–10% dichloro-
methane–hexanes, isocratic gradient) afforded 2-
oxocyclohexyl benzoate [(R)-3d, white solid, 42.2 mg,
77%]. The enantiomeric ratio of (R)-3d prepared this way
was determined to be 95:5 by chiral stationary phase
HPLC analysis (Chiralpak OD-H: 10% iso-propanol–
hexanes, 24 C, 1.0 mL/min, λ = 254 nm, tR(major) = 7.5 min,
tR(minor) = 10.5 min).
Following the general procedure
B
using 2-
bromocyclohex-2-en-1-yl benzoate [(R)-1g, 70.3 mg, 250
μmol, 1 equiv]. Reaction time was 12 h. Purification by
automated flash-column chromatography (eluting with
7.5% ethyl acetate–10% dichloromethane–hexanes, iso-
cratic gradient) afforded 2-oxocyclohexyl benzoate [(R)-
3d, white solid, 48.6 mg, 89%]. The enantiomeric ratio of
(R)-3d prepared this way was determined to be 95:5 by
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The Journal of Organic Chemistry
chiral stationary phase HPLC analysis (Chiralpak OD-H: equiv), and a solution of tert-butyl hydroperoxide in non-
1
2
3
4
5
6
7
8
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 12 h at 24 C. The product
mixture was concentrated to dryness and the residue ob-
tained was filtered through a short column of silica gel
and the short column was rinsed with 50% ethyl acetate–
hexanes (100 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 20% ether–hexane, isocratic gradi-
ent) to afford benzyl 4-(((trifluoromethyl)sulfonyl)oxy)-
3,6-dihydropyridine-1(2H)-carboxylate (1k, colorless oil,
87.9 mg, 96%).
10% iso-propanol–hexanes, 24 C, 1.0 mL/min, λ = 254 nm,
tR(major) = 7.5 min, tR(minor) = 10.5 min).
1H and 13C NMR data for (R)-2-oxocyclohexyl benzoate
[(R)-3d] prepared in this way were in agreement with its
racemic form.
Control Studies for the Hydrolysis of methyl 4-(1-
acetoxyvinyl)benzoate (1j, Table S1, Entry 1). A 10-mL
round-bottomed flask fitted with a rubber septum was
9
charged
sequentially
with
methyl
4-(1-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
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55
56
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58
59
60
acetoxyvinyl)benzoate (1j, 55.1 mg, 250 μmol, 1 equiv) and
lithium acetylacetoante (39.8 mg, 375 μmol, 1.50 equiv).
The reaction vessel was evacuated and refilled using a
balloon of dioxygen. This process was repeated two times.
Methanol (830 μL), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 12 h at 24 C. The product
mixture was concentrated to dryness and the residue ob-
tained was filtered through a short column of silica gel
and the short column was rinsed with 50% ethyl acetate–
hexanes (100 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 20% ethyl acetate–hexane, isocrat-
ic gradient) to afford methyl 4-acetylbenzoate (3f, white
solid, 43.3 mg, 97%).
A 10-mL round-bottomed flask fitted with a rubber sep-
tum was charged sequentially with benzyl 4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1k, 91.3 mg, 250 μmol, 1 equiv). The
reaction vessel was evacuated and refilled using a balloon
of dioxygen. This process was repeated two times. Meth-
anol (830 μL), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 12 h at 24 C. The product
mixture was concentrated to dryness and the residue ob-
tained was filtered through a short column of silica gel
and the short column was rinsed with 50% ethyl acetate–
hexanes (100 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 20% ether–hexane, isocratic gradi-
ent) to afford benzyl 4-(((trifluoromethyl)sulfonyl)oxy)-
3,6-dihydropyridine-1(2H)-carboxylate (1k, colorless oil,
86.8 mg, 95%).
A 10-mL round-bottomed flask fitted with a rubber sep-
tum was charged sequentially with methyl 4-(1-
acetoxyvinyl)benzoate (1j, 55.1 mg, 250 μmol, 1 equiv).
The reaction vessel was evacuated and refilled using a
balloon of dioxygen. This process was repeated two times.
Methanol (830 μL), triethylsilane (199 μL, 1.25 mmol, 5.00
equiv), and a solution of tert-butyl hydroperoxide in non-
ane (~5.5 M, 45.5 μL, 250 μmol, 1.00 equiv) were added
sequentially to the reaction vessel via syringe. The reac-
tion mixture was stirred for 12 h at 24 C. The product
mixture was concentrated to dryness and the residue ob-
tained was filtered through a short column of silica gel
and the short column was rinsed with 50% ethyl acetate–
hexanes (100 mL). The filtrates were combined and the
combined filtrates were concentrated. The residue ob-
tained was purified by automated flash-column chroma-
tography (eluting with 20% ethyl acetate–hexane, isocrat-
ic gradient) to afford methyl 4-(1-acetoxyvinyl)benzoate
(1j, white solid, 52.5 mg, 95%).
Control Studies for the Hydrolysis of 2-(1-(2-
chlorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane (1t, Table S1, Entry 3). A 10-mL round-
bottomed flask fitted with a rubber septum was charged
sequentially with 2-(1-(2-chlorophenyl)vinyl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane (1t, 66.1 mg, 250 μmol, 1
equiv) and lithium acetylacetoante (39.8 mg, 375 μmol,
1.50 equiv). The reaction vessel was evacuated and re-
filled using a balloon of dioxygen. This process was re-
peated two times. Methanol (830 μL), triethylsilane (199
μL, 1.25 mmol, 5.00 equiv), and a solution of tert-butyl
hydroperoxide in nonane (~5.5 M, 45.5 μL, 250 μmol, 1.00
equiv) were added sequentially to the reaction vessel via
syringe. The reaction mixture was stirred for 12 h at 24 C.
The product mixture was concentrated to dryness and the
residue obtained was filtered through a short column of
silica gel and the short column was rinsed with 50% ethyl
acetate–hexanes (100 mL). The filtrates were combined
and the combined filtrates were concentrated. The resi-
due obtained was purified by automated flash-column
chromatography (eluting with hexanes initially, grading
to 12% ether–hexanes, linear gradient) to afford separately
2-(1-(2-chlorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-
Control Studies for the Hydrolysis of benzyl 4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-
dihydropyridine-1(2H)-carboxylate (1k, Table S1, En-
try 2). A 10-mL round-bottomed flask fitted with a rub-
ber septum was charged sequentially with benzyl 4-
(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-
1(2H)-carboxylate (1k, 91.3 mg, 250 μmol, 1 equiv) and
lithium acetylacetoante (39.8 mg, 375 μmol, 1.50 equiv).
The reaction vessel was evacuated and refilled using a
balloon of dioxygen. This process was repeated two times.
Methanol (830 μL), triethylsilane (199 μL, 1.25 mmol, 5.00
ACS Paragon Plus Environment