Palladium(II)-catalyzed enantioselective synthesis of 2-vinyl oxygen heterocycles

Article abstract of DOI:10.1021/jo202553a

2-Vinylchromanes (1), 2-vinyl-1,4-benzodioxanes (2), and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazines (3) can be prepared in high yields (90-98%) and excellent enantiomeric purities (87-98% ee) by [COP-OAc] ₂-catalyzed cyclization of phenolic (E)-allylic trichloroacetimidate precursors. Deuterium-labeling and computational experiments are consistent with these cyclization reactions taking place by an anti-oxypalladation/syn- deoxypalladation mechanism. 2-Vinylchromanes can also be prepared in good yields and high enantiomeric purities from analogous (E)-allylic acetate precursors, which constitutes the first report that acetate is a competent leaving group in COP-catalyzed enantioselective S_N2′ substitution reactions.

Full text of DOI:10.1021/jo202553a

Article
pubs.acs.org/joc
Palladium(II)-Catalyzed Enantioselective Synthesis of 2-Vinyl Oxygen
Heterocycles
Jeffrey S. Cannon, Angela C. Olson, Larry E. Overman,* and Nicole S. Solomon†
Department of Chemistry, 1102 Natural Sciences II, University of California, Irvine, California 92697-2025, United States
S
* Supporting Information
ABSTRACT: 2-Vinylchromanes (1), 2-vinyl-1,4-benzodioxanes
(2), and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazines (3) can be
prepared in high yields (90−98%) and excellent enantiomeric
purities (87−98% ee) by [COP-OAc]2-catalyzed cyclization of
phenolic (E)-allylic trichloroacetimidate precursors. Deuterium-
labeling and computational experiments are consistent with these
cyclization reactions taking place by an anti-oxypalladation/syn-deoxypalladation mechanism. 2-Vinylchromanes can also be
prepared in good yields and high enantiomeric purities from analogous (E)-allylic acetate precursors, which constitutes the first
report that acetate is a competent leaving group in COP-catalyzed enantioselective SN2′ substitution reactions.
INTRODUCTION
■
2-Alkenyl- and 2-alkylchromanes (4),1 1,4-benzodioxanes (5),
and 2,3-dihydro-2H-1,4-benzoxazines (6) are heterocyclic
fragments found in many molecules exhibiting useful
therapeutic properties.2 The corresponding enantioenriched
2-vinyl heterocycles2-vinylchromanes (1), 2-vinyl-1,4-benzo-
dioxanes (2), and 2,3-dihydro-2-vinyl-2H-1,4-benzoxazines
(3)would be attractive precursors for the enantioselective
synthesis of many heterocycles 4−6 (eq 1).3 Previously
Figure 1. Selected palladium(II) catalysts of the COP family.
reported catalytic enantioselective methods for preparing 2-
RESULTS AND DISCUSSION
■
vinyl heterocycles 1−3 involve Pd(0)- or Ir(I)-catalyzed
cyclization reactions that proceed via η3-allyl intermediates to
form the allylic C−O σ-bond.4−6 The development of an
alternative palladium(II)-catalyzed construction of enantioen-
Enantioselective Synthesis of 2-Vinylchromanes, 2-
Vinyl-1,4-benzodioxanes, and 2,3-Dihydro-2-vinyl-2H-
1,4-benzoxazines from Allylic Trichloroacetimidate
Precursors. Our studies began by examining the cyclization
of phenolic (E)-allylic imidate 11a10 in the presence of 2 mol %
of various palladium(II) catalysts (Table 1). At 38 °C in
CH2Cl2, the COP complexes [(Sp,R)-COP-OAc]2 (7) and
(Rp,S)-COP-acac (10) catalyzed the formation of 2-vinyl-
chromane (1a) in high yields and 89 and 80% ee, respectively
(entries 1 and 2). As expected, allylic imidate rearrangement to
form transposed allylic amide 12 was a significant competing
process when chloride-bridged complex ent-9 was employed
(entry 3).11 Trichloroacetamidate-bridged dimer 8, previously
reported by our group to be a kinetically poor catalyst for allylic
trichloroacetimidate rearrangements,8 did not suppress com-
riched 2-vinyl heterocycles 1−3 is the subject of this account.
Our investigations in this area are an outgrowth of the
recently reported enantioselective synthesis of 3-phenoxy-1-
alkenes from the reaction of phenols and allylic trichloroace-
timidates using palladium(II) catalysts of the COP family
(Figure 1).7−9 Herein we disclose our studies of the
intramolecular variant of this chemistry, in which tethered
(E)-allylic imidates yield 2-vinylchromanes (1), 2-vinyl-1,4-
benzodioxanes (2), and 2,3-dihydro-2-vinyl-2H-1,4-benzoxa-
zines (3) in good yields and high enantiomeric purities (eq 2).
We report also that the enantioselective synthesis of chromane
1 can be accomplished with substrates having an acetate rather
than a trichloroacetimidate leaving group.
Received: December 15, 2011
Published: February 8, 2012
© 2012 American Chemical Society
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Table 1. Catalytic Enantioselective Synthesis of 2-Vinylchromanes 1a−c
a
b
b
c
entry
substrate
R
catalyst (mol %)
temp (°C)
yield (%) 12
yield (%)1
ee (%) 1
d
1
2
3
4
5
6
7
(E)-11a
(E)-11a
(E)-11a
(E)-11a
(E)-11a
(E)-11a
(E)-11b
(E)-11b
(E)-11c
(Z)-11a
H
H
H
H
H
H
7 (2)
38
38
38
38
23
23
23
23
23
23
86
72
41
81
89 (R)
10 (2)
80 (S)
80 (S)
87 (R)
ent-9 (2)
8 (2)
43
13
e
e
7 (0.5)
ent-7 (0.5)
7 (0.5)
7 (0.5)
7 (0.5)
ent-7 (0.5)
91
94 (R)
e
e
97
92 (S)
e
e
4-Br
96
80
f
e
e
8
4-Br
94
90
g
e
d,e
9
4-OMe
92
91 (R)
e
e
10
H
92
9 (R)
a
b
c
[11] = 0.2 M; reaction time 8−18 h. Isolated yield after purification on silica gel. Determined by HPLC analysis using an enantioselective
stationary phase. Absolute configuration determined by comparison of optical rotation data with that reported in the literature.4b Mean values of
duplicate reactions. The solvent was CHCl3. Reaction time was 30 h.
d
e
f
g
Table 2. Catalytic Enantioselective Synthesis of 2-Vinyl-1,4-benzodioxanes (2, 17) and 2-Vinyl-2H-1,4-benzoxazines (3)
a
b
entry
X
R
imidate
catalyst (mol %)
time (h)
product
yield (%)
ee (%)
c
1
2
3
4
5
O
H
13
13
14
15
16
7 (0.5)
7 (2)
72
18
15
72
18
2
92
90
98
30
0
92 (S)
c
O
H
2
94 (S)
c
NTs
O
H
7 (2)
3
98 (S)
d
Me
H
ent-7 (5)
7 (5)
17
18
85
S
a
b
Mean yields after purification on silica gel of reactions performed in duplicate. Determined by HPLC analysis using a enantioselective stationary
c
phase (mean value of duplicate reactions). Absolute configuration determined by comparison of optical rotation data with those reported in the
literature.6c,d Absolute configuration was not established.
d
pletely the competitive formation of allylic amide 12 (entry 4).
Reactions were sufficiently rapid that a catalyst loading of 0.5
mol % could be employed in reactions carried out at room
temperature where enantioselectivity was improved to 92−94%
ee (entries 5 and 6). With [COP-OAc]2 identified as the most
effective catalyst, several additional solvents were examined.
Enantioselectivity was enhanced to 98% ee in toluene-d8;
however, competitive formation of amide 12 was observed in
this solvent.12 The best combination of catalyst rate and
enantioselectivity was obtained in CH2Cl2 at room temper-
ature, conditions that we utilized in most subsequent
experiments. The 4-bromo- and 4-methoxyphenol analogues
cyclized similarly, although enantioselection was lower with the
bromophenol precursor, and catalysis rate lower with the
methoxy congener (entries 7−9). As observed in related
bimolecular reactions,8 enantioselectivity in the cyclization of
the 4-bromophenol precursor was increased when CHCl3 was
employed as the solvent (entry 8). In marked contrast, the Z
allylic imidate stereoisomer cyclized to form 2-vinylchromane
(1a) of negligible enantiomeric purity (entry 10).
COP catalyst 7, 2-vinylbenzodioxane 2 was formed in 92% ee;
however, a reaction time of 72 h was required (entry 1).
Increasing the catalyst loading to 2 mol % gave 2 and 3 in high
yield and 94% and 98% ee, respectively, after reaction times of
15−18 h (entries 2 and 3). The E-trisubstituted allylic
precursor 15 provided benzodioxane 17 in 85% ee, albeit in
only 30% yield after a reaction time of 72 h (entry 4). Although
the yield of 17 was modest, this transformation is notable
because it represented the first example of COP-catalyzed
formation of a tetrasubstituted stereocenter.13 The reaction
could not be extended to the formation of 2,3-dihydro-2-vinyl-
2H-1,4-benzothiopyran (18), presumably as a result of
coordination of the palladium(II) catalyst to sulfur.12
Enantioselective Synthesis of 2-Vinylchromanes from
Allylic Acetate Precursors. Trichloroacetimidates are widely
used leaving groups, largely because they can be prepared in
high yields from trichloroacetonitrile and most alcohols
including quite labile onesunder mild conditions (catalytic
DBU at room temperature).14,15 The disadvantage in their use
is the production of trichloroacetamide (MW = 144) as a
byproduct. In a preliminary survey, we found that acetate was
an adequate leaving group for the [COP-OAc]2-catalyzed
cyclization of phenolic (E)-allylic acetate 19a to form 2-
vinylchromane (Table 3).16 In CH2Cl2, cyclohexane, or
2-Vinyl-1,4-benzodioxane (2) and 2,3-dihydro-2-vinyl-2H-
1,4-benzoxazine (3) can be prepared in similar fashion in high
yield and enantiopurity, although the catalysis rate is somewhat
slower (Table 2). For example, in the presence of 0.5 mol % of
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Table 3. Catalytic Enantioselective Synthesis of 2-Vinylchromane ent-1a from Allylic Acetate Precursor (E)-19a18
a
b
c
d
entry
solvent
CH2Cl2
temp (°C)
additive
conversion (%)
ee (%)
1
2
3
40
40
40
60
23
23
23
23
23
23
23
23
none
none
none
none
33
27
43
71
73
>95
93
41
26
55
88
64
84
85
84
91
91
82
73
84
94
93
92
93
toluene
cyclohexane
MeOH
e
4
e
e
e
,
,
f
f
5
6
7
8
9
CH2Cl2
cyclohexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
K2CO3
K2CO3
K3PO4
Et3N
CsF
e
e
e
e
,
,
,
f
10
11
12
KF
g
KF
h
KF
a
b
c
d
[(E)-19a] = 0.2 M, unless otherwise indicated. 1 equiv was used. Determined by 1H NMR analysis using an internal standard. Determined by
e
f
HPLC analysis using a enantioselective stationary phase. Reaction was heterogeneous. When the identical reaction was performed in the absence of
ent-7, only (E)-19a was observed by H NMR analysis. [(E)-19a] = 1.0 M. 1 mol % of [(Rp,S)-COP-OAc]2 (ent-7) was employed.
g
h
1
a
Table 4. Catalytic Enantioselective Synthesis of 2-Vinylchromane ent-1a from Allylic Acetate Precursors 19
b
c
d
entry
R
19
solvent
time (h)
yield (%)
ee (%)
1
2
3
4
5
H
(E)-19a
(E)-19b
(E)-19b
(E)-19c
(Z)-19a
CH2Cl2
CH2Cl2
CHCl3
CH2Cl2
24
6
89
82
92
95
91
94 (S)
88
4-Br
4-Br
4-OMe
H
10
36
24
90
95 (S)
18−51 (S)
CH2Cl2
b
a
c
All reactions reported in this table were heterogeneous. [19] = 1.0 M. Mean yields after purification on silica gel of reactions performed in
duplicate. Determined by HPLC analysis using a enantioselective stationary phase (mean value of duplicate reactions).
d
toluene, acetate (E)-19a cyclized in the presence of 2 mol % of
[COP-OAc]2 to form ent-1a in 84−85% ee (entries 1−3),
whereas significantly lower enantioselectivity was observed in
CH3CN, DMF, and THF. Though the use of the alcoholic
solvents EtOH, i-PrOH, cyclohexanol, or t-BuOH typically
resulted in low conversions (5−20%) and moderate enantio-
selectivities (72−84% ee), to our surprise, excellent enantiose-
lectivity was obtained in MeOH. Increasing the reaction
temperature to 60 °C gave rise to chromane ent-1a in 71% yield
and 91% ee after 20 h using 2 mol % of [(Rp,S)-COP-OAc]2
(ent-7) (entry 4). However, enantiomeric purity of the product
ent-1a begins to erode at ∼15−20 h, which is attributed to
protodemetalation of [COP-OAc]2 at 60 °C to generate an
achiral palladium(II) catalyst. More success was realized by
adding bases. For example, adding K2CO3 (1 equiv) increased
conversion in reactions carried out at room temperature in
CH2Cl2 or cyclohexane to 73% and >95%, respectively (entries
5 and 6). Since enantioselectivity was higher in CH2Cl2, further
optimization of the base was carried out in this solvent (entries
7−12). Heterogeneous bases performed better than Et3N
(entry 8). As expected in the heterogeneous reactions,17
conversions and enantioselectivities were highly dependent
upon the physical state of the solid bases employed.
Conversions were generally highest when K2CO3 was used;
however, reproducible yields and enantioselectivities were best
achieved using powdered, dried KF with rapid stirring. The
optimal conditions for the conversion of 19 to ent-1a were
found to be 2 mol % of [(Rp,S)-COP-OAc]2 (ent-7), 1 equiv of
KF, [19] = 1.0 M CH2Cl2, 23 °C (entry 11).
The results of the synthesis of 2-vinylchromanes ent-1a−c
from the corresponding allylic acetate precursors under these
optimized conditions are summarized in Table 4. In all three
cases, yields (89−95%) and enantioselectivities (88−95%) were
excellent. The (Z)-allylic ester (Z)-19a was also transformed to
chromane ent-1a under these conditions, although as observed
with the corresponding trichloroacetimidate precursor, enan-
tioselectivity was low (entry 5).
Geometry of the Intramolecular SN2′ Reaction. To gain
insight into the mechanism of the [COP-OAc]2-catalyzed
cyclization reactions in both the imidate and acetate series, the
cyclization of two enantioenriched deuterium-labeled substrates
was examined (eqs 3 and 4). As in our study of the geometry of
related bimolecular SN2′ reactions,7b the allylic alcohol
precursors of deuterated enantioenriched imidate and acetate
cyclization substrates were prepared by enantioselective Keck
reduction of the corresponding enal.12,19 In both series, chirality
transfer was complete within experimental error and in accord
with an antarafacial SN2′ geometry.
The antarafacial geometry of the SN2′ cyclization to form 2-
vinylchromane (1a) from both the (E)-allylic trichloroacetimi-
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study. All atoms were represented by the def2-TZVP basis set24
except for the carbon and hydrogen atoms of the
tetraphenylcyclobutadiene unit of catalyst ent-7, which were
represented by the SZ.benzene basis set.25
For each double-bond isomer, two pathways were inves-
tigated: anti-oxypalladation where the catalyst ent-7 was bound
to the imidate nitrogen and the Re (pathways (E)-I or (Z)-I) or
Si face (pathways (E)-II or (Z)-II) of the double bond (Figure
2).7b Oxypalladation of Re-bound catalyst complex 24 occurs by
transition structure 25 to provide palladated benzopyran
complex 26 (Figure 2, pathway (E)-I); this elementary step
requires 0.3 kcal/mol in activation energy and is exergonic by
21.0 kcal/mol. Deoxypalladation of 26 would yield (S)-2-
vinylchromane. The Si-bound complex 21 undergoes oxy-
palladation with an activation energy of 1.4 kcal/mol by
transition structure 22 to give palladated-chromane complex 23
with the overall release of 20.1 kcal/mol (Figure 2, pathway
(E)-II). Further reaction of this intermediate would form (R)-
2-vinylchromane. Oxypalladation via pathway (E)-I to form the
observed S enantiomer of 1a is calculated to be favored by
ΔΔE⧧ of 3.7 kcal/mol. In contrast, the transition-state energy
differences for oxypalladation of the two (Z)-imidate complexes
(pathways (Z)-I and (Z)-II) are calculated to differ in energy
by only 0.8 kcal/mol, consistent with the low selectivity
observed in the cyclization of the (Z)-imidate precursor.
Analysis of the two calculated transition structures, 22 and
25, for cyclization of the (E)-allylic imidate substrate provided
some insight into the factors contributing to the high levels of
enantioselectivity observed in the [COP-OAc]2-catalyzed
cyclization reaction (Figure 3).26 The closest contact (2.36
Å) seen in low energy transition structure 25 is between H4 and
the cyclopentadiene fragment (HCp), with the remaining
interatomic distances being outside of van der Waals contact.
In contrast, oxypalladation transition structure 22 that leads to
the minor observed enantiomer shows several destabilizing
steric interactions. In particular, imidate hydrogen H4 is 2.26 Å
from the cyclopentadiene fragment (HCp), and H5 is 2.73 Å
from the tetraphenylcyclobutadiene fragment (Cfloor). Unlike
transition structure 25, structure 22 has van der Waals contacts
between the hydrogens of the methylene chain (H4 and H5) of
the substrate and the COP ligand (Cfloor and HCp).27
date and (E)-allylic acetate precursors is identical to the
geometry of the bimolecular reaction of (E)-allylic imidates and
phenol in the presence of COP catalyst 8.7b In the context of an
oxypalladation/deoxypalladation mechanism, this result re-
quires that the two steps occur with opposite geometries. In
our earlier study of [COP-OAc]2-catalyzed allylic esterification
of (Z)-allylic imidates, computational modeling provided
evidence for an anti-oxypalladation/syn-deoxypalladation
mechanism.7b,20 Such a sequence for the formation of
vinylchromane (S)-1a is illustrated in Scheme 1.
Scheme 1. anti-oxypalladation/syn-deoxypalladation
Sequence for Forming (S)-1a
CONCLUSION
■
Using phenol-tethered (E)-allylic trichloroacetimidate precur-
sors, the catalytic enantioselective synthesis of 2-vinylchro-
manes, 2-vinyl-1,4-benzodioxanes, and 2,3-dihydro-2-vinyl-2H-
1,4-benzoxazines depicted in eq 2 takes place at room
temperature in 90−98% yield and 87−98% ee under neutral
conditions using 0.5 mol % of the palladacyclic catalyst [COP-
OAc]2. For the preparation of 2-vinylchromane (1a), 2-vinyl-
1,4-benzodioxane (2), and 2,3-dihydro-4-(4-toluenesulfonyl)-2-
vinyl-2H-1,4-benzoxazine (3), the catalytic enantioselective
syntheses reported herein are the first to provide these
products in both >90% yield and >90% ee.4−6 We also
demonstrate for the first time that acetate is a competent
leaving group in COP-catalyzed enantioselective SN2′ sub-
stitution reactions. In this way, 2-vinylchromanes 1a−c were
prepared in 82−95% yield and 88−95% ee.
Computational Studies. As the oxypalladation step has
been determined to be both rate- and enantiodetermining in
the [COP-OAc]2-catalyzed bimolecular reaction of (Z)-allylic
trichloroacetimidates with carboxylic acid nucleophiles,7b this
step of the [COP-OAc]2-catalyzed cyclization of (E)- and (Z)-
imidates 11a to form 2-vinylchromane was studied computa-
tionally. The objective was to ascertain whether or not an anti-
oxypalladation/syn-deoxypalladation mechanism would: (a)
explain the observation that stereoinduction was much higher
in the [COP-OAc]2-catalyzed cyclization of E allylic imidate
(E)-11a than the corresponding Z stereoisomer, and (b)
rationalize preferential formation of the S enantiomer of
dihydrobenzopyran 1a from the cyclization of (E)-11a
catalyzed by [(Rp,S)-COP-OAc]2 (ent-7). The TURBOMOLE
v6.221 program at the B3-LYP level of theory22 with a
continuum solvation model (COSMO)23 was utilized for this
Deuterium-labeling experiments establish that the catalytic
enantioselective cyclizations of both the (E)-allylic trichloro-
acetimidate and acetate precursors proceed by an antarafacial
geometry identical to that of the bimolecular reaction of (E)-
allylic trichloroacetimidates with phenols.7b DFT-modeling
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Figure 2. Calculated reaction coordinate diagrams for oxypalladation of (E)- and (Z)-allylic trichloroacetimidates 11a with COP catalyst ent-7.
clear colorless oil: 90% ee by enantioselective HPLC analysis [OJ
studies of the synthesis of 2-vinylchromane from the allylic
imidate precursor are consistent with an anti-oxypalladation/
syn-deoxypalladation identical to that of the corresponding
bimolecular reaction. We speculate that cyclization of the allylic
acetate precursor takes place in a similar fashion (Scheme 1),
although additional experimentation will be required to
establish this point. The computational studies rationalize the
observation that enantioselection is significantly higher with the
E than the Z allylic trichloroacetimidate substrate as well as the
overall sense of stereoinduction. This model for stereo-
induction supports earlier findings that the positioning of the
tetraphenylcyclobutadiene group beneath the palladium square-
plane is a key factor in achieving high levels of enantioselection
in reactions catalyzed by COP complexes.7b
column; flow: 0.5 mL/min; 100% n-hexane; λ = 230 nm; major
25
enantiomer tR 2=5 28.85 min, minor enantiomer tR = 32.63 min]; [α]D
25
25
−63.4, [α]577 −67.7, [α]546 −78.5, [α]435 −133.1 (c 0.40,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.20−7.18 (m, 2H), 6.74 (d,
J = 8.3, 1H), 5.96 (ddd, J = 16.3, 10.6, 5.6, 1H), 5.37 (d, J = 17.3, 1H),
5.25 (d, J = 10.6, 1H), 4.57−4.53 (m, 1H), 2.87−2.80 (m, 1H), 2.77−
2.72 (m, 1H), 2.09−2.04 (m, 1H), 1.87−1.79 (m, 1H); 13C NMR
(125 MHz, CDCl3) δ 153.7 (C), 137.2 (CH), 132.1 (CH), 130.3
(CH), 124.1 (C), 118.7 (CH), 116.7 (CH), 112.3 (C), 76.3 (CH),
27.1 (CH2), 24.1 (CH2); IR (thin film) 3083, 2927, 1648, 1236, 1040,
992 cm−1; HRMS (GC−MS) m/z calcd for C11H11BrO, (M)+
237.9993, found 237.9985.
(R)-2,3-Dihydro-6-methoxy-2-vinyl-2H-1-benzopyran (1c).
Following the general procedure for imidate cyclization with catalyst
7 (0.001 M in CH2Cl2, 0.6 mL, 0.0006 mmol), imidate (E)-11c (40
mg, 0.11 mmol) was converted to 1c (19 mg, 0.10 mmol, 92%), a clear
colorless oil: 91% ee by enantioselective HPLC analysis [OJ column +
OJ guard; flow: 0.5 mL/min; 99:1 n-hexane/2-propanol; λ = 210 nm;
major enantiomer tR = 24.82 min, minor enantiomer tR = 27.55 min];
EXPERIMENTAL SECTION
■
General Procedure for Synthesis of 2-Vinylheterocycles
from Allylic Trichloroacetimidate Precursors. A sealable 0.5-dram
glass vial equipped with a Teflon cap was charged with the
trichloroacetimidate precursor (0.077 mmol). A solution of [(Sp,R)-
COP-OAc]2 (7) or its enantiomer (ent-7) (0.001 M in CH2Cl2 or
CHCl3, 0.4 mL, 0.0004 mmol) was added via syringe. The reaction vial
was sealed under an Ar atmosphere, and the orange solution was
maintained at room temperature. After the reported reaction time, the
solution was concentrated in vacuo, and the residue was purified by
flash chromatography on silica gel to afford the 2-vinylheterocycle
product.
25
[α]D25 −83.7, [α]57725 −86.6, [α]54625 −99.3, [α]43525 −161.5, [α]405
1
−188.8 (c 0.54, CHCl3). H NMR and optical rotation data were
consistent with previously reported values.4b
(S)-2,3-Dihydro-2-vinyl-2H-1,4-benzodioxane (2).29 Following
the general procedure for imidate cyclization with catalyst 7 (0.004 M
in CH2Cl2, 0.6 mL, 0.0023 mmol), imidate 13 (38 mg, 0.12 mmol)
was converted to 2 (17 mg, 0.11 mmol, 90%), a clear colorless oil: 94%
ee by enantioselective HPLC analysis [OJ column + OJ guard; flow:
0.5 mL/min; 99:1 n-hexane/2-propanol; λ = 280 nm; major
enantiomer tR = 18.90 min, minor enantiomer tR = 20.19 min];
[α]D −6.5, [α]577 −3.7, [α]546 −4.1 (c 0.16, CHCl3). H NMR
and optical rotation data were consistent with previously reported
values.6c
(R)-2,3-Dihydro-2-vinyl-2H-1-benzopyran (1a). Following the
general procedure for imidate cyclization with catalyst 7 (0.001 M in
CH2Cl2, 0.4 mL, 0.0004 mmol), imidate (E)-11a (25 mg, 0.077
mmol) was converted to 1a (11 mg, 0.070 mmol, 91%), a clear
colorless oil: 94% ee by enantioselective HPLC analysis [OJ column +
OJ guard; flow: 0.5 mL/min; 100% n-hexane; λ = 280 nm; major
25
25
25
1
(S)-2,3-Dihydro-4-(4-toluenesulfonyl)-2-vinyl-2H-1,4-ben-
zoxazine (3).29 Following the general procedure for imidate
cyclization with catalyst 7 (0.004 M in CH2Cl2, 0.5 mL, 0.00021
mmol), imidate 14 (50 mg, 0.10 mmol) was converted to 3 (32 mg,
0.10 mmol, 98%), a pale yellow oil: 98% ee by enantioselective HPLC
analysis [AD column; flow: 1.0 mL/min; 80:20 n-hexane:isopropanol;
λ = 280 nm; minor enantiomer tR 2=5 6.09 min, major enantiomer tR =
25
enantiomer tR = 22.56 min, minor enantiomer tR = 25.41 min]; [α]D
−76.5, [α]57725 −85.0, [α]54625 −95.4, [α]43525 −168.8, [α]40525 −202.3
(c 0.27, CHCl3). H NMR and optical rotation data were consistent
1
with previously reported values.4b
(R)-6-Bromo-2,3-dihydro-2-vinyl-2H-1-benzopyran (1b).28
Following the general procedure for imidate cyclization with catalyst
7 (0.001 M in CHCl3, 0.4 mL, 0.0004 mmol), imidate (E)-11b (30
mg, 0.075 mmol) was converted to 1b (17 mg, 0.070 mmol, 94%), a
25
25
25
6.49 min]; [α]D +72.8, [α]577 +70.9, [α]546 +75.0, [α]435
1
+195.3, (c 0.25, CHCl3). H NMR and optical rotation data were
consistent with previously reported values.6d
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127.4 (CH), 121.9 (C), 120.3 (CH), 117.0 (CH), 116.1 (t, JCD = 23.8,
CDH), 76.2 (CH), 27.6 (CH2), 24.3 (CH2); IR (thin film) 3081,
2919, 1231, 1048, 975 cm−1; HRMS (CI) m/z calcd for C11H12DO,
(M + H)+ 162.1029, found 162.1023.
General Procedure for Synthesis of 2-Vinylchromanes from
Allylic Acetate Precursors. A sealable, oven-dried 0.5-dram glass vial
equipped with a stir bar and a Teflon cap was charged with [(Rp,S)-
COP-OAc]2 (ent-7) or its enantiomer (7) (2.7 mg, 0.0018 mmol) and
KF (5.3 mg, 0.091 mmol). The vial was sealed with a Teflon cap then
flame-dried and backfilled with Ar twice. Once the vial cooled to room
temperature, acetate (0.091 mmol) in CH2Cl2 or CHCl3 (0.09 mL, 1.0
M) was added via syringe. The reaction vial was sealed under an Ar
atmosphere and placed in an aluminum block, and the reaction was
stirred vigorously at room temperature. After the reported reaction
time, the heterogeneous brown reaction mixture was filtered, the
filtrate was concentrated in vacuo, and then the residue was purified by
flash chromatography on silica gel to afford the 2-vinylchromane
product.
(S)-2,3-Dihydro-2-vinyl-2H-1-benzopyran (ent-1a). Following
the general procedure for acetate cyclization with catalyst ent-7 (2.7
mg, 0.0018 mmol), acetate (E)-19a (1.0 M in CH2Cl2, 0.09 mL, 0.091
mmol) was converted to ent-1a (13 mg, 0.081 mmol, 89%), a clear
colorless oil: 94% ee by enantioselective HPLC analysis [OJ column +
OJ guard; flow: 0.5 mL/min; 100% n-hexane; λ = 280 nm; minor
1
enantiomer tR = 20.94 min, major enantiomer tR = 22.92 min]. H
NMR data were consistent with previously reported values.4b
(S)-6-Bromo-2,3-dihydro-2-vinyl-2H-1-benzopyran (ent-
1b).28 Following the general procedure for acetate cyclization with
catalyst ent-7 (2.0 mg, 0.0013 mmol), acetate (E)-19b (1.0 M in
CHCl3, 0.07 mL, 0.067 mmol) was converted to ent-1b (15 mg, 0.061
mmol, 92%), a clear colorless oil: 90% ee by enantioselective HPLC
analysis [OJ column; flow: 0.5 mL/min; 100% n-hexane; λ = 230 nm;
minor enantiomer tR = 30.55 min, major enantiomer tR = 32.78 min].
See characterization data for 1b for spectral details.
(S)-2,3-Dihydro-6-methoxy-2-vinyl-2H-1-benzopyran (ent-
1c). Following the general procedure for acetate cyclization with
catalyst ent-7 (1.8 mg, 0.0012 mmol), acetate (E)-19c (1.0 M in
CH2Cl2, 0.06 mL, 0.060 mmol) was converted to ent-1c (10.8 mg,
0.057 mmol, 95%), a clear colorless oil: 95% ee by enantioselective
HPLC analysis [OJ column + OJ guard; flow: 0.5 mL/min; 99:1 n-
hexane/2-propanol; λ = 210 nm; minor enantiomer tR = 22.64 min,
major enantiomer tR = 24.19 min]. 1H NMR data were consistent with
previously reported values.4b
Figure 3. Calculated transition structures for intramolecular oxy-
palladation of (E)-allylic trichloroacetimidates.
(S,E)-2-(2-Deuterovinyl)-1-benzopyran ((E)-ethenyl-2-d-(S)-
1a).31,32 Following the general procedure for acetate cyclization
with catalyst ent-7 (2.7 mg, 0.0018 mmol), acetate (E)-1-d-19a (20
mg, 0.090 mmol) was converted to (E)-ethenyl-2-d-(S)-1a (14 mg,
0.083 mmol, 92%), a clear colorless oil. Analysis by electrospray mass
spectrometry indicated a >96:4 ratio of d1-2-d-(S)-1a:d0-2-d-(S)-1a.
The E/Z ratio was calculated to be 82:18 using 1H NMR
spectroscopy: 91% ee by enantioselective HPLC analysis [OJ column
+ OJ guard; flow: 0.5 mL/min; 100% n-hexane; λ = 280 nm; minor
enantiomer tR = 20.82 min, major enantiomer tR = 22.48 min]. See
characterization data above for spectral details.
(R)-2,3-Dihydro-2-methyl-2-vinyl-1,4-benzodioxane
(17).28,29 Following the general procedure for imidate cyclization with
catalyst ent-7 (0.01 M in CH2Cl2, 0.3 mL, 0.0030 mmol), imidate 15
(20 mg, 0.059 mmol) was converted to 17 (3.2 mg, 0.018 mmol,
30%), a pale yellow oil: 85% ee by enantioselective HPLC analysis [OJ
column; flow: 0.5 mL/min; 99.5:0.5 n-hexane/2-propanol; λ = 280
nm; major enantiomer tR = 13.59 min, minor enantiomer tR = 14.95
min]; [α]D25 −3.6, [α]57725 −3.0, [α]54625 −8.1, [α]43525 −6.0, (c 0.05,
CHCl3). 1H NMR data were consistent with previously reported
values.30
Synthesis of Cyclization Precursors. 2-(4,4-Dibromobut-3-
enyl)phenol (34). Using a procedure by Kinoshita,33 chroman-
2-ol (33) (2.00 g, 13.3 mmol) was treated with CBr4 (8.83 g,
26.6 mmol) and PPh3 (13.9 g, 53.3 mmol). The crude light
yellow residue was purified by flash chromatography (99.5:0.5
CH2Cl2−acetone) to provide dibromide 34 (3.65 g, 11.9 mmol,
(S,E)-2-(2-Deuterovinyl)-1-benzopyran ((E)-ethenyl-2-d-(S)-
1a).31,32 Following the general procedure for imidate cyclization
with catalyst ent-7 (0.001 M in CH2Cl2, 0.4 mL, 0.0004 mmol),
imidate (E)-1-d-11a (25 mg, 0.077 mmol) was converted to (E)-
ethenyl-2-d-(S)-1a (9 mg, 0.058 mmol, 75%), a clear colorless oil.
Analysis by electrospray mass spectrometry indicated a >96:4 ratio of
d1-2-d-(S)-1a:d0-2-d-(S)-1a. The E:Z-ratio was calculated to be 80:20
using 1H NMR spectroscopy: 92% ee by enantioselective HPLC
analysis [OJ column + OJ guard; flow: 0.5 mL/min; 100% n-hexane; λ
= 280 nm; minor enantiomer tR = 22.23 min, major enantiomer tR =
1
90%) as a pale yellow oil: H NMR (500 MHz, CDCl3) δ
7.13−7.11 (m, 2H), 6.90 (t, J = 7.4, 1H), 6.75 (d, J = 7.9, 1H),
6.47 (t, J = 7.2, 1H), 4.74−4.70 (m, 1H), 2.75 (t, J = 7.7, 2H),
2.44 (app q, J = 7.5, 2H); 13C NMR (125 MHz, CDCl3) δ
153.6 (C), 138.1 (CH), 130.5 (CH), 127.7 (CH), 126.9 (C),
121.0 (CH), 115.4 (CH), 89.3 (C), 33.2 (CH2), 28.3 (CH2);
IR (thin film) 3541, 3032, 2927, 1591, 753 cm−1; HRMS (CI)
m/z calcd for C10H11Br2O, (M + H)+ 305.9078, found
305.9074.
25
24.51 min]; [α]D 2.5, (c 0.33, CH2Cl2); 1H NMR (500 MHz,
CDCl3) δ 7.12−7.09 (m, 1H), 7.06 (d, J = 7.4, 1H), 6.87−6.84 (m,
2H), 5.38 (d, J = 17.2, 1H), 4.58−4.56 (m, 1H), 2.91−2.84 (m, 1H),
2.81−2.76 (m, 1H), 2.11−2.06 (m, 1H), 1.90−1.83 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 154.6 (C), 137.6 (CH), 129.6 (CH),
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2-(5-Hydroxypent-3-ynyl)phenol (35). Using a modification of
the procedure by Kinoshita,33 a solution of 34 (3.55 g, 11.6 mmol) in
THF (39 mL) was cooled to −78 °C in a 100-mL round-bottomed
flask. A solution of n-BuLi (2.0 M in hexane, 21 mL, 42.0 mmol) was
added via syringe over 20 min. The reaction mixture was stirred at −78
°C for 40 min, and then paraformaldehyde (1.04 g, 34.8 mmol) was
added in a single portion. The reaction mixture was allowed to warm
to 0 °C, stirred for 1 h, allowed to warm to ambient temperature, and
then stirred for 1 h. Saturated aqueous NH4Cl (60 mL) was added,
and the resulting mixture was extracted with EtOAc (3 × 50 mL),
dried over Na2SO4, filtered, and concentrated in vacuo to give a pale
yellow residue that was purified by flash chromatography (97.5:2.5 to
92:8 CH2Cl2−acetone) to provide propargyl alcohol 35 (1.33 g, 7.6
the reaction mixture, which was allowed to stir for 18 h then filtered
through a short pad of silica gel using EtOH as the eluent. The organic
layer was concentrated in vacuo to yield alkene (Z)-36 (506 mg, 2.84
1
mmol, 100%) as a pale yellow oil: H NMR (500 MHz, CDCl3) δ
7.10−7.07 (m, 2H), 6.86 (t, J = 7.4, 1H), 6.78 (d, J = 7.9, 1H), 5.70−
5.66 (m, 2H), 4.07 (d, J = 6.2, 2H), 2.71 (t, J = 7.4, 2H), 2.43 (app q, J
= 7.3, 2H); 13C NMR (125 MHz, CDCl3) δ 154.1 (C), 133.2 (CH),
130.8 (CH), 128.8 (CH), 127.8 (C), 127.6 (CH), 120.5 (CH), 115.6
(CH), 58.3 (CH2), 30.6 (CH2), 27.8 (CH2); IR (thin film) 3367,
2932, 1592, 1180, 1017, 721 cm−1; HRMS (CI) m/z calcd for
C11H16NO, (M + NH4 − H2O)+ 178.1232, found 178.1240.
(Z)-5-(2-Hydroxyphenyl)pent-2-enyl 2′,2′,2′-trichloroaceti-
midate ((Z)-11a). Following the procedure described for the
preparation of (E)-11a, alcohol (Z)-36 (100 mg, 0.561 mmol) was
treated with DBU and Cl3CCN. After 2 h, the reaction mixture was
concentrated in vacuo and the residue was purified by flash
chromatography (98.5:0.5:1 CH2Cl2−acetone−Et3N) to provide
imidate (Z)-11a (136 mg, 0.424 mmol, 76%) as a pale yellow oil:
1H NMR (500 MHz, CDCl3) δ 8.29 (br s, 1H), 7.12−7.09 (m, 2H),
6.87 (t, J = 7.4, 1H), 6.78 (d, J = 8.1, 1H), 5.91 (br s, 1H), 5.83 (dt, J =
10.6, 7.9, 1H), 5.67 (dt, J = 10.8, 6.8, 1H), 4.87 (d, J = 6.8, 2H), 2.73
(t, J = 7.8, 2H), 2.48 (app q, J = 7.7, 2H); 13C NMR (125 MHz,
CDCl3) δ 163.2 (C), 154.0 (C), 135.2 (CH), 130.5 (CH), 128.6
(CH), 127.5 (C), 123.3 (CH), 120.8 (CH), 115.6 (CH), 91.6 (C),
65.4 (CH2), 30.5 (CH2), 28.0 (CH2); IR (thin film) 3333, 3029, 2944,
1650, 1608, 1593 cm−1; HRMS (ESI) m/z calcd for C13H14Cl3NO2Na,
(M + Na)+ 343.9988, found 343.9981.
6-Bromochroman-2-ol (38). A 250-mL round-bottomed flask
was charged with 6-bromochroman-2-one (37)36 (9.9 g, 44 mmol)
and toluene (110 mL). The solution was cooled to −78 °C, and
DIBAL (25% in toluene, 30 mL, 48 mmol) was added over 10 min via
syringe. The reaction mixture was stirred at −78 °C for 4 h and then
allowed to warm to 0 °C. Water (50 mL) and saturated aqueous
Rochelle’s salt (75 mL) were added, and the resultant mixture was
allowed to warm to room temperature and stirred for 1 h. The biphasic
mixture was extracted with Et2O (3 × 70 mL), and the organic layer
was dried over Na2SO4, filtered, then concentrated in vacuo to yield a
residue that was purified by flash chromatography (98.5:1.5 CH2Cl2−
acetone) to provide lactol 38 (8.2 g, 36 mmol, 82%) as a pale yellow
oil. Product was of sufficient purity to be carried on to the next step.
1H NMR data were consistent with previously reported values.37
(E)-Ethyl 5-(5-bromo-2-hydroxyphenyl)pent-2-enoate (39).
In a 250-mL round-bottomed flask, lactol 38 (8.19 g, 35.6 mmol) was
dissolved in benzene (100 mL) and then treated with carbethox-
ymethylenetriphenylphosphorane (13.1 g, 37.5 mmol) in benzene
(100 mL), and the solution was maintained at room temperature for
15 h. Evaporation of solvent using a rotary evaporator left a viscous oil
that was dissolved in CH2Cl2 (70 mL). Celite (2 g) was added to the
suspension, and the organic solvent was removed in vacuo to yield a
powder that was loaded on silica gel and purified by flash
chromatography (92:8 to 0:100 hexanes−EtOAc) to provide ester
39 (6.95 g, 24.5 mmol, 67%) as a white solid: mp 87−89 °C; 1H NMR
(500 MHz, CDCl3) δ 7.22 (s, 1H), 7.18 (dd, J = 8.5, 2.4, 1H), 7.06−
7.00 (m, 1H), 6.65 (d, J = 8.5, 1H), 5.87 (dd, J = 15.6, 1.4, 1H), 5.75
(br s, 1H), 4.21 (q, J = 3.4, 2H), 2.74 (t, J = 7.3, 2H), 2.54−2.49 (m,
2H), 1.30 (t, J = 4.4, 3H); 13C NMR (125 MHz, CDCl3) δ 167.3 (C),
153.0 (C), 148.6 (CH), 132.9 (CH), 130.3 (CH), 129.7 (C), 121.8
(CH), 117.1 (CH), 112.7 (C), 60.6 (CH2), 32.2 (CH2), 28.7 (CH2),
14.4 (CH3); IR (thin film) 3381, 2983, 1693, 1272, 1039 cm−1; HRMS
(ESI) m/z calcd for C13H15BrO3Na, (M + Na)+ 321.0102, found
321.0098.
1
mmol, 65%) as a clear colorless oil: H NMR (500 MHz, CDCl3) δ
7.16−7.11 (m, 2H), 6.90 (t, J = 7.4, 1H), 6.79 (d, J = 7.9, 1H), 4.96 (s,
1H), 4.25 (s, 2H), 2.87 (t, J = 7.3, 2H), 2.55 (t, J = 7.3, 2H); 13C NMR
(125 MHz, CDCl3) δ 153.8 (C), 130.7 (CH), 128.0 (CH), 127.0 (C),
121.0 (CH), 115.8 (CH), 86.5 (C), 79.3 (C), 51.5 (CH2), 29.8 (CH2),
19.6 (CH2); IR (thin film) 3364, 2929, 2223, 1181, 1006 cm−1; HRMS
(ESI) m/z calcd for C11H12O2Na, (M + Na)+ 199.0735, found
199.0730.
(E)-2-(5-Hydroxypent-3-enyl)phenol ((E)-36). Using a modifi-
cation of a procedure by Denmark,34 Red-Al (65% in toluene, 0.66
mL, 2.1 mmol) and Et2O (0.6 mL) were cooled to 0 °C in a 10-mL
round-bottomed flask. A solution of alkyne 35 (150 mg, 0.85 mmol) in
Et2O (0.6 mL) was added via syringe over 5 min, and then the solution
was allowed to warm to room temperature. After 16 h, the solution
was cooled to 0 °C, and saturated aqueous Rochelle’s salt (5 mL) was
added slowly. The mixture was stirred for 1 h, extracted with EtOAc (3
× 5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash chromatography (94:6 CH2Cl2−acetone)
to yield alkene (E)-36 (107 mg, 0.600 mmol, 71%) as a clear colorless
1
oil: H NMR (500 MHz, CDCl3) δ 7.12−7.07 (m, 2H), 6.87 (t, J =
7.4, 1H), 6.76 (d, J = 8.0, 1H), 5.78 (dt, J = 15.4, 6.6, 1H), 5.68 (dt, J =
15.4, 5.8, 1H), 5.48 (br s, 1H), 4.10 (d, J = 5.4, 2H), 2.72 (t, J = 7.4,
2H), 2.38 (app q, J = 7.3, 2H); 13C NMR (125 MHz, CDCl3) δ 153.8
(C), 133.1 (CH), 130.4 (CH), 129.4 (CH), 128.0 (C), 127.4 (CH),
120.8 (CH), 115.5 (CH), 63.9 (CH2), 32.5 (CH2), 29.9 (CH2); IR
(thin film) 3307, 3035, 2850, 1668, 966 cm−1; HRMS (ESI) m/z calcd
for C11H14O2Na, (M + Na)+ 201.0892, found 201.0892.
(E)-5-(2-Hydroxyphenyl)pent-2-enyl 2′,2′,2′-trichloroaceti-
midate ((E)-11a). In a 10-mL round-bottomed flask, alcohol (E)-36
(25 mg, 0.14 mmol) was dissolved in CH2Cl2 (0.56 mL), and then
DBU (24 μL, 0.17 mmol) was added via syringe. Trichloroacetonitrile
(17 μL, 0.17 mmol) was added via syringe, and the solution was
maintained at room temperature. After 1 h, the reaction mixture was
concentrated in vacuo, and the residue was purified by flash
chromatography (98.5:0.5:1 CH2Cl2−acetone−Et3N) to provide
1
imidate (E)-11a (43 mg, 0.13 mmol, 96%) as a pale yellow oil: H
NMR (500 MHz, CDCl3) δ 8.28 (br s, 1H), 7.12−7.08 (m, 2H), 6.88
(t, J = 7.4, 1H), 6.76 (d, J = 7.9, 1H), 5.95 (dt, J = 15.4, 6.6, 1H), 5.73
(dt, J = 15.3, 6.2, 1H), 4.82 (br s, 1H), 4.76 (d, J = 5.9, 2H), 2.74 (t, J
= 7.7, 2H), 2.45−2.40 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 163.0
(C), 153.7 (C), 136.2 (CH), 130.5 (CH), 127.8 (C), 127.4 (CH),
123.7 (CH), 120.9 (CH), 115.5 (CH), 91.6 (C), 70.1 (CH2), 32.5
(CH2), 29.7 (CH2); IR (thin film) 3328, 3067, 2927, 1658, 1607, 1592
cm−1; HRMS (CI) m/z calcd for C13H18Cl3N2O2, (M + NH4)+
339.0434, found 339.0436.
(Z)-2-(5-Hydroxypent-3-enyl)phenol ((Z)-36). Using a mod-
ification of a procedure by Taber,35 a 10-mL round-bottomed flask was
evacuated and refilled with nitrogen three times. The flask was charged
with Ni(OAc)2·4H2O (106 mg, 0.426 mmol) and evacuated and
refilled with nitrogen three additional times before degassed EtOH
(1.5 mL) and NaBH4 (20 mg, 0.54 mmol) were added to form a black
suspension. Ethylenediamine (0.11 mL, 1.7 mmol) was added via
syringe, followed by a degassed aqueous solution of NaOH (2.0 M, 7
μL, 0.01 mmol). Alkyne 35 (500 mg, 2.84 mmol) was dissolved in
degassed EtOH (1.5 mL) and added via syringe to the black
suspension. Hydrogen gas was bubbled vigorously through the
reaction mixture for 5 min, then a balloon of H2 was placed over
(E)-4-Bromo-2-(5-hydroxypent-3-enyl)phenol ((E)-40). A 25-
mL round-bottomed flask was charged with ester 39 (500 mg, 1.76
mmol) and toluene (4.4 mL). The solution was cooled to −78 °C, and
DIBAL (25% in toluene, 2.2 mL, 3.5 mmol) was added over 5 min via
syringe. The reaction mixture was stirred at −78 °C for 3.5 h and then
allowed to warm to 0 °C. Water (5 mL) and saturated aqueous
Rochelle’s salt (5 mL) were added, and the resultant mixture was
allowed to warm to room temperature and stirred for 1 h. The biphasic
mixture was extracted with CH2Cl2 (3 × 10 mL), and the organic layer
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was dried over Na2SO4, filtered, and then concentrated in vacuo to
yield a residue that was purified by flash chromatography (98:2 to 96:4
CH2Cl2−MeOH) to provide alcohol (E)-40 (243 mg, 0.945 mmol,
54%): 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 7.17 (dd, J = 8.5,
2.4, 1H), 6.64 (d, J = 8.5, 1H), 5.75 (dt, J = 15.3, 6.5, 1H), 5.67 (dt, J =
18.0, 6.4, 1H), 4.11 (d, J = 5.8, 2H), 2.67 (t, J = 7.7, 2H), 2.37−2.33
(m, 2H); 13C NMR (125 MHz, CDCl3) δ 153.0 (C), 133.0 (CH),
132.6 (CH), 130.4 (C), 130.0 (CH), 129.6 (CH), 117.2 (CH), 112.7
(C), 63.8 (CH2), 32.3 (CH2), 29.7 (CH2); IR (thin film) 3325, 3029,
2927, 1669, 812 cm−1; HRMS (ESI) m/z calcd for C11H13BrO2Na, (M
+ Na)+ 278.9997, found 278.9995.
(E)-5-(5-Bromo-2-hydroxyphenyl)pent-2-enyl 2′,2′,2′-tri-
chloroacetimidate ((E)-11b). Following the procedure described
for the preparation of (E)-11a, alcohol (E)-40 (243 mg, 0.945 mmol)
was treated with DBU and Cl3CCN. After 1 h, the reaction mixture
was concentrated in vacuo, and the residue was purified by flash
chromatography (98.5:0.5:1 CH2Cl2−acetone−Et3N) to provide
imidate (E)-11b (272 mg, 0.677 mmol, 72%) as a pale yellow
powder: mp 108−111 °C; 1H NMR (500 MHz, CDCl3) δ 8.29 (br s,
1H), 7.23 (s, 1H), 7.18 (dd, J = 8.4, 2.4, 1H), 6.64 (d, J = 8.5, 1H),
5.91 (dt, J = 15.5, 6.7, 1H), 5.70 (dt, J = 15.4, 6.1, 1H), 4.94 (br s, 1H),
4.76 (d, J = 6.0, 2H), 2.70 (t, J = 7.2, 2H), 2.42−2.38 (m, 2H); 13C
NMR (125 MHz, CDCl3) δ 163.0 (C), 152.9 (C), 135.5 (CH), 133.1
(CH), 130.3 (C), 130.1 (CH), 124.0 (CH), 117.2 (CH), 112.8 (C),
91.6 (C), 70.0 (CH2), 32.3 (CH2), 29.5 (CH2); IR (thin film) 3326,
3033, 2922, 1657, 971 cm−1; HRMS (ESI) m/z calcd for
C13H13BrCl3NO2Na, (M + Na)+ 421.9093, found 421.9083.
K2CO3 (0.100 g, 0.726 mmol) was added, and the suspension was
stirred for 5 min. (E)-2-((4-Bromobut-2-en-1-yl)oxy)tetrahydro-2H-
pyran (47)38 (0.170 g, 0.726 mmol) in DMF (1.1 mL) was added via
syringe, and the reaction mixture was allowed to warm to room
temperature. After 20 h, water (20 mL) and brine (10 mL) were
added, and the mixture was extracted with CH2Cl2 (3 × 10 mL), dried
over Na2SO4, filtered, and concentrated in vacuo to yield a residue that
was purified by flash chromatography (75:25 hexanes−Et2O) to
provide ether 48 (147 mg, 0.557 mmol, 77%) as a clear colorless oil:
1H NMR (500 MHz, CDCl3) δ 6.95−6.81 (m, 4H), 6.04−5.95 (m,
2H), 5.67 (s, 1H), 4.66 (t, J = 3.5, 1H), 4.62 (d, J = 4.1, 2H), 4.31 (dd,
J = 13.4, 4.2, 1H), 4.05 (dd, J = 13.6, 4.9, 1H), 3.88 (td, J = 11.0, 2.8,
1H), 3.54−3.51 (m, 1H), 1.89−1.83 (m, 1H), 1.78−1.72 (m, 1H),
1.64−1.54 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 146.0 (C), 145.7
(C), 131.1 (CH), 127.0 (CH), 121.9 (CH), 120.2 (CH), 114.8 (CH),
112.3 (CH), 98.3 (CH), 69.1 (CH2), 66.9 (CH2), 62.4 (CH2), 30.7
(CH2), 25.5 (CH2), 19.6 (CH2); IR (thin film) 3393, 2942, 1609,
1115, 972 cm−1; HRMS (ESI) m/z calcd for C15H20O4Na, (M + Na)+
287.1259, found 287.1261.
(E)-4-(2-Hydroxyphenoxy)but-2-enyl 2′,2′,2′-trichloroaceti-
midate (13). In a 5-mL round-bottomed flask, protected alcohol 48
(30 mg, 0.11 mmol) and p-TsOH·H2O (4 mg, 0.02 mmol) were
dissolved in MeOH (3.0 mL). The solution was refluxed for 3 h and
then allowed to cool to room temperature. The solvent was removed
in vacuo to yield a viscous oil that was dissolved in CH2Cl2 (0.57 mL),
and then DBU (23 μL, 0.16 mmol) was added via syringe.
Trichloroacetonitrile (14 μL, 0.14 mmol) was added via syringe, and
the solution was maintained at room temperature. After 10 min, the
reaction mixture was concentrated in vacuo, and the residue was
purified by flash chromatography (60:40:1 pentane−Et2O−Et3N) to
provide imidate 13 (28 mg, 0.086 mmol, 76%) as a pale yellow oil: 1H
NMR (500 MHz, CDCl3) δ 8.37 (br s, 1H), 6.96 (d, J = 7.8, 1H),
6.91−6.82 (m, 3H), 6.13 (dt, J = 15.8, 5.1, 1H), 6.06 (dt, J = 16.1, 4.9,
1H), 5.65 (s, 1H), 4.87 (d, J = 5.1, 2H), 4.66 (d, J = 5.0, 2H); 13C
NMR (125 MHz, CDCl3) δ 162.6 (C), 146.0 (C), 145.5 (C), 129.1
(CH), 127.3 (CH), 122.1 (CH), 120.3 (CH), 115.0 (CH), 112.3
(CH), 91.4 (C), 68.8 (CH2), 68.5 (CH2); IR (thin film) 3411, 3338,
2926, 1663, 1473, 982 cm−1; HRMS (ESI) m/z calcd for
C12H12Cl3NO3Na, (M + Na)+ 345.9781, found 345.9787.
(E)-2-(5-Hydroxypent-3-enyl)-4-methoxyphenol ((E)-42). A
50-mL round-bottomed flask was charged with (E)-5-(2-((tert-
butyldimethylsilyl)oxy)-5-methoxyphenyl)pent-2-en-1-ol (41)4a (1.63
g, 5.05 mmol) and THF (25 mL), and then TBAF (1.0 M in THF, 7.6
mL, 7.6 mmol) was added. The reaction mixture was stirred at room
temperature for 2 h, and then the reaction mixture was concentrated in
vacuo and the residue was purified by flash chromatography (70:30 to
50:50 to 40:60 hexanes−EtOAc) to provide diol (E)-42 (714 mg, 3.43
1
mmol, 85%) as a clear colorless oil: H NMR (500 MHz, CDCl3) δ
6.70−6.69 (m, 2H), 6.64−6.62 (m, 1H), 5.78 (dt, J = 15.4, 6.5, 1H),
5.69 (dt, J = 15.4, 5.8, 1H), 4.10 (d, J = 5.1, 2H), 3.76 (s, 3H), 2.69 (t,
J = 7.4, 2H), 2.40−2.35 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
153.3 (C), 148.0 (C), 133.0 (CH), 129.5 (C), 129.1 (CH), 116.2
(CH), 116.0 (CH), 111.9 (CH), 63.6 (CH2), 55.9 (CH3) 32.4 (CH2),
30.0 (CH2); IR (thin film) 3366, 2935, 1611, 1509, 971 cm−1; HRMS
(ESI) m/z calcd for C12H16O3Na, (M + Na)+ 231.0997, found
231.0994.
(E)-N-(4-Hydroxybut-2-enyl)-N-(2-hydroxyphenyl)-4-methyl-
benzenesulfonamide (50). In a 250-mL round-bottomed flask,
PPh3 (889 mg, 3.39 mmol) was added to a mixture of N-(2-
hydroxyphenyl)-4-methylbenzenesulfonamide (43) (0.800 g, 3.39
mmol), (E)-4-((tetrahydro-2H-pyran-2-yl)oxy)but-2-en-1-ol (44)38
(583 mg, 3.39 mmol), and diethyl azodicarboxylate (40% in toluene,
1.5 mL, 3.4 mmol) in THF (39 mL) at 0 °C. The reaction mixture was
allowed to warm to room temperature. After 18 h, the reaction mixture
was concentrated in vacuo to give a residue that was filtered through
silica gel using 75:25 petroleum ether−EtOAc as eluent. The pale
yellow oil and p-TsOH·H2O (77 mg, 0.41 mmol) were dissolved in
MeOH (12 mL) and refluxed for 18 h. The solution was allowed to
cool to room temperature, and the solvent was removed in vacuo. The
residue was purified by flash chromatography (70:30 to 60:40
petroleum ether-EtOAc) to provide diol 50 (437 mg, 1.31 mmol,
(E)-5-(2-Hydroxy-5-methoxyphenyl)pent-2-enyl 2′,2′,2′-tri-
chloroacetimidate ((E)-11c). A 0.5-dram glass vial equipped with
a Teflon cap was charged with NaH (60% dispersion in mineral oil, 11
mg, 0.26 mmol) and Et2O (0.2 mL). The suspension was cooled to 0
°C and stirred for 15 min. Diol (E)-42 (50 mg, 0.24 mmol) was added
in 0.28 mL of Et2O via syringe. Trichloroacetonitrile (25 μL, 0.25
mmol) was added via syringe, and the reaction mixture was stirred at 0
°C for 1 h. The suspension was allowed to warm to room temperature
and stirred for 15 min. The reaction mixture was filtered through silica
gel using 50:50:1 CH2Cl2−acetone−Et3N as the eluent. The filtrate
was concentrated in vacuo, and the residue was purified by flash
chromatography (98.5:0.5:1 CH2Cl2−acetone−Et3N) to yield imidate
(E)-11c (60 mg, 0.17 mmol, 71%) as a clear colorless oil. Imidate (E)-
11c was used directly in the [COP-OAc]2 (7)-catalyzed cyclization
1
64%) as a pale yellow oil: H NMR (500 MHz, DMSO) δ 9.53 (s,
1H), 7.56 (d, J = 8.2, 2H), 7.35 (d, J = 8.1, 2H), 7.11 (td, J = 8.0, 1.5,
1H), 6.93 (dd, J = 7.8, 1.5, 1H), 6.79 (dd, J = 8.1, 1.1, 1H), 6.72 (td, J
= 7.6, 1.1, 1H), 5.57 (dt, J = 15.5, 4.6, 1H), 5.50 (dt, J = 15.5, 5.9, 1H),
4.64 (t, J = 5.4, 1H), 4.13 (d, J = 5.5, 2H), 3.78 (t, J = 4.2, 2H), 2.39 (s,
3H); 13C NMR (125 MHz, DMSO) δ 154.9 (C), 142.8 (CH), 137.2
(CH), 133.9 (CH), 132.0 (C), 129.4 (2C), 127.3 (CH), 124.8 (CH),
124.2 (CH), 118.6 (CH), 116.4 (CH), 60.6 (CH2), 50.9 (CH2), 21.0
(CH3); IR (thin film) 3416, 3049, 2923, 1598, 1337, 1090 cm−1;
HRMS (ESI) m/z calcd for C17H19NO4SNa, (M + Na)+ 356.0933,
found 356.0931.
(E)-4-(N-(2-Hydroxyphenyl)-4-methylphenylsulfonamido)-
but-2-enyl 2′,2′,2′-trichloroacetimidate (14). Following the
procedure described for the preparation of (E)-11a, alcohol 50 (193
mg, 0.579 mmol) was treated with DBU and Cl3CCN. After 1 h, the
reaction mixture was concentrated in vacuo and the residue was
1
reactions: H NMR (500 MHz, CDCl3) δ 8.29 (br s, 1H), 6.70−6.69
(m, 2H), 6.64−6.62 (m, 1H), 5.94 (dt, J = 15.4, 6.7, 1H), 5.72 (dt, J =
15.4, 6.2, 1H), 4.76 (d, J = 6.2, 2H), 4.61 (br s, 1H), 3.76 (s, 3H), 2.71
(t, J = 7.3, 2H), 2.44−2.39 (m, 2H); 13C NMR (125 MHz, CDCl3) δ
162.9 (C), 153.9 (C), 147.5 (C), 135.9 (CH), 129.1 (C), 123.9 (CH),
116.3 (CH), 116.1 (CH), 112.0 (CH), 91.6 (C), 70.0 (CH2), 55.8
(CH3), 32.6 (CH2), 30.0 (CH2); IR (thin film) 3372, 3334, 2924,
1660, 1080, 971 cm−1; HRMS (ESI) m/z calcd for C14H16Cl3NO3Na,
(M + Na)+ 374.0093, found 374.0082.
(E)-2-(4-Tetrahydro-2H-pyran-2-yloxy)but-2-enyloxy)phenol
(48). In a 5-mL round-bottomed flask, catechol (45) (0.400 g, 3.63
mmol) in DMF (11 mL) was cooled to 0 °C. In a single portion,
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1
purified by flash chromatography (99.5:0.5:1 CH2Cl2−acetone−Et3N)
to provide imidate 14 (249 mg, 0.521 mmol, 90%) as a pale yellow oil:
1H NMR (500 MHz, DMSO) δ 9.57 (br s, 1H), 9.25 (br s, 1H), 7.57
(d, J = 8.2, 2H), 7.35 (d, J = 8.2, 2H), 7.10 (td, J = 8.1, 1.3, 1H), 6.92
(d, J = 7.8, 1H), 6.79 (d, J = 8.1, 1H), 6.70 (t, J = 7.7, 1H), 5.78−5.68
(m, 2H), 4.62 (d, J = 4.5, 2H), 4.19 (d, J = 4.0, 2H), 2.38 (s, 3H); 13C
NMR (125 MHz, DMSO) δ 159.7 (C), 154.9 (C), 142.8 (C), 137.2
(C), 132.0 (CH), 129.6 (CH), 129.4 (CH), 129.3 (CH), 127.3 (CH),
126.6 (CH), 124.8 (C), 118.7 (CH), 116.5 (CH), 90.7 (C), 67.6
(CH2), 50.6 (CH2), 21.0 (CH3); IR (thin film) 3436, 3336, 2924,
49 (319 mg, 1.14 mmol, 80%) as a pale yellow oil: H NMR (500
MHz, CDCl3) δ 7.42 (dd, J = 7.7, 1.6, 1H), 7.28−7.23 (m, 1H), 6.98
(dd, J = 8.1, 1.1, 1H), 6.88−6.84 (m, 1H), 6.68 (s, 1H), 5.73 (dt, J =
15.2, 7.5, 1H), 5.41 (dt, J = 15.2, 5.5, 1H), 4.56 (t, J = 2.9, 1H), 4.11
(dd, J = 12.9, 4.8, 1H), 3.89 (dd, J = 13.0, 6.3, 1H), 3.83 (td, J = 11.0,
3.0, 1H), 3.52−3.46 (m, 1H), 3.32 (d, J = 7.5, 2H), 1.85−1.79 (m,
1H), 1.73−1.68 (m, 1H), 1.62−1.51 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ 157.3 (C), 136.7 (CH), 136.4 (C), 131.5 (CH), 130.7
(CH), 127.6 (CH), 120.8 (CH), 114.9 (CH), 97.8 (CH), 66.7 (CH2),
62.2 (CH2), 38.8 (CH2), 30.7 (CH2), 25.6 (CH2), 19.5 (CH2); IR
(thin film) 3404, 2940, 1470, 1119, 966 cm−1; HRMS (ESI) m/z calcd
for C15H20O3SNa, (M + Na)+ 303.1031, found 303.1029.
1664, 1344, 1090 cm−1
; HRMS (ESI) m/z calcd for
C19H19Cl3N2O4SNa, (M + Na)+ 499.0029, found 499.0024.
(E)-2-(4-Hydroxybut-2-enylthio)phenol (51). In a 25-mL
round-bottomed flask, protected alcohol 49 (319 mg, 1.14 mmol)
and p-TsOH·H2O (43 mg, 0.23 mmol) were dissolved in MeOH (9.5
mL), and the solution was refluxed for 6 h and then allowed to cool to
room temperature. After 18 h, the solvent was removed in vacuo, and
the residue was purified by flash chromatography to yield alcohol 51
(E)-tert-Butyldimethyl(3-methyl-4-(2-triisopropylsilyloxy)-
phenoxy)but-2-enyloxy)silane (54). In a 200-mL round-bottomed
flask, PPh3 (1.34 g, 5.11 mmol) was added to a mixture of 2-
((triisopropylsilyl)oxy)phenol (52) (1.30 g, 4.87 mmol), (E)-4-((tert-
butyldimethylsilyl)oxy)-2-methylbut-2-en-1-ol (53)39 (1.12 mg, 5.17
mmol), and diethyl azodicarboxylate (40% in toluene, 2.3 mL, 5.2
mmol) in THF (54 mL) at 0 °C. The reaction mixture was allowed to
warm to room temperature. After 3 h, the reaction mixture was
concentrated in vacuo to give a residue that was purified by flash
chromatography (99.5:0.5 to 98.5:1.5 pentane−Et2O) to provide ether
1
(142 mg, 0.723 mmol, 64%) as a clear colorless oil. H NMR data
were consistent with those previously reported.40
(E)-4-(2-Hydroxyphenylthio)but-2-enyl 2′,2′,2′-trichloroace-
timidate (16). Following the procedure described for the preparation
of (E)-11a, alcohol 51 (132 mg, 0.673 mmol) was treated with DBU
and Cl3CCN. After 5 min, the reaction mixture was concentrated in
vacuo, and the residue was purified by flash chromatography
(98.5:0.5:1 CH2Cl2−acetone−Et3N) to provide imidate 16 (191 mg,
0.563 mmol, 84%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ
8.30 (br s, 1H), 7.42 (dd, J = 7.7, 1.4, 1H), 7.29−7.25 (m, 1H), 6.99
(d, J = 8.2, 1H), 6.86 (t, J = 7.6, 1H), 6.66 (s, 1H), 5.87 (dt, J = 15.3,
7.5, 1H), 5.48 (dt, J = 15.3, 5.8, 1H), 4.69 (d, J = 5.8, 2H), 3.33 (d, J =
7.5, 2H); 13C NMR (125 MHz, CDCl3) δ 162.4 (C), 157.3 (C), 136.7
(CH), 131.5 (CH), 129.8 (CH), 127.0 (CH), 120.7 (CH), 117.7 (C),
114.9 (CH), 91.4 (C), 68.6 (CH2), 38.4 (CH2); IR (thin film) 3408,
3337, 2916, 1662, 1470, 984 cm−1; HRMS (GC−MS) m/z calcd for
C12H16Cl3N2O2S, (M + NH4)+ 356.9998, found 357.0004.
(E)-5-(2-Hydroxyphenyl)pent-2-enyl acetate ((E)-19a). In a
25-mL round-bottomed flask, alcohol (E)-36 (700 mg, 3.93 mmol) in
THF (5.9 mL) was cooled to 0 °C, and then acetic anhydride (1.1 mL,
12 mmol) was added via syringe. BF3·OEt2 (0.12 mL, 0.98 mmol) was
added via syringe, and the solution was maintained at 0 °C. After 1.5 h,
cold aqueous NaHCO3 (5% solution, 10 mL) was added, the mixture
was stirred for 2 min, extracted with CH2Cl2 (3 × 10 mL), dried over
Na2SO4, filtered, and concentrated in vacuo to yield a residue that was
purified by flash chromatography (80:20 hexanes−Et2O) to give
acetate (E)-19a (691 mg, 3.14 mmol, 80%) as a clear colorless oil: 1H
NMR (500 MHz, CDCl3) δ 7.12−7.08 (m, 2H), 6.87 (t, J = 7.4, 1H),
6.76 (d, J = 7.9, 1H), 5.86 (dt, J = 15.4, 7.7, 1H), 5.61 (dt, J = 15.4, 6.6,
1H), 5.16 (br s, 1H), 4.53 (d, J = 6.5, 2H), 2.72 (t, J = 7.4, 2H), 2.41−
2.37 (m, 2H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 171.4
(C), 153.7 (C), 135.9 (CH), 130.4 (CH), 127.8 (C), 127.4 (CH),
124.4 (CH), 120.9 (CH), 115.5 (CH), 65.4 (CH2), 32.5 (CH2), 30.0
(CH2), 21.2 (CH3); IR (thin film) 3411, 2925, 1739, 1672, 1235, 965
cm−1; HRMS (ESI) m/z calcd for C13H16O3Na, (M + Na)+ 243.0997,
found 243.0992.
1
54 (1.61 g, 3.17 mmol, 65%) as a clear colorless oil: H NMR (500
MHz, CDCl3) δ 6.90−6.86 (m, 3H), 6.83−6.81 (m, 1H), 5.72 (m,
1H), 4.41 (s, 2H), 4.28 (d, J = 6.2, 2H), 1.77 (s, 3H), 1.32−1.26 (m,
3H), 1.13 (d, J = 6.1, 18H), 0.93 (s, 9H), 0.09 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 150.3 (C), 145.9 (C), 132.6 (C), 128.3 (CH), 121.4
(CH), 121.1 (CH), 120.5 (CH), 114.2 (CH), 74.3 (CH2), 60.1
(CH2), 26.1 (CH3), 18.1 (C, CH3), 14.3 (CH3), 13.0 (CH), −5.0
(CH3); IR (thin film) 3064, 2947, 1267, 1116, 1073, 921 cm−1; HRMS
(ESI) m/z calcd for C26H48O3Si2Na, (M + Na)+ 487.3040, found
487.3038.
(E)-2-(4-Hydroxy-2-methylbut-2-enyloxy)phenol (55). A 50-
mL round-bottomed flask was charged with bis-silyl ether 54 (1.61 g,
3.17 mmol) and THF (16 mL), and then TBAF (1.0 M in THF, 7.0
mL, 7.0 mmol) was added. The reaction mixture was stirred at room
temperature for 3 h, and then the reaction mixture was concentrated in
vacuo and the residue was purified by flash chromatography (94:6
CH2Cl2−acetone) to provide diol 55 (616 mg, 3.17 mmol, 100%) as a
1
clear colorless oil: H NMR (500 MHz, CDCl3) δ 6.95 (d, J = 7.7,
1H), 6.94−6.80 (m, 3H), 6.23 (br s, 1H), 5.77 (t, J = 6.6, 1H), 4.44 (s,
2H), 4.23 (d, J = 6.9, 2H), 2.60 (br s, 1H), 1.76 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 145.9 (C), 145.8 (C), 133.8 (C), 127.2 (CH),
121.8 (CH), 120.1 (CH), 115.1 (CH), 112.5 (CH), 73.8 (CH2), 58.8
(CH2), 14.0 (CH3); IR (thin film) 3418, 2924, 1679, 1596, 845 cm−1;
HRMS (ESI) m/z calcd for C11H14O3Na, (M + Na)+ 217.0841, found
217.0841.
(E)-4-(2-Hydroxyphenoxy)-3-methylbut-2-enyl 2′,2′,2′-tri-
chloroacetimidate (15). Following the procedure described for the
preparation of (E)-11a, alcohol 55 (26 mg, 0.13 mmol) was treated
with DBU and Cl3CCN. After 5 min, the reaction mixture was
concentrated in vacuo, and the residue was purified by flash
chromatography (97.5:1.5:1 CH2Cl2−acetone−Et3N) to provide
1
imidate 15 (41 mg, 0.12 mmol, 91%) as a pale yellow oil: H NMR
(500 MHz, CDCl3) δ 8.33 (br s, 1H), 6.95 (dd, J = 7.8, 1.5, 1H),
6.91−6.80 (m, 3H), 5.88−5.85 (m, 1H), 5.64 (s, 1H), 4.91 (d, J = 6.7,
2H), 4.54 (s, 2H), 1.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 162.6
(C), 145.9 (C), 145.6 (C), 137.3 (C), 121.9 (CH), 121.4 (CH),
120.11 (CH), 115.0 (CH), 112.4 (CH), 91.4 (C), 73.6 (CH2), 65.4
(CH2), 14.3 (CH3); IR (thin film) 3414, 3337, 2923, 1662, 1501, 988
cm−1; HRMS (ESI) m/z calcd for C13H14Cl3NO3Na, (M + Na)+
359.9937, found 359.9928.
(E)-2-(4-(Tetrahydro-2H-pyran-2-yloxy)but-2-enylthio)-
phenol (49). Following the procedure described for the preparation
of 48, 2-mercaptophenol (46) (902 mg, 7.15 mmol) was alkylated
using (E)-2-((4-bromobut-2-en-1-yl)oxy)tetrahydro-2H-pyran (47).38
After 24 h, water (20 mL) and brine (10 mL) were added, and the
mixture was extracted with CH2Cl2 (3 × 20 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to yield a residue that was purified
by flash chromatography (70:30 hexanes−Et2O) to provide thioether
(Z)-5-(2-Hydroxyphenyl)pent-2-enyl acetate ((Z)-19a). Fol-
lowing the procedure described for the preparation of (E)-19a, alcohol
(Z)-36 (100 mg, 0.561 mmol) was acetylated using acetic anhydride
(0.16 mL, 1.7 mmol) to give a residue that was purified by flash
chromatography (80:20 hexanes−Et2O) to provide acetate (Z)-19a
(93 mg, 0.42 mmol, 75%) as a clear colorless oil: 1H NMR (500 MHz,
CDCl3) δ 7.11−7.08 (m, 2H), 6.88 (t, J = 7.4, 1H), 6.80 (d, J = 7.7,
1H), 5.78−5.68 (br m, 2H), 5.58−5.53 (m, 1H), 4.59 (d, J = 7.2, 2H),
2.69 (t, J = 7.4, 2H), 2.45 (app q, J = 8.0, 2H), 2.07 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 171.6 (C), 154.0 (C), 134.8 (CH), 130.5 (CH),
127.6 (CH), 127.4 (C), 123.9 (CH), 120.7 (CH), 115.7 (CH), 60.5
(CH2), 30.4 (CH2), 28.1 (CH2), 21.2 (CH3); IR (thin film) 3306,
3026, 2929, 1731, 1609, 754 cm−1; HRMS (ESI) m/z calcd for
C13H16O3Na, (M + Na)+ 243.0997, found 243.0997.
(E)-5-(5-Bromo-2-hydroxyphenyl)pent-2-enyl acetate ((E)-
19b). Following the procedure described for the preparation of (E)-
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19a, allylic alcohol (E)-40 (100 mg, 0.389 mmol) was acetylated using
acetic anhydride (0.11 mL, 1.2 mmol) to give a residue that was
purified by flash chromatography (80:20 to 75:25 pentane−Et2O) to
provide acetate (E)-19b (89 mg, 0.30 mmol, 77%) as a pale yellow oil:
1H NMR (500 MHz, CDCl3) δ 7.21 (s, 1H), 7.18−7.16 (m, 1H), 6.65
(d, J = 8.4, 1H), 5.82 (dt, J = 15.4, 6.8, 1H), 5.59 (dt, J = 15.4, 6.5,
1H), 5.28 (br s, 1H), 4.52 (d, J = 6.4, 2H), 2.68 (t, J = 7.4, 2H), 2.36
(app q, J = 7.3, 2H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
171.5 (C), 152.9 (C), 135.3 (CH), 133.0 (CH), 130.4 (C), 130.0
(CH), 124.8 (CH), 117.2 (CH), 112.8 (C), 65.4 (CH2), 32.3 (CH2),
29.5 (CH2), 21.2 (CH3); IR (thin film) 3459, 3021, 2924, 1710, 1269,
966 cm−1; HRMS (ESI) m/z calcd for C13H15BrO3Na, (M + Na)+
321.0102, found 321.0105.
1435, 1108 cm−1; HRMS (ESI) m/z calcd for C18H26O3SiNa, (M +
Na)+ 341.1549, found 341.1544.
5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1,1-dideuteropent-
2-yn-1-ol (58). In a 1-L round-bottomed flask, a solution of ynoate 57
(9.0 g, 28 mmol) in Et2O (140 mL) was cooled to 0 °C. Lithium
aluminum deuteride (1.76 g, 42.0 mmol) was added portionwise over
30 min, and gas evolution was observed. After the reaction mixture was
stirred at 0 °C for 45 min, water (50 mL) was added slowly, followed
by aqueous NaOH solution (0.1 N, 20 mL), followed by more water
(50 mL). The resulting mixture was allowed to warm to ambient
temperature, extracted with Et2O (4 × 75 mL), dried over Na2SO4,
filtered, and concentrated in vacuo to give a residue that was purified
by flash chromatography (90:10 hexanes−EtOAc) to provide
propargyl alcohol 58 (6.23 g, 21.1 mmol, 75%) as a clear colorless
oil. Analysis by electrospray mass spectrometry indicated a 327:5:1
ratio of d2-58:d1-58:d0-58: 1H NMR (500 MHz, CDCl3) δ 7.19 (d, J =
7.5, 1H), 7.13−7.10 (m, 1H), 6.91 (t, J = 7.4, 1H), 6.81 (d, J = 8.1,
1H), 2.83 (t, J = 7.7, 2H), 2.50 (t, J = 7.6, 2H), 1.05 (s, 9H), 0.26 (s,
6H); 13C NMR (125 MHz, CDCl3) δ 153.7 (C), 131.2 (C), 130.5
(CH), 127.5 (C), 121.1 (CH), 118.5 (CH), 86.2 (C), 78.8 (C), 50.9
(quintet, JCD = 22.4, CD2), 30.3 (CH2), 26.0 (CH2), 19.4 (CH3), 18.3
(C), −4.0 (CH3); IR (thin film) 3243, 3030, 2929, 2248, 1453, 1175
cm−1; HRMS (ESI) m/z calcd for C17H24D2O2SiNa, (M + Na)+
315.1725, found 315.1725.
(E)-5-(2-Hydroxy-5-methoxyphenyl)pent-2-enyl acetate ((E)-
19c). Following the procedure described for the preparation of (E)-
19a, allylic alcohol (E)-42 (60 mg, 0.29 mmol) was acetylated using
acetic anhydride (54 μL, 0.58 mmol) to give a residue that was purified
by flash chromatography (90:10 hexanes−EtOAc) to provide acetate
1
(E)-19c (52 mg, 0.21 mmol, 72%) as a clear colorless oil: H NMR
(500 MHz, CDCl3) δ 6.71−6.62 (m, 3H), 5.85 (dt, J = 15.3, 6.7, 1H),
5.60 (dt, J = 15.3, 6.4, 1H), 4.60 (br s, 1H), 4.52 (d, J = 6.4, 2H), 3.76
(s, 3H), 2.69 (t, J = 7.5, 2H), 2.38 (app q, J = 7.2, 2H), 2.07 (s, 3H);
13C NMR (125 MHz, CDCl3) δ 171.2 (C), 153.8 (C), 147.6 (C),
135.7 (CH), 129.1 (C), 124.6 (CH), 116.2 (CH), 116.0 (CH), 112.0
(CH), 65.4 (CH2), 55.8 (CH3), 32.6 (CH2), 30.0 (CH2), 21.2 (CH3);
IR (thin film) 3397, 3028, 2917, 1708, 1611, 801 cm−1; HRMS (ESI)
m/z calcd for C14H18O4Na, (M + Na)+ 273.1103, found 273.1109.
Synthesis of Deuterium-Labeled Cyclization Precursors (E)-
1-d-11a and (E)-1-d-19a. tert-Butyl (2-(4,4-dibromobut-3-
enyl)phenoxy)dimethylsilane (56). A. 250-mL round-bottomed
flask was charged with alcohol 34 (12.0 g, 39.2 mmol).
Dimethylformamide (26 mL) was added by syringe, followed
by imidazole (5.34 g, 78.4 mmol), then TBSCl (6.80 g, 45.1
mmol). The reaction mixture was stirred for 2 h, then water
(100 mL) was added. The resulting mixture was extracted with
Et2O (4 × 75 mL). The combined organic extracts were dried
over Na2SO4, filtered, and then concentrated in vacuo to give a
light yellow residue that was purified by flash chromatography
(99.75:0.25 hexanes−Et2O) to provide silyl ether 56 (14.2 g,
(Z)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1,1-dideutero-
pent-2-en-1-ol (59). Following the procedure described for the
preparation of (Z)-36,35 propargyl alcohol 58 (3.65 g, 12.5 mmol) was
reduced using catalytic Ni(OAc)2·4H2O (466 mg, 1.87 mmol) to give
a residue that was purified by filtering the reaction mixture through a
short pad of silica gel using EtOH as the eluent. The organic layer was
concentrated in vacuo to yield alkene 59 (3.68 g, 12.5 mmol, 100%) as
a pale yellow oil. Analysis by electrospray mass spectrometry indicated
1
a 226:4:1 ratio of d2-59:d1-59:d0-59: H NMR (500 MHz, CDCl3) δ
7.13−7.08 (m, 2H), 6.90 (t, J = 7.4, 1H), 6.82 (d, J = 7.9, 1H), 5.61−
5.59 (m, 2H), 2.69 (t, J = 7.5, 2H), 2.39 (app q, J = 7.2, 2H), 1.05 (s,
9H), 0.26 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 153.7 (C), 132.1
(CH), 132.1 (C), 130.7 (CH), 129.1 (C), 127.2 (CH), 120.9 (CH),
118.5 (CH), 57.8 (quintet, JCD = 21.5, CD2), 30.5 (CH2), 27.8 (CH2),
25.9 (CH3), 18.3 (C), −4.0 (CH3); IR (thin film) 3338, 3017, 2930,
1107, 755, 701 cm−1; HRMS (ESI) m/z calcd for C17H26D2O2SiNa,
(M + Na)+ 317.1882, found 317.1884.
1
33.7 mmol, 86%) as a clear colorless oil: H NMR (500 MHz,
CDCl3) δ 7.16−7.11 (m, 2H), 6.94 (t, J = 6.6, 1H), 6.83 (d, J =
8.0, 1H), 6.44 (t, J = 7.1, 1H), 2.75 (t, J = 7.5, 2H), 2.42 (app q,
J = 7.5, 2H), 1.06 (s, 9H), 0.29 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 153.8 (C), 138.3 (CH), 131.2 (C), 130.4 (CH),
127.5 (CH), 121.3 (CH), 118.6 (CH), 89.1 (C), 33.6 (CH2),
28.8 (CH2), 26.0 (CH3), 18.4 (C), −4.0 (CH3); IR (thin film)
3020, 2955, 1600, 922, 810 cm−1; HRMS (CI) m/z calcd for
C16H28Br2NOSi, (M + NH4)+ 436.0307, found 436.0291.
Methyl 5-(2-(tert-butyldimethylsilyloxy)phenyl)pent-2-
(Z)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1-deuteropent-
2-enal ((Z)-60). In a 100-mL round-bottomed flask, a solution of 59
(1.0 g, 3.4 mmol) in CH2Cl2 (34 mL) was cooled to 0 °C. N,N-
Diisopropylethylamine (4.1 mL, 24 mmol) was added via syringe, and
the solution was maintained at 0 °C for 10 min. DMSO (2.4 mL, 34
mmol) was added via syringe, the solution was maintained at 0 °C for
10 min, and then SO3·pyridine (2.16 g, 13.6 mmol) was added in a
single portion. The reaction mixture was stirred at 0 °C for 45 min,
saturated aqueous NaHCO3 (40 mL) was added, and the resulting
mixture was extracted with CH2Cl2 (3 × 30 mL). The organic layer
was washed with water (2 × 30 mL), dried over Na2SO4, filtered, and
concentrated in vacuo to give a pale yellow residue. After azeotropic
removal of pyridine with toluene (2 × 100 mL), the residue (988 mg,
3.37 mmol, 99%, 90:10 Z:E by 1H NMR analysis) was carried directly
to the next synthetic step. Analysis by electrospray mass spectrometry
ynoate (57). Using a modification of a procedure by Kinoshita,33
a
solution of bromide 56 (14.2 g, 33.7 mmol) in THF (110 mL) was
cooled to −78 °C in a 1-L round-bottomed flask. A solution of n-BuLi
in hexane (1.6 M, 52 mL, 84 mmol) was added to the clear solution via
syringe over 20 min. The pale yellow reaction mixture was stirred at
−78 °C for 30 min, and then methyl chloroformate (7.80 mL, 101
mmol) was added via syringe over 5 min. The reaction mixture was
allowed to warm to 0 °C, stirred for 10 min, and then allowed to warm
to ambient temperature and stirred for 15 min. Saturated aqueous
NH4Cl (120 mL) was added, and the resulting mixture was extracted
with Et2O (3 × 75 mL), dried over Na2SO4, filtered, and concentrated
in vacuo to give a pale yellow residue that was purified by flash
chromatography (99:1 hexanes−Et2O) to provide ynoate 57 (10.6 g,
33.3 mmol, 99%) as a pale yellow oil: 1H NMR (500 MHz, CDCl3) δ
7.17 (d, J = 7.5, 1H), 7.14−7.11 (m, 1H), 6.91 (t, J = 7.5, 1H), 6.80 (d,
J = 8.1, 1H), 3.76 (s, 3H), 2.88 (t, J = 7.7, 2H), 2.61 (t, J = 7.7, 2H),
1.03 (s, 9H), 0.26 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 154.4 (C),
153.7 (C), 130.5 (CH), 130.2 (C), 127.9 (CH), 121.2 (CH), 118.5
(CH), 89.5 (C), 73.2 (C), 52.7 (CH3), 29.4 (CH2), 25.9 (CH3), 19.3
(CH2), 18.3 (C), −4.0 (CH3); IR (thin film) 3011, 2931, 2239, 1718,
1
indicated a >96:4 ratio of d1-(Z)-60:d0-(Z)-60: H NMR (500 MHz,
CDCl3) δ 7.13−7.05 (m, 2H), 6.89 (t, J = 7.3, 1H), 6.82 (d, J = 8.3,
1H), 6.69−6.63 (m, 1H), 5.94 (d, J = 11.2, 1H), 2.89 (app q, J = 7.5,
2H), 2.81 (t, J = 7.3, 2H), 1.03 (s, 9H), 0.25 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 190.6 (t, JCD = 25.7, CDO), 153.7 (C), 152.3 (CH),
130.6 (CH), 130.6 (C), 130.5 (CH), 127.7 (CH), 121.2 (CH), 118.6
(CH), 30.3 (CH2), 28.4 (CH2), 25.9 (CH3), 18.3 (C), −4.0 (CH3); IR
(thin film) 3023, 2955, 2857, 1668, 1252, 927 cm−1; HRMS (ESI) m/z
calcd for C17H25DO2SiNa, (M + Na)+ 314.1663, found 314.1659.
(E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1-deuteropent-
2-enal ((E)-60). In a 25-mL round-bottomed flask, (Z)-60 (938 mg,
3.22 mmol) was dissolved in hexanes (10 mL). Silica gel (500 mg) and
pyridine (0.20 mL, 2.5 mmol) were added in a single portion and the
slurry was stirred at ambient temperature for 15 h. The reaction
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Article
mixture was filtered and concentrated in vacuo, then pyridine was
reaction mixture was concentrated in vacuo and the residue was
purified by flash chromatography (97:2:1 toluene−acetone−Et3N) to
provide imidate (E)-1-d-11a (101 mg, 0.312 mmol, 56%) as a pale
yellow oil. Analysis by electrospray mass spectrometry indicated a
azeotropically removed with toluene (2 × 25 mL) to give aldehyde
1
(E)-60 (938 mg, 3.22 mmol, 100%, >20:1 E:Z by H NMR analysis)
as a clear colorless oil. Analysis by electrospray mass spectrometry
1
24
24
indicated a >96:4 ratio of d1-(E)-60:d0-(E)-60: H NMR (500 MHz,
>96:4 ratio of d1-(E)-1-d-11a:d0-(E)-1-d-11a: [α]D −43.8, [α]577
23
23
1
CDCl3) δ 7.13−7.10 (m, 2H), 6.91−6.82 (m, 2H), 6.81 (d, J = 7.8,
1H), 6.14 (d, J = 15.5, 1H), 2.80 (t, J = 7.3, 2H), 2.63 (app q, J = 6.8,
2H), 1.02 (s, 9H), 0.25 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 193.9
(t, JCD = 26.3, CDO), 158.2 (CH), 153.7 (C), 133.1 (t, JCD = 3.8,
CH), 131.0 (C), 130.2 (CH), 127.6 (CH), 121.3 (CH), 118.6 (CH),
33.1 (CH2), 29.2 (CH2), 25.9 (CH3), 18.3 (C), −4.0 (CH3); IR (thin
film) 3033, 2930, 2857, 1711, 1491, 1146 cm−1; HRMS (ESI) m/z
calcd for C17H25DO2SiNa, (M + Na)+ 314.1663, found 314.1655.
(S,E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1-deutero-
pent-2-en-1-ol ((E)-61).31 Using a modification of a procedure by
Keck,19 titanium isopropoxide (89 μL, 0.32 mmol) was added to a
stirring mixture of (R)-BINOL (184 mg, 0.644 mmol), trifluoroacetic
acid (0.5 M in CH2Cl2, 0.13 mL, 0.064 mmol), molecular sieves (4 Å,
1.7 g), and diethyl ether (12 mL) in a 100-mL round-bottomed flask.
The red-orange mixture was heated to reflux for 1 h and allowed to
cool to room temperature, and α,β-unsaturated aldehyde (E)-60 (938
mg, 3.22 mmol) in Et2O (10 mL) was added. The resulting mixture
was stirred at room temperature for 10 min and then cooled to −78
°C, and Bu3SnH (1.0 mL, 3.9 mmol) was added dropwise. The
reaction mixture was then transferred to a −20 °C freezer and left for
18 h, without stirring. The mixture was removed from the freezer, and
saturated aqueous NaHCO3 (10 mL) was added. The mixture was
stirred for 1 h at room temperature and then filtered through a pad of
Celite. The layers were separated, and the aqueous layer was extracted
with Et2O (3 × 5 mL). The combined organic layers were washed with
water (2 × 5 mL), dried over Na2SO4, filtered, and concentrated in
vacuo to give a residue that was purified by flash chromatography
(88:12 hexanes−Et2O) to provide allylic alcohol (E)-61 (488 mg, 1.67
mmol, 62% brsm) as a clear colorless oil. A modified Mosher’s ester
analysis12 of the product showed it to be of 65% enantiomeric excess
and predominantly the (S) enantiomer. Analysis by electrospray mass
−40.2, [α]546 −27.2, [α]435 −24.6, (c = 0.17, CH2Cl2); H NMR
(500 MHz, CDCl3) δ 8.30 (br s, 1H), 7.13−7.08 (m, 2H), 6.88 (t, J =
7.5, 1H), 6.76 (d, J = 8.0, 1H), 5.96 (dt, J = 15.4, 6.7, 1H), 5.86 (br s,
1H), 5.73 (dd, J = 15.5, 6.1, 1H), 4.76 (d, J = 5.4, 1H), 2.75 (t, J = 7.8,
2H), 2.43 (app q, J = 7.3, 2H); 13C NMR (125 MHz, CDCl3) δ 163.1
(C), 153.8 (C), 136.4 (CH), 130.4 (CH), 127.9 (C), 127.3 (CH),
123.4 (CH), 120.7 (CH), 115.4 (CH), 91.6 (C), 69.9 (t, JCD = 21.3,
CDH), 32.5 (CH2), 29.6 (CH2); IR (thin film) 3332, 3036, 2928,
1660, 1593, 972 cm−1
; HRMS (ESI) m/z calcd for
C13H13DCl3NO2Na, (M + Na)+ 345.0051, found 345.0056.
(S,E)-1-Deutero-5-(2-hydroxyphenyl)pent-2-enyl acetate
((E)-1-d-19a). Following the procedure described for the preparation
of acetate (E)-19a, allylic alcohol (E)-62 (50 mg, 0.28 mmol) was
acetylated using acetic anhydride (80 μL, 0.84 mmol) to give a residue
that was purified by flash chromatography (85:15 to 80:20 pentane-
Et2O) to provide acetate (E)-1-d-19a (55 mg, 0.25 mmol, 89%) as a
clear colorless oil. Analysis by electrospray mass spectrometry
25
indicated a >96:4 ratio of d1-(E)-1-d-19a:d0-(E)-1-d-19a: [α]D
25
25
1
−16.8, [α]577 −18.4, [α]546 −15.3, (c = 0.16, CH2Cl2); H NMR
(500 MHz, CDCl3) δ 7.12−7.06 (m, 2H), 6.88 (t, J = 7.4, 1H), 6.76
(d, J = 7.9, 1H), 5.86 (dt, J = 15.6, 6.5, 1H), 5.60 (dd, J = 15.6, 6.4,
1H), 4.74 (br s, 1H), 4.50 (d, J = 5.8, 1H), 2.72 (t, J = 7.5, 2H), 2.39
(app q, J = 7.0, 2H), 2.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
171.2 (C), 153.6 (C), 135.9 (CH), 130.4 (CH), 127.8 (C), 127.4
(CH), 124.5 (CH), 121.0 (CH), 115.5 (CH), 65.1 (t, JCD = 21.3,
CDH), 32.6 (CH2), 29.7 (CH2), 21.2 (CH3); IR (thin film) 3408,
3035, 2918, 1708, 1242, 969 cm−1; HRMS (ESI) m/z calcd for
C13H15DO3Na, (M + Na)+ 244.1060, found 244.1054.
(S,E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1-deutero-
pent-2-enyl (R)-3′,3′,3′-trifluoro-2′-methoxy-2′-phenylpropa-
noate ((1S,2′R)-(E)-63). In a 5-mL round-bottomed flask, allylic
alcohol (E)-61 (5 mg, 0.02 mmol), DMAP (0.2 mg, 0.002 mmol), and
(R)-2-trifluoromethyl-2-methoxy-2-phenylacetic acid (5 mg, 0.02
mmol) were dissolved in CH2Cl2 (0.34 mL). N,N′- Dicyclohex-
ylcarbodiimide (5 mg, 0.02 mmol) was added at room temperature,
and the reaction mixture was stirred for 18 h. Saturated aqueous
NaHCO3 (1 mL) was added, and the resulting mixture was extracted
with Et2O (3 × 0.5 mL), dried over Na2SO4, filtered, and concentrated
in vacuo to give a residue that was purified by flash chromatography
(95:5 pentane-Et2O). The ester product (7 mg, 0.01 mmol, 80%) was
obtained as a 82.5:17.5 mixture of (1S,2′R)-(E)-63:(1R,2′R)-(E)-63 as
a clear colorless oil. Analysis by electrospray mass spectrometry
indicated a >96:4 ratio of d1-(1S,2′R)-(E)-63:d0-(1S,2′R)-(E)-63.
23
spectrometry indicated a >96:4 ratio of d1-(E)-61:d0-(E)-61: [α]D
24
24
24
−2.7, [α]577 −3.6, [α]546 −3.8, [α]435 −3.3, (c = 0.33, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ 7.12 (d, J = 7.4, 1H), 7.08 (t, J = 7.9,
1H), 6.88 (t, J = 7.3, 1H), 6.79 (d, J = 7.9, 1H), 5.75 (dt, J = 15.5, 6.5,
1H), 5.66 (dd, J = 15.4, 5.8, 1H), 4.07 (br s, 1H), 2.68 (t, J = 7.6, 2H),
2.34 (app q, J = 7.8, 2H), 1.03 (s, 9H), 0.25 (s, 6H); 13C NMR (125
MHz, CDCl3) δ 153.7 (C), 133.1 (CH), 132.4 (C), 130.4 (CH), 129.4
(CH), 127.1 (CH), 121.1 (CH), 118.5 (CH), 63.6 (t, JCD = 22.5,
CDH), 32.8 (CH2), 30.5 (CH2), 26.0 (CH3), 18.4 (C), −4.0 (CH3);
IR (thin film) 3338, 3022, 2929, 1105, 755, 701 cm−1; HRMS (ESI)
m/z calcd for C17H27DO2SiNa, (M + Na)+ 316.1819, found 316.1818.
(S,E)-2-(5-Deutero-5-hydroxypent-3-enyl)phenol ((E)-62). In
a 25-mL round-bottomed flask, silyl ether (E)-61 (468 mg, 1.59
mmol) was dissolved in THF (8.0 mL). A solution of TBAF (1.0 M in
THF, 1.9 mL, 1.9 mmol) was added via syringe. After 18 h, the
reaction mixture was concentrated in vacuo to give a pale yellow
residue that was purified by flash chromatography (90:10 to 85:15
CH2Cl2−acetone) to provide diol (E)-62 (285 mg, 1.59 mmol, 100%)
as a clear colorless oil. Analysis by electrospray mass spectrometry
25
25
Major diastereomer (1S,2′R)-(E)-63: [α]D 28.1, [α]577 28.7,
25
1
[α]546 31.9, (c = 1.10, CH2Cl2); H NMR (500 MHz, CDCl3) δ
7.53−7.52 (m, 2H), 7.41−7.40 (m, 3H), 7.10−7.06 (m, 2H), 6.87 (d, J
= 6.7, 1H), 6.78 (d, J = 7.9, 1H), 5.90 (dt, J = 15.3, 6.7, 1H), 5.62 (dd,
J = 15.4, 6.6, 1H), 4.71 (d, J = 6.5, 1H), 3.55 (s, 3H), 2.67 (t, J = 7.5,
2
2H), 2.35 (app q, J = 7.1, 2H), 1.01 (s, 9H), 0.24 (s, 6H); H NMR
(61 MHz, CDCl3) δ 4.81 (s, 12H); 13C NMR (125 MHz, CDCl3) δ
166.5 (C), 153.7 (C), 138.0 (CH), 132.5 (C), 132.0 (C), 130.3 (CH),
129.7 (CH), 128.5 (CH), 127.5 (CH), 127.2 (CH), 124.6 (C), 122.8
(CH), 122.3 (C), 121.1 (CH), 118.5 (CH), 66.8 (t, JCD = 23.5, CDH),
55.6 (CH3), 32.7 (CH2), 30.2 (CH2), 25.9 (CH3), 18.3 (C), −4.0
(CH3); IR (thin film) 3034, 2930, 1748, 1453, 1253, 1169 cm−1;
HRMS (ESI) m/z calcd for C27H34DF3O4SiNa, (M + Na)+ 532.2217,
found 532.2202.
24
24
indicated a >96:4 ratio of d1-(E)-62:d0-(E)-62: [α]D −8.3, [α]577
−8.5, [α]54624 −10.7, [α]43524 −3.9, (c = 0.11, CH2Cl2); 1H NMR (500
MHz, CDCl3) δ 7.12−7.06 (m, 2H), 6.86 (t, J = 7.9, 1H), 6.78 (d, J =
7.7, 1H), 6.62 (br s, 1H), 5.77 (dt, J = 15.4, 6.5, 1H), 5.65 (dd, J =
15.5, 5.8, 1H), 4.07 (d, J = 5.4, 1H), 2.72 (t, J = 7.8, 2H), 2.51 (br s,
1H), 2.38 (app q, J = 7.2, 2H); 13C NMR (125 MHz, CDCl3) δ 154.0
(C), 133.4 (CH), 130.3 (CH), 128.8 (CH), 128.2 (C), 127.3 (CH),
120.5 (CH), 115.5 (CH), 63.4 (t, JCD = 21.3, CDH), 32.5 (CH2), 29.8
(CH2); IR (thin film) 3336, 3070, 2922, 1180, 1042, 973 cm−1; HRMS
(ESI) m/z calcd for C11H13DO2Na, (M + Na)+ 202.0954, found
202.0951.
(S,E)-5-(2-(tert-Butyldimethylsilyloxy)phenyl)-1-deutero-
pent-2-enyl (S)-3′,3′,3′-trifluoro-2′-methoxy-2′-phenylpropa-
noate ((1S,2′S)-(E)-63). Following the procedure described for the
preparation of (1S,2′R)-(E)-63, allylic alcohol (E)-61 (5 mg, 0.02
mmol) was acylated using (S)-2-trifluoromethyl-2-methoxy-2-phenyl-
acetic acid (5 mg, 0.02 mmol) to give a residue that was purified by
flash chromatography (95:5 pentane-Et2O). The ester product (6 mg,
0.01 mmol, 69%) was obtained as a 82.5:17.5 mixture of (1S,2′S)-(E)-
(S,E)-1-Deutero-5-(2-hydroxyphenyl)pent-2-enyl 2′,2′,2′-tri-
chloroacetimidate ((E)-1-d-11a). Following the procedure de-
scribed for the preparation of (E)-11a, alcohol (E)-62 (100 mg,
0.558 mmol) was treated with DBU and Cl3CCN. After 30 min, the
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63:(1R,2′S)-(E)-63 as a clear colorless oil. Analysis by electrospray
mass spectrometry indicated a >96:4 ratio of d1-(1S,2′S)-(E)-63:d0-
(4) Pd(0)-catalyzed synthesis of 2-vinyl-2H-1-benzopyrans:
(a) Trost, B. M.; Shen, H. C.; Dong, L.; Surivet, J.-P.; Sylvain, C. J.
Am. Chem. Soc. 2004, 126, 11966−11983. (b) Trost, B. M.; Shen, H.
C.; Dong, L.; Surivet, J.-P. J. Am. Chem. Soc. 2003, 125, 9276−9277.
(c) Labrosse, J.-R.; Poncet, C.; Lhoste, P.; Sinou, D. Tetrahedron:
Asymmetry 1999, 10, 1069−1078.
25
(1S,2′S)-(E)-63. Major diastereomer (1S,2′S)-(E)-63: [α]D −28.6,
25
24
1
[α]577 −30.8, [α]546 −35.7, (c = 1.60, CH2Cl2); H NMR (500
MHz, CDCl3) δ 7.54−7.52 (m, 2H), 7.41−7.40 (m, 3H), 7.10−7.06
(m, 2H), 6.87 (d, J = 7.3, 1H), 6.79 (d, J = 7.9, 1H), 5.90 (dt, J = 15.3,
6.6, 1H), 5.62 (dd, J = 15.3, 6.5, 1H), 4.77 (d, J = 6.2, 1H), 3.55 (s,
3H), 2.67 (t, J = 7.5, 2H), 2.35 (app q, J = 7.0, 2H), 1.01 (s, 9H), 0.24
(s, 6H); 2H NMR (61 MHz, CDCl3) δ 4.74 (s, 12H); 13C NMR (125
MHz, CDCl3) δ 166.5 (C), 153.7 (C), 138.0 (CH), 132.5 (C), 132.0
(C), 130.3 (CH), 129.7 (CH), 128.5 (CH), 127.5 (CH), 127.2 (CH),
124.6 (C), 122.8 (CH), 122.3 (C), 121.1 (CH), 118.5 (CH), 66.8 (t,
JCD = 21.9, CDH), 55.6 (CH3), 32.7 (CH2), 30.2 (CH2), 25.9 (CH3),
18.4 (C), −4.0 (CH3); IR (thin film) 3032, 2930, 1748, 1453, 1254,
1169 cm−1; HRMS (ESI) m/z calcd for C27H34DF3O4SiNa, (M +
Na)+ 532.2217, found 532.2198.
(5) Ir(I)-catalyzed synthesis of 2-vinyl-2H-1-benzopyrans: Welter, C.;
Dahnz, A.; Brunner, B.; Streiff, S.; Dubon, P.; Helmchen, G. Org. Lett.
̈
2005, 7, 1239−1242.
(6) Pd(0)-catalyzed synthesis of 2-vinylbenzodioxanes and 2-vinyl-
2H-1,4-benzoxazines: (a) Ito, K.; Imahayashi, Y.; Kuroda, T.; Eno, S.;
Saito, B.; Katsuki, T. Tetrahedron Lett. 2004, 45, 7277−7281.
(b) Massacret, M.; Lakhmiri, R.; Lhoste, P.; Nguefack, C.;
Abdelouahab, F. B. B.; Fadel, R.; Sinou, D. Tetrahedron: Asymmetry
2000, 11, 3561−3568. (c) Massacret, M.; Lhoste, P.; Lakhmiri, R.;
Parella, T.; Sinou, D. Eur. J. Org. Chem. 1999, 2665−2673. (d) Lhoste,
P.; Massacret, M.; Sinou, D. Bull. Soc. Chim. Fr. 1997, 134, 343−347.
(e) Yamazaki, A.; Achiwa, I.; Achiwa, K. Tetrahedron: Asymmetry 1996,
7, 403−406. (f) Massacret, M.; Goux, C.; Lhoste, P.; Sinou, D.
Tetrahedron Lett. 1994, 35, 6093−6096.
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental methods, tables of additional optimiza-
tion experiments and reaction of imidate 16 with Pd(OAc)2,
synthetic schemes for the synthesis of cyclization precursors, 1H
and 13C NMR data for new compounds, and copies of
chromatography traces used to determine enantiomeric purity.
General computational details, calculated close contacts in
transition structures 22, 25, 28, and 31, three-dimensional
models of 28 and 31, and XYZ coordinates. This material is
available free of charge via the Internet at http://pubs.acs.org.
(7) (a) Kirsch, S. F.; Overman, L. E.; White, N. S. Org. Lett. 2007, 9,
911−913. (b) Cannon, J. S.; Kirsch, S. F.; Overman, L. E.; Sneddon,
H. F. J. Am. Chem. Soc. 2010, 132, 15192−15203.
(8) Olson, A. C.; Overman, L. E.; Sneddon, H. F.; Ziller, J. W. Adv.
Synth. Catal. 2009, 351, 3186−3192.
(9) (a) Stevens, A. M.; Richards, C. J. Organometallics 1999, 18,
1346−1348. (b) Anderson, C. E.; Kirsch, S. F.; Overman, L. E.;
Richards, C. J.; Watson, M. P. Org. Synth. 2007, 84, 148−155.
(c) Anderson, C. E.; Overman, L. E.; Richards, C. J.; Watson, M. P.;
White, N. Org. Synth. 2007, 84, 139−147.
(10) Prepared using conventional chemistry; see the Experimental
Section.
(11) Anderson, C. E.; Overman, L. E. J. Am. Chem. Soc. 2003, 125,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: leoverma@uci.edu.
12412−12413.
(12) See the Supporting Information for more details.
(13) When imidate 15 was subjected to reaction conditions in the
absence of catalyst, 2-vinylbenzodioxane 17 was not observed in the
1H NMR of the crude reaction mixture, indicating that trichloro-
acetamidate ionization followed by nucleophilic attack of phenol is not
likely.
Present Address
†Gilead Sciences, Inc., Process Development, 333 Lakeside
Drive, Foster City, CA 94404.
Notes
The authors declare no competing financial interest.
(14) Numata, M.; Sugimoto, M.; Koike, K.; Ogawa, T. Carbohydr.
Res. 1987, 163, 209−225.
ACKNOWLEDGMENTS
■
(15) Carpenter, N. E.; Overman, L. E. In Organic Reactions;
Overman, L. E., Ed.; Wiley: Hoboken, 2005; Vol. 66, pp 1−107.
(16) Other COP catalysts were found to be less effective.12
(17) For example, see: Meyers, C.; Maes, B. U. W.; Loones, K. T. J.;
We thank the NSF (CHE-9726471) for financial support.
Additional unrestricted support from Amgen, Merck, and Pfizer
is also gratefully acknowledged. The NIH Predoctoral Fellow-
ship Program (1F31GM089137) and the UC Irvine Faculty
Mentor Program are acknowledged for financial support of
A.C.O and BMS for fellowship support for J.S.C. Computa-
tional studies were performed on hardware purchased with
funding from CRIF (CHE-0840513), and NMR and mass
spectra were obtained at UC Irvine using instrumentation
acquired with the assistance of NSF and NIH shared
instrumentation programs. Three-dimensional renderings of
computed structures were generated using the CYLview
program.41
Bal, G.; Lemier
6010−6017.
̀
e, G. L. F.; Dommisse, R. A. J. Org. Chem. 2004, 69,
(18) These entries represent a small selection of reaction
optimization data. A complete report of solvents and additives
examined can be found in the Supporting Information.
(19) Keck, G. E.; Krishnamurthy, D. J. Org. Chem. 1996, 61, 7638−
7639.
(20) For a recent comprehensive review of Pd(II)-catalyzed
nucleopalladation of alkenes, see: McDonald, R. I.; Liu, G.; Stahl, S.
S. Chem. Rev. 2011, 111, 2981−3019.
(21) (a) TURBOMOLE V6.2, Turbomole GmbH: Karlsruhe,
Germany, 2009; http://www.turbomole.com. (b) Treutler, O.;
Ahlrichs, R. J. Chem. Phys. 1995, 102, 346−354.
(22) (a) Slater, J. C. Quantum Theory of Molecules and Solids, Vol. 4:
The Self-Consistent Field for Molecules and Solids; McGraw-Hill: New
York, 1974. (b) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980,
58, 1200−1211. (c) Becke, A. D. Phys. Rev. A 1988, 38, 3098−3100.
(d) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785−789.
(e) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989,
157, 200−206. (f) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652.
(g) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623−11627.
REFERENCES
■
(1) The systematic name for chromane is 3,4-dihydro-2H-1-
benzopyran.
(2) A substructure search in SciFinder of chromane structure 4 (R1 =
an alkyl side chain and the oxacyclic ring otherwise unsubstituted) and
substance role = biological study finds >2800 compounds.
(3) For two illustrative examples, see: (a) Carreno, M. C.;
̃
́
Hernandes-Torres, G.; Urbano, A.; Colobert, F. Eur. J. Org. Chem.
2008, 12, 2035−2038. (b) Liu, Y.-C.; Sperry, J.; Rathwell, D. C. K.;
Brimble, M. A. Synlett 2009, 5, 793−797.
1972
dx.doi.org/10.1021/jo202553a | J. Org. Chem. 2012, 77, 1961−1973

The Journal of Organic Chemistry
Article
(23) Klamt, A.; Schuurmann, G. J. Chem. Soc., Perkin Trans. 2 1993,
̈
̈
799−805.
(24) (a) Eichkorn, K.; Weigend, F.; Treutler, O.; Ahlrichs, R. Theor.
Chem. Acc. 1997, 97, 119−124. (b) Schafer, A.; Huber, C.; Ahlrichs, R.
̈
J. Chem. Phys. 1994, 100, 5829−5835. (c) Weigend, F.; Furche, F.;
Ahlrichs, R. J. Chem. Phys. 2003, 119, 12753−12762.
(25) For further computational details, see the Supporting
Information.
(26) A table of calculated close contacts can be found in the
Supporting Information.
(27) The corresponding models for transition structures 28 and 31
for cyclization of (Z)-11a can be found in the Supporting Information.
(28) The absolute configuration of this compound has been
tentatively assigned based on the stereochemical assignment of
products 1a and 1c, for which the absolute configuration has been
established.4b
(29) The change in absolute configuration is a consequence of
different CIP priorities of substituents at the stereocenter.
(30) Birch, A. J.; Maung, M.; Pelter, A. Aust. J. Chem. 1969, 22,
1923−1932.
(31) Different batches of (E)-61, the precursor to (E)-1-d-11a and
(E)-1-d-19a, were formed with different enantiomeric excesses. The
enhancement of all batches was sufficient to determine the
stereospecificity of the reactions depicted in eqs 3 and 4. The same
level of stereospecificity was observed when starting imidates ((E)-1-
d-11a) or acetates ((E)-1-d-19a) of different enantiomeric purities
were exposed to the reaction conditions.
(32) The NMR data provided for this compound12 was obtained
using a synthetic sequence that originated from (E)-61 with 72% ee.
Therefore, the NMR spectra indicate that the major/minor isomer
ratio of the product is approximately 86:14.
(33) Mori, M.; Tonogaki, K.; Kinoshita, A. Org. Synth. 2005, 81, 1−
13.
(34) Jones, T. K.; Denmark, S. E. Org. Synth. 1986, 64, 182−185.
(35) (a) Taber, D. F.; Herr, R. J.; Gleave, D. M. J. Org. Chem. 1997,
62, 194−198. (b) Brown, C. A.; Ahuja, V. K. J. Org. Chem. 1973, 38,
2226−2230.
(36) Davies, S. G.; Pyatt, D. J. Organomet. Chem. 1990, 387, 381−
390.
(37) Verdaguer, X.; Berk, S. C.; Buchwald, S. L. J. Am. Chem. Soc.
1995, 117, 12641−12642.
(38) Caldwell, J. J.; Cameron, I. D.; Christie, S. D. R.; Hay, A. M.;
Johnstone, C.; Kerr, W. J.; Murray, A. Synthesis 2005, 19, 3293−3296.
(39) Marecak, D. M.; Horiuchi, Y.; Arai, H.; Shimonaga, M.; Maki,
Y.; Koyama, T.; Ogura, K.; Prestwich, G. D. Bioorg. Med. Chem. Lett.
1997, 7, 1973−1978.
(40) Crich, D.; Krishnamurthy, V.; Brebion, F.; Karatholuvhu, M.;
Subramanian, V.; Hutton, T. K. J. Am. Chem. Soc. 2007, 129, 10282−
10294.
(41) CYLview, 1.0b: Legault, C. Y. Universite
http://www.cylview.org.
́
de Sherbrooke, 2009;
1973
dx.doi.org/10.1021/jo202553a | J. Org. Chem. 2012, 77, 1961−1973