Kinetic resolution in asymmetric epoxidation using iminium salt catalysis

Article abstract of DOI:10.1021/jo401345m

The first reported examples of kinetic resolution in epoxidation reactions using iminium salt catalysis are described, providing up to 99% ee in the epoxidation of racemic cis-chromenes.

Full text of DOI:10.1021/jo401345m

Article
pubs.acs.org/joc
Kinetic Resolution in Asymmetric Epoxidation using Iminium Salt
Catalysis
Philip C. Bulman Page,*,† Louise F. Appleby,† Yohan Chan,† David P. Day,† Benjamin R. Buckley,‡
Alexandra M. Z. Slawin,§ Steven M. Allin,∥ and Michael J. McKenzie⊥
†School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, Norfolk NR4 7TJ, U.K.
‡Department of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, U.K.
§School of Chemistry, University of St. Andrews, Fife KY16 9ST, U.K.
∥School of Science & Technology, Nottingham Trent University, Clifton, Nottinghamshire NG11 8NS, U.K.
⊥Charnwood Molecular Ltd, The Heritage Building, 7 Beaumont Court, Prince William Road, Loughborough, Leicestershire LE11
5GA, U.K.
S
* Supporting Information
ABSTRACT: The first reported examples of kinetic resolution in epoxidation reactions using iminium salt catalysis are
described, providing up to 99% ee in the epoxidation of racemic cis-chromenes.
INTRODUCTION
■
Asymmetric epoxidation of alkenes to generate optically active
epoxides is an extremely powerful synthetic tool,1 and the
development of effective organocatalytic systems for epox-
idation has received considerable attention.2 The most
successful organocatalytic methods for epoxidation are those
utilizing dioxiranes and those utilizing oxaziridinium salts.
Chiral ketones, precursors to dioxiranes, such as those of Yang,3
Figure 1. Iminium salt catalysts.
Denmark,4 Armstrong,5 and Shi,6 have achieved high
enantioselectivities, with observed values of up to 97% ee.
iminium precursors in similar epoxidation processes by us13 and
others.14
Oxaziridinium salts, first reported by Lusinchi in 1976,7 are also
reactive reagents for oxygen transfer to nucleophilic substrates,
such as sulfides and alkenes, and may be generated catalytically
by use of iminium salts in the presence of a stoichiometric
oxidant, typically oxone.8
We reported the first very high enantioselectivities in the
asymmetric epoxidation of alkenes using iminium salt catalysts,
and we have developed nonaqueous conditions for these
processes using tetraphenylphosphonium monoperoxysulfate
(TPPP)15 as the oxidant.16 We have used the process, for
example, in the syntheses of levcromakalim 4,17 (−)-lomatin 5
and (+)-trans-khellactone 6,18 and scuteflorin,19 utilizing
iminium salt catalysts 1 and 3 (Figure 2). Kinetic resolution
in these iminium salt-catalyzed epoxidation processes has not
We have developed a range of catalysts for epoxidation
reactions based on biphenylazepinium (e.g., 1), binaphthylaze-
pinium (e.g., 2), and dihydroisoquinolinium (e.g., 3) moieties
containing a chiral appendage on the nitrogen atom, with the
most successful to date containing the 1,3-dioxane motif
(Figure 1).9 We have also shown that alternative oxidants may
be used in iminium salt-catalyzed epoxidation reactions, such as
hydrogen peroxide,10 sodium hypochlorite,11 and electrochemi-
cally generated oxidants.12 Amines have also been used as
Received: June 21, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 2. Levcromakalim, lomatin, khellactone, epigallocatechin-3-gallate, and catechin.
a
been reported, and given the high levels of enantioselectivities
observed in the epoxidation of 2-substituted benzopyrans under
our conditions, we decided to evaluate these substrates as
possible candidates for kinetic resolution using iminium salt
catalyst 3, the most enantioselective for chromene substrates.
This core structure is also found in a range of natural products,
including a number of flavonoids isolated from green tea
extracts (up to 40% of the dry weight),20 such as
epigallocatechin-3-gallate (EGCG) 7 and catechin 8.
Scheme 1
a
Reagents and conditions: (i) (EtO)3CH (1.2 equiv), NH4NO3 (0.25
equiv), ethanol (50 mL), 24 h, r.t.; (ii) phenol (2 equiv), 3-picoline
(0.25 equiv), p-xylene (40 mL), 16 h, reflux.
RESULTS AND DISCUSSION
■
Kinetic resolution of racemic alkenes using asymmetric
epoxidation is an attractive topic for asymmetric catalysis, as
racemic alkenes are generally cheap and readily available, but is
potentially more challenging than the asymmetric epoxidation
of prochiral alkenes. Kinetic resolution in asymmetric
epoxidation has been observed previously by Sharpless,21
Jacobsen,22 Katsuki,23 and Shi.24
Table 1. Synthesis of Racemic C6-Substituted Chromenes
We report herein the first successful demonstration of
iminium salt-catalyzed epoxidation as a tool for kinetic
resolution of 2-substituted benzopyrans. A number of
procedures have been reported to achieve the synthesis of
2H-chromenes, including inter alia: via an allene intermediate
through a Claisen rearrangement,25 oxidation of allylphenols,26
iodination of allylphenols,27 using metal phenoxides and
carbonyls,28 using palladium catalysis,29 dehydration of
chromenols,30 using the Wittig reaction,31 using metathesis,32
and using the Petasis reaction.33 Substrates 13a−13c, 14a−14c,
15a−15c, and 16a−16c, containing the benzopyran core
structure, were prepared quickly by us in two steps using the
procedure reported by North.34 This route allows easy variation
of substituents at both the C2 and the C6 positions of the
chromenes using the corresponding dialkylacetals and phenols.
We have found diethyl acetals 9−12 to be the most reactive
substrates for this reaction, the dimethyl acetals being much less
reactive. The diethyl acetals were prepared from the
corresponding aldehydes in good yields and were subsequently
reacted with 4-chloro-, 4-cyano-, and 4-nitro-phenol to give the
corresponding chromenes 13−16 (Scheme 1, Table 1).
The chromenes were submitted to standard epoxidation
reaction conditions using m-CPBA (Scheme 2, Table 2).
Diastereoisomeric ratios (trans:cis) for the epoxide products
a
Scheme 2
a
Reagents and conditions: (i) m-CPBA, CH2Cl2, 1−8 h, 0 °C.
1
were obtained using H NMR spectroscopy carried out on the
Asymmetric epoxidation of ( )-6-cyano-2-methyl-chromene
13b under our standard nonaqueous conditions using catalyst 3
(Scheme 3) gave a promising initial result; a higher selectivity
toward the product where the methyl group at C2 is trans to
the epoxide moiety was observed compared to that observed
when m-CPBA was used. At 52% conversion, chiral HPLC and
1H NMR spectroscopic data of the mixture of inseparable
inseparable mixture of diastereoisomers, and ranged from 1:1 to
exclusively trans with increasing bulk of the R1 substituent at
C2. Decomposition was observed when chromenes containing
a chloro R2 substituent at C6 were submitted to the epoxidation
conditions; neither the epoxides nor the corresponding diols
were isolated from the reaction mixtures.
B
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. Epoxidation of Racemic Chromenes Using m-CPBA
starting material
conversion (%)
epoxide
epoxide d.r.
13a
13b
14a
14b
15a
15b
16a
16b
100
100
100
100
100
100
81
(
)-17a
)-17b
)-18a
)-18b
)-19a
)-19b
)-20a
)-20b
2:1
(
(
(
(
(
(
(
1:1
2:1
3.5:1
trans only
trans only
4:1
80
4:1
Figure 3. Directions of approach of active oxidant.
diastereoisomers showed a 3:1 diastereoisomeric ratio, 86% ee
for the major epoxide diastereoisomer 21, 97% ee for the minor
epoxide diastereoisomer 22, and 37% ee for the unreacted
starting material.
catechins, in quantitative yield. Alcohol 23 was then converted
to the corresponding sulfonyl ester 24 by treatment with 10S-
camphorsulfonyl chloride in 43% yield (Scheme 4).
Single-crystal X-ray analysis of 24 confirmed our assignment
of absolute and relative configurations (see the Supporting
Information).
A number of chiral chromenes have previously been
synthesized as single enantiomers.35 On the basis of these
reports and the optical rotation of our recovered chromene
starting materials, we were able to assign the absolute
configurations of the products obtained. The diastereofacial
selectivity observed in the epoxidation of prochiral chromenes
using catalyst 3 corresponds to the expected outcome based on
our earlier work with this group of catalysts,17−19 providing
further confirmation. Figure 3 indicates the preferred trajectory
of oxidation of these substrate types when using iminium salt 3.
Encouraged by the results obtained for compound 13b, we
tested further chiral benzopyran substrates, allowing different
electronic and steric influences to be investigated (Table 3).
In all cases, we again found that the compounds containing
the chloro substituent on the aromatic ring were unstable to the
epoxidation reaction conditions. The best results were obtained
with compounds containing nitro and cyano substituents on
the aromatic ring. In one case, chromene 13a, the epoxidation
reaction was run for a longer reaction time, reaching 84%
conversion after 1 week. The diastereoisomeric ratio of the
product epoxides was still 2.5:1, with a 70% ee observed for the
major trans isomer and a 80% ee for the minor cis isomer. The
remaining alkene was isolated with 64% ee. As expected, the
observed krel values increase with the size of the 2-substituent in
the alkene substrates.
CONCLUSION
■
Kinetic resolution has been shown for the first time to be
feasible in iminium salt-catalyzed asymmetric epoxidation.
Enantioselectivities for epoxidation of racemic 2-substituted
chromene substrates were good in all cases for the major
epoxide diastereoisomer and were generally higher still for the
minor diastereoisomer, with moderate enantioselectivity
observed in the recovered starting material (15−50% ee).
Increasing the size of the 2-substituent in the chromene
substrates provided increases in diastereoselectivity and
enantioselectivity, presumably due to steric effects.
EXPERIMENTAL SECTION
■
General Comments. HRMS measurements were conducted using
APCI for the ionization method and an orbitrap mass analyzer.
Enantiomeric excesses were determined by chiral high-performance
liquid chromatography using a Chiracel OD-H 5 μm particle size
column. All HPLC samples were run using hexane−isopropanol
mixtures as eluent.
General Procedure for Acetal Formation.37 The aldehyde was
dissolved in the corresponding dried alcohol (molecular sieve) (100
mL). Ammonium nitrate (0.25 equiv) and triethylorthoformate (1.2
equiv) were added to the solution. The solution was stirred under a
nitrogen atmosphere at room temperature for 24 h, and quenched with
saturated aqueous sodium hydrogen carbonate (20 mL). The mixture
was extracted using dichloromethane (4 × 20 mL), the solution dried
over magnesium sulfate, and the organic solvents were removed under
To confirm unequivocally the absolute configuration of the
major enantiomer obtained in these reactions, epoxide (+)-19b
was reductively ring-opened by hydrogenolysis over a palladium
on carbon catalyst to give alcohol 23, containing the 2-
substituted 3-hydroxybenzopyran core structure typical of the
a
Scheme 3
a
Reagents and conditions: (i) iminium salt 3 (10 mol %), TPPP (4 equiv), CHCl3, −30 °C, 24 h. NB: the upper structures of each pair are the major
enantiomers in each case
C
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Kinetic Resolution of Olefins Using Asymmetric Epoxidation Mediated Using Catalyst 3
epoxide d.r.
d
major epoxide
trans-diastereoisomer ee (%)
minor epoxide
cis-diastereoisomer ee (%)
recovered chromene
b
c
c
c
e
starting material conv. (%)
epoxide
(trans:cis)
ee (%)
krel
13a
13b
14a
14b
15a
15b
16a
16b
48
52
50
56
26
37
38
36
(−)-17a
(−)-17b
(−)-18a
(−)-18b
(+)-19a
(+)-19b
(−)-20a
(−)-20b
2.5:1
87
86
87
73
76
74
76
88
97
97
98
92
26
37
40
41
17
14
42
50
2.3
2.9
3:1
4:1
3.4
3.5:1
2.8
trans only
trans only
10:1
3.4
1.9
82
99
8.0
16:1
27.9
a
All reactions were carried out with substrate (1 equiv), catalyst (10 mol %), and tetraphenylphosphonium monoperoxysulfate (TPPP) (4 equiv) in
b
c
CHCl3 at −30 °C. Conversion was determined from the 1H NMR spectra of the crude reaction mixture. Enantioselectivity was determined using
d
chiral stationary phase HPLC with a Chiralcel OD-H column. Diastereoisomeric ratios were determined from the 1H NMR spectra of the reaction
e
mixture after workup. krel = ln[(l − C)(1 − ee)]/ln[(l − C)(1 + ee)], where C is the fraction of 13, 14, 15, or 16 consumed and ee is the percentage
enantiomeric excess/100.21,22,36
a
Scheme 4
a
Reagents and conditions: (i) Pd/C, H2 (1 atm), MeOH, r.t., 20 min, quantitative yield; (ii) (10S)-(+)-camphorsulfonyl chloride (1 equiv), Et3N (2
equiv), PhMe, r.t., 24 h, 43%.
reduced pressure. The crude acetal was purified by vacuum distillation
(35−45 °C, 2 mbar) to afford a pure colorless liquid product.
General Procedure for the Formation of Chromenes. The
phenol (2 equiv) was dissolved in p-xylene, and 3-picoline (0.25 equiv)
and the corresponding acetal (1 equiv) were added. The reaction
mixture was heated under reflux under nitrogen for 24 h. The solvent
was removed under reduced pressure. The product was purified by
column chromatography using a petroleum ether/toluene mixture as
eluent, yielding the chromene as a pure crystalline or oily product.
General Procedure for the Formation of Racemic Epoxides.
The chromene and meta-chloroperbenzoic acid (1 equiv) were
dissolved in dichloromethane (5 mL) at 0 °C, and stirred until the
reaction reached completion. Saturated aqueous sodium hydrogen
carbonate (2 mL) was added. The organic layer was extracted with
water and brine, and the aqueous washings were extracted with further
dichloromethane. The combined organic extracts were dried over
magnesium sulfate, and solvents were removed under reduced
pressure. The crude product was purified by column chromatography
using an ethyl acetate/petroleum ether/triethylamine mixture as
eluent.
General Procedure for the Formation of Chiral Epoxides.
Tetraphenylphosphonium monoperoxysulfate (4 equiv) and iminium
salt (10 mol %) were dissolved in chloroform (20 mL per 0.1 g of
chromene) and cooled to −30 °C. The required chromene (1 equiv)
dissolved in chloroform (2 mL per 0.1 g of chromene) was then added
slowly over 10 min to the reaction mixture. The reaction progress was
monitored by 1H NMR spectroscopy of the crude reaction mixture. At
50% conversion, the reactions were quenched by the addition of
diethyl ether (20 mL per 0.1 g of chromene). The catalyst was
removed using filtration through Celite and washed with diethyl ether
(10 mL per 0.1 g of chromene), and the combined organic solvents
were removed under reduced pressure. The crude product was purified
by column chromatography using an ethyl acetate/petroleum ether/
triethylamine mixture as eluent.
1,1-Diethoxybut-2-ene 9.37−39 1,1-Diethoxybut-2-ene was pre-
pared using the general procedure for acetal formation from
crotonaldehyde (10 g, 143 mmol), yielding the desired compound 9
as a colorless liquid (10.6 g, 51%) after purification by vacuum
1
distillation (2 mbar, 35−38 °C). H NMR (300 MHz, CDCl3): δH
1.17 (6H, t, J = 7 Hz), 1.65 (3H, dd, J = 7, 2 Hz), 3.38−3.45 (2H, m),
3.50−3.61 (2H, m), 4.77 (1H, d, J = 6 Hz), 5.48 (1H, ddq, J = 16, 6, 2
Hz), 5.78 (1H, ddq, J = 16, 7, 1 Hz). 13C NMR (75 MHz, CDCl3): δC
14.9, 17.2, 60.7, 101.7, 128.9, 129.5.
(3,3-Diethoxyprop-1-enyl)benzene 10.40,41 (3,3-Diethoxy-
prop-1-enyl)benzene was prepared using the general procedure for
acetal formation from trans-cinnamaldehyde (12 g, 91 mmol), yielding
the desired compound 10 as a colorless liquid (15.6 g, 83%) after
1
purification by vacuum distillation (2 mbar, 37−40 °C). H NMR
(300 MHz, CDCl3): δH 1.25 (6H, t, J = 7 Hz), 3.40−3.83 (4H, m),
5.06 (1H, dd, J = 5, 1 Hz), 6.21 (1H, dd, J =16, 5 Hz), 6.71 (1H, d, J =
16 Hz), 7.08−7.47 (5H, m). 13C NMR (75 MHz, CDCl3): δC 15.1,
60.9, 101.5, 126.76, 126.83, 128.0, 128.6, 132.93, 136.3.
1,1-Diethoxyhex-2-ene 11.42 1,1-Diethoxyhex-2-ene was pre-
pared using the general procedure for acetal formation from hex-2-enal
(3 g, 30.6 mmol), yielding compound 11 as a colorless liquid (2.1 g,
40%) after purification by vacuum distillation (2 mbar, 35−37 °C). 1H
NMR (300 MHz, CDCl3): δH 0.79 (3H, t, J = 7.35 Hz), 1.09 (6H, t, J
= 7.05 Hz), 1.24−1.37 (2H, m), 1.93 (2H, dd, J = 8, 15 Hz), 3.31 −
3.51 (4H, m), 4.71 (1H, d, J = 6 Hz), 5.37 (1H, dd, J = 6, 16 Hz), 5.68
(1H, dt, J = 7, 16 Hz). 13C NMR (75 MHz, CDCl3): δC 13.3, 14.9,
21.7, 33.9, 60.6, 101.7, 127.5, 134.6.
1,1-Diethoxy-4-methylpent-2-ene 12.43 1,1-Diethoxy-4-meth-
ylpent-2-ene was prepared from 4-methyl-2-pentenal (2.0 g, 20.4
mmol), using the general procedure for acetal formation, yielding the
desired compound 12 as a pale yellow liquid (2.75 g, 78%) after
D
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
1
purification by vacuum distillation (2 mbar, 42−45 °C). H NMR
(300 MHz, CDCl3): δH 0.88 (6H, d, J = 7 Hz), 1.08 (6H, t, J = 6 Hz),
2.10−2.28 (1H, m), 3.23−3.41 (2H, m), 3.40−3.55 (2H, m), 4.69
(1H, d, J = 6 Hz), 5.30 (1H, dd, J = 16, 6 Hz), 5.65 (1H, dd, J = 16, 6
Hz). 13C NMR (75 MHz, CDCl3): δC 14.5, 21.4, 30.0, 60.0, 101.3,
124.3, 140.8.
1130, 1005. H NMR (300 MHz, CDCl3): δH 0.94 (3H, t, J = 7 Hz),
1.40−1.84 (4H, m), 4.91−5.04 (1H, m), 5.74 (1H, dd, J = 10, 3 Hz),
6.33 (1H, dd, J = 10, 2 Hz), 6.77 (1H, d, J = 8 Hz), 7.19 (1H, d, J = 2
Hz), 7.35 (1H, dd, J = 8, 2 Hz). 13C NMR (75 MHz, CDCl3): δC 13.7,
17.7, 37.8, 76.0, 103.9, 116.8, 119.2, 122.2, 122.4, 127.5, 130.1, 133.4,
157.4. HRMS m/z: 200.1065 [M + H]+; [C13H13NO + H]+ requires
200.1070. HPLC trace (90:10 hexane/isopropanol, 1 mL/min); 5.11
min (50.47%), 5.47 min (49.53%).
6-Nitro-2-methyl-chromene 13a.25 Compound (13a) was
prepared using the general procedure for chromene formation from
4-nitrophenol (3.19 g, 23.0 mmol) and 1,1-diethoxybut-2-ene 9 (1.65
g, 11.49 mmol), yielding compound (13a) as a yellow crystalline solid
(1.01 g, 46%; mp = 67−69 °C, lit.25 66−66.5 °C) after purification by
column chromatography using a petroleum ether/toluene (1:1)
mixture as eluent. νmax (film)/cm−1: 1575, 1506, 1480, 1373, 911.
1H NMR (300 MHz, CDCl3): δH 1.49 (3H, d, J = 7 Hz), 5.14−5.22
(1H, m), 5.80 (1H, dd, J = 10, 3 Hz), 6.41 (1H, dd, J = 10, 2 Hz), 6.81
(1H, d, J = 9 Hz), 7.87 (1H, d, J = 3 Hz), 8.02 (1H, dd, J = 9, 3 Hz).
13C NMR (75 MHz, CDCl3): δC 22.0, 73.2, 116.4, 121.4, 122.3, 125.5,
128.7, 159.2. HRMS m/z: 191.0578 [M+]; C10H9NO3 requires
191.0577. HPLC trace (90:10 hexane/isopropanol, 1 mL/min); 5.7
min (48.76%), 5.97 min (51.24%).
6-Chloro-2-propyl-chromene 14c. Compound (14c) was
prepared using the general procedure for chromene formation from
4-chlorophenol (1.50 g, 11.7 mmol) and 1,1-diethoxyhex-2-ene 11
(1.0 g, 5.85 mmol), yielding compound (14c) as a yellow liquid (0.9 g,
74%) after purification by column chromatography using a petroleum
ether/toluene (1:1) mixture as eluent. νmax (film)/cm−1: 2960, 2873,
1
1481, 1378, 1235, 1010, 878. H NMR (300 MHz, CDCl3): δH 0.95
(3H, t, J = 7 Hz), 1.42−1.82 (4H, m), 4.80−4.89 (1H, m), 5.72 (1H,
dd, J = 10, 3 Hz), 6.32 (1H, dd, J = 10, 2 Hz), 6.70 (1H, d, J = 9 Hz),
6.93 (1H, d, J = 3 Hz), 7.03 (1H, dd, J = 9, 3 Hz). 13C NMR (75 MHz,
CDCl3): δC 13.8, 17.9, 37.3, 75.1, 117.2, 123.0, 123.3, 125.5, 126.0,
127.3, 128.6, 152.1. HRMS m/z: 209.0722 [M + H]+; [C12H13ClO +
H]+ requires 209.0728. HPLC trace (99:1 hexane/isopropanol, 30
min, 0.5 mL/min); 7.61 min (56. 49%), 7.90 min (43.51%).
6-Cyano-2-methyl-chromene 13b.25 Compound (13b) was
prepared using the general procedure for chromene formation from 4-
cyanophenol (1.65 g, 13.9 mmol) and 1,1-diethoxybut-2-ene 9 (1.0 g,
6.93 mmol), yielding compound (13b) as a cream solid (0.90 g, 76%;
mp = 53−55 °C, lit.25 55.5−56 °C) after purification by column
chromatography using a petroleum ether/toluene (1:1) mixture as
eluent. νmax (film)/cm−1: 2360, 2342, 2225, 1605, 1488, 1373, 1253,
6-Nitro-2-phenyl-chromene 15a.25 Compound (15a) was
prepared using the general procedure for chromene formation from
4-nitrophenol (1.0 g, 7.2 mmol) and (3,3-diethoxyprop-1-enyl)-
benzene 10 (0.73 g, 3.56 mmol), yielding compound (15a) as a
cream solid (0.5 g, 55%; mp = 104−106 °C) after purification by
column chromatography using a petroleum ether/toluene (3:2)
mixture as eluent. νmax (film)/cm−1: 3063, 3034, 1647, 1612, 1576,
1480, 1343, 1261, 913. 1H NMR (300 MHz, CDCl3): δH 5.94 (1H, dd,
J = 10, 3 Hz), 6.07 (1H, dd, J = 3, 2 Hz), 6.59 (1H, dd, J = 10, 2 Hz),
6.81 (1H, d, J = 9 Hz), 7.35−7.46 (5H, m), 7.93 (1H, d, J = 3 Hz),
8.01 (1H, dd, J = 9, 3 Hz). 13C NMR (75 MHz, CDCl3): δC 78.5,
116.3, 120.9, 122.3, 122.4, 125.6, 127.2, 129.0, 129.1, 139.5, 141.8,
158.6. m/z: 254.0799 [M + H]+; [C15H11NO3 + H]+ requires
254.0812. HPLC trace (95:5 hexane/isopropanol, 0.5 mL/min); 23.55
min (49.20%), 24.66 min (50.80%).
1
765. H NMR (400 MHz, CDCl3): δH 1.46 (3H, d, J = 7 Hz), 5.08−
5.14 (1H, m), 5.75 (1H, dd, J = 10, 3 Hz), 6.33 (1H, dd, J = 10, 2 Hz),
6.79 (1H, d, J = 8 Hz), 7.22 (1H, d, J = 2 Hz), 7.38 (1H, dd, J = 8, 2
Hz). 13C NMR (100 MHz, CDCl3): δC 21.9, 72.7, 104.2, 117.1, 119.4,
122.1, 122.3, 128.6, 130.4, 133.6, 157.3. HRMS m/z: 171.0678 [M+];
C11H9NO requires 171.0679. HPLC trace (90:10 hexane/isopropanol,
1 mL/min); 5.93 min (49.45%), 6.41 min (50.55%).
6-Chloro-2-methyl-chromene 13c.25 Compound (13c) was
prepared using the general procedure for chromene formation from 4-
chlorophenol (2.95 g, 23.04 mmol) and 1,1-diethoxybut-2-ene 9 (1.66
g, 11.52 mmol), yielding compound (13c) as a yellow liquid (0.892 g,
43%) after purification by column chromatography using a petroleum
ether/toluene (1:1) mixture as eluent. νmax (film)/cm−1: 3050, 2977,
2932, 1767, 1645, 1481, 1368, 1208. 1H NMR (300 MHz, CDCl3): δH
1.44 (3H, d, J = 7 Hz), 4.95−5.03 (1H, m), 5.70 (1H, dd, J = 10, 3
Hz), 6.31 (1H, dd, J = 10, 2 Hz), 6.71 (1H, d, J = 9 Hz), 6.94 (1H, d, J
= 3 Hz), 7.05 (1H, dd, J = 9, 3 Hz). 13C NMR (75 MHz, CDCl3): δC
21.4, 71.8, 117.5, 123.0, 123.3, 125.8, 126.2, 128.4, 128.8, 152.2.
HRMS m/z: 180.0338 [M+]; C10H9ClO requires 180.0342. HPLC
trace (98:2 hexane/isopropanol, 0.5 mL/min); inseparable: 10.20 min
(100%).
6-Cyano-2-phenyl-chromene 15b.44 Compound (15b) was
prepared using the general procedure for chromene formation from 4-
cyanophenol (1.0 g, 8.4 mmol) and (3,3-diethoxyprop-1-enyl)benzene
10 (0.86 g, 4.16 mmol), yielding compound (15b) as a white
crystalline powder (0.43 g, 44%; mp = 123−125 °C) after purification
by column chromatography using a petroleum ether/toluene (1:1)
mixture as eluent. νmax (film)/cm−1: 3033, 2222, 1677, 1602, 1570,
1489, 1374, 1251, 1229, 1128, 893, 825. 1H NMR (300 MHz, CDCl3):
δH 5.90 (1H, dd, J = 10, 3 Hz), 6.02 (1H, dd, J = 3, 2 Hz), 6.52 (1H,
dd, J = 10, 2 Hz), 6.80 (1H, d, J = 8 Hz), 7.29 (1H, d, J = 2 Hz), 7.35−
7.45 (6H, m). 13C NMR (75 MHz, CDCl3): δC 78.0, 104.4, 117.0,
119.1, 121.7, 122.2, 126.3, 127.1, 128.9, 129.0, 130.4, 133.8, 139.7,
156.8. m/z: 251.1180 [M + NH4]+; [C16H11NO + NH4]+ requires
251.1179. HPLC trace (99.5:0.5 hexane/isopropanol, 0.5 mL/min,
230 nm); 41.34 min (47.94%), 43.47 min (52.06%).
6-Nitro-2-propyl-chromene 14a. Compound (14a) was pre-
pared using the general procedure for chromene formation from 4-
nitrophenol (1.0 g, 7.18 mmol) and 1,1-diethoxyhex-2-ene 11 (0.62 g,
3.59 mmol), yielding compound (14a) as a viscous orange liquid (0.7
g, 89%) after purification by column chromatography using a
petroleum ether/toluene (1:1) mixture as eluent. νmax (film)/cm−1:
2961, 1614, 1580, 1515, 1483, 1342, 1242, 1091, 1002, 747. 1H NMR
(400 MHz, CDCl3): δH 0.96 (3H, t, J = 7 Hz), 1.40−1.85 (4H, m),
4.99−5.11 (1H, m), 5.79 (1H, dd, J = 10, 3 Hz), 6.40 (1H, dd, J = 10,
3 Hz), 6.79 (1H, d, J = 9 Hz), 7.84 (1H, d, J = 3 Hz), 8.00 (1H, dd, J =
9, 3 Hz). 13C NMR (100 MHz, CDCl3): 13.7, 17.7, 37.9, 76.5, 116.1,
121.5, 122.1, 123.3, 125.3, 127.6, 141.6, 159.3. HRMS m/z: 220.0962
[M + H]+; [C12H13NO3 + H]+ requires 220.0968. HPLC trace (90:10
hexane/isopropanol, 1 mL/min); 4.89 min (49.49%), 5.18 min
(50.51%).
6-Cyano-2-propyl-chromene 14b. Compound (14b) was
prepared using the general procedure for chromene formation from
4-cyanophenol (1.73 g, 14.5 mmol) and 1,1-diethoxyhex-2-ene 11
(1.25 g, 7.25 mmol), yielding compound (14b) as a straw-yellow
colored liquid (1.40 g, 97%) after purification by column
chromatography using a petroleum ether/toluene (1:1) mixture as
eluent. νmax (film)/cm−1: 2960, 2874, 2225, 1605, 1489, 1381, 1253,
6-Chloro-2-phenyl-chromene 15c.25 Compound (15c) was
prepared using the general procedure for chromene formation from
4-chlorophenol (1.0 g, 7.62 mmol) and (3,3-diethoxyprop-1-enyl)-
benzene 10 (0.78 g, 3.81 mmol), yielding compound (15c) as a
viscous colorless liquid (0.12 g, 13%) after purification by column
chromatography using a petroleum ether/toluene (1:1) mixture as
eluent. νmax (film)/cm−1: 3032, 1639, 1477, 1424, 1368, 1261, 1231,
1
1200, 1121, 1034, 814, 755, 697. H NMR (300 MHz, CDCl3): δH
5.88 (1H, dd, J = 10, 3 Hz), 5.94 (1H, dd, J = 3, 2 Hz), 6.47 (1H, dd, J
= 10, 2 Hz), 6.72 (1H, d, J = 9 Hz), 7.02 (1H, d, J = 3 Hz), 7.08 (1H,
dd, J = 9, 3 Hz), 7.37−7.49 (5H, m). 13C NMR (75 MHz, CDCl3): δC
77.4, 117.5, 122.8, 123.3, 126.0, 126.2, 126.3, 127.2, 128.8, 128.9,
129.2, 140.4, 151.8. m/z: 243.0561 [M + H]+; [C15H11ClO + H]+
requires 243.0571. HPLC trace (99.9:0.1 hexane/isopropanol, 0.25
mL/min); inseparable: 104.77 min (100%).
6-Nitro-2-isopropyl-chromene 16a. Compound (16a) was
prepared using the general procedure for chromene formation from
4-nitrophenol (0.80 g, 5.54 mmol) and 1,1-diethoxy-4-methylpent-2-
E
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
ene 12 (0.48 g, 2.77 mmol), yielding compound (16a) as a pale yellow
viscous oil (0.2 g, 33%) after purification by column chromatography
using a petroleum ether/toluene (3:2) mixture as eluent. νmax (film)/
cm−1: 3073, 2965, 2874, 1613, 1579, 1335, 1241, 1089. 1H NMR (400
MHz, CDCl3): δH 1.00 (6H, dd, J = 8, 7 Hz), 1.95−2.03 (1H, m),
4.82−4.84 (1H, m), 5.77 (1H, dd, J = 10, 3 Hz), 6.43 (1H, dd, J = 10,
2 Hz), 6.77 (1H, d, J = 9 Hz), 7.81 (1H, d, J = 3 Hz), 7.97 (1H, dd, J =
9, 3 Hz). 13C NMR (75 MHz, CDCl3): δC 17.1, 17.6, 34.2, 81.6, 115.9,
121.5, 122.2, 123.1, 125.5, 126.1, 141.5, 160.0. m/z: 237.1229 [M +
NH4]+; [C12H13NO3 + NH4]+ requires 237.1234. HPLC trace (90:10
hexane/isopropanol, 1 mL/min); 4.84 min (48.91%), 5.12 min
(51.09%).
6-Cyano-2-isopropyl-chromene 16b. Compound (16b) was
prepared using the general procedure for chromene formation from 4-
cyanophenol (0.97 g, 8.1 mmol) and 1,1-diethoxy-4-methylpent-2-ene
12 (0.7 g, 4.05 mmol), yielding compound (16b) as a colorless viscous
oil (0.25 g, 31%) after purification by column chromatography using a
petroleum ether/toluene (3:2) mixture as eluent. νmax (film)/cm−1:
3053, 2965, 2931, 2874, 2225, 1603, 1489, 1379, 1252, 1130. 1H NMR
(300 MHz, CDCl3): δH 0.97 (6H, dd, J = 7, 5 Hz), 1.90−2.01 (1H,
m), 4.74−4.77 (1H, m), 5.72 (1H, dd, J = 10, 3 Hz), 6.35 (1H, dd, J =
10, 2 Hz), 6.75 (1H, d, J = 8 Hz), 7.16 (1H, d, J = 2 Hz), 7.32 (1H, dd,
J = 8, 2 Hz). 13C NMR (75 MHz, CDCl3): δC 17.1, 17.5, 33.9, 81.0,
103.7, 116.5, 119.3, 122.3, 122.9, 125.9, 130.2, 133.5, 158.0. m/z:
200.1062 [M + H]+; [C13H13NO + H]+ requires 200.1070. HPLC
trace (90:10 hexane/isopropanol, 1 mL/min); 5.02 min (49.90%),
5.42 min (50.10%).
6-Chloro-2-isopropyl-chromene 16c. Compound (16c) was
prepared using the general procedure for chromene formation from 4-
chlorophenol (1.59 g, 12.4 mmol) and 1,1-diethoxy-4-methylpent-2-
ene 12 (1.06 g, 6.2 mmol), yielding compound (16c) as a colorless oil
(0.21 g, 16%) after purification by column chromatography using a
petroleum ether/toluene (3:2) mixture as eluent. νmax (film)/cm−1:
3050, 2963, 2931, 2873, 1637, 1481, 1234, 1203, 1123, 1019, 997, 878,
814, 698. 1H NMR (300 MHz, CDCl3): δH 1.00 (6H, dd, J = 7, 1 Hz),
1.93−2.04 (1H, m), 4.61−4.65 (1H, m), 5.73 (1H, dd, J = 10, 3 Hz),
6.36 (1H, dd, J = 10, 2 Hz), 6.70 (1H, d, J = 9), 6.92 (1H, d, J = 3 Hz),
7.03 (1H, dd, J = 9, 3 Hz). 13C NMR (75 MHz, CDCl3): δC 17.5, 17.6,
33.4, 80.2, 116.9, 123.3, 123.6, 125.3, 125.6, 126.0, 128.7, 152.7. HPLC
trace (99.9:0.1 hexane/isopropanol, 0.25 mL/min); 14.80 min
(49.74%), 15.87 min (50.26%).
mixture as eluent. [αD] = −58.4°, (c 0.005 g/mL CH2Cl2). HPLC
trace (99.5:0.5 hexane/isopropanol, 0.5 mL/min); 58.29 min (0.40%)
cis, 70.71 min (26.78%) cis, 91.36 min (68.02%) trans, 97.75 min
(4.79%) trans.
6-Cyano-2-methyl-chromene Epoxide 17b.30 Using General
Procedure A. 6-Cyano-2-methyl-chromene 13b (1.10 g, 6.42 mmol)
and meta-chloroperbenzoic acid (1.10 g, 6.42 mmol) were dissolved in
dichloromethane (100 mL) at 0 °C, and left to react for 6 h. The
racemic epoxide was isolated as a cream solid (1.02 g, 85%) after
purification by column chromatography using a petroleum ether/ethyl
acetate/triethylamine (3:1:0.1) mixture as eluent. νmax (film)/cm−1:
2917, 2849, 2227, 1615, 1581, 1495, 1253, 1229, 1159, 873. 1H NMR
(300 MHz, CDCl3): δH 1.33 (3H, d, J = 7 Hz, trans), 1.58 (3H, d, J = 7
Hz, cis), 3.63 (1H, dd, J = 4, 1 Hz, trans), 3.69 (1H, dd, J = 4, 1 Hz,
cis), 3.87 (1H, d, J = 4 Hz, trans), 3.92 (1H, d, J = 4 Hz, cis), 4.37 (1H,
q, J = 6 Hz, cis), 4.82 (1H, q, J = 6 Hz, trans), 6.88 (2H, d, J = 9 Hz, cis
and trans), 7.52 (2H, dd, J = 9, 2 Hz, cis and trans), 7.64 (1H, d, J = 2
Hz, trans), 7.66 (1H, d, J = 2 Hz, cis). 13C NMR (75 MHz, CDCl3): δC
16.5, 18.4, 48.0, 49.4, 58.8, 59.1, 69.3, 69.5, 104.4, 104.5, 118.4, 118.7,
119.2, 121.1, 121.4, 133.9, 134.1, 134.3, 134.5, 155.7, 157.7. HRMS m/
z: 187.0628 [M+]; C11H9NO2 requires 187.0633. HPLC trace
(99.5:0.5 hexane/isopropanol, 0.5 mL/min); 76.82 min (22.87%),
119.490 min (27.75%), 127.70 min (23.05%), 137.62 min (26.33%).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (0.9 g, 2 mmol) and iminium salt 3 (0.036 g, 0.05 mmol)
were dissolved in chloroform (20 mL) and cooled to −30 °C. 6-
Cyano-2-methyl-chromene 13b (0.085 g, 0.50 mmol) dissolved in
chloroform (2 mL) was then added slowly over 10 min to the reaction
mixture. The reaction was quenched at 52% conversion, and
enantioenriched 6-cyano-2-methylchromene epoxide was isolated as
a cream solid (0.031 g, 33%; mp = 77−79 °C) after purification by
column chromatography using a petroleum ether/ethyl acetate/
triethylamine (3:1:0.1) mixture as eluent. [αD] = −74°, (c 0.01 g/
mL CHCl3). HPLC trace (99.5:0.5 hexane/isopropanol, 0.5 mL/min);
74.88 min (0.50%) cis, 116.04 min (5.14%) trans, 125.01 min
(28.11%) cis, 132.81 min (66.26%) trans.
6-Nitro-2-propyl-chromene Epoxide 18a. Using General
Procedure A. 6-Nitro-2-propyl-chromene 14a (0.310 g, 1.43 mmol)
and meta-chloroperbenzoic acid (0.245 g, 1.43 mmol) were dissolved
in dichloromethane (50 mL) at 0 °C, and left to stir for 5 h. The
racemic epoxide was isolated as a yellow oil (0.265 g, 79%) after
purification by column chromatography using a petroleum ether/ethyl
acetate/triethylamine (10:1:0.1) mixture as eluent. νmax (film)/cm−1:
2961, 2874, 1619, 1591, 1516, 1486, 1340, 1244, 1088. 1H NMR (400
MHz, CDCl3): δH 0.96 (3H, t, J = 7 Hz, trans), 1.04 (3H, t, J = 7 Hz,
cis), 1.45−2.02 (8H, m, cis and trans), 3.67 (1H, dd, J = 4, 1 Hz, trans),
3.76 (1H, dd, J = 4, 1 Hz, cis), 3.94 (1H, d, J = 4 Hz, trans), 3.99 (1H,
d, J = 4 Hz, cis), 4.26−4.30 (1H, m, cis), 4.70−4.73 (1H, m, trans),
6.91 (1H, d, J = 9 Hz, trans), 6.92 (1H, d, J = 9 Hz, cis), 8.14 (1H, dd, J
= 9, 3 Hz, cis), 8.15 (1H, dd, J = 9, 3 Hz, trans), 8.28 (1H, d, J = 3 Hz,
trans), 8.31 (1H, d, J = 3 Hz, cis), (ratio of trans:cis = 2:1). 13C NMR
(100 MHz, CDCl3): δC 14.0, 14.1, 18.4, 19.0, 33.3, 35.1, 48.6, 49.4,
58.4, 73.3, 73.6, 118.1, 118.7, 120.7, 121.1, 126.1, 126.2, 126.3, 126.6,
141.6, 141.7, 157.9, 159.6. HRMS m/z: 236.0911 [M + H]+;
[C12H13NO4 + H]+ requires 236.0918. HPLC trace (99.5:0.5 hexane/
isopropanol, 0.5 mL/min); 41.77 min (13.78%), 51.76 min (13.55%),
59.50 min (39.42%), 65.630 min (33.25%).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (2.31 g, 5.12 mmol) and iminium salt 3 (0.092 g, 0.128
mmol) were dissolved in chloroform (60 mL) and cooled to −30 °C.
6-Nitro-2-propyl-chromene 14a (0.28 g, 1.28 mmol) dissolved in
chloroform (6 mL) was then added slowly over 10 min to the reaction
mixture. The reaction was quenched at 50% conversion, and
enantioenriched 6-nitro-2-propyl-chromene epoxide was isolated as a
yellow oil (0.12 g, 40%) after purification by column chromatography
using a petroleum ether/ethyl acetate/triethylamine (10:1:0.1)
mixture as eluent. [αD] = −35°, (c 0.01 g/mL CHCl3). HPLC trace
(99.5:0.5 hexane/isopropanol, 0.5 mL/min); 40.45 min (0.37%),
49.52 min (17.40%), 57.23 min (72.28%), 61.39 min (9.96%).
6-Nitro-2-methyl-chromene Oxide 17a. Using General Proce-
dure A. 6-Nitro-2-methyl-chromene 13a (0.205 g, 1.07 mmol) and
meta-chloroperbenzoic acid (0.184 g, 1.07 mmol) were dissolved in
dichloromethane (40 mL) at 0 °C, and left to stir for 8 h. The racemic
epoxide was isolated as a cream solid (0.20 g, 90%; mp = 86−88 °C)
after purification by column chromatography using a petroleum ether/
ethyl acetate/triethylamine (3:1:0.1) mixture as eluent. νmax (film)/
cm−1: 3075, 2984, 2935, 1620, 1591, 1521, 1487, 1341, 1257, 1094,
1
878, 746. H NMR (300 MHz, CDCl3): δH 1.36 (3H, d, J = 7 Hz,
trans), 1.61 (3H, d, J = 7 Hz, cis), 3.66 (1H, dd, J = 4, 1 Hz, trans), 3.73
(1H, d, J = 4 Hz, cis), 3.95 (1H, d, J = 4 Hz, trans), 4.00 (1H, d, J = 4
Hz, cis), 4.43 (1H, q, J = 7 Hz, cis), 4.87 (1H, q, J = 7 Hz, trans), 6.90
(2H, d, J = 9 Hz, cis and trans), 8.14 (2H, dd, J = 9, 3 Hz, cis and
trans), 8.28 (1H, d, J = 3 Hz, trans), 8.31 (1H, d, J = 3 Hz, cis), (ratio
of trans:cis, 2:1). 13C NMR (75 MHz, CDCl3): δC 16.6, 18.3, 48.1,
49.5, 58.6, 58.8, 69.7, 69.9, 117.9, 118.6, 120.3, 120.6, 125.9, 126.0,
126.2, 126.4, 141.5, 141.6, 157.6, 159.4. HRMS m/z: 206.0461 [M −
H]−; [C10H9NO4 − H]− requires 206.0459. HPLC trace (99.5:0.5
hexane/isopropanol, 0.5 mL/min); 60.31 min (21.22%), 74.09 min
(21.79%), 95.06 min (28.69%), 100.87 min (28.29%).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (1.71 g, 3.8 mmol) and iminium salt 3 (0.068 g, 0.095
mmol) were dissolved in chloroform (40 mL) and cooled to −30 °C.
6-Nitro-2-methyl-chromene 13a (0.182 g, 0.95 mmol) dissolved in
chloroform (4 mL) was then added slowly over 10 min to the reaction
mixture. The reaction was quenched at 48% conversion, and
enantioenriched 6-nitro-2-methylchromene epoxide was isolated as a
cream solid (0.065 g, 33%) after purification by column chromatog-
raphy using a petroleum ether/ethyl acetate/triethylamine (3:1:0.1)
F
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6-Cyano-2-propyl-chromene Epoxide 18b. Using General
Procedure A. 6-Cyano-2-propyl-chromene 14b (0.150 g, 0.75
mmol) and meta-chloroperbenzoic acid (0.130 g, 0.75 mmol) were
dissolved in dichloromethane (25 mL) at 0 °C, and left to stir for 5 h.
The racemic epoxide was isolated as a colorless oil (0.13 g, 81%) after
purification by column chromatography using a petroleum ether/ethyl
acetate/triethylamine (5:1:0.1) mixture as eluent. νmax (film)/cm−1:
2963, 2925, 2224, 1745, 1610, 1579, 1494, 1247, 1170. 1H NMR (400
MHz, CDCl3): δH 0.96 (3H, t, J = 7 Hz, trans), 1.03 (3H, t, J = 7 Hz,
cis), 1.45−1.85 (8H, m, cis and trans), 3.65 (1H, dd, J = 4, 1 Hz, trans),
3.74 (1H, d, J = 4 Hz, cis), 3.87 (1H, d, J = 4 Hz, trans), 3.91 (1H, d, J
= 4 Hz, cis), 4.20−4.23 (1H, m, cis), 4.66−4.69 (1H, m, trans), 6.89
(1H, d, J = 9 Hz, trans), 6.90 (1H, d, J = 9 Hz, cis), 7.52−7.55 (2H, m,
cis and trans), 7.64 (1H, d, J = 2 Hz, trans), 7.67 (1H, d, J = 2 Hz, cis)
(ratio of trans:cis, 3.5:1). 13C NMR (75 MHz, CDCl3) δC: 13.6, 13.8,
18.1, 18.6, 32.9, 34.9, 48.1, 49.0, 58.3, 72.7, 73.0, 104.5, 118.4, 118.7,
119.1, 121.7, 133.9, 134.0, 134.3, 134.6, 156.0. HRMS m/z: 238.0840
[M + Na]+; [C13H13NO2 + Na]+ requires 238.0838. HPLC trace
(99.5:0.5 hexane/isopropanol, 0.5 mL/min); 27.14 min (10.86%),
36.32 min (38.48%), 38.24 min (10.67%), 39.82 min (39.99%).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (2.15 g, 4.76 mmol) and iminium salt 3 (0.086 g, 0.12
mmol) were dissolved in chloroform (50 mL) and cooled to −30 °C.
6-Cyano-2-propyl-chromene 14b (0.24 g, 1.19 mmol) dissolved in
chloroform (5 mL) was then added slowly over 10 min to the reaction
mixture. The reaction was quenched at 56% conversion, and
enantioenriched 6-cyano-2-propyl-chromene epoxide was isolated as
a colorless oil (0.1 g, 39%) after purification by column
chromatography using a petroleum ether/ethyl acetate/triethylamine
(5:1:0.1) mixture as eluent. [αD] = −22°, (c 0.004 g/mL, CH2Cl2).
HPLC trace (99.5:0.5 hexane/isopropanol, 0.5 mL/min); 27.10 min
(0.93%), 36.17 min (10.56%), 37.63 min (21.42%), 39.38 min
(67.09%).
6-Nitro-2-phenyl-chromene Epoxide 19a. Using General
Procedure A. 6-Nitro-2-phenyl-chromene 15a (0.22 g, 0.87 mmol)
and meta-chloroperbenzoic acid (0.15 g, 0.87 mmol) were dissolved in
dichloromethane (40 mL) at 0 °C, and left to stir for 8 h. The racemic
epoxide was isolated as a colorless solid (0.22 g, 94%; mp = 120−122
°C) after purification by column chromatography using a petroleum
ether/ethyl acetate/triethylamine (4:1:0.1) mixture as eluent. νmax
(film)/cm: 3071, 2928, 1620, 1591, 1515, 1485, 1339, 1236, 1041.
1H NMR (300 MHz, CDCl3): δH 3.94 (1H, dd, J = 4, 1 Hz), 4.13 (1H,
d, J = 4 Hz), 5.73 (1H, s), 6.92 (1H, d, J = 9 Hz), 7.27−7.38 (5H, m),
8.17 (1H, dd, J = 9, 3 Hz), 8.36 (1H, d, J = 3 Hz) (only trans observed).
13C NMR (75 MHz, CDCl3) δC: 48.8, 58.1, 75.7, 100.4, 118.6, 120.7,
126.2, 126.9, 127.2, 129.4, 129.6, 136.3, 158.1. HRMS m/z: 287.1025
[M + NH4]+; [C15H11NO4 + NH4]+ requires 287.1026. HPLC trace
(90:10 hexane/isopropanol, 1 mL/min); 26.63 min (48.44%), 43.18
min (51.56%).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (3.36 g, 7.44 mmol) and iminium salt 3 (0.132 g, 0.186
mmol) were dissolved in chloroform (100 mL) and cooled to −30 °C.
6-Nitro-2-phenyl-chromene 15a (0.47 g, 1.86 mmol) dissolved in
chloroform (10 mL) was then added slowly over 10 min to the
reaction mixture. The reaction was quenched at 26% conversion, and
enantioenriched 6-nitro-2-phenyl-chromene epoxide was isolated as a
colorless solid (0.075 g, 15%) after purification by column
chromatography using a petroleum ether/ethyl acetate/triethylamine
(4:1:0.1) mixture as eluent. [αD] = +51°, (c 0.01 g/mL, CH2Cl2);
HPLC trace (90:10 hexane/isopropanol, 1 mL/min); 23.97 min
(88.13%), 37.01 min (11.87%).
6-Cyano-2-phenyl-chromene Epoxide 19b. Using General
Procedure A. 6-Cyano-2-phenyl-chromene 15b (0.165 g, 0.71 mmol)
and meta-chloroperbenzoic acid (0.12 g, 0.71 mmol) were dissolved in
dichloromethane (30 mL) at 0 °C, and left to stir for 8 h. The racemic
epoxide was isolated as a cream solid (0.160 g, 90%) after purification
by column chromatography using a petroleum ether/ethyl acetate/
triethylamine (4:1:0.1) mixture as eluent. νmax (film)/cm−1: 3057,
2903, 2223, 1610, 1577, 1491, 1242, 997. 1H NMR (300 MHz,
CDCl3) δH 3.94 (1H, dd, J = 4, 1 Hz), 4.08 (1H, d, J = 4 Hz), 5.73
(1H, s), 6.93 (1H, d, J = 9 Hz), 7.28−7.39 (5H, m), 7.58 (1H, dd, J =
9, 2 Hz), 7.74 (1H, d, J = 2 Hz) (only trans observed). 13C NMR (75
MHz, CDCl3) δC: 48.5, 58.2, 75.2, 104.7, 118.6, 118.9, 121.3, 127.0,
129.1, 129.3, 134.0, 134.8, 136.3, 156.1. HRMS m/z: 250.0859 [M +
H]+; [C16H11NO2 + H]+ requires 250.0863. HPLC trace (90:10
hexane/isopropanol, 1 mL/min); 29.21 min (48.01%), 38.23 min
(51.99%).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (3.61 g, 8.0 mmol) and iminium salt 3 (0.144 g, 0.2 mmol)
were dissolved in chloroform (100 mL) and cooled to −30 °C. 6-
Cyano-2-phenyl-chromene 15b (0.47 g, 2.0 mmol) dissolved in
chloroform (10 mL) was then added slowly over 10 min to the
reaction mixture. The reaction was quenched at 37% conversion, and
enantioenriched 6-cyano-2-phenyl-chromene epoxide was isolated as a
cream solid (0.12 g, 24%; mp = 136−138 °C) after purification by
column chromatography using a petroleum ether/ethyl acetate/
triethylamine (4:1:0.1) mixture as eluent. [αD] = +72°, (c 0.01 g/
mL, CH2Cl2); HPLC trace (90:10 hexane/isopropanol, 1 mL/min);
26.23 min (88.99%), 34.17 min (11.01%).
6-Nitro-2-isopropyl-chromene Epoxide 20a. Using General
Procedure A. 6-Nitro-2-isopropyl-chromene 16a (0.26 g, 1.2 mmol)
and meta-chloroperbenzoic acid (0.2 g, 1.2 mmol) were dissolved in
dichloromethane (50 mL) at 0 °C, and left to stir for 8 h. The racemic
epoxide was isolated as a yellow oil (0.14 g, 50%) after purification by
column chromatography using a petroleum ether/ethyl acetate/
triethylamine (5:1:0.1) mixture as eluent. νmax (film)/cm−1: 2965,
2923, 1620, 1591, 1520, 1486, 1341, 1256, 1089. 1H NMR (400 MHz,
CDCl3): δH 0.97 (6H, d, J = 9 Hz, cis or trans), 1.09 (6H, d, J = 9 Hz,
cis or trans), 1.99−2.09 (1H, m, trans), 2.20−2.28 (1H, m, cis), 3.73
(1H, dd, J = 6, 1 Hz, trans), 3.85 (1H, d, J = 6 Hz, cis), 3.94 (1H, d, J =
6 Hz, cis), 3.96 (1H, d, J = 6 Hz, trans), 4.00 (1H, d, J = 8 Hz, cis), 4.47
(1H, d, J = 8 Hz, trans), 6.91 (1H, d, J = 12 Hz, trans), 6.94 (1H, d, J =
12 Hz, cis), 8.15 (2H, dd, J = 12, 4 Hz, C7-H, cis and trans), 8.28 (1H,
d, J = 4 Hz, trans), 8.31 (1H, d, J = 4 Hz, cis) (ratio of trans:cis, 4:1)
13C NMR (75 MHz, CDCl3): δC 18.2, 18.3, 18.4, 19.1, 31.5, 31.8, 48.5,
48.7, 56.2, 56.9, 78.1, 78.8, 117.9, 118.2, 120.6, 121.0, 126.1, 126.2,
126.3, 126.7, 141.4, 159.0, 160.2, 169.5. HRMS m/z: 236.0915 [M +
H]+; [C12H13NO4 + H]+ requires 236.0918. HPLC trace (99.5:0.5
hexane/isopropanol, 0.5 mL/min); 35.78 min (8.19%, cis), 52.39 min
(9.52%, cis), 60.19 min (41.27%, trans), 65.78 min (41.02%, trans).
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (1.17 g, 2.6 mmol) and iminium salt 3 (0.046 g, 0.065
mmol) were dissolved in chloroform (30 mL) and cooled to −30 °C.
6-Nitro-2-isopropyl-chromene 16a (0.14 g, 0.65 mmol) dissolved in
chloroform (3 mL) was then added slowly over 10 min to the reaction
mixture. The reaction was quenched at 38% conversion, and
enantioenriched 6-nitro-2-isopropyl-chromene epoxide was isolated
as a yellow oil (0.035 g, 25%) after purification by column
chromatography using a petroleum ether/ethyl acetate/triethylamine
(5:1:0.1) mixture as eluent. [αD] = −63°, (c 0.004 g/mL, CH2Cl2).
HPLC trace (99.5:0.5 hexane/isopropanol, 0.5 mL/min); 35.74 min
(0.73%, cis), 56.13 min (7.46%, cis), 63.05 min (11.07%, trans), 68.42
min (80.73%, trans).
6-Cyano-2-isopropyl-chromene Epoxide 20b. Using General
Procedure A. 6-Cyano-2-isopropyl-chromene 16b (0.29 g, 1.44 mmol)
and meta-chloroperbenzoic acid (0.25 g, 1.44 mmol) were dissolved in
dichloromethane (60 mL) at 0 °C, and left to stir for 5 h. The racemic
epoxide was isolated as a colorless oil (0.17 g, 55%) after purification
by column chromatography using a petroleum ether/ethyl acetate/
triethylamine (5:1:0.1) mixture as eluent. νmax (film)/cm−1: 2967,
2932, 2877, 2226, 1616, 1582, 1495, 1251, 1134, 1008, 876. 1H NMR
(400 MHz, CDCl3): δH 0.97 (6H, d, J = 7 Hz, cis or trans), 1.08 (6H,
d, J = 7 Hz, cis or trans), 1.97−2.06 (1H, m, trans), 2.20−2.27 (1H, m,
cis), 3.72 (1H, dd, J = 4, 1 Hz, trans), 3.83 (1H, d, J = 4 Hz, cis), 3.87
(1H, d, J = 4 Hz, cis), 3.89 (1H, d, J = 4 Hz, trans), 3.95 (1H, d, J = 6
Hz, cis), 4.42 (1H, d, J = 6 Hz, trans), 6.89 (2H, d, J = 9 Hz, cis and
trans), 7.53 (2H, dd, J = 9, 2 Hz, cis and trans), 7.63 (1H, d, J = 2 Hz,
trans), 7.67 (1H, d, J = 2 Hz, cis) (ratio of trans:cis 4:1). 13C NMR
(100 MHz, CDCl3): δC 18.7, 19.3, 31.5, 48.6, 56.6, 77.8, 78.5, 118.5,
118.9, 134.2, 134.8. HRMS m/z: 216.1021 [M + H]+; [C13H13NO2 +
G
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
H]+ requires 216.1022. HPLC trace (99.5:0.5 hexane/isopropanol, 0.5
mL/min); 42.44 min (10.10%), 64.01 min (39.00%), 80.14 min
(9.96%), 84.10 min (40.94%).
Notes
The authors declare no competing financial interest.
Using General Procedure B. Tetraphenylphosphonium monoper-
oxysulfate (27.4 g, 60.8 mmol) and iminium salt 3 (1.09 g, 1.52 mmol)
were dissolved in chloroform (300 mL) and cooled to −30 °C. 6-
Cyano-2-isopropyl-chromene 16b (3.0 g, 15.2 mmol) dissolved in
chloroform (30 mL) was then added slowly over 10 min to the
reaction mixture. The reaction was quenched at 36% conversion, and
enantioenriched 6-cyano-2-isopropyl-chromene epoxide was isolated
as a colorless oil (0.75 g, 23%) after purification by column
chromatography using a petroleum ether/ethyl acetate/triethylamine
(5:1:0.1) mixture as eluent. [αD] = −52°, (c 0.01 g/mL, CH2Cl2).
HPLC trace (99.5:0.5 hexane/isopropanol, 0.5 mL/min); 43.17 min
(0.12%), 71.15 min (17.11%), 81.47 min (5.04%), 89.15 min
(77.73%).
ACKNOWLEDGMENTS
■
This investigation has enjoyed the support of the EPSRC, the
University of East Anglia, Charnwood Molecular Ltd, and the
ERDF (IS:CE-Chem & INTERREG IVa Programme 4061).
We acknowledge the support of The Royal Society (PCBP:
Industry Fellowship). We are also indebted to the EPSRC Mass
Spectrometry Unit, Swansea.
REFERENCES
■
(1) (a) Sharpless, K. B. Aldrichimica Acta 1983, 16, 67. (b) Gorzynski
Smith, J. Synthesis 1984, 629. (c) Behrens, C. H.; Katsuki, T. Coord.
Chem. Rev. 1995, 140, 189. Katsuki, T.; Martin, V. S. Org. React. 1996,
48, 1.
(2) (a) Armstrong, A. Angew. Chem., Int. Ed. 2004, 43, 1460.
(b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726.
(c) MacMillan, D. W. C.; Brochu, M. P.; Brown, S. P. J. Am. Chem. Soc.
2004, 126, 4108.
(3) (a) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-
H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491. (b) Yang, D.;
Wang, X. C.; Wong, M.-K.; Yip, Y.-C.; Tang, M.-W. J. Am. Chem. Soc.
1996, 118, 11311. (c) Yang, D.; Wong, M.-K.; Yip, Y.-C.; Wang, X. C.;
Tang, M.-W.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1998, 120,
5943. (d) Yang, D.; Yip, Y.-C.; Tang, M.-W.; Wong, M.-K.; Cheung,
K.-K. J. Org. Chem. 1998, 63, 9888.
Formation of Alcohol (+)-23.45 Epoxide (+)-19b (1 g, 4.02
mmol) was dissolved in anhydrous methanol (50 mL) in a flame-dried
round-bottom flask. The solution was then purged with nitrogen, and a
catalytic amount of palladium/carbon was added to the stirring
solution, followed by the addition of hydrogen gas (1 atm). The
reaction was allowed to stir at room temperature, with the reaction
progress monitored by thin-layer chromatography. Upon reaction
completion, the reaction mixture was filtered through Celite, and
remaining organic solvents were removed under reduced pressure.
Alcohol 23 (1 g, 99%) was isolated as a colorless oil after column
chromatography using a petroleum ether/ethyl acetate (1:1) mixture
as eluent. [αD] = +28.0° (c 0.01 g/mL, CH2Cl2). νmax (film)/cm−1:
1
3424, 2224, 1579, 1492, 1245. H NMR (400 MHz, CDCl3): 1.84
(4) (a) Forbes, D. C.; Hays, D. S.; DePue, J. S.; Wilde, R. G.;
Denmark, S. E. J. Org. Chem. 1995, 60, 1391. (b) Matsuhashi, H.;
Crudden, C. M.; Wu, Z.; Denmark, S. E. J. Org. Chem. 1997, 62, 8288.
(c) Wu, Z.; Denmark, S. E. J. Org. Chem. 1997, 62, 8964. (d) Wu, Z.;
Denmark, S. E. J. Org. Chem. 1998, 63, 2810. (e) Wu, Z.; Denmark, S.
E. Synlett 1999, 847. (f) Matsuhashi, H.; Denmark, S. E. J. Org. Chem.
2002, 67, 3479.
(5) (a) Armstrong, A.; Hayter, B. R. Chem. Commun. 1998, 621.
(b) Armstrong, A.; Ahmed, G.; Dominguez-Fernandez, B.; Hayter, B.
R.; Wailes, J. S. J. Org. Chem. 2002, 67, 8610.
(6) (a) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
(b) Wang, Z.-X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62,
2328. (c) Wang, Z.-X.; Shi, Y. J. Org. Chem. 1998, 63, 3099. (d) Wang,
Z.-X.; Shi, Y. J. Org. Chem. 1997, 62, 8622. (e) Cao, G. A.; Wang, Z.-
X.; Tu, Y.; Shi, Y. Tetrahedron Lett. 1998, 39, 4425. (f) Zhu, Y.; Tu, Y.;
Yu, H.; Shi, Y. Tetrahedron Lett. 1998, 39, 7819. (g) Yong, T.; Wang,
Z.-X.; Frohn, M.; He, M.; Yu, H.; Tang, Y.; Shi, Y. J. Org. Chem. 1998,
63, 8475. (h) Warren, J. D.; Shi, Y. J. Org. Chem. 1999, 64, 7675.
(i) Frohn, M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem.
Soc. 1999, 121, 7718. (j) Shu, L.; Shi, Y. Tetrahedron Lett. 1999, 40,
8721. (k) Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807. (l) Tian, H.;
She, X.; Xu, J.; Shi, Y. Org. Lett. 2001, 3, 1929. (m) Tian, H.; She, X.;
Yu, H.; Shu, L.; Shi, Y. J. Org. Chem. 2002, 67, 2435. (n) Wu, X.-Y.;
She, X.; Shi, Y. J. Am. Chem. Soc. 2002, 124, 8792.
(1H, d, J = 4 Hz), 2.92 (1H, dd, J = 16, 9 Hz), 3.09 (1H, dd, J = 16, 5
Hz), 4.08−4.22 (1H, m), 4.91 (1H, d, J = 8 Hz), 6.99 (1H, d, J = 8
Hz), 7.35−7.49 (7H, m). 13C NMR (100 MHz, CDCl3): 32.2, 67.4,
82.4, 104.4, 117.6, 119.1, 121.5, 126.9, 129.0, 129.1, 132.0, 134.4,
137.1, 157.7; m/z found [M + Na]+ 274.0842; [C16H13NO2 + Na]+
requires 274.0838.
Formation of (10S)-Camphorsulfonyl Ester (+)-24.46 Alcohol
23 (1.0 g, 1 equiv, 3.98 mmol), (10S)-(+)-camphorsulfonyl chloride
(996 mg, 1 equiv, 3.98 mmol) and dry toluene (50 mL) were added to
a flame-dried round-bottom flask under nitrogen. To the stirring
solution, triethylamine (1.1 mL, 2 equiv, 7.96 mmol) was slowly
added, and left to stir for 24 h. Upon reaction completion, excess
organic solvents were removed under reduced pressure. Purification by
column chromatography using a petroleum ether/ethyl acetate (6:1)
mixture as eluent afforded colorless crystalline 28. Slow recrystalliza-
tion from dichloromethane/hexane afforded ester 24 (6-cyano-(2R)-
phenyl-(3S)-camphor(16S,19R)-sulfonylester chromene), as long
colorless crystals (0.8 g, 43%; mp = 153−155 °C). [αD] = +44.0° (c
0.02 g/mL, CH2Cl2). νmax (film)/cm−1: 2963, 2226, 1743, 1493, 1246,
1
906, 726. H NMR (400 MHz, CDCl3): 0.77 (3H, s), 0.98 (3H, s),
1.35−1.41 (1H, m), 1.52−1.59 (1H, m), 1.88−2.01 (2H, m), 2.08
(1H, t, J = 4 Hz), 2.22−2.37 (2H, m), 2.65 (1H, d, J = 15 Hz), 3.11
(2H, m), 3.35 (1H, d, J = 15 Hz), 5.22−5.25 (1H, m), 5.45 (1H, d, J =
5 Hz), 7.05 (1H, d, J = 9 Hz), 7.33−7.38 (6H, m), 7.48 (1H, d, J = 9
Hz). 13C NMR (100 MHz, CDCl3): 19.6, 19.7, 24.9, 26.8, 28.9, 42.4,
42.7, 47.9, 48.3, 57.9, 75.3, 78.9, 104.7, 117.6, 118.9, 119.5, 126.0,
129.0, 129.1, 132.4, 134.2, 136.7, 157.0, 214.0; m/z found [M +
NH4]+: 483.1945; [C26H27NO5S + NH4]+ requires 483.1948.
(7) (a) Picot, A.; Milliet, P.; Lusinchi, X. Tetrahedron Lett. 1976, 17,
1573. (b) Milliet, P.; Picot, A.; Lusinchi, X. Tetrahedron Lett. 1976, 17,
1577. (c) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett. 1987,
28, 6061. (d) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett.
1988, 29, 3941. (e) Bohe,
Tetrahedron Lett. 1993, 34, 7271. (f) Bohe,
X. Tetrahedron 1999, 55, 141.
(8) (a) Bohe, L.; Kammoun, M. Tetrahedron Lett. 2002, 43, 803.
(b) Bohe, L.; Kammoun, M. Tetrahedron Lett. 2004, 45, 747.
(c) Aggarwal, V. K.; Wang, M. F. Chem. Commun. 1996, 191.
(d) Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou, K. Synlett 1997,
1075. (e) Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou, K.;
Wailes, J. S. Tetrahedron 1999, 55, 2341. (f) Gluszynska, A.;
Mackowska, I.; Rozwadowska, M. D.; Sienniak, W. Tetrahedron:
Asymmetry 2004, 15, 2499. (g) Biscoe, M. R.; Breslow, R. J. Am. Chem.
Soc. 2005, 127, 10812. (h) Minakata, S.; Takemiya, A.; Nakamura, K.;
Ryu, I.; Komatsu, M. Synlett 2000, 1810. (i) Wong, M.-K.; Ho, L.-M.;
́
L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X.
́
L.; Lusinchi, M.; Lusinchi,
ASSOCIATED CONTENT
■
S
* Supporting Information
́
1H and 13C NMR spectra; chromatograms and spectra for ee
determination by GC, HPLC, and NMR techniques; X-ray data
and ORTEP figure for 24, including CIF files. This material is
available free of charge via the Internet at http://pubs.acs.org.
́
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: p.page@uea.ac.uk.
H
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Zheng, Y.-S.; Ho, C.-Y.; Yang, D. Org. Lett. 2001, 16, 2587.
(j) Crosthwaite, J. M.; Farmer, V. A.; Hallett, J. P.; Welton, T. J.
Mol. Catal. A 2008, 279, 148. (k) Lacour, J.; Monchaud, D.; Marsol, C.
Tetrahedron Lett. 2002, 43, 8257. (l) Novikov, R.; Lacour, J.
Tetrahedron: Asymmetry 2010, 21, 1611. (m) Novikov, R.; Vachon,
J.; Lacour, J. Chimia 2007, 61, 236. (n) Vachon, J.; Lauper, C.; Ditrich,
K.; Lacour, J. Tetrahedron: Asymmetry 2006, 17, 2334. (o) Vachon, J.;
Perollier, C.; Monchaud, D.; Marsol, C.; Ditrich, K.; Lacour, J. J. Org.
Chem. 2005, 70, 5903. (p) Vachon, J.; Rentsch, S.; Martinez, A.;
Marsol, C.; Lacour, J. Org. Biomol. Chem. 2007, 5, 501. (q) Wong, O.
A.; Shi, Y. Chem. Rev. 2008, 108, 3958. (r) Novikov, R.; Bernardinelli,
G.; Lacour, J. Adv. Synth. Catal. 2009, 351, 596. (s) Novikov, R.;
Bernardinelli, G.; Lacour, J. Adv. Synth. Catal. 2008, 350, 1113.
(9) (a) Page, P. C. B.; Buckley, B. R.; Farah, M. M.; Blacker, A. J. Eur.
J. Org. Chem. 2009, 3413 and references therein. (b) Page, P. C. B.;
Farah, M. M.; Buckley, B. R.; Blacker, A. J. J. Org. Chem. 2007, 72,
4424. (c) Page, P. C. B.; Buckley, B. R.; Appleby, L. F.; Alsters, P. A.
Synthesis 2005, 3405.
(10) Page, P. C. B.; Parker, P.; Rassias, G. A.; Buckley, B. R.; Bethell,
D. Adv. Synth. Catal. 2008, 350, 1867.
(11) Page, P. C. B.; Parker, P.; Buckley, B. R.; Rassias, G. A.; Bethell,
D. Tetrahedron 2009, 65, 2910.
(12) Page, P. C. B.; Marken, F.; Williamson, C.; Chan, Y.; Buckley, B.
R.; Bethell, D. Adv. Synth. Catal. 2008, 350, 1149.
(13) Page, P. C. B.; Farah, M. M.; Buckley, B. R.; Blacker, A. J.;
Lacour, J. Synlett 2008, 1381.
(14) (a) Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem.
Soc. 2000, 122, 8317. (b) Adamo, M. F. A.; Aggarwal, V. K.; Sage, M.
A. J. Am. Chem. Soc. 2002, 124, 11223. (c) Aggarwal, V. K.; Lopin, C.;
Sandrinelli, F. J. Am. Chem. Soc. 2003, 125, 7596. (d) Ho, C.-Y.; Chen,
Y.-C.; Wong, M.-K.; Yang, D. J. Org. Chem. 2005, 70, 898.
(15) Campestrini, S.; Di Furia, F.; Labat, G.; Novello, F. J. Chem. Soc.,
Perkin Trans. 2 1994, 2175.
(30) Buckle, D. R.; Eggleston, D. S.; Houge-Frydrych, C. S. V.; Pinto,
I. L.; Readshaw, S. A.; Smith, D. G.; Webster, R. A. B. J. Chem. Soc.,
Perkin Trans. 1 1991, 2763.
(31) (a) Begasse, B.; Le Corre, M. Tetrahedron 1980, 36, 3409.
(b) Billeret, D.; Blondeau, D.; Sliwa, H. Synthesis 1993, 881.
(32) (a) Harrity, J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H.
J. Am. Chem. Soc. 1997, 119, 1488. (b) Harrity, J. P. A.; La, D. S.;
Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998,
120, 2343. (c) Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864.
(d) Ramachary, D. B.; Narayana, V. V.; Ramakumar, K. Eur. J. Org.
Chem. 2008, 3907.
(33) (a) Wang, Q.; Finn, M. G. Org. Lett. 2000, 2, 4063. (b) Liu, F.;
Evans, T.; Das, B. C. Tetrahedron Lett. 2008, 49, 1578. (c) Petasis, N.
A.; Butkevich, A. N. J. Organomet. Chem. 2009, 694, 1747.
(d) Candeias, N. R.; Veiros, L. F.; Afonso, C. A. M.; Gois, P. M. P.
Eur. J. Org. Chem. 2009, 1859.
(34) North, J. T.; Kronenthal, D. R.; Pullockaran, A. J.; Real, S. D.;
Chen, H. Y. J. Org. Chem. 1995, 60, 3397.
(35) (a) Gross, J. L. Tetrahedron Lett. 2003, 44, 8563. (b) Wipf, P.;
Weiner, W. S. J. Org. Chem. 1999, 64, 5321. (c) Tuckmantel, W.;
̈
Kozikowski, A. P.; Romanczyk, L. J. J. Am. Chem. Soc. 1999, 121,
́ ́
12073. (d) Rios, R.; Sunden, H.; Ibrahem, I.; Cordova, A. Tetrahedron
Lett. 2007, 48, 2181. (e) You, S.; He, H. Process for Preparation of 1-
Oxabenzoheterocycle Compounds. China Patent CN 101921252 A,
22 December 2010; application no. CN20101217729 20100702.
(36) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
(37) Trost, B. M.; Ball, Z. T.; Joge, T. J. Am. Chem. Soc. 2002, 124,
̈
7922.
(38) Newman-Evans, R. H.; Simon, R. J.; Carpenter, B. K. J. Org.
Chem. 1990, 55, 695.
(39) Canepa, C.; Prandi, C.; Sacchi, L.; Venturello, P. J. Chem. Soc.,
Perkin Trans. 1 1993, 1875.
(40) Sheshenev, A. E.; Baird, M. S.; Croft, A. K.; Bolesov, I. G.
Tetrahedron 2009, 65, 10036.
(16) (a) Page, P. C. B.; Buckley, B. R.; Barros, D.; Blacker, A. J.;
Marples, B. A.; Elsegood, M. R. J. Tetrahedron 2007, 63, 5386 and
references therein. (b) Page, P. C. B.; Buckley, B. R.; Barros, D.;
Blacker, A. J.; Heaney, H.; Marples, B. A. Tetrahedron 2006, 62, 6607.
(17) Page, P. C. B.; Buckley, B. R.; Heaney, H.; Blacker, A. J. Org.
Lett. 2005, 7, 375.
(18) Page, P. C. B.; Appleby, L. F.; Day, D. P.; Chan, Y.; Buckley, B.
R.; Allin, S. M.; McKenzie, M. J. Org. Lett. 2009, 11, 1991.
(19) Bartlett, C. J.; Day, D. P.; Chan, Y.; Allin, S. M.; McKenzie, M.
J.; Slawin, A. M. Z.; Page, P. C. B. J. Org. Chem. 2012, 77, 772.
(20) Balentine, D. A.; Wiseman, S. A.; Bouwens, L. C. M. Crit. Rev.
Food Sci. Nutr. 1997, 37, 693.
(41) Stambouli, A.; Chastrette, F.; Amouroux, R.; Chastrette, M.
Tetrahedron. Lett. 1986, 27, 4149.
(42) Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron 1986, 42, 6447.
(43) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A. J. Org. Chem.
2005, 70, 4542.
(44) Clausen, D. J.; Floreancig, P. E. J. Org. Chem. 2012, 77, 6574.
(45) (a) Hill, M. L.; Raphael, R. A. Tetrahedron Lett. 1986, 27, 1293.
(b) Morel, A. F.; Larghi, E. L. Tetrahedron: Asymmetry 2004, 15, 9.
(46) Boyko, V. I.; Yakovenko, A. V.; Yu, I.; Matvieiev, O. I.;
Kalchenko, O. V.; Shishkin, S. V.; Shishkina, S. V.; Kalchenko, V. I.
Tetrahedron 2008, 64, 7567.
(21) Martin, V. S.; Woodard, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,
M.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 6237.
(22) (a) Van der Velde, S. L.; Jacobsen, E. N. J. Org. Chem. 1995, 60,
5380. (b) Keith, J. M.; Larrow, G. F.; Jacobsen, E. N. Adv. Synth. Catal.
2001, 343, 5.
(23) Noguchi, Y.; Irie, R.; Fukuda, T.; Katsuki, T. Tetrahedron Lett.
1996, 37, 4533.
(24) Frohn, M.; Zhou, X.; Zhang, J.-R.; Tang, Y.; Shi, Y. J. Am. Chem.
Soc. 1999, 121, 7718.
(25) (a) Harfenist, M.; Thom, E. J. Org. Chem. 1972, 37, 841.
(b) Subramanian, R. S.; Balasubramanian, K. K. Tetrahedron Lett.
1988, 29, 6797.
(26) (a) Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Chem. Soc.,
Chem. Commun. 1979, 836. (b) Inoue, T.; Inoue, S.; Sato, K. Bull.
Chem. Soc. Jpn. 1990, 63, 1062.
(27) (a) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S.
Tetrahedron Lett. 1979, 2545. (b) Jurd, L.; Manners, G. D. Synthesis
1980, 618.
(28) Sartori, G.; Casiraghi, G.; Bolzoni, L.; Casnati, G. J. Org. Chem.
1979, 44, 803.
(29) (a) Hosokawa, T.; Kono, T.; Uno, T.; Murahashi, S.-I. Bull.
Chem. Soc. Jpn. 1986, 59, 2191. (b) Garcías, X.; Ballester, P.; Saa,
́
J. M.
Tetrahedron Lett. 1991, 32, 7739.
I
dx.doi.org/10.1021/jo401345m | J. Org. Chem. XXXX, XXX, XXX−XXX