Non-aqueous iminium salt mediated catalytic asymmetric epoxidation

Article abstract of DOI:10.1016/j.tet.2005.10.084

A range of substituted dihydroisoquinolinium salts has been tested in the catalytic asymmetric epoxidation of simple alkenes using our newly developed non-aqueous conditions employing tetraphenylphosphonium monoperoxysulfate (TPPP) as oxidant, giving ees of up to 97%.

Full text of DOI:10.1016/j.tet.2005.10.084

Tetrahedron 62 (2006) 6607–6613
Non-aqueous iminium salt mediated catalytic asymmetric
epoxidation
a
a
b
Philip C. Bulman Page,a, Benjamin R. Buckley, David Barros, A. John Blacker,
*
Harry Heaneya and Brian A. Marplesa
aDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK
bNPIL Pharmaceuticals (UK) Ltd., PO Box 521, Leeds Road, Huddersfield, HD2 1GA, UK
Received 26 August 2005; revised 13 October 2005; accepted 13 October 2005
Available online 5 June 2006
Abstract—A range of substituted dihydroisoquinolinium salts has been tested in the catalytic asymmetric epoxidation of simple alkenes using
our newly developed non-aqueous conditions employing tetraphenylphosphonium monoperoxysulfate (TPPP) as oxidant, giving ees of up to
97%.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the use of oxone as stoichiometric oxidant, a base (2 mol
equiv of Na2CO3 per equiv of oxone) and water/acetonitrile
as solvent mixture.
In 1976, it was established that oxaziridinium salts are ex-
tremely reactive reagents for oxygen transfer to nucleophilic
substrates.1 Since then, there has been significant interest in
developing effective iminium salt catalysts for epoxidation
of olefins.2 The primary oxidant used is oxone and the reac-
tions are usually performed at 0 ꢀC in the presence of a base.
In addition to an organic solvent, usually acetonitrile, water
is an essential cosolvent, required in order to provide suffi-
cient oxone solubility.
The principal limitation of this system is the restricted range
of temperatures at which the epoxidation can be performed
(ca. ꢁ5 ꢀC to ambient). The upper temperature limit results
from the relatively fast decomposition of oxone in basic
media at room temperature. The lower limit is determined
by the requirement for an aqueous solution (the normal
ratio of solvents is (CH3CN/H2O; 1:1); aqueous acetonitrile
freezes at ꢁ8 ꢀC. An additional drawback arising from the
dependency on oxone is the large quantity of inorganic salt
byproducts produced in the reaction.
We have previously described our approach to new types of
cyclic chiral iminium salts, functionalised with chiral units
at the nitrogen atom.3 These enantiomerically pure iminium
salts have been successfully employed in the catalytic asym-
metric epoxidation of unfunctionalised alkenes, the dioxane-
derived catalysts 1–5 giving ees of up to ca. 60%,4 catalyst 6
giving ees of up to 97%,5 and catalyst 7 ees of up to 95%.6
We have recently described new reaction conditions for imi-
nium salt-catalysed epoxidation, which eliminate the use of
both water and base.7 This was achieved through the identi-
fication of an effective oxidant, tetraphenylphosphonium
monoperoxysulfate (TPPP), that is soluble in organic sol-
vents. When oxone is treated with tetraphenylphosphonium
chloride, TPPP is produced as a colourless solid (Eq. 1).
The standard conditions employed by ourselves and others
in epoxidation reactions catalysed by iminium salts involve
BPh4
O
BPh4
BPh4
O
BPh4
N
N
O
O
N
N
O
O
O
O
O
Ph
Ph
S
O
R
1 R = H; 2 R = NO2
5
6
7
3 R = SMe; 4 R = OMe
* Corresponding author. Tel.: +44 1509 222581; fax: +44 1509 223926; e-mail: p.c.b.page@lboro.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.084

6608
P. C. B. Page et al. / Tetrahedron 62 (2006) 6607–6613
TPPP has previously been used for the oxidation of man-
ganese(III) porphyrins.8
a change in the configuration of the enantiomer of epoxide
formed preferentially, to the (+)-(1R,2R) isomer, is observed
in every case.
Ph4P+ Clꢁ+ Oxone ð2KHSO5:KHSO4:K2SO4Þ
The thiomethyl catalyst 3 also gives the (+)-(1R,2R) enantio-
mer of 1-phenylcyclohexene preferentially, but only be-
tween temperatures of 0 ꢀC and ꢁ50 ꢀC (Table 1, entries
3, 8, 12); at ꢁ78 ꢀC the (ꢁ)-(1S,2S) enantiomer is preferen-
tially formed (Table 1, entry 18). We reason that this is due to
rapid oxidation of the sulfide to the sulfone at temperatures
above ꢁ78 ꢀC, generating catalyst 6 in situ. Catalyst 4,
which contains an electron-donating methoxy substituent,
and has the opposite absolute stereochemistry to catalysts
1, 2, 3 and 6, produces the (+)-(1R,2R) epoxide enantiomer
preferentially, regardless of temperature. Catalyst 4 thus ex-
hibits the same facial selectivity as unsubstituted catalyst 1
(and catalyst 3 at low temperatures).
ð1Þ
/Ph4P+ ðHSO5Þꢁ
We were pleased to find that the use of TPPP in place of
oxone induces efficient epoxidation in organic solvents in
the absence of water and furthermore that the presence of
base is now not required; indeed, addition of base actually
suppresses the epoxidation process. Use of this oxidant also
enables greater scope for reaction monitoring and analysis,
as water is no longer required. Reactions can be carried out
at low temperature, and, when carried out in deuteriated sol-
vent, monitored by NMR spectroscopy. We describe herein
the catalytic asymmetric epoxidation of several unfunction-
alised alkenes using catalysts 2–6 under the new anhydrous
conditions, employing (TPPP) as stoichiometric oxidant.
The catalysts were first tested in the asymmetric epoxidation
of 1-phenylcyclohexene at varying temperatures using TPPP
in dichloromethane (Table 1).
In the case of catalyst 3, to prove that the active catalyst at
temperatures above ꢁ78 ꢀC was indeed the corresponding
sulfone 6, a standard epoxidation reaction was performed
in deuteriated dichloromethane solution and the reaction
1
mixture was subjected to H NMR spectroscopic analysis.
The chemical shift for the methyl group attached to sulfur
had shifted from d 2.42 to 3.03, confirming that the sulfide
had been oxidised to the sulfone, by comparison with
authentic catalyst 6. The sulfoxide intermediate was not
observed.
As the temperature is reduced there is an increase in enantio-
meric excess at the expense of rate of conversion to epoxide.
It is interesting that, while catalyst 1 gives the (ꢁ)-(1S,2S)
epoxide, when the catalyst contains a strongly electron-with-
drawing nitro or sulfone substituent (catalysts 2 and 6),
In order to determine the effects of solvent on the reaction,
several other solvents were screened using our three most
enantioselective catalysts 1, 4 and 6 (Table 2). TPPP was
found to be insoluble in carbon tetrachloride, ethyl acetate
and dimethoxyethane. In dimethylformamide, the TPPP
dissolved but no reaction occurred. TPPP is also soluble in
dichloroethane, however, and epoxidation reactions of
Table 1. Catalytic asymmetric epoxidation of 1-phenylcyclohexene using
TPPP in CH2Cl2
a
Entry Temp (ꢀC) Catalystb Conversion (%)c ee (%)d Configuratione
1
2
3
4
5
0
ꢁ30
ꢁ45
ꢁ78
1
2
100
100
72
—
100
16
25
16
—
33
(ꢁ)-(1S,2S)
(+)-(1R,2R)
(+)-(1R,2R)
—
3
4f
6
(+)-(1R,2R)
Table 2. Asymmetric epoxidation of 1-phenylcyclohexene using various
solventsa
6
7
8
9
10
1
2
—
100
92
76
100
—
28
33
25
36
37g
30
33
—
42
—
(+)-(1R,2R)
(+)-(1R,2R)
(+)-(1R,2R)
(+)-(1R,2R)
Solvent Catalystb Time/h Conversion/%c ee/%d Configuratione
3
4f
6
CH3CN
CH2Cl2
C2H4Cl2
1
1.0
0.2
2.5
42
30
89
43f
44
45
37f
25
36
(ꢁ)-(1S,2S)
(+)-(1R,2R)
(ꢁ)-(1S,2S)
(ꢁ)-(1S,2S)
(+)-(1R,2R)
(+)-(1R,2R)
4g
6
11
12
13
14
15
1
2
70
54
67
—
96
(ꢁ)-(1S,2S)
(+)-(1R,2R)
(+)-(1R,2R)
—
1
4
4
4
70
76
100
3
4g
6
4f
6
(+)-(1R,2R)
1
24
24
4
29
87
97
24
17
32
(ꢁ)-(1S,2S)
(+)-(1R,2R)
(+)-(1R,2R)
16
17
18
19
20
1
2
15
0
15
13
—
23h
—
(ꢁ)-(1S,2S)
—
(ꢁ)-(1S,2S)
(+)-(1R,2R)
—
4g
6
3
50h
29h
—
4f
6
CHCl3
1
24
24
12
52
73
100
33
11
48
(ꢁ)-(1S,2S)
(+)-(1R,2R)
(+)-(1R,2R)
4g
6
a
Epoxidation conditions: iminium salt (10 mol %), TPPP (2 equiv),
CH2Cl2, 4 h.
a
Epoxidation conditions: iminium salt (10 mol %), TPPP (2 equiv),
solvent, ꢁ30 ꢀC.9 Catalyst configuration (4S,5S).
Catalyst configuration (4S,5S) unless otherwise stated.
Conversions were evaluated from the 1H NMR spectra by integration of
alkene and epoxide signals.
b
c
Catalyst configuration (4S,5S) unless otherwise stated.
Conversions were evaluated from the 1H NMR spectra by integration of
alkene and epoxide signals.
b
c
Enantiomeric excesses were determined by 1H NMR spectroscopy in the
presence of (+)-Eu(hfc)3 (0.1 mol equiv).
d
e
Enantiomeric excesses were determined by 1H NMR spectroscopy in the
presence of (+)-Eu(hfc)3 (0.1 mol equiv).
d
e
The absolute configurations of the major enantiomers were determined by
comparison of optical rotation with literature values.
Catalyst configuration (4R,5R).
The absolute configurations of the major enantiomers were determined by
comparison of optical rotation with literature values.
Reaction carried out at ꢁ40 ꢀC.
f
g
h
f
Reaction carried out at ꢁ40 ꢀC.
g
Reaction time 8 h.
Catalyst configuration (4R,5R).

P. C. B. Page et al. / Tetrahedron 62 (2006) 6607–6613
6609
1-phenylcyclohexene performed in this solvent gave almost
identical results to those obtained with dichloromethane for
catalysts 6 and 4. Curiously, catalyst 1 was far less reactive in
this medium and gave a reduced ee (24% compared to 37%).
When the reactions were repeated in chloroform, we
observed a dramatic decrease in ee for catalyst 4, while cat-
alyst 1 gave similar results to those obtained in dichloro-
methane (33% ee). Catalyst 6 in chloroform, however,
gave the best ee for 1-phenylcyclohexene (48% ee) that we
have observed with this series of iminium salt catalysts.
Interestingly, in acetonitrile at ꢁ30 ꢀC we observed a similar
degree of enantioselectivity to that seen in the reaction car-
ried out in chloroform (48% ee, (+)-(1R,2R) enantiomer),
but producing the opposite (ꢁ)-(1S,2S)-enantiomer of phe-
nylcyclohexene oxide in 45% ee. The origins of these sol-
vent effects upon enantioselectivity remain unclear.
Using our most enantioselective catalyst 6, we next carried
out asymmetric epoxidations of several other unfunctional-
ised alkenes in acetonitrile and in chloroform solution at
a standard temperature of ꢁ40 ꢀC, using 10 mol % catalyst
(Table 3). Remarkably, changing the reaction solvent was
found to switch the major enantiomer of epoxide generated
from all trans- and tri-substituted alkenes tested. Further,
trans-stilbene, usually a poor substrate with our catalysts
(less than 5% ee was observed under our original aqueous
conditions using the same catalyst and oxone), afforded
the (+)-(R,R) enantiomer of trans-stilbene oxide in 67% ee
when the reaction was carried out in chloroform solution,
but the (ꢁ)-(S,S) isomer, in 30% ee, when performed in
acetonitrile. With the exception of a-methylstilbene, it is
clear from Table 3 that chloroform is the solvent of choice
for catalyst 6 and the enantiomeric excesses are far better
Table 3. Catalytic asymmetric epoxidation of various alkenes using TPPP and catalyst 6a
Solvent
Alkene
Ph
Oxone/CH3CN/H2O
CH3CN
CHCl3
Yield (%)b ee (%)c Configurationd Yield (%)b ee (%)c Configurationd Yield (%)b ee (%)c Configurationd
100e
39
(ꢁ)-(1S,2S)
73
45
(ꢁ)-(1S,2S)
77
48
(+)-(1R,2R)
Ph
100e
100e
100e
<5
32
50
(ꢁ)-(S,S)
(ꢁ)-(1S,2R)
(+)-(S)
13e
42
30
48
27
(ꢁ)-(S,S)
(ꢁ)-(1S,2R)
(+)-(S)
31
35
67
2
(+)-(R,R)
(+)-(1R,2S)
(ꢁ)-(R)
Ph
Ph
Ph
CH
Ph
3
25
11e
63
Ph
Ph
Ph
100e
47
(ꢁ)-(1S,2R)
56
38
(ꢁ)-(1S,2R)
98
59
(+)-(1R,2S)
—
—
61
—
—
45
—
71
—
80
53
—
56
(+)-(1S,2R)
—
85
83
89
70
61
82
(+)-(1S,2R)
(+)-(1S,2R)
(ꢁ)-(1S,2R)
—
(ꢁ)-(1S,2R)
(ꢁ)-(1S,2R)
O N
2
—
—
—
—
—
—
52
88
(ꢁ)-(1S,2S)
O
Cl
—
—
—
—
—
—
—
63
—
80
—
76
59
93
97
(ꢁ)-(1S,2S)
(ꢁ)-(1S,2S)
O
NC
(ꢁ)-(1S,2S)
O
a
Epoxidation conditions: iminium salt 6 (10 mol %), TPPP (2 equiv), ꢁ40 ꢀC, 24 h.
Enantiomeric excesses were determined by 1H NMR spectroscopy in the presence of (+)-Eu(hfc)3 (0.1 mol equiv) or by chiral HPLC using a Chiracel OD
column.
The absolute configurations of the major enantiomers were determined by comparison of optical rotation with literature values.
Conversions, evaluated from the 1H NMR spectra by integration of alkene and epoxide signals.
b
c
Isolated yields unless otherwise stated.
d
e

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P. C. B. Page et al. / Tetrahedron 62 (2006) 6607–6613
than those observed when employing TPPP in acetonitrile as
well as in the original aqueous conditions using oxone.
Activity-polAAar 2001 instrument, operating at l¼
589 nm, corresponding to the sodium D line, at the tem-
peratures indicated. Microanalyses were performed on
a Perkin–Elmer Elemental Analyser 2400 CHN. All chro-
matographic manipulations used silica gel as the adsorbent.
Reactions were monitored using thin layer chromatography
(TLC) on aluminium-backed plates coated with Merck
Kieselgel 60 F254 silica gel. TLC plates were visualised by
UV radiation at a wavelength of 254 nm, or stained by expo-
sure to an ethanolic solution of phosphomolybdic acid (acid-
ified with concentrated sulfuric acid), followed by charring
where appropriate. Reactions requiring anhydrous condi-
tions were carried out using glassware dried overnight at
150 ꢀC, under a nitrogen atmosphere unless otherwise
stated. Reaction solvents were used as obtained commer-
cially unless otherwise stated. Light petroleum (bp 40–
60 ꢀC) was distilled from calcium chloride prior to use.
Ethyl acetate was distilled over calcium sulfate or chloride.
Dichloromethane was distilled over calcium hydride.
Tetrahydrofuran was distilled under a nitrogen atmosphere
from the sodium/benzophenone ketyl radical or from lithium
aluminium hydride. Enantiomeric excesses were determined
either by proton nuclear magnetic resonance spectroscopy in
the presence of europium (III) tris[3-(hepta-fluoropropyl-
hydroxymethylene)-(+)-camphorate] as the chiral shift
reagent, or by chiral HPLC using a Chiracel OD column
on a TSP Thermo-Separating-Products Spectra Series P200
instrument, with a TSP Spectra Series UV100 ultraviolet ab-
sorption detector set at 254 nm and a Chromojet integrator.
Good enantiomeric excesses were also observed for cis-a-
methyl styrene (70% ee) and dihydronaphthalene (82%
ee). The level of enantioselectivity observed here is remark-
able given that the corresponding reaction carried out under
our standard aqueous conditions with oxone afforded di-
hydronaphthalene oxide in only 45% ee. The enantiomeric
excess for the epoxidation of indene is somewhat lower
(61% ee), but is still much higher than other reported ees
for this epoxidation when mediated by oxaziridinium salts.4
Epoxidation of the non-aryl cis-hept-2-ene produced epox-
ide with quantitative conversion but with low ee. Electron-
deficient alkenes are also poor substrates.
Finally, we turned our attention to the epoxidation of benzo-
pyran substrates. We were delighted to observe excellent
enantioselectivities in the epoxidations of 6-nitro-, 6-chloro-
and 6-cyano-2,2-dimethylbenzopyrans, with ees up to an
unprecedented 97%.5 It is interesting to note here that,
in these cases, whichever solvent was employed, the same
enantiomer of epoxide was observed.
2. Conclusions
A range of iminium salt asymmetric epoxidation catalysts
has been tested under non-aqueous conditions at various
temperatures in a number of solvents; from these we have
identified catalyst 6 as one of the most enantioselective.
The reaction solvent has a profound effect on the epoxida-
tion of trans- and tri-substituted alkenes and in many cases
we are able to produce either enantiomer as the major prod-
uct by choice of acetonitrile or chloroform as solvent. In
terms of enantiomeric excesses, the optimum reaction tem-
perature appears to be ꢁ40 ꢀC and chloroform the solvent
of choice. These conditions have provided enantiomeric
excesses of up to 97%, in the epoxidation of 6-cyano-2,2-
dimethylbenzopyran.
3.2. General procedure for the preparation of di-
hydroisoquinolinium salts from 2-(2-bromoethyl)-
benzaldehyde and primary amines
2-(2-Bromoethyl)benzaldehyde (1.60 equiv, 1.10 if freshly
distilled) was cooled using an ice bath and a solution of
the amine in ethanol (10 ml per g of amine) was added drop-
wise. After the addition was complete, the ice bath was re-
moved and the reaction mixture was stoppered to retain
HBr and stirred overnight. A solution of sodium tetraphenyl-
borate or other anion-exchanging salt (1.10 equiv) in the
minimum amount of acetonitrile was added in one portion
to the reaction mixture. After stirring for 5 min, the organic
solvents were removed under reduced pressure. Ethanol was
added to the residue, followed by water. The resulting pre-
cipitate was collected by filtration and washed with addi-
tional ethanol followed by diethyl ether. If no solid was
materialised after the addition of the water, the mixture
was allowed to settle and the ethanol/water phase was dec-
anted. The gummy residue was triturated in hot ethanol or
methanol, inducing precipitation of the organic salt immedi-
ately or upon slow cooling of the hot alcoholic solution.
Small quantities of acetonitrile may be added during this
process to aid solubility.
3. Experimental
3.1. General
All infrared spectra were obtained using a Perkin–Elmer
Paragon 1000 FTIR spectrophotometer; thin film spectra
1
were acquired using sodium chloride plates. All H and
13C NMR spectra were measured at 250.13 and
62.86 MHz with a Bruker AC 250 MHz spectrometer or at
400.13 and 100.62 MHz with a Bruker DPX 400 MHz spec-
trometer, in deuteriochloroform solution unless otherwise
stated, using TMS (tetramethylsilane) as the internal refer-
ence. Mass spectra were recorded using a Jeol-SX102 instru-
ment utilising electron-impact (EI), fast atom bombardment
(FAB) and by the EPSRC national mass spectrometry ser-
vice at the University of Wales, Swansea, utilising electro-
spray (ES). Analysis by GC–MS utilised a Fisons GC
8000 series (AS 800), using a 15 mꢂ0.25 mm DB-5 column
and an electron-impact low resolution mass spectrometer.
Melting points were recorded using an Electrothermal-IA
9100 melting point instrument and are uncorrected.
Optical rotation values were measured with an Optical
3.2.1. (+)-N-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-
5-yl)-3,4-dihydroisoquinolinium tetraphenylborate (1).4
Prepared according to the general procedure from (4S,5S)-5-
amino-2,2-dimethyl-4-phenyl-1,3-dioxane (3.00 g, 14.4
mmol) and purified by recrystallisation from acetone/diethyl
ether to give 1 as a yellow solid (6.93 g, 75%), mp 169–
170 ꢀC; [a]D20 +38.6 (c 2.70, CH3CN); nmax(Nujol)/cmꢁ1
1637, 1603, 1571, 1480, 1266, 1202, 1166, 1108, 1073; dH

P. C. B. Page et al. / Tetrahedron 62 (2006) 6607–6613
6611
(250 MHz, CD3CN), 1.65 (3H, s), 1.94 (3H, s), 2.39–2.48
(1H, m), 2.70–2.82 (1H, m), 3.25–3.40 (1H, m), 3.81–3.97
(1H, m), 4.00–4.10 (1H, m), 4.30 (1H, d, J 13.7 Hz), 4.58
(1H, dd, J 13.7, 3.1 Hz), 5.70 (1H, d, J 2.8 Hz), 6.81 (4H,
t, J 7.2 Hz), 7.35–7.40 (6H, m), 7.46 (1H, t, J 7.3 Hz),
7.65–7.74 (2H, m), 8.92 (1H, s); dC (62.50 MHz, CD3CN)
17.9, 24.1, 28.7, 51.6, 61.4, 65.5, 70.7, 104.9, 121.9,
124.3, 125.4, 125.7, 128.1, 128.5, 128.6, 128.0, 134.4,
135.8, 137.0, 137.7, 138.7, 163.5, 167.5; m/z 322.1809;
C21H24NO2 (cation) requires 322.1807.
1.88. C46H46BNO3$0.5Et2O requires C, 77.92; H, 6.54; N,
1.98; nmax(film)/cmꢁ1 1639, 1604, 1573, 1514, 1382,
1254, 1202, 1107, 1031; dH (400 MHz, CDCl3) 1.51 (3H,
s), 1.52 (3H, s), 2.20–2.25 (1H, m), 2.31–2.35 (1H, m),
2.85–2.90 (1H, m), 3.00–3.10 (1H, m), 2.96–3.07 (1H, m),
3.56 (1H, d, J 14.4 Hz), 3.72 (3H, s), 3.90 (1H, dd, J 14.0,
2.8 Hz), 5.11 (1H, d, J 2.4 Hz), 6.79 (2H, d, J 2.0 Hz),
6.87 (4H, t, J 7.2 Hz), 7.02 (8H, t, J 7.6 Hz), 7.23–7.24
(2H, m) 7.24–7.31 (1H, m), 7.41–7.57 (8H, m), 7.60–7.69
(1H, m), 8.25 (1H, s); dC (100 MHz, CDCl3) 18.4, 24.6,
29.4, 50.5, 55.4, 61.9, 64.9, 70.5, 100.4, 114.4, 122.2,
123.7, 125.9, 127.3, 127.9, 128.7, 129.5, 134.0, 134.7,
136.2, 138.8, 159.8, 163.8, 169.5; m/z 352.1915;
C22H26NO3 (cation) requires 352.1913.
3.2.2. (+)-N-((4S,5S)-2,2-Dimethyl-4-(4-nitrophenyl)-
1,3-dioxan-5-yl)-3,4-dihydroisoquinolinium tetraphenyl-
borate (2).4 Prepared according to the general procedure
from (+)-(4S,5S)-5-amino-2,2-dimethyl-4-(4-nitrophenyl)-
1,3-dioxane (0.19 g, 0.8 mmol) and purified by recrystallisa-
tion from CH2Cl2/hexane to give 2 as yellow plates (0.36 g,
74%); mp 176–178 ꢀC (dec); [a]2D0 +107.7 (c 1.30, acetone).
Found C, 77.73; H, 6.23; N, 4.00. C45H43BN2O4$0.5H2O re-
quires C, 77.66; H, 6.38; N, 4.03; nmax(film)/cmꢁ1 1635,
1604, 1571, 1524, 1478, 1384, 1202, 1163, 1107, 1032; dH
(400 MHz, acetone-d6), 1.72 (3H, s, CH3), 1.76 (3H, s),
2.70–2.80 (1H, m), 2.88–2.96 (1H, m), 3.65–3.74 (1H, m),
4.19–4.23 (1H, m), 4.54 (1H, d, J 13.6 Hz), 4.61–4.70 (1H,
m), 4.82 (1H, dd, J 13.6, 2.8 Hz), 6.11 (1H, d, J 2.4 Hz),
6.80 (4H, t, J 6.8 Hz), 6.94 (8H, t, J 7.2 Hz), 7.36 (8 H, m),
7.51 (1H, t, J 7.6 Hz), 7.59–7.88 (3H, m), 7.85 (2H, d,
J 8.4 Hz), 7.95 (2H, d, J 8.8 Hz), 9.28 (1H, s); dC (100 MHz,
acetone-d6), 19.2, 25.9, 30.0, 52.8, 63.4, 66.4, 71.9, 102.2,
122.7, 125.3, 125.8, 126.4, 128.3, 129.7, 129.8, 135.9,
137.4, 138.4, 140.1, 145.0, 149.0, 165.0, 169.5; m/z
367.1658; C21H23N2O4 (cation) requires 367.1658.
3.2.5. (+)-N-((4S,5S)-2,2-Dimethyl-4-(4-(methylsulfonyl)-
phenyl)-1,3-dioxan-5-yl)-3,4-dihydroisoquinolinium
tetraphenylborate (6).5 Prepared according to the general
procedure from (4S,5S)-5-amino-2,2-dimethyl-4-(4-(methyl-
sulfonyl)phenyl)-1,3-dioxane (0.75 g, 2.96 mmol) and pu-
rified by recrystallisation from CH2Cl2/hexane to give 6 as
yellow plates (1.55 g, 73%); mp 199–201 ꢀC (dec); [a]D20
+126.7 (c 1.20, acetone). Found C, 75.62; H, 6.32; N, 1.84.
C46H46BNO4S$0.5H2O requires C, 75.79; H, 6.50; N, 1.92;
nmax(film)/cmꢁ1 1636, 1603, 1572, 1478, 1383, 1314,
1266, 1202, 1150, 1076, 1032, 956; dH (400 MHz, acetone-
d6), 1.69 (3H, s), 1.72 (3H, s), 2.60–2.69 (1H, m), 2.85–2.96
(1H, m), 3.00 (3H, s), 3.65–3.72 (1H, m), 4.12–4.20
(1H, m), 4.49 (1H, d, J 13.6 Hz), 4.50–4.64 (1H, m), 4.77
(1H, dd, J 13.6, 2.8 Hz), 6.05 (1H, d, J 2.8 Hz), 6.80 (4H, t,
J 7.2 Hz), 6.92 (8H, t, J 7.2 Hz), 7.31–7.44 (8H, m), 7.49
(1H, t, J 7.6 Hz), 7.73–7.83 (3H, m), 7.82 (2H, d, J 8.2 Hz),
7.95 (2, d, J 8.2 Hz), 9.28 (1H, s); dC (100 MHz, acetone-
d6), 18.8, 25.4, 29.5, 44.3, 52.3, 62.9, 66.1, 71.5, 101.7,
122.3, 125.3, 126.1, 127.6, 128.8, 129.3, 129.4, 135.4,
137.0, 137.0, 137.9, 142.4, 143.2, 165.0, 168.9; m/z
400.1586; C22H26NO4S (cation) requires 400.1583.
3.2.3. (+)-N-((4S,5S)-2,2-Dimethyl-4-(4-(methylthio)-
phenyl)-1,3-dioxan-5-yl)-3,4-dihydroisoquinoliniumtetra-
phenylborate (3).4 Prepared according to the general
procedure from (4S,5S)-5-amino-2,2-dimethyl-4-(4-(methyl-
thio)phenyl)-1,3-dioxane (0.50 g, 2.0 mmol) and purified by
recrystallisation from CH2Cl2/hexane to give 3 as yellow
plates (1.00 g, 73%); mp 146–148 ꢀC (dec); [a]D20 +115.9
(c 1.41, acetone). Found C, 79.05; H, 6.59; N, 1.93.
C46H46BNO2S$0.5H2O requires C, 79.27; H, 6.66; N, 2.01;
nmax(film)/cmꢁ1 3053, 2996, 2360, 2341, 1634, 1603, 1571,
1478, 1265, 1201, 1162, 1108, 1075; dH (250 MHz, ace-
tone-d6) 1.66 (3H, s), 1.72 (3H, s), 2.42 (3H, s), 2.66–2.84
(1H, m), 2.90–3.03 (1H, m), 3.62–3.74 (1H, m), 4.13–4.26
(1H, m), 4.50–4.55 (2H, m), 4.78 (1H, dd, J 13.8, 3.1 Hz),
5.91 (1H, d, J 2.6 Hz), 6.78 (4H, t, J 7.2 Hz), 6.92 (8H, t,
J 7.40 Hz), 7.34 (8H, m), 7.40–7.56 (6H, m), 7.76–7.87
(2H, m), 9.30 (1H, s); dC (100 MHz, acetone-d6) 15.4,
18.8, 25.4, 30.0, 52.3, 62.7, 66.5, 71.5, 101.4, 122.3,
125.3, 126.1, 126.9, 127.4, 129.2, 129.3, 133.9, 135.2,
137.0, 137.8, 139.5, 140.5, 165.0, 168.5; m/z 368.1682;
C22H26NO2S (cation) requires 368.1684.
3.2.6. Tetraphenylphosphonium monoperoxysulfate.
OxoneÔ triple salt (2KHSO5:KHSO4:K2SO4) (15.0 g,
48.8 mmol with respect to KHSO5) was dissolved in deion-
ised water (300 ml) and the solution was stirred at 10–15 ꢀC
(water bath). A solution of tetraphenylphosphonium chlo-
ride (15.0 g, 40.0 mmol) in distilled dichloromethane
(300 ml) was added over 5 min and the mixture stirred for
an additional 30 min. The organic layer was separated and
the solvent was removed under reduced pressure at room
temperature. The colourless residue, the crude salt, was
transferred to a fritted glass funnel and washed with distilled
water (2ꢂ75 ml). The solid was dissolved in dichloro-
methane (180 ml) and the solution was dried (MgSO4).
Hexane was added until cloudiness developed and the flask
was placed in the freezer (ꢁ20 ꢀC) overnight, producing a
colourless precipitate of the salt about 85% pure in peroxide
(15.4 g, 70%). dH (250 MHz, CDCl3) 7.62–7.65 (8H, m),
7.76–7.81 (8H, m), 7.88–7.92 (4H, m), 8.92 (1H, s).
3.2.4. (L)-N-((4R,5R)-2,2-Dimethyl-4-(4-methoxy-
phenyl)-1,3-dioxan-5-yl)-3,4-dihydroisoquinolinium
tetraphenylborate (4).4 Prepared according to the general
procedure from (ꢁ)-(4R,5R)-5-amino-2,2-dimethyl-4-(4-
methoxyphenyl)-1,3-dioxane (0.40 g, 1.7 mmol) and puri-
fied by recrystallisation from CH2Cl2/hexane to give 4 as
yellow plates (0.83 g, 74%); mp 171–173 ꢀC (dec); [a]D20
ꢁ108.6 (c 1.40, acetone). Found C, 77.70; H, 6.50; N,
3.3. General procedure for catalytic asymmetric epoxi-
dation of simple alkenes mediated by iminium salts
using tetraphenylphosphonium monoperoxysulfate
Tetraphenylphosphonium monoperoxysulfate (2 equiv with
respect to the alkene) was dissolved in the desired solvent

6612
P. C. B. Page et al. / Tetrahedron 62 (2006) 6607–6613
(2 ml per 0.1 g oxidant) and the solution cooled to the re-
quired temperature. To this was added the iminium salt as
a solution in the solvent (0.5 ml per 0.1 g oxidant). This imi-
nium salt solution was cooled to the same temperature as the
solution containing the oxidant and added dropwise to it over
15–20 min; the temperature of the reaction vessel was moni-
toredto minimiseincrease intemperatureduringtheaddition.
A solution of the alkene in the reaction solvent (0.5 ml per
0.1 g oxidant) was added dropwise. The mixture was stirred
at the reaction temperature until the alkene was completely
consumed according to TLC. Diethyl ether (pre-cooled to
the reactiontemperature)(20 ml per0.1 g oxidant)was added
to induce precipitation of the remaining oxidant and the
mixture filtered through Celite. The solvents were removed,
diethyl ether (40 ml) was added to the residue and the
solution was passed through a short pad of silica gel to re-
move catalyst residues. The solvents were removed to give
the epoxide. If the reaction does not reach completion then
the epoxide can be separatedfrom the alkene by column chro-
matography, eluting with ethyl acetate/light petroleum 1:99.
1118, 1065, 1027, 980; dH (400 MHz, CDCl3) 1.46 (3H, s),
3.96 (1H, s), 7.30–7.46 (10H, m); dC (100 MHz, CDCl3)
17.1, 63.5, 67.5, 125.6, 126.9, 127.7, 127.9, 128.6, 129.2,
136.4, 142.8.
3.5.2. Triphenylethylene oxide.10 Colourless oil, which
slowly solidified; mp 66–67 ꢀC, (lit. mp 75 ꢀC); nmax(neat)/
cmꢁ1 3062, 3030, 2957, 2925, 2856, 1605, 1596, 1499,
1471, 1448, 1262, 1221, 741, 698, 621; dH (250 MHz,
CDCl3) 4.39–4.41 (1H, m), 7.10–7.47 (15H, m); dC
(62.5 MHz, CDCl3) 68.0, 68.3, 126.3, 126.8, 127.5, 127.6,
127.7, 127.8, 128.0, 128.2, 128.6, 135.4, 135.9, 141.1.
3.5.3. 1-Phenylcyclohexene oxide.11 Colourless oil;
nmax(neat)/cmꢁ1 3084, 1602, 1495, 1446, 1359, 1249,
1173, 1132, 1079, 1030, 993, 974; dH (250 MHz, CDCl3)
1.22–1.35 (1H, m), 1.53–1.64 (3H m), 1.99–2.06 (2H, m)
2.16–2.18 (1H, m), 2.26–2.32 (1H, m), 3.10 (1H, t,
J 2.0 Hz), 7.28–7.44 (5 H, m); dC (62.5 MHz, CDCl3)
19.8, 20.1, 24.7, 28.2, 60.1, 61.8, 125.3, 127.1, 128.2, 142.8.
3.4. General procedure for the catalytic asymmetric
epoxidation of alkenes mediated by iminium salts using
oxone
3.5.4. 1-Phenyl-3,4-dihydronaphthalene oxide.11 Pale
yellow solid; mp 104–106 ꢀC, (lit.12 mp 94–97 ꢀC);
nmax(Nujol)/cmꢁ1 1602, 1486, 1307, 1155, 1074, 1042,
953; dH (250 MHz, CDCl3) 2.10 (1H, td, J 5.8, 13.7 Hz),
2.49–2.60 (1H, m), 2.77 (1H, dd, J 5.6, 15.5 Hz), 2.98–
3.06 (1H, m), 3.71 (1H, d, J 3.1 Hz), 7.11–7.31 (4H, m),
7.45–7.61 (5H, m); dC (62.5 MHz, CDCl3) 22.1, 25.4,
60.9, 63.0, 126.0, 127.7, 127.9, 128.1, 128.2, 128.6, 129.8,
135.0, 137.5, 138.8.
Oxone (2 equiv with respect to alkene) was added with stir-
ring to an ice-cooled solution of sodium carbonate (4 equiv)
in water (12 ml per 1.50 g of sodium carbonate) and the
resulting foaming solution was stirred for 5–10 min, until
most of the initial effervescence subsided. A solution of the
iminium salt (10 mol % with respect to alkene) in acetonitrile
(6 ml per 1.50 g of sodium carbonate used) was added, fol-
lowed by a solution of the alkene in acetonitrile (6 ml per
1.50 g of sodium carbonate used). The suspension was stirred
with ice bath cooling until the substrate was completely con-
sumed according to TLC. The reaction mixture was diluted
with ice-cooled diethyl ether (20 ml per 100 mg substrate)
and the same volume of water was added immediately. The
aqueous phase was washed four times with diethyl ether
and the combined organic solutions washed with brine and
dried (MgSO4). Filtration and removal of the solvents gave
a yellow or light brown residue, which was purified by
column chromatography, typically using ethyl acetate/light
petroleum (1:99), to provide the pure epoxide.
3.5.5. trans-Stilbene oxide.13 Colourless solid; mp 66–
67 ꢀC, (lit.14 mp 61–63 ꢀC); nmax(Nujol)/cmꢁ1 1601, 1492,
1284, 1176, 1157, 1094, 1072, 1025; dH (400 MHz,
CDCl3) 3.84 (2H, s), 7.28—7.37 (10H m); dC (100 MHz,
CDCl3) 63.3, 126.0, 128.6, 129.3, 137.6.
3.5.6. Indene oxide.9 Colourless oil; nmax(neat)/cmꢁ1 3027,
2917, 1482, 1464, 1390, 1372, 1232, 1183, 1142, 829, 758,
745, 723; dH (250 MHz, CDCl3) 2.97 (1H, dd, J 2.7,
18.1 Hz), 3.21 (1H, d, J 17.6 Hz), 4.13 (1H, t, J 3.0 Hz),
4.26 (1H, dd, J 1.1, 2.8 Hz), 7.14–7.29 (3H, m), 7.49 (1H,
dd, J 1.7, 6.6 Hz); dC (100 MHz, CDCl3) 34.6, 57.6, 59.1,
125.2, 126.1, 126.3, 128.6, 141.0, 143.6.
3.5. General procedure for the formation of racemic
epoxides
3.5.7. 1,2-Dihydronaphthylene oxide.13 Colourless oil;
nmax(neat)/cmꢁ1 3059, 3028, 2930, 2850, 1602, 1493,
1316, 1129, 1088, 1030, 964; dH (400 MHz, CDCl3) 1.60–
1.70 (1H, m), 2.31–2.39 (1H, m), 2.45 (1H, dd, J 15.6
5.6 Hz), 2.65–2.70 (1H, m), 3.65 (1H, t, J 4.0 Hz), 3.78
(1H, d, J 4.4 Hz), 7.01 (1H, d, J 7.2 Hz), 7.14–7.23 (2H,
m), 7.33 (1H, d, J 7.2 Hz); dC (100 MHz, CDCl3) 22.2,
24.8, 55.2, 55.5, 126.5, 128.8, 128.8, 129.9, 132.9, 137.1.
The alkene was dissolved in CH2Cl2 (10 ml/g) and the solu-
tion cooled using an ice bath. A solution of m-CPBA
(2 equiv) in CH2Cl2 (10 ml/g, pre-dried over MgSO4) was
added. The reaction was allowed to reach ambient tem-
perature and stirred until complete consumption of the sub-
strate was observed by TLC. Saturated aqueous NaHCO3
(10 ml/g) was added and the layers were separated. The
organic layer was washed with saturated aqueous NaOH
(1.0 M, 10 ml/g) and dried (MgSO4). The solvents were
removed under reduced pressure and the residue purified
by column chromatography, typically eluting with ethyl
acetate/light petroleum (1:99), to give the pure epoxide.
3.5.8. cis-b-Methylstyrene oxide.13 Colourless oil;
nmax(neat)/cmꢁ1 3061, 2994, 1604, 1496, 1450, 1258,
1149, 953, 853, 742, 700, 619; dH (250 MHz, CDCl3)
1.12, (3H, d, J 5.4 Hz), 3.32–3.40 (1H, m), 4.08 (1H, d,
J 4.3 Hz), 7.24–7.39 (5H, m); dC (62.5 MHz, CDCl3) 12.8,
55.4, 57.8, 126.9, 127.7, 128.3, 135.8.
3.5.1. trans-a-Methylstilbene oxide.9 Colourless oil;
nmax(neat)/cmꢁ1 3061, 1602, 1495, 1449, 1381, 1279, 1157,
3.5.9. cis-2,3-Epoxyheptene.15 Colourless oil, 68% yield;
nmax(neat)/cmꢁ1 2959, 2930, 2874, 1390, 1259, 1218,

P. C. B. Page et al. / Tetrahedron 62 (2006) 6607–6613
6613
Tetrahedron: Asymmetry 2004, 15, 2499; Aggarwal, V. K.;
Wang, M. F. J. Chem. Soc., Chem. Commun. 1996, 191;
Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou, K. Synlett
1997, 1075; Armstrong, A.; Ahmed, G.; Garnett, I.;
Gioacolou, K.; Wailes, J. S. Tetrahedron 1999, 55, 2341;
Minakata, S.; Takemiya, A.; Nakamura, K.; Ryu, I.;
Komatsu, M. Synlett 2000, 1810; Wong, M.-K.; Ho, L.-M.;
Zheng, Y.-S.; Ho, C.-Y.; Yang, D. Org. Lett. 2001, 16, 2587;
Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002,
1151, 1114, 1032, 752; dH (400 MHz, CDCl3) 0.93 (3H, t,
J 8.0 Hz), 1.20 (3H, d, J 4.0 Hz), 1.32–1.50 (6H, m), 2.86–
2.91 (1H, m), 2.99–3.06 (1H, m); dC (100 MHz, CDCl3)
12.2, 13.0, 21.6, 26.2, 27.6, 51.6, 56.1.
3.5.10. 6-Cyanobenzopyran oxide.16 Colourless oil, which
solidified; nmax(film)/cmꢁ1 3089, 3038, 2979, 2934, 2226,
1615, 1579, 1490, 1346, 1279, 1157, 1107, 1046, 955; dH
(400 MHz, CDCl3) 1.22 (3H, s), 1.52 (3H, s), 3.47 (1H, d,
J 4.4 Hz), 3.86 (1H, d, J 4.4 Hz), 6.79 (1H, d, J 8.4 Hz),
7.45 (1H, dd, J 2.0, 8.4 Hz), 7.58 (1H, d, J 2.4 Hz); dC
(100 MHz, CDCl3) 23.4, 25.9, 50.3, 62.7, 75.1, 104.7,
119.0, 119.2, 121.5, 134.2, 134.8, 156.87.
´
43, 8257; Vachon, J.; Perollier, C.; Monchaud, D.; Marsol,
C.; Ditrich, K.; Lacour, J. J. Org. Chem. 2005, 70, 5903.
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J. Chem. Soc., Perkin Trans. 1 2000, 3325.
4. Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.;
Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z.
J. Org. Chem. 2001, 66, 6926; Page, P. C. B.; Rassias, G. A.;
Barros, D.; Ardakani, A.; Bethell, D.; Merrifield, E. Synlett
2002, 580; Page, P. C. B.; Buckley, B. R.; Rassias, G. A.;
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Lett. 2005, 7, 375.
6. Page, P. C. B.; Buckley, B. R.; Blacker, A. J. Org. Lett. 2004, 6,
1543.
3.5.11. 6-Nitrobenzopyran oxide.16 Colourless oil, which
solidified; nmax(film)/cmꢁ13075, 2926, 2850, 1621, 1590,
1518, 1344, 1281, 1209, 1160, 1088, 955; dH (400 MHz,
CDCl3) 1.33 (3H, s), 1.63 (3H, s), 3.57 (1H, dd, J 4.4 Hz),
4.00 (1H, d, J 4.4 Hz), 6.89 (1H, d, J 9.0 Hz), 8.15 (1H,
dd, J 2.8, 9.0 Hz), 8.30 (1H, d, J 2.8 Hz); dC (100 MHz,
CDCl3) 23.1, 25.5, 50.0, 62.1, 75.2, 118.5, 120.3, 125.8,
126.3, 141.5, 158.3.
3.5.12. 6-Chlorobenzopyran oxide.16 Colourless oil:
nmax(film)/cmꢁ13080, 2985, 2933, 1611, 1579, 1478, 1366,
1339, 1268, 1237, 1202, 1168, 1103, 1087, 1036, 954;
dH (400 MHz, CDCl3) 1.17 (3H, s), 1.50 (3H, s), 3.41
(1H, dd, J 4.4 Hz), 3.77 (1H, d, J 4.4 Hz), 6.67 (1H, d,
J 8.6 Hz), 7.11 (1H, dd, J 2.6, 8.6 Hz), 7.24 (1H, d,
J 2.6 Hz); dC (100 MHz, CDCl3) 22.5, 25.6, 50.4, 62.6,
73.4, 119.4, 121.6, 125.7, 129.2, 130.2, 151.2.
7. Page, P. C. B.; Barros, D.; Buckley, B. R.; Ardakani, A.;
Marples, B. A. J. Org. Chem. 2004, 69, 3595.
8. Campestrini, S.; Di Furia, G.; Labat, G.; Novello, F. J. Chem.
Soc., Perkin Trans. 1 1994, 2175.
9. Sasaki, H.; Irie, R.; Hamada, T.; Suzuki, K.; Katsuki, T.
Tetrahedron 1994, 50, 11827; Boyd, D. R.; Sharma, N. D.;
Bowers, N. I.; Goodrich, P. A.; Groocok, R. M. Tetrahedron:
Asymmetry 1996, 7, 1559; Sola, L.; Vidal-Ferran, A.;
Moyano, A.; Pericas, M. A.; Riera, A. Tetrahedron:
Asymmetry 1997, 8, 1559.
10. Fleiser, R.; Galle, D.; Braun, M. Liebigs Annalen 1997, 6,
1189.
Acknowledgements
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This investigation has enjoyed the support of the EPSRC and
NPIL Pharmaceuticals (UK) Ltd. We are also indebted to the
EPSRC Mass Spectrometry Unit, Swansea.
References and notes
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´