Asymmetric epoxidation using iminium salt organocatalysts featuring dynamically controlled atropoisomerism

Article abstract of DOI:10.1021/jo300915u

Introduction of a pseudoaxial substituent at a stereogenic center adjacent to the nitrogen atom in binaphthyl- and biphenyl-derived azepinium salt organocatalysts affords improved enantioselectivities and yields in the epoxidation of unfunctionalized alkenes. In the biphenyl-derived catalysts, the atropoisomerism at the biphenyl axis is controlled by the interaction of this substituent with the chiral substituent at nitrogen.

Full text of DOI:10.1021/jo300915u

Article
pubs.acs.org/joc
Asymmetric Epoxidation Using Iminium Salt Organocatalysts
Featuring Dynamically Controlled Atropoisomerism
Philip C. Bulman Page,*,† Christopher J. Bartlett,† Yohan Chan,† David Day,† Phillip Parker,‡
Benjamin R. Buckley,‡ Geracimos A. Rassias,§ Alexandra M. Z. Slawin,∥ Steven M. Allin,⊥ Jerome Lacour,#
́
̂
and Andre Pinto#
́
†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.
§GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
∥School of Chemistry, University of St. Andrews, Fife KY16 9ST, U.K.
⊥Department of Chemistry & Forensics, Nottingham Trent University, Clifton, Nottinghamshire SG5 5BG, U.K.
#Dep
artement de Chimie Organique, Universite de Geneve, quai Ernest Ansermet 30, CH-1211 Geneve 4, Switzerland
́
́
̀
̀
S
* Supporting Information
ABSTRACT: Introduction of a pseudoaxial substituent at a
stereogenic center adjacent to the nitrogen atom in
binaphthyl- and biphenyl-derived azepinium salt organo-
catalysts affords improved enantioselectivities and yields in
the epoxidation of unfunctionalized alkenes. In the biphenyl-
derived catalysts, the atropoisomerism at the biphenyl axis is
controlled by the interaction of this substituent with the chiral
substituent at nitrogen.
We were the first to report enantioselective iminium salt
epoxidation catalysts bearing an exocyclic chiral stereocontrol-
ling group as a substituent on the nitrogen atom, such as
dihydroisoquinolium salt 3,6 biphenylazepinium salts 4 and 5,7
and binaphthazepinium salt 6.8 High enantioselectivities are
observed with arylalkene substrates, suggesting an interaction
between the aryl unit of the substrate with the aryl groups of
the catalysts. In some cases, the corresponding amines may be
used as catalysts, generating the iminium species in situ.9 These
organocatalytic processes are typically driven using oxone as
stoicheiometric oxidant but can also be driven by hydrogen
peroxide,10 bleach,11 and even electrochemical methods.12 We
have also investigated the incorporation of simple chiral and
achiral N-alkyl substituents into the binaphthazepinium ring, as
in 7 and 8, respectively.13 Iminium salt catalysts containing a
chiral nitrogen substituent can give increased enantiocontrol
over those containing an achiral nitrogen substituent; in the
case of the binaphthyl-derived systems, matched and
mismatched effects are observed between the axial chirality of
the binaphthyl unit and the chirality of the nitrogen substituent.
In our hands, the dioxane core of (S,S)-(+)-acetonamine has
provided catalysts generating excellent yields and induction of
enantioselectivity in epoxidation reactions; this can be seen, for
example, in a comparison of biphenylazepinium salts 4 and 5,
INTRODUCTION
■
Epoxides are versatile building blocks widely used in synthesis.1
The past 30 years have seen the development of many
methodologies capable of efficient asymmetric epoxidation of
various types of alkene.2 Recently, asymmetric epoxidation
using organocatalysts has received increasing attention. Chiral
oxaziridines can be generated catalytically and are effective for
asymmetric sulfur oxidation but are not generally useful for
epoxidation.3 Dioxiranes such as 1,4 and oxaziridinium salts
such as 2, first reported by Lusinchi,5 have proven to be two of
the most effective types of organocatalyst for asymmetric
oxygen transfer to weakly nucleophilic substrates such as
unfunctionalized alkenes.
Received: May 5, 2012
© XXXX American Chemical Society
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which induce 29% and 60% ee respectively when using 1-
phenylcyclohexene as substrate under typical aqueous reaction
conditions using oxone as reoxidant.7 The effect of the
controlled axial chirality of the binaphthyl unit can be seen in
the epoxidation of the same substrate using catalyst 6, which
provides 91% ee.8
case, with diastereoisomeric ratios ranging from 5:1 to 11:1. We
believe that the new substituent groups occupy a pseudoaxial
position in each isomer,15 the major isomer having an R axial
chirality and the minor, S, so minimizing steric interaction with
the large nitrogen substituent, in common with other systems
of this type,16 and with the nearby proton at C-3 of the adjacent
aromatic ring, effects likely to be more pronounced for the
larger substituents. The 1H chemical shifts of the newly
introduced methyl groups in 11 appear at 0.68 and 0.41 ppm,
consistent with a pseudoaxial orientation.16 A double stereo-
chemical relay has thus taken place, where the chirality of the
nitrogen substituent has controlled the atropoisomerism of the
biphenyl axis, which has in turn controlled the stereochemistry
of addition and asymmetry of the new substituents.
The major diastereoisomers, in each case the first eluting
from silica gel chromatography, were treated with NBS to
generate the iminium bromide salts, which underwent ion-
exchange to generate the tetraphenyl borate iminium salts 15−
18 in good to excellent yields as single diastereoisomers
(Scheme 1). The new iminium double bonds are sited
exclusively in the azepinium ring on the opposite side of the
nitrogen atom from the newly introduced substituents, a result
of loss of the one remaining more exposed, kinetically reactive
pseudoaxial proton, again in common with other systems of this
type.16 It is thus the lesser substituted iminium bond
regioisomers that were obtained, with complete retention of
In considering further refinements to catalyst structure, we
conjectured that the introduction of a further substituent at the
methylene unit adjacent to the azepinium nitrogen atom in the
biphenyl- and binaphthyl- derived catalysts, as in 9 and 10,
might provide increased enantiocontrol in the epoxidation
process for two reasons. First, a substituent in this position was
expected to provide additional steric control over any process
occurring around the iminium double bond. Second, in the case
of the biphenyl-derived catalysts 9, the presence of a substituent
at this position was also expected to affect the equilibrium
position of the atropoisomerism around the biphenyl axis,
perhaps driving it exclusively toward one rotamer; this was
expected to influence the enantioselectivity in subsequent
epoxidation, particularly as the related but configurationally
stable binaphthyl unit exerts a very strong influence on
enantiocontrol.
1
stereochemistry at the α-position in each instance. The H
chemical shift of the methyl group of 15 appears at 0.98 ppm,
again as expected for a pseudoaxial orientation.16
A single-crystal X-ray structure of the methyl-substituted
iminium salt 15 (Figure 1) indeed shows that the new methyl
group occupies a pseudoaxial position, hindering the si face of
the iminium unit, and also shows the relationship between the
new asymmetric center (R) and the biphenyl axis (Rax).
Conformational control results from similar factors to those
operating in 11: avoidance of steric interaction between the
new substituent and the nitrogen substituent, and between the
new substituent and the hydrogen atom at the 3-position of the
adjacent aromatic ring. The stereochemistry of each of 16−18
was assigned by analogy with that of 15.
These new generation iminium salt catalysts were tested for
their ability to induce enantiocontrol in the asymmetric
epoxidation of 1-phenylcyclohex-1-ene using our standard
aqueous reaction conditions with Oxone (2 equiv) as
stoichiometric oxidant (water/acetonitrile (1:1), sodium
carbonate (4 equiv), catalyst (5 mol %), Oxone (2 equiv)),
and those inducing the highest enantiocontrol were then used
in the epoxidation of several representative alkenes (Table 1).17
We were very pleased to observe generally increased
enantiocontrol for the new generation catalysts, particularly
catalyst 15, containing an added methyl substituent and
inducing up to 82% ee and 100% conversion, and catalyst 18,
containing a benzyl substituent and giving up to 77% ee and
100% conversion.
In order to investigate further the proposition that it is the
atropoisomerism of the biphenyl axis that determines the
stereochemistry of introduction of the added substituents, and
to provide insight into the factors affecting the resulting
induced enantioselectivity, we next investigated the correspond-
ing binaphthyl-derived catalysts, which have a fixed axial
chirality. One of the most enantioselective iminium salt
catalysts reported to date is the binaphthyl-based iminium
salt catalyst 6,8 a “matched” enantioselectivity system again
RESULTS AND DISCUSSION
■
We chose for initial experimentation the (S,S)-acetonamine-
derived biphenyl iminium salt catalyst 5, which imparts good to
high levels of enantiocontrol in asymmetric epoxidation. At
−80 °C, four isomers can be seen in the NMR spectrum of 5,
corresponding to atropoisomerism about the biphenyl axis and
to rotation around the exocyclic C−N bond.14 We believe on
the basis of NOESY experiments that the two major isomers
correspond to a pair of isomers about the C−N bond, each
having the R axial conformation; the ratio of the Rax pair to the
Sax pair is then 89:11, and the ratio of the two pairs of observed
C−N rotamers 83:17. The analogous binaphthyl system (see
below) possesses a similar ratio of the two observed C−N
rotamers of 88:12.
Substituents were introduced by addition of Grignard
reagents (methyl, isopropyl, phenyl, benzyl) at −78 °C,
generating pairs of diastereoisomeric amines 11−14 in each
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Scheme 1.
0.12 ppm for 21, derived from 6), as expected for a pseudoaxial
orientation. Single-crystal X-ray analysis of 21 clearly shows the
expected pseudoaxial orientation of the methyl substituent and
the Rax axial chirality (Figure 2). Since both 21 and its Sax
diastereoisomer 22 incorporate the new methyl groups in a
pseudoaxial orientation, it is clear that the chirality of the N-
substituent plays little or no role in controlling the stereo-
chemistry of addition of the Grignard reagent.
Oxidation of the amines and isolation of the azepinium
tetrafluoroborate salts 26−30 were achieved as for the biphenyl
salts in 64−72% yields as single diastereoisomers. As expected,
the lesser substituted iminium bond regioisomers were
obtained, with complete retention of stereochemistry at the
α-position (Scheme 3). The chemical shifts of the newly
introduced methyl substituents appeared far upfield in each
case, again supporting a pseudoaxial orientation (e.g., 26: 0.15
ppm; 27: 0.75 ppm). Indeed, single crystal X-ray analysis of 27
clearly shows the axial orientation of the methyl substituent and
the Sax configuration of the binaphthyl unit (Figure 3).
Figure 1. Single-crystal X-ray structure of 15.
containing a nitrogen substituent derived from (S,S)-aceton-
amine, and having (Rax) axial chirality. For this study, we
decided to use two diastereoisomeric pairs of catalysts, our
(S,S)-acetonamine-derived binaphthylazepinium salts 6 and 19,
and the (S)- and (R)- 3,3-dimethylbutylamine-derived binaph-
thylazepinium salts 7 and 20,18 as well as the isopropylamine-
derived C2-symmetric catalyst 8.
Accordingly, we next introduced a methyl group substituent
into these catalysts using chemistry similar to that used for the
biphenyl series: The binaphthyl azepinium salts were treated
with methylmagnesium bromide at −78 °C, generating the
tertiary amines 21−25 in 68−99% yields. Unlike the biphenyl
systems, however, all of the additions were completely
diastereoselective (Scheme 2). The chemical shift of the
newly introduced methyl groups are all at very high field (e.g.,
C
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a
Table 1. Asymmetric Epoxidation of Alkenes Mediated by
Biphenyl Catalysts
Scheme 2
a
a
Reagents and conditions: (i) MeMgBr, THF, −78 °C to rt, 12 h.
a
Epoxidation conditions: iminium salt catalyst (5 mol %), Oxone (2
equiv), Na2CO3 (4 equiv), MeCN/H2O (1:1), 0 °C; 1−12 h.
b
Conversions were evaluated from the 1H NMR spectra by integration
c
of the alkene and epoxide signals. Absolute configurations of the
major enantiomers were determined by comparison of optical rotation
Figure 2. Single-crystal X-ray analysis of amine 21.
d
with those reported in the literature. ee was determined using chiral
e
stationary phase (CSP) GC. ee was determined using 1H NMR
spectroscopy in the presence of europium(III) tris [3-(heptafluor-
opropylhydroxymethylene)-(+)-camphorate] as chiral shift reagent. ee
was determined using CSP HPLC.
on both enantioselectivity and reactivity in the epoxidation
process. This suggests that the effect that the methyl group has
on reactivity and enantioselectivity may be manifested through
some interaction between itself and the chiral pendent amine, a
discussion of which is presented below.
We have also developed nonaqueous conditions for the use
of iminium salt catalysts,19 which have proved particularly
effective for epoxidation of cyclic cis-alkenes, and we have
reported highly enantioselective syntheses of levcromakalim,20
lomatin,21 and scuteflorin A22 using these conditions. Finally,
we tested the new substituted biphenyl catalysts under these
nonaqueous conditions and were again pleased to observe high
levels of enantioselectivity and higher catalyst reactivity in
several cases (Table 3).
f
The new salts were tested as catalysts in the epoxidation of a
range of alkenes. Table 2 provides a comparison of the new
methyl-substituted catalysts with their respective parent
catalysts.
In almost every case for the “matched” systems, incorpo-
ration of the methyl substituent into the catalyst structure
improved the levels of enantiocontrol imparted, in some cases
dramatically, while the levels of enantiocontrol decreased on
incorporation of the methyl substituent in the “mismatched”
system 19/27. The reactivity of the methyl-substituted catalysts
was, however, decreased; conversions were generally lower for
28/29 than their parent nonmethylated catalysts 7/20.
Interestingly, incorporation of the methyl substituent into the
C2-symmetric isopropyl-substituted pair 8/30 had little effect
Comparison with Table 1 shows that the biphenyl catalysts
generally show reduced reactivity under the nonaqueous
conditions, reaction times to completion are much increased,
and indeed the binaphthyl-derived catalysts are insufficiently
D
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a
Scheme 3
Table 2. Asymmetric Epoxidation of Alkenes Mediated by
Binaphthyl Catalysts
a
a
Reagents and conditions: (i) NBS (1.1 equiv), CH2Cl2, rt, 10 min;
NaBPh4, EtOH, 1 h.
a
Epoxidation conditions (6, 26, 19, 27, 8, 30): iminium salt catalyst (5
Figure 3. Single-crystal X-ray analysis of iminium salt 27.
mol %), Oxone (2 equiv), NaHCO3 (5 equiv), MeCN/H2O (1:1), 0
°C, 17 min to 13 h. Epoxidation conditions (20, 29, 7, 28): iminium
salt catalyst (5 mol %), Oxone (1 equiv), 18-crown-6 (2.5 mol %),
NaHCO3 (4 equiv), dichloromethane/H2O (3:2), 0 °C, 2 h.
reactive to be effective under these conditions, with no
observed conversion over 48 h.
b
Conversions were evaluated from the 1H NMR spectra by integration
There are a number of potential mechanisms by which the
introduction of the new substituents could affect the
enantioselectivity of the catalyzed epoxidation process.
In the case of the BINAP-based system, it has been suggested
that the dihedral angle of the BINAP system is one of the
controlling parameters determining enantioselectivity in
epoxidation using these catalyst types.18 Sandstrom has
shown that the λmax absorbance value of aromatic axially chiral
species is dependent on the dihedral angle.23 Examination of
the CD spectra of our catalysts, however, shows that the λmax
values are almost identical in all cases, suggesting that the
dihedral angle is the same for both the methylated species and
c
of alkene and epoxide signals. Enantiomeric excesses were determined
d
by chiral HPLC using a Chiracel OD-H column. Enantiomeric
excesses were determined by 1H NMR spectroscopy in the presence of
europium(III) tris [3-(heptafluoropropylhydroxymethylene)-(+)-cam-
e
phorate]. Absolute configurations of the major enantiomers were
determined by comparison of optical rotations with those reported in
the literature.
the parent catalysts or that this method is insufficiently sensitive
in our case. A change in the dihedral angle may therefore not be
responsible for the observed increased enantioselectivities of
the methylated catalysts.
E
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a
Table 3. Asymmetric Epoxidation of Alkenes Mediated by Biphenyl Catalysts under Nonaqueous Conditions.
a
b
Epoxidation conditions: iminium salt catalyst (10 mol %), TPPP (2 equiv), CHCl3, 0 °C. Conversions were evaluated from the 1H NMR spectra
c
d
by integration of the alkene and epoxide signals. ee was determined using chiral HPLC using a Chiracel OD-H column. Absolute configurations of
the major enantiomers were determined by comparison of optical rotation with those reported in the literature.
Generation of the purported oxaziridinium salt oxygen
transfer agents from the iminium salt catalysts could take
place at both faces of the iminium species, giving rise to
diastereoisomeric pairs of oxaziridinium salts, each isomer of a
pair potentially inducing different enantioselectivity from the
other, and at different rates.10 It is conceivable that the
introduction of the new substituents could alter the ratio of
these diastereoisomers and their reactivities by introducing
steric hindrance at one face, thus altering the overall observed
enantiocontrol. This effect on the ratio of diastereoisomers
generated, however, could only arise if diastereoisomeric pairs
of oxaziridinium salts are indeed generated from the parent
catalysts. We have shown in a simpler system that only one
diastereoisomer of the oxaziridinium salt is generated under the
reaction conditions used here; furthermore, Houk has shown
with a simpler N-Me system that the intermediate formed by
the addition to 31 by Oxone, leading to the formation of the
minor diastereoisomer 32, was 8.1 kcal mol−1 higher in energy
than the intermediate leading to the major diastereoisomer 33,
noting that the difference was due to steric repulsion between a
monoperoxysulfate oxygen atom and the arene hydrogen atom
at the 3 position (Scheme 4).24
that shown in 34, with the two indicated C−H bonds having a
syn-periplanar relationship, are favored. Introduction of the
methyl substituent significantly increases the proportion of
conformations close to that shown in 35, with the two indicated
C−H bonds having an anti-periplanar relationship (Figure 4,
Figure 4. Illustration of the syn- and anti-periplanar rotamers 34, 35.
Table 4. Ratios of Rotamers about the Exocyclic C−N Bond
for the Two Generations of Catalyst, Determined by NOESY
at −80 °C
syn-periplanar
anti-periplanar
6
88
60
12
40
28
39
0
Scheme 4
26
19
27
7
72
61
100
80
28
8
20
0
100
100
30
0
Although the barrier to rotation about the exocyclic C−N
bond of the catalysts is similar, at about 11−12 kcal mol−1 in
both the methylated and parent catalyst structures, as shown by
VT-NMR experiments, the introduction of the new sub-
stituents is likely to alter the relative population of rotamers,
and this could in turn affect the enantiocontrol in the catalyzed
epoxidation process.14 NOESY experiments performed at −80
°C suggest that in the parent systems conformations close to
Table 4). This arrangement would be expected to provide a less
reactive catalyst, as there is greater steric bulk around the site of
oxygen transfer (presumed to be on the opposite face from the
new methyl substituents).
This model may also explain why little difference in
enantioselectivity was observed between the two isopropyl-
amine-derived catalysts 8 and 30. In this case, there was no
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General Procedure for the Oxidation of Alkenes Using
Chiral Iminium Salts under Nonaqueous Conditions. Tetraphe-
nylphosphonium monoperoxysulfate (2 equiv) and the iminium salt
catalyst (10 mol %) were dissolved in chloroform (10 mL) at −30 °C.
The alkene substrate (1 equiv), dissolved in the minimum amount of
chloroform, was added slowly with stirring, and the mixture stirred
until the reaction was completion. Reaction progress was monitored
by thin-layer chromatography. When the reaction was complete,
diethyl ether (10 mL) was added. The mixture was filtered through
Celite and washed with diethyl ether (2 × 10 mL), and the solvents
were removed under reduced pressure. The crude product was purified
using column chromatography on silica gel (ethyl acetate/petroleum
ether/triethylamine).
General Procedure for the Addition of Grignard Reagents to
Biphenyl Azepinium Salts. The azepinium salt was dissolved in
anhydrous THF (30 mL per g of salt) under a nitrogen atmosphere
and cooled to −78 °C. The Grignard reagent (10 equiv) was added
dropwise over 5 min to the cold solution. The reaction mixture was
stirred and allowed to reach ambient temperature over 2 h, cooled to 0
°C, and quenched with a saturated solution of ammonium chloride (2
mL per g of salt). The solvents were then removed under reduced
pressure, and the residue was dissolved in dichloromethane (20 mL
per g of salt). The mixture was washed twice with water, once with
saturated brine, and dried over MgSO4. The solution was filtered and
silica gel added, and the solvent was removed under reduced pressure.
The crude reaction mixture was purified by column chromatography
on silica gel using ethyl acetate/petrol/triethylamine to yield the
desired amine.
General Procedure for the Synthesis of Substituted
Biphenyl Azepinium Tetraphenylborate Salts. A solution of N-
bromosuccinimide (1.2 equiv) in CH2Cl2 (15 mL per g of NBS) was
added to a solution of the amine in CH2Cl2 (15 mL per g of amine)
and the reaction mixture heated under reflux for 2 h, allowed to cool to
ambient temperature, extracted with water and saturated brine, and
dried over MgSO4. The solvent was removed under reduced pressure.
The residue was then dissolved in ethanol and a solution of sodium
tetraphenylborate (1 equiv) dissolved in the minimal amount of
acetonitrile was added. The reaction mixture was stirred over 10 min,
forming a yellow precipitate. The precipitate was collected by filtration
and washed with cold ethanol to yield the product as a yellow
crystalline solid.
difference between the rotameric ratio, with both catalysts
entirely favoring the syn-periplanar rotamers.
CONCLUSIONS
■
Stereocontrolled introduction of a substituent at a carbon atom
adjacent to the nitrogen atom in binaphthyl- and biphenyl-
derived azepinium salts affords new organocatalysts for
asymmetric epoxidation, offering considerably improved
enantioselectivities in many cases. The new substituent
occupies a pseudoaxial position, and in the biphenyl-derived
catalysts controls both the atropoisomerism at the biphenyl axis
and the regiochemistry of introduction of the iminium double
bond. We provide evidence to show that in the instances where
the methyl substituent affects the reactivity and enantiocontrol
demonstrated in the epoxidation process, it is by altering the
ratio of sp2N−sp3C rotamers.
EXPERIMENTAL SECTION
■
General Experimental Details. Infrared spectra were acquired as
nujol mulls or as thin films of their solution in dichloromethane on
sodium chloride plates. Liquid samples were run neat.
1H and 13C NMR spectra were measured respectively at 400.13 and
100.62 MHz, or at 300.05 and 75.45 MHz, respectively. The solvent
used for NMR spectroscopy was deuteriated chloroform unless stated
otherwise, using tetramethylsilane as the internal reference. Chemical
shifts are given in parts per million (ppm) and J values are given in
hertz (Hz).
Optical rotation values were measured with instruments operating
at λ = 589 nm, corresponding to the sodium D line at the temperatures
indicated. The solvents used for these measurements were of
spectrophotometric grade. The solutions for these measurements
were prepared in volumetric flasks for maximum accuracy of the
volume of solvent used.
Enantiomeric excesses were determined by either chiral shift proton
NMR experiments, chiral gas chromatography flame ionization (GC−
FID), or chiral high-performance liquid chromatography (chiral
HPLC).
The chiral shift proton nuclear magnetic resonance spectra were
recorded in deuteriated chloroform on an instrument operating at
400.13 MHz, in the presence of europium(III) tris [3-(heptafluor-
opropylhydroxymethylene)-(+)-camphorate], [(+)-Eu(hfc)3], as the
chiral shift reagent and tetramethylsilane as the internal standard.
The chiral columns used for the determination of enantiomeric
excesses (ee) of nonracemic mixtures by chiral HPLC were Chiralcel
OD-H and Eurocel 01-5 μm, operated on a Hitachi Elite LaChrome
2000 series instrument. Solvents used (hexane and 2-propanol) were
of HPLC grade.
Reactions requiring anhydrous conditions were carried out under a
nitrogen atmosphere unless otherwise stated, using glassware dried for
16 h at 150 °C. Reaction solvents were obtained commercially dry,
except for the following 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.
General Procedure for the Oxidation of Alkenes Using
Chiral Iminium Salts under Aqueous Conditions. Sodium
carbonate (4.0 equiv) was dissolved in water (1 mL) and acetonitrile
(1 mL), and the suspension cooled to 0 °C. Oxone (2.0 equiv) was
added and the mixture stirred for 10 min. The iminium salt catalyst (5
mol %) was added and the mixture stirred for a further 10 min. The
alkene substrate (1 equiv) was added and the reaction progress
followed using thin-layer chromatography. When the reaction was
complete, diethyl ether (20 mL) was added. The mixture was washed
twice with water and once with saturated brine and dried over MgSO4.
The solvents were removed under reduced pressure. The crude
product was purified using column chromatography on silica gel (ethyl
acetate/petroleum ether/triethylamine).
6-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-methyl-6,7-di-
hydro-5H-dibenzo[c,e]azepine 11a and 11b. Prepared according
to the general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-dioxan-5-
yl)-5H-dibenzo[c,e]azepinium tetraphenylborate 5 (1.0 g, 1.42 mmol)
and methylmagnesium bromide (4.7 mL, 14.20 mmol, 10 equiv). The
crude mixture was purified by column chromatography using 96:1:3
petroleum ether 40−60/ethyl acetate/triethylamine as eluent to give
the desired compound as a pair of diastereoisomers 11a and 11b.
First eluting diastereoisomer (major) 11a: colorless solid (0.36 g,
63%); νmax(film) /cm−1 3413, 3062, 3025, 2987, 2927, 2859, 2775,
2358, 1956, 1604, 1479, 1449, 1377, 1263, 1238, 1196, 1147, 1084,
956, 940, 852, 803, 755, 736, 695; [α]20 +30.3° (c 0.30, CHCl3); δH
D
(400 MHz; CDCl3 55 °C) 0.68 (3 H, d, J 7.0 Hz), 1.64 (3 H, s), 1.69
(3 H, s), 3.19 (1 H, q, J 4.1 Hz), 3.79 (2 H, s), 4.20 (1 H, dd, J 2.4 and
12.4 Hz), 4.32 (2 H, dd, J 4.8 and 12.3 Hz), 5.31 (1 H, s), 7.18−7.14
(2 H, m), 7.36−7.29 (3 H, m), 7.45−7.37 (5 H, m), 7.49 (1 H, dd, J
1.4 and 7.6 Hz), 7.53 (2 H, d, J 7.3 Hz); δC (100 MHz; CDCl3 55 °C)
19.6, 21.2, 29.1, 53.7, 58.6, 58.8, 63.2, 74.4, 99.4, 126.3, 126.6, 127.0,
127.1, 127.4, 127.6, 127.7, 127.8, 128.4, 128.5, 128.9, 138.1, 139.5,
140.4, 141.3, 141.4; m/z found (ESI) for [M]+ 398.2168,
[C27H29NO2]+ requires 399.2198.
Second eluting diastereoisomer (minor) 11b: yellow oil (65 mg,
11%); νmax(film) /cm−1 2982, 2922, 2854, 1449, 1379, 1197, 1079,
854, 755, 698; [α]20D +69.0° (c 1.1, CHCl3); δH (400 MHz; CDCl3, 50
°C) 0.41 (3 H, d, J 7 Hz), 1.49 (3 H, s), 1.53 (3 H, s), 3.10 (1 H, q, J 2
Hz), 3.60 (1 H, d, J 12 Hz), 3.76 (1 H, q, J 7 Hz), 3.94 (1 H, d, J 12
Hz), 4.23 (2 H, dq, J 4 and 12 Hz), 5.26 (1 H, d, J 4 Hz), 6.92 (1 H, d,
J 7 Hz), 7.14−7.30 (5 H, m), 7.31−7.36 (5 H, m), 7.42 (1 H, dd, J 2
and 8 Hz), 7.50 (2 H, dd, J 1 and 7 Hz); δC (100 MHz; CDCl3, 50 °C)
G
dx.doi.org/10.1021/jo300915u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
19.6, 23.5, 29.1, 51.2, 62.3, 62.6, 65.6, 73.9, 99.4, 126.2, 126.7, 126.8,
127.3, 127.4, 127.60, 127.63, 128.0, 128.9, 129.4, 129.5, 138.0, 139.3,
140.1, 141.2, 141.5; m/z found (ESI) for [M + H]+ 400.2267,
[C27H30NO2]+ requires 400.2277.
Second eluting diastereoisomer (minor) 14b: yellow oil (0.045 g,
13%); νmax(film)/cm−1 3062, 3026, 2990, 2921, 1603, 1496, 1450,
1380, 1199, 1080, 909, 756, 736, 698; [α]20 +89 (c 1.2, CHCl3); δH
D
(400 MHz; CDCl3) 1.47 (3 H, s, C7H3), 1.50 (3 H, s, C8H3), 1.76 (1
H, dd, J 8 and 12 Hz, C11HH), 1.99 (1 H, dd, J 8 and 12 Hz, C11HH),
3.09 (1 H, q, J 4 Hz, NC5H), 3.58 (1 H, d, J 12 Hz, NC10HH), 3.88 (1
H, dd, J 6.4 and 8.8 Hz, NC10HH), 4.03 (1 H, d, J 12 Hz, OC4HH),
4.24 (2 H, d, J 4 Hz, OC4HH), 5.23 (1 H, d, J 4 Hz, OC6HPh), 6.46−
6.52 (2 H, m Ar−CH), 6.90 (2 H, t, J 8 Hz, Ar-CH), 6.95−7.01 (3 H,
m, Ar-CH), 7.14 (1 H, td, J 1.3 and 7.5 Hz, Ar-CH), 7.18−7.26 (2 H,
m, Ar-CH), 7.27−7.36 (4 H, m, Ar-CH), 7.38−7.44 (4 H, d, J 8 Hz,
Ar-H); δC (100 MHz; CDCl3,) 19.6, 29.1, 44.3, 51.3, 62.9, 63.2, 73.7,
73.8, 99.4, 125.5, 126.2, 126.8, 127.0, 127.7, 127.82, 127.84, 127.86,
128.8, 129.1, 129.1, 129.6, 131.0, 137.8, 139.2, 139.3, 140.3, 141.5. m/z
found (ESI) for [M + H]+ 476.2573, [C33H34NO2]+ requires
476.2590.
6-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-isopropyl-6,7-
dihydro-5H-dibenzo[c,e]azepine 12. Prepared according to the
general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl)-5H-
dibenzo[c,e]azepinium tetraphenylborate 5 (0.50 g, 0.71 mmol) and
isopropylmagnesium chloride (2 M in THF, 3.6 mL, 7.10 mmol, 10
equiv) The crude reaction mixture was purified by column
chromatography using 96:1:3 petroleum ether 40−60/ethyl acetate/
/triethylamine as eluent to give the desired amine (0.22 g, 72%);
νmax(film) /cm−1 3359, 3060, 2957, 2920, 2855, 2358, 2336, 1726,
1711, 1692, 1661, 1608, 1551, 1535, 1514, 1449, 1378, 1260, 1197,
1080, 850, 800, 754, 697. [α]20 +98.3° (c 0.96, CHCl3). δH (400
D
MHz; CDCl3) 0.02 (3 H, d, J 6 Hz, 0.57−0.68 (1 H, m), 0.73 (3 H, d,
J 6 Hz), 1.54 (3 H, s), 1.59 (3 H, s), 2.97−3.02 (1 H, m), 3.28 (1 H, d,
J 10 Hz), 3.57 (1 H, d, J 12 Hz), 4.19 (1 H, d, J 12 Hz), 4.34 (1 H, d, J
12 Hz), 4.43 (1 H, dd, J 12, 4 Hz), 5.19 (1 H, d, J 3 Hz), 6.23 (1 H, d,
J 7 Hz), 7.00 (1 H, t, J 7 Hz), 7.14 (1 H, d, J 7.2 Hz), 7.18−7.33 (9 H,
m), 7.36−7.42 (2 H, m). δC (100 MHz; CDCl3) 19.3, 20.3, 21.1, 28.8,
34.4, 52.8, 63.4, 66.5, 75.4, 76.2, 99.6, 126.5, 126.7, 126.8, 127.0, 127.1,
127.4, 127.5, 127.9, 128.3, 128.7, 131.4, 138.2, 138.5, 139.2, 140.5,
141.6; m/z found (ESI) for [M − H]+ 426.2439; [C29H32NO2]+
requires 426.2433.
6-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-methyl-5H-
dibenzo[c,e]azepinium Tetraphenylborate 15. Prepared accord-
ing to the general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-
dioxan-5-yl)-5-methyl-6,7-dihydro-5H-dibenzo[c,e]azepine 11a (0.16
g, 0.40 mmol), N-bromosuccinimide (0.09 g, 0.48 mmol, 1.2 equiv),
and sodium tetraphenylborate (0.14 g, 0.40 mmol, 1 equiv) to give the
desired tetraphenylborate azepinium salt as a yellow powder (0.20 g,
68%): νmax(film)/cm−1 3054, 3002, 2884, 2160, 1629, 1386, 1201,
1109, 735, 704; [α]20 −62.9 (c 0.96, CHCl3); δH (400 MHz;
D
6-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-phenyl-6,7-di-
hydro-5H-dibenzo[c,e]azepine 13. Prepared according to the
general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl)-
5H-dibenzo[c,e]azepinium tetraphenylborate 5 (0.50 g, 0.71 mmol)
and phenylmagnesium chloride (3.2 mL, 7.10 mmol, 10 equiv). The
crude reaction mixture was purified by column chromatography using
96:1:3 petroleum ether 40−60/ethyl acetate/triethylamine as eluent to
give the desired amine (0.28 g, 85%): νmax(film)/cm−1 3343, 2987,
2988, 2854, 2366, 1656, 1638, 1598, 1479, 1444, 1371, 1343, 1322,
1265, 1240, 1197, 1176, 1150, 1136, 1801, 1064, 1026, 1008, 955, 921,
876, 852, 780, 763, 733, 697, 657, 610; [α]20D +46 (c 1.03, CHCl3); δH
(400 MHz; CDCl3) 1.58 (3 H, s), 1.64 (3 H, s), 3.08 (1 H, q, J 3 Hz),
3.80 (1 H, d, J 12 Hz), 4.07 (1 H, d, J 12 Hz), 4.33 (2 H, d. J 2 Hz),
5.28 (1 H, d, J 3 Hz), 5.49 (1 H, s), 6.29 (2 H, d, J 7 Hz), 6.62 (2 H, t,
J 8 Hz), 6.70 (1 H, t, J 7 Hz), 6.88 (1 H, d, J 7 Hz), 7.00 (1 H, dt, J 8, 1
Hz), 7.10 (1 H, dt, J 8, 1 Hz), 7.15 (1 H, dd, J 7, 1 Hz), 7.20−7.38 (9
H, m); δC (100 MHz; CDCl3) 18.9, 29.5, 54.1, 59.9, 63.4, 67.9, 74.5,
99.4, 124.5, 126.1, 126.4, 126.5, 126.8, 127.1, 127.3, 127.37, 127.39,
128.2, 128.6, 129.1, 130.9, 137.7, 139.7, 140.4, 140.8, 145.5; m/z found
(ESI) for [M]+ 461.2355, [C32H31NO2]+ requires 461.2355.
(CD3)2SO, 80 °C) 0.98 (3 H, d, J 7 Hz), 1.73 (3 H, s), 1.76 (3 H, s),
4.45 (1 H, dd, J 14, 1 Hz), 4.77 (1 H, dd, J 14, 3 Hz), 4.87 (1 H, dd, J
3, 1 Hz), 5.77 (1 H, q, J 7 Hz), 5.87 (1 H, d, J 3 Hz), 6.79−6.85 (4 H,
m), 6.95 (8 H, t, J 8 Hz), 7.08−7.15 (3 H, m), 7.23−7.32 (11 H, m),
7.52 (2 H, sextuplet, J 7, 2 Hz), 7.66−7.74 (2 H, m), 7.81 (1 H, dd, J 8,
1 Hz), 7.93 (1 H, dt, J 7, 2 Hz), 7.96 (1 H, dd, J 8, 1 Hz), 9.33 (1 H,
s); δC (100 MHz; (CD3)2SO) 14.8, 18.5, 29.2, 54.8, 62.1, 67.2, 70.2,
100.5, 121.6, 125.0, 125.3, 125.38, 125.42, 125.5, 128.0, 128.4, 128.8,
129.0, 129.6, 129.9, 130.4, 130.6, 134.1, 135.1, 135.7, 136.0, 136.6,
137.5, 140.9, 162.6, 163.3, 163.9, 164.6, 170.4; m/z found (ESI) for
[iminium cation]+ 398.2115, [C27H28NO2]+ requires 398.2120.
6-(2,2-Dimethyl-4-phenyl-[1,3]dioxan-5-yl)-5-isopropyl-5H-
dibenzo[c,e]azepinium Tetraphenylborate 16. Prepared accord-
ing to the general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-
dioxan-5-yl)-5-isopropyl-6,7-dihydro-5H-dibenzo[c,e]azepine 12 (0.15
g, 0.35 mmol), N-bromosuccinimide (0.08 g, 0.42 mmol, 1.2 equiv),
and sodium tetraphenylborate (0.12 g, 0.35 mmol, 1 equiv) to give the
desired tetraphenylborate azepinium salt as a yellow powder (0.22 g,
83%): νmax(film) /cm−1 3385, 2964, 2926, 2359, 2339, 1714, 1636,
1557, 1455, 1385, 1201, 1079, 960, 841, 763, 752, 700, 667; [α]20
D
6-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-benzyl-6,7-di-
hydro-5H-dibenzo[c,e]azepine 14a and 14b. Prepared according
to the general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-dioxan-5-
yl)-5H-dibenzo[c,e]azepinium tetraphenylborate 5 (0.50 g, 0.71
mmol) and benzylmagnesium chloride (2.0 M in THF, 3.5 mL, 7.10
mmol, 10 equiv). The crude mixture was purified by column
chromatography using 96:1:3 petroleum ether 40−60/ethyl acetate/
triethylamine as eluent to give the desired compound as a pair of
diastereoisomers 14a and 14b.
First eluting diastereoisomer (major) 14a: colorless solid (0.21 g,
0.45 mmol, 60%): νmax(film)/cm−1 3414, 3060, 3024, 2989, 2935,
2856, 2359, 2339, 1602, 1495, 1481, 1450, 1379, 1348, 1309, 1263,
1237, 1198, 1177, 1147, 1080, 1029, 952, 852, 800, 778, 755, 736, 698,
668; [α]20D −11.8 (c 1.02, CHCl3); δH (400 MHz; CDCl3 55 °C) 1.63
(3 H, s), 1.72 (3 H, s), 1.89−1.83 (1 H, m), 2.20 (1 H, dd, J 5.6 and
12.8 Hz), 3.00 (1 H, s), 3.78 (1 H, d, J 11.2 Hz), 3.94 (1 H, d, J 11.2
Hz), 4.17 (1 H, d, J 12.4 Hz), 4.24 (1 H, dd, J 4.4 and 12.4 Hz), 4.53
(1 H, dd, J 6.0 and 9.6 Hz), 5.28 (1 H, d, J 3.2 Hz), 6.63 (1 H, d, J 7.2
Hz), 6.68 (2 H, d, J 7.6 Hz), 7.01−7.09 (4 H, m), 7.26−7.34 (3 H, m),
7.35−7.40 (3 H, m), 7.43−7.47 (2 H, m), 7.52−7.54 (3 H, m); δC
(100 MHz; CDCl3 55 °C) 19.4, 29.4, 43.0, 54.2, 60.9, 63.8, 68.3, 74.3,
99.5, 125.3, 126.2, 126.8, 127.1, 127.1, 127.4, 127.6, 127.8, 127.9,
128.0, 128.2, 129.18, 129.21, 130.9, 137.9, 138.8, 139.0, 140.4, 141.6.
m/z found (ESI) for [M − H]+ 474.2426, [C33H32NO2]+ requires
474.2433.
−8.1 (c 0.64, CHCl3); δH (400 MHz; (CD3)2SO, 80 °C) 0.44 (3 H, d,
J 6 Hz), 0.99 (3 H, d, J 6 Hz), 1.47−1.56 (1 H, m), 1.69 (3 H, s), 1.70
(3 H, s), 4.62 (1 H, d, J 14 Hz), 4.76 (1 H, dd, J 14, 3 Hz), 4.81−4.83
(1 H, m), 5.83 (1 H, d, J 2 Hz), 6.75−6.83 (5 H, m), 6.89 (1 H, t, J 7
Hz), 6.92 (9 H, t, J 7 Hz), 7.19−7.26 (8 H, m), 7.38 (2 H, t, J 7 Hz),
7.44−7.50 (2 H, m), 7.58 (1 H, d, J 8 Hz), 7.63−7.69 (1 H, m), 7.75−
7.79 (1 H, m), 7.96 (2 H, d, J 4 Hz), 8.11 (1 H, d, J, 8 Hz), 9.63 (1 H,
s); δC (100 MHz; (CD3)2SO) 18.7, 19.2, 19.4, 26.2, 29.0, 61.5, 68.0,
70.7, 80.1, 100.9, 115.4, 121.7, 124.7, 125.1, 125.40, 125.43, 125.47,
125.51, 126.9, 128.0, 128.1, 128.9, 129.1, 129.6, 129.7, 130.3, 130.4,
130.6, 133.2, 135.3, 135.4, 135.8, 136.2, 141.2, 162.6, 163.3, 164.0,
164.6, 169.3; m/z found (ESI) for [iminium cation]+ 426.2438,
[C29H32NO2]+ requires 426.2433.
6-(2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-phenyl-5H-
dibenzo[c,e]azepinium Tetraphenylborate 17. Prepared accord-
ing to the general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-
dioxan-5-yl)-5-phenyl-6,7-dihydro-5H-dibenzo[c,e]azepine 13 (0.14 g,
0.30 mmol), N-bromosuccinimide (0.07 g, 0.36 mmol, 1.2 equiv), and
sodium tetraphenylborate (0.10 g, 0.30 mmol, 1 equiv) to yield the
desired tetraphenylborate azepinium salt as a yellow powder (0.20 g,
86%): νmax(film) /cm−1 3057, 3024, 2921, 2360, 1628, 1595, 1448,
1260, 1086, 1027, 800, 756, 698; [α]20 −21.2 (c 0.98, CHCl3); δH
D
(400 MHz; (CD3)2SO, 80 °C) 1.77 (3 H, s, 1.88 (3 H, s), 4.66 (1 H,
d, J 14 Hz), 4.88 (1 H, dd, J 14, 3 Hz), 5.11 (1 H, s), 5.93 (1 H, d, J 2
Hz), 6.48−6.54 (2 H, m), 6.80 (3 H, t, J 7 Hz), 6.93 (11 H, t, J 7 Hz),
H
dx.doi.org/10.1021/jo300915u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
6.98−7.03 (3 H, m), 7.08 (2 H, d, J 7 Hz), 7.20−7.26 (8 H, m), 7.46−
7.53 (2 H, m), 7.56−7.69 (7 H, m), 7.88 (1 H, d, J 8 Hz), 9.66 (1 H,
s); δC (100 MHz; (CD3)2SO) 18.7, 29.2, 60.9, 66.8, 70.3, 73.0, 100.1,
101.1, 115.3, 121.6, 124.4, 125.2, 125.36, 125.40, 125.43, 125.5, 127.8,
127.9, 128.6, 129.1, 129.2, 129.5, 130.5, 130.6, 130.7, 133.2, 134.76,
134.82, 135.4, 135.7, 136.27, 136.3, 140.8, 162.6, 163.2, 163.9, 164.6,
170.7; m/z found (ESI) for [iminium cation]+ 460.2271,
[C32H30NO2]+ requires 460.2276.
Hz), 3.97 (1 H, d, J = 12.4 Hz), 4.19 (1 H, dd, J 12.4 Hz, 3.6 Hz), 4.44
(1 H, q, J 6.8 Hz), 5.12 (1 H, s), 7.06−7.33 (13 H, m), 7.72−7.80 (4
H, m); δC (75 MHz; CDCl3) 19.2, 21.1, 29.3, 54.1, 59.9, 60.1, 63.9,
72.3, 99.4, 125.09, 125.14, 125.3, 125.6, 126.3, 126.7, 127.4, 127.5,
127.6, 127.8, 127.9, 128.2, 128.4, 128.6, 128.9, 131.9, 132.0, 132.6,
132.8, 133.1, 135.0, 136.4, 140.0, 140.3; m/z found (ESI) for [M +
H]+ 500.2576, [C35H34NO2]+ requires 500.2584.
(Sax)-4-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-3-
methyl-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepine 22.
Prepared according to the general procedure from (Sax)-N-[(4S,5S)-
5-(4-phenyl-2,2-dimethyl-1,3-dioxanyl)]-7H-dinaphtho[2,1-c;1′,2′-e]-
azepinium tetraphenylborate 19 (390 mg, 0.49 mmol) and isolated as a
5-Benzyl-6-(2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl)-5-ben-
zyl-5H-dibenzo[c,e]azepinium Tetraphenylborate 18. Prepared
according to the general procedure from 6-(2,2-dimethyl-4-phenyl-1,3-
dioxan-5-yl)-5-phenyl-6,7-dihydro-5H-dibenzo[c,e]azepine 14a (0.17
g, 0.35 mmol), N-bromosuccinimide (0.08 g, 0.43 mmol, 1.2 equiv,)
and sodium tetraphenylborate (0.12 g, 0.35 mmol, 1 equiv) to yield
the desired tetraphenylborate azepinium salt as a yellow powder (0.24
g, 84%): νmax(film) /cm−1 3372, 2960, 2359, 1708, 1639, 1619, 1448,
colorless foam (210 mg, 78%): [α]20 +227.1 (c 0.93, acetone); νmax
D
(neat)/cm−1 2991, 2920, 1714, 1596, 1498, 1449, 1378, 1221, 1197,
1079, 1014, 854, 819, 768, 752, 698; δH (400 MHz; acetone-D6) 0.15
(3 H, d, J 7.1 Hz), 1.38 (3 H, s), 1.51 (3 H, s), 3.28 (1 H, m), 3.55 (1
H, d, J 11.4 Hz), 4.00- 4.19 (2 H, m), 4.26 (1 H, d, J 11.4 Hz), 4.37 (1
H, dd, J 12.4, 3.5 Hz), 5.38 (1 H, d, J 4.0 Hz), 7.09 (1 H, d, J 8.3 Hz),
7.17−7.29 (4 H, m), 7.33−7.41 (4 H, m), 7.45 (1 H, ddt, J 8.7, 6.7, 1.1
Hz), 7.57−7.61 (3 H, m), 7.78 (1 H, d, J 8.3 Hz), 7.90 (1 H, d, J 8.3
Hz), 8.00 (1 H, d, J 8.2 Hz), 8.04 (1 H, d, J 8.3 Hz); δC (75 MHz;
acetone-D6) 19.3, 22.78, 28.83, 52.1, 62.89, 63.93, 66.8, 74.3, 99.6,
126.1, 126.4, 126.5, 126.6, 126.9, 127.2, 127.8, 128.1, 128.3, 129.1,
129.2, 129.3, 129.9, 132.7, 133.0, 133.7, 133.9, 134.0, 135.7, 137.5,
140.8, 141.7; m/z found (ESI) for [M + H]+ 500.2577, [C35H34NO2]+
requires 500.2584.
1383, 1260, 1201, 1083, 1027, 799, 751, 700. [α]20 −18.5 (c 1.06,
D
CHCl3); δH (400 MHz; (CD3)2SO, 80 °C) 1.65 (3 H, s), 1.67 (3 H,
s), 2.53 (2 H, d, J 8 Hz), 3.52 (1 H, d, J 14 Hz), 4.46 (1 H, dd, J 14, 3
Hz), 4.73−4.77 (1 H, m), 5.68 (1 H, t, J 8 Hz), 5.78 (1 H, d, J 3 Hz),
6.80 (4 H, t, J 7 Hz), 6.83−6.88 (2 H, m), 6.89 (1 H, d, J 7 Hz), 6.93
(8 H, t, J 7 Hz), 6.98−7.04 (3 H, m), 7.17−7.28 (13 H, m), 7.32 (1 H,
dt, J 7, 1 Hz), 7.47 (1 H, dt, J 7, 1 Hz), 7.68 (1 H, d, J 8 Hz), 7.84 (1
H, dt, J 8, 1 Hz), 8.02−8.08 (3 H, m), 8.10 (1 H, d, J 8 Hz), 9.54 (1 H,
s); δC (100 MHz; (CD3)2SO) 18.4, 29.1, 32.9, 61.3, 67.9, 70.3, 100.6,
121.6, 124.9, 125.36, 125.39, 125.43, 125.5, 127.6, 128.1, 128.9, 129.0,
129.2, 129.89, 129.94, 130.0, 130.2, 130.5, 134.1, 135.2, 135.3, 137.2,
141.3, 162.6, 163.3, 163.9, 164.6, 170.4; m/z found (ESI) for [iminium
cation]+ 474.2427, [C33H32NO2]+ requires 474.2433.
(Rax)-4-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-3-
methyl-3H-dinaphtho[2,1-c:1′,2′-e]azepinium Tetraphenylbo-
rate 26. Prepared according to the general procedure from (Rax)-4-
((4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl)-3-methyl-4,5-dihy-
dro-3H-dinaphtho[2,1-c:1′,2′-e]azepine 21 (480 mg, 0.96 mmol) and
isolated as an orange-yellow powder (542 mg, 69%: mp 127−128 °C
General Procedure for the Addition of Methyl Grignard
Reagent to Binaphthyl Azepinium Salts. A solution of
methylmagnesium bromide in diethyl ether (3M, 10 equiv) was
added dropwise with stirring to a solution of iminium salt in THF (50
mL per g of iminium salt) at −78 °C. After being stirred at −78 °C for
1 h, the mixture was allowed to reach ambient temperature overnight.
Saturated aqueous ammonium chloride (5 mL per g of iminium salt)
was added, and the organic solvents removed under reduced pressure.
The mixture was dissolved in ethyl acetate and filtered and the organic
layer separated and washed with water (2 × 60 mL per g of iminium
salt) and brine (50 mL per g of iminium salt). The organic layer was
dried over magnesium sulfate, and the solvents were removed under
reduced pressure to give the crude azepine, which was purified using
flash column chromatography on silica gel, typically eluting with 5:1
light petroleum/ethyl acetate buffered with 2% triethylamine.
General Procedure for the Synthesis of Methyl-Substituted
Binaphthylazepinium Tetraphenylborate Salts. N-Bromosucci-
nimide (1.1 equiv) was added to a solution of the azepine substrate in
dichloromethane (30 mL per g of azepine). The resulting yellow
solution was stirred for 10 min. The organic layer was separated,
washed with water (2 × 60 mL per gram of azepine) and brine (30
mL), and dried over magnesium sulfate. The solvents were removed
under reduced pressure, and the resulting crude yellow/orange foam
redissolved in ethanol (60 mL per gram of azepine). A solution of
sodium tetraphenylborate (1.1 equiv) in a minimum amount of
acetonitrile was added, resulting in the formation of an orange
precipitate. The solvents were removed under reduced pressure to
yield the crude iminium salt as an orange-brown foam, which was
recrystallized from ethanol and washed with cold ethanol followed by
hexane and diethyl ether. The fine orange powder was dried in a
vacuum oven at 60 °C overnight.
dec; [α]20 −302.5 (c 1.05, acetone); νmax (neat)/cm−1 3055, 2983,
D
2358, 2335, 1633, 1612, 1580, 1551, 1464, 1426, 1380, 1262, 1238,
1201, 1164, 1111, 1031, 958, 857, 816, 749, 733, 702, 668, 631, 611;
δH (300 MHz; acetonitrile-d3) 1.00 (3 H, d, J 7.1 Hz), 1.69 (3 H, s),
1.76 (3 H, s), 4.35 (1 H, dd, J 13.8, 1.1 Hz), 4.44 (1 H, td, J 2.9, 1.1
Hz), 4.73 (1 H, dd, 13.8, 3.0 Hz), 5.61 (1 H, q, J 6.9 Hz), 5.67 (1 H, d,
J 2.9), 6.47 (1 H, t, J 7.5 Hz), 6.67 (2 H, t, J 7.8 Hz), 6.81−6.89 (5 H,
m), 6.95−7.06 (10 H, m), 7.16−7.24 (1 H, m), 7.25−7.37 (11 H, m),
7.55 (1 H, ddd, J 8.1, 6.8, 1.1 Hz), 7.73 (2 H, ddd, J 7.9, 4.9, 1.7 Hz),
8.01 (1 H, d, J 8.2 Hz), 8.02 (1 H, d, J 8.3 Hz), 8.12 (1 H, d, J 8.3 Hz),
8.21 (1 H, d, J 8.5 Hz), 9.31 (1 H, s); δC (75 MHz; acetonitrile-d3)
13.8, 18.0, 28.9, 62.0, 68.4, 69.7, 71.1, 101.2, 122.0, 124.8, 124.9,
125.82−125.93 (8C, 8 × CH arom), 126.2, 126.4, 127.1, 127.2, 127.9,
128.1, 128.5, 128.7, 129.0, 129.49, 129.50, 131.0, 131.9, 132.0, 133.0,
134.0, 135.8, 135.9, 136.0, 138.9, 142.1, 164.1 (4 C, q, J = 49.0 Hz),
169.2; m/z found (ESI) for [iminium cation]+ 498.2415,
[C35H32NO2]+ requires 498.2428.
(Sax)-4-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-3-
methyl-3H-dinaphtho[2,1-c:1′,2′-e]azepinium Tetraphenylbo-
rate 27. Prepared according to the general procedure from (Sax)-4-
((4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl)-3-methyl-4,5-dihy-
dro-3H-dinaphtho[2,1-c:1′,2′-e]azepine 22 (170 mg, 0.34 mmol) and
isolated as bright yellow powder (201 mg, 72%): mp 203−205 °C dec;
[α]20 +421.4 (c 0.99, acetone); νmax (neat)/cm−1 3054, 2986, 1631,
D
1611, 1586, 1554, 1464, 1426, 1379, 1240, 1198, 1120, 1086, 1048,
1030, 952, 834, 821, 753, 733, 701, 672; δH (400 MHz; acetone-d6)
0.75 (1 H, d, J 7.1 Hz), 1.73 (3 H, s), 1.74 (3 H, s), 4.29 (1 H, d, J 13.9
Hz), 4.88 (1 H, dd, J 13.9, 2.9 Hz), 5.01 (1 H, t, J 2.7 Hz), 6.02 (1 H,
d, J 2.9 Hz), 6.05 (1 H, q, J 7.1 Hz), 6.78 (4 H, t, J 7.2 Hz), 6.93−7.04
(11 H, m), 7.24−7.46 (13 H, m), 7.59 (1 H, t, J 7.2 Hz), 7.75−7.81 (2
H, m), 7.95 (1 H, d, J 8.6 Hz), 8.12 (1 H, d, J 8.2 Hz), 8.17 (1H, d, J
8.2 Hz), 8.28 (1 H, d, J 8.6 Hz), 8.29 (1 H, d, J 8.3 Hz), 9.47 (1 H, s);
δC (75 MHz; acetone-d6) 12.4, 17.9, 28.6, 61.8, 68.8, 69.2, 71.8, 101.0,
121.5, 125.3, 125.5, 126.6, 127.1, 127.19, 127.25, 127.29, 128.2, 128.3,
128.7, 128.8, 129.0, 129.3, 129.4, 129.6, 131.0, 131.7, 131.8, 132.9,
134.0, 135.9, 139.6, 141.8, 164.3 (4 C, q, J = 49.0 Hz), 176.2; m/z
found (ESI) for [iminium cation]+ 498.2413, [C35H32NO2]+ requires
498.2428.
(Rax)-4-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-3-
methyl-4,5-dihydro-3H-dinaphtho[2,1-c:1′,2′-e]azepine 21.
Prepared according to the general procedure from (Rax)-N-[(4S,5S)-
5-(4-phenyl-2,2-dimethyl-1,3-dioxanyl)]-7H-dinaphtho[2,1-c;1′,2′-e]-
azepinium tetraphenylborate 6 (1.20 g, 1.49 mmol) and isolated as a
colorless solid (510 mg, 68%): mp 200−201 °C dec; [α]20 −152.35
D
(c 0.68, CHCl3); νmax (neat)/cm−1 3044, 2987, 2857, 1496, 1448,
1378, 1196, 1144, 1101, 1078, 1016, 952, 907, 850, 818, 767, 749, 727,
697; δH (400 MHz; CDCl3) 0.12 (3 H, d, J 6.9 Hz), 1.50 (3 H, s), 1.59
(3 H, s), 2.87 (1 H, s), 3.52 (1 H, d, J 11.5 Hz), 3.72 (1 H, d, J 11.4
I
dx.doi.org/10.1021/jo300915u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(3R, Rax)-4-((R)-3,3-Dimethylbutan-2-yl)-3-methyl-4,5-dihy-
dro-3H-dinaphtho[2,1-c:1′,2′-e]azepine 24. Prepared according
to the general procedure from 20 (0.50 g, 0.72 mmol), and isolated as
a colorless foam, (0.29 g, 99%): [α]21D −291.3 (c = 1.03, CHCl3); νmax
(neat)/cm−1 3046, 2953, 2912, 2860, 1739, 1505, 1469, 1455, 1377,
1364, 1325, 1313, 1248, 1218, 1199, 1166, 1147, 1110, 1071, 997, 815;
(400 MHz; acetone-d6) 0.51 (3 H, d, J 7.1 Hz), 0.98 (1 H, d, J 7.1 Hz),
1.04 (9 H, s), 2.73 (1 H, q, J 6.9 Hz), 3.29 (1 H, d, J 10.8 Hz), 3.70 (1
H, d, J 10.8 Hz), 4.11 (1 H, q, J 7.0 Hz), 7.25−7.32 (2 H, m), 7.35 (1
H, d, J 8.4 Hz), 7.41−7.51 (3 H, m), 7.59 (1 H, d, J 8.3 Hz), 7.64 (1
H, d, J 8.3 Hz), 7.98−8.08 (4 H, m); δC (100 MHz; acetone-d6) 10.5,
22.5, 27.7, 35.8, 49.4, 70.2, 73.0, 125.4, 125.5, 125.8, 125.9, 127.0,
127.1, 127.9, 128.4, 128.6, 128.9, 129.0, 129.1, 132.0, 132.1, 132.3,
133.1, 133.2, 135.3, 136.8, 140.3; m/z found (ESI) for [M + H]+
394.2531, [C29H32N]+ requires 394.2529.
1088, 1032, 960, 817, 732, 702, 670, 632, 611; δH (400 MHz; acetone-
d6) 1.18 (9 H, s), 1.33 (3 H, d, J 6.9 Hz), 1.74 (3 H, br s), 4.55 (1 H,
br s), 5.89 (1 H, q, J 7.0 Hz), 6.73 (4 H, t, J 7.2 Hz), 6.88 (8 H, t, J 7.4
Hz), 7.07 (1 H, d, J 8.6 Hz), 7.29 (9 H, m), 7.45 (2 H, m), 7.55 (1 H,
ddd, J 8.0, 6.8, 1.1 Hz), 7.78−7.80 (1 H, m), 7.85 (1 H, br s), 8.06 (1
H, d, J 8.2 Hz), 8.10 (1 H, br s), 8.21 (1 H, d, J 8.3 Hz), 8.22 (1 H, d, J
8.5 Hz), 8.34 (1 H, d, J 8.6 Hz), 9.52 (1 H, br s); δC (75 MHz;
MeCN-d3) 13.6, 26.1, 35.7, 80.6, 121.5, 125.3, 125.7, 127.2, 127.3,
128.1, 128.7, 129.0, 129.3, 129.8, 129.9, 130.8, 131.5, 132.0, 132.7,
133.9, 135.9, 136.3, 141.6, 164.3 (4 C, q, J = 49.0 Hz); m/z found
(ESI) for [iminium cation]+ 392.2372; [C29H30N]+ requires 392.2373.
(−)-(3R,Rax)-4-Isopropyl-3-methyl-3H-dinaphtho[2,1-c:1′,2′-
e]azepin-4-ium Tetraphenylborate 30. Prepared according to the
general procedure from 25 (0.32 g, 0.92 mmol) and isolated as a bright
yellow powder (0.43 g, 71%): mp 209.0−218.3 °C dec; [α]20
D
−358.38 (c = 0.99, acetone); νmax (neat)/cm−1 2053, 1652, 1591,
1578, 1552, 1474, 1461, 1524, 1376, 1359, 1262, 1211, 1134, 1109,
1045, 1030, 969, 867, 823, 796, 746, 735, 702; δH (300 MHz; DMSO-
d6) 1.05 (3 H, d, J 7.1 Hz), 1.44 (3 H, d, J 6.5 Hz), 1.57 (3 H, d, J 6.5
Hz), 4.57 (1 H, sept, J 6.5 Hz), 5.90 (1 H, q, J 7.1 Hz), 6.76 (4 H, t, J
7.2 Hz), 6.90 (8 H, t, J 7.3 Hz), 6.97 (1 H, d, J 8.5 Hz), 7.17 (8 H, m),
7.26 (1 H, ddd, J 8.2, 6.8, 1.3 Hz), 7.34 (1 H, d, J 8.6 Hz), 7.45 (1 H,
ddd, J 8.0, 6.8, 1.2 Hz), 7.53 (1 H, ddd, J 8.0, 6.8, 1.0 Hz), 7.76 (1 H,
ddd, J 8.0, 6.8, 1.0 Hz), 7.90 (1 H, d, J 8.5 Hz), 8.07 (2 H, m), 8.23 (2
H, t, J 8.6 Hz), 8.36 (1 H, d, J 8.6 Hz), 9.52 (1 H, s); δC (75 MHz;
DMSO) 14.3, 19.4, 20.0, 60.2, 66.7, 121.7, 125.5, 125.8, 126.6, 126.7,
126.9, 127.0, 127.1, 128.0, 128.7, 129.0, 129.2, 129.3, 130.2, 131.3,
131.4, 132.0, 133.3, 134.7, 135.0, 135.8, 140.2, 140.4, 163.6 (4 C, q, J =
49.0 Hz), 167.5; m/z found (ESI) for [iminium cation]+ 350.1904,
[C26H24N]+ requires 350.1903.
(3R, Rax)-4-((S)-3,3-Dimethylbutan-2-yl)-3-methyl-4,5-dihy-
dro-3H-dinaphtho[2,1-c:1′,2′-e]azepine 23. Prepared according
to the general procedure from 7 (0.50 g, 0.72 mmol), and isolated as a
yellow foam (0.29 g, 99%): [α]20 −185.6 (c = 0.97, CHCl3); νmax
D
(neat)/cm−1 2950, 2920, 1688, 1505, 1458, 1431, 1388, 1364, 1321,
1245, 1226, 1217, 1206, 1173, 1158, 1137, 1080, 1006, 863, 817; (400
MHz; acetone-d6) 0.52 (3 H, d, J 7.1 Hz), 1.00 (9 H, s), 1.10 (1 H, d, J
7.0 Hz) 2.63 (1 H, q, J 7.0 Hz), 3.65 (1 H, d, J 10.9 Hz), 3.68 (1 H, d,
J 11.0 Hz), 4.26 (1 H, q, J 7.1 Hz), 7.25−7.31 (3 H, m), 7.40 (1 H, d, J
8.6 Hz), 7.44−7.51 (2 H, m), 7.57 (1 H, d, J 8.4 Hz), 7.67 (1 H, d, J
8.3 Hz), 7.99−8.05 (4 H, m); δC (100 MHz; acetone-d6) 11.6, 22.6,
27.1, 36.8, 57.5, 59.9, 69.6, 126.3, 126.4, 126.6, 126.7, 127.9, 128.0,
129.2, 129.3, 129.5, 129.6, 129.9, 130.5, 132.8, 133.0, 133.8, 134.1,
134.2, 136.1, 137.2, 140.8; m/z found (ESI) for [M + H]+ 394.2530,
[C29H32N]+ requires 394.2529.
Crystallographic Data. X-ray diffraction studies for 15, 21, and 27
were performed at 93K using a Rigaku MM007/Mercury diffrac-
tometer (confocal optics Mo Kα radiation). Intensity data were
collected using ω steps accumulating area detector frames spanning at
least a hemisphere of reciprocal space for all structures (data were
integrated using CrystalClear). All data were corrected for Lorentz,
polarization, and long-term intensity fluctuations. Absorption effects
were corrected on the basis of multiple equivalent reflections.
Structures were solved by direct methods and refined by full-matrix
least-squares against F2 (SHELXTL). Hydrogen atoms were assigned
riding isotropic displacement parameters and constrained to idealized
geometries.25
15: C51H48BNO2, M = 717.71, orthorhombic, space group
P2(1)2(1)2(1), a = 11.283(2) Å, b = 15.681(3) Å, c = 22.336(5) Å,
U = 3951.9(13) Å3, Z = 4, Dc = 1.206 Mg m−3, μ = 0.072 mm−1. Of
25306 measured data, 5313 were unique to give R1= 0.0535 and wR2 =
0.1053, GOF= 0.960.
(−)-(3R, Rax)-4-Isopropyl-3-methyl-4,5-dihydro-3H-
dinaphtho[2,1-c:1′,2′-e]azepine 25. Prepared according to the
general procedure from 8 (0.70 g, 1.07 mmol), and isolated as a
colorless crystalline solid (0.32 g, 85%): [α]20 −375.3 (c = 1.02,
D
CHCl3); νmax (neat)/cm−1 3044, 2958, 2802, 1594, 1505, 1458, 1363,
1317, 1243, 1164, 1101, 1057, 979, 948, 862, 810, 767, 749, 699, 674,
628; δH (300 MHz; CDCl3) 0.50 (3 H, d, J 7.2 Hz), 1.05 (3 H, d, J 6.5
Hz), 1.13 (3 H, d, J 6.7 Hz), 3.12 (1 H, sept, J 6.6 Hz), 3.44 (1 H, d, J
10.5 Hz), 3.64 (1 H, d, J 10.5 Hz), 4.23 (1H, q, J 7.2 Hz), 7.26 (3 H,
m), 7.38 (1 H, dd, J 8.6, 0.9 Hz), 7.46 (2 H, m), 7.61 (1 H, d, J 8.4
Hz), 7.66 (1 H, d, J 8.3 Hz), 8.01 (4 H, m); δC (75 MHz; CDCl3)
18.9, 21.2, 24.5, 53.1, 57.0, 60.0, 126.3, 126.4, 126.6, 126.7, 127.9,
128.0, 129.2, 129.3, 129.4, 129.66, 129.73, 130.4, 132.8, 133.0, 133.87,
133.93, 134.1, 135.8, 137.2, 141.0; m/z found (ESI) for [M + H]+
352.2064, [C26H26N]+ 352.2060.
(−)-(3R,Rax)-4-((R)-3,3-Dimethylbutan-2-yl)-3-methyl-3H-
dinaphtho[2,1-c:1′,2′-e]azepin-4-ium Tetraphenylborate 29.
Prepared according to the general procedure from (3R,Rax)-4-((R)-
3,3-dimethylbutan-2-yl)-3-methyl-4,5-dihydro-3H-dinaphtho[2,1-
c:1′,2′-e]azepine 24 (0.25 g, 0.64 mmol) and isolated as a fine yellow
powder (0.33 g, 72%): mp 108−109 °C dec; [α]20D −324.00 (c = 1.00,
acetone); νmax (neat)/cm−1 3054, 2981, 1610, 1585, 1557, 1464, 1425,
1373, 1120, 1089, 1032, 817, 731, 702, 666, 611; δH (400 MHz;
acetone-d6) 0.97 (9 H, s), 1.29 (3 H, d, J 7.1 Hz), 1.80 (3 H, s), 4.59
(1 H, q, J 6.9 Hz), 5.88 (1 H, q, J 7.1 Hz), 6.74 (4 H, t, J 7.1 Hz), 6.89
(8 H, t, J 7.4 Hz), 7.06 (1 H, d, J 8.6 Hz), 7.25−7.35 (11 H, m), 7.42
(1 H, m), 7.56 (1 H, ddd, J 8.1, 6.8, 1.1 Hz), 7.77 (1 H, ddd, J 8.1, 6.8,
1.2 Hz), 7.82 (1 H, d, J 8.5 Hz), 8.04 (1 H, d, J 8.6 Hz), 8.07 (1 H, d, J
8.2 Hz), 8.19 (1 H, d, J 8.3 Hz), 8.26 (1 H, d, J 8.4 Hz), 8.33 (1 H, d, J
8.5 Hz), 9.67 (1 H, s); δC (75 MHz; acetone-d6) 12.2, 14.7, 26.5, 35.8,
62.1, 81.8, 122.3, 126.1, 126.6, 128.0, 128.1, 128.2, 128.3, 128.9, 129.5,
129.8, 130.1, 130.4, 131.0, 131.7, 132.1, 132.8, 133.3, 134.6, 136.9,
137.2, 140.7, 142.7, 165.3 (4 C, q, J = 49.0 Hz), 171.6; m/z found
(ESI) for [iminium cation]+ 392.2370, [C29H30N]+ requires 392.2373.
(−)-(3R,11cRa)-4-((S)-3,3-Dimethylbutan-2-yl)-3-methyl-3H-
dinaphtho[2,1-c:1′,2′-e]azepin-4-ium Tetraphenylborate 28.
Prepared according to the general procedure from 23 (0.27 g, 0.69
mmol) and isolated as a fine orange-yellow powder (0.31 g, 64%): mp
21: C35H33NO2, M = 717.71, orthorhombic, space group P2(1)-
2(1)2(1), a = 11.198(3) Å, b = 12.171(3) Å, c = 19.804(5) Å, U =
2699.0(11) Å3, Z = 4, Dc = 1.230 Mgm−3, μ = 0.075 mm−1. Of 17103
measured data, 4914 were unique to give R1= 0.0526 and wR2
=
0.1188, GOF = 0.978.
27·3CH2Cl2: C62H58BNO2Cl6, M = 1072.60, orthorhombic, space
group P2(1)2(1)2(1), a = 11.458(2) Å, b = 17.247(3) Å, c =
27.663(6) Å, U = 5466.5(19) Å3, Z = 4, Dc = 1.303 Mg m−3, μ = 0.359
mm−1. Of 34687 measured data, 9884 were unique to give R1= 0.1056
and wR2 = 0.2036, GOF = 0.882.
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
for 15, 21, 27, including CIF files. This information is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
131−132 °C dec; [α]20 −259.56 (c = 0.90, acetone); νmax (neat)/
Corresponding Author
*E-mail: p.page@uea.ac.uk.
D
cm−1 3056, 2986, 1612, 1587, 1552, 1478, 1426, 1381, 1261, 1119,
J
dx.doi.org/10.1021/jo300915u | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3941. Bohe,
́
L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahedron
Notes
Lett. 1993, 34, 7271. Bohe,
1999, 55, 141. Bohe, L.; Kammoun, M. Tetrahedron Lett. 2002, 43,
803. Bohe, L.; Kammoun, M. Tetrahedron Lett. 2004, 45, 747.
́
L.; Lusinchi, M.; Lusinchi, X. Tetrahedron
The authors declare no competing financial interest.
́
́
ACKNOWLEDGMENTS
■
Aggarwal, V. K.; Wang, M. F. 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. Gluszynska, A.; Mackowska, I.;
Rozwadowska, M. D.; Sienniak, W. Tetrahedron: Asymmetry 2004,
15, 2499. Biscoe, M. R.; Breslow, R. J. Am. Chem. Soc. 2005, 127,
10812. Minakata, S.; Takemiya, A.; Nakamura, K.; Ryu, I.; Komatsu,
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A.; Hallett, J. P.; Welton, T. J. Mol. Catal. A 2008, 279, 148. Lacour, J.;
Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002, 43, 8257. Novikov,
R.; Lacour, J. Tetrahedron: Asymmetry 2010, 21, 1611. Novikov, R.;
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Ditrich, K.; Lacour, J. Tetrahedron: Asymmetry 2006, 17, 2334. Vachon,
J.; Perollier, C.; Monchaud, D.; Marsol, C.; Ditrich, K.; Lacour, J. J.
Org. Chem. 2005, 70, 5903. Vachon, J.; Rentsch, S.; Martinez, A.;
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This investigation has enjoyed the support of Loughborough
University, the University of East Anglia, the EPSRC,
GlaxoSmithKline, and the ERDF (ISCE-Chem & INTERREG
IVa programme 4061). We also acknowledge the support of
The Royal Society (PCBP: Industry Fellowship). We are
indebted to the EPSRC Mass Spectrometry Unit, Swansea.
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