Towards heterogeneous organocatalysis: Chiral iminium cations supported on porous materials for enantioselective alkene epoxidation

Article abstract of DOI:10.1039/c3cy00352c

Enantiomerically pure iminium cations have been supported on a microporous support (zeolite Y) and on a mesoporous support (Al-MCM-41). These materials are effective asymmetric catalysts for the epoxidation of a range of aryl alkenes, giving high conversions quickly and with enantioselectivities similar to or in some cases even higher than are achievable using the corresponding iminium tetraphenylborates under homogeneous conditions. The catalysts can be simply recycled by filtration and washing. The methodology is illustrated in the synthesis of two natural products, (-)-(3′S)-lomatin and (+)-(3′S,4′R)-trans-khellactone, showing the general efficacy of our approach. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cy00352c

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Towards heterogeneous organocatalysis: chiral
iminium cations supported on porous materials
Cite this: DOI: 10.1039/c3cy00352c
for enantioselective alkene epoxidation†
Philip C. Bulman Page,*a Andrew Mace,a Damien Arquier,b Donald Bethell,c
Benjamin R. Buckley,d David J. Willockb and Graham J. Hutchingsb
Enantiomerically pure iminium cations have been supported on a microporous support (zeolite Y) and
on a mesoporous support (Al-MCM-41). These materials are effective asymmetric catalysts for the
epoxidation of a range of aryl alkenes, giving high conversions quickly and with enantioselectivities
similar to or in some cases even higher than are achievable using the corresponding iminium
tetraphenylborates under homogeneous conditions. The catalysts can be simply recycled by filtration
and washing. The methodology is illustrated in the synthesis of two natural products, (ꢀ)-(30S)-lomatin
and (+)-(30S,40R)-trans-khellactone, showing the general efficacy of our approach.
Received 20th May 2013,
Accepted 14th June 2013
DOI: 10.1039/c3cy00352c
www.rsc.org/catalysis
high enantiomeric excesses. Organocatalysis is the term used to
describe the acceleration of (organic) reactions by the presence
Introduction
Catalytic methods have the potential to transform the production
of chemicals across a very broad range of applications. Indeed,
catalytic methods are used routinely in bulk chemical manufacture,
but these simple methods, employing heterogeneous catalysts,
often supported metals, are not generally applicable for the
production of chiral products, which are now commonly
required in the pharma, agrochemical, and fine chemical
sectors. Asymmetric homogeneous catalysis, where chiral com-
pounds are generated in solution with high enantiomeric
purity, has been the subject of intense research over a number of
years, and resulted in the award of the Nobel prize for chemistry to
Noyori, Sharpless, and Knowles in 2001. There are difficulties,
however, in adapting this type of process for commercial purposes.
In recent years, organocatalysis has become increasingly
used in enantioselective synthetic processes, where it has
proved very successful, achieving rapid reactions leading to
of catalytic species derived only from carbon, hydrogen, and
other non-metallic elements, such as nitrogen, oxygen and
sulfur. Metal atoms, if present in the reaction system, are not
involved in the transition state for the reaction, although
organocatalysis has been combined with other types of catalysis,
including that by metals.1 Catalysis arising from simple proton
transfers to or from organic catalysts is not usually included in
the canon, which requires direct bonding of the organocatalyst
with one or more of the reactants during the catalyst turnover.
Thus proline is an organocatalyst for aldol reactions not because
of its basic nitrogen atom but rather because of its nucleophilic
reaction with carbonyl groups to generate reactive iminium
intermediates.2 Almost invariably, organocatalytic reactions are
conducted in the liquid phase (homogeneous or two-phase), and
this limits their application in commercial fine chemicals
production because of the problems associated with separation
of the (often expensive) catalyst from the products and its
subsequent reuse. There is a clear need for the adaptation of
organocatalysts so as to render them heterogeneous, thereby
permitting separation of products and catalyst by simple filtra-
tion in batch reactions and permitting the development of
processes using flow reactors. In this paper we describe an
approach to heterogenization of organocatalysts, which is applic-
able to iminium salt catalysis of alkene epoxidation.
a School of Chemistry, University of East Anglia, Norwich Research Park, Norwich,
Norfolk NR4 7TJ, UK. E-mail: p.page@uea.ac.uk; Fax: +44 (0)1603 593008;
Tel: +44 (0)1603 591061
b Cardiff Catalysis Institute, School of Chemistry, Cardiff University, Park Place,
Cardiff CF10 3AT, UK. E-mail: hutch@cardiff.ac.uk; Fax: +44 (0)2920 874030;
Tel: +44 (0)2920 874024
c Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
d Department of Chemistry, Loughborough University, Ashby Road, Loughborough,
Leicestershire LE11 3TU, UK
Oxidation is one of the most important types of transformation
in chemistry. Selective oxidation is an important requirement for
wide range of processes, and is particularly problematic in the
† Electronic supplementary information (ESI) available: Full tables of results,
figures, full experimental detail. See DOI: 10.1039/c3cy00352c
c
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production of pharmaceutical and agrochemical actives and
intermediates. Existing processes, both stoicheiometric and
catalytic, suffer from a range of deficiencies, including limited
substrate specificity, scale-up issues, catalytic activity and turn-
over, and the generation of considerable waste streams derived
from the bulk or co-oxidant. For example, in the pharmaceutical
industry, typically 10–1000 kg of chemical waste are produced per
kg of product on a scale of 100–1000 tons per year of product.3
A considerable amount of this waste is unrecoverable inorganic
waste produced by using oxidation or reduction reagents. For
these reasons, many oxidation procedures successful on the
laboratory scale have found very limited industrial application
to date. Use of such stoicheiometric oxidizing reagents, with the
concomitant production of inorganic by-products, necessarily
brings inherent environmental disadvantages and other hazards.
Chiral epoxides are extremely useful building blocks for
asymmetric synthesis,4 and the development of effective systems
for the asymmetric epoxidation of alkenes has received considerable
attention.5 Catalysts for enantioselective epoxidation in particular,
however, are few, and, while successful systems are known, they
were all developed as homogeneous systems.6 The goal of
devising a reusable heterogeneous catalyst for asymmetric
oxidation, particularly alkene epoxidation, has been achieved
in recent years.7
Scheme 1 Mediation of alkene epoxidation by oxaziridinium cations.
tetrafluoroborate were less selective, though more so than
perchlorate. Subsequently, we demonstrated that use of tetra-
phenylphosphonium peroxymonosulfate (TPPP), which is soluble
in organic solvents, as oxidant allows reactions to be conducted
in homogeneous solution at low temperatures and in the absence
of water.16
All the heterogeneous epoxidation catalysts developed
hitherto have contained metals as key components, active in
the transition state for reaction. Our aim was to develop a
heterogeneous organocatalyst for epoxidation. Oxaziridinium
salts generated, for example, by oxidation of iminium salts are
useful electrophilic oxidants for alkene epoxidation, and the
precursor iminium salts may be used catalytically under homo-
geneous conditions. Building on the original discovery by
Lusinchi of epoxidation using iminium salt catalysis,8 we and
others9 have had considerable success over the past decade in
elaborating a range of iminium salts that are effective catalysts
at low loadings for enantioselective epoxidation using Oxone
(2KHSO5ꢁKHSO4ꢁK2SO4) as the stoicheiometric oxidant. We
have shown that oxaziridinium salts based on dihydroisoquino-
lines and dibenzazepines, generated transiently from iminium
ions in the presence of a range of stoicheiometric oxidants,
including Oxone, hydrogen peroxide,10 bleach,11 and even electro-
chemical oxidation,12 can be used to generate epoxides with very
high enantioselectivities of up to 97% ee. All these reactions are
generally taken to involve conversion of the chiral iminium cation
into a chiral oxaziridinium intermediate capable of transferring
The aim of the present investigation was to heterogenize
some of our iminium salts by immobilization in porous solids;
by using microporous zeolite Y and mesoporous AlMCM-41,
which are both acids, anion exchange could take place, and the
original counter-anions could be replaced by the polyanionic
solid. We now show that such supported iminium salts are
effective as heterogeneous catalysts for the epoxidation of
alkenes; in general, rates of reaction are somewhat reduced
below those achieved in solution phase reactions, but enantio-
selectivities are usually similar, and in some cases are even
higher, presumably as a result of confinement and conforma-
tional restriction within the pores of the support. We also
report on the separation and reusability of the supported
catalysts, and we describe the application of one of the cata-
lysts in the highly enantioselective synthesis of two natural
products.
Results and discussion
Preparation and characterization of supported iminium cations
an oxygen atom directly to
a prochiral alkene substrate
(Scheme 1), hence the role of the iminium salt is as a catalyst.
The chirality of our iminium salts is provided by the attachment In this paper we describe the use of cation exchange to introduce
of an asymmetric exocyclic group to the key iminium nitrogen iminium cations into porous materials and to retain them there.
atom, with an asymmetric centre directly bonded. Examples are We have previously employed such a general procedure to intro-
shown below (1,13 2,14 and 315). Epoxidation reactions are typi- duce copper(II) cations into zeolite Y to produce heterogeneous
cally conducted in aqueous acetonitrile (which forms a two-phase catalysts used for enantioselective alkene aziridination.17
system under the reaction conditions in all cases when the
The iminium cations used in the present work have been
oxidant is added). The counter-ions investigated also proved to previously used in standard two phase or homogeneous liquid
modulate the enantioselectivity: tetraphenylborate and periodate phase conditions.9–11 They fall into three structural groups:
ions gave the highest ee, while hexafluorophosphate and (i) dihydroisoquinolinium cations, e.g. 1; (ii) dibenzazepinium
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cations, e.g. 2; and (iii) dinaphthazepinium salts, e.g. 3. In all carbon, hydrogen and nitrogen, with nitrogen values now
three categories, chirality is incorporated via the N-substituent, providing a crucial measure of maximum iminium incorpora-
but cations in the third category have an additional axial chiral tion. Iminium contents appeared generally somewhat lower
element in that the synthesis started from (R)-1,10-binaphthalene- than found with zeolite Y. In one instance the presence of the
2,20-diol. All were prepared first as the bromide salts but were iminium cation was confirmed by solid-state 13C NMR spectro-
purified and characterized, after anion exchange, as their tetra- scopy on the supported catalyst (see ESI†).
phenylborate salts, before use in epoxidations under the standard
homogeneous or two-phase liquid conditions as indicated above.
For incorporation into heterogeneous catalysts, the bromide salts
were used directly.
Catalytic enantioselective epoxidation
In initial experiments, directed towards establishing that epox-
idation using the heterogeneous catalysts was feasible and was
not adversely affected by considerations of mass transport,
zeolite Y was used as the support for a group of eight different
iminium cations having the dihydroisoquinolinium structure
but with a range of chiral N-substituents (Fig. 1).
In the present investigation, initial experiments to support
the iminium cations involved the use of ammonium zeolite Y
(faujasite; pore diameter 7.4 Å, cavity size 12 Å). This was stirred
for 24 hours in ethanol with an equal weight of the appropriate,
freshly prepared iminium bromide in order to allow cation
exchange to occur. The cation-exchanged zeolite was filtered
from the mixture, washed successively with ethanol and diethyl
ether until the washings were free of bromide ions, and then
dried at room temperature under vacuum for at least four
hours. Thereafter it was stored before use in a vacuum desic-
cator. Such catalysts are designated Yn, where Y indicates the
support and n represents the iminium salt from which the
cation was obtained. Characterization of these materials was by
conventional elemental analysis for carbon, hydrogen and
nitrogen. It was observed that the ratios of the three elements
did not correspond to that expected if the iminium cations were
their only source, nor could the figures be fitted on the
assumption that the original ammonium ions had been incom-
pletely exchanged. It was concluded that some solvent
(assumed to be ethanol) remained trapped in the zeolite and,
on this basis, the composition of the solid could be uniquely
assigned from the analytical figures. Supported iminium cata-
lysts prepared in this way contained typically 0.6–0.8 mmol
iminium cation per gram of solid (12–15% by weight), a roughly
equivalent molar amount of ammonium cation and around
twice the molar amount of ethanol. Amounts of the supported
catalyst required to simulate the concentrations used in homo-
geneous and two-phase liquid systems were calculated from
these analyses.
Reactions were conducted using the heterogeneous cata-
lysts, and the results compared with those for reactions under
similar conditions using the corresponding soluble iminium
tetraphenylborate as the catalysts in liquid phase, with several
alkenes. In both types of reaction, the catalyst loading was
nominally either 5 or 10% of the initial quantity of alkene,
although uncertainties in the iminium content of the sup-
ported catalyst, arising from the imprecision of the elemental
analyses, made the correspondence difficult to achieve exactly.
Reactions were carried out with careful stirring in aqueous
acetonitrile (1 : 1) at 0 1C with a twofold excess of Oxonet and
followed to 100% alkene conversion by tlc. The work-up was
extremely simple, requiring only addition of solvent and filtra-
tion. We were encouraged by the observation that in almost all
cases epoxidation using the heterogeneous catalyst was com-
parable in rate to reactions in the homogeneous liquid phase.
An exception was a catalyst incorporating one of the most bulky
of the iminium cations investigated, Y1; compared to the
homogeneous reaction, typically complete in 5 minutes at
0 1C, this catalyst led to much slower heterogeneous epoxida-
tion of 1-phenylcyclohexene, although with an identical enan-
tiomeric excess (40%) (Table 1). This catalyst was, however,
inactive for the epoxidation of 1-phenyldihydronaphthalene,
In subsequent experiments, a mesoporous aluminosilicate
material Al MCM-41 (made with cetyltrimethyl ammonium
bromide, ratio Si/Al = 12, N2 physisorption surface area:
912 m2 gꢀ1, diameter of pore (BJH): 29.0 Å) was used to support
the iminium cations; these catalysts are designated Mn. The
procedure was similar to that used for zeolite Y, the alumino-
silicate being calcined prior to use, and the mixture of iminium
bromide in ethanol and the support mixed in a Schlenk tube.
The mixture was subjected to three cycles of freezing in a liquid
nitrogen bath under vacuum followed by thawing under nitro-
gen. Such temperature cycling aids degassing of solvent and
solid support to minimize bubble formation at the liquid/solid
interface, and helps to facilitate the ingress of the iminium
cations to the pores. After filtration, and washing with ethanol
and diethyl ether, the solid catalyst was dried under vacuum,
usually at room temperature, before storage in a desiccator.
The catalysts were routinely characterized by microanalysis for Fig. 1 Iminium ions supported in zeolite Y.
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Table
1
Catalytic asymmetric epoxidation of unfunctionalized alkenes
might occur from the larger pores of the support, one of the
catalysts, M13, was stirred for 24 h in a range of solvents, and,
after filtration, the filtrate was evaporated and the residue
analysed by NMR spectroscopy. Cation 13 was found in residues
from the following solvents, all water-miscible: acetonitrile, (1 : 1)-
aqueous acetonitrile, acetone and ethanol, we believe with a
hydroxide counter-ion. No leaching was observed with toluene,
chloroform or dichloromethane. Accordingly we sought to use the
heterogeneous catalysts of the M-series under hydrophobic condi-
tions. To this end we prepared tetraphenylphosphonium mono-
mediated by dihydroisoquinolinium salts 1a
eeb/%
Conversionc/%
Time/min
Configurationd
40
100
5
(ꢀ)-1S,2S
+
peroxysulfate, PPh4 HSO5ꢀ, from the triple salt Oxone and
tetraphenylphosphonium chloride.18 It was recrystallized from a
mixture of dichloromethane and hexane to give a solid that, on
analysis, was found to have a peroxide content of 85%. This
material allowed epoxidation of a range of alkenes to be conducted
in homogeneous dichloromethane solution using iminium tetra-
phenylborates as efficiently as those using Oxone,15 and also in the
presence of Al-MCM-41-supported iminium cations. Moreover it
permitted epoxidations to be conducted at temperatures very
much lower than were possible under the original Oxone/aqueous
acetonitrile regime, with consequent advantages with respect to ee
and peroxymonosulfate stability.
40
61
360
(ꢀ)-1S,2S
49
—
100
5
(ꢀ)-1S,2R
0e
—
—
a
Epoxidation conditions: iminium salt 1 (10 mol%), Oxone (2 eq.),
b
Na2CO3 (4 eq.), MeCN : H2O (1 : 1), 0 1C. Enantiomeric excess deter-
mined by 1H-NMR spectroscopy with Eu(hfc)3 (0.1 eq.) as chiral shift
c
reagent or by chiral HPLC on a Chiralcel OD Column. Conversion
evaluated from the 1H-NMR spectra by integration of alkene versus
d
epoxide peaks. The absolute configuration of the major enantiomer
was determined by comparison to those reported in the literature. No
e
We illustrate the efficiency of heterogeneous epoxidation by
the results shown in Table 2 for the reaction of a series of
6-substituted chromenes with tetraphenylphosphonium perox-
conversion after 6 h.
perhaps as a result of restriction by the small pore size of zeolite ymonosulfate as the stoicheiometric oxidant catalysed by M2 in
Y (see also Table S1, ESI†).
dichloromethane at ꢀ20 1C. The very high ees induced in the
Despite the general success of iminium salts supported on corresponding homogeneous epoxidation system (shown in
zeolite Y as catalysts for alkene epoxidation, filtration of the parentheses) were paralleled by the new heterogeneous MCM
heterogeneous catalyst Y1 from the reaction mixture at the end catalyst M2, with excellent conversions, and giving the same
of the reaction, washing with ethanol followed by diethyl ether major enantiomers of the products, as indicated. For example,
and drying in vacuo at room temperature for 4 h, yielded a solid the MCM catalyst induces up to 99% ee in the epoxidation of
which showed no detectable catalytic activity. Possible reasons chromenes, where the corresponding homogeneous catalytic
for this are (i) the catalyst was degraded under the reaction system gives up to 97% ee. Particularly noteworthy is the fourth
conditions; (ii) the catalyst, because its bulk prevents incor- entry, where the M2 catalyst produced epoxide with 94% ee
poration of 1 within the pores of zeolite Y, is held only on the compared with the homogeneous system at only 74% ee; the
outer surface from which it is detached during reaction and considerable increase in ee under the heterogeneous condi-
recovery. The latter explanation can, however, be regarded as tions perhaps results from conformational restrictions in the
unlikely, since removal by filtration of the catalyst from an transition state due to confinement in the MCM pores.
epoxidation after partial reaction led to no further conversion
Fig. 2 provides a schematic illustration of iminium ion 13 in
of the alkene in the filtrate; there is therefore no evidence of a 29 Å diameter MCM-41 channel. The channel structure is
leaching of the catalytic cations under the reaction conditions. obtained from a supercell of the dense silica cristobalite phase
Further development of heterogeneous enantioselective into which 29 Å diameter channels have been cut with a wall
epoxidation used the mesoporous aluminosilicate Al-MCM-41 thickness of 7 Å. The resulting dangling bonds have been
in conjunction with iminium cations. This support, the frame- capped with hydrogen atoms to represent the surface termina-
work of which is anionic as a result of the presence of tion by hydroxylation that will occur during the synthesis
incorporated aluminium, was chosen so as to ensure that there procedure. Si atoms have then been randomly replaced by Al
would be sufficient space within the pores to accommodate the to give the experimental Si/Al ratio of 12. The porous structure
bulkiest iminium cations. Because of our concern that leaching has also been optimized using a molecular mechanics approach,
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Table 2 Epoxidation of chromenes by MCM catalyst M2
evidence in the spectra of the presence of the iminium salts
and/or tetraphenylphosphonium cations or their degradation
products; clogging of the pores by these materials could clearly
have an adverse effect on alkene epoxidation. The iminium
cations (or the derived oxaziridinium cations) may undergo
slow degradation under the epoxidation conditions, reactions
slow enough to be undetectable in the original homogeneously
catalysed conditions, which were generally complete within an
hour, but becoming significant in the much lengthier reaction
times used for the heterogeneous reactions. In this respect it is
perhaps significant that in a series of successive reactions using
catalyst M2 in the epoxidation of 1-phenylcyclohexene in
CH2Cl2 at ꢀ40 1C over 6 h, conversions were 56, 43 and 20%;
successive reactions run for 24 h gave conversions of 100, 50
(increased to 63% when the catalyst was dried after recovery at
60 1C.) and 0%. We were therefore very pleased to observe that
stirring the recovered catalyst for 24 h in dichloromethane prior
to drying led to much more effective re-use, with both the first
and second runs providing 100% conversion in the same
reaction time. Although the third use led to a lower conversion
of 53%, due possibly to catalyst losses, these promising results
provide a proof of concept that our catalysts can be reused as
well as providing enhanced enantioselection for the immobi-
lized catalysts.
R
Conv./%
Temp./1C
Time/h
eea/%
CN
Cl
NO2
H
100
100
100
71
ꢀ20
ꢀ20
ꢀ20
ꢀ20
4.5
4.5
9.8
4.5
98 (96)
92 (87)
99 (97)
94 (74)
a
Values in parentheses indicate the ees obtained in the corresponding
homogeneous reaction.
which reduced the crystallinity of the channel walls. This
illustration gives an impression of the relative size of the
organocatalyst and channel structure.
Reusability of the catalysts
After their first use, M-series catalysts were recovered by simple
filtration and successive washing with dichloromethane, fol-
lowed by drying under vacuum, usually at room temperature,
for a minimum of 4 h. The dried solid was then used in a
standard epoxidation with fresh alkene and TPPP. In a few
experiments the drying temperature was raised to 60 1C in an
effort to facilitate the removal of solvent and traces of water;
this procedure seemed to lead to a small improvement in the
conversion achieved on subsequent reuse of the catalyst.
Table 3 shows a selection of representative results, which
indicate that the catalysts are reusable, and, most importantly,
enantiomeric excesses remained constant throughout. In gen-
eral, however, declining epoxidation rates and conversions were
observed upon reuse. In all the cases shown, further recycling
of the catalyst resulted in conversions that were too low to be
detectable (see also Table S3, ESI†).
Application to total synthesis of natural products
One of the MCM-based catalysts, M13, was used in a short
asymmetric synthesis of two simple pyranocoumarin natural
products (Scheme 2). Coumarins are widely distributed in
nature, both in linear and non-linear form, and have been
shown to exhibit a broad range of pharmacological profiles,19
including anti-bacterial,20 anti-inflammatory,21 anti-cancer,22
and anti-HIV23 activity. Naturally occurring pyranocoumarins
We sought to understand the reasons for the reduced
activity on reuse of the catalysts. Examination by MAS NMR
spectroscopy of catalysts after use did not show the signals
characteristic of residual iminium cation. There was, however,
Table 3 Reusability of Al-MCM-41-supported catalyst M2
Useb,c
Conv./%
Temp./1C
Time/h
eea/%
1
2
3
56
43
20
ꢀ40
ꢀ40
ꢀ40
6
6
6
32 (29)
32
32
1
2
3
100
50
0
ꢀ40
ꢀ40
ꢀ40
24
24
24
32 (29)
32
—
1
2
3
100
63
0
ꢀ40
ꢀ40
ꢀ40
24
24
24
32
32
—
1
2
3
100
100
53
ꢀ40
ꢀ40
ꢀ40
24
24
24
31
32
32
a
Values in parentheses indicate the ees obtained in the corresponding
b
homogeneous reactions. Catalyst dried at 60 1C prior to re-use.
c
Catalyst stirred in dichloromethane for 24 hours prior to drying and
Fig. 2 An illustration of iminium ion 13 in a MCM-41 channel.
re-use.
c
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the stoicheiometric oxidant, since this combination allows
reactions to be carried out at low temperatures. We have
demonstrated that the catalysts can be simply recycled by
filtration and washing and can then be successfully reused
for epoxidation. In general, however, at the present stage of
development, the recycled catalysts lead to falling conversions
on each reuse for reasons that are at present unclear. Never-
theless we believe that we have the prototype of a reusable
heterogeneous iminium catalyst for alkene epoxidation, using
peroxymonosulfate as the stoicheiometric oxidant, that can in
favourable cases deliver high enantioselectivities.
Experimental section
Al-MCM-41
The variant of MCM-41 used throughout this research is
Al-MCM-41, which contains a high alumina content. Al-MCM-41
was prepared by adding tetraethylorthosilicate to a solution of
hexadecyltrimethylammonium bromide containing aluminium
isopropoxide. Following static heating at 110 1C for 96 h and
calcination at 550 1C, Al-MCM-41 was obtained in 66% yield.
Scheme 2 Synthesis of (ꢀ)-lomatin & (+)-trans-khellactone.
include seselin 14, predominantly isolated from Plumbago
zeylanica, Naucleopsis caloneura, Carum roxburghianum, and
Citrus grandis;24 and both enantiomers of lomatin 15, isolated
from Lomatium nuttallii and various Umbelliferae.25 Seselin has
shown cytotoxic activity against Vero monkey cells, with IC50
General procedure for the synthesis of dihydroisoquinolinium
zeolite-Y salts from 2-(2-bromoethyl)benzaldehyde and primary
amines
values of 12 mg mLꢀ1 and >20 mg mLꢀ1 26
(+)-trans-khellactone
.
16 shows cytotoxic activity against P-388 lymphocytic leukaemia
systems (ED50 2.8 mg mLꢀ1).
A solution of amine (5–10 mmol) in ethanol (10 mL per g of
amine) was added dropwise to an ice-cooled solution of 2-(2-
bromoethyl)benzaldehyde (1.1 eq.) in ethanol (10 mL per g of
amine). The reaction mixture was stirred overnight at ambient
temperature. Ammonium zeolite-Y (1 : 1 wt/wt with respect to
amine) was added in one portion and the reaction stirred at
ambient temperature overnight. The zeolite-Y catalyst was washed
with ethanol (3 ꢂ 15 mL) and diethyl ether (3 ꢂ 15 mL) and dried
under vacuum at room temperature for at least 4 hours. The catalyst
was stored in a desiccator at room temperature.
Seselin was prepared in 94% yield from 7-hydroxycoumarin
by reaction with 3-methylbut-2-enal diethyl acetal in the
presence of 3-picoline under microwave irradiation.27 Epoxida-
tion of seselin under our standard conditions using the M13
catalyst at ꢀ20 1C gave the (30S,40S)-epoxide in 93% ee in a
conversion of 74% over 4.5 h. The isolated yield was 64%. This
compares quite well with epoxidation using the corresponding
homogeneous catalyst containing iminium ion 2, at 95% ee,
and with epoxidation using the homogeneous catalyst containing
iminium ion 1, at 97% ee.27 We have also shown that subsequent
reductive ring-opening of the epoxide with sodium cyanoboro-
hydride gave the alcohol (ꢀ)-(30S)-lomatin in 92% yield, while
acid-catalysed hydrolytic ring-opening of the epoxide gave
(+)-(30S,40R)-trans-khellactone in 95% yield, in each case without
loss of enantiopurity.
General procedure for the synthesis of dihydroisoquinolinium
Al-MCM-41 salts from 2-(2-bromoethyl)benzaldehyde and
primary amines
A solution of amine (5–10 mmol) in ethanol (10 mL per g of
amine) was added dropwise to an ice-cooled solution of 2-(2-
bromoethyl)benzaldehyde (1.1 eq.) in ethanol (10 mL per g of
amine). The reaction mixture was stirred overnight at ambient
temperature and transferred to a Schlenk tube. Al-MCM-41
(1 : 1 wt/wt with respect to amine) was added in one portion
Conclusions
We have successfully produced enantiomerically pure iminium and the mixture stirred, followed by the evacuation of air from
cations supported on a microporous support (zeolite Y) and on the Schlenk tube. The mixture was cooled in liquid nitrogen
a mesoporous support (Al-MCM-41) and have shown that such until the solution attained freezing point. After 10 min at this
materials are effective catalysts for the asymmetric epoxidation temperature the solution was allowed to thaw under a nitrogen
of a range of aryl alkenes, giving high conversions quite quickly atmosphere. The evacuation, freezing and thawing process was
and with enantioselectivities close to or in some cases even repeated twice more, and the Al-MCM-41 catalyst recovered by
higher than are achievable using the corresponding iminium filtration. The Al-MCM-41 catalyst was washed with ethanol
tetraphenylborates under homogeneous conditions. The best (3 ꢂ 15 mL) and diethyl ether (3 ꢂ 15 mL) and dried under
results are obtained using dichloromethane as the liquid vacuum at room temperature for at least 4 hours. The catalyst
phase and tetraphenylphosphonium monoperoxysulfate as was stored in a desiccator at room temperature.
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General procedure for the synthesis of biphenyl azepinium Al- The mixture was cooled in liquid nitrogen until the solution
MCM-41 salts from 2-[2-(bromoethyl)phenyl]benzene
carbaldehyde and primary amines
attained freezing point. After 10 min at this temperature the
solution was allowed to thaw under a nitrogen atmosphere. The
evacuation, freezing and thawing process was repeated twice
more, and the Al-MCM-41 catalyst was recovered by filtration.
The Al-MCM-41 catalyst was washed with ethanol (3 ꢂ 15 mL)
and diethyl ether (3 ꢂ 15 mL), and dried under vacuum at room
temperature for at least 4 hours. The catalyst was stored in a
desiccator at room temperature.
A solution of amine (5–10 mmol) in ethanol (10 mL per g of
amine) was added dropwise to an ice-cooled solution of 2-(2-
bromoethyl)benzaldehyde (1.1 eq.) in ethanol (10 mL per g of
amine). The reaction mixture was stirred overnight at ambient
temperature and transferred to a Schlenk tube. Al-MCM-41
(1 : 1 wt/wt with respect to amine) was added in one portion
and the mixture stirred, followed by the evacuation of air from
the Schlenk tube. The mixture was cooled in liquid nitrogen
until the solution attained freezing point. After 10 min at this
temperature the solution was allowed to thaw under a nitrogen
atmosphere. The evacuation, freezing and thawing process was
repeated twice more, and the Al-MCM-41 catalyst recovered by
filtration. The Al-MCM-41 catalyst was washed with ethanol
(3 ꢂ 15 mL) and diethyl ether (3 ꢂ 15 mL), and dried under
vacuum at room temperature for at least 4 hours. The catalyst
was stored in a desiccator at room temperature.
(+)-N-((4S,5S)-2,2-Dimethyl-4-(4-(methylsulfonyl)phenyl)-1,3-
dioxan-5-yl)-3,4-dihydroisoquinolinium Al-MCM-41
Prepared according to the general procedure from (4S,5S)-5-
amino-2,2-dimethyl-4-(4-(methylsulfonyl)phenyl)-1,3-dioxane (1.5 g,
5.26 mmol) to yield the product as a colourless powder (1.60 g from
1.50 g of Al-MCM-41); found C, 13.67; H, 1.66; N, 0.80 (ratio found
C : H : N 13.7 : 1.7 : 0.8), C22H26NO4S requires C, 65.97; H, 6.54; N,
3.50% (ratio required C : H : N 13.7 : 1.4 : 0.7). Catalyst loading of
Al-MCM-41 (15.8%).
(S)-2-(3,3-Dimethylbutan-2-yl)-3,4-dihydroisoquinolinium
zeolite-Y
General procedure for the synthesis of binaphthalene
azepinium Al-MCM-41 salts from (R)-binaphthalene azepines
Prepared according to the general procedure from (S)-3,3-
dimethylbutan-2-amine (1.5 g, 14.85 mmol) to yield the product
as a colourless powder (1.59 g from 1.50 g of ammonium
zeolite-Y); found C, 14.48; H, 2.60; N, 1.75 (ratio found C : H : N
14.5 : 2.6 : 1.8), C15H22N requires C, 83.28; H, 10.25; N, 6.47%
(ratio required C : H : N 14.5 : 1.8 : 1.1). Catalyst loading of
zeolite-Y (17.4%).
N-Bromosuccinimide (1.2 eq.) and azo-bis-isobutyronitrile
(0.05 eq.) were added to a solution of the azepine in dichloro-
methane (5 mL per g of azepine), and the mixture heated to
reflux for 2 h. The reaction mixture was allowed to cool and the
solvent removed under reduced pressure. The residue was
redissolved in ethanol and the mixture stirred overnight
at ambient temperature, and transferred to a Schlenk tube.
Al-MCM-41 (1 : 1 wt/wt with respect to amine) was added in one
portion and the mixture stirred, followed by the evacuation of
air from the Schlenk tube. The mixture was cooled in liquid
nitrogen until the solution attained freezing point. After 10 min
at this temperature the solution was allowed to thaw under a
nitrogen atmosphere. The evacuation, freezing and thawing
process was repeated twice more, and the Al-MCM-41 catalyst
recovered by filtration. The Al-MCM-41 catalyst was washed
with ethanol (3 ꢂ 15 mL) and diethyl ether (3 ꢂ 15 mL), and
dried under vacuum at room temperature for at least 4 hours.
The catalyst was stored in a desiccator at room temperature.
(R)-2-(2-Hydroxy-1-phenylethyl)-3,4-dihydroisoquinolinium
zeolite-Y
Prepared according to the general procedure from (R)-phenyl-
glycinol (1.5 g, 10.95 mmol) to yield the product as a colourless
powder (1.61 g from 1.50 g of ammonium zeolite-Y); found C,
15.38; H, 2.14; N, 1.68 (ratio found C : H : N 15.4 : 2.1 : 1.7),
C
17H18NO requires C, 80.92; H, 7.19; N, 5.55% (ratio required
C : H : N 15.4 : 1.4 : 1.1). Catalyst loading of zeolite-Y (17.9%).
(S)-2-(2-Hydroxypropyl)-3,4-dihydroisoquinolinium zeolite-Y
Prepared according to the general procedure from (S)-1-amino-
propan-2-ol (1.5 g, 19.95 mmol) to yield the product as a colour-
less powder (1.60 g from 1.50 g of ammonium zeolite-Y); found
C, 12.28; H, 2.14; N, 1.72 (ratio found C : H : N 12.3: 2.1 : 1.7),
C12H12NO requires C, 75.75; H, 8.48; N, 7.36% (ratio required
C : H : N 12.3 : 1.6 : 1.2). Catalyst loading of zeolite-Y (15.1%).
General procedure for the synthesis of binaphthalene
azepinium Al-MCM-41 salts from (R)-20-(bromomethyl)-[1,10]-
binaphthyl-2-carbaldehyde and primary amines
A solution of the amine in ethanol (10 mL per g of amine) was
added dropwise to a solution of (R)-20-bromomethyl-[1,10]-
binaphthalenyl-2-carboxaldehyde (1.10 equivalent with respect
to the amine) in ethanol (10 mL per g of carboxaldehyde) at
40 1C. The mixture was maintained at 40 1C with stirring
(S)-2-(1-Hydroxy-3-methylbutan-2-yl)-3,4-
dihydroisoquinolinium zeolite-Y
overnight. The yellow mixture was allowed to cool to ambient Prepared according to the general procedure from (+)-(S)-vali-
temperature. The residue was redissolved in ethanol and the nol (1.5 g, 14.55 mmol) to yield the product as a colourless
mixture stirred overnight at ambient temperature, and trans- powder (1.55 g from 1.50 g of ammonium zeolite-Y); found C,
ferred to a Schlenk tube. Al-MCM-41 (1 : 1 wt/wt with respect to 16.33; H, 2.52; N, 2.03 (ratio found C : H : N 16.3 : 2.5 : 2.0),
amine) was added in one portion and the mixture stirred,
C14H20NO requires C, 76.81; H, 8.43; N, 6.89% (ratio required
followed by the evacuation of air from the Schlenk tube. C : H : N 16.3 : 1.9 : 1.4). Catalyst loading of zeolite-Y (19.6%).
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(S)-2-(1-Hydroxypropan-2-yl)-3,4-dihydroisoquinolinium zeolite Y (ꢀ)-2-[(4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]-5H-
dibenzo[c,e]azepinium Al-MCM-41
Prepared according to the general procedure from (S)-2-amino-
propan-1-ol (1.5 g, 19.95 mmol) to yield the product as a Prepared according to the general procedure from L-aceton-
colourless powder (1.56 g from 1.50 g of ammonium zeolite-Y); amine (1.5 g, 7.23 mmol) to yield the product as a colourless
found C, 14.16; H, 2.18; N, 1.92 (ratio found C : H : N powder (1.65 g from 1.50 g of Al-MCM-41); found C, 9.63; H,
14.2: 2.2 : 1.9), C12H12NO requires C, 75.75; H, 8.48; N, 1.49; N, 0.53 (ratio found C : H : N 9.6 : 1.5 : 0.5), C26H26NO2
7.36% (ratio required C : H : N 14.2 : 1.1 : 1.0). Catalyst loading requires C, 81.22; H, 6.82; N, 3.64% (ratio required C : H : N
of zeolite-Y (16.3%).
9.6 : 0.8 : 0.4). Catalyst loading of Al-MCM-41 (10.9%).
General procedure for catalytic asymmetric epoxidation of
simple alkenes mediated by iminium salts using Oxone
2-(2,4,6-Tribromophenyl)-3,4-dihydroisoquinolinium zeolite Y
Prepared according to the general procedure from 2,4,6-tribromo-
aniline (1.0 g, 3.03 mmol) to yield the product as a colourless
powder (1.66 g from 1.50 g of ammonium zeolite-Y); found C,
19.96; H, 1.78; N, 1.93 (ratio found C : H : N 20.0 : 1.8 : 1.9),
C15H13NBr3 requires C, 40.49; H, 2.49; N, 3.15% (ratio required
C : H : N 20.0 : 1.4 : 1.6). Catalyst loading of zeolite-Y (23.0%).
Oxone (2 equivalents) was added to an ice-cooled solution of
sodium carbonate (4 eq.) in water (12 mL per 1.50 g of sodium
carbonate) with stirring. The resulting foaming solution was
stirred for 5–10 minutes until the initial effervescence sub-
sided. The iminium salt (10 mol% with respect to the alkene
substrate) was added as a solution in acetonitrile (6 mL per
1.50 g of sodium carbonate), followed by the alkene as a
solution in acetonitrile (6 mL per 1.50 g of sodium carbonate).
The suspension was stirred at the same temperature until the
substrate was completely consumed according to TLC analysis.
The reaction mixture was diluted with ice-cooled diethyl ether
(20 mL per 100 mg substrate) followed immediately by the same
volume of water. The aqueous phase was washed four times
with diethyl ether, and the organic fractions were combined,
washed with brine, and dried. Subsequent filtration and
removal of solvents under reduced pressure yielded a yellow
or light brown residue. Column chromatography could be
performed using ethyl acetate : light petroleum (1 : 99) to isolate
the pure epoxide.
2-(2,6-Dimethylphenyl)-3,4-dihydroisoquinolinium zeolite Y
Prepared according to the general procedure from 2,6-dimethyl-
aniline (1.5 g, 12.45 mmol) to yield the product as a colourless
powder (1.61 g from 1.50 g of ammonium zeolite-Y); found C,
15.10; H, 2.11; N, 1.75 (ratio found C : H : N 15.1 : 2.1 : 1.8),
C
15H13NBr3 requires C, 86.40; H, 7.68; N, 5.93% (ratio required
C : H : N 15.1 : 1.8 : 1.2). Catalyst loading of zeolite-Y (18.1%).
(R)-N-[(4S,5S)-5-(4-(4-Methanesulfonyl)phenyl)-2,2-dimethyl-
1,3-dimethyl-1,3-dioxanyl)]-7H-dinaphtho[2,1-c;1020-
e]azepinium Al-MCM-41
Prepared according to the general procedure from (4S,5S)-5-
amino-2,2-dimethyl-4-(4-(methylsulfonyl)phenyl)-1,3-dioxane (1.5 g,
5.26 mmol) to yield the product as a colourless powder (1.62 g from
1.50 g of Al-MCM-41); found C, 6.84; H, 1.28; N, 0.74 (ratio found
C : H : N 6.8 : 1.2 : 0.8), C35H32NO4S requires C, 74.71; H, 5.73; N,
2.49% (ratio required C : H : N 6.8 : 0.5 : 0.2). Catalyst loading of
Al-MCM-41 (7.5%).
Tetraphenylphosphonium monoperoxysulfate28
Oxone triple salt (2KHSO5 : KHSO4 : K2SO4) (15.00 g, 48.80 mmol
with respect to KHSO5) was dissolved in deionised water
(300 mL) and stirred at 10–15 1C. A solution of tetraphenyl-
phosphonium chloride (15.00 g, 40.00 mmol) in distilled
dichloromethane (300 mL) was added gradually over 5 minutes.
After an additional 30 minutes, stirring was interrupted and the
organic layer separated. The solvent was removed under
reduced pressure at room temperature. The crude colourless
salt was transferred to a sintered glass funnel and washed with
distilled water (2 ꢂ 75 mL), dissolved in dichloromethane
(180 mL), and dried over magnesium sulfate. Hexane was
added to the solution until cloudiness developed. The flask
was placed at ꢀ20 1C overnight to produce a colourless solid
(15.70 g, 71%), approximately 85% pure in peroxide. dH (400 MHz:
CDCl3) 7.64 (8H, m, 8 ꢂ CH arom.), 7.78 (8H, m, 8 ꢂ CH arom.).
7.89 (4H, m 4 ꢂ CH arom., para to P), 8.92 (1H, br s, OH).
(R)-N-[(4S,5S)-5-(4-Phenyl)-2,2-dimethyl-1,3-dioxanyl)]-7H-
dinaphtho[2,1-c;1020-e]azepinium Al-MCM-41
Prepared according to the general procedure from L-acetona-
mine (1.5 g, 7.23 mmol) to yield the product as a colourless
powder (1.63 g from 1.50 g of Al-MCM-41); found C, 6.61; H,
1.49; N, 0.37 (ratio found C : H : N 6.6 : 1.5 : 0.4), C34H30NO2
requires C, 84.27; H, 6.24; N, 2.89% (ratio required C : H : N
6.6 : 0.5 : 0.2). Catalyst loading of Al-MCM-41 (7.3%).
(ꢀ)-N-{(4S,5S)-2,2-Dimethyl-4-[4-(methylsulfonyl)phenyl]-1,3-
dioxan-5-yl}-5H-dibenzo[c,e]azepinium Al-MCM-41
Prepared according to the general procedure from (4S,5S)-5-amino-
2,2-dimethyl-4-(4-(methylsulfonyl)phenyl)-1,3-dioxane (1.5 g,
5.26 mmol) to yield the product as a colourless powder
(1.61 g from 1.50 g of Al-MCM-41); found C, 9.31; H, 1.59; N,
General procedure for catalytic asymmetric epoxidation of
simple alkenes mediated by iminium salts using
tetraphenylphosphonium monoperoxysulfate
0.59 (ratio found C : H : N 9.3 : 1.6 : 0.6), C27H28NO4S requires C, Tetraphenylphosphonium monoperoxysulfate (2 eq. with
70.10; H, 6.10; N, 3.03% (ratio required C : H : N 9.3 : 0.8 : 0.4). respect to the alkene substrate) was dissolved in the desired
Catalyst loading of Al-MCM-41 (10.5%).
solvent (2 mL per 0.10 g oxidant) and cooled to the required
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temperature. A pre-cooled solution of the iminium salt in the solvents removed under reduced pressure. Diethyl ether
reaction solvent (0.50 mL per 0.10 g oxidant) at the same (40 mL) was added to the residue and the solution obtained
temperature was added dropwise over 15–20 minutes. The was passed through a short pad of silica to remove the catalyst
reaction vessel temperature was monitored to minimize tem- residues. The solvent was again removed under reduced pres-
perature fluctuation during addition. The alkene was added as sure to yield seselin epoxide as a colourless solid (0.150 g, 64%)
a solution in the reaction solvent (0.50 mL per 0.10 g oxidant) in of 93% ee (HPLC conditions: hexane : isopropanol (90 : 10),
the same manner as the catalyst. The mixture was stirred at the oven temp. 20 1C, column Eurocel 01 250 ꢂ 4.6 mm, 5 mm
same temperature until the substrate was completely con- particle size, flow rate 1 mL minꢀ1).
sumed according to TLC analysis. Diethyl ether (20 mL per
0.10 g oxidant), pre-cooled to the reaction temperature was
added to precipitate the remaining oxidant. The solution was
Acknowledgements
This investigation has enjoyed the support of the EPSRC,
Loughborough University, the University of Cardiff, and the
ERDF (ISCE-Chem & INTERREG IVa programme 4061). We
acknowledge the support of The Royal Society (PCBP: Industry
Fellowship). We are also indebted to the EPSRC Mass Spectro-
metry Unit, Swansea.
filtered through Celite, and the solvents removed under
reduced pressure. Diethyl ether (40 mL) was added to the brown
residue obtained, and the solution passed through a short pad
of silica to remove catalyst residues. The solvent was again
removed under reduced pressure to yield the epoxide. Column
chromatography could be performed using ethyl acetate : light
petroleum (1 : 99) to isolate the pure epoxide.
Notes and references
General procedure for the formation of racemic epoxides for
enantiomeric excess determinations
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The alkene was dissolved in dichloromethane (10 mL per g of
alkene) and cooled to 0 1C. A solution of m-CPBA (2 eq.) in
dichloromethane (10 mL per g of alkene), pre-dried over
MgSO4, was added. The reaction was allowed to attain ambient
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pure samples of the epoxides were obtained through column
chromatography, typically eluting with ethyl acetate : light pet-
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Homogeneous. Seselin (0.110 g, 0.5 mmol) was dissolved in
dichloromethane (24 mL), and the solution cooled to ꢀ20 1C.
Catalyst 13, with a tetraphenylborate counter-ion, (0.036 g,
0.05 mmol) and TPPP (0.570 g, 1.00 mmol) were added, and
the mixture was stirred at ꢀ20 1C for 24 hours. Diethyl ether
was added (25 mL) to precipitate the remaining oxidant. The
solution was filtered through Celite and the solvents removed
under reduced pressure. Diethyl ether (20 mL) was added to the
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as a colourless solid (0.080 g, 71%) of 95% ee (HPLC conditions:
hexane : isopropanol (90 : 10), oven temp. 20 1C, column Eurocel
01 250 ꢂ 4.6 mm, 5 mm particle size, flow rate 1 mL minꢀ1).
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dichloromethane (24 mL), and the solution cooled to ꢀ20 1C.
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added, and the mixture was stirred at ꢀ20 1C for 24 hours.
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oxidant. The solution was then filtered through Celite and the
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