New organocatalysts for the asymmetric catalytic epoxidation of alkenes mediated by chiral iminium salts

Article abstract of DOI:10.1055/s-2002-22699

New iminium salt organocatalysts for catalytic asymmetric epoxidation based upon dibenzazepinium salts are reported, providing ee of up to ca 60%.

Full text of DOI:10.1055/s-2002-22699

580
LETTER
New Organocatalysts for the Asymmetric Catalytic Epoxidation of Alkenes
Mediated by Chiral Iminium Salts
New
O
rgancat
h
alysts for the
i
A
sym
l
metric
iCatalyt
p
ic Epoxidation of
AC
lkenes . Bulman Page,* Gerasimos A. Rassias, David Barros, Adel Ardakani, Donald Bethell,1 Eric Merifield2
Department of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, England
E-mail: p.c.b.page@lboro.ac.uk
Received 5 February 2002
Ph
Abstract: New iminium salt organocatalysts for catalytic asym-
metric epoxidation based upon dibenzazepinium salts are reported,
providing ee of up to ca 60%.
Ph
R1
ee : 30 to 60%
O
Oxone (2 eq), Na2CO3 (4 eq)
R1
R2
CH3CN : H2O (1:1), O °C, 2 h
R2
Key words: epoxidation, asymmetric, iminium salt, catalysis
BPh4
N
C*
5 mol %
Oxaziridinium salts were first reported in 1976 by Lusin-
chi,3 and are extremely reactive reagents for oxygen trans-
fer to nucleophilic substrates, including sulfides and
alkenes.4,5 Dihydroisoquinolinium salts 1 (Figure 1) cata-
lyze the epoxidation of simple olefins in the presence of
Oxone as the stoichiometric oxidant, the corresponding
racemic oxaziridinium salts being presumed to be the ac-
tive oxidants.6 The first enantiomerically pure oxaziridin-
ium salt 2 was shown by Lusinchi to induce asymmetric
epoxidation of alkenes,7 and the corresponding iminium
salt catalyses epoxidation using Oxone , typically in
aqueous acetonitrile as the solvent mixture; ee of up to ca
40% have been obtained. A binaphthalene-derived imini-
um salt has been reported to catalyze asymmetric epoxi-
dation of simple alkenes under similar conditions.8
Scheme 1
BPh4
BPh4
N+
N
O
3
4
Ph
O
Figure 2
the observed enantiomeric excesses of up to ca 60% leave
room for improvement.
In our ongoing programme to develop new and more se-
lective catalysts based on iminium salts we have prepared
the first members of a new family of catalysts, in which
the dihydroisoquinolinium moiety has been replaced by a
biphenyl structure fused to a seven-membered azepinium
salt. Again, the chirality resides in the exocyclic nitrogen
substituent. A BINAP-derived seven-membered ring sys-
tem achiral at the nitrogen substituent has been previously
reported.8
Armstrong and others have shown that even acyclic imin-
9
ium salts can mediate epoxidation by Oxone
.
Ph
X
BF4
N
N
O
R
1
2
The preparation of this new family of catalysts is carried
out by treatment of 2,2 -bis(hydroxymethyl)biphenyl 5
with HBr to give the dibenzoxepine 6 in 88% yield. Reac-
tion of this material with bromine gives rise to bromoalde-
hyde 7 directly in 59% yield. Cyclocondensation with an
amine then produces the iminium salt catalyst
(Scheme 2).
Figure 1
We have previously described a new type of cyclic chiral
iminium salt epoxidation catalyst containing the asym-
metric centres in an exocyclic substituent at the nitrogen
atom of a dihydroisoquinolinium salt, as illustrated in
Scheme 1. Two of the most effective systems are catalysts
3 and 4, giving ees of up to ca 60% (Figure 2).10
We report here the synthesis and use as epoxidation cata-
lysts of two new iminium salts prepared following this
procedure: the (–)-IPC catalyst 8 and the dioxolane cata-
lyst 9 (Figure 3), produced in 60% and 68% yields respec-
tively from the corresponding amine and the
bromoaldehyde 7.11 These two amine precursors were se-
lected as they are the amine parents of two of the more ef-
fective of our dihydroisoquinolinium catalysts 3 and 4.
These salts catalyze the asymmetric epoxidation of un-
functionalized alkenes using Oxone in aqueous aceto-
nitrile. Complete retention of stereochemistry is observed,
suggesting a single-step oxygen transfer process. Good
yields of epoxides are obtained (typically 60 to 70%), but
In the Table is shown a comparison of the results of cata-
lytic epoxidation reactions using catalysts 4, 8, and 9 un-
der our standard conditions. It is clear that both of the new
Synlett 2002, No. 4, 29 03 2002. Article Identifier:
1437-2096,E;2002,0,04,0580,0582,ftx,en;D00402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
New Organocatalysts for the Asymmetric Catalytic Epoxidation of Alkenes
581
Table Catalytic Asymmetric Epoxidation Using Catalysts 4, 8
Br
and 9a
OH
OH
Br2, CCl4
HBr conc
O
O
Catalyst
Epoxide
4
8
9
80 °C, 1h
88 %
0 °C to reflux
In each case: conv/%b; ee/%c; reaction time/
min; major enantiomer
5
64d, 20, 5,
90, 3, 5,
100, 24, 10,
Me
Ph
O
O
O
59 %
(+)-R
(+)-R
(+)-R
56d, 15, 120, 95, 0, 5
90, 15, 10,
Ph
Ph
(–)-S,S
(–)-S,S
Ph
Ph
BPh4
R
52d, 52, 60,
93, 14, 10,
95, 37, 5,
RNH2
Br
N
(–)-1S,2S
(+)-1R,2R
(–)-1S,2S
EtOH, NaBPh4
Me
O
54d, 59, 40,
(+)-S
100, 17, 10,
(+)-S
90, 59, 3,
(+)-S
O
7
Ph
6
Ph
Ph
Scheme 2
55d, 41, 5,
(–)-1S,2S
100, 29, 5,
(+)-1R,2R
100, 60, 3,
(–)-1S,2S
O
Ph
64d, 49, 5,
(–)-1S,2R
95, 38, 10,
(–)-1S,2R
90, 41, 3,
(–)-1S,2R
Ph
BPh4
O
O
BPh4
N
N
O
9
8
Ph
O
52, 17, 5,
95, 8, 5,
100, 10, 3,
(+)-1S,2R
(+)-1S,2R
(+)-1S,2R
Figure 3
a Conditions: Oxone™ (2 equiv), sodium carbonate (4 equiv), wa-
ter/acetonitrile (1:1), 0 °C, 5 mol% catalyst.
b Conversion evaluated by 1H NMR spectroscopy by integration of
alkene versus epoxide.
seven-membered ring catalysts are more reactive in the
epoxidation reaction than is the six-membered ring cata-
lyst 4. Catalyst 8 however gives poorer ees than catalyst 4
in all cases. Catalyst 9 provides ees of up to 60%, although
with a somewhat different pattern of selectivity from cat-
alyst 4, for example giving an improved 60% ee for phe-
nylcyclohexene, but an identical 59% ee for
triphenylethylene, and even a 15% ee for trans-stilbene,
which is not enantioselectively oxidized by any of our
other catalysts except 4. All the reactions with catalyst 9
are complete in ten minutes or less at 0 °C. In two cases,
methylstilbene and phenylcyclohexene oxides, the major
enantiomers produced are different for the two new cata-
lysts 8 and 9. This behaviour mirrors that of the corre-
sponding dihydroisoquinolinium salt catalysts; the
reasons remain unclear at present. A complicating feature
of these processes is that two diastereoisomeric oxaziri-
dinium salts may be formed by attack of oxidant at the si
or re face of the iminium species. Each might deliver the
oxygen atom to either of the prochiral faces of the alkene
substrate with a different degree of enantiocontrol, and
they may be in competition for the alkene substrate.
c Ee determined by 1H NMR spectroscopy using Eu(hfc)3 (0.1 mol
equiv) as shift reagent.
d Isolated yield.
References
(1) Robert Robinson Laboratories, Department of Chemistry,
University of Liverpool, Oxford Street, Liverpool L69 3BX,
England.
(2) AstraZeneca Charnwood, Bakewell Road, Loughborough,
Leicestershire LE11 5RH, England.
(3) (a) Milliet, P.; Picot, A.; Lusinchi, X. Tetrahedron Lett.
1976, 1573. (b) Milliet, P.; Picot, A.; Lusinchi, X.
Tetrahedron Lett. 1976, 1577.
(4) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett.
1987, 28, 6061.
(5) Hanquet, G.; Lusinchi, X.; Milliet, P. Tetrahedron Lett.
1988, 29, 3941.
(6) (a) Hanquet, G.; Lusinchi, X.; Milliet, P. C. R. Hebd.
Seances Acad. Sci. 1991, 313 ( S11), 625. (b) Lusinchi, X.;
Hanquet, G. Tetrahedron 1997, 53, 13727.
(7) (a) Bohé, L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X.
Tetrahedron Lett. 1993, 34, 7271. (b) Bohé, L.; Lusinchi,
M.; Lusinchi, X. Tetrahedron 1999, 55, 141.
(8) Aggarwal, V. K.; Wang, M. F. Chem. Commun. 1996, 191.
(9) (a) Armstrong, A.; Ahmed, G.; Garnett, I.; Gioacolou, K.
Synlett 1997, 1075. (b) Armstrong, A.; Draffan, A. G.
Synlett 1998, 646. (c) Armstrong, A.; Ahmed, G.; Garnett,
I.; Gioacolou, K.; Wailes, J. S. Tetrahedron 1999, 55, 2341.
(d) Minakata, S.; Takemiya, A.; Nakamura, K.; Ryu, I.;
Acknowledgement
We are indebted to the EPSRC, The Leverhulme Trust, and Astra-
Zeneca for financial support.
Synlett 2002, No. 4, 580–582 ISSN 0936-5214 © Thieme Stuttgart · New York

582
P. C. B. Page et al.
LETTER
Komatsu, M. Synlett 2000, 1810. (e) Wong, M.-K.; Ho, L.-
M.; Zheng, Y.-S.; Ho, C.-Y.; Yang, D. Org. Lett. 2001,
2587.
(3.85 g, 18.8 mmol).12 The product was isolated as yellow
plates (9.0 g, 68%), mp 187–188 °C(dec); [ ]20D –44.0 (c
1.01, CH3CN). Found: C, 85.23; H, 6.52; N, 1.96.
(10) (a) Page, P. C. B.; Rassias, G. A.; Barros, D.; Bethell, D.;
Schilling, M. B. J. Chem. Soc, Perkin Trans. 1 2000, 3325.
(b) Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.;
Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z.
J. Org. Chem. 2001, 6926.
C50H46BNO2 requires C, 85.34; H, 6.59; N, 1.99. max(film)/
cm–1: 3055, 3038, 2999, 1633, 1579, 1480, 1451, 1385,
1203, 1114, 848, 735, 706. 1H NMR (400 MHz, DMSO-d6,
115 °C): = 1.71 (3 H, s), 1.74 (3 H, s), 4.32 (1 H, d, J = 21.8
Hz), 4.49 (1 H, d, J = 21.6 Hz), 4.68–4.77 (1 H, m), 4.72
(1 H, dd, J = 5.20, 21.8 Hz), 5.15 (1 H, d, J = 22.2 Hz), 5.82
(1 H, d, J = 4.1 Hz), 6.75 (4 H, t, J = 11.4 Hz), 6.88 (8 H, t,
J = 11.5 Hz), 7.11–7.16 (5 H, m), 7.20–7.25 (8 H, m), 7.55–
7.63 (3 H, m), 7.64–7.69 (3 H, m), 7.92–7.94 (2 H, m), 9.03
(1 H, s); 13C NMR (100 MHz, DMSO-d6, 120 °C): = 18.05,
28.41, 42.73, 60.81, 66.12, 70.48, 99.87, 120.42, 124.10,
124.16, 124.19, 124.39, 127.32, 127.59, 128.19, 129.00,
129.39, 132.58, 133.57, 134.95, 135.23, 140.48, 163.32,
171.11; m/z = 384.1968; C26H26NO2(cation) requires
384.1964.
(11) 5,7-Dihydrodibenzo[c,e]oxepine
A suspension of 2,2 -biphenyl dimethanol, (4.22 g, 19.5
mmol), in hydrobromic acid (60 mL, 24% in water), was
heated to 100 °C for 40 min. The cloudy solution was
allowed to cool and the aq phase extracted with diethyl ether
(3 50 mL). The organic layers were washed with sat. aq
sodium hydrogen carbonate (50 mL) and brine (50 mL) and
dried over magnesium sulfate. The solvent was removed
under reduced pressure to yield a colorless solid, which was
recrystallized from ethyl acetate/light petroleum to give
colorless crystals (3.25 g, 88%), mp 71–72 °C. Found: C,
85.57; H, 6.10. C14H12O requires C, 85.68; H, 6.17.
max(film)/cm–1: 1567, 1197, 1073, 1042, 903, 891, 754, 602.
1H NMR (400 MHz, CDCl3): = 4.42 (4 H, s), 7.45–7.50 (4
H, m), 7.53–7.58 (2 H, m), 7.60–7.63 (2 H, m); 13C NMR
(100 MHz, CDCl3): = 67.53, 127.46, 128.24, 128.91,
129.69, 135.16, 141.19; m/z = 196.0887; C14H12O [M+]
requires 196.0888.
2-[2-(Bromoethyl)phenyl]benzene Carbaldehyde
To an ice-cooled solution of 5,7-dihydrodibenzo[c,e]oxe-
pine (2.00 g, 10.2 mmol), in carbon tetrachloride (50 mL), in
a round bottom flask equipped with a reflux condenser was
added molecular bromine (1.76 g, 11.0 mmol), in carbon
tetrachloride (6 mL), dropwise over 5 min (the reaction
turned deep red). The cooling bath was removed and the
reaction mixture heated under reflux until pale yellow and
liberation of HBr ceased (ca 1 h). The solvent was removed
under reduced pressure, diluted with diethyl ether (100 mL),
washed with sat. aq sodium carbonate (2 50 mL) and brine
(50 mL) and dried over magnesium sulfate. The solvents
were removed under reduced pressure to yield a pale yellow
oil, which was recrystallized from ethyl acetate/light
petroleum to give a colorless solid (1.66 g, 59%), mp 56–
58 °C; max(nujol)/cm–1: 1694, 1594, 1255, 1221, 1197, 761.
1H NMR (250 MHz, CDCl3): = 4.30 (2 H, dd, J = 27.1, 10.1
Hz), 7.22 (1 H, dd, J = 7.8, 1.6 Hz), 7.32–7.50 (3 H, m), 7.55
(2 H, dd, J = 6.1, 1.5 Hz), 7.66 (1 H, dd, J = 7.4, 1.6 Hz), 8.07
(1 H, dd, J = 8.2, 1.6 Hz), 9.74 (1 H, s); 13C NMR (100 MHz,
CDCl3): = 33.83, 129.96, 130.88, 131.02, 131.40, 133.00,
133.05, 133.39, 135.95, 136.41, 138.28, 140.16, 145.63,
194.08; m/z = 275.9977; C14H11BrO [M+] requires 275.9974.
General Procedure for the Synthesis of Dibenzo[c,e]aze-
pinium Salts from 2-[2-(Bromoethyl)phenyl]benzene
Carbaldehyde and Primary Amines
(+)-6-[(1R,2R,3R,5S)-2,6,6-Trimethylbicyclo[3.1.1]hept-
3-yl]-5H-dibenzo[c,e]azepinium Tetraphenylborate
Prepared according to the general procedure from (–)-
isopinocamphenylamine (3.12 g, 20.5 mmol).13 The product
was isolated as yellow plates (8.0 g, 60%), mp 212 °C (dec);
[ ]20D +22.4 (c 1.00, CH3CN). Found: C, 87.81; H, 7.20; N,
1.95. C48H48BN 0.3 H2O requires C, 87.79; H, 7.37; N, 2.13.
max(nujol)/cm–1: 1630, 1599, 1580, 1557, 1209, 756, 705,
612. 1H NMR (400 MHz, DMSO-d6, 80 °C): = 1.02 (3 H,
d, J = 11.3 Hz), 1.14 (3 H, s), 1.35 (3 H, s), 1.48 (1 H, d, J =
16.8 Hz), 2.02 (1 H, td, J = 9.3, 2.6 Hz), 2.10–2.31 (2 H, m),
2.55–2.74 (3 H, m), 4.84–5.12 (3 H, m), 6.80 (4 H, t, J = 11.4
Hz), 6.93 (8 H, t, J = 11.8 Hz), 7.20–7.29 (8 H, m), 7.61–7.92
(6 H, m), 8.02 (1 H, td, J = 11.6, 2.2 Hz), 8.07–8.16 (1 H, m),
9.69 (1 H, s); 13C NMR (100 MHz, DMSO-d6, 80 °C):
19.92, 23.76, 28.97, 33.69, 34.80, 40.00, 41.12, 42.15,
=
48.36, 53.99, 74.28, 122.23, 125.96, 127.77, 129.41, 129.65,
129.94, 130.31, 130.69, 131.08, 131.12, 135.41, 135.74,
136.55, 137.93, 141.90, 164.50, 171.15; m/z 330.2228;
C24H28N(cation) requires 330.2222.
General Procedure for Catalytic Asymmetric
Epoxidation of Unfunctionalized Alkenes Mediated by
Iminium Salts
To an ice-cooled solution of sodium carbonate (4 equiv), in
water (12 mL per 1.20 g of sodium carbonate), Oxone (2
equiv) is added with stirring, and the resulting foaming
solution is stirred for 5–10 min, until most of the
effervescence subsides. The iminium salt (5 mol% with
respect to the substrate) is added as a solution in acetonitrile
(6 mL per 1.20 g of sodium carbonate used), followed by the
alkene substrate (1 equiv), also as a solution in acetonitrile in
the same volume as the solution of the catalyst. The
suspension is stirred at 0 °C until the substrate is completely
consumed (TLC analysis). The reaction mixture is diluted
with ice-cooled diethyl ether (20 mL per 100 mg substrate)
and this is immediately followed by the addition of the same
volume of water. The aq phase is extracted four times with
diethyl ether, the organic solutions are combined, washed
with brine, and dried over magnesium sulfate. Filtration and
evaporation of the solvents furnishes the product as a yellow
or light brown residue which is purified by column
chromatography, typically using ethyl acetate/light
petroleum 1:99 to produce the pure epoxide.
A solution of the amine in ethanol, (10 mL per g of amine, 1
equiv), is added dropwise to a pre-cooled solution of 2-[2-
(bromoethyl)phenyl]benzene carbaldehyde (1.10 equiv) in
ethanol (10 mL per g) at 0 °C. The reaction mixture is stirred
overnight while attaining ambient temperature. Sodium
tetraphenylborate, (1.10 equiv), dissolved in the minimum
amount of acetonitrile, is added in one portion and the
reaction mixture stirred for 5 min. The solvents are removed
under reduced pressure and ethanol is added to the residue,
followed by water. The resulting solid is collected by
filtration and washed with ethanol followed by diethyl ether.
(–)-2-[(4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl]-
5H-dibenzo[c,e]azepinium Tetraphenylborate
(12) Nordin, I. C.; Thomas, J. A. Tetrahedron Lett. 1984, 25,
5723.
(13) The IUPAC name for (–)-isopinocamphenylamine is (–)-6-
(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-
ylamine.
Prepared according to the general procedure from
(+)-(4S,5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-amine
Synlett 2002, No. 4, 580–582 ISSN 0936-5214 © Thieme Stuttgart · New York