New chiral binaphthalene-derived iminium salt organocatalysts for asymmetric epoxidation of alkenes

Article abstract of DOI:10.1021/jo070255w

(Chemical Equation Presented) A series of binaphthalene-fused azepinium salts has been generated and used as organocatalysts in the asymmetric epoxidation of unfunctionalized alkenes, giving rise to ees of up to 84%.

Full text of DOI:10.1021/jo070255w

New Chiral Binaphthalene-Derived Iminium Salt Organocatalysts
for Asymmetric Epoxidation of Alkenes
Philip C. Bulman Page,*,† Mohamed M. Farah,† Benjamin R. Buckley,† and
A. John Blacker‡
Department of Chemistry, Loughborough UniVersity, Loughborough, Leicestershire LE11 3TU, England,
and NPIL Pharmaceuticals (UK) Ltd, P O Box 521, Leeds Road, Huddersfield HD2 1GA, U.K.
p.c.b.page@lboro.ac.uk
ReceiVed February 23, 2007
A series of binaphthalene-fused azepinium salts has been generated and used as organocatalysts in the
asymmetric epoxidation of unfunctionalized alkenes, giving rise to ees of up to 84%.
Introduction
organocatalyst for the asymmetric epoxidation of alkenes are
chiral dioxiranes, oxaziridinium salts, oxaziridines, and amines.4
Chiral dioxiranes, derived in situ from the oxidation of chiral
ketones by the triple salt oxone (KHSO5‚KHSO4‚K2SO4), have
emerged as one group of the most effective mediators of
asymmetric epoxidation of alkenes.5 Excellent enantioselectivi-
ties have been achieved with trisubstituted and trans-alkenes,
while moderate to good selectivity is achieved for other alkenes.6
The main limiting factor in chiral dioxirane-catalyzed epoxi-
dation is the high catalyst loading required, presumably due to
decomposition of the catalysts, for example through Baeyer-
Villiger oxidation.7
The development of catalytic asymmetric epoxidation of
unfunctionalized alkenes is an ongoing synthetic endeavor due
to the enormous synthetic versatility of epoxides. The chiral
manganese salen complexes independently developed by Ja-
cobsen and Katsuki can give remarkably high enantioselectivity
for cis-alkenes.1 However, trans-alkenes tend to be poor
substrates. Recently, catalytic methods based on metal-free
organic molecules (organocatalysis) have emerged as a powerful
complement to metal- and biocatalysis.2 From a practical point
of view, the use of organocatalysis has the advantages that the
catalysts are commonly inexpensive and stable, and hence some
reactions can be performed under aerobic and even wet
conditions. The practical advantages of organocatalysis, coupled
with the need to improve enantioselectivity and extend the
generality of application in terms of substrate structure, have
spurred the development of organocatalytic asymmetric epoxi-
dation methods.3 Currently, the most utilized types of chiral
(4) Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A. Chem. ReV. 2001,
101, 3499.
(5) Reviews: Frohn, M.; Shi, Y. Synthesis 2000, 1979-2000; Shi, Y.
Acc. Chem. Res. 2004, 37, 488; Yang, D. Acc. Chem. Res. 2004, 37, 497;
Imashiro, R.; Seki, M. J. Org. Chem. 2004, 69, 4216; Li, W.; Fuchs, P. L.
Org. Lett. 2003, 5, 2853; Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58,
2481; Denmark, S. E.; Matsuhashi, H. J. J. Org. Chem. 2002, 67, 3479;
Bortolini, O.; Fantin, G.; Fogagnolo, M.; Forlani, R.; Maietti, S.; Pedrini,
P. J. Org. Chem. 2002, 67, 5802; Armstrong, A.; Hayter, B. R.; Moss, W.
O.; Reeves, J. R.; Wailes, J. S. Tetrahedron: Asymmetry 2000, 11, 2057;
Armstrong, A.; Moss, W.; Reeves, J. R. Tetrahedron: Asymmetry 2001,
12, 2779; Armstrong, A.; Tsuchiya, T. Tetrahedron 2006, 62, 257.
(6) Wang, Z. X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806; Tian, H.
Q.; Shu, L. H.; Yu, H. W.; Shi, Y. J. Am. Chem. Soc. 2000, 122, 11551;
Tian, H. Q.; She, X. G.; Xu, J. X.; Shi, Y. Org. Lett. 2001, 3, 1929; Tian,
H. Q.; She, X. G.; Yu, H. W.; Shu, L. H.; Shi, Y. J. Org. Chem. 2002, 67,
2435; Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5794.
* Author to whom correspondence should be addressed. Phone: 44-1509-
222-580. Fax: 44-1509-223-926.
† Loughborough University.
‡ NPIL Pharmaceuticals.
(1) For a review, see (a) Jacobsen, E. N.; Wu, M. H. in ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.;
Springer: Berlin, 1999; Vol. 2, p649.
(2) See for example, Saeyad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719; Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726; Dalko,
P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(3) Armstrong, A. Angew. Chem., Int. Ed. 2004, 43, 1460.
(7) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; Depue, J. S.; Wilde, R.
G. J. Org. Chem. 2002, 60, 1391.
10.1021/jo070255w CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/17/2007
4424
J. Org. Chem. 2007, 72, 4424-4430

Chiral Iminium Salt Organocatalysts
FIGURE 1. Examples of chiral iminium salts from the literature.
Chiral oxaziridines have extensively been utilized by Davis8
and ourselves9 for the asymmetric oxidation of sulfides to
sulfoxides. The use of chiral oxaziridines in the asymmetric
epoxidation of alkenes is, however, less versatile, although the
first (achiral) catalytic epoxidation using such reagents has
recently been reported.10 A close relative of oxaziridine-mediated
epoxidation involves the use of oxaziridinium salts. Oxaziri-
dinium salts generated in situ from iminium salts with oxone
were shown by Lusinchi to be effective electrophilic oxidants
for epoxidation of alkenes, rendering the development of
catalytic processes possible.11 The first enantiomerically pure
iminium salt to be used in this way was 1, with the controlling
asymmetric centers sited in the saturated ring of a dihydroiso-
quinolinium salt, and was shown to catalyze epoxidation of
alkenes, affording ees of up to about 40% (Figure 1).12 Even
exocyclic iminium salts such as 2, derived from condensation
of enantiopure pyrrolidine moieties with aromatic aldehydes,
can afford moderate ees (up to 22%) with relatively high catalyst
loadings necessary (up to 100 mol %), perhaps due to in situ
hydrolysis of the iminium units.13
an electron-withdrawing substituent (such as hydroxyl and
fluorine groups) at the â-position to the amine group to be
beneficial for catalytic activity.
Our own contribution has been to design chiral iminium salts
that contain asymmetric centers in the exocyclic nitrogen
substituent, based upon the reasoning that such designs would
bring the enantiocontrolling asymmetric centers closer to the
site of oxygen transfer and hence potentially increase enantio-
selectivity.16 Accordingly, we have reported several series of
catalysts including a number, e.g., 3-6, that contain chiral
moieties related to (4S,5S)-5-amino-2,2-dimethyl-4-phenyl-1,3-
dioxane (acetonamine).
While catalyst 3 gives moderate enantioselectivity (up to 59%
ee), catalyst 4, incorporating a biphenyl structure, was found
to be highly reactive, inducing complete epoxidation of alkenes
within 1-10 min in aqueous acetonitrile at 0 °C; it is thus the
most reactive iminium salt epoxidation catalyst discovered to
date.17 Lacour has reported the epoxidation of alkenes catalyzed
by 4 but using an enantiomerically pure TRISPHAT counterion
and a biphasic CH2Cl2/water solvent system.18 Catalyst 5,
containing a p-methylsulfonyl group, excelled in the epoxidation
of cyclic cis-alkenes, affording up to 97% ee.19 We have also
developed a range of azepinium salt catalysts containing a
binaphthalene backbone and exocyclic N-isopinocampheyl or
N-aminoacetal groups. In this group, catalyst 6 proved to be
the most reactive and enantioselective, giving up to 95% ee.20
Some years ago, Aggarwal described a binaphthalene-fused
azepinium salt catalyst 7, prepared from dibromide 8,21 bearing
Recently, chiral secondary amines have been shown to
catalyze the asymmetric epoxidation of alkenes, giving up to
66% ee.14 Yang also screened a range of chiral secondary amines
for catalytic activity.15 These studies revealed the presence of
(8) Davis, F. A.; Haracal, M. E.; Awad, S. B. J. Am. Chem. Soc. 1983,
105, 3123; Davis, F. A.; Lal, S. G. J. Org. Chem. 1988, 53, 5004; Davis,
F. A.; Thimma Reddy, R.; Weismiller, M. C. J. Am. Chem. Soc. 1989,
111, 5964; Davis, F. A.; Reddy, R. E.; Kasu, P. V. N.; Portonovo, P. S.;
Carroll, P. J. J. Org. Chem. 1997, 62, 3625.
(9) Page, P. C. B.; Heer, J. P.; Bethell, D.; Collington, E. W.; Andrews,
D. M. Tetrahedron: Asymmetry 1995, 6, 2911; Rebek, J.; McCready, R. J.
Am. Chem. Soc. 1980, 102, 5602; Page, P. C. B.; Heer, J. P.; Bethell, D.;
Collington, E. W.; Andrews, D. M. Tetrahedron Lett. 1994, 35, 3625.
(10) Brodsky, B. H.; Du Bois, J. J. Am. Chem. Soc. 2005, 127, 15391.
(11) Hanquet, G.; Lusinchi, X.; Millet, P. Tetrahedron Lett. 1987, 28,
6061; Hanquet, G.; Lusichi, X.; Millet, P. Tetrahedron Lett. 1988, 29, 3941;
Hanquet, C.; Lusinchi, X.; Milliet, P. C. R. Acad. Sci. Paris 1991, 313 S.
II, 625; Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727.
(12) Bohe´, L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahedron Lett.
1993, 34, 7271; Bohe´ L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999,
55, 141.
(15) Ho, C. Y.; Chen, Y. C.; Wong, M. K.; Yang, D. J. Org. Chem.
2005, 70, 898.
(16) Page, P. C. B.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Org.
Chem. 1998, 63, 2774; Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani,
A.; Buckley, B.; Bethell, D.; Smith, T. A. D.; Slawin, A. M. Z. J. Org.
Chem. 2001, 66, 6926; Page, P. C. B.; Rassias, G. A.; Bethell, D.; Schilling,
M. B. J. Chem. Soc., Perkin Trans 1 2000, 3325.
(17) Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.; Buckley,
B.; Bethell, D.; Merifield, E. Synlett 2002, 4, 580.
(18) (a) Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002,
43, 8257; (b) Vachon, J.; Pe´rollier, C.; Monchaud, D.; Marsol, C.; Ditrich,
K.; Lacour, J. J. Org. Chem. 2005, 70, 5903; Vachon, J.; Lauper, K. H.;
Ditrich, K.; Lacour, J. Tetrahedron: Asymmetry 2006, 17, 2334; Vachon,
J.; Rentsch, S.; Martinez, A.; Marsol, C.; Lacour, J. Org. Biomol. Chem.
2007, 5, 501.
(13) Armstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K. Synlett 1997,
1075; Armstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K.; Wailes, S.
Tetrahedron 1999, 55, 2341.
(14) Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J. Am. Chem.
Soc. 2000, 122, 8317; Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A. J.
Am. Chem. Soc. 2002, 124, 11223; Aggarwal, V. K.; Lopin, C.; Sandrinelli,
F. J. Am. Chem. Soc. 2003, 125, 7596.
(19) Page, P. C. B.; Buckley, B. R.; Heaney, H.; Blacker, A. J. Org.
Lett. 2005, 7, 375.
(20) Page, P. C. B.; Buckley, B. R.; Blacker, A. J. Org. Lett. 2004, 6,
1543.
J. Org. Chem, Vol. 72, No. 12, 2007 4425

Page et al.
SCHEME 1
TABLE 1. Preparation of Iminium Salt Catalysts from Dibromide
8 and Bromoaldehyde 10
an achiral methyl group as the nitrogen substituent, which was
reported to give up to 71% ee in the epoxidation of 1-phenyl-
cyclohexene.22 Other achiral nitrogen substituents in this system
were claimed in the patent literature, together with reported ees
for the epoxidation of 1-phenylcyclohexene mediated by the
methyl-, ethyl-, and benzyl-substituted catalysts.23 We conjec-
tured that the enantioselectivity of these azepinium salt catalysts
might be enhanced if a sterically bulkier group were added at
the nitrogen atom, and we describe herein the synthesis of
iminium salts 9a-e and their use as organocatalysts in the
epoxidation of several alkenes.
Results and Discussion
The required binaphthyl azepinium salts were readily prepared
in good yields over two steps from bromoaldehyde 10 as we
have described previously (9a, 9b) by cyclocondensation with
primary amines,20 or from (R)-2,2′-bis(bromomethyl)[1,1′]-
binaphthalene 8 (9c, 9d, 9e) by double displacement of bromide
from 8 with primary amines followed by oxidation to the
iminium species and cation exchange in good overall yields
(Scheme 1, Table 1).
With these catalysts in hand, three alkene substrates were
tested, initially with catalysts 9a and 9b, derived from tert-
butylamine and 2,6-xylidene, respectively, under our standard
aqueous conditions, using a 1:1 ratio of acetonitrile to water as
solvent in the presence of Na2CO3 (Table 2).
As illustrated in Table 2, both catalyst 9a and 9b were
relatively unreactive, leading for example to maximum conver-
sions of 78% and 40%, respectively, when 1-phenylcyclohexene
was used as a substrate (Table 2). Prolonged reaction times of
up to 6 h did not improve the conversions. The poor reactivity
of these catalysts is highlighted by the epoxidation of trans-R-
methylstilbene and triphenylethylene, where extremely poor
conversions to epoxides were observed. Catalyst 9a, however,
afforded an excellent 84% ee in the epoxidation of 1-phenyl-
cyclohexene, so proving to be much more enantioselective than
9b (40% ee).
base rather than Na2CO3), an increase in conversion was
observed when using catalysts 9a and 9b and trans-R-methyl-
stilbene as a substrate. These conditions, however, tend to
produce diol products in some cases, presumably through in
situ hydrolysis of the epoxides, an effect which is exacerbated
by use of an increased proportion of water.
This observed increase in conversion may arise from the
increase in substrate solubility with added organic solvent. Use
of a 10:1 ratio of acetonitrile to water with Na2CO3 as base
does not, however, produce a significant increase in conversion.
The slightly acidic conditions might also be responsible for the
increased conversion, as oxone is known to decompose at higher
pH.25 Despite the high enantioselectivity provided by catalyst
9a, we abandoned its further use due to its poor reactivity, which
perhaps results from high steric bulk at the nitrogen substituent.
We next screened catalysts 9c-e, with a range of structural
features in the nitrogen substituents but with less bulk than 9a
proximal to the azepinium ring, under these reaction conditions
(Table 2). Catalysts 9c and 9e provide identical reactivity.
Catalyst 9e imparts higher enantioselectivities for most substrates
than does catalyst 9c and is similar in enantioselectivity to 9a
while providing much greater reactivity and thus providing the
Interestingly, when the reaction conditions were amended to
those of Yang,24 to use a 10:1 ratio of acetonitrile to water as
solvent and slightly more acidic conditions (use of NaHCO3 as
(21) Hawkins, J. M.; Fu, G. C. J. Org. Chem. 1986, 51, 2820; Hawkins,
J. M.; Lewis, T. A. J. Org. Chem. 1994, 59, 649.
(22) Aggarwal, V. K.; Wang, F. M. Chem. Commun. 1996, 191.
(23) Aggarwal, V. K. GB patent 9516309, Aug 9, 1995; Aggarwal, V.
K. WO patent 9706147, Feb 20, 1997; Aggarwal, V. K. US patent 6,063,920,
May 16, 2000.
(24) Wong, M. K.; Ho, L. M.; Zheng, Y. S.; Ho, C. Y.; Yang, D. Org.
Lett. 2001, 3, 2587.
(25) For details of the stability of Oxone, see www.dupont.com/oxone/
techinfo/index.html.
4426 J. Org. Chem., Vol. 72, No. 12, 2007

Chiral Iminium Salt Organocatalysts
TABLE 2. Asymmetric Epoxidation of Alkenes with Catalysts 9a-e
a Conversions were evaluated from the 1H NMR spectra by integration of alkene/diol/ epoxide signals. b Isolated yield. c Enantiomeric excesses were
1
determined by H NMR spectroscopy with Eu(hfc)3 (10 mol %) as chiral shift reagent, or by chiral HPLC on a Chiralcel OD column, or by chiral GC on
a Chiraldex B-DM column. d The absolute configurations of the major enantiomers were determined by comparison with literature values. e Epoxidation
conditions: iminium salt (5 mol %), Oxone (2 equiv), Na2CO3 (4 equiv), MeCN:H2O (1:1), 0 °C, 2 h. f Epoxidation conditions: iminium salt (5 mol %),
Oxone (2 equiv), NaHCO3 (5 equiv), MeCN:H2O (10:1), 0 °C, 2 h.
best balance of selectivity and reactivity, presumably resulting
in part from the size and shape of the isopropyl nitrogen
substituent. For example, 1-phenylcyclohexene and trans-R-
methyl stilbene are epoxidized with 82% and 64% ee, respec-
tively, using catalyst 9e compared to 72% and 51% ee with
catalyst 9c. Catalyst 9d was less enantioselective than 9c and
9e, affording similar enantioselectivities (up to 71% ee) to the
catalyst 7 developed by Aggarwal.22
position of the aromatic ring (Table 2). Once again, we observed
excellent conversions to epoxides and moderate enantioselec-
tivities. Interestingly, all the cycloalkenes gave poorer enantio-
selectivities than 1-phenylcyclohexene and 1-phenyl-3,4-dihy-
dronaphthalene. It is also unclear why alkenes containing a para-
substituted electron-withdrawing (SO2Me) group and alkenes
containing an electron-donating (OMe) group both gave lower
enantioselectivities than the parent 1-phenylcyclohexene.
A number of other alkenes were next subjected to epoxidation
mediated by catalyst 9e (Table 3).
Because of the slightly more acidic nature of the reaction
mixture, hydrolysis of some of the epoxides to the corresponding
diols occurs in some instances, particularly for 1-phenyl-3,4-
dihydronaphthalene and p-methoxy-1-phenylcyclohexene sub-
strates, where complete conversion to the corresponding diols
is observed in 2 h. When 1-phenylcyclohexene was used as a
substrate, we observed between 11 and 20% conversion to the
Catalyst 9e proved to be the most effective catalyst of this
series, achieving >90% conversion for all substrates and
moderate to good enantioselectivities (21-83% ee). Catalyst
9e was also utilized in the epoxidation of a range of cycloalkenes
incorporating groups with different electronic effects at the para-
J. Org. Chem, Vol. 72, No. 12, 2007 4427

Page et al.
TABLE 3. Asymmetric Epoxidation of Alkenes with Catalyst 9ea
a Epoxidation conditions: iminium salt (5 mol %), Oxone (2 equiv), NaHCO3 (5 equiv), MeCN:H2O (10:1), 0 °C, 2 h, unless otherwise indicated.
b Conversions were evaluated from the 1H NMR spectra by integration of alkene/diol/epoxide signals. c Isolated yield. d Enantiomeric excesses were determined
1
by H NMR spectroscopy with Eu(hfc)3 (10 mol %) as chiral shift reagent, or by chiral HPLC on a Chiralcel OD column, or by chiral GC on a Chiraldex
B-DM column. e The absolute configurations of the major enantiomers were determined by comparison with literature values except where indicated.
f Epoxidation conditions: iminium salt (5 mol %), Oxone (2 equiv), Na2CO3 (4 equiv), MeCN:H2O (1:1), 0 °C, 2 h. g Reaction under Yang’s conditions
(footnote a) is capricious. h The absolute configurations of the major enantiomers were assigned by analogy with other examples on the basis of substrate
and catalyst structure, and spectroscopic evidence.
4428 J. Org. Chem., Vol. 72, No. 12, 2007

Chiral Iminium Salt Organocatalysts
5 min, and the solvents were removed under reduced pressure. The
yellow residue was dissolved in dichloromethane (40 mL per gram
of amine) and washed with water (2 × 30 mL per gram of amine)
and brine (2 × 30 mL per gram of amine), the organic phase was
dried (Na2SO4), and the solvents were removed in Vacuo. The
yellow solid was recrystallized from ethanol, washed with ethanol
followed by hexanes, and dried at 90 °C.
diol. This hydrolysis of the epoxide products was obviated by
use of our more basic epoxidation conditions (Oxone, Na2CO3,
MeCN:H2O (1:1)).
Recent studies by Lacour have shown biphenyl- and binaph-
thyl-derived tertiary azepines and their corresponding iminium
salts both to be effective epoxidation catalysts in the presence
of Oxone and sodium bicarbonate, leading to epoxides of almost
identical enantioselectivities and configurations.26 The amines
were observed to perform best in terms of both enantioselectivity
and conversion when monophasic 10:1 acetonitrile/water reac-
tion conditions were used, while the iminium salts in some cases
gave better results in biphasic 3:2 dichloromethane/water
conditions in the presence of 18-crown-6, which presumably
acts as a phase transfer catalyst.
(R)-N-2,6-Dimethylphenyl-7H-dinaphtho[2,1-c;1′,2′-e]azepin-
ium Tetraphenylborate (9b). Prepared according to the general
procedure, method 1, from 2,6-dimethylaniline (0.103 g, 0.85
mmol), but heated under reflux for 16 h. The product was isolated
as yellow powder (0.53 g, 79%), mp 211-214 °C; [R]20D ) -725.0
(c 0.96, acetone); Found: C, 89.68; H, 6.03; N, 1.85. C54H44BN‚
0.3 H2O requires C, 89.69; H, 6.21; N, 1.94%; νmax (film)/cm-1
3052, 1608, 1583, 1544, 1505, 1426, 1416, 1378, 1265, 1168, 1032,
1
817; H NMR (400 MHz, d6-DMSO): δ 1.33 (3H, s), 2.43 (3H,
We have therefore tested tertiary azepine 11 (5 mol %) as a
catalyst in the epoxidation of trans-R-methylstilbene under these
reaction conditions.
s), 5.42 (2H, s), 6.77-6.81 (4H, m), 6.93 (8H, t, J ) 7.4 Hz), 7.09
(1H, d, J ) 8.6 Hz), 7.17-7.25 (9H, m), 7.35 (1H, ddd, J ) 8.5
Hz, 6.9 Hz, 1.3 Hz), 7.45-7.47 (2H, m), 7.52-7.54 (2H, m), 7.56
(1H, ddd, J ) 8.0 Hz, 6.8 Hz, 1.0 Hz), 7.82 (1H, d, J ) 8.4 Hz),
7.86(1H, ddd, J ) 8.1 Hz, 5.9 Hz, 2.0 Hz), 8.14 (1H, d, J ) 8.1
Hz), 8.21 (1H, d, J ) 8.7 Hz), 8.29 (2H, d, J ) 8.6 Hz), 8.47 (1H,
d, J ) 8.7 Hz), 9.80 (1H, s); 13C NMR (100 MHz, d6-DMSO): δ
16.5, 17.7, 59.9, 121.5, 125.3, 126.1, 126.7, 126.9, 126.9, 127.1,
127.4, 127.9, 128.7, 128.8, 128.9, 129.3, 129.4, 129.5, 130.6, 130.7,
130.7, 131.2, 131.3, 131.4, 132.1, 133.0, 133.3, 135.2, 135.5, 136.2,
141.5, 143.0, 163.3, 173.1; m/z 398.1911; C30H24N (cation) requires
398.1909.
General Procedure for the Synthesis of Iminium Salt Cata-
lysts. Method 2: From (R)-2,2′-Bis(bromomethyl)[1,1′]bi-
naphthalene (8) and Primary Amines. The primary amine (1.1
equiv) was added to a nitrogen-purged stirred solution of (R)-2,2′-
bis(bromomethyl)[1,1′]binaphthalene (8) and potassium carbonate
(3 equiv) in acetonitrile (10 mL per gram of dibromide) at room
temperature. The reaction mixture was heated under reflux overnight
or until disappearance of starting material was observed by TLC.
The mixture was diluted with dichloromethane (40 mL per gram
of dibromide) and washed with water (2 × 30 mL per gram of
dibromide) and brine (2 × 30 mL per gram of dibromide). The
organic phase was separated and dried (Na2SO4). N-Bromosuccin-
imide (1.2 equiv) was added to the resulting crude amine product
in dichloromethane, and the mixture was heated under reflux for 3
h, after which time the reaction mixture was allowed to cool to
room temperature. The solvent was removed in Vacuo and the
residue redissolved in ethanol. A solution of sodium tetraphenyl-
borate (1.1 equiv) in a minimum amount of acetonitrile was added
in one portion. The resulting mixture was stirred for 5 min, after
which the solvents were removed in Vacuo. The yellow residue
was dissolved in dichloromethane (40 mL per gram of dibromide)
and washed with water (2 × 30 mL per gram of dibromide) and
brine (2 × 30 mL per gram of dibromide), the organic phase was
dried (Na2SO4), and the solvents were removed in Vacuo. The
yellow solid was recrystallized from ethanol, washed with ethanol
followed by hexanes, and dried at 90 °C.
Interestingly, little epoxidation (9%) of the substrate was
achieved over 2 h under the 10:1 acetonitrile:water conditions
of Yang using NaHCO3 as base. Addition of catalytic 18-
crown-6 did not improve conversion (<5%) over the same
reaction time; this procedure does not appear to have been
previously tested. The biphasic 3:2 dichloromethane/water
conditions developed by Lacour were also unsuccessful (<5%
conversion) in this case. For comparison, the corresponding
iminium salt catalyst 9e gave 100% conversion under the 10:1
acetonitrile:water conditions at 0 °C over 2 h.
In conclusion, we have prepared a range of novel chiral
binaphthalene-derived catalysts achiral at the nitrogen atom and
utilized them in the asymmetric epoxidation of unfunctionalized
alkenes. The N-isopropyl-substituted catalyst 9e proved to be
the most reactive and enantioselective, affording up to 83% ee
and is superior in enantioselection to the N-methyl analogue 7
for a range of alkene substrates. Appropriate choice of reaction
conditions allows for the successful epoxidation of relatively
unreactive substrates and for the isolation of sensitive epoxides
without hydrolysis. Catalyst 9e is also more reactive than the
corresponding tertiary azepine 11.
Experimental Procedures
(R)-N- Isopropyl-7H-dinaphtho[2,1-c;1′,2′-e]azepinium Tet-
raphenylborate (9e). Prepared according to the general procedure,
method 2, from isopropylamine (1.5 g, 3.41 mmol). The product
General Procedure for the Synthesis of Iminium Salt Cata-
lysts. Method 1: From (R)-2′-(Bromomethyl)[1,1′]binaphthalene-
2-carboxaldehyde and Primary Amines. A solution of the amine
in ethanol (10 mL per gram of amine) was added dropwise to a
solution of (R)-2′-(bromomethyl)[1,1′]binaphthalenyl-2-carboxal-
dehyde (10) (1.1 equiv with respect to (wrt) amine) in ethanol (10
mL per gram of carboxaldehyde) at 40 °C. The reaction mixture
was stirred at 40 °C overnight. The yellowish mixture was left to
cool to room temperature before addition of a solution of sodium
tetraphenylborate (1.10 equiv) in the minimum amount of aceto-
nitrile in one portion. The reaction mixture was stirred for a further
isolated as yellow powder (1.58 g, 71%); mp 159-162 °C; [R]20
D
) -440.0 (c 0.65, acetone); Found: C, 87.59; H, 6.38; N, 2.23.
C49H42BN‚1.0 H2O requires C, 87.36; H, 6.58; N, 2.08%; νmax
(film)/cm-1 3050, 2994, 1947, 1637, 1585, 1552, 1472, 1427, 1374,
1
1263, 1133, 1031, 959, 845, 818, 738, 707; H NMR (400 MHz,
d6-acetone): δ 1.53 (3H, d, J ) 6.6 Hz), 1.56 (3H, d, J ) 6.6 Hz),
4.59-4.67 (2H, m), 5.37 (1H, d, J ) 13.7 Hz), 6.57-6.63 (4H,
m), 6.77 (8H, t, J ) 7.3 Hz), 6.94 (1H, d, J ) 8.8 Hz), 7.16-7.26
(9H, m), 7.29-7.40 (2H, m), 7.45 (1H, ddd, J ) 7.0 Hz, 6.8 Hz,
1.0 Hz), 7.67 (1H, ddt, J )6.4 Hz, 3.3 Hz, 1.6 Hz), 7.87 (1H, d, J
) 8.4 Hz), 7.91 (1H, d, J ) 8.6 Hz), 7.97 (1H, d, J ) 8.2 Hz),
8.09 (1H, d, J ) 8.3 Hz) 8.14 (1H, d, J ) 8.5 Hz), 8.20 (1H, d, J
(26) Gonc¸alves, M. H.; Martinez, A.; Grass, S.; Page, P. C. B.; Lacour,
J. Tetrahedron Lett. 2006, 47, 5297.
J. Org. Chem, Vol. 72, No. 12, 2007 4429

Page et al.
) 8.7 Hz), 9.31 (1H, s); 13C NMR (100 MHz, d6-acetone): δ 20.9,
21.1, 53.9, 66.7, 122.3, 126.1, 126.7, 127.0, 127.8, 128.1, 128.5,
129.6, 129.7, 130.1, 130.2, 130.7, 131.1, 132.1, 131.8, 132.4, 132.5,
132.8, 134.7, 135.3, 136.2, 137.0, 137.4, 164.9, 168.2; m/z
336.1755; C25H22N (cation) requires 336.1752.
mL), followed by a solution of the alkene (0.5 mmol) in acetonitrile
(0.85 mL). The reaction mixture was stirred at 0 °C until complete
conversion of the substrate was observed by TLC. Diethyl ether at
0-5 °C (20 mL) was added to the reaction mixture, followed by
water at 0-5 °C (20 mL). The aqueous phase was extracted with
diethyl ether (2 × 20 mL), the combined organic extracts were
washed with brine (2 × 20 mL) and dried (Na2SO4), and the solvent
was removed in Vacuo. Pure epoxides were obtained by column
chromatography using petroleum ether (40-60 °C) as eluent.
Method 2. A mixture of alkene (0.4 mmol) and catalyst (5 mol
%) was dissolved in acetonitrile (1 mL) and water (0.1 mL) and
the mixture cooled to 0 °C. A mixture of Oxone (0.492 g, 0.8 mmol,
2 equiv) and sodium hydrogen carbonate (0.168 g, 5 equiv, 2 mmol)
was added as a solid in one portion to the mixture with vigorous
stirring. The mixture was stirred at 0 °C until complete conversion
of the alkene was observed by TLC. Diethyl ether (10 mL) was
added, and the reaction mixture was filtered through a pad of mixed
MgSO4 and sodium bisulfite. The solvent was removed in Vacuo.
Pure epoxides were obtained by column chromatography using
petroleum ether (40-60 °C) as eluent.
(R)-N-Isopropyl-2,7-dihydrodinaphtho[2,1-c;1′,2′-e]azepine (11).
N-Isopropylamine (0.24 g, 4.09 mmol) was added to a nitrogen-
purged stirred solution of (R)-2,2′-bis(bromomethyl)[1,1′]bi-
naphthalene (8) (1.50 g, 3.41 mmol) and potassium carbonate (1.41
g, 10.22 mmol) in acetonitrile (10 mL) at room temperature. The
reaction mixture was heated under reflux overnight. The mixture
was diluted with dichloromethane (40 mL) and washed with water
(2 × 30 mL) and brine (2 × 30 mL). The organic phase was
separated and dried (Na2SO4), and the solvent was removed in
Vacuo to afford a yellow residue. Purification by column chroma-
tography using EtOAc/petroleum ether (50:50) as eluent afforded
the product as colorless solid (1.03 g, 89%). A pure sample was
obtained by trituration in acetone (1-2 mL) for 5 min and collecting
the colorless crystals by filtration; mp 158-159 °C; [R]20
)
D
-491.8 (c 0.98, acetone); υmax (film)/cm-1 3048, 2965, 2806, 1507,
1460, 1376, 1122, 1032, 908, 816, 748; 1H NMR (400 MHz,
CDCl3): 1.05 (3H, d, J ) 6.4 Hz), 1.19 (3H, d, J ) 6.3 Hz), 2.64-
2.71 (1H, septet), 3.17 (2H, d, J ) 12.4 Hz), 3.82 (2H, d, J ) 12.4
Hz), 7.15-7.19 (2H, m), 7.34-7.40 (4H, m), 7.50 (2H, d, J ) 8.2
Hz), 7.85 (4H, d, J ) 8.2 Hz); 13C NMR (100 MHz, CDCl3): 21.3,
21.9, 52.3, 52.9, 125.4, 125.7, 127.5, 128.0, 128.3, 128.3, 131.3,
133.1, 133.3, 135.0; m/z 337.1826; C25H23N requires 337.1831.
General Procedure for Asymmetric Epoxidation. Method 1.
Sodium carbonate (4 equiv wrt alkene) was dissolved in water (1.7
mL), and the mixture was cooled to 0 °C. Oxone (2 equiv) was
added as a solid to the cooled mixture, and the resulting slurry
was vigorously stirred at 0 °C for 5 min. To the mixture was added
a solution of the catalyst (5 mol % wrt alkene) in acetonitrile (0.85
Acknowledgment. This investigation has enjoyed the sup-
port of the EPSRC and NPIL Pharmaceuticals (UK) Ltd. We
are indebted to the Royal Society for an Industry Fellowship
(to PCBP), and to the EPSRC Mass Spectrometry Unit,
Swansea.
Supporting Information Available: Full experimental detail,
1H and 13C NMR spectra for synthesized compounds, hplc/gc/NMR
traces for ee measurements. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO070255W
4430 J. Org. Chem., Vol. 72, No. 12, 2007