Biphasic enantioselective olefin epoxidation using tropos dibenzoazepinium catalysts

Article abstract of DOI:10.1021/jo050629q

Several novel chiral iminium TRISPHAT [tris(tetrachlorobenzenediolato) phosphate(V)] salts combining a diphenylazepinium core, chiral exocyclic appendages, and lipophilic counterions have been prepared and tested in biphasic enantioselective olefin epoxidation conditions. Interestingly, the iminium salts derived from commercially available (S)- or (R)-1,2,2-trimethylpropylamine can display efficiency similar to those made from L-acetonamine. Variable-temperature NMR spectroscopy (VT-NMR) and circular dichroism (CD) experiments were performed in search of a correlation between good enantioselectivity in the products and high diastereomeric control of the biphenyl axial chirality of the catalysts.

Full text of DOI:10.1021/jo050629q

Biphasic Enantioselective Olefin Epoxidation Using Tropos
Dibenzoazepinium Catalysts
Je´roˆme Vachon,† Ce´line Pe´rollier,† David Monchaud,† Claire Marsol,† Klaus Ditrich,§ and
Je´roˆme Lacour*,†
De´partement de Chimie Organique, Universite´ de Gene`ve, quai Ernest-Ansermet 30, CH-1211 Gene`ve 4,
Switzerland, and BASF Aktiengesellschaft, Forschung Feinchemikalien & Biokatalyse,
67056 Ludwigshafen, Germany
Jerome.Lacour@chiorg.unige.ch
Received March 31, 2005
Several novel chiral iminium TRISPHAT [tris(tetrachlorobenzenediolato)phosphate(V)] salts
combining a diphenylazepinium core, chiral exocyclic appendages, and lipophilic counterions have
been prepared and tested in biphasic enantioselective olefin epoxidation conditions. Interestingly,
the iminium salts derived from commercially available (S)- or (R)-1,2,2-trimethylpropylamine can
display efficiency similar to those made from L-acetonamine. Variable-temperature NMR spectros-
copy (VT-NMR) and circular dichroism (CD) experiments were performed in search of a correlation
between good enantioselectivity in the products and high diastereomeric control of the biphenyl
axial chirality of the catalysts.
Chiral epoxides are not only useful precursors for
organic chemists but are also useful for frequently met
structures in natural products in relation to their biologi-
cal activities.1 Quite a few efficient methods exist for their
preparation from olefins, and many of them use transi-
tion-metal catalysts such as the Katsuki-Sharpless or
Katsuki-Jacobsen protocols.2 In recent years, much
effort has been devoted to the development of organo-
catalyzed epoxidation conditions that afford metal-free
procedures; the catalysts are perhydrate, ketone or
oxaziridine, and amine moieties as well as oxoammonium
or iminium salts.3,4
been particularly studied.5 High degrees of selectivity
have been achieved using, for instance, 11-membered
ring C2-symmetric R,R′-diacyloxyketone6 or fructose-
derived cyclohexanones as catalysts.5c,7 These efficient
ketone-mediated reactions often need to be carefully
monitored, as moving a few tenths of a unit away from a
7.8-8.0 pH region may lead to a rapid decomposition of
the hydrogen persulfate oxidant in basic conditions (pH
> 8). Although, on the contrary, if lower pH conditions
(pH < 7.5) are used or obtained during the course of the
reaction, then a rapid decomposition of the ketone
(4) Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem. Soc.
2003, 125, 7596-7601. Ho, C. Y.; Chen, Y. C.; Wong, M. K.; Yang, D.
J. Org. Chem. 2005, 70, 898-906.
Ketone-catalyzed epoxidation of olefins using Oxone
(KHSO5‚KHSO4‚K2SO4) as a stoichiometric oxidant has
(5) (a) Armstrong, A. Angew. Chem., Int. Ed. 2004, 43, 1460-1462.
(b) Imashiro, R.; Seki, M. J. Org. Chem. 2004, 69, 4216-4226. (c)
Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5794-5798. (d) Zhang, Z.-G.; Wang, X.-Y.; Sun, C.; Shi, H.-
C. Youji Huaxue 2004, 24, 7-14. (e) Li, W.; Fuchs, P. L. Org. Lett.
2003, 5, 2853-2856. (f) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002,
58, 2481-2495. (g) Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A.
Chem. Rev. 2001, 101, 3499-3548.
† Universite´ de Gene`ve.
§ BASF Aktiengesellschaft, Forschung Feinchemikalien & Bioka-
talyse.
(1) Contelles, J. M.; Moilna, M. T.; Anjum, S. Chem. Rev. 2004, 104,
2857-2900.
(2) Comprehensive Asymmetric Catalysis I-III; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 2. Xia, Q.
H.; Ge, H. Q.; Ye, C. P.; Liu, Z. M.; Su, K. X. Chem. Rev. 2005, 105,
1603-1662.
(6) Yang, D.; Yip, Y. C.; Tang, M. W.; Wong, M. K.; Zheng, J. H.;
Cheung, K. K. J. Am. Chem. Soc. 1996, 118, 491-492.
(3) Adam, W.; Saha-Moller, C. R.; Ganeshpure, P. A. Chem. Rev.
2001, 101, 3499-3548.
(7) Shi, Y. Acc. Chem. Res. 2004, 37, 488-496. Tu, Y.; Wang, Z. X.;
Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806-9807.
10.1021/jo050629q CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/29/2005
J. Org. Chem. 2005, 70, 5903-5911
5903

Vachon et al.
to 59% with compound 4 on trans-stilbene). Rather high
catalyst loading is unfortunately required (10 mol % for
2, 100 mol % for 3, and between 20 and 50 mol % for 4)
due probably to in-situ hydrolysis of the iminium moieties
under the aqueous reaction conditions.
The second class involves endocyclic chiral iminium
salts. As mentioned before, the first nonracemic example
was salt [1][BF4].11 Using this derivative, a modest level
of selectivity was achieved (ee up to 35%). In 1996,
Aggarwal and co-workers reported axially chiral, con-
figurationally stable, binaphthyl-derived catalyst
[5][BF4]; this compound is particularly efficient for the
epoxidation of 1-phenylcyclohexene (71% ee).17 A mecha-
nistic rationale was proposed to explain the absolute
sense of configuration of the resulting epoxides.18 In 1998,
Page and co-workers modified the core structure of
catalyst 1 by introducing stereogenic elements outside
rather than inside of the six-membered ring heterocycle.19
A strong influence of the chiral appendage was noticed,
as L-(+)-acetonamine20 derived iminium 6a displayed
quite higher selectivity than, for instance, 6c made from
(1S,2S)-2-benzyloxycyclohexylamine (ee 41% and <5%,
respectively, with 1-phenyl-cyclohexene). Very recently,
Page and co-workers reported a modification of catalyst
6a carrying a para-methylsulfonyl group (iminium 6f)
that behaves as a very efficient asymmetric catalyst for
benzopyran derivatives, in particular.21
FIGURE 1. Known iminium nonracemic catalysts and high-
est enantiomeric excesses achieved.
catalysts is observed via Baeyer-Villiger, similar to
oxidation of the carbonyl moieties.8,9
Iminium salts are an interesting alternative to ketones.
These compounds are effective oxygen-transfer reagents
toward nucleophilic substrates and electron-rich unfunc-
tionalized olefins, in particular. Moreover, the propensity
of oxaziridinium species to be readily prepared by the
reaction of iminium ions with Oxone renders the develop-
ment of catalytic processes possible.10 The first example
of an asymmetric iminium-catalyzed reaction was re-
ported in 1993 using dihydroisoquinolinium cation 1 as
a catalyst (Figure 1); this system has been inspired by
the studies of the Orsay group since 1976.11,12 The
reaction conditions (solvent, temperature) were later
optimized, and the mechanism was further studied.13
Since this pioneering work, several groups have proposed
successful enantioselective variants (Figure 1).
A second generation of iminium catalysts with exocylic
chiral appendages was later developed independently by
the groups of Loughborough22 and our own.23 These
catalysts utilize the same diphenylazepinium cation 7a
derived from D-(-)- or L-(+)-acetonamine and differ only
-
by the nature of the counterion BPh4 and TRISPHAT
[tris(tetrachlorobenzenediolato)phosphate(V)], respec-
tively.24 Unlike derivatives 6a, 6c, and 6f, compound 7a
possesses a cyclic skeleton, which is chiral. Literature
precedents show that biphenyl species of this type exist
as two atropisomers (Ra and Sa) that interconvert freely
in solution by rotation around the stereogenic axis.25
Direct comparison of the BPh4 salts of seven-membered
ring 7a and six-membered 6a showed that most of the
There are essentially two classes of nonracemic imi-
nium ion catalysts. One class is constituted of exocyclic
chiral iminium salts such as compounds [2][BF4],14
[3][ClO4],15 and [4][X]16 made by the condensation of
enantiopure pyrrolidine moieties with aldehydes or ke-
tones. Decent levels of stereoselective induction were
obtained using these cations (enantiomeric excess (ee) up
(17) Aggarwal, V. K.; Wang, M. F. Chem. Commun. 1996, 191-192.
Aggarwal, V. K. WO Patent 9706147, 1997.
(18) Washington, I.; Houk, K. N. J. Am. Chem. Soc. 2000, 122,
2948-2949.
(19) 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, 6926-6931. Page, P. C. B.; Rassias, G. A.; Barros, D.; Bethell, D.;
Schilling, M. B. J. Chem. Soc., Perkin Trans. 1 2000, 3325-3334. Page,
P. C. B.; Rassias, G. A.; Bethell, D.; Schilling, M. B. J. Org. Chem.
1998, 63, 2774-2777.
(8) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; Depue, J. S.; Wilde,
R. G. J. Org. Chem. 1995, 60, 1391-1407.
(9) For more technical details on Oxone see Internet site: http://
www.dupont.com/oxone/techinfo/.
(10) Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727-13738.
Hanquet, G.; Lusinchi, X.; Milliet, P. C. R. Acad. Sci., Ser. II: Mec.,
Phys., Chim., Sci. Terre Univers 1991, 313, 625-628.
(11) Bohe, L.; Hanquet, G.; Lusinchi, M.; Lusinchi, X. Tetrahedron
Lett. 1993, 34, 7271-7274. Milliet, P.; Picot, A.; Lusinchi, X. Tetra-
hedron Lett. 1976, 1573-1576.
(12) Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55, 141-
154.
(13) Bohe, L.; Lusinchi, M.; Lusinchi, X. Tetrahedron 1999, 55, 155-
166. Lusinchi, X.; Hanquet, G. Tetrahedron 1997, 53, 13727-13738.
(14) Minakata, S.; Takemiya, A.; Nakamura, K.; Ryu, I.; Komatsu,
M. Synlett 2000, 1810-1812.
(15) Armstrong, A.; Ahmed, G.; Garnett, I.; Goacolou, K.; Wailes, J.
S. Tetrahedron 1999, 55, 2341-2352.
(16) Wong, M.-K.; Ho, L.-M.; Zheng, Y.-S.; Ho, C.-Y.; Yang, D. Org.
Lett. 2001, 3, 2587-2590.
(20) L-(+)-Acetonamine corresponds to (4S,5S)-5-amino-2,2-dimeth-
yl-4-phenyl-1,3-dioxane.
(21) Page, P. C. B.; Buckley, B. R.; Heaney, H.; Blacker, A. J. Org.
Lett. 2005, 7, 375-377.
(22) Page, P. C. B.; Rassias, G. A.; Barros, D.; Ardakani, A.; Bethell,
D.; Merifield, E. Synlett 2002, 580-582.
(23) Lacour, J.; Monchaud, D.; Marsol, C. Tetrahedron Lett. 2002,
43, 8257-8260.
(24) TRISPHAT 9 is a chiral anion which can be prepared and
isolated in enantiomerically pure form (∆ or Λ enantiomers: Favarger,
F.; Goujon-Ginglinger, C.; Monchaud, D.; Lacour, J. J. Org. Chem.
2004, 69, 8521-8524). Previous results (ref 23) have, however, shown
that the configuration of the anion plays no role in the stereoselectivity
of the epoxidation reaction, and hence, the use of the anion is only in
racemic form.
(25) Vial, L.; Gonc¸alves, M.-H.; Morgantini, P.-Y.; Weber, J.; Ber-
nardinelli, G.; Lacour, J. Synlett 2004, 1565-1568. Vial, L.; Lacour,
J. Org. Lett. 2002, 4, 3939-3942. Ooi, T.; Uematsu, Y.; Kameda, M.;
Maruoka, K. Angew. Chem., Int. Ed. 2002, 41, 1551-1554.
5904 J. Org. Chem., Vol. 70, No. 15, 2005

Biphasic Enantioselective Olefin Epoxidation
FIGURE 3. Possible stereocontrol by chiral exocyclic append-
ages.
performed at -40 °C, and a further increase in selectivity
was observed for some substrates.21,27
For the initial selection of nonracemic catalyst of type
6a, a rather extensive screening of chiral exocyclic
appendages was performed by Page and co-workers.19
Many enantiopure primary amine precursors were at-
tached to the dihydroisoquinolinium skeleton, and the
resulting compounds were tested. For the diphenylaze-
pinium systems, with the exception of (-)-isopinocam-
phenylamine which leads to a less selective catalyst than
L-(+)-acetonamine, no other chiral appendage has been
reported to date. With the twisted seven-membered ring
of 7a being sufficiently different from the “planar”
dihydroisoquinolinium framework of 6, it was debatable
whether L-(+)-acetonamine was the best auxiliary in this
case. Herein, we report a series of novel diphenylaze-
pinium moieties (7b-e) prepared from commercially
available, nonracemic primary amines and a comparison
of their efficiency in biphasic TRISPHAT mediated ep-
oxidation reactions.
As already mentioned, two atropisomeric conforma-
tions exist for the seven-membered ring backbone of
catalysts 7a-e. The presence of the chiral exocyclic
auxiliaries results in the formation of diastereomeric
structures that equilibrate rapidly in solution with,
possibly, a drift of the conformational equilibrium toward
one preferred (Ra) or (Sa) diastereomer as a consequence
of intramolecular discriminating interactions (Figure 3).28
Care was thus taken in this study to characterize the
structure of the diphenylazepinium cations by variable-
temperature NMR spectroscopy (VT-NMR) and circular
dichroism (CD) in search of a correlation between good
enantioselectivity in the products and high diastereo-
meric control of the biphenyl axial chirality of the
catalysts.
FIGURE 2. Proposed catalytic cycle of biphasic epoxidation
reaction.
reaction rates, conversions, and enantioselectivities were
enhanced by the use of the larger ring size catalysts.22
Recently, Page and co-workers were able to synthesize
and isolate three enantiopure forms of the four possible
stereoisomers of 8a which combine Aggarwal’s confor-
mationally rigid dinaphthazepinium skeleton (Ra and Sa
atropisomers) with Page’s L-(+)- or D-(-)-acetonamine
moiety.17,19 Only one pair of enantiomeric catalysts, (Ra,
L) and (Sa, D), displayed high reactivity and selectivity
(up to 95% ee for the epoxidation of 1-phenyl-3,4-
dihydronaphthalene); the mismatched diastereomers lead
to essentially poor conversions under the same reaction
conditions.
Traditionally, the epoxidation reactions are performed
in mixtures of CH3CN and water. This combination is a
good solvent for all reagents, including the lipophilic
olefins as well as the polar BF4- or PF6- salts of iminium
cations.17 Previously, using salt [7a][TRISPHAT] (Figure
2), strict biphasic CH2Cl2/water conditions could be used
and an enhancement of the selectivity of the epoxidation
reaction as well as a good recovery of the epoxides was
demonstrated.23 In fact, the lipophilicity of TRISPHAT
anion 9 confers to its salts an affinity for organic solvents
and, once dissolved, the ion pairs do not partition in
aqueous layers. Consequently, a tight containment of the
reagents in two liquid phases occurs, with the organic
TRISPHAT salts in the organic layer and Oxone in the
aqueous phase. Addition of a catalytic amount of 18-
Crown-6 (2.5 mol %) establishes a transport mechanism
of KHSO5/KHSO4 between aqueous and organic layers
and permits the oxidation in CH2Cl2 of the iminium
cation into the reactive oxaziridinium form (Figure 2).
As mentioned, slightly better results were obtained using
these conditions, in which the oxidation occurs only in
the CH2Cl2 phase.26 A similar observation was recently
reported by Page and co-workers who developed strict
anhydrous conditions using pure CH2Cl2 as solvent and
tetraphenylphosphonium monoperoxybisulfate (TPPP) as
a stoichiometric oxidant. The reactions can now be
Results and Discussion
Catalyst Preparation. One of our goals was thus to
vary the nature of the chiral appendage linked to the
diphenylazepinium catalytic framework of 7. Care was
taken to select, in addition to L-(+)-acetonamine a, acyclic
and cyclic amines that were commercially available in
both enantiomeric forms. For the initial screening, we
arbitrarily selected the enantiomers of amines a-e
carrying (S) stereogenic centers at the carbon R to the
sp2 nitrogen atom. These amines are detailed in Figure
4. Only compound 7b was prepared in both enantiomeric
forms, for reasons that will be detailed later.
Synthesis of the derived diphenylazepinium catalysts
7a-e was realized in three steps, following a general and
reproducible protocol. After the ozonolysis of phenan-
(26) One can wonder whether the increased stereoselectivity of the
epoxidation reaction in less polar CH2Cl2 vs CH3CN results from a
“destabilization” of the cationic spiro diastereomeric transition states
and, hence, in more discriminating stereoselective interactions.
(27) Page, P. C. B.; Barros, D.; Buckley, B. R.; Ardakani, A.; Marples,
B. A. J. Org. Chem. 2004, 69, 3595-3597.
(28) Mikami, K.; Yamanaka, M. Chem. Rev. 2003, 103, 3369-3400.
J. Org. Chem, Vol. 70, No. 15, 2005 5905

Vachon et al.
Significantly, catalyst [7b][9], in which (S)-1,2,2-tri-
methylpropylamine b has replaced the L-(+)-acetonamine
a moiety, shows results comparable to those of iminium
salt [7a][9] in conversions and enantioselectivity. With
olefins 12-16, these two catalysts afford epoxides of the
same absolute configurations. As can be expected, the
opposite sense of induction was obtained when the
catalyst made from the (R)-1,2,2-trimethylpropylamine,
[ent-7b][9], was used. Compound [7c][9] leads to slightly
lower enantioselectivities (from 76 to 62% ee from olefin
13). This catalyst, derived from (1S,2S)-2-benzyloxy-
cyclohexylamine c, is, however, quite more efficient than
the previously reported 6c. Catalysts [7d][9] and [7e][9]
that contain stereogenic centers R to the nitrogen atom,
bearing a small alkyl chain (Me, Et) and an aromatic
group (1-naphthyl, phenyl), afford epoxides with a drastic
decrease of the enantioselectivity (for olefin 13, 29 and
3% ee, respectively), although with a decent amount of
conversions. Generally, the best results were obtained
with 1-phenyl-3,4-dihydronaphthalene 13 as a substrate.
Finally, catalysts [7b][9] and [7d][9], albeit both prepared
from S-configured acyclic R-branched amines, afford the
epoxide of olefin 12 with opposite configurations, (-)-
(1S,2S)- and (+)-(1R,2R)-1-phenylcyclohex-1-ene oxide,
respectively (Table 1).33 The same observation can be
made for the oxidation product of 13.
FIGURE 4. Selected amines for the formation of catalysts
7a-e.
SCHEME 1. Synthesis of Catalysts [7a][9] to
[7e][9]
The effect of the temperature was studied with cata-
lysts [7a][9] to [7e][9] because, as Page and co-workers
have observed, a lower temperature can lead to an
increase in the enantioselectivity of the epoxidation
reaction.27 Because of the presence of water in the
biphasic CH2Cl2/water/18-C-6 protocol, we could not reach
very low temperatures. The presence of 4 equiv of
NaHCO3 (1.0 M) and 1.1 equiv of Oxone (0.27 M)
saturated the aqueous phase, and the experiments could
be performed at -5 °C as a lower limit.34 However, for
practical reasons, most experiments were carried out at
0 °C; all reagents were soluble in both phases. Catalyst
[7b][9] was selected for the initial screening, and the
results of the reactions of olefins 12-16 with Oxone in
its presence are summarized in Table 2. Using the same
time frame (2 h) as was used for the reactions at room
temperature, we observed, in the particular case of
1-phenyl-3,4-dihydronaphthalene 13, quite better conver-
sions (100% vs 72% at 20 °C) and ee’s (80% vs 70%). No
significant improvement was noticed with the other
olefins.
threne (ozone, NaI, AcOH), giving biphenyl-2,2′-dicar-
baldehyde 10 (61%),29 and reductive amination in the
presence of enantiopure amines a-e, NaBH3CN, and
AcOH, the desired compounds 11a-e were afforded in
decent to good yields (70-83%). Oxidation of the azepines
with NBS and a catalytic amount of AIBN in CCl4 at 20
°C afforded the diphenylazepinium ions as their bromide
salts;30 this milder room-temperature protocol is pre-
ferred to the I2/KOAc procedure.23,31 The crude reaction
mixtures were directly submitted to ion-exchange
metathesis with 1.2 equiv of the racemic
[Et2NH2][TRISPHAT] salt, [Et2NH2][9]. The lipophilicity
of TRISPHAT anion 9 modified profoundly the chromato-
graphic properties of cations associated with it, and the
resulting ion pairs, [7a][9] to [7e][9], were poorly retained
on polar chromatographic phase (Al2O3, pH 9.9, CH2Cl2),
allowing their isolation in modest to decent yields (Scheme
1, 50-66%).32
Catalysis. Catalysts [7a][9] to [7e][9] were then tested
using the biphasic CH2Cl2/water/18-C-6 protocol detailed
previously.23 Prochiral di- and trisubstituted unfunction-
alized alkenes 12-16 were used as substrates, and the
results are reported in Table 1.
With these results in hand, the study was continued
at four different temperatures using the better substrate,
13, and catalyst [7b][9] (Table 3). Good conversions were
always obtained using temperatures from 4 to -5 °C. For
the enantioselectivity, a moderate but definite increase
in asymmetric induction was obtained at each decreasing-
temperature step.
Finally, all iminium catalysts, [7a][9] to [7e][9], were
tested using substrate 13 under the biphasic conditions
at 0 °C, and the results are reported in Table 4.
(31) Leonard, N. J.; Leubner, G. W. J. Am. Chem. Soc. 1949, 71,
3408-3411.
(32) Lacour, J.; Barche´chath, S.; Jodry, J. J.; Ginglinger, C. Tetra-
hedron Lett. 1998, 39, 567-570.
(33) Such an observation has been previously reported, although in
other context: Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo,
Y.; Ito, S. Tetrahedron Lett. 1992, 33, 1651-1654.
(29) Agranat, I.; Rabinovitz, M.; Shaw, W. C. J. Org. Chem. 1979,
44, 1936-1941.
(30) Mary, A.; Renko, D. Z.; Guillou, C.; Thal, C. Bioorg. Med. Chem.
1998, 6, 1835-1850.
5906 J. Org. Chem., Vol. 70, No. 15, 2005

Biphasic Enantioselective Olefin Epoxidation
TABLE 1. Epoxidation of Olefins at 20 °C Using Catalysts [7a][9] to [7e][9]a
catalyst
results
12
13
14
15
16
[7a][9]
ee %c
69d
76
85
23
42
80
17
67
(-)-(S,S)
14
62
(-)-(S,S)
conversion %b
configuration
ee %c
100f
82
(-)-(1S,2S)
(+)-(1R,2S)
(+)-(S)
29
69
(+)-(S)
28
79
(-)-(R)
17
70
(+)-(S)
2
57
e
7
(-)-(1S,2S)
[7b][9]
65d
70
72
41
84
conversion %b
configuration
ee %c
100f
(-)-(1S,2S)
(+)-(1R,2S)
70
63
(-)-(1S,2S)
[ent-7b][9]
[7c][9]
40
94
conversion %b
configuration
ee %c
(-)-(1S,2R)
62
68
(+)-(1R,2S)
29
66
(-)-(1S,2R)
3
62
e
(+)-(1R,2R)
55d
25
81
6
61
(-)-(S,S)
4
48
e
3
57
e
conversion %b
configuration
ee %c
100f
(-)-(1S,2S)
(-)-(1S,2S)
[7d][9]
[7e][9]
21d
5
conversion %b
configuration
ee %c
87f
53
(+)-(1R,2R)
e
5d
50f
e
10
conversion %b
configuration
58
(+)-(S)
70
(-)-(1S,2S)
a Conditions: 5 mol % catalyst [7a][9] to [7e][9], 2.5 mol % 18-C-6, 1.1 equiv of Oxone, 4.0 equiv of NaHCO3, CH2Cl2/H2O (3:2), 20 °C,
2 h. Average of at least two runs. b Conversion calculated using naphthalene as an internal standard unless otherwise stated. c Determined
by CSP-HPLC (Chiralcel OD-H) unless otherwise stated. d Determined by CSP-GC (Chiraldex Hydrodex â-3P). e Enantiomeric excesses
too low to allow a precise determination of the absolute configuration. f Conversion calculated with dodecane as an internal reference.
TABLE 2. Low-Temperature (0 °C) Epoxidation of
12-16 in the Presence of [7b][9]a
catalysts 7a-e. Diphenylazepines of type 11, precursors
to compounds 7, are known to undergo rapid conforma-
tional equilibration in solution with energy barriers (∆Gq)
in the range of 12-14 kcal/mol-1 25,35
Even faster equili-
.
bration was possible for iminium derivatives 7 in view
of literature precedents, indicating that a change of
hybridization of two atoms from sp3 to sp2 within seven-
membered diphenyl ring frameworks usually enhances
the rate of rotation around the biaryl bond.36 Because of
the presence of the chiral appendages resulting in the
formation of diastereomeric structures, the possibility of
a nonequal distribution of the (Ra) and (Sa) diastereo-
mers was considered. Care was thus taken to character-
ize the structure of the diphenylazepinium cations by
VT-NMR and CD in search of a possible correlation
between good enantioselectivity in the products and high
diastereomeric control of the biphenyl axial chirality of
the catalysts.
1H NMR analysis of salts [7c][9], [7d][9], and [7e][9]
confirmed the postulated assumption of a fast equilibri-
um among diastereomeric (Ra) and (Sa) structures as
single (broad) and double (sharp) sets of signals were
observed for these systems at 298 and 233 K, respec-
tively. The signal of the iminium proton (δ 8.7-10.0-ppm
region) was particularly useful to monitor the stereo-
dynamics (Figure 5). Two signals appeared at 233 K due
to a relatively slow interconversion of the atropisomers
0 °C
conversion %b
20 °C
conversion %b
olefin
ee %c
ee %c
12
13
14
15
16
66d
80
31
46
17
68e
100
61
65d
70
29
41
14
100e
72
69
75
84
62
64
a Conditions: 5 mol % catalyst [7b][9], 2.5 mol % 18-C-6, 1.1
equiv of Oxone, 4.0 equiv of NaHCO3, CH2Cl2/H2O (3:2), 2 h.
Average of at least two runs. b Conversion was calculated using
an internal standard (naphthalene) unless otherwise stated.
c Determined by CSP-HPLC (Chiralcel OD-H) unless otherwise
stated. d Determined by CSP-GC (Chiraldex Hydrodex â-3P).
e Conversion calculated with dodecane as an internal reference.
In general, conversions were better at 0 °C than at
room temperature. Better ee’s were measured in all cases.
Interestingly, catalyst [7b][9] leads to essentially the
same ee at 0 °C as[7a][9], whereas a noticeable difference
was observed at room temperature.
(35) Rashidi-Ranjbar, P.; Taghvaei-Ganjali, S.; Wang, S. L.; Liao,
F. L.; Heydari, A. J. Chem. Soc., Perkin Trans. 2 2001, 1255-1260.
Superchi, S.; Casarini, D.; Laurita, A.; Bavoso, A.; Rosini, C. Angew.
Chem., Int. Ed. 2001, 40, 451-454. Saudan, L. A.; Bernardinelli, G.;
Kundig, E. P. Synlett 2000, 483-486. Tichy, M.; Budesinsky, M.;
Gunterova, J.; Zavada, J.; Podlaha, J.; Cisarova, I. Tetrahedron 1999,
55, 7893-7906. Kiupel, B.; Niederalt, C.; Nieger, M.; Grimme, S.;
Vo¨gtle, F. Angew. Chem., Int. Ed. Engl. 1998, 37, 3031-3034. Suth-
erland, I. O.; Ramsay, M. V. J. Tetrahedron 1965, 21, 3401-3408.
(36) Tichy, M.; Ridvan, L.; Holy, P.; Zavada, J.; Cisarova, I.; Podlaha,
J. Tetrahedron: Asymmetry 1998, 9, 227-234 and references therein.
Discussion
As already mentioned, two atropisomeric conforma-
tions exist for the seven-membered ring backbone of
(34) Solubilities in water: (a) NaHCO3 at 0 and 20 °C, 0.82 and 1.14
mmol/mL-1, respectively; (b) Oxone at 20 °C, 0.42 mmol/mL-1
.
J. Org. Chem, Vol. 70, No. 15, 2005 5907

Vachon et al.
TABLE 3. Temperature Effect on the Epoxidation of 13 by Oxone in the Presence of [7b][9]a
temperature
25 °C
4 °C
0 °C
-5 °C
ee %b
70
72
76
80
81
conversion %c
configuration
100
100
100
(+)-(1R, 2S)
(+)-(1R, 2S)
(+)-(1R, 2S)
(+)-(1R, 2S)
a Conditions: 5 mol % catalyst [7b][9], 2.5 mol % 18-C-6, 1.1 equiv of Oxone, 4.0 equiv of NaHCO3, CH2Cl2/H2O (3:2), 2 h. Average of
at least two runs. b Determined by CSP-HPLC (Chiralcel OD-H). c Conversion was calculated using an internal standard (naphthalene).
TABLE 4. Low-Temperature (0 °C) Epoxidation of 13 by
Oxone: Catalyst Studya
0 °C
20 °C
catalyst
ee %b
conversion %c
ee %b
conversion %c
[7a][9]
[7b][9]
[7c][9]
[7d][9]
[7e][9]
79
80
70
35
7
91
100
94
76
70
62
29
3
84
72
68
66
62
92
100
a Conditions: 5 mol % catalyst [7a][9] to [7e][9], 2.5 mol % 18-
C-6, 1.1 equiv of Oxone, 4.0 equiv of NaHCO3, CH2Cl2/H2O (3:2),
2 h. Average of at least two runs. b Determined by CSP-HPLC
(Chiralcel OD-H). c Conversion was calculated using an internal
standard (naphthalene).
FIGURE 6. VT-NMR (CD2Cl2) of salts [7a][9] (500 MHz) and
[7b][9] (400 MHz).
TABLE 5. Diastereomeric Ratios and Excesses (233 K),
Rotamer Ratios (298 K), Cotton Effects (∆E), and
Enantiomeric Excesses for the Oxidation of 13 with
Catalysts [7a][9] to [7e][9] at 0 °C
epoxide from 13
compound dr de %
rr
∆ꢀ (357 nm) ee % configuration
[7a][9]
52:48
60:40
0.5
1.7
3.4
0.5
0.0
79
80
70
35
6
(+)-(1R,2S)
(+)-(1R,2S)
(+)-(1R,2S)
(-)-(1S,2R)
(+)-(1R,2S)
[7b][9] 56:44
8
0
[7c][9]
[7d][9] 59:41 18
[7e][9] 69:31 28
50:50
situation (Figure 6). At 298 K, both spectra present two
broad signals in the iminium region, whereas only one
is observed for salts of cations 7c, 7d, and 7e. When the
temperature is lowered, one signal becomes sharp whereas
the others broaden or split in two. A total of three signals
is observed for [7b][9] at 233 K. This behavior is not
accountable by the previous analysis of just two diaster-
eomeric structures occurring at 233 K.
Previously, we and others have shown that slow
rotation around N(sp2)-C(sp3, tertiary) bonds can occur
when bulky substituents (R1, R2 (Figure 7)) are attached
to the carbon.38,39 For some acridinium derivatives,
rotation barriers of 18.2, 20.1, and 16.7 kcal/mol-1 were
FIGURE 5. VT-NMR (500 MHz, CD2Cl2) of salts [7c][9],
[7d][9], and [7e][9] and resulting diastereoselectivity (233 K;
diastereomeric ratio 50:50, 59:41, 69:31, respectively).
on the NMR time scale and collapse with increasing
temperature. Compounds [7c][9], [7d][9], and [7e][9] thus
behaved as expected. Low diastereomeric enrichment (dr
from 50:50 to 69:31) was observed because ratios between
the (Sa) and (Ra) atropisomers could be measured by
integration of the signals at 233 K and these are reported
in Table 5. If one considers that NMR coalescence is
reached at 298 K for these three systems, then ap-
proximate energy barriers in the range of 12-14 kcal/
mol-1 can be rapidly estimated.37
(37) The relationship ∆Gq ) RTc (22.96 + ln(Tc/∆ν)) was used to
determine the activation energy, ∆Gq, from the coalescence tempera-
ture, Tc (K), and the frequency of separation of the peaks, ∆ν (Hz).
Salts [7a][9] and [7b][9] present a more complex
behavior and, at first sight, a rather puzzling NMR
5908 J. Org. Chem., Vol. 70, No. 15, 2005

Biphasic Enantioselective Olefin Epoxidation
FIGURE 8. CD spectra of (a) [7a][9] (- - -), (b) [7b][9]
(- - -), (c) [7c][9] (- ‚ ‚ -), (d) [7d][9] (- ‚ -), and (e) [7e][9]
(straight line) in CH2Cl2 (10-5 M, 20 °C).
FIGURE 7. Conformations of catalyst 7 as a combination of
rotameric and atropisomeric geometries.
conjugated iminium moiety extends the absorbance of the
cations to the 300-400-nm region in which the chiral
exocyclic appendages are CD silent. The use of racemic
TRISPHAT also ensures a lack of participation of tetra-
chlorocatecholate chromophores. The spectra of salts
[7a][9] to [7e][9] are reported in Figure 8.
To our surprise, only compounds [7c][9] and [7b][9]
displayed measurable negative and positive Cotton effects
at 300 and 350 nm, respectively (10-5 M, CH2Cl2, 20 °C).
This was unexpected in view of the NMR results for
which low diastereomeric excesses were observed for the
other samples (with the exception of [7a][9]). Only a
concentration dependence of the stereoselective induction
can be invoked to explain these results because the NMR
samples were measured in quite higher concentration
(10-3 M) than the CD samples. Because good biaryl
twisting was expected for the more effective catalysts
[7b][9] and [7c][9], the lack of induction for compound
[7a][9] is surprising.
In conclusion, no direct or obvious correlation was
found between the enantioselectivity of the epoxidation
reactions and a stereocontrol of the twisted biaryl bond
of the seven-membered ring by exocyclic chiral append-
ages. Catalysts of type 7 exist as complex mixtures of
biaryl (Ra) and (Sa) atropisomers and rotamers around
the N(sp2)-C(sp3) bond. Most probably, the barriers of
interconversion between these conformers have low ener-
gies in comparison with the transition-state energies
leading to oxaziridinium intermediates or epoxide prod-
ucts. The reaction mechanism most probably follows the
Curtin-Hammet principle and, as shown, a conforma-
tional analysis of the initial catalysts yields little infor-
mation for the understanding of the selectivity.
However, the results have also shown that (S)-1,2,2-
trimethylpropylamine derived iminium catalyst 7b can
be essentially as efficient as derivative 7a. As this bulky
amine is commercially available in both enantiomeric
forms, which is not the case for acetonamine, its use in
the formation of 7b seems to be an interesting develop-
ment in this iminium catalyzed chemistry. Furthermore,
measured for the derivatives of amines a, b, and c,
respectively; the structures derived from amines a and
b displayed the slowest motions.40 In view of these
results, it is likely that such hindered rotation around
the N(sp2)-C(sp3) bond also occurs for salts [7a][9] and
[7b][9], leading to a maximum of four atropisomers
(Figure 7). Because it is improbable that the barrier of
interconversion between the biaryl atropisomers changes
upon a modification of the exocyclic appendage, the two
signals observed at 298 K must correspond to rotamers
with 52:48 and 60:40 ratios in the case of salts
[7a][9]and [7b][9], respectively. For salt [7b][9], as the
sample is cooled to 233 K, one of the signals is split and
the ratio between the (Ra) and (Sa) conformers reaches
a 67:33 value.41 The analysis of the signals of salt
[7a][9] could not be pursued due to the “disappearance”
of one of the signals at 233 K caused, most probably, by
a very large difference of the chemical shifts of the
diastereomeric iminium proton signals at low tempera-
ture. The selectivity ratios and excesses measured in
these NMR experiments are summarized in Table 5.
Conformational studies of biphenyl moieties can also
be performed by CD, as the predominance of one equili-
brating atropisomer leads to the appearance of Cotton
effects in the UV region. The positive or negative nature
of the bands depends on the configuration of the biaryl
moiety.42 For series of compounds with the same inter-
ring angle, the intensity of the Cotton effect is propor-
tional to the enantiomeric or diastereomeric excesses in
solution. For salts [7a][9] to [7e][9], the presence of the
(38) Uncuta, C.; Paun, I.; Deleanu, C.; Plaveti, M.; Balaban, A. T.;
Roussel, C. New J. Chem. 1997, 21, 1055-1065. Balaban, T. S.;
Gheorghiu, M. D.; Roussel, C.; Balaban, A. T. Z. Naturforsch. 1985,
40B, 1555-1557. Balaban, A. T.; Gheorghiu, M. D.; Balaban, T. S. J.
Mol. Struct. 1984, 114, 363-366. Balaban, A. T.; Dinculescu, A.
Tetrahedron 1984, 40, 2547-2553. Seeman, J. I.; Schug, J. C.; Viers,
J. W. J. Org. Chem. 1983, 48, 2399-2407. Katritzky, A. R.; Vassilatos,
S. N.; Alajarin Ceron, M. Org. Magn. Reson. 1983, 21, 587-595.
Seeman, J. I.; Galzerano, R.; Curtis, K.; Schug, J. C.; Viers, J. W. J.
Am. Chem. Soc. 1981, 103, 5982-5984. Balaban, A. T.; Uncuta, C.;
Dinculescu, A.; Elian, M.; Chiraleu, F. Tetrahedron Lett. 1980, 21,
1553-1556.
(39) Laleu, B.; Herse, C.; Laursen, B. W.; Bernardinelli, G.; Lacour,
J. J. Org. Chem. 2003, 68, 6304-6308.
(40) Although the NMR behavior of the acridinium salt derived from
amine d was not studied, one can estimate its rotation barrier is in
the range of 12 kcal/mol-1; a value that has been determined for the
(1)-phenylpropan-1-amine. See ref 39.
(42) An empirical rule formulated by Mislow and co-workers states
that nonconjugated bridged biphenyls with a (S) configuration (P
helicity) and an inter-ring angle of ca. 45° will have a negative Cotton
effect centered at 240-250 nm: Mislow, K.; Glass, M. A. W.; O’Brien,
R. E.; Rutkin, P.; Steinberg, D. H.; Weiss, J.; Djerassi, C. J. Am. Chem.
Soc. 1962, 84, 1455. Its predictability was later confirmed by Sand-
stro¨m: Borecka, B.; Cameron, T. S.; Linden, A.; Rashidy-Ranjbar, P.;
Sandstro¨m, J. J. Am. Chem. Soc. 1990, 112, 1185.
(41) The other signal only sharpens as the temperature is decreased.
For this rotamer, it seems that the signals of the iminium proton of
the (Ra) and (Sa) conformers are isochronous.
J. Org. Chem, Vol. 70, No. 15, 2005 5909

Vachon et al.
128.4 (CH), 127.9 (CH), 127.6 (CH), 127.4 (CH), 127.0 (CH),
69.0 (CH-N), 53.2 (NCH2), 27.3 (CH2), 10.4 (CH2); HRMS calcd
for C23H24N+ ([M + H]+) 314.1903, found 314.1887.
temperature experiments have shown that a decrease of
only 20 °C can have a positive impact on enantiomeric
excesses.
6-N-((S)-1-(2-Naphthyl)ethyl)-5H-dibenz[c,e]azepine
(11e). Starting from 500 mg of 10, compound 11e was obtained
as a pale yellow solid (650 mg, 77%) after chromatography over
basic alumina using c-Hex then c-Hex/EtOAc 9:1 as eluents:
Experimental Section
General Procedure for the Synthesis of Azepines 11a
to 11e. To a solution of biphenyl-2,2′-dicarboxaldehyde 10 (1.0
equiv)29 in CH3CN (6 mL per 0.1 g of dicarboxaldehyde) was
added the corresponding enantiopure amine, a-e (2.0 equiv).
After 15 min of stirring, NaBH3CN (2.0 equiv) was added, and
the reaction was stirred for 20 h before the addition of AcOH
(∼5 equiv). After 1 h, the reaction mixture was diluted with
2% MeOH/CH2Cl2 (30 mL), washed with 1 M NaOH (until pH
> 10), dried over Na2SO4, and concentrated under reduced
pressure. The compound was obtained after purification over
silica gel or basic alumina.
Rf ) 0.6 (SiO2, c-Hex/EtOAc 9:1); mp 80-85 °C; [R]20 -72.0
D
(c 0.1, CH2Cl2); IR (neat) 3056, 2971, 2795, 1600, 1506, 1480,
1450, 1366, 1301, 1266, 1218, 1192, 1175, 1144, 1122, 1090,
1
1069, 1018, 1008, 942, 922, 894, 857, 821, 779, 746 cm-1; H
NMR (400 MHz, CDCl3) δ 8.09-8.04 (m, 4H), 7.92-7.90 (m,
1H), 7.71-7.60 (m, 6H), 7.58-7.51 (m, 4H), 4.00 (q, CHN, J
) 6.6 Hz, 1H), 3.80 (d, J ) 12.4 Hz, 2H), 3.58 (d, J ) 12.6 Hz,
2H), 1.75 (d, CH3, J ) 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 143.9 (CIV), 141.5 (CIV), 135.4 (CIV), 133.9 (CIV), 133.1 (CIV),
130.01 (CH), 128.7 (CH), 128.1 (CH), 128.0 (CH), 127.9 (CH),
127.8 (CH), 127.7 (CH), 126.1 (CH), 125.8 (CH), 62.8 (CH), 53.4
(CH2), 22.9 (CH3); MS-ES (+) m/z (relative intensity) 350.3
(100%), 197.5 (62%), 139.7 (70%); HRMS calcd for C26H24N+
([M + H]+) 350.1903, found 350.1904.
6-N-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-
5H-dibenz[c,e]azepine (11a). Starting from 1.0 g of 10,
compound 11a was obtained as a white solid (714 mg, 77%)
after chromatography over silica gel using c-Hex/EtOAc 4:1
as eluent: Rf ) 0.3 (SiO2, c-Hex/EtOAc 4:1); mp 115-120 °C;
Racemic Diethylammonium TRISPHAT Salt or
[H2NEt2][9]. Under a nitrogen atmosphere, in a flame-dried
250 mL two-necked round-bottomed flask equipped with a
magnetic stirring bar, an addition funnel for solids, and a
reflux condenser (topped with a gas outlet connected to a
concentrated NaOH trap), 6.0 g of tetrachlorocatechol (crystal-
lized and sublimed) (24.2 mmol, 3 equiv) was added portion-
wise as a solid over a 30 min period to a 50 °C solution of 1.68
g of PCl5 (8.1 mmol, 1 equiv) in toluene (20 mL) (HClg
evolution). Dry toluene (20 mL) was further added to wash
the glassware. After 14 h of stirring at 70 °C, the reaction was
cooled to room temperature (precipitation) and concentrated
in vacuo. The resulting gray powder was suspended in CH2-
Cl2 (43 mL). A solution of diethylamine (8.1 mmol, 1 equiv) in
CH2Cl2 (17 mL) was then slowly added, leading to the
precipitation of a white solid. After 12 h of stirring at 25 °C to
ensure maximum precipitation, reaction was filtered over a
Bu¨chner funnel. The solid was washed with CH2Cl2 and dried
under reduced pressure to afford the desired ammonium
TRISPHAT salt (5.72 g, 86%): mp 220 °C (decomposition); 1H
NMR (400 MHz, DMSO-d6) δ 8.16 (br, NH2, 2H), 2.92 (q,
NCH2, J ) 7.1 Hz, 4H), 1.16 (t, Me, J ) 7.1 Hz, 6H); 13C NMR
(100 MHz, DMSO-d6) δ 141.6 (CIV, JCP ) 6.6 Hz), 122.6 (CIV),
113.6 (CIV, JCP ) 19.8 Hz), 41.8 (CH2), 11.5 (CH3); 31P NMR
(162 MHz, DMSO-d6) δ -80.83; MS-ES (-) m/z (relative
intensity) 768.5. Anal. Calcd for C22H12Cl12NO6P‚0.1C5H12: C,
31.79; H, 1.57. Found: C, 31.82; H, 1.70.
General Procedure for the Synthesis of the Iminium
TRISPHAT Salts [7a][9] to [7e][9]. To a solution of azepines
11a-e (1 equiv) in CCl4 (3 mL/1 mmol of substrate) was added
NBS (1.3 equiv) and AIBN (0.05 equiv) as solids. The flask
was protected with an aluminum foil. The mixture was stirred
overnight. The reaction was diluted with water (15 mL/1 mmol
of substrate) and extracted with CH2Cl2 (2 × 10 mL). The
organic phase was dried (MgSO4) and filtered. A solution of
salt [Me2NH2][9] (1.2 equiv) in acetone was added, and the
crude evaporated under reduced pressure. Salts [7a][9] to
[7e][9] were then isolated by chromatography over silica gel
or basic alumina.
20
[R]D +95.5 (c 0.6, EtOH); IR (neat) 2856, 1450, 1257, 1073,
1
750 cm-1; H NMR (400 MHz, CDCl3) δ 7.40 (m, 13H), 5.25
(d, J ) 3.3 Hz, 1H), 4.29 (d, J ) 2.8 Hz, 2H), 3.72 (d, J ) 12.5
Hz, 2H), 3.54 (d, J ) 12.5 Hz, 2H), 3.00 (s, 1H), 1.63 (s, 3H),
1.62 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.0 (CIV), 140.2
(CIV), 136.7 (CIV), 129.4 (CH), 127.9 (CH), 127.8 (CH), 127.4
(CH), 126.8 (CH), 126.3 (CH), 99.1 (CIV), 74.8 (CH), 62.2 (CH2),
60.9 (CH), 54.0 (CH2), 29.5 (CH3), 30.0 (CH2), 19.0 (CH3); MS-
EI m/z (relative intensity) 385 (1%), 179 (100%); HRMS calcd
for C26H27NO2 385.20418 (100%), found 385.20040.
6-N-((S)-1,2,2-Trimethylpropyl)-5H-dibenz[c,e]aze-
pine (11b). Starting from 250 mg of 10, compound 11b was
obtained as a colorless oil (266 mg, 80%) after chromatography
over basic alumina using c-Hex as eluent: Rf ) 0.6 (Al2O3
basic, c-Hex); [R]20D +38.7 (c 0.1, MeOH); IR (neat) 3064, 3017,
1
2950, 2866, 1481, 1450, 1356, 1096, 751, 609 cm-1; H NMR
(400 MHz, CDCl3) δ 7.5-7.4 (m, 8H), 3.60 (CH2N, 2H), 2.67
(q, CHN, J ) 7.1 Hz, 1H), 1.15 (d, CH3, J ) 7.1 Hz, 3H), 1.03
(s, t-Bu, 9H); 13C NMR (100 MHz, CDCl3) δ 141.0 (CIV), 137.1
(CIV), 129.8 (CH), 127.8 (CH), 127.4 (CH), 127.4 (CH), 68.7
(CHN), 54.7 (CH2N), 36.8 (CIV), 27.1 (CH3), 11.6 (CH3); MS-
EI m/z (relative intensity) 222 (100%), 279 (1%); HRMS calcd
for C20H26N+ ([M + H]+) 280.2060, found 280.2043.
6-N-((S)-trans-2-Phenylmethoxycyclohexyl)-5H-Di-
benz[c,e]azepine (11c). Starting from 250 mg of 10, com-
pound 11c was obtained as a colorless oil (377 mg, 83%) after
chromatography over basic alumina using c-Hex then c-Hex/
AcOEt (90:10) as eluent: Rf ) 0.4 (Al2O3 basic, c-Hex/EtOAc
9:1); [R]20 +43.3 (c 0.1, MeOH); IR (neat) 3062, 3027, 2928,
D
1
2856, 1450, 1084, 748, 697 cm-1; H NMR (300 MHz, CDCl3)
δ 7.6-7.3 (m, 8H), 4.69 (CHO, 1H), 3.75 (2 × CH2N and CH-
O, 5H), 2.91 (m, CHN, 1H), 2.29 (m, CH, 1H), 2.02 (m, CH,
1H), 1.82 (m, CH2, 2H), 1.67-1.32 (m, 2 × CH2, 4H); 13C NMR
(75 MHz, CDCl3) δ 141.2 (CIV), 139.3 (CIV), 136.7 (CIV), 129.9
(CH), 128.3 (CH), 128.0 (CH), 127.9 (CH), 127.7 (CH), 127.6
(CH), 127.3 (CH), 78.2 (CH), 71.0 (CH2), 67.4 (CH), 52.7 (CH2),
30.9 (CH2), 28.1 (CH2), 24.7 (CH2), 24.1 (CH2); MS-ES (+) m/z
(relative intensity) 382.3 (100%), 284.2 (24%); HRMS calcd for
C27H30NO+ ([M + H]+) 384.2322, found 384.2311.
[6-N-((4S,5S)-2,2-Dimethyl-4-phenyl-1,3-dioxan-5-yl)-
5H-dibenz[c,e]azepinium][9] or [7a][9]. Starting from 250
mg of 11a, salt [7a][9] was obtained as a pale yellow solid (456
mg, 61%) after chromatography over silica gel using CH2Cl2
as eluent: Rf ) 0.3 (SiO2, CH2Cl2); mp 200 °C (decomposition);
6-N-(S-1-Phenylpropyl)-5H-dibenz[c,e]azepine (11d).
Starting from 250 mg of 10, compound 11d was obtained as a
colorless oil (260 mg, 70%) after chromatography over silica
gel using c-Hex/EtOAc 9:1 as eluent: Rf ) 0.4 (SiO2, c-Hex/
EtOAc 4:1); [R]20D -49.0 (c 0.1, MeOH); IR (neat) 3061, 3023,
[R]20 +28.0 (c 0.1, CH2Cl2); IR (neat) 1625, 1581, 1537 cm-1
;
D
2969, 2791, 1451, 1023, 748, 701 cm-1
;
1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3) δ 9.34-8.83 (br, CHdN, 2H), 7.87-
7.17 (m, 13H), 5.87 (s, CH-Ar, 1H), 5.34-4.00 (m, CH2-N and
CHN and CH2-O, 5H), 1.86 (s, CH3, 3H), 1.77 (s, CH3, 3H);
31P NMR (162 MHz, CDCl3) δ -80.9, -80.80; MS-ES (-) m/z
(relative intensity) 769.0 (44%, TRISPHAT), 113.7 (100%);
MS-ES (+) m/z (relative intensity) 152.7 (100%), 384.4 (16%,
CDCl3) δ 7.53-7.29 (m, 13H), 3.58 (Ar-CH2-N, J ) 12.4 Hz,
2H), 3.29 (Ar-CH2-N, J ) 12.4 Hz, 2H), 3.42 (dd, CH-N, J
) 9.6 and 3.8 Hz, 1H), 2.14-2.07 (m, CH, 1H), 1.81-1.73 (m,
CH2, 1H), 0.69 (t, CH3, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3)
δ 143.4 (CIV), 141.3 (CIV), 135.3 (CIV), 129.9 (CH), 128.8 (CH),
5910 J. Org. Chem., Vol. 70, No. 15, 2005

Biphasic Enantioselective Olefin Epoxidation
M); CD (CH2Cl2, 10-5 M) λ (∆ꢀ) 244 (8.6), 265 (-1.5), 320 (0.8);
UV (CH2Cl2, 10-5 M) λ (log ꢀ) 237 (4.82), 300 (4.41), 356 (3.95).
Anal. Calcd for C44H26Cl12NO8P‚H2O: C, 45.13; H, 2.41.
Found: C, 44.75; H, 2.47.43
CH2, 2H), 1.13-0.69 (br, CH3, 3H);31P NMR (162 MHz, CDCl3)
δ -80.97, -81.01; MS-ES (-) m/z (relative intensity) 768.5
(100%, TRISPHAT); MS-ES (+) m/z (relative intensity) 194.5
(70%, M-C9H11), 312.3 (100%, M); CD (CH2Cl2, 10-5 M) λ (∆ꢀ)
237 (-3); UV (CH2Cl2, 10-5 M) λ (log ꢀ) 227 (4.795), 240 (4.74),
301 (4.34), 363 (3.50). Anal. Calcd for C41H22Cl12NO6P: C,
45.55; H, 2.05. Found: C, 45.38; H, 2.25.43
[6-N-((S)-1,2,2-Trimethylpropyl)-5H-dibenz[c,e]aze-
pinium][9] or [7b][9]. Starting from 250 mg of 11b, salt [7b]-
[9] was obtained as a pale yellow solid (544 mg, 58%) after
chromatography over basic alumina with CH2Cl2 as eluent:
Rf ) 0.9 (Al2O3 basic, CH2Cl2); mp 160 °C (decomposition);
[R]20D -31.2 (c 0.1, CH2Cl2); IR (neat) 2923, 1636, 1597, 1556,
1445, 1389, 1302, 1236, 1091, 1046, 1008, 989, 818, 760, 718,
668 cm-1; 1H NMR (400 MHz, CDCl3) δ 9.49 and 9.20 (2s, CHd
N, 1H), 8.1-7.0 (m, 8H), 4.82-4.33 (m, CH2-N and CHN, 3H),
1.75 (m, CH3, 3H), 1.19 (s, t-Bu, 9H); 31P NMR (162 MHz,
CDCl3) δ -80.92, -81.00; MS-ES (-) m/z (relative intensity)
768.5 (100%, TRISPHAT); MS-ES (+) m/z (relative intensity)
194.5 (100%, M - C6H13), 278.5 (25%, M); CD (CH2Cl2, 10-5
M) λ (∆ꢀ) 252 (-6), 277 (-2), 296 (-3), 351 (2); UV (CH2Cl2,
10-5 M) λ (log ꢀ) 227 (4.75), 239 (4.70), 301 (4.27), 356 (3.49).
Anal. Calcd for C38H24Cl12NO6P: C, 43.59; H, 2.31. Found: C,
43.47; H, 2.51.43
[6-N-((S)-1-(2-Naphthyl)ethyl)-5H-dibenz[c,e]azepinium]-
[9] or [7e][9]. Starting from 627 mg of 11e, salt [7e][9] was
obtained as a pale yellow solid (1.31 g, 66%) after chromatog-
raphy over basic alumina with CH2Cl2 as eluent: Rf ) 0.9
(Al2O3 basic, CH2Cl2); mp 220 °C (decomposition); [R]20D -28.2
(c 0.1, CH2Cl2); IR (neat) 1641, 1597, 1556, 1444, 1389, 1301,
1236, 1008, 989, 819, 718, 668 cm-1 1H NMR (400 MHz,
;
CDCl3, 298 K) δ 2.27 (br, Me, 3H), 4.38 (br, N-CH, 1H), 4.88
(br, CHN, 1H), 6.13 (br, CHN, 1H), 6.55 (br, 1H), 7.08 (br, 1H),
7.25-7.95 (m, 11H), 8.26 (s, 1H), 9.95 (br, NdCH, 1H); 31P
NMR (162 MHz, CDCl3) -80.97, -81.01; MS-ES (-) m/z
(relative intensity) 768.5 (100%, TRISPHAT); MS-ES (+) m/z
(relative intensity) 348.3 (55%), 194.5 (100%), 155.6 (100%);
CD (CH2Cl2, 10-5 M) λ (∆ꢀ) 235 (-9); UV (CH2Cl2, 10-5 M) λ
(log ꢀ) 229 (5.08), 301 (4.36). Anal. Calcd for C44H22Cl12NO6P:
C, 47.31; H, 1.99. Found: C, 47.51; H, 2.21.43
[6-N-((S)-trans-2-Phenylmethoxycyclohexyl)-5H-dibenz-
[c,e]azepinium][9] or [7c][9]. Starting from 350 mg of 11c,
salt [7c][9] was obtained as a pale yellow solid (526 mg, 50%)
after chromatography over basic alumina with CH2Cl2 as
eluent: Rf ) 0.9 (Al2O3 basic, CH2Cl2); mp 185 °C (decomposi-
Biphasic Asymmetric Epoxidation Procedure. In a 10
mL flask equipped with a magnetic stirring bar, NaHCO3 (67.0
mg, 0.80 mmol, 4.0 equiv) was added to 800 µL of water. Oxone
(132.0 mg, 0.21 mmol, 1.0 equiv) was then added, and the
solution was stirred for 2 min until effervescence subsided. A
400-µL portion of a 0.5 mol/L solution of the alkene (0.20 mmol,
1.0 equiv) and naphthalene/dodecane (0.20 mmol, 1.0 equiv,
internal reference) in CH2Cl2 was added. The catalyst (10.0
µmol, 5 mol %) in CH2Cl2 (600 µL) was added, followed by a
solution of 18-crown-6 (1.0 mg, 5.0 µmol, 2.5 mol %) in CH2-
Cl2 (200 µL). The reaction mixture was then stirred at room
temperature for 2 h.
tion); [R]20 -8.0 (c 0.1, CH2Cl2); IR (neat) 2935, 1707, 1641,
D
1597, 1556, 1446, 1389, 1302, 1236, 1074, 990, 819, 759, 718,
1
668 cm-1; H NMR (400 MHz, CDCl3) δ 8.95 (s, CHdN, 1H),
7.97-7.45 (m, 8H), 7.19-6.89 (m, 5H), 4.44-3.67 (m, 6H), 2.49
(br, 1H), 2.12 (br, 1H), 1.93 (br, 3H), 1.39 (br, 3H);31P NMR
(162 MHz, CDCl3) δ -80.83, -80.87; MS-ES (-) m/z (relative
intensity) 768.5 (100%, TRISPHAT); MS-ES (+) m/z (relative
intensity) 382.4 (100%, M); CD (CH2Cl2, 10-5 M) λ (∆ꢀ) 252
(-11), 282 (-2), 300 (-3), 357 (4); UV (CH2Cl2, 10-5 M) λ (log
ꢀ) 227 (4.79), 240 (4.75), 300 (4.35), 351 (3.55). Anal. Calcd for
C45H28Cl12NO6P: C, 46.95; H, 2.45. Found: C, 47.22; H, 2.73.43
[6-N-((S)-1-Phenylpropyl)-5H-dibenz[c,e]azepinium]-
[9] or [7d][9]. Starting from 250 mg of 11d, salt [7d][9] was
obtained as a pale yellow solid (552 mg, 64%) after chroma-
tography over basic alumina with CH2Cl2 as eluent: Rf ) 0.9
(Al2O3 basic, CH2Cl2); mp 195 °C (decomposition); [R]20D -31.7
(c 0.1, CH2Cl2); IR (neat) 1640, 1598, 1556, 1445, 1389, 1301,
Acknowledgment. We are grateful for financial
support of this work by the Swiss National Science
Foundation, the Federal Office for Education and Sci-
ence, and the Sandoz Family Foundation (C.P., C.M.,
J.L.). We thank Roche Diagnostics for a generous gift
of L-acetonamine a.
1
1236, 990, 819, 758, 718, 700, 668 cm-1; H NMR (500 MHz,
Supporting Information Available: 1H NMR, VT-NMR,
and CD spectra of compounds [7a][9] to [7e][9]; collective
spectral data (1H and 13C NMR) of salt [Et2NH2][9]; and
compounds 11a-e. This material is available free of charge
via the Internet at http://pubs.acs.org.
CDCl3) δ 9.86 (br, CHN, 1H), 7.85-7.06 (m, 13H), 5.61 (m,
NCH, 1H), 4.75 (m, CHN, 1H), 4.19 (m, NCH, 1H), 2.38 (m,
(43) Assignment in 13C NMR spectroscopy could not be performed
due to the low resolution of the spectra resulting from the slow
interconversion of the biphenyl moiety on the NMR time scale, leading
to a broadening of the NMR signals.
JO050629Q
J. Org. Chem, Vol. 70, No. 15, 2005 5911