Fluorinated chiral secondary amines as catalysts for epoxidation of olefins with oxone

Article abstract of DOI:10.1021/jo048378t

(Chemical Equation Presented) We have synthesized a series of chiral cyclic secondary amines having different substitution patterns and have screened them as catalysts for the asymmetric epoxidation of olefins using Oxone. The highest enantiomeric excess (61%) occurred for the epoxidation of 1-phenylcyclohexene catalyzed by a secondary amine bearing a fluorine atom at the β-position relative to the amino center. Our experimental results provide further support to the notion that the amine plays a dual role - as a phase transfer catalyst and an Oxone activator - in these epoxidation reactions. The slightly acidic reaction conditions we employed in this work obviate the need to preform ammonium salts, which are the actual catalysts that mediate the epoxidations.

Full text of DOI:10.1021/jo048378t

Fluorinated Chiral Secondary Amines as Catalysts for
Epoxidation of Olefins with Oxone
Chun-Yu Ho, Ying-Chun Chen, Man-Kin Wong, and Dan Yang*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. China
yangdan@hku.hk
Received September 14, 2004
We have synthesized a series of chiral cyclic secondary amines having different substitution patterns
and have screened them as catalysts for the asymmetric epoxidation of olefins using Oxone. The
highest enantiomeric excess (61%) occurred for the epoxidation of 1-phenylcyclohexene catalyzed
by a secondary amine bearing a fluorine atom at the â-position relative to the amino center. Our
experimental results provide further support to the notion that the amine plays a dual rolesas a
phase transfer catalyst and an Oxone activatorsin these epoxidation reactions. The slightly acidic
reaction conditions we employed in this work obviate the need to preform ammonium salts, which
are the actual catalysts that mediate the epoxidations.
Introduction
amines could promote epoxidation of alkenes when using
Oxone as the oxidant. During our ongoing studies on
these iminium salt-catalyzed epoxidations, Aggarwal and
co-workers reported that amines and amine‚HCl salts
could catalyze alkene epoxidation.7a,b More recently,
The development of efficient methods for asymmetric
epoxidation of alkenes has attracted considerable atten-
tion1,2 because chiral epoxides are versatile building
blocks in organic synthesis.3 In addition, many biologi-
cally active compounds and natural products contain
epoxide functionalities.4 Over the years, our research
group has devoted considerable effort toward the devel-
opment of methods for the stereoselective epoxidation of
alkenes.2a,5,6
Recently, we developed an asymmetric epoxidation
protocol that uses chiral iminium salts generated in situ
from amines and aldehydes under slightly acidic condi-
tions.6 Interestingly, we found that some cyclic secondary
(4) For examples of the total syntheses of natural products contain-
ing epoxides, see: (a) Jose´, M. C.; Mar´ıa, T. M.; Shazia, A. Chem. Rev.
2004, 104, 2857-2900. (b) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J.
Am. Chem. Soc. 2003, 125, 5095-5106. (c) Yang, D.; Ye, X. Y.; Xu, M.
J. Org. Chem. 2000, 65, 2208-2217. (d) Paquette, L. A.; Gao, Z.; Ni,
Z.; Smith, G. F. J. Am. Chem. Soc. 1998, 120, 2543-2552. (e) Alcaraz,
L.; Macdonald, G.; Ragot, J. P.; Lewis, N.; Taylor, R. J. K. J. Org. Chem.
1946, 11, 3526-3527. (f) Nicolaou, K. C.; Sarabia, F.; Ninkovic, S.;
Finlay, M. R. V.; Boddy, C. N. C. Angew. Chem., Int. Ed. Engl. 1998,
37, 81-84. (g) Nicolaou, K. C.; Winssinger, N.; Pastor, J.; Ninkovic,
S.; Sarabia, F.; He, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou,
P.; Hamel, E. Nature 1997, 387, 268-272.
(5) For asymmetric epoxidations with chiral dioxiranes, see: (a)
Yang, D.; Jiao, G. S.; Yip, Y. C.; Lai, T. H.; Wong, M. K. J. Org. Chem.
2001, 66, 4619-4624. (b) Yang, D.; Yip, Y. C.; Chen, J.; Cheung, K. K.
J. Am. Chem. Soc. 1998, 120, 7659-7660. (c) Yang, D.; Wong, M. K.;
Yip, Y. C.; Wang, X. C.; Tang, M. W.; Zheng, J. H.; Cheung, K. K. J.
Am. Chem. Soc. 1998, 120, 5943-5952. (d) Yang, D.; Wang, X. C.;
Wong, M. K.; Yip, Y. C.; Tang, M. W. J. Am. Chem. Soc. 1996, 118,
11311-11312. (e) 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.
(6) For asymmetric epoxidations with iminium salts generated in
situ from amines and aldehydes, see: Wong, M. K.; Ho, L. M.; Zheng,
Y. S.; Ho, C. Y.; Yang, D. Org. Lett. 2001, 3, 2587-2590.
(7) For amine-catalyzed epoxidations, see: (a) Adamo, M. F. A.;
Aggarwal, V. K.; Sage, M. A. J. Am. Chem. Soc. 2000, 122, 8317-
8318. (b) Adamo, M. F. A.; Aggarwal, V. K.; Sage, M. A J. Am. Chem.
Soc. 2002, 124, 11223. (c) Aggarwal, V. K.; Lopin, C.; Sandrinelli, F.
J. Am. Chem. Soc. 2003, 125, 7596-7601.
(1) For reviews on asymmetric epoxidation of allylic alcohols, see:
(a) Katsuki, T. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, Germany, 1999;
Vol. 2, pp 621-648. (b) Johnson, R. A.; Sharpless, K. B. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; New York, 1993; pp 103-158.
(2) For recent reviews on asymmetric epoxidation, see: (a) Yang,
D. Acc. Chem. Res. 2004, 37, 497-505. (b) Shi, Y. Acc. Chem. Res. 2004,
37, 488-496. (c) Adam, W.; Saha-Moeller, C. R.; Ganeshpure, P. A.
Chem. Rev. 2001, 101, 3499-3548. (d) Frohn, M.; Shi, Y. Synthesis
2000, 14, 1979-2000. (e) Jacobsen, E. N.; Wu, M. H. In Comprehensive
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, Germany, 1999; Vol. 2, pp 649-678. (f) Denmark,
S. E.; Wu, Z. Synlett 1999, 847-859. (g) Jacobsen, E. N. In Catalytic
Asymmetric Synthesis; Ojima, I., Ed.; New York, 1993; pp 159-202.
(3) Behrens, C. H.; Sharpless, K. B. Aldrichim. Acta 1983, 16, 67-
80.
10.1021/jo048378t CCC: $30.25 © 2005 American Chemical Society
Published on Web 01/08/2005
898
J. Org. Chem. 2005, 70, 898-906

Catalysts for Epoxidation of Olefins with Oxone
SCHEME 1. Epoxidation Mechanism Proposed
Recently by Aggarwal et al.
skeleton and a â-hydroxyl substitutent into secondary
amines can improve their catalytic efficiency in the
epoxidation of olefins.
Next we examined a series of 2-substituted pyrrolidines
(8b-h) for their catalytic activities. Amines 8b-d that
bear either a â-hydroxyl or OMe group gave better
conversions and yields than did pyrrolidine itself (cf.
entries 9-11 with entry 8). Notably, amine 8c, which
bears a bulky CPh2OH substituent, gave moderate
conversion, yield, and enantioselectivity (78% yield based
on 59% conversion, 33% ee; entry 10).7c,10 In addition,
while amine 8e bearing a â-amino group also gave high
alkene conversion (90%; entry 12), we found that L-
proline 8f and its carboxylic acid derivatives 8g,h were
not effective in promoting epoxidation (conversion <22%;
entries 13-15).
Aggarwal et al. proposed a new mechanism for the
epoxidation in which the amine‚HCl salts most likely
function as phase transfer catalysts and Oxone activators
(Scheme 1).7c,8
Furthermore, we discovered that substituents on the
4-position of the pyrrolidine ring exhibited a remarkable
effect on the substrate conversion:11 Whereas amine 9a,
which bears an acetoxy group at the 4-position, gave <5%
conversion (entry 16), amines 9b and 9c, which feature
hydroxyl and OMOM groups, respectively, at the 4-posi-
tion resulted in up to 96% conversion of the alkene
(entries 17 and 18). These results suggest that the
incorporation of a suitable heteroatom â to the pyrrolidine
amino group can be beneficial to the catalytic efficiency.
Design of Amines That Provide High Catalytic
Efficiency and Better Chiral Induction in Epoxi-
dation. As described in the previous section, amine 8c
bearing a bulky CPh2OH group at the 2-position of the
pyrrolidine ring gave good reactivity, but moderate
enantioselectivity. We decided to improve the reactivity
and the enantioselectivity by systematically modifying
the structure of 8c. Accordingly, we synthesized amines
10, 12a-g, and 13a-c, which have various heteroatom
substituents positioned â to the amino group, and per-
formed epoxidation reactions of 1-phenylcyclohexene
catalyzed by 5 mol % of those amines in the presence of
lower amounts of Oxone (2 equiv) and NaHCO3 (5
equiv);11 Table 2 summarizes our results. Under these
reaction conditions, 1-phenylcyclohexene epoxide was the
major product, along with 1-phenylcyclohexene-1,2-cis-
diol.12 We found that amine 10 and Aggarwal’s amine
11a, which bear OMe and H groups, respectively, at their
benzylic positions, gave higher conversions and yields
(100% conversion, 73-87% yield; entries 2-3) than did
8c, which bears an OH group (58% conversion, 41% yield;
entry 1).7c,10 More importantly, 12a, which bears a
fluorine atom located â to the amino center, provided the
highest catalytic efficiency and enantioselectivity (100%
conversion, 87% yield, 50% ee; entry 4).13-15 Further
increases in enantioselectivity (up to 56% ee) were
In this paper, we report our results obtained from a
systematic investigation of the amine-catalyzed epoxi-
dation. In particular, we have discovered that substitu-
ents on the cyclic skeleton of the secondary amine exert
significant effects on the catalytic efficiency and enantio-
selectivity of the epoxidation.
Results and Discussion
Preliminary Screening of Amine Catalysts for
Epoxidation of Alkenes. During our studies on the
asymmetric alkene epoxidation catalyzed by chiral imi-
nium salts generated in situ from amines and aldehydes,
we found that amines themselves could promote epoxi-
dation under slightly acidic reaction conditions.6 To
investigate the substituent effect that the amines have
on the epoxidation, we screened a variety of amines using
our previously reported epoxidation conditions (Table 1).
We conducted the epoxidation reactions by adding a
mixture of Oxone (0.4 mmol) and NaHCO3 (1 mmol) to a
solution of amine (0.1 mmol) and trans-stilbene (0.1
mmol) in CH3CN (2.0 mL) and H2O (0.2 mL) at room
temperature.
We found that cyclic secondary amines are better
catalysts than are acyclic primary and secondary amines
in terms of their activity in catalyzing the epoxidation of
trans-stilbene (cf. entries 1 and 2 with entries 3, 4, and
8). It is noteworthy that the use of amine 4, which
possesses an oxygen atom â to the amino group, resulted
in a faster reaction than did amine 3 (cf. entries 3 and
4). Other secondary amines, such as 5 and 6, that bear
â-hydroxyl groups also displayed high conversions (up to
89%) and yields (92-96%) for trans-stilbene epoxidation
within 3 h (cf. entries 5 and 6 with entry 2).9 It is worth
highlighting that these simple, cheap, and commercially
available achiral amines (amines 5 and 6) are effective
epoxidation catalysts. Amine 6 can be applied to the
complete epoxidation of trans-stilbene, trans-methylstil-
bene, and â-methylstyrene in 90% isolated yield after 5
h. In contrast, we found that primary amino alcohol 7
was ineffective: it resulted in <1% alkene conversion
(entry 7). These preliminary screening results indicate
that incorporating the structural features of a cyclic
(10) In the amine-catalyzed epoxidation of trans-stilbene with amine
8c, the amine subsequently decomposed to give benzophenone and
nitrone. (a) Su, Z.; Mariano, P. K.; Falvey, D. E.; Yoon, U. C.; Oh, S.
W. J. Am. Chem. Soc. 1998, 120, 10676-10686. (b) Murahashi, S.-I.;
Imada, Y.; Ohtake, H. J. Org. Chem. 1994, 59, 6170-6172.
(11) The procedures for the preparation of amines 9a-c, 10, 12b-
g, 13a-c, and 14 are provided in the Supporting Information.
(12) We found that under our slightly acidic reaction system, cis-
1,2-diol is the major hydrolysis product of 1-phenylcyclohexene oxide.
This finding is in agreement with literature reports that the cis-1,2-
diol is more stable than the trans-1,2-diol. (a) Berti, G.; Bottari, F.;
Macchia, B.; Macchia, F. J. Org. Chem. 1952, 17, 6227-6234. (b)
Choudary, B. M.; Chowdari, N. S.; Jyothi, K.; Kantam, M. L. Tetra-
hedron 1965, 12, 3277-3283.
(8) Armstrong, A. Angew. Chem., Int. Ed. 2004, 43, 1460-1462.
(9) The reasons why â-hydroxylamines efficiently promote epoxi-
dation of olefins are under investigation.
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Ho et al.
TABLE 1. Amine-Catalyzed Epoxidation of trans-Stilbenea
a Unless otherwise indicated, all epoxidation reactions were performed at room temperature over 5 h with 0.1 mmol of trans-stilbene,
0.1 mmol of amine, 0.4 mmol of Oxone, and 1 mmol of NaHCO3 in 2 mL of CH3CN and 0.2 mL of H2O. b Conversion calculated from the
recovery of trans-stilbene after flash column chromatography. c Yield based on conversion after flash column chromatography. d Determined
by chiral HPLC analysis (Daicel OD column); the major enantiomer of the epoxide has the (S,S) configuration. e 3 h. f Using D-prolinol,
the configuration of the major enantiomer of the epoxide was (R,R). g 40 min.
achieved when the epoxidation reactions were conducted
at 0 or -20 °C (entries 5 and 6). Although the reaction
proceeded more slowly at -20 °C, no diol side product
was formed. These results reflect the importance of
incorporating an electronegative atom (fluorine) at the
â-position relative to the amino group.
Aggarwal et al. reported that increasing the steric bulk
of the aryl group of the amine catalyst (from phenyl to
R-naphthyl) led to an increase in the enantioselectivity
of 1-phenylcyclohexene epoxidation (from 46% to 59%;
Scheme 2).7c We also attempted to improve the enantio-
selectivity of the epoxide formation by modifying the aryl
900 J. Org. Chem., Vol. 70, No. 3, 2005

Catalysts for Epoxidation of Olefins with Oxone
TABLE 2. Amine-Catalyzed Epoxidation of 1-Phenylcyclohexenea
a Unless otherwise indicated, all of the epoxidation reactions were performed at room temperature for 2 h with 0.4 mmol of
1-phenylcyclohexene, 5 mol % of amine catalyst, 0.8 mmol of Oxone, and 2 mmol of NaHCO3 in 1 mL of CH3CN and 0.1 mL of H2O.
b Based on conversion and determined by integration of 1H NMR spectra relative to an internal standard (nitrobenzene). c Enantiose-
lectivities determined by 1H NMR spectroscopy with Eu(hfc)3 (Aldrich no. 16,474-7) as a chiral shift reagent; the configuration of the
major enantiomer of the epoxide was (S,S). d 4 h. e Reaction performed at 0 °C. f Reaction performed at -20 °C.
group of the amine catalysts (Table 2; entries 7-13). In
contrast to Aggarwal’s findings,7c we found that introduc-
ing sterically more demanding groups to our amines did
not provide any significant improvement in the enantio-
selectivity of epoxidation. We obtained similar ee values
for the epoxidation catalyzed by 12b-e at room temper-
ature (45-52% ee; entries 4, 7, and 9-11). At -20 °C,
we achieved the highest enantioselectivity (61% ee) with
complete suppression of diol formation when the epoxi-
dation was catalyzed by amine 12b.
Interestingly, we found that the electronic properties
of the aryl ring of the amine have a significant influence
on alkene conversion and enantioselectivity (entries 12
and 13).16,17 The introduction of electron-withdrawing
substituents (F and CF3 groups) on the aryl ring led to
decreases in the values of conversion, yield, and ee. As
J. Org. Chem, Vol. 70, No. 3, 2005 901

Ho et al.
SCHEME 2. Effect That the Steric Demand of the
Amine Catalyst Has on the Enantioselectivity of
1-Phenylcyclohexene Epoxidation Reported by
Aggarwal et al.7c
exhibited good reactivity in promoting epoxidation (Table
1, entries 17 and 18), we screened amines 13a-c, which
have hydroxyl, methoxy, and difluoro substituents at the
4-position of 12a, for their catalytic activities (Table 2;
entries 14-16).11,16,17 We found that these functionalities
(OH, OMe, and F) at the 4-position of the pyrrolidine ring
resulted in low catalytic efficiencies (16-52% alkene
conversion, 5-37% ee; entries 14-16), especially for 13c,
which bears two fluorine atoms. These results are similar
to the trend we observed for amines 12a, 12f, and 12g.
Asymmetric Epoxidation of Various Alkenes Cata-
lyzed by Amine 12a. We selected amine 12a as the
catalyst for the epoxidation of alkenes having different
substitution patterns; Table 3 summarizes the results.
We found that the epoxidation proceeded smoothly in the
presence of 5-10 mol % of 12a for most of the substrates
(entries 1-6), except for cis-stilbene and trans-4-octene
(entries 7 and 8).19 We obtained higher enantioselectivi-
ties for the epoxidation of 1-phenylcyclohexene (entry 1)
than for any of the other substrates (entries 2-5). It is
interesting to note that our fluorinated amine gave
significantly higher ee values for the epoxidation of aryl
olefins than for aliphatic olefins (entries 1 and 2). In the
epoxidation of 1-phenylcyclohexene, 2.5 mol % of catalyst
12a could be employed to give 73% conversion within a
reaction time of 3 h, with the ee value of the product
epoxide remaining essentially the same (50%). In contrast
to Aggarwal’s case, the epoxidation of trans-stilbene can
be achieved by using 10 mol % of amine 12a without the
need to preform the ammonium‚HSO5 complex and use
excess amounts of the catalyst (entry 3).7c For epoxidation
of trans-methylstilbene and â-methylstyrene (entries 4
and 5), we required the addition of 10 mol % of amine to
effect epoxidation. In the epoxidation of R-methylstyrene,
complete conversion was obtained within 3 h. However,
the corresponding epoxide was not stable in the reaction
system and readily hydrolyzed to the corresponding diol
(entry 6).
indicated in Table 2, amine 12g, which bears two CF3
groups on the aryl rings, gave racemic epoxide in 31%
conversion (entry 13). Because the corresponding am-
monium salts are the actual catalysts for the epoxidation
reactions,7c the presence of electron-withdrawing sub-
stituents on the aryl ring may disfavor protonation of the
amine by means of inductive or electrostatic effects that,
consequently, decrease the catalyst’s concentration, which
results in lower values of conversion and ee.16,17 Another
explanation is that the extra F substituents on the aryl
ring may increase the hydrophobicity of the amine
catalysts, which makes the amine less effective as a
phase transfer catalyst.18
On the basis of our observation that amines possessing
hydroxyl or OMOM groups at the 4-position (9b or 9c)
(13) Fluorinated amine 12a was first prepared and studied as a
potential auxiliary for asymmetric alkylation reactions and as a chiral
shift agent for the analysis by 1H NMR spectroscopy of the enantio-
meric purities of chiral carboxylic acids and alcohols. See: (a) O’Hagan,
D.; Royer, F.; Tavasli, M. Tetrahedron: Asymmetry 2000, 11, 2033-
2036. (b) Bailey, D. J.; O’Hagan, D.; Tavasli, M. Tetrahedron: Asym-
metry 1997, 8, 149-153.
(14) For examples of the use of fluorinated compounds as enzyme
substrate mimics, see: (a) Welch, J. T.; Eswarakrishnan, S. Fluorine
in Bioorganic Chemistry; Wiley & Sons: New York, 1991. (b) Seebach,
D. Angew Chem., Int. Ed. Engl. 1990, 29, 1320-1367. (c) Mann, J.
Chem. Soc. Rev. 1987, 16, 381-436. (d) Welch, J. T. Tetrahedron 1987,
43, 3123-3197. (e) Bondi, A. J. Phys. Chem. 1964, 68, 441-451.
(15) For the X-ray crystallographic structure of amine 12a‚HCl salts,
see: Batsanov, A. S.; Howard, J. A. K. Acta Crystallogr., Sect. C 2000,
C56 10, e467-e468.
(16) For recent examples of electronic effects of catalysts affecting
enantioselectivity, see: (a) Cavallo, L.; Jacobsen, H. J. Org. Chem.
2003, 68, 6202-6207. (b) Palucki, M.; Finney, N. S.; Pospisil, P. J.;
Gueler, M. L.; Ishida, T.; Jacobsen, E. N. J. Am. Chem. Soc. 1998,
120, 948-954. (c) Yang, D.; Yip, Y. C.; Chen, J.; Cheung, K. K. J. Am.
Chem. Soc. 1998, 120, 7659-7660. (d) RajanBabu, T. V.; Casalnuovo,
A. L. J. Am. Chem. Soc. 1996, 118, 6325-6326. (e) Schnyder, A.;
Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. Engl. 1995, 34, 931-
933. (f) Park, S. B.; Murata, K.; Matsumoto, H.; Nishiyama, H.
Tetrahedron: Asymmetry 1995, 10, 2487-2494. (g) Larrow, J. F.;
Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem.
1994, 59, 1939-1942. (h) Chang, S.; Heid, R. M.; Jacobsen, E. N.
Tetrahedron Lett. 1994, 5, 669-672. (i) Jacobsen, E. N.; Zhang, W.;
Gu¨ler, M. L. J. Am. Chem. Soc. 1991, 113, 6703-6704.
Mechanistic Studies. We conducted a series of
experiments to gain insight into the identity of the active
oxidizing species that are responsible for the epoxidation
reactions. Our experimental results support Aggarwal’s
proposal: the secondary amines act as phase transfer
catalysts and Oxone activators.7c
Aggarwal et al. reported that the oxidation products
of amines, such as nitrones, hydroxylamines, and N-
hydroxylactams, were not the active oxidizing species
responsible for epoxidation.7c In our current study, we
also found that the oxidation products of 12a20 were
inactive toward epoxidation: no substrate conversion was
observed when 12a was left to stir under the reaction
conditions for 1 h prior to the addition of 1-phenylcyclo-
hexene.
In Figure 1 we plot the conversion of 1-phenylcyclo-
hexene against the reaction time when 5 mol % of 12a
(19) For the determination of the ee values of trans-stilbene oxide
and trans-â-methylstyrene oxide, see: (a) Wang, Z. X.; Tu, Y.; Frohn,
M.; Shi, Y. J. Org. Chem. 1997, 62, 2328-2329. For trans-R-methyl-
stilbene oxide, see: (b) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem.
1994, 59, 4378-4380.
(20) A nitrone was detected by ESI-MS analysis to be the major
oxidation product of amine 12a. For catalytic oxidation of secondary
amines to nitrones, see: (a) Murahashi, S. I. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2443-2465. (b) Murahashi, S. I.; Mitsui, H.; Shiota,
T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1736-1744.
(17) For examples of electronic field effects and inductive effects
affecting chemical reactivity, see: (a) Yang, D.; Yip, Y. C.; Jiao, G. S.;
Wong, M. K. J. Org. Chem. 1998, 63, 8952-8956. (b) Bowden, K.;
Grubbs, E. J. Chem. Soc. Rev. 1996, 171-177. (c) Stock, L. M. J. Chem.
Educ. 1972, 49, 400-404.
(18) For the use of fluorine atoms to improve the hydrophobicity of
a catalyst, see: Wu, J. J.; Fu, L.; Chuang, K. T. Appl. Catal. 1991, 72,
71-80.
902 J. Org. Chem., Vol. 70, No. 3, 2005

Catalysts for Epoxidation of Olefins with Oxone
TABLE 3. Synergistic Effect Observed in the Heterogeneous Epoxidation Systema
a Unless otherwise indicated, all of the epoxidation reactions were performed at room temperature with 0.4 mmol of alkene, 5 mol %
of amine, 0.8 mmol of Oxone, and 2 mmol of NaHCO3 in 1 mL of CH3CN and 0.1 mL of H2O. b Based on conversion and determined by
integration of 1H NMR spectra relative to an internal standard (nitrobenzene). c Enantioselectivities determined by 1H NMR spectroscopy
with Eu(hfc)3 (Aldrich no. 16,474-7) as a chiral shift reagent. d 10 mol % of amine was used.
of ee of the chiral epoxide remained essentially un-
changed (ca. 50% ee) during the course of the reaction,
which indicates that there was a consistent chiral
intermediate responsible for the asymmetric epoxidation.
It is likely that 12a was converted into its corresponding
ammonium salt under the slightly acidic conditions at
the beginning of the reaction (0-10 min). After the
complete protonation of 12a, the epoxidation rate reached
a maximum value (10-40 min) and then leveled off after
40 min.
Electrophilic Nature of the Active Oxidizing
Species. To probe the electronic nature of the active
oxidizing species in our reaction system, we conducted
epoxidation reactions of several 1-arylcyclohexenes that
bear substituents on the phenyl ring that have different
electronic properties (p-OMe, H, and m-F) using 5 mol
% of 12a as the catalyst;21,22 Table 4 summarizes the
results. We note that, within a 30-min reaction time,
FIGURE 1. A plot of conversion percent versus time for the
epoxidation of 1-phenylcyclohexene catalyzed by amine 12a.
(21) For substrate syntheses, see: (a) Collins, D. J.; Molinski, T.
F.; Sjoevall, J. Aust. J. Chem. 1983, 36, 361-370. (b) Shabarov, Y.;
Blagodatskikh, S. A.; Levina, M. I. Zh. Org. Khim. 1975, 11, 1223-
1225.
(22) For recent examples of substrate electronic effects affecting
enantioselectivity, see: (a) Wang, M.-X.; Lin, S.-J.; Liu, C.-S.; Zheng,
Q.-Y.; Li, J.-S. J. Org. Chem. 2003, 68, 4570-4573. (b) Abdi, S. H. R.;
Kureshy, R. I.; Khan, N. H.; Bhadbhade, M. M.; Suresh, E. J. Mol.
Catal. A: Chem. 1999, 1-2, 185-194. (c) Zhang, H.; Xue, F.; Mak, T.
C. W.; Chan, K. S. J. Org. Chem. 1996, 61, 8002-8003. (d) Corey, E.
J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153-9156.
Reaction conditions: 0.4 mmol of 1-phenylcyclohexene, 5 mol
% of catalyst, 0.8 mmol of Oxone, and 2 mmol of NaHCO3 in
1 mL of CH3CN and 0.1 mL of H2O at room temperature. The
conversions were determined by integration of 1H NMR spectra
relative to an internal standard (nitrobenzene).
was used as the catalyst for epoxidation. The sigmoidal
curve we obtained reveals that an initial induction period
was required for the epoxidation. In addition, the value
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Ho et al.
TABLE 4. Catalytic Epoxidation of Alkenes with Amine 12aa
a Unless otherwise indicated, all the epoxidation reactions were performed at room temperature for 30 min with 0.4 mmol of substrate,
5 mol % of amine catalyst, 0.8 mmol of Oxone, and 2 mmol of NaHCO3 in 1 mL of CH3CN and 0.1 mL of H2O. b Based on conversion and
determined by integrating 1H NMR spectra relative to an internal standard (nitrobenzene). c Enantioselectivities were determined by 1H
NMR spectroscopy with Eu(hfc)3 (Aldrich no. 16,474-7) as a chiral shift reagent; the configuration of the major enantiomer of the epoxide
was (S,S). d Yield of the corresponding diol: the epoxide was not stable in the reaction system and was readily hydrolyzed. e The value
of ee of the diol was not determined.
higher conversion occurred for the electron-rich p-OMe-
substituted substrate (60% conversion; entry 1) than for
the electron-deficient m-F-substituted one (21% alkene
conversion; entry 3). The lower reaction rate for the less-
electron-rich alkene indicates that the active oxidizing
species has an electrophilic nature. This trend is in
agreement with the phase transfer catalyst mechanism
proposed by Aggarwal in which the electrophilic am-
monium ion‚HSO5 complex is the active oxidizing species.7c
Epoxidation with Free Amines and Amine‚HCl
Salts. Aggarwal and co-workers reported that preforming
the amine‚HCl salts provides more reproducible results
and higher enantioselectivities relative to the use of free
amines to catalyze the epoxidation of olefins.7c This
finding led us to perform experiments side-by-side to
compare the reactivities of free amines 12a, 12b, and 14
with those of the corresponding amine‚HCl salts toward
epoxidation (Table 5).
Under our reaction system, we did not observe any
significant improvement in conversion, yield, or enanti-
oselectivity when using the HCl salts of our fluorinated
amines 12a and 12b (entries 1-4); only the preformed
HCl salt of the nonfluorinated amine 14 displayed an
enhanced enantioselectivity (cf. entries 5 and 6).
We speculate that the discrepancy between our results
and those reported by Aggarwal may arise from differ-
ences in the reaction systems and the amines used
(Scheme 3).
catalysts under our epoxidation conditions provided
reproducible results. In addition, the presence of elec-
tronegative fluorine atoms may stabilize the positively
charged ammonium salts through favorable charge-dipole
interactions or mild hydrogen bond formation with an
ammonium proton (Figure 2).23 We believe that the
presence of the fluorine atom on the amines and the
slightly acidic reaction medium we employed are the
reasons why we had no difficulty in reproducing the
epoxidation results when using free amines. At this stage,
however, it is still difficult to draw a clear conclusion of
the transition state geometry to explain the configuration
of the epoxides.
Amines as Both Phase Transfer Catalysts and
Oxone Activators Demonstrated in a Heteroge-
neous Epoxidation System. We employed amine 12a
also for the epoxidation of 1-phenylcyclohexene in a
heterogeneous solvent system (1 mL of CH2Cl2 and 0.5
mL of H2O); Table 6 summarizes the results. The alkene
conversion was only 22% (entry 1) when the amine
catalyst 12a was used alone. It is known that 18-crown-6
is a good phase transfer catalyst and can increase the
solubility of Oxone in the organic solvents, which favors
epoxidation.24 In the absence of our amine catalyst to
provide Oxone activation, however, the use of 18-crown-6
alone resulted in only a 7% conversion of the alkene
(entry 2). Notably, the conversion increased significantly
to 53% when amine 12a and 18-crown-6 were both added
as cocatalysts (entry 3). These results reveal that,
although Oxone transfer to the organic layer has an
important effect on the rate of this catalysis, the efficient
Relative to Aggarwal’s amine-catalyzed epoxidation
system,7c our system uses lower amounts of NaHCO3 and
no pyridine is added; thus, we provide a more acidic
reaction medium to facilitate the protonation of amines.
Under our slightly acidic reaction conditions,6 the free
amines are readily converted in situ to the corresponding
ammonium salts necessary for epoxidation. The induction
period of the first 10 min of the sigmoidal curve indicated
in Figure 1 might be the time required for the amine
protonation. It is worth noting that using free amines as
(23) For studies on fluorine atoms as hydrogen bond acceptors using
the Cambridge Structural Database System, see: (a) Howard, J. A.
K.; Hoy V. J.; O’Hagan, D.; Smith G. T. Tetrahedron 1996, 38, 12613-
12622. (b) Shimoni, L.; Glusker, J. P. Struct. Chem. 1994, 5, 383-
397. (c) Murray-Rust, P.; Stalling, W. C.; Monti, C. T.; Preston, R. K.;
Glusker, J. P. J. Am. Chem. Soc. 1983, 105, 3206-3214.
(24) For a heterogeneous solvent system that uses 18-crown-6 and
Oxone to perform epoxidation, see: Lacour, J.; Monchaud, D.; Marsol,
C. Tetrahedron Lett. 2002, 43, 8257-8260.
904 J. Org. Chem., Vol. 70, No. 3, 2005

Catalysts for Epoxidation of Olefins with Oxone
TABLE 5. Effects That the Electronic Properties of the Substrates Have on the Rates of Epoxidationa
a Unless otherwise indicated, all of the epoxidation reactions were performed at room temperature for 2 h with 0.4 mmol of
1-phenylcyclohexene, 5 mol % of amine catalyst, 0.8 mmol of Oxone, and 2 mmol of NaHCO3 in 1 mL of CH3CN and 0.1 mL of H2O.
b Based on conversion and determined by integrating 1H NMR spectra relative to an internal standard (nitrobenzene). c Enantioselectivities
were determined by 1H NMR spectroscopy with Eu(hfc)3 (Aldrich no. 16,474-7) as a chiral shift reagent; the configuration of the major
enantiomer of the epoxide was (S,S). d The HCl salt of the amine was prepared by adding an excess amount of 3 M HCl in Et2O to the
corresponding amine in CH2Cl2 solution at 0 °C and then concentrating the solution.
SCHEME 3. The Differences between Aggarwal’s and Our Epoxidation Conditions
activation of Oxone provided by amine 12a is equally
important to alkene conversion. Once a sufficient amount
of Oxone is transferred to the organic layer by 18-crown-
6, our amine catalyst 12a can activate Oxone toward
alkene epoxidation.
the amines have on epoxidation, we discovered that cyclic
secondary amines are efficient catalysts and that an
electronegative fluorine atom located at the â-position
relative to the amino group is beneficial and can further
improve the catalytic efficiency. Under our slightly acidic
reaction conditions, the fluorinated amine can be proton-
ated in situ, which obviates the need to preform the
ammonium salts that are necessary for epoxidation. The
role proposed for the amines by Aggarwal and co-
workerssthat they act as phase transfer catalysts and
Oxone activatorssis supported by our experimental
results. The insights obtained from this study should
Conclusion
In summary, we have developed an efficient protocol
for the asymmetric epoxidation of olefins catalyzed by
chiral fluorinated secondary amines. Through a system-
atic investigation of the effects that the substituents of
J. Org. Chem, Vol. 70, No. 3, 2005 905

Ho et al.
FIGURE 2. Stabilization of the ammonium salts by the fluorine substituent.
TABLE 6. Parallel Tests of the Effects of Using Free
Amines and Their Corresponding HCl Salts to Promote
Epoxidationa
General Procedure for the Amine-Catalyzed Epoxi-
dation of 1-Phenylcyclohexene (Table 2, entry 1). A
mixture of Oxone (0.8 mmol) and NaHCO3 (2 mmol) was added
to a round-bottom flask containing a stirred solution of amine
12a (5 mol %) and 1-phenylcyclohexene (0.4 mmol) in CH3CN
(1 mL) and H2O (0.1 mL) at room temperature. After being
stirred for 2 h, the mixture was filtered through NaHSO3 and
MgSO4 and concentrated under reduced pressure. The residue
was subjected to 1H NMR spectroscopic analysis to determine
the percentage conversion and the yield of epoxide and diol
by using nitrobenzene as an internal standard. The enantio-
meric excess of the epoxide was determined by 1H NMR
spectroscopy by using Eu(hfc)3 (Aldrich no. 16,474-7) as a chiral
shift reagent.
amine
loading
(mol %)
18-crown-6
loading
(mol %)
conversion
(%)b
yield
(%)b
ee
entry
(%)c
General Procedure for the Amine-Catalyzed Epoxi-
dation of Other Substrates (Table 3). The experimental
procedure is the same as reported for the amine-catalyzed
epoxidation of 1-phenylcyclohexene, with the exception that
the amine catalyst loading was increased.
1
2
3
5
22
7
56
97
75
11
n.d.
39
5
5
5
53
a Unless otherwise indicated, all of the epoxidation reactions
were performed at room temperature with 0.4 mmol of 1-phenyl-
cyclohexene, the indicated mol % of catalyst, 0.8 mmol of Oxone,
and 2 mmol of NaHCO3 in 1 mL of CH2Cl2 and 0.5 mL of H2O.
b Based on conversion and determined by integrating 1H NMR
spectra relative to an internal standard (nitrobenzene). c Enantio-
selectivities were determined by 1H NMR spectroscopy with
Eu(hfc)3 (Aldrich no. 16,474-7) as a chiral shift reagent; the
configuration of the major enantiomer of the epoxide was (S,S).
Procedure for the Amine-Catalyzed Epoxidation of
1-Phenylcyclohexene in the Presence of 18-Crown-6. A
mixture of Oxone (0.8 mmol) and NaHCO3 (2 mmol) was added
to a round-bottom flask containing amine 12a (5 mol %),
cocatalyst 18-crown-6 (5 mol %), and 1-phenylcyclohexene (0.4
mmol) in CH2Cl2 (1 mL) and H2O (0.5 mL) at room tempera-
ture. After being stirred for 2 h, the reaction mixture was
filtered through NaHSO3 and MgSO4 and concentrated under
reduced pressure. The residue was subjected to 1H NMR
spectroscopic analysis to determine the percentage conversion
and the yield of epoxide and diol by using nitrobenzene as an
internal standard. The enantiomeric excess of the epoxide was
determined by 1H NMR spectroscopy by using Eu(hfc)3 (Aldrich
no. 16,474-7) as a chiral shift reagent.
further stimulate the development of new generations of
organocatalysts for asymmetric reactions.
Experimental Section
General Procedure for the Amine-Catalyzed Epoxi-
dation of trans-Stilbene (Table 1, entry 8). A mixture of
Oxone (0.4 mmol) and NaHCO3 (1 mmol) was added to a
round-bottom flask containing a solution of pyrrolidine (0.1
mmol) and trans-stilbene (0.1 mmol) in CH3CN (2.0 mL) and
H2O (0.2 mL) at room temperature. After being stirred for 5
h, the reaction mixture was diluted with CH2Cl2 (50 mL) and
washed with saturated NaHCO3 solution (3 × 20 mL). The
organic layer was dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified
by flash column chromatography to provide trans-stilbene
epoxide (1.7 mg, 50% yield based on 19% conversion) as a white
solid.
Acknowledgment. This work was supported by the
University of Hong Kong, the Hong Kong Research
Grants Council, and the HKU Generic Drug Research
Program. We thank Dr. M. S. M. Yuen for preliminary
screening of the amines.
Supporting Information Available: Experimental de-
tails for the preparation of amine catalysts and spectral
characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO048378T
906 J. Org. Chem., Vol. 70, No. 3, 2005