Asymmetric allylic oxidation reactions catalyzed by a chiral nonracemic and C2-symmetric 2,2′-bipyridyl copper(i) complex

Article abstract of DOI:10.1039/b513374m

Chiral, nonracemic and C₂-symmetric 2,2'-bipyridyl ligand in copper(I)-catalyzed asymmetric allylic oxidation reactions of three cyclic alkenes 2a-c (n=1 -3) with tert-butyl peroxybenzoate, was analyzed. The active copper(I)-catalyst for these

Full text of DOI:10.1039/b513374m

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Asymmetric allylic oxidation reactions catalyzed by a chiral nonracemic
and C2-symmetric 2,2ꢀ-bipyridyl copper(I) complex
Michael P. A. Lyle and Peter D. Wilson*
Received (in Pittsburgh, PA, USA) 20th September 2005, Accepted 4th November 2005
First published as an Advance Article on the web 24th November 2005
DOI: 10.1039/b513374m
The evaluation of a chiral, nonracemic and C2-symmetric
2,2ꢀ-bipyridyl ligand in copper(I)-catalyzed asymmetric allylic
oxidation reactions of a series of cyclic alkenes with tert-butyl
peroxybenzoate is reported (up to 91% ee, the highest reported
enantioselectivity for a bipyridyl ligand copper(I) complex to
date).
up to 80% ee were achieved when the reactions were performed in
acetonitrile at relatively low temperatures (−20 ◦C). High enantio-
selectivities of up to 99% ee have subsequently been achieved for
this reaction.9 However, there still remains a significant problem in
that these catalytic asymmetric processes suffer from exceedingly
slow reaction rates. In some cases, the reaction has taken up
to three weeks to reach a satisfactory level of conversion.9,10 It
has been found that chiral nonracemic and C2-symmetric 2,2ꢀ-
bipyridyl copper(I)-complexes are very active catalysts for this
reaction in that they provide much faster reaction rates.11 However,
the enantioselectivities obtained, thus far, have been somewhat
lower than with bisoxazoline complexes.12 We also chose to study
this asymmetric process because of the inherent usefulness of the
reaction products in target-oriented synthesis.13
The chiral nonracemic and C2-symmetric 2,2ꢀ-bipyridyl ligand
(L*) 1 was evaluated in the copper(I)-catalyzed allylic oxidation
reactions of three cyclic alkenes 2a–c (n = 1–3) (Table 1). The
active copper(I)-catalyst for these reactions was generated, by a
standard method, on reduction of the complex formed between
5 mol% of copper(II) triflate and 5.25 mol% of the bipyridyl
ligand 1 with 5.25 mol% of phenylhydrazine in either acetone or
acetonitrile.14,15 These two solvents and reaction conditions were
chosen because they have provided the highest enantioselectivities
in related catalytic reactions.6 Following the formation of the
catalytic species, the resultant bright red reaction mixtures were
treated with the stoichiometric oxidant, tert-butyl peroxybenzoate,
and an excess (5 equivalents) of the cyclic alkenes 2a–c.
We have previously reported an efficient synthesis of a chiral
nonracemic and C2-symmetric 2,2ꢀ-bipyridyl ligand 1 (Fig. 1).1,2
In addition, we have demonstrated that this bipyridyl ligand is
an outstanding chiral director in asymmetric copper(I)-catalyzed
cyclopropanation reactions of a series of alkenes and diazoesters.1
The corresponding cyclopropanes were isolated in good yield
(up to 82%) and in very high enantioselectivities and diastere-
oselectivities (up to 99% ee and >95 : 5 dr). The application of
this bipyridyl ligand in asymmetric copper(II)-catalyzed Friedel–
Crafts alkylation reactions of a series of substituted indoles with
methyl trifluoropyruvate has also been demonstrated.2 In this
case, the corresponding 3,3,3-trifluoro-2-hydroxy-2-indole-3-yl-
propionic acid methyl esters were isolated in good yield (up to
79%) and in high enantiomeric excess (up to 90%).
The allylic oxidation reaction of cyclopentene 2a (n = 1) in
acetone at room temperature for 24 h afforded the desired reaction
product 3a (n = 1) in good yield (64%) and in relatively low
enantioselectivity (32% ee) (Table 1, entry 1). On repeating this
reaction in acetonitrile for 16 h, the reaction product 3a was
isolated in similar yield and enantioselectivity (69% and 34% ee,
respectively) (Table 1, entry 2). The allylic oxidation reaction of
cyclohexene 2b (n = 2) in acetone at room temperature for 16 h
afforded the corresponding reaction product 3b (n = 2) in good
yield (67%) and in higher enantiomeric excess (65%) (Table 1,
entry 3). Moreover, the enantioselectivity of this reaction was
substantially increased (84% ee) on employing acetonitrile as the
solvent at room temperature (Table 1, entry 4). In this instance,
however, the reaction rate was slower and the reaction product 3b
was isolated in slightly lower yield (56%) after 72 h. In view of
these encouraging results, we attempted to increase the enantios-
electivity of this reaction by repeating it at a lower temperature.
The product 3b was isolated in moderate yield (51%) and good
enantiomeric excess (81%) when the allylic oxidation reaction was
performed at 0 ◦C for 48 h (Table 1, entry 5). Moreover, a further
enhancement of enantioselectivity was observed when the reaction
Fig. 1 Chiral nonracemic and C2-symmetric 2,2ꢀ-bipyridyl ligand 1.
In this paper and in regard to the further exploration of the
versatility of our chiral nonracemic 2,2ꢀ-bipyridyl ligand 1 (>99%
ee) in catalytic asymmetric synthesis, we report a study of the
application of this ligand in copper(I)-catalyzed asymmetric allylic
oxidation reactions.3,4 The specific reaction type we chose to
study was first reported in 1959 by Kharasch and Sosnovsky.5,6
It was shown that alkenes, such as cyclohexene, can be oxidized
with a stoichiometric amount of tert-butyl peroxybenzoate in the
presence of a catalytic amount of copper(I) bromide. This afforded
the corresponding racemic allylic ester in good yield (70%).
Asymmetric versions of this catalytic allylic oxidation reaction
using chiral nonracemic bisoxazoline copper(I)-complexes were
first reported independently by Pfaltz and co-workers and Andrus
and co-workers in 1995.7,8 In these cases, enantioselectivities of
Department of Chemistry, Simon Fraser University, 8888 University Drive,
Burnaby, British Columbia, Canada V5A 1S6. E-mail: pwilson@sfu.ca;
Fax: 1 604 291-3765; Tel: 1 604 291-5654
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Table 1 Asymmetric allylic oxidation reactions of cyclic alkenes 2a–c
Entry
Substrate
n
Solvent
Reaction temperature
Reaction time/h
Yield (%)a
Ee (%)b
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2b
2b
2c
2c
1
1
2
2
2
2
3
3
Acetone
MeCN
Acetone
MeCN
Acetone
MeCN
Acetone
MeCN
rt
rt
rt
rt
24
16
16
72
48
96
16
16
64
69
67
56
51
45
72
76
32
34
65
84
81
91
36
40
0 ◦
0 ◦
rt
C
C
rt
a Isolated yield, based on the amount of tert-butyl peroxybenzoate employed, after purification by flash chromatography. b Determined by analytical
chiral HPLC (Daicel Chiralcel OD column).
was performed in acetonitrile at 0 ◦C for 96 h (91% ee). However,
the yield was again somewhat compromised (45%) (Table 1, entry
6). To the best of our knowledge, this is the highest reported
enantioselectivity for an asymmetric allylic oxidation reaction with
a chiral nonracemic 2,2ꢀ-bipyridyl ligand. In addition, the rate of
this reaction was significantly greater than has been achieved with
several bisoxazoline ligands which have been shown to be highly
enantioselective.9 The allylic oxidation reaction of cycloheptene
2c (n = 3) in acetone for 16 h afforded the reaction product 3c
(n = 3) in good yield (72%) but only in relatively low enantiomeric
excess (36%) (Table 1, entry 7). When the corresponding reaction
was performed in acetonitrile for 16 h, the reaction product
3c was formed in similar yield and enantioselectivity (72% and
40% ee, respectively) (Table 1, entry 8). Collectively, the results
of these asymmetric catalytic reactions indicate that the process
is highly substrate-dependent. The absolute stereochemistry of
each of the above reaction products 3a–c (n = 1–3) was assigned
as (S) on comparison of the optical rotations with literature
values.10
radical which in turn was generated by a copper(I)-mediated
homolytic cleavage reaction of the oxygen–oxygen bond of tert-
butyl peroxybenzoate) to one of the less hindered quadrants of the
intermediate C2-symmetric copper(II) benzoate complex 4. The
resultant copper(III) species 5 then would undergo a pericyclic
rearrangement (or direct reductive elimination) to afford the
observed product (1S)-cyclohex-2-enyl benzoate 3b and regenerate
the initial catalytic copper(I) complex.16
In conclusion, we have evaluated our new chiral nonracemic
and C2-symmetric 2,2ꢀ-bipyridyl ligand 1 in copper(I)-catalyzed
asymmetric allylic oxidation reactions of the cyclic alkenes 2a–
c (n = 1–3) with tert-butyl peroxybenzoate. On performing the
reaction of cyclohexene 2b (n = 2) in acetonitrile at 0 ◦C for
96 h, the corresponding product, (1S)-cyclohex-2-enyl benzoate
3b (n = 2), was isolated in 45% yield and in high enantiomeric
excess (91%). The yields and enantioselectivities of these copper(I)-
catalyzed processes were found to be dependent on the substrate,
solvent and reaction temperature.
Studies are currently underway to improve the enantioselec-
tivities that can be obtained with this new type of exceptionally
promising chiral nonracemic 2,2ꢀ-bipyridyl ligand, in various
metal-catalyzed asymmetric processes, by modification of the
substituents of the cyclic acetal moieties of the 2,2ꢀ-bipyridine.
We are grateful to the Natural Sciences and Engineering Re-
search Council of Canada (NSERC) and Simon Fraser University
(SFU) for financial support. We also wish to acknowledge the
Canadian Foundation for Innovation (CFI), the British Columbia
Knowledge Development Fund (BCKDF) and AstraZeneca
Canada, Inc. for support of our research program. M.P.A.L.
thanks SFU for an entrance scholarship and graduate research
fellowships.
A rationalization of the stereochemical outcome of the
copper(I)-catalyzed asymmetric allylic oxidation reactions of the
cyclic alkenes 2a–c (shown for cyclohexene 2b) is illustrated below
(Fig. 2).
Fig. 2 Rationalization of the stereochemical outcome of the asymmetric
allylic oxidation reactions.
References
1 M. P. A. Lyle and P. D. Wilson, Org. Lett., 2004, 6, 855.
2 M. P. A. Lyle, N. D. Draper and P. D. Wilson, Org. Lett., 2005, 7, 901.
3 For reviews on the synthesis and applications of chiral nonracemic 2,2ꢀ-
bipyridines and 1,10-phenanthrolines, see: (a) G. Chelucci and R. P.
Thummel, Chem. Rev., 2002, 102, 3129; (b) N. C. Fletcher, J. Chem.
The asymmetry of the process is most likely the result of
the approach of the cyclohexenyl radical (generated by abstrac-
tion of a hydrogen atom from cyclohexene by a tert-butoxy
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Soc., Perkin Trans. 1, 2002, 1831; (c) A. V. Malkov and P. Kocˇovsky´,
Curr. Org. Chem., 2003, 7, 1737.
13 For example, (1S)-cyclohex-2-enyl benzoate is a key starting material
in a notable synthesis of the inflammation mediator leukotriene B4, see:
R. Hayes and T. W. Wallace, Tetrahedron Lett., 1990, 31, 3355. The
preparation of the former compound by catalytic means represents
a marked improvement over previous routes which required multiple
steps from carbohydrate-based starting materials.
14 For discussion and experimental procedures regarding the use of
phenylhydrazine in the generation of copper(I) complexes from cop-
per(II) species, see: ref. 10 and citations therein.
4 For discussions on the coordination chemistry of 2,2ꢀ-bipyridines and
1,10-phenanthrolines, see: (a) J. Reedijk, in Comprehensive Coordination
Chemistry, ed. G. Wilkinson, R. D. Gillard and J. A. McCleverty,
Pergamon Press, Oxford, 1987, vol. 2, pp. 73–98; (b) C. Kaes, A. Katz
and M. W. Hosseini, Chem. Rev., 2000, 100, 3553.
5 M. S. Kharasch, G. Sosnovsky and N. C. Yang, J. Am. Chem. Soc.,
1959, 81, 5819.
6 For a review, see: M. B. Andrus and X. Chen, Tetrahedron, 1997, 53,
16229.
7 A. S. Gokhale, A. B. E. Minidis and A. Pfaltz, Tetrahedron Lett., 1995,
36, 1831.
8 M. B. Andrus, A. B. Argade, X. Chen and M. G. Pamment, Tetrahedron
Lett., 1995, 36, 2945.
15 General procedure for copper(I)-catalyzed asymmetric allylic oxidation
reactions: To a screw-cap vial was added copper(II) trifluoromethane-
sulfonate (6.3 mg, 17 lmol), the chiral nonracemic C2-symmetric
bipyridyl ligand 1 (8.5 mg, 18 lmol) and the reaction solvent (acetone
or acetonitrile, 2.5 mL). The resultant solution was stirred at room
temperature for 1 h. Phenylhydrazine (2.0 lL, 20 lmol) was added
and the reaction mixture was stirred for an additional 5 min at room
temperature. The reaction mixture was then cooled to 0 ◦C in certain
instances (see: Table 1). One of the cyclic alkenes 2a–c (n = 1–3,
1.8 mmol) and tert-butyl peroxybenzoate (67 lL, 0.35 mmol) were
added. The reaction was monitored by thin-layer chromatography (di-
ethyl ether–hexanes, 1 : 1) until the oxidant, tert-butyl peroxybenzoate,
had beenconsumed. The reaction mixture was concentrated in vacuo
to afford the crude product. The benzoates (S)-3a–c were isolated in
pure form as colourless oils by flash chromatography using hexanes–
diethyl ether (5 : 1) as the eluant. (1S)-Cyclohex-2-enyl benzoate (S)-3b:
1H NMR (400 MHz, CDCl3) d 1.65–1.76 (1H, m), 1.78–2.21 (5H, m),
5.49–5.55 (1H, m), 5.80–5.87 (1H, m), 5.98–6.04 (1H, m), 7.40–7.66
(4H, m), 8.06 (1H, d, J = 7.3 Hz), 8.13 (1H, d, J = 7.3 Hz); 13C NMR
(101 MHz, CDCl3) d 19.1, 25.1, 28.5, 68.8, 125.8, 128.4, 128.6, 129.7,
130.4, 132.9, 133.0, 133.9, 166.4; IR (neat) mmax 2941, 1713, 1602, 1584,
1453, 1428, 1326, 1271, 1178, 1112, 1070, 1026, 918 cm−1; MS (CI) m/z
(rel. intensity) 203 (M + H, 14), 181 (87), 159 (24), 91 (55). Analytical
chiral HPLC analysis using a Daicel Chiralcel OD column [hexanes–
isopropanol (250 : 1), flow rate at 0.50 mL min−1, detection at k =
220 nm, tMAJOR = 26.1 min, tMINOR = 29.0 min]. (1S)-Cyclopent-2-enyl
benzoate (S)-3a: Analytical chiral HPLC as above [tMAJOR = 32.4 min,
tMINOR = 43.6 min]. (1S)-Cyclohept-2-enyl benzoate (S)-3c: analytical
chiral HPLC as above [tMAJOR = 19.2 min, tMINOR = 23.5 min].
9 M. B. Andrus and Z. Zhou, J. Am. Chem. Soc., 2002, 124, 8806.
10 A related pyridine bisdiphenyloxazoline type ligand, although highly
enantioselective (up to 86% ee), has required reaction times of up to
seventy five days. This also resulted in relatively low yields of the desired
reaction products in some instances, see: G. Sekar, A. DattaGupta and
V. K. Singh, J. Org. Chem., 1998, 63, 2961.
11 A pinene-derived bipyridyl ligand has been shown to be particularly
effective for copper(I)-catalyzed asymmetric allylic oxidation reactions
(reaction times of ca. 30 min and up to 75% ee), see: (a) A. V. Malkov,
M. Bella, V. Langer and P. Kocˇovsky´, Org. Lett., 2000, 2, 3047. This
research group has also reported the evaluation of a closely related
carene-derived ligand in which the maximum enantioselectivity reached
82% ee. However, the reaction time required was 96 h and the isolated
yield of the reaction product [(1R)-cyclohept-2-enyl benzoate] was
only 35%, see: (b) A. V. Malkov, D. Pernazza, M. Bell, M. Bella, A.
Massa, F. Teply´, P. Meghani and P. Kocˇovsky´, J. Org. Chem., 2003, 68,
4727.
12 In addition to bisoxazolines, chiral nonracemic bicyclic proline deriva-
tives, tridentate trisoxazolines ligands and a pinene-derived 1,10-
phenanthroline ligand have also been found to perform well in
copper(I)-catalyzed asymmetric allylic oxidation reactions, see: (a) M. J.
Soˇdergren and P. G. Andersson, Tetrahedron Lett., 1996, 37, 7577; (b) Y.
Kohmura and T. Katsuki, Tetrahedron Lett., 2000, 41, 3941; (c) G.
Chelucci, G. Loriga, G. Murineddu and G. A. Pinna, Tetrahedron Lett.,
2002, 43, 3601.
16 A related mechanistic interpretation has been reported by Andrus and
Zhou (ref. 9).
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