Enantioselective hydroxylation of benzylic C-H bonds by D4-symmetric chiral oxoruthenium porphyrins

Article abstract of DOI:10.1039/a904100a

A D₄-symmetric chiral dioxoruthenium(VI) porphyrin can effect stoichiometric and catalytic enantioselective hydroxylation of benzylic C-H bonds to give enantioenriched aryl alcohols, the highest ee of 76% being attained in the catalytic oxidation of 4-ethyltoluene with 2,6-dichloropyridine N-oxide as terminal oxidant; the oxidations proceed via a rate-limiting H-atom abstraction to germinate a benzylic radical intermediate.

Full text of DOI:10.1039/a904100a

Enantioselective hydroxylation of benzylic C–H bonds by D4-symmetric chiral
oxoruthenium porphyrins†
Rui Zhang, Wing-Yiu Yu, Tat-Shing Lai and Chi-Ming Che*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong. E-mail: cmche@hku.hk
Received (in Cambridge, UK) 21st May 1999, Accepted 20th July 1999
A D4-symmetric chiral dioxoruthenium(vi) porphyrin can
effect stoichiometric and catalytic enantioselective hydrox-
ylation of benzylic C–H bonds to give enantioenriched aryl
alcohols, the highest ee of 76% being attained in the catalytic
oxidation of 4-ethyltoluene with 2,6-dichloropyridine N-
oxide as terminal oxidant; the oxidations proceed via a rate-
limiting H-atom abstraction to germinate a benzylic radical
intermediate.
Under pseudo-first order conditions, the ethylbenzene oxida-
tion by [RuVI(Por*)O2] in 1,2-dichloroethane (with 2% w/w
Hpz) exhibited isosbestic UV-vis spectral changes from RuVI to
RuIV porphyrin (isosbestic points at 350, 415 and 444 nm). At
313 K, the second-order rate constant (k2) is (7.7 ± 0.4) 3 1024
dm3 mol21 s21. The second-order rate constants for the
oxidation of para-substituted ethylbenzenes had been meas-
ured, and a linear dual-parameter Hammett correlation between
log krel [krel = k2(4-substituted ethylbenzene)/k2(ethylbenzene)]
·
+
Despite significant advances in asymmetric alkene epoxida-
tions,1 the development of protocols for highly enantioselective
hydroxylations of saturated C–H bonds has met with limited
success. Groves and Viski first described the catalytic enantio-
selective benzylic C–H bond hydroxylations using a chiral iron
porphyrin catalyst.2 Recently, with the use of chiral Mn(salen)
catalysts, ethylbenzene can be oxidized enantioselectively to
1-phenylethanol in 22% yield and 53% ee.3 We herein describe
a highly enantioselective benzylic C–H bond hydroxylation
based on oxoruthenium complexes supported by a D4-symmet-
ric chiral porphyrin.
and the sJJ and sp constants5 was established: log kre·l = +
(0.57 ± 0.04) sJJ· 2 (0.36 ± 0.01) sp (R = 0.99; |rJJ /r+| =
+
1.58),† consistent with a rate-limiting benzylic radical inter-
mediate formation. The primary kinetic isotope effect (kH/kD)
for the oxidation of ethylbenzene-d10 was found to be 8.9
(313 K), in accord with a rate-limiting step involving substantial
C–H bond cleavage.6
A catalytic quantity of either [RuII(Por*)(CO)(EtOH)] or
[RuVI(Por*)O2] can effect hydroxylation of ethylbenzene using
2,6-dichloropyridine N-oxide (Cl2pyNO) as terminal oxidant to
produce (S)-1-phenylethanol in 62% yield and 72% ee at 25 ºC
(Table 1, entry 1). More importantly, the catalytic reactions
afforded the alcohols in much higher enantioselectivity. Ben-
zene is the solvent of choice, while the use of CH2Cl2 led to a
lower ee of 62% (Table 1, entry 1). Likewise, other para-
substituted ethylbenzenes were oxidized to their (S)-1-aryl-
ethanols in 62–76% ee and 28–72% yields under the ruthenium-
catalyzed conditions (entries 2–6). Notably, the catalytic
asymmetric 2-ethylnaphthalene oxidation afforded 1-naph-
thylethanol in 75% ee and 66% yield (Table 1, entry 7). In all
cases, only alcohols and ketones were formed, and the
combined alcohol and ketone yields have a mass balance of
98% of the amount of substrate consumed.
The
complexes {H2Por*
[RuII(Por*)(CO)(EtOH)]
and
[RuVI(Por*)O2]
=
5,10,15,20-tetrakis[(1S,4R,5R,8S)-
1,2,3,4,5,6,7,8-octahydro-1,4:5,8-dimethanoanthracen-9-yl]-
porphyrin} were prepared by the literature methods.4 In a
The effect of para-substituents on the chiral ruthenium
porphyrin-catalyzed asymmetric hydroxylation of ethylben-
zenes has been examined. Both electron-donating and -with-
drawing substituents can promote the reaction, and the relative
rate constants (log krel), established by competitive experiments,
correlate linearly with the sJJ· and sp substituent constants:5
+
log krel = + (0.78 ± 0.05) sJJ· 2 (0.71 ± 0.02) sp+ (R = 0.99,
·
|rJJ /r+| = 1.1, Fig. 1). A primary kinetic isotope effect (kH / kD)
of 11.2 (298 K) was found for the catalytic oxidation of
ethylbenzene-d10.
degassed CH2Cl2 solution (containing 2% w/w pyrazole), an
excess of ethylbenzene reacted with [RuVI(Por*)O2] to afford a
mixture of 1-phenylethanol (32%) and acetophenone (33%) at
room temperature; the (S)-1-phenylethanol was obtained in
45% ee (Table 1, entry 1). This features the first well-
characterized chiral oxo-metal complex capable of hydroxylat-
ing saturated C–H bonds enantioselectively. Similarly, the
stoichiometric oxidations of substituted ethylbenzenes, 2-ethyl-
naphthalene, indane and tetrahydronaphthalene by [RuVI-
(Por*)O2] also furnished enantioenriched (S)-alcohols, and the
oxidation of 2-ethylnaphthalene registered the highest ee of
58% ee (Table 1, entry 7). In all cases, a bis-pyrazolato-
ruthenium(iv) porphyrin, [RuIV(Por*)(pz)2], was isolated in
> 85% yield at the end of the oxidation.
It is known that ruthenium porphyrin-catalyzed alkane
oxidations using 2,6-dichloropyridine N-oxide proceed through
a reactive oxoruthenium intermediate.7 Thus, the high ee
observed in the catalytic ethylbenzene hydroxylations would
suggest that the chiral ‘RuNO’ intermediate should preferen-
tially abstract the pro-S hydrogen atom of ethylbenzene, if a
hydrogen atom abstraction mechanism is operative.2a Because
oxidation of benzyl alcohol by reactive oxoruthenium com-
plexes involves a rate-limiting C–H bond cleavage analogous to
the hydroxylation of aromatic hydrocarbons,6d,8 the (S)-isomer
of racemic 1-phenylethanol is expected to be more readily
oxidized to acetophenone, leaving an excess of (R)-1-phenyl-
ethanol. However, when racemic 1-phenylethanol (1 mmol)
was subjected to the ruthenium-catalyzed conditions {[RuII-
(Por*)(CO)(EtOH)] (0.5 mmol) and Cl2pyNO (3 mmol) in
C6H6}, we found that only a 4% excess of (R)-1-phenylethanol
and 97% yield of acetophenone were produced at 42% alcohol
† Experimental and kinetic data, including UV-vis spectral traces, dual-
parameter Hammett correlation studies and representative chiral GLC
chromatograms, are available from the author at the address given above.
Chem. Commun., 1999, 1791–1792
1791

Table 1 Enantioselective oxoruthenium mediated benzylic hydroxylations
[RuVI(Por*)O2]a
[RuII(Por*)(CO)(EtOH)] + Cl2pyNOe
Alcohol
Ketone yield
(%)f (total
turnovers)
Alcohol
Ketone
yield (%)c
Entry
1
Substrate
Product
yield (%)b
Ee (%)
t/h
Conv. (%)
yield (%)f
Ee (%)
32
30d
45 (S)
37 (S)d
33
34d
12
12g
13
10g
62
67g
72 (S)
62 (S)g
37 (112)
32g
2
3
4
5
6
31
36
35
27
44
51 (S)
58 (S)
55 (S)
41 (S)
55 (S)
32
30
31
34
26
30
10
18
8
20
11
23
14
15
72
60
28
63
65
76 (S)
72 (S)
74 (S)
74 (S)
62 (S)
24 (224)
38 (129)
70 (262)
36 (164)
32 (190)
8
7
8
32
48
47
58 (S)
9 (S)
31
25
24
20
6
15
54
42
62
65
60
75 (S)
12 (S)
12 (S)
38 (168)
34 (551)
40 (475)
9
18 (S)
2
a
Stoichiometric oxidation: to a degassed CH2Cl2 solution (2 cm3) containing pyrazole (0.05 g) and alkane (1.0 mmol) was added [RuVI(Por*)O2] (30
mmol) under argon; the mixture was then stirred at room temperature for 12 h. The ruthenium complex was removed by filtration through a short alumina
column. After addition of 1,4-dichlorobenzene as internal standard, aliquots were analyzed by GLC for product identification and quantification. b Yields
c
d
were based on the ruthenium oxidant used. The ketone yields were calculated based on a stoichiometric ratio of oxidant-to-ketone = 2+1. In C6H6.
e Catalytic oxidations: a mixture of alkane (0.5 mmol), [RuII(Por*)(CO)(EtOH)] (0.5 mmol) and Cl2pyNO (0.55 mmol) was stirred in dry and degassed C6H6
(5 cm3). Aliquots were analyzed by chiral capillary GC equipped with J & W scientific Cyclodex-B or B-PM chiral column for quantification and ee
determination. f Yields were based on the amount of alkane consumed. g In CH2Cl2.
arise from the preferential collapse of the benzylic radical on the
pro-S face versus the pro-R face at the oxygen atom rebound
step, due to the good fit of the substrate into the chiral cavity.
We acknowledge financial support from The University of
Hong Kong, the Hong Kong Research Grants Council and the
Hong Kong University Foundation.
Notes and references
1 E. N. Jacobsen, in Comprehensive Organometallic Chemistry II, ed. G.
Wilkinson, F. G. A. Stone, E. W. Abel and L. S. Hegedus, Pergamon,
New York, 1995, vol. 12, ch. 11.1; T. Katsuki, Coord. Chem. Rev., 1995,
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Wang, M.-K. Wong, Y.-C. Yip and M.-W. Tang, J. Am. Chem. Soc.,
1996, 118, 11 311.
2 (a) Enantioselectivity of 77% was reported for the catalytic asymmetric
hydroxylation of (S)-(1-deuterioethyl)benzene, see: J. T. Groves and P.
Viski, J. Am. Chem. Soc., 1989, 111, 8537; (b) J. T. Groves and P. Viski,
J. Org. Chem., 1990, 55, 3628.
3 K. Hamachi, R. Irie and T. Katsuki, Tetrahedron Lett., 1996, 37, 4979.
4 T.-S Lai, R. Zhang, K.-K. Cheung, H.-L. Kwong and C.-M. Che, Chem.
Commun., 1998, 1583; T.-S. Lai, H.-L. Kwong, R. Zhang and C.-M. Che,
J. Chem. Soc., Dalton Trans., 1998, 3559; A. Berkessel and M.
Frauenkron, J. Chem. Soc., Perkin Trans. 1, 1997, 2265.
Fig. 1 Dual-parameter Hammett correlation for the ruthenium catalyzed
enantioselective hydroxylation of para-substituted ethylbenzenes (p-
YC6H4Et; Y = MeO, Me, F, Cl and H).
5 X.-K. Jiang, Acc. Chem. Res., 1997, 30, 283.
6 (a) C.-M. Che, C. Ho and T.-C. Lau, J. Chem. Soc., Dalton Trans., 1991,
1259; (b) C. Ho, W.-H. Leung and C.-M. Che, J. Chem. Soc., Dalton
Trans., 1991, 2933; (c) C.-M. Che, W.-T. Tang, K.-Y. Wong and C.-K.
Li, J. Chem. Soc., Dalton Trans., 1991, 3277; (d) W.-C. Cheng, W.-Y.
Yu, C.-K. Li and C.-M. Che, J. Org. Chem., 1995, 60, 6840.
7 J. T. Groves, M. Bonchio, T. Carofiglio and K. Shalyaev, J. Am. Chem.
Soc., 1996, 118, 8961; C.-J. Liu, W.-Y. Yu and C.-M. Che, J. Org. Chem.,
1998, 63, 7364; Z. Gross and S. Ini, Inorg. Chem., 1999, 38, 1446.
8 C.-M. Che, W.-T. Tang, W.-O. Lee, K.-Y. Wong and T.-C. Lau, J. Chem.
Soc. Dalton Trans., 1992, 1551; L. Roecker and T. J. Meyer, J. Am.
Chem. Soc., 1987, 109, 746.
Scheme 1
consumption. The low degree of kinetic resolution for the
catalytic (±)-1-phenylethanol oxidation is in constrast to the
high ee of the catalytic ethylbenzene hydroxylation reactions.
Assuming an oxygen rebound mechanism (Scheme 1),9 we
postulate that the production of enantioenriched alcohols may
9 J. T. Groves and G. A. McClusky, J. Am. Chem. Soc., 1976, 98, 859; J. T.
Groves and P. Viski, J. Am. Chem. Soc., 1989, 111, 8537.
Communication 9/04100A
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Chem. Commun., 1999, 1791–1792