Catalytic asymmetric cross-dehydrogenative coupling: Activation of C-H bonds by a cooperative bimetallic catalyst system

Article abstract of DOI:10.1039/c3cc41315b

A cooperative bimetallic catalyst system was applied in the catalytic asymmetric cross-dehydrogenative coupling of β-ketoesters and xanthene. Various optically active xanthene derivatives bearing a quaternary stereogenic carbon center were obtained in moderate to good yields (up to 90%) with excellent enantioselectivities (up to 99% ee). Meanwhile, a transition-state model was proposed to explain the origin of the asymmetric induction.

Full text of DOI:10.1039/c3cc41315b

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Catalytic asymmetric cross-dehydrogenative coupling:
activation of C–H bonds by a cooperative bimetallic
catalyst system†
Cite this: Chem. Commun., 2013,
49, 3470
Received 20th February 2013,
Accepted 7th March 2013
Weidi Cao, Xiaohua Liu, Ruixue Peng, Peng He, Lili Lin and Xiaoming Feng*
DOI: 10.1039/c3cc41315b
www.rsc.org/chemcomm
A cooperative bimetallic catalyst system was applied in the catalytic distinct multiple functionalities in
a simultaneous manner.
asymmetric cross-dehydrogenative coupling of b-ketoesters and However, to the best of our knowledge, this approach has not been
xanthene. Various optically active xanthene derivatives bearing a applied in catalytic asymmetric CDC reactions. We herein developed
quaternary stereogenic carbon center were obtained in moderate to a catalytic asymmetric CDC reaction of a-substituted b-ketoesters
good yields (up to 90%) with excellent enantioselectivities (up with xanthene. By using a chiral NiII–FeII hetero-bimetallic coopera-
to 99% ee). Meanwhile, a transition-state model was proposed to tive catalyst system, good yields and excellent enantioselectivities
explain the origin of the asymmetric induction.
were achieved for various optically pure xanthene derivatives bearing
a quaternary stereogenic carbon center.
Catalytic asymmetric cross-dehydrogenative coupling reaction (CDC
Initially, we examined the CDC reaction between tert-butyl
reaction) has attracted great attention because it provides efficient indanone carboxylate 1a as a representative pronucleophile and
methods to construct versatile and useful building blocks.1 Under xanthene using TBHP as the oxidant. A series of metal salts such as
oxidative conditions, two C–H bonds could be directly coupled to CuI, ZnII, FeII and NiII chelated with L-proline-derived N,N0-dioxide
form a new C–C bond without prior installation of functional groups. L18 were used to catalyze the coupling reaction (Table 1, entries 1–4).
For the activation of sp3 C–H bond in this reaction, the generation of To our delight, the desired product 3a was obtained in 47% yield
a carbocation mediated by an oxidant is the key step.2 Therefore, with 77% ee by using nickel(II) as the central metal. Nevertheless,
seeking stable carbocations in situ is extremely significant. CDC a considerable amount of byproduct 3a0 from a-hydroxylation of
reactions of amines or ethers, which could stabilize the carbocation b-ketoester 1a was also detected (Table 1, entry 4). Comparatively,
by an a-heteroatom, with nucleophiles have been widely reported.1,3 iron(II) salt gave a higher yield of 3a but as a racemate (Table 1,
However, the asymmetric oxidative coupling of an unreactive entry 3). Then we modified the catalysts with different nickel salts
benzylic C–H bond has remained a challenge due to the instability (Table 1, entries 5–7), and found that the counterions had a crucial
of the generating carbocation.4 Xanthene, which contains a benzylic influence on the reaction. NiF2 did not promote the reaction at all
C–H bond, is pharmaceutically and biochemically active and has (Table 1, entry 5), whereas excellent enantioselectivity (97% ee) and
been widely used as dyes and fluorescent materials.5 At present, only moderate yield were obtained with NiBr2 (Table 1, entry 7). The
two examples of asymmetric CDC reaction of xanthene with alde- structure of the N,N0-dioxide ligands was also found to affect both
hydes have been described subsequently by Cozzi’s4a and Jiao’s the reactivity and enantioselectivity. Although the combination of L5
groups.4c MacMillan-type organocatalysts were used to promote the and NiBr2 promoted the reaction with up to 99% ee, only moderate
process with up to 93% ee.
yield of the desired product 3a was generated as the result of the side
With regard to chiral catalysts used for sp3 C–H-activation- reaction (Table 1, entry 11). Considering the high yield catalyzed by
based asymmetric C–C bond formation via CDC reaction, chiral L-Fe(II), and the excellent enantiomeric excess catalyzed by L5-NiBr2,
mono-metal complexes,3,4b organocatalysts4a,c and metal–organic we next examined the CDC reaction with a bimetallic cooperative
cooperative catalysts6 have been employed. In recent years, bimetallic catalyst. Firstly, a mixture of 10 mol% of NiBr2, 10 mol% of Fe(BF4)2ꢀ
cooperative catalysis has emerged as an attractive strategy to achieve 6H2O, and 20 mol% of L5 was composed to catalyze this reaction. It
high efficiency and selectivity in asymmetric reactions7 due to the was found to our delight that the yield of the product 3a was
obviously improved, but with a small loss of enantiomeric excess
Key Laboratory of Green Chemistry & Technology, Ministry of Education,
(87% yield, 79% ee; Table 1, entry 12 vs. 11). Then the amount of
Fe(II) species was decreased to minimize the disadvantage to the
enantioselectivity. Entries 13 and 14 showed that the enantiomeric
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: xmfeng@scu.edu.cn; Fax: +86 28 85418249; Tel: +86 28 85418249
† Electronic supplementary information (ESI) available: Additional experimental
excess enhanced gradually upon reducing the amount of Fe(BF4)2ꢀ
and spectroscopic data. CCDC 910798. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc41315b
6H2O with the high yield of 3a maintained. When 1 mol% of
c
3470 Chem. Commun., 2013, 49, 3470--3472
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Table 1 Optimization of the reaction conditions
Entrya Metal
Ligand Yield of 3a b (%) ee of 3a c (%)
1
2
3
4
5
6
7
8
CuBr
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
67 (20)
34 (16)
88 (o5)
47 (29)
Trace (-)
46 (24)
49 (36)
33 (47)
25 (63)
42 (50)
51 (40)
87 (o5)
88 (o5)
90 (o5)
66 (23)
0
0
0
Zn(BF4)2ꢀ6H2O
Fe(BF4)2ꢀ6H2O
Ni(BF4)2ꢀ6H2O
NiF2
NiCl2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2/Fe(BF4)2ꢀ6H2O L5
NiBr2/Fe(BF4)2ꢀ6H2O L5
NiBr2/Fe(BF4)2ꢀ6H2O L5
NiBr2/Fe(BF4)2ꢀ6H2O L5
77
—
75
97
96
85
33
99
79
93
99
99
Fig. 1 Substrate scope for the 1-indanone derivatives. Unless otherwise noted,
all reactions were performed with NiBr2/Fe(BF4)2ꢀ6H2O/L5 (10 mol%, 1 : 0.2 : 1.2),
1 (0.10 mmol), 2 (0.11 mmol), TBHP in decane (5.0–6.0 M, 20 mL) at 30 1C for 10 h.
Relative and absolute stereochemical configurations were determined by X-ray
analysis and circular dichroism spectrum. The results in parentheses were
obtained by using NiBr2/L5 (10 mol%, 1 : 1) as the catalyst.
9
10
11
12d
13e
14f
15g
a
xanthene was directly oxidized to 9H-xanthen-9-one by TBHP, and
a trace amount of the desired CDC product 5a was generated. To
our delight, after a slight modification of the ligand, by altering
the ligand L5 to L2, and increasing the amount of xanthene and
TBHP, the corresponding coupling product 5a was obtained in
70% yield with 99% ee. For the 7-substituted-1-tetralone derivatives
5c and 5d and 5f, promising yields with excellent enantiomeric
excess were obtained. While 5-methoxy-1-tetralone 5b and
5,7-dimethyl-1-tetralone 5e displayed low yields (Fig. 2).
To show the synthetic utility of the catalyst system, the gram-
scaled reaction was performed with a gram quantity of b-ketoester
1a. As shown in Scheme 1a, the reaction proceeded smoothly to give
the desired product 3a in 87% yield with 99% ee. Due to the
potential biological activities of b-hydroxy esters and xanthene,
Unless otherwise noted, all reactions were performed with L-metal
(10 mol%, 1 : 1), 1a (0.10 mmol), 2 (0.11 mmol), TBHP (tBuOOH; 20 mL
5.0–6.0 M in decane) at 30 1C for 24 h. The yields in parentheses are the
b
c
isolated yields of 3a0. Isolated yield. Determined by chiral HPLC
d
e
analysis. Ni(II)/Fe(II)/L5 (10 mol%, 1/1/2). Ni(II)/Fe(II)/L5 (10 mol%,
1/0.5/1.5).
f
g
Ni(II)/Fe(II)/L5 (10 mol%, 1/0.2/1.2). Ni(II)/Fe(II)/L5
(10 mol%, 1/0.1/1.1).
Fe(BF4)2ꢀ6H2O was added, a slight increase in the CDC product was
observed, although the byproduct was inhibited simultaneously
(Table 1, entry 15 vs. entry 11). Therefore, 2 mol% of Fe(BF4)2ꢀ
6H2O, 10 mol% of NiBr2 and 12 mol% of L5 as the catalyst were
optimized to initiate the CDC reaction (Table 1, entry 14).
With the optimal conditions established, the scope of the
reaction was then probed (Fig. 1). High yields with excellent ee
values were observed for a range of substituted indanone
pronucleophiles bearing tert-butyl ester substituents (68–90%
yield, 97–99% ee, 3a–3h). The electronic effect has no influence on
the enantioselectivity, and the yields were slightly affected by either
the electron-donating or -withdrawing substituent. In two instances,
the acceleration of the reactivity with the assistance of Fe(BF4)2 was
further confirmed. The yields of the products were significantly
increased in the presence of the cooperative bimetallic catalyst
system (for 3g from 37% to 68%, and for 3h from 43% to 76%).
In addition, the substrate with the more hindered substituent
located on the ester side could also give the corresponding product
3i with good results (72% yield, 99% ee). In all cases, a small
amount of a-hydroxylation byproduct 3 and 9H-xanthen-9-one from
xanthene were detected.
To extend the application of this protocol, further examination
of the substrates was focused on forming 1-tetralone derivatives.
However, under the same reaction conditions (Table 1, entry 14),
Fig. 2 Substrate scope for the 1-tetralone derivatives. All the reactions were
performed with NiBr2/Fe(BF4)2ꢀ6H2O/L2 (10 mol%, 1 : 0.2 : 1.2), 4 (0.10 mmol), 2
(0.20 mmol), TBHP in decane (5.0–6.0 M, 40 mL) at 30 1C for 20 h.
c
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b-ketoester chelated with Ni/L5, because the latter is strongly
shielded by the nearby aromatic ring and the tert-butyl of
b-ketoester which results in the R-configured product (Fig. 3).
In summary, we have developed a one-pot and highly
enantioselective oxidative cross-dehydrogenative coupling
reaction of a-substituted b-ketoesters with xanthene catalyzed
by a cooperative bimetallic catalyst system. Various optically
active xanthene derivatives bearing a quaternary stereogenic
carbon center were obtained in moderate to good yields (up to
90%) with excellent ee values (up to 99% ee) under mild
conditions. Meanwhile, a transition-state model was proposed
to explain the origin of the asymmetric induction and more
proof for the catalyzed mechanism is underway in our group.
We appreciate the National Natural Science Foundation of
China (No. 21021001 and 21172151), the Ministry of Education
(No. 20110181130014), and National Basic Research Program of
China (973 Program: No. 2010CB833300) for financial support.
Scheme 1 (a) Gram-scaled version of the reaction, (b) the synthesis of b-hydroxy
esters.
Notes and references
Scheme 2 Control experiments.
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the reduction of 3a was probed, which generated a single
diastereoisomer of b-hydroxy ester 6 in excellent yield without
the loss of enantioselectivity (Scheme 1b).
Control experiments were then performed to understand the
activation model of the reaction (Scheme 2). The use of
10 mol% of Fe(BF4)2 promoted the reaction with 47% yield.
The combination of 2 mol% of the ligand L5 and Fe(BF4)2
resulted in high isolated yield although no stereocontrol was
found (85% yield). When the reaction was carried out with the
cooperation of 2 mol% L5–Fe(BF4)2 in the presence of 10 mol%
L5–NiBr2, the yield of the product 3a was improved from 51%
to 90% with the 99% ee value maintained. Furthermore, a
significant loss of yield was observed by slightly decreasing the
amount of the chiral ligand L5. On the basis of the results
described above, we conclude that the L5–NiBr2 complex plays
an important role in the chiral induction of the reaction, and at
the same time the L5–Fe(BF4)2 complex accelerates the reaction
rate for the generation of product 3a (see ESI† for details).
Meanwhile, based on the absolute configuration of product 3d,
a possible asymmetric catalytic model was proposed. Carbo-
cations preferred to attack the Re face rather than the Si face of
Fig. 3 Proposed transition-state model and the absolute configuration of 3d.
c
3472 Chem. Commun., 2013, 49, 3470--3472
This journal is The Royal Society of Chemistry 2013