Highly enantioselective Friedel-Crafts alkylation of indoles and pyrrole with β,γ-unsaturated α-ketoesters catalyzed by heteroarylidene-tethered bis(oxazoline) copper complexes

Article abstract of DOI:10.1039/c2cc34803a

The simple and cheap chiral catalyst, heteroarylidene-tethered Ph-bis(oxazoline)-Cu(OTf)₂, can efficiently catalyze the asymmetric F-C alkylation of indoles and pyrrole with β,γ-unsaturated α-ketoesters. The 3-indolyl adducts were obtained in u

Full text of DOI:10.1039/c2cc34803a

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COMMUNICATION
Highly enantioselective Friedel–Crafts alkylation of indoles and pyrrole
with b,c-unsaturated a-ketoesters catalyzed by heteroarylidene-tethered
bis(oxazoline) copper complexesw
Lei Liu, Hongli Ma, Yumei Xiao, Fengpei Du, Zhaohai Qin, Nan Li and Bin Fu*
Received 5th July 2012, Accepted 26th July 2012
DOI: 10.1039/c2cc34803a
The simple and cheap chiral catalyst, heteroarylidene-tethered
Ph-bis(oxazoline)–Cu(OTf)2, can efficiently catalyze the asymmetric
F–C alkylation of indoles and pyrrole with b,c-unsaturated
a-ketoesters. The 3-indolyl adducts were obtained in up to
>99% ee. Moreover, the 2-pyrrolyl adducts were achieved in
up to 92% ee for the first time.
Fig. 1 The representative malonate-type bis(oxazoline).
The asymmetric Friedel–Crafts (F–C) reaction of arene is a
In our previous studies, the heteroarylidene-tethered
powerful and versatile carbon–carbon bond-forming process
in organic synthesis.1 The asymmetric F–C reaction of indole
bis(oxazoline) 3 and 4 (Fig. 1) explored by us demonstrated
excellent catalytic performance in the F–C reaction of indoles
provides an efficient way to synthesize the enantiomerically
with alkylidene malonate esters (up to 99% yield and >99% ee).8
The strategy that two oxazoline rings tethered to an sp2
hybridized carbon can modulate the bridge angle, then tune
the bite angle and the geometry of malonate-type BOX–metal
complexes, which play significant roles in the asymmetric
induction, proved to be successful.9 Besides, the effect of
another substituent attached to the double bond cannot be
neglected. In our efforts to develop highly enantioselective
reactions using a simple and cheap catalytic system, we found
recently that the heteroarylidene-tethered BOX–Cu(OTf)2
could efficiently catalyze the F–C alkylation of b,g-unsaturated
a-ketoesters with indoles and pyrrole in high yields with
excellent enantioselectivities. Herein we report our intensive
studies on this subject.
enriched indole derivatives.2 which are the potential intermediates
for many natural products and biologically active compounds.3
Among various types of substrates used in the asymmetric
F–C reactions of indoles, b,g-unsaturated a-ketoesters have
attracted much attention during the past decade. Jørgensen et al.4
and Desimoni et al.5 reported, respectively, the asymmetric F–C
alkylation of indoles with b,g-unsaturated a-ketoesters utilizing
tert-butyl-bis(oxazoline) (BOX)–Cu(II) complexes and py-BOX–
Sc(OTf)3 complexes as catalysts, affording the alkylated products
with high to excellent enantioselectivities (up to >99% ee).
Recently, Feng et al. explored the chiral N,N0-dioxide-AgAsF6–
Sm(OTf)3 complexes to catalyze the same F–C reaction.6
Interestingly, they found that different metal ions can lead to
the reversal of the product configuration. Very recently, Luo
et al. reported that phosphoric acid–MgF2 as an organic
catalyst was applied to the same reaction,7 offering relatively
low enantioselectivities (82–92% ee) than those obtained using
Lewis acid catalysts. Noticeably, among a variety of chiral
catalysts used for the successful asymmetric F–C reactions of
indoles, rare success has been achieved for the F–C reaction of
pyrrole, in particular unprotected pyrrole under the same
reaction conditions. Thus, the development of a cheap, easily
accessible and highly efficient chiral catalytic system with
broad generality is very challenging and in great demand.
Our research began with the optimization of ligands by
using indole and b,g-unsaturated a-keto butyric acid methyl
ester as model substrate.4–6 The results are summarized in
Table 1. Under the catalysis of 5 mol% ligand–Cu(OTf)2
complexes the reaction proceeded smoothly in diethyl ether
at room temperature, affording the desired indole adduct
with good to high yields but mostly poor ee values (Table 1,
entries 1–6). After the screening of ligands, thienyl methylidene-
tethered BOX 3a with the phenyl group on the oxazoline ring was
found to be the optimal ligand, affording the alkylated product in
99% yield with 65% ee (Table 1, entry 1). Subsequently, the effect
of solvent was tested. Strong solvent dependency was observed in
the reaction. Lower reactivity or poorer enantioselectivity was
observed in toluene, THF and ethanol. However in halogenated
solvents such as CH2Cl2 and CHCl3 a high reactivity was
observed, and only two minutes were required for the complete
conversion. Dichloromethane was chosen for further optimization
because it furnished much better results than chloroform for
Department of Applied Chemistry, China Agricultural University,
Beijing, 100193, P. R. China. E-mail: fubinchem@cau.edu.cn;
Fax: +86-10-62732873; Tel: +86-10-62732873
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data for all compounds,
crystallographic data. CCDC 884030. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc34803a
c
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Table 2 Reactions of various indoles with b,g-unsaturated a-ketoestersa
Table 1 Optimization of ligands, solvents and temperaturea
Entry R1
R2
Time
Product Yieldb (%) eec (%)
Entry Ligands Solvent Temp (1C) Time
Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
3a
3b
3c
4a
4b
4c
3a
3a
3a
3a
3a
3a
3a
3ad
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Toluene
THF
EtOH
CHCl3
CH2Cl2
CH2Cl2 ꢀ40
CH2Cl2 ꢀ78
CH2Cl2 ꢀ78
0
0
0
0
0
0
0
0
0
0
0
30 min 99
65(S)
7(S)
9(R)
51(S)
39(S)
0
13(S)
61(S)
13(S)
23(S)
67(S)
92(S)
>99(S)
>99(S)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
5-Me
7-Me
5-MeO
5-Cl
6-Cl
6-F
2-ClPh
3-BrPh
30 min 7b
30 min 7c
2,4-Cl2Ph 30 min 7d
95
99
95
99
90
94
88
95
89
92
95
90
92
94
90
90
86
81
>99
>99
>99
>99
99
>99
>99
>99
>99
>99
94
1.5 h
1.5 h
99
99
30 min 99
4-FPh
4-BrPh
4-CNPh 1 h
4-NO2Ph 2 h
30 min 7e
30 min 7f
1.5 h
12 h
3.5 h
3 h
99
90
80
90
7g
7h
4-CF3Ph 30 min 7i
9
30 min 50
2 min 99
2 min 99
5 min 99
10 min 99
9
3-MePh
4-MePh
4-MeOPh 30 min 7l
Ph
Ph
Ph
Ph
Ph
Ph
30 min 7j
30 min 7k
10
11
12
13
14
10
11
12
13
14
15
16
17
18
30 min 7m
30 min 7n
30 min 7o
30 min 7p
30 min 7q
30 min 7r
>99
97
99
2 h
99
a
98
All reactions were conducted under nitrogen using 5 mol% of the
b
c
>99
>99
96
catalyst. Isolated yield. Determined by chiral HPLC and the absolute
configuration by comparison of optical rotation with the literature.
6-CO2Me Ph
8 h
7s
d
1 mol% catalyst loading.
a
All reactions were conducted under nitrogen using 5 mol% of
c
b
3a–Cu(OTf)2 at ꢀ78 1C. Isolated yield. Determined by chiral
enantioselectivity (Table 1, entries 11 and 10, 67% vs. 23% ee).
Next, the effect of temperature was examined. To our delight,
the enantioselectivity could be dramatically improved to
92% ee at ꢀ40 1C, and >99% ee at ꢀ78 1C, while the high
reactivity is still maintained (Table 1, entries 12 and 13). The
catalyst loading can be reduced to 1 mol% without a loss of
enantioselectivity, albeit a prolonged reaction time was needed
(Table 1, entry 14). It is noteworthy that the indole product 7a
achieved by BOX 3a is S-configured, which is opposite to that
obtained using t-Bu-BOX by Jørgensen et al.4 and py-BOX by
Desimoni et al.5
HPLC.
Subsequently, a wide range of substituted g-phenyl b,g-unsaturated
a-ketoesters was tested. All reactions worked very well to afford the
pyrrole adducts in 82–99% yields (Table 3, entries 2–15). In all
cases, high enantioselectivities were achieved in the range 85–92%,
indicating that the substituents on the phenyl ring have a slight
influence on the enantioselectivity. It should be noted that the
reaction was complete within 5 min in the presence of 5 mol%
of the catalyst for most of the substrates, except for a few cases
of b,g-unsaturated a-ketoesters with an electron-withdrawing
4-FPh, 3-BrPh or 3-NO2Ph group (Table 3, entries 2, 9 and 11).
Encouraged by the preliminary results, the scope of
the reaction was further investigated under the optimized
reaction conditions (5 mol% 3a–Cu(OTf)2, CH2Cl2 as solvent,
ꢀ78 1C). Various indoles and different substituted g-phenyl
b,g-unsaturated a-ketoesters were examined, as summarized in
Table 2. In most cases the reaction proceeded to completion
within 30 minutes, except for a few b,g-unsaturated a-ketoesters
with electron-withdrawing substituents such as 4-CNPh,
4-CF3Ph, 4-NO2Ph groups and indole with 6-CO2Me (entries
6, 7 and 18). To our delight, all the cases showed excellent
enantioselectivity in the range 94–>99%, suggesting that the
position and the electronic properties of the substituents on the
phenyl ring or indole moiety did not affect either the reactivity
or selectivity of the reaction. In most cases, 3a–Cu(OTf)2 gave
higher enantioselectivity and reactivity in this reaction than the
previously reported methods.4–6
Table 3 Reactions of pyrrole with b,g-unsaturated a-ketoestersa
Entry
R
Time
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
4-FPh
4-ClPh
5 min
30 min
5 min
5 min
5 min
5 min
5 min
5 min
30 min
5 min
30 min
5 min
5 min
5 min
5 min
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
95
90
96
96
99
85
97
90
94
90
87
96
82
90
86
92
92
90
90
91
86
88
85
90
88
89
91
88
90
92
4-BrPh
4-CNPh
4-NO2Ph
4-CF3Ph
2-ClPh
3-BrPh
3-CNPh
3-NO2Ph
4-MePh
4-MeOPh
3-MePh
3-MeOPh
9
To further explore the scope of the application of 3a–Cu(OTf)2,
we next investigated the asymmetric F–C alkylation of pyrrole
with b,g-unsaturated a-ketoesters. To date there has been no
report on the asymmetric version of this reaction in the literature,
although asymmetric F–C reaction of pyrrole with other activated
alkenes has been reported.10 First, we performed the reaction of
pyrrole with g-phenyl b,g-unsaturated a-ketoester in CH2Cl2 at
ꢀ78 1C using 5 mol% 3a–Cu(OTf)2. The desired pyrrole adduct
8a was achieved in 95% yield and with 92% ee (Table 3, entry 1).
10
11
12
13
14
15
a
All reactions were conducted under nitrogen using 5 mol% of
b
c
3a–Cu(OTf)2 at ꢀ78 1C. Isolated yield. Determined by chiral
HPLC.
c
9282 Chem. Commun., 2012, 48, 9281–9283
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providing a practical method to synthesize enantiopure 3-in-
dolyl and 2-pyrrolyl derivatives. Further studies to extend this
catalytic system to other asymmetric reactions are currently
underway in our laboratory.
We are grateful for financial support from the Ministry of
Science and Technology of China (No. 2009BAK61B04,
No.2011BAE06B02), and the National Natural Science Founda-
tion of China (No. 21172255).
Fig. 2 X-ray crystal structure of 8e.
Notes and references
1 For recent reviews, see: (a) T. B Poulsen and K. A. Jørgensen,
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Fig. 3 Proposed transition state for the F–C reaction.
For comparison, Evans’ ligand BOX 1a and cyclopropane-
tethered BOX 2a (n = 1) (Fig. 1) bearing the phenyl group
were employed in this catalytic reaction under the same
conditions, giving only 37% ee and 21% ee. These results
demonstrated that 3a–Cu(OTf)2 was superior to other catalysts in
this asymmetric F–C reaction. The absolute configuration of the
product 8e was determined to be S through XRD analysis of its
single crystal11 (Fig. 2). By analogy other pyrrole adducts 8a–o
were also assigned to be S-configured. To our best knowledge, this
study represents the first successful example of enantioselective
F–C reaction of unprotected pyrrole with b,g-unsaturated
a-ketoesters.
A mechanism as illustrated in Fig. 3 is proposed to explain
the observed results. The b,g-unsaturated a-ketoester coordinates
to the copper center in an approximately tetrahedral geometry in
the 3a–Cu(OTf)2 complex,12 pyrrole attacks the b,g-unsaturated
a-ketoester preferably from the Si face, leading to the formation
of the predominant S-configured adduct. The same transition
could also be postulated for the reaction of indole. The higher
reactivity could be attributed to the electronic effect of oxazo-
line rings tethered to the heteroarylidene skeleton, and the
high enantioselectivity comes from the well-defined chiral
environment around the copper center. Not only the phenyl
group on the oxazoline ring, but also the remote thiophene
moiety tethered to the double bond and the unsymmetry of the
catalyst have a cooperative impact on the enantioselectivity.
In conclusion, we have demonstrated that the 3a–Cu(OTf)2
complex efficiently catalyzes the asymmetric F–C alkylation
of indoles and pyrrole with b,g-unsaturated a-ketoesters.
Compared with the previously published catalysts, better
enantioselectivities and yields for indole adducts were obtained in
most cases. Moreover, it is the first time to realize the asymmetric
F–C alkylation of unprotected pyrrole with b,g-unsaturated
a-ketoesters in good yield with high enantioselectivity. The
reaction features a high efficiency of the catalyst, high yields,
excellent enantioselectivities, in particular the cheap and
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9281–9283 9283