Diarylprolinol silyl ether catalyzed asymmetric friedel-crafts alkylation of indoles with α,β-unsaturated aldehydes: Enhanced enantioselectivity and mechanistic investigations

Article abstract of DOI:10.1002/ejoc.201001404

A highly enantioselective Friedel-Crafts alkylation of indoles with α,β-unsaturated aldehydes with excellent enantioselectivities (up to >99%ee) has been developed, and this improved method offers substantial advantages over traditional approaches, not on

Full text of DOI:10.1002/ejoc.201001404

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001404
Diarylprolinol Silyl Ether Catalyzed Asymmetric Friedel–Crafts Alkylation of
Indoles with α,β-Unsaturated Aldehydes: Enhanced Enantioselectivity and
Mechanistic Investigations
Zi-Hui Shi,[a] Hao Sheng,[a] Ke-Fang Yang,[a] Jian-Xiong Jiang,[a] Guo-Qiao Lai,*[a]
Yixin Lu,[b] and Li-Wen Xu*[a]
Keywords: Alkylation / Organocatalysis / Silicon / Reaction mechanisms / Asymmetric synthesis
A highly enantioselective Friedel–Crafts alkylation of indoles
with α,β-unsaturated aldehydes with excellent enantio-
selectivities (up to Ͼ99%ee) has been developed, and this
improved method offers substantial advantages over tradi-
tional approaches, not only by avoiding the use of acids or
bases, but also in terms of the higher level of stereoselecti-
vity. In addition, we have demonstrated through a plausible
mechanism that the role of silicon in the diarylprolinol silyl
ethers (Jørgensen–Hayashi organocatalyst) not only serves as
a bulky group to induce steric repulsion but also serves as a
Lewis acidic promoter to accelerate the reaction between the
secondary amine and the substrate (α,β-unsaturated alde-
hyde).
3-Substituted indoles are important motifs in natural
products and they are biologically significant molecules;
their synthesis through the iminium-based organocatalytic
Friedel–Crafts alkylation of α,β-unsaturated aldehydes has
been studied.[7,8] The diarylprolinol silyl ether catalyzed
asymmetric Friedel–Crafts alkylation of indoles with α,β-
unsaturated aldehydes has recently been reported by the
groups of Bao[9] and Wang[10] independently. Excellent en-
antiomeric excess of the Friedel–Crafts adducts (up to
98%ee) was attainable in the reported reactions; however,
large amounts of a tertiary amine as additive (Et3N, 50–
100 mol-%) and an expensive solvent (methyl tert-butyl
ether, MTBE) were required for these reactions. Herein, we
report an improved protocol for the Friedel–Crafts alkyl-
ation of indoles with α,β-unsaturated aldehydes; a modified
diarylprolinol silyl ether containing tertiary amine moiety
was used as the highly enantioselective organocatalyst,
which resulted in the formation of 3-alkylated products
with 98Ǟ99%ee. Moreover, mechanistic insights will also
be presented in this report.
Introduction
Since 2000,[1] the organocatalytic creation of structurally
diverse molecules from readily available and simple starting
materials has drawn much attention.[2] Although enormous
asymmetric organocatalytic reactions have been reported in
the past decade, the design of efficient organocatalysts, es-
pecially in a predictable manner, remains elusive.[3] Re-
cently, the role that silicon-containing bulky groups might
play in asymmetric catalysis has been well recognized.[4]
Among the known organocatalysts with bulky silyl groups,
diarylprolinol silyl ethers are arguably the most famous and
powerful.[5] Since it was first introduced by Jørgensen and
Hayashi independently in 2005,[6] the past few years have
witnessed an explosive growth in the applications of diaryl-
prolinol silyl ethers in asymmetric organocatalytic reac-
tions. Prolinol silyl ethers have been applied to various or-
ganic transformations, including aldol reactions, Mannich
reactions, oxidations and reductions, α- and γ-hetereo-
functionalizations, cycloadditions, and domino reactions,
via either enamine or iminium intermediates.[4,5]
Results and Discussion
[a] Key Laboratory of Organosilicon Chemistry and Material
Technology of Ministry of Education, Hangzhou Normal Uni-
versity,
Initially, we prepared interesting and fine-tuned diaryl-
prolinol ethers 5 and 6 containing imidazole and tertiary
amine moieties that showed excellent catalytic activities in
aqueous Michael reactions of aldehydes to nitroolefins.[11]
To achieve the highly enantioselective Friedel–Crafts alkyl-
ation of indoles with α,β-unsaturated aldehydes, we relied
on diarylprolinol ethers 4–6 for the model Friedel–Crafts
addition of indole (1a) to trans-cinnamaldehyde (2a) under
Hangzhou 310012, P. R. China
Fax: +86-571-28865135
E-mail: liwenxu@hznu.edu.cn
licpxulw@yahoo.com
[b] Department of Chemistry and Medicinal Chemistry Program,
Life Sciences Institute, National University of Singapore,
3 Science Drive 3, Republic of Singapore, 117543
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001404.
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Asymmetric Friedel–Crafts Alkylation of Indoles
standard conditions (Scheme 1 and Table 1). Preliminary Table 1. Optimization of reaction conditions: representative re-
sults.[a]
experiments on the reaction of 1a to 2a using catalysts 4–6
revealed that catalyst 5 provided the best results (Table 1,
Entries 1–3), which may be due to the existence of the terti-
ary amine moiety at the aromatic ring of diarylprolinol silyl
ether 5. This is in accordance with the previous report that
the addition of a tertiary amine is important for the en-
hancement in the enantioselectivities.[10] Indeed, catalyst 5,
which is easily prepared from l-proline and (4-bro-
mophenyl)-N,N-dimethylmethanamine, had a very positive
effect on asymmetric induction in comparison to that of
catalyst 4 under different conditions. For example, catalyst
4 bearing no additional group gave the product with only
moderated enantioselectivities (49–73%ee) in most of sol-
vents, which are lower than those obtained with catalyst
5 (76–92%ee) under almost the same conditions (Table 1;
Entry 5 vs. 4, entry 7 vs. 6, entry 9 vs. 8, and entry 11 vs.
10). In particular, when the reaction was performed in ace-
tonitrile without any additive, the best enantioselectivity
obtained was 92%ee with good isolated yields of this two-
step transformation at room temperature (Table 1, Entry 6).
Correspondingly, catalyst 4 resulted in only moderate
enantioselectivity in acetonitrile (72%ee). Interestingly and
unexpectedly, it is should be noted that we found that cata-
lyst 6 containing an imidazole moiety was inactive in this
reaction. Furthermore, the addition of a large amount of
Entry Cat.
Solvent
Time
[h]
T
[°C]
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4
5
6
5
4
5
4
5
4
5
4
5
5
5
4
5
5
MeOH
MeOH
MeOH
THF
THF
CH3CN
CH3CN
CH2Cl2
CH2Cl2
EtOH
EtOH
toluene
36
45
72
45
36
45
36
45
36
45
36
45
45
45
36
45
45
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
65
84
trace
48
33
80
46
86
42
96
42
75
29
59
78
65
51
73[d]
76
–
87
63[d]
92
72[d]
85
60[d]
77
49[d]
79
HMDSO[e]
CH3CN/H2O
MTBE/Et3N
CH3CN
CH3CN
76
90
–20
–20
–40
96[f]
98
99
[a] Reaction conditions: cinnamaldehyde (2a; 0.5 mmol, 1 equiv.),
indole (1a; 0.6 mmol, 1.2 equiv.), catalyst 4–6 (20 mol-%), and sol-
vent (0.5 mL). [b] Total isolated yield for two-step operation.
[c] Determined by chiral HPLC analysis. [d] From ref.[9]: cinnamal-
dehyde (0.5 mmol, 1 equiv.), indole (1.0 mmol, 2 equiv.), catalyst 4
(15 mol-%), and solvent (1.0 mL). [e] HMDSO = hexamethyl dis-
iloxane (Me3SiOSiMe3). [f ] Ref.[10]
tertiary amine to this reaction did not result in any improve- termined that catalyst 5 gives better enantioselectivity than
ment. Although subsequent experiments showed acidic ad- those reported for other organocatalysts in previous meth-
ditives could improve the catalytic activity of 6 in this reac- ods[7–10] under the same conditions.
tion, the yields were still poor; for example, the addition of
With these conditions in hand, the scope of the asymmet-
p-ClPhCOOH (40 mol-%) as additive resulted in only 29% ric Friedel–Crafts alkylation of indoles was subsequently
yield and 43%ee.
explored by using 5 as the organocatalyst and acetonitrile
as the solvent (Scheme 2). Several indoles containing elec-
tron-neutral, electron-deficient, and electron-rich substitu-
ents proceeded equally well with α,β-unsaturated aldehydes
to give the corresponding products with good results with
promising enantioselectivities. To the best of our knowl-
edge, these examples of organocatalyst-promoted Friedel–
Crafts alkylation of indoles with α,β-unsaturated aldehydes
showed
the
highest
enantioselectivities
reported
(98Ǟ99%ee). Notably, although a simple increase in the
reaction time was sufficient to obtain the Friedel–Crafts ad-
ducts in good yield, these reactions were carried out for
45 h to differentiate the reactivities of the substrates. In ad-
dition, these results showed that the use of fine-tuned di-
arylprolinol ether 5 containing a tertiary amine moiety as
the catalyst in the Friedel–Crafts alkylation of indoles with
α,β-unsaturated aldehydes resulted in a higher level of
enantioselectivity in comparison to those obtained with the
Scheme 1.
With catalyst 5 in hand and on the basis of these prelimi- use of catalyst 4 reported by Bao et al.[9] and Wang et al.[10]
nary results, a beneficial effect on the asymmetric induction in 2009.
was found by lowering the temperature (Table 1, Entries 16
Why do diarylprolinol silyl ethers 4–6 show different
and 17), whereas lowering the temperature to –40 °C led to catalytic activity in the asymmetric Friedel–Crafts alkyl-
a further improvement in the enantioselectivity (99%ee, ation of indoles? Some reasons could be concluded from
51% yield; Table 1, Entry 17). When the reaction was per- the iminium mechanism, in which selective attack is affected
formed at –20 °C the enantioselectivity was also found to by the 2-substituent (diaryl and silicon-based bulky group)
be excellent (98%ee, 65% yield; Table 1, Entry 16). On the on the pyrrolidine ring.[12] In previous discussions of pos-
basis of other reports[9,10] and the present findings, we de- sible mechanisms involving the iminium intermediate of di-
Eur. J. Org. Chem. 2011, 66–70
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67

G.-Q. Lai, L.-W. Xu et al.
SHORT COMMUNICATION
interesting to consider the functionality of the silicon atom
in this amino organocatalyst. Herein, in light of previous
mechanistic studies of diarylprolinol silyl ether catalyzed
transformations[12] and the aforementioned asymmetric
Friedel–Crafts alkylation of indoles with α,β-unsaturated
aldehydes, we report the preliminary investigation of the
mechanism, with an emphasis on the role of silicon, by
comparing the differences in enantioselectivity of catalysts
4–6 with the aid of 29Si NMR spectroscopy.
On the basis of experimental results and 29Si NMR
analysis (Supporting Information), the mechanism of di-
arylprolinol silyl ether catalyzed Friedel–Crafts alkylation
of indoles was proposed (Scheme 3). It is speculated that
the silicon atom in the diarylprolinol silyl ethers not only
serves as a bulky group to strengthen steric repulsion, but
it also serves as a promoter/activator to accelerate the initial
step of the reaction between the secondary amine and the
substrate (α,β-unsaturated aldehyde). In this hypothesis, the
possible activated silicon species is able to facilitate the in-
teraction between the secondary amine and the α,β-unsatu-
rated aldehyde, which provides iminium intermediate 8 ef-
ficiently and quickly.[15] In addition, in the catalytic cycle,
the bulky silicon group at C-2 on the pyrrolidine is essential
for high enantioselectivity.[12]
Scheme 2. Catalytic asymmetric Friedel–Crafts alkylation of ind-
oles.
arylprolinol silyl ethers,[12c,12e] the contribution of silicon
was only limited to a shielding effect as a result of the steric
repulsion caused by the bulky group. However, other effects
of silicon were completely overlooked in previous mechan-
istic studies. In fact, silicon has an energetically accessible
d orbital, so it can act as a Lewis acid.[13,14] Therefore, it is
Conclusions
In summary, we have developed a highly enantioselective
Friedel–Crafts alkylation of indoles with α,β-unsaturated
aldehydes with excellent enantioselectivities (up to
Ͼ99%ee). This improved method offers substantial advan-
tages over the traditional approaches, not only by avoiding
the use of any acids or bases but also in terms of the high
level of stereoselectivity. In addition, on the basis of experi-
mental results and 29Si NMR spectroscopic analysis, we
have demonstrated a possible mechanism in which the role
of the silicon atom in diarylprolinol silyl ethers (Jørgensen–
Hayashi catalyst) not only serves as a bulky group to induce
steric repulsion but also serves as a Lewis acidic promoter
to facilitate the crucial step involving the formation of the
iminium intermediate derived from the secondary amine
and the substrate (α,β-unsaturated aldehyde). Furthermore,
this work shows that modification of the Jørgensen–Haya-
shi catalyst with the introduction of an amino group on
the diarylprolinol silyl ether increases the stereoselectivity
in certain asymmetric transformations and sets the basis for
further development.
Experimental Section
General Remarks: All reagents and solvents were used directly with-
out purification. Flash column chromatography was performed
1
over silica (200–300 mesh). H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively, with an Advance
(Bruker) 400 MHz spectrometer and were referenced to the internal
solvent signals. Thin-layer chromatography was performed by using
Scheme 3. Proposed mechanism for the 5-catalyzed Friedel–Crafts
alkylation of indole with α,β-unsaturated aldehyde.
68
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Asymmetric Friedel–Crafts Alkylation of Indoles
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Typical Procedure for the Asymmetric Friedel–Crafts Alkylation of
Indoles with α,β-Unsaturated Aldehydes: To a solution of catalyst
(S)-5 (32 mg, 0.10 mmol, 20 mol-%) dissolved in CH3CN (1 mL) in
a 12-mL vial at room temperature was added cinnamaldehyde
(66 mg, 0.5 mmol). The mixture was stirred for 30 min, and indole
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of NaBH4 (57 mg, 1.5 mmol) was added, followed by the addition
of MeOH (1 mL). Then, the –20 °C cooling bath was replaced by
an ice bath, and the mixture was stirred for a further 20 min. The
mixture was slowly added to sat. NH4Cl (5 mL) at 0 °C and ex-
tracted with Et2O (10 ϫ 3 mL). The organic layer was collected,
washed with H2O (5 mL) and brine (5 mL), then dried with anhy-
drous Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by silica gel column chromatography (EtOAc/hex-
ane, 1:1) to afford 3a (98%ee). This is a known compound with
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8.0 Hz, 1 H), 7.25–7.34 (m, 5 H), 7.16 (dd, J = 7.2, 15.4 Hz, 2 H),
7.07 (s, 1 H), 7.03 (t, J = 7.2 Hz, 1 H), 4.42 (t, J = 8.0 Hz, 1 H),
3.63–3.73 (m, 2 H), 2.44–2.52 (m, 1 H), 2.24–2.33 (m, 1 H) ppm.
HPLC (Daicel Chiralpak OD-H, hexane/2-propanol = 80:20, flow
rate = 1.0 mL/min): tr = 15.34, 18.40 min.
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Supporting Information (see footnote on the first page of this arti-
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the Friedel–Crafts adducts; 29Si NMR spectra of diarylprolinol silyl
ethers 4–6 and their enamine and iminium intermediates; circular
dichroism and UV/Vis absorption spectra of catalysts 4–6 in
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Acknowledgments
This project was supported by the National Natural Science Foun-
dation of China (NSFC, No. 20973051), the Zhejiang Provincial
Natural Science Foundation of China (ZPNSFC, Y4090139) and
the Hangzhou Science and Technology Program (20090231 T03).
X. L. W. is greatly indebted to Prof. Shibasaki Masakatsu, The
University of Tokyo, and Prof. Chun-Gu Xia, Lanzhou Institute of
Chemical Physics (CAS), for their help.
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G.-Q. Lai, L.-W. Xu et al.
SHORT COMMUNICATION
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lation of indoles with α,β-unsaturated aldehydes. The use of
triethylamine or an organic acid as additive improved the reac-
tivity but the yield was still low (Ͻ30% yield) along with long
reaction time (96 h).
[15] Except for catalyst 6, which showed poor activity in this reac-
tion, we found that the catalytic activity of pyrrolidine without
a functional group was very low in the Friedel–Crafts alky-
Received: October 15, 2010
Published Online: November 30, 2010
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