Chiral phosphoric acid catalyzed highly enantioselective friedel-crafts alkylation reaction of c3-substituted indoles to ?2,?3-Unsaturated ?±-ketimino esters

Article abstract of DOI:10.1021/ol5035222

A highly enantioselective C2 Friedel-Crafts alkylation reaction of 3-substituted indoles to ?2,?3-unsaturated ?±-ketimino esters has been developed. This reaction was efficiently catalyzed by a chiral phosphoric acid catalyst. The corresponding C2-substituted indole derivatives, bearing an ?±-ketimino ester motif, were obtained in moderate to high yields (up to 93%) and with high enantioselectivities (up to >99% ee).

Full text of DOI:10.1021/ol5035222

Letter
pubs.acs.org/OrgLett
Chiral Phosphoric Acid Catalyzed Highly Enantioselective Friedel−
Crafts Alkylation Reaction of C3-Substituted Indoles to β,γ-
Unsaturated α‑Ketimino Esters
Bo Bi,† Qin-Xin Lou,† Yu-Yang Ding, Sheng-Wei Chen, Sha-Sha Zhang, Wen-Hui Hu,*
and Jun-Ling Zhao*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190
Kaiyuan Avenue, Guangzhou 510530, China
S
* Supporting Information
ABSTRACT: A highly enantioselective C2 Friedel−Crafts alkylation
reaction of 3-substituted indoles to β,γ-unsaturated α-ketimino esters has
been developed. This reaction was efficiently catalyzed by a chiral
phosphoric acid catalyst. The corresponding C2-substituted indole
derivatives, bearing an α-ketimino ester motif, were obtained in moderate
to high yields (up to 93%) and with high enantioselectivities (up to >99%
ee).
Despite those recent advances, the development of efficient
methods allowing the direct asymmetric synthesis of C2-
substituted indole derivatives via Friedel−Crafts alkylation
under mild condition remains a challenge. Herein, we present
our study on the chiral phosphoric acid catalyzed and highly
enantioselective Friedel−Crafts reaction of 3-substituted indoles
to β,γ-unsaturated α-ketimino esters, generating C2-function-
alized indole derivatives.
he indole skeleton is one of the most important ring
Tsystems that can be found in many naturally occurring
products and pharmaceuticals.1,2 Consequently, there has been a
strong demand for the development of efficient methods to allow
the direct functionalization of indoles. The catalytic asymmetric
Friedel−Crafts reaction3 using chiral metal complexes or chiral
organocatalysts is one of the most practical and atom-economical
approaches for the synthesis of optically active indole derivatives.
Because the electrophilic substitution preferentially occurred at
the C3 position of indoles, most of the efforts have been devoted
to the functionalization of indole derivatives have focused on the
substitution of the C3 position of indoles. Therefore, the direct
asymmetric alkylation of the less active C2 position has been less
studied.
β,γ-Unsaturated α-ketimino esters are versatile electrophiles
that have been used in a wide range of organic transformations,9
for example, aza-Diels−Alder reaction,9a,f 1,4-conjugate addition
reaction,9b,g asymmetric-transfer hydrogenation reaction,9c N-
alkylation/vinylogous aldol reaction,9d and aza-Morita−Baylis−
Hillman reaction.9e We expect that those components could also
serve as a starting material for Friedel−Crafts alkylation.
In recent years, chiral phosphoric acids have been widely
utilized as efficient enantioselective organocatalysts for numer-
ous organic reactions.10 Among the reactions investigated, the
activation of imines by BINOL-based phosphoric acids 1 has
proven to be an attractive and efficient method for constructing
nitrogen-containing chiral centers.11 The asymmetric Friedel−
Crafts alkylation of electron-rich aromatic compounds to imines
using chiral phosphoric acid catalysts has been one of the most
extensively studied areas in the past decade.12 Taking advantage
of the highly efficient activation of imines of phosphoric acid, we
envisaged that β,γ-unsaturated α-ketimino esters 2 might serve as
electrophiles for the asymmetric Friedel−Crafts reaction with 3-
substituted indoles, affording C2-functionalized indole deriva-
tives bearing an α-ketimino ester motif to enable many further
transformations.
The Pictet−Spengler reaction3a,4 of C3-substituted indoles is
the most commonly used strategy, but it is confined by the
limited scope of substrates. Some indirect protocols have also
been reported, which need the preactivation of the indole C2 via
the syntheses of intermediates with an active C2 position, for
example, the 1,4-conjugate addition of 2-indolyl trifluoroborate
salts to enals developed by MacMillan5 and the Friedel−Crafts
alkylation/oxidation of 4,7-dihydroindoles,6 which are pyrrole
derivatives that lead to reaction at the C2 position.
2-Substituted indoles are potential intermediates for many
alkaloids and pharmacologically important substances,3c and the
development of novel and efficiently catalyzed asymmetric
syntheses of these compounds appears to be of great
importance.7,8 Recently, Xiao and co-workers realized an
efficient asymmetric Friedel−Crafts alkylation/N-hemiacetaliza-
tion cascade reaction of C3-substituted indoles and β,γ-
unsaturated α-ketoesters promoted by a copper(II)−bioxazoline
complex.8a Feng and co-workers also reported a chiral N,N′-
dioxide−Ni(II) complex catalyzed Friedel−Crafts alkylation of
N-methylskatole to β,γ-unsaturated α-ketoesters.8b
Received: December 9, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol5035222
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Letter
a
There are many possible pathways in this reaction. One
pathway is the C3 nucleophilic addition of 3-substituted indole to
β,γ-unsaturated α-ketimino esters to give dearomatization
products, which is a known process for indole alkylation
chemistry.13 On the other hand, β,γ-unsaturated α-ketimino
esters are ambident electrophiles that undergo 1,2- or 1,4-
nucleophilic addition processes by hydrogen-bond activation of
the imine motif with an acid catalyst (Scheme 1). It is therefore
Table 1. Optimization of the Reaction Conditions
Scheme 1. Possible Reactions of 3-Substituted Indoles to β,γ-
Unsaturated α-Ketimino Esters
b
c
entry
catalyst
solvent
yield (%)
ee (%)
1
1a
1b
1c
1d
1e
1f
DCM
DCM
DCM
DCM
DCM
DCM
DCM
25
92
69
82
80
63
78
32
65
35
72
45
64
53
0
11
25
81
15
24
28
97
80
95
93
81
97
97
2
3
4
5
6
7
1g
1d
1d
1d
1d
1d
1d
1d
8
toluene
9
ClCH2CH2Cl
xylene
10
11
12
13
14
CHCl3
toluene/DCM (1:1)
toluene/DCM (2:1)
toluene/DCM (4:1)
more challenging to control the regioselectivity, which relies on
the nucleophiles and catalytic reagents.9g Compared to active
β,γ-unsaturated α-ketoesters and β,γ-unsaturated N-sulfonyli-
mines, β,γ-unsaturated N-phenylcycloimines 2 are less studied
because of their low reactivity, which is another challenge that we
must face. As a result, there has been no report of β,γ-unsaturated
N-phenylcycloimines 2 participating in asymmetric Friedel−
Crafts alkylation with indoles to date, even though the adducts
could be used in the synthesis of unnatural indolyl amino acid
derivatives that possess many interesting biological activities.
To begin our investigation, the reaction of 3-methylindole
(3a) and 2a was chosen as a model reaction. We first examined
the catalysis of the Friedel−Crafts reaction with 10 mol %
phosphoric acid 1b in dichloromethane at room temperature. To
our delight, the reaction proceeded with only the C2 1,4-
conjugate addition process, and the corresponding adduct (4aa)
was obtained in high yield (92%) but with low enantioselectivity
(11% ee, Table 1, entry 2). Different BINOL-based phosphoric
acids (1a−g) bearing substituents in the 3,3′-position were
screened (Table 1). Phosphoric acid 1d was found to be the best
catalyst with respect to enantioselectivity (Table 1, entry 4). The
product 4aa was isolated in 82% yield and 81% ee in 72 h.
Having identified the best catalyst (1d), the effect of the
reaction solvent was also surveyed to further enhance the
enantioselectivity. As shown in Table 1, the reaction medium has
a substantial influence on both the reactivity and stereo-
selectivity. Performing the reaction in toluene resulted in the
highest stereoselectivity (97% ee) but low reactivity (32% yield,
Table 1, entry 8), while the reaction in dichloromethane led to a
better yield and acceptable enantioselectivity (Table, entry 4).
Those results suggested that a mixture of dichloromethane and
toluene might improve the efficiency of the reaction. Experi-
ments indicated that this was the case, and the best result in terms
of yield (64%) and enantioselectivity (97% ee) was obtained
using a 2:1 ratio of toluene and dichloromethane (Table 1, entry
13).
a
Reactions were performed with 2a (0.1 mmol), 3a (0.3 mmol), and
b
c
catalyst (0.01 mmol) in solvent (0.9 mL). Isolated yield. Determined
by HPLC analysis using a chiral stationary phase.
and the results are summarized in Table 2. The electronic nature
of the substituents on the phenyl ring of β,γ-unsaturated α-
ketimino esters have little effect on the stereoselectivity of the
Table 2. Friedel−Crafts Alkylation of 3-Methylindole to
Various β,γ-Unsaturated α-Ketimino Esters
a
b
c
entry
R1
4
yield (%)
ee (%)
1
Ph (2a)
4aa
4ba
4ca
4da
4ea
4fa
64
78
83
44
49
46
31
75
67
97
99
98
97
97
97
97
97
98
96
98
97
96
95
97
95
90
97
2
4-NO2C6H4 (2b)
3-NO2C6H4 (2c)
4-OCH3C6H4 (2d)
3-OCH3C6H4 (2e)
4-CH3C6H4 (2f)
2-CH3C6H4 (2g)
4-BrC6H4 (2h)
3-BrC6H4 (2i)
3
4
5
6
7
4ga
4ha
4ia
8
9
d
10
11
12
13
14
15
16
17
18
5-Br, 2-FC6H3 (2j)
4-ClC6H4 (2k)
3-ClC6H4 (2l)
4ja
30 (41)
4ka
4la
68
67
77
70
58
70
65
58
4-FC6H4 (2m)
4ma
4na
4oa
4pa
4qa
4ra
4-isopropylC6H4 (2n)
1-naphthyl (2o)
2-thienyl (2p)
2-furyl (2q)
4-CF3C6H4 (2r)
a
Reactions were performed with 2 (0.1 mmol), 3a (0.3 mmol), and 1d
b
c
With the optimal reaction conditions identified, the Friedel−
Crafts alkylation reactions of 3-methylindole to a variety of
aromatic β,γ-unsaturated α-ketimino esters (2) were surveyed,
(0.01 mmol) in solvent (0.9 mL). Isolated yield. Determined by
HPLC analysis using a chiral stationary phase. Reaction time is 120 h
with 45% unreacted 2j retrieved.
d
B
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Letter
reaction; both the electron-donating and electron-withdrawing
groups on the aromatic ring were tolerated, yielding the expected
products in high stereoselectivity (90−99% ee, Table 2, entries
1−14 and 18). β,γ-Unsaturated α-ketimino esters (2) with
electron-donating groups such as methoxyl afforded products
with lower yields (Table 2, entries 4−7), while electron-
withdrawing groups resulted in high reactivities (Table 2, entries
2 and 3).
Scheme 3. Scale Up Reaction and Reduction of 4ka
The substrate scope of 3-substituted indole for this Friedel−
Crafts alkylation reaction was also examined, and the results are
presented in Table 3. In general, the reaction proceeded
a
Table 3. Scope of Substituted Indoles
b
c
entry
R2, R3
4
yield (%)
ee (%)
1
2
Me, H (3a)
4aa
4ab
4ac
4ad
4ae
4af
64
62
97
98
Et, H (3b)
d
3
NHBoc, H (3c)
Me, 4-Me (3d)
Me, 5-Me (3e)
Me, 6-Me (3f)
Me, 7-Me (3g)
Me, 4-BnO (3h)
Me, 5-BnO (3i)
Me, 6-BnO (3j)
Me, 5-Cl (3h)
93
92
4
69
97
5
85
97
6
84
97
Figure 1. X-ray structure of 4ka.
7
4ag
4ah
4ai
71
>99
99
8
75
9
75
98
10
11
4aj
87
>99
employing Hantzsch ester as a hydrogen donor; the resulted α-
amino acid derivative 5 was obtained in 65% yield with excellent
stereoselectivity (98% ee, 9.5:1 dr, Scheme 2). Compound 5 was
an important building intermediate in organic synthesis and
could be converted to amino alcohol 6 according to the
procedure reported by Maruoka and co-workers.15
4ah
<10
a
Reactions were performed with 2a (0.1 mmol), 3 (0.3 mmol), and 1d
b
c
(0.01 mmol) in solvent (0.9 mL). Isolated yield. Determined by
HPLC analysis using a chiral stationary phase. Used 20 mol % of the
catalyst 1d.
d
In conclusion, we have developed a chiral phosphoric acid
catalyzed Friedel−Crafts alkylation reaction of 3-substituted
indole to β,γ-unsaturated α-ketimino esters. This highly
enantioselective protocol gives C2-functionalized indole deriv-
atives bearing a synthetically versatile α-ketimino ester motif. A
wide range of β,γ-unsaturated α-ketimino esters react smoothly
with 3-substituted indoles to afford the corresponding adducts
with moderate to high yields and high stereoselectivities. More
importantly, this strategy could be used for the synthesis of a 2-
indolyl-α-amino acid skeleton, which is the backbone of many
biologically interesting compounds.
smoothly with substrates bearing electron-donating groups,
such as phenoxy and methyl, on the benzene position of 3-
methylindole, to afford the products in high yields and
stereoselectivities (Table 3, entries 3−10). In contrast, the
reaction was suppressed by the introduction of electron-
withdrawing groups, and only trace amounts of the correspond-
ing adduct were detected when 5-chloroskatole (3h) was used
(Table 3, entry 11). The C3 Friedel−Crafts alkylation of 2a and
simple indole (4i) was also tested under the optimal reaction
conditions, and the C3-functionalized product 4ai was obtained
in high yield but with poor stereoselectivity (Scheme 2, see also
Table S1 in the Supporting Information).
ASSOCIATED CONTENT
■
S
* Supporting Information
Scheme 2. C3 Friedel−Crafts Alkylation of 2a and 3i
Typical experimental procedure and characterization for all
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
To exploit the potential of the Friedel−Crafts alkylation
process, the reaction was scaled up to 3.5 mmol of 2k and 10.5
mmol of 3-methylindole (3a). The corresponding product 4ka
could be obtained in 75% yield without a deleterious effect on
stereoselectivity (Scheme 3). The absolute configuration of the
new chiral center of 4ka was assigned as S by X-ray
crystallographic analysis (Figure 1).14 Compound 4ka undergoes
a Brønsted acid catalyzed transfer hydrogenation reaction by
*E-mail: hu_wenhui@gibh.ac.cn.
*E-mail: zhao_junling@gibh.ac.cn.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/ol5035222
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Letter
(11) For a review, see: Terada, M.; Momiyama, N. In Chiral Amine
Synthesis: Methods, Developments and Applications; Nugent, T. C., Ed.;
Wiley-VCH: Weinheim, 2010.
(12) For selected examples, see: (a) Kang, Q.; Zhao, Z. A.; You, S. L.
Tetrahedron 2009, 65, 1603. (b) Wanner, M. J.; Hauwert, P.;
Schoemaker, H. E.; Gelder, R. D.; Maarseveen, J. H. V.; Hiemstra, H.
Eur. J. Org. Chem. 2008, 180. (c) Yu, P.; He, J.; Yang, L.; Pu, M.; Guo, X.
J. Catal. 2008, 260, 81. (d) Yu, P.; He, J.; Guo, C. X. Chem. Commun.
2008, 2355.
(13) For selected examples, see: (a) Zhuo, C. X.; Zhang, W.; You, S. L.
Angew. Chem., Int. Ed. 2012, 51, 12662. (b) Wu, Q. F.; Zheng, C.; You, S.
L. Angew. Chem., Int. Ed. 2012, 51, 1680. (c) Spangler, J. E.; Davies, H.
M. L. J. Am. Chem. Soc. 2013, 135, 6802. (d) Zhu, S.; MacMillan, D. W.
C. J. Am. Chem. Soc. 2012, 134, 10815.
(14) CCDC 103590 (4ka) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from the Cambrige Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Grant No. 21102145) and the Guangdong Pearl River Nova
Program (Grant No. 2012J2200014) for financial support.
REFERENCES
■
(1) (a) Sundberg, R. J. In The Chemistry of Indoles; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Academic Press: New York, 1996.
(b) Ryan, K. S.; Drennan, C. L. Chem. Biol. 2009, 16, 351. (c) Brown, R.
K. In Indoles; Houlihan, W. J., Ed.; Wiley-Interscience: New York, 1972.
(2) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
(c) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
́
Substances, 4th ed.; Thieme: New York, 2001. (d) Bonjoch, J.; Sole, D.
Chem. Rev. 2000, 100, 3455. (e) Cox, E. D.; Cook, J. M. Chem. Rev. 1995,
95, 1797. (f) Humphery, G. R.; Kuether, J. T. Chem. Rev. 2006, 106,
2875.
(15) Kano, T.; Takechi, R.; Kobayashi, R.; Maruoka, K. Org. Biomol.
(3) For reviews on catalytic asymmetric Friedel−Crafts alkylation of
indoles, see: (a) Lancianesi, S.; Parlmieri, A.; Petrini, M. Chem. Rev.
2014, 114, 7108. (b) You, S. L.; Zeng, M. Synlett 2010, 1289. (c) Bartoli,
G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39, 4449.
(d) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(e) You, S. L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190.
(f) Poulsen, T. B.; Jøgensen, K. A. Chem. Rev. 2008, 108, 2903.
(g) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed.
2004, 43, 550.
Chem. 2014, 12, 724.
(4) For selected examples, see: (a) Liewa, L. P.; Fleminga, J. M.;
Longeon, A.; Mouray, E.; Florent, I.; Bourguet-Kondracki, M. L.;
Coppa, B. R. Tetrahedron 2014, 70, 4910. (b) Wang, J. Q.; Deng, Q. M.;
Wu, L.; Xu, K.; Wu, H.; Liu, R. R.; Gao, J. R.; Jia, Y. X. Org. Lett. 2014, 16,
776. (c) Edwankar, C. R.; Edwankar, R. V.; Namjoshi, O. A.; Liao, X.;
Cook, J. M. J. Org. Chem. 2013, 78, 6471. (d) Gao, J. R.; Wu, H.; Xiang,
B.; Yu, W. B.; Han, L.; Jia, Y. X. J. Am. Chem. Soc. 2013, 135, 2983.
(e) Cai, Q.; Liang, X. W.; Wang, S. G.; Zhang, J. W.; Zhang, X.; You, S. L.
Org. Lett. 2012, 14, 5022. (f) Huang, D.; Xu, F.; Lin, X.; Wang, Y.
Chem.Eur. J. 2012, 18, 3148.
(5) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(6) For selected examples, see: (a) Kang, Q.; Zheng, X. J.; You, S. L.
Chem.Eur. J. 2008, 14, 3539. (b) Hong, L.; Liu, C. X.; Sun, W. S.;
Wang, L.; Wong, K. Y.; Wang, R. Org. Lett. 2009, 11, 2177. (c) Hong, L.;
Sun, W. S.; Liu, C. X.; Wang, L.; Wong, K. Y.; Wang, R. Chem.Eur. J.
2009, 15, 11105. (d) Sheng, Y. F.; Li, G. Q.; Kang, Q.; Zhang, A. J.; You,
S. L. Chem.Eur. J. 2009, 15, 3351. (e) Zeng, M.; Kang, Q.; He, Q. L.;
You, S. L. Adv. Synth. Catal. 2008, 350, 2169.
(7) For early racemic examples on C2 Friedel−Crafts alkylation, see:
(a) Wang, S. Y.; Ji, S. J. Tetrahedron 2006, 62, 1527. (b) Zeng, X. F.; Ji, S.
J.; Wang, S. Y. Tetrahedron 2005, 61, 10235.
(8) For recent examples on asymmetric C2 Friedel−Crafts alkylation,
see: (a) Cheng, H. G.; Lu, L. Q.; Wang, T.; Yang, Q. Q.; Liu, X. P.; Li, Y.;
Deng, Q. H.; Chen, J. R.; Xiao, W. J. Angew. Chem., Int. Ed. 2013, 52,
3250. (b) Zhang, Y. L.; Liu, X. H.; Zhao, X. H.; Zhang, J. L.; Zhou, L.;
Lin, L. L.; Feng, X. M. Chem. Commun. 2013, 11311. (c) Tan, W.; Li, X.;
Gong, Y. X.; Ge, M. D.; Shi, F. Chem. Commun. 2014, 15901. (d) Shi, F.;
Zhu, R. Y.; Dai, W.; Wang, C. S.; Tu, S. J. Chem.Eur. J. 2014, 20, 2597.
́
(9) (a) He, L.; Laurent, G.; Retailleau, P.; Folleas, B. T.; Brayer, J.;
Masson, G. Angew. Chem., Int. Ed. 2013, 52, 11088. (b) Paracios, F.;
Vicario, J. Org. Lett. 2006, 8, 5405. (c) Kang, Q.; Zhao, Z. A.; You, S. L.
Org. Lett. 2008, 10, 2031. (d) Tanaka, H.; Mizota, I.; Shimizu, M. Org.
Lett. 2014, 16, 2276. (e) Yao, Y.; Li, J. L.; Dong, L.; Chen, Y. C. Chem.
Eur. J. 2013, 19, 9447. (f) Han, B.; He, Z. Q.; Li, J. L.; Li, R.; Jiang, K.;
Liu, T. Y.; Chen, Y. C. Angew. Chem., Int. Ed. 2009, 48, 5474. (g) Qiu, L.;
Gao, L. X.; Tang, J. X.; Wang, D. W.; Guo, X.; Liu, S. Y.; Yang, L. P.; Li, J.;
Hu, W. H. J. Org. Chem. 2014, 79, 4142.
(10) For reviews, see: (a) Terada, M. Bull. Chem. Soc. Jpn. 2010, 83,
101. (b) Yu, X.; Wang, W. Chem.Asian J. 2008, 3, 516. (c) Akiyama, T.
Chem. Rev. 2007, 107, 5744. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev.
2007, 107, 5713. (e) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal.
2006, 348, 999.
D
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