Asymmetric Friedel-Crafts alkylation of indoles with 2-nitro-3-arylacrylates catalyzed by a metal-templated hydrogen bonding catalyst

Article abstract of DOI:10.1016/j.tetlet.2015.06.046

Abstract An asymmetric Friedel-Crafts alkylation of indoles with 2-nitro-3-arylacrylates catalyzed by a metal-templated hydrogen bonding catalyst has been established. The asymmetric induction relies on chirality transfer solely from the octahedral metal

Full text of DOI:10.1016/j.tetlet.2015.06.046

Accepted Manuscript
Asymmetric Friedel-Crafts Alkylation of Indoles with 2-Nitro-3-Arylacrylates
Catalyzed by a Metal-Templated Hydrogen Bonding Catalyst
Jingfen Liu, Lei Gong, Eric Meggers
PII:
S0040-4039(15)01052-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.046
TETL 46438
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 May 2015
12 June 2015
16 June 2015
Please cite this article as: Liu, J., Gong, L., Meggers, E., Asymmetric Friedel-Crafts Alkylation of Indoles with 2-
Nitro-3-Arylacrylates Catalyzed by a Metal-Templated Hydrogen Bonding Catalyst, Tetrahedron Letters (2015),
doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.046
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Asymmetric Friedel-Crafts Alkylation of Indoles with 2-Nitro-3-Arylacrylates
Catalyzed by a Metal-Templated Hydrogen Bonding Catalyst
Jingfen Liua, Lei Gonga,*, Eric Meggersa,b,*
a Key Laboratory for Chemical Biology of Fujian Province and Department of Chemical Biology,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s
Republic of China
b Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35043 Marburg,
Germany
* Corresponding author. Tel.: +86-592-2185821. E-mail address: gongl@xmu.edu.cn (L. Gong),
meggers@chemie.uni-marburg.de (E. Meggers).

Abstracts
An asymmetric Friedel-Crafts alkylation of indoles with 2-nitro-3-arylacrylates catalyzed by a
metal-templated hydrogen bonding catalyst has been established. The asymmetric induction relies on
chiraility transfer solely from the octahedral metal stereocenter via three weak hydrogen bonds. All
the products are provided with good to excellent enantioselectivities while modest
diastereoselectivities, which can be converted into a variety of valuable indole-containing chiral
building blocks including tryptophan derivatives.
Graphical abstract
Keywords
Asymmetric catalysis; Friedel-Crafts alkylation; hydrogen bond; metal-template; iridium.
2

Introduction
Asymmetric catalysts need to be chiral in order to provide the necessary asymmetric induction in
the course of their catalysis. This chirality is typically based on carbon, phosphorus, and/or sulfur
stereocenters, but also axial chirality of biaryl systems, or planar chirality of (half-)sandwich
complexes.1 However, examples in which the chirality originates only at a metal center (metal
centrochirality) are much less investigated,2,3 presumably due to previous synthetic challenges. We
recently introduced a convenient auxiliary-mediated methodology for the synthesis of chiral
octahedral metal complexes which only contain achiral ligands and therefore draw their chirality
exclusively from the metal center,4-8 and we demonstrated that such chiral-only-at-metal complexes
could serve as highly powerful catalysts for a variety of asymmetric transformations.9-15 As an
example, we developed a hydrogen-bond-mediated chiral iridium(III) complex as a very efficient
catalyst for the Friedel-Crafts alkylation of indoles with β-nitroacrylates, thereby implementing
all-carbon quaternary stereocenters with excellent enantioselectivities.10 We were then wondering if
related catalysts would be suitable for α-nitroacrylate substrates, thereby creating two consecutive
stereocenters. Herein, we report our efforts into the direction and demonstrate that the obtained
Friedel-Crafts alkylation products are valuable chiral building blocks for a range of transformations.
Scheme 1. Asymmetric Friedel-Crafts alkylation with chiral-at-metal catalysts.
3

Results and discussion
We started our investigation with the previously developed catalyst Λ-Ir110 and found that at a
catalyst loading of 3 mol% it catalyzed the reaction of α-nitroacrylate 1a with indole 2a to provide the
Friedel-Crafts alkylation product 3a with a very modest diastereoselectivity of 1.5:1 but both
diastereomers were formed with respectable enantioselectivities of 84% and 82% e.e. (Table 1, entry
1). The main enantiomers of the two diastereomers were assigned the absolute configurations 2R,3S
(major) and 2S,3S (minor) by comparison with chiral HPLC retention times reported by Liu and Chen
et al.16 When we next replaced the 3,5-dimethylphenyl moieties of Λ-Ir1 against more bulky
carbazolyl groups (Λ-Ir2), the enantioselectivities dropped significantly, indicating that steric
hindrance at this position was disadvantageous for this class of substrates (entry 2). And indeed,
removal of the aryl groups altogether, providing catalyst Λ-Ir3, resulted in the formation of the two
diastereomers with improved enantioselectivities of 86% and 84% e.e. (entry 3). Finally, replacing the
benzoxazole moieties against benzothiazoles led to the optimized catalyst Λ-Ir4, which provided the
two diastereomers with increased 89% and 92% e.e. (entry 4).
With Λ-Ir4 in hand, we next turned our attention to optimizing the reaction conditions for the
reaction 1a+2a→3a as shown in Table 2. Testing different solvents (entries 1-5) revealed that
methylene chloride is the solvent of choice. Reducing the temperature did not improve the
stereoselectivities (entries 6 and 7). However, we found that the catalyst loading could be reduced to
0.5 mol% while still providing a satisfactory reaction time of 24 hours for complete conversion at
room temperature with a diastereoselectivity of 2:1 and 95% e.e. for each diastereomer at the
optimized concentration of 1.0 M (entries 8-11). A further reduction of the catalyst loading to 0.2
mol% resulted in an undesirable drop in stereoselectivities (entry 12).
4

Table 1
Optimization of the chiral-at-metal hydrogen bonding catalysta
Entry Catalyst
Reaction time (h)
Conv. (%)b
d.r.c
e.e. (%)d
1
2
3
6
6
5
5
100
100
100
100
60:40
47:53
56:44
56:44
84/82
66/77
86/84
89/92
Λ-Ir1
Λ-Ir2
Λ-Ir3
Λ-Ir4
4
a
Reaction conditions: To a solution of (Z)-ethyl 2-nitro-3-(p-tolyl)acrylate 1a (0.040
mmol) in freshly distilled toluene (40 µL) in a brown glass vial, iridium catalyst (1.2
µmol, BArF- = tetrakis[(3,5-di-trifluoromethyl)phenyl]borate), and then indole 2a (0.060
mmol) were added and the reaction was stirred at room temperature (20 °C) for 5-6 h
under argon atmosphere.
b Conversion determined by 1H-NMR.
c Diastereomeric ratio determined by 1H-NMR.
d E.e values determined by HPLC analysis on a chiral stationary phase.
5

Table 2
Optimization of reaction conditions with Λ-Ir4a
Entry
1
Solvent
PhCH3
PhCF3
TBME
THF
Conc. (M) Temp. (°C) time (h)b d.r.c
e.e. (%)d
89/92
90/90
80/80
60/60
95/95
96/95
95/95
95/95
95/95
89/83
95/94
92/90
Λ-Ir4 (mol%)
3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
0.5
1.0
20
20
20
20
20
0
5
56:44
57:43
53:47
55:45
66:34
68:32
65:35
60:40
66:34
55:45
68:32
65:35
2
3
4.5
56
100
5
3
3
4
3
5
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
6
3
18
36
15
24
7
7
3
-20
20
20
20
20
20
8
1
9
0.5
0.5
0.5
0.2
10
11
12
38
36
a Reaction conditions: To a solution of (Z)-ethyl 2-nitro-3-(p-tolyl)acrylate 1a (0.040 mmol) in
the indicated solvent (40 µL for entries 1-10; 20 µL for entry 11 and 80 µL for entry 12) in a
brown glass vial, chiral iridium complex Λ-Ir4 (0.2-3.0 mol%) and then indole 2a (0.060
mmol) were added and the reaction was stirred at the indicated temperature under an
atmosphere of argon.
b Time of full conversion as determined by 1H-NMR.
c Diastereomeric ratio determined by 1H-NMR.
d E.e value determined by HPLC analysis on a chiral stationary phase.
6

Mechanistically, the obtained absolute S-configuration at the 3-position (β-position to the nitro
group) is consistent with a transition state in which the nitroacrylate forms two hydrogen bonds with
the pyrazole amide through the two oxygen atoms of the nitro group and the indole donates a
hydrogen bond to one carboxamide moiety, thereby bringing the nucleophile in position for a Re face
addition to the β-position of the nitroacrylate.17 The observed high enantioselectivities can be
explained with a strong electronic and entropic advantage of this ternary hydrogen-bonded transition
state over the uncatalyzed reaction. The steric demand of the carboxylic ester group also offers an
explanation for the observation that the catalysts Λ-Ir1 and Λ-Ir2 are inferior over the sterically less
hindered derivatives Λ-Ir3 and Λ-Ir4. Importantly, the low diastereoselectivities reveal that the
protonation of the α-position in the course of the nucleophilic indole addition at the β-position does
not occur with a significant stereocontrol. Thus, indole addition to the nitroacrylate and proton
transfer cannot occurs concerted and we hypothesize that after the nitronate intermediate that is
formed after the initial indole addition, has a long enough life time to become protonated after partial
dissociation from the catalyst.18
b)
a)
NEt2
O
S
H
N
N
N
+
COCF3
Ir
N
N
N
H
H
Re face attack
N
O
N
O
S
CONEt2
O
Ar
OR
Figure 1. a.) Proposed transition state of the asymmetric Friedel-Crafts alkylation catalyzed by Λ-Ir4.
Atoms involved in hydrogen bonding are highlighted in blue. b.) A crystal structure of the major
diasteromer of asymmetric Friedel-Crafts alkylation product 3h, for which the absolute configuration
7

was assigned as 2R,3S.
Next, we investigated the substrate scope of the Friedel-Crafts reaction of indoles with
(Z)-2-nitro-3-arylacrylates (Figure 2). The use of (Z)-ethyl 2-nitro-3-phenylacrylate resulted in the
desired product 3c in 96% yield with high enantioselectivities of 94% and 92% e.e. for the two
diastereomers. While diastereoselectivities remain low for all investigated reactions, yields and
enantioselectivities are typically high. The (Z)-2-nitro-3-arylacrylates tolerate methyl groups (products
3a,b) and electron withdrawing functional groups (products 3d-g) in the phenyl moiety, the ethyl ester
can be replaced by a methyl (product 3h) and isopropyl (product 3i) ester, whereas the phenyl group
can be replaced by a naphthyl moiety (product 3j). Furthermore, substituted indoles are also tolerated
(products 3k-n), whereas the methylation of the NH-group leads to a significant decrease in
enantioselectivities of both diastereomers (12%/39% e.e.) and is therefore consistent with our
mechanistic picture that a hydrogen bond between the indole NH group and the carboxamide moiety
of the catalyst is a requirement for obtaining high enantioselectivities (Figure 1a). A crystal structure
of the major diastereomer of product 3h confirmed the assigned absolute and relative configurations
(Figure 1b, see more details in Supporting Information).
8

Figure 2. Substrate scope. See Supplementary data for more details.
9

Due to the presence of indole in many natural products and pharmaceutically active compounds,
chiral indole-containing compounds constitute potentially useful synthetic building blocks.19-21 We
therefore investigated further conversions of this class of Friedel-Crafts alkylation products and used
the product 3c as our model system.22 Importantly, as can be seen from the results in Scheme 2, the
enantioselectivities were only reduced slightly in the course of the developed transformations. For
example, the diastereomeric mixture of 3c was smoothly converted to the tryptophan derivatives
(2R,3S)-4 (95% e.e.) and (2S,3S)-4 (94% e.e.) through reduction of the nitro group with hydrogen and
palladium hydroxide.23,24 The two diastereomers could be resolved easily by standard flash
chromatography on a silica gel column. Furthermore, the reduction of the ester with LiAlH4 at -78 °C
for 5 min provided the two alcohols (2R,3S)-5 and (2S,3S)-5 which could also be resolved by standard
flash chromatography on silica gel. Alternatively, the complete removal of the ester group, leading to
(S)-6, was accomplished by increasing the reaction time with LiAlH4 to overnight at the elevated
temperature of -60 °C. Finally, the complete removal of the nitro group, resulting in the ester (S)-7
could be achieved by treatment of 3c with azobisisobutyronitrile (AIBN) and tri-n-butyltin hydride at
100 °C for 1 h.
10

Scheme 2. Friedel-Craft alkylation products as building blocks for further transformations as
demonstrated for the product 3c.
Conclusions
In conclusion, we here reported the asymmetric Friedel-Crafts alkylation of indoles with
2-nitro-3-arylacrylates catalyzed by a metal-templated hydrogen bonding catalyst which can
orchestrate a network of hydrogen bonds in the ternary transition state. While the diastereoselectivities
are very modest, the two diastereomers are formed with good to excellent enantioselectivities and can
be converted to a number of valuable indole-containing chiral building blocks.
11

Acknowledgements
We gratefully acknowledge funding from the National Natural Science Foundation of P. R. China
(grant nos. 21272192, 21201143, and 21472154), the Program for Changjiang Scholars and
Innovative Research Team of P. R. China (PCSIRT), the National Thousand Talents Program of P. R.
China, and the 985 Program of the Chemistry and Chemical Engineering disciplines of Xiamen
University.
Supplementary material
Crystallographic data (excluding structure factors) for the structures in this paper have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 1063136
and 1063137. Supplementary data (experimental procedures, characterization data of all new
compounds, as well as NMR, CD and HPLC traces of partial compounds) associated with this article
can be found in the online version.
References and notes
1. Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books,
Sausalito, California, 2009.
2. For different aspects of metal-centered chirality, see: (a) Pierre, J. Coord. Chem. Rev. 1998,
178-180, 1183-1192; (b) Knof, U.; von Zelewsky, A. Angew. Chem. Int. Ed. 1999, 38, 302-322;
(c) Amouri, H.; Gruselle, M.; Chirality in Transition Metal Chemistry, Wiley, Chichester, UK,
2008; (d) Meggers, E. Eur. J. Inorg. Chem. 2011, 2911-2926; (e) Crassous, J. Chem. Commun.
2012, 48, 9684-9692; (f) Constable, E. C. Chem. Soc. Rev. 2013, 42, 1637-1651.
12

3. For reviews covering chiral-at-metal complexes in catalysis, see: (a) Brunner, H. Angew. Chem.
Int. Ed. 1999, 38, 1194-1208; (b) Knight, P.; Scott, P. Coord. Chem. Rev. 2003, 242, 125-143; (c)
Fontecave, M.; Hamelin, O.; Ménage, S. Top. Organomet. Chem. 2005, 15, 271-288; (d) Bauer, E.
B. Chem. Soc. Rev. 2012, 41, 3153-3167; (e) Gong, L.; Chen, L.-A.; Meggers, E. Angew. Chem.
Int. Ed. 2014, 53, 10868-10874; (f) Cao, Z.-Y.; Brittain, W. D. G.; Fossey, J. S.; Zhou, F. Catal.
Sci. Technol. 2015, DOI: 10.1039/c5cy00182j.
4. Gong, L.; Mulcahy, S. P.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2009, 131, 9602-9603.
5. Gong, L.; Lin, Z.; Harms, K.; Meggers, E. Angew. Chem. Int. Ed. 2010, 49, 7955-7957.
6. Meggers, E. Chem. Eur. J. 2010, 16, 752-758.
7. Gong, L.; Wenzel, M.; Meggers, E. Acc. Chem. Res. 2013, 46, 2635-2644.
8. Helms, M.; Lin, Z.; Gong, L.; Harms, K.; Meggers, E. Eur. J. Inorg. Chem. 2013, 4164-4172.
9. Chen, L.-A.; Xu, W.; Huang, B.; Ma, J.; Wang, L.; Xi, J.; Harms, K.; Gong, L.; Meggers, E. J.
Am. Chem. Soc. 2013, 135, 10598-10601.
10. Chen, L.-A.; Tang, X.; Xi, J.; Xu, W.; Gong, L.; Meggers, E. Angew. Chem. Int. Ed. 2013, 52,
14021-14025.
11. Huo, H.; Fu, C.; Harms, K.; Meggers, E. J. Am. Chem. Soc. 2014, 136, 2990-2993.
12. Ma, J.; Ding, X.; Hu, Y.; Huang, Y.; Gong, L.; Meggers, E. Nat. Commun. 2014, 5, 5531.
13. Huo, H.; Fu, C.; Wang, C.; Harms, K.; Meggers, E. Chem. Commun. 2014, 50, 10409-10411.
14. Huo, H.; Shen, X.; Wang, C.; Zhang, L.; Röse, P.; Chen, L.-A.; Harms, K.; Marsch, M.; Hilt, G.;
Meggers, E. Nature 2014, 515, 100-103.
15. Wang, C.; Chen, L.-A.; Huo, H.; Shen, X.; Harms, K.; Gong, L.; Meggers, E. Chem. Sci. 2015, 5,
1094-1100.
16. Sui, Y.; Liu, L.; Zhao, J.-L.; Wang, D.; Chen, Y.-J. Tetrahedron 2007, 63, 5173-5183.
13

17. Alternatively, the nitroacrylate might form the double hydrogen bond with the pyrazole amide
moiety of the catalyst through only one oxygen of the nitro group in addition to the carbonyl
group of the ester. However, the stereochemical consequences would be identical.
18. Some other reasons for the low diastereoselectivities can be ruled out. Firstly, only a slight Z→E
isomerization of nitroacrylates was observed in presence of 0.5 mol% Λ-Ir4 after 24 hours.
Secondly, despite the acidity of the CH-group in α-position of the nitro group in the
Friedel-Crafts product, no product racemization was observed in the absence or presence of the
catalyst. See Supplementary data for more details.
19. Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873-2920.
20. Waldmann, H.; Hu, T. S.; Renner, S.; Menninger, S.; Tannert, R.; Oda, T.; Arndt, H.-D. Angew.
Chem. Int. Ed. 2008, 47, 6473-6477.
21. Ilisz, I.; Fodoor, G.; Berkecz, R.; Iványi, R.; Szente, L.; Péter, A. J. Chromatogr. A 2009, 1216,
3360-3365.
22. For accessing chiral indole derivatives through Friedel-Crafts alkylations, see: (a) Gao, Y.; Du,
D.-M. Tetrahedron: Asymmetry 2013, 24, 1312-1317; (b) Lyzwa, D.; Dudziński, K.;
Kwiatkowski, P. Org. Lett. 2012, 14, 1540-1543; (c) Huo, C.; Kang, L.; Xu, X.; Jia, X.; Wang, X.;
Xie, H.; Yuan, Y. Tetrahedron Lett. 2014, 55, 954-958; (d) Evans, D. A.; Fandrick, K. R.; Song,
H-J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029-10041; (e) Liu, Y.; Shang, D.;
Zhou, X.; Liu, X.; Feng, X. Chem. Eur. J. 2009, 15, 2055-2058; (f) Hong, L.; Wang, L.; Chen, C.;
Zhang, B.; Wang, R. Adv. Synth. Catal. 2009, 351, 772-778; (g) Singh, P. K.; Singh, V. K. Org.
Lett. 2008, 10, 4121-4124; (h) Liu, Y.; Zhou, X.; Shang, D.; Liu, X.; Feng, X. Tetrahedron 2010,
66, 1447-1457; (i) Arai, T.; Awata, A.; Wasai, M.; Yokoyama, N.; Masu, H. J. Org. Chem. 2011,
14

76, 5450-5456; (j) Jia, Y.; Yang, W.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 4739-4746; (k)
Zhang, Y.; Liu, X.; Zhao, X.; Zhang, J.; Zhou, L.; Lin, L.; Feng, X. Chem. Commun. 2013, 49,
11311-11313; (l) Jia, S.-J.; Du, D.-M. Tetrahedron: Asymmetry 2014, 25, 980-988; Oyama, H.;
Nakada, M. Tetrahedron: Asymmetry 2015, 26, 195-202; (m) Mor, K.; Wakazawa, M.; Akiyama,
T. Chem. Sci. 2014, 5, 1799-1803; (n) Kaur, J.; Kumar, A.; Chimni, S. S. 2014, Tetrahedron Lett.
55, 2138-2141; (o) Sato, T.; Arai, T. Synlett 2014, 25, 349-354.
23. Feu, K. S.; Deobald, A. M.; Narayanaperumal, S.; Corrȇa, A. G.; Paixão, M. W. Eur. J. Org. Chem.
2013, 5917-5922.
24. Johansson, H.; Jørgensen, T. B.; Gloriam, D. E.; Bräuner-Osborne, H.; Pedersen, D. S. RSC Adv.
2013, 3, 945-960.
15