Enantioselective Friedel-Crafts alkylation of indole with nitroalkenes in the presence of bifunctional squaramide organocatalysts

Article abstract of DOI:10.1016/j.tetlet.2021.153153

A series of chiral bifunctional quinine and 2-aminoDMAP based squaramide organocatalysts are evaluated in Friedel-Crafts alkylation of indoles with nitroolefins. These 3-substituted indole derivatives are synthesized in the presence of sterically encumber

Full text of DOI:10.1016/j.tetlet.2021.153153

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective Friedel-Crafts alkylation of indole with nitroalkenes in
the presence of bifunctional squaramide organocatalysts
⇑
Esra Dündar, Cihangir Tanyeli
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of chiral bifunctional quinine and 2-aminoDMAP based squaramide organocatalysts are evalu-
ated in Friedel-Crafts alkylation of indoles with nitroolefins. These 3-substituted indole derivatives are
synthesized in the presence of sterically encumbered tert-butyl squaramide/quinine with high enantios-
electivity (up to >99% ee) and moderate chemical yields (up to 80%) by representing as chiral precursors
for very important biologically active molecules. Besides, this asymmetric transformation provides a very
simple, efficient, clean and environmental friendly route. In addition, this process has very mild reaction
conditions such as ambient temperature and usage of only 2 mol% catalyst loading compared to previous
studies in literature.
Received 12 March 2021
Revised 29 April 2021
Accepted 3 May 2021
Available online xxxx
Keywords:
Asymmetric synthesis
Organocatalysis
Squaramide organocatalyst
Friedel-Crafts alkylation
Indole
Ó 2021 Elsevier Ltd. All rights reserved.
Introduction
different 3-substituted indole derivatives with up to 50% ee, by
using 10–20 mol% catalyst loading at À30 °C. After two years,
The Friedel-Crafts alkylation is one of the most substantial reac-
tion type to construct a new CAC bond in organic chemistry [1].
Due to indole’s unique structure in pharmaceutical environment
[2], and chemical diversity of nitro unit of nitroalkenes [3], these
compounds are precious starting materials for many synthetic
transformations. The Friedel-Crafts alkylation of indole with
nitroalkenes is a key reaction in order to get 3-substituted indole
derivatives which are useful intermediates for biologically active
compounds such as tryptamines [4], and 1,2,3,4-tetrahydro-b-car-
bolines [5]. The asymmetric version of this reaction is catalyzed
mostly by the combination of ligands and metal complexes [6],
charged organocatalysts [7] and inorganic materials [8]. Moreover,
the organocatalysis which environmental friendly side was tested
firstly by Ricci [9] et al. in 2005 in the presence of a simple thiourea
organocatalyst with the usage of 20 mol% and synthesized 3-sub-
stitued indole derivatives with high enantioselectivities (up to
89% ee) at À24 °C. In the same year, this asymmetric Friedel-Crafts
alkylation reaction was catalyzed with H-bonding bis-sulfon-
amides by Jorgensen [10] and his co-workers. They reached up to
only 63% ee in the presence of 2 mol% sulfonamides at À24 °C
and then, made recrystallization in order to increase the enantios-
electivities. In 2006, bis-aryl thioureas were used as organocata-
lysts by Connon [11] et al. in that reaction. They synthesized 7
almost under the same harsh reaction conditions (10% mol catalyst
loading at À35 °C with benzene and DCE as solvent system) with
Connon, the phosphoric acid was tested in model reaction by
Akiyama [12] et al. They managed to synthesize 14 different prod-
ucts with high enantioselectivities up to 94% and moderate yields.
In 2011, Zhang [13] and his co-workers used the 5 mol% phospho-
ric acids in the Friedel-Crafts alkylation. Unfortunately, they only
managed to reach up to 47% ee with 23 different products at
20 °C. In 2016, Chen [14] et al. synthesized 12 different 3-substi-
tuted indole derivatives in the presence of 10 mol% secondary
amine-amide organocatalyst with high enantioselectivities (up to
95% ee) and chemical yields at 35 °C (Scheme 1). In spite of these
reports, a great demand has still been going on for improving the
reaction conditions of that Friedel-Crafts alkylation of indole with
nitroolefins.
Chiral bifunctional squaramides as an example to Brønsted
base/H-bond donor organocatalysts are pioneered by Rawal [15]
and since then, are being improved as well as tested in different
type of reactions. In our research group, chiral bifunctional squar-
amides were synthesized [16–18] and evaluated named reactions
such as Michael additions [17], Aza-Henry [19], Friedel-Crafts
[20], Mannich reactions [21], and Sulfa-Michael addition [22].
Inspired by these studies, the Friedel-Crafts alkylation of indoles
with nitroalkenes was tested in the presence of chiral bifunctional
squaramides in order to improve the reaction conditions.
⇑
Corresponding author.
E-mail address: tanyeli@metu.edu.tr (C. Tanyeli).
https://doi.org/10.1016/j.tetlet.2021.153153
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: E. Dündar and C. Tanyeli, Enantioselective Friedel-Crafts alkylation of indole with nitroalkenes in the presence of bifunctional
squaramide organocatalysts, Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153153

E. Dündar and C. Tanyeli
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. A literature comparison of Ic in organocatalysis 1a + 2a.
Table 1
Optimization Study.a
Entry
Cat.
Solvent
Cat. Load. (mol%)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ia
Ib
Ic
Id
IIa
IIb
Ia
Ib
Ic
Ic
Ic
Ic
Ic
Ic
Ic
Ic
Ic
Ic
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
2
2
2
2
2
2
5
5
5
10
2
2
2
2
2
2
2
2
45
47
24
24
44
44
45
45
24
24
51
44
92
51
46
2
16
18
45
14
56
42
20
19
38
54
44
24
trace
26
34
32
26
23
77
84
91
8
rac
12
81
88
89
91
72
78
56
82
78
71
84
88
9
DCM
DCM
10
11
12
13
14
15d
16e
17f
18g
Chloroform
Xylene
Dioxane
Toluene
Toluene
DCM
DCM
DCM
46
48
a
Reaction conditions: 1a (0.2 mmol, 1 eq.), 2a (0.2 mmol, 1 eq.), catalyst, DCM (0.5 mL).
Isolated yields.
b
c
d
e
f
Determined by HPLC with chiral stationary phase.
Temperature is 50 °C.
H+ sponge is used as an additive.
NaOAc is used as an additive.
Concentration is 1 M.
g
2

E. Dündar and C. Tanyeli
Tetrahedron Letters xxx (xxxx) xxx
Results and discussion
Chiral bifunctional quinine (Ia, Ib, Ic and Id) and 2-AminoDMAP
(IIa and IIb) based squaramide organocatalysts were evaluated in
our model Friedel-Crafts alkylation of indole (1a) with trans-b-
nitrostyrene (2a).
Scheme 2. Friedel-Crafts Alkylation of Pyrrole (4a) with trans-b-nitrostyrene (2a).
Firstly, all six organocatalysts were tested in that reaction by
using 2 mol% catalyst loading in DCM at room temperature. While
organocatalysts (Ia, Ib, and Ic) afforded the product 3aa with high
enantioselectivity values (Table 1, entries 1–3, respectively),
organocatalysts (Id, IIa and IIb) gave nearly racemic product 3aa
(Table 1, entries 4–6, respectively).
Further optimization studies continued with quinine based
squaramide organocatalysts. Due to low chemical yield values with
2 mol%, we increased the catalyst loading to 5 mol% and 10 mol%
(Entries 7–10, respectively). By comparing the results with 2 mol
%, no improvement was observed in terms of chemical yield and
reaction duration parameters whereas a slight increase in ee values
for organocatalyst Ia and Ib as 77% to 81% and 84% to 88% (Entries
7–8, respectively). In the light of these data, organocatalyst Ic was
chosen as the best one for Friedel-Crafts alkylation of indole (1a)
with trans-b-nitrostyrene (2a) in terms of enantioselectivity and
chemical yield. In the further optimization studies, although the
effect of solvent (Entries 11–14), temperature (Entry 15), additive
(Entry 16–17) and concentration (Entry 18) were investigated,
we could not get better result than entry 3.
Fig. 1. A proposed transition state model.
Most of nitroolefins bearing either electron-donating or with-
drawing groups afforded the Friedel-Crafts alkylation product
[23] with excellent enantioselectivities (up to 92%) and moderate
chemical yield values (up to 80%). However, the thienyl substituted
product 3ag resulted in lower enantioselectivity value compared to
With the optimized condition in hand, the scope of the stereos-
elective organocatalytic Friedel-Crafts alkylation reaction was
explored using 14 nitroolefin and 4 indole derivatives to observe
the effect of electron-donating and electron-withdrawing groups.
The results were summarized in Table 2.
Table 2
Derivatization Study.a
Entry
Indole
R1
R2
R3
Product
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5-OBn
7-OBn
7-Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ba
3ca
3da
3eb
24
44
46
49
51
28
30
47
50
42
47
24
54
54
46
46
47
24
45
27
38
32
22
74
78
80
78
57
37
33
49
79
63
55
43
15
91
85
91
87
89
87
56
90
80
74
92
77
76
69
73
67
>99
18
4-MeOC6H4 (2b)
4-MeC6H4 (2c)
4-ClC6H4 (2d)
4-BrC6H4 (2e)
2-Furyl (2f)
2-Thienyl (2g)
2-ClC6H4 (2h)
2-MeOC6H4 (2i)
3-BrC6H4 (2j)
3-MeOC6H4 (2k)
2,4-(Cl)2C6H3 (2l)
2,5-(MeO)2C6H3 (2m)
2-PhCH2OC6H4 (2n)
Ph (2a)
9
10
11
12
13
14
15
16
17
18
Ph (2a)
Ph (2a)
4-MeOC6H4 (2b)
a
b
c
Reaction conditions: 1a-1e (0.2 mmol, 1 eq.), 2a-2n (0.2 mmol, 1 eq.), catalyst, DCM (0.5 mL).
Entries 1–11, Conversions, determined by GC–MS & entries 12–18, Isolated yields.
Determined by HPLC with chiral stationary phase.
3

E. Dündar and C. Tanyeli
Tetrahedron Letters xxx (xxxx) xxx
other derivatives (Table 2, entry 7). The stereoselectivity of Friedel-
Crafts reactions were apparently insensitive to the substitution
pattern on aromatic ring (o-, m-, or p-) of nitroolefins, as well as
the electronic nature (entries 1–14 of Table 2).
Also, indole derivatives [24] and pyrrole were tested (Table 2,
entries 15–18 & Scheme 2).
The absolute configuration of products 3aa-3eb and 5aa were
assigned as S by comparing HPLC data and optical rotation values
with literature.[7d,6h,6k,8c,7c] We proposed a transition state
model in Fig. 1 to understand the selectivity of Friedel-Crafts alky-
lation of indole (1a) with trans-b-nitrostyrene (2a) in the presence
of bifunctional quinine derived squaramide organocatalyst Ic. In
this model, the deprotonation of indole (1a) occurs by a H-bond
interaction with the basic part of the catalyst while acidic part acti-
vates the trans-b-nitrostyrene (2a) through double H-bond. Then,
coordinated indole (1a) to basic site of organocatalyst Ic attacks
the re-face of the activated trans-b-nitrostyrene (2a) and give the
expected product. This transition state model is supported with
entry 2 and 18 of Table 2.
References
[1] G.A. Olah, R. Khrisnamurti, G.K.S. Prakash, Comprehensive Organic Synthesis,
Pergamon Press, New York, 1991.
[2] a) J.F. Austin, D.W.C. MacMillan, J. Am. Chem. Soc. 124 (2002) 1172–1173;
b) A. Kleeman, J. Engel, B. Kutscher, D. Reichert, Pharmaceutical Substances,
Thieme, New York, 2001.
[3] N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001.
[4] a) J.P. Yevic, F.D. Zocca, Curr. Med. Chem. 4 (1997) 295–312;
b) J. Arendt, S. Deacon, Chronobiol. Int. 14 (1997) 185–204.
[5] H.J. Zhu, B.T. Zhao, G.Y. Zuo, C.U. Pittman, W.M. Ma, X. Hao, J. Tetrahedron:
Asymmetry. 12 (2001) 2613–2619.
[6] a) Liu, H.; Du, M. D. Adv. Synth. Catal. 2010, 352, 1113 – 1118. (b) Kim, H. Y.;
Kim, S.; Oh, K. Angew. Chem. Int. Ed. 2010, 49, 4476-4478. (c) Li, W. J. Catal.
Commun. 2014, 52, 53–56. (d) Liu, H.; Lu, S. F.; Xu, J.; Du, D. M. Chem. Asian J.
2008, 3, 1111-1121. (e) Guo, F.; Lai, G.; Xiong, S.; Wang, S.; Wang, Z. Chem. Eur.
J. 2010, 16, 6438 – 644. (f) Jia, Y. X.; Zhu, S. F.; Yang, Y.; Zhou, Q. L. J. Org. Chem.
2006, 71, 75-80. (g) O’Reilly, S.; Aylward, M.; Keogh-Hansen, C.; Fitzpatrick, B.;
McManus, H. A.; Müller-Bunz, H.; Guiry, P. J. J. Org. Chem. 2015, 80,
10177À10186. (h) Venkatanna, K.; Kumar, S. Y.; Karthick, M.; Padmanaban,
R.; Ramanathan, C.R. Org. Biomol. Chem. 2019, 17, 4077–4086. (i) Wu, J.; Li, X.;
Wu, F.; Wan, B. Org. Lett. 2011, 13, 4834-4837. (j) Sato, T.; Arai, T. Synlett 2014,
25, 349–354. (k) Islam, M. S.; Majid, A. M. A.; Al-Othman, Z. A.; Barakat, A.
Tetrahedron: Asymmetry. 2014, 25, 245–251.
[7] (a) J. Ma, S.R. Kass, J. Org. Chem. 84 (2019) 11125–11134;
(b) Y. Fan, S.R. Kass, J. Org. Chem. 82 (2017) 13288–13296;
(c) A.K. Chittoory, G. Kumari, S. Mohapatra, P.P. Kundu, T.K. Maji, C. Narayana,
S. Rajaram, Tetrahedron 70 (2014) 3459–3465;
Conclusion
(d) M. Madhu Ganesh, D. Seidel, J. Am. Chem. Soc. 130 (2008) 16464–16465.
[8] (a) H. Xiong, L. Li, E. Liu, J. Cheng, G. Zhang, Inorg. Chem. Commun. 84 (2017)
24–27;
To sum up, the Friedel-Crafts alkylation of indoles with nitroo-
lefins was tested in the presence of sterically encumbered tert-
butyl squaramide/quinine in this study. By usage of different
nitroolefin and indole derivatives, 3-substituted indole products
were synthesized with excellent enantioselectivities (up to >99%
ee) and moderate chemical yields (up to 80%) by carrying out the
reaction at room temperature and only using 2 mol% catalyst
loading.
(b) G. Zhang, Inorg. Chem. Commun. 40 (2014) 1–4;
(c) C. Didaskalou, J. Kupai, L. Cseri, J. Barabas, E. Vass, T. Holtzl, G. Szekely, ACS
Catal. 8 (2018) 7430–7438.
[9] P.R. Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew. Chem. Int. Ed. 44 (2005)
6576–6579.
[10] W. Zhuang, R.G. Hazell, K.A. Jørgensen, Org. Biomol. Chem. 3 (2005) 2566–
2571.
[11] M.E. Fleming, T. McCabe, S.J. Connon, Tetrahedron Lett. 47 (2006) 7037–7042.
[12] J. Itoh, K. Fuchibe, T. Akiyama, Angew. Chem. Int. Ed. 47 (2008) 4016–4018.
[13] H.Y. Tang, Z.B. Zhang, Phosphorus Sulfur, and Silicon 186 (2011) 2038–2046.
[14] K. Huang, X. Pei, X. Yin, Z. Chen, J. Asian, Org. Chem. 29 (2017) 595–600.
[15] J.P. Malerich, K. Hagihara, V.H. Rawal, J. Am. Chem. Soc. 130 (2008) 14416–
14417.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
[16] M. Isßık, M.Y. Unver, C. Tanyeli, J. Org. Chem. 80 (2015) 828–835.
[17] E. Kanberog˘lu, C. Tanyeli, J. Asian, Org. Chem. 5 (2016) 114–119.
[18] W. Yang, D.M. Du, Org. Lett. 12 (2010) 5450–5453.
[19] D. Susam, C. Tanyeli, New J. Chem. 41 (2017) 3555–3561.
[20] S. Karahan, C. Tanyeli, New J. Chem. 41 (2017) 9192–9202.
Acknowledgement
_
[21] (a) D. Ißsibol, S. Karahan, C. Tanyeli, Tetrahedron Lett. 59 (2018) 545–546;
(b) S. Karahan, C. Tanyeli, Org. Biomol. Chem. 18 (2020) 479–487.
[22] D. Hasılcıog˘ulları, C. Tanyeli, Tetrahedron Lett. 59 (2018) 1414–1416.
[23] A.V. Kumar, K.R. Rao, Tetrahedron Lett. 52 (2011) 5188–5519.
[24] (a) R.J. Tang, T. Milcent, B. Crousse, RSC Adv. 8 (2018) 10314–10317;
(b) E.A. Hall, L.R. Redfern, M.H. Wang, K.A. Scheidt, ACS Catal. 6 (2016) 3248–
3252.
_
We are grateful to TÜBITAK for financial support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153153.
4