Triarylaminium salt facilitated Friedel-Crafts reaction of indoles with enamides and vinyl ethers

Article abstract of DOI:10.1016/j.tetlet.2013.12.055

Commercially available stable radical cation triarylaminium salt can be used as an efficient initiator for Friedel-Crafts reaction of indoles with enamides to regioselectively construct complex indole derivatives and for double Friedel-Crafts reaction of

Full text of DOI:10.1016/j.tetlet.2013.12.055

Tetrahedron Letters 55 (2014) 954–958
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Triarylaminium salt facilitated Friedel–Crafts reaction of indoles
with enamides and vinyl ethers
⇑
Congde Huo , Lisheng Kang, Xiaolan Xu, Xiaodong Jia, Xicun Wang, Haisheng Xie, Yong Yuan
Key Laboratory of Eco-Environment-Related Polymer Materials Ministry of Education, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou,
Gansu 730070, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Commercially available stable radical cation triarylaminium salt can be used as an efficient initiator for
Friedel–Crafts reaction of indoles with enamides to regioselectively construct complex indole derivatives
and for double Friedel–Crafts reaction of indoles with vinyl ethers to offer 3,30-Bis(indolyl)alkane
derivatives. The ready availability of the starting materials and the usefulness of the products make this
strategy attractive.
Received 13 October 2013
Revised 5 December 2013
Accepted 17 December 2013
Available online 21 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Friedel–Crafts reaction
Indole
Enamide
Vinyl ether
Triarylaminium salt
2-Oxo-1-pyrrolidines1 and indoles2 are both ubiquitous struc-
tural motifs that can be found in many natural products and
marketed drugs. Putting these two heterocyclic skeletons together
has been discovered to exhibit good activities in the therapy of
common diseases such as attention deficit hyperactivity disorder,
cardiac arrhythmia, and asthmatic syndrome.3 However, existing
synthetic methods for these compounds significantly lack effi-
ciency. Friedel–Crafts (FC) alkylation of indole was one of the most
powerful routes to synthesize complex indole derivatives. Great
progress has been made in FC alkylation of indole with electron-
deficient olefins.4 Nevertheless, the applications of electron-rich
olefins in such a reaction still remain a challenge. In recent years,
enamide has attracted considerable attention in organic synthesis
as nucleophile.5 However, the utilization of enamide as electro-
phile was relatively rare.6 The development of an efficient proce-
dure for the alkylation of indoles with electron-rich olefins such
as enamides under mild conditions is highly desired. During our
studies on the stable radical cation salt induced transformations,
we have demonstrated that one electron oxidation can carry out
polarity umpolung and provide unconventional access to various
target molecules.7 So it is expected that FC reaction between elec-
tron-rich heteroarenes such as indoles and electron-rich enamides
may take place by radical cation initiation. As part of our ongoing
program to expand the scope and generality of this chemistry, in
this Letter, we report tris(4-bromophenyl)-aminium hexachloro-
antimonate (TBPA+ꢀSbCl6ꢁ) induced regioselective FC reactions
between indoles and enamides to offer complex indole derivatives.
And we here also report a novel double FC reaction between in-
doles and vinyl ethers to generate 3,30-Bis(indolyl)alkane (BIA)
derivatives.
To begin our study, N-vinylpyrrolidin-2-one (2a) was chosen as
a model substrate to react with indole (1a) in the presence of cat-
alytic amount of TBPA+ꢀSbCl6ꢁ at room temperature. No reaction
was observed in the absence of initiator. But as shown in Table 1,
it was fortunately found that TBPA+ꢀSbCl6ꢁ was sufficient to pro-
mote the reaction; high yield of product 3aa was isolated after a
short reaction time of 0.5 h. It should be noted that the reaction
was regiospecific because only C3-alkylated (from 1a) and Mark-
ovnikov addition (from 2a) product was observed. Solvent effects
and initiator loading were screened and the results are shown
in Table 1ꢁ. The best yield of 3aa was achieved with 2 mol %
TBPA+ꢀSbCl6 in chloroform. In order to avoid the influence of the
trace amount of SbCl5 or any other possibly existing trace amounts
of Lewis acids or Brönsted acids in TBPA+ꢀSbCl6ꢁ, an equimolar
amount of hindered non-nucleophilic base 2,6-di-tert-butylpyri-
dine (DBP) was added as an acid scavenger.8 No obvious inhibition
was observed and the reaction performed as effectively as before
but a little slower (chloroform, rt, 4 h) (Scheme 1).
With the optimal reaction conditions in hand, the scope and
generality of this protocol were investigated using a variety of
indoles and N-vinylamides (Table 2).9 Different indoles were
tested first. Indoles with electron donating groups or electron
⇑
Corresponding author.
E-mail addresses: huocongde@nwnu.edu.cn, huocongde1978@hotmail.com
(C. Huo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.055

C. Huo et al. / Tetrahedron Letters 55 (2014) 954–958
955
Table 1
steric hindrance played a poor role in the reaction. N-Me and N-Bn
protected indoles also gave the corresponding products in high
yields (Table 2, 3ia, 3ja). The scope of the enamide counterpart
in this reaction had also been evaluated. When N-vinylcaprolactam
(2b) and N-vinyl-acetamide (2c) were used, the reaction proceeded
smoothly to afford the desired products in high yields (Table 2,
3ab, 3ib, 3ac, 3ic). However, when N-methyl-N-vinyl-acetamide
(2d) was employed, to our surprise, a double FC reaction occurred
and BIA product 4a was obtained in good yield (84%, Table 3, entry
1). That is to say, N-vinylamides 2d acted as an equivalent of eth-
anal to participate in the construction of BIA structure which had
also been observed by Zhang et al. in 2011.6c This is an interesting
result because 3,30-Bis(indolyl)alkanes (BIAs) were widely isolated
from various terrestrial and marine natural sources which exhibit a
range of important biological activities.10 To extend the scope of
this finding, we next tested vinyl Ethers. To our delight, the reac-
tion of N-vinyl Ethers 2e or 2f with indoles furnished the desired
BIA products 4b–4i with good yields.11 The method was also exam-
ined on a larger scale to evaluate its practicability. The reaction
between N-vinylpyrrolidin-2-one 2a and indole 1a has been
performed on a 20 mmol scale (>2 g each) in a single batch and
no significant yield loss was observed and the reaction was still
completed within half an hour.
Screening of reaction conditionsa
N
N
1a
+
O
O
2a
N
H
N
H
3aa
Conditions
NMR Yieldb (%) (3aa)
2% TBPA+Å, DCM, rt, 0.5 h
2% TBPA+Å, DEM, rt, 0.5 h
2% TBPA+Å, CHCl3, rt, 0.5 h
2% TBPA+Å, MeCN, rt, 0.5 h
2% TBPA+Å, THF, rt, 0.5 h
2% TBPA+Å, MeOH, rt, 0.5 h
5% TBPA+Å, CHCl3, rt, 0.5 h
1% TBPA+Å, CHCl3, rt, 0.5 h
78
83
85
70
NDc
ND
83
80
76
2% TBPA+Å, 2% DBP, DCM, rt, 4 h
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), solvent (1 mL), room tem-
perature, 0.5 h.
b
Yields were determined by NMR spectroscopy.
Not detected by NMR.
c
withdrawing groups on C5, C2 all worked well with N-vinylpyrroli-
din-2-one under the present reaction conditions (Table 2, 3aa–3ja).
The indoles with C2 substituents delivered the corresponding
alykyated indoles in high yields (Table 2, 3ga, 3ha), illustrating that
A plausible radical cation mediated chain mechanism for the
reaction of N-vinylpyrrolidin-2-one with indole is proposed in
Scheme 2. Firstly, N-vinylamide 2a was oxidized by TBPA+ꢀSbCl6ꢁ
R
X
O
R
O
R1
R2
N
R1
R2
OH
O
O
R4
X = O, NH
R
R
R1
R2
R5 R3
N
OH
R3
X
R4
R5
O
O
R1
N
R2
N
R3
O
R4
OR
O
R1
R4
R1
O
R2
R2
R3
O
This work
2a-d
2e-f
R1
N
R4
O
R3
R
R
R
R
R4
O
R2
R1
R2
N
TBPA SbCl6
DCM, rt, 0.5h
TBPA SbCl6
DCM, rt, 0.5h
HN
HN
HN
NH
O
1
4
3
O
O
R1
R2
O
N
HN
HN
NH
R3
Examples of bioactive analogs of 3 & 4
Scheme 1. TBPA+ꢀSbCl6ꢁ induced Friedel–Crafts type reaction.

956
C. Huo et al. / Tetrahedron Letters 55 (2014) 954–958
Table 2
Table 3
Scope of TBPA+ꢀSbClꢁ6 initiated Friedel–Crafts reaction of indoles with enamides
Scope of TBPA+ꢀSbClꢁ6 initiated double Friedel–Crafts reaction of indoles with vinyl
ethers
R1
N
R1
N
2
R2
2
R2
+
R
R4
O
R3
R
R
R
O
O
Conditionsa
R4
N
H
N
H
3
1
Conditionsa
HN
HN
NH
N
N
1
4
O
O
O
N
N
N
HN
N
HN
NH
H
H
O
3aa (85 %), [81 %]b
3ba (81 %)
4a (84 %)
2d
N
N
O
N
N
N
N
N
N
Br
O
O
2d
4b (84 %)
N
H
N
H
3ca (77 %)
3da (74 %)
O
N
2e
4b (75 %)
N
O
N
O
O2N
NC
N
H
O
N
H
N
Bn
N
3ea (66 %)
3fa (61 %)
2e
Bn
Bn
4c (71 %)
N
O
N
O
O
N
N
N
Ph
Ph Ph
4d (77 %)
2e
Ph
N
H
N
H
O2N
O2N
NO2
3ga (78 %)
3ha (72 %)
O
HN
HN
HN
NH
N
N
2e
4e (65 %)
4f (75 %)
O
O
N
N
O
Ph
2f
3ia (88 %)
3ja (82 %)
HN
N
NH
N
O
N
O
O
N
N
2f
N
N
H
4g (67 %)
4h (73 %)
Br
Br
Br
Br
Br
Br
3ab (85 %)
3ib (86 %)
O
H
N
H
N
HN
N
2f
HN
N
NH
O
O
N
N
H
O
3ac (80 %)
3ic (76 %)
N
a Standard reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), TBPA+ꢀSbClꢁ6 (0.02 mmol),
2f
4i (77 %)
CHCl3 (10 mL), room temperature, 0.5 h. Isolated yields were reported in brackets
under every product.
a Standard reaction conditions:
(0.02 mmol), ClCH2CH2Cl (10 mL), room temperature, 1 h. Isolated yields were
reported in brackets under every product.
1 (2.0 mmol), 2 )
(1.0 mmol), TBPA+ꢀSbCl6ꢁ
b 20 mol scale.

C. Huo et al. / Tetrahedron Letters 55 (2014) 954–958
957
H
N
H
N
D
Route I
Route II
N
HN
HN
O
O
HN
B
O
- AcNHMe
C
N
N
NH
HN
HN
E
HN
O
N
A
O
NH
O
F
SET
Initiation
3aa
N
N
HN
HN
NH
O
4a
O
2a or 2d
Scheme 2. Proposed mechanism.
to its radical cation intermediate A, which will serve as an electro-
phile. Indole 1a was then attacked by the above electron deficient
intermediate A to produce the radical cation intermediate B. Inter-
mediate B was then transferred to intermediate C after a hydrogen
extraction. Intermediate C would then undergo the second electron
transfer from substrate 2a to produce the products 3aa and regen-
erate a new radical cation intermediate A at the same time. Chain
propagation continued until all substrates were converted to the
products. When 2d was hired, Intermediate B would first undergo
a fragmentation to generate intermediate E. Intermediate E was
then attacked by another molecule of indole to produce the radical
cation intermediate F. Intermediate F would then undergo the sec-
ond electron transfer from substrate 2d to produce the products 4a
and regenerate a new radical cation intermediate A at the same
time.
In summary, we have demonstrated that enamides can be used
as useful electrophiles in the stable radical cation salt initiated FC
alkylation of indoles. This atom-economical and environmentally
friendly procedure uses an inexpensive nonmetal catalyst with
low loadings and establishes a new type of FC alkylation between
indoles with enamides. And we have also developed a simple and
highly efficient approach to construct pharmaceutically active
BIA compounds through TBPA radical cation induced double FC
reaction of indoles with vinyl ethers. Applications of this method-
ology to other reactions are currently under investigation in our
laboratory.
References and notes
1. Chu, X.-Q.; Wang, S.-Y.; Ji, S.-J. RSC Adv. 2013, 3, 8380. and references cited
therein.
2. (a) The Chemistry of Heterocyclic Compounds; Taylor, E. C., Saxton, J. E., Eds.;
Wiley-Interscience: New York, 1994; Vol. 25, (b) Sundberg, R. J. Indoles;
Academic: New York, 1996; (c) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005,
22, 761; (d) Saracoglu, N. Top. Heterocycl. Chem. 2007, 11, 145; (e) Horton, D. A.;
Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (f) Humphrey, G. R.;
Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (g) Ueda, H.; Satoh, H.; Matsumoto, K.;
Sugimoto, K.; Fukuyama, T.; Tokuyama, H. Angew. Chem., Int. Ed. 2009, 48, 7600;
(h) Garg, N. K.; Sarpong, R.; Stoltz, B. M. J. Am. Chem. Soc. 2002, 124, 13179.
3. (a) Kenda, B.; Quesnel, Y.; Ates, A.; Michel, P.; Turet, L.; Mercier, J.
WO2006128693, 2006; (b) Gobert, J.; Geerts, J.-P.; Bodson, G. EP0162036, 1985.
4. (a) Yang, H.; Hong, Y.-T.; Kim, S. Org. Lett. 2007, 9, 2281; (b) Bartoli, G.;
Bartolacci, M.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L.;
Torregiani, E. J. Org. Chem. 2003, 68, 4594; (c) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.;
Zhou, Q.-L. J. Org. Chem. 2006, 71, 75; (d) Yasuda, M.; Somyo, T.; Baba, A. Angew.
Chem., Int. Ed. 2006, 45, 793; (e) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 10250; (f) Rozenman, M. M.; Kanan, M. W.; Liu, D. R. J. Am. Chem. Soc.
2007, 129, 14933.
5. (a) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45,
2254; (b) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546;
(c) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett.
2009, 11, 4620; (d) Zu, L.; Xie, H.; Li, H.; Wang, J.; Yu, X.; Wang, W. Chem. Eur. J.
2008, 14, 6333; (e) Baudequin, C.; Zamfir, A.; Tsogoeva, S. B. Chem. Commun.
2008, 4637.
6. (a) Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292; (b) Jia, Y.-X.;
Zhong, J.; Zhu, S.-F.; Zhang, C.-M.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2007, 46,
5565; (c) Niu, T. M.; Huang, L. H.; Wu, T. X.; Zhang, Y. H. Org. Biomol. Chem.
2011, 9, 273; (d) Jiang, R.; Wu, X.-J.; Zhu, X.; Xu, X.-P.; Ji, S.-J. Eur. J. Org. Chem.
2010, 5946; (e) Jiang, R.; Xu, H.-Y.; Xu, X.-P.; Chu, X.-Q.; Ji, S.-J. Org. Biomol.
Chem. 2011, 9, 5659.
7. (a) Huo, C.; Xu, X.; An, J.; Jia, X.; Wang, X.; Wang, C. J. Org. Chem. 2012, 77, 8310;
(b) Huo, C.; Xu, X.; Jia, X.; Wang, X.; An, J.; Sun, C. Tetrahedron 2012, 68, 190; (c)
Huo, C.; An, J.; Xu, X.; Jia, X.; Wang, X.; Kang, L. Tetrahedron Lett. 2013, 54, 1145;
(d) Huo, C.; An, J.; Chang, W.; Jia, X.; Kang, L.; Wu, M. Tetrahedron 2013, 69,
6375; (e) Huo, C.; Sun, C.; Hu, D.; Jia, X.; Xu, X.; Liu, Z. Tetrahedron Lett. 2011, 52,
7008; (f) Huo, C.; Wei, R.; Zhang, W.; Yang, L.; Liu, Z. Synlett 2005, 161–163; (g)
Huo, C.; Jia, X.; Zhang, W.; Yang, L.; Liu, Z. Synlett 2004, 251–254.
8. (a) Reynolds, D. W.; Lorenz, K. T.; Chiou, H.-S.; Bellville, D. J.; Pabon, R. A.; Bauld,
N. L. J. Am. Chem. Soc. 1987, 109, 4960; (b) Gassman, P. G.; Singleton, D. A. J. Am.
Chem. Soc. 1984, 106, 7993; (c) Bellville, D. J.; Wirth, D. W.; Bauld, N. L. J. Am.
Chem. Soc. 1981, 103, 718.
Acknowledgment
We thank the National Natural Science Foundation of China
(21262029, 21002080) and the Natural Science Foundation of
Gansu Province (1107RJYA026) for financially supporting this
work.
9. General procedure for TBPA+ꢀSbClꢁ6 induced reaction of indoles with
enamides. Indole (1, 1 mmol) and N-vinylpyrrolidin-2-one (2, 1 mmol) were
dissolved in CHCl3 (10 mL) at ambient temperature; TBPA+ꢀSbCl6ꢁ (0.02 mmol)
was then added in one portion under stirring. The reactions were performed
at room temperature and completed within 0.5 h as monitored by TLC.
The products were isolated by column chromatographic separation.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.12.
055.

958
C. Huo et al. / Tetrahedron Letters 55 (2014) 954–958
Representative spectral data for the product: 1-(1-(1H-indol-3-
11. General procedure for TBPA+ꢀSbClꢁ6 induced reaction of indoles with vinyl
ethers. Indoles (1, 2 mmol) and vinyl ethers (2, 1 mmol)ꢁwere dissolved in
ClCH2CH2Cl (10 mL) at ambient temperature; TBPA+ꢀSbCl6 (0.02 mmol) was
then added in one portion under stirring. The reactions were performed at
room temperature and completed within 1 hour as monitored by TLC. The
products were isolated by column chromatographic separation. Representative
spectral data for the product: 3,30-(ethane-1,1-diyl)bis(1H-indole) (4a).
(218 mg, 84%). white solid. 1H NMR (400 MHz, CDCl3) d 7.82 (s, 2H), 7.61 (d,
J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.6 Hz,
2H), 6.91 (s, 2H), 4.71 (q, J = 7.2 Hz, 1H), 1.84 (d, J = 7.2 Hz, 3H). HRMS (EI) Calcd
for C18H16N2: [M]+ 260.1313; Found, 260.1320.
yl)ethyl)pyrrolidin-2-one (3aa). (194 mg, 85%). White solid. 1H NMR
(400 MHz, CDCl3) d 8.56 (s, 1H), 7.64 (d, J = 8.0 Hz,1H), 7.39 (d, J = 8.0 Hz,
1H), 7.21 (t, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.11 (t, J = 7.6 Hz, 1H), 5.80 (q,
J = 7.0 Hz, 1H), 3.28 (dt, J = 9.0, 5.6 Hz, 1H), 2.88 (dt, J = 9.0, 5.6 Hz, 1H), 2.45
(m, 2H), 1.93 (m, 1H), 1.80 (m, 1H), 1.61 (d, J = 7.0 Hz, 3H). HRMS (EI) Calcd
for C14H16N2O: [M]+ 228.1263; Found, 228.1268.
10. (a) Huo, C.; Sun, C.; Wang, C.; Jia, X.; Chang, W. ACS Sustainable Chem. Eng. 2013,
1, 549; (b) Huo, C.; Wang, C.; Sun, C.; Jia, X.; Wang, X.; Chang, W.; Wu, M. Adv.
Synth. Catal. 2013, 355, 1911; (c) Shiri, M.; Zolfigol, M. A.; Kruger, H. G.;
Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250. and references cited therein.