FeCl3 catalyzed intermolecular reaction between enol ethers and anilines: Access to 2,3-substituted indoles through aryl group migration

Article abstract of DOI:10.1016/j.tetlet.2020.152583

An intermolecular FeCl₃ catalyzed reaction between anilines and enol ethers is described. A variety of enol ethers and aromatic amines undergo a C[sbnd]C bond formation followed by cyclization via C[sbnd]N bond formation to afford the 2,3-disubstituted indoles, involving an unexpected aryl group migration. In this methodology, anilines act as bis-nucleophiles, wherein the initial attack occurs at the α-position of enol ether from the ortho position of aniline followed by the subsequent reaction of the amine moiety of aniline at the β-position, leading to the indole framework. This method is simple, obviates the use of expensive/hazardous transition-metal catalysts, and offers a wide range of substrate scope.

Full text of DOI:10.1016/j.tetlet.2020.152583

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FeCl3 catalyzed intermolecular reaction between enol ethers and anilines: Ac‐
cess to 2,3-substituted indoles through aryl group migration
Tapan Kumar Jena, Faiz Ahmed Khan
PII:
S0040-4039(20)31082-0
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152583
TETL 152583
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15 October 2020
19 October 2020
Please cite this article as: Jena, T.K., Khan, F.A., FeCl3 catalyzed intermolecular reaction between enol ethers and
anilines: Access to 2,3-substituted indoles through aryl group migration, Tetrahedron Letters (2020), doi: https://
doi.org/10.1016/j.tetlet.2020.152583
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FeCl3 catalyzed intermolecular reaction between enol ethers
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through aryl group migration
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Tapan Kumar Jena and Faiz Ahmed Khan*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
FeCl3 catalyzed intermolecular reaction between enol ethers and anilines: Access
to 2,3-substituted indoles through aryl group migration
Tapan Kumar Jena, Faiz Ahmed Khan
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi, Sangareddy, Telangana 502285, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An intermolecular FeCl3 catalyzed reaction between anilines and enol ethers is described. A
variety of enol ethers and aromatic amines undergo a C-C bond formation followed by
cyclization via C-N bond formation to afford the 2,3-disubstituted indoles, involving an
unexpected aryl group migration. In this methodology, anilines act as bis-nucleophiles, wherein
the initial attack occurs at the α-position of enol ether from the ortho position of aniline followed
by the subsequent reaction of the amine moiety of aniline at the β-position, leading to the indole
framework. This method is simple, obviates the use of expensive/hazardous transition-metal
catalysts, and offers a wide range of substrate scope.
Available online
Keywords:
Methyl enol ethers
Indoles
2009 Elsevier Ltd. All rights reserved.
C-C, C-N bond
Aryl group migration
alternative method for Fischer indole synthesis was demonstrated
by Buchwald group from arylhydrazones and halo arenes.9 Pd-
Introduction:-
Indole nucleus is a ubiquitous structural motif present in
numerous natural products and pharmaceutically related
compounds, and its syntheses attract much interest. In the field of
natural products, compounds in clinical trials and marketed drugs
are filled with molecules containing indole moiety in their
structures as exemplified in Figure 1.1 As a result, many methods
have been utilized to synthesize the indole derivatives, as
evidenced in the literature.2 Among them, C2- and C3-
disubstituted indoles are of great interest due to the virtue of
leading to discovery of interesting biological functions.3 The
broad applicability of this heterocycle system continues to hold a
fascination for a chemist to develop an efficient methodology.
catalyzed indolization of haloanilines with alkynes also used for
the syntheses of disubstituted indole derivatives.10 Ring-opening
strategy of 2H-azirines also involved for the construction of 2,3-
disubstituted indoles.11 Synthesis of 3-substituted indoles via a
1,2-aryl shift was also explored in the literature.12 An acid-
catalyzed two-step synthesis of azaindole derivatives was
demonstrated by Hoelder and co-worker from chloroamino-N-
heterocycles and Ethoxyvinylborolane through Suzuki-Miyaura
coupling reaction.13 Although many routes are available for the
construction of indole derivatives, but for the synthesis of 2-
methyl-3-aryl or 2,3-diaryl indoles from methyl enol ethers via
aryl group migration has remained unexplored. In continuation of
our earlier work on enol ether, where it was used as a
nucleophile,14 as well as an electrophile,15 herein, we report an
acid-catalyzed novel method for the synthesis of 2-methyl-3-aryl
substituted indoles from methyl enol ethers and anilines through
aryl group migration.
In past decades several methods have been described from a
variety of substrates to synthesize indole derivatives, which
includes Fischer indole synthesis,4a-4c Rh (I) catalyzed reaction of
N-propargylanilines,4d oxidative coupling of alkynes with
acetanilides,4e transition metal-catalyzed intermolecular C-H
functionalization,4f-4j and among them few are shown in Scheme
1. Similarly, other metal-catalyzed intramolecular reactions were
also well explored. In this context, palladium-catalyzed reactions
which involve, oxidative cyclization of N-arylenamines,5,6
microwave-assisted reaction via intramolecular arene-olefin
coupling,7 amination of aromatic C-H bonds with oxime
acetates,8 being used in the reactions. While other advanced
syntheses of these moieties were also reported, however,
Figure 1. Biologically active 2,3-disubstituted indole scaffold.
intermolecular synthesis of indole attracts much interest. An
———
 Corresponding author. Tel.: (040) 2301 6084; e-mail: faiz@chy.iith.ac.in

2
Tetrahedron
7
8
9
FeCl3 (0.2) CH3NO2
90
90
90
18
8
52
83
57
FeCl3 (0.5) CH3NO2
Bi(OTf)3
(0.5)
CH3NO2
CH3NO2
CH3NO2
18
10
11
BF3.OEt2
(0.5)
90
90
13
24
37
pTSA
ND
(0.5)
12
13
TFA (0.5)
CH3NO2
CH3NO2
90
90
24
24
ND
ND
MsOH
(0.5)
14
TfOH
(0.5)
CH3NO2
90
24
Tracec
Scheme 1. Previous reports
15
16
FeCl3 (0.3) CH3NO2
FeCl3 (0.4) CH3NO2
50
70
14
11
57
64
Results and Discussion
Previously, we have synthesized thiazolines using thiourea as a
nucleophile with methyl enol ethers via C-N and C-S bond
formation. In continuation of this, we became interested to know
the reactivity of methyl enol ethers using aniline as nucleophilic
source. Our initial attempts furnished an unexpected product
which was identified as 2-methyl-3-aryl indole, formed via aryl
group migration. Further, to improve the yield, several
optimizations were carried out using different solvents,
temperatures, and catalysts (Table 1) and compound 1a (1-
methoxy- 4-(1 methoxyprop-1-en -2-yl)benzene and 4-methoxy
aniline (2a) were chosen as a model substrate.
aReaction conditions: 1a (0.393 mmol), 2a (0.589 mmol),
catalyst (quantity noted), solvent (4 mL) under N2 atm. Isolated
yield after column chromatography. AT = Ambient temperature.
ND = Not detected. cTLC observation with authentic compound.
b
Initially, different acids such as pTSA, TfOH, TFA, MsOH, in
DCM (dichloromethane) at ambient temperature were tried and
found to be inactive for the product formation (Table 1, entries 1-
4). Lewis acid such as FeCl3 in the presence of solvent CH3CN
(acetonitrile) also remains inactive even up-to reflux temperature
(Table 1, entries 5 and 6). Gratifyingly, FeCl3 (20 mol%) in
nitromethane (CH3NO2) found to be effective in delivering an
interesting new product with aryl group migration from enol
ether to form 3a in 52% yield (entry 7, Table 1). When the
reaction was performed by using FeCl3 (50 mol%) in CH3NO2 at
Table 1. Optimization for reaction conditionsa
o
90 C, the yield has improved to 83% (entry 8, Table 1). Lewis
acids like Bi(OTf)3 and BF3.OEt2 also catalyze the reactions
(entries 9 and 10, Table 1), although they were not as effective as
FeCl3. The screening of solvents indicates that only CH3NO2 is
promoting the product formation, and in other solvents such as
CH2Cl2 (DCM), CH3CN unreacted starting materials were
observed. Bronsted acids like pTSA, TFA, MsOH didn’t furnish
the product, while TfOH gave traces (entries 11-14, Table 1).
Optimizations conducted using 30 mol% and 40 mol% of FeCl3
at 50 oC and 70 oC respectively (entries 15-16), furnished
moderate yields. After screening different acids, anhydrous FeCl3
was found to exhibit the highest reactivity. The evaluation of the
Entry
Catalyst
(equiv)
Solvent
Temp Time Yield
(oC)
(h)
(%)b
1
2
pTSA
(0.5)
DCM
DCM
AT
24
ND
TfOH
(0.5)
AT
24
ND
3
4
TFA (1.0)
DCM
DCM
AT
AT
24
12
ND
ND
o
substrate scope was then carried out in CH3NO2 at 90 C, using
0.5 equivalent of FeCl3 as the catalyst (Table 1 entry 8).
MsOH
(0.5)
Having optimized condition in our hand, we examined
different substituted anilines as shown in Scheme 2. Electron-
donating, as well as electron-withdrawing groups on anilines, are
well tolerated in this method (3a-3k, Scheme 2). First,
compounds with donating (–OMe) substituents on aryl group of
5
6
FeCl3 (0.2)
FeCl3 (0.2)
CH3CN
CH3CN
AT
12
12
ND
ND
reflux

3
aniline (2a, 2b) were reacted with compound 1a under the
optimized reaction condition and gave the products 3a-3b in
good yields. Similarly, simple aniline as well as alkyl substituted
anilines also delivered the indole derivatives as expected (3c-3i)
in good yields. Moderate electron-withdrawing substituents like –
F, -Br group on anilines reacted smoothly with 1a and gave the
products 3j and 3k in moderate yields. However, no product
formation achieved when p-niroaniline was reacted with
compound 1a under the optimized condition. One of the
synthesized compound 3c was also confirmed with single crystal
X-ray analysis.
aReaction conditions: 1 (0.4 mmol), 2a (0.6 mmol), catalyst (0.5
b
equiv), solvent (4 mL) under N2 atm. for 4-18 h. Isolated yield
after column chromatography.
Scheme 3. Substrate scope of enol ether.
Based on the products obtained from the scope of enol ethers
and anilines, a plausible mechanism can be rationalized as
follows in Scheme 4. Initially, in the presence of Fe-catalyst
could facilitate the attack of C-nucleophile from the ortho
position of aniline to the α-position of enol ether to form the
intermediate A. The intermediate A where the imine nitrogen is
present would undergo tautomerization to furnish the
intermediate B. Further, formation of intermediate C would take
place via attack of oxygen lone pair of OMe group to the “Fe”
metal. In the next step, intermediate C may trigger anchimeric
assistance followed by N-nucleophile attack, resulting in aryl
migration, to give the intermediate D. In the last step, MeOH
elimination would take place to deliver the indole derivatives 3 or
4.
aReaction conditions: 1a (0.4 mmol), 2 (0.6 mmol), catalyst (0.5
equiv), solvent (4 mL) under N2 atm. for 4-18 h. Isolated yield
b
after column chromatography.
Scheme 2. Substrate scope of aromatic amines.
Further to extend the scope of the reactions, different substituted
enol ethers were reacted with compound 2a. As shown in
Scheme 3, electron-donating and electron-withdrawing
substituted enol ethers reacted well under the optimized reaction
condition, and afforded the expected product in moderate to good
yields. First, acetophenone derived enol ethers with methoxy
substituent underwent the reactions and gave the indole
derivatives in good yields (4a-4d, Scheme 3). Alkyl substituted
enol ether reacted moderately and yielded the indole derivatives
(4e and 4f) in 67% and 66% respectively. Simple acetophenone
derived enol ether (1h) also furnished the indole derivative (4g)
in moderate yield. Compound 1 with substituents like –F, -Cl,
were successfully transformed into the expected indole products
(4h and 4i) in 60% and 62% yields, respectively. Unfortunately,
indole formation was not observed with 3-nitroacetophenone
derived enol ether. Benzophenone derived enol ethers also
furnished the product in good yields (4j, 4k).
Scheme 4. Plausible reaction mechanism
Conclusion.
In conclusion, we have described a catalytic and an efficient
method for the synthesis of 2,3-disubstituted indoles via two

4
Tetrahedron
Tomasic, T.; Smodis, D.; D’Amore, C.; Fiorucci, S.; Kikelj. D. J.
Med. Chem. 2014, 57, 4819-4833.
consecutive bond formation, C-C and C-N. We have also
proposed a plausible reaction mechanism where anilines acts as
bisnucleophiles. Aryl group migration from enol ether was
observed in this protocol. Electron-donating, as well as
moderately electron-withdrawing groups, were well tolerated in
this methodology.
4. (a) Park, I. K.; Suh, S. E.; Lim, B. Y.; Cho, C. G. Org.
Lett., 2009, 11, 5454-5456. (b) Gore, S.; Baskaran, S.; König,
B. Org. Lett., 2012, 14, 4568-4571. (c) Porcheddu, A.; Mura, M.
G.; Luca, L. D.; Pizzetti, M.; Taddei, M. Org. Lett., 2012, 14,
6112-6115. (d) Saito, A.; Oda, S.; Fukaya, H.; Hanzawa, Y. J.
Org. Chem. 2009, 74, 1517–1524. (e) Stuart, D. R.; Bertrand-
Laperle, M.; Burgess, K. M. N.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 16474-16475. (f) Oh, Y.; Han, S. H.; Mishra, N. K.;
De, U.; Lee, J.; Kim, H. S.; Jung, Y. H.; Kim. I. S. Eur. J. Org.
Chem. 2017, 42, 6265–6273. (g) Aulwurm, U. R.; Melchinger, J.
U.; Kisch, H. Organometallics 1995, 14, 3385-3395. (h) Shi, Z.;
Glorius, F. Angew. Chem.,Int.Ed. 2012, 51, 9220-9222; Angew.
Chem. 2012, 124, 9354-9356. (i) N.Kuhl, N. Schröder, F. Glorius,
Adv. Synth. Catal. 2014, 356, 1443-1460. (j) Z. Chen, B. Wang, J.
Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem.Front. 2015, 2,
Acknowledgments
We gratefully acknowledge Department of Science and
Technology, Science and Engineering Research Board
(EMR/2017/003484), India for financial support. TKJ thanks
MHRD, India for the award of the research fellowship.
1107-1295.
References and notes
5. Wurtz, S.; Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F.
Angew. Chem., Int. Ed. 2008, 47, 7230-7233.
6. Neumann, J. J.; Rakshit, S.; Drꢁge, T.; Wꢂrtz, S.; Glorius, F.
Chem. Eur. J. 2011, 17, 7298-7303.
7. Nguyen, H. H.; Kurth. M. J. Org Lett. 2013, 15, 362–365.
8. Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676–3677.
9. Wagaw, S.; Yang, B. H.; Buchwald. S. L. J. Am. Chem. Soc.,
1998, 120, 6621-6622.
10. Shen, M.; Li, G.; Lu, B. Z.; Hossain, A.; Roschangar, F.; Farina,
V.; Senanayake, C. H. Org. Lett., 2004, 6, 4129-4132.
11. Jana, S.; Clements, M. D.; Sharp, B. K.; Zheng. N. Org. Lett.,
2010, 12, 3637-3739.
12. Levesque, P.; Fournier, P. A. J. Org. Chem. 2010, 75, 7033–7036.
13. Whelligan, D. K. Thomson, D. W.; Taylor, D.; Hoelder, S. J. Org.
Chem. 2010, 75, 11–15.
1. (a) Sundberg, R. J. New York: Academic Press; 1996. (b)
Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761–793. (c)
Welsch. M. E.; Snyder. S. A.; Stockwell, B. R. S. Curr Opin
Chem Biol. 2010, 14, 347–361. (d) Kaushik N. K.; Kaushik, N.;
Attri, P.; Kumar, N.; Kim, C. H.; Verma, A. K.; Choi, E. H.
Molecules, 2013, 18, 6620–6662. (e) Sonsona, I. G. Synlett. 2015,
26, 2325–2326. (f) Sravanthi, T. V.; Manju, S. L. Eur. J. Pharm.
Sci. 2016, 91, 1–10. (g) Shiono, Y.; Akiyama, K.; Hayashi, H.
Biosci., Biotechnol., Biochem. 2000, 64, 103-110. (h) Mitani, H.;
Kimura, M. Cardiovasc. Drug Rev. 2000, 18, 284-303 (i) Flynn,
B. L.; Hamel, E.; Jung, M. K.; J. Med. Chem. 2002, 45, 2670–
2673; (j) Pietzscha, J.; Laubea, M.; Bechmann, N.; Pietzscha, F-J.;
Kniess, T.; CLIN. HEMORHEOL. MICRO. 2015, 61, 615-632.
2. (a) Chaisan, N.; Kaewsri, W.; Thongsornkleeb, C.; Tummatorn, J.;
Ruchirawat. S. Tetrahedron Lett. 2018, 59, 675–680. (b) Taber, D.
F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195–7210. (c)
Vicente, R. Org. Biomol. Chem. 2011, 9, 6469–6480. (d) Li, P.;
Weng, Y.; Xu, X.; Cui. X. J. Org. Chem. 2016, 81, 3994−4001.
(e) Inman, M.; Carbone, A.; Moody, C. J. J. Org. Chem. 2012, 77,
1217-1232. (f) Inman, M.; Moody, C. J.; Chem. Commun. 2011,
47, 788-790 (g) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1999, 121, 10251-10263. (h) Alex, K.; Tillack, A.;
Schwarz, N.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 2304-
2307.
14. Jena, T. K.; Khan, F. A. J. Org. Chem. 2019, 84, 14270-14280.
15. Jena, T. K.; Khan, F. A. Tetrahedron Lett. 2020, 151675.
(doi.org/10.1016/j.tetlet.2020.151675).
16. Strohmeie, J.; Angerer, E. V. Arch. Pharm. (Weinheim) 1985, 318,
421431.
17. Singsardar, M.; Chakraborty, A.; Jana, S.; Hajra, A.
ChemistrySelect 2017, 2, 8893 – 8897.
18. Zhang, J.; Yin, Z.; Leonard, P.; Wu, J.; Sioson, K.; Liu, C.; Lapo,
R.; Zheng, S. Angew. Chem. Int. Ed. 2013, 52, 1753 –1757.
Supplementary Material
3. (a) Miller, C. P.; Collini, M. D.; Tran, B. D.; Harris, H. A.;
Kharode, Y. P.; Marzolf, J. T.; Moran, R. A.; Henderson, R. A.;
Bender, R. H. W.; Unwalla, R. J.; Greenberger, L. M.; Yardley, J.
P.; Abou-Gharbia, M. A.; Lyttle, C. R.; Komm. B. S. J. Med.
Chem. 2001, 44, 1654-1657. (b) Hodnik, ꢀ.; Masic, L. P.;
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5
Research Highlights
 FeCl3 catalyzed C-C, C-N bond formation
between methyl enol ethers and anilines.
 2,3-disubstituted indole formation via aryl
group migration.
 Anilines act as bis-nucleophiles.