Fe(OTf)3-Catalyzed Aromatization of Substituted 3-Methyleneindoline and Benzofuran Derivatives: A Selective Route to C-3-Alkylated Indoles and Benzofurans

Article abstract of DOI:10.1002/ejoc.201500540

A simple and convenient approach was developed to the selective synthesis of 3-substituted indoles and benzofurans by the isomerization of 3-methyleneindoline and benzofuran derivatives catalyzed by Fe(OTf)₃. The salient features of this method are the easy availability of substrates, high yield, mild reaction conditions, tolerance of a variety of functional groups, and use of an environmentally friendly catalyst. A possible mechanism has also been proposed for the isomerization process.

Full text of DOI:10.1002/ejoc.201500540

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500540
Fe(OTf)3-Catalyzed Aromatization of Substituted 3-Methyleneindoline and
Benzofuran Derivatives: A Selective Route to C-3-Alkylated Indoles and
Benzofurans
Sandip Kundal,[a] Swapnadeep Jalal,[a] Kartick Paul,[a] and Umasish Jana*[a]
Keywords: Indoles / Benzofurans / Aromatization / Iron / Isomerization / Homogeneous catalysis
A simple and convenient approach was developed to the se-
lective synthesis of 3-substituted indoles and benzofurans by
mild reaction conditions, tolerance of a variety of functional
groups, and use of an environmentally friendly catalyst. A
the isomerization of 3-methyleneindoline and benzofuran de- possible mechanism has also been proposed for the isomer-
rivatives catalyzed by Fe(OTf)3. The salient features of this
method are the easy availability of substrates, high yield,
ization process.
catalyzed nucleophilic substitution of indolylmethyl Meld-
rum’s acids.[11] Intermolecular hydroarylation of indoles
with alkenes in the presence of [(PPh3)AuCl]/AgOTf[12a]
and with alkynes in the presence of ruthenium complexes/
TFA[12b] have also been demonstrated.
However, many of these methods involve strongly acidic
conditions, expensive and toxic reagents, complex handling,
and result in low yields of products. Moreover, in all these
methods indoles have been used as starting material, so the
methods suffer from unavailability of suitably substituted
indole derivatives. Thus, it is highly desirable to develop a
catalytic method to furnish functionalized 3-alkyl-substi-
tuted indoles from easily available starting materials.
Introduction
Indoles and benzofurans are common structural motifs
found in numerous natural products, pharmaceutical
agents, functional materials, and agrochemicals.[1,2] There-
fore, the synthesis of substituted indoles and benzofurans
has attracted great interest.[3,4] Among the family of substi-
tuted indoles, C-3-substituted indoles are the key structural
units of many promising therapeutic agents[5] such as anti-
cancer, antimigraine, antidepressant, anti-inflammatory,
antiestrogen, and antagonist drugs. Moreover, C-3-substi-
tuted indoles are also very useful for the construction of
many biologically active compounds.[6]
Consequently, numerous synthetic methods have been
developed for the preparation of C-3-alkylindoles,[7] such as
substitution of indole with alkyl halides in the presence of
acids or bases, conjugate addition of indoles to α, β-unsatu-
rated compounds, direct substitution of π-activated
alcohols with indoles or epoxides and aziridine ring open-
ing by indoles in the presence of various metal catalysts
and Brønsted acids. Besides these, procedures involving the
generation of reactive alkylideneindolenine intermediates
followed by selective nucleophilic addition have also been
developed to produce a large array of 3-substituted ind-
oles.[8] Very recently, Beller et al. reported ruthenium-cata-
lyzed carbon–carbon bond formation between indole and
benzylic and aliphatic amines.[9] Yus and co-workers devel-
oped a noncatalytic C-3 alkylation using activated benzyl
alcohol through a hydrogen-transfer strategy with an excess
amount of KOH.[10] Armstrong et al. described a Sc(OTf)3-
In continuation of our ongoing program in developing
environmentally friendly and inexpensive iron-catalyzed
syntheses of heterocyclic molecules,[13] we thought that the
simple aromatization of 3-methyleneindoline derivatives
would be a very selective and practical method for the syn-
thesis of C-3-substituted indole derivatives (Scheme 1).
However, literature search reveals that, although plenty of
methods are available for the synthesis of various indole
derivatives by means of palladium-catalyzed reactions from
aniline derivatives,[3d,14] no selective method has been devel-
oped for the synthesis of C-3-substituted indole derivatives.
During our recent study on the synthesis of benzo[b]carbaz-
ole derivatives,[13f] we observed that these reaction condi-
tions did not work for substituted 3-methyleneindoline de-
[a] Department of Chemistry, Jadavpur University,
Kolkata 700 032, West Bengal, India
E-mail: jumasish2004@yahoo.co.in
umasishjana@gmail.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500540.
Scheme 1. Synthetic strategies for 3-substituted indoles.
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S. Kundal, S. Jalal, K. Paul, U. Jana
SHORT COMMUNICATION
rivatives. So, we decided to perform a thorough investiga- Table 1. Optimization of reaction conditions for the isomerization
of 2a to indole derivative 3a.[a]
tion of this transformation. In this paper, we now report a
selective and general synthesis of 3-substituted indoles and
benzofurans by aromatization of 3-methyleneindoline and
benzofuran derivatives with use of Fe(OTf)3 as catalyst.
Results and Discussion
The required starting material, 3-methyleneindoline de-
rivative 2, was prepared in high yield by using our previous
method involving a domino Heck–Suzuki coupling of 2-
bromo-N-propargylanilide 1 with arylboronic acid deriva-
tives, as outlined in Scheme 2.[13f] After having a series of
3-methyleneindoline derivatives 2, we next tried to optimize
the reaction conditions for the isomerization of 3-methyl-
eneindoline derivatives.
Scheme 2. Preparation of substituted 3-methyleneindolines. Reac-
tion conditions: Pd(OAc)2 (5 mol-%), PCy3 (10 mol-%), K2CO3
(2.5 m), EtOH, toluene, reflux.
At first, a large number of Lewis and Brønsted acids
were screened by using 2a as the model substrate (Table 1).
We first examined the isomerization of 2a to 3a in the pres-
ence of FeCl3 (10 mol-%) at 80 °C in 1,2-dichloroethane;
[a] Reaction conditions: Substrate 2a (0.23 mmol), 1,2-dichloro-
ethane (2 mL), catalyst (0.023 mmol). [b] Isolated yield of pure
product.
however, no reaction took place even after prolonged heat- mation. A moderately strong Lewis acid is probably more
ing (Table 1, entry 1). Interestingly, we noticed that when efficient for this transformation. Thus, Fe(OTf)3 (10 mol-%)
the reaction mixture was heated to 135 °C in chlorobenzene in 1,2-dichloroethane at 60 °C was defined as the optimal
a trace amount of isomerized product 3a was formed after reaction conditions for further study.
heating for 12 h (Table 1, entry 2).
Next, the isomerization of a large array of 3-methyl-
Encouraged by these results, we then screened other eneindoline derivatives 2a–2j was investigated under these
commonly used iron salts such as FeBr3 and Fe(OTf)3 for reaction conditions; the results are presented in Table 2. We
this transformation. We found that FeBr3 did not initiate were pleased to observe that this isomerization process was
the reaction, whereas Fe(OTf)3 (10 mol-%) gave 90% yield quite general and smoothly afforded a variety of disubsti-
at 60 °C within 3 h. Moreover, we also observed that the tuted and monosubstituted alkylideneindole derivatives in
reaction was sluggish when we reduced the amount of very good to excellent yields. The reaction was not mark-
Fe(OTf)3, and further increasing the amount of catalyst did edly affected by the substituents on any of the aryl rings.
not improve the yield. Next, we also screened other metal For example, aryl rings (R4) including those bearing an
salts such as In(OTf)3, AgOTf, and AgSbF6; we found that electron-donating group such as p-OMe (Table 2, entries 3
In(OTf)3 did not work under similar conditions, but the and 4) and electron-withdrawing groups such as p-Cl and
isomerization took place with AgOTf (10 mol-%) and p-COMe (Table 2, entries 5, 6 and 7) were compatible, and
AgSbF6 (10 mol-%) at 60 °C and gave product 3a in 73% all gave the corresponding C-3-substituted indoles in good
and 76% yields, respectively (Table 1, entries 6 and 7). to excellent yields. Functional groups such as –CHO,
Brønsted acids such as p-toluenesulfonic acid monohydrate –COMe, and –Cl are very useful for further synthetic trans-
(PTSA·H2O) and triflic acid (TfOH) also afforded the de- formations to construct a library of C-3-substituted indole
sired products, but not in higher yields (74% and 82%) derivatives for biological studies. Similarly, both substituted
(Table 1, entries 8 and 9). Finally, we also tested this isom- and unsubstituted aryl rings (R3) were also tolerated and
erization with stoichiometric amounts of bases such as gave high yields of the desired products.
K3PO4 in DMF at 100 °C (Table 1, entry 10). Although,
Moreover, aryl- and alkyl-substituted alkylideneindole
this strategy has been reported for the synthesis of 3-substi- derivative 2h (Table 2, entry 8) was also smoothly converted
tuted benzofuran derivatives,[15] it did not work for the syn- into the desired C-3-substituted indole derivative 3h in good
thesis of indole derivative 3a. These results demonstrated yield. In addition, monosubstituted alkylideneindole deriv-
that Fe(OTf)3 has higher catalytic activity for this transfor- ative 2i (Table 2, entry 9) could also be aromatized to 3-
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A Selective Route to C-3-Alkylated Indoles and Benzofurans
Table 2. Fe(OTf)3-catalyzed isomerization of 2a–2j to C-3-substi- stoichiometric amounts of bases such as K3PO4 in DMF
tuted indoles 3a–3j.[a]
solvent at 100 °C, the present method is superior as only
catalytic amounts (10 mol-%) of an environmentally
friendly iron salt is required and it works at lower tempera-
ture (60 °C).
Table 3. Fe(OTf)3-catalyzed isomerization of 4a–4d to C-3-substi-
tuted benzofurans 5a–5d.[a]
[a] Reaction conditions: Substrate (0.23 mmol), catalyst (0.023 mmol),
and 1,2-dichloroethane (2 mL). [b] Isolated yield of pure product.
Therefore, an Fe(OTf)3-catalyzed isomerization of 3-
methyleneindoline and benzofuran derivatives to corre-
sponding 3-substituted indoles and benzofuran derivatives
is very straightforward. Fe(OTf)3 was found to be the best
among the catalysts studied. Fe(OTf)3 was prepared from
FeCl3 (99.5%) and TfOH according to a literature pro-
cedure.[16] Moreover, we noticed that TfOH was also effec-
tive for this transformation and gave 82% yield (Table 1,
entry 9); hence, there was a chance that this reaction may
also be catalyzed by in situ generated TfOH. To check this,
we carried out this reaction in the presence of a sterically
hindered non-nucleophilic base such as 2,6-di-tert-butyl-4-
methylpyridine (Scheme 3). We observed that no significant
[a] Reaction conditions: Substrate (0.23 mmol) and 1,2-dichloro-
ethane (2 mL). [b] Isolated yield of pure product.
benzyl indole derivative 3i in 75% yield in the presence
10 mol-% Fe(OTf)3. Further study shows that, instead of
N-Ts derivative 2j (Table 2, entry 10), the substrate contain-
ing N-Ms also worked smoothly and gave the desired 3-
alkylindole derivative 3j in quantitative yield.
Furthermore, we also applied this methodology to the
synthesis of 3-alkylbenzofurans. To our delight, the reac-
tions proceeded smoothly in the presence of 10 mol-%
Fe(OTf)3, affording the corresponding 3-alkylbenzofurans
5a–5d (Table 3) in good to excellent yields. This aromatiza-
tion was not affected by the presence of a variety of func-
tional groups such as p-OMe, m-CF3, and m-NO2 on aryl
ring R1. This method was also very efficient for the synthe-
sis of naphthyl-substituted benzofuran derivative 4e in 92%
yield (Table 3, entry 5). Compared to a recently developed
method for the aromatization of 2,3-dihydro-methyl-
enebenzofuran derivatives in basic medium that required of Fe(OTf)3 and base.
Scheme 3. Study of the reaction in the presence of a combination
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S. Kundal, S. Jalal, K. Paul, U. Jana
SHORT COMMUNICATION
reaction (monitored by TLC), the solvent was evaporated, and the
product was purified by column chromatography (silica gel 60–
120 mesh) and eluted with pet ether (60–80 °C)/EtOAc (97:3, v/v)
to afford compound 3a (or 5a). The product was characterized by
1H NMR and 13C NMR spectroscopy as well as HRMS.
changes occur when we added pyridine as base in combina-
tion with Fe(OTf)3. The combination of catalysts also gave
a high yield of the desired product, but no such isomeriza-
tion took place in the presence of pyridine base. So, we
concluded that possibly TfOH was not generated during the
course of the reaction and Fe(OTf)3 was the real catalyst
for this transformation.
A plausible mechanism for the isomerization, based on
the above experimental observations, is shown in Scheme 4.
We believe that iron(III) triflate coordinates to the double
bond of 2a and thus polarizes the alkene double bond. This
activation triggers the deprotonation of the –CH2– group,
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental details and 1H and 13C NMR spectra for
all compounds are provided.
Acknowledgments
S. K. thanks the University Grants Commission (UGC), India, for
leads to the isomerization of the double bond, and affords his fellowship. S. J. and K. P. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for their fellow-
ships.
iron-bound product 2aЈ. Then, demetalation of 2aЈ by rapid
protonolysis releases indole derivative 3a and regenerates
Fe(OTf)3 for the next catalytic cycle.
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Conclusions
We have developed an Fe(OTf)3-catalyzed synthesis of 3-
alkylindole and 3-alkylbenzofuran derivatives in good to
high yields under mild conditions from 3-methyleneindoline
and benzofuran derivatives. A variety of functionalized 3-
alkylidene indole and benzofuran derivatives could easily
be prepared by a palladium-catalyzed domino Heck–Suzuki
coupling reaction. The advantages of this methodology are
easily available starting materials, toleration of various
functional groups, excellent regioselectivity, and the use of
an environmentally friendly and inexpensive iron catalyst.
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Experimental Section
General Procedure: To a solution of 2a (or 4a) in dry 1,2-dichloroe-
thane was added anhydrous Fe(OTf)3. The mixture was stirred at
60 °C under an argon atmosphere for 3 h. After completion of the
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A Selective Route to C-3-Alkylated Indoles and Benzofurans
S. Sarkar, K. Paul, U. Jana, Org. Biomol. Chem. 2014, 12,
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Received: April 28, 2015
Published Online: July 27, 2015
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