Hydrated ferric sulfate catalyzed synthesis of 3-[(alkyl/arylthio)(aryl) methyl]-1H-indole derivatives through one-pot reaction This work is dedicated to Late Dr. Uttara Debi who was compassionate and amicable in nature

Article abstract of DOI:10.1016/j.tetlet.2013.11.056

A wide variety of 3-[(alkyl/arylthio)(aryl)methyl]-1H-indole derivatives (4a-z) were synthesized through a one-pot three-component reaction from indoles, aromatic aldehydes, and thiols at room temperature using hydrated ferric sulfate as a Lewis acid catalyst. The key features of the present protocol are mild and simple reaction procedure, moderate to good yields, requirement of inexpensive and reusable catalyst, no formation of dithioacetals derivatives from the corresponding aldehydes as well as bis-(indolyl) methane derivatives.

Full text of DOI:10.1016/j.tetlet.2013.11.056

Accepted Manuscript
Hydrated ferric sulfate catalyzed synthesis of 3-[(alkyl/arylthio) (aryl)meth-
yl]-1H-indole derivatives through one-pot reaction
Ajaz A. Dar, Shahzad Ali, Abu T. Khan
PII:
S0040-4039(13)02003-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.056
TETL 43851
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 July 2013
13 November 2013
16 November 2013
Please cite this article as: Dar, A.A., Ali, S., Khan, A.T., Hydrated ferric sulfate catalyzed synthesis of 3-[(alkyl/
arylthio) (aryl)methyl]-1H-indole derivatives through one-pot reaction, Tetrahedron Letters (2013), doi: http://
dx.doi.org/10.1016/j.tetlet.2013.11.056
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.

Hydrated ferric sulfate catalyzed synthesis of 3-[(alkyl/arylthio)
(aryl)methyl]-1H-indole derivatives through one-pot reaction≠
Ajaz A. Dar,a Shahzad Ali a and Abu T. Khana,b,*
aDepartment of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
bAliah University, DN 18, 8th Floor, Sector V, Kolkata-700091, West Bengal, India.
Tel.: +91 361 2582305; fax: +91 361 2582349
atk@iitg.ernet.in (A.T. Khan)
Abstract: A wide variety of 3-[(alkyl/arylthio)(aryl)methyl]-1H-indole derivatives (4a-z) were
synthesized through a one-pot three-component reaction from indoles, aromatic aldehydes and
thiols at room temperature using hydrated ferric sulfate as a Lewis acid catalyst. The key features
of the present protocol are mild and simple reaction procedure, moderate to good yields,
requirement of inexpensive and reusable catalyst, no formation of dithioacetals derivatives from
the corresponding aldehydes as well as bis-(indolyl) methane derivatives.
Keywords: Three-component reactions, Indoles, Aromatic aldehydes, Thiols, Hydrated ferric
sulfate [Fe2(SO4)3•xH2O].
Indoles and 3-substituted indole derivatives exhibit interesting biological properties and many of
them are found as such in nature.1-3 Recently various research groups have paid considerable
attention to synthesize these compounds due to their wide range of biological activities such as
antioxidant, antibacterial, anti-insecticidal and anticancer activity.4 Numerous synthetic methods
have been developed for their synthesis using either indole or 3-indolecarboxaldehyde. By
employing powerful carbon-carbon bond forming reactions, the synthesis of 3-substituted indole
derivatives were achieved using Mannich reaction,5 Friedel–Crafts alkylation reactions of indoles,6
conjugate addition of indoles to unsaturated carbonyl compounds and the reaction of two
equivalents of indoles with carbonyl groups in the presence of a protic acid7 or Lewis acid.8-10
Interestingly, 3-substituted indole derivatives containing sulfur atom is not explored yet. As a
matter of fact, the synthesis of these compounds containing sulfur atom is highly desirable because
they might exhibit interesting pharmacological activities.11

Hydrated ferric sulfate [Fe2(SO4)3•xH2O] has received considerable attention as a mild,
inexpensive and reusable Lewis acid catalyst for various organic transformations namely
tetrahydropyranylation of alcohols,12 preparation of acylals from aldehydes,13 2,3-unsaturated
glycosides via Ferrier rearrangement,14 per-O-acetylation of sugars,15 synthesis of
tetrahydroquinoline derivatives16 and 1H-pyrazole-4-carbodithioate.17 Recently, we have developed
numerous multicomponent reactions (MCRs) for the synthesis of new organic molecules.18 We
conceived that hydrated ferric sulfate can be exploited further for the synthesis of 3-
[(alkyl/arylthio)(aryl)methyl]-1H-indole derivatives at room temperature from indoles, aromatic
aldehydes and thiols using one-pot three-component reaction, which is shown in Scheme 1.
Scheme 1
We have chosen p-chlorobenzaldehyde, indole and ethanethiol as the model substrates to find out
a suitable reaction condition. At first, the reaction was conducted with a mixture of p-
chlorobenzaldehyde, indole and ethanethiol in 3 mL of ethanol in the absence of a catalyst at
room temperature and the desired product, 3-[(p-chlorophenyl)(ethylthio)methyl]-1H-indole
(4b), was isolated only in 12% yield after 12 h of stirring (Table 1, entry 1). Interestingly, when
the same reactions were examined in the presence of 5, 10 and 15 mol% hydrated ferric sulfate in
ethanol (3 mL) at room temperature, the required product 4b was obtained in 42%, 73% and 74%
of yields respectively (Table 1, entries 2-4). It was noted that the yield of the product 4b did not
improve significantly by further increasing the amount of catalyst. Various reactions were also
scrutinized with the same combination of the substrates in presence of other Lewis acid catalysts
such as anhydrous ferric chloride, hydrated ferrous chloride, ceric ammonium nitrate (CAN),
nickel chloride hexahydrate and vanadyl acetylacetonate and we have isolated the product 4b in
70%, 68%, 16%, 63% and 58% yield, respectively (Table 1, entries 5-9). To find out a suitable
solvent, the same reactions were also performed in different solvents such as dichloromethane
(CH2Cl2), acetonitrile (CH3CN), water (H2O), tertrahydrofuran (THF), 1,4-dioxane,
dimethylformamide (DMF) and 1,2-dichloroethane (C2H4Cl2) (Table 1, entry 9-16). Though
anhydrous ferric chloride and hydrated ferrous chloride provide similar yield, we have chosen
hydrated ferric sulfate because of the reusability of the catalyst. From these observations, we
conclude that the best result was obtained using 10 mol% catalyst in ethanol in terms of yields
and reaction time.

Table 1
After optimizing the reaction conditions, the reaction of indole, benzaldehyde and ethanethiol
was performed under optimized manner and it afforded the desired product 4a in 70% yield. In
order to find the scope of the reaction a wide variety of aromatic aldehydes were treated with
indole and ethanethiol under identical reaction conditions and the desired products 4c-h were
obtained from moderate to good yields (Table 2, entries 3-8) depending upon the type and
position of substitution on the aromatic ring. It was observed that aromatic aldehydes containing
electron-withdrawing groups in the ring provided better yield as compared to the aldehydes
having electron-donating substituent, which may be due to low electrophilicity of the aldehyde
functionality in presence of electron-rich substituent. Similarly, ortho-substituted aromatic
aldehydes also provide lower yield due to steric hindrance. We have also examined the reactions
with different aliphatic thiols namely propanethiol, benzylthiol and 2-mercaptoethanol with
indole and various aromatic aldehydes under similar reaction conditions and we have isolated the
desired products 4i-m from moderate to good yields (Table 2, entries 9-13). Encouraged by these
successful results, we tried to extend our protocol using various aromatic thiols. Then, a reaction
was carried out with indole, benzaldehyde and thiophenol under identical reaction conditions,
which gave only 24% desired product along with bis-(indolyl) methane derivative 30% (Table 2,
entry 14). The formation of low yield of the expected product might be due to less
nucleophilicity of thiophenol. However, when the reactions were executed with indole,
benzaldehyde with p-methylthiophenol or p-methoxythiophenol, respectively, it afforded the
desired products in 64% and 67% yield (Table 2, entries 15 & 16). From these observations, it is
clear that substituted thiophenols containing electron-rich substituent in the ring provided much
better yields as compared to thiophenol. It is worthwhile to mention that our protocol also
provided the desired product 4q albeit in low yield with aromatic thiol containing electron-
withdrawing group (Table 2, entry 17). Subsequently, we have examined the reaction with
indole, different aromatic aldehydes containing electron-rich as well as electron-withdrawing
substituent in the ring and electron-rich thiophenols and the corresponding desired products 4r-w
from moderate to good yields. It was observed that aromatic aldehydes having electron-
withdrawing substituents provided better yield as compared to the aromatic aldehydes having
electron-donating substituent (Table 2, entries 18-23). Interestingly, p-nitrobenzaldehyde also
provided the desired product 4x in 40% yield on reaction with indole and p-nitrothiophenol

under the experimental conditions. Likewise, the desired product 4y was obtained from indole, 2-
naphthylaldehyde and 4-methylthiophenol under identical conditions. Apart from indole, the
reaction was performed by using 5-bromoindole, p-chlorobenzaldehyde and ethanethiol under
the experimental reaction condition the desired product 4z was obtained in 69% yield (Table 2,
entry 26). However, when a reaction was carried out with indole, cyclohexanecarboxaldehyde
and p-methylthiophenol in 3 mL of ethanol using the same amount of catalyst under identical
reaction condition, we have isolated the corresponding bis-(indolyl) methane derivative in 40%
yield instead of the desired product.
Table 2
1
All the products 4a-z were characterized by recording IR, H NMR, 13C NMR spectra and
elemental analyses. The formation of the products can be rationalized as follows: There are two
possible mechanistic pathways, which are shown in Scheme 2. In pathway a, an aromatic
aldehyde reacts with indole to give intermediate iminium ion A, which reacts with thiol
immediately to furnish the final product 4. Alternatively, a thiol may react with an aromatic
aldehyde to provide a reactive sulfonium ion intermediate B, which may react with indole to
afford the final product 4 in (pathway b). However, we believe that the ‘pathway a’ is more
favourable as we have obtained the desired product 4q even with a less nucleophilic aromatic thiol
such as p-nitrothiophenol. Hydrated ferric sulphate, [Fe2(SO4)3•xH2O] acts as a Lewis acid in the
present transformation.
Scheme 2
Moreover, the structure of 4e was further confirmed by single XRD crystallographic data.
Figure 1
The catalyst [Fe2(SO4)3•xH2O] was recovered conveniently from the reaction mixture at the end of
the reaction after each cycle. After completion of the reaction, the ethanol was removed in a
rotatory evaporator and the crude residue was dissolved in 10 mL of dichloromethane. On adding
dichloromethane, the catalyst was separated out and it was filtered off through a Büchner funnel.
The required product 4c was isolated after concentrating dichloromethane followed by purification
through a silica gel column chromatography. The reusability of the recovered catalyst was

examined for another four successive cycles with a similar set of reactions and the results are
shown in Table 3. Due to loss of the catalyst in each cycle, the yield decreased relatively.
Table 3
In summary, we have achieved the synthesis of 3-[(alkyl/arylthio)(aryl)methyl]-1H-
indole derivatives from indoles, aromatic aldehydes and various aliphatic/aromatic thiols using a
catalytic amount of hydrated ferric sulfate at room temperature. We did not observe the
formation of bis-(indolyl) methane derivatives as well as dithioacetals derivatives of the
corresponding aromatic aldehydes in the present protocol. This reaction strategy involves use of
a cheap and non-toxic hydrated ferric sulfate as the catalyst. Using this method, we are able to
synthesize numerous 3-[(alkyl/arylthio)(aryl)methyl]-1H-indole derivatives from indoles,
aromatic aldehydes and a wide variety of thiols.
Acknowledgements
A. A. D. is thankful to IIT Guwahati for his research fellowship and S. A. is grateful to UGC,
New Delhi for his research fellowship. We acknowledge the Department of Science &
Technology, New Delhi for financial support for creating single crystal XRD facility to the
Department of Chemistry under FIST programme. We are thankful to CIF, IIT Guwahati for
providing the NMR instrument facility. We also acknowledge Prof. D. C. Deka, Guwahati
University for recording NMR spectra. The authors are also grateful to Prof. Gautam Barua,
Former Director, IIT Guwahati for providing the general research facility to carry out this work.
We are thankful to the referees for their valuable comments and suggestions.
Supplementary data
1
Supplementary data (detailed experimental procedures, Crystallographic data in CIF, H, 13C
NMR Spectra and spectral data for all compounds) associated with this article can be found, in
the online version, at http://dx.doi.org/........

References and notes
≠
This work is dedicated to Late Dr. Uttara Debi who was compassionate and amicable in nature.
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York, 1970; (b)
Zhang, H. C.; Bonaga, L. V. R.; Ye, H.; Derian, C. K.; Damiano, B. P.; Maryanoff, B. E.
Bioorg. Med. Chem. Lett. 2007, 17, 2863.
2. (a) Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175. (b) Faulkner, D. J. Nat.
Prod. Rep. 1999, 16, 155.
3. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
4. Jiang, B.; Yang, C. G.; Wang, J. J. Org. Chem. 2001, 66, 4865 and references therein.
5. Dai, H. G.; Li, J. T.; Li, T. S. Synth. Commun. 2006, 36, 1829.
6. (a) Ke, B.; Qin, Y.; He, Q.; Huang, Z.; Wang, F. Tetrahedron Lett. 2005, 46, 1751; (b)
Zhao, J. L.; Liu, L.; Zhang, H. B.; Wu, Y. C.; Wang, D.; Chen, Y. J. Synlett 2006, 96.
7. Reddy, A. V.; Ravinder, K.; Reddy, V. L. N.; Goud, T. V.; Ravikanth, V.;
Venkateswarlu, Y. Synth. Commun. 2003, 33, 3687.
8. (a) Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047; (b) Harrington, P. E.; Kerr, M. A.
Can. J. Chem. 1998, 76, 1256.
9. (a) Babu, G.; Sridhar, N.; Perumal, P. T. Synth. Commun 2000, 30, 1609; (b) Chen, D.;
Yu, L.; Wang, P. G. Tetrahedron Lett. 1996, 37, 4467; (c) Mi, X.; Luo, S.; He, J.; Cheng,
J. P. Tetrahedron Lett. 2004, 45, 4567; (d) Nagarajan, R.; Perumal, P. T. Tetrahedron
2002, 58, 1229; (e) Wang, L.; Han, J. H.; Sheng, T.; Fan, J. Z.; Tang, X. Synlett 2005,
337.
10. (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.; Selva, S.; Umani-Ronchi,
A. J. Org. Chem. 2002, 67, 3700; (b) Yadav, J. S.; Abraham, S.; Subba Reddy, B. V.;
Sabitha, G. Synthesis 2001, 2165; (c) Manabe, K.; Aoyama, N.; Kobayashi, S. Adv.
Synth. Catal. 2001, 174; (d) Yadav, J. S.; Subba Reddy, B. V.; Murthy, V. S. R.; Mahesh
Kumar, G.; Madan, C. Synthesis 2001, 783; (e) Kumar, A.; Sharma, S.; Maurya, R. A.
Tetrahedron Lett. 2009, 50, 5937; (f) Fridkin, G.; Boutard, N.; Lubell, W. D. J. Org.
Chem. 2009, 74, 5603; (g) Kobayashi, K.; Shirai, Y.; Konishi, H. Heterocycles 2009, 78,
2033.

11. (a) Kondo, T.; Mitsudo, T.-A. Chem. Rev. 2000, 100, 3205; (b) Gilchrist, T. L.
Heterocyclic Chemistry, 3rd ed.; Addison Wesley Longman: Essex, 1997; (c) Okazaki,
R. In Organosulfur Chemistry; Academic: London, 1995; Vol. 1, pp 225. (d) Dewick, P.
M. Medicinal Natural Products, 2nd ed.; John Wiley & Sons: West Sussex, England,
2002; (e) Vardanyan, R. S.; Hruby, V. J. Synthesis of Essential Drugs; Elsevier:
Amsterdam, 2006. (f) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992.
12. Li, L.; Zhu, L.; Zhang, X.; Zhang, G.; Qu, G. Can. J. Chem. 2005, 83, 1120.
13. Zhang, X.; Li, L.; Zhang, G. Green Chem. 2003, 5, 646.
14. Zhang, G.; Liu, Q.; Shi, L.; Wang, J. Tetrahedron 2008, 64, 339.
15. Shi, L.; Zhang, G.; Pan, F. Tetrahedron 2008, 64, 2572.
16. Khan, A. T.; Das, D. K.; Khan, M. M. Tetrahedron Lett. 2011, 52, 4539.
17. Khan, A. T.; Gosh, A.; Basha, R. S.; Mir, M. H. Asian. J. Org. Chem. 2013, 2, 126.
18. (a) Khan, A. T.; Das, D. K. Tetrahedron Lett. 2012, 53, 2345; (b) Khan, A. T.; Basha, R.
S.; Lal. M. Tetrahedron Lett. 2012, 53, 2211; (c) Khan, A. T.; Lal. M.; Ali, S.; Khan, M.
M. Tetrahedron Lett. 2011, 52, 5327; (d) Khan, A.T.; Ali, S.; Dar, A. A.; Lal, M.
Tetrahedron Lett. 2011, 52, 5157; (e) Khan, A. T.; Das, D. K.; Khan, M. M. Tetrahedron
Lett. 2011, 52, 4539; (f) Khan, A. T.; Khan, M. M. Tetrahedron Lett. 2011, 52, 3455; (g)
Khan, A. T.; Lal, M.; Khan, M. M. Tetrahedron Lett. 2010, 51, 4419.
19. General procedure: Hydrated ferric sulfate (0.042 g, 0.1 mmol) was added to a stirred
mixture of indole (1 mmol) and aldehyde (1 mmol) in 3 mL of ethanol at room
temperature. Subsequently, thiol (1.2 mmol) was added into it and stirring was further
continued. After completion of the reaction as monitored by TLC, ethanol was removed
in rotary evaporator and the crude residue was extracted with dichloromethane (2 × 15
mL). The organic layer was washed with water followed by brine solution. The organic
extract was dried over anhydrous sodium sulfate and it was concentrated in a rotary
evaporator. Finally, the crude residue was passed through a silica gel column to obtain
the desired pure product. All the desired products were eluted with ethyl acetate: hexane
(1:9) mixture during column chromatography except for the compounds 4m and 4x,
which were eluted with 1:1 mixture of the same solvent system.

Graphical abstract
Hydrated ferric sulfate catalyzed synthesis of 3-[(alkyl/arylthio) (aryl)methyl]-
1H-indole derivatives through one-pot reaction
Ajaz A. Dar, Shahzad Ali and Abu T. Khan*

Scheme 1. Synthesis of 3-[(alkyl/arylthio)(aryl)methyl]-1H-indoles

Table 1. Optimization for reaction conditionsa
Entry
Catalyst
Solvent
Catalyst (mol %)
Time/h
Yield (%)b
1
2
No catalyst
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
FeCl3
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
CH2Cl2
CH3CN
H2O
0
12
6.0
4.0
4.0
5.0
5.0
5.0
5.0
5.0
4.0
4.0
5.0
5.0
5.0
5.0
5.0
12
42
73
74
70
68
16
63
58
66
68
27
67
25
30
65
5
3
10
15
10
10
10
10
10
10
10
10
10
10
10
10
4
5
6
FeCl2.xH2O
CAN
7
8
NiCl2.6H2O
VO(acac)2
9
10
11
12
13
14
15
16
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
Fe2(SO4)3.H2O
THF
Dioxane
DMF
C2H4Cl2
aAll the reactions were carried out using indole (1 mmol), p-chlorobenzaldehyde (1 mmol) and
ethanethiol (1.2 mmol) in 3 mL of solvent at room temperature. bIsolated yield.

Table 2. Fe2(SO4)3·xH2O catalyzed synthesis of substituted 3-thiolalkyl/arylated indoles
Entry
1
Indole
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
Aldehyde
Benzaldehyde
Substituent/R
Producta Yield (%)b
Et
70
73
72
53
74
25
30
75
69
71
51
61
62
24
64
67
20
68
49
46
4a
4b
4c
4d
4e
4f
2
p-Chlorobenzaldehyde
p-Bromobenzaldehyde
p-Methoxybenzaldehyde
p-Nitrobenzaldehyde
o-Chlorobenzaldehyde
o-Nitrobenzaldehyde
m- Nitrobenzaldehyde
Benzaldehyde
Et
3
Et
Et
4
5
Et
6
Et
7
Et
4g
4h
4i
8
Et
9
Pr
10
11
12
13
14
15
16
17
18
19
20
p- Chlorobenzaldehyde
p- Methylbenzaldehyde
Benzaldehyde
Pr
4j
Pr
4k
4l
C6H5CH2
HOCH2CH2
C6H5
Benzaldehyde
4m
4n
4o
4p
4q
4r
4s
Benzaldehyde
Benzaldehyde
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
Benzaldehyde
Benzaldehyde
p- Bromobenzaldehyde
p- Methylbenzaldehyde
p- Methoxybenzaldehyde
4t

21
22
23
24
25
26
p- Nitrobenzaldehyde
p- Cyanobenzaldehyde
p-Fluorobenzaldehyde
p- Nitrobenzaldehyde
2-Naphthaldehyde
p-MeOC6H4
p-MeC6H4
p-MeOC6H4
p-NO2C6H4
p-MeC6H4
Et
71
70
66
40
68
69
1a
1a
1a
1a
1a
1b
4u
4v
4w
4x
4y
4z
p-Chlorobenzaldehyde
aAll the reactions were performed using 1 (1 mmol), aldehyde (1 mmol) and thiol (1.2 mmol).
bIsolated yield.
Scheme 2. Plausible mechanism for the formation of the product 4.

Figure 1. X-ray structure of compound 4e (CCDC 930601)
Table 3. Results of the study on the recovery and reusability of [Fe2(SO4)3•xH2O]a
Yield (%)b
Round
Catalyst recovered/mg
Reaction time (h)
1
2
3
4
5
126
121
117
113
106
4.0
4.0
4.0
4.0
4.0
72
70
67
61
55
a All the reaction were performed with 3 mmol scale of the reactants using 9 mL of ethanol at
room temperature. b Isolated yield.