Facile synthesis of bis(indolyl)alkanes catalyzed by cu(clo 4)2.6h2o under solvent free conditions

Article abstract of DOI:10.2174/157017811796504963

Copper perchlorate hexahydrate is found to be an efficient catalyst for the electrophilic substitution of indole with carbonyl compounds to prepare bis(indolyl)methane derivatives without solvent in excellent yield at room temperature.

Full text of DOI:10.2174/157017811796504963

Letters in Organic Chemistry, 2011, 8, 461-463
461
Facile Synthesis of Bis(indolyl)alkanes Catalyzed by Cu(ClO4)2.6H2O
Under Solvent Free Conditions
Mukulesh Baruah*
Department of Chemistry and Biochemistry, South Dakota State University, Box 2202, Brookings, SD 57007, USA
Received March 14, 2011: Revised April 20, 2011: Accepted May 17, 2011
Abstract: Copper perchlorate hexahydrate is found to be an efficient catalyst for the electrophilic substitution of indole
with carbonyl compounds to prepare bis(indolyl)methane derivatives without solvent in excellent yield at room tempera-
ture.
Keywords: Bis(Indolyl)methanes, carbonyl compounds, Cu(ClO4)2.6H2O, indole,.
The importance of indole and its derivatives is well
known in the field of medicinal chemistry and biology [1].
Bis(indolyl)alkanes are naturally occurring biologically use-
ful class of compounds. Many of their biologically important
derivatives were isolated from terrestrial and marine natural
sources [2]. For example, vibrindole A (3,3/-diindolyl-
ethane) possesses antibacterial properties and 3, 3/-
diindolylmethane shows anti-cancer activity [3]. Synthesis of
bis(indolyl)alkanes therefore, is receiving significant inter-
ests in drug design. The electrophilic substitution reaction of
indole with carbonyl compounds catalyzed by acid is one of
the attractive methods for this synthesis. Many reagents such
as acetic acid [4], InCl3 [5], In(OTf)3 [6], InF3 [7], Dy(OTf)3
[8], Ln(OTf)3 [9], LiClO4 [10], ZrCl4 [11] TBATB [12],
FeCl3 [13], NBS [14], KHSO4 [15], NaHSO4 . SiO2 [16],
Copper perchlorate hexahydrate is an inexpensive Lewis
acid reported to catalyze many organic reactions for example
O-, N-, and S- acetylation [33], hydrocyanation of aldehydes
[34], addition of indole to alkylidene malonates [35], and so
on [36]. However, this reagent has never been reported as a
catalyst for the electrophilic substitution reaction of indole
with carbonyl compounds. Herein we wish to report the use
of copper perchlorate hexahydrate as a catalyst for this sub-
stitution reaction which was found very effective for clean
and fast formation of corresponding bis(indolyl)methanes
without any solvent (Scheme 1).
In the present typical reaction conditions [37], carbonyl
compounds were mixed well with indole and catalytic
amounts of Cu(ClO4)2.6H2O. Reaction mixtures were then
kept at room temperature for required time and the pro-
R2
R1
R1
R2
Cu(ClO4)2.6H2O (5mol%)
Neat, RT
2
O
NH
NH
NH
R1 = Alkyl. Aryl
R2 = H, Alkyl
1
2
Scheme 1. Cu(ClO4)2.6H2O catalyzed synthesis of bisindolylmethanes.
PPh3.HClO4 [17], CAN [18], zeolites [19], clay [20],
H3PMo12O40.xH2O [21], CuBr2 [22], Cu(BF4)2.SiO2 [23],
CuSO4.5H2O [24], trichloro-1,3,5-triazine [25], hexamethyl-
enetetraamine-bromine [26], ion-exchange resin [27], ionic
liquids in combination with In(OTf)3 or FeCl3 . 6H2O [28],
Bi(NO3)3.5H2O [29], oxalic acid dehydrate [30], fluoroboric
acid on silica [31], and boric acid [32] etc. have been used to
carry out this transformation. However, some of the reported
methods have some drawbacks like, use of expensive rea-
gents, longer reaction times, low yields of products, and use
of additional microwave energy. Therefore new reagents and
mild conditions for this reaction are still interesting.
gresses were monitored by TLC. Aldehydes were observed
to be more reactive than ketones as acetone and cyclohex-
anone (Table 1) have shown formation of products in mod-
erate yield with longer reaction times. 5 mole % amount of
catalyst to the aldehydes was observed sufficient for this
conversion in 5 to 20 minutes with high yield at room tem-
perature. The effect of electron donating and electron with-
drawing substituents on the aromatic ring of aldehydes did
not show huge differences in the reactivity.
We also have studied the solvents effect on this catalyst
by performing the reactions of p-Nitrobenzadehyde and ani-
saldehyde with indole in Methanol, THF, Dichloro-methane
and acetonitrile (Table 2). Consequently it was observed
that, in methanol no reactions occurred until 5hrs for both
the cases. In THF and dichloromethane, the reactions were
clean but the formation of products was very slow. Acetoni-
*Address correspondence to this author at the Department of Chemistry and
Biochemistry, South Dakota State University, Box 2202, Brookings, SD
57007, USA; Tel: +1 6056885167; Fax: +1 605-688-6364;
E-mail: mukulesh.baruah@sdstate.edu
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

462 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Mukulesh Baruah
Table 1
Entry
Cu(ClO4)2.6H2O-Catalyzed Synthesis of Bis(indolyl)methane Derivatives
Carbonyl compounds
Time (min)
Yielda (%)
Ref.b
a
b
c
d
CHO
5
94
98
95
95
[20]
[11]
[26]
[26]
MeO
CHO
8
O2N
CHO
10
10
Cl
F
CHO
CHO
CHO
CHO
e
f
10
10
10
5h
5h
96
95
90
57
55
[31]
[29(a)]
[12]
Br
HO
g
h
O
[11]
i
O
[10]
aIsolated yields.
bAll products were characterized by comparing their 1H NMR data and melting points of solids with the literature reports.
Table 2. Studied Solvents and Conditions
Entry
Solvent
Time
Yield (%)
1
2
3
4
5
Neat
MeCN
THF
5-30 minutes
50-97
80
40 minutes
4h
5h
4h
90
MeOH
CH2Cl2
trace
90
trile was proved to be the best choice since the reactions
were at similar rate as neat but gave lower yields and trace
amount of a side product was observed due to the reaction of
nitrile and indole.
tocol. Solvent free conditions have established this procedure
as nature friendly.
ACKNOWLEDGEMENTS
MB greatly acknowledges the current fellowship of
BCAAP (Biological Control and Analysis by Applied Pho-
tonics) at SDSU. The lab facilities provided by Prof. Dr.
Ronald Utecht and Prof. Dr. Fathi Halaweish at SDSU are
deeply acknowledged. Author is thankful to Mousoomi Bora
for the help in preparing this manuscript.
In conclusion, we have described a novel efficient
method for the electrophilic substitution of indole with car-
bonyl compounds using copper perchlorate hexahydrate as a
catalyst at room temperature without solvent. This method is
rapid, clean, high yielding and possesses easy work up pro-

Facile Synthesis of Bis(indolyl)alkanes Catalyzed
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
463
[21]
Zolfigol, M. A.; Salehi, P.; Shiri, M. An efficient procedure for the
preparation of mono- and di-bis-indolyl methanes catalyzed by
molibdatophosphoric acid. Phosphorus, Sulfur Silicon Relat. Elem.,
2004, 179, 2273-2277.
REFERENCES
[1]
Sundberg, R.J. The Chemistry of Indoles, Academic press: New
York, 1970.
Bell, R.; Carmelli, S.; Sar, N. Vibrindole A, a Metabolite of the
Marine Bacterium, Vibrio parahaemolyticus, Isolated from the
Toxic Mucus of the Boxfish Ostracion cubicus. J. Nat. Prod., 1994,
57, 1587-1590.
[22]
[23]
Mo, L.P.; Ma, Z-C.; Zhang, Z-H. CuBr2 catalyzed synthesis of
Bis(indolyl)methanes. Synth. Commun., 2005, 35, 1997-2004.
Meshram, G.A.; Patil, V.D. Simple and efficient method for syn-
thesis of Bis(indolyl)methanes with Cu(BF4)2.SiO2 under mild con-
ditions. Synth. Commun., 2010, 40, 29-38.
[2]
[24]
[25]
Suresh, D. K.; Sandhu, J.S. CuSO4.5H2O, A novel and efficient
catalyst for the synthesis of Bisindolylmethanes. J. Ind. Chem Soc.,
2009, 86, 488-490.
[3]
[4]
[5]
Hong, C.; Firestone, G.L.; Bjelanes, L.F. Bcl-2 family-mediated
apoptotic effects of 3,3ꢀ-diindolylmethane (DIM) in human breast
cancer cells. Biochem. Pharmacol. 2002, 63(6), 1085-1097.
Kamal, A.; Qureshi, A.A. Synthesis of substituted di-
indolylmethanes in aqueous medium at room temperature. Tetrahe-
dron, 1963, 19, 513-520.
Babu, G.; Sridhar, N.; Perumal, P.T. A convenient method of syn-
thesis of bis-indolylmethanes: Indium trichloride-catalyzed reac-
tions of indole with aldehydes and Sciff’s bases. Synth. Commun.,
2000, 30, 1609-1614.
Nagarajan, R.; Perumal, P.T. InCl3- and In(OTf)3- catalyzed reac-
tions: Synthesis of 3-acetyl indoles, bisindolylmethane and in-
dolylquinoline derivatives. Tetrahedron, 2002, 58, 1229-1232.
Bandgar, B.P.; Shikh, K.A. Organic reactions in aqueous medium:
InF3 catalyzed synthesis of bis(indolyl)methanes in water under
mild conditions. J. Chem. Res. Synop., 2004, 1, 34-36.
Mi, X-L.; Luo, S-Z.; He, J-Q.; Cheng, J-P. Dy(OTf)3 in ionic liq-
uid: An efficient catalytic system for reaction of indole with alde-
hydes / ketones or imines. Tetrahedron Lett., 2004, 45, 4567-4570.
Chen, D.; Yu, L.; Wang, P.G. Lewis acid-catalyzed reactions in
protic media. Lanthanide catalyzed reactions of indoles or ketones.
Tetrahedron Lett. 1996, 37, 4467-4470.
Yadav, J.S.; Subba Reddy, B.V.; Murthy, C.V.S.R.; Kumar, G.M.;
Madan, Ch. Lithium perchlorate-catalyzed reactions of indoles: An
expeditious synthesis of bis(indolyl)methanes. Synthesis, 2001, 5,
783-787.
Zhang, Z.H.; Yin, L.; Wang, Y.M. An Efficient and Practical Proc-
ess for the Synthesis of Bis(indolyl)methanes Catalyzed by Zirco-
nium Tetrachloride. Synthesis, 2005, 12, 1949-1954.
Lin, X.F.; Cui, S.-L.; Wang, Y.G. Mild and Efficient Synthesis of
bis-Indolylmethanes Catalyzed by Tetrabutylammonium Tribro-
mide. Synth. Commun., 2006, 36, 3153-3160.
Xia, M.; Wang, S-H.; Yuan, W-B. Lewis Acid Catalyzed Electro-
philic Substitution of Indole with Aldehydes and Schiff's Bases
Under Microwave Solvent-Free Irradiation. Synth. Commun., 2004,
34(17), 3175-3182.
Koshima, H.; Matsuaka, W. N-Bromosuccinimide catalyzed con-
densations of indoles with carbonyl compounds under solvent free
conditions. J. Heterocycl. Chem., 2002, 39, 1089-1091.
Nagarajan, R.; Perumal, P. T. Potassium hydrogen sulfate-
catalyzed reactions of indoles: A mild expedient synthesis of bis-
indolylmethanes. Chem. Lett., 2004, 33, 288-289.
Ramesh, C.; Banerjee, J.; Pal, R.; Das, B. Silica supported sodium
hydrogen sulfate and amberlyst-15: Two efficient heterogeneous
catalysts for facile synthesis of bis- and tris(1H-indole-3-
yl)methanes from indoles and carbonyl compounds. Adv. Synth.
Catal., 2003, 345, 557-559.
Nagarajan, R.; Perumal, P.T. Electrophilic substitution of indoles
catalyzed by triphenyl phophonium perchlorate: synthesis of 3-
acetyl indoles and bis-indolylmethane derivatives. Synth. Commun.,
2002, 32, 105-109.
Ramesh, C.; Rabindranath, N.; Das, B. Electrophilic substitution
reactions of indoles with carbonyl compounds using ceric ammo-
nium nitrate: A novel and efficient method for the synthesis of di-
and tri-indolylmethanes. J. Chem. Res. Synop., 2003, 1, 72-74.
Karthik, M.; Tripathi, A.K.; Gupta, N.M.; Palanichamy, M.; Mu-
rugesan, V. Zeolite-catalyzed electrophilic substitution reactions of
indoles with aldehydes: Synthesis of bis(indolyl)methanes. Catal.
Commun., 2004, 5, 371-375.
Sharma, G.V.M.; Reddy, J.J.; Lakshmi, P.S.; Krishna, P.R. A ver-
satile
and
practical
synthesis
of
bis(indoyl)methanes/bis(indolyl)glycoconjugates catalyzed by
trichloro-1,3,5-triazine. Tetrahedron Lett., 2004, 45, 7729-7732.
Bandgar, B.P.; Bettigeri, S.V.; Joshi, N.S. Hexamethyle-
netetraamine-bromine–catalyzed rapid and efficient synthesis of
bis(indolyl)methanes. Monatsh. Chem., 2004, 135, 1265-1273.
Feng, X-L.; Guan, C-J.; Zhao, C-X. Ion exchange resin–catalyzed
condensation of indole and carbonyl compounds-Synthesis of bis-
indolylmethanes. Synth. Commun., 2004, 34, 487-492.
[26]
[27]
[28]
[29]
[6]
[7]
[8]
[9]
[10]
Ji, S-J.; Zhou, M-F.; Gu, D-G.; Wang, S-Y.; Loh, T-P. Efficient
synthesis of bis(indolyl)methanes catalyzed by Lewis acids in ionic
liquids. Synlett, 2003, 13, 2077-2079.
(a) Khodaei, M.M.; Mohammadpoor-Baltork, I.; Memarian, H.R.;
Khosropour, R.; Nikofar, K.; Ghanbary, P. Synthesis of 3-
substituted indole promoted by activated method catalyzed by
Bi(NO3)3· 5H2O. J Heterocyclic Chem., 2008, 45, 1-5.; (b) De-
odhar, D.K.; Bhat, R.P.; Samant, S.D. Bismuth(III) nitrate penta-
hydrate: an efficient catalyst for the synthesis of
bis(indolyl)methanes under mild condition. Ind. J Chem. Sec B:
Org Chem including Med. Chem., 2007, 46B, 1455-1458.; (c) Igle-
sias, L.; Aguliar, C.; Bandyopadhyay, D.; Banik, B.K. A new Bis-
muth nitrate-catalyzed electrophilic substitution of indoles with
carbonyl compounds under solvent free conditions. Synth. Com-
mun., 2010, 40, 3678-3682.
[11]
[12]
[13]
[30]
Ghorbani-Vaghei, R.; Veisi, H.; Keypour, H.; Dehghani-
Firouzabadi, A.A.
A practical and efficient synthesis of
bis(indolyl)methanes in water, and synthesis of di-, tri-, and
tetra(bis-indolyl)methanes under thermal conditions catalyzed by
oxalic acid dehydrate. Mol. Divers., 2010, 14(1), 87-96.
Bandgar, B.P.; Patil, A.V.; Kamble, V.T. Fluoroboric acid ab-
sorbed on silica gel catalyzed synthesis of bisinolyl alkanes under
mild and solvent-free conditions. ARKIVOC, 2007, xvi, 252-259.
Yadav, J.S.; Gupta, M.K.; Jain, R.; Yadav, N.N.; Reddy, B.V.S. A
practical synthesis of bis(indolyl)methanes employing boric acid.
Monatsh Chem., 2010, 141, 1001-1004.
Jeyakumar, K.; Chand, D.K. Copper perchlorate: Efficient acetyla-
tion catalyst under solvent free conditions. Journal of Molecular
Catalysis A: Chemical, 2006, 255, 275-282.
Majhi, A.; Kim, S.S.; Kim, H.S. Copper perchlorate hexahydrate: a
highly efficient catalyst for the cyanosilylation of aldehydes. Appl.
Organometal. Chem., 2008, 22, 407-411.
Zhou, J.; Tang, Y. Sidearm effect: Improvement of the enanti-
omeric excess in the asymmetric Michael addition of indoles to al-
kylidene malonates. J. Am. Chem. Soc., 2002, 124, 9030-9031.
Dalpozzo, R.; Bartoli, G.; Sambri, L.; Melchiorre, P. Perchloric
acid and its salts: very powerful catalysts in organic chemistry.
Chem. Rev., 2010, 110, 3501-3551.
General Procedure: In a small vial, Indole (1mmol), carbonyl com-
pounds (0.5 mmol) and 10mg (5% to the carbonyl compounds) of
Cu(ClO4)2.6H2O were placed and mixed well with a spatula.
Within minutes, the reaction mixtures were turned to a dark colored
oily paste which was then kept at room temperature for appropriate
time. The progression was monitored by TLC by dissolving small
amount in dichloromethane. After completion, dichloromethane
(15mL) was added and the solution was washed with water
(5mL).The separated organic part was dried over anhydrous so-
dium sulfate, concentrated in vacuo and purified by column chro-
matography over silica using ethyl acetate:hexane(4:6) as eluent.
The yields for individual products are given in Table 1.
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
Chakrabarty, M.; Ghosh, N.; Basak, R.; Harigaya, Y. Dry reactions
of indoles with carbonyl compounds on montmorilonite K10 clay:
A mild expedient synthesis of diindolylalkanes and vibrindole A.
Tetrahedron Lett., 2002, 43, 4075-4078.