Phospho Sulfonic Acid: A Highly Efficient and Novel Catalyst for Formation of Bis(Indolyl)Alkanes from Aldehydes and Indole under Aqueous Conditions

Article abstract of DOI:10.1134/S0023158419040049

Bis(indolyl)alkanes are a class of alkaloids that possess significant biological activities. Every year, the varieties of bis(indolyl)alkanes isolated from natural sources are increasing. Nevertheless, the deficiency of natural products from natural sourc

Full text of DOI:10.1134/S0023158419040049

ISSN 0023-1584, Kinetics and Catalysis, 2019, Vol. 60, No. 4, pp. 522–535. © Pleiades Publishing, Ltd., 2019.
Phospho Sulfonic Acid: A Highly Efficient and Novel Catalyst
for Formation of Bis(Indolyl)Alkanes from Aldehydes and Indole
under Aqueous Conditions
Muhammad Faisala, *, Fayaz Ali Larika, Muhammad Salmana, and Aamer Saeeda, **
aDepartment of Chemistry, Quaid-i-Azam University, Islamabad, 45320 Pakistan
*e-mail: mfaisal4646@gmail.com
**e-mail: aamersaeed@yahoo.com
Received August 1, 2018; revised December 6, 2018; accepted February 1, 2019
Abstract—Bis(indolyl)alkanes are a class of alkaloids that possess significant biological activities. Every year,
the varieties of bis(indolyl)alkanes isolated from natural sources are increasing. Nevertheless, the deficiency
of natural products from natural sources led to a decrease in the exploration of natural products for biological
investigations. Corresponding to this fact, there is a demand to develop efficient protocols for the construc-
tion of bis(indolyl)alkanes. In this regards, we have prepared phospho sulfonic acid (PSA), which is a non-
corrosive, highly reactive, inexpensive and low toxic catalyst, and have applied to construct bis(indo-
lyl)alkanes. The catalyst was prepared by reaction of diammonium hydrogen phosphate with chloro sulfuric
acid and was fully characterized by FTIR spectrometry. PSA has been used as a solid acid catalyst to promote
the electrophilic substitution reaction of indole with aldehydes under water to furnish a library of bis(indo-
lyl)alkanes in excellent yields over short reaction times. The present method eliminates use of toxic catalyst
and solvent, and tolerates a series of functional groups. The catalyst can be reused several times without any
important activity loss. The methodology has several advantages, for example, simple experimental proce-
dure, cost efficiency (use of inexpensive catalyst), ease of preparation and handling of the catalyst and no side
reactions.
Keywords: bis(indolyl)methanes, bis(indolyl)alkanes, phospho sulfonic acid, catalyst, synthesis
DOI: 10.1134/S0023158419040049
INTRODUCTION
growth factor receptor kinase [9], serve as topoisomer-
ase IIR catalytic inhibitors [10], have anti-tumori-
genic activity [11], have growth inhibitory potency on
prostate cancer cell lines [12], prevent the process of
proliferation in breast tumor cells [13], bring apoptosis
in prostate cancer [14], prevent mammary tumor
growth [15], are active against colon cancer [16], have
development inhibitory potency on lung cancer cells
[17], prevent renal cell carcinoma growth and bladder
cancer growth [18], have analgesic and anti-inflam-
matory activities [19], have growth promoting activity
[2], have radical scavenging activity [1] and are also
employed as glass-forming high-triplet energy materi-
als and tranquilizers [20]. Vibrindole A was demon-
strated for the first time to exhibit anti-bacterial
potency against Bacillus subtilis, Scaphirhynchus albus,
and Staphylococcus aureus [21]. Thus, indole and its
derivatives have been a topic of research interest. In
light of their potential therapeutic applications, the
development of new strategies and procedures for the
construction of these entities continues to attract
important levels of attention from synthetic organic
Indole analogs are richly found in a diversity of
natural plants and exhibit various physiological prop-
erties and are potentially bioactive compounds [1].
Bis(indolyl)alkanes (also called bis(indolyl)methanes
or bis(indolyl)methane) are important derivatives of
indole. A large number of bis(indolyl)methanes have
been separated from marine and terrestrial natural
sources, for instance, sponges, tunicates and parasitic
bacteria, and some of these possess important phar-
maceutical biological profiles.
Bis(indolyl)alkanes are observed to assist estrogen
metabolism in both men and women and is probable
to have an application in inhibition of breast cancer
[2]. Recently, cancer chemotherapy with bis(indo-
lyl)alkanes were reviewed [3]. 3,3'-Diindolylmethane
and its analogous are also employed as dietary supple-
ments for humans [4]. Bis(indolyl)alkanes serve as
cytodifferentiating agents [5], have inhibitory activities
on phenobarbital-induced hepatic CYP gene expres-
sion [6], exhibit antibiotic activity and antibacterial
activity [7], exhibit antimicrobial and antifungal activ-
ities [8], use as inhibitors of the platelet-derived chemists.
522

PHOSPHO SULFONIC ACID: A HIGHLY EFFICIENT
523
O
NH
N
H
N
O
O
HN
N
H
N
H
NH
NH
HN
Streptindole
N
NH
H
Tris-indoline
Arsindoline A
1,2,3-Tris-(1H-indol-3-yl)butane
O
NH
O
NH
Arsindoline B
NH
Tris-(1H-indol-3-yl)methane
Structures of bis(indolyl)alkanes separated from natural products.
HN
NH
HN
NH
HN
HN
Vibrindole A
Arundine
Attributed to the symmetric skeleton of the reusable, efficient, new and simple method for the for-
bis(indolyl)alkane entity, they are easy to prepare from
two units of indole and acetone/aldehyde using
reagents and catalysts. In the past decades, several
reagents and catalysts have been disclosed for the for-
mation of bis(indolyl)alkanes from carbonyl com-
pounds and indoles such as trityl chloride [22],
P2O5/SiO2 [23], silica chloride [24], MgSO4 [25],
NBS [26], I2 [27] and ionic liquids [28]. Other cata-
lysts such as Re(PFO)3, Ln(OTf)3, Dy(OTf)3, LnCl3,
In(OTf)3, InCl3, ZrOCl2, LiClO4, PEG–O–C6H4–
SO3H, SnCl2 ⋅ 2H2O, Bi(OTf)3, NbCl5, SbCl3, VCl3,
NaBF4, H4SiMo12O40, H3PMo12O40, silica sulfuric
acid [29–32], SiO2/AlCl3 [33], pyridinium tribromide
[34], zirconyl dodecyl sulfate [35], Al2O3 [36], FeCl3 ·
6H2O [37], ZnO [38] and GaCl3 [39] have also been
reported for this transformation. Further, protic acids
such as oxalic acid [40], cellulose sulfuric acid [41],
NH4Cl [42], oxone [43], and montmorillonite clay [44]
were also utilized to promote these transformations.
mation of these medicinally significant entities is still
demanding. As part of our continued passion in con-
struction of highly beneficial approaches for the devel-
opment of heterocyclic entities of pharmaceutical
importance [46–48], herein, we wish to describe
phospho sulfonic acid (PSA), which is observed to be
highly efficient, clean and economically valuable cat-
alyst in reaction of aromatic aldehydes with indole
under water as solvent to furnish bis(indolyl)alkanes.
PSA as a heterogeneous and solid acid catalyst was
simply synthesized by the stirring of diammonium
hydrogen phosphate (DAP) and chlorosulfuric acid in
dichloromethane (DCM) at room temperature. A
possible mechanism for construction of bis(indo-
lyl)alkane core is proposed to interpret the observed
reactivity. The present approach is also compared with
previous reported approaches.
However, many of these catalysts are expensive,
and are sometimes decomposed or deactivated by
nitrogen containing reactants. Even when the required
reactions progress, more than stoichiometric amounts
of catalysts are desired [45]. Moreover, in most of the
reported methods chlorinated solvents such as chloro-
form are used as a reaction medium and/or for the
separation of catalyst which is not in accord with green
chemistry protocols. Some of the documented proce-
dures suffered from the cumbersome work-up proce-
dures, low product yields, prolonged reaction times
(e.g., 4–10 h) and application of an additional ultra-
sound or microwave irradiation [1, 2]. Hence, the
EXPERIMENTAL
Materials and General Methods
All reagents were of high-grade quality and
1
obtained from Merck, Fluka and Aldrich. H NMR,
C13 NMR and P31 NMR spectra were measured on a
Bruker Avance 300 MHz spectrometer using tetrame-
thylsilane as an internal standard (in DMSO-d6) at room
temperature. FT-IR measurements were performed
using KBr disc on JASCO IR-A-302 spectrometer.
Melting points were taken in a Riechert Thermover
construction environmentally friendly, convenient, instrument and are uncorrected.
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FAISAL et al.
1H NMR, δH, ppm: 7.93 (s), 7.35–7.42 (m, 6H), 7.28–
Catalyst Preparation
7.31 (m, 2H), 7.14–7.22 (m, 3H), 7.11 (t, J = 6.9 Hz,
2H), 6.66 (s, 2H), 5.86 (s, 1H); 13C NMR, δ, ppm:
145.2, 137.0, 128.6, 128.5, 127.1, 126.3, 124.0, 121.2,
119.5, 118.4, 111.9, 110.9, 31.6. Anal. calcd. for
C23H18N2: N, 8.69; H, 5.63; C, 85.68. Found: N, 8.64;
H, 5.63; C, 85.63. The spectral data are in good agree-
ment with the literature values [49].
A 50 mL vacuum flask was fitted with a constant
pressure dropping funnel. A vacuum system was cou-
pled with gas outlet through an alkali trap and adsorbing
solution (water). The vacuum flask was charged with
diammonium hydrogen phosphate (2 g, 15 mmol).
Then, over a time period of 40–50 min at room tempera-
ture, solution of chlorosulfuric acid (5.24 g, 45 mmol)
in CH2Cl2 (5 mL) was poured drop wise into the flask.
Thereafter, the resulting mixture was stirred for about
2 h, while the residual hydrochloric acid and ammonia
gases was removed via suction system. After that, to iso-
late the unreacted chlorosulfuric acid, washing of result-
ing mixture was carried out by using CH2Cl2 (3 × 10 mL).
Lastly, phospho sulfonic acid was obtained as a solid
white powder (8.50 g, 83%); free-flowing precipitate
could be stored at r. t. for almost 160 days. The melting
point was found to be 127–130°C.
Bis(indolyl)methane 8a.
S
NH
HN
8a
3,3'-(Thiopen-2-ylmethylene)bis(1H-indole)
Appearance: yellowish solid; Rf = 0.87 (n-hexane :
EtOAc = 5 : 5); m. p. 146–147°C; 1H NMR, δH, ppm:
7.94 (s), 6.97–7.45 (m, 11H), 6.86 (s, 2H), 6.08 (s,
1H); 13C NMR, δ, ppm: 145.5, 136.7, 128.9, 126.3,
125.3, 123.5, 122.6, 121.8, 120.0, 119.3, 111.5, 110.3,
35.9. Anal. calcd. for C21H16N2S: S, 9.76; N, 8.53; H,
4.91; C, 76.80. Found: S, 9.73; N, 8.53; H, 4.93; C,
76.81. The spectral data are in good agreement with
the literature values [49].
General Procedure for the Preparation
of Bis(Indolyl)Alkanes
In 100-mL round bottom flask, a mixture of alde-
hyde (1 mmol) and indole (2 mmol) was charged to a
stirring solution of phospho sulfonic acid (0.06 g) in
H2O (40 mL), and the resulting reaction contents was
vigorously stirred at 100°C for appropriate period of
time (2–3 h). After completion of the reaction, as
observed by thin-layer chromatography (EtOAc : PET
ether = 1 : 2), the reaction content was filtered and
washed with distilled water to separate the catalyst.
The residue contains crude bis(indolyl)alkane prod-
ucts and filtrate contains phospho sulfonic acid
(recovered catalyst). The resulting residue was decon-
taminated via silica gel-mediated chromatographic
purification technique using EtOAc in PET ether
solution (2 : 8) as eluent to furnish the required prod-
ucts. After washing filtrate with EtOAc and then dry-
ing, the obtained phospho sulfonic acid was reused for
subsequent reactions. All the products were identified
by comparing the analytical data (melting point, IR,
1H NMR) with those reported data.
Bis(indolyl)methane 8b.
O
NH
HN
8b
3,3'-(Furan-2-ylmethylene)bis(1H-indole)
Appearance: brownish solid; Rf = 0.56 (n-hexane :
EtOAc (1 : 9)); m. p. 315–317°C; IR, cm–1: 670, 757,
1021, 1093, 1216, 1419, 1456, 1600, 2399, 3019, 3477;
1H NMR, δH, ppm: 8.00 (s), 7.08–7.43 (m, 11H), 6.90
(s, 2H), 5.97 (s, 1H); 13C NMR, δ, ppm: 142.0, 135.9,
126.3, 124.3, 121.7, 119.7, 119.3, 118.0, 112.2, 111.3,
110.2, 106.5, 34.8. Anal. calcd. for C21H16N2O: C,
80.75; H, 5.16; N, 8.97; O, 5.12. Found: C, 80.73; H,
5.14; N, 8.94; O, 5.13. The spectral data are in good
agreement with the literature values [50].
Representative Spectral Data
Bis(indolyl)methane 3.
Bis(indolyl)methane 8c.
NH
NH
HN
3
3,3'-(Phenylmethylene)bis(1H-indole)
Appearance: yellowish solid; Rf = 0.49 (n-hexane :
NH
Tri(1H-indol-3-yl)methane
HN
8c
EtOAc = 5 : 5); m.p. 140–142°C; IR, cm–1: 669, 757,
1017, 1093, 1215, 1419, 1456, 1522, 1601, 3019, 3478;
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PHOSPHO SULFONIC ACID: A HIGHLY EFFICIENT
525
Appearance: yellowish solid; Rf = 0.34 (n-hexane :
EtOAc (4:6)); m. p. 161–164°C; H NMR, δH, ppm:
Bis(indolyl)methane 8f.
1
H3C
10.59 (s, 3H), 7.52 (d, J = 7.9 Hz, 3H), 7.35 (d, J = 7.9
Hz, 3H), 7.05 (m, 3H), 6.86–6.91 (m, 6H), 6.11 (s,
1 H); 13C NMR, δ, ppm: 136.4, 126.6, 123.0, 120.5,
119.1, 118.1, 117.8, 111.2, 30.8. Anal. calcd. for
C25H19N3: C, 83.08; H, 5.30; N, 11.63. Found: C,
83.03; H, 5.34; N, 11.63. The spectral data are in good
agreement with the literature values [51].
NH
HN
8f
Bis(indolyl)methane 8d.
3,3'-(p-Tolylmethylene)bis(1H-indole)
Appearance: brown solid; Rf = 0.34 (n-hexane :
Cl
EtOAc (5 : 5)); m.p. 98–99°C; IR, cm–1: 669, 759,
1021, 1091, 1215, 1417, 1456, 1512, 1602, 3020, 3480;
1H NMR, δH, ppm: 7.94 (bs, 2H), 6.85–7.40 (m,
OH
12H), 6.64 (s, 2H), 5.84(s, 1H), 2.31 (s, 3H); 13C
NMR, δ, ppm: 39.8, 55.9, 119.2, 119.9, 121.9, 123.5,
127.1, 128.9, 136.7. Anal. calcd. for C24H20N2: C,
85.68; H, 5.99; N, 8.33. Found: C, 85.69; H, 5.93; N,
8.34. The spectral data are in good agreement with the
literature values [53].
NH
HN
8d
2-Chloro-6-[di(1H-indol-3-yl)methyl]phenol
Appearance: brown solid; Rf = 0.78 (n-hexane :
EtOAc (5 : 5)); m.p. 201–203°C; IR, cm–1: 805, 1139,
1245, 1469, 1552, 3286, 3325, 3395; H NMR, δH,
Bis(indolyl)methane 8g.
1
H3CO
ppm: 5.77 (s, 1H), 6.23 (s, 1H), 6.70 (s, 2H), 6.74 (d,
J = 10.0 Hz, 1H), 7.06–6.95 (m, 3H), 7.18 (q, J = 8.6
Hz, 3H), 7.34 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 7.6 Hz,
2H), 7.90 (s, 2H); 13C NMR, δ, ppm: 34.0, 111.0,
118.0, 119.3, 119.8, 120.1, 120.6, 122.0, 123.5, 126.8,
127.0, 128.5, 131.4, 136.7, 149.1. Anal. calcd. for
C23H17ClN2O: C, 74.09; H, 4.60; Cl, 9.51; N, 7.51; O,
4.29. Found: C, 74.19; H, 4.62; Cl, 9.56; N, 7.56; O,
4.25. The spectral data are in good agreement with the
literature values [52].
NH
HN
8g
3,3'-[(4-Methoxyphenyl)methylene]bis(1H-indole)
Appearance: brown solid; Rf = 0.78 (n-hexane :
EtOAc (1 : 9)); m.p. 179–182°C; IR, cm–1: 759, 1033,
Bis(indolyl)methane 8e.
1091, 1216, 1336, 1417, 1456, 1455, 1509, 1610, 2838,
1
3019, 3480; H NMR, δH, ppm: 7.89 (bs, 2H), 7.26–
7.40 (m, 6H), 7.2 (t, 2H), 7.03 (t, 2H), 6.83 (d, 2H),
6.64 (d, 2H), 5.84 (s, 1H), 3.77 (s,3H); 13C NMR, δ,
ppm: 38.6, 55.2, 110.9, 113.6, 119.2, 119.4, 119.9, 120,
121.9, 123.5, 127.1, 136.2, 136.7. Anal. calcd. for
C24H20N2O: C, 81.79; H, 5.72; N, 7.95; O, 4.54.
Found: C, 81.73; H, 5.73; N, 7.93; O, 4.54. The spec-
tral data are in good agreement with the literature val-
ues [54].
OH
NH
HN
8e
2-(tert-Butyl)-6-[di(1H-indol-3-yl)methyl]phenol
Bis(indolyl)methane 8h.
Appearance: pale yellowish solid; Rf = 0.43 (n-
hexane : EtOAc (5 : 5)); m.p. 189–191°C; IR, cm–1:
Cl
1
729, 1132, 1261, 1394, 1549, 3278, 3336, 3386; H
NMR, δH, ppm: 1.34 (s, 9H), 5.56 (s, 1H), 5.94 (s,
1H), 6.77 (s, 2H), 7.03–6.97 (m, 4H), 7.18 (t, J = 7.2
Hz, 4H), 7.37 (t, J = 7.6 Hz, 4H), 8.00 (s, 2H); 13C
NMR, δ, ppm: 29.7, 34.6, 36.2, 111.1, 116.9, 118.8,
119.5, 119.9, 121.4, 122.3, 123.7, 125.3, 126.8, 127.6,
129.4, 136.8, 153.4. Anal. calcd. for C27H26N2O: C,
82.20; H, 6.64; N, 7.10; O, 4.06. Found: C, 82.20; H,
6.65; N, 7.6; O, 4.05. The spectral data are in good
agreement with the literature values [52].
Cl
NH
HN
8h
3,3'-[(2,3-Dichlorophenyl)methylene]bis(1H-indole)
Appearance: yellowish solid; Rf = 0.34 (n-hexane :
EtOAc (5 : 5)); m.p. 96–98°C; IR, cm–1: 740, 1090,
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FAISAL et al.
1
Bis(indolyl)methane 8k.
1328, 1471, 1515, 1623, 2853, 2925, 3400; H NMR,
δH, ppm: 6.30 (s, 1H), 6.60 (d, J = 1.2 Hz, 2H), 7.05
(dd, J = 7.6, J = 7.2 Hz, 2H), 7.20–7.12 (m, 4H),
7.40–7.34 (m, 5H), 7.88 (br s, 2H); 13C NMR, δ, ppm:
36.7, 111.2, 117.7, 119.50, 119.6, 122.2, 123.8, 126.8,
127.7, 130.2, 130.6, 132.3, 132.6, 136.7, 143.3. Anal.
calcd. for C23H16Cl2N2: C, 70.60; H, 4.12; Cl, 18.12;
N, 7.16. Found: C, 70.60; H, 4.14; Cl, 18.13; N, 7.15.
The spectral data are in good agreement with the liter-
ature values [55].
HO
HN
NH
8k
Bis(indolyl)methane 8i.
2-[Di(1H-indol-3-yl)methyl]naphthalene-2-ol
Appearance: yellowish solid; Rf = 0.78 (n-hex-
ane:EtOAc (5:5)); m.p. 246–248°C; IR, cm–1: 755,
1
OH
1132, 1312, 1513, 1605, 3283, 3327, 3409; H NMR,
δH, ppm: 6.48 (s, 1H), 6.74 (s, 1H), 6.78 (s, 2H), 6.98
(q, J = 5.0 Hz, 3H), 7.19 (t, J = 7.4 Hz, 3H), 7.30 (d,
J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.40 (d, J =
8.8 Hz, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.98 (s, 2H),
8.13 (d, J = 8.4 Hz, 1H); 13C NMR, δ, ppm: 32.2,
109.9, 111.3, 116.4, 119.4, 119.7, 122.4, 122.6, 123.0,
123.8, 126.7, 128.7, 129.0, 129.4, 132.8, 137.0, 153.9.
Anal. calcd. for C27H20N2O: C, 83.48; H, 5.19; N,
7.21; O, 4.12. Found: C, 83.45; H, 5.15; N, 7.24; O,
4.14. The spectral data are in good agreement with the
literature values [52].
NH
HN
8i
2-[Di(1H-indol-3-yl)methyl]phenol
Appearance: golden oil; Rf = 0.67 (n-hexane :
EtOAc (5 : 5)); 1H NMR, δH, ppm: 5.82 (s, 1H), 6.50
(br s, 1H), 6.59 (s, 2H), 6.89 (t, 2H, J = 6.5 Hz), 7.03–
7.09 (m, 2H), 7.11–7.23 (m, 6H), 7.45 (d, 2H, J = 7.8
Hz), 7.64 (s, 2H); 13C NMR, δ, ppm: 154.4, 137.2,
136.8, 130.1, 129.5, 127.9, 126.8, 124.5, 122.3, 120.8,
120.0, 119.5, 117.6, 111.3, 29.8. Anal. calcd. for
C23H18N2O: C, 81.63; H, 5.36; N, 8.28; O, 4.73.
Found: C, 81.64; H, 5.34; N, 8.24; O, 4.74. The spec-
tral data are in good agreement with the literature val-
ues [56].
Bis(indolyl)methane 8l.
CH3
H3C
Bis(indolyl)methane 8j.
NH
HN
8l
OCH3
O2N
3,3'-[(3,5-Dimethylphenyl)methylene]bis(1H-indole)
Appearance: white soild; Rf = 0.45 (n-hexane :
EtOAc (1 : 9)); m.p. 94–97°C; IR, cm–1: 795, 1145,
1285, 1482, 1572, 3316, 3349; 1H NMR, δH, ppm: 2.23
(s, 6H), 5.79 (s, 1H), 6.65 (s, 2H), 6.83 (s, 1H), 7.01–
6.95 (m, 4H), 7.16–7.12 (m, 2H), 7.33 (d, J = 8.0 Hz,
2H), 7.40 (d, J = 8.0 Hz, 2H), 7.86 (s, 2H); 13C NMR,
δ, ppm: 21.3, 40.0, 110.8, 119.1, 119.9, 121.7, 123.5,
126.4, 127.1, 127.7, 136.6, 137.4, 143.8. Anal. calcd for
C25H22N2: C, 85.68; H, 6.33; N, 7.99. Found: C,
85.65; H, 6.34; N, 8.00. The spectral data are in good
agreement with the literature values [52].
OH
NH
HN
8j
2-[Di(1H-indol-3-yl)methyl]-6-methoxy-4-nitrophenol
Appearance: yellowish solid; Rf = 0.65 (n-hexane :
EtOAc (1 : 9)); m. p. 229–230°C; IR, cm–1: 824, 1249,
1438, 1562, 3294, 3371, 3401; 1H NMR, δH, ppm: 3.91
(s, 3H), 6.23 (s, 1H), 6.79 (s, 2H), 6.86 (t, J = 7.2 Hz,
2H), 7.02 (t, J = 7.4 Hz, 2H), 7.23 (d, J = 7.6 Hz, 2H),
7.34 (d, J = 8.0 Hz, 2H), 7.63 (s, 2H), 10.34 (s, 1H),
10.81 (s, 2H); 13C NMR, δ, ppm: 32.2, 56.7, 105.0,
112.0, 117.0, 118.1, 118.7, 119.0, 121.4, 124.1, 126.9,
132.1, 137.0, 139.4, 147.5, 150.9. Anal. calcd. for
C24H19N3O4: C, 69.72; H, 4.63; N, 10.16; O, 15.48.
Found: C, 69.75; H, 4.65; N, 10.14; O, 15.44. The
spectral data are in good agreement with the literature
values [52].
Bis(indolyl)methane 8m.
H3CO
H3CO
NH
3,3'-[(3,4-Dimethoxyphenyl)methylene]bis(1H-indole)
HN
8m
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527
Appearance: yellowish solid; Rf = 0.34 (n-hexane : tral data are in good agreement with the literature val-
EtOAc (5 : 5)); m.p. 196–197°C; IR, cm–1: 759, 1033,
1091, 1216, 1336, 1418, 1456, 1512, 1604, 3020, 3480;
1H NMR, δH, ppm: 7.91 (bs, 2H, NH), 7.29–7.43 (m,
4H), 7.17 (t, 2H), 7.0 (t, 3H), 6.78 (d, 2H), 6.65 (d,
2H), 5.83 (s, 1H), 3.85 (s, 3H), 3.76 (s, 3H); 13C
NMR, δ, ppm: 39.8, 55.8, 111, 112.3, 119.2, 119.8,
121.9, 123.5, 127.1, 136.7, 147.4. Anal. calcd. for
C25H22N2O2: C, 78.51; H, 5.80; N, 7.32; O, 8.37.
Found: C, 78.54; H, 5.81; N, 7.36; O, 8.35. The spec-
tral data are in good agreement with the literature val-
ues [57].
ues [58].
Bis(indolyl)methane 8p.
NO2
HN
NH
8p
3,3'-[(2-Nitrophenyl)methylene]bis(1H-indole)
Appearance: black-red solid; Rf = 0.45 (n-hexane :
EtOAc (1 : 9)); m. p. 138–140°C; IR, cm–1: 727, 1239,
Bis(indolyl)methane 8n.
1
O2N
1326, 1426, 1521, 1649, 3022, 3345; H NMR, δH,
ppm: 6.42 (d, J =1.6 Hz, 2H), 6.61 (s, 1H), 6.94 (t, J =
7.6 Hz, 2H), 7.10 (t, J = 7.2 Hz, 2H), 7.20–7.18 (m,
2H), 7.25–7.22 (m, 2H), 7.34–7.29 (m, 3H), 7.77–
7.73 (m, 3H); 13C NMR, δ, ppm: 34.8, 111.4, 117.5,
119.5, 119.7, 122.2, 124.0, 124.4, 126.8, 127.3, 131.1,
132.5, 136.7, 138.1, 149.8. Anal. calcd. for C23H17N3O2:
C, 75.19; H, 4.66; N, 11.44; O, 8.71. Found: C, 75.11;
H, 4.68; N, 11.47; O, 8.72. The spectral data are in
good agreement with the literature values [58].
HN
NH
8n
3,3'-[(4-Nitrophenyl)methylene]bis(1H-indole)
Bis(indolyl)methane 8q.
Appearance: yellowish solid; Rf = 0.45 (n-hexane :
EtOAc (1 : 9)); m.p. 221–222°C; IR, cm–1: 775, 1150,
1296, 1490, 1586, 3329, 3356; 1H NMR, δH, ppm: 6.11
(s, 1H), 6.94–6.90 (m, 4H), 7.11–7.07 (m, 2H), 7.36
(d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.67 (t,
J = 8.8 Hz, 2H), 8.19 (d, J = 8.8 Hz, 2H); 13C NMR,
δ, ppm: 41.0, 112.3, 118.3, 119.6, 120.0, 122.3, 124.1,
124.7, 127.8, 130.6, 137.9, 147.3, 154.1. Anal. calcd. for
C23H17N3O2: C, 75.19; H, 4.66; N, 11.44; O, 8.71.
Found: C, 75.12; H, 4.65; N, 11.46; O, 8.72. The spec-
tral data are in good agreement with the literature val-
ues [58].
Cl
HN
NH
8q
3,3'-[(4-Chlorophenyl)methylene]bis(1H-indole)
Appearance: whitish solid; Rf = 0.56 (n-hexane :
EtOAc (1 : 9)); m.p. 74–75°C; IR, cm–1: 670, 759,
1015, 1091, 1216, 1417, 1456, 1523, 1600, 2927, 3020,
3478; 1H NMR, δH, ppm: 5.86 (s, 1H), 6.63 (d, J= 1.6 Hz,
2H), 7.01 (t, J = 7.6 Hz, 2H), 7.18 (dd, J = 8.4, J = 7.6 Hz,
2H), 7.28–7.24 (m, 4H), 7.36 (d, J = 8.4 Hz, 4H), 7.93
(br s, 2H); 13C NMR, δ, ppm: 39.6, 111.1, 119.2, 119.4,
119.8, 122.1, 123.6, 126.9, 128.4, 130.1, 131.8, 136.7,
142.6. Anal. calcd. for C23H17ClN2: C, 77.41; H, 4.80;
Cl, 9.94; N, 7.85. Found: C, 77.44; H, 4.79; Cl, 9.91;
N, 7.82. The spectral data are in good agreement with
the literature values [59].
Bis(indolyl)methane 8o.
NO2
HN
NH
8o
3,3'-[(3-Nitrophenyl)methylene]bis(1H-indole)
Appearance: reddish solid; Rf = 0.78 (n-hexane :
Bis(indolyl)methane 8r.
EtOAc (1 : 9)); m. p. 260–262°C; 1H NMR, δH, ppm:
5.98 (s, 1H), 6.64 (s, 2H), 7.03 (dd, J = 5.6, J = 7.6 Hz,
2H), 7.19 (t, J = 7.6 Hz, 2H), 7.44–7.33 (m, 5H), 7.69
(d, J = 7.6 Hz, 1H), 7.99 (br s, 2H), 8.08 (d, J = 8.0 Hz,
1H), 8.20 (s, 1H); 13C NMR, δ, ppm: 39.9, 111.3,
118.2, 119.4, 119.5, 121.5, 122.3, 123.6, 123.7, 126.6,
129.1, 134.9, 136.7, 146.4, 148.4. Anal. calcd. for
C23H17N3O2: C, 75.19; H, 4.66; N, 11.44; O, 8.71.
Found: C, 75.16; H, 4.64; N, 11.43; O, 8.72. The spec-
Cl
HN
NH
8r
3,3'-[(3-Chlorophenyl)methylene]bis(1H-indole)
KINETICS AND CATALYSIS Vol. 60 No. 4 2019

528
FAISAL et al.
Appearance: whitish solid; Rf = 0.45 (n-hexane :
RESULTS AND DISCUSSION
1
EtOAc (1 : 9)); m.p. 91–94°C; H NMR, δH, ppm:
5.84 (s, 1H), 6.61 (d, J = 1.6 Hz, 2H), 7.03 (dd, J =
8.8, J = 8.0 Hz, 2H), 7.24–7.15 (m, 5H), 7.38–7.33
(m, 5H), 7.87 (br s, 2H); 13C NMR, δ, ppm: 40.0,
111.1, 119.0, 119.4, 119.8, 122.1, 123.6, 126.4, 126.8,
126.9, 128.8, 129.5, 134.1, 136.7, 146.2. Anal. calcd. for
C23H17ClN2: C, 77.41; H, 4.80; Cl, 9.94; N, 7.85.
Found: C, 77.42; H, 4.82; Cl, 9.93; N, 7.83. The spec-
tral data are in good agreement with the literature val-
ues [59].
Phospho Sulfonic Acid Preparation and Properties
Over the past few years, the application of recycla-
ble solid acid catalysts has received significant atten-
tion in organic synthesis as a result of their profitable
and environmental benefits. These types of reagents
not only make simpler purification processes but also
help in reducing the liberation of toxic reaction resi-
dues into the environment [60–62]. The solid acid
catalysts are simply removed from the reaction mix-
ture by filtration or centrifugation without the need for
neutralization, thereby enabling more eco-friendly
processes. Phospho sulfonic acid (PSA) as a new solid
acid catalyst was reported by Kiasat et al. in 2013. It has
been employed as a promising solid acid catalyst in
various organic functionalizations [60, 63].
Bis(indolyl)methane 8s.
Cl
PSA as a heterogeneous and solid acid catalyst was
simply synthesized by the stirring of DAP and chloro-
sulfuric acid in DCM at room temperature (Scheme 1).
The yield was 83% and the melting point was observed
to be 127–130°C. It is observed that this reaction is
clean and easy because the by-products of the reaction
are NH3 and HCl gases, which are evolved immedi-
ately from there action flask. It is also noticed that
PSA is a non-volatile, non-corrosive, recyclable, and
eco-friendly solid acid catalyst. Moreover, it also
offers numerous advantages such as cleaner reactions,
long catalytic life, excellent solubility in water, safe
and inexpensive in comparison to classical catalysts.
Moreover, it displayed high thermal stability, reactiv-
ity and catalytic activities, and can easily be handled
and removed from the reaction content [63–65].
HN
NH
8s
3,3'-[(2-Chlorophenyl)methylene]bis(1H-indole)
Appearance: reddish solid; Rf = 0.45 (n-hexane :
EtOAc (1 : 9)); m.p. 73–74°C; IR, cm–1: 730, 1208,
1
1305, 1424, 1517, 1615, 3016, 3425; H NMR, δH,
ppm: 6.31 (s, 1H), 6.49 (d, J = 1.7 Hz, 2H), 7.06–6.97
(m, 2H), 7.20–7.09 (m, 5H), 7.28 (d, J = 8.5 Hz, 2H),
7.40 (t, J = 7.5 Hz, 3H), 7.70 (br s, 2H); 13C NMR, δ,
ppm: 36.7, 111.2, 118.3, 119.3, 119.9, 122.1, 123.9,
126.7, 127.0, 127.6, 129.5, 130.4, 133.9, 136.7, 141.4.
Anal. calcd. for C23H17ClN2: C, 77.41; H, 4.80; Cl,
9.94; N, 7.85. Found: C, 77.42; H, 4.81; Cl, 9.84; N,
7.83. The spectral data are in good agreement with the
literature values [59].
NH+4
O
O
HO P O−
O−
3ClSO3H
+
+ 3HCl
HO SO P OSO H
+ 2NH3
3
3
r.t.
OSO3H
NH+4
Scheme 1. Synthesis of phospho sulfonic acid.
The signal at 730 cm–1 is due to S–O stretching vibra-
tions. The O=S=O symmetric and asymmetric
stretching signals, and stretching S–O signal precisely
confirmed the presence of the SO3 group linkage [63–
Characterization of Phospho Sulfonic Acid
One of the useful methods for an examination of
catalyst development is infrared spectroscopy.
Accordingly, the formation of the phospho sulfonic
acid was determined by spectrum of infrared spec-
trometer via the potassium bromide disc approach
(Fig. 1). As illustrated in Fig. 1, the sharp peaks in the
range of 3422–3336 cm–1 and range of 3172–3085 cm–1
are related to the O–H stretch of the SO3H group [61,
65]. Appearance of signals at 1048 and 998 cm–1 are
owing to stretching vibration of P=O and P–O bonds,
respectively. The sulfonic acid loading of PSA was calcu-
lated based on titration of the proton-exchanged brine
solution and shown the loading of 11.0 mmolSO H/g of
3
62]. The signal at 1237 cm–1 is owing to the S=O
asymmetric stretching and signal at 1147 cm–1 is
acidic catalyst [66].
In order to investigate the structure and purity of
attributed to the S=O symmetric stretching vibrations. synthesized PSA, 31P NMR of PSA was carried out
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PHOSPHO SULFONIC ACID: A HIGHLY EFFICIENT
(Fig. 2). Orthophosphate is a salt or ester of ortho-
529
phosphoric acid, or any compound containing the tri-
valent group −PO4. Hence, a peak at –4 ppm indicat-
ing the presence of O=P(OX)3 in the structure of PSA.
Further, a single peak of phosphorous of PSA in spec-
trum demonstrates the absence of starting material in
catalyst material, revealing that the synthesized PSA is
highly pure.
4000 3600 3200 2800 2400 2000 1600 1200 800 400
In order to study the thermal stability of the PSA,
thermal gravimetric analysis (TGA) was performed in
the range of temperature from 20 to 280°C (Fig. 3). In
the TGA curve, two-stage decomposition is noticed
corresponding to different weight lose ranges. The first
stage is from 20 to 241°C, accompanied by a weight
loss of around 8.03% and corresponding to desorption
of trapped water and organic solvents, which were
used in synthesis the catalyst. The second decomposi-
tion stage occurred from 241 to 416°C, accompanied by a
large weight loss of approximately 83% and corresponding
to the thermal decomposition of catalyst and/or breaking
of bonds. From the TGA, it can be deduced that PSA
could be employed safety in organic reactions due to large
thermal stability up to around 210°C.
Wavelength, cm–1
Fig. 1. FT-IR spectrum of the phospho sulfonic acid.
O
X
O
P
O
X
O
X
40
20
0
ppm
–20
–40
31
Fig. 2. P NMR spectrum of PSA.
Catalytic Activity of Phospho Sulfonic Acid and Reaction
Conditions Optimization
100
Initially, we decided to investigate the efficiency of
PSA as a catalyst in the synthesis of bis(indo-
lyl)alkanes. To optimize the reaction conditions,
benzaldehyde 2 was selected as a model for the elec-
trophilic substitution reaction with indole 1. Benzal-
dehyde 2 (1 mmol) was reacted with indole 1 (2 mmol)
in the presence of phospho sulfonic acid as a catalyst
under various conditions (Table 1). Several different
solvents were screened against the model reaction,
including water, chloroform, acetonitrile, ethanol,
methanol and tetrahydrofuran (THF), which gave the
best results in terms of the reaction time and yield.
Following a period of screening, the optimal reaction
conditions for the model reaction were determined to
be 1 mmol aldehyde, 2 mmol benzaldehyde, and 0.06 g
of the phospho sulfonic acid catalyst in 30 mL of H2O
at refluxing, as shown in Table 1. It is interesting to
note that further increases in the amount of catalyst or
temperature did not lead to any improvements in the
reaction time or yield. In the solvent free conditions,
even in the presence of 0.06 g of the catalyst at 100°C,
the yields are low. The yields of 3 were measured by 1H
NMR spectroscopy using 1,3,5-trimethylbenzene as
an internal standard. Noteworthy, the beauty of this
methodology is that the reaction takes place in water
to afford the product in acceptable yield. Recently,
organic reactions conducted in aqueous media have
received much attention, because water is nontoxic,
80
60
40
20
0
200
400
600
800
1000
Tempertaure, °C
Fig. 3. The TGA curve of PSA.
ronment [67, 68]. Water not only increases the rate
and yield of reactions, but also enhances enantioselec-
tivity in chiral synthesis. In addition, reactions in
aqueous media illustrate unique selectivity and reac-
tivity that are not frequently noticed in organic envi-
ronment [69].
Plausible Mechanistic Pathway of the Synthesis
of Bis(Indolyl)Alkanes
In the initial step, proton on phospho sulfonic acid
activate the carbonyl unit of the aromatic aldehyde,
resulting in formation of complex 4 via attack by
cheap, abundantly available and benign to the envi- indole on carbonyl group of aldehyde and removal of
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530
FAISAL et al.
proton of phospho sulfonic acid (Scheme 2). Next, abstraction of proton by nucleophilic attack is
abstraction of proton by nucleophilic attack of phos- enhanced, and complex 7 is converted into 3, and the
pho sulfonic acid on proton of indole and subsequent catalyst phospho sulfonic acid then enters another cat-
phospho sulfonic acid-assisted elimination of water alytic cycle (Scheme 2). The study of mechanism
via rearrangement afforded intermediate 6. Then, reveals that water also plays important role during
another indole molecule is coupled with intermediate reaction. All the steps of reactions were also acceler-
6 via an aza-Michael addition reaction to deliver inter- ated by water attributed to enforced hydrophobic
mediate 7. Finally, through the significant collabora- interactions during the activation process and
tion between nitrogen and phospho sulfonic acid in 7, enhanced hydrogen bonding.
H
H
H
N
N
N
-H2O
H
2
4
O δ+
H
H
5
1
OH
OH
H
OSO3H
O
S
O
S
O
S
O
O
O
O
O
H
P
O
O
O
O
OSO3H
O
HO3SO P OSO3H
O
HO3SO P OSO3H
O
N
H
NH
H
HN
NH
HN
6
N
7
3
OSO3H
O
O
S
O
S
H
OSO3H
HO3SO
O
O
O
O
P
O
S
O
O
P
O
P
O
O
O
O
OSO3H
OSO3H
HO3SO
Scheme 2. Proposed reaction for construction of bis(indolyl)alkane framework.
Reusability of Phospho Sulfonic Acid Catalyst
72% in reaction time of 130 min. In fourth run, the
catalyst gives 70% yield in reaction time of 140 min.
This indicated that the phospho sulfonic acid was an
operative and recyclable catalyst for the preparation of
bis(indolyl)alkanes. The decrease in product yield
with number of reuses is might be owing to handling
loss during work-up. For this, we have also performed
the recovery wt % of catalyst after each cycle and
decrease in wt % from 100 to 91% was noticed (Fig. 4).
The recyclability of the phospho sulfonic acid cat-
alyst was also studied in the same model reaction
under optimized conditions (Fig. 4). Upon reaction
completion, the recovered catalyst by filtration was
washed with thoroughly with water and then EtOAc.
After drying, it was reused for subsequent reactions.
The procedure was repeated and the results indicated
that the catalyst could be recycled for almost four
times with only a small loss of activity. Briefly, the
fresh catalyst afforded 3 in 92% yield in reaction time
of 120 min. In first cycle, the catalyst provides 3 in
86% yield in the same period of reaction time. In sec-
Synthesis of Library of Bis(Indolyl)Alkanes
To demonstrate the generality of the procedure, the
ond cycle, the catalyst delivers 3 in 81% yield in reac- reaction protocol was then extended towards a library
tion time of 130 min. In third run, the catalytic effi- of aromatic aldehydes 7 with indole 1 and the conse-
ciency decreases significantly, i.e., yield of 3 becomes quences are illustrated in Table 2. Pleasingly, current
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PHOSPHO SULFONIC ACID: A HIGHLY EFFICIENT
Table 1. Yield of bis(indolyl)alkane at different reaction conditions*
531
CHO
Phospho sulfonic acid
Solvent
+
N
H
NH
HN
2
1
3
1H NMR yield, %***
Entry
Solvent
Phospho sulfonic acid, g
t, min
T, °C**
1
2
H2O
0.04
0.04
0.04
0.04
0.04
0.04
0.06
0.08
0.06
0.06
0.06
0.06
0.06
0.06
0.06
120
160
140
120
120
140
120
120
160
160
140
120
120
140
120
100
60
87
83
82
86
82
81
92
91
92
86
87
89
85
85
81
CHCl3
CH3CN
EtOH
3
82
4
5
80
65
CH3OH
6
7
THF
H2O
65
100
100
100
60
8
H2O
9
H2O
10
11
12
13
14
15
CHCl3
CH3CN
EtOH
82
80
65
CH3OH
THF
No solvent
65
100
* Reaction conditions: benzaldehyde (1 mmol), indole (2 equiv), phospho sulfonic acid in refluxing solvent.
** Oil bath temperature.
1
*** H NMR yields, using 1,3,5-trimethylbenzene as an internal standard.
technique tolerates a series of functional groups, for rins) in excellent isolated yields over short reaction
times under the optimized conditions. Both deactivat-
ing (Table 2, entries 4, 8, 14–19) and electron-donat-
ing/electron-releasing (Table 2, entries 5–7, 9–12)
substituents had no significant effect on the reaction
yields. However, in-depth analysis reveals interesting
finding that substrates having electron-donating
groups (Table 2, entries 6, 7 and 13) para to the posi-
tion of the electrophilic substitution afforded excellent
yields in the somewhat smaller time. Most probably, it
is because an electron releasing unit increases the den-
sity of electron at the p-position to it, resulting that
position more vulnerable to electrophilic attack. On
the reaction results, the presence of halo substituent
on the ring of aldehydes had an insignificant effect
(Table 2, entries 8, 17–19). Heteroaromatic aldehydes
also afforded the respective bis(indolyl)alkanes in high
yields (Table 2, entries 1–3). Additionally, the condi-
tions of reaction were mild enough to bring any dam-
age to the acid-sensitive moieties (Table 2, entries 4, 5,
9–11). Hence, the experimental technique is very con-
venient, effective and simple, and has the capability to
tolerate a diversity of functional groups.
example, halo, methoxy and hydroxyl, and a broad
spectrum of aromatic aldehydes containing an elec-
tron-donating (i.e., CH3, OCH3 and OH; Table 2,
entries 5–7, 9–12) or electron-withdrawing/deacti-
vating (i.e., Cl and NO2; Table 2, entries 4, 8, 14–19)
group at the para-, meta- or ortho-position of their
benzene ring were readily converted to the corre-
sponding 3,3'-(arylmethylene)bis(4-hydroxycouma-
120
100
80
60
40
20
0
Fresh
Run1
Run2
Run3
Run4
Isolated yield, %
Recovered catalyst, wt %
Fig. 4. Reusability of phospho sulfonic acid catalyst in the
synthesis of 3.
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532
FAISAL et al.
Table 2. Synthesis of library of bis(indolyl)alkanes
Ar
H
O
+
Phospho sulfonic acid
H2O, 100°C, 80−160 min
Ar
H
N
H
Yield = 80−98%
1
NH
Melting point, °C
7
HN
8a−8s
R1
Entry
Product
Yield, %*
Time, min
experimented
reported [ref.]
1
2
3
2-Thienyl
2-Furyl
3-Indolyl
8a
8b
8c
8d
8e
81
82
86
89
82
120
130
120
140
160
146–147
315–317
161–164
201–203
189–191
150–153 [49]
316–318 [50]
160–161 [51]
202–204 [52]
188–190 [52]
4** 2-OH-3-ClC6H3
5
2-OH-3-tBuC6H3
6
7
8
9
10
4-CH3C6H4
4-OCH3C6H4
2,3-Di-ClC6H3
2-OHC6H4
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
97
98
83
80
84
85
91
97
83
87
89
81
84
83
80
90
98–99
179–182
96–98
95–97 [53]
179–181 [54]
96–97 [55]
120
120
160
160
140
80
130
120
140
140
130
120
Liquid
Liquid [56]
228–230 [52]
245–248 [52]
94–96 [52]
198–200 [57]
220–222 [58]
260–261 [58]
140–141 [58]
74–75 [59]
2-OH-3-OCH3-5-NO2C6H2
229–230
246–248
94–97
196–197
221–222
260–262
138–140
74–75
11*** 2-OHNp
12
13
14
15
16
17
18
19
3,5-CH3C6H3
4,5-Di-OCH3C6H3
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
91–94
73–74
91–92 [59]
72–73 [59]
* Isolated yield.
** 0.7 g of phospho sulfonic acid catalyst is used.
*** 0.8 g of phospho sulfonic acid catalyst is used.
Table 3. Comparison of phospho sulfonic acid catalytic performance with other reported catalysts
Entry
Reagent and conditions
Time, min
Yield, %*
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H6P2W18O62, solvent-free, 110°C
Silica sulfuric acid, solvent-free, r. t.
Zeolite, CH2Cl2, r. t.
AlPW12O40, CH3CN, r. t.
La(PFO)3, EtOH
Zeokarb-225, CH3CN
PPh3 · HClO4, CH3CN
Zn(HSO4)2
In(OTf)3, CH3CN
40
40
120
15
30
450
30
180
25
720
40
8
96
95
88
92
90
95
61
91
71
95
84
95
90
94
92
92
92
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79]
[80]
[81]
[82]
[83]
[84]
[85]
[70]
Ln(OTf)3, EtOH⋅H2O
ZrOCl2 · 8H2O, solvent-free, 50°C
[Bmim]Br, microwave (400 W), 150°C
Trityl chloride, solvent-free, r. t.
P2O5/SiO2, solvent-free, r. t.
MgSO4, solvent-free, 50°C
PEG-SO3H, H2O, r. t.
20
30
25
20
Phospho sulfonic acid, H2O, 100°C
120
This work
* Isolated yield.
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PHOSPHO SULFONIC ACID: A HIGHLY EFFICIENT
533
Characterization of Bis(Indolyl)Alkanes
encourage present and future synthetic chemists to
employ this approach and enlarge the area of bis(indo-
lyl)alkane preparation.
All synthesized bis(indolyl)alkanes were verified
through FTIR, 1H and 13C NMR spectroscopic tech-
niques. Along with peaks of substituent, heteroaro-
matic or/and aromatic proton in proton of bis(indo-
lyl)alkanes, the spectra showed peaks at δ = 3.72–3.78
(t, =CH–R, R = n-alkyl) or 5.71–4.86 (s, =CH–R,
R = hetaryl, aryl) and at δ = 8.81–8.06 (br s, NH),
respectively [52]. The remaining peaks of protons in
spectra were noticed in the expected ranges. In the 13C
NMR spectra of the bis(indolyl)alkanes, the peaks in
the range of 54.2–32.3 ppm were noticed. The peaks
are owing to carbon of Ar–CH, evidencing the con-
struction of bis(indolyl)alkane moieties. The FTIR
spectra of the bis(indolyl)alkanes displayed the char-
acteristic signals at 1580–1613 (C=C–N), 1660–1676
(aromatic C=C), 2850–2860 (aliphatic C–H), 3037–
3062 (aromatic C–H) and 3170–3747 (N–H) cm–1 [59].
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