A Star-Shaped Triazine-Based Vitamin B5 Copper(II) Nanocatalyst for Tandem Aerobic Synthesis of Bis(indolyl)methanes

Article abstract of DOI:10.1002/ejoc.202000270

In this work, the catalytic efficiency of a novel bio-relevant triazine (TA)-based pantothenate (vitamin B₅) copper(II) complex [Cu(II)-TA/B₅] in the aerobic oxidation of benzyl alcohols and tandem synthesis of bis(indolyl)methanes was exploited. The star-shaped catalyst was characterized by different techniques such as FT-IR, EDX, ICP, TEM, and TGA. TEM images revealed a honeycomb structure resulting from the accumulation of nanoparticles with size ranging between 2–6 nm. The high yields and excellent selectivity were obtained for the production of various benzaldehydes and bis(indolyl)methanes under aerobic conditions. Recycling tests, spectroscopic data, and leaching experiments testified that the title heterogeneous bio-relevant catalyst preserved its activity and structural integrity during oxidation and coupling reactions. The presented catalytic systems qualify all requirements for efficient catalytic systems for applied goals.

Full text of DOI:10.1002/ejoc.202000270

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: A Novel Star-Shaped Triazine-Based Vitamin B5 Copper
(II) Nanocatalyst for Tandem Aerobic Synthesis of
Bis(indolyl)methanes
Authors: Benyamin Hasanpour, Maasoumeh Jafarpour, Ameneh
Eskandari, and Abdolreza Rezaeifard
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000270
Link to VoR: https://doi.org/10.1002/ejoc.202000270
01/2020

10.1002/ejoc.202000270
European Journal of Organic Chemistry
A Novel Star-Shaped Triazine-Based Vitamin B5 Copper (II)
Nanocatalyst for Tandem Aerobic Synthesis of Bis(indolyl)methanes
Benyamin Hasanpour,[a] Maasoumeh Jafarpour,*[a] Ameneh Eskandari,[a] and
Abdolreza Rezaeifard*[a]
[a]
Benyamin Hasanpour, Prof. Dr. Maasoumeh Jafarpour,
Dr. Ameneh Eskandari, Prof. Dr. Abdolreza Rezaeifard
Catalysis Research Laboratory, Department of Chemistry,
Faculty of Science, University of Birjand, Birjand, 97179-414, Iran.
E-mail: mjafarpour@birjand.ac.ir (M. Jafarpour), http://cv.birjand.ac.ir/jafarpour/en
rrezaeifard@birjand.ac.ir (A. Rezaeifard); http://cv.birjand.ac.ir/rezaeifard/en
Supporting information for this article is given via a link at the end of the document.
Abstract: In this work, the catalytic efficiency of a novel bio-relevant triazine (TA)-based
pantothenate (vitamin B5) copper(II) complex [Cu(II)-TA/B5] in the aerobic oxidation of benzyl
alcohols and tandem synthesis of bis(indolyl)methanes was exploited. The star-shaped catalyst
was characterized by different techniques such as FT-IR, EDX, ICP, TEM and TGA. TEM
images revealed a honeycomb structure resulting from accumulation of nanopaticles with size
ranging between 2-6 nm. The high yields and excellent selectivity were obtained for production
of various benzaldehydes and bis(indolyl)methans under aerobic conditions. Recycling tests,
spectral data and leaching experiments testified that the title heterogeneous bio-relevant catalyst
preserved its activity and structural integrity during oxidation and coupling reactions. The
presented catalytic systems qualify all requirements for efficient catalytic systems for applied
goals.
1
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
Introduction
The use of biologically active materials has always been the ultimate source of inspiration for
scientists working across all disciplines. Among these, biocatalysts, an emerging group of
catalysts, which facilitate the syntheses of complex organic molecules by chemo-, region-, and
stereoselective bond-forming reactions are of extreme interest.[1] Because of high turnover
numbers and frequencies, mild reaction conditions, high product selectivity, and low
environmental impact, biocatalysts have been employed for both simplified chemical synthesis
routes and improved outcomes.[2]
Vitamins constitute a group of large number of chemically unrelated organic compounds which
are necessary for all animals to maintain normal metabolic functions. They are different from the
other biological compounds in that generally cannot be synthesized in amount sufficient to meet
bodily needs and hence must be supplied in the diets. Relatively small quantities of vitamins are
needed to complete their functions, which are of a catalytic or regulatory nature, facilitating or
controlling vital chemical reactions in the body's cells. [3] Vitamin B5, also known as pantothenic
acid, is an essential vitamin consists of pantoic acid and β-alanine bound in amide linkage, which
serve as the metabolic precursor for coenzyme A. In the form of coenzyme A and as a
component of acyl carrier protein, pantothenic acid is a participant in a myriad of metabolic
reactions involving lipids, proteins, and carbohydrates. [4]
Metal complexes of vitamins have been prepared either as a single ligand or as mixed ligand
complexes in order to disclose various stereochemical arrangements of the ligands around the
metal atom and different types of connection between the complexes. Recently, more attention
has been paid to catalytic activity of the vitamin transition metal complexes to imitate and
[5]
understand the function of biochemical catalysts.
Among the transition metals, copper has
been the most studied metal ions because of its inherent electronic properties, accessible redox
potentials and particularly taking part in many biological functions such as structural shaping,
electron transfer and catalysis. [6] The presence of copper in the active sites of different enzymes,
[6]
makes it an appropriate choice for the development of catalysts for alcohol oxidation, a
fundamental bio-relevant transformation which is also of extreme interest in organic synthesis. [7]
The oxidation products of alcohols, carbonyl compounds, are key materials in the production of
[7]
many valuable fine chemicals.
Condensation of carbonyl compound particularly aldehydes
with a two-fold excess of indole molecule produces biologically and medicinally important
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European Journal of Organic Chemistry
bis(indolyl)methanes (BIM), [8] which have attracted much attention in organic synthesis. They
are widely found in the structure of many bioactive compounds extracted from various plants can
act on the central nervous system and are used as antibiotics. Other methods such as C-H bond
activation/C-C bond forming of alcohols and indoles to bis(indolyl)methanes with I2/O2 and NBS
have been reported. [9] However, side reactions such as multiple condensations, polymerizations,
and rearrangements are common to occur in many of the reported protocols for the synthesis of
BIM derivatives. [10]
Following our research on the synthesis and catalytic applications of transition metal vitamin
[11]
complexes,
herein, we wish to design a novel bio-relevant catalyst, consisting of Cu(II)
pantothenate complex attached to triazine ring. The as-prepared copper (II) complex proved to be
efficient and recyclable catalyst for the selective aerobic oxidation of benzylic alcohols to
aldehydes followed by coupling with indole molecules through carbon-carbon bond to afford the
Bis(indolyl)methane without any side reactions (Scheme 1).
Scheme 1. One pot synthesis of bis(indolyl)methanes through aerobic oxidation of benzylic
alcohols catalyzed by [Cu(II)-TA/B5]
3
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Results and Discussion
Synthesis and Characterization of Catalyst
As shown in scheme 2, reaction of cyanuric chloride (CC) with vitamin B5 (panthothenic acid)
was carried out in THF under ultrasonic agitation to substitute chlorine atoms of cyanuric
chloride to afford vitamin B5 triazine derivative (TA/B5) as a star-shaped ligand. The copper (II)
complex of the as-prepared ligand [Cu(II)-TA/B5] was obtained by adding Cu(OAc)2 under
ultrasonic agitation followed by reflux for 16 h (Scheme 2). The Cu content of [Cu(II)-TA/B5]
complex was found to be 3.2 mmol g-1 based on ICP-AES analysis.
Scheme 2. Preparation route for [Cu(II)-TA/B5]
The FT-IR spectra of vitamin B5, TA/B5 ligand and [Cu(II)-TA/B5] nanocomplex are depicted in
Figure S1. The spectrum of B5 (Fig. S1a) reveals the presence of major bands at 1606 and 1576
cm-1 attributed to the acid and amide carbonyl groups. Broad peak at 3410 cm-1 corresponds to
the hydroxyl groups which overlaps with the N-H amide peak. The significant spectral changes
in Fig. S1b affirms the formation of TA-B5 ligand. The appearance of a new band at 1776 cm-1
and vanishing the broad peak of O-H testify the formation of ester group. Also, the intense band
at 1692 cm-1 is attributed to C=N triazine ring. A shift in N-H amide band from 3212 to 3206 as
4
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
Figure 1. TEM images of [Cu(II)-TA/B5] nanocomplex
well as appearance of new peaks at 593 and 495 cm-1 in Fig. S1c testify the coordination of the
TA-B5 ligand to the Cu(II) center.
The TEM images in Figure 1, shows a honeycomb structure resulting from accumulation of
[Cu(II)-TA/B5] nanopaticles with size ranging between 2-6 nm.
The TGA curve (Figure S2, ESI) demonstrates its thermostability up to 150 ºC and the organic
parts decomposition continued up to 800 ºC. Compositional analysis through energy dispersive
X-ray (EDX) spectrometer (Figure S3) confirmed the presence of Cu atoms alonside C, N and O
in nanocomplex.
Catalytic Tests
Aerobic Oxidation of Alcohols
Elucidating the catalytic role of the as-prepared [Cu(II)-TA/B5] nanocomplex, some control
experiments were conducted. A catalyst-free reaction using 4-chlorobenzyl alcohol (0.125 mmol)
as a model substrate in combination with TEMPO (10 mol%) in EtOH (0.2 mL) under air led to
isolation of starting alcohol. Parent materials such as Cu(OAc)2, vitamin B5, TA-B5 ligand as
well as [Cu(II)-B5] complex were also inferiour catalysts for aforementioned reaction under the
same catalyst concentration (5 mol%, Figure 2). Nevertheless, a small amount of the as-prepared
[Cu(II)-TA/B5] nanocomplex triggered the oxidation reaction in combination with (2,2,6,6-
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European Journal of Organic Chemistry
Figure 2. Comparison of the catalytic activity of [Cu(II)-TA/B5] with parent materials (5 mol%)
in the oxidation of 4-chlorobenzyl alcohol (0.125 mmol) in the precense of TEMPO (10 mol%)
at 70 °C under air after 8 h in 0.2 mL EtOH.
tetramethylpiperidin-1-yl) oxyl TEMPO and the conversion reached to about 80% after 8 h and
the pertinent aldehyde was formed as the sole product.
Afterward, the reaction conditions were optimized with respect to different factors such as
solvent, temperature, catalyst and TEMPO amounts and also oxidant nature (Figure 3). The high
conversion rates were observed in EtOH and water as green solvents at 70 ºC. Nevertheless,
apart from the benefits of solubility of materials in ethanol, more selectivity was obtained in this
solvent. Our findings revealed that the catalytic efficiency affected seriously by TEMPO and the
reaction needs 8 mol% of this additive for reaching to the highest performance (Figure 3, iv, v).
The other common oxidants such as O2, H2O2, TBHP, Oxone® and tetra-n-butylammonium
Oxone® (TBAOX) was tested in the title model reaction under optimized conditions. The highest
oxidation performances were observed under air as well as continuous stream of oxygen and
magnetic stirring is more effective than ultrasonic agitation (Figure 4). Obviously, the
conducting the reaction under air in an open-flask agitated by a magnetic stirrer is preferred
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European Journal of Organic Chemistry
Figure 3. The screening results for the solvent type (i) and solvent amount (ii), temperature (iii),
additive, IBA: Isobutyraldeyde, NHPI: N-Hydroxyphthalimide, NHSI: N-Hydroxysuccinimide
(iv), TEMPO amount (v) and catalyst amount (vi). The reactions for oxidation of 4-chlorobenzyl
alcohol (0.125 mmol, 0.018 g) were run for 8 h under air in an open-flask in 0.2 ml ethanol at 70
°C using 8 mol% TEMPO and 5 mol% catalyst, except in each case where the desired factor is
varied (see experimental details in SI).
(Figure 4). Based on the aforementioned screening results, aerobic oxidation of 0.125 mmol 4-
chlorobenzyl alcohol in EtOH (0.2 mL) at 70 °C needs 8 mol% TEMPO (0.01 mmol, 0.0017 g),
and 5 mol% [Cu(II)-TA/B5] catalyst (0.006 mmol, 0.002 g) to furnish the highest yield of the
pertinent aldehyde.
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
Figure 4. (i) The effect of various oxidants in the oxidation of 4-chlorobenzyl alcohol (0.125
mmol) (ii) and agitation conditions: (method A) open flask under air agitated by
ultrasonic waves, (method B): open flask under air agitated by a magnetic stirrer, (method C): a
continuous stream of O2 (5-7 mL min-1) agitated by a magnetic stirrer. The reactions were run in
EtOH (0.2 mL) at 70 °C using 5 mol% [Cu(II)-TA/B5] and 8 mol% TEMPO for 8 h.
Under this optimized conditions, a wide range of primary and secondary benzylic alcohols (1a-o)
oxidized effeciently and selectively as given in Table 1 (2a-o). Based on our data, the oxidation
performance affected by electronic properties of substrates. Electron-withdrawing groups on the
phenyl rings of alcohols accelerated the reaction (entries 2h and 2i), while the electron-releasing
groups reduced the reactivity (entries 2b-2g). The chemoselectivity of the procedure is
noteworthy. When cinnamyl alcohol as an allylic alcohol subjected to the reaction condition, the
olefin moiety remained intact and the unsaturated carbonyl compounds was produced
exclusively (entry 2j). Moreover, 4-(methylthio)benzyl alcohol, oxidized selectively to the
corresponding aldehyde in 68% yield and more susceptible sulfide group was tolerated in the
reaction (entry 2n). It should be noted that the title catalytic oxidation system was ineffective for
aerobic oxidation of aliphatic primary and secondary alcohols.
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a-c
Table 1. Aerobic oxidation of benzylic alcohols catalyzed by [Cu(II)-TA/B5].
2a, 83%, 7.5h
2b, 79%, 7h
2c, 83%, 7h
2d, 81%, 7.5h
2i, 79%, 6.75h
2e, 78%, 8h
2f, 72%, 8h
2g, 74%, 8.5h
2h, 87%, 6.25h
2j, 78%, 6.5h
2k, 72%, 6.5h
2l, 77%, 6h
2m, 63%, 6h
2n, 68%, 9h
2o, 72%, 7.5h
aReaction conditions: Alcohol: 0.125 mmol, TEMPO: 8 mol% (0.01 mmol, 0.0017 g), catalyst: 5mol% (0.006
b
mmol, 0.002 g) in EtOH (0.2 mL) in an open-flask over a hot plate stirrer at 70 °C under air. The products were
c
identified by comparison of GC retention times and NMR spectral data with authentic samples. GC Yield. The
selectivity of products was >99% based on GC analysis.
Aerobic Tandem Synthesis of Bis(indolyl)methanes
The promising results obtained in the oxidation of benzyl alcohols to the related aldehydes which
are key intermediates in organic synthesis prompted us to apply this catalytic system for tandem
synthesis of bis(indolyl)methanes. Following the completion of the oxidation of alcohol under
aerobic condition mentioned above, indole was added to the reaction mixture to produce
bis(indolyl)methanes. Nevertheless, our screening study (Figure 5) demonstrated that the
reaction needed more catalyst and TEMPO, so that a solvent-free condition (i) at 80 °C (ii) using
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
Figure 5. The screening results for the solvent type (i), temperature (ii), additive, IBA:
Isobutyraldeyde, NHPI: N-Hydroxyphthalimide, NHSI: N-Hydroxysuccinimide (iii), TEMPO
amount (iv) catalyst amount (v) and oxidant type (vi). The reactions were run under air in an
°
open-flask under solvent-free condition at 80 C using 10 mol% TEMPO and 8 mol% catalyst,
except in each case where the desired factor is varied (see experimental details in SI).
10 mol% (0.012 mmol, 0.002 g) TEMPO (II, iv) and 8 mol% (0.01 mmol, 0.003 g) [Cu(II)-
TA/B5] nanocatalyst (v) under air (vi) was the best condition for tandem synthesis of
bis(indolyl)methanes from alcohols.
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Table 2. Aerobic bis(indolyl)methanes synthesis via condensation of benzyl alcohols and Indoles
by [Cu(II)-TA/B5] a,b
4a, 79%, 6.25h
4b, 80%, 6.5h
4c, 74%, 7.5h
4d, 65%, 8.75h
4e, 83%, 5.75h
4f, 55%, 9.5h
4g, 70%, 9.75h
a
Reaction conditions: 1.25 mmol: 2.62 mmol: 10 mol% (0.012 mmol, 0.002 g): 8 mol% (0.01 mmol, 0.003 g) for
b
alcohol: indole: TEMPO: catalyst, solvent-free condition and magnetic stirrer under air at 80 ˚C. The products
were identified by NMR spectroscopy. cThe reported yields are the isolated products.
With the optimized conditions in hand, the catalytic performance of the [Cu(II)-TA/B5]
nanocomplex in the reaction of benzylic alcohols and indoles in the coupling reaction was
investigated (Table 2). As shown in Table 2, structurally and electronically diverse benzylic
alcohols and indoles are desired substrates for this reaction, so that bis(indolyl)methanes were
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
produced in good to high yields of (65-83%). However, as mentioned in the previous section,
alcohols substituted by electron-releasing groups exhibited less reactivity (entry 4d). As
expected, no coupling reaction occurred when benzylic alcohols were replaced by aliphatic ones.
Recyclability and Stability of Catalyst
The recyclability and heterogeneous nature of catalyst were examined in the aerobic oxidation of
4-chlorobenzylalcohol (1e) as a model substrate and tandem aerobic bis(indolyl)methanes (4b)
synthesis. After each run according to experimental section, the catalyst was separated from the
product by centrifugation followed by decantation (3×5 ml EtOH for aerobic oxidation of benzyl
alcohols and 3×5 ml EtOAc for aerobic bis(indolyl)methanes synthesis), dried in vacuum oven
and then reused. Indeed, the catalyst showed a superb performance during five consecutive
cycles (Figure 6). In order to clarify whether the reaction takes place at the surface of the solid
catalyst as a truly heterogeneous reaction or leached Cu(II) drives the homogeneous reaction, the
hot filtration test was done. The filtrate solution containing 4-chlorobenzylalcohol produced just
5% of the pertinent aldehyde after 8 h ruling out any homogeneous catalysis resulting from Cu-
leaching as confirmed by ICP-AES analysis. The stability of catalyst during oxidation of alcohol
as well as synthesis of bis(indolyl)metane was also demonstrated by FT-IR spectra of recycled
catalyst (Figure S4). The lacking of any noticeable changes after five runs testified the structural
stability of catalyst during aerobic oxidation and coupling reactions. Thus, the present
methodologies employing a heterogeneous and reusable bio-relevant copper catalyst under air as
an ideal oxidant in green ethanol for alcohol oxidation and solvent-free condition for coupling
reaction without formation of any by-products qualify all requirements of cost-effective and eco-
friendly catalytic systems for applied goals. .
Conclusion
In summary, we have successfully synthesized a novel star-shaped [Cu(II)-TA/B5] nanocatalyst
by incorporating of Cu(OAc)2 within 2,4,6-tripantothenate-1,3,5-triazine under ultrasonic
agitation. The catalytic system involves oxidation of alcohols to aldehydes followed by
condensation with indol derivatives to afford bis(indolyl)methanes in one-pot operation with
good to excellent yield without any side reactions. Notably, the presented catalytic oxidation
systems showed remarkable selectivity. The use of air as an environmentally friendly oxidant
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European Journal of Organic Chemistry
Figure 6. Recycling study of [Cu(II)-TA/B5] catalyst in model reactions (compounds 2e, 4b),
according to procedures mentioned in experimental sections.
under the influence of a reusable and durable active bio-relevant catalyst with low catalyst
loading, along with easy isolation of organic products is the strengths of the presented work.
Experimental Section
General: All chemicals were purchased from Chemical Companies. The FT-IR spectra were
recorded on NICOLET system. TEM images were obtained by TEM instrumentation (Philips
CM 10). Progresses of the reactions were monitored by TLC using silica-gel SIL G/UV 254
plates and also by GC-FID on a Shimadzu GC-16A instrument using a 25 m CBP1-25 (0.32 mm
ID, 0.5 mm coating) capillary column. Thermogravimetric analysis (TGA) of powders carried
out on Netzsch-TGA 209 F1 under air flow at a uniform heating rate of 10 ˚C min-1 in the range
of 30-800˚C. EDX performed by TESCAN Vega Model. The Cu content of the catalyst was
measured by an inductively coupled plasma optical emission spectrometry (ICP-OES), using the
Optima-7300 ICP analyzer.
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Preparation of [Cu(II)-TA/B5] Nanocatalyst
A solution of 0.18 g cyanuric chloride (1 mmol) in 5 mL dry THF was gradually added to 0.44 g
vitamin B5 (2 mmol) in 5 mL dry THF at 60 °C under ultrasonic agitation. After adding 0.138 g
K2CO3 (1 mmol), the reaction mixture remained under the same condition for 3 h and afterward,
it was stirred for 12 h at 70 °C. The reaction mixture was centrifuged and the resulted solid
(TA/B5) was washed with THF and dried in a vacuum oven at 70 ºC. Then, an ethanolic solution
of Cu(OAc)2 was added drop by drop to a solution of TA/B5 (0.2 g) in 10 mL EtOH under
ultrasonic agitation at 60 ˚C, and remained under the same condition for 3 h. Heating the solution
at 70 °C for 16 h, resulted a green powder which was washed with ethanol and dried under air.
General procedure for aerobic oxidation of benzyl alcohols (2a-o)
To a mixture of benzyl alcohols (0.125 mmol) and 2mg [Cu(II)-TA/B5] catalyst (0.006 mmol, 5
mol%) in EtOH (0.2 mL) was added 1.7 mg TEMPO (0.01 mmol, 8 mol%), and the reaction
mixture was stirred under air at 70 °C for the required time. The reaction progress was monitored
by GC, and the yields of products were determined by GC analysis. The pure product was
secured by plate silica chromatography using n-hexane/EtOAc (10:3).
Benzaldehyde (2a)[12]: Colorless liquid. 1H NMR (400 MHz, CDCl3):  ppm= 10.1 (s, 1 H), 7.9-
7.5 (m, 5 H). 13C NMR (100 MHz, CDCl3):  ppm= 192.0, 136.2, 135.1, 129.3, 128.1.
2-Methybenzaldehyde (2b)[12]: Colorless liquid. 1H NMR (400 MHz, CDCl3):  ppm= 10.3 (s, 1
H), 7.8 (dd, J = 7.6, 1.2 Hz, 1 H), 7.5 (dd, J = 7.6, 1.2 Hz, 1 H), 7.4-7.0 (m, 2 H), 2.6 (s, 3 H).
13C NMR (100 MHz, CDCl3):  ppm= 191.0, 137.3, 134.1, 133.7, 131.3 129.6, 127.3, 19.6.
1
4-Methylbenzaldehyde (2c)[12]: Colorless liquid. H NMR (400 MHz, CDCl3):  ppm= 9.96 (s,
13
1H, CHO), 7.77 (d, J=8.1 Hz, 2H, Ar-H), 7.33 (d, J=7.8 Hz, 2H), 2.44 (s, 3H, CH3). C NMR
(100 MHz, CDCl3): 191.9, 145.5, 134.1, 129.7, 21.8.
1
4-tert-butylbenzaldehyde (2d)[12]: Colorless liquid. H NMR (400 MHz, CDCl3):  ppm= 9.98
(s, 1 H, CHO), 7.82 (d, J = 8.4, 2 H, Ar-H), 7.55 (d, J = 8.4 Hz, 2 H, Ar-H), 1.35 (s, 9H, 3CH3).
13C NMR (100 MHz, CDCl3):  ppm= 192.0, 158.4, 134.0, 129.7, 125.9, 35.3, 31.0.
1
4- Chlorobenzaldehyde (2e)[12]: White solid; m.p.: 44-45 ˚C. H NMR (400 MHz, CDCl3): 
ppm= 9.90 (s, 1 H, CHO), 7.70 (dd, J = 8.8, 2.0 Hz, 2 H, Ar-CH), 7.70 (dd, J = 8.6, 2.0 Hz, 2 H,
Ar-CH). 13C NMR (100 MHz, CDCl3):  ppm= 191.0, 135.0, 132.4, 130.9, 129.7.
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2- Chlorobenzaldehyde (2f)[12]: Colorless liquid. 1H NMR (400 MHz, CDCl3):  ppm= 10.40 (s,
13
1 H, CHO), 7.90 (dd, J = 8.0, 1.6 Hz, 1 H, Ar-CH), 7.50-7.30 (m, 3 H, Ar-CH). C NMR (100
MHz, CDCl3):  ppm= 188.0, 138.1, 134.1, 133.7, 131.3, 129.6, 127.5.
1
4-Methoxybenzaldehyde (2g)[12]: Yellow liquid. H NMR (400 MHz, CDCl3):  ppm= 9.83 (s,
1 H, CHO), 8.17-7.55 (m, 2 H, Ar-CH), 6.59 (d, J= 8.7Hz, 2H, Ar-CH), 3.83 (m, 3 H, OCH3).
13C NMR (100 MHz, CDCl3):  ppm= 190.6, 164.4, 131.8, 129.8, 114.2, 55.4.
1
4-Nitrobenzaldehyde (2h)[12]: Yellow crystalline powder; m.p.: 104-106 ˚C. H NMR (400
MHz, CDCl3):  ppm= 10.18 (s, 1 H, CHO), 8.41 (d, J = 8.0 Hz, 2 H, Ar-CH), 8.10 (d, J = 8.0
Hz, 2 H, Ar-CH). 13C NMR (100 MHz, CDCl3):  ppm= 190.2, 151.0, 139.9, 130.4, 124.2.
2- Nitrobenzaldehyde (2i)[12]: Pale yellow solid; m.p.: 44-45 ˚C. 1H NMR (400 MHz, CDCl3): 
ppm= 10.40 (s, 1 H, CHO), 8.10 (dd, J = 7.6, 1.6 Hz, 1 H, Ar-CH), 7.90 (dd, J = 7.2, 1.6 Hz, 1
13
H, Ar-CH), 7.80-7.70 (m, 2 H, Ar-CH). C NMR (100 MHz, CDCl3):  ppm= 188.1, 149.6,
134.1, 133.7, 131.3, 129.6, 124.5.
1
Trans-Cinnamaldehyde (2j)[12]: Yellow oil. H NMR (400 MHz, CDCl3):  ppm= 9.71 (d, J =
7.6 Hz, 1 H, CHO), 7.49-7.57 (m, 2 H, Ar-CH), 7.42-7.45 (m, 4 H), 6.73 (q, J = 7.6 Hz, 1H). 13C
NMR (100 MHz, CDCl3):  ppm= 193.6, 152.6, 133.8, 131.1, 128.9, 128.7, 128.4, 128.2.
1
Acetophenone (2k)[12]: Colorless liquid. H NMR (400 MHz, CDCl3):  ppm= 7.90 (d, J = 7.2
Hz, 2 H, Ar-CH), 7.50 (t, J = 7.2 Hz, 1 H, Ar-CH), 7.40 (t, J = 8.0 Hz, 2 H, Ar-CH), 2.60 (s, 3 H,
CH3). 13C NMR (100 MHz, CDCl3):  ppm= 198.1, 137.1, 133.1, 128.5, 128.3, 26.6.
1
α-Tetralone (2l)[12]: Colorless liquid. H NMR (400 MHz, CDCl3):  ppm= 8.07-8.05 (m, 1 H,
Ar-CH ), 7.5-7.4 (m, 1 H, Ar-CH), 7.35-7.31 (m, 1 H, Ar-CH,), 7.29-7.27 (m, 1 H, Ar-CH), 3.0
13
(t, J = 6 Hz, 2 H), 2.60 (t, J = 6 Hz, 2 H), 2.20-2.10 (m, 2 H). C NMR (100 MHz, CDCl3): 
ppm= 198.4, 144.5, 133.4, 132.6, 128.8, 127.1, 126.6, 39.2, 29.7, 23.3.
1
Benzophenone (2m)[12]: White solid; m.p.: 49-50 ˚C. H NMR (400 MHz, CDCl3):  ppm=
7.85-7.83 (m, 2 H, Ar-CH), 7.60 (t, J = 7.6 Hz, 1 H, Ar-CH), 7.50 (t, J = 7.6 Hz, 2 H, Ar-CH).
13C NMR (100 MHz, CDCl3):  ppm= 196.8, 137.6, 132.4, 130.1, 128.3.
1
4-Methylthiobenzaldehyde (2n)[12]: Yellow liquid. H NMR (400 MHz, CDCl3):  ppm= 9.90
(s, 1 H, CHO), 7.80 (d, J = 8.8 Hz, 2 H, Ar-CH), 7.30 (d, J = 8.4 Hz, 2 H, Ar-CH), 2.50 (s, 3 H,
SCH3). 13C NMR (100 MHz, CDCl3):  ppm= 191.2, 147.9, 132.9, 130.0, 125.2, 14.7.
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
1
2-Furaldehyde (2o)[12]: Colorless liquid. H NMR (400 MHz, CDCl3):  ppm= 9.63 (s, 1 H,
CHO), 7.67 (d, J = 1.0 Hz, 1 H, Ar-CH), 7.23 (t, J = 4.8 Hz, 1 H, Ar-CH), 6.58 (dd, J = 4.4, 1.9
Hz, 1H, Ar-CH). 13C NMR (100 MHz, CDCl3):  ppm= 177.7, 152.8, 147.9, 112.4.
General procedure for aerobic bis(indolyl)methanes synthesis via condensation of benzyl
alcohols and indoles (4a-g)
3 mg [Cu(II)-TA/B5] catalyst (8 mol%, 0.01 mmol) was added to a mixture of benzyl alcohols
(0.125 mmol), 34 mg 2-methylindole (0.262 mmol) and 2 mg TEMPO (10 mol%, 0.0128 mmol),
and stirred under air and solvent-free condition at 80 °C for the required time. The reaction
progress was monitored by TLC. After completion of the reaction, ethyl acetate (5 mL) was
added to the mixture and then [Cu(II)-TA/B5] nanocatalyst (solid phase) was separated by
centrifuging followed by decantation (3×5 mL ethyl acetate). Desired product (liquid phase) was
extracted by plate chromatography eluted with n-hexane/EtOAc (10/6).
3,3'-(phenylmethylene)bis(2-methyl-1H-indole) (4a): Red solid. m.p.: 244-246˚C (243―245
°C)[13]; 1H NMR (400 MHz, DMSO-d6): δ ppm: 10.72(s, 2H, NH), 7.27-7.18 (m, 7H, Ar-CH),
6.91-6.87 (m, 2H, Ar-CH), 6.81 (d, J=8.0 Hz, 2H, Ar-CH), 6.69-6.66 (m, 2H, Ar-CH), 5.93(s,
1H, CH), 2.07(s, 6H, CH3); 13C NMR (100 MHz, DMSO-d6): δ ppm: 144.0, 135.2, 132.2, 129.0,
128.4, 128, 125.8, 119.6, 118.56, 118, 112.5, 110.4, 38.8, 12.3.
3,3'-((4-chlorophenyl)methylene)bis(2-methyl-1H-indole) (4b): Pink solid. m.p.: 233-235 ˚C
(202-204)[13]; 1H NMR (400 MHz, DMSO-d6): δ ppm: 10.76(s, 2H, NH), 7.3 (d, J = 7.1 Hz, 2H),
7.23-7.18 (m, 4H, Ar-CH), 6.90 (t, J = 7.5 Hz, 2H, Ar-CH), 6.81 (d, J = 7.9 Hz, 2H, Ar-CH),
13
6.70 (t, J = 7.5 Hz, 2H, Ar-CH), 5.92 (s, 1H, CH), 2.08 (s, 6H, CH3); C NMR (100 MHz,
DMSO-d6): δ ppm: 142.5, 135.2, 132.0, 131.4, 130.0, 129.0, 121.0, 119.5, 113, 110.0, 38.8, 12.4.
3,3'-(p-tolylmethylene)bis(2-methyl-1H-indole) (4c): Purple solid. m.p.: 176-177 ˚C (175-
176)[13]; 1H NMR (400 MHz, DMSO-d6): δ ppm: 10.69 (s, 2H, NH), 7.21 (d, J = 8.0 Hz, 2H, Ar-
CH), 7.08-7.04 (m, 4H, Ar-CH), 6.90-6.87 (t, J = 7.5 Hz, 2H, Ar-CH), 6.84-6.82 (d, J = 7.9 Hz,
2H, Ar-CH), 6.69 (t, J =7.9 Hz, 2H, Ar-CH), 5.88 (s, 1H, CH), 2.28 (s, 3H, CH3), 2.05 (s, 6H,
2CH3); 13C NMR (100 MHz, DMSO-d6): δ ppm: 140.6, 135.2, 131.8, 130.0, 129.6, 129.0, 120.7,
119.5, 119.0, 113.7, 109.8, 100.0, 38.8, 21.2, 12.5.
3,3'-((4-methoxyphenyl)methylene)bis(2-methyl-1H-indole) (4d): Pink solid. m.p.: 207-210
˚C (194-195)[13]; 1H NMR (400 MHz, DMSO-d6): δ ppm: 10.68 (s, 2H, NH), 7.20 (d, J = 8.0 Hz,
16
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
2H, Ar-CH), 7.08 (d, J = 8.5 Hz, 2H, Ar-CH), 6.90-6.81 (m, 6H, Ar-CH), 6.69-6.66 (m, 2H, Ar-
13
CH), 5.85 (s, 1H, CH), 3.72 (s, 3H, OCH3), 2.06 (s, 6H, 2CH3). C NMR (100 MHz, DMSO-
d6): δ(ppm): 157.5, 135.9, 135.2, 131.7, 129.4, 128.7, 121.0, 119.7, 119.0, 113.5, 114.0, 109.8,
55.5, 38.4, 12.2.
3,3'-((4-nitrophenyl)methylene)bis(2-methyl-1H-indole) (4e): Yellow solid. m.p.: 239-241 ˚C
(240-242 )[13]; 1H NMR (400 MHz, DMSO-d6): δ ppm: 10.82 (s, 2H, NH), 8.10 (d, J=9.2 Hz, 2H,
Ar–H) 7.51-7.48 (d, J = 7.6 Hz, 2H, Ar-CH), 7.22-7.24 (m, J = 8.0 Hz, 4H, Ar-CH), 6.93-6.89
13
(m, 4H, Ar-CH), 5.90 (s, 1H), 2.03 (s, 6H, CH3). C NMR (100 MHz, DMSO-d6): δ(ppm):
152.0, 146.4, 135.0, 132.0, 130, 128.6, 123.5, 121.0, 119.5, 119.0, 111.8, 110.2, 39.5, 12.5.
3,3'-((4-chlorophenyl)methylene)bis(1H-indole) (4f): Pink solid. m.p.: 78-80 ˚C (79―80
1
°C)[13]; H NMR (400 MHz, DMSO-d6): δ ppm: 10.84(s, 2H, NH), 7.37-7.30(m, 6H, Ar-CH),
7.26(d, J=7.6 Hz, 2H, Ar-CH), 7.06-7.02(m, 2H, Ar-CH), 6.89-6.82(m, 4H, Ar-CH), 5.85(s, 1H,
13
CH); C NMR (100 MHz, DMSO-d6): δ(ppm): 144.2, 136.6, 130.3, 130.2, 128.0, 126.5, 123.7,
121.0, 119.0, 118.3, 117.6, 111.5, 39.0.
3,3'-((4-chlorophenyl)methylene)bis(5-bromo-1H-indole) (4g): Red solid. m.p.: 212-214˚C
(206―208 °C)[13]; 1H NMR (400 MHz, DMSO-d6): δ ppm: 11.10 (s, 2H, NH), 7.42 (s, 2H, Ar-
CH), 7.34-7.33(m, 6H, Ar-CH), 7.16 (dd, J=2.0, 8.8 Hz, 2H, Ar-CH), 6.90 (d, J=1.6 Hz, 2H, Ar-
13
CH), 5.90 (s, 1H, CH); C NMR (100 MHz, DMSO-d6): δ(ppm): 143.4, 135.3, 130.6, 130.0,
128.3, 128.2, 125.3, 123.6, 121.1, 117.2, 113.7, 111.0, 38.1.
Reusability of Catalyst
To a mixture of benzyl alcohol (0.125 mmol) and 2mg [Cu(II)-TA/B5] nanocomplex (5 mol%,
0.006 mmol) in EtOH (0.2 mL) was added 1.7 mg TEMPO (8 mol%, 0.01 mmol), and the
reaction mixture was stirred under air at 70 °C for the required time. At the end of the reaction,
the mixture was cooled to room temperature, [Cu(II)-TA/B5] was separated by centrifuging
followed by decantation (3×5 ml ethanol and then ethyl acetate) and dried in a vacuum oven at
50 °C. Catalyst recovery was also investigated in the aerobic bis(indolyl)methanes synthesis.
Acknowledgment
Support for this work by Research Council of University of Birjand is highly appreciated.
17
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10.1002/ejoc.202000270
European Journal of Organic Chemistry
Keywords: Panthothenic acid (Vitamin B5), Triazine, Copper complex, Nano-bio-complex,
Aerobic oxidation, Bis(indolyl)methanes (BIMs)
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Table of content
Aerobic Oxidation
A bio-relevant Cu(II) vitamin B5 complex anchored on triazine ring resulting in a novel reusable
star-shaped catalyst for TEMPO mediated aerobic oxidation of benzylic alcohols followed by
coupling with indole derivatives producing bis(indolyl)methanes in desired yields and excellent
selectivity.
21
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