Catalyst- And solvent-free Csp2-H functionalization of 4-hydroxycoumarinsviaC-3 dehydrogenative aza-coupling under ball-milling

Article abstract of DOI:10.1039/d1gc01341f

A one-pot procedure for the synthesis of biologically relevant coumarin hydrazones using a three-component reaction between 4-hydrocoumarins, primary aromatic amines andtert-butyl nitrite under ball-milling in the absence of any catalysts/additives and so

Full text of DOI:10.1039/d1gc01341f

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PAPER
Catalyst- and solvent-free Csp2–H functionalization
of 4-hydroxycoumarins via C-3 dehydrogenative
aza-coupling under ball-milling†‡
Cite this: Green Chem., 2021, 23,
4762
Goutam Brahmachari, * Indrajit Karmakar and Pintu Karmakar
A one-pot procedure for the synthesis of biologically relevant coumarin hydrazones using a three-com-
ponent reaction between 4-hydrocoumarins, primary aromatic amines and tert-butyl nitrite under ball-
milling in the absence of any catalysts/additives and solvents has been developed. The mechanical force
implements the Csp2–H functionalization of 4-hydroxycoumarins via C-3 dehydrogenative aza-coupling
with ease. The product was isolated by simple washing of the crude reaction residue with aqueous
ethanol, followed by simple filtration. No chromatographic purification was required. Catalyst- and
solvent-free reaction conditions, use of ball-milling as a green tool, lack of a need for chromatographic
purification, broad substrate scope and tolerance for various functional groups, high yields of products at
short reaction times (no more than 6 min), a clean reaction profile, and gram-scale synthetic applicability
make this procedure green and cost-effective.
Received 16th April 2021,
Accepted 28th May 2021
DOI: 10.1039/d1gc01341f
rsc.li/greenchem
practices, ball-milling that offers intense mechanical grinding
(mechanochemistry) is regarded as a powerful and sustainable
1. Introduction
The generation of carbon–heteroatom bonds is fundamental alternative tool for chemical synthesis and enables the discov-
for the synthesis of bioactive natural products, pharmaceuti- ery of new chemical reactivities.5 As a result, the last decade
cals and useful materials.1 Among various synthesis strategies has witnessed considerable advances in mechanosynthesis
for constructing carbon–heteroatom bonds, the desired C–H involving a wide array of covalent bond-forming reactions,6
bond functionalization within diverse molecular scaffolds has and the application of this green tool featured a handful of
already emerged as an advantageous and fascinating protocol advantages, including avoidance or reduced use of bulk
in modern organic synthesis.2 Although such a functionali- organic solvents, shortened reaction time, enhanced yields,
zation strategy offers a handful of synthetic advantages,2,3 it improved selectivity and minimized ecological impacts.7
has several shortcomings, particularly the use of costly and
Researchers screened coumarins, an important class of
sensitive metal catalysts, toxic and harmful organic solvents, potentially bioactive natural and unnatural O-heterocycles, as
excess oxidants, and harsh reaction conditions on many building blocks in a plethora of organic transformations in
occasions.4 Hence, green chemistry-directed C–H functionali- the recent past.8 Coumarins, thus, offered the basic structural
zation for useful chemical conversions draws much attention motifs of many potent drug candidates including anti-
among synthetic chemists at large. As part of green chemistry coagulants,9 antibiotics,10 antioxidants,11 anticancer drugs,12
antituberculosis drugs,13 anti-inflammatories,14 and many
more.15 Coumarin derivatives are used as additives in foods
Laboratory of Natural Products & Organic Synthesis, Department of Chemistry,
Visva-Bharati (a Central University), Santiniketan-731 235, West Bengal, India.
E-mail: brahmg2001@yahoo.co.in, goutam.brahmachari@visva-bharati.ac.in
†This paper is dedicated to Professor Vinod K. Singh on the occasion of his
62nd birthday.
and cosmetics,16 fragrances and perfumes,17 and agrochem-
icals.18 Such molecules find extensive application also as fluo-
rescent sensors,19 optical brighteners,20 fluorescent transthyr-
etin folding sensors,21 and molecular photonic devices.22 On
the other hand, hydrazone derivatives, frequently found in
‡Electronic supplementary information (ESI) available: Physical and spectral
data of all the synthesized compounds 4a–4u, scanned copies of respective 1H numerous biologically potent and pharmaceutically beneficial
NMR, 13C NMR, DEPT-135, 19F NMR, and HRMS spectra for all of them, X-ray
molecules23 and fluorescent chemosensors,24 can act as
auxiliaries in asymmetric synthesis,25 photoswitches in photo-
single crystallographic analysis for a representative entry, (E)-3-(2-(3,5-bis(tri-
fluoromethyl)phenyl)hydrazono)chroman-2,4-dione (4k), and calculations of
pharmacology,26 and linkers in preparing bifunctional mole-
E-factors for all the synthesized compounds. CCDC 2070059 for 4k. For ESI and
cules27 and as ligands or directing groups in organic
crystallographic data in CIF or other electronic format, see DOI: 10.1039/
d1gc01341f
synthesis.28
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As part of our ongoing endeavours in green chemistry ment in the product yield and reaction time was observed. We
research,29 we thus felt the interest to design a green and then performed the model reaction by conventional stirring
milder approach to synthesize a series of diversely substituted with the help of a magnetic stirrer in the absence or presence
coumarin hydrazones with somewhat enhanced bioactivity of different solvents such as acetonitrile, dimethyl sulfoxide,
and material properties in anticipation. To our delight, we 1,4-dioxane, ethanol and water at room temperature (Table 1,
have now successfully developed, for the first time, a catalyst- entries 11–18). A comparable yield of 81% for 4a was obtained
and solvent-free, efficient and practical method for regio- at 240 min (4 h) when the reaction was carried out in aceto-
selective Csp2–H functionalization of 4-hydroxycoumarins via nitrile (Table 1, entry 11). Since this conventional method
C-3 dehydrogenative aza-coupling under ball-milling (Scheme 1). required a much longer reaction time and for the use of
Mechanosynthesis of (E)-3-(2-arylhydrazono)chroman-2,4-diones organic solvents, very reasonably, we opted for the ball milling
(coumarin hydrazones, 4) was, therefore, achieved upon high- technique! Eventually, we developed a mechanochemistry-
speed ball-milling of a mixture of 4-hydroxycoumarins (1), driven protocol for the catalyst- and solvent-free Csp2–H
primary aromatic amines (2) and tert-butyl nitrite (3) under cata- functionalization of 4-hydroxycoumarins, leading to the syn-
lyst- and solvent-free conditions. A clean reaction profile, avoid- thesis of diversely substituted (E)-3-(2-arylhydrazono)chro-
ance of both solvents and catalysts, use of no solid supports, mane-2,4-diones (4) via C-3 aza-coupling. Compound 4a was
energy efficiency, lack of a need for column chromatographic characterized by the conventional spectral (1H NMR, 13C NMR,
purification, excellent regioselectivity, good to excellent yields, DEPT-135, and HRMS) studies. The overall results are summar-
short reaction times, and gram-scale synthetic applicability are ized in Table 1.
the key advantages of this newly developed protocol.
After the reaction conditions were established, we then pro-
ceeded to check the viability of this newly developed protocol
by carrying out a set of eleven varying reactions from the
mixture of 4-hydroxycoumarin (1a; 3.0 mmol), tert-butyl nitrite
(3.0 mmol) and differently substituted primary aromatic
2. Results and discussion
We commenced our study with the model reaction between amines (2b–2l; 3.0 mmol each) having both electron-donating
unsubstituted 4-hydroxycoumarin (1a), aniline and tert-butyl and electron-withdrawing groups such as methyl, methoxyl,
nitrite targeting the desired product, (E)-3-(2-phenylhydrazono) bromo, chloro, dichloro, nitro, trifluoromethyl, bis-trifluoro-
chromane-2,4-dione (4a), through ball milling. In our first methyl, trifluoromethoxy, thiomethyl (–SCH3), and thiotrifluor-
attempt, a mixture of 1a (3.0 mmol), aniline (3.0 mmol) and omethyl (–SCF3) groups. All the reactions took place smoothly
tert-butyl nitrite (3.0 mmol) was milled using 7 stainless steel with excellent yields in a range of 81–95% within 4–5 min
balls (10 mm in diameter) for 5 min (with 10 s breaks at 1 min (Table 2, products 4b–4l). Thus, both the electron-releasing
interval) at 500 rpm without the use of any surface, solvents and electron-withdrawing substituents present in the aromatic
and catalysts/additives. We were delighted to obtain 4a in an nuclei of the primary amines were well tolerated under ball
excellent yield of 88% upon washing the crude product with milling conditions. With these encouraging results in hand,
aqueous ethanol (1 : 1 v/v; 10 mL) (without the aid of tedious we then performed another set of nine more reactions between
column chromatography), followed by drying in open air substituted 4-hydroxycoumarins (viz. 4-hydroxy-6-methyl-
(Table 1, entry 4). To check whether the yield could be coumarin 1b, 4-hydroxy-7-methylcoumarin 1c, 4-hydroxy-7-
improved, milling parameters, such as the number of balls, methoxycoumarin 1d, and 6-chloro-4-hydroxycoumarin 1e),
frequency and milling time, including nitrite reagents (sodium tert-butyl nitrite and varying anilines under the optimized
nitrite was also tried) and their proportions, were varied reaction conditions. All these reactions were also found to be
(Table 1, entries 1–3 and 5–10); however, no marked improve- implemented smoothly, thereby affording the desired (E)-3-(2-
Scheme 1 Mechanochemistry-driven Csp2–H functionalization of 4-hydroxycoumarins via C-3 dehydrogenative aza-coupling.
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Table 1 Optimization of the reaction conditions for the synthesis of diversely substituted (E)-3-(2-arylhydrazono)chromane-2,4-diones (4)
Entry
Solvent (1 mL)
Nitrite reagent (3) (equiv.)
Condition
No. of balls/rpm
Time (min)
Yielda,b (%)
1
2
3
4
5
6
7
8
—
—
—
—
—
—
—
—
—
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Ball milling
Stirring at rt
Stirring at rt
Stirring at rt
Stirring at rt
Stirring at rt
Stirring at rt
Stirring at rt
Stirring at rt
7/500
7/500
7/500
7/500
7/600
7/500
8/500
6/500
7/400
7/500
—
—
—
—
—
—
—
—
60
10
5
5
5
5
5
8
10
25
240
600
240
600
480
300
600
600
—
43
68
88
84
89
87
85
74
56
81
68
70
55
45
79
26
12
tBuONO (0.5)
tBuONO (0.75)
tBuONO (1.0)
tBuONO (1.0)
tBuONO (1.5)
tBuONO (1.0)
tBuONO (1.0)
tBuONO (1.0)
NaNO2 (1.0)
tBuONO (1.0)
tBuONO (1.0)
tBuONO (1.0)
tBuONO (1.0)
tBuONO (1.0)
NaNO2 (1.0)
tBuONO (1.0)
NaNO2 (1.0)
9
—
—
10
11
12
13
14
15
16
17
18
CH3CN
DMSO
1,4-Dioxane
EtOH
H2O
CH3CN
—
—
a Reaction conditions: a mixture of 4-hydroxycoumarin (1a; 3.0 mmol) and aniline (2a; 3.0 mmol) was reacted with tert-butyl nitrite (1 equiv.) or
sodium nitrite (1 equiv.) either under ball milling (using a 25 mL stainless steel jar and balls of 10 mm diameter) in the absence of any catalysts
and solvents or by simple stirring at room temperature (25–28 °C) in the presence of different solvents without any further additives. b Isolated
yields.
arylhydrazono)chromane-2,4-diones 4m–4u in similar yields leading to the formation of substituted (E)-3-(2-arylhydrazono)
ranging from 78–86% within a very short time scale of 4–6 min chromane-2,4-diones (4). Initially, a diazonium salt 5 is gener-
(Table 2, products 4m–4u). However, primary aliphatic amines ated from the reaction between anilines 2 and tert-butyl nitrite
(viz. n-butylamine, i-butylamine, benzylamine, and c-hexyla- 3, the electrophilic azo-nitrogen of which is then attacked by
mine) were found not to yield the desired product(s) as 4-hydroxycoumarins (1) through its nucleophilic C-3 position
expected. Table 2 summarizes the overall results.
under the reaction conditions, thereby giving rise to 3-(phenyl-
The synthesized products (4a–4u) were purified by washing diazenyl)chromane-2,4-diones 6. Intermediate 6 rapidly tauto-
the crude products with aqueous ethanol (1 : 1 v/v; 10 mL), fol- merizes to its enol form 4′, which in turn further tautomerizes
lowed by drying in open air (see the Experimental section). All to the more stable desired E-isomer of product 4. The reaction
the compounds were fully characterized based on their follows an ionic pathway and supports the experimental obser-
detailed spectral studies, including 1H NMR, 13C NMR, vations that the conversion is not influenced by radical scaven-
DEPT-135, 19F NMR (for fluorine atom-containing molecules gers (viz. TEMPO, BQ, and BHT).
such as 4i, 4j, 4k, 4o, 4p, and 4u), and HRMS. To our delight,
we were successful in developing suitable crystals for (E)-3-(2- optimization of the three electronic structures, viz. E- and
(3,5-bis(trifluoromethyl)phenyl)hydrazono)chroman-2,4-dione Z-isomers of the keto form 4 and the enol form 4′, calculated
To validate our presumption, we performed geometry
(4k; Table 2), and the results of its single-crystal X-ray analysis at the DFT/B3LYP level along with the 6-31++G(d,p) basis set
[CCDC 2070059;‡ unit cell parameters: a = 31.1491(1) Å using Gaussion09 software.31 The respective optimized ener-
(α = 90°), b = 7.2268(4) Å (β = 92.130(4)°), c = 13.9792(7) Å gies were determined to be −912.8341 a.u., −912.8327 a.u. and
(γ = 90°), C2/c] documented in this present communication −912.7978 a.u., thereby indicating their relative stability in the
(see the ESI‡) are in full structural agreement. The ORTEP and order of (E)-4 > (Z)-4 > 4′. The relatively greater stability of both
packing diagram of the molecule is presented in Fig. 1.
E- and Z-isomers of 4 compared to 4′ is attributed to the intra-
tert-Butyl nitrite (TBN) acts as a versatile reagent in imple- molecular hydrogen bonding of type N–H⋯O present only
menting a wide range of chemical transformations, including within the structures of 4. Interestingly, the strength of this
diazotization.30 We thus herein propose a plausible mecha- N–H⋯O type intramolecular hydrogen bonding (with a calcu-
nism (Scheme 2) for the mechanochemistry-driven C-3 lated length of 1.82 Å) in the Z-isomer of 4 is less than that of
dehydrogenative aza-coupling of 4-hydroxycoumarins (1), the E-isomer (1.76 Å), which makes the latter relatively more
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Table 2 Synthesis of diversely functionalized (E)-3-(2-arylhydrazono)chromane-2,4-diones (4)a,b
a Reaction conditions: a mixture of 4-hydroxycoumarins (1; 3.0 mmol) and aromatic amines (2; 3.0 mmol) was ground with tert-butyl nitrite
(3; 3.0 mmol) under ball milling using 7 stainless steel balls (10 mm in diameter) in a 25 mL stainless steel jar at 500 rpm for 4–6 min (with 10 s
breaks at 1 min interval) in the absence of any catalysts and solvents. b Isolated yields; NR = no reaction.
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Fig. 1 (a) The ORTEP view of the molecule 4k, showing the atom-labelling scheme (displacement ellipsoids are drawn at the 40% probability level,
and H atoms are shown as small spheres of arbitrary radii). (b) The packing arrangement of 4k viewed along the b-axis.
Scheme 2 Proposed mechanism for the mechanochemistry-driven Csp2–H functionalization of 4-hydroxycoumarins via C-3 dehydrogenative aza-
coupling.
stable. This energy consideration acts as the driving force for
the energetically favourable tautomerization of 4′ predomi-
nantly to (E)-4, and the configuration received support from
the X-ray crystallographic analysis (Fig. 1). The energy profile
diagram (Fig. 2) summarizes the overall observations.
To evaluate the greenness of this newly developed method,
we herein calculated (see the ESI‡) the E-factor (g g−1) for all
the synthesized compounds (4a–4u) as one of the essential
green metrics.32 The calculated E-factors (g g−1) are found to
be in the range of 0.64–0.35, which indicates the considerable
greenness of this present method. Water and tert-butanol are
the green wastes in this transformation, as shown in the
mechanism (Scheme 2). Furthermore, we checked the effective-
ness of this catalyst- and solvent-free protocol for a gram-scale
reaction with the model entry (Table 2, entry 3). The reaction
proceeded satisfactorily, furnishing the desired product 4c in a
similar yield within almost the same time frame compared to Fig. 2 Energy profile diagram.
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Scheme 3 Representative gram-scale experiment.
the lower millimolar scale (see the Experimental section). The reported as J values in Hz. Mass spectrometry was performed
large-scale reaction afforded the target product, (E)-3-(2-(p- using a Microtek Q-Tof Micro YA 263 Waters spectrometer.
tolyl)hydrazono)chromane-2,4-dione (4c), in 94% yield within X-ray single crystallographic data were collected using an
6 min (Scheme 3).
X’Calibur CCD area-detector diffractometer. The melting
points were recorded using a Chemiline CL-725 melting point
apparatus and are uncorrected. Thin layer chromatography
(TLC) was performed using silica gel 60 F254 (Merck) plates. A
PM 100 (Retsch GmbH, Germany) ball-milling apparatus was
used for all the reactions.
3. Conclusion
In conclusion, we have accomplished a mechanochemistry-
driven, simple, straightforward and efficient synthesis protocol
for a series of pharmaceutically interesting diversely functiona-
lized (E)-3-(2-arylhydrazono)chromane-2,4-diones (4) from a
one-pot three-component reaction between 4-hydrocoumarins
(1), primary aromatic amines (2) and tert-butyl nitrite (3) under
ball-milling without the aid of any catalysts/additives and sol-
vents. The empowering mechanical force applied herein is
sufficient to implement the facile Csp2–H functionalization of
4-hydroxycoumarins to furnish the coumarin hydrazones via
C-3 dehydrogenative aza-coupling. This mechanical force
negates the use of catalytic activation and harsh pushing con-
ditions that are typically required for the conventional solu-
tion-based methods. Also, this protocol does not require any
acids and bases for preparing such stable azo-dyes. The oper-
ational simplicity, use of commercially available low-cost start-
ing materials with a broad substrate scope, avoidance of cata-
lysts/additives, use of no toxic organic solvents in the entire
process, lack of the need for chromatographic purification,
reaction at ambient temperature under ball-milling, a clean
reaction profile, excellent regioselectivity, high yields of pro-
ducts at short reaction times (in minutes), energy efficiency,
and gram-scale synthetic applicability make this procedure
green and cost-effective.
4.2 General procedure for the synthesis of substituted
(E)-3-(2-arylhydrazono)chroman-2,4-dione (4)
A mixture of 4-hydroxycoumarins (1; 3.0 mmol), aromatic
primary amines (2; 3.0 mmol) and tert-butyl nitrite
(3; 3.0 mmol; d: 0.867 g mL−1; purity: 90%) was subjected to
ball-milling at 500 rpm using a 25 mL stainless steel jar with
seven balls (10 mm in diameter) of the same material for
4–6 min. The ball-milling operation was performed in an
inverted rotation direction, with 10 s breaks at 1 min interval.
The progress of the reaction was monitored by TLC. On com-
pletion of the reaction, 10 mL of aqueous ethanol (1 : 1 v/v)
was added to the crude product and shaken well to dissolve
out unreacted reactants and other intermediates/impurities,
and then the undissolved solid mass was filtered off to obtain
the pure products 4 (4a–4u) upon drying in open air. All the
structures of the synthesized compounds were confirmed by
spectroscopic studies, including 1H-NMR, 13C-NMR,
DEPT-135, 19F-NMR (for fluorine atom-containing molecules
such as 4i, 4j, 4k, 4o, 4p, and 4u), and HRMS. The physical
and spectral data of one representative compound 4a are given
herein, and those for all the other synthesized compounds 4b–
4u are documented in the ESI.‡
(E)-3-(2-Phenylhydrazono)chroman-2,4-dione (4a). Reddish
yellow amorphous solid; yield: 88% (702 mg; 3.0 mmol scale);
1
mp = 165–166 °C. H NMR (400 MHz, DMSO-d6): δ = 15.66 (br
s, 1H, –NH), 7.93 (d, 1H, J = 7.2 Hz, Ar–H), 7.41–7.69 (m, 3H,
Ar–H), 7.49 (t, 2H, J = 7.6 Hz, Ar–H), 7.36–7.30 (m, 3H, Ar–H)
4. Experimental section
4.1 General
All chemicals (analytical grade) were purchased from reputed ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ = 177.57 (oxo CO),
companies and used without further purification. 1H, 13C, 158.24 (lactone CO), 154.00 (C), 140.87 (C), 136.38 (CH), 129.90
DEPT-135 and 19F NMR spectra were recorded at 400 MHz, (2C, CH), 127.87 (CH), 126.37 (CH), 124.63 (CH), 122.50 (C),
100 MHz and 376 MHz, respectively, on a Bruker DRX spectro- 120.16 (C), 117.86 (2C, CH), 117.31 (CH) ppm. HRMS: m/z
meter using DMSO-d6 and CDCl3 as solvents. Chemical shifts 289.0584 [M + Na]+ calcd for C15H10N2O3Na, found: m/z
were reported in δ (ppm), relative to the internal standard, 289.0597.
TMS. The signals observed are described as s (singlet), d
Further structural confirmation for a representative entry,
(doublet), t (triplet), and m (multiplet). Coupling constants are (E)-3-(2-(3,5-bis(trifluoromethyl)phenyl)hydrazono)chroman-
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2,4-dione (4k), based on single X-ray crystallographic studies,
is also provided (see the ESI‡).
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4.3 Gram-scale synthesis of compound 4c
A mixture of 4-hydroxycoumarin (1a; 5.0 mmol; 0.810 g),
p-toluidine (2c; 5.0 mmol; 0.535 g) and tert-butyl nitrite
(3; 5.0 mmol; 0.575 g) was ball-milled in a 25 mL stainless
steel jar with seven balls (10 mm in diameter) of the same
material at 500 rpm for 6 min in a similar manner as
described earlier. On completion of the reaction (as monitored
by TLC), the crude product was added with 15 mL of aqueous
ethanol (1 : 1 v/v), shaken well, filtered off and dried to obtain
the desired product, (E)-3-(2-(p-tolyl)hydrazono)chroman-2,4-
dione (4c), in pure form with 94% yield (1.313 g).
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There are no conflicts of interest to declare.
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Acknowledgements
IK is grateful to the UGC, New Delhi, for providing him with a
Senior Research Fellowship. The authors are also thankful to
IACS, Kolkata, for extending the HRMS measurement facility,
and the Department of Chemistry, Visva-Bharati, for all-
around support.
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