An expedient solvent-free C-benzylation of 4-hydroxycoumarin with styrenes

Article abstract of DOI:10.1016/j.mencom.2021.01.039

An efficient straightforward solvent-free C(3)-benzylation of 4-hydroxycoumarin with styrenes is performed by heating the reactants in the presence of p-toluenesulfonic acid. By this procedure, benzylated 4-hydroxycoumarin derivatives which exhibit variou

Full text of DOI:10.1016/j.mencom.2021.01.039

Mendeleev
Communications
Mendeleev Commun., 2021, 31, 123–124
An expedient solvent-free C-benzylation
of 4-hydroxycoumarin with styrenes
Rana Chatterjee,a Anindita Mukherjee,b Sougata Santra,b
Grigory V. Zyryanov,*b,c Oleg N. Chupakhinb,c and Adinath Majee*a
a Department of Chemistry, Visva-Bharati University, 731235 Santiniketan, India.
E-mail: adinath.majee@visva-bharati.ac.in
b Institute of Chemical Engineering, Ural Federal University, 620002 Ekaterinburg, Russian Federation.
E-mail: gvzyryanov@gmail.com
c I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620219 Ekaterinburg, Russian Federation
DOI: 10.1016/j.mencom.2021.01.039
Oꢅ
O
Oꢅ
Me
An efficient straightforward solvent-free C(3)-benzylation of
4-hydroxycoumarin with styrenes is performed by heating
the reactants in the presence of p-toluenesulfonic acid. By
this procedure, benzylated 4-hydroxycoumarin derivatives
which exhibit various biological activities were obtained.
ꢅ
O
ꢈsOꢅ ꢉ20 molꢃꢊ
neatꢆ ꢂ0 ο
ꢇ
Ar
C
Ar
O
O
metalꢄfree
solventꢄfree
oꢀen atmosꢀhere
uꢀ to ꢁꢂꢃ yield
Phenꢀrocoumon
synthesis
short reaction time
Keywords: 4-hydroxycoumarin, styrene, p-toluenesulfonic acid, benzylation, solvent-free.
Coumarin and its derivatives are of a biological and pharma-
ceutical importance.1-3 Substituted 4-hydroxycoumarins play a
crucial role in the manufacture of various active organic
molecules. Among them, 3-alkylated 4-hydroxycoumarins such
as warfarin, coumatetralyl, phenprocoumon, difenacoum,
brodifacoum, flocoumafen, etc. exhibit anti-HIV,4 antiviral,5
antifungal,6 anti-inflammatory,7 anti-arthritis,8 antibacterial,9
antioxidant,10 anticancer11 activities. Some of these derivatives
are known to be anticoagulants and act as a vitamin K antagonist.12
On the other hand, 4-hydroxycoumarins serve as good Michael
donors in various reactions.13-14 Several methods have been
employed to achieve C3-alkylation of 4-hydroxycoumarin. Most
of them comprise the reaction with benzylic alcohols in the
presence of different catalytic reagents like Bi(OTf)3,15 iodine,16
C-benzylation of 4-hydroxycoumarin with styrenes under neat
conditions (Scheme 1).†
We have initiated our study taking model 4-hydroxycoumarin
1 and styrene 2a in the presence of 20 mol% of p-toluenesulfonic
acid (TsOH) when the reactants were stirred in water at 80°C for
4 h (Table 1, entry 1) to afford 61% of the target product 3a.
Surprisingly, in various organic solvents the yields were even lower
(entries 2-6).At that point, we were interested to perform the reaction
under neat conditions, which provided a satisfactory yield (78%)
of product 3a (entry 7). Application of other available Brønsted
acids rather than TsOH gave nothing of the product (entries 8-12).
Table 1 Optimization of the reaction conditions for model reaction
between 4-hydroxycoumarin 1 (1 mmol) and styrene 2a (1.5 mmol).
Fe(ClO4)3·xH2O,17 amberlite
IR-120,18 TMSOTf,19
Catalyst
(mol%)
Yield of 3a
Entry
Solventa
T/ºC
t/h
FeCl3·6H2O,20 with the processes being carried out in organic
solvents. Nitrimines were also employed to synthesize such
compounds.21 Besides, Rueping et al. reported C3-alkylation of
4-hydroxycoumarin with olefins in the presence of bismuth(iii)
trifluoromethanesulfonate.15 In this regard, our research was
aimed to improve this strategy in view of environmentally
acceptable chemicals, catalysts and conditions. During the last
five years, we have developed several reaction protocols
concerning 4-hydroxycoumarin and organocatalysis that
multiply satisfy the environmental issues.22-25 Herein, we
report p-toluenesulfonic acid-catalyzed mild and efficient
(%)b
1
2
TsOH (20)
TsOH (20)
TsOH (20)
TsOH (20)
TsOH (20)
TsOH (20)
TsOH (20)
TFA (20)
H2O
80
80
80
80
80
80
80
80
80
80
80
80
120
50
80
80
80
80
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
3
4
4
61
49
28
33
16
21
EtOH
CH2Cl2
1,4-dioxane
toluene
MeCN
neat
3
4
5
6
7
78
8
neat
trace
-
trace
trace
trace
79
9
HCl (20)
neat
10
11
12
13
14
15
16
17
18
HCO2H (20)
AcOH (20)
PhCO2H (20)
TsOH (20)
TsOH (20)
TsOH (20)
TsOH (20)
TsOH (10)
TsOH (30)
neat
†
neat
General procedure for the synthesis of compounds 3a-h. A mixture of
neat
4-hydroxycoumarin 1 (162 mg, 1 mmol), styrene 2a-h (1.5 mmol) and
TsOH (0.034 g, 20 mol%) was stirred at 80°C for 4-6 h (TLC control).
After completion, the reaction mixture was cooled and extracted with
ethyl acetate (3 × 15 ml) and water (2 × 10 ml). The organic layer was
separated and dried over Na2SO4. After evaporation of the solvent under
reduced pressure, the crude product was purified by column chromato-
graphy on silica gel (60–120 mesh) using light petroleum/ethyl acetate
(94:6 to 92:8, v/v) as eluent to afford the pure products 3a-h. For
details, see Online Supplementary Materials.
neat
neat
37
neat
76
neat
68
neat
45
neat
78
a 2 ml mmol-1 b Isolated yield.
.
© 2021 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 123 –

Mendeleev Commun., 2021, 31, 123–124
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2021.01.039.
Oꢀ
O
R
Oꢀ
R
i
ꢊ
Ar
Ar
References
O
O
O
1 A. Lacy and R. O’Kennedy, Curr. Pharm. Des., 2004, 10, 3797.
2 F. G. Medina, J. G. Marrero, M. Macías-Alonso, M. C. González,
I. Córdova-Guerrero, A. G. T. García and S. Osegueda-Robles, Nat.
Prod. Rep., 2015, 32, 1472.
3 G. Athanasellis, G. Melagraki, H. Chatzidakis, A. Afantitis, A. Detsi,
O. Igglessi-Markopoulou and J. Markopoulos, Synthesis, 2004, 11,
1775.
ꢀ
ꢁa−ꢂ
ꢃa−ꢄ
a Ar ꢁ Phꢂ Rꢁ ꢀꢂ ꢃꢄꢅ
b Ar ꢁ 2ꢆMeCꢇꢀꢈꢂ Rꢁ ꢀꢂ ꢃ0ꢅ
c Ar ꢁ ꢈꢆMeCꢇꢀꢈꢂ Rꢁ ꢀꢂ ꢃꢉꢅ
e Ar ꢁ ꢈꢆClCꢇꢀꢈꢂ Rꢁ ꢀꢂ ꢃꢈꢅ
f Ar ꢁ ꢋꢆBrCꢇꢀꢈꢂ Rꢁ ꢀꢂ ꢃ2ꢅ
g Ar ꢁ ꢈꢆꢌCꢇꢀꢈꢂ Rꢁ ꢀꢂ ꢃꢋꢅ
d Ar ꢁ ꢈꢆMeOCꢇꢀꢈꢂ Rꢁ ꢀꢂ ꢃꢃꢅ ꢄ Ar ꢁ Phꢂ Rꢁ Meꢂ ꢇꢄꢅ
4 D. Yu, M. Suzuki, L. Xie, S. L. Morris-Natschke and K.-H. Lee, Med.
Res. Rev., 2003, 23, 322.
5 B. S. Kirkiacharian, E. Clercq, R. Kurkjian and C. Pannecouque, J. Pharm.
Chem., 2008, 42, 265.
6 Z. H. Chohan, A. U. Shaikh, A. Rauf and C. T. Supuran, J. Enz. Inhib.
Med. Chem., 2006, 21, 741.
ꢁi Ar ꢁ ꢋꢆO2NCꢇꢀꢈꢂ Rꢁ ꢀꢂ no ꢍroduct
ꢁꢂ Ar ꢁ ꢈꢆMeOCꢎOꢏCꢇꢀꢈꢂ Rꢁ ꢀꢂ no ꢍroduct
Scheme 1 Reagents and conditions: i, 1/2 = 1:1.5 (mol/mol), TsOH
(20 mol%), neat, 80 °C, 4 h (6 h for 3f).
Heating plays an important role in this reaction. The yield was not
improved noticeably by raising the temperature to 120°C (entry 13)
while a lower yield was obtained on lowering the temperature
(entry 14). By prolongation or shortening the reaction time the
yield was not raised (entries 15,16). We have observed that
20 mol% of TsOH as the catalyst provided better yield (78%)
compared to that (45%) when 10 mol% of TsOH was used
(entry 17). Increase in the catalyst loading to 30 mol% did not
affect the reaction outcome (entry 18). After considering the above
experiments, the optimum conditions were selected to be heating
neat mixture of 4-hydroxycoumarin 1 (1 mmol), styrene 2a
(1.5 mmol) and 20 mol% of TsOH at 80°C for 4 h.
Based on the optimized reaction conditions, we checked the
scope and limitations of our reaction procedure (see Scheme 1).
Styrenes with alkyl and halogen substituents in arene moiety
2b-g reacted closely to their parent analogue 1a and gave the
corresponding products 3b-g in satisfactory yields. To our
delight, we have successfully synthesized phenprocoumon 3h in
68% yield by coupling b-methylstyrene 2h with 4-hydroxy-
coumarin 1. Unfortunately but not surprisingly, styrenes 2i,j with
electron-withdrawing groups in arene core did not react to give
desired products 3i,j.
We were interested to prepare anticoagulant drug phenpro-
coumon 3h in gram scale range. For this purpose, the reaction
between 4-hydroxycoumarin 1 (10 mmol) and b-methylstyrene 2h
(15 mmol) under the optimized conditions afforded 1.7 g (61%)
of the desired product 3h.
In summary, we have developed an efficient procedure for the
direct C-benzylation of 4-hydroxycoumarin with styrenes using
available, cheap and metal-free catalyst under solvent-free and
open-air conditions. By this simple and green procedure, we can
synthesize various important 4-hydroxycoumarin derivatives
including phenprocoumon in good yields.
7 A. C. Luchini, P. Rodrigues-Orsi, S. H. Cestari, L. N. Seito,
A. Witaicenis, C. H. Pellizzon and L. C. Di Stasi, Biol. Pharm.
Bull., 2008, 31, 1343.
8 D. Chiarino, G. C. Grancini, V. Frigeni and A. Carenzi, Eur. Pat. Appl.,
1988, EP 284017.
9 G. Cravotto, S. Tagliapietra, R. Cappello, G. Palmisano, M. Curini and
M. Boccalini, Arch. Pharm. Chem. Life Sci., 2006, 339, 129.
10 F. Pérez-Cruz, S. Serra, G. Delogu, M. Lapier, J. D. Maya, C. Olea-Azar,
L. Santana and E. S. Uriarte, Bioorg. Med. Chem. Lett., 2012, 22, 5569.
11 K. P. Barot, S. V. Jain, L. Kremer, S. Singh and M. D. Ghate, Med.
Chem. Res., 2015, 24, 2771.
12 N. Au and A. E. Rettie, Drug Metab. Rev., 2008, 40, 355.
13 M. Rullo and L. Pisani, Chem. Heterocycl. Compd., 2018, 54, 394.
14 R. F. Fatykhov, M. I. Savchuk, E. S. Starnovskaya, M. V. Bobkina,
D. S. Kopchuk, E. V. Nosova, G. V. Zyryanov, I. A. Khalymbadzha,
O. N. Chupakhin, V. N. Charushin and V. G. Kartsev, Mendeleev
Commun., 2019, 29, 299.
15 M. Rueping, B. J. Nachtsheim and E. Sugiono, Synlett, 2010, 10, 1549.
16 X. Lin, X. Dai, Z. Mao and Y. Wang, Tetrahedron, 2009, 65, 9233.
17 P. Thirupathi and S. S. Kim, Tetrahedron, 2010, 66, 2995.
18 C. R. Reddy, B. Srikanth, R. Narsimha and D. S. Shin, Tetrahedron,
2008, 64, 11666.
19 P. Theerthagiri and A. Lalitha, Tetrahedron Lett., 2010, 51, 5454.
20 J. Kischel, K. Mertins, D. Michalik, A. Zapf and M. Beller, Adv. Synth.
Catal., 2007, 349, 865.
21 V. V. Angeles-Dunham, D. M. Nickerson, D. M. Ray and A. E. Mattson,
Angew. Chem., Int. Ed., 2014, 53, 14538.
22 S. Mahato, S. Santra, R. Chatterjee, G. V. Zyryanov, A. Hajra and
A. Majee, Green Chem., 2017, 19, 3282.
23 R. Chatterjee, S. Santra, G. V. Zyryanov and A. Majee, Synthesis, 2019,
51, 2371.
24 R. Chatterjee, S. Mahato, S. Santra, G. V. Zyryanov, A. Hajra and
A. Majee, ChemistrySelect, 2018, 3, 5843.
25 R. Chatterjee, S. Santra, G. V. Zyryanov and A. Majee, J. Heterocycl.
Chem., 2020, 57, 1863.
A. Majee acknowledges financial support from the CSIR
Major Research Project (Ref. no. 02(0383)/19/EMR-II).
A. Mukherjee and S. Santra thank the Russian Science
Foundation for funding (Grant no. 20-73-10205). G. V. Zyryanov
and O. N. Chupakhin are grateful to the Grants Council of the
President of the Russian Federation (no. NSh-2700.2020.3) for
funding.
Received: 26th August 2020; Com. 20/6296
– 124 –