Microwave assisted benzylation of naphthols and 4-hydroxycoumarin under catalyst & solvent free conditions

Article abstract of DOI:10.1016/j.tetlet.2016.07.010

An expeditious and highly practical, microwave assisted benzylation of naphthols and 4-hydroxycoumarin has been developed under catalyst-free & solvent-free conditions. Alcohols undergo heat induced dehydration to form ethers, which collapse reversibly to form the carbocation which was captured immediately by a suitable nucleophile to furnish the benzylated compounds.

Full text of DOI:10.1016/j.tetlet.2016.07.010

Accepted Manuscript
Microwave Assisted Benzylation of Naphthols and 4-Hydroxycoumarin under
Catalyst & Solvent Free Conditions
Ravikrishna Dada, Garima Singh, Abhishek Pareek, Saeen Kausar, Srinivasarao
Yaragorla
PII:
S0040-4039(16)30831-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.010
TETL 47872
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 May 2016
1 July 2016
2 July 2016
Please cite this article as: Dada, R., Singh, G., Pareek, A., Kausar, S., Yaragorla, S., Microwave Assisted Benzylation
of Naphthols and 4-Hydroxycoumarin under Catalyst & Solvent Free Conditions, Tetrahedron Letters (2016), doi:
http://dx.doi.org/10.1016/j.tetlet.2016.07.010
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Microwave Assisted Benzylation of Naphthols and 4-Hydroxycoumarin under Catalyst &
Solvent Free Conditions
Ravikrishna Dada, Garima Singh, Abhishek Pareek, Saeen Kausar, Srinivasarao Yaragorla

1
Tetrahedron Letters
Microwave Assisted Benzylation of Naphthols and 4-Hydroxycoumarin under
Catalyst & Solvent Free Conditions
Ravikrishna Dada, a Garima Singh, a Abhishek Pareek, a Saeen Kausar, a Srinivasarao Yaragorla a
a SY-Organic & Medicinal Chemistry Laboratory, Department of Chemistry, Central University of Rajasthan, Bandarsindri, NH-8, Ajmer, Rajasthan, 305817,
India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An expeditious and highly practical, microwave assisted benzylation of naphthols and 4-
hydroxycoumarin has been developed under catalyst-free & solvent-free conditions. Alcohols
undergo heat induced dehydration to form ethers, which collapse reversibly to form the
carbocation which was captured immediately by a suitable nucleophile to furnish the benzylated
compounds
Available online
Keywords:
Benzylation
Microwave reaction
Catalyst-free
Solvent-free
Ethers
2009 Elsevier Ltd. All rights reserved.
Dehydration
SN1
Carbon-Carbon bond formation is one of the fundamental and
key reactions in the organic synthesis.1 Nucleophilic substitution
of benzylic alcohols by various nucleophiles such as naphthols2-9
or coumarins10 is one of the important and highly studied C-C
bond forming reactions. In general, the direct nucleophilic
substitution reaction of benzylic alcohols was achieved by the
use of excess of sulphuric acid or phosphoric acid2 and
stoichiometric amounts of Lewis acids.3 As the hydroxyl
functionality is not a good leaving group, it needs to be activated
by converting into a better leaving group and then treated with a
nucleophile under suitable conditions.4 For example benzylation
of naphthols has been reported from the benzylic alcohols using
p-TsOH.H2O, polymer-bound p-TsOH,5 I2,6 ionic liquids,7 metal
salts8 such as Bi, La, Sc, Hf, Fe, Au, InCl3 and Amberlyst-15.9
Similarly, benzylic alcohols were treated with 4-
hydroxycoumarin with variety of catalysts such as Pd,10a Co,10b
Cu,10c BF3OEt2,10d InCl3,10e Indium bromide,10f FeCl3,10g
Bi(OTf)3,10h lanthanide triflates,10i p-TsOH,10j dodecyl benzene
From Last few years, our research has been focussed to develop
novel synthetic protocols for the synthesis of biologically
important heterocyclic molecules maintaining some of the
sustainable principles.13 In this process, we developed “On-Water
Synthesis” of oxindole derivatives, synthesis of various
benzopyran and benzofuran molecules under solvent-free
conditions using environmentally benign calcium salts as
catalysts. In continuation, herein we report a microwave assisted
Catalyst and solvent free benzylation of naphthols and 4-
hydroxycoumarin with various benzylic alcohols.
sulfonic acid (DBSA),10k molecular iodine,10l PMA/SiO2,10m
Our initial investigations began by heating benzhydrol (1a, 1.5
o
10n
and TMSOTf10o for the preparation of
mmol) and 2-naphthol (2a, 1 mmol) at 90 C and found that 1-
B(C6F5)3
benzhydrylnaphthalen-2-ol (3a) was formed in 35% yield after
pharmaceutically
important
C3-benzylated
coumarin
derivatives.11
12 h. Encouraged by this preliminary observation we repeated the
o
reaction at 120 C and were glad to isolate 90% of 3a after 4 h.
Owing to the global and environmental changes, scientists are
very keen in developing and practicing the green chemistry
approaches.12 During the process several innovations were
Neither water nor toluene was found to be useful when 1a and 2a
were refluxed for 12 h. This indicated that the reaction works
better under solvent-free conditions. The reaction was repeated in
explored, to list
a
few, multicomponent reactions,
o
microwave irradiation14 at 110 C and found that the reaction
Cascade/Domino/Tandem approaches, microwave reactions, on-
water synthesis, solvent-free reactions, catalyst-free reactions and
the reactions with atom & step economy.12
———
gave better result in 20 min (84%). The raise in temperature to
o
140 C was found to yield 3a in 90% after 20 min and hence
considered to be the best condition (Figure 1). After finding the
 Corresponding author. Tel.: +91-463-238535; fax: +91-463-238722; e-mail: srinivasarao@curaj.ac.in

2
Tetrahedron
optimum conditions15 for the benzylation of 2-naphthol (3a)
Similar way 1-(4-bromophenyl)ethan-1-ol (1c) and benzyl
alcohol (1d) reacted -with 2-naphthol under microwave
irradiation to furnish the benzylated naphthols 3c and 3d in 86,
81% yields. Encouraged by the scope of various benzylic
alcohols in the reaction (Table 1) we aimed to check the
reactivity of some more naphthols such as 6-bromo-2-naphthol
(2b) and 1-naphthol (2c). As planned, benzylic alcohols 1a and
1b were treated with naphthol 2b to yield the benzyl derivatives
3e and 3f in 81, 85% yields and they furnished 3g, 3h in 88, 85%
yields with 1-naphthol (Table 1, entries 5-8). Excelled by the
scope of various naphthols and alcohols in the methodology, we
were driven to look at the reactivity of other nucleophiles such as
4-hydroxy coumarin, indole and malanonitrile (Table 1, entries 9-
15). Interestingly, benzylic alcohols 2a, 2b reacted with 4-
hydroxycoumarin under mw conditions at 140 oC and yielded the
respective C3-benzylated 4-hydroxy coumarins 3i and 3j in 91,
84% yields after 20 min. Other benzylic alcohols 2c and 2d also
showed the similar reactivity towards 4-hydroxycoumarin to
furnish the respective coumarin derivatives 3k and 3l in 82, 78%
yields (Table 1, entries 11,12). It was observed that indole and
malononitrile could not benzylated with benzhydrol (2a) under
catalyst free mw irradiation, rather we found that benzhydrol
underwent dehydration to yield the respective ether. This
observation lead us to investigate the plausible mechanism for
the reaction process which is described in figure 2. Trityl alcohol
neither reacted with naphthol nor dehydrated to give the ether
(entry 15).
with benzhydrol (1a), we were interested to check the scope of
this catalyst free and solvent free method and hence 2-naphthol
was treated with 1-phenylethan-1-ol (1b) and the product 3b was
isolated in 90% (Table 1).
An interesting observation was made when 2-naphthol was heated
with 2-(hydroxy(phenyl)methyl)phenol (1e) at 140 oC, the reaction
proceeded through a cascade benzylation followed by dehydration to
yield the 4-aryl-dibenzoxanthene 3m in 72% yield. The scope of this
was extended to other benzylic alcohols 1f and 1g with 2-naphthol
to furnish the respective dibenzoxanthenes 3n and 3o in good yields
(Scheme 1). This cascade benzylation/dehydration strategy was
extended to 4-hydroxycoumarin (Scheme 2), as planned the reaction
furnished the 4-aryl pyranocoumarins 3p, 3q and 3r in good yields.
The plausible mechanism for the benzylation of naphthol has
been described in figure 1. Initially benzylic alcohols (1a)
undergo dehydration at high temperature to produce the ether
(1aa), which collapse reversibly to yield the benzylic
carbocation. Immediately, a suitable nucleophile (naphthol) could
capture the carbocation possibly SN1 pathway to produce the
desired product 3a (Figure 2). To authenticate this idea, ether 1aa
was isolated and treated with 2-naphthol (2a) under the same
conditions to furnish the product 3a (Scheme 3).

3
References
1.
2.
(a) Corey, E. J. Angew. Chem., Int. Ed. 1991, 30, 455. (b) Chemler,
S. R.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544.
(a) Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1973, 38, 1388. (b)
Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1972, 37, 4227. (c)
Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1969, 34, 3571. (d)
Khalaf, A. A.; Roberts, R. M. J. Org. Chem. 1971, 36, 1040. (e)
Sundberg, R. J.; Laurino, J. P. J. Org. Chem. 1984, 49, 249. (f)
Davis, B. R.; Johnson, S. J.; Woodgate, P. D. Aust. J. Chem. 1987,
40, 1283.
3.
4.
(a) Coote, S. J.; Davies, S. G.; Middlemiss, D.; Naylor, A.
Tetrahedron Lett. 1989, 30, 3581. (b) The benzylic alcohol bearing
strong electron-donating group reacts without any catalyst. See:
Takahashi, H.; Kashiwa, N.; Kobayashi, H.; Hashimoto, Y.;
Nagasawa, K. Tetrahedron Lett. 2002, 43, 5751.
For reactions of benzyl acetates, benzyl halides, benzyl ethers, and
benzyl carbonates for nucleophilic substitution reactions, see: (a)
Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew. Chem.
Int. Ed. 2005, 44, 3913. (b) Shiina, I.; Suzuki, M. Tetrahedron Lett.
2002, 43, 6391. (c) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.;
Beller, M. Angew. Chem. Int. Ed. 2005, 44, 238.
5.
6.
7.
8.
Sanz, R.; Martinez, A.; Miguel, D.; Alvarez-Gutierrez, J. M.;
Rodriguez, F. Adv. Synth. Catal. 2006, 348, 1841
Srihari, P.; Bhunia, D. C.; Sreedhar, P.; Yadav, J. S. Synlett. 2008,
1045.
Earle, M. J.; McCromac, P. B.; Seddon, K. R. Chem. Commun.
1998, 2245.
(a) Rueping, M.; Nachtsheim, B. J.; Ieawsuwan, W. Adv. Synth.
Catal. 2006, 348, 1033. (b) Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.;
Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340. (c) Noji, M.;
Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161. (d) Liu, J.; Muth,
E.; Flore, U.; Henkel, G.; Merz, K.; Sauvageau, E.; Schwake, E.;
Dyker, G. Adv. Synth. Catal. 2006, 348, 456. (e) Yasuda, M.;
Somyo, T.; Baba, A. Angew. Chem. Int. Ed. 2006, 45, 793.
Das, B.; Veeranjayanelu, B.; Krishnaiah, M.; Balasubramanyam, P.
Synthetic Commun. 2009, 39, 1929.
To further support the proposed mechanism through ether
formation, 1-phenylethan-1-ol (1b) was heated under mw
irradiation and the mixture of ether and styrene (by dehydration)
was isolated. This mixture was further treated with 1-naphthol
(2c) under the optimized conditions to furnish the benzyl
derivative 3h in 85% yield (Scheme 4).
9.
10. (a) Muzart, J. Tetrahedron 2005, 61, 4179. (b) Mukhopadhyay, M.;
Iqbal, J. Tetrahedron Lett. 1995, 36, 6761. (c) Baruah, J. B.;
Samuelson, A. G. J. Organomet. Chem. 1989, 361, 57. (d) Li, Y.;
Yu, Z.; Wu, S. J. Org. Chem. 2008, 73, 5647. (e) Bisaro, F.; Pretat,
G.; Vitale, M.; Poli, G. Synlett 2002, 1823. (f) Yasuda, M.; Somyo,
T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793. (g) Vicennati, P.;
Cozzi, P. G. Eur. J. Org. Chem. 2007, 2248. (h) Jana, U.; Biswas,
S.; Maiti, S. Tetrahedron Lett. 2007, 48, 4065 and references cited
therein. (i) Salehi, P.; Iranpoor, N.; Behbahani, F. K. Tetrahedron
1998, 54, 943. (j) Rueping, M.; Nachtsheim, B. J.; Kuenkel, A. Org.
Lett. 2007, 9, 825. (k) Huang, W.; Wang, J.; Shen, Q.; Zhou, X.
Tetrahedron Lett. 2007, 48, 3969. (l) Sang, R.; Martinez, A.;
Miguel, D.; Alvarez-Gutierrez, J. M.; Rodriguez, F. Adv. Synth.
Catal. 2006, 348, 1841. (m) Shirakawa, S.; Kobayashi, S. Org. Lett.
2007, 9, 311. (n) Rao, W.; Tay, A. H. L.; Goh, P. J.; Choy, J. M. L.;
Ke, J. K.; Chan, P. W. H. Tetrahedron Lett. 2008, 49, 122. (o)
Yadav, J. S.; Subba Reddy, B. V.; Pandurangam, T.; Rao, K. V. R.;
Praneeth, K.; Narayanakumar, G. G. K. S.; Madavi, C.; Kunwar, A.
C. Tetrahedron Lett. 2008, 49, 4296. (p) Reddy, C. R.; Jithender, E.
Tetrahedron Lett. 2009, 50, 5633. (q) Theerthagiri, P.; Lalitha, A.
Tetrahedron Lett. 2010, 51, 5454.
11. (a) Naser-Hijazi, B.; Stolze, B.; Zanker, K. S. Second Proceedings
of the International Society of Coumarin Investigators; Springer:
Berlin, 1994. (b) Murakami, A.; Gao, G.; Omura, M.; Yano, M.; Ito,
C.; Furukawa, H.; Takahashi, D.; Koshimizu, K.; Ohigashi, H.
Bioorg. Med. Chem. Lett. 2000, 10, 59. (c) Xia, Y.; Yang, Z.-Y.;
Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.-H.; Lee, K.-H. J.
Med. Chem. 2001, 44, 3932. (d) Itoigawa, M.; Ito, C.; Tan, H. T.-
W.; Kuchide, M.; Tokuda, H.; Nishino, H.; Furukawa, H. Cancer
Lett. 2001, 169, 15. (e) Spino, C.; Dodier, M.; Sotheeswaran, S.
Bioorg. Med. Chem. Lett. 1998, 8, 3475.
The reaction of 1-phenylethan-1-ol (1b) showed that styrene as
an intermediate in the reaction (Scheme 4). Taking this as
advantage we extended the scope of the benzylation methodology
to styrene (Scheme 5) and synthesized the naphthol derivatives
3b and 3h in good yields.
In summary, we developed a facile microwave assisted catalyst
and solvent free benzylation of naphthols and 4-hydroxy
coumarin. This methodology was also extended to a cascade
benzylation/dehydration
to
furnish
the
unsymmetric
dibenzoxanthenes. Control experiments suggested that the
reaction proceeds through SN1 pathway.
Acknowledgments
RD, GS and AP thank Central University of Rajasthan for the
fellowship and SY thank Council of Scientific and Industrial
Research (CSIR)-India for the financial support under Extramural
Research Grant -No. 02(0200)/14/EMR-II.
12. (a) Matlin, M. A.; Mehta, G.; Hopf, H.; Krief, A. Nature Chemistry,
2015, 7, 941. (b) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev.,

4
Tetrahedron
2009, 38, 2993 and references cited therein. (c) Malacria, M.
Chem. Rev., 1996, 96, 289. (d) Tietze, L. F. Chem. Rev., 1996, 96,
115. (e) Climent, M. J.; Corma, A.; Iborra, S.; Sabater, M. J. ACS
Catal. 2014, 4, 870.
13. (a) Yaragorla, S.; Dada, R.; Pareek, A.; Singh, G. RSC Adv. 2016, 6,
28865. (b) Yaragorla, S.; Saini, P. L.; Pareek, A.; Almansour, A. I.;
Arumugam, N. Tetrahedron Lett. 2016, 57, 2034. (c) Yaragorla, S.;
Saini, P. L.; Vijaya Babu, P.; Almansour, A. I.; Arumugam, N.
Tetrahedron Lett. 2016, 57, 2351. (d) Yaragorla, S.; Dada, R.;
Singh, G. Synlett 2016, 27, 912. (e) Yaragorla, S.; Singh, G.; Dada,
R. Tetrahedron Lett. 2016, 57, 591. (f) Yaragorla, S.; Singh, G.;
Dada, R. Tetrahedron Lett. 2015, 56, 5924. (g) Yaragorla, S.;
Pareek, A.; Dada, R. Tetrahedron Lett. 2015, 56, 4770. (h)
Yaragorla, S.; Saini, P. L.; Singh, G. Tetrahedron Lett. 2015, 56,
1649. (i) Yaragorla, S.; Singh, G.; Saini, P.; Reddy, M. K.
Tetrahedron Lett. 2014, 55, 4657.
14. domestic mw (IFB) with mw output 900W, power source 230 V~50
Hz, mw frequency 2450 MHz.
15. General experimental procedure for the synthesis Benzyl derivatives
3: A mixture of benzylic alcohol (1, 1.5 mmol) and nucleophile (2, 1
mmol, naphthol/4-hydroxycoumarin) was weighed into
a
microwavable glass tube (regular microwave vials with screw-cap)
and subjected to mw-irradiation14 at 120 oC for 20 minutes. After
completion the reaction mixture was diluted with minimum amount
of dichloromethane and absorbed on silicagel (work up procedure is
not required) and was purified on silica gel column chromatography
using ethyl acetate and petroleum ether as the eluents to afford the
desired benzylated product (3). See the supporting information for
the spectral data and copies of 1H and 13C NMR spectra.

5
Highlights of the Work:
 A Catalyst free method for benzylation of
naphthols & 4-hydroxycoumarin
 Solvent free method
 Short reaction time under microwave irradiation
 Good Substrate Scope and Yields
 Step-economy and atom-economy