Cu/Ag mediated peroxide-free synthesis of benzoylated naphthol derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.152487

A peroxide-free methodology was developed for the synthesis of benzoylated naphthol/phenol derivatives through oxidative deamination reaction performed under aerobic reaction conditions. A synergistic combination of Cu(OTf)₂ and Ag₂O was used to convert the aminonaphthols and aminophenols to the corresponding benzoylated derivatives. The definite role of atmospheric oxygen to assist the reaction was proved by performing the reaction in the argon atmosphere.

Full text of DOI:10.1016/j.tetlet.2020.152487

Tetrahedron Letters 61 (2020) 152487
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu/Ag mediated peroxide-free synthesis of benzoylated naphthol
derivatives
Subramaniyan Prasanna Kumari, Pavithira Suresh, Vijayashree Muthukumar,
⇑
Subramaniapillai Selva Ganesan
Department of Chemistry, School of Chemical and Biotechnology, SASTRA Deemed University, Thanjavur-613401, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 April 2020
Revised 17 September 2020
Accepted 21 September 2020
Available online 28 September 2020
A peroxide-free methodology was developed for the synthesis of benzoylated naphthol/phenol deriva-
tives through oxidative deamination reaction performed under aerobic reaction conditions. A synergistic
combination of Cu(OTf)2 and Ag2O was used to convert the aminonaphthols and aminophenols to the cor-
responding benzoylated derivatives. The definite role of atmospheric oxygen to assist the reaction was
proved by performing the reaction in the argon atmosphere.
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative deamination
Aminonaphthol
Metal catalysis
Water
Bioactive molecule
Introduction
reagent system [10]. Hence, the identification of a peroxide-free
method for the oxidative deamination of readily available aminon-
Benzoylated naphthol/phenol derivatives represent an impor-
tant class of highly biologically relevant molecules. Substituted
benzoylated derivatives exhibit anti-HIV [1], immunomodulatory
[2], anti-proliferative [3] and plant growth promoter [4] activities.
They also exhibit cytotoxic [5] and antihyperglycemic activities [6].
Representative examples of bioactive skeletons are given in Fig. 1.
The previously reported synthesis of benzoylated naphthols
requisite to perform the reaction with a stoichiometric amount of
corrosive and hygroscopic AlCl3 in the toxic carbon-di-sulfide sol-
vent under reflux reaction conditions [7]. They can also be pre-
pared by utilizing expensive rhodium metal catalyst with aryl
boronic acids or with reagents like butyl lithium or N-heterocyclic
carbenes [8a–b]. Tran et al., reported microwave-assisted C-ben-
zoylation of phenols/naphthols under solvent-free condition as
well as in ionic liquid medium [9]. However, the reaction failed
to achieve an appreciable yield with 2-naphthol substrates. In
addition, the reaction invariably required microwave-assisted
heating up to 160 °C or 220 °C. Apart from the aforementioned
methods, benzoylated naphthol derivatives can also be accessed
by the oxidative deamination of readily available aminonaphthols.
Previously reported such oxidative deamination requires the use of
excess amounts of toxic and expensive t-butylhydroperoxide
aphthol [11] is always attractive. It should be noted that oxidative
deamination is an important biological pathway responsible for
the biotransformation of neurotransmitters such as serotonin and
catecholamine [12].
Results and discussion
The success of the proposed oxidative deamination reaction lar-
gely depends on the suitable choice of catalyst and oxidant. Hence,
it was decided to harness the efficiency of Cu(II) and Ag(I) as cata-
lyst and oxidant respectively. The use of copper salts in the reac-
tion medium would facilitate the transformation of amines to the
corresponding iminium ion intermediates [13]. The choice of Ag
(I) as oxidant comes from the fact that it has been used as a sin-
gle-electron-transfer (SET) oxidant in diverse organic transforma-
tions [14a]. In addition, Ag(I) readily abstract the sp3 CAH
protons from the substrate to form radicals [14b]. Thus, Ag(I) salts
efficiently activates the organic substrates for free radical mediated
organic transformations. Apart from promoting free radical reac-
tions, Ag(I) assisted functionalization of naphthol derivatives were
also reported in the literature [15]. It should be noted that the
in situ generated Ag(0) clusters have the ability to interact with
molecular oxygen [16,17]. Such interactions are essential for the
re-oxidation of in situ generated Cu(I) to catalytically active Cu(II)
to sustains the catalytic cycle [13].
⇑
Corresponding author.
E-mail address: selva@biotech.sastra.edu (S. Selva Ganesan).
https://doi.org/10.1016/j.tetlet.2020.152487
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

S. Prasanna Kumari, P. Suresh, V. Muthukumar et al.
Tetrahedron Letters 61 (2020) 152487
Fig. 1. Bioactive benzoylated phenol/naphthol derivatives.
Apart from the suitable oxidant and catalyst, the nature of the
leaving group also has a profound influence on the course of the
oxidative deamination reaction. Since cyclic tertiary amines show
better leaving group efficiency than the corresponding acyclic
counterparts [10], the reaction was screened with both morpholine
and pyrrolidine derived substrates (Table 1).
Preliminary investigations on oxidative deamination reaction
performed with substrate 1a’ with Ag2O and copper triflate didn’t
yield the desired product (Table 1, Entry 1). Change of inorganic
oxidant to NHPI or use of copper(II) acetate didn’t change the
course of the reaction (Table 1, Entry 2–3). It was presumed that
the presence of an oxygen atom in the morpholine moiety could
have interacted with the Cu(II) catalyst and thereby suppress the
formation of the desired product [18]. Hence, it was decided to
replace the morpholine with a pyrrolidine moiety. To our delight,
the substrate 1a gave the desired product 2a in 64% yield (Table 1,
entry 4). A marginal increment in the reaction temperature from
80 °C to 100 °C, substantially improved the yield of the product
to 87% (Table 1, entry 5). To identify the role of surfactant, the reac-
tion was performed with non-ionic (Brij 58), cationic (CTAB) and
anionic (SDS) surfactants (Table 1, entries 6–8). The products were
obtained in 58%, 78% and 84% yields. These results show that the
addition of the surfactant didn’t improve the yield of the product
(Table 1, entry 5 vs 6–8).
Table 1
Optimization of reaction conditionsa
S.No
Substrate
Oxidant/Catalyst
Solv./Surfactant
Temp.(oC)
Time(h)
Yieldb(%)
1
2
3
1a’
1a’
1a’
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
Ag2O/Cu(OTf)2
NHPIc/ Cu(OTf)2
NHPIc/ Cu(OAc)2
Ag2O/ Cu(OTf)2
Ag2O/ Cu(OTf)2
Ag2O/Cu(OTf)2
Ag2O/ Cu(OTf)2
Ag2O/ Cu(OTf)2
Ag2O/ Cu(OAc)2
Ag2O/ CuCl2
H2O
H2O
H2O
H2O
80
80
100
80
24
5
5
24
5
5
5
5
5
5
5
5
5
5
5
8
—
Unclean
Unclean
64
87
58
78
84
41
47
63
58
64
4
5d
6
H2O
100
100
100
100
100
100
100
100
100i
100
100
100
H2O/Brij 58e
H2O/CTABe,f
H2O/SDSe,g
H2O
7
8
9
10
11
12
13
14j
15
16
H2O
H2O
Ag2O/ CuBr
MnO2/ Cu(OTf)2
Ag2O/ Cu(OTf)2
Ag2O/ Cu(OTf)2
IPr-Ag-Cl/ Cu(OTf)2
Ag2O/ Cu(OTf)2
H2O
DMCh
H2O
42
H2O
H2O
less than 5
88
a
Unless otherwise mentioned, all the reactions were performed with 0.1 mmol of substrate, 0.05 mmol of Ag2O and 0.005 mmol of Cu(OTf)2 in H2O (1.5 mL). bYields are for
the isolated products. cN-hydroxyphthalimide. dReaction performed less than 5 h showed the presence of unreacted starting materials. eReaction performed with 10 mol% of
surfactant. Cetyltrimethylammonium bromide. gSodium dodecyl sulfate. hDimethyl carbonate. For the reaction performed at 80 °C, the formation of the product was not
f
i
j
observed. Reaction was performed under argon atmosphere.
2

S. Prasanna Kumari, P. Suresh, V. Muthukumar et al.
Tetrahedron Letters 61 (2020) 152487
Fig. 2. Scope and limitation of the substrate.
To identify the role of the anion in the catalyst, we have com-
pared the efficiency of the copper(II) triflate with copper(II) acetate
and copper(II) chloride salts (Table 1, entries 9–10). In both cases,
the formation of the product was obtained in inferior yield as com-
pared to that of copper(II) triflate (Table 1, entry 5 vs 9–10). We
presume, unlike chloride or acetate anions, strongly electron with-
drawing triflate anion increases the electrophilicity of Cu(II) cation
to a greater extend and facilitate the reaction towards completion.
Interestingly, apart from copper(II) salts, reaction performed with
copper(I) bromide also gave the desired product in 63% yield
(Table 1, entry 11). We presume, in situ oxidation of Cu(I) to Cu
(II) by aerobic oxygen or Ag2O could have resulted in the formation
of the product.
drawing substituents may assist the facile removal of hydrogen
radical from the tertiary carbon atom. Inductively electron with-
drawing halogen substituents also gave the desired products 2f
and 2g in good yields. The p-cresol derived aminophenol substrate
gave the product 2h in 75% yield.
To compare the efficiency of Ag2O oxidant, we have performed
the reaction with MnO2 (Table 1, entry 12). However, the 2a was
formed in only 58% yield. This result shows that Ag2O is the suit-
able oxidant to perform the reaction. To identify the role of the
aqueous medium, we have performed the reaction in dimethyl car-
bonate solvent (Table 1, entry 13). However, only 64% of the pro-
duct 2a was obtained. These results substantiated that water is
the suitable solvent to perform the reaction. To ascertain the role
of atmospheric oxygen to facilitate the reaction, we have per-
formed the reaction under an argon atmosphere (Table 1, entry
14). The product 2a was obtained in 42% yields. We presume the
formation of the product could have been facilitated by the oxida-
tion of the in situ reduced copper salt to catalytically active Cu(II)
by the Ag2O. It should be noted here that reducing the amount of
Ag2O from 50 mol% to 25 mol% reduced the yield of the product
and the formation of the product was observed in less than 5%
yield if the Ag2O was replaced with IPr-Ag-Cl (Table 1, entry 15).
Like aminonaphthols, the aminophenol 1b also gave the desired
product 2b in good yields (Table 1, entry 16). After optimizing
the reaction conditions, the scope of the reaction was screened
for diverse pyrrolidinyl derived substrates (1a–n) and the products
2a–n were obtained in appreciable yields (Fig. 2).
The oxidative deamination reaction was performed with sub-
strates having electron donating or withdrawing groups. The pres-
ence of electron withdrawing nitro substituent greatly accelerated
the synthesis of 2e. However, electron donating substituents took a
relatively longer time to complete the reaction (2c/2d (8–9 h) vs 2e
(3 h)). In addition, the electron donating substituents yield the
products in lesser yields (2c/2d (61%, 44% vs 2e (82%)). This clearly
demonstrated the vital role of electronic effect on the oxidative
deamination reaction. We presume the presence of electron with-
Chart 1. Mechanistic investigations.
3

S. Prasanna Kumari, P. Suresh, V. Muthukumar et al.
Tetrahedron Letters 61 (2020) 152487
Scheme 1. Three-component one-pot synthesis of 2a.
Akin to phenol derivatives, naphthol substrates with electron
withdrawing substituents gave better yield than the electron
donating substitutents (Yield of 2i–j vs 2k–l). The formaldehyde
derived substrate gave the product 2m in 66% yield. The scope of
the methodology was extended for the synthesis of key intermedi-
ate 2n which can be readily converted to the molecules with
immunomodulatory and plant growth promotor activities [2,4].
To demonstrate the practical utility of this method, we have also
performed the gram-scale synthesis of 2a started with one gram
of 1a substrate. The reaction took 10 h for completion and the pro-
duct 2a was obtained in 72% yield (Fig. 2). The addition of SDS sur-
factant reduced the reaction time to 6 h and enhanced the yield of
2a to 78%.
thol/naphthol. Mechanistic investigations revealed that the oxygen
in the atmosphere also assists to drive the reaction in the forward
direction.
Representative procedure for the synthesis of benzoylated
naphthol derivatives:
In a 10 mL reaction vial, aminonaphthol 1a (30 mg, 0.1 mmol),
silver oxide (11.59 mg, 0.05 mmol), copper triflate (1.81 mg,
0.005 mmol) were taken in water (1.5 mL) and the reaction vial
was closed with crimper cap. The vial was heated in an oil bath
at 100 °C. After completion of the reaction, the reaction mixture
was diluted with water and extracted with ethyl acetate
(3 Â 10 mL). The combined organic extracts were dried over anhy-
drous sodium sulphate, filtrated and the organic solvents were
evaporated under reduced pressure to afford the crude residue.
The crude residue was purified by column chromatography using
silica gel (100–200 mesh) with hexane and ethyl acetate as eluent
(9:1) to afford the pure product. The same procedure was followed
for the synthesis of benzoylated phenol derivatives.
Mechanistic investigations
To confirm the role of the radical pathway, the reaction was
performed in the presence of radical quencher TEMPO (Chart 1
(I)). As expected the formation of the product 2a was not observed.
This shows that the reaction could proceed via a radical pathway.
In order to identify the role of reaction atmosphere, the reaction
was performed in the presence of oxygen and argon atmosphere
(Chart 1(II)). In the presence of oxygen, the 2a was obtained in
85% yield. We presume the presence of oxygen could have assisted
the in situ retrieval of the catalytically active Cu(II) species from
reduced copper salt and gave the product 2a in good yields. How-
ever, In the presence of argon, the product was formed in a rela-
tively lesser 42% yield. We presume, in the absence of an oxygen
atmosphere, the oxidation of reduced copper salt to catalytically
active Cu(II) could have been facilitated only by the silver oxide
[19] and hence the product 2a was formed in lesser yields.
To identify the role of the hydroxyl functional group, we have
performed the reaction with substrates 1o and 1p (without –OH
group). Under optimized reaction condition, both 1o and 1p gave
the products 2o and 2p in 72% and 58% yield respectively (Chart 1
(III)). These results show that the hydroxyl group of the substrates
didn’t play a significant role in the oxidative deamination reaction.
It should be noted here that the oxidative deamination reaction
performed with 1q (O-methylated) substrate at elevated tempera-
ture gave the desired product with concomitant O-demethylation
(Chart 1(III)). The reaction performed without Ag2O and Cu(OTf)2
gave the product 2a in 49% and 41% respectively (Chart 1(IV)).
Based on the mechanistic investigations, a plausible mechanism
for the formation of 2a was proposed in the supporting informa-
tion. In addition, we have also successfully carried out the oxida-
tive deamination reaction of in situ generated aminonaphthol 1a.
The product 2a was obtained in 68% yield (Scheme 1). Thus the
proposed methodology was useful for the one-pot transformation
of naphthol to the corresponding benzoylated derivatives.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgment
Financial support from the Council of Scientific and Industrial
Research, CSIR (80(0085)/16/EMR-II) and Science and Engineering
Research Board, DST-SERB (No. EMR/2016/000317) is gratefully
acknowledged by S.S.G. S.P.K. thank SASTRA Deemed University
for providing financial support. All the authors thank the SASTRA
Deemed University for providing lab space and NMR facility.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152487.
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