Mild and Metal-Free Protocol toward the Synthesis of Triarylmethanes by Reactions of (Hetero)Arylboronic Acids and ortho-Hydroxyarylaldehydes

Article abstract of DOI:10.1021/acs.joc.9b02807

Herein, we have reported a metal-free, mild, and novel protocol for the synthesis of various triarylmethanes (TRAMs) in moderate to good yields via the reactions of aryl boronic acids and ortho-hydroxyarylaldehydes in the presence of stoichiometric amount

Full text of DOI:10.1021/acs.joc.9b02807

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Article
A mild and metal-free protocol towards the synthesis of triarylmethanes
by reactions of (hetero)arylboronic acids and ortho-hydroxyarylaldehydes
Irfana Jesin, A. Antony Haritha Mercy, Ravindra S., Ramesh Kataria, and Ganesh Chandra Nandi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02807 • Publication Date (Web): 11 Jan 2020
Downloaded from pubs.acs.org on January 12, 2020
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A mild and metal-free protocol towards the synthesis of triarylmethanes by
reactions of (hetero)arylboronic acids and ortho-hydroxyarylaldehydes
Irfana Jesin C. P.,a A. Antony Haritha Mercy,a Ravindra S.,a Ramesh Kataria,b Ganesh Chandra
Nandi*a
aDepartment of Chemistry, National Institute of Technology-Tiruchirappalli-620015, Tamilnadu,
India. E-mail: ganeshnandi@gmail.com; nandi@nitt.edu
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bDepartment of Chemistry & Centre for Advanced Studies in Chemistry, Panjab University,
Chandigarh-160014, India
R1
R1
Br
Ar
Br2
Suzuki-
Miyaura
Reaction
OH
OH
R1
CHO
B(OH)2
Et3N (2.0 equiv)
R2
R2
20-72 % yield
(3 examples)
R2
R2
OH
OH
+
46-71 % yield
(3 examples)
DCE
80 C, 15 h
R1
R2
R1
R1
R2
R2
# First metal-free, mild, one-pot
process with aryl boronic acid
as substrate
15-82 % yield
(29 examples)
Ar
O
O
or
# Both symetrical and
unsymetrical triarylmethanes
R2
R2
R2
R2
66 % yield
(1 example)
73-84 % yield
(2 examples)
Synthetic Utilizations
ABSTRACT: Herein, we have reported a metal-free, mild and novel protocol for the synthesis
of various triarylmethanes (TRAMs) in moderate to good yields via the reactions of aryl boronic
acids and ortho-hydroxyarylaldehydes in the presence of stoichiometric amounts of Et3N in
dichloroethane at 80 °C. Additionally, the synthetic utilities of few synthesized TRAMs were
proven by carrying out bromination on the –OH containing aryl part, and followed by
functionalization of the bromine through a palladium-catalyzed Suzuki−Miyaura cross-coupling
reaction with arylboronic acids in good yields. The –OH group was also alkylated and arylated
through simple alkylation and Chan-Lam reaction respectively.
INTRODUCTION
Triarylmethane (TRAM) and its derivatives are highly captivating molecules in synthetic organic
chemistry due to their structural and physical properties. Since the discovery of the
triphenylmethyl radical by Gomberg in 1900s,1 triaryl and tri-hetero arylmethanes have attracted
much attention from organic chemists and many such compounds have found widespread
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applications in synthetic, medicinal, and industrial chemistry. They are ubiquitous and found
mainly in technologically and medicinally relevant molecules including as useful protective
groups,2 photochromic agents,3 dyes,4 and building blocks for dendrimers.5 Additionally, ring
hydroxylated TRAMs exhibit antioxidant, antitumor, antitubercular, antiviral, antifungal and
anti-inflammatory activities (Figure 1).6
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OH
O
OMe
Me2N(H2C)2O
H3C
HO
S
MeO
OMe
O
OH
HO2C
N
HO
OCH3
OH
Anti-tuberculosis agent
OMe
CH3
GPR40 modulor
(diabetes treatment)
Melanervin, flavanoid
Anti-cancer agent
Figure 1. Representative examples of compounds containing hydroxylated TRAM skeleton.
The common methods for the synthesis of triaryl system is the biarylation of aldehydes through
Friedel-Craft reaction conditions (with various types of Lewis and Bronsted acids as catalysts).7
But the approach is limited to nucleophilic and electron rich arenes and often results in the
formation of unwanted regioisomers. In order to overcome these shortcomings, a few transition
metal catalyzed routes also have been developed.8 The routes include the reactions between
diarylmethane (or methanol or its derivatives) and suitably substituted arene nucleophile in the
presence of various transition metal catalysts (Scheme 1). But these protocols require
prefunctionaliztions to be a suitable coupling partner along with the use of expensive catalysts.
In the context of biological and synthetic importance of TRAMs and its derivatives, the
demand for the development of environmentally benign and practical method for the synthesis of
triarylmethanes is increasingly important in organic synthesis. Herein, we have reported a novel,
metal-free and mild protocol for the synthesis of symmetrical and unsymmetrical TRAMs in
moderate to good yields via the reactions of (hetero)aryl boronic acids and ortho-
hydroxyarylaldehydes in the presence of stoichiometric amounts of triethylamines (Et3N) in
dichloroethane. To the best of our knowledge, it is the first report of metal-free synthesis of
TRAMs with (hereto)arylboronic acid as a substrate. The ortho-OH group of arylaldehyde is the
driving force for this reaction. The synthesized TRAMs were further structurally modified by
carrying out bromination, followed by functionalization of the bromine through palladium-
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catalyzed Suzuki−Miyaura cross-coupling reaction. The –OH group was also alkylated and
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arylated through simple alkylation and Chan-Lam reaction respectively
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Previous Methods
H
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Ar2
Ar2
OH
Ar2
H
Ar2
Ar2
LA or BA
CHO
Ar1
+
Ar1
Ar1
LA or BA
(Through Friedel-Craft reactions)
[Pd] / [Rh] /
[Ni] /[Cu]/ [Fe]
X
Ar3
Ar2
+
X1
Ar3
Ar1
Ar2
Ar1
X1 = H, Br,
B(OH)2
X = H, Br,
OR, SO2R
(Various transition metal-catalyzed reactions)
Present Method
R1
B(OH)2
Et3N (2.0 equiv.)
CHO
OH
OH
+
DCE
80 C, 15 h
R1
R2
1
2
3
R2
R2
Scheme 1. Previous and present routes for the synthesis of TRAMs
RESULTS AND DISCUSSION
The optimization process was initiated with the reaction of salicylaldehyde (1a, 1.0 equiv) and 4-
methoxyboronic acid (2a, 2.0 equiv) in the presence of stoichiometric amount of Et3N as base in
DCM at 40 °C for 15 h. Only 10% of corresponding TRAM (3a) was obtained (Table 1, entry 1).
In order to increase the yield, the reaction was performed in a sealed tube at 80 °C, and
interestingly, 64% of 3a was formed (Table 1, entry 2). Replacement of DCM with DCE as
solvent at 80 °C, delightedly increased the yield to 72% in 15 h (Table 1, entry 3). A further
increase in temperature or time did not improve the product formation. Screening of other
solvents such as; CHCl3, Dioxane, MeOH, Toluene and H2O (at 80 °C) were not successful as
these provided poor or no yield (Table 1, entries 4-9). An attempt to perform the reaction under
solvent-free conditions afforded 50% of product (Table 1, entry 10). After obtaining suitable
solvent DCE (at 80 °C) for this transformation, we next examined the effect of other
organic/inorganic bases (Table 1, entries 11-15), but our efforts were not productive. A control
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