Copper-mediated arylation with arylboronic acids: Facile and modular synthesis of triarylmethanes

Article abstract of DOI:10.3762/bjoc.12.49

A facile and modular synthesis of triarylmethanes was achieved in good yield via a two-step sequence in which the final step is the copper(II)-catalyzed arylation of diarylmethanols with arylboronic acids. By using this protocol a variety of symmetrical and unsymmetrical triarylmethanes were synthesized. As an application of the newly developed methodology, we demonstrate a highyielding synthesis of the triarylmethane intermediate towards an anti-breast-cancer drug candidate.

Full text of DOI:10.3762/bjoc.12.49

Copper-mediated arylation with arylboronic acids: Facile and
modular synthesis of triarylmethanes
H. Surya Prakash Rao* and A. Veera Bhadra Rao
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 496–504.
Department of Chemistry, Pondicherry University, Pondicherry 605
014, India Telephone: +914132654411; Fax: +914132656230
doi:10.3762/bjoc.12.49
Received: 22 November 2015
Accepted: 04 March 2016
Published: 11 March 2016
Email:
H. Surya Prakash Rao* - hspr.che@pondiuni.edu.in;
A. Veera Bhadra Rao - hspr.che@pondiuni.edu.in
This article is part of the Thematic Series "Copper catalysis in organic
synthesis".
* Corresponding author
Keywords:
Guest Editor: S. R. Chemler
copper; modular synthesis; triarylmethanes
© 2016 Rao and Rao; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A facile and modular synthesis of triarylmethanes was achieved in good yield via a two-step sequence in which the final step is the
copper(II)-catalyzed arylation of diarylmethanols with arylboronic acids. By using this protocol a variety of symmetrical and un-
symmetrical triarylmethanes were synthesized. As an application of the newly developed methodology, we demonstrate a high-
yielding synthesis of the triarylmethane intermediate towards an anti-breast-cancer drug candidate.
Introduction
The triarylmethanes form an exclusive group of organic mole- Genuine triarylmethane 4, having three different aryl groups on
cules wherein three aryl groups are attached to the central sp3- the central CH, is a proven anti-breast-cancer agent [20]. In ad-
hybridized carbon atom bearing a hydrogen atom [1-4]. Al- dition to 4, several other triarylmethanes exhibit interesting bio-
though the group can be restricted to such molecules, many logical activity, including oestrogen receptor binding affinity
closely related derivatives that have a triarylmethane motif (like [21], inhibition of hepatic cholesterol [22], inhibition of aldose
those having a heteroatom attached to the central carbon atom reductase [23], antiproliferative [24], antiviral, cytotoxic [25],
or the central carbon is sp2 hybridized) have been included in antifungal [26], anti-HIV [27-29] and antibacterial activity [30].
this class [5]. Molecules with a triarylmethane motif are ubiqui- Although rare, there are a few natural products, for example,
tous and found mainly in technologically and medicinally rele- melanervin (5), a flavanoid bearing the triarylmethane motif
vant molecules like dyes [6-9], pH indicators [10-12], fluores- [31,32].
cent probes [13-18] and antibacterial drugs [19]. For example,
malachite green (1) is a dye, cresol red (2) is a pH indicator and Triarylmethanes are typically synthesized by a Friedel–Crafts-
turbomycin (3) is an antibacterial medicinal drug (Figure 1). type substitution of the three alkoxy groups in a trialkyl ortho-
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Beilstein J. Org. Chem. 2016, 12, 496–504.
Figure 1: Representative examples of triarylmethanes.
formate (Scheme 1A, method 1) [33-35] or by sequential two- recently been directed towards transition metal-catalyzed cross-
step addition of electron-rich aromatic nucleophiles to activated couplings [43-48] or CH arylation followed by an arylative
arene aldehydes followed by substitution of the resulting desulfonation [49,50]. The coupling reactions provide an oppor-
hydroxy group with another electron-rich aromatic compound tunity to install an unactivated aryl group on a carbon bearing
(Scheme 1A, method 2) [36-39]. Both of the approaches are two more aryl groups to synthesize the triarylmethane motif.
limited in scope and suffer from drawbacks such as (a) electron- Recently, we reported a copper-catalyzed C–C bond formation
rich aromatic systems that are required as nucleophiles and by substitution of the labile C(4)SMe group in 4H-chromenes or
therefore, not amenable for the synthesis of triarylmethanes C(3)–OH in isoindolinones with aryl/alkenyl groups by employ-
with electron-withdrawing groups, (b) the regioselectivity in the ing the corresponding boronic acids [51,52]. Continuing these
substitution at the aromatic ring that depends on the ortho- or efforts, we designed a copper-catalyzed synthesis of a variety of
para-directing nature of the substituent and also by the steric triarylmethanes through substitution of C(sp3)–OH in diaryl-
hindrance offered by the substitution, (c) the methods are rarely methanols with arylboronic acids (Scheme 1B). We reasoned
modular and not suitable for the preparation of triarylmethanes that since diarylmethanols with two different aromatic rings can
with three different aryl groups, and finaly, (d) Lewis [40,41] or be made by a wide variety of methods [53,54] (e.g., addition of
protic acids [42] are required to catalyze the reactions. To over- an aryl carbanion to an aryl aldehyde and a further step with a
come the above-mentioned difficulties, many efforts have variety of aryl boronic acids), it should be possible to provide a
Scheme 1: General methods and proposed method for the synthesis of triarylmethanes.
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Beilstein J. Org. Chem. 2016, 12, 496–504.
unique opportunity for the modular synthesis of unsymmetrical chlorobenzene (Scheme 2) at 80 °C provided the coupled prod-
triarylmethanes. If successful, the method could provide an op- uct triphenylmethane (11a) in 64% yield. When the reaction
portunity for the synthesis of a combinatorial library of the was conducted under oxygen atmosphere, the yield of 11a fell
coveted molecules. Herein, we report a copper(II) triflate-cata- to 46%. Under these aerobic conditions, we isolated biphenyl
lyzed modular synthesis of triarylmethanes by employing (13) generated through homocoupling of phenylboronic acid.
diarylmethanols 9 and arylboronic acids 10. It is advantageous Attempts to improve the yield by the use of bases such as
to employ a base metal catalyst such as copper(II) triflate Na2CO3 (10 mol %) and K2CO3 (10 mol %) were not success-
instead of palladium [55,56] or nickel (Ni) [57] catalysts and to ful. The yield of triphenylmethane (11a) was further reduced in
avoid the use of phosphine ligands as it is less expensive and these cases. The base was employed to trap the boric acid,
more readily facilitates purification.
which is likely to be the side product of the reaction. From the
above experiments, we concluded that chlorobenzene was the
most suitable solvent for the synthesis of triphenylmethane
Results and Discussion
We selected the copper-mediated cross-coupling reaction of (11a).
diphenylmethanol (9a) with phenylboronic acid (10a) for the
synthesis of triphenylmethane (11a) to optimize the reaction Next, we turned our attention to evaluate different copper salts
conditions and catalyst loading. Based on our accrued experi- to optimize the yield of triphenylmethane (11a); these efforts
ence [52], in a first attempt, we employed Cu(OTf)2 (10 mol %) have been summarized in Table 1. We screened various Cu(II)
in refluxing 1,2-dichlorethane (DCE) to effect C–C coupling, catalysts such as Cu(OAc)2 (64%, Table 1, entry 1),
but the reaction provided (phenoxymethylene)dibenzene (12) Cu(CF3COO)2 (46%, Table 1, entry 2) Cu(acac)2 (36%,
as the only product formed through the C–O coupling Table 1, entry 3), CuSO4·5H2O (36%, Table 1, entry 4), CuBr2
(Chan–Lam–Evans coupling product) [58-60] in 64% yield. (14%, Table 1, entry 5), CuCl2·2H2O (24%, Table 1, entry 6)
and CuO (no reaction, Table 1, entry 8), which did not provide
To obtain the desired triphenylmethane (11a) as the sole prod- the desired triphenylmethane (11a) in better yield. However,
uct, we screened various alternative solvents (Scheme 2). Of the 20 mol % of Cu(OTf)2 (Table 1, entry 17) delivered the desired
solvents investigated, toluene gave a mixture of triphenyl- triphenylmethane (11a) in good yield (78%) after chromato-
methane (11a) and the toluene-incorporated product (p-tolyl- graphic purification. We screened other borderline Lewis acids
methylene)dibenzene (14) in 36% and 52% yield, respectively such as Sc(OTf)3, Yb(OTf)3, Zn(OTf)2 and Fe(OTf)3, but the
(Scheme 2). Solvents like acetonitrile (polar, aprotic) and reaction did not afford triphenylmethane (11a) at all, which in-
dioxane (oxygenated, aprotic) did not provide the triphenyl- dicated that Cu(II) and not TfOH is responsible for the transfor-
methane (11a). On the other hand, the higher-boiling, nonpolar mation. Thus, the optimal conditions for the copper-mediated
Scheme 2: Role of solvent and reaction conditions in the Cu(OTf)2-mediated coupling of diphenylmethanol (9a) with phenylboronic acid (10a) for the
preparation of triphenylmethane (11a).
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Beilstein J. Org. Chem. 2016, 12, 496–504.
Table 1: Screening of metal catalysts for the arylation reaction.
Entry
Catalyst
Time (h)
Catalyst (mol %)
Yield (%)a
1
Cu(OAc)2·H2O
Cu(OOCCF3)2
Cu(acac)2
CuSO4·5H2O
CuBr2
21
18
21
19
16
16
21
12
21
21
19
12
12
12
21
21
18
12
12
12
12
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
10
10
10
10
64
46
2
3
36
4
36
5
14
6
CuCl2·H2O
Cu(OTf)2
CuO
24
7
68
8
n.r.
42
9
CuI
10
11
12
13
14
15
16
17
18
19
20
21
CuBr
14
CuCl
28
Cu2O
n.r.
n.r.
n.r.
42
Cu(I)BrSMe2
Cu(PPh3)2Br
CuMeSal
CuTc
27
Cu(OTf)2
Sc(OTf)3
Fe(OTf)3
Zn(OTf)2
Yb(OTf)3
78
n.r.
n.r.
n.r.
n.r.
an.r. = no reaction.
coupling involve heating equimolar amounts of diphenyl-
methanol (9a) and phenylboronic acid (10a) in chlorobenzene at
80 °C in the presence of 20 mol % of Cu(OTf)2 under a blanket
of oxygen-free nitrogen.
Based on the above observations, we propose a mechanism for
the copper-mediated coupling of phenylboronic acid with
diphenylmethanol, leading to triphenylmethane and boric acid
(Scheme 3). At the start of the cascade, the first step is the
transmetallation of the copper(II) into phenylboronic acid to
form reactive PhCu(OTf) (15) and B(OH)2(OTf) [61]. The
intermediate 15 then reacts with diphenylmethanol 9 to provide
the intermediate 16. Formation of the intermediate 16 can
be attributed to Lewis acidic characteristics of 15 and Lewis
Scheme 3: A plausible mechanism for the formation of triaryl-
methanes 11.
basic characteristics of diphenylmethanol (9a). The crucial C–C generation of a stable C–C bond in 11, a Cu–O bond in 17, and
bond formation with simultaneous C–O bond cleavage subse- boric acid at the cost of weak Ar–Cu and C–OH bonds in 16
quently occurs in 16 to give the triarylmethane 11 and and 9, respectively [52].
copper(OH)(OTf) (17). The reaction of 17 with arylboronic acid
10 regenerates 15 and results in the formation of stable boric With the optimized reaction conditions in hand, we examined
acid. The driving force for the triarylmethane formation is the the scope of the cross-coupling reaction for the synthesis of a
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variety of triarylmethanes from diphenylmethanol (9a). Ten 2,6-dimethoxyphenylboronic acid instead of the C(1) carbon, as
more arylboronic acids were employed in the coupling reaction illustrated in 11m (Scheme 4). Structure of 11l was readily con-
and good yields (77–92%) of the corresponding triaryl- firmed on the basis of 13C NMR and DEPT-135 spectra. We
methanes 11b–k were realized (Table 2). The arylboronic acids surmise that the initially formed, transmetallated product 18 re-
10b–k were selected considering their structural diversity and arranged to the more stable 18a before it could react with
electron density in the aryl ring. Efficient cross-coupling could diphenylmethanol (9a, Scheme 4).
be noted irrespective of the presence of strongly electron-with-
drawing (10b,c to 11b,c; Table 2, entries 1 and 2), mildly elec- The scope of the copper-catalyzed coupling reaction of diaryl-
tron-withdrawing (10d,e to 11d,e; Table 2, entries 3 and 4), methanols 9b–d with phenylboronic acid (10a) was explored by
strongly electron-donating (10f to 11f; Table 2, entry 5) or changing one or both of the aryl rings in the diarylmethanol
mildly electron-donating (10g to 11g; Table 2, entry 6) groups (Table 3) [62]. The copper-catalyzed reaction of phenyl(pyren-
at the C(4) position of the phenyl ring. The robust nature of the 1-yl)methanol (9b) with phenylboronic acid (10a) was very
protocol was demonstrated by reacting ortho-methoxyphenyl- facile and the product triarylmethane 11n was obtained in 72%
boronic acid (10h) to efficiently generate the desired triaryl- yield (Table 3, entry 1). Similarly, the reaction of anthracen-9-
methane 11h (Table 2, entry 7). The transformation showed that yl(phenyl)methanol (9c) with phenylboronic acid (10a) provi-
apart from the insensitivity towards electronic effects, the ded the corresponding triarylmethane 11o in 82% yield
copper-mediated cross-coupling reaction is not very sensitive to (Table 3, entry 2). The last example in the genre is interesting,
steric crowding in the neighborhood of the reaction center. as one of the aryl rings is ferrocene in 11p. The reaction of
Next, we employed heteroaromatic boronic acids, such as furan- ferrocene-1-yl(phenyl)methanol (9d) with phenyboronic acid
2-ylboronic acid (10i; Table 2, entry 8), thiophen-2-ylboronic (10a) was facile and it provided diphenylmethylferrocene (11p)
acid (10j; Table 2, entry 9) and benzo[b]thiophen-2-ylboronic without any difficulty in 71% yield.
acid (10k; Table 2, entry 10) in the coupling reaction and the
reactions furnished the corresponding triarylmethanes 11a–k in Modular synthesis of triarylmethanes
excellent yield. The transformations showed that heteroaro- The synthetic method that we developed, through which three
matic groups, including those bearing a sulfur atom, react effi- different aromatic rings on the central carbon can be assembled
ciently to provide triarylmethanes.
in a two-step protocol, is modular in nature. The first step is the
synthesis of diarylmethanol and the second step is the replace-
However, when we employed 2,6-dimethoxyphenylboronic acid ment of the hydroxy group in the resulting diarylmethanol by a
10l, surprisingly, we isolated the triarylmethane 11l, in which third aryl group by employing arylboronic acid under copper
the C–C bond formation took place on the C(3) carbon of the catalysis. As a proof of principle, we present the synthesis of
Table 2: Scope of the Cu-catalyzed arylation with various arylboronic acids.
Entry
Ar in arylboronic acid
Triarylmethane
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
10b: 4-CF3C6H4
10c: 4-FC6H4
11b
11c
11d
11e
11f
4
10
6
92
77
79
91
81
81
88
85
89
86
10d: 4-ClC6H4
10e: 4-BrC6H4
4
10f: 4-MeOC6H4
10g: 4-MeC6H4
10h: 2,5-(OMe)2C6H3
10i: 2-furyl
5
11g
11h
11i
6
6
8
10j: 2-thiophenyl
10k: 2-benzothiophenyl
11j
8
11k
10
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Scheme 4: Copper-catalyzed C–C bond formation synthesis of triarylmethane 10l.
Table 3: Scope of diarylmethanol 9b–d in the copper-catalyzed coupling reaction.
Entry
Diarylmethanol
Arylboronic acid
Triarylmethanea
1
10a
9b
11n (14 h, 72%)
2
10a
9c
11o (16 h, 83%)
3
10a
9d
11p (16 h, 71%)
4
10f
9b
11q (16 h, 68%)
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Beilstein J. Org. Chem. 2016, 12, 496–504.
Table 3: Scope of diarylmethanol 9b–d in the copper-catalyzed coupling reaction. (continued)
5
10k
9b
11r (12 h, 72%)
6
10m
9d
11s (4 h, 64%)
aTime required for completion of the reaction and yield of the isolated and purified triarylmethanes are given in the parenthesis.
three examples of triarylmethanes 11q–s that bear three differ- when kept as a solution in hexane. However, the compound was
ent aromatic rings (Table 3). The copper-catalyzed coupling stable as a solid for at least two months when refrigerated
reaction of phenyl(pyren-1-yl)methanol (9b) with 4-methoxy- (+5 °C).
phenylboronic acid (10f) and benzo[b]thiophen-2-ylboronic
acid (10k) provided the respective pyrene-containing unsym- To demonstrate an application of our newly developed
metrical triarylmethanes 11q–r in good yields (Table 3). Next, Cu(OTf)2-catalyzed C–C coupling reaction for the synthesis of
the coupling reaction of phenyl(ferrocenyl)methanol (9d) with triarylmethanes, we designed a synthesis of the precursor 22
thiophen-3-ylboronic acid (10m) provided triarylmethane 11s, (Scheme 5) for the anti-breast-cancer agent 4 (Figure 1). Any
which has ferrocene, thiophene and phenyl rings installed on the method for the synthesis of 4 needs to take into account that it
central carbon. The triarylmethane 11s was found to be unstable has two phenyl rings with different alkoxy groups at the respec-
Scheme 5: Synthesis of anti-breast-cancer agent intermediate 22.
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Beilstein J. Org. Chem. 2016, 12, 496–504.
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