LDA-Mediated Synthesis of Triarylmethanes by Arylation of Diarylmethanes with Fluoroarenes at Room Temperature

Article abstract of DOI:10.1021/acs.orglett.5b02602

A practical and convenient approach for the secondary C(sp³)-H arylation of diarylmethanes with various fluoroarenes is described. The reaction proceeds smoothly in the presence of LDA (lithium diisopropylamide) at room temperature and affords triarylmethanes in moderate to high yields.

Full text of DOI:10.1021/acs.orglett.5b02602

Letter
pubs.acs.org/OrgLett
LDA-Mediated Synthesis of Triarylmethanes by Arylation of
Diarylmethanes with Fluoroarenes at Room Temperature
Xinfei Ji, Tao Huang, Wei Wu, Fang Liang, and Song Cao*
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology (ECUST),
Shanghai 200237, China
S
* Supporting Information
ABSTRACT: A practical and convenient approach for the
secondary C(sp3)−H arylation of diarylmethanes with various
fluoroarenes is described. The reaction proceeds smoothly in
the presence of LDA (lithium diisopropylamide) at room
temperature and affords triarylmethanes in moderate to high
yields.
riarylmethanes (TAMs) are often found as structural
frameworks in pharmaceuticals and polymers, especially
practical methods for the synthesis of triarylmethanes is an
important goal of organic synthesis.
T
in leuco dyes due to their special photochemical and
photophysical properties.1 Because of their importance in
organic synthesis, considerable attention has been devoted to
the development of efficient methods for the synthesis of
triarylmethane derivatives.2 The traditional method for the
synthesis of triarylmethane derivatives is Friedel−Crafts
arylation of diarylmethanols in the presence of different
Lewis acids.3 In recent years, a number of novel approaches
toward triarylmethanes have been reported (Scheme 1, a−e).4
The cleavage and functionalization of carbon−fluorine
bonds have attracted considerable attention from many
chemists because of their important application in practical
organic synthesis.6 The replacement of fluorine atom on the
electron-deficient fluoroaromatics via nucleophilic aromatic
substitution (SNAr) with nucleophiles is a traditional method
for the functionalization of aryl fluorides.7 However, aryl
fluorides with an electron-donating group would deactivate
the SNAr reaction, and rather higher reaction temperature and
prolonged reaction time are required to ensure a smooth
reaction.8
The transition-metal-catalyzed cross-coupling of fluoroar-
enes with organometallics such as Grignard, organozinc
reagents, and organoboron compounds,9 which involve the
activation of the C−F bond, has become a powerful tool for
the functionalization of fluoroarenes. However, the method-
ology suffers from the use of toxic nickel catalyst, expensive
palladium catalyst, and complicated ligands.10
Scheme 1. Recent Methods for the Synthesis of
Triarylmethanes
Defluorination of fluoroarenes via arynes in the presence of
strong base, although known as a simple alternative for the
cleavage of carbon−fluorine bonds, has not attracted enough
attention in fluorine and organic chemistry.11 To date, only a
few limited reports have been found in the literature.12 The
obvious drawback of this method is the use of very low
reaction temperatures, typically −78 °C, thus limiting the
scope and generality of the protocol.13 In continuation of our
interest in the cleavage and functionalization of carbon−
fluorine bonds,14 we herein report an efficient and mild
method for the synthesis of triarylmethanes by arylation of
diarylmethanes with fluoroarenes in the presence of LDA
(lithium diisopropylamide) at room temperature (Scheme 1,
f).
Although these reported methodologies are facile and
straightforward, the limitations of these approaches include
the use of an expensive ligand, an expensive palladium salt,
the limited diversity of the starting materials, and harsh
reaction conditions with regard to temperature and acidity.5
Hence, the development of environmentally benign and
Received: September 9, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initially, diphenylmethane 1a and fluorobenzene 2a were
used as model reactants for the optimization of the arylation
reaction conditions, and the results are shown in Table 1.
Scheme 2. Reactions of 1a with Various Substituted
Fluorobenzenes 2a−l
a,b
a,b
Table 1. Optimization of the Reaction Conditions
b
entry
2a (equiv)
base (equiv)
solvent
yield (%)
1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
KHMDS (3.0)
LiHMDS (3.0)
NaHMDS (3.0)
t-BuOK (3.0)
Cs2CO3 (3.0)
t-BuOLi (3.0)
t-BuLi (3.0)
LDA (3.0)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
hexane
DMSO
NMP
DMF
0
0
2
3
0
4
0
5
0
6
0
7
0
8
64
93
89
86
61
35
47
36
0
9
LDA (3.0)
10
11
12
13
14
15
16
17
18
LDA (3.0)
LDA (2.5)
LDA (2.0)
LDA (1.5)
LDA (3.0)
LDA (3.0)
LDA (3.0)
LDA (3.0)
0
a
Reaction conditions: 1a (1.0 mmol), 2a−e,g−j (1.5 mmol), 2f (3.0
mmol), 2k (1.2 mmol), LDA (3.0 mmol), THF (5 mL), rt, 1−4 h, Ar.
LDA (3.0)
0
a
b
b
c
Reagents and conditions: 1a (1.0 mmol), solvent (5 mL), 4 h. Yields
Isolated yield. GC−MS yield.
were determined by GC analysis and based on 1a.
Among several bases tested, LDA turned out to be the only
suitable base for the reaction, while other bases were totally
ineffective and no product could be detected (entries 1−8).
When the amount of fluorobenzene 2a was increased to 1.5
equiv, diphenylmethane 1a was successfully converted to the
corresponding arylated product 3aa in excellent yield (entry
9). Further increasing the amount of 2a resulted in lower
yield (entry 10). Moreover, the amount of LDA added has an
important influence on the reaction yield. When the amount
of LDA was reduced from 3.0 to 1.5 equiv of 1a, the yield
decreased sharply and only 35% of 3aa was obtained (entries
11−13). Further screening of different solvents disclosed that
THF proved to be effective for the reaction and provided the
best results, while no reaction occurred in aprotic polar
solvents such as DMSO, NMP, and DMF (entries 9 and 14−
18).
electron-rich fluoroarenes might proceed via aryne inter-
mediates. To further confirm this hypothesis, two additional
experiments were performed. When the highly electron-rich
aryl fluoride such as 2-fluoro-1,4-dimethoxybenzene was used
as substrate, the reaction also proceeded smoothly and no
regioisomer was observed (3af). However, when 2-fluoro-1,3-
dimethylbenzene was used as substrate, no desired product
was formed (3ae). These experiments clearly indicated that
the arynes were generated in situ from the electron-rich
fluoroarenes with LDA in the first step of the reaction.
The fluoroarene possessing mildly electron-withdrawing
group gave the desired products in lower yield than those
with electron-donating substituents, and a mixture of para-
and meta-isomers was obtained (3ah). However, when
fluoroarene having two mildly electron-withdrawing groups
was subjected to the optimized reaction conditions, only a
moderate yield of product was obtained (3ai) and no
regioisomer was detected. Much to our delight, fluoroarenes
bearing a strong electron-withdrawing group (2j) and
fluoropyridine (2k and 2l) afforded the arylated products in
high yields without the formation of other isomers (3aj, 3ak,
and 3al). On the basis of these experimental results, we
assumed that the reaction of diphenylmethane 1a with
electron-poor aryl fluorides might proceed via a classical
SNAr pathway.
To explore the substrate scope, we examined the reaction
of a range of substituted fluorobenzenes with 1a under the
optimized reaction conditions (Table 1, entry 9). As shown in
Scheme 2, in most cases, fluoroarenes 2a−l proceeded
smoothly and afforded the arylation products 3aa−al in
moderate to good yields. The fluoroarenes bearing electron-
withdrawing groups or an electron-neutral group (2a) gave
higher yields than those containing electron-donating groups
on the aromatic rings (2j versus 2g). Notably, fluoroarenes
containing electron-donating groups provided a mixture of
regioisomers (3ab,ac,ad,ag; the structures of the ortho-, meta-,
Subsequently, the reactions of fluorobenzene 2a with
various diarylmethanes were investigated (Scheme 3). Despite
the inertness of C−F bond of fluorobenzene, most of the
reactions proceeded smoothly at room temperature. Generally,
1
and para-isomers were determined by their H NMR spectra
and the literature). These results implied that the reaction of
B
DOI: 10.1021/acs.orglett.5b02602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Reactions of 2a with Various Diarylmethanes
1b−h
Scheme 5. Reactions of 9H-Fluorene 1i with Substituted
Fluorobenzenes
a,
b
a,b
a
Reaction conditions: 1b−h (1.0 mmol), 2a (1.5 mmol), LDA (3.0
b
mmol), THF (5 mL), rt, 1−4 h, Ar. Isolated yield.
the electron-poor diarylmethanes gave good yields whereas
the electron-rich diarylmethanes provided lower yield (3ba).
To evaluate the scope of the reaction further, several
diarylmethanes, 9H-fluorene 1i and 9H-xanthene 1j were
reacted with different fluoroarenes (Schemes 4−6). Generally,
a
Reaction conditions: 1i (1.0 mmol), 2a, 2b, 2g, 2j, 2k, 2m (1.5
b
mmol), LDA (3.0 mmol), THF (5 mL), rt, 1−4 h, Ar. Isolated yield.
Scheme 6. Reactions of 9H-Xanthene 1j with Substituted
Fluorobenzenes
Scheme 4. Reactions of Diarylmethanes with Substituted
Fluorobenzenes
a,b
a,b
a
Reaction conditions: 1j (1.0 mmol), 2a,b,m (1.5 mmol), and 2f (3.0
b
mmol), LDA (3.0 mmol), THF (5 mL), rt, 1−4 h, Ar. Isolated yield.
C(sp3)−H arylation of diarylmethanes, 9H-fluorene, and 9H-
xanthene with various readily available fluoroarenes. This
direct arylation was promoted only by LDA. More
importantly, with this protocol, both unreactive C−F bonds
such as the C−F bond in 2f and 2g and reactive C−F bonds
such as the C−F bond in 2j could be readily cleaved in the
presence of LDA at room temperature within short reaction
times. The arylation of diphenylmethanes with electron-rich
aryl fluorides proceeded via aryne intermediates, whereas
electron-poor fluoroarenes proceed via a classical SNAr
pathway. Furthermore, the arylation process exhibited good
substrate scope and functional group tolerance, and a variety
of triarylmethane derivatives were obtained in moderate to
high yields. Further efforts to extend the applications of this
method are underway in our laboratory.
a
Reaction conditions: 1c,d,f−h (1.0 mmol); 2g,j−l (1.5 mmol), 2f
b
(3.0 mmol), LDA (3.0 mmol), THF (5 mL), rt, 1−4 h, Ar. Isolated
yield.
the reaction proceeded smoothly at room temperature to yield
arylated products, and the observed trend was the same as
that seen for above-mentioned fluoroarenes and diaryl-
methanes: electron-rich fluoroarenes tended to afford two
regioisomers (3cg,dg,ib,ig,jb), whereas electron-poor fluoroar-
enes afforded only one isomer (3cj,dk,fk,gk,hl,ij,ik,im,jm).
In summary, we have developed a facile and transition-
metal-free synthesis of triarylmethanes by the secondary
C
DOI: 10.1021/acs.orglett.5b02602
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02602.
■
S
Experimental details and spectroscopic data for
compounds 3 (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*Tel: +86-21-64253452. E-mail: scao@ecust.edu.cn.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National
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