Synthesis of Tetraarylmethanes by the Triflic Acid-Promoted Formal Cross-Dehydrogenative Coupling of Triarylmethanes with Arenes

Article abstract of DOI:10.1055/s-0036-1588563

The formal cross-dehydrogenative coupling of triarylmethanes with arenes promoted by triflic acid and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone is described. This method provides a variety of tetraarylmethane derivatives in good to excellent yields from triarylmethanes that can be readily prepared by our previous methods. Control experiments suggest a possible catalytic cycle involving the generation of a trityl cation intermediate followed by nucleophilic addition of the arene.

Full text of DOI:10.1055/s-0036-1588563

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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A
en
M. Nambo et al.
Letter
Synlett
Synthesis of Tetraarylmethanes by the Triflic Acid-Promoted
Formal Cross-Dehydrogenative Coupling of Triarylmethanes with
Arenes
Masakazu Nambo*a
Jacky C.-H. Yima
Ar1
Ar1
Kevin G. Fowlera
Cathleen M. Crudden*a,b
cat. TfOH
DDQ
H
Ar4
Ar4
H
Ar2
Ar2
Ar3
Ar3
electron-rich
arenes and
heteroarenes
a Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya
University, Chikusa, Nagoya, 464-8602, Japan
mnambo@itbm.nagoya-u.ac.jp
b Queen’s University, Department of Chemistry, Chernoff Hall,
Kingston, Ontario, K7L 3N6, Canada
16 examples, up to 99% yield
cruddenc@chem.queensu.ca
Dedicated to Professor Victor Snieckus, colleague, mentor, and
friend on the occasion of his 80th birthday.
Received: 15.06.2017
Accepted after revision: 19.07.2017
Published online: 26.09.2017
with aryl Grignard reagents has also been developed,8 but
new synthetic methods for structurally diverse, particularly
nonsymmetric, tetraarylmethanes are still needed.
DOI: 10.1055/s-0036-1588563; Art ID: st-2017-r0475-l
Our group has developed modular and selective synthe-
ses of arylmethane derivatives using transition-metal catal-
ysis.9 In particular, we have found that cheap, readily avail-
able, methyl phenyl sulfone can be transformed into valu-
able triarylmethanes in only three steps through either Pd-
or Sc-catalyzed sequential arylations (Scheme 1).
Abstract The formal cross-dehydrogenative coupling of triarylmeth-
anes with arenes promoted by triflic acid and 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone is described. This method provides a variety of
tetraarylmethane derivatives in good to excellent yields from triaryl-
methanes that can be readily prepared by our previous methods. Con-
trol experiments suggest a possible catalytic cycle involving the genera-
tion of a trityl cation intermediate followed by nucleophilic addition of
the arene.
Our previous work:
This work:
Modular synthesis of triarylmethanes
Cross dehydrogenative coupling of
triarylmethanes with arenes
Key words cross-coupling, dehydrogenation, tetraarylmethanes, tri-
arylmethanes, arylation, organocatalysis
Ar1Br
Ar2I
Ar1
Ar1
Ar3B(OR)2
Polyarylated methanes are important frameworks in
medicinal chemistry and materials science.1 A number of
useful synthetic methods, including cross-coupling reac-
tions, have been developed to access these structures, im-
prove selectivity, and increase molecular diversity. Despite
significant advances in the synthesis of di- and triarylmeth-
anes,2 synthetic routes toward tetraarylmethanes, which
show unique chemical and physical properties as function-
alized organic materials,3 are still based on classical meth-
ods. For example, Friedel–Crafts arylations of triarylmetha-
nol4 or trityl chloride5 with some electron-rich arenes or
substitutions with organometallic reagents have been em-
ployed.6 However, these methods often require multiple
steps to prepare the corresponding triarylmethyl sub-
strates.
In a transition-metal-catalyzed route, Yorimitsu and
Ohshima first reported the formation of tetraarylmethanes
by the Pd-catalyzed C–H diphenylation of 4-benzylpyri-
dine.6 Recently, the Walsh group established Pd-catalyzed
C–H arylations of di- and triarylmethanes bearing azaaryl
groups to afford a variety of tetraarylmethanes.7 The Ni-
catalyzed cross-coupling reaction of tetrachloromethane
or Ar3H
H
Ar4H
Ar4
H
H
SO2Ph
H
Ar2
Ar2
Pd, Sc cat.
(3 steps)
TfOH
DDQ
Ar3
Ar3
Straightforward Synthesis of Tetraarylmethanes (total 4 steps)
Scheme 1 The cross-dehydrogenative coupling of triarymethanes with
electron-rich arenes.
We saw the next challenge as expanding our sequential
arylation strategy to permit the concise synthesis of
tetraarylmethanes by arylating the remaining C(sp3)–H
bond in triarylmethanes. As an alternative method to
deprotonative arylation,6,7 we focused on the cross-dehy-
drogenative coupling approach, which has emerged as an
ideal transformation to form a C–C bond from two different
C–H bonds.10 We envisioned that abstracting the benzylic
C–H bond of triarylmethanes with an oxidant might gener-
ate reactive trityl cation intermediates that would subse-
quently react with nucleophilic arenes to afford tetraaryl-
methanes.11 Here, we describe the cross-dehydrogenative
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
M. Nambo et al.
Letter
Synlett
coupling of triarylmethanes with electron-rich arenes using
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an
oxidant (Scheme 1).12
benzene (2b) gave the corresponding product 3ab in 95%
yield, whereas 1,3-dimethoxybenzene (2c) gave a slightly
decreased yield of 3ac, probably due to steric effects. In-
deed, no product was observed when the more-electron-
rich but sterically hindered 1,3,5-trimethoxybenzene was
used. Although N,N-dimethylaniline did not afford the de-
sired product, electron-rich hetaromatics were well-toler-
ated. 2-Substituted thiophenes 2d–f reacted in high yield
regioselectively at the 5-position. Benzofuran (2g) and N-
tosylindole (2h) also gave the corresponding coupling prod-
ucts 3ag and 3ah in nearly quantitative yields.
Our initial studies focused on the use of triphenylmeth-
ane (1a) and anisole (2a) as model substrates for the formal
cross-dehydrogenative coupling (Table 1). The reaction in
the presence of DDQ alone gave 1-methoxy-4-tritylbenzene
(3a) in only 10% yield (Table 1, entry 1). Inspired by previ-
ous reports on the activation of DDQ by the addition of ac-
ids,13 several acid catalysts were screened. The addition of
TFA, BF3·Et2O, or H2SO4 led to increased product yields;
however, the unexpected byproduct 9-(4-methoxyphenyl)-
9-phenyl-9H-fluorene (4a) was also formed (entries 2–4).
Triflate metal salts such as Cu(OTf)2 or Sc(OTf)3 improved
the yield of product 3a (entries 5 and 6), but through con-
trol experiments we showed that TfOH, potentially generat-
ed from triflate salts, was a suitable catalyst for this C–H
coupling reaction. Under these simple conditions, the yield
of 3a reached 77% (entry 7). Decreasing the amount of 2a or
DDQ resulted in lower yields (entries 8 and 9), and when re-
action was conducted at 80 °C, the yield was also signifi-
cantly decreased (entry 10).
10 mol% TfOH
2 equiv DDQ
Ph
Ph
H
Ar
ArH
Ph
Ph
DCE (0.33 M)
100 °C, 6 h
(5 equiv)
Ph
1a
Ph
2
3
Ph
Ph
Ph
Ph
Ph
OMe
OMe
OMe
OMe
OMe
Ph
Ph
Ph
Ph
MeO
74% (3aa)
95% (3ab)
74% (3ac)
MeO
Ph
Ph
Ph
Ph
Ph
Ph
NMe2
Table 1 Optimization of the Cross-Dehydrogenative Coupling of
Triphenylmethane (1a) with Anisole (2a)a
S
Cl
Ph
Ph
Ph
MeO
n.d.
n.d.
94% (3ad)
p-Anis
OMe
Ph
10 mol% catalyst
2 equiv DDQ
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
p-Anis
DCE (0.33 M)
100 °C, 6 h
Ph
Ph
O
S
S
Ph
Br
Ph
Ph
Ph
Ph
H
1a
2a
3a
4a
72% (3ae)
87% (3af)
98% (3ag)
Entry
Catalyst
Yield (%) of 3ab
Yield (%) of 4ab
Ph
1
2
–
10
<1
8
NTs
TFA
14
Ph
Ph
99% (3ah)
3
BF3·Et2O
H2SO4
Cu(OTf)2
Sc(OTf)3
TfOH
TfOH
TfOH
TfOH
28
1
4
45
9
Scheme 2 The scope of cross-dehydrogenative coupling of 1a with
arenes 2
5
67
12
9
6
69
7
77 (74)c
25
6
The structures of 3ag and 3ah were successfully con-
8d
9e
10f
24
3
firmed by X-ray crystallographic analysis (Figure 1)14
39
49
3
a Conditions: 1a (1 equiv), 2a (5 equiv), catalyst (10 mol %), DCE (0.33 M),
100 °C, 6 h.
b Yield by GC with dodecane as internal standard.
c Isolated yield.
d 2a (3 equiv).
e DDQ (1 equiv).
f At 80 °C.
With the optimized conditions in hand, we examined
the scope of the dehydrogenative coupling with regard to
the arene (Scheme 2). The reaction with 1,2-dimethoxy-
Figure 1 X-ray crystal structure of 3ag and 3ah (H atoms have been
omitted for clarity.)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
M. Nambo et al.
Letter
Synlett
Next, we performed the reactions of various triaryl-
methanes 1 using 1-benzofuran (2g) as the coupling part-
ner (Scheme 3). Triarylmethanes bearing 4-tert-butyl (1b),
4-methoxy (1c), or 4-fluoro groups (1d) gave the corre-
sponding monosubstituted tetraphenylmethanes 3bg–dg in
good yields. The electron-deficient triarylmethane bearing
a 4-CF3 group (1e) also afforded the desired product 3eg in
moderate yield on prolonging the reaction time to 13 hours.
Furthermore, a 4-bromo substituent (1f) was well tolerated,
which will be beneficial for further transformations and is
typically not compatible with metal-catalyzed cross-cou-
pling reactions. The reaction of substrate 1g having a bulky
2-methoxy group proceeded with good yield giving product
3gg. Bis(p-methoxyphenyl)phenylmethane (1h) and tris(p-
methoxyphenyl)methane (1i) reacted with lower yields
than 1c, suggesting that stabilization of the newly generat-
ed trityl cation by 4-methoxy groups might decrease their
reactivity with arenes.13 Notably, the nonsymmetric and
highly functionalized tetrarylmethane 3jg was obtained in
good yield.
H
O
2g
(5 equiv)
Ar1
Ar1
10 mol% TfOH
2 equiv DDQ
H
DCE (0.33 M)
100 °C, 6 h
Ar2
O
Ar2
Ar3
Ar3
1
3
R
R = t-Bu, 86% (3bg)
R = OMe, 84% (3cg)
R = F, 87% (3dg)
R = CF3, 71%a (3eg)
R = Br, 85% (3fg)
O
MeO
OMe
To understand the mechanism of this dehydrogenative
coupling, several control experiments were conducted
(Scheme 4). When the reaction of 1a in DCE–H2O was car-
ried out in the absence of arenes, triphenylmethanol was
obtained in 55% GC yield (Scheme 4, a). This result is consis-
tent with the production of a trityl cation intermediate,
generated from triarylmethane in the presence of TfOH and
DDQ. Additionally, byproduct 4a was not observed under
standard reaction conditions (Scheme 4b); therefore, the
formation of 4a through oxidative cyclization (Scholl reac-
tion)15,16 of 3a can be ruled out. Ohta et al. reported the in-
termolecular Friedel–Crafts-type cyclization of trityl cat-
ions promoted by TfOH to afford 9-phenyl-9H-fluorene
(5a), albeit in low yield.17 To examine the possibility of the
formation of 4a through the reaction of 5a with 2a, we ex-
amined this reaction independently. Byproduct 4a was ob-
tained in 86% yield, leading us to infer that the trityl cation
intermediate can be converted into 5 under acidic condi-
tions, which then reacts in a dehydrogenative coupling with
arenes.
O
O
MeO
87% (3gg)
40% (3hg)
MeO
MeO
O
O
t-Bu
MeO
MeO
<5% (3ig)
83% (3jg)
Scheme 3 The scope of cross-dehydrogenative couplings of triaryl-
methanes 1 with benzofuran 2g.
a Reaction time 13 h.
From these experiments, the proposed catalytic cycle
for the dehydrogenative coupling is shown in Scheme 5. Tri-
arylmethane 1 reacts with DDQ, which is itself activated by
a catalytic amount of TfOH, to generate trityl cation inter-
mediate A. Subsequently, A reacts with the arene to provide
the desired tetraarylmethane 3 in a Friedel–Crafts fashion,
along with regeneration of TfOH. As a minor reaction path-
way, the formation of 9-arylfluorene 5 from A followed by
dehydrogenative coupling with an arene gives the 9,9-dia-
rylfluorene 4.
derivatives can be easily prepared in good yields by this
simple protocol. Notably, this method, combined with our
previously reported methods for the synthesis of triaryl-
methanes, results in a modular and straightforward route to
functionalized tetraarylmethanes, which represent useful
starting points to develop new highly arylated organic ma-
terials. Further investigations toward the development of
new methods for synthesizing polyarylated structures are
ongoing in our laboratory.
In summary, we have described a new type of cross-de-
hydrogenative coupling of triarylmethanes with arenes un-
der oxidative condition.18 A wide range of tetraarylmethane
Funding Information
This work was supported by KAKENHI from JSPS (26810056 and
17K17805 to M.N.). M.N. thanks the Chugai Pharmaceutical Company
Award in Synthetic Organic Chemistry, Japan. J.C.-H.Y. is a recipient of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
M. Nambo et al.
Letter
Synlett
hedron 2006, 62, 6731. For selected examples, see: (e) Panda, G.;
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10 mol% TfOH
2 equiv DDQ
a)
Ph
Ph
Ph
Ph
H
OH
DCE/H2O = 5:1 (0.33 M)
100 °C, 6 h
Ph
Ph
1a
55% yield (GC)
10 mol% TfOH
2 equiv DDQ
b)
Ph
MeO
OMe
Ph
DCE (0.33 M)
100 °C, 6 h
(no conversion)
(2) For recent advances for the synthesis of polyarylated alkanes by
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(e) Zhou, Q.; Cobb, K. M.; Tan, T.; Watson, M. P. J. Am. Chem. Soc.
2016, 138, 12057.
Ph
3a
Ph
H
OMe
10 mol% TfOH
2 equiv DDQ
Ph
DCE (0.33 M)
100 °C, 6 h
(86%)
4a
H
5a
2a (5 equiv)
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Scheme 4 Control experiments
Ar1
Ar2
HOTf
O
H
Ar3
OH
Cl
Cl
CN
1
Cl
Cl
CN
DDQ
TfOH
CN
CN
O
OH
Ar
H
Ar2
OTf
Ar1
Ar3
– TfOH
5
A
Ar Ar4
OTf
Ar1
Ar1
Ar2
Ar4
H
H
Ar4
Ar2
Ar3
Ar3
4
3
Scheme 5 Proposed catalytic cycle for the cross-dehydrogenative cou-
pling
(8) Gartia, Y.; Biswas, A.; Stadler, M.; Nasini, U. B.; Ghosh, A. J. Mol.
Catal. A: Chem. 2012, 363–364, 322.
(9) (a) Nambo, M.; Crudden, C. M. Angew. Chem. Int. Ed. 2014, 53,
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Lett. 2015, 17, 50. (c) Nambo, M.; Ariki, Z. T.; Canseco-Gonzalez,
D.; Beattie, D. D.; Crudden, C. M. Org. Lett. 2016, 18, 2339.
(d) Nambo, M.; Keske, E. C.; Rygus, J. P. G.; Yim, J. C.-H.; Crudden,
C. M. ACS Catal. 2017, 7, 1108.
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(b) Scheuermann, C. J. Chem. Asian J. 2010, 5, 436. (c) Yeung, C.
S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Liu, C.; Yuan, J.;
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a JSPS postdoctoral fellowship for research in Japan (16F16749). We
also thank JSPS and NU for funding this research through The World
Premier International Research Center Initiative (WPI) program
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Acknowledgment
We thank Dr. Yasutomo Segawa for assistance with the X-ray crystal-
structure analysis.
Supporting Information
(11) For examples of reactions of trityl cation with arenes, see:
(a) Sugihara, Y.; Saito, J.; Murata, I. Angew. Chem., Int. Ed. Engl.
1991, 30, 1174. (b) Kusuhara, N.; Sugano, Y.; Takagi, H.; Miyake,
H.; Yamamura, K. Chem. Commun. 1997, 1951. (c) Lv, J.; Zhang,
Q.; Zhong, X.; Luo, S. J. Am. Chem. Soc. 2015, 137, 15576.
(12) For recent examples of cross-dehydrogenative coupling using
DDQ, see: (a) Li, Y.-Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi, Z.-J. Angew.
Chem. Int. Ed. 2009, 48, 3817. (b) Liu, H.; Cao, L.; Sun, J.; Fossey, J.
S.; Deng, W.-P. Chem. Commun. 2012, 48, 2674. (c) Ma, Y.;
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588563.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
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References and Notes
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Zhang, D.; Yan, Z.; Wang, M.; Bian, C.; Gao, X.; Bunel, E. E.; Lei, A.
Org. Lett. 2015, 17, 2174. (d) Guo, S.; Li, Y.; Wang, Y.; Guo, X.;
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71. This fluorene-formation process might be similar to a Nazrov
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(18) 1-Methoxy-4-tritylbenzene (3aa); Typical Procedure
A 10-mL sealable reaction tube equipped with a magnetic stir-
ring bar and a septum was evacuated, flame-dried under
vacuum, cooled to r.t., and backfilled with argon. The tube was
then charged with Ph3CH (1a; 24.4 mg, 0.1 mmol) and DDQ
(45.4 mg, 0.2 mmol, 2 equiv) under a constant stream of argon.
The tub was evacuated for 5 min and refilled with argon. This
cycle was repeated twice more. DCE (0.3 mL), TfOH (0.9 μL,
0.01 mmol, 10 mol%), and anisole 2a (51 μL, 0.5 mmol, 5 equiv)
were added, and the vessel was sealed. The mixture was stirred
at 100 °C for 6 h then cooled to r.t. EtOAc (~5 mL) was added,
and the solution was passed through a pad of Celite with
copious washings with EtOAc. The solvent was evaporated
under reduced pressure to give a crude product that was puri-
fied by preparative TLC (hexane–EtOAc, 50:1) to give a white
solid; yield: 25.9 mg (74%).
(13) In the reaction of 1i with 2g, we did not observe the formation
of the corresponding triarylmethanol; however, the p-quinone
methide 6 (Figure 2) was detected by GC/MS. The formation of
such p-quinone methides from p-methoxy-substituted triary-
methanol derivatives under acidic conditions through O-
demethylation has been reported, see: (a) Levine, R.; Sommers,
J. R. J. Org. Chem. 1974, 39, 3559. (b) Wada, M.; Watanabe, T.;
Natsume, S.; Mishima, H.; Kirishima, K.; Erabi, T. Bull. Chem. Soc.
Jpn. 1995, 68, 3233. (c) Taljaard, B.; Taljaard, J. H.; Imrie, C.;
Caira, M. R. Eur. J. Org. Chem. 2005, 2607; Thus a less reactive
trityl cation could decompose to give a p-quinone methide
before coupling with the arene.
p-Anis
O
p-Anis
6
Figure 2
(14) CCDC 1553011 and 1553012 contains the supplementary crys-
tallographic data for compounds 3ag and 3ah, respectively. The
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/getstruc-
tures.
(15) (a) Zhai, L.; Shukla, R.; Rathore, R. Org. Lett. 2009, 11, 3474.
(b) Zhai, L.; Shukla, R.; Wadumethrige, S. H.; Rathore, R. J. Org.
Chem. 2010, 75, 4748.
1H NMR (400 MHz, CDCl3): δ = 3.78 (s, 3 H), 6.80 (dm, J = 9.2 Hz,
2 H), 6.80 (dm, J = 9.2 Hz, 2 H), 7.16–7.26 (m, 15 H). 13C NMR
(150 MHz, CDCl3): δ = 55.2, 64.3, 112.7, 125.8, 127.4, 131.1,
132.2, 139.0, 147.0, 157.5. HRMS (DART): m/z calcd for C26H22O:
350.1671; found: 350.1663.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E