Synthesis of tetraarylmethanes via a Friedel-Crafts cyclization/desulfurization strategy

Article abstract of DOI:10.1016/j.tetlet.2018.09.056

Tetraarylmethanes are an important class of molecules that contain four aryl groups bonded to a central carbon atom. The shape/three-dimensionality of these molecules makes them suitable for organic light-emitting diodes (OLEDs), organic solar cells, hydrogen storage, and even drug-delivery. Despite their importance, there are only a few methods available for their preparation. Herein, we report a simple procedure for the preparation of tetraarylmethanes that involves a bismuth-catalyzed Friedel-Crafts cyclization followed by a desulfurization reaction mediated by Raney nickel.

Full text of DOI:10.1016/j.tetlet.2018.09.056

Accepted Manuscript
Synthesis of tetraarylmethanes via a Friedel-Crafts cyclization/desulfurization
strategy
Paul J. Griffin, Matthew A. Fava, St. John T. Whittaker, Kristopher J. Kolonko,
Arthur J. Catino
PII:
S0040-4039(18)31158-4
https://doi.org/10.1016/j.tetlet.2018.09.056
TETL 50295
DOI:
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
15 August 2018
18 September 2018
21 September 2018
Please cite this article as: Griffin, P.J., Fava, M.A., Whittaker, t.J.T., Kolonko, K.J., Catino, A.J., Synthesis of
tetraarylmethanes via a Friedel-Crafts cyclization/desulfurization strategy, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.09.056
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Synthesis of tetraarylmethanes via a Friedel-
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Crafts cyclization/desulfurization strategy
Paul J. Griffin, Matthew A. Fava, St. John T. Whittaker, Kristopher J. Kolonko, and Arthur J. Catino

1
Tetrahedron Letters
Synthesis of tetraarylmethanes via a Friedel-Crafts cyclization/desulfurization
strategy
Paul J. Griffina, Matthew A. Favaa, St. John T. Whittakera, Kristopher J. Kolonkob, and Arthur J. Catinoa*
aDepartment of Chemistry, The University of Scranton, Scranton, PA 18510 USA
bStewart’s Advanced Instrumentation and Technology (SAInT) Center, Siena College, Loudonville, NY 12211 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Tetraarylmethanes are an important class of molecules that contain four aryl groups bonded to a
central carbon atom. The shape/three-dimensionality of these molecules makes them suitable for
organic light-emitting diodes (OLEDs), organic solar cells, hydrogen storage, and even drug-
delivery. Despite their importance, there are only a few methods available for their preparation.
Herein, we report a simple procedure for the preparation of tetraarylmethanes that involves a
bismuth-catalyzed Friedel-Crafts cyclization followed by a desulfurization reaction mediated by
Raney nickel.
Available online
Keywords:
tetraarylmethanes
tetraphenylmethane
bismuth catalysis
Friedel-Crafts cyclization
desulfurization
2009 Elsevier Ltd. All rights reserved.
Tetraarylmethanes contain four aryl groups (typically
phenyl) bonded to a central carbon atom. The shape/three-
dimensionality of these molecules has made them suitable for
organic light-emitting diodes (OLEDs),1 organic solar cells,2
hydrogen storage,3 and even drug-delivery.4 Despite their
importance, there are only a few methods available for their
preparation. The most commonly used method involves
Friedel-Crafts addition to a triaryl halomethane mediated by a
Lewis acid (Fig. 1).5,6 A major limitation of this method is
that the aryl group must be substituted with a strong electron-
donating group (EDG). As this group is typically unwanted,
additional steps are required to remove it. Another drawback
is that only para-substituted tetraarylmethane products can be
obtained either in the Friedel-Crafts reaction or in subsequent
reactions.
to be a pyridine (or a related heterocycle) and does not allow
access to simple substituted tetraphenylmethanes.
Figure 2. Synthesis of tetraarylmethanes via palladium-catalyzed
cross-coupling reported by Walsh and Mao.8
Our strategy to prepare tetraarylmethanes with all phenyl
groups and diverse substitution/electronics was to expand
upon the Friedel-Crafts addition by performing the reaction
intramolecularly. We were particularly attracted to triaryl-
methanols containing a sulfur-tethered benzene moiety
(Fig. 3). The close proximity of the tethered benzene to the
site of attack and the formation of a thermodynamically
favorable thioxanthene ring would eliminate the need for
strong electron-donating groups and harsh reaction conditions.
Subsequent removal of the sulfur atom by conventional
methods9 would then provide the tetraarylmethane.
EDG
EDG
Lewis
acid
X
Ar
Ar
+
Ar
Ar
Ar
Ar
Figure 1. Preparation of tetraarylmethanes by Friedel-Crafts
addition to triaryl halomethanes.
Recently, chemists have begun exploring transition metal
cross-coupling as a viable strategy to prepare these
compounds.7 A notable example was reported by Walsh and
Mao in 2017 in which various triaryl motifs containing a
benzylic proton were used with palladium catalysis to
construct tetraarylmethanes (Fig. 2).8 Although this was a
major step toward a general method, it requires one aryl group
Figure 3. Synthetic plan to prepare tetraarylmethanes via Friedel-
Crafts cyclization/desulfurization (this work).

We began our study by preparing a variety of 2-thiophenyl
triarylmethanols using a modified procedure reported by
Shimizu and co-workers (Table 1).10 Treatment of 2-
thiophenylbenzophenone11 with an aryl Grignard reagent in
THF at reflux gave the corresponding triarylmethanol in poor
to moderate yield. We found that the reaction was sensitive to
the electronic nature of the aryl Grignard reagent with those
containing electron-donating groups giving the lowest yields.
Analysis of the crude reaction mixture revealed a significant
amount of biphenyl products derived from nucleophilic
aromatic substitution of the Grignard followed by loss of
thiophenolate. This side reaction could be mitigated by using
electron-deficient aryl Grignard reagents (Entries 10 and 11);
however, no reaction was observed with trifluoromethyl- and
perfluoro-aryl Grignard reagents (Entries 12 and 13). These
results led us to consider “harder” nucleophiles to enhance
reactivity at the carbonyl group. Gratifyingly, aryl lithium
reagents, prepared via metal-halogen exchange from the
corresponding bromides, performed very well across a range
of substituents. During the course of optimization we found
that the highest yields were obtained when a solution of 2-
thiophenyl-benzophenone was added immediately after aryl
lithium formation at -78 °C. Allowing the aryl lithium reagent
to warm to 0 °C followed by addition of the benzophenone
gave lower yields and increased biphenyl formation.
isolated by filtration through a plug of silica followed by
rinsing with dichloromethane. With the exception of the 2-
methoxy-substituted product 3h, all reactions gave highly
crystalline products with sharp melting points after the
evaporation of dichloromethane.
Table 1. Synthesis of triarylmethanol starting materials
Entry
Ar
M = MgBra
M = Lib
yield 2 (%) yield 2 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5 (2a)
66
48
68
55
28
26
54
37
55
83
75
nr
80
83
94
94
56
55
82
85
98
83
95
61
nr
4-CH3C6H4 (2b)
3-CH3C6H4 (2c)
2-CH3C6H4 (2d)
4-OCH3C6H4 (2e)
4-t-Bu-C6H4 (2f)
3,5-(OCH3)2C6H4 (2g)
2-OCH3C6H4 (2h)
2-naphthyl (2i)
4-FC6H4 (2j)
Figure 4. Friedel-Crafts cyclizations catalyzed by
bismuth(III) triflate.
3-FC6H4 (2k)
4-CF3C6H4 (2l)
C6F5
We next explored conditions to convert the 9,9-diarylthio-
xanthenes to tetraphenylmethanes. We were initially drawn to
nickel boride, generated in situ from nickel chloride and
sodium borohydride, for its ease of preparation and wide
applicability.14 As such, treatment of 3a with nickel boride
gave 21% yield of tetraphenylmethane 4a (Fig. 5).15 While
troubleshooting the reaction we noted very poor solubility of
both the starting material and the product in the reaction
solvent. Attempts to increase the amount of THF and/or
increase the temperature to enhance solubility resulted in
decreased yields. To test the hypothesis that solubility was the
problem and not the stability of the thioxanthene ring, we
prepared 9-phenyl-thioxanthene (5)16 and subjected it to the
optimized reaction conditions (vide infra). Both the product
and starting material are soluble in MeOH/THF (3:1). The
reaction of 5 with nickel boride gave >95% conversion (60%
isolated yield) of triphenylmethane (6).
nr
aReactions were conducted using 2.5 equivalents of arylmagnesium bromide in
THF at reflux for 3-8 hours. bReactions were conducted using 2.5 equivalents of
aryllithium in THF at -78 °C for 5-10 minutes. Percent yields are for isolated
products and “nr” refers to no reaction.
With a variety of triarylmethanols in hand, we explored
conditions for the subsequent Friedel-Crafts cyclization to
form 9,9-diarylthioxanthenes (Fig. 4). It was previously
reported that the cyclization of 2a can be accomplished with
sulfuric acid in acetic acid at reflux.10 Seeking milder
conditions that would tolerate a wide range of substitution and
an easier work-up, we explored catalytic Lewis acids. We
ultimately found that bismuth triflate (Bi(OTf)3) in
dichloromethane at reflux, as described by Rueping and co-
workers for the benzylation of arenes,12 gave the highest yield
for the cyclization of 2a.13 Application of these conditions to
the remaining triaryl-methanols proceeded smoothly to give
thioxanthane ring products in good to excellent yields. The
reactions were complete in 1-4 hours and the products were

3
With optimized reaction conditions in hand, we
conducted desulfurizations across all of our 9,9-
diarylthioxanthenes (Fig. 6). The reactions showed complete
consumption of the starting material in 2-6 hours as judged by
1
TLC and/or H NMR analysis of reaction aliquots. Isolated
yields were moderate to good and in only one case failed to
give the intended product. All the products were highly stable
and exhibited high melting points.
Figure 5. Desulfurization of thioxanthenes mediated by
nickel boride.
Of particular note is that this method enables the synthesis
of tetraphenylmethanes that contain either electron-
withdrawing or electron-donating groups having ortho-, meta-
or para-substitution (Fig. 6). Interestingly, the methyl group
in tetraphenylmethane 4d exhibits a chemical shift anisotropy
of almost 1 ppm (upfield) indicating that this substituent
probably resides above one of the benzene rings in the
molecule.17 Polycyclic aromatic compounds such as
naphthalene can also be readily introduced (4i). A limitation
of this method is the use of Raney nickel as there are
functional groups that would undergo reaction.18 We
examined other methods for desulfurization such as with
alkali-metal19 or with potassium tert-butoxide/hydrosilane,20
however, they were unsuccessful with our substrates.
Finally, we were pleased to find that this methodology can
be used to prepare bis-substituted tetraarylmethanes (Fig. 7).
For example, reaction of methyl 2-(phenylthio)benzoate (7)21
with 4-fluorophenyl lithium (generated in situ by metal-
halogen exchange) using our previously described conditions
gave triarylmethanol 8. Subsequent treatment with bismuth
triflate followed by desulfurization with Raney nickel gave
the bis-fluoro-substituted tetraphenylmethane 10 in good
overall yield.
Based on this outcome, we turned our attention to Raney
nickel, which unlike nickel boride, can function in a solely
aprotic solvent such as THF. Treatment of 3a in THF with
commercially available 2800® Raney nickel slurry resulted in
consumption of the starting material and only a trace amount
of tetraphenylmethane. Once again, the problem was
solubility, particularly that of the product (for comparison the
reaction of 5 with Raney nickel gave 97% yield of 6).
Tetraphenylmethane has poor solubility in many organic
solvents. Consequently, any attempt to remove the nickel
residues after the reaction also removed the product. After
some experimentation, we implemented a few simple
procedural changes to overcome this problem. These include
1) decanting the water from the commercial Raney nickel
slurry and then washing it with THF to remove any residual
water, 2) conducting the reaction at 75 °C, and 3) performing
a hot decantation in the workup followed by washing with hot
THF and toluene for maximum extraction of the product.
Figure 7. Synthesis of a bis-substituted tetraphenylmethane
using the described methodology.
In summary, we have reported a general method for the
preparation of tetraarylmethanes that overcomes many of the
limitations in both intermolecular Friedel-Crafts and transition
metal-catalyzed routes. We have shown that 2-thiophenyl
triarylmethanols are readily obtained by nucleophilic addition,
that a catalytic amount of bismuth triflate enables cyclization
under extremely mild conditions, and that desulfurization is
viable with Raney nickel to give
a
variety of
tetraphenylmethanes. Future work will address the expansion
of scope using other electrophiles that contain a sulfur-
tethered benzene moiety (e.g. 7), the development of an
asymmetric variant to prepare chiral tetraarylmethanes, and
the preparation of useful tetraarylmethanes for various
applications.
Figure 6. Desulfurization with Raney nickel to give various
tetraarylmethanes.

Acknowledgments
We are grateful to the University of Scranton for support of
this research. We thank also thank Michael Fennie and Nicholas
Sizemore for helpful discussions and laboratory assistance.
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at

5
Department of Chemistry
Loyola Science Center
Highlights
for
“Synthesis of tetraarylmethanes via a Friedel-Crafts
cyclization/desulfurization strategy”
1. Tetraarylmethanes prepared with all
phenyl groups and diverse substitution
2. Friedel-Crafts cyclization gives 9,9-
diarylthioxanthene precursors
3. Tetraarylmethanes obtained by
desulfurization with Raney nickel
4. Tetraarylmethanes with electron-
withdrawing or electron-donating groups
5. Nucleophilic addition to benzophenone to
form triarylmethanols