Arylative Desulfonation of Diarylmethyl Phenyl Sulfone with Arenes Catalyzed by Scandium Triflate

Article abstract of DOI:10.1021/acs.orglett.6b00744

A scandium-triflate-catalyzed arylative desulfonation of diarylmethyl phenyl sulfones with arenes and heteroarenes was established. A variety of both sulfone and arene substrates were reacted to afford symmetric and nonsymmetric triarylmethanes in good yields. Further transformations of the resulting triarylmethanes and application to the concise synthesis of a bactericidal agent analogue were also demonstrated.

Full text of DOI:10.1021/acs.orglett.6b00744

Letter
pubs.acs.org/OrgLett
Arylative Desulfonation of Diarylmethyl Phenyl Sulfone with Arenes
Catalyzed by Scandium Triflate
Masakazu Nambo,*,† Zachary T. Ariki,‡ Daniel Canseco-Gonzalez,† D. Dawson Beattie,‡
and Cathleen M. Crudden*,†,‡
†Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, 464-8601 Nagoya, Japan
‡Department of Chemistry, Queen’s University, Chernoff Hall, Kingston, Ontario K7L 3N6, Canada
S
* Supporting Information
ABSTRACT: A scandium-triflate-catalyzed arylative desulfonation
of diarylmethyl phenyl sulfones with arenes and heteroarenes was
established. A variety of both sulfone and arene substrates were
reacted to afford symmetric and nonsymmetric triarylmethanes in
good yields. Further transformations of the resulting triaryl-
methanes and application to the concise synthesis of a bactericidal
agent analogue were also demonstrated.
he triarylmethane motif is a privileged structure1 that is
Table 1. Optimization of Arylative Desulfonation of
Diphenylmethyl Phenyl Sulfone 1a with 2-Ethylthiophene 2a
a
2
Tfound in compounds with high biological activity and is a
key substructure in fluorescent organic materials3 and probes.4
To prepare triarylmethanes, a variety of chemical trans-
formations including Friedel−Crafts reactions,5 dehydroxyla-
tions of triarylmethanol derivatives,6 and transition-metal-
catalyzed cross-coupling reactions have been developed.7
Recently, we described a highly modular synthesis of triaryl-
methanes via a Pd-catalyzed sequential arylation of methyl
phenyl sulfone (Scheme 1).8 The key step in the sequence is a
unique C−SO2R bond activation, which is used to install the final
aryl group via a Pd-catalyzed coupling with arylboronic acids.
As an alternative strategy, we examined the use of mild Lewis
acid catalysts to couple sulfones with simple, nonfunctionalized
arenes. Although there have been two previous reports
describing the arylation of sulfones,9 substrate limitations in
these reports are significant. Herein, we describe a method for the
synthesis of a wide range of triarylmethanes from diarylmethyl
phenyl sulfones without the need for precious metals or specific
electronic requirements on the coupling partners. This method is
b
entry
acid catalyst (mol %)
temp (°C)
GC yield (%)
1
2
3
4
5
6
7
8
9
FeCl3·6H2O (10)
Mg(OTf)2 (10)
Zn(OTf)2 (10)
AgOTf (10)
80
80
80
80
80
80
80
60
120
80
80
80
8
<1
<1
28
36
49
Cu(OTf)2 (10)
In(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (5)
TfOH (10)
d
83 (79)
16
59
53
15
38
c
10
11
12
a
Conditions: 1a (1 equiv), 2a (3 equiv), acid catalyst, solvent (0.25
b
M), 12 h. GC yield was determined using dodecane as an internal
standard. 2 equiv of 2a was used. Isolated yield.
c
d
Scheme 1. Synthesis of Triarymethanes and Derivatives via
Pd-Catalyzed Sequential Arylation and Transformation
illustrated in the preparation of a derivative of an antimyco-
bacterial compound.
We began by screening various Lewis acid catalysts for the
arylative desulfonation of diphenylmethyl phenyl sulfone 1a,
using 2-ethylthiophene 2a as the arylation partner (Table 1).
Transition metal catalysts, such as FeCl3·6H2O, which were
reported by Kim in a related transformation,9b gave the desired
product 3aa in only 8% yield using 10% catalyst (entry 1). To
find more effective catalysts, we focused on triflate salts. Although
Received: March 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00744
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Letter
Chart 1. Scope of Arylative Desulfonation of 1a with Electron-
Rich Heteroarenes and Arenes
Scheme 2. Derivatization of 3dd
a
10). TfOH, which could be generated from Sc(OTf)3 with trace
amounts of water, showed a lower yield, suggesting that this
reaction is accelerated by the scandium cation (entry 12).
With optimized conditions in hand, we examined the scope of
the arylative desulfonation of diphenylmethyl phenyl sulfone
with various heteroarenes and arenes (Chart 1). 2-Substituted
thiophenes such as 2-phenyl-, 2-chloro-, and 2-bromothiophene
selectively reacted at the 5 position to give the corresponding
products in good yields. When nonsubstituted thiophene was
used, a mixture of mono- and dibenzhydrylated products was
formed (see Supporting Information). Triarylmethanes bearing
2,5-dimethylated-3-furyl and 1-tosyl-3-pyrrolyl groups were
obtained in moderate yield. Benzo[b]thiophene and 2,3-
benzofuran reacted smoothly at the 2 position, while N-
tosylindole reacted at the 3 position. Electron-rich benzenes
were also reactive. For example, the reaction with 1,3,5-
trimethoxybenzene afforded product in good yield, and the
reaction of anisole gave products as a 10:1 mixture of p- and o-
a
Conditions: 1a (1 equiv), 2 (3 equiv), Sc(OTf)3 (10 mol %), DCE
b
(0.25 M), 80 °C, 12 h. Yield was p-isomer; p-isomer/o-isomer = 10:1
(determined by H NMR). Reaction was conducted in benzene at
100 °C.
c
1
Mg(OTf)2 and Zn(OTf)2 showed poor reactivity (entries 2 and
3), AgOTf, Cu(OTf)2, and In(OTf)3 afforded the desired
product in moderate yields (entries 4−6), and Sc(OTf)3
emerged as the best catalyst (entry 7).10 When the reaction
was performed by varying the reaction temperature or using 2
equiv of 2a, the yield was not improved (compare entries 7 and
a
Chart 2. Synthesis of Nonsymmetric Triarylmethanes
a
Conditions: 1 (1 equiv), 2 (3 equiv), Sc(OTf)3 (10 mol %), DCE (0.25 M), 80 °C, 12 h.
B
DOI: 10.1021/acs.orglett.6b00744
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Letter
electron-withdrawing p-trifluoromethyl group reacted smoothly
when paired with a methoxy group on another aryl ring.
Remarkably, sulfones bearing bulky aryl groups such as o-tolyl
and mesityl groups also reacted in good yield. A decrease in
reactivity was observed relative to unhindered substrates, but
these substrates illustrate the high utility of this reaction for the
synthesis of diverse, even sterically hindered, triarylmethanes.
Another significant advantage of the Sc-catalyzed method is
that haloarenes can be employed in either partner without
reaction at the halide. These substrates would lead to complex
mixtures in Pd-catalyzed routes, and their inclusion in the
triarylmethane products provides valuable opportunities for
iterative coupling. Compounds 3dd, 3ec, 3fn, and 3ha are all
capable of undergoing a second metal-catalyzed coupling
reaction. To illustrate this concept, 3dd was subjected to Pd-
catalyzed Suzuki−Miyaura arylation with p-tolylboronic acid,
yielding 4. Buchwald−Hartwig amination with N-methylaniline
was successful, yielding 5, and cyanation with Zn(CN)2 yielded 6
(Scheme 2). In addition, a unique 2,2′-bithiophene-bridged
triarylmethane 7 was obtained by NiCl2(dppp)-catalyzed
dimerization of 3dd in the presence of stoichiometric
magnesium.
Scheme 3. Pd- and Sc-Catalyzed Selective Synthesis of
Regioisomers
a
Condition: 8q or 8g (2 equiv), 5 mol % of [PdCl(allyl)]2, 10 mol %
of SlPr·HCl, 3 equiv of NaOH, dioxane/H2O = 5:3, 150 °C, 12 h.
b
Condition: 2g (3 equiv), 10 mol % of Sc(OTf)3, DCE, 80 °C, 12 h.
Scheme 4. Synthesis of Bactericidal Agent Analogue 10
An added feature of the Sc-catalyzed method is that it can also
provide access to compounds inaccessible using our previously
developed Pd-catalyzed method.8 For example, while the
reaction of 1a with benzo[b]thiophene-3-boronic acid 8q
afforded C3 product 3aq in 50% yield, coupling with isomeric
boronic acid 8g gives less than 5% yield, most likely due to rapid
protodeborylation of 8g. However, as described in Scheme 3, the
Sc-catalyzed reaction of 1a with 2g selectively affords 3ag in 66%
yield, illustrating the power of this complementary approach to
the concise synthesis of triarylmethanes.
Finally, we illustrated the utility of this approach in the
synthesis of a bactericidal agent analogue. The Srivastava group
discovered that triarylmethanes such as 9 bearing a 2-thienyl
group showed antimycobacterial activity in vitro and in vivo
against M. tuberculosis, M. fortuitum, and other nontubercular
mycobacteria.11 Thus, modification of 9 focusing on the
thiophene ring would be an attractive method to investigate
structure−activity relationships and find more potent analogues.
As shown in Scheme 4, (p-fluorophenyl)(p-methoxyphenyl)-
methyl phenyl sulfone 1l can be prepared from methyl phenyl
sulfone through two stepwise Pd-catalyzed C−H arylations.
Subsequent reaction with thiophene 2a gave triarylmethane 3la
in 69% yield. Demethylation with BCl3/(n-Bu)4NI followed by
alkylation afforded 10 in 51% yield over the two steps. Based on
this simple procedure, a wide variety of biologically active
triarylmethanes should be accessible.
In conclusion, we have established a general and easily
accomplished Sc-catalyzed arylative desulfonation of diary-
lmethyl phenyl sulfones employing a variety of heteroarenes
and arenes. This method can provide a wide variety of
triarylmethanes, including those that are inaccessible by Pd-
catalyzed reactions alone or which require sensitive aryl boronic
acids. Several applications of this reaction were demonstrated by
further transformations using transition metal catalysts and the
synthesis of an antitubercular agent analogue. Further inves-
tigation of other transformations based on catalytic C−SO2 bond
activation and syntheses of biologically active triarylmethanes is
currently underway.
regioisomers. Triphenylmethane 3al was obtained when benzene
was used as a solvent. p-Substituted phenols proved to be useful
substrates, yielding the corresponding triarylmethanes bearing
unprotected o-hydroxy groups in good yields. Interestingly,
triarylamine and pyrene, which are widely used for organic
electronic materials, could be installed, albeit with lower
efficiency.
Next, we applied this reaction to the synthesis of non-
symmetric triarylmethanes using diarylmethyl phenyl sulfones as
the starting materials. Representative results are shown in Chart
2. Electronically and structurally diverse triarylmethanes could be
prepared in moderate to excellent yields. Substituents on the aryl
group in sulfone substrates were not confined to electron-
donating groups, with groups such as p-methyl, -fluoro, -chloro,
and -bromo being well-tolerated. Even a sulfone bearing an
C
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Letter
B.-S.; Morgan, C.; Huang, R.; Yang, X.; Walsh, P. J. Chem. Sci. 2016, 7,
611−618.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00744.
■
S
(8) Nambo, M.; Crudden, C. M. Angew. Chem., Int. Ed. 2014, 53, 742−
746.
(9) (a) Thirupathi, P.; Kim, S. S. J. Org. Chem. 2009, 74, 7755−7761.
(b) Thirupathi, P.; Kim, S. S. Eur. J. Org. Chem. 2010, 2010, 1798−1808.
(10) Selected recent examples of Sc(OTf)3-catalyzed reactions:
Experimental procedures and characterization data (PDF)
(a) Rivero, A. R.; Fernan
J. Org. Chem. 2015, 80, 1207−1213. (b) Kucin
́
dez, I.; Ramírez de Arellano, C.; Sierra, M. A.
AUTHOR INFORMATION
Corresponding Authors
́
́
■
Hreczycho, G. Adv. Synth. Catal. 2015, 357, 3936−3942. (c) Hajra, S.;
Maity, S.; Maity, R. Org. Lett. 2015, 17, 3430−3433. (d) Jadhav, S. D.;
Singh. J. Org. Chem. 2016, 81, 522−531.
*E-mail: mnambo@itbm.nagoya-u.ac.jp.
*E-mail: cruddenc@chem.queensu.ca.
Notes
(11) Kashyap, V. Kr.; Gupta, R. Kr.; Shrivastava, R.; Srivastava, B. S.;
Srivastava, R.; Parai, M. K.; Singh, P.; Bera, S.; Panda, G. J. Antimicrob.
Chemother. 2012, 67, 1188−1197.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by KAKENHI from JSPS (26810056 to
M.N.). M.N. thanks the Hattori Hokokai Foundation for
financial support. JSPS and NU are acknowledged for funding
of this research through The World Premier International
Research Center Initiative (WPI) program.
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