Development of Versatile Sulfone Electrophiles for Suzuki-Miyaura Cross-Coupling Reactions

Article abstract of DOI:10.1021/acscatal.6b03434

The development of fluorinated sulfone derivatives as versatile electrophiles for Suzuki-Miyaura cross-coupling reactions is described. Introducing electron-withdrawing groups on the aryl ring of the sulfone facilitates the Pd-catalyzed activation of C-SO₂ bonds. Cross-coupling reactions with fluorinated sulfone electrophiles are reported, leading to a variety of multiply arylated products in good yields. The reactivity of this unusual electrophile is benchmarked versus common electrophiles and its use in iterative cross-couplings for concise synthesis of biologically active molecules is described.

Full text of DOI:10.1021/acscatal.6b03434

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Letter
Development of Versatile Sulfone Electrophiles
for Suzuki-Miyaura Cross-Coupling Reactions
Masakazu Nambo, Eric C Keske, Jason Peter Gregory Rygus, Jacky C.H. Yim, and Cathleen M. Crudden
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b03434 • Publication Date (Web): 19 Dec 2016
Downloaded from http://pubs.acs.org on December 20, 2016
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Development of Versatile Sulfone Electrophiles for Suzuki-Miyaura
Cross-Coupling Reactions
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Masakazu Nambo*1, Eric C. Keske2, Jason P. G. Rygus2, Jacky C.-H. Yim1, and Cathleen M. Crud-
den*1,2
1Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya, Japan; 2Queen's University,
Department of Chemistry, Chernoff Hall, Kingston, Ontario, Canada
KEYWORDS: Sulfone, Suzuki-Miyaura Cross-Coupling, C–SO2 Activation, Palladium Catalysis, Iterative Coupling.
ABSTRACT: The development of fluorinated sulfone derivatives as versatile
electrophiles for Suzuki-Miyaura cross coupling reactions is described. Intro-
ducing electron withdrawing groups on the aryl ring of the sulfone facilitates
the Pd-catalyzed activation of C–SO2 bonds. Cross coupling reactions with
fluorinated sulfone electrophiles are reported leading to a variety of multiply
arylated products in good yields. The reactivity of this unusual electrophile is
benchmarked vs. common electrophiles and its use in iterative cross-cou-
plings for concise synthesis of biologically active molecules is described.
Directing groups capable of influencing local reactivity are
essential in modern organic synthesis.1 In order to be truly
useful, directing groups need to be readily removed or
transformed, a feat that is often the weakest point in a
synthetic method. The sulfone is an interesting functional
group that permits the rapid functionalization of adjacent
positions via deprotonation/alkylation, arylation or conjugate
addition reactions.2 However, after these reactions, removal
of the sulfonyl group using Na amalgam or other highly
reducing conditions is virtually the only choice (Figure 1).3
Therefore the development of methods to introduce
functional groups in place of the sulfone will provide
tremendous opportunities for facile access to complex
side with traditional electrophiles, providing alternative
avenues for iterative couplings.7 Unlike benzylic halides,
benzylic sulfones have low toxicity, are easily handled, and
can be carried through multiple transformations.
Figure 1. Transition metal-catalyzed desulfonative cross-
4
molecules.2a, Recently, our group reported preliminary
studies on the use of the sulfone as an electrophile in cross-
coupling reactions directed towards the modular synthesis of
triarylmethanes.5
Despite the significance of this desulfonative coupling
approach,4d the reaction required high reaction temperatures
and was only effective with highly activated doubly benzylic
sulfones. These two limitations are likely caused by the
inherently low reactivity of the C–SO2 bond. In particular, the
lack of reactivity outside the benzhydryl substrate class does
not bode well for the use of the sulfone as a general
electrophile in cross-coupling chemistry. Herein we describe
fluorinated sulfone electrophiles that can be employed in
cross coupling of a variety of substrates (Figure 1). These
rationally designed sulfones participate in iterative couplings
with high selectivity, enabling the efficient synthesis of
multiply-arylated alkanes6 at temperatures as low as 40 °C.
The versatile sulfone electrophile can be employed side-by-
coupling for the synthesis of multiply arylated methanes.
We began our studies with benzyl phenyl sulfone 1a, a
simple substrate that gives very low yields with simple phenyl
sulfones as the coupling partners. Even at temperatures up to
150 °C yields were unacceptably low (Table 1, entries 1, 2). We
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hypothesized that the introduction of electron-withdrawing
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groups on the sulfone would increase its eletrophilicity and
facilitate metal-catalyzed C–SO2 bond activation by
stabilizing the sulfinic acid anion equivalent generated during
C–SO2 bond activation. Indeed, sulfones bearing electron-
deficient substituents such as p-fluorophenyl, pyridyl, and p-
trifluoromethylphenyl groups gave the desired product in
significantly higher yield (Table 1, entries 3-5, 7). Although the
pentafluorophenyl group was not effective (entry 8), 3,5-
bis(trifluoromethyl)phenyl sulfone 2a showed high reactivity
(entries 9-11). A simple trifluoromethyl group as in triflone 3a
also proved highly successful, giving the desired product in
91% yield (entry 12).
Table 2. Pd-catalyzed α-arylation of sulfone template 1 with
bromoarenes 7.
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Table 1. Investigation of substituent effect for desulfonative
arylation and optimization of reaction conditions.
lones 3 were reacted with various arylboronic acids to give the
desired coupling products in good to excellent yields.
Heteroarylboronic acids were less reactive, but at 5% catalyst
loading, yields of 62-90% were routinely obtained. Electron-
rich (5cb) and electron-deficient functional groups were
tolerated in both partners (5gc). Esters (5ia), phenols (5jn),
heteroaromatics (5ko, 5os and 5pt), primary amides (5os) and
π-extended groups (6lp) all gave the desired products in good
yields. Bulky mesityl groups presented little problem (5mq),
even in both partners, although in this case, reduced yields
were observed (5mr).
Fluorinated sulfone electrophiles can be readily prepared
from ,methyl aryl sulfone 6, which is itself an air stable
solidthat is easily prepared from simple starting materials on
a multi-gram scale without chromatographic purification
(Scheme 1).8 Starting from compound 6, a variety of benzyla
ted sulfones 2 can be prepared in good yields, without any
double arylation (Table 2).9 The reaction was compatible with
important functional groups including ketone, ester, and
amide groups. Bulky aryl groups such as 2-methoxyphenyl, 1-
naphthyl, and mesityl groups were installed efficiently, and
heteroaryl bromides afforded arylation products in good
yields.
Having demonstrated that fluorinated sulfones serve as
competent electrophiles in Suzuki-Miyaura cross couplings,
we then sought to determine whether the arylation and
coupling sequence could be accomplished in one-pot. In the
event, N- MOM-5-bromoindole 7n and p-benzyloxyphenyl-
boronic acid 4u were sequentially reacted with 6 in the pres-
ence of Pd catalysts to afford the desired product 5nu in 71%
yield, in one-pot, on gram scale (Scheme 2).
Scheme 2. One-pot gram-scale synthesis of unsymmetric
diarylmethane 5nu (RF = 3,5-(CF3)2C6H3).
Scheme 1. Gram-scale synthesis of 6.
The use of these more highly functional fluorinated sulfones
in the Suzuki-Miyaura coupling reaction was then examined
(Table 3). Bis(trifluoromethyl)aryl sulfones 2 and trif-
Fluorinated sulfones 2 can also be used in the synthesis of
triarylmethanes under extremely mild conditions. Thus aryla-
tion of naphthyl derivative 2l with iodobenzene can be affect-
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Table 3. Pd-catalyzed desulfonative arylation of mono-arylated sulfones 2 and 3 with arylboronic acids 4.
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ed using only Cs2CO3 as base, and the resulting diarylmethyl
sulfone undergoes desulfonative coupling in excellent yield at
only 40 ºC (Scheme 3a). This demonstrates the higher activity
of the C–SO2 bond in fluorinated systems compared to simple
phenyl derivatives, which require 120 °C to undergo desul-
fonative coupling.5
halides underwent coupling when treated with simple triaryl
or trialkylphosphine-modified Pd catalysts, while sulfones
were unreactive under these conditions, requiring NHC–based
catalysts for C–SO2 bond activation. An important exception
to this is the use of bulky electron-rich phosphines such as
SPhos, which are able to promote the coupling of both halides
and sulfones (Supporting information). Since the latter
requires higher temperatures, we are able to effect the
sequential one-pot introduction of two different aryl groups
using the same charge of Pd and same ligand. Thus compound
10 could be produced by reaction of p-chlorobenzyl sulfone 2f
with two different boronic acids through merely a solvent
switch and increase in temperature (Scheme 4a). Product 10
is one step away from a selective CYP17 inhibitor, under study
for the treatment of prostate cancer.11 Dibenzylic substrate 2q
was reacted sequentially and in the same pot with p-
anisylboronic acid 4b and p-trifluoromethylphenyl-boronic
acid 4c to give unsymmetric 1,4-(diarylmethyl)benzene 11 in
75% yield (Scheme 4b).
Sulfones are known to acidify α-protons, which can also be
used to introduce isotopic labels prior to desulfonative
coupling. For example, when the reaction of 2h with p-
tolylboroxine was carried out in mixture of dioxane and D2O,
coupling product 9 was obtained along with complete
incorporation of deuterium at the benzylic position (Scheme
3b). Alternative methods for the preparation of deuterated
diarylmethanes require reaction of diarylketones with
expensive metal deuterides10a or H2/D2O in the presence of
metal catalysts10b and would not be compatible with the
ketone functionality present in 9 (Scheme 3b).
Scheme 3. Sequential α-functionalization and Pd-catalyzed
desulfonative arylations (RF = 3,5-(CF3)2C6H3).
Scheme 4. Application to one-pot iterative cross-coupling
reactions (RF = 3,5-(CF3)2C6H3).
To test the ability of the sulfone to participate in iterative
coupling reactions in substrates containing multiple
electrophiles, we prepared derivatives of 2 bearing aryl
chlorides, and benzylic bromides (Scheme 4). In all cases, the
Finally, the utility of this sequential desulfonative cross
coupling was demonstrated by the concise synthesis of the
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synthetic thyroid hormone receptor β-selective analog, GC-24
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as a potential agent for the treatment of obesity and
arteriosclerosis (Scheme 5).12 The Pd-catalyzed α-arylation of
6 with functionalized bromoarene 7r gave the corresponding
arylmethyl sulfone 2r, which was smoothly converted into
bromomethyl benzylsulfone 2s by the use of HBr in AcOH,
without any effect on the sulfonyl group. The sequential one-
pot cross-coupling of 2s with phenylboronic acid 4a and 4-
benzyloxy-2,6-dimethylphenylboronic acid 4v was then
carried out to give 1,3-diarylmethylbenzene 12 in 66% yield.
Removal of the benzyl group followed by alkylation provided
ester 13. Demethylation and basic hydrolysis furnished GC-
24. Overall, the synthesis of GC-24 was accomplished in 10
steps from commercially available materials in 42% yield. The
high modularity and easy accessibility of our method provides
enormous opportunities for the rapid discovery of potent
thyroid hormone mimics.
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AUTHOR INFORMATION
Corresponding Author
*mnambo@itbm.nagoya-u.ac.jp
*cruddenc@chem.queensu.ca
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This work was supported by KAKENHI from JSPS (26810056 to
M.N.). JSPS and NU are acknowledged for funding of this re-
search through The World Premier International Research Center
Initiative (WPI) program. The Natural Sciences and Engineering
Research Council of Canada (NSERC) is thanked for Discovery
Grant funding to CMC and scholarship funding to ECK and JPGR.
The Canada Foundation for Innovation (CFI) is thanked for infra-
structure funding and Queen's University is thanked for Queen's
Graduate Fellowships to ECK and JPGR.
Scheme 5. Short step synthesis of GC-24.
ABBREVIATIONS
SIPr⋅HCl, 1,3-Bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium
chloride; mCPBA, m-Chloroperbenzoic acid; XPhos, 2-(Dicyclo-
hexylphosphino)-2',4',6'-tri-i-propyl-1,1'-biphenyl; CPME, Cyclo-
pentyl methyl ether; Bz, Benzoyl; MOM, Methoxymethyl;
RuPhos,
2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-bi-
phenyl; SPhos, 2-Dicyclohexylphosphino-2',6'-dimethoxybi-
phenyl.
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In conclusion, we have demonstrated that fluorinated
sulfone derivatives are effective electrophiles for Pd-
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and selective synthesis of multiply-arylated methanes.
Structurally diverse arylmethanes have many potential
applications for organic materials and pharmaceuticals, and
can be obtained in a facile and modular manner using our
method. Most importantly, we have established a new
electrophile capable of activation through transition-metal
catalysts and compatible with diverse functionality.
Mechanistic investigations, theoretical calculation and the
development of other unique C–SO2 bond transformations
are currently underway in our laboratory.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS
Publications website
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Molander, G. A. Science, 2014, 345, 433–436. (b) Mondal, S.; Panda,
Experimental details and NMR spectra (PDF)
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