Modular synthesis of triarylmethanes through palladium-catalyzed sequential arylation of methyl phenyl sulfone

Article abstract of DOI:10.1002/anie.201307019

Triarylmethanes, which are valuable structures in materials, sensing and pharmaceuticals, have been synthesized starting from methyl phenyl sulfone as an inexpensive and readily available template. The three aryl groups were installed through two sequential palladium-catalyzed C-H arylation reactions, followed by an arylative desulfonation. This method provides a new synthetic approach to multisubstituted triarylmethanes using readily available haloarenes and aryl boronic acids, and is also valuable for the preparation of unexplored triarylmethane-based materials and pharmaceuticals. Unsymmetric triarylmethanes have been synthesized starting from methyl phenyl sulfone as an inexpensive and readily available template. The three aryl groups were installed through two sequential palladium-catalyzed C-H arylation reactions, followed by an arylative desulfonation. Copyright

Full text of DOI:10.1002/anie.201307019

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DOI: 10.1002/anie.201307019
Palladium Catalysis
Modular Synthesis of Triarylmethanes through Palladium-Catalyzed
Sequential Arylation of Methyl Phenyl Sulfone**
Masakazu Nambo* and Cathleen M. Crudden*
Abstract: Triarylmethanes, which are valuable structures in
materials, sensing and pharmaceuticals, have been synthesized
starting from methyl phenyl sulfone as an inexpensive and
readily available template. The three aryl groups were installed
À
through two sequential palladium-catalyzed C H arylation
reactions, followed by an arylative desulfonation. This method
provides a new synthetic approach to multisubstituted triaryl-
methanes using readily available haloarenes and aryl boronic
acids, and is also valuable for the preparation of unexplored
triarylmethane-based materials and pharmaceuticals.
Scheme 1. Synthesis of triarylmethanes through Pd-catalyzed sequen-
tial arylations.
À
stepwise C H arylation reactions are followed by a simulta-
The synthesis of triarylmethanes and related structures has
neous,
Pd-catalyzed
desulfonation/arylation
process
attracted much attention in the area of medicinal chemistry
and materials science.[1] Indeed, the triarylmethane motif is
ubiquitous in dyes,[1a,2] fluorescent probes,[3] natural prod-
ucts,[4] and biologically active compounds.[5] Although the
Friedel–Crafts reaction is a simple and widely employed
method for the construction of triarylmethane structures,[6]
this reaction is only applicable to nucleophilic and electron-
rich arenes and often results in the formation of undesired
regioisomers. The reductive dehydroxylation of triarylmetha-
nol derivatives is another common method for the multi-step
synthesis of triarylmethanes.[7] Recently, a few transition-
metal-catalyzed routes have been developed that begin to
address these shortcomings.[8,9] Complementary to these
methods that require prefunctionalization for the preparation
of suitable coupling partners to promote these catalytic
reactions, we report a new method that employs methyl
phenyl sulfone as a simple and readily available starting
material for the synthesis of triarylmethanes. Three sequential
catalytic arylations are employed to transform methyl phenyl
sulfone into valuable triarylmethane products. The present
method involves two types of catalytic transformations: Two
(Scheme 1).
To accomplish the modular synthesis of triarylmethanes
with sufficient generality, we focused on the unique properties
of the sulfonyl group: Its electron-withdrawing character
dramatically increases the acidity of the protons that are
attached to the sp3-hybridized carbon atom in the a-position
of the SO2 group,[10] and this functional group simultaneously
has the potential to behave as a leaving group for organic
reactions.[11] Inspired by recent progress in Pd-catalyzed
3
arylation of acidic C(sp ) H bonds[8e–i,12] and aryl substitution
À
of alkyl electrophiles,[7a–b] we envisioned that these reactions
could be used to accomplish the direct installation of three
aryl groups on the a-carbon atom of the sulfonyl group, which
results in a modular straightforward synthesis of triaryl-
methanes from readily available building blocks.
Building on the pioneering work of Zhou et al.[12f] and
Walsh and co-workers,[13] we chose methyl phenyl sulfone as
our building block for the synthesis of triarylmethanes
because of the high acidity of the protons at the a-position
of the sulfone (pKa ꢀ 29 in DMSO).[10a] For the first arylation,
we focused on the mono-selective arylation of methyl phenyl
sulfone, with the considerable challenge that after arylation,
the a-protons are significantly more acidic, which can lead to
the formation of undesired diarylated products. The use of
Pd(OAc)2 and XPhos[14] as the catalyst precursors resulted in
exclusive mono-arylation, which is crucial for the introduction
of three different aryl groups and the synthesis of unsym-
metric triarylmethanes (Table 1).
[*] Dr. M. Nambo, Dr. C. M. Crudden
Institute of Transformative Bio-Molecules (WPI-ITbM)
Nagoya University
Nagoya 464-8602 (Japan)
E-mail: mnambo@itbm.nagoya-u.ac.jp
Dr. C. M. Crudden
Department of Chemistry, Queen’s University
90 Bader Lane, Kingston, Ontario, K7L 3N6 (Canada)
E-mail: cruddenc@chem.queensu.ca
Several key features of this reaction can be seen in
Table 1. First, as observed by Walsh and co-workers,[13]
whereas lithium and sodium bases effectively promoted the
reaction, no product was observed when KOtBu was
employed (entries 3–5). This could be ascribed to a counterion
effect on the transmetalation of the sulfone enolate to
palladium.[15] Second, the most selective and highest yielding
transformation was observed when XPhos (L5) was employed
as the ligand for palladium. In this case, the desired product
was obtained in 92%, and the diarylated product was not
[**] Dr. Shohei Saito is thanked for assistance with X-ray crystal-
structure analysis. JSPS and Nagoya University are acknowledged
for funding of this research through the WPI program. We thank Dr.
Kenichiro Itami for valuable suggestions.
Supporting information for this article, including experimental
procedures, characterization data for all arylation products, and the
CIF file of 6hhh, is available on the WWW under http://dx.doi.org/
10.1002/anie.201307019.
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[a]
À
À
Table 1: Optimization of the first C H arylation of methyl sulfone.
Table 2: Scope of the Pd-catalyzed C H arylation of methyl phenyl
sulfone with bromoarenes.[a]
Entry
x:y
Ligand
Base
Solvent
2a[b] [%]
4aa[b] [%]
Entry
Ar1
2
Yield[b] [%]
1
2
3
4
5
6
7
8
1:2
2:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
LiOtBu
LiOtBu
LiOtBu
NaOtBu
KOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
CPME
CPME
CPME
CPME
CPME
dioxane
toluene
DMF
CPME
CPME
CPME
CPME
CPME
72
61
68
54
<1
39
37
<1
57
84
70
92
79
5
3
2
1
<1
6
1
2
3
4
5
6
C6H5 (1a)
2a
2b
2c
2d
2e
2 f
86
78
74
70
82
56
79
34
p-MeC6H4 (1b)
p-MeOC6H4 (1c)
p-BnOC6H4 (1d)
p-FC6H4 (1e)
p-CF3C6H4 (1 f)
1-naphthyl (1g)
3-thienyl (1h)
2
7
2g
2h
<1
<1
2
4
<1
<1
8[c]
9
[a] Conditions: methyl phenyl sulfone (3 equiv), Ar1Br (1 equiv),
Pd(OAc)2 (10 mol%), XPhos (20 mol%), LiOtBu (3 equiv), CPME
(0.15m), 1208C, 12 h. [b] Yields of isolated products. [c] Reaction time:
24 h. Bn=benzyl.
10
11
12
13
[a] Conditions: methyl phenyl sulfone, PhBr, Pd(OAc)2 (10 mol%), ligand
(20 mol%), base (3 equiv), solvent (0.15m), 1208C, 12 h. [b] Determined
by GC analysis using dodecane as the internal standard. CPME=cyclo-
pentyl methyl ether.
À
Table 3: Scope of the Pd-catalyzed C H arylation of mono-arylated
sulfones with iodoarenes.[a]
Entry
Ar1
Ar2
4
Yield[b] [%]
1[c]
2
3
4
5
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
C6H5 (3a)
4aa
4ac
4ae
4ba
4cc
4dc
4eb
4 fa
4 ff
82
68
46
83
75
66
78
86
47
79
42
30
p-MeOC6H4 (3c)
p-FC6H4 (3e)
C6H5 (3a)
p-MeOC6H4 (3c)
p-MeOC6H4 (3c)
p-MeC6H4 (3b)
C6H5 (3a)
p-CF3C6H4 (3 f)
C6H5 (3a)
C6H5 (3a)
observed.[16] When an even bulkier ligand, namely tBuXPhos
(L6), was employed, the diarylated product was not observed,
but the yield of the desired product also decreased. These
results corroborate that steric factors control the degree of
arylation, with more sterically hindered ligands preventing
the second arylation. Consistent with this, when product 2a
was re-exposed to the reaction conditions of the first
arylation, only 15% of the diarylated product 4aa was
observed after twelve hours of reaction (Supporting Infor-
mation, Table S1, entry 2).
With reasonable conditions in hand for the mono-
selective reaction between methyl phenyl sulfone and bro-
mobenzene, we examined the scope of this reaction (Table 2).
Bromoarenes that bear electron-donating (entries 2–4) or
electron-withdrawing groups (entries 5 and 6) all reacted to
afford the corresponding mono-arylated products in good
yield. Sterically hindered substrates, such as 1-bromonaph-
thalene (1g), also reacted efficiently (entry 7). Furthermore,
heteroaromatic substrates, such as 3-bromothiophene, were
also converted into the corresponding products, albeit in
lower yields (entry 8).
p-MeC6H4 (2b)
p-MeOC6H4 (2c)
p-BnOC6H4 (2d)
p-FC6H4 (2e)
p-CF3C6H4 (2 f)
p-CF3C6H4 (2 f)
1-naphthyl (2g)
3-thienyl (2h)
3-thienyl (2h)
6
7
8[d]
9
10[c]
11
12[e]
4ga
4ha
4hh
3-thienyl (3h)
[a] Conditions: mono-arylated sulfone (1 equiv), Ar2I (1.5 equiv),
[{PdCl(allyl)}2] (5 mol%), P(tBu)3·HBF4 (20 mol%), KOtBu (3 equiv),
dioxane (0.19m), 808C, 12 h. [b] Yields of isolated products. [c] Reaction
time: 12 h. [d] Reaction conducted at 608C. [e] Reaction conducted at
1208C with Ar2I (3 equiv).
phenyl sulfone (2a) with iodobenzene (3a) at 808C in dioxane
using P(tBu)3 as the ligand and KOtBu as the base.[18]
Under these optimized reaction conditions, the second
arylation could be carried out with a considerable variety of
iodoarenes (Table 3). Electron-neutral or electron-rich aryl
iodides, such as phenyl (3a), p-tolyl (3b), or p-anisyl iodide
(3c), yielded the corresponding diarylmethyl phenyl sulfones
in good yields (entries 1, 2, 4–7). On the other hand, para-
fluoro- and p-trifluoromethyl-substituted iodobenzenes (3e
and 3 f) gave the desired products in lower yields (entries 3
and 9). However, this differential reactivity was not problem-
atic, as electron-withdrawing groups were well tolerated on
the sulfone component. For example, para-(trifluoromethyl)-
À
Next, we investigated the C H arylation of mono-arylated
methyl sulfones with aryl halides (2nd arylation). Similar
À
sulfone derivatives have been employed in Pd-catalyzed C H
arylations with aryl halides by the groups of Yorimitsu,
Oshima,[17] and Walsh.[13] Building on these results, we focused
on the effect of base, ligand, and solvent, and were ultimately
À
able to effect the Pd-catalyzed C H arylation of benzyl
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benzyl phenyl sulfone (2 f) reacted with iodobenzene (3a) in
high yield at 608C (entry 8). The increase in reactivity could
(3.0 equiv). Under these conditions, the desired product was
obtained in 49% yield (entry 7). Whereas the use of K3PO4 as
a mild base showed similar reactivity (entry 8), replacement
of SIPr with other NHC ligands, such as IMes, ICy, and IAd,
resulted in lower reactivity (entries 9–11).
The use of aqueous solutions of NaOH was also effective
(entry 12), and the yield of the product was improved to 93%
when the reaction was conducted at higher concentrations
(entry 13). With this system, we successfully reduced the
amount of 5b without loss of reactivity (92%, entry 14).
Commercially available Pd NHC complexes, such as PEPPSI-
IPr,[20] showed similar reactivity (entry 15). The pinacol ester
of p-tolylboronic acid also gave the arylated product in
excellent yield (entry 16).[21]
À
arise from the higher acidity of the C H bond in 2e. The
phenylation of sterically hindered 1-naphthylmethyl phenyl
sulfone (2g) provided the product in high yield (entry 10).
3-Thienylmethyl phenyl sulfone (2h) was also reactive, but
the products were formed in lower yields (entries 11 and 12).
The final challenge that remained to complete our
synthesis of triarylmethanes, namely conversion of the
À
À
C SO2Ph moiety into a C Ar group with complete regiose-
lectivity, had very little precedent.[19] Arylboron compounds,
which are air-stable, shelf-stable, functional-group-compat-
ible, and commercially available compounds, were our first
choice as a nucleophile. To rule out the possibility that Pd-
catalyzed desulfonylative arylation of diarylmethyl phenyl
sulfones may lead to diarylphenylmethenes, p-tolylboronic
acid (5b) was selected as a coupling partner (Table 4). In early
experiments, it was found that the use of typical phosphine
(monodentate and bidentate) and amine ligands did not give
the desired arylation product (entries 1–6). Our first “hit”
came with the use of the N-heterocyclic carbene SIPr, which
was employed as its HCl salt in the presence of LiOtBu
With optimized conditions in hand, the variation of the
aryl boronic acid in the arylation of 4aa was assessed
(Table 5). The reaction took place with electronically and
Table 5: Scope of the arylation of 4aa with aryl boronic acid 5.[a]
Table 4: Optimization of the Pd-catalyzed arylation of 4aa with p-
tolylboronic acid (5b).[a]
Entry
Ar3
6
Yield[b] [%]
1
2
3
4
C6H5 (5a)
6aaa
6aab
6aac
6aai
6aae
6aaf
6aaj
6aak
6aal
6aah
6aam
6aan
90
85
92
88
89
83
80
82
60
70
52
45
p-MeC6H4 (5b)
p-MeOC6H4 (5c)
p-Me2NC6H4 (5i)
p-FC6H4 (5e)
p-CF3C6H4 (5 f)
p-TMSC6H4 (5j)
p-AcC6H4 (5k)
o-MeC6H4 (5l)
3-thienyl (5h)
3-furyl (5m)
5
6[c]
7
Entry Ligand (mol%)
Base
Solvent
6aab[b] [%]
8
1
2
3
4
5
6
7
8
PPh3 (20)
XPhos (20)
P(tBu)3·HBF4 (20) LiOtBu dioxane
dppe (10)
LiOtBu dioxane
LiOtBu dioxane
<1%
<1%
<1%
<1%
<1%
<1%
49%
46%
23%
8%
<1%
69%
9[c,d]
10[c]
11[c]
12[c]
LiOtBu dioxane
LiOtBu dioxane
LiOtBu dioxane
LiOtBu dioxane
K3PO4 dioxane
K3PO4 dioxane
K3PO4 dioxane
K3PO4 dioxane
3-pyridyl (5n)
dppf (10)
[a] Conditions: 4aa (1 equiv), 5 (2 equiv), [{PdCl(allyl)}2] (5 mol%),
SIPr·HCl (10 mol%), NaOH (3 equiv), dioxane/H2O=5:3, 1208C, 12 h.
[b] Yields of isolated products. [c] Reaction conducted at 1508C.
[d] PEPPSI-IPr (10 mol%) was used as the catalyst. TMS=trimethylsilyl.
2,2’-bpy (10)
SIPr·HCl (10)
SIPr·HCl (10)
IMes·HCl (10)
ICy·HBF4 (10)
IAd·HBF4 (10)
SIPr·HCl (10)
SIPr·HCl (10)
9
10
11
12
13[c]
NaOH dioxane/H2O=10:3
NaOH dioxane/H2O=5:3
NaOH dioxane/H2O=5:3
93%
structurally diverse aryl boronic acids, with high yields in
almost all cases. Aryl boronic acids with an electron-donating
group, such as p-methyl, p-methoxy, or p-N,N-dimethylamino,
all reacted in high yield. Although the electron-poor para-
(trifluoromethyl)phenylboronic acid (5e) showed lower reac-
tivity under standard conditions, simply increasing the
temperature by 308C gave the desired product in good yield
(entry 6). Functional groups, such as trimethylsilyl and acetyl,
were well tolerated (entries 7, 8). The reaction with bulky
ortho-tolylboronic acid (5l) was improved by the use of
PEPPSI-IPr as the catalyst (entry 9). Notably, heteroaryl
moieties, such as 3-thienyl, 3-furyl, and 3-pyridyl substituents,
could also be installed in good to moderate yields (entries 10–
12).
14[c,d] SIPr·HCl (10)
92%
(85%)[e]
91%
15[c,d] PEPPSI-IPr
NaOH dioxane/H2O=5:3
NaOH dioxane/H2O=5:3
16[c,d,f] SIPr·HCl (10)
93%
[a] Conditions: 4aa (1 equiv), 5b (3 equiv), [{PdCl(allyl)}2] (10 mol%),
ligand, base (3 equiv), solvent (0.1m), 1208C, 12 h. [b] Yield determined
by GC analysis using dodecane as the internal standard. [c] Concen-
tration: 0.13m. [d] 5b (2 equiv). [e] Yield of isolated product given in
parentheses. [f] The pinacol ester of p-tolylboronic acid (2 equiv) was
used. 2,2’-bpy=2,2’-bipyridine, dppe=1,2-bis(diphenylphosphino)-
ethane, dppf=diphenylphosphinoferrocene, IAd=1,3-di(adamantyl)
imidazol-2-ylidene, ICy=N,N’-(dicyclohexyl) imidazol-2-ylidene,
IMes=1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene, SIPr=N,N’-
bis(2,6-(diisopropyl)phenyl)imidazolin-2-ylidine, PEPPSI-IPr=[1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palla-
dium(II) dichloride, XPhos=2-dicyclohexylphosphino-2’,4’,6’-triisopro-
pylbiphenyl.
After the third arylation had been demonstrated with
diphenyl substrate 4aa, we examined the synthesis of
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Scheme 3. Synthesis of anti-breast-cancer agent 7.
In summary, we have shown that a variety of triaryl-
À
methanes can be synthesized by Pd-catalyzed C H arylation
followed by arylative desulfonylation. This method does not
only provide a new synthetic approach to multisubstituted
triarylmethanes starting from readily available haloarenes
and aryl boronic acids, but is also applicable to the prepara-
tion of unexplored triarylmethane-based materials and phar-
maceuticals. During this study, we have developed a unique
Pd-catalyzed substitution of the sulfonyl group with an aryl
moiety, which could become a more general carbon–carbon
bond-forming reaction. Investigations of the mechanism and
the applicability of this reaction towards the syntheses of
biologically active molecules are currently ongoing in our
laboratory.
Scheme 2. Synthesis of unsymmetric triarylmethanes by Pd-catalyzed
arylative desulfonylation. Conditions: 4 (1 equiv), 5 (2 equiv),
[{PdCl(allyl)}2] (5 mol%), SIPr·HCl (10 mol%), NaOH (3 equiv), diox-
ane/H2O=5:3, 1208C, 12 h. [a] Reaction conducted at 1508C.
[b] PEPPSI-IPr (10%) was used as the catalyst.
Received: August 9, 2013
Revised: October 10, 2013
Published online: December 4, 2013
unsymmetric triarylmethanes (Scheme 2). Electronically and
structurally diverse triarylmethanes can be prepared in good
to excellent yields using this simple and straightforward
procedure. Importantly, triarylmethanes that possess thienyl,
furyl, or pyridyl groups, which are difficult to install using
typical Friedel–Crafts reaction conditions, were readily pre-
pared. The structure of tris(3-thienyl)methane 6hhh was
confirmed by single-crystal X-ray diffraction analysis (for
details, see the Supporting Information).
The utility of this method was demonstrated by the
concise synthesis of an anti-breast-cancer agent (7;
Scheme 3).[22] The reaction of (para-benzyloxyphenyl)(para-
methoxyphenyl)methyl phenyl sulfone (4dc) with 9-phenan-
threneboronic acid (5o) gave triarylmethane 6dco in 90%
yield. Removal of the benzyl group followed by alkylation
gave 7 in 87% yield. Overall, compound 7 was obtained in
36% yield from 1d in five steps. This result indicates that this
method can provide facile access to biologically active
compounds and can be employed to generate unique
chemical libraries that are based on triarylmethanes for the
screening of biologically active compounds.
À
Keywords: C H activation · N-heterocyclic carbenes ·
palladium · sulfones · Suzuki–Miyaura coupling
.
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À
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The reaction is sensitive to heat; when the reaction was
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À
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assist the elimination of the sulfonyl group. The reaction that we
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mechanism.
À
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converted, and 19% of 4,4’-dimethylbiphenyl (derived from
ArB(OH)2) was observed by GC even under optimized con-
ditions.
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746
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