Palladium-Catalyzed Triarylation of sp3 C?H Bonds in Heteroarylmethanes: Synthesis of Triaryl(heteroaryl)methanes

Article abstract of DOI:10.1002/adsc.201701347

A straightforward method for the palladium-catalyzed triarylation of heteroarylmethanes at the methyl group has been developed. The reaction works with a variety of aryl halides, enabling the rapid synthesis of triaryl(heteroaryl)methanes in moderate to e

Full text of DOI:10.1002/adsc.201701347

Title: Palladium-Catalyzed Triarylation of sp3 C–H Bonds in
Heteroarylmethanes: Synthesis of Triaryl(heteroaryl)methanes
Authors: shuguang zhang, Bowen Hu, Zhipeng Zheng, and Patrick J.
Walsh
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10.1002/adsc.201701347
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Palladium-Catalyzed Triarylation of sp3 C–H Bonds in
Heteroarylmethanes: Synthesis of Triaryl(heteroaryl)methanes
Shuguang Zhang, b Bowen Hu,b Zhipeng Zhengb and Patrick J. Walsha,b*
a
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic
Innovation Center for Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing, 211816, People’s
Republic of China
b
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, Pennsylvania 19104-6323, United States
e-mail: pwalsh@sas.upenn.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A straightforward method for the palladium-
catalyzed triarylation of heteroarylmethanes at the methyl
group has been developed. The reaction works with a variety
of aryl halides, enabling the rapid synthesis of
triaryl(heteroaryl)methanes in moderate to excellent yields.
Keywords: palladium-catalyzed; aryl halides; triarylation;
tetraarylmethanes
Our research group has been interested in the catalytic
functionalization of weakly acidic sp3-hybridized C–H
bonds through deprotonative cross-coupling processes
(DCCP),[7] which are mechanistically similar to
carbonyl α-arylation reactions.[8] DCCP involve
weakly acidic substrates (pKa > 25) that are reversibly
deprotonated in the presence of the transition metal
catalyst and subsequently functionalized. Based on
this approach, we developed a palladium-catalyzed
DCCP for direct arylation of aryl(heteroaryl)methanes
and diaryl(heteroaryl)methanes with aryl chlorides
using palladium catalysts based on tricyclohexyl
phosphine (PCy3) or cataCXium A (Ad2P-n-Bu, Ad =
adamantyl)[9] to construct triaryl(heteroaryl)methanes
in good to excellent yields (Scheme 1f).[10]
General methods for the direct arylation of benzylic
methyl groups to construct tetraarylmethanes have not
been developed to our knowledge, although the
diarylation of benzylic methyl groups to form
triarylmethanes has been reported.[2e,11] Based on our
prior studies,[10] we hypothesized that DCCP of
benzylic methyl groups in the presence of a palladium
catalyst should provide tetraarylmethanes via a tandem
triarylation. The success of this process depends on
identifying a catalyst that is able to perform arylations
on 3 distinct coupling partners, as shown in Scheme 2.
Herein, we present a novel palladium catalyzed
triarylation of heteroaryl methyl groups for the
efficient synthesis of tetraarylmethane derivatives
(Scheme 2).
Introduction
Tetraarylmethanes, and related derivatives, are
ubiquitous building blocks and exhibit a wide range of
applications.[1] Their synthesis, therefore, has attracted
much attention. It is surprising, however, that
transition metal-catalyzed C–H functionalization
reactions, which are among the most versatile methods
in organic synthesis, have witnessed only limited
success in the synthesis of tetraarylmethanes.[2] We are
aware of only a few relevant examples: Yorimitsu,
Oshima and co-workers noted formation of 8% yield
of a tetraarylmethane (Scheme 1a).[3] Wu and Huang
(Scheme 1b and 1c) independently reported
palladium-catalyzed arylations of fluorene and
monoarylfluorene derivatives with aryl bromides for
the synthesis of diarylfluorenes.[4] Nambo and
Crudden outlined a sequential palladium-catalyzed
arylation to generate triarylacetonitrile products. The
triarylacetonitriles were subsequently transformed into
triaryl(heteroaryl)methanes in 45–57% yield (Scheme
1d).[5] Nishibayashi presented a copper-catalyzed
enantioselective propargylation of indoles with
propargylic esters to construct all carbon quaternary
stereocenters bearing an alkyne. Subsequent
derivatization of the terminal alkyne with phenylazide
generated enantioenriched all carbon substituted
tetraarylmethanes with 28% yield and 78% ee
(Scheme 1e).[6]
1
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10.1002/adsc.201701347
Advanced Synthesis & Catalysis
In light of the significance of heteroaryl groups in
medicinal chemistry and material science,[14] we
focused our studies on the coupling between 2-
methylbenzothiazole 1a and chlorobenzene 5a. We
initially examined the tandem triarylation reaction
under conditions we previously reported for
constructing triaryl(heteroaryl)methanes from benzyl-
substituted heterocycles using Pd(OAc)2, cataCXium
A (Ad2P-n-Bu), and NaOt-Bu in 1,4-dioxane for 12 h
o
at 100 C (Scheme 1f).[10] With 5.0 mol % Pd(OAc)2
and 10.0 mol % cataCXium A, the arylation of 2-
methylbenzothiazole (1a) with chlorobenzene led to
tetraarylmethane in 14% assay yield (AY) and
1
triarylmethane in 22% AY (AY determined by H
NMR analysis, Table 1, entry 1). With this promising
lead, we screened three additional bases (KOt-Bu,
LiHMDS and NaHMDS) under the same conditions.
Unfortunately, all three bases led to decomposition
products (entries 2–4). From our previous work[15] we
found that solvents play an important role in DCCP.
We, therefore, screened five additional solvents (DME,
THF, CPME, toluene and o-xylene) at 100° C with a
12 h reaction time. Among these, DME and THF
afforded 3 and 6% AY of triarylmethane, respectively
(entries 5 and 6). CPME, toluene and o-xylene
generated 11–23% AY of tetraarylmethane and 33–
62% AY of triarylmethane (entries 7–9).
The results in entries 7–9 suggest that the reactions had
o
not reached completion after 12 h at 100 C. The
temperature was, therefore, increased to 130 °C with
o-xylene solvent. We were pleased to find that after 12
h at the higher temperature the tetraarylmethane
product 4a was obtained in 96% AY (entry 10). When
the reaction time was reduced to 6 h, the
tetraarylmethane was formed in 96% AY and 93%
isolated yield (entry 11). A control reaction indicated
that in the absence of the palladium catalyst, the
reaction did not yield tetra-, tri-, or diarylation
products (entry 12). It is noteworthy that no
monoarylated product was detected in any of the
entries. It is interesting that very similar reaction
Scheme 1. Transition Metal Catalyzed Approaches to
Tetraarylmethanes
Despite intensive efforts by medicinal chemists to
prepare novel molecular scaffolds that exhibit
biological activity, such structures are nearly always
either linear or disk-shaped.[12] Very few examples of
bioactive sphere-like molecules are known. We
conjectured that the reason for this is that the synthesis
of sphere-like molecules is more labor intensive. To
address this issue, we initiated a program in the
exhaustive arylation of benzylic C–H’s.[10,13]
conditions
[Pd(OAc)2,
PCy3,
Ph–Cl,
2-
o
methylbenzothiazole, NaOt-Bu, 130 C in o-xylene)
were employed by Li and coworkers.[11b] Their reaction
gave 96% of the diarylation product, however, with no
formation of tetraarylmethane derivatives. The
contrast between Li’s publication and entry 10 of
Table 1 highlights how relatively small changes in
ligand structure can have a dramatic impact on
reaction outcome.
Scheme 2. Palladium Catalyzed Tandem Triarylation
Reaction of Heteroaryl Methyl Groups to Generate
Tetraarylmethane Derivatives.
Table 1. Optimization of Trisarylation of 2-
Methylbenzothiazole with Chlorobenzenea
Results and Discussion
2
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10.1002/adsc.201701347
Advanced Synthesis & Catalysis
required LiOt-Bu as base to afford the desired products.
Use of NaOt-Bu resulted in decomposition with no
products isolable. In general, when yields for the
triarylation are low, no significant byproducts derived
from mono- or diarylation were observed by 1H NMR.
We attribute the low yields to decomposition of the
starting aryl halides under the basic reaction conditions.
Despite considerable effort, heteroaryl halides 5-
bromo-1-methyl-1H-indole and 3-bromopyridine[16]
were not successfully coupled under our current
conditions.
Temp
3ab
4ab
Entry
Solvent
Base
(oC)
100 1,4-dioxane NaOt-Bu
100 1,4-dioxane KOt-Bu
100 1,4-dioxane LiHMDS
100 1,4-dioxane NaHMDS
100
100
100
100
100
130
130
130
(%)
(%)
1
2
3
4
5
6
7
8
9
21
0
0
0
3
14
0
0
0
0
DME
THF
CPME
toluene
o-xylene
o-xylene
o-xylene
o-xylene
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
6
0
Table 2. Scope of Aryl Halides 5 in Benzylic C–H Arylation
of 2-Methylbenzothiazole 1aa
33
55
62
0
0
0
11
11
23
96
96(93)c
0d
10
11
12
a)
Reaction conditions: All reactions were conducted on a
0.20 mmol scale using Pd(OAc)2 (5.0 mol %), cataCXium
A (10.0 mol %), 1.0 equiv of 1a, 5.0 equiv of 5a and 5.0
b)
equiv of base in 2 mL of solvent for 12 h. Assay yields
determined by 1H NMR spectroscopy of the crude reaction
mixtures with internal standard CH2Br2. c) The reaction time
d)
is 6 h and isolated yield. Without palladium and ligand,
reaction time is 6 h.
With the optimized reaction conditions in hand [2-
methylbenzothiazole (1a, 1.0 equiv), aryl chloride (5,
5.0
equiv),
NaOt-Bu
(5.0
equiv),
Pd(OAc)2/cataCXium A (5.0 mol %/10.0 mol %), o-
xylene (0.10 M) at 130 °C], we explored the scope of
aryl chlorides in their coupling with 2-
methylbenzothiazole (Table 2). Overall, a variety of
aryl chlorides led to the formation of
triaryl(heteroaryl)methanes (4) with moderate to
excellent yields (49–96%). The DCCP was compatible
with aryl chlorides bearing alkyl or neutral substituents
giving the desired products in 86–96% yield (4a–4c).
A range of aryl chlorides, bearing both electron-
withdrawing and electron-donating groups, was
suitable for coupling with 2-methylbenzothiazole.
Thus, aryl chlorides bearing 4-COPh, 4-F, 3-CN and
3-CF3 groups resulted in tetraarylmethane products
4d–4g in 83–89% yield. Reactions with 3-
chloroanisole and 1-chloro-3,5-dimethoxybenzene
furnished the products 4h and 4i in 96 and 95% yield,
respectively. Good yields were obtained using electron
rich aryl chlorides with 4-OMe, 4-NMe2 and a
protected catechol (4j–4l, 71–86% yield). Heteroaryl
a)
Isolated yield on 0.20 mmol scale; Reactions
conducted using 1a (1.0 equiv), aryl chloride (5.0
equiv) and NaOt-Bu (5.0 equiv) in o-xylene (0.10 M)
at 130 °C. Reactions conducted using aryl chloride
(6.0 equiv) and NaOt-Bu (6.0 equiv).
conducted using aryl chloride (6.0 equiv) and LiOt-Bu
b)
c)
Reactions
halides
such
as
6-bromoquinoline,
1-(4-
d)
e)
chlorophenyl)-1H-pyrrole and 5-bromobenzofuran
proved to be suitable electrophiles and underwent
coupling with 2-methylbenzothiazole to furnish
products (4m–4o) in 49–56% yield. It is noteworthy
that aryl chlorides bearing more sensitive groups, such
as 4-COPh, 3-CN and 1-(4-chlorophenyl)-1H-pyrrole,
(6.0 equiv).
Reaction time 18 h.
Reactions
conducted using aryl bromide (6.0 equiv) and NaOt-
Bu (6.0 equiv).
After demonstrating the broad scope of the triarylation
of 2-methylbenzothiazole we examined the
3
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10.1002/adsc.201701347
Advanced Synthesis & Catalysis
conducted using aryl chloride (6.0 equiv) and LiOt-Bu (6.0
equiv).
triarylation of other methyl heteroaromatics (1) with
aryl halides 5 (Table 3). Under our optimized
conditions, 2-methylbenzoxazole, N-methyl 2-
methylbenzimidazole and 2-methylquinoline readily
coupled with 1-bromo-4-tert-butylbenzene to afford
the coupling products in good yields (4p–4r, 50–93%
Heteroaryl halides such as 5-bromo-1-methyl-1H-
indole underwent coupling with 4-methylpyrimidine
to afford the products 4y in 42% yield. When the
coupling of 2-methylbenzoxazole was conducted with
1-(4-chlorophenyl)-1H-pyrrole and NaOt-Bu, no
desired products were detected. Switching to the
milder base LiOt-Bu, however, resulted in 57% yield.
Although some of the yields in Tables 2 and 3 are only
moderate, it must be borne in mind that they represent
the sum of 3 distinct coupling events (Scheme 2).
To demonstrate the potential utility of this method, the
gram scale reactions of 2-methylbenzothiazole (1a)
with 6-bromoquinoline (5m) and 1-(4-chlorophenyl)-
1H-pyrrole (5n) were performed. The desired products
4m and 4n were obtained in 43 and 51% yield,
respectively (Scheme 3), suggesting the reaction is
scalable, even with heteroaryl substrates.
yield).
2-Methyl-1,8-naphthyridine,
3-
methylpyridazine and 2-methylpyriazine also
underwent facile coupling with 1-chloro- or 1-bromo-
4-tert-butylbenzene to furnish the desired products
(4s–4u, 61–91% yield). 4-Methylpyrimidine was a
suitable substrate, undergoing coupling with 1-chloro-
4-tert-butylbenzene and chlorobenzene to produce the
triarylated products 4w and 4x in 82 and 83% yield,
respectively. When using stronger base, KOt-Bu, 4-
methylpyridine also coupled with chlorobenzene to
obtain the corresponding compound 4v in 71% yield.
This result indicates that the use of heteroarylmethanes
with ortho-directing groups is not necessary for
successful coupling.
Table 3. Scope of Aryl Halides 5 in Benzylic C–H Arylation
of Methyl Heteroaromatics 1a
Scheme 3. Triarylation of 2-methylbenzothiazole (1a) with
6-bromoquinoline (5m) and 1-(4-chlorophenyl)-1H-pyrrole
(5n) on gram scale
Conclusion
In summary, a palladium-catalyzed deprotonative
cross-coupling process (DCCP) for direct arylation of
methyl substituted heteroaromatics with aryl halides to
synthesize triaryl(heteroaryl)methanes has been
developed. Under our reaction conditions, a broad
scope of methyl substituted heteroaromatics and aryl
halides have successfully been coupled. It is
impressive that a single catalyst can promote the
efficient arylation of the starting material (ArHetero
-
CH3) and intermediates [CH2(ArHetero)Ar and
CH(ArHetero)Ar2] to yield tetraarylmethane derivatives
in up to 96% yield. We anticipate that this method will
enable rapid assembly of tetraarylmethane derivatives
previously difficult to prepare and will be useful in the
synthesis of sphere-like molecules for examination in
medicinal chemistry.
a)
Isolated yield on 0.20 mmol scale; Reactions conducted
using 1 (1.0 equiv), aryl chloride (5.0 equiv) and NaOt-Bu
(5.0 equiv) in o-xylene (0.10 M) at 130 °C. Reactions
conducted using aryl bromide (6.0 equiv) and NaOt-Bu (6.0
equiv). Reaction time 18 h. Reactions conducted using
Pd(OAc)2 (10 mol%), cataCXium A (20 mol%), aryl
chloride (6.0 equiv) and KOt-Bu (6.0 equiv). e) Reactions
b)
c)
d)
4
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10.1002/adsc.201701347
Advanced Synthesis & Catalysis
Experimental Section
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General Methods
All reactions were conducted under an inert atmosphere of
dry nitrogen. Dry solvents were purchased from Sigma-
Aldrich and used without further purification. Unless
otherwise stated, reagents were commercially available and
used as purchased. Chemicals were obtained from Sigma-
Aldrich, Acros, Alfa-Aesar, TCI and solvents were
purchased from Fisher Scientific. TLC was performed with
Merck TLC Silicagel60 F254 plates with detection under UV
light at 254 nm. Silica gel (230–400 mesh, Silicycle) was
used for flash chromatography. The H NMR and 13C{1H}
1
NMR spectra were obtained using a Brüker AM-500
Fourier-transform NMR spectrometer at 500 and 125 MHz,
respectively. Chemical shifts are reported in units of parts
per million (ppm) downfield from tetramethylsilane (TMS,
δ 0.00 ppm) for 1H NMR, CDCl3 (δ 77.16 ppm) and 13C{1H}
NMR and all coupling constants are reported in hertz. The
infrared spectra were obtained with KBr plates using a
Perkin-Elmer Spectrum 100 Series FTIR spectrometer.
High resolution mass spectrometry (HRMS) data were
obtained on a Waters LC-TOF mass spectrometer (model
LCT-XE Premier) using chemical ionization (CI) or
electrospray ionization (ESI) in positive or negative mode,
depending on the analyte.
[2]
General Procedure for the Pd-catalyzed Triarylation of
Methyl Heteroaromatics
An oven-dried 8 mL reaction vial equipped with a stir bar
was charged with methyl heteroaromatics (1, 0.20 mmol,
1.0 equiv) and aryl halides (5, 5.0–6.0 equiv) in a glove box
under a nitrogen atmosphere at room temperature. A stock
solution containing Pd(OAc)2 (2.2 mg, 0.01 mmol, 5.0
mol %) and cataCXium A (7.2 mg, 0.02 mmol, 10.0 mol %)
in 2 mL of dry o-xylene was taken up by syringe and added
to the reaction vial under nitrogen. Next, NaOt-Bu (5.0–6.0
equiv) was added to the reaction mixture. The vial was
capped, removed from the glove box, and stirred for 6 h at
130 °C. After cooling to room temperature, the reaction
mixture was opened to air. Water (10 mL) was then added
and the solution was extracted with ethyl acetate (3 × 10
mL). The combined organic phase was dried over Na2SO4
and was concentrated in vacuo. The crude material was
loaded onto a deactivated silica gel column and purified by
flash chromatography to afford the products.
[3]
[4]
T. Niwa, H. Yorimitsu, K. Oshima, Org. Lett. 2007,
9, 2373-2375.
a) J. -J. Chen, S. Onogi, Y. -C. Hsieh, C.-C. Hsiao,
S. Higashibayashi, H. Sakurai, Y.-T. Wu, Adv.
Synth. Catal. 2012, 354, 1551-1558; b) X. Cao, W.
Yang, C. Liu, F. Wei, K. Wu, W. Sun, J. Song, L.
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[5]
[6]
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a) J. Zhang, A. Bellomo, A. D. Creamer, S. D.
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[7]
Acknowledgements
We gratefully acknowledge the financial support from Nanjing
Tech University and SICAM Fellowship from Jiangsu National
Synergetic Innovation Center for Advanced Materials. We thank
the National Science Foundation (CHE-1464744) and National
Institutes of Health (NIGMS 104349) for financial support.
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When using 3-bromopyridine as the substrate,
there was only triarylmethane formed in 77% AY
under the same reaction conditions.
[10]
[11]
[12]
6
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10.1002/adsc.201701347
Advanced Synthesis & Catalysis
FULL PAPER
Palladium-Catalyzed Triarylation of sp3 C–H Bonds
in
Heteroarylmethanes:
Synthesis
of
Triaryl(heteroaryl)methanes
Adv. Synth. Catal. Year, Volume, Page – Page
Shuguang Zhang, b Bowen Hu,b Zhipeng Zheng,b
and Patrick J. Walsha,b*
7
This article is protected by copyright. All rights reserved.