Palladium-Catalyzed Benzylic Arylation of Pyridylmethyl Silyl Ethers: One-Pot Synthesis of Aryl(pyridyl)methanols

Article abstract of DOI:10.1021/acs.orglett.6b00450

An efficient palladium-catalyzed direct arylation of pyridylmethyl silyl ethers with aryl bromides is described. A Pd(OAc)₂/NIXANTPHOS-based catalyst provides aryl(pyridyl)methyl alcohol derivatives in good to excellent yields (33 examples, 57-100% yield). This protocol is compatible with different silyl ether protecting groups, affording either the protected or the free alcohols in an effective one-pot process. The scalability of the reaction is demonstrated.

Full text of DOI:10.1021/acs.orglett.6b00450

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Benzylic Arylation of Pyridylmethyl Silyl Ethers:
One-Pot Synthesis of Aryl(pyridyl)methanols
Alexandra R. Rivero,†,‡ Byeong-Seon Kim,† and Patrick J. Walsh*,†
†Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States
‡Departamento de Química Organ
́
ica I, Facultad de Ciencias Quımicas, Universidad Complutense de Madrid, 28040 Madrid, Spain
́
S
* Supporting Information
ABSTRACT: An efficient palladium-catalyzed direct arylation of
pyridylmethyl silyl ethers with aryl bromides is described. A
Pd(OAc)2/NIXANTPHOS-based catalyst provides aryl(pyridyl)-
methyl alcohol derivatives in good to excellent yields (33 examples,
57−100% yield). This protocol is compatible with different silyl ether
protecting groups, affording either the protected or the free alcohols
in an effective one-pot process. The scalability of the reaction is demonstrated.
pyridyl nitrogen, preventing its coordination while also
itrogen heterocycles are among the most widespread
1
Nstructural components of pharmaceuticals. Among these, increasing the acidity of the benzylic hydrogens and facilitating
the catalytic process.3j,5 Although effective, these methods have
pyridines are frequent subunits of medicinally relevant
molecules and materials.1g−n Specifically, the aryl(pyridyl)-
limited substrate scope and reduced synthetic efficiency. The
coordination of the pyridyl group to palladium and inhibition
methanol core is commonly found in drug candidates, either as
or deactivation of the catalyst is also problematic.6
the free alcohol or ether (Figure 1).2
Given the success of deprotonative cross-coupling processes
(DCCP) in the functionalization of a variety of weakly acidic
sp3 C−H bonds,7 we envisioned application of this approach to
the functionalization of substituted pyridines.7q,u We recently
reported the Pd(OAc)2/NIXANTPHOS-catalyzed DCCP of
pyridylmethyl ethers to generate either arylated secondary
ethers (Scheme 1A) or tertiary alcohols via tandem arylation/
[1,2]-Wittig rearrangement (Scheme 1B).7u Secondary aryl-
(pyridyl)methanols (Figure 1) are also highly desirable but not
accessible via the chemistry in Scheme 1A or B.
We hypothesized that pyridylmethyl silyl ethers might
undergo reversible deprotonation in the presence of a
palladium catalyst and aryl bromides to generate arylated silyl
ethers or the corresponding free alcohols (Scheme 1C). Herein,
we report the catalytic arylation of pyridylmethyl silyl ethers to
afford either the silyl protected or free alcohols, using a
Pd(NIXANTPHOS)-based catalyst.
Based on the general utility of the Pd(OAc)2/NIXANT-
PHOS-based catalyst in a range of reactions,7j−u we began by
investigating the benzylic C−H arylation of 2-pyridylmethyl
silyl ether 1a with bromobenzene 2a using Pd(OAc)2 (1 mol
%) and NIXANTPHOS (1.5 mol %, see Table 1 for structure).
Several combinations of silyl amide bases MN(SiMe3)2 (M =
Li, Na, K) and solvents [toluene, 1,4-dioxane, THF, 2-
methyltetrahydrofuran (2-MeTHF), cyclopentyl methyl ether
(CPME), and 1,2-dimethoxyethane (DME)] were evaluated to
identify suitable reaction conditions (Table 1, entries 1−10).
Figure 1. Biologically active compounds containing aryl(pyridyl)-
methanol subunits.
Palladium-catalyzed benzylic arylation of picolinyl derivatives
has been employed to access heterocyclic building blocks.3
Traditionally, such reactions require the presence of directing
groups, such as 2-(2-pyridyl)ethanols,3b pyridine N-oxides,3d,4
N-iminopyridines,3e or 2-(2-pyridyl)acetic acids.3h Other
methods for the benzylic functionalization of substituted
pyridines rely on the addition of activating agents. For instance,
a Lewis acid can be added to the reaction mixture to bind the
Received: February 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00450
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Organic Letters
Letter
(2a) to 1.0 equiv still gave 98% yield (entry 13). Furthermore,
only a small drop in the reaction yield (from 98% to 89%) was
found when the NIXANTPHOS loading was dropped from 1.5
to 1.0 mol % (entries 13 and 14).
Scheme 1. Pd-Catalyzed Benzylic C−H Arylation of
Pyridylmethyl Ethers
With the optimized reaction conditions in hand [pyridyl-
methyl silyl ether (1, 1 equiv), aryl bromide (2, 1 equiv),
LiN(SiMe3)2 (1.5 equiv), Pd(OAc)2/NIXANTPHOS (1 mol %
each), DME (0.2 M) at 85 °C], we explored the scope of aryl
bromides in the DCCP (Scheme 2). In general, a variety of aryl
Scheme 2. Scope of Aryl Bromides 2 in Benzylic C−H
a
Arylation of 2-Pyridylmethyl Silyl Ether 1a
Table 1. Optimization of Benzylic C−H Arylation of 2-
a
Pyridylmethyl Silyl Ether 1a
a
Isolated yields with reactions conducted on a 0.2 mmol scale using 1a
(1 equiv), Ar−Br (1 equiv), and LiN(SiMe3)2 (1.5 equiv) in DME (0.2
b
M) at 85 °C for 6 h. 24 h.
bromides (2a−g) led to the formation of aryl(2-pyridyl)methyl
silyl ethers 3 with good to high yields (69−88%). The arylation
was compatible with aryl bromides bearing electron-donating
substituents 4-t-Bu, 4-OMe, 4-NMe2 (3ac−ae, 84−88% yield)
or electron-withdrawing 4-F and 4-Cl (3af and 3ag in 85% and
70% yield, respectively).
b
entry M (equiv)
solvent
temp (°C) time (h) yield (%)
1
Li (3)
toluene
dioxane
THF
45
45
45
45
45
45
45
45
45
45
45
85
85
85
12
12
12
12
12
12
12
12
12
12
18
3
0
22
71
42
66
100
45
48
15
82
70
98
98
89
2
Li (3)
3
Li (3)
The presence of the 2-pyridyl groups in Scheme 2 might lead
to the conclusion that chelation is a prerequisite for arylation.
Thus, we examined the 4-pyridyl analogues to probe this
question and expand the method (Scheme 3). The arylation of
4-pyridylmethyl silyl ether 1b took place at room temperature,
suggesting these substrates are more reactive than the 2-pyridyl
derivatives. This result is consistent with the greater acidity of
4-methylpyridine over 2-methylpyridine.8 The reactions of 4-
pyridylmethyl silyl ethers provided the desired products with a
broad range of aryl bromides. These include electronically
neutral (Ph, 2-naphthyl, 4-t-Bu,) and electron-rich (4-OMe, 4-
NMe2) aryl bromides, which provided products 3ba−be in 83−
97% yield. Aryl bromides with electron-withdrawing groups,
such as 4-F and 4-Cl, 3-CF3, formed products 3bf−bh in 74−
95% yield. In addition, more challenging substrates, such as
sterically hindered 2-bromotoluene and heterocycles (3-
bromopyridine, 6-bromoquinoline, 5-bromobenzofuran, and
N-methyl-5-bromoindole) successfully underwent DCCP at
room temperature (3bi−bm, 57−85%), albeit at 5 mol %
catalyst loading (Scheme 3). Moreover, the scalability of the
method was evaluated by performing the arylation of 4-
pyridylmethyl silyl ether 1b with bromobenzene (2a) on a 4
mmol scale. The desired product (3ba) was obtained in 91%
yield (1.09 g, Scheme 3).
4
Li (3)
2-MeTHF
CPME
DME
5
Li (3)
6
Li (3)
7
Na (3)
Na (3)
Na (3)
K (3)
THF
8
CPME
DME
9
10
11
12
13
CPME
DME
Li (1.5)
Li (1.5)
Li (1.5)
Li (1.5)
DME
c
c
DME
3
d
14
DME
3
a
Reactions were conducted on a 0.2 mmol scale using 1a (1 equiv), 2a
(1.2 equiv), Pd(OAc)2 (1 mol %), and NIXANTPHOS (1.5 mol %).
Yield determined by H NMR spectroscopy of the crude reaction
b
1
c
d
mixture. 1 equiv of 2a was used. 1 mol % of Pd(OAc)2 and 1 mol %
of NIXANTPHOS.
It was found that LiN(SiMe3)2 in DME provided a
quantitative yield of the desired coupling (Table 1, entry 6).
Unfortunately, attempts to decrease the amount of LiN-
(SiMe3)2 from 3 equiv to 1.5 equiv resulted in incomplete
reaction after 18 h at 45 °C (entries 6 and 11). Increasing the
temperature from 45 to 85 °C and using 1.5 equiv of
LiN(SiMe3)2 led to 98% yield after 3 h (entry 12). We were
surprised to find that reducing the amount of bromobenzene
Next, we assessed different silyl groups. In order to evaluate
the impact of silyl group size on the arylation reaction outcome,
B
DOI: 10.1021/acs.orglett.6b00450
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Letter
a
Scheme 3. Scope of Aryl Bromides 2 in Benzylic C−H
Scheme 4. Scope of Arylation of Pyridylmethyl Silyl Ethers
a
Arylation of 4-Pyridylmethyl Silyl Ether 1b
a
Isolated yields with reactions conducted on a 0.2 mmol scale using 1
(1 equiv), Ar−Br (1 equiv), and LiN(SiMe3)2 (3 equiv) in DME (0.2
b
c
M) at 25 °C for 16 h. Conducted at 85 °C. 2 mol % of Pd(OAc)2
and 2 mol % of NIXANTPHOS at 85 °C. LiN(SiMe3)2 (1.5 equiv)
d
for 1.5 h.
Scheme 5. One-Pot Arylation/Deprotection of
a
Pyridylmethyl Silyl Ethers
a
Isolated yields with reactions conducted on a 0.2 mmol scale using 1b
(1 equiv), Ar−Br (1 equiv), and LiN(SiMe3)2 (1.5 equiv) in DME (0.2
b
c
d
M) at 25 °C for 6 h. 24 h. LiN(SiMe3)2 (3 equiv). 5 mol %
Pd(OAc)2 and 5 mol % of NIXANTPHOS.
triisopropylsilyl (TIPS) ether and trimethylsilyl (TMS) ether
protecting groups were examined.
Both 2- and 4-pyridine derivatives with TIPS and TMS
groups coupled with aryl bromides to provide the desired
products in good to excellent yields (57−100%, Scheme 4). 2-
Pyridyl-containing substrates with bulky TIPS groups required
3 equiv of base and 2 mol % catalyst loading for complete
conversion.
Finally, we explored the feasibility of a one-pot arylation/
desilylation sequence to generate free secondary alcohols.
Substrates with different silyl groups were arylated under the
standard reaction conditions and then directly treated with 1.5
equiv of TBAF. As shown in Scheme 5, 4-pyridylmethyl silyl
ether 1b and 2-pyridylmethyl silyl ether 1e provided the
corresponding alcohols 4ba and 4ea respectively, with high
yields (94% and 84%). The 3-pyridylmethyl silyl ether 1g is
more challenging because of the higher pKa of the benzylic C−
H’s.8 After some optimization, we found that 3 equiv of
LiN(SiMe3)2, 2 equiv of 4-tert-butylbromobenzene (2c), and 5
mol % catalyst loading in DME at 85 °C generated arylation
product. Workup with 1.5 equiv of TBAF provided the free
alcohol 4gc in 66% yield.
a
Isolateds yields with reactions conducted on a 0.2 mmol scale using 1
(1 equiv), Ar−Br (1 equiv), and LiN(SiMe3)2 (1.5 equiv) in DME (0.2
b
c
M) at 85 °C for 1.5 h. Conducted at 25 °C. Ar−Br (2 equiv),
LiN(SiMe3)2 (3 equiv), 5 mol % of Pd(OAc)2, and 5 mol % of
NIXANTPHOS for 24 h.
groups. A convenient one-pot cross-coupling/desilylation
sequence was demonstrated to directly obtain arylated
secondary alcohols. Our method has advantages over the
addition of organometallic reagents, such as organolithiums and
Grignard reagents, to aldehydes. Many more aryl bromides are
commercially available than aryl Grignard reagents. Further-
more, our method circumvents the use of aldehydes, which are
often contaminated with oxidation products. We anticipate that
this method will be useful in the synthesis of aryl pyridylmethyl
alcohols for exploration of their structure−activity relationship.
In summary, a deprotonative cross-coupling process for the
direct arylation of pyridylmethyl silyl ethers has been
developed. In most cases, this method requires 1 equiv of
aryl bromide, 1.5 equiv of base, and many substrates react well
at 1 mol % catalyst loading. Electron-donating and electron-
withdrawing aryl bromides as well as heteroaryl bromides
undergo the coupling in good to excellent yields. In addition,
the reaction is compatible with different sized silyl-protecting
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00450.
■
S
Experimental details and characterization data for all new
compounds (PDF)
C
DOI: 10.1021/acs.orglett.6b00450
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pwalsh@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by NIH/NIGMS
(GM 104349) and the National Science Foundation (CHE-
1464744). A.R.R. acknowledges the Spanish MEC for an FPU
grant and a Visiting Scientist Fellowship to University of
Pennsylvania.
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Trongsiriwat, N.; Jia, T.; Carroll, P. J.; Dreher, S. D.; Tudge, M. T.;
Yin, H.; Robinson, J. R.; Schelter, E. J.; Walsh, P. J. J. Am. Chem. Soc.
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