Efficient Synthesis of Bulky 2,2’-Bipyridine and (S)-Pyridine-Oxazoline Ligands

Article abstract of DOI:10.1002/adsc.202001218

Bulky N,N’-bidentate ligands can furnish catalysts with enhanced catalytic activity compared to commercially available ligands. Straightforward methods to effectively synthesize a broad range of these ligands, however, are uncommon. In this work, a simple and efficient method is developed for the synthesis of bulky N,N’-bidentate ligands, including 2,2’-bipyridines and enantioenriched pyridine-oxazolines. The Pd/NIXANTPHOS catalyst system enabled synthesis of a series of bulky 2,2’-bipyridine-based ligands and (S)-pyridine oxazoline-based enantioenriched ligands with good to excellent yields. The ligands have been benchmarked in the aminofluorination of styrene. (Figure presented.).

Full text of DOI:10.1002/adsc.202001218

Title: Efficient synthesis of bulky 2,2’-bipyridine and (<i>S</i>)-pyridine-
oxazoline ligands
Authors: Zhipeng Zheng and Patrick J. Walsh
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
Very Important Publication
FULL PAPER
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Efficient Synthesis of Bulky 2,2’-Bipyridine and (S)-Pyridine-Oxazoline
Ligands
Zhipeng Zheng a and Patrick J. Walsh a*
a Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, PA
(USA) E-mail: pwalsh@sas.upenn.edu, Office: (215) 573-2875
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######.
One drawback to these new catalytic processes is that existing
methods for the synthesis of these bulky ligands involved
laborious multistep procedures and only offered limited structural
diversity. For example, the bulky pyridine-oxazoline ligand
(Ph2PyOx, Scheme 2a) was obtained through a 4-step synthesis
with low overall yield (14%). Additionally, in order to synthesize
ligands with diverse aryl groups [e.g. (3,5-tBu2-C6H3)2PyOx,
Scheme 2a], two additional steps were required. The development
of efficient and broadly applicable methods to synthesize bulky
bidentate nitrogen-based ligands, such as 2,2’-bipyridine and
pyridine-oxazoline, is expected to facilitate the development of
new catalytic reactions.
Abstract. Bulky N,N’-bidentate ligands can furnish catalysts with
enhanced catalytic activity compared to commercially available
ligands. Straightforward methods to effectively synthesize a
broad range of these ligands, however, are uncommon. In this
work, a simple and efficient method is developed for the
synthesis of bulky N,N’-bidentate ligands, including 2,2’-
bipyridines and enantioenriched pyridine-oxazolines. The
Pd/NIXANTPHOS catalyst system enabled synthesis of a series
of bulky 2,2’-bipyridine-based ligands and (S)-pyridine
oxazoline-based enantioenriched ligands with good to excellent
yields.
The ligands have been benchmarked in the
aminofluorination of styrene.
Keywords: bulky ligand; palladium catalysis; 2,2’-bipyridine
ligands; (S)-pyridine-oxazoline ligands
Introduction
It is well established that new reactivity of transition metal
complexes can be engendered by the use of ligands with novel
steric and electronic properties. In catalysis, nowhere is this more
evident than in palladium catalyzed coupling reactions with bulky
monodentate phosphine ligands[1] and the Xantphos family of
ligands[2]. These ligands have enabled new transformations that
have had an enormous impact on synthetic chemistry. Of course,
the design and synthesis of new ligands for transition metal
catalysts has enable new transformations across all areas of
catalysis[3]. To this end, efficient synthetic methods for the
preparation of ligands with diverse structures are in high demand.
While many transformations have been introduced with
commercially available bidentate 2,2’-bipyridine derivatives
(bpy), the use of bulky NN’-bidentate ligands[4] has been gaining
attention. For example, bulky N,N’-bidentate ligands derived
from 2,2'-bipyridine and enantioenriched pyridine-oxazolines
have been used in metal-catalyzed carbon dioxide reduction[4c, d]
(Scheme 1a), enantioselective alkene difunctionalization
reactions[4e-g, 4i] (Scheme 1b) and enantioselective electrochemical
homocoupling reactions[4h] (Scheme 1c) with enhanced catalytic
activity. In these reactions, the bulky ligands were implemented
to prevent undesirable catalyst dimerization[4c, 5] or to increase the
Scheme 1. Examples of bulky groups enhancing reactivity with
2,2’-bipyridine and (S)-PyOx ligated catalysts.
Our group has developed palladium-catalyzed methods for
stepwise arylation[6] of weakly acidic (pKa>25) methyl groups
metal center’s electrophilicity toward binding olefin substrates[4f]
.
1
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
utilizing the deprotonative cross-coupling process (DCCP)[7] in
the presence of bases (Scheme 2b). We[6c] and others,[8] have
reported the stepwise arylation of methyl groups on nitrogen-
containing hetero-aromatic rings with good to excellent yields.
Inspired by these results, we envisioned a straightforward
palladium-catalyzed approach for synthesis of bulky 2,2’-
bipyridine and enantioenriched pyridine-oxazoline ligands
through arylation of methyl groups adjacent to the pyridyl
nitrogen (Scheme 2c). This method starts from commercially
making the subsequent deprotonation, and often arylation,
faster[13]
. In contrast, arylation of triarylmethane derivatives is
difficult due to the increased steric hindrance, particularly when
using palladium catalysts with bulky bidentate phosphine
ligands[6c, 14], such as NIXANTPHOS.
Table 1. Optimization of the bis-arylation and tetra-arylation of
6,6'-dimethyl-2,2'-bipyridine
available
6,6’-dimethyl-2,2’-bipyridine
(Me2Bpy)
and
conveniently synthesized chiral (S)-6-methyl-2-oxazoline-
pyridine [(S)-PyOx)] derivatives[9] with variable alkyl
substituents at the chiral center. At the outset of our work, we
anticipated that control over the extent of arylation would be
possible in some cases. We envisioned that the key to obtaining
ligands in high yields and selectivity would hinge on the use of
appropriate amounts of aryl bromide and base. Herein, we report
methods to efficiently synthesize bulky bipyridyl and
enantioenriched pyridine-oxazoline ligands using palladium-
catalyzed deprotonative cross-coupling approaches.
Entry
Solvent
Base
3aa
4aa
(AY%)[a]
1.5
(AY%)[a]
28
1
2
3
4
5
THF
NaOtBu
THF
KOtBu
28
31
29
0
48
32
65
22
THF
LiN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
THF
1,4-dioxane
6
7
CPME
NaN(SiMe3)2
NaN(SiMe3)2
0
0
23
6
2-Me-THF
8
DME
DME
DME
DME
DME
DME
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
NaN(SiMe3)2
58
28
0
9[b]
10[c]
11[d]
12[f]
>95
>95
>95
92
0
4
5
13[c][f]
>95
0
[a]
Assay yield determined by 1H NMR using CH2Br2 as internal
standard.
[b] 6.0 equiv of base and bromobenzene were used
[c] 5.0 equiv of NaN(SiMe3)2 and 6 equiv of bromobenzene were used
[d] 4.5 equiv of NaN(SiMe3)2 and 6 equiv of bromobenzene were used
[e] 5.0 equiv of NaN(SiMe3)2 and 5 equiv of bromobenzene were used
[f] Reaction time: 1 h
We initially aimed at the synthesis of bis-arylated product (4aa,
Table 1). To begin with, 3 equiv of bromobenzene and 3 equiv of
four different bases [NaOtBu, KOtBu, LiN(SiMe3)2 and
NaN(SiMe3)2] were examined in THF for the coupling. These
initial conditions gave the bis-arylated product (4aa) and tetra-
arylated product (3aa) as mixtures with combined assay yields
(AY, determined by 1H NMR using CH2Br2 as internal standard)
ranging from 29% to 94% (entries 1 – 4, Table 1). Even though
use of NaN(SiMe3)2 gave the highest yield of 4aa (65%), it did
not offer a high selectivity of 4aa over 3aa, which complicated
the purification. In order to find conditions to synthesize 4aa with
high yield and selectivity, NaN(SiMe3)2 was used with other
solvents (DME, 1,4-dioxane, CPME, and 2-Me-THF).
Unfortunately, these conditions gave either low reactivity (entries
5 – 7) or low selectivity (entry 8) for the synthesis of 4aa. These
results indicated that it is difficult to find conditions to synthesize
bis-arylated 4aa with high yield and selectivity. On the other
hand, we were pleased to find that DME favored the formation of
tetra-arylated product (3aa, 58%, entry 8, Table 1). This result
Scheme 2. Reported and proposed synthesis of bulky pyridine
ligands (a,c); use of DCCP in the methyl arylation process (b).
Results and Discussion
Reaction development and optimization. Based on our previous
[6a, 6b, 7a, 7b, 10]
work
involving van Leeuwen’s NIXANTPHOS
ligand[2, 11] (see Table 1 for structure), we began to study coupling
of 6,6'-dimethyl-2,2'-bipyridine (1a, 1 equiv) and bromobenzene
(2a, 3 equiv) with Pd(OAc)2 (5 mol%) and NIXANTPHOS (7.5
mol%) as the catalyst. We targeted diarylation of the azaaryl
methyl groups to provide bulky diarylmethyl substituents. In
general, it is very difficult to perform mono-arylation of an
azaaryl methyl group, because after the first arylation, the pKa of
the remaining hydrogens drop by over 5 orders of magnitude[12]
,
2
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
[b] The reaction was conducted using LiN(SiMe3)2 (5.0 equiv) in 1,4-
dioxane (0.10 M) at 80º C for 12 h.
implied that increasing equivalents of base and bromobenzene
should favor formation of the tetra-arylated 3aa, as might be
[c] The reaction was conducted using LiN(SiMe3)2 (5.0 equiv) in 1,4-
dioxane (0.10 M) at 80 ºC for 24 h.
expected.
When
6
equiv each of NaN(SiMe3)2 and
bromobenzene in DME were used, 3aa was exclusively formed
(95% AY, entry 9, Table 1). Lowering the amount of
NaN(SiMe3)2 to 5 equiv did not impact the yield of 3aa (98%,
entry 10, Table 1). Further lowering NaN(SiMe3)2 to 4.5 equiv
(entry 11) generated a mixture of 3aa and 4aa. Reducing the
amount of bromobenzene to 5 equiv (entry 12) also generated a
mixture of 3aa and 4aa.
We next optimized the reaction time. Monitoring the
reaction via TLC showed the reaction to be complete in 1 h, with
an AY of 97% (1H NMR, entry 13, Table 1). Based on the
optimization above, our conditions for synthesis of tetra-arylated
product 3a used for further study were 6 equiv of aryl bromide,
Pd(OAc)2 (5 mol%), NIXANTPHOS (7.5 mol%), 5 equiv of
NaN(SiMe3)2 and DME as solvent at 80 ºC for 1 h (entry 13).
Optimization and scope with electron poor aryl bromides. To
enable reactivity of electron poor aryl bromides, high throughput
experimentation (HTE) was used to screen solvents and bases for
the reaction with 3-bromoanisole (2k). These studies (see the
Supporting Information, Table S1, Table S2 and Figure S1)
showed the combination of 1,4-dioxane and LiN(SiMe3)2 as
optimal. We suspect that LiN(SiMe3)2 is more strongly
aggregated in solution than NaN(SiMe3)2 making it less basic and
reducing side reactions with aryl bromides bearing electron
withdrawing groups. Under the newly optimized conditions 1a
and 3-bromoanisole (2k) were converted to the tetra-anisole 2,2’-
bipyridine ligand in 88% yield (3ak, Table 2). Use of 1-bromo-
3,5-dimethoxy-bromobenzene (2l) and 1-bromo-4-fluorobenzene
(2m) furnished 3al and 3am in ≥92% yield. When 3-
bromobenzotrifluoride (2n) was used, the reaction time was
extended to 24 h, furnishing the product 3an in 93% yield.
Scope with electron rich aryl bromides. With the optimized
conditions for the tetra-arylation in hand, the scope was examined
(Table 2). We desired to prepare a series of tetra-arylated ligands
with different steric parameters. Six aryl bromides, therefore,
were chosen (Table 2, 2b – 2g) bearing one or two methyl or tert-
butyl groups, as aryl groups with methyl[8b] and tert-butyl[4g, 15]
substituents are often incorporated in ligands for enhanced
reactivity. The corresponding products (3ab – 3ag) were obtained
in good to excellent yields (86 – 93%). Use of aryl bromides with
electron donating groups, including 4-OMe (2h), 4-NMe2 (2i),
and 4-pyrrolidyl (2j) also furnished products in good yields (3ah
– 3aj, 50 – 95%). The reaction was unsuccessful with 2-
bromotoluene under the standard reaction conditions.
Aryl bromides with electron withdrawing groups (EWG),
however, were not compatible with the current reaction
conditions. For example, the use of 3-bromoanisole (2k)
generated the corresponding product in < 10% with 1a and 2k
being recovered. Increasing the reaction time to 12 h led to 30%
yield (with the rest of 1a and 2k decomposed).
Synthesis of bis-arylated bipyridine ligands. The unsymmetrical
bis-arylated products are also potentially valuable ligands with
less steric bulk compared to the tetra-arylated derivatives.
Therefore, an efficient synthesis of the bis-arylated products was
developed by lowering the amount of base and aryl bromide to
2.5 equiv each (Table 3). Under otherwise identical conditions,
bromobenzene (2a) and 1-bromo-3,5-dimethylbenzene (2d)
reacted with 1a to afford the bis-arylated products in 74 and 78%
yield (4aa, 4ad) with the corresponding tetra-arylated product in
20 and 18% yield (3aa, 3ad), respectively. The separation of the
bis- and tetra-arylated products was relatively straightforward
through column chromatography using hexanes and ethyl acetate
as eluent. Use of 4-bromoanisole (2h) afforded the bis- and tetra-
arylated products as
a mixture (4ah: 70%, 3ah: 28%).
Interestingly, aryl bromides with electron withdrawing groups (i.e.
2n, 3-CF3 group and 2o, 4-CN group) afforded bis-arylated
product exclusively in 88 and 95% yield. We note that the first
arylation is slow and the second is much faster due to the ease of
deprotonation of the mono-arylated intermediates. The third
arylation will be slower than the first, because most of the aryl
bromide has been consumed and its concentration will be low.
Table 2. Substrate scope for the tetra-arylated 2,2’-bipyridine
ligands[a]
Table 3. Substrate scope for the bis-arylated bipyridine ligands [a]
N
N
Ar
Pd(OAc)2 (5 mol%)
NIXANTPHOS (7.5 mol%)
4a
Ar
Ar–Br
+
+
N
N
NaN(SiMe3)2 (2.5 equiv)
DME (0.1M)
80 ºC, 1 h
1a
0.20 mmol
2
N
N
2.5 equiv
Ar
Ar
Ar
Ar
3a
[a] Isolated yield on 0.20 mmol scale;
3
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
[a] Isolated yield on 0.20 mmol scale;
The reaction was conducted using LiN(SiMe3)2 (2.5 equiv) in 1,4-
with an extended -system was also successfully coupled with
the (S)-PyOx ligand to form bis-arylated 4cp in 75% yield.
[b]
dioxane (0.10 M) at 80 ºC for 12 h.
o
Given that (S)-PyOx arylations can be conducted at 40 C,
compared to the arylation of the Bpy derivatives at 80 oC, we
attempted the mono-arylation of 1b and 1c. When 1.5 equiv
bromobenzene (2a) and 1.5 equiv of NaN(SiMe3)2 were used
with 1b and 1c, the corresponding mono-phenylated products 5ba
and 5ca were obtained in 72 and 69% yield with the
corresponding bis-arylated byproducts (4ba, 12%; 4ca, 10%).
The separation of the mono-arylated and the bis-arylated products
was relatively simple through column chromatography,
permitting isolation of clean mono-arylated products. Similarly,
mono-arylated 5cp with a 2-naphthyl group was obtained in 50%
yield as a mixture with its bis-arylated counterpart (4cp, 15%).
Mono-arylated 5cq with a sterically hindered 1-naphthyl group
was obtained exclusively in 58% yield without formation of its
bis-arylated counterpart. This result indicated that the sterically
hindered 1-naphthyl group retarded the second arylation under
these conditions. Compared to the synthetic routes[4e-g] described
in the Introduction involving 4 – 6 steps, this work provides an
efficient method to synthesize bulky and enantioenriched (S)-
pyridine-oxazoline ligands in two steps starting from
commercially available 6-methyl-2-pyridinecarbonitrile and -
amino alcohols[9] with reasonable to good yields. Although it
was viewed as unlikely that the stereocenter in the pyridine
oxazoline-based ligands would be racemized by the base under
these mild conditions, we viewed it as prudent to verify this
hypothesis using chiral phase SFC (see Supporting Information
for details). Thus, ligands 4ba, 4ca and 5ca were analyzed and
found to have ee values of at least 99%.
Substrate scope of bulky chiral pyridine oxazoline ligands. We
next desired to apply our method to the synthesis of a series of
bulky enantioenriched pyridine oxazoline-based ligands. Not
surprisingly, the preparation of our pyridine oxazoline ligands
required slightly modified reaction conditions (see the Supporting
Information, Table S2, for optimization). The results of this
optimization process indicated use of 3 equiv of aryl bromide and
2.4 equiv of NaN(SiMe3)2 at 40 ºC for 14 h was the best of the
conditions examined. Using these conditions, reaction of
bromobenzene (2a,
3
equiv) and (S)-4-isopropyl-2-(6-
methylpyridin-2-yl)-4,5-dihydro oxazole (1b), or its tBu
counterpart 1c, yielded bis-phenylated products 4ba and 4ca in
81 and 79% yields, respectively (Table 4).
Table 4. substrate scope of bulky (S)-pyridine-oxazoline-based
ligands [a]
Synthesis of unsymmetrical NN’-bidentate ligands. Next, we
were interested in preparing unsymmetrical Bpy ligands. Thus,
starting from bis-arylated product 4ao containing two 4-
cyanophenyl groups (Scheme 3), arylation of the remaining
methyl group with 4-bromoanisole (2h) afforded the
unsymmetrical product 3aoh in 86% yield. Similarly, further
arylation of mono-phenylated (S)-PyOx compound 5ca, with 1-
bromo-3,5-di-tert-butylbenzene (2g) furnished bis-arylated (S)-
PyOx product 4cag in 83% yield as a 1:1 diastereomeric mixture.
[a] Isolated yield on 0.20 mmol scale
[b] 1.5 equiv of aryl bromide and 1.5 equiv of base were used
Aryl bromides with electron donating groups (i.e. 2h, 4-OMe
group and 2i, 4-NMe2 group) also successfully coupled with 1b to
form products 4bh and 4bi in 60 and 72% yields. Products with
aryl groups bearing 3,5-dimethyl or 3,5-di-tert-butyl substituents
were obtained in good yields (4cd: 78%, 4cg: 75%). Aryl
bromide 2n with an electron withdrawing 3-CF3 group was also
compatible with the reaction conditions, giving product 4cn in
63%. Here, the lower temperature (40o C) may be key to the
success of this electron poor aryl bromide in the presence of
NaN(SiMe3)2 base [in contrast to Table 2 where the milder base
LiN(SiMe3)2 had to be used at 80o C]. 2-Bromonaphthalene (2p)
Scheme 3. Synthesis of an unsymmetrical 2,2’-bipyridine-based
ligand and bis-arylated (S)-PyOx ligand with two different aryl
groups
4
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
Gram scale synthesis. To demonstrate the utility of this reaction,
gram-scale syntheses of tetra-arylated 2,2’-bipyridine-based
ligands 3ad and 3ae were conducted. As shown in Scheme 4a,
the products were obtained in 83 and 88% yield, respectively,
after recrystallization. The gram scale synthesis of bis-arylated
4an also offered the product in 86% yield (Scheme 4b). The
synthesis of (S)-PyOx ligands 4ba and 4cg were also scaled up
successfully with 80 and 79% yields (Scheme 4c). These results
show that our method can be used to prepare significant
quantities of ligands.
reactions show that the bulky ligands prepared herein exhibit
different reactivity than their commercial counterparts.
Table 5. Catalytic activity of the bulky and non-bulky 2,2’-
bipyridine ligands[a].
[a] The yield of 7 was determined by 19F NMR using PhCF3 as the
internal standard
[b] This result is consistent with literature (23%) under identical
conditions.[16]
Conclusion
An efficient and convenient method is advanced to synthesize
bulky N,N’-bidentate ligands. Using this method, twenty bulky
2,2’-bipyridine and thirteen bulky (S)-pyridine-oxazoline ligands
were obtained in yields up to 95% and over 99% ee for the chiral
PyOx ligands. Key to this method is the use of
a
Pd(NIXANTPHOS)-based catalyst system that we have
demonstrated to perform with high efficiency in the coupling of
weakly acidic azaaryl methyl groups with aryl bromides in the
presence of silyl amide bases. The straightforward access to these
ligands makes them attractive for catalyst development.
Experimental Section
Scheme 4. Gram scale synthesis of bulky 2,2’-bipyridine-based
(a,b) and (S)-PyOx-based ligands (c)
General Methods: All reactions were carried out under dry
nitrogen. Anhydrous dimethoxyethane (DME) and 1,4-dioxane
were purchased from Sigma Aldrich and directly used. Unless
otherwise stated, reagents were commercially available and used
as received without further purification. Chemicals were
purchased from Sigma-Aldrich, Acros, Alfa Aesar or Matrix
Scientific. TLC was performed with Merck TLC Silicage l60
F254 plates and detection was under UV light at 220 nm. Flash
chromatography was performed with silica gel (230–400 mesh,
Silicycle). The 1H and 13C{1H} NMR spectra were obtained using
a Bruker AM-500 Fourier-transform NMR spectrometer at 500
and 125 MHz or a Bruker AVIII 400 NMR spectrometer at 400
and 100 MHz, respectively. Chemical shifts are reported in units
of parts per million (ppm) downfield from tetramethylsilane
(TMS), and all coupling constants are reported in hertz (Hz). The
infrared spectra were obtained using a Perkin-Elmer Spectrum
100 Series FTIR spectrometer. High resolution mass
spectrometry (HRMS) and low-resolution mass spectrometry data
were obtained on a Waters LC-TOF mass spectrometer (model
Catalytic activity with bulky bipyridine ligands. The
aminofluorination of alkenes is a useful method to difunctionalize
olefins. Liu and coworkers[16] have observed that the commercial
ligand 6,6’-dimethyl-2,2’-bipyridine (1a) catalyzed a styrene
aminofluorination reaction with a modest yield (23%). We
envisioned that our bulky bipyridine ligands could be more active
ligands for this aminofluorination process. This is based on the
assumption that the bulky ligands should have weaker
coordination with the palladium center and make the palladium
center more electrophilic toward binding the styrene. Such a
hypothesis has been demonstrated in Liu’s work[4f]. From a
preliminary activity study, we observed that our bulky bipyridine
ligand 4aa exhibited enhanced activity compared to 1a in the
styrene aminofluorination reaction[16] under
the literature
conditions. Interestingly, the tetra-phenylated 2,2’-bipydirine
ligand (3aa) did not impart reactivity to the palladium. The
reason for this is not clear at this time, but it may be due to the
increased steric hindrance of the ligand. These preliminary
5
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
LCT-XE Premier) or a Waters SQD mass spectrometer equipped
with an Acquity HPLC using chemical ionization (CI) or
electrospray ionization (ESI) in positive or negative mode,
depending on the analyte. Melting points were determined on a
Unimelt Thomas-Hoover melting point apparatus and are
uncorrected.
To an oven-dried 8 mL reaction vial equipped with a stir bar was
charged 6,6’-dimethyl-2,2’-bipyridine (1a, 0.20 mmol, 1.0 equiv)
and base [NaN(SiMe3)2 (for 4aa, 4ad, 4ah) or LiN(SiMe3)2 (for
4an, 4ao), 2.5 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 mol %) and NIXANTPHOS (8.3 mg, 0.015
mmol, 7.5 mol %) in 2 mL of dry in DME (for 4aa, 4ad, 4ah) or
1,4-dioxane (for 4an, 4ao) was stirred for 10 min at 25 ºC before
it was taken up by a syringe and added to the reaction vial under
nitrogen. Next, aryl bromide (2.50 equiv) was added to the
reaction mixture through a syringe (if the aryl bromide was a
solid, it was added along with 1a and the base). The vial was
capped, removed from the glove box, and stirred for 1 – 12 h at
80 °C. The resulting cloudy, orange or red solution was cooled to
room temperature, opened to air and quenched with 3 drops of
water. The reaction mixture was then passed through a short pad
of silica gel packed into a syringe. The pad was then rinsed with
10 mL ethyl acetate and 20 mL CH2Cl2 and the filtrate was
collected. The volatile materials were removed under reduced
pressure. The resulting crude material was loaded onto a silica gel
column and purified by flash chromatography (eluted with
hexanes and ethyl acetate or hexanes and CH2Cl2) to afford the
desired products.
General Procedure A: for the Synthesis of tetra-arylated 2,2’-
bipydidine ligands
To an oven-dried 8 mL reaction vial equipped with a stir bar was
charged 6,6’-dimethyl-2,2’-bipyridine (1a, 0.20 mmol, 1.0 equiv)
and base [NaN(SiMe3)2, 5.0 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 mol %) and
NIXANTPHOS (8.3 mg, 0.015 mmol, 7.5 mol %) in 2 mL of dry
DME was stirred for 10 min at 25 ºC before it was taken up by a
syringe and added to the reaction vial under nitrogen. Next, aryl
bromide (6.0 equiv) was added to the reaction mixture through a
syringe (if the aryl bromide was a solid, it was added along with
1a and the base). The vial was capped, removed from the glove
box, and stirred for 1 h at 80 °C. The resulting cloudy, orange or
red solution was cooled to room temperature, opened to air and
quenched with 3 drops of water. The reaction mixture was then
passed through a short pad of silica gel packed into a syringe. The
pad was then rinsed with 10 mL ethyl acetate and 20 mL CH2Cl2
and the filtrate was collected. The volatile materials were
removed under reduced pressure. The resulting crude material
was loaded onto a silica gel column and purified by flash
chromatography (eluted with hexanes and ethyl acetate or
hexanes and CH2Cl2) to afford the desired products.
General procedure D: for the synthesis of bis-arylated (S)-
PyOx ligands
To an oven-dried 8 mL reaction vial equipped with a stir bar was
charged with (S)-6-methyl-2-oxazoline-pyridine derivatives (1b
or 1c, 0.20 mmol, 1.0 equiv) and base [NaN(SiMe3)2, 2.4 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
mol %) and NIXANTPHOS (8.3 mg, 0.015 mmol, 7.5 mol %) in
2 mL of dry DME was stirred for 10 min at 25 ºC before it was
taken up by a syringe and added to the reaction vial under
nitrogen. Next, aryl bromide (3.0 equiv) was added to the
reaction mixture through a syringe. Notice that if the aryl
bromide was a solid, it was added along with 1 and the base. The
vial was capped, removed from the glove box, and stirred for 14 h
at 40 °C. The resulting cloudy, orange or red solution was cooled
to room temperature, opened to air and quenched with 3 drops of
water. The reaction mixture was then passed through a short pad
of silica gel loaded into a syringe. The pad was then rinsed with
10 mL ethyl acetate and 20 mL CH2Cl2 and the solvent was
removed under reduced pressure. The crude material was loaded
onto a deactivated silica gel column and purified by flash
chromatography (eluted with hexanes and ethyl acetate) to afford
the desired products.
General Procedure B: for the synthesis of tetra-arylated 2,2’-
bipydidine ligands from electron poor aryl bromides
To an oven-dried 8 mL reaction vial equipped with a stir bar was
charged 6,6’-dimethyl-2,2’-bipyridine (1a, 0.20 mmol, 1.0 equiv)
and base [LiN(SiMe3)2, 5.0 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 mol %) and
NIXANTPHOS (8.3 mg, 0.015 mmol, 7.5 mol %) in 2 mL of dry
1,4-dioxane was stirred for 10 min at 25 ºC before it was taken up
by syringe and added to the reaction vial under nitrogen. Next,
aryl bromide (6.0 equiv) was added to the reaction mixture
through a syringe (if the aryl bromide was a solid, it was added
along with 1a and the base). The vial was capped, removed from
the glove box, and stirred for 12 h or 24 h at 80 °C. The resulting
cloudy, orange or red solution was cooled to room temperature,
opened to air and quenched with 3 drops of water. The reaction
mixture was then passed through a short pad of silica gel packed
into a syringe. The pad was then rinsed with 10 mL ethyl acetate
and 20 mL CH2Cl2 and the filtrate was collected. The volatile
materials were removed under reduced pressure. The resulting
crude material was loaded onto a silica gel column and purified
by flash chromatography (eluted with hexanes and ethyl acetate
or hexanes and CH2Cl2) to afford the desired products.
General procedure E: for the synthesis of mono-arylated (S)-
PyOx ligands
To an oven-dried 8 mL reaction vial equipped with a stir bar was
charged (S)-6-methyl-2-oxazoline-pyridine derivatives (1b or 1c,
0.20 mmol, 1.0 equiv) and base [NaN(SiMe3)2, 1.5 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 mol %)
and NIXANTPHOS (8.3 mg, 0.015 mmol, 7.5 mol %) in 2 mL of
dry DME was stirred for 10 min at 25 ºC before it was taken up
by a syringe and added to the reaction vial under nitrogen. Next,
General Procedure C: for the Synthesis of bis-arylated 2,2’-
bipydidine ligands
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001218
Advanced Synthesis & Catalysis
aryl bromide (1.5 equiv) was added to the reaction mixture
through a syringe. Notice that if the aryl bromides was a solid, it
was added along with 1 and the base. The vial was capped,
removed from the glove box, and stirred for 14 h at 40 °C. The
resulting cloudy, orange or red solution was cooled to room
temperature, opened to air and quenched with 3 drops of water.
The reaction mixture was then passed through a short pad of
silica gel loaded into a syringe. The pad was then rinsed with 10
mL ethyl acetate and 20 mL CH2Cl2 and the solvent was removed
under reduced pressure. The crude material was loaded onto a
silica gel column and purified by flash chromatography (eluted
with hexanes and ethyl acetate) to afford the desired products.
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Acknowledgements
P.J.W. thanks the National Science Foundation (CHE-1902509) for
financial support.
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10.1002/adsc.202001218
Advanced Synthesis & Catalysis
FULL PAPER
Efficient synthesis of bulky 2,2’-bipydidine and (S)-
pyridine-oxazoline ligands
Adv. Synth. Catal. Year, Volume, Page – Page
Zhipeng Zheng, Patrick J. Walsh*
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