A Polystyrene-Cross-Linking Tricyclohexylphosphine: Synthesis, Characterization and Applications to Pd-Catalyzed Cross-Coupling Reactions of Aryl Chlorides

Article abstract of DOI:10.1002/asia.201801651

A polystyrene-cross-linking tricyclohexylphosphine (PS-TCP) was synthesized through radical emulsion polymerization of 4-tert-butylstyrene as a monomer and tris(trans-4-styrylcyclohexyl)phosphine as a threefold cross-linker. The PS-TCP showed enhanced ligand performance compared to the corresponding polystyrene-triphenylphosphine hybrid PS-TPP and tricyclohexylphosphine in Pd-catalyzed Suzuki–Miyaura and Buchwald–Hartwig reactions of aryl chlorides.

Full text of DOI:10.1002/asia.201801651

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CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: A Polystyrene-Cross-Linking Tricyclohexylphosphine: Synthesis,
Characterization and Applications to Pd-Catalyzed Cross-
Coupling Reactions of Aryl Chlorides
Authors: Masaya Sawamura, Junya Arashima, and Tomohiro Iwai
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To be cited as: Chem. Asian J. 10.1002/asia.201801651
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A Polystyrene-Cross-Linking Tricyclohexylphosphine: Synthesis,
Characterization and Applications to Pd-Catalyzed Cross-
Coupling Reactions of Aryl Chlorides
Junya Arashima, Tomohiro Iwai,* and Masaya Sawamura*
Abstract:
A polystyrene-cross-linking tricyclohexylphosphine
(PS-TCP) was synthesized through radical emulsion
polymerization of 4-t-butylstyrene as a monomer and tris(trans-4-
styrylcyclohexyl)phosphine as a three-fold cross-linker. The PS-
TCP showed enhanced ligand performance compared to the
corresponding polystyrene-triphenylphosphine hybrid PS-TPP
and tricyclohexylphosphine in Pd-catalyzed Suzuki–Miyaura and
Buchwald–Hartwig reactions of aryl chlorides.
The present report describes the synthesis of a polystyrene-
cross-linking trialkylphosphine PS-TCP (Figure 1, right) that has
a tricyclohexylphosphine core. The preferred mono-P-ligation of
transition metals was indicated by 31P CP/MAS spectroscopy. The
PS-TCP possessed enhanced ligand performance compared to
PS-TPP and tricyclohexylphosphine in Pd-catalyzed cross-
coupling reactions of aryl chlorides.
For the synthesis of the desired three-fold cross-linking
phosphine (PS-TCP), a cross-linked polymer was constructed in
the form of a phosphine-borane adduct (PS-TCP-BH3) because
trialkylphosphines are prone to oxidation in air (Scheme 1).[6] Thus,
commercially available 4-phenylcyclohexanone (1) was
converted to alkyl chloride 3 through reduction with NaBH4
followed by chlorination with CCl4 and PPh3.[7] Formylation at the
para position of the benzene ring of 3 using TiCl4 and Cl2CHOCH3
gave aldehyde 4 along with trace amounts of isomers. Silica gel
column chromatography followed by recrystallization from hexane
yielded analytically pure 4 in 39% yield based on 2. Subsequent
Wittig reaction afforded 4-styryl-substituted cyclohexyl chloride 5.
Magnesiation and reaction with PCl3, followed by treatment with
BH3·THF, furnished TCP-BH3. Although the crude product
contained small amounts of isomers from stereochemistry of the
cyclohexane ring, isomerically pure TCP-BH3 with an all-
equatorial configuration was obtained by silica gel column
chromatography and reprecipitation from CH2Cl2/hexane. The all-
equatorial configuration of three 1,4-disubstituted cyclohexane
rings was assigned by analogy to the corresponding a-
Trialkylphosphines are widely used as ligands in transition metal
catalysis, and are more effective than triarylphosphines for
increasing the electron density of the metal center.[1] In particular,
the role of sterically demanding trialkylphosphines is well-
established in Pd-catalyzed cross-coupling reactions of aryl
chlorides,[2] which are generally less reactive compared to the
corresponding bromides and iodides.
Recently, a new type of polystyrene-triphenylphosphine hybrid
PS-TPP (Figure 1, left), which contains a phosphine unit triply
linked between polystyrene chains, was developed.[3] Due to
spatial isolation of the P center in the polymer matrix, PS-TPP
allowed selective mono-P-ligation to transition metals. As a result,
PS-TPP enabled Pd-catalyzed cross-coupling reactions of aryl
chlorides, regardless of its moderate electron-donating ability.
Thus, the three-fold cross-linking strategy was expanded to the
use of a trialkylphosphine as a cross-linker core.[4,5]
(PS)
Previous work
P
This work
P
(PS)
(PS)
(PS)
tBu
tBu
(PS)
methylstyrene
derivative
a-Me-styrene-TCP-BH3,
the
(PS)
(PS)
stereochemistry of which was determined by single-crystal X-ray
diffraction analysis (Figure 2).[8] This molecular structure was
expected to be suitable for effective spatial isolation of the P
center of the tricyclohexylphosphine-based ligand after cross-
linking the polystyrene chains at the 4-position of the cyclohexyl
rings.
(PS)
(PS)
tBu
tBu
(PS)
(PS)
tBu
(PS)
PS-TPP
PS-TCP
tBu
Figure 1. Polystyrene cross-linking phosphines.
The radical emulsion polymerization of 4-t-butylstyrene (6) in
the presence of TCP-BH3 as a three-fold cross-linker (6/TCP-BH3
~60:1, Scheme 1) gave the polystyrene-phosphine hybrid PS-
TCP-BH3. Subsequently, BH3-deprotection with piperidine in
refluxing toluene afforded the free phosphine PS-TCP. Upon BH3-
deprotection, the 31P CP/MAS NMR signal shifted upfield from 29
to 7 ppm, indicating efficient deprotection in the polymer matrix
(Figure 3). The PS-TCP in dry form was stable against P-oxidation
in air and showed swelling properties similar to PS-TPP.[9] The P
loading of PS-TCP (6/TCP-BH3 62:1) in the polystyrene resins
[*]
Prof. Dr. M. Sawamura
Institute for Chemical Reaction Design and Discovery (WPI-
ICReDD), Hokkaido University
Kita 21, Nishi 10, Kita-ku, Sapporo, Hokkaido 001-0021 (Japan)
E-mail: sawamura@sci.hokudai.ac.jp
J. Arashima, Dr. T. Iwai, Prof. Dr. M. Sawamura
Department of Chemistry, Faculty of Science, Hokkaido University
Sapporo, Hokkaido 060-0810 (Japan)
E-mail: iwai-t@sci.hokudai.ac.jp
Homepage: https://wwwchem.sci.hokudai.ac.jp/~orgmet/
Supporting information for this article is given via a link at the end
of the document.
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29
(a)
was estimated to be 0.16 mmol/g based on combustion elemental
analysis for P. This value, designated as [P]anal (0.16 mmol/g), was
larger than expected from the value [P]calcd, which was calculated
on the basis of the monomers used (0.095 mmol/g).
PS-TCP-BH3
R3P=O
NaBH4
(1.1 eq)
CCl4 (1.4 eq)
PPh3 (1.3 eq)
46
O
OH
Cl
MeOH
CH2Cl2
–78 to 15 °C
overnight
40 °C, 4 h
3 ~65%
an E2 elimination
product (~10%)
1
2 81%
0
δ / ppm
120
100
80
60
40
20
–20
–40
–60
–80
–100 –120
TiCl4 (4 eq based on 3)
CH3OCHCl2 (2 eq based on 3)
O
H
CH2=PPh3 (1.4 eq)
Cl
CH2Cl2, 0 °C to rt, overnight
THF, 0 °C to rt
overnight
7
(b)
4 39% (2 steps, based on 2)
PS-TCP
1) Mg (8 eq based on 5)
THF, rt, 1 h
P
BH3
Cl
2) PCl3 (1 eq)
3
THF, 0 °C to rt, 3 h
3) BH3·THF (1 eq)
THF, 0 °C to rt, 1 h
TCP-BH3 35%
5 91%
(4.5 eq for the next reaction)
R3P=O
(PS)
X
(PS)
4-tBu-styrene (6, ~60 eq)
AIBN (1.2–1.3 eq)
45
P
tBu
(PS)
NaCl, acacia gum
PhCl/H2O (1:20)
80 °C, 24 h
(PS)
tBu
0
120
100
80
60
40
20
–20
–40
–60
–80
–100 –120
(PS)
δ / ppm
Figure 3. 31P CP/MAS NMR spectra of (a) PS-TCP-BH3 and (b) PS-
TCP.
(PS)
X = BH3; PS-TCP-BH3
X = lone pair; PS-TCP
piperidine (excess)
toluene, 120 °C, 4 h
tBu
Scheme 1. Preparation of PS-TCP.
26
(PS)
Rh Cl
(PS)
P
tBu
(PS)
(PS)
tBu
(PS)
(PS)
R3P=O
tBu
[RhCl(cod)(PS-TCP)]
45
‡
‡
spinning
*
side bands
‡
*
*
0
120
100
80
60
40
20
–20
–40
–60
–80
–100 –120
δ / ppm
Figure 4. 31P CP/MAS NMR spectrum obtained from PS-TCP and
[RhCl(cod)]2 (P/Rh 1:2 based on [P]calcd).
Figure 2.
ORTEP drawing of a-Me-styrene-TCP-BH3 (30%
probability level, H atoms, except for the BH3 moiety, and disordered
sections are omitted for clarity).
Next, reactions of PS-TCP with [PdCl2(PhCN)2] were
conducted in benzene at room temperature at different P/Pd ratios
(P/Pd 1:2, 1:1 and 2:1 based on [P]eff, 0.15 mmol/g). The 31P
CP/MAS NMR spectra indicated that PS-TCP preferentially
formed a 1:1 P/Pd complex [Pd(II)-(PS-TCP)] (53–57 ppm) over
a P/Pd 2:1 complex [Pd(II)-(PS-TCP)2] (24–27 ppm), irrespective
of P loading relative to Pd (Figure 5). With excess P atoms (P/Pd
2:1, Figure 5c), the free PS-TCP remained uncoordinated.[11] In
contrast, the corresponding soluble ligand tricyclohexylphosphine
was completely consumed during reaction with [PdCl2(PhCN)2] in
C6D6 at the same P loading ratios (P/Pd 1:2, 1:1 and 2:1; Figure
S6 in SI). When 2 equivalents of tricyclohexylphosphine relative
to Pd were used (P/Pd 2:1, Figure S6c), a bis-P-ligating complex
[PdCl2(PCy3)2] (31P NMR in C6D6; 25.6 ppm) was formed
exclusively. These results indicate that polystyrene-cross-linking
is effective for realizing effective mono-P-ligation of the
tricyclohexylphosphine-based ligand. The NMR studies also
suggested that the 4-phenyl-cyclohexane linkers between the P
The coordination properties of PS-TCP toward transition
metals were investigated using 31P CP/MAS NMR spectroscopy.
Reaction with an excess amount of [RhCl(cod)]2 was conducted
in benzene at room temperature (P/Rh 1:2 based on [P]calcd). The
resulting yellow beads were collected by filtration. The 31P
CP/MAS NMR spectrum showed a new peak at 26 ppm (Figure
4), indicating clean formation of a mono-P-ligating complex
[RhCl(cod)(PS-TCP)] assigned by comparison with the
corresponding soluble complex [RhCl(cod)(PCy3)] (31P NMR in
C6D6; 27.3 ppm).[10] The spectrum also indicated that all of the
polymer-embedded P atoms participated in metal complexation.
Measurement of the amount of unreacted [RhCl(cod)]2 allowed
estimation of Rh loading in the polystyrene resin, which was
calculated to be 0.15 mmol/g. This value was comparable to the
[P]anal value (0.16 mmol/g), determined by combustion elemental
analysis, and can be defined as effective P loading [P]eff for metal
complexation.
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center and cross-linking points of PS-TCP may be too long to
cause complete inhibition of the bis-P-ligation in the polymer
matrix.
of aryl chlorides (65%, entry 2).[3a,b] A single-point-grafted
polystyrene-tricyclohexylphosphine hybrid PS-monopod-TCP
(5%, entry 3) and a soluble counterpart tricyclohexylphosphine
(<1%, entry 4) were much less effective, indicating that the three-
fold cross-linking is essential. Under the present conditions, PS-
TCP showed better ligand performance than did Buchwald’s
(dicyclohexylphosphino)biphenyl-type ligands such as XPhos
(80%, entry 5), SPhos (57%, entry 6), or RuPhos (76%, entry 7),
which are widely used in cross-coupling reactions of aryl
chlorides.[14] The (PS-TCP)-Pd catalyst system was easily
recovered and could be reused at least three times, although with
gradually decreasing yields (1st run, 97%; 2nd run, 96%; 3rd run,
89%; 4th run, 86%).
(a)
57
[Pd(II)-(PS-TCP)]
[Pd(II)-(PS-TCP)2]
spinning side bands
*
26
*
*
0
150 140 120
100
80
60
40
20
δ / ppm
–20
–40
–60
–80 –100 –120
Table 1. Pd-catalyzed Suzuki–Miyaura coupling between 7a and 8a.[a]
(b)
56
[PdCl2(PhCN)2] (1 mol%)
Ligand (2 mol%)
[Pd(II)-(PS-TCP)]
+
MeO
Cl
MeO
Ph
PhB(OH)2
R3P=O
KF (3 eq)
THF (1 mL), 25 °C, 18 h
9a
7a (0.25 mmol)
8a (1.5 eq)
[Pd(II)-(PS-TCP)2]
Entry
Ligand
Yield [%][b]
42
1
2
3
4
5
6
7
PS-TCP
PS-TPP
96 (96)
65
27
spinning side bands
*
*
*
PS-monopod-TCP
PCy3
5
<1
0
150 140 120
100
80
60
40
20
δ / ppm
–20
–40
–60
–80 –100 –120
XPhos
80
SPhos
57
(c)
7
PS-TCP
[Pd(II)-(PS-TCP)2]
RuPhos
76
44
[a] Conditions: 7a (0.25 mmol), 8a (0.375 mmol), [PdCl2(PhCN)2] (1
R3P=O
mol%), ligand (2 mol% based on [P]calcd, 0.095–0.098 mmol/g), KF
1
53
[Pd(II)-(PS-TCP)]
(0.75 mmol), THF (1 mL), 25 °C, 18 h. [b] Yields determined by H
NMR analysis. Isolated yield shown in parentheses.
(PS)
24
P
P
P
spinning side bands
RO
*
*
*
tBu
(PS)
RO
PS-monopod-TCP
(DVB-co-cross-linked)
XPhos
R = Me; SPhos
R = iPr; RuPhos
0
150 140 120
100
80
60
40
20
δ / ppm
–20
–40
–60
–80 –100 –120
Figure 5. 31P CP/MAS NMR spectra obtained from PS-TCP and
[PdCl2(PhCN)2] [P/Pd at a ratio of (a) 1:2, (b) 1:1, and (c) 2:1 based
on [P]eff].
Within the (PS-TCP)-Pd system, several aryl chlorides and
arylboronic acids participated in the coupling reactions (Scheme
2). Notably, p-chloro-N,N-dimethylaniline, which was strongly
deactivated electronically by the NMe2 group, successfully
coupled with 8a to give biaryl 9b. The reactions of electron-
deficient and heteroaryl chlorides occurred smoothly at 25 or
60 °C (9c and 9d). Electron-rich and -poor arylboronic acids
served as suitable substrates (9e and 9f).
The preferred mono-P-ligation of PS-TCP supported by
NMR analysis for P–Pd coordination promoted its use as a
coordinating ligand in Pd-catalyzed Suzuki–Miyaura coupling of
aryl chlorides,[12] in which the utility of bulky trialkylphosphines has
been established.[2] Reaction between 4-chloroanisole (7a), as an
example of an electronically deactivated aryl chloride, and
phenylboronic acid (8a) was conducted with 1 mol% Pd catalyst
prepared in situ from [PdCl2(PhCN)2] as a Pd precursor (P/Pd 2:1
based on [P]calcd, 0.095–0.098 mmol/g, 6/TCP-BH3 60–62:1) with
KF as a base in THF at 25 °C for 18 h.[13] The results are
summarized in Table 1.
The PS-TCP induced the coupling reaction, giving the
desired product 9a in 96% yield (Table 1, entry 1). Its catalytic
activity was significantly greater than that with PS-TPP, which is
known to be useful in the Pd-catalyzed cross-coupling reactions
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