Preparation of Aryl(dicyclohexyl)phosphines by C-P Bond-Forming Cross-Coupling in Water Catalyzed by an Amphiphilic-Resin-Supported Palladium Complex

Article abstract of DOI:10.1055/s-0036-1590926

Aryl(dicyclohexyl)phosphines were prepared by a catalytic C-P bond-forming cross-coupling reaction of haloarenes with dicyclohexylphosphine under heterogeneous conditions in water containing an immobilized palladium complex coordinated to an amphiphilic polystyrene-poly(ethylene glycol) resin supported di(tert -butyl)phosphine ligand.

Full text of DOI:10.1055/s-0036-1590926

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
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Y. Hirai, Y. Uozumi
Letter
Synlett
Preparation of Aryl(dicyclohexyl)phosphines by C–P Bond-Form-
ing Cross-Coupling in Water Catalyzed by an Amphiphilic-Resin-
Supported Palladium Complex
Yoshinori Hirai
Yasuhiro Uozumi*
Institute for Molecular Science (IMS), Okazaki 444-8787, Japan
uo@ims.ac.jp
◊ Visiting scientist from KANEKA corporation
Dedicated to Professor Victor A. Snieckus on the occasion of his
80th birthday
Received: 03.08.2017
Accepted after revision: 11.09.2017
Published online: 16.10.2017
bearing a highly coordinative phosphine ligand might be
capable of resisting product inhibition to realize a catalytic
C–P bond-forming cross-coupling reaction.
DOI: 10.1055/s-0036-1590926; Art ID: st-2017-r0609-l
Abstract Aryl(dicyclohexyl)phosphines were prepared by a catalytic
C–P bond-forming cross-coupling reaction of haloarenes with dicyclo-
hexylphosphine under heterogeneous conditions in water containing
an immobilized palladium complex coordinated to an amphiphilic poly-
styrene–poly(ethylene glycol) resin supported di(tert-butyl)phosphine
ligand.
R
R
Pd(OAc)2/DiPPF
+
X
HP
P
t-BuONa, toluene
80 °C, 6–18 h
X = Br, Cl
DiPPF =
up to 87% yield
Key words phosphines, haloarenes, C–P bond, cross-coupling, aque-
ous media, polymer support, palladium
P(i-Pr)2
P(i-Pr)2
Fe
Scheme 1 Representative results of Buchwald’s pioneering work
Because of their presence in many catalytically active
transition-metal complexes, trialkylphosphines have
aroused considerable interest from the synthetic organic
chemistry community. In particular, aryl(dicyclohex-
yl)phosphines have recently been widely and successfully
used as powerful ligands for driving palladium-catalyzed
cross-coupling reactions, including aromatic aminations
(the Buchwald–Hartwig reaction) and C–C bond-forming
coupling reactions of aryl chlorides. However, despite the
versatile synthetic utility of aryl(dicyclohexylphosphines),
there have been few reports on their preparation by cataly-
sis, whereas a number of catalytic methods have been re-
ported for preparing triarylphosphines.1,2 Indeed, to the
best of our knowledge, well-developed research on the cata-
lytic preparation of aryl(dialkyl)phosphines has been limit-
ed to Muruda and Buchwald’s report on the palladium-cat-
alyzed cross-coupling of aryl halides with dialkylphos-
phines in the presence of a 1,1′-bis(diphenyl)ferrocene
(DiPPF) ligand (Scheme 1).3 One of the major problems as-
sociated with the catalytic preparation of aryl(dicyclohex-
yl)phosphines lies in the coordinating nature of the prod-
ucts, which can poison the catalytic transition-metal spe-
cies (i.e., product inhibition). However, a palladium complex
We have developed a series of amphiphilic polystyrene–
poly(ethylene glycol) (PS–PEG) resin-supported phos-
phine–palladium complexes that smoothly catalyze various
palladium-mediated reactions, including C–C,4 C–N,5 and
C–S6 bond-forming cross-coupling reactions in water under
heterogeneous conditions, to meet the requirements of
green, safe, and clean organic synthesis.7,8
We previously reported a Buchwald–Hartwig amination
of aryl halides with diarylamines in water to form triaryl-
amines in the presence of a palladium complex of a PS–PEG
resin-supported
alkyl[di(tert-butyl)]phosphine
ligand
(Scheme 2).5 This success in C–X bond-forming cross-cou-
pling prompted us to examine the cross-coupling of aryl ha-
lides with dicyclohexylphosphine in water in the presence
of the resin-supported palladium complexes to realize a
catalytic synthesis of aryl(dicyclohexyl)phosphines. The al-
kyl[di(tert-butyl)]phosphine should coordinate to palladi-
um more strongly than the aryl(dicyclohexyl)phosphine,
thereby preventing product inhibition in the catalytic
preparation of aryl(dicyclohexyl)phosphines.9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
Y. Hirai, Y. Uozumi
Letter
Synlett
aryl(dicyclohexyl)phosphines by C–P bond-forming cross-
coupling in water with a heterogeneous palladium complex
might be feasible. Here we report our results demonstrating
that coupling reactions of various aryl halides with dicyclo-
hexylphosphine do indeed proceed in water in the presence
of a palladium complex of a PS–PEG resin-supported al-
kyl[di(tert-butyl)]phosphine ligand.
Authors' previous work (ref. 5)
R
R
[Pd]/L (cat)
Br
N
+
HN
base, H2O
This work
R
R
[Pd]/L (cat)
Br
P
+
HP
base, H2O
PS-
PEG
PS-
PEG
L1 =
P
L2 =
P
PS-
PEG
L =
P
Figure 1
Scheme 2 C–X cross-couplings with a PS–PEG-supported phosphine li-
gand
First, we examined the coupling reaction of bromoben-
zene (1) with dicyclohexylphosphine (2) in the presence of
various transition-metal catalysts (Table 1). A palladium
complex, prepared in situ by mixing di-μ-chlorobis[(η3-al-
lyl)palladium(II)] ([PdCl(η3-C3H5)]2) and amphiphilic poly-
styrene–poly(ethylene glycol) resin-supported di(tert-bu-
tyl)phosphine (PS–PEG-P(t-Bu)2; L1; Figure 1)5 smoothly
promoted the C–P coupling under aqueous conditions.
When a mixture of bromobenzene (1; 1.1 equiv), dicyclo-
The use of heterogeneous reaction conditions (e.g.,
aqueous–organic, solid–liquid) should markedly facilitate
the isolation of the desired products with high chemical pu-
rity. Furthermore, switching of a given organic transforma-
tion to aqueous and heterogeneous conditions has been
rapidly gaining in importance because of its ability to pro-
vide safe and green chemical processes. Consequently, we
had good reason to believe that the catalytic preparation of
Table 1 Coupling of Bromobenzene (1a) with Dicyclohexylphosphine 2 with Various Transition-Metal Catalystsa
cat
+
Br
HP
P
base, solvent
1a
0.55 mmol
2
3a
0.50 mmol
Entry
Catalyst
Solvent
Base
KOH
Time (h)
Conversion (%) of 2b Yield (%) of 3ac
1
2
[PdCl(η-C3H5)]2/L1 (Pd/P = 1:1)
(3rd use)
H2O
10
20
2
>99
<5
90
–
3
[PdCl(η-C3H5)]2/L1 (Pd/P = 1:2)
(3rd use)
H2O
KOH
>99
>99
>99
35
89
94
95
–
4
12
30
24
24
24
24
24
24
10
5
(5th use)
6
[PdCl(η-C3H5)]2/L1 (Pd/P = 1:2)
[PdCl(η-C3H5)]2/L1 (Pd/P = 1:2)
[PdCl(η-C3H5)]2/L1 (Pd/P = 1:2)
[PdCl(η-C3H5)]2/L2 (Pd/P = 1:2)
CuI
H2O
NaOH
7
H2O
Cs2CO3
t-BuOLi
KOH
<5
–
8
toluene
H2O
53
–
9
<5
–
10
11
12
toluene
toluene
DMF
Cs2CO3
Cs2CO3
DABCO
<5
–
CuI/MeNH(CH2)2NHMe
NiCl2/dpped
<5
–
40
36
a Reaction conditions: 1a (mol)/2 (mol)/Pd (mol)/H2O (L) = 0.55:0.5:0.05:0.5–1.0, 100 °C, N2.
b Determined by GC analysis.
c Isolated yield.
d dppe = 1,2-bis(diphenylphosphino)ethane.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
Y. Hirai, Y. Uozumi
Letter
Synlett
hexylphosphine (2; 1 equiv), [PdCl(η3-C3H5)]2 (10 mol% Pd),
and L1 (P/Pd = 1:1) was agitated with shaking in 20 M aque-
ous KOH at 100 °C for ten hours, complete conversion of 2
was observed by GC analysis. The reaction mixture was
cooled and filtered, and the resin beads were rinsed five
times with small portions of degassed toluene to give a 90%
isolated yield of dicyclohexyl(phenyl)phosphine (3) by
chromatographic purification (Table 1, entry 1). When we
reused the recovered resin catalyst without any additional
charge of palladium, we observed a significant decrease in
its catalytic performance (second use: 90% yield after 30 h;
third use: <5% yield after 20 h; Table 1, entry 2). When the
reaction was carried out in the presence of an excess of L1
(Pd/P = 1:2), the C–P coupling exhibited a better and more-
stable performance, giving a quantitative conversion and an
89% isolated yield of phosphine 3a within two hours, under
otherwise similar conditions (Table 1, entry 3); further-
more, the recovered resin catalyst was successfully reused
several times, although a longer reaction time was required
to accomplish the C–P coupling (Table 1, entries 4 and 5).
The palladium–L1 complex showed a much poorer catalytic
performance with sodium hydroxide or cesium carbonate
as the base (Table 1, entries 6 and 7). The reaction carried
out in toluene in the presence of t-BuOLi resulted in a mod-
erate conversion (Table 1, entry 8). When PS–PEG-support-
ed triarylphosphine L2 was used instead of L1 under similar
conditions in water, the reaction did not proceed (Table 1,
entry 9). Copper iodide did not catalyze the C–P coupling of
bromobenzene (1a; Table 1, entries 10 and 11), although
CuI is known to promote the aromatic phosphinylation of
iodobenzene.10 The C–P coupling in the presence of a
NiCl2/1,2-bis(diphenylphosphino)ethane (dppe) catalyst in
DMF gave a 36% yield of 3a (Table 1, entry 12).11
Having identified an effective catalytic system for the C–
P coupling, we next examined the reactions of a variety of
haloarenes under similar conditions.12 Scheme 3 summa-
rizes some representative results. Aryl bromides bearing
electron-withdrawing or electron-donating groups (CF3,
Me, or OMe) underwent the C–P coupling under the stan-
dard coupling conditions to afford the corresponding
aryl(dicyclohexyl)phosphines 3b–o in 73–91% isolated
yield. The ortho, meta, and para substituents were all toler-
ated, showing that the catalytic performance was not
strongly affected by steric factors associated with the aryl
halide. Note that 1-chloro-4-(trifluoromethyl)benzene (1b-
Cl) reacted with dicyclohexylphosphine (2) to give a 66%
yield of phosphine 3b, whereas the corresponding bromo
compound, 1-bromo-4-(trifluoromethyl)benzene (1b-Br),
gave a 78% yield of 3b. The heteroaromatic bromopyridines
3k–m and bromothiophenes 3n and 3o also underwent
coupling to give the corresponding dicyclohexyl(het-
aryl)phosphines 3k–o in 73–88% yield.
[PdCl(η3-C3H5)]2/L1
(10 mol% Pd)
R
R
Br
P
+
2
KOH, H2O
100 °C
1b–o
3b–o
F3C
CF3
PCy2
F3C
PCy2
PCy2
3b: 78%
(66% from ArCl)
3c: 80%
3f: 83%
3d: 81%
CH3
H3C
H3C
PCy2
PCy2
PCy2
3e: 91%
3g: 85%
OMe
MeO
MeO
PCy2
PCy2
PCy2
PCy2
PCy2
3h: 77%
3k: 75%
3i: 85%
3j: 86%
N
N
N
PCy2
3l: 81%
PCy2
3m: 88%
PCy2
S
S
3n: 73%
3o: 88%
Scheme 3 C–P coupling reactions of various aryl halides
The wide substrate tolerance, in particular the compati-
bility of the reaction with ortho substituents and with ni-
trogen heterocycles, prompted us to apply our catalytic C–P
coupling to the preparation of biphenyl-2-yl(dicyclohex-
yl)phosphine (3p; Cyclohexyl JohnPhos)13 and (4S)-2-[2-
(dicyclohexylphosphino)phenyl]-4-isopropyl-4,5-dihydro-
1,3-oxazole (3q)14 (Scheme 4). Cyclohexyl JohnPhos (3p) is
an effective phosphine ligand for a variety of cross-coupling
reactions, such as the Buchwald–Hartwig aromatic amina-
tion. 2-Bromobiphenyl (1p) reacted with dicyclohexylphos-
phine (2) under the standard catalytic conditions to give an
81% isolated yield of Cyclohexyl JohnPhos (3p). A series of
homochiral aryl(oxazolyl)phosphines have been developed
to realize various asymmetric catalytic organic transforma-
tions, and (4S)-2-[2-(dicyclohexylphosphino)phenyl]-4-
isopropyl-4,5-dihydro-1,3-oxazole (3q) is a representative
example of these ligands. (4S)-2-(2-bromophenyl)-4-iso-
propyl-4,5-dihydro-1,3-oxazole (1q), which was readily
prepared from 2-bromobenzoic acid and (S)-valinol, react-
ed with dicyclohexylphosphine (2) under the standard C–P
coupling conditions to give an 82% isolated yield of the de-
sired phosphine 3q in its homochiral form.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
Y. Hirai, Y. Uozumi
Letter
Synlett
(3) For a pioneering study on C–P coupling reaction of arylhalides
and dicyclohexylphosphine, see: Murada, M.; Buchwald, S. L.
Tetrahedron 2004, 60, 7397.
[PdCl(η3-C3H5)]2/L1
(10 mol% Pd)
+
2
KOH, H2O
100 °C
(4) For studies on cross-coupling in water with polymeric palla-
dium complexes from the author’s group (selected publica-
tions), see for Suzuki–Miyaura coupling: (a) Uozumi, Y.; Danjo,
H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384. (b) Uozumi, Y.;
Nakai, Y. Org. Lett. 2002, 4, 2997. Heck reaction: (c) Uozumi, Y.;
Kimura, T. Synlett 2002, 2045. Sonogashira reaction:
(d) Uozumi, Y.; Kobayashi, Y. Heterocycles 2003, 59, 71. Asym-
metric alkylation: (e) Uozumi, Y.; Shibatomi, K. J. Am. Chem. Soc.
2001, 123, 2919. Asymmetric cross-coupling: (f) Uozumi, Y.;
Matsuura, Y.; Arakawa, T.; Yamada, Y. M. A. Angew. Chem. Int.
Ed. 2009, 48, 2708. Sonogashira coupling: (g) Suzuka, T.; Okada,
Y.; Ooshiro, K.; Uozumi, Y. Tetrahedron 2010, 66, 1064. Allylic
arylation: (h) Sarkar, S. M.; Uozumi, Y.; Yamada, Y. M. A. Angew.
Chem. Int. Ed. 2011, 50, 9437. Suzuki–Miyaura coupling:
(i) Yamada, Y. M. A.; Sarkar, S. M.; Uozumi, Y. J. Am. Chem. Soc.
2012, 134, 3190. Heck reaction: (j) Sato, T.; Sarkar, S. M.;
Uozumi, Y.; Yamada, Y. M. A. ChemCatChem 2015, 7, 2141.
Hiyama coupling: (k) Ohtaka, A.; Kotera, T.; Sakon, A.; Ueda, K.;
Hamasaka, G.; Uozumi, Y.; Shinagawa, T.; Shimomura, O.;
Nomura, R. Synlett 2016, 27, 1202. Asymmetric C–C coupling:
(l) Uozumi, Y.; Matsuura, Y.; Suzuka, T.; Arakawa, Y.; Yamada, Y.
M. A. Synthesis 2017, 49, 59.
Br
PCy2
1p
3p 81%
O
[PdCl(η3-C3H5)]2/L1
(10 mol% Pd)
O
N
N
+
2
KOH, H2O
100 °C
Br
PCy2
1q
3q 82%
Scheme 4 Preparation of synthetically useful phosphines
In summary, we have developed a novel C–P bond-form-
ing catalytic protocol with an amphiphilic polymeric palla-
dium complex of the sterically demanding alkylphosphine
ligand L1; the reaction was carried out in water under het-
erogeneous conditions to realize a high level of chemical
greenness. The synthetic utility of this protocol was
demonstrated by the preparation of the catalytically useful
aryl(dicyclohexyl)phosphines 3p and 3q. Although the
range of tolerated phosphine substrates is currently limited
to dicyclohexylphosphine,15 further synthetic applications
of this C–P coupling, in particular the expansion of its sub-
strate tolerance toward alkylphosphines, is currently under
investigation in our laboratory, and will be reported in due
course.
(5) (a) Hirai, Y.; Uozumi, Y. Chem. Asian J. 2010, 5, 1788. (b) Hirai,
Y.; Uozumi, Y. Chem. Commun. 2010, 45, 1103.
(6) Hirai, Y.; Uozumi, Y. Chem. Lett. 2011, 40, 934.
(7) For recent reviews on heterogeneous-switching of transition-
metal catalysis, see: (a) Uozumi, Y. Immobilized Catalysts Solid
Phases, Immobilization and Applications, In Topics in Current
Chemistry;
2
V4o2.
l
Kirschning, A., Ed.; Springer: Berlin, 2004, 77; DOI:
10.1007/b96874. (b) Guinó, M.; Hii, K. K. M. Chem. Soc. Rev.
2007, 36, 608. (c) Wang, Z.; Chen, G.; Ding, K. Chem. Rev. 2009,
109, 322. (d) Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815.
(e) Lamblin, M.; Nassar-Hardy, L.; Hierso, J.-C.; Fouquet, E.;
Felpin, F.-X. Adv. Synth. Catal. 2010, 352, 33. (f) Hierso, J.-C.;
Uozumi, Y. Synlett 2016, 27, 1177.
Funding Information
(8) For recent reviews on aqueous-switching of organic reactions,
see: (a) Jessop, P. G. Green Chem. 2011, 13, 1391. (b) Simon, M.-
O.; Li, C.-J. Chem. Soc. Rev. 2012, 41, 1415. (c) Dixneuf, P. H.;
Cadierno, V. Metal-Catalyzed Reactions in Water; Wiley-VCH:
Weinheim, 2013. (d) Zhang, F.; Li, H. Chem. Sci. 2014, 5, 3695.
(9) It has been reported that coordination ability of tricyclohexyl-
phosphine to palladium is 580 times larger than dicyclohexyl-
phenylphosphine to indicate high coordinating potential of PS-
PEG-supported trialkylphosphine lighands. Minakawa, M.;
Takenaka, K.; Uozumi, Y. Eur. J. Inorg. Chem. 2007, 1629.
(10) (a) Van Allen, D.; Venkataraman, D. J. Org. Chem. 2003, 68, 4591.
(b) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315.
(c) Tani, K.; Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org.
Lett. 2007, 9, 2529. (d) Zhang, H.; Zhang, X.-Y.; Dong, D.-Q.;
Wang, Z.-L. RCS Adv. 2015, 65, 52824.
This work was supported by the ACCEL program, which is sponsored
by the JST. We also acknowledge the financial support for this work
provided by the JSPS (Grant-in-Aid for Scientific Research on Innova-
tive Area #2707 ‘Middle Molecular Strategy’).
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590926 and from the author.
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References and Notes
(1) For recent reviews on C–P cross coupling, see: (a) Tappe, F. M. J.;
Trepohl, V. T.; Oestreich, M. Synthesis 2010, 3037. (b) Glueck, D.
S. Top. Organomet. Chem. 2010, 31, 65. (c) Berger, O.; Petit, C.;
Deal, E. L.; Montchamp, J.-L. Adv. Synth. Catal. 2013, 335, 1361.
(2) For studies on C–P coupling reactions with palladium catalysis,
see: (a) Machnitzki, P.; Nickel, T.; Stelzer, O.; Landgrafe, C. Eur. J.
Inorg. Chem. 1998, 1029. (b) Kwong, F. Y.; Chan, K. S. Chem.
Commun. 2000, 1069. (c) Damian, K.; Clarke, M. L.; Cobley, C. J.
Appl. Organometal. Chem. 2009, 23, 272; see also ref. 1c.
(11) Cai, D.; Hughes, D. L.; Verhoeven, T. R.; Reider, P. J. Tetrahedron
Lett. 1995, 36, 7991.
(12) General Procedure for the Catalytic Phosphinylation of
Haloarenes
A mixture of L1 (480 mg, 0.10 mmol of P), [PdCl(η3-C3H5)]2 (9
mg, 0.025 mmol), arylhalides (1, 0.55 mmol), and dicyclohexyl-
phosphine (2, 99 mg, 0.50 mmol) in 20 M KOH aqueous solution
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Y. Hirai, Y. Uozumi
Letter
Synlett
(0.5–1.0 mL) under nitrogen atmosphere was agitated with
shaking for several hours upon heating at 100 °C. After being
cooled, the reaction mixture was filtered, and the aqueous fil-
trate was extracted with degassed toluene (2 × 2 mL). Recovered
catalyst resin beads were extracted with degassed toluene (4 × 2
mL). The combined extract was dried over anhydrous Na2SO4
and concentrated in vacuo to give a crude residue. The residue
was purified by silica gel flash chromatography (eluent:
degassed n-hexane/Et2O = 10:0 to 9:1) to give an aryldicyclo-
hexylphosphine 3.
2-(Dicyclohexylphosphine)biphenyl (3p; Scheme 4)
CAS: 247940-06-3; colorless solid; 142 mg (81% yield); mp 78–
80 °C. 1H NMR (500 MHz, CDCl3, 25 °C): δ = 7.58–7.60 (m, 1 H),
7.25–7.38 (m, 8 H), 1.55–1.84 (m, 12 H), 1.00–1.27 (m, 10 H).
MS (ESI+): m/z = 350 [M+].
(13) Compound 3p (CAS : 247940-06-3): Kendall, A. J.; Zakharov, L.
N.; Tyler, D. R. Inorg. Chem. 2016, 55, 3079; and references cited
therein.
(14) Compound 3q (CAS 180260-74-6): Ikeda, R.; Kuwano, R. Chem.
Eur. J. 2016, 25, 8610; and references cited therein.
Selected Data
(15) Because of the unique reactivity as well as the coordinating
ability of the substrates (R2PH) and the products (R2ArP), thor-
ough condition screening should be required for each individual
substrate. Thus, for examples, the coupling of Ph2PH and t-
Bu2PH with PhBr gave only 33% and <10% of the products, Ph3P
and t-Bu2PhP, respectively, under the present conditions.
Dicyclohexylphenylphosphine (3a; Table 1 Entry 1)
CAS: 6476-37-5; yellow oil; 123 mg (90% yield). 1H NMR (500
MHz, CDCl3, 25 °C): δ = 7.37–7.42 (m, 2 H), 7.25–7.27 (m, 3 H),
1.51–1.86 (m, 12 H), 0.88–1.29 (m, 10 H). MS (ESI+): m/z = 274
[M+].
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E