Ni-catalyzed construction of C-P bonds from electron-deficient phenols via the in situ aryl C-O activation by PyBroP

Article abstract of DOI:10.1039/c2cc31718d

The C-P bond forming reaction using electron-deficient phenol substrates was considerably challenging. Herein, we present a new protocol that allows for one-pot construction of C-P bonds via the cross-coupling of phenols and phosphine oxide or phosphite i

Full text of DOI:10.1039/c2cc31718d

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COMMUNICATION
Ni-catalyzed construction of C–P bonds from electron-deficient phenols
via the in situ aryl C–O activation by PyBroPw
Yu-Long Zhao,ab Guo-Jie Wub and Fu-She Han*ac
Received 8th March 2012, Accepted 18th April 2012
DOI: 10.1039/c2cc31718d
The C–P bond forming reaction using electron-deficient phenol
substrates was considerably challenging. Herein, we present a
new protocol that allows for one-pot construction of C–P bonds
via the cross-coupling of phenols and phosphine oxide or phosphite
in the presence of a nickel catalyst.
use of inexpensive and highly stable NiCl2(dppp) as catalyst
makes our new protocol an appealing option for the construction
of C–P bonds from phenols.
To identify a suitable activator for phenols, the reactivity of
several naphthol derivatives (1) activated by different reagents
was examined through the coupling with diphenylphosphine
oxide (2) by referring the previous conditions used for C–C
coupling,7b i.e., NiCl2(dppp) (10 mol%), K3PO4 (2.0 equiv.) in
dioxane (3 mL) at 100 1C for 18 h (Scheme 1). The results
showed that among the five naphthol derivatives screened, aryl
sulfamate and BOP were inactive, producing only a trace
amount of the desired product. Mesylate and tosylate afforded
the coupled product 3a in low yields of 19% and 34%,
respectively. Delightedly, naphthol activated by PyBroP could
be coupled much more efficiently to give 3a in 56% yield,
indicating that PyBroP is a promising activator in promoting
the cross-coupling of phenols and phosphorus nucleophiles. In
addition to its relatively high activation efficiency, a notable
advantage offered by the PyBroP activator is that the reaction
might be carried out via a one-pot procedure depending on
an appropriate optimization of the reaction parameters as
exemplified by extensive examples of C–C couplings.7a,b,8
Accordingly, we optimized the reaction conditions aimed at
achieving the transformation through a one-pot procedure
employing naphthol 1a and diphenylphosphine oxide 2 as a
model reaction (Table 1). Typically, the reaction was carried
out by stirring the mixture of 1a, PyBroP, and base under
Owing to their wide availability and structural diversity,
phenols have been the most extensively used substrates in
transition-metal-catalyzed Csp2–X bond cross-couplings. So
far, a myriad of protocols have been developed for effective
construction of C–C1 and C–N bonds.2 In stark contrast, the
C–P bond forming reactions using phenol substrates are far
more challenging. Only very recently, sporadic examples on Pd and
Ni-catalyzed cross-coupling of aryl triflates have been reported.3
While these first examples exemplified that phenols are potential
coupling partners for C–P bond formation, their general use poses
severe limitations owing to the inherent instability of aryl triflates
for handling and storage as well as the requirement of a high
reaction temperature usually over 180 1C.3d
Thus, the development of a new method for practical and reliable
C–P coupling from phenols is urgent and very important due to the
great importance of phosphorus compounds in a broad range of
areas such as functional materials science4 and biochemistry,5 and
most popularly in catalytic chemistry as ligands.6 On the basis of
our longstanding experience in developing new activation methods
or catalyst systems aimed at efficient construction of C–C bonds
from phenolic compounds,7 we have recently paid particular
attention to the C–P bond forming reactions from phenols. Herein,
we present that NiCl2(dppp) (dppp = 1,3-bis(diphenylphosphino)-
propane) is a promising catalyst that allows for the cross-coupling
of phenols and phosphine oxide or H-phosphite activated in situ by
PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate).
Most significantly, the reaction can be performed via a one-pot
operation without the need to isolate the activated phenol
intermediates, thereby improving significantly the reaction
efficiency. Consequently, this advantage combined with the
a Changchun Institute of Applied Chemistry, Chinese Academy of
Sciences, 5625 Renmin Street, Changchun, Jilin 130022, China.
E-mail: fshan@ciac.jl.cn; Tel: +86-431-8526-2936
b Department of Chemistry, Northeast Normal University, Changchun,
Jilin 130024, China
c State Key Laboratory of Fine Chemicals, Dalian 116024, China
w Electronic supplementary information (ESI) available: Experimental
1
procedures, H-, 13C-, and 31P-NMR and HRMS data, and copies of
Scheme 1 Comparison of the reactivity of various naphthol derivatives
1H-, 13C-, and 31P-NMR spectra. See DOI: 10.1039/c2cc31718d
activated by different reagents.
c
5868 Chem. Commun., 2012, 48, 5868–5870
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Table 1 Optimization of the reaction conditions for the one-pot
construction of C–P bonds from phenol mediated by PyBroPa
Having established the optimized conditions for this challenging
reaction, we then examined the feasibility of the method by varying
the phenol components (Table 2). A range of a- and b-naphthol
derivatives whose structures are unsubstituted (3a and 3b) or
decorated by electron-deficient CN, CO2Me, and Ph (3c–3f)
underwent smooth coupling with diphenylphosphine oxide 2
to afford the corresponding coupled products in excellent
yields. Moreover, good yield was also obtained for a sterically
hindered naphthol (3d). The reaction of naphthol derivatives
modified by a strong electron-donating OMe group (3g) and
the non-fused phenols (3h–3j), which have been shown to be
weak electrophiles in Suzuki–Miyaura coupling,9 also proved
to be somewhat more challenging in their C–P bond forming
reaction. Nevertheless, the yield could be improved substantially
when the reaction was carried out either by elevating the reaction
temperature to 120 1C or by increasing the catalyst loading,
except for the excessively deactivated 4-methoxyphenol (3k).
Next, we shifted our attention to the cross-coupling of
N-heteroaromatic phenols because the coupled products are
not only interesting in medicinal chemistry10 and nucleic acid
chemistry,11 but also are anticipated to be novel N,P-hybrid
bidentate ligands in catalytic chemistry.12 Here, we showed
that the fused N-heteroaryl phenols such as 2-OH quinoline,
Ratio of
Entry Catalyst (mol%) 1a/PyBroP/2 Base
Yieldb
Solvent (%)
1
2
3
4
5
6
7
8
PdCl2 (5)
1/1.5/1.5
1/1.5/1.5
1/1.5/1.5
1/1.5/1.5
K3PO4 Dioxane Tracec
K3PO4 Dioxane N.R.c
K3PO4 Dioxane Trace
K3PO4 Dioxane 50
K3PO4 Dioxane 56
K2CO3 Dioxane 65
K2CO3 Toluene Trace
Pd(OAc)2 (5)
PdCl2(dppf) (5)
NiCl2(dppp) (5)
NiCl2(dppp) (10) 1/1.5/1.5
NiCl2(dppp) (10) 1/1.5/1.5
NiCl2(dppp) (10) 1/1.5/1.5
NiCl2(dppp) (10) 1/1.5/1.5
NiCl2(dppp) (10) 1/1.1/1.5
NiCl2(dppp) (10) 1/1.1/1.3
NiCl2(dppp) (10) 1/1.1/1.1
NiCl2(dppe) (10) 1/1.1/1.5
NiCl2(dppf) (10) 1/1.1/1.5
NiCl2(PCy3)2 (10) 1/1.1/1.5
K2CO3 MeCN
K2CO3 MeCN
K2CO3 MeCN
K2CO3 MeCN
K2CO3 MeCN
K2CO3 MeCN
K2CO3 MeCN
83
93
86
80
80
83
79
9
10
11
12
13
14
a
Reaction conditions: Naphthol 1a (0.5 mmol), PyBroP, base (4.0 equiv.)
in solvent (3 mL) at 100 1C for 3 h; then catalyst and diphenylphosphine
b
oxide 2 were recharged in situ and heated at 100 1C for 18 h. Isolated
yield. 5 mol% of dppp was used as supporting ligand.
c
Table 2 One-pot cross-coupling of various phenols with diphenyl
phosphine oxide 2 mediated by PyBroPa
heating for several hours to form a phenolic phosphonium salt,
then diphenylphosphine oxide 2 and the catalyst were recharged
in situ and the resulting mixture was stirred continuously for
additional hours. Some representative results are presented in
Table 1. While several palladium catalysts were inactive for this
reaction (entries 1–3), a nickel catalyst was far more active than
palladium under the same conditions, affording the coupled
product 3a in 50% yield (entry 4). However, extensive efforts
aimed at improving the yield of the coupled product by
increasing the amount of catalyst loading or by changing the
base proved to be less effective, giving rise to only a slight
increase in the yield (entries 4–6). After exhaustive investigation
we observed that the coupling reaction was influenced markedly
by the nature of solvents. Typically, replacement of dioxane
with the less polar toluene solvent decreased dramatically the
yield of 3a from 65% to only a trace amount (entries 6 vs. 7). In
contrast, the use of the more polar MeCN produced 3a in 83%
yield (entry 8). Further detailed optimization revealed that the
yield of 3a could be improved to 93% when the molar ratio of
PyBroP was decreased from 1.5 to 1.1 equivalents (entry 9).
Most possibly, this is attributed to the detrimental influence of
excess PyBroP on the activity of catalyst. However, decrease
in the equivalents of 2 led to a slight decrease in the yield
(entries 10 and 11). Finally, although good yields were obtained
for several other nickel catalysts such as NiCl2(dppe),
NiCl2(dppf), and NiCl2(PCy3)2 (entries 12–14), the catalytic
efficiency of these catalysts is slightly lower than NiCl2(dppp).
Thus, the optimized conditions for this one-pot coupling reaction
are naphthol 1a, PyBroP (1.1 equiv.), base (4.0 equiv.) in MeCN
(3 mL) at 100 1C for 3 h; then NiCl2(dppp) (10 mol%) and
diphenylphosphine oxide 2 (1.5 equiv.) were recharged in situ and
heated at 100 1C for 18 h. Under the optimized conditions, the
coupled product could be obtained in 93% yield.
a
Unless otherwise noted, the reaction conditions were: Phenol 1
(0.5 mmol), PyBroP (0.55 mmol, 1.1 equiv.), K2CO3 (2.0 mmol, 4.0 equiv.)
in MeCN (3 mL) at 100 1C for 3 h; then NiCl2(dppp) (10 mol%) and
diphenylphosphine oxide 2 (0.75 mmol, 1.5 equiv.) were recharged in situ
b
and heated at 100 1C; isolated yield. 20 mol% of catalyst was employed.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5868–5870 5869

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Table 3 One-pot cross-coupling of various phenols with dialkyl
H-phosphite mediated by PyBroPa
avenue for the C–P bond forming reaction and should find
extensive applications owing to the great importance of
phosphorus compounds in a broad spectrum of areas. Further
implication of this work is that it would promote the investigation
of more efficient protocols for C–P coupling of phenols. A detailed
mechanistic study for this reaction is currently underway.
Financial support from Hundred Talent Program and
Academy-Locality Cooperation Program of CAS, and State
Key Laboratory of Fine Chemicals (KF1008) is acknowledged.
Notes and references
1 For recent extensive reviews on C–C bond formation, see:
(a) D.-G. Yu, B.-J. Li and Z.-J. Shi, Acc. Chem. Res., 2010,
43, 1486; (b) B. M. Rosen, K. W. Quasdorf, D. A. Wilson,
N. Zhang, A.-M. Resmerita, N. K. Garg and V. Percec, Chem.
Rev., 2011, 111, 1346; (c) B.-J. Li, D.-G. Yu, C.-L. Sun and
Z.-J. Shi, Chem.–Eur. J., 2011, 17, 1728.
2 For some examples on C–N bond formation, see: (a) D. S. Surry
and S. L. Buchwald, Chem. Sci., 2011, 2, 27; and references cited
therein; (b) T. Shimasaki, M. Tobisu and N. Chatani, Angew.
Chem., Int. Ed., 2010, 49, 2929; (c) J.-H. Huang and L.-M. Yang,
Org. Lett., 2011, 13, 3750.
a
Unless otherwise noted, the reaction conditions were: Phenol 1
(0.5 mmol), PyBroP (0.55 mmol, 1.1 equiv.), K2CO3 (2.0 mmol, 4.0 equiv.)
in MeCN (3 mL) at 100 1C for 3 h; then NiCl2(dppp) (10 mol%) and
H-phosphite 4 (0.75 mmol, 1.5 equiv.) were recharged in situ and heated at
b
120 1C for 10 h; isolated yield. 20 mol% of catalyst was employed.
3 (a) M. Toffano, C. Dobrota and J.-C. Fiaud, Eur. J. Org. Chem.,
2006, 650; (b) M. Kalek, A. Ziadi and J. Stawinski, Org. Lett.,
2008, 10, 4637; (c) M. Kalek, M. Jezowska and J. Stawinski, Adv.
Synth. Catal., 2009, 351, 3207; (d) G. Yang, C. Shen, L. Zhang and
W. Zhang, Tetrahedron Lett., 2011, 52, 5032.
6-(5H)-phenanthridinone, N–H free carbazole, and 8-OH quinoline
underwent smooth coupling with diphenylphosphine oxide 2
to afford the coupled products 3l–3o in high to excellent yields.
In addition, 2-, 3-, and 4-OH pyridines were also viable
substrates to afford the corresponding products 3p–3r in good
yields. These 1,3- and 1,4-N,P-type compounds are expected to
be interesting ligands upon reducing to triarylphosphine in
addition to their latent biological properties. It should be
mentioned that the moderate yield for 3r resulted from the
troublesome column purification to remove the impurity
contaminated by tripyrrolidinophosphine oxide, a by-product
generated from PyBroP, since the reaction proceeded well as
detected by TLC monitoring.
4 For selected publications, see: (a) T. Bock, H. Mohwald and
¨
¨
R. Mulhaupt, Macromol. Chem. Phys., 2007, 208, 1324;
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14, 3866; (c) S. Jin and K. E. Gonsalves, Macromolecules, 1998,
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S. R. Kasibhatla, T. Jiang, F. Taplin, J. D. Jacintho, H. Li, Z. Sun,
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Poelje, S. C. Potter and M. D. Erion, J. Med. Chem., 2011, 54, 153;
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L. Horsfall, D. Dehareng, M. Kupper, J.-M. Frere, K. Hoffmann,
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6 For some representative examples, see: (a) M.-N. Birkholz,
Z. Freixa and P. W. N. M. van Leeuwen, Chem. Soc. Rev., 2009,
38, 1099; (b) D. S. Glueck, Chem.–Eur. J., 2008, 14, 7108.
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Commun., 2011, 47, 12840; (b) G.-J. Chen, J. Huang, L.-X. Gao
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and N. Chatani, Angew. Chem., Int. Ed., 2008, 47, 4866.
10 W. Jiang, G. Allan, J. J. Fiordeliso, O. Linton, P. Tannenbaum,
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Finally, to further demonstrate the broad applicability of
the methodology, we investigated the couplings of an array of
phenols with H-dialkylphosphite (4) (Table 3). The data showed
that various naphthol derivatives including the unsubstituted
(5a–c) and electron-deficient CN, CO2Me, and Ph modified ones
(5d–g) were coupled successfully under the optimized conditions.
Additionally, a sterically hindered substrate was also tolerated
(5e). Finally, moderate to high yields were obtained for the
non-fused and heteroaromatic phenols (5h–j), albeit a relatively
higher catalyst loading was necessary in some cases.
In summary, we have developed a new protocol for the
construction of C–P bonds via the NiCl2(dppp)-catalyzed
cross-coupling of conventionally challenging phenol substrates.
The method displays a broad feasibility that is amenable not only
to various phenol derivatives including the common phenol and
N-heteroaryl substrates, but also to different types of phosphorus
nucleophiles such as phosphine oxide and phosphite. Most
attractively, the method allows the cross-coupling to be carried
out in a one-pot procedure without the need for isolating the
activated phenol intermediate, thereby improving greatly the
reaction efficiency. Finally, the use of a cheap and highly stable
nickel catalyst represents an added advantage of the method.
Consequently, we believe that the method would open a new
12 K. H. Chung, C. M. So, S. M. Wong, C. H. Luk, Z. Zhou,
C. P. Lau and F. Y. Kwong, Chem. Commun., 2012, 48, 1967; and
references therein.
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5870 Chem. Commun., 2012, 48, 5868–5870
This journal is The Royal Society of Chemistry 2012