Aryl phosphoramides: useful electrophiles for suzuki-miyaura coupling catalyzed by a NiCl2/dppp system (dppp=1,3-bis(diphenylphosphino) propane)

Article abstract of DOI:10.1002/chem.201000420

Chemical Equation presantation Suzuki-Miyaura coupling: We disclose a new strategy for phenol activation in the first Suzuki-Miyaura coupling of phenol derivatives activated by forming aryl bis(2-oxo-3-oxazolidinyl)phosphines as a highly efficient and broadly applicable methodology for the diverse synthesis of biaryls and heterobiaryls (see scheme). The use of readily available, stable NiCl₂/dppp as the catalyst system also provides an important advance.

Full text of DOI:10.1002/chem.201000420

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DOI: 10.1002/chem.201000420
Aryl Phosphoramides: Useful Electrophiles for Suzuki–Miyaura Coupling
Catalyzed by a NiCl2/dppp System (dppp=1,3-
Bis(diphenylphosphino)propane)
Yu-Long Zhao,[a, b] You Li,[b] Yu Li,[a] Lian-Xun Gao,[a] and Fu-She Han*[a]
The transition-metal-catalyzed cross-coupling of phenol
derivatives has emerged as an extremely attractive method
in synthetic chemistry, because of the many advantages per-
taining to the use of phenol derivatives.[1] So far, aryl tri-
flates or nonaflates have frequently been investigated,[1–3]
but their high cost and instability are deterrents to their ex-
tensive use.[4] As more affordable and manipulatable substi-
tutes aryl sulfonates,[5–7] ethers,[8] and phosphates[9] are viable
electrophiles. However, the successful coupling of these
inert electrophiles often exhibits marked substrate specifici-
ty and necessitates rigorous catalysis, wherein air-sensitive,
transition-metal complexes and bulky, electron-rich phos-
phine or N-heterocyclic-carbene ligands are usually re-
quired. More significantly, although the coupling reactions
of phenol derivatives have been extensively studied, cou-
plings under milder, more appealing Suzuki–Miyaura condi-
tions are relatively rare.[5b–f,7,8c] Particularly, the Suzuki–
Miyaura coupling of aryl phosphates has not been realized
and has been shown to be extremely difficult, as exemplified
by the Pd0- and Ni0-catalyzed coupling reactions of an O,O-
diphenyl-O-vinylphosphate, which occur exclusively with
vinyl functions under Suzuki–Miyaura conditions.[9e,f]
ACTHGNURTEN(UNGN PCy3)2Cl2] and PCy3 (or PCy3HBF4) ligands. The ready
availability of aryl substrates and the facile handling of the
catalysts render these processes highly attractive. Despite
these significant advances, the coupling efficiency of most of
these processes (except for aryl sulfamates) is moderate for
non-fused, aromatic aryl substrates, even in the presence of
a large excess of the boronic acid (4.0–5.0 equivalents) and
the base (7.2–9.0 equiv). Therefore, the development of a
system that allows efficient Suzuki–Miyaura coupling re-
mains a challenge. Herein, we present the first Suzuki–
Miyaura reactions of aryl phosphoramides as a highly effi-
cient and broadly applicable methodology for the diverse
synthesis of biaryls and heterobiaryls, which uses a cheaper,
as well as much more stable, catalyst system consisting of
NiCl2 and 1,3-bis(diphenylphosphino)propane (dppp).
During our search for a new methodology for phenol acti-
vation, we shifted our attention from the conventionally in-
vestigated aryl carbonyl- and sulfonyl-based derivatives to
aryl phosphoramides (Scheme 1) and chose bis(2-oxo-3-
Recently, the Suzuki–Miyaura reactions of aryl esters,[10]
carbamates,[11] carbonates,[11a] and sulfamates[11a] have been
successfully achieved by using [NiACTHUNRGTNEG(UN PCy3)2Cl2] (Cy=cyclo-
hexyl) as the catalyst or a catalyst system composed of [Ni-
Scheme 1. New strategy for the activation of phenol derivatives; Tf=tri-
flate, Ts=tosyl, Ms=methane sulfonyl, and Piv=pivaloyl.
[a] Dr. Y.-L. Zhao, Y. Li, Prof. Dr. L.-X. Gao, Prof. Dr. F.-S. Han
Changchun Institute of Applied Chemistry
Chinese Academy of Sciences, 5625 Renmin Street
Changchun, Jilin 130022 (China)
oxazolidinyl)phosphinic chloride (BOP-Cl)[12] as the reagent.
We reasoned that the BOP moiety would be an effective
leaving group after the abstraction of a phenolic oxygen
atom, thanks to the electron-withdrawing nature of the two
oxazolidinyl groups attached to the phosphorus atom, there-
by facilitating the oxidative addition of a metal into the aryl
Tel : (+86)431-8526-2936
E-mail: fshan@ciac.jl.cn
[b] Dr. Y.-L. Zhao, Y. Li
Department of Chemistry, Northeast Normal University
Changchun, Jilin 130024 (China)
À
C O bond. Indeed, BOP-Cl exhibits an outstanding ability
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000420.
À
to activate the C O bonds in carboxylic acids as seen its use
Chem. Eur. J. 2010, 16, 4991 – 4994
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4991

in the formation of amides, esters, and thioesters,[12] although
tron-rich (Table 1, entries 1–4), electron-neutral (Table 1,
entry 5), or electron-deficient groups (Table 1, entries 6 and
7). Consequently, good to excellent yields were obtained for
all boronic acids examined.
These preliminary results are in sharp contrast to the re-
ported examples in which electron-deficient ligands such as
À
its use in activating the phenolic C O bond is virtually un-
known.
To examine the coupling efficiency of phenol substrates
activated by BOP-Cl (known here as aryl BOPs), the cross-
coupling of 1-naphthyl BOP (1a)[13] with 4-methoxyphenyl-
boronic acid (2a) was performed under Suzuki–Miyaura
conditions (Table 1). To our delight, a careful survey of vari-
dppp and dppe proved to be inefficient for the [Ni
ACHTUNGTRENNUNG(cod)2]-
(cod=cyclooctadiene) and [Ni(PCy3)2Cl2]-catalyzed Suzuki–
AHCTUNGTRENNUNG
Miyaura couplings of phenol derivatives such as aryl tosyla-
tes[5d] and esters.[10a] However, in comparison with the fre-
quently used [NiACHTUNTRGENNUG(cod)2] and [NiCAHUTGNTRENN(GUN PCy3)2Cl2] catalysts and
Table 1. Coupling of 1-naphthyl BOP (1a) with various arylboronic acids
2a–e.[a]
PCy3 and PCy3HBF4 ligands, the NiCl2 catalyst and the
dppp, dppb, or dppe ligands employed herein are more af-
fordable[15] and, most importantly, exhibit a much higher re-
sistance to air and water disruption.[16] In addition, the use
of nonhygroscopic K2CO3 as the base instead of the fre-
[8,10,11]
quently used hygroscopic K3PO4
represents an added
Boronic
acid (2)
Ligand
Product (3)
Yield
[%][b]
merit, since it has been shown that the hygroscopicity of
K3PO4 is detrimental to this reaction.[11b] Thus, the improved
air and water stability of our catalyst system and base are of
crucial importance for the Ni0-catalyzed Suzuki–Miyaura re-
actions of phenol derivatives when large-scale operations
are considered. Also, the aryl BOP substrates can be easily
prepared from the reaction of phenols with BOP-Cl[13] and
display high stability, as shown by the fact that the reactivity
remains unchanged after storage for least a couple of
months under atmospheric conditions. Finally, it is particu-
larly noteworthy that aryl phosphates, which are homo-
logues of aryl BOPs, were shown to be unreactive under
Suzuki–Miyaura conditions catalyzed by either by Pd0 or by
Ni0.[9e,f] These results further reflect the high reactivity of
aryl BOPs. Consequently, due to these indisputable advan-
tages, we believe that the methodology presented in this
work will provide an important advance in transition-metal-
catalyzed Suzuki–Miyaura coupling of phenol derivatives, al-
though the cost of the preparation of aryl BOPs is higher
than that for the preparation of other substrates.
To further probe the applicability of this methodology,
coupling reactions of a range of aryl BOPs (1b–m) with 4-
methoxy- or 4-methylphenylboronic acid (2a and b) were
carried out under the optimized conditions (Table 2). 2-
Naphthyl BOP (1b) underwent smooth coupling to give 4a
in 84% yield (Table 2, entry 1). In addition, naphthyl ana-
logues with a strongly electron-donating OMe group (1c,
Table 2, entries 2 and 3) or a strongly electron-withdrawing
CN group (1d, Table 2, entries 4 and 5) can also be convert-
ed into the corresponding biaryl products 4b–e in high
yields. Moreover, the non-fused aromatic (i.e., less electron-
deficient) substrates also serve as superb electrophiles (1e–j,
Table 2, entries 6–13), producing the desired products 4 f–m
in excellent yield for a variety of derivatives including those
with electron-rich, -neutral, and -deficient substituents on
the phenyl periphery. Such an effective Ni-catalyzed cou-
pling of non-fused aryl substrates was previously observed
1
2
3
2a
2a
2a
dppp
dppb
dppe
96
84
76
4
5
6
7
2b
2c
2d
2e
dppp
dppp
dppp
dppp
79[c]
90[c]
92
75
[a] Reaction conditions: 1-naphthyl BOP (1a) (0.5 mmol), boronic acid
2a–e (1.0 mmol), NiCl2 (10 mol%), ligand (20 mol%), K2CO3
(4.0 equiv), dioxane (6 mL), 1008C, 16–24 h. [b] Isolated yield. [c] Yield
was determined by quantitative 1H NMR spectroscopy due to the con-
tamination of a small amount of inseparable by-product derived from the
homo-coupling of the boronic acids.
ous reaction parameters including the metal source, ligand,
base, solvent, and temperature revealed that the coupling
could proceed efficiently using a catalyst system composed
of NiCl2 and dppp, affording the desired product (3a)[14] in
96% yield under the optimized conditions of boronic acid
(2.0 equiv), NiCl2 (10 mol%), dppp (20 mol%), K2CO3
(4.0 equiv) in dioxane at 1008C (Table 1, entry 1). In addi-
tion, 1,4-bis(diphenylphosphino)butane (dppb) and 1,2-bis-
ACHTUNGTRENNUNG(diphenylphosphino)ethane (dppe) were ideal ligands, pro-
viding 3a in 84 and 76% yields, respectively (Table 1, en-
tries 2 and 3). Under the optimized conditions, cross-cou-
plings of 1-naphthyl BOP (1a) with several boronic acids
(2b–e) were evaluated. The reaction was tolerant of various
boronic acids the structures of which were modified by elec-
only with aryl sulfamates by using [NiACTHUNTGRNEG(UN PCy3)2Cl2] as the cat-
alyst.[11a] Notably, the transformation was tolerant of a broad
range of functional groups. Both naphthyl and phenyl BOPs
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Aryl Phosphoramides
COMMUNICATION
Table 2. Cross-coupling of various aryl BOPs (1b–m) with 4-methoxyl-
and 4-methylphenylboronic acids (2a and b).[a]
Table 2, entry 16) proved to be somewhat challenging, pro-
viding the biaryl 4p in only 46% yield (Table 2, entry 16).
In summary, we have presented a new strategy for phenol
activation by using BOP-Cl and have demonstrated for the
first time that Suzuki–Miyaura couplings of the derived aryl
BOPs can be an efficient and broadly applicable method for
the synthesis of biaryls and heterobiaryls. As an important
advantage, this method exhibits high reaction efficiency, par-
ticularly towards non-fused aromatic substrates, although,
the cost of the synthesis of aryl BOPs is somewhat more ex-
pensive than alternative reagents. In addition, the use of a
cheaper and, more significantly, markedly more stable NiCl2
and dppp catalyst system, and the nonhygroscopic K2CO3 as
the base further reinforces the value of this transformation.
Finally, the reactivity of aryl BOPs, as exemplified by their
Suzuki–Miyaura reaction, implies that aryl BOPs may also
be suitable partners for other cross-couplings, such as Stille
and Heck reactions, which are also appealing transforma-
tions catalyzed by transition metals. These reactions remain
largely unexplored for the use of phenol derivatives as the
electrophiles. Investigations into these reactions and the or-
thogonal reactivity of aryl BOP and other substrates, such
as aryl sulfonates, esters, carbamates, carbonates, sulfamates,
and halides, are currently underway.
Ar-OBOP (1)
Product (4)
Yield
[%][b]
1
1b
4a
84
4b;
R=OMe
4c;
2
3
1c
1c
76
75
R=Me
4d;
R=OMe
4e;
4
5
1d
1d
92
92
R=Me
6
7
8
1e
1 f
1g
4 f
4g
4h
75
76
92
4i;
R=OMe
4j;
9
1h
1h
89
80
10
Experimental Section
R=Me
General procedure for the preparation of biaryls: the coupling of 1-naph-
thyl BOP (1a) and 4-methoxyphenylboronic acid (2a) as a representative
example: NiCl2 (0.05 mmol, 6.39 mg) and dppp (0.1 mmol, 41.2 mg) were
added to a 25 mL Schlenk tube equipped with a magnetic stirring bar,
and the tube was evacuated under high vacuum and backfilled with N2
(3ꢁ10 min). Dried dioxane (2 mL) was then injected by using a syringe
and the reaction mixture was stirred for 3 h at 1008C to give a dark red
heterogeneous solution. After cooling, the reaction vessel was charged in
situ with 1-naphthyl BOP (1a; 0.5 mmol, 181 mg), 4-methoxyphenylbor-
onic acid (2a; 1.0 mmol, 152 mg), anhydrous K2CO3 (2.0 mmol, 276 mg),
and dry dioxane (4 mL). The reaction mixture was further stirred at
1008C for 24 h. After completion of the reaction (as monitored by TLC),
the reaction mixture was poured into water (30 mL) and then extracted
with CH2Cl2 (3ꢁ10 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure to
yield the corresponding crude product, which was purified by silica gel
column chromatography (hexane/CH2Cl2 =10:1, v/v) to give the desired
1-(4-methoxyphenyl)naphthalene (3a) as a white powder (112 mg, 96%).
11
1i
4k
82
4l;
R=OMe
4m;
12
13
1j
1j
74[c]
71
R=Me
14
15
1k
1l
4n
80[c]
85
4o
16
1m
4p
46
[a] Reaction conditions: aryl BOP 1a–m (0.5 mmol), boronic acid 2
(1.0 mmol), NiCl2 (10 mol%), dppp (20 mol%), K2CO3 (4.0 equiv), diox-
ane (6 mL), 1008C, 16–24 h. [b] Isolated yield. [c] Yield was determined
by quantitative 1H NMR spectroscopy due to the contamination of a
small amount of inseparable by-product derived from the homo-coupling
of the boronic acid.
Acknowledgements
with a cyano substituent can be converted to cyano substi-
tuted products in excellent yields (Table 2, entries 4, 5, 9,
and 10). In contrast, we note, from the literature, that efforts
to realize a similar product by the Ni0-catalyzed Suzuki–
Miyaura coupling of 4-cyanophenyl carbamate gave only a
28% isolated yield owing to a competing reaction between
the cyano and carbamate groups.[11b] Finally, heteroaromatic
derivatives are also good substrates (1k and l, Table 2, en-
tries 14 and 15), delivering products 4n and o in high yields.
However, the reaction of sterically hindered substrates (1m,
The authors are grateful to CIAC for financial support. Y.-L. Zhao
thanks the support of CPSF (20090451144).
Keywords: biaryls · nickel · phenols · phosphane ligands ·
Suzuki–Miyaura coupling
[1] For reviews, see: a) J. S. Blakeney, R. C. Reid, G. T. Le, D. P. Fairlie,
Chem. Rev. 2007, 107, 2960; b) J.-P. Corbet, G. Mignani, Chem. Rev.
2006, 106, 2651.
Chem. Eur. J. 2010, 16, 4991 – 4994
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4993

F.-S. Han et al.
[2] For recent examples of the use of triflates as substrates, see: a) P.
Nilsson, M. Larhed, A. Hallberg, J. Am. Chem. Soc. 2001, 123, 8217;
b) D.-Y. Lee, J. F. Hartwig, Org. Lett. 2005, 7, 1169; c) J. P. Wolfe, H.
Tomori, J. P. Sadighi, J. Yin, S. L. Buchwald, J. Org. Chem. 2000, 65,
1158.
[3] For recent examples of the use of nonaflates as substrates, see: a) J.
Hçgermeier, H.-U. Reissig, I. Brꢂdgam, H. Hartl, Adv. Synth. Catal.
2004, 346, 1868; b) J. D. Hicks, A. M. Hyde, A. M. Cuezva, S. L.
Buchwald, J. Am. Chem. Soc. 2009, 131, 16720 and references there-
in.
[4] In some reactions, triflates were hydrolyzed completely to phenols
under the reaction conditions, see: a) Q. Shen, J. F. Hartwig, J. Am.
Chem. Soc. 2006, 128, 10028; b) K. L. Jones, A. Porzelle, A. Hall,
M. D. Woodrow, N. C. O. Tomkinson, Org. Lett. 2008, 10, 797; c) A.
Porzelle, M. D. Woodrow, N. C. O. Tomkinson, Org. Lett. 2009, 11,
233.
[5] For examples of tosylates and benzenesulfonates, see: a) X. Huang,
K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L. Buchwald, J.
Am. Chem. Soc. 2003, 125, 6653; b) D. Zim, V. R. Lando, J. Dupont,
A. L. Monteiro, Org. Lett. 2001, 3, 3049; c) H. N. Nguyen, X.
Huang, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125, 11818; d) Z.-Y.
Tang, Q.-S. Hu, J. Am. Chem. Soc. 2004, 126, 3058; e) V. Percec,
G. M. Golding, J. Smidrkal, O. Weichold, J. Org. Chem. 2004, 69,
3447; f) J. Kuroda, K. Inamoto, K. Hiroya, T. Doi, Eur. J. Org.
Chem. 2009, 2251; g) R. H. Munday, J. R. Martinelli, S. L. Buchwald,
J. Am. Chem. Soc. 2008, 130, 2754; h) L. Zhang, J. Wu, J. Am.
Chem. Soc. 2008, 130, 12250.
hardt, T. Skrydstrup, J. Org. Chem. 2009, 74, 3536; for Heck cross-
coupling of alkenyl phosphates, see: c) A. L. Hansen, J.-P. Ebran, M.
Ahlquist, P.-O. Norrby, T. Skrydstrup, Angew. Chem. 2006, 118,
3427; Angew. Chem. Int. Ed. 2006, 45, 3349; d) J.-P. Ebran, A. L.
Hansen, T. M. Gøgsig, T. Skrydstrup, J. Am. Chem. Soc. 2007, 129,
6931; for Suzuki–Miyaura coupling of alkenyl phosphates, see:
e) A. L. Hansen, J.-P. Ebran, T. M. Gøgsig, T. Skrydstrup, J. Org.
Chem. 2007, 72, 6464; f) H. Fuwa, M. Sasaki, Org. Lett. 2007, 9,
3347; g) for a Pd0-catalyzed Suzuki–Miyaura and Sonogashira cou-
pling of tautomerizable a-N-heteroaromatic amides activated with
phosphonium salt, see: F.-A. Kang, Z. Sui, W. V. Murray, J. Am.
Chem. Soc. 2008, 130, 11300; h) F.-A. Kang, J. C. Lanter, C. Cai, Z.
Sui, W. V. Murray, Chem. Commun. 2010, 46, 1347–1349.
[10] a) K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 2008,
130, 14422; b) B.-T. Guan, Y. Wang, B.-J. Li, D.-G. Yu, Z.-J. Shi, J.
Am. Chem. Soc. 2008, 130, 14468; c) L. J. Gooßen, K. Gooßen, C.
Stanciu, Angew. Chem. 2009, 121, 3621; Angew. Chem. Int. Ed. 2009,
48, 3569.
[11] a) K. W. Quasdorf, M. Riener, K. V. Petrova, N. K. Garg, J. Am.
Chem. Soc. 2009, 131, 17748; b) A. Antoft-Finch, T. Blackburn, V.
Snieckus, J. Am. Chem. Soc. 2009, 131, 17750.
[12] J. Diago-Meseguer, A. L. Palomo-Coll, J. R. Fernꢃndez-Lizarbe, A.
Zugaza-Bilbao, Synthesis 1980, 547.
[13] See the Supporting Information for the preparation and characteri-
zation of aryl BOPs.
[14] See the Supporting Information for the experimental procedures,
characterization data, and 1H and 13C NMR spectra for all coupling
products.
[6] For examples of mesylates, see references [5e–g] and C. M. So, Z.
Zhou, C. P. Lau, F. Y. Kwong, Angew. Chem. 2008, 120, 6502;
Angew. Chem. Int. Ed. 2008, 47, 6402.
[15] The ligand costs of PCy3 and PCy3HBF4 are at least four times
higher than dppp, dppe, and dppb by Kanto Kagaku Co., Inc. The
approximate catalyst costs by Strem Chemicals are: NiCl2 (98%)=
[7] For imidazolylsulfonates, see: J. Albaneze-Walker, R. Raju, J. A.
Vance, A. J. Goodman, M. R. Reeder, J. Liao, M. T. Maust, P. A.
Irish, P. Espino, D. R. Andrews, Org. Lett. 2009, 11, 1463.
[8] a) J. W. Dankwardt, Angew. Chem. 2004, 116, 2482; Angew. Chem.
Int. Ed. 2004, 43, 2428; b) S. Ueno, E. Mizushima, N. Chatani, F. Ka-
kiuchi, J. Am. Chem. Soc. 2006, 128, 16516; c) M. Tobisu, T. Shima-
saki, N. Chatani, Angew. Chem. 2008, 120, 4944; Angew. Chem. Int.
Ed. 2008, 47, 4866.
985 CNYmolÀ1, [Ni
205018 CNYmolÀ1 (CNY=Chinese Yuan).
[16] As a caution, in the reagent catalogues PCy3 is air and moisture sen-
sitive, [Ni(cod)2] is sensitive to many media including air, moisture,
light, and heat and [Ni(PCy3)2Cl2] is relatively more stable than [Ni-
(cod)2], but is also sensitive to air and moisture. However, no such
caution is noted for NiCl2, dppp, dppb, or dppe.
(cod)2]=95722 CNYmolÀ1, and [NiCl
ACHTUTGNRENNUG 2ACHTUNGTRENNUNG(PCy3)2]=
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
[9] For Kumada cross-coupling of aryl and alkenyl phosphates, see:
a) N. Yoshikai, H. Matsuda, E. Nakamura, J. Am. Chem. Soc. 2009,
131, 9590; b) D. Gauthier, S. Beckendorf, T. M. Gøgsig, A. T. Lind-
Received: February 17, 2010
Published online: March 31, 2010
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Chem. Eur. J. 2010, 16, 4991 – 4994