Direct application of phenolic salts to nickel-catalyzed cross-coupling reactions with aryl grignard reagents

Article abstract of DOI:10.1002/anie.200907359

(Figure Presented) You're nickel'd pal! The first successful coupling reaction with the direct application of naphtholates as electrophiles (see scheme, X = halide) improves both the step economy and atom economy of cross-coupling reactions whilst decreas

Full text of DOI:10.1002/anie.200907359

Communications
DOI: 10.1002/anie.200907359
À
C O Bond Activation
Direct Application of Phenolic Salts to Nickel-Catalyzed
Cross-Coupling Reactions with Aryl Grignard
Reagents**
Da-Gang Yu, Bi-Jie Li, Shu-Fang Zheng, Bing-Tao Guan, Bi-Qing Wang, and
Zhang-Jie Shi*
Angewandte
Chemie
4566
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4566 –4570

Angewandte
Chemie
Since the 1970s, much attention has been paid to cross-
coupling reactions. Many reactions have been named, which
demonstrates the importance of these developments.[1]
Undoubtedly, the cross-coupling reaction has already
become one of the most powerful tools in organic synthesis.[2]
Amongst these developments, the construction of biaryl
scaffolds have been particular extensively investigated
because of its diversified applications in drug discovery,
material chemistry, and the construction of natural products.[3]
In the early stages of this development, aryl iodides and
bromides were successfully employed as electrophiles in
cross-coupling reactions because of their relatively high
reactivities.[1a–b] With the development of efficient catalytic
systems, the less-reactive aryl chlorides and fluorides were
also successfully used as coupling partners.[2a,4] However, the
relatively high cost of aryl halides and their toxicity to the
environment have limited their applications. Furthermore,
most organic halides are difficult to prepare, which might
result in an economic and ecological problem in large scale
syntheses.[5]
Figure 1. Design of cross-coupling from a phenol or phenolate using
organometallic reagents. X=I, Br, Cl; R=aryl, alkenyl, alkyl;
R1 =R2 =alkyl, aryl, NR’2;[M]=metal complex.
and phosphates in cross-coupling reactions.[9] Notably, recent
advances indicated that aryl carboxylates, carbamates, and
anisole derivatives are also potential substrates.[10] However,
the use of such groups limits their efficiency for overall yields
and step economy. Obviously, a direct transformation from
phenol itself or its inorganic salt would be the best choice to
solve such a problem as it avoids the extra steps of group
transfer and the generation of organic wastes.
Obviously, such a design faces a formidable, and yet to be
overcome, enthalpy barrier. The bond dissociation energy
(BDE) seemed to indicate that direct cleavage of the aryl C
O bond on phenol is impossible. The phenolic anion is a good
s-donor ligand, which could bind to the metal catalyst and
More recently, a variety of cross-coupling reactions
À
involving direct C H transformation have been rapidly
À
developed. Towards the key target of constructing C C
À
bonds, the direct functionalization of C H bonds has the
advantages of lower costs, less waste production, and higher
step economy.[6] Although great progress has been made in
this area, many challenges remain. For example, relatively
harsh conditions, high catalyst loading, as well as the require-
ment for directing groups or specific substrates make such
chemistry less desirable for practical application.[7]
À
À
Compared with the above-mentioned electrophiles, read-
ily available phenol substrates and their derivatives provide
impede the transition-metal-induced cleavage of the C O
bond. Furthermore, formation of the phenolic salt enhances
the BDE to completely nullify any potential cleavage.[11]
Previous reports have demonstrated the difficulty of such
transformations, although the cross-coupling product was
occasionally observed in some cases.[10f,h] Contrary to this
traditional analysis, herein we report the first successful
example of the cross-coupling reactions of magnesium
phenolate with Grignard reagents to construct biaryl scaf-
folds.
À
an alternative route to C C bond formation (Figure 1).
Previous work using phenol as a coupling partner involved
initial transformation into a more active species. For instance,
aryl triflates have long been successfully used as an efficient
electrophile because of their relatively high reactivity.[8]
Subsequent studies developed other, less-reactive sulfonates
[*] D.-G. Yu, B.-J. Li, B.-T. Guan, Prof. Dr. Z.-J. Shi
Beijing National Laboratory of Molecular Sciences (BNLMS), PKU
Green Chemistry Centre and Key Laboratory of Bioorganic
Chemistry and Molecular Engineering, Ministry of Education,
College of Chemistry, Peking University, Beijing 100871 (China)
Starting from the phenolic salt, we envisioned that metal
ions could act as Lewis acids that are tightly coordinated by
the oxygen atom of the phenoxide. Presumably, the oxygen
atom lone pair coordinates with different metal centers to
form regular frameworks. With inorganic salts, we proposed
that such coordination might induce the reorganization of the
Prof. Dr. Z.-J. Shi
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences, Shanghai 200032 (China)
Fax: (+86)10-6276-0890
E-mail: zshi@pku.edu.cn
Homepage: http://www.chem.pku.edu.cn/zshi/
À
electronic structure of the phenolic C O bond. The reorgan-
À
ization of the electron density might then activate the C O
bond for further cross-coupling reactions. In this proposed
reaction, the metal ions would act as electron-withdrawing
groups. With this in mind, 2-NapOMgBr (Nap = naphthyl)
was prepared and its single crystal was grown in a tetrahy-
drofuran/toluene solution (Figure 2).[13] Analysis of the X-ray
structure revealed two features. 1) A dimer was formed in
which both oxygen atoms coordinated with two magnesium
ions to form a four-membered-ring core. Bromine and thf
ligands were also ligated to each magnesium ion. 2) With the
S. F. Zheng, Prof. B.-Q. Wang
Chemistry and Material Sciences, Sichuan Normal University
Chengdu, Sichuan 610068 (China)
[**] We thank Prof. Wen-Xiong Zhang, Dr. Neng-Dong Wang and Dr.
Wen-Hua Wang for the crystallographic analysis and Mr. Zhen-Xing
Li for assistance in the PXRD studies. Support of this work by the
NSFC (No. 20672006, 20821062, 20832002, 20925207, GZ419) and
the “973” Project from the MOST of China (2009CB825300) is
gratefully acknowledged.
assistance of both Mg2+ centers, the activated phenol C O
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907359.
bond length was 1.336 ꢀ, as predicted, and thus has the
Angew. Chem. Int. Ed. 2010, 49, 4566 –4570
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4567

Communications
equivalents of PhMgBr to 5.0 equivalents induced complete
conversion of 2-naphthol into 2-phenyl naphthalene. As some
arylMgBr reagents are hard to prepare and relatively
expensive, the commercially available MeMgBr was used to
deprotonate the naphthol to reduce costs and increase the
carbon-atom economy. When 1.2 equivalents of MeMgBr
were used, followed by the cross-coupling with PhMgBr, the
desired product was isolated in 89% yield.
We then tested different aryl Grignard reagents
(Scheme 1). Steric effect did not have a significant influence
on the reactivity (3a, 3b and 3c); however, high steric
Figure 2. Preparation and structural determination of a magnesium
phenolate complex. Ellipsoids set at 30% probability. Hydrogen atoms
removed for clarity.
potential to be cleaved in the cross-coupling reaction as it is as
À
long as that of the corresponding naphthol C O bond.
With this confirmation, we tested the cross-coupling
reaction of phenoxide with phenyl Grignard reagent
PhMgBr. Different metal counterions were also tested.
When 2-NapOLi and 2-NapOK were submitted to the
cross-coupling conditions in the presence of NiF2 and addi-
tional PCy3, the desired coupling product was observed, albeit
with a very low efficiency. Interestingly, a better result was
obtained when 2-NapONa was used as a substrate. Satisfac-
torily, both the prepared (2-NapO)2Mg and 2-NapOMgBr
showed much improved reactivity and the desired product
was obtained in moderate yields in both cases, with partial
substrate recovery. It is important to note that the halide
substituent on the Grignard reagent is critical to the reaction
and BrÀ was found to be the best (Figure 3).
Scheme 1. Biaryl products synthesized from naphthol with various aryl
Grignard reagents by nickel catalysis. Reaction conditions: 1 (0.2–
0.4 mmol), NiF2 (10 mol%), PCy3 (40 mol%), MeMgBr (120 mol%),
and ArMgBr 2 (200 mol%) in toluene (0.75 mL) and DIPE (0.25 mL),
1208C, 24 hours. All reported yields are the avarage yields of at least
two experiments.
hindrance decreased the rate of reaction and the desired
product was produced in relatively low yield (3d). The tert-
butyl-protected alcohol 3e was also compatible with this
transformation. Notably, the dialkylamino group (3 f) toler-
ated this transformation and the cross-coupling reaction
proceeded smoothly. Furthermore, heterocyclic groups at
the benzylic position, such as pyrrole (3g), tolerated the
reaction conditions.
Figure 3. Coupling reaction of 2-naphtholate and PhMgX (GC yield).
TMS=trimethylsilyl, TBS=tert-butyldimethylsilyl.
Screening of the reaction conditions indicated that non-
polar solvents were suitable for this transformation; the best
solvent system was a 3:1 mixture of toluene and diisopropyl
ether (DIPE). This solvent system might retain the core
framework owing to their low coordinating ability. NiF2 in the
presence of PCy3 as a ligand showed the highest reactivity for
this transformation.
To simplify the reaction process, we prepared 2-
NapOMgBr in situ, as the Grignard reagents were used as
the reaction partners. Fortunately, increasing the number of
Various substituted naphthols were subsequently inves-
tigated. Alkyl, aryl, and alkenyl substituents did not hinder
À
the transformation (3h), and importantly, the C Si group (3i),
which is then available for further elaboration, was also
tolerated successfully. Similarly, the TBS-protected hydroxy
group (3j) was compatible with the reaction. N-containing
groups, such as N-tetrahydroquinilinyl (3k) and N-pyrrolyl
(3l), also performed well. Those products might have
potential application in drug discovery and materials chemis-
4568 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4566 –4570

Angewandte
Chemie
try. Unfortunately, at present, phenol derivatives do not
successfully undergo this transformation.
preparation of complex scaffolds by using readily available
phenol derivatives. Most importantly, these studies challenge
the traditional consideration of the stability of phenol and its
phenolic species, thus opening a direct route to useful core
structures from phenol derivatives through cross-coupling
reactions. Further expansion of substrate scope, mechanistic
investigation, and extension of this idea to other synthetic
transformations are underway.
Preliminary studies were conducted to understand the
reaction mechanism. The solid [{2-NapOMgBr(thf)2}2] was
suspended in the mixed solvent system and heated to the
reaction conditions that resulted in the salt being partial
dissolved. After removal of the solvent under vacuum and
recovery of the salts, the 1H NMR and 13C NMR spectroscopy
of the solid residue did not show significant changes from the
original data. Further IR and powder X-ray diffraction
(PXRD) analysis of the recovered material suggested that Experimental Section
Typical procedure for the Kumada-Tamao-Corriu coupling of naph-
the structure of the magnesium salts did not decompose under
the reaction conditions (see the Supporting Information).
Therefore, we considered that such a scaffold of the dimer was
directly involved in cross-coupling.
thol derivatives: 2-naphthol (1a; 57.6 mg, 0.4 mmol), NiF2 (3.9 mg,
0.04 mmol), and PCy3 (44.8 mg, 0.16 mmol) were added to an oven-
dried Schlenk tube that contained a stirrer bar. The tube was degassed
3 times and 0.5 mL of freshly distilled THF was added. Then,
MeMgBr (0.48 mmol) was added by syringe at room temperature,
and the mixture was stirred at room temperature for 5 minutes. After
addition of PhMgBr (0.8 mmol), the solvent was removed with a cold
trap under reduced pressure. Next, toluene (0.75 mL) was added and
the solution was stirred at room temperature for a further 5 minutes.
After iPr2O (0.25 mL) was added, the solution was stirred at room
temperature for another 10 minutes. The mixture was then stirred at
1208C for 24 hours under a N2 atmosphere. The mixture was cooled to
room temperature, quenched with EtOH, and filtered through a short
silica column. The solvent was removed and the product was purified
by column chromatography on silica gel. All reactions were carried
out on a 0.4 mmol scale, apart from 3j and 3l (0.2 mmol). 3 f and 3k
were obtained after 36 and 34 hours, respectively).
The transformation was thought to go through the Ni0/NiII
catalytic cycle (Figure 4). NiX2 was first reduced to Ni0 species
4 with the support of the PCy3 ligand. In the presence of
MeMgBr, magnesium phenoxide salt 5 was generated. With
Received: December 31, 2009
Revised: February 9, 2010
Published online: April 14, 2010
À
Keywords: biaryls · C O activation · cross-coupling ·
homogeneous catalysis · nickel
.
[1] a) N. Miyaura, Cross-coupling Reactions: A Practical Guide,
Springer, Berlin, 2002; b) F. Diederich, A. de Meijere, Metal-
Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim,
2004; c) K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc.
1972, 94, 4374 – 4376; d) R. F. Heck, Acc. Chem. Res. 1979, 12,
146 – 151; e) E.-I. Negishi, Acc. Chem. Res. 1982, 15, 340 – 348;
f) A. Suzuki, Acc. Chem. Res. 1982, 15, 178 – 184; g) V. J. K.
Stille, Angew. Chem. 1986, 98, 504 – 519; Angew. Chem. Int. Ed.
Engl. 1986, 25, 508 – 524; h) K. Sonogashira, J. Organomet.
Chem. 2002, 653, 46 – 49; i) T. Hiyama, E. Shirakawa, Top. Curr.
Chem. 2002, 219, 61 – 85; j) B. M. Trost, Acc. Chem. Res. 1980, 13,
385 – 393; k) J. Tsuji, Tetrahedron 1986, 42, 4361 – 4401.
[2] a) A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350 – 4386;
Angew. Chem. Int. Ed. 2002, 41, 4176 – 4211; b) A. R. Muci, S. L.
Buchwald, Top. Curr. Chem. 2002, 219, 131 – 209; c) D. A.
Culkin, J. F. Hartwig, Acc. Chem. Res. 2003, 36, 234 – 245.
[3] a) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005,
117, 4516 – 4563; Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489;
b) I. Cepanec, Synthesis of Biaryls, Elsevier, Amsterdam, 2004;
c) J. Hassan, M. Sꢁvignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359 – 1469.
Figure 4. Catalytic Pathway of the cross-coupling between phenolic salt
and Grignard reagents. Ar=substituted naphthyl, S=solvent,
L=ligand, X=halide, n=0–2.
the assistance of Mg2+ in the complex, the phenoxide C O
À
bond was slightly activated, and further underwent oxidative
addition to the Ni0 species. After transmetalation with RMgX,
through the proposed 6-membered transition state (7), the
biaryl NiII species 8 was formed. Finally, reductive elimination
released the desired product 3, concurrently regenerating the
Ni0 species 4 to facilitate the catalytic cycle. However, in the
presence of NiF2, the catalytic efficacy was highly promoted.
Therefore, the potential NiII/NiIV cycle that involved a nickel
fluoride ate complex could not be elucidated as in the
previous report.[12]
In conclusion, we have demonstrated the first successful
cross-coupling reaction of 2-naphthol derivatives with various
aryl Grignard reagents. This study suggested that MOÀ
species might be a useful leaving group for different trans-
formations. Not only did this unprotected process offer
significant enhancement in process economy and atom
economy, it also decreases the expense of the design and
[4] a) A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110, 3586 – 3587;
Angew. Chem. Int. Ed. 1998, 37, 3387 – 3388; b) D. W. Old, J. P.
Wolfe, S. L. Buchwald, J. Am. Chem. Soc. 1998, 120, 9722 – 9723;
c) N. Yoshikai, H. Matsuda, E. Nakamura, J. Am. Chem. Soc.
2009, 131, 9590 – 9599.
Angew. Chem. Int. Ed. 2010, 49, 4566 –4570
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 4569

Communications
[5] P. B. De La Mare, Electrophilic Halogenation, Cambridge Uni-
N. K. Garg, J. Am. Chem. Soc. 2009, 131, 17748 – 17749; e) A.
Antoft-Finch, T. Blackburn, V. Snieckus, J. Am. Chem. Soc. 2009,
131, 17750 – 17752; f) E. Wenkert, E. L. Michelotti, C. S. Swin-
dell, J. Am. Chem. Soc. 1979, 101, 2246 – 2247; g) J. W. Dank-
wardt, Angew. Chem. 2004, 116, 2482 – 2486; Angew. Chem. Int.
Ed. 2004, 43, 2428 – 2432; h) E. Wenkert, E. L. Michelotti, C. S.
Swindell, M. Tingoli, J. Org. Chem. 1984, 49, 4894 – 4899; i) M.
Tobisu, T. Shimasaki, N. Chatani, Angew. Chem. 2008, 120,
4944 – 4947; Angew. Chem. Int. Ed. 2008, 47, 4866 – 4869; j) M.
Tobisu, T. Shimasaki, N. Chatani, Chem. Lett. 2009, 38, 710 – 711;
k) T. Shimasaki, Y. Konno, M. Tobisu, N. Chatani, Org. Lett.
2009, 11, 4890 – 4892.
versity Press, New York, 1976.
[6] a) D. Stuart, R. K. Fagnou, Science 2007, 316, 1172 – 1175;
b) R. G. Bergman, Nature 2007, 446, 391 – 393; c) D. Alberico,
M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174 – 238.
[7] a) H. Chen, S. Schlecht, T. C. Semple, J. F. Hartwig, Science 2000,
287, 1995 – 1997; b) B.-J. Li, S.-D. Yang, Z.-J. Shi, Synlett 2008, 7,
949 – 957.
[8] A. Huth, I. Beetz, I. Schumann, Tetrahedron 1989, 45, 6679 –
6682.
[9] a) A. H. Roy, J. F. Hartwig, J. Am. Chem. Soc. 2003, 125, 8704 –
8705; b) H. N. Nguyen, X. Huang, S. L. Buchwald, J. Am. Chem.
Soc. 2003, 125, 11818 – 11819; c) Z.-Y. Tang, Q.-S. Hu, J. Am.
Chem. Soc. 2004, 126, 3058 – 3059; d) L. Zhang, J. Wu, J. Am.
Chem. Soc. 2008, 130, 12250 – 12251; e) F.-A. Kang, Z. Sui, W. V.
Murray, Eur. J. Org. Chem. 2009, 461 – 479.
[10] a) B.-T. Guan, Y. Wang, B.-J. Li, D.-G. Yu, Z.-J. Shi, J. Am.
Chem. Soc. 2008, 130, 14468 – 14470; b) B.-J. Li, Y.-Z. Li, X.-Y.
Lu, J. Liu, B.-T. Guan, Z.-J. Shi, Angew. Chem. 2008, 120, 10278 –
10281; Angew. Chem. Int. Ed. 2008, 47, 10124 – 10127; c) K. W.
Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 2008, 130,
14422 – 14423; d) K. W. Quasdorf, M. Riener, K. V. Petrova,
[11] J. B. Pedley, R. D. Naylor, S. P. Kirby, Thermochemical Data of
Organic Compounds, 2nd ed., New York, Chapman and Hall,
1986.
[12] T. Hatakeyama, S. Hashimoto, K. Ishizuka, M. Nakamura, J.
Am. Chem. Soc. 2009, 131, 11949 – 11963.
[13] CCDC 769550 ([{2-NapOMgBr(thf)2}2]) contains the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
4570
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 4566 –4570