Cross-coupling reactions of aryl pivalates with boronic acids

Article abstract of DOI:10.1021/ja806244b

The first cross-coupling of acylated phenol derivatives has been achieved. In the presence of an air-stable Ni(II) complex, readily accessible aryl pivalates participate in the Suzuki-Miyaura coupling with arylboronic acids. The process is tolerant of considerable variation in each of the cross-coupling components. In addition, a one-pot acylation/cross-coupling sequence has been developed. The potential to utilize an aryl pivalate as a directing group has also been demonstrated, along with the ability to sequentially cross-couple an aryl bromide followed by an aryl pivalate, using palladium and nickel catalysis, respectively. Copyright

Full text of DOI:10.1021/ja806244b

Published on Web 10/08/2008
Cross-Coupling Reactions of Aryl Pivalates with Boronic Acids
Kyle W. Quasdorf, Xia Tian, and Neil K. Garg*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles, California 90095
Received August 7, 2008; E-mail: neilgarg@chem.ucla.edu
Scheme 1
Transition metal catalyzed cross-coupling reactions have emerged
as a powerful method for constructing carbon-carbon (C-C) and
carbon-heteroatom (C-X) bonds.1 Whereas methodologies for the
cross-coupling of aryl halides have significantly improved,1,2 less
progress has been made toward the coupling of the corresponding
phenol derivatives.1 Given that phenols are cheap and readily available,
and that oxygenation can be used to direct the installation of functional
groups on an aromatic ring, practical methods that allow for the cross-
coupling of phenol derivatives are extremely attractive.
Table 1. Cross-Couplings of Various Aryl Pivalates with
Arylboronic Acid 2a or 2ba
Of the known methods for cross-coupling phenol derivatives,1,3-5
there are no examples that utilize simple O-acylated phenols.6 Such
a process would be of great value, given that O-acylated phenols
are (a) simple to prepare, (b) among the most affordable phenol
derivatives available,7 (c) stable to a variety of reaction conditions,
and (d) able to direct the installation of other functional groups
onto an aromatic ring. Furthermore, this cross-coupling would
presumably begin by the selective oxidative addition of a metal
into the aryl C-O bond of the O-acylated phenol (Figure 1), a
transformation that has never been achieved.8 Here, we describe
the first cross-coupling reactions of O-acylated phenol derivatives,
involving the Ni-catalyzed reaction of aryl pivalates.
Figure 1. Cross-coupling of O-acylated phenol derivatives.
The Suzuki-Miyaura coupling was chosen as our starting point
because of the numerous advantages that pertain to using boronic
acids (i.e., low toxicity, wide availability, stability to water and
air, and high functional group tolerance).1,9 Several challenges were
apparent from the outset of our endeavors. First, the O-acylated
phenol substrates we intended to employ could be prone to
hydrolysis under typical Suzuki-Miyaura conditions involving
strong base. Thus, robust pivalate esters (-OC(O)CMe3) were
selected as the acylated phenol derivatives of choice. In addition,
we postulated that the activation energy for oxidative addition
between a transition metal and the aryl C-O bond of an acylated
phenol derivative would be fairly high. Since fused aromatic
a Conditions: NiCl2(PCy3)2 (5 mol%), ArB(OH)2 (4 equiv), K3PO4
(7.2 equiv), toluene (0.3 M), 110 °C, 24 h. b Isolated yields.
c Conditions: NiCl2(PCy3)2 (10 mol%), ArB(OH)2 (5 equiv), K3PO4 (9
equiv), toluene (0.3 M), 110 °C, 24 h. d Conditions: NiCl2(PCy3)2 (5
mol%), ArB(OH)2 (2.5 equiv), K3PO4 (4.5 equiv), toluene (0.3 M), 80
°C, 24 h.
systems are generally activated toward oxidative addition,1a,4
naphthol derivative was first examined.
a
An extensive survey of various reaction parameters (e.g., choice of
metal,10 ligand,11 solvent, base, additives, and temperature) led to the
identification of a catalyst system that facilitates the desired cross-
coupling. Under optimal conditions (i.e., NiCl2(PCy3)2 (5 mol%) and
K3PO4 (4.5 equiv) in toluene at 80 °C), coupling of naphthyl pivalate
1 and phenylboronic acid (2a)12 afforded biaryl product 3a in 92%
yield (Scheme 1). The Ni(II) precatalyst13 of choice is readily
available14 and also shows marked stability to air. Therefore, all
reactions are routinely carried out on the benchtop rather than in a
glovebox, circumventing a common limitation of related Ni(0)
processes.3b,4
nylboronic acid (2b) with the pivalate derivative of 2-naphthol
proceeded in 92% yield (entry 1). In addition, the reaction proved
tolerant of an electron-withdrawing (-CO2Me, entry 2) and -donating
group (-OMe, entry 3) on the naphthyl ring. The corresponding
reactions of non-fused aryl pivalates proved more challenging.
Nonetheless, employing additional equivalents of boronic acid and
increasing catalyst loading to 10 mol% significantly improved the
yields of cross-coupled products. For instance, p- and o-tolyl pivalates
afforded products in 65% and 79% yields (entries 4 and 5), respec-
tively. A non-fused aromatic substrate bearing a p-methoxy substituent
The scope of this methodology was first examined by varying the
aryl pivalate component (Table 1). Cross-coupling of p-methoxyphe-
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14422 J. AM. CHEM. SOC. 2008, 130, 14422–14423
10.1021/ja806244b CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cross-Coupling of Pivalate 1 with Various Arylboronic
aqueous K3PO4, 90 °C). Next, aryl pivalate 7 underwent smooth cross-
coupling under our Ni-catalyzed conditions to afford triaryl product 8 in
88% yield.
Acidsa
In summary, we have discovered the first cross-coupling reactions
of O-acylated phenol derivatives. The method relies on the use of a
readily available, air-stable Ni(II) complex to facilitate the Suzuki-
Miyaura coupling of aryl pivalates. In addition, a one-pot acylation/
cross-coupling sequence has been developed. Moreover, the potential
to utilize an aryl pivalate as a directing group has been demonstrated,
along with the ability to sequentially cross-couple an aryl bromide
followed by an aryl pivalate. Studies aimed at probing mechanistic
aspects of these findings are currently underway.
Acknowledgment. The authors are grateful to the University of
California, Los Angeles and Boehringer Ingelheim for financial support.
We also thank Quark Glass and Materia Inc. for the donation of
laboratory glassware and chemicals, respectively. Profs. Kwon and
Jung are acknowledged for chemicals and pertinent discussions.
a Conditions: Pivalate 1 (1 equiv), NiCl2(PCy3)2 (5 mol%), ArB(OH)2
(2.5 equiv), K3PO4 (4.5 equiv), toluene (0.3 M), 24 h. b Isolated yields.
also participated in the cross-coupling reaction (entry 6). Finally, a
substrate derived from N-methyl-2-hydroxycarbazole underwent smooth
cross-coupling (entry 7), as did a vinyl pivalate derived from tetralone
(entry 8).
Supporting Information Available: Detailed experimental procedures
and compound characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
We have also found that a range of arylboronic acids participate
in the Ni-catalyzed cross-coupling of naphthyl pivalate 1 (Table
2). For instance, cross-coupling of electron-rich boronic acid 2b,
bearing a p-methoxy substituent, furnished biaryl adduct 3b in 95%
yield (entry 1). Electron-deficient boronic acid 2c can also be
utilitized in the desired cross-coupling reaction (entry 2). Finally,
Me-substitution is tolerated at the p, m, and o-positions as
demonstrated by the coupling of substrates 2d-f (entries 3-5),
respectively, although the o-substituted substrate (entry 5) requires
elevated temperatures and proceeds in modest yield.
Figure 2 highlights two unprecedented and powerful variations of the
cross-coupling methods described herein. As pivalylation protocols typi-
cally proceed quantitatively and with minimal byproduct formation, we
hypothesized that a one-pot acylation/cross-coupling sequence of phenol
derivatives could be possible. Gratifyingly, our efforts to achieve the one-
pot conversion of 1-naphthol (4) to biaryl adduct 3b were successful,
affording the desired product in 86% yield. Next, to demonstrate the
directing ability of aryl pivalates,15 naphthyl pivalate 1 was selectively
brominated at C4 to afford bromopivalate 5 in 84% yield.16 Postulating
that the pivalate functional group of 5 would not be reactive toward Pd(0),
orthogonal cross-coupling reactions of the bromide and pivalate groups
were attempted next. In the first cross-coupling, treatment of substrate 5
with indolylboronic ester 6 under Pd-catalysis led to the selective reaction
of the aryl bromide to afford biaryl product 7, with the robust pivalate
group remaining intact, despite the harsh basic conditions employed (i.e.,
References
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(4) The Suzuki-Miyaura coupling of electron-deficient aryl methyl ethers was
recently reported; see: Tobisu, M.; Shimasaki, T.; Chatani, N. Angew.
Chem., Int. Ed. 2008, 47, 4866–4869.
(5) Of the known methods for phenol coupling, the most common involves
formation and reaction of the corresponding aryl triflates. However, these
species are somewhat costly to prepare (see ref 7b), unable to serve as
directing groups, and susceptible to base-promoted hydrolysis. Aryl
mesylates and tosylates can also be utilized, although their utility does not
yet appear to be general.
(6) For unsuccessful attempts to effect the cross-coupling of O-acetylated
phenols using Ni-catalysis, see: Guan, B.; Xiang, S.; Wu, T.; Sun, Z.; Wang,
B.; Zhao, K.; Shi, Z. Chem. Commun. 2008, 1437–1439; see also ref 4.
(7) Approximate reagent costs by Aldrich Chemical Co., Inc. are: (a)
Trimethylacetyl chloride (pivaloyl chloride) ) $10 per mol. (b) Triflic
anhydride ) $310 per mol. (c) Methanesulfonyl chloride ) $10 per mol.
(d) Iodomethane ) $24 per mol.
(8) For the insertion of Ni(0) into the acyl C-O bond of acylated phenols,
see: Yamamoto, T.; Ishizu, J.; Kohara, T.; Komiya, S.; Yamamoto, A. J. Am.
Chem. Soc. 1980, 102, 3758–3764.
(9) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b) Suzuki,
A. Chem. Commun. 2005, 4759–4763. (c) Doucet, H. Eur. J. Org. Chem.
2008, 2013–2030.
(10) The more expensive and commonly used d8 transition metal, palladium,
was completely ineffective at promoting the desired transformation under
a variety of reaction conditions.
(11) In the presence of Ni(0), other ligands such as PPh3, dppe, dppf, and dppp
provided trace amounts of cross-coupled products.
(12) An excess of the arylboronic acid component is required because the trimeric
boroxine, which comprises between 30 and 60% of commercially available
arylboronic acids, is completely unreactive under these anhydrous conditions.
(13) In the presence of excess arylboronic acid, NiCl2(PCy3)2 is thought to
undergo reduction to an active Ni(0) catalyst; see ref 3a.
(14) NiCl2(PCy3)2, will soon be commercially available from Strem Chemicals
Inc. (catalog #28-0091) or can be prepared in multigram quantities following
a simple one-step protocol; see: (a) Stone, P. J.; Dori, Z. Inorg. Chim. Acta
1970, 5, 434–438. (b) Barnett, K. W. J. Chem. Educ. 1974, 51, 422–423.
(15) Arenes that possess an-OC(O)R substituent are known to undergo
electrophilic aromatic substitution to afford ortho/para substituted products;
see: Smith, M. B.; March, J. March’s AdVanced Organic Chemistry, 6th
ed.; John Wiley & Sons, Inc.: NJ, 2007; p 668.
(16) The formation of ortho-brominated products was not observed, likely
because of the steric bulk imposed by the pivalate group.
Figure 2. One-pot acylation/cross-coupling sequence and orthogonal cross-
coupling reactions.
JA806244B
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