Nickel-catalyzed C-O activation of phenol derivatives with potassium heteroaryltrifluoroborates

Article abstract of DOI:10.1021/ol101592r

A general method based on nickel-catalyzed C-O activation of various phenol derivatives with potassium (hetero)aryltrifluoroborates has been developed. A large number of heterobiaryls can be easily obtained with yields up to 99% using methanesulfonate cross-coupling partners.

Full text of DOI:10.1021/ol101592r

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4022-4025
Nickel-Catalyzed C-O Activation of
Phenol Derivatives with Potassium
Heteroaryltrifluoroborates
Gary A. Molander* and Floriane Beaumard
Roy and Diana A. Vagelos Laboratories, Department of Chemistry, UniVersity of
PennsylVania, Philadelphia, PennsylVania 19104-6323
gmolandr@sas.upenn.edu
Received July 9, 2010
ABSTRACT
A general method based on nickel-catalyzed C-O activation of various phenol derivatives with potassium (hetero)aryltrifluoroborates has
been developed. A large number of heterobiaryls can be easily obtained with yields up to 99% using methanesulfonate cross-coupling partners.
Transition-metal-catalyzed cross-coupling reactions are among
the most powerful transformations available to create
carbon-carbon or carbon-heteroatom bonds. In particu-
lar, the Suzuki-Miyaura reaction represents one of the
most common and reliable methods because of its toler-
ance of a wide range of functional groups, as well as the
commercial availability and stability of its reagents.1
Usually, aryl halides and triflates serve as electrophilic
coupling partners, but there often remain some limitations
of these reaction partners because of their toxicity, their
cost, or their inaccessibility.
An alternative is to use phenol derivatives bearing more
environmentally sound, less expensive, and easier to handle
nucleofuges. Palladium catalysts have shown promising
results for the activation of the C-O bond when sulfonates
such as tosylates2 or mesylates3 were used as leaving groups
(LGs) but have been completely ineffective with the corre-
sponding esters.4 More reactive nickel catalysts have been
used in cross-couplings of diverse phenol derivatives.
Relatively unreactive tosylate5 and mesylate5b,6 groups were
first engaged with success with arylboronic acid derivatives.
Recently, ester- and amide-type nucleofuges (pivaloyl, acetyl,
(2) For Pd-catalyzed cross-coupling of aryl tosylates, see: (a) Roy, A. H.;
Hartwig, J. F. Organometallics 2004, 23, 194–202. (b) Petersen, M. D.;
Boye, S. V.; Nielsen, E. H.; Willumsen, J.; Sinning, S.; Wiborg, O.; Bols,
M. Bioorg. Med. Chem. 2007, 15, 4159–4174. (c) Nguyen, H. N.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11818–11819. (d) Zhang,
L. A.; Meng, T. H.; Wu, J. J. Org. Chem. 2007, 72, 9346–9349. (e) So,
C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org. Chem. 2008, 73,
7731–7734.
(3) For Pd-catalyzed cross-coupling of aryl mesylates, see: (a) Percec,
V.; Bae, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60, 1060–1065. (b) So,
C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47, 8059–
8063. (c) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009, 11,
3954–3957. (d) Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. J. Org.
Chem. 2010, 75, 5109–5112.
(4) (a) Quasdorf, K. W.; Tian, X.; Garg, N. K. J. Am. Chem. Soc. 2008,
130, 14422–14423. (b) Li, Z.; Zhang, S. L.; Fu, Y.; Guo, Q. X.; Liu, L.
J. Am. Chem. Soc. 2009, 131, 8815–8823.
(5) For recent examples of Ni-catalyzed Suzuki cross-coupling of aryl
tosylates, see: (a) Zim, D.; Lando, V. R.; Dupont, J.; Monteiro, A. L. Org.
Lett. 2001, 3, 3049–3051. (b) Percec, V.; Golding, G. M.; Smidrkal, J.;
Weichold, O. J. Org. Chem. 2004, 69, 3447–3452. (c) Tang, Z. Y.; Hu,
Q. S. J. Am. Chem. Soc. 2004, 126, 3058–3059. (d) Tang, Z.-Y.; Spinella,
S.; Hu, Q.-S. Tetrahedron Lett. 2006, 47, 2427–2430. (e) Lipshutz, B. H.;
Butler, T.; Swift, E. Org. Lett. 2008, 10, 697–700.
(1) (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483. (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168. (c) Martin, R.;
Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–1473.
10.1021/ol101592r  2010 American Chemical Society
Published on Web 08/17/2010

benzoyl, carbonate, sulfamate, carbamate)4a,7 as well as methyl
ethers8 have also been successfully used, emphasizing the
importance of nickel as a general catalyst in C-O activation
processes. Nearly all of these protocols employ a large excess
(2-5 equiv) of the organoboron coupling partner.
With the optimized conditions established for the pivaloyl
LG 1d, we next attempted to extend the process to various
LGs on naphthol in the Suzuki-Miyaura cross-coupling with
potassium furan-3-yltrifluoroborate (Table 1). Thus, the
Despite the significant advances in the pool of available
electrophiles and their cross-coupling, much effort remains
to generalize the transformation. To date, very few examples
of palladium-catalyzed C-O activation have been described
with heteroarylboronic acids. Buchwald first reported a very
efficient palladium cross-coupling of tosylated2c and
mesylated3c phenols with an excess of the boron reagent (2
equiv). With the same kind of catalytic system, but decreas-
ing the loading of the boron species to 1.1 equiv, Wu
observed a low yield in the cross-coupling of tosylated phenol
with potassium thiophene-2-yltrifluoroborate.2d During the
course of our investigation, Kwong reported a palladium-
catalyzed C-O activation of heteroaryl mesylates with a
single potassium heteroaryltrifluoroborate in excess (2 equiv)
to afford heterobiaryls with yields up to 82%.3d Moreover,
all nickel-catalyzed systems have been limited to arylboronic
acid derivatives. In view of the ubiquity of heterobiaryls in
natural products, polyaromatic molecules, pharmaceuticals,
and other useful materials, it is of interest to develop general
protocols to forge C(heteroaryl)-C(aryl or heteroaryl) bonds.
Potassium organotrifluoroborates have emerged as alterna-
tive coupling partners that provide some advantages to
sensitive boronic acid derivatives, which more easily undergo
protodeboronation.9 Herein, we disclose the first nickel-
catalyzed Suzuki cross-coupling of phenol derivatives with
potassium heteroaryltrifluoroborates. The developed reaction
proceeds with exceptional heterocycle compatibility and
generally high yields.
Table 1. Influence of the Nucleofuge on Naphthol for the
Nickel-catalyzed C-O Activation
a Relative GC yield determined using dodecane as the internal standard.
sulfonate LGs gave the best results, with mesylate 1a (which
afforded the desired compound in quantitative GC yield)
functioning better than the tosylate 1b and the sulfamate 1c.
Both ester (Piv and Boc)- and amide (CONEt2)-type LGs,
even though they are less reactive, are also well-tolerated.
The benzoyl group proved much less efficient, and the methyl
ether is not suitable under these conditions.
Encouraged by these results, we pursued our study by
varying the potassium heteroaryltrifluoroborates with two
classes of derivatives: mesylates (1a) and pivaloylates (1d)
(Table 2). We synthesized six heterobiaryls 2a-f from these
derivatized naphthols (Table 2, entries 1-6), and the same
tendency as previously described was observed: the mesyl-
ated compounds always afforded the heteroaryls with higher
yields than the pivaloyl compounds.11 Although the yields
are moderate with the pivaloyl substrate, the current method
complements and even improves upon previous methods in
its use of reduced quantities of the organoboron reagent4a
and is the first metal-catalyzed cross-coupling reaction
between a phenolic pivaloylate and a heteroarylboron reagent.
We initially chose the pivaloyl-protected naphthol as the
substrate for the C-O activation. An extensive screening of
various reaction parameters (e.g., choice of solvent, nickel
catalyst, ligand, base, etc.) was carried out10 and revealed
the essential role of Ni(COD)2 as a catalyst, while other Ni(II)
and Ni(0) species failed. This reaction unusually occurs in
the presence of a large amount of water in a protic solvent
(tert-butyl alcohol/H2O in a 1/1 ratio).7a,c Moreover, we were
able to reduce the loading of potassium organotrifluoroborate
to 1.3 equiv.
(6) For examples of Ni-catalyzed Suzuki cross-coupling of aryl mesyl-
ates, see: (a) Percec, V.; Bae, J. Y.; Hill, D. H. J. Org. Chem. 1995, 60,
1060–1065. (b) Ueda, M.; Saitoh, A.; Oh-tani, S.; Miyaura, N. Tetrahedron
1998, 54, 13079–13086. (c) Kobayashi, Y.; William, A. D.; Mizojiri, R. J.
Organomet. Chem. 2002, 653, 91–97. (d) Kuroda, J. I.; Inamoto, K.; Hiroya,
Five-membered, six-membered, and benzannulated het-
erocycles have successfully been engaged with a mesylated
naphthol with yields up to 95% (Table 2, entry 8). 3-Furanyl
and 3-thiophene-yl derivatives were coupled with very high
yields, 93% and 90%, respectively (Table 2, entries 1 and
3). Although the 2-boronated counterparts usually suffer from
facile protodeboronation, the desired products 2c and 2g were
obtained with good yields. Pyridine derivatives, known as
difficult cross-coupling partners owing to their low stability
K.; Doi, T. Eur. J. Org. Chem. 2009, 2251–2261
.
(7) (a) Guan, B. T.; Wang, Y.; Li, B. J.; Yu, D. G.; Shi, Z. J. J. Am.
Chem. Soc. 2008, 130, 14468–14470. (b) Quasdorf, K. W.; Riener, M.;
Petrova, K. V.; Garg, N. K. J. Am. Chem. Soc. 2009, 131, 17748–17749.
(c) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am. Chem. Soc. 2009,
131, 17750–17752. (d) Xu, L.; Li, B. J.; Wu, Z. H.; Lu, X. Y.; Guan, B. T.;
Wang, B. Q.; Zhao, K. Q.; Shi, Z. J. Org. Lett. 2010, 12, 884–887
.
(8) Tobisu, M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008,
47, 4866–4869.
(9) (a) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240–9261. (b) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973–980. (c) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am.
Chem. Soc. 2009, 131, 6961.
(11) For potassium thiophene-2- and 3-yltrifluoroborates with pivaloyl-
protected naphthol, the best yields were obtained with slightly different
optimized conditions: a mixture of dioxane/H2O (1/1), c ) 0.05, and
t-BuPCy2.
(10) See the Supporting Information for more details about the screen-
ing.
Org. Lett., Vol. 12, No. 18, 2010
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same kind of C-O activation, emphasizing the role of nickel
as an efficient and cost-effective catalyst.14
We next evaluated the tolerance of the method by
introducing functionalized potassium aryltrifluoroborates
(Table 3). We were pleased to observe that both electron-
Table 2. Scope of Potassium Heteroaryltrifluoroborates
Table 3. Scope of Potassium Aryltrifluoroborates
a Dioxane/H2O (1/1), c ) 0.05, and t-BuPCy2. b Relative GC yield
determined using dodecane as an internal standard. c With 10% of impurities
that cannot be separated.
donating (Table 3, entries 2-5) and electron-withdrawing
groups (Table 3, entries 7, 9, and 10) on the aryl ring did
not affect the reaction. The desired compounds 3a-e,g,i,j
were obtained with yields above 71%. The position of the
methoxy substituent on the aryl ring was also varied, and
even in the more sterically hindered ortho-position, the
desired compound 3e was obtained with a yield of 85%. The
low yields observed with the aldehyde and ester substituents
underscore the limits of the method. The aldehyde substrate
afforded a complex mixture of products, whereas the ester
substrate only proceeded to ∼60% conversion, even after
extended periods of time.
and electron deficiency,12 react efficiently to afford the
desired compounds 2d and 2e in good yields (Table 2, entries
4 and 5). Pyrimidine, quinoline, benzofuran, isoquinoline,
and indole derivatives are also very good nucleophilic
partners, leading to the desired compounds 2f,h,j-l with
yields ranging from 74% to 95%. Even indole derivative 2m
was obtained in 90% yield. Only the 2-benzothiophene was
more sensitive to protodeboronation, affording 2i in a yield
of 42%.
Notably, by increasing the scale of the reaction to 5.0
mmol, the Ni(COD)2 loading can be decreased to 2 mol %
to obtain 2a with a yield of 86% (compared to 93% on a
0.25 mmol scale).13 Importantly, a comparable loading of
the more expensive palladium catalyst is required for the
Various mesylated heteroaryls were also investigated with
the potassium furan-3-yltrifluoroborate as coupling partners
(13) 1-NaphthOMs (1 equiv), furan-3-ylBF3K (1.3 equiv), Ni(COD)2
(2 mol %), PCy3HBF4 (4 mol %), and K3PO4 (7.2 equiv), 110 °C, 24 h.
(14) Current prices for the catalysts are as follows: bis(1,5-cycloocta-
diene)nickel(0), $27/1 g; palladium(II) acetate, $59/1 g.
(12) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685–4696.
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Org. Lett., Vol. 12, No. 18, 2010

(Table 4). The cross-couplings proceeded in very high yields
ranging from 70% to 99% for all the pyridine derivatives
Table 5. Scope of Functionalized Mesylated Phenols with
Various Potassium Heteroaryltrifluoroborates
Table 4. Scope of Heteroaryl Mesylates
eroaryltrifluoroborates. Promising results were obtained when
the pivaloyl moiety was used as the nucleofuge, and very
good yields were achieved when the mesyl group was
employed. The reaction is very tolerant of a large range of
activated and deactivated nucleophilic potassium heteroaryl-
and functionalized aryltrifluoroborates. Numerous electro-
philic heteroaryl and functionalized aryl partners can also
be introduced with high cross-coupling yields. Moreover,
scaling up the reaction, the nickel catalyst loading can be
decreased to 2 mol %, affording a very efficient and
inexpensive method for C-O activation.
5a-e (Table 4, entries 1-5). Benzothiazole 4f also appears
to be a good electrophilic partner to obtain the desired
heterobiaryl 5f in 77% yield. Only indole partner 4g showed
a lower reactivity, affording the desired compound 5g in a
moderate yield.
Finally, functionalized aryl mesylates were also tested with
different potassium heteroaryltrifluoroborates (Table 5). The
various electronic properties of the different substituents on
the electrophilic counterpart do not seem to influence the
reaction. Heteroaryls bearing a nitrile (6b), a methoxy group
(6c), a ketone (6d), or an ester (6e) were obtained with good
to excellent yields (Table 5, entries 1-5). Even a hindered,
deactivated aryl mesylate (entry 6) reacts with potassium
isoquinolin-5-yltrifluoroborate to generate the desired com-
pound 6f with a yield of 39%.
Acknowledgment. We thank the NIGMS (R01 GM035249)
for their generous support. We acknowledge Frontier Sci-
entific for its donation of heteroarylboronic acids. Dr. Rakesh
Kohli (University of Pennsylvania) is acknowledged for
obtaining HRMS data.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have disclosed the first general nickel-
catalyzed method for C-O activation with potassium het-
OL101592R
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