Ni-catalyzed mild arylation of α-halocarbonyl compounds with arylboronic acids

Article abstract of DOI:10.1021/ol702456z

A simple yet powerful Ni catalyst can be used to promote direct arylations of α-halocarbonyl compounds, including a range of esters, amides, and ketones, with various arylboronic acids under mild conditions. The method tolerates β-hydrogens and functional groups in the substrates and offers reactivity and selectivity profiles that are complementary to those found in the well-established Buchwald-Hartwig approach.

Full text of DOI:10.1021/ol702456z

ORGANIC
LETTERS
2007
Vol. 9, No. 26
5601-5604
Ni-Catalyzed Mild Arylation of
-Halocarbonyl Compounds with
Arylboronic Acids
r
Chao Liu, Chuan He, Wei Shi, Mao Chen, and Aiwen Lei*
College of Chemistry and Molecular Sciences, Wuhan UniVersity,
Wuhan, Hubei 430072, China
aiwenlei@whu.edu.cn
Received October 19, 2007
ABSTRACT
A simple yet powerful Ni catalyst can be used to promote direct arylations of
r-halocarbonyl compounds, including a range of esters, amides,
and ketones, with various arylboronic acids under mild conditions. The method tolerates
and offers reactivity and selectivity profiles that are complementary to those found in the well-established Buchwald
â
-hydrogens and functional groups in the substrates
Hartwig approach.
−
R-Functionalization1,2 using readily available R-halocarbonyl
compounds represents one of the most versatile and valuable
methods for organic synthesis. Direct arylation of these
compounds would lead to efficient syntheses of the â-blocker
drug, avenolol, and a number of important nonsteroidal anti-
inflammatory drugs (NSAIDs) such as naproxen and ibu-
profen (Scheme 1). Since 1997, Buchwald and Hartwig have
pioneered palladium-catalyzed arylation of enolates of
ketone, ester, or amide using aryl halides as electrophiles
(Scheme 1, Path I).3,4 Their method has received much
attention because it could produce important synthetic
building blocks that are otherwise inefficient to prepare by
other technologies.5 However, those enolate nucleophiles
were usually generated from their corresponding carbonyl
compounds by deprotonation of R-hydrogens with strong
bases, conditions that could jeopardize the method’s func-
tional group tolerance capability. Very recently, Hartwig et
al. reported a mild and efficient arylation protocol from Zn-
enolate, silyl enol ether, and other precursors.6-8 We
anticipated that an alternative arylation strategy employing
Scheme 1. R-Arylation of Carbonyl Compounds and Its
Potential Applications
(1) Millard, A. A.; Rathke, M. W. J. Am. Chem. Soc. 1977, 99, 4833-
4835.
(2) Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2002, 41, 953-956.
(3) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382-
12383.
(4) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108-
11109.
(5) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245.
10.1021/ol702456z CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/04/2007

R-halocarbonyl compounds as the electrophiles and ArM as
the nucleophiles might achieve the same goal while at the
same time offering a greater level of synthetic flexibility
(Scheme 1, Path II). Moreover, such ArM precursors as ArB-
(OR)2 are usually less toxic, fairly stable, readily available,
and broadly compatible with an array of functional groups.9-17
Goossen and Deng et al. had previously investigated the
reactions of R-bromoacetic acid derivatives with ArB(OH)2
in the presence of palladium catalysts. The yields were
moderate to good in most cases, but the substrates were
limited to unsubstituted acetic acid derivatives.18-20 R-Bro-
mosulfoxides were also reported as suitable electrophiles to
react with ArB(OH)2.21 In 2007, we disclosed R-alkynylation
of R-bromoester or amides under mild conditions promoted
by some palladium catalysts.22 However, the substrates
employed in all the aforementioned transformations have
been limited to R-bromoacetic acid derivatives where â-hy-
dride elimination was not an issue in catalysis. Very recently,
Fu et al. reported an elegant approach of coupling R-halo-
carbonyl compounds with Csp3-Zn and ArSiF3 reagents, by
employing Ni-based catalysts23 ligated with pybox or amino
alcohols.24,25
cross-coupling systems we uncovered recently.29 We pro-
posed that the complexity of the reactions involving R-ha-
locarbonyl compounds likely arose from the tautomerization
between intermediates IA and IB (Figure 1), which were
Figure 1. Possible reaction pathways involving R-halocarbonyl
compounds.
In our continued efforts to investigate arylations of
R-halocarbonyl compounds bearing â-hydrogen with ArB-
(OH)2, we found that homocoupling product biaryls were
predominantly obtained.26 In these cases, R-halocarbonyl
compounds seemed to serve as agents in promoting oxidative
homocoupling reactions,26-28 rather than function effectively
as coupling partners, which was in marked contrast to some
generated through oxidative addition of R-halocarbonyl
compounds with the palladium catalysts. As illustrated in
Figure 1, among the several reaction pathways initiated from
oxidative addition and transmetalation intermediates, only
path B to D offers the potential of arylating R-halocarbonyl
compounds, while path A and path B to C would result in
(6) Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2006, 45, 5852-5855.
(7) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 4976-4985.
(8) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824-15832.
(9) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007, 9,
757-760.
a
Table 1. Arylation of R-Bromoesters with PhB(OH)2
(10) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N.
Tetrahedron Lett. 2002, 43, 5649-5651.
(11) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
(12) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem.,
Int. Ed. 2002, 41, 3056-3058.
(13) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.;
Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390-391.
(14) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith,
M. R., III. Science 2002, 295, 305-308.
(15) Mkhalid, I. A. I.; Conventry, D. N.; Albesa-Jove, D.; Batsanov, A.
S.; Howard, J. A. K.; Perutz, R. N.; Marder, T. B. Angew. Chem., Int. Ed.
2006, 45, 489-491.
(16) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R.
E., Jr.; Smith, M. R., III. J. Am. Chem. Soc. 2006, 128, 15552-15553.
(17) Shimada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B.
Angew. Chem., Int. Ed. 2001, 40, 2168-2171.
(18) Goossen, L. J. Chem. Commun. 2001, 669-670.
(19) Liu, X.-X.; Deng, M.-Z. Chem. Commun. 2002, 622-623.
(20) Duan, Y.-Z.; Deng, M.-Z. Tetrahedron Lett. 2003, 44, 3423-3426.
(21) Rodriguez, N.; Cuenca, A.; De Arellano, C. R.; Medio-Simon, M.;
Peine, D.; Asensio, G. J. Org. Chem. 2004, 69, 8070-8076.
(22) Shi, W.; Liu, C.; Yu, Z.; Lei, A. Chem. Commun. 2007, 2342-
2344.
(23) Tamaru, Y. Modern Organonickel Chemistry; Wiley-VCH: Wein-
heim, Germany, 2005.
(24) Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-4595.
(25) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem., Int. Ed.
2007, 46, 3556-3558.
(26) Lei, A.; Zhang, X. Tetrahedron Lett. 2002, 43, 2525-2528.
(27) Lei, A.; Zhang, X. Org. Lett. 2002, 4, 2285-2288.
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a 1:2:catalyst ) 2:1:0.05 (0.5 mmol scale); solvent 1 mL; additive 2
mmol; naphthalene 0.5 mmol. The yields were determined by GC.
5602
Org. Lett., Vol. 9, No. 26, 2007

This finding prompted us to explore the utility of Ni-
catalyzed arylations of a range of R-bromoesters and amides
with phenylboronic acid. As summarized in Table 2, the Ni-
(PPh3)4 catalytic system proved to be broadly applicable as
in nearly all the cases the products were obtained in good to
high yields. Arylations with bromoacetates appeared to be
particularly efficient (Table 2, entries 1-3).31 Those R-bro-
moesters bearing â-hydrogens were well-tolerated (Table 2,
entries 4-9). The arylation of R-bromolactone formed the
product in 74% yield using anhydrous K3PO4 with only a
trace amount of biphenyl (<5%) detected by GC. It merits
a note here that the role of the base seemed to be critical as
no product could be isolated when the reaction was carried
out in the presence of K3PO4‚3H2O. The protocol could also
be extended to R-bromoamides to afford arylated derivatives
effectively (Table 2, entries 10-15). It is noteworthy that
the free NH of primary and secondary amides was fairly
compatible with these reaction conditions (Table 2, entries
12-15). Additionally, a substrate containing two Br atoms
at the R- and γ-positions displayed good selectivity (Table
2, entry 8).
Table 2. Arylation of R-Bromoesters or Amides with
PhB(OH)2
a
Table 3. Arylation of R-Bromoacetic Acid Derivatives with
Arylboronic Acidsa
a Reaction conditions: refer to Supporting Information, isolated yield.
b GC yield.
the formation of biaryl byproducts. Herein, we report a highly
efficient and versatile catalytic system that was shown to
differentiate well these competing pathways and lead to
arylations of a series of R-halocarbonyl compounds bearing
â-hydrogens with various arylboronic acids.
a Reaction conditions: refer to Supporting Information, isolated yield.
b At a 1.5 mmol scale, at 80 °C.
Our initial efforts focused on the reaction of â-hydrogen-
bearing R-bromoester 2 with phenylboronic acid using Pd-
(PPh3)4 as the catalyst precursor.30 As listed in Table 1, the
formation of the desired arylation product 5 proved to be
rather fruitless under a variety of conditions (<10% yield,
Table 1, entries 1-13). The major byproduct was the
biphenyl derived from homocoupling of phenylboronic acid.
However, we were delighted to find that 5 could be obtained
in 82% yield when Ni(PPh3)4 was used as the catalyst
precursor in the presence of K3PO4 in toluene (Table 1, entry
14).
Furthermore, as shown in Table 3, we found that the
method could be readily extended to substituted arylboronic
acids to generate arylated products in good to excellent
yields. For example, arylation of p-chlorobenzenylboronic
acid with ethyl 2-bromohexanoate (Table 3, entry 1) afforded
the product in 95% yield. It is noteworthy that the ArBr
moiety was tolerated under these mild conditions, which may
(30) Durandetti, M.; Gosmini, C.; Perichon, J. Tetrahedron 2006, 63,
1146-1153.
(31) Ten percent yields of the biphenyl was detected by GC in the
reaction of the methyl bromoester (Table 2, entry 1). The reactions of the
ethyl bromoester and the tert-butyl bromoacetate produced the biphenyl in
6 and 5% GC yields, respectively (Table 2, entries 2 and 3).
(29) Zhao, Y.; Wang, H.; Hou, X.; Hu, Y.; Lei, A.; Zhang, H.; Zhu, L.
J. Am. Chem. Soc. 2006, 128, 15048-15049.
Org. Lett., Vol. 9, No. 26, 2007
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otherwise cause problems for its oxidative addition reactivity
as reported in Buchwald-Hartwig approaches. The reaction
produced the corresponding product in 75% yield (Table 3,
entry 2).
Table 5. Arylation of 3-Chlorobutan-2-onea
The R-haloketones are also viable substrates for this
process, as evidenced by the results compiled in Table 4.
Table 4. Ni-Catalyzed R-Arylation of Ketonesa
a Reaction conditions: refer to Supporting Information, GC yield.
reactions of 3-chlorobutan-2-one took place smoothly at the
more hindered site to give the products in 60-67% yield,
which offered complementary results to those of the Buch-
wald-Hartwig method (Table 5).
In conclusion, we have discovered that Ni(PPh3)4 served
as a highly effective catalyst for the arylations of a wide
variety of R-halocarbonyl compounds with various aryl-
boronic acids. Compared to those Pd-catalyzed arylations
using aryl halides, the Ni-based catalysis approach is notably
more advantageous in that it is capable of bringing about
arylations with readily available substrates and offering more
robust profiles in such important issues as functional group
tolerance and reaction selectivity. This method is simple,
general, and practical and thus holds promise for the
preparation of structurally diverse arylated carbonyl com-
pounds. The mechanism is currently under investigation in
our laboratory and will be reported in due course.
a Reaction conditions: refer to Supporting Information, isolated yield.
The reaction of 2′-bromoacetophenone with phenylboronic
acid led to the formation of 1,2-diphenylethanone in 66%
yield. Both 2′-chloroacetophenone and 2′-bromopropiophe-
none bearing a methyl group at the R-position afforded
arylated products in high yields. Again, we observed that
the halide moieties (ArCl and ArBr) were well-tolerated
under these reaction condition.
Regioselective arylation using unsymmetric ketones such
as butan-2-one represented a major challenge in the Buch-
wald-Hartwig approach employing palladium catalysts
where the arylations tend to take place at less hindered sites
when the ketones have two enolizable positions. In our
system, remarkably, we found that the arylations could be
controlled regioselectively. As shown in Table 5, the
Acknowledgment. This work was assisted financially by
the National Natural Science Foundation of China (20502020)
and a startup fund from Wuhan University.
Supporting Information Available: Detailed experi-
mental procedure and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL702456Z
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Org. Lett., Vol. 9, No. 26, 2007