Chemoselective and regiospecific suzuki coupling on a multisubstituted sp3-Carbon in 1,1-diborylalkanes at room temperature

Article abstract of DOI:10.1021/ja105176v

The palladium-catalyzed Suzuki-Miyaura cross-coupling on a multisubstituted sp³-carbon in 1,1-diborylalkanes was achieved at room temperature. The generation of a monoborate intermediate by virtue of the adjacent B atom could result in the chemoselective coupling reaction under ambient conditions.

Full text of DOI:10.1021/ja105176v

Published on Web 07/26/2010
Chemoselective and Regiospecific Suzuki Coupling on a Multisubstituted
sp3-Carbon in 1,1-Diborylalkanes at Room Temperature
Kohei Endo,*,† Takahiro Ohkubo,‡ Munenao Hirokami,‡ and Takanori Shibata*,‡
Waseda Institute for AdVanced Study, Shinjuku, Tokyo, 169-8050, Japan and Department of Chemistry and
Biochemistry, School of AdVanced Science and Engineering, Waseda UniVersity, Shinjuku, Tokyo, 169-8555, Japan
Received June 14, 2010; E-mail: kendo@aoni.waseda.jp; tshibata@waseda.jp
Scheme 1. Typical Byproducts in SMC Using Alkylborans
Abstract: The palladium-catalyzed Suzuki-Miyaura cross-cou-
pling on a multisubstituted sp3-carbon in 1,1-diborylalkanes was
achieved at room temperature. The generation of a monoborate
intermediate by virtue of the adjacent B atom could result in the
chemoselective coupling reaction under ambient conditions.
Suzuki-Miyaura cross-coupling (SMC) has been identified as
a reliable method for C-C bond formation, especially for the
Scheme 2. Possible Scheme of SMC Using 1,1-Diborylalkanes
synthesis of complex molecules.1,2 However, cross-coupling on an
sp3-carbon has recently been shown to have severe drawbacks.
ꢀ-Hydride elimination, regioisomerization, and protodeboronation
are challenging processes that generate side-products. There have
been only a few reports2a,3 of successful SMC on a multisubstituted
sp3-carbon in organoboron compounds except for cyclopropylborane
derivatives.4 Fu and Hartwig independently reported the use of
secondary alkylboronic acids.3 Dreher and Molander as well as van
den Hoogenband independently reported the use of secondary alkyl
3a
[P(t-Bu)3]2 in dioxane. To our surprise, the reaction proceeded
efficiently at room temperature to give the desired product 3a in
potassium trifluoroborate salts, which are a relatively tolerable
94% yield (eq 1). Side products, which are typical for the SMC of
coupling partner against protodeboronation.5 Recently, Suginome
alkylboronates, were not observed. The boronate moiety attached
reported the use of R-(acylamino)benzylboronates without ꢀ-C-H
to the product 3a was intact and did not participate in further
bonds and Crudden reported the use of benzylboronate derivatives
coupling, even in the presence of excess amounts of 2a-I.
for the coupling reaction.6 These studies revealed some challenging,
and still unsolved, problems: (1) the structure of multisubstituted
alkylboron compounds is limited, such as to cycloalkyl, isopropyl,
and benzyl boron compounds; (2) a high reaction temperature and
long reaction time are required; and (3) isomerized byproducts are
generated in many cases (Scheme 1). In this paper, we describe a
new approach to the chemoselective and regiospecific SMC of 1,1-
diborylalkanes7 on a multisubstituted sp3-carbon atom bearing
Screening of the reaction conditions clarified that the reaction
ꢀ-C-H bonds at room temperature.
at elevated temperature promotes protodeboronation; accordingly,
the reaction at room temperature prevented side reactions. The Ni
catalyst system reported by Fu for the cross-coupling reaction using
primary alkylboron compounds with secondary alkyl halides8b,c was
not suitable and gave only the protodeboronated compound derived
from 1a. Therefore, the use of a Pd catalyst is required to achieve
the present reaction. The choice of base was important; the use of
strong bases, such as LiOH, NaOH, and KOH, was effective, and
other bases, such as K3PO4, Cs2CO3, Na2CO3, and Ag2O, did not
give the product 3a at room temperature.
The scope of haloarenes and 1,1-diborylalkanes is shown in Table
1. Every reaction proceeded at room temperature.10 A wide variety
of aryl bromides were available and gave the corresponding
products in good to excellent yields. The use of 1-mol % Pd-
[P(t-Bu)3]2 gave the corresponding product in high yield (entry 4).
The electron-rich aryl bromides 2e, 2h, 2l, and 2p afforded the
corresponding boronates 3, respectively (entries 4, 7, 11, and 15).
Bromofluorobenzenes could take part in the reaction (entries 5, 8,
and 12). The sterically hindered aryl bromides 2k, 2o, and 2q gave
The cross-coupling reaction of alkylboron compounds generally
suffers from a slow transmetalation step,2d,8 subsequent ꢀ-hydride
elimination and/or protodeboronation, which requires a high reaction
temperature and/or an excess amount of alkylboron compounds to
achieve a high yield. We assumed that the use of 1,1-diborylalkanes
could overcome these unsolved problems through rapid transmeta-
lation and/or stabilization of the corresponding σ-alkylpalladium
intermediate due to the boronate moiety attached at the carbon atom
R to the Pd atom.9 The subsequent cross-coupling reaction gives
mono-boronate compounds, which would resist transmetalation
under mild conditions. However, the chemoselectivity for mono-
borate and/or di-borate intermediates, which generate R-Pd,B,
R-Pd,Pd, and/or R-Pd,Borate intermediates, would be problematic
(Scheme 2). We examined the reaction of 1,1-diborylalkane 1a (1.5
equiv) and 4-iodoanisole (2a-I) in the presence of 5 mol % Pd-
† Waseda Institute for Advanced Study.
‡ Waseda University.
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J. AM. CHEM. SOC. 2010, 132, 11033–11035 11033

C O M M U N I C A T I O N S
Table 1. Wide Scope of 1,1-Diborylalkanes 1 and Aryl Bromides 2
Table 2. Generation of Borate Intermediate at Room Temperature
entry
R, X, Y (11B, δ ppm)
+ KOH (11B, δ ppm, ratio)
1
2
3
4
1e; Ph, H, Bpin (34.8)
4; Ph, H, SiMe3 (34.8)
5; n-C6H13, Bpin, H (33.4)
6; Ph, H, H (34.4)
35.5, -0.6 (1/1)
34.6 (no borate)
34.0, 10.5 (15/1)
34.4 (no borate)
To investigate the selective formation of a monoborate interme-
diate, we performed the NMR analyses of a mixture of 1e and KOH
(3 equiv) in dioxane-d8 (see Supporting Information for details).
As a result, two singlet peaks appeared at 35.5 and -0.6 ppm, and
their integration ratio was almost 1 to 1; the high field shift suggests
the formation of a borate moiety (Table 2, entry 1).1b Therefore,
the treatment of 1 could give a monoborate intermediate even
in the presence of an excess amount of KOH; the further addition
of KOH did not change the integration ratio. The subsequent
addition of a stoichiometric amount of Pd[P(t-Bu)3]2 and 4-bro-
moanisole (2e) to the mixture of borate in dioxane-d8 from 1e and
KOH gave the product 3t. In stark contrast, the treatment of 1,1-
borylsilylalkane 4, and primary alkyl-(Bpin) 6 with KOH (3 equiv)
in dioxane-d8 did not change the chemical shift (entries 2 and 4).
The Si atom of 4 does not induce the generation of a borate
intermediate at room temperature; the impressive virtue of the
adjacent B atom of 1,1-diborylalkanes is seen as being for borate
generation. Although 1,2-diborylalkane 5 gave a small borate peak,
the coupling reaction did not proceed at room temperature (entry
3, eq 4). Thus, the adjacent B atom in 1,1-diborylalkanes could
promote the transmetalation between a borate intermediate and
ArPdX. The influence of the adjacent B atom on a borate moiety
as a ꢀ-anion equivalent seems to be a characteristic feature in the
present study, since a Si atom generally stabilizes an R-carbanion.
In addition, there are no side products via ꢀ-hydride elimination
from 1,1-diborylalkanes; the adjacent B atom could stabilize
σ-alkylpalladium intermediates as an R-carbanion congener. DFT
calculations were performed using the B3LYP/6-31G** level of
theory. The LUMO maps of 1,1-diborylalkane and 1,1-borylsilyl-
alkane are shown in Figure 1. A large LUMO distribution is
observed around the B-B moiety in 1,1-BB, and a delocalized
LUMO distribution is observed around each B atom and Si atom
in 1,1-BSi. The LUMO map indicates that the assistance of an
adjacent B atom in 1,1-diborylalkanes could result in the generation
of a monoborate intermediate at room temperature.
a NMR yields. Isolated yields were described in parentheses. b The
reaction in the presence of Pd[P(t-Bu)3]2 (1 mol %) gave the product 3e
in 92% NMR yield. c NMR yields could not be determined due to the
complicated spectra. d The yield of corresponding deboronated product
of 3 was described. e The yield of corresponding alcohol after oxidation
was described.
the corresponding products in good yields (entries 10, 14, and 16).
The reactions of various 1,1-diborylalkanes gave the corresponding
products 3a, 3r-u in good yields (entries 17-21). The characteristic
feature of the present reaction is shown in the chemoselective cross-
coupling on an sp3-carbon derived from 1,1-diborylalkane 1b with
aryl bromide 2r bearing a primary alkyl-(Bpin) moiety; the reaction
gave the product 3v selectively (eq 2; see Supporting Information
for details). We next carried out the reactions of congeners of 1,1-
diborylalkanes, such as 1,1-borylsilylalkane 411a and 1,2-diboryl-
alkane 5,11b to ascertain the influence of the bis(pinacolboryl) group
(eqs 3 and 4). The reactions of 4 and 5 did not give the coupling
product under the same reaction conditions as those in Table 1.
These results suggest that the bis(pinacolboryl) group plays a pivotal
role in promoting the coupling reaction on a multisubstituted sp3-
carbon under mild conditions. This influence of the bis(pinacolboryl)
group can be explained as follows. Primary alkyl-(9-BBN) and
primary alkylboronic acids readily give the corresponding borate
intermediate at room temperature with a relatively strong base, such
as KOH, TlOH, or KOt-Bu.1,2,8a Nevertheless, alkyl-(Bpin) scarcely
gives the corresponding borate intermediate at room temperature.
SMC of primary alkyl-(Bpin) using PdCl2(dppf) and TlOH or some
other bases gave the coupling product in low yield; accordingly, a
relatively stronger Lewis acidic boron moiety should be required
for alkylboron compounds to achieve SMC.
There are two possible pathways in SMC: the stepwise trans-
metalation of ArPdX with a borate intermediate and the direct
transmetalation of ArPdOH with boron compounds.1b The former
mechanism is more likely in the present study (Figure 2). Trans-
metalation between ArPdX and potassium borate provides a σ-alkyl-
PdAr intermediate, which undergoes reductive elimination to give
the product 3. Since the vacant orbital of boron can stabilize a
C-metal bond, the relatively stabilized R-B,Pd intermediate would
prevent the ꢀ-hydride elimination to generate alkenes and regioi-
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C O M M U N I C A T I O N S
somers as side products (see Supporting Information for details).9
The present study clearly indicates that SMC on a multisubstituted
sp3-carbon could proceed at room temperature when the corre-
sponding borate intermediate is generated with a suitable base and
a σ-alkyl-PdAr intermediate bearing ꢀ-C-H bonds is sufficiently
stable before reductive elimination.
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
(1) For reviews, see: (a) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(b) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4544. (c) Suzuki, A.; Brown, H. C. Organic Syntheses Via
Boranes; Aldrich Chemical Co., Inc.: Milwaukee, WI, 2002; Vol. 3. (d)
Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (e) Bellina,
F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419.
(2) (a) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.; Suzuki,
A. J. Am. Chem. Soc. 1989, 111, 314. (b) Sato, M.; Miyaura, N.; Suzuki,
A. Chem. Lett. 1989, 18, 1405. (c) Ridgway, B. H.; Woerpel, K. A. J.
Org. Chem. 1998, 63, 458. (d) Matos, K.; Soderquist, J. A. J. Org. Chem.
1998, 63, 461.
(3) (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020.
(b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
(4) For SMC of cyclopropylboron derivatives, see: (a) Hildebrand, J. P.;
Marsden, S. P. Synlett 1996, 893. (b) Wang, X.-Z.; Deng, M.-Z. J. Chem.
Soc., Perkin Trans. 1 1996, 2663. (c) Rubina, M.; Rubin, M.; Gevorgyan,
V. J. Am. Chem. Soc. 2003, 125, 7198. Review: (d) Doucet, H. Eur. J.
Org. Chem. 2008, 2013.
Figure 1. LUMO maps of 1,1-BB and 1,1-BSi.
(5) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257. (b) van den Hoogenband, A.; Lange, J. H. M.;
Terpstra, J. W.; Koch, M.; Visser, G. M.; Visser, M.; Korstanje, T. J.;
Jastrzebski, J. T. B. H. Tetrahedron Lett. 2008, 49, 4122.
(6) (a) Ohmura, T.; Awano, T.; Suginome, M. Chem. Lett. 2009, 38, 664. (b)
Imao, D.; Glasspoole, B. W.; Laberge, V. S.; Crudden, C. M. J. Am. Chem.
Soc. 2009, 131, 5024.
(7) (a) Shimizu, M.; Schelper, M.; Nagao, I.; Shimono, K.; Kurahashi, T.;
Hiyama, T. Chem. Lett. 2006, 35, 1222. (b) Endo, K.; Hirokami, M.;
Shibata, T. Synlett 2009, 1331. (c) Endo, K.; Hirokami, M.; Shibata, T. J.
Org. Chem. 2010, 75, 3469.
(8) For the reaction of primary alkyl-(9-BBN) or primary alkylboronic acids
with alkyl halides proceeds at ambient conditions with the improved
catalysts, see: (a) Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C.
J. Am. Chem. Soc. 2002, 124, 13662. (b) Saito, B.; Fu, G. C. J. Am. Chem.
Soc. 2007, 129, 9602. (c) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2008,
130, 6694.
(9) (a) Nakamura, M.; Hara, K.; Hatakeyama, T.; Nakamura, E. Org. Lett.
2001, 3, 3137. (b) Nakamura, M.; Hatakeyama, T.; Hara, K.; Fukudome,
H.; Nakamura, E. J. Am. Chem. Soc. 2004, 126, 14344. (c) Hatakeyama,
T.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130, 15688.
(10) Due to the almost same Rf value of 1,1-diborylalkanes 1 and products 3 as
well as the instability of 3 to column chromatography purification, the
isolated yields are generally lower than NMR yields. Therefore, we
reconfirmed the yield of products as alcohols after the oxidation of the
crude mixture (see Supporting Information).
Figure 2. Plausible reaction mechanism.
In conclusion, we have demonstrated the usefulness of 1,1-
diborylalkanes for chemoselective and regiospecific SMC at room
temperature. The key to success is the generation of a monoborate
intermediate by virtue of the adjacent B atom in 1,1-diborylalkanes.
The present results constitute a new example of protection-free
chemoselective cross-coupling on a multisubstituted sp3-carbon.12
Therefore, the use of 1,1-diborylalkanes may be a convenient and
practical approach for the coupling of functionalized molecules at
room temperature.1b Other types of reactions, including cross-
coupling reactions using multimetallic compounds and an asym-
metric version, and mechanistic studies are underway in our
laboratory.
(11) (a) Matteson, D. S.; Majumdar, D. J. Chem. Soc., Chem. Commun. 1980,
39. (b) Ishiyama, T.; Yamamoto, M.; Miyaura, N. Chem. Commun. 1997,
689.
(12) For chemoselective Suzuki coupling of protected borons on sp2-carbon atom,
see: (a) Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007,
129, 758. (b) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129,
6716. (c) Noguchi, H.; Shioda, T.; Chou, C.-M.; Suginome, M. Org. Lett.
2008, 10, 377. (d) Iwadate, N.; Suginome, M. Org. Lett. 2009, 11, 1899.
(e) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2009,
131, 6961. (f) Iwadate, N.; Suginome, M. J. Am. Chem. Soc. 2010, 132,
2548. (g) Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D. Org. Lett.
2010, 12, 2314. For chemoselective Suzuki coupling of 1,2-diboraethane
on sp3-carbon atom using different boron moieties of 9-BBN and potassium
trifluoroborate, see: (h) Molander, G. A.; Sandrock, D. L. Org. Lett. 2009,
11, 2369.
Acknowledgment. This work was financially supported by a
Grant-in-Aid for Young Scientists (B) (No. 21750108) from the
Japan Society for the Promotion of Science and Waseda University
Grant for Special Research Projects. K.E. thanks the Society of
Synthetic Organic Chemistry, Japan for a Teijin Pharma Award.
Supporting Information Available: The experimental procedure,
NMR experiments, DFT calculations, and physical properties of new
JA105176V
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