Chemoselective Suzuki coupling of diborylmethane for facile synthesis of benzylboronates

Article abstract of DOI:10.1021/ol201115k

The chemoselective Pd-catalyzed Suzuki-Miyaura cross-coupling reaction using a diborylmethane is reported. The use of an equimolar amount of base with a diborylmethane realized chemoselective coupling for the synthesis of various benzylboronate derivatives. Sterically hindered aryl bromides can give products in moderate to excellent yields.

Full text of DOI:10.1021/ol201115k

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3368–3371
Chemoselective Suzuki Coupling of
Diborylmethane for Facile Synthesis of
Benzylboronates
Kohei Endo,*,†,‡ Takahiro Ohkubo,§ and Takanori Shibata*,§
Waseda Institute for Advanced Study, Shinjuku, Tokyo, 169-8050, Japan, PRESTO,
Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama,
332-0012, Japan, and Department of Chemistry and Biochemistry, School of Advanced
Science and Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan
kendo@aoni.waseda.jp; tshibata@waseda.jp
Received April 27, 2011
ABSTRACT
The chemoselective Pd-catalyzed SuzukiꢀMiyaura cross-coupling reaction using a diborylmethane is reported. The use of an equimolar amount
of base with a diborylmethane realized chemoselective coupling for the synthesis of various benzylboronate derivatives. Sterically hindered aryl
bromides can give products in moderate to excellent yields.
SuzukiꢀMiyaura cross-coupling (SMC) is a reliable
method for CꢀC bond formation, typically between sp2-
carbons. There are numerous reports concerning improve-
ments in catalysts, which realize the cross-coupling reaction
of less-reactive substrates even under mild conditions.1
However, the severe limitations of SMC at an sp3-carbon
require the further modification of catalysts and reaction
conditions.1b,2 We previously reported chemoselective and
regiospecific SMC using 1,1-diborylalkanes at room
temperature.3 The key to success was the notable ability
of a 1,1-diborylalkane to generate a monoborate intermedi-
ate with KOH as a base. The coupling reaction of a 1,1-
diborylalkane facilitated SMC on a multisubstituted sp3-
carbon to give a monoboronate product; the subsequent
cross-coupling to give a 1,1-diarylalkane is typically termi-
nated due to the inefficient generation of a borate inter-
mediate from a secondary alkylboron compound at room
temperature. There have been several reports of SMC using
secondary alkyl boronic acids or boronate esters under limited
conditions. With a cyclopropylboronic acid, SMC proceeded
in high to excellent yields.4 Other cycloalkylboronic acids also
participated in SMC with moderate to good yields.5 The use
of secondary alkylboron compounds, such as isopropyl and
secondary butyl, gives the desired products, and some give a
mixture of regioisomers.6 Recently, the regiospecific and/or
† Waseda Institute for Advanced Study.
‡ PRESTO, Japan Science and Technology Agency (JST).
§ Waseda University.
(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. (f) Jana, R.;
Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417.
(4) (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.
(5) (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.
(2) (a) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203. (b)
Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597. (c)
Molander, G. A.; Petrillo, D. E. Org. Lett. 2008, 10, 1795. (d) Molander,
G. A.; Canturk, B. Org. Lett. 2008, 10, 2135. (e) Dreher, S. D.; Dormer,
P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130,
9257. (f) Molander, G. A.; Snadrock, D. L. Org. Lett. 2009, 11, 2369. (g)
(6) (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.
ꢀ
Molander, G. A.; Shin, I.; Jean-Gerard, L. Org. Lett. 2010, 12, 4384. (h)
Molander, G. A.; Hiebel, M.-A. Org. Lett. 2010, 12, 4876.
(3) Endo, K.; Ohkubo, T.; Hirokami, M.; Shibata, T. J. Am. Chem.
Soc. 2010, 132, 11033.
ꢀ
(c) Sandrock, D. L.; Jean-Gerard, L.; Chen, C.; Dreher, S. D.;
Molander, G. A. J. Am. Chem. Soc. 2010, 132, 17108.
r
10.1021/ol201115k
Published on Web 06/06/2011
2011 American Chemical Society

stereospecific SMC of a secondary benzylboronate ester was
reported.7 Typically, the aforementioned SMC of secondary
alkylboron compounds requires heating conditions. In this
context, our previous strategy using 1,1-diborylalkanes is
reasonable for obtaining unreactive secondary alkylboronate
esters as products at room temperature for the chemoselective
synthesis.
for 1,1-diborylalkane 1b11 gave the corresponding product
4a in high yield; accordingly, the same reaction conditions
are not suitable for the use of diborylmethane 1a.
Scheme 1. SMC of Diborylalkanes
To further develop our strategy in the present paper, we
focused on the reaction of bis(pinacolatoboryl)methane
1a,8 which gives a primary benzylboronate ester as a
product. This reaction is challenging because SMC using
primary alkylboron compounds including benzylboron
compounds would take place under mild conditions in
some cases.9,10 Unexpectedly, our attempt to use dibor-
ylmethane 1a with 4-bromoanisole (2a) failed in the pre-
sence of Pd[P(t-Bu)3]2 (5 mol %) and 3 equiv of KOH
added to 1a in H2O and dioxane; 2a was recovered almost
quantitatively (Scheme 1). The typical reaction conditions
Figure 1. LUMO map and 11B NMR spectra.
(7) (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. (c) Ohmura, T.; Awano, T.;
Suginome, M. J. Am. Chem. Soc. 2010, 132, 13191.
(8) (a) Castle, R. B.; Matteson, D. S. J. Organomet. Chem. 1969, 20,
19. (b) Matteson, D. S. Synthesis 1975, 147.
To clarify the difference between diborylmethane 1a and
1,1-diborylalkane 1b, the characteristic features of dibor-
ylmethane 1a were considered (Figure 1). DFT calculation
for a diborylmethane depicted a large distribution of
LUMO around boron moieties, which is similar to that
of a 1,1-diborylalkane.3 NMR analyses of a borate gener-
ated in dioxane-d8 showed an obvious difference; the
strong intensity of a borate moiety was observed even in
the presence of an equimolar amount of KOH (b-I). Two
singlet peaks appeared at 34 and ꢀ2 ppm derived from
diborylmethane 1a, and their integration ratio was 1 to 4.8
when an equimolar amount of KOH was used. Notably,
the borate detected at ꢀ2 ppm showed a very broad peak
from ꢀ20 to 25 ppm. In contrast, the previous 11B NMR
analyses of a borate intermediate derived from a 1,1-
diborylalkane showed that the integration ratio of a free
boronate moiety and a borate moiety is almost 1 to 1 even
in the presence of excess KOH; thus, a monoboronate
intermediate could be generated exclusively (b-II). The
spectrum of a 11B NMR experiment using 1a is unexpected
since the presence of an equimolar amount of KOH should
(9) For SMC of primary benzylboron compounds, see: (a) O’Connor,
S. J.; Barr, K. J.; Wang, L.; Sorensen, B. K.; Tasker, A. S.; Sham, H.;
Ng, S.-C.; Cohen, J.; Devine, E.; Cherian, S.; Saeed, B.; Zhang, H.;
Lee, J. Y.; Warner, R.; Tahir, S.; Kovar, P.; Ewing, P.; Alder, J.;
Mitten, M.; Leal, J.; Marsh, K.; Bauch, J.; Hoffman, D. J.; Sebti,
S. M.; Rosenberg, S. H. J. Med. Chem. 1999, 42, 3701. (b) Molander,
G. A.; Ito, T. Org. Lett. 2001, 3, 393. (c) Flaherty, A.; Trunkfield, A.;
Barton, W. Org. Lett. 2005, 7, 4975. (d) Nilsson, J.; Nielsen, E. Ø.;
Liljefors, T.; Nielsen, M.; Sterner, O. Bioorg. Med. Chem. Lett. 2008,
18, 5713. For SMC of primary alkylboron compounds, see: (e)
Kirchhoff, J. H.; Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 13662. (f) Arentsen, K.; Caddick, S.; Cloke,
F. G. N.; Herring, A. P.; Hitchcock, P. B. Tetrahedron Lett. 2004, 45,
3511. (g) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.;
Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem.;
Eur. J. 2006, 12, 4743. (h) Valente, C.; Baglione, S.; Candito, D.;
O’Brien, C. J.; Organ, M. G. Chem. Commun. 2008, 735. (i) Owston,
N.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 11908. (j) Lu, Z.; Fu, G. C.
Angew. Chem., Int. Ed. 2010, 49, 6676.
(10) For the syntheses of primary benzylboron derivatives, see: (a)
Falck, J. R.; Bondlela, M.; Ye, J.; Cho, S.-D. Tetrahedron Lett. 1999, 40,
5647. (b) Shimada, S.; Batsanov, A. S.; Howard, J. A. K.; Marder, T. B.
Angew. Chem., Int. Ed. 2001, 40, 2168. (c) Ishiyama, T.; Ishida, K.;
Takagi, J.; Miyaura, N. Chem. Lett. 2001, 30, 1082. (d) Ishiyama, T.;
Oohashi, Z.; Ahiko, T.; Miyaura, N. Chem. Lett. 2002, 31, 780. (e)
Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. Synth. Commun.
~
2002, 32, 2513. (f) Pintaric, C.; Laza, C.; Olivero, S.; Dunach, E.
Tetrahedron Lett. 2004, 45, 8031. (g) Boebel, T. A.; Hartwig, J. F.
Organometallics 2008, 27, 6013. (h) Pintaric, C.; Olivero, S.; Gimbert,
Y.; Chavant, P. Y.; Dunach, E. J. Am. Chem. Soc. 2010, 132, 11825.
(11) (a) Endo, K.; Hirokami, M.; Shibata, T. Synlett 2009, 1131. (b)
Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem. 2010, 75, 3469.
~
Org. Lett., Vol. 13, No. 13, 2011
3369

generate at most one borate moiety, and the integration
ratio should be 1 to1 ifa borate is generated quantitatively.
The addition of 3 equiv of KOH to 1a increased the
intensity of a borate peak, which might include a diborate
intermediate.
typical SMC at an sp3-carbon requires excess base to
complete the reaction.1b In our previous report, 3 equiv
of KOH to a 1,1-diborylalkane were required. In contrast,
excess KOH prevented the present reaction using dibor-
ylmethane 1a. We examined the effects of other bases, such
as NaOH, LiOH, K3PO4, KF, Cs2CO3, and Ag2O (entries
3ꢀ8). The reaction proceeded, but the yield was not
improved. A slight increase in the amount of diboryl-
methane realized a quantitative yield of 3a (entry 9).13
Table 1. Screening of Reaction Conditions
Figure 2. Possible borate intermediates.
The possible intermediates are shown in Figure 2. Since
the mixture of 1a and an equimolar amount of KOH
showed a broad peak at ꢀ2 ppm, the generation of a
monoborate intermediate 1a-(OH), a monoborate inter-
mediate 1a-bidentate-(OH), the corresponding hydrated
complex 1a-(OH)-H2O, and/or a diborate intermediate
1a-(OH)2 can be proposed.12 The relatively strained cyclic
structure of a 1a-bidentate-(OH) intermediatewould givea
hydrated complex 1a-(OH)-H2O. The oligomeric borate
intermediates might exist in equilibrium. The transmetala-
tion of 1a-(OH), 1a-bidentate-(OH), and/or 1a-(OH)-H2O
with ArPdX would lead to the product 3a. Therefore, a
borate-hydrated complex and/or oligomers could be pre-
dominant for the unexpected integration ratio in the
presence of an equimolar amount of KOH as shown in
(b-I).
We tested the reaction conditions of diborylmethane 1a
for SMC to investigate the influence of the amount of base
(Table 1). The previous reaction conditions using excess
KOH to diborylmethane 1a gave a trace amount of the
corresponding product 3a. Under the previously reported
conditions, SMC of 1,1-diborylalkane 1b proceeded with
an almost homogeneous mixture. In contrast, the same
reaction conditions for diborylmethane 1a gave a hetero-
geneous gel-like mixture (entry 1). As a result, the conver-
sion of 4-bromoanisole (2a) was very low even after 24 h. A
drastic changewas observed whenanequimolar amount of
KOH added to diborylmethane 1a was used (entry 2). The
reaction took place under a homogeneous mixture to
give the desired 3a in high yield. In a typical SMC, excess
base contributes to the generation of a more reactive borate
intermediate, the hydrolysis of PdIIX occurs to the more
reactive PdIIOH species, competitive complexation with
HOBR2 takes place, as well as other processes; therefore,
entry
base
x
y
time (h)
yield (%)a
1
2
3
4
5
6
7
8
9b
KOH
KOH
NaOH
LiOH
K3PO4
KF
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
4.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2
24
24
24
24
24
24
24
24
1
trace
84
82
77
16
6
Cs2CO3
Ag2O
KOH
14
16
>98
a NMR yields with internal standard were described. b The use of
Pd[P(t-Bu)3]2 (1 mol %) gave the product 3a in 89% yield after 24 h.
A wide variety of coupling products were obtained under
the optimum reaction conditions (Table 2).14,15 The use of
bromoanisole, -toluene, and -fluorobenzene gave the pro-
ducts in high to excellent yields (entries 1ꢀ8, and 11).
Fluoro-compounds could be used without protodeborona-
tion, as noted in our previous report.3 Sterically hindered
aryl bromides could also be used; 1-bromo-2-isopropylben-
zene (2i) and 2-bromo-1,10-biphenyl (2j) gave the desired
products in highyields (entries 9 and 10). Furthermore, 2,6-
disubstituted bromobenzene gave the products in high to
(13) The protodeboronation of primary alkylboron compounds in
protic conditions proceeds much more rapidly than that of secondary
and tertiary alkylboron compounds; see: (a) Brown, H. C.; Murray, K. J.
Tetrahedron 1986, 42, 5497. The protodeboronation of benzylboron
compounds proceeds more rapidly than other primary alkylboron
compounds; see: (b) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc.
1960, 82, 1504. (c) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1960, 82,
4708.
(14) Due to almost the same Rf values of diborylmethane 1a and
products 3aꢀp as well as the instability of products to column chroma-
tography purification, the isolated yields were generally lower than
NMR yields.
(15) The reaction using p-chloroanisole did not proceed at all,
although the typical SuzukiꢀMiyaura coupling between aryl chlorides
and aryl boronic acids proceeds using Pd[P(t-Bu)3]2 as a catalyst. See
ref 5a.
(12) See the Supporting Information for the DFT calculations of
borate intermediates.
3370
Org. Lett., Vol. 13, No. 13, 2011

3n in 57% isolated yield (entry 14). The reaction of the
sterically hindered naphthalene derivative 2o took place to
give the product 3o in a high yield (entry 15).
Table 2. Scope of Aryl Bromides
The compatibility of a primary alkylboronate moiety
was demonstrated (Scheme 2). The reaction of diboryl-
methane 1a and aryl bromide 2punder the same conditions
as described in Table 2 gave the desired product 3p bearing
benzylboronate and phenethylboronate moieties. The pre-
sent result serves as an attractive chemoselective cross-
coupling reaction exclusively with diborylmethane 1a.
Scheme 2. Chemoselective SMC of Diborylmethane
In conclusion, we have demonstrated the chemoselective
Pd-catalyzed SuzukiꢀMiyaura cross-coupling of diboryl
methane for the synthesis of various benzylboronate deri-
vatives. The key to success for efficient conversion is the
predominant generation of a monoborate intermediate
using an equimolar amount of KOH with diborylmethane
1a. The generation of a diborate intermediate with excess
KOH seems to be detrimental. The products, benzylbor-
onate derivatives, are somewhat unstable under the reac-
tion conditions for a long period of time; thus, the use of an
equimolar amount of KOH is important to avoid side
reactions. The further development of multiborylmethane
derivatives are ongoing in our laboratory.
Acknowledgment. This work was supported by the
JST PRESTO program, a Grant-in-Aid for Young
Scientists (B) (No. 21750108 and 23750049) from the
Japan Society for the Promotion of Science, and a
Waseda University Grant for Special Research Pro-
jects. We appreciate valuable comments by the re-
viewers during the review process.
a NMR yields with internal standard were described. Isolated yields
were described in parentheses.
Supporting Information Available. The experimental
procedure and physical properties of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
excellent yields (entries 12 and 13). Notably, the highly
bulky aryl bromide 2-bromo-1,3,5-triisopropylbenzene
(2n) could participate in the reaction to give the product
Org. Lett., Vol. 13, No. 13, 2011
3371