Anthranilamide: A simple, removable ortho -directing modifier for arylboronic acids serving also as a protecting group in cross-coupling Reactions

Article abstract of DOI:10.1021/ol200764g

Anthranilamide (AAM) serves as a bifunctional modifier on the boron atom in catalytic transformations of arylboronic acids. It makes boronyl groups unreactive in Suzuki-Miyaura coupling and promotes Ru-catalyzed ortho-silylation. Suzuki-Miyaura coupling of AAM-modified bromophenylboronic acids with tolylboronic acid gave 1,1′-biaryl-4-boronic acid bearing AAM on the boron atom, which subsequently underwent Ru-catalyzed ortho-silylation at the 3-position by virtue of the ortho-directing effect of the AAM group.

Full text of DOI:10.1021/ol200764g

ORGANIC
LETTERS
2011
Vol. 13, No. 10
2662–2665
Anthranilamide: A Simple, Removable
ortho-Directing Modifier for Arylboronic
Acids Serving also as a Protecting Group
in Cross-Coupling Reactions
Hideki Ihara,†,§ Masashi Koyanagi,† and Michinori Suginome*,†,‡
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto University, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan, and JST,
CREST, Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
suginome@sbchem.kyoto-u.ac.jp
Received March 22, 2011
ABSTRACT
Anthranilamide (AAM) serves as a bifunctional modifier on the boron atom in catalytic transformations of arylboronic acids. It makes boronyl
groups unreactive in SuzukiꢀMiyaura coupling and promotes Ru-catalyzed ortho-silylation. SuzukiꢀMiyaura coupling of AAM-modified
bromophenylboronic acids with tolylboronic acid gave 1,10-biaryl-4-boronic acid bearing AAM on the boron atom, which subsequently
underwent Ru-catalyzed ortho-silylation at the 3-position by virtue of the ortho-directing effect of the AAM group.
Much interest has focused on the synthesis and use of
arylboronic acids in organic synthesis.1 In addition to the
conventional synthesis using transmetalation with more
nucleophilic organometallicreagentssuchas Grignardand
organolithium reagents, catalytic CꢀB bond formation
reactions have gained increasing attention. Transition-
metal-catalyzed CꢀH and CꢀX borylations are recog-
nized as the most promising, efficient access to arylboronic
acids.2,3 Efforts are now devoted to the synthesis of
organoboronic acids with retention of the boron function-
ality throughout the synthesis.4 For this purpose, robust
protecting groups for organoboronic acids, especially in
† Kyoto University.
‡ JST, CREST.
§ A temporary graduate student from Sumitomo Chemical Co., Ltd.
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60, 7508. (b) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997,
62, 6458. (c) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 2000, 65, 164. (d) Takagi, J.; Takahashi, K.; Ishiyama, T.;
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r
10.1021/ol200764g
Published on Web 04/21/2011
2011 American Chemical Society

useful in the synthesis of elaborated arylboronic acids that
are otherwise difficult to synthesize. Our interest has
focused on finding a simple modifier on the boron atom
serving both as an ortho-directing group in the o-CꢀH
functionalization reactions and asa protecting group in the
cross-coupling reactions (Scheme 1). Such a bifunctional
modifier would allow us to develop new synthetic access to
highly elaborated arylboronic acids, which is in turn bene-
ficial for the synthesis of highly functionalized arene deriva-
tives. Herein, we describe the use of anthranilamide as such a
bifunctional agent for arylboronic acid synthesis. It shows a
higher ability for ortho-direction and much higher robust-
ness toward SMC and isolation procedures than PZA.
Scheme 1. Use of a Removable Modifier on the Boron Atom
That Serves As Both Protecting and ortho-Directing Group for
the Synthesis of Highly Functionalized Arene Derivatives
Scheme 2. Stabilities of Modified Phenylboronic Acids
the SuzukiꢀMiyaura cross-coupling reaction, have been
developed.5,6 They have made possible the synthesis of
rather complex organoboronic acids through iterative
SuzukiꢀMiyaura coupling.4,7,8 As a new boron-retaining
strategy, we recently reported use of 2-(pyrazol-5-yl)-
aniline (PZA) as an agent for Ru-catalyzed ortho-
silylation,9,10 in which coordination of the sp2-nitrogen
atom of PZA to the catalyst is crucial.11ꢀ13 These boron-
retaining syntheses of arylboronic acids are particularly
(5) (a) Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007,
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Tetrahedron 2010, 66, 297.
(8) Short reviews on iterative SuzukiꢀMiyaura coupling: (a) Manabe,
K.; Ishikawa, S. Chem. Commun. 2008, 3829. (b) Tobisu, M.; Chatani, N.
Angew. Chem., Int. Ed. 2009, 48, 3565. (c) Wang, C.; Glorius, F. Angew.
Chem., Int. Ed. 2009, 48, 5240.
(9) For ortho-directed CꢀH silylation, see: Williams, N. A.; Uchi-
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Kakiuchi, F.; Igi, K.; Matsumoto, M.; Chatani, N.; Murai, S. Chem.
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Chatani, N.; Murai, S. Chem. Lett. 2002, 396. (d) Kakiuchi, F.;
Matsumoto, M.; Tsuchiya, K.; Igi, K.; Hayamizu, T.; Chatani, N.;
Murai, S. J. Organomet. Chem. 2003, 686, 134. Tobisu, M.; Ano, Y.;
Chatani, N. Chem. Asian J. 2008, 3, 1585.
(10) For representative CꢀH silylations without using directing
groups, see: Klare, H. F. T.; Oestreich, M.; Ito, J.; Nishiyama, H.; Ohki,
Y.; Tatsumi, K. J. Am. Chem. Soc. 2011, 133, 3312 and reference therein.
(11) Ihara, H.; Suginome, M. J. Am. Chem. Soc. 2009, 131, 7502.
(12) For directed metalation (stoichiometric), see: (a) Beak, P.;
Snieckus, V. Acc. Chem. Res. 1982, 15, 306. (b) Snieckus, V. Chem.
Rev. 1990, 90, 879–933. (c) Antoft-Finch, A.; Blackburn, T.; Snieckus, V.
J. Am. Chem. Soc. 2009, 131, 17750 and references therein.
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Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
N.; Chatani, N. Nature 1993, 366, 529. For earlier pioneering work, see:
(b) Lewis, L. N.; Smith, J. F. J. Am. Chem. Soc. 1986, 108, 2728.
Reviews: (c) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013. (d) Handbook
of CꢀH Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim, 2005.
After brief screening of some 1,3,2-diazaboracyclohex-
ane structures, we found that PhB(aam) 1a (see Scheme 2
and Table 1 for the structure), which was prepared by
condensation of PhB(OH)2 with commercially available
anthranilamide in toluene under reflux in high yield, shows
high stability toward moisture, oxygen, and even chroma-
tography on silica gel.14 The stabilities of the cyclic diami-
noborane derivatives were compared in DMSO/D2O
(10:1) at room temperature (Scheme 2). To our surprise,
even PhB(pin) decomposed gradually under these reaction
conditions. The half-life was determined to be 78 h by 1H
NMR measurement. In contrast, PhB(dan) showed no
hint of decomposition under the same reaction conditions.
PhB(mida) (mida: N-methyliminodiacetato) was also ro-
bust, although it too underwent slow hydrolysis (t1/2
=
140 h). Although less stable than the DAN and MIDA
protecting groups, AAM exhibited much higher stability
than the previous directing group PZA.
Ru-catalyzed ortho-silylation of PhB(aam) (1a) with
dimethylphenylsilane proceeded in high yield in the pre-
senceofRuH2(CO)(PPh3)3 withnorbornene asa hydrogen
scavenger at 135 °C (Table 1).5bꢀd The ortho-silylated
product 2aa was isolated by silica gel flash column chro-
matography. Among the hydrosilanes examined for the
(14) (a) Chissick, S. S.; Dewar, M. J. S.; Maitlis, P. M. J. Am. Chem.
Soc. 1959, 81, 6329. (b) Chissick, S. S.; Dewar, M. J. S.; Maitlis, P. M.
J. Am. Chem. Soc. 1961, 83, 2708.
Org. Lett., Vol. 13, No. 10, 2011
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Table 1. ortho-Silylation of Arylboronic Acids Using
Anthranilamide as an ortho-Directing Agenta
Scheme 3. AAM-Directed Silylation of 3-Thiopheneboronic
Acid Derivative 1j
PZA-modified o-tolylboronic acid does not give the de-
sired ortho-silylation product at all. The 2-naphthyl deri-
vative was silylated at the 3-position selectively in good
yield (entry 11) as observed in the PZA system.
1-Naphthylboronic acid gave the 2-silylated product 2i
selectively, albeit in low yield, whereas the corresponding
PZA derivative was not reactive at all (entry 12). A
remarkable difference between the present AAM and the
previous PZA system has been demonstrated by the reac-
tion of 3-thienyl derivative 1j (Scheme 3). In both systems,
the firstsilylationtakesplaceatthe2-positions. Thesecond
silylation in the AAM system took place at the 4-position
of the thiophene ring, in contrast to exclusive silylation at
the 5-position in the PZA system via nondirected
silylation.15 This clearly suggests that the AAM group
has a stronger directing ability than does PZA. In these
syntheses of ortho-silylated organoboronic acids, the
AAM group on the boron atoms was readily converted
into the PIN group by acid-catalyzed ligand exchange
(Scheme 4). Hydrolysis of 2aa was accomplished cleanly
in the presence of aqueous acid at room temperature,
giving the corresponding arylboroxine in high yield.
Scheme 4. Acid-Mediated Conversion of ArB(aam) to ArB(pin)
a Reagents and conditiona: 1 (0.25 mmol), RuH2(CO)(PPh3)3 (15
μmol), norbornene (1.25 mmol), hydrosilane (1.25 mmol), and toluene
(0.13 mL) at 135 °C (bath temperature) for 20 h unless otherwise noted.
b NMR yield. Isolated yields in parentheses. c 3 h. d 37 h. e 51 h.
reaction, dimethylphenylsilane showed the highest reactiv-
ity. Triethylsilane, which was the most reactive in the PZA-
directed reaction, resulted in a slightly lower yield. It
should be remarked here that no silylation at the phenyl
ring of anthranilamide took place at all. Using dimethyl-
phenylsilane, isolated AAM-modified substituted aryl-
boronic acids were subjected to the silylation reaction.
Arylboronic acids having electron-donating and electron-
withdrawing groups at their para-positions afforded the
corresponding ortho-silylated products in high yields
(entries5ꢀ8). m-Tolylboronicacidderivative1funderwent
silylation at the less sterically demanding ortho-position
selectively in high yield (entry 9). Although the yield was
low, o-Me-substituted 1g afforded ortho-silylated 1,2,3-
trisubstituted benzene derivative 2g (entry 10). Note that
Attempted ortho-silylation of p-bromophenylboronic
acid derivative 1k resulted in the substitution of the
bromine group by a silyl group (Scheme 5). Instead, we
carried out SuzukiꢀMiyaura coupling of 1k with p-tolyl-
boronic acid. In the presence of SPhos (2-dicyclohexylpho-
sphino-20,60-dimethoxy-1,10-biphenyl) as a ligand, the
coupling proceeded at room temperature with complete
retention of the AAM group on the boron atom. The
isolated AAM derivative of biphenylboronic acid 4k
(15) Non-directed, Ir-catalyzed silylation of thiophenes has been
reported. Lu, B.; Falck, J. R. Angew. Chem., Int. Ed. 2008, 47, 7508.
2664
Org. Lett., Vol. 13, No. 10, 2011

Scheme 5. Cross-Coupling/Silylation Sequence with
Bromo-Substituted Arylboronic Acids
Scheme 6. Reactions of Phenylboronic Acid Drrivatives
6a and 6b Modified by N-Methylated Anthranilamides
6b bearing a methyl group on the amide nitrogen was not
reactiveatall. These results suggest thatthe amidenitrogen
rather than the aniline nitrogen serves as the coordinating
element in the Ru-catalyzed ortho-silylation. It may be
presumed that a tautomerized form, which carries an sp2
lone pair on the nitrogen atom, may play a key role in
coordination to the catalyst.
In summary, anthranilamide has been established as a
new directing agent for transition-metal-catalyzed o-CꢀH
silylation. The B(aam) group exhibited higher ability in
ortho-direction in comparison with the previously reported
B(pza) group. The stronger directing effect resulted in
ortho-silylation of sterically demanding arylboronic acids
such as o-tolylboronic acid and 1-naphthylboronic acid,
albeit in low yields, which could not be achieved with the
B(pza) group. Furthermore, a sharp switch of regioselec-
tivity was observed in the silylation of 2-silylated 3-thiophe-
neboronic acid. The AAM group also serves as a protecting
group in the SuzukiꢀMiyaura coupling reaction, enabling
the synthesis of silylated biphenylboronic acids through a
cross-coupling/ortho-silylation sequence. Application of
these directing groups in other catalytic CꢀH functionaliza-
tions is being undertaken in this laboratory.
underwent Ru-catalyzed silylation selectively at the ortho
position, giving silylborylbiphenyl 5k. The sequential
cross-coupling/ortho-silylation protocol could also be ap-
plied to m-bromoboronic acid derivative 1l, affording 5l
(room temperature, 14 h). The B(aam) group was com-
pletely retained even in the attempted cross-coupling of 1l
with p-tolylboronic acid at 80 °C, giving the same coupling
product in 94% yield (1.5 h). In the corresponding trans-
formation of o-bromophenylboronic acid, the first step, i.e.,
coupling with TolB(OH)2, proceeded in high yield, although
ortho-silylation afforded the silylated biphenyl only in low
yield. In these examples, the AAM group serves not only as
a directing group but also as a protecting group for the
boronyl group in the SuzukiꢀMiyaura coupling reaction.
To gain insight into the origin of the directing effect of
the AAM group, we compared two N-methylated deriva-
tives 6a and 6b of anthranilamides in the ortho-silylation
reactions (Scheme 6). Anthranilamide 6a bearing a methyl
group on the aniline nitrogen atom underwent the ortho-
silylation smoothly under the same reaction conditions as
those for the parent anthranilamide. In contrast, its isomer
Acknowledgment. This work was supported in part by
Grant-in-Aid for Scientific Research from MEXT.
Supporting Information Available. Experimental pro-
cedures and spectral data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 10, 2011
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