Anthranilamide (aam)-substituted arylboranes in direct carbon-carbon bond-forming reactions

Article abstract of DOI:10.1039/c8cc10252j

Anthranilamide (aam)-substituted arylboranes, which were reported to serve as masked boranes in the Suzuki-Miyaura coupling, have been found to be directly cross-coupled just by use of an aqueous medium. The excellent stability of 2-pyridyl-B(aam) toward protodeborylation allowed their smooth cross-coupling.

Full text of DOI:10.1039/c8cc10252j

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DOI: 10.1039/C8CC10252J
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Anthranilamide (aam)-substituted arylboranes in direct carbon–
carbon bond-forming reactions
Shintaro Kamio, Ikuo Kageyuki, Itaru Osaka, and Hiroto Yoshida*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Anthranilamide (aam)-substituted arylboranes, which were
reported to serve as masked boranes in the Suzuki–Miyaura
coupling, have been found to be directly cross-coupled just by use
of an aqueous medium. The excellent stability of 2-pyridyl–B(aam)
toward protodeborylation allowed their smooth cross-coupling.
B(aam)
X
Ar2
Ar1

Pd cat.
Pd cat.
Ar1 B(OH)2
Ar2
X
Arylboron compounds with an anthranilamide (aam)
substituent on the boron center [Ar–B(aam)]1 have proven to
be useful reagents in the Suzuki–Miyaura cross-coupling (SMC):
their reactivity toward transmetalation can temporarily be
masked,1-4 thus allowing a C(aryl)–halogen bond in the same
molecule to be chemoselectively cross-coupled with another
arylboronic acid. The latent reactivity of the remaining C(aryl)–
B(aam) bond can then be unmasked by its conversion into the
respective boronic acid [C(aryl)–B(OH)2] via acidic deprotection,
leading to precise and reliable synthesis of oligoarenes (Scheme
1).
The B(aam) moieties also serve as directing groups for
catalytic ortho-C(aryl)–H silylation,1 however the high synthetic
potency of Ar–B(aam) was not fully utilized, because they were
only accessible by dehydrative condensation of Ar–B(OH)2 with
aam. Recently, we have reported that installation of a B(aam)
unit into aromatic frameworks becomes feasible by the
palladium-catalyzed Miyaura–Ishiyama-type coupling5 with a
new unsymmetrical diboron [(pin)B–B(aam)],6,7 which expands
structural diversity of Ar–B(aam) to be accessed (Scheme 2).
Of note is that 2-pyridyl–B(aam), which cannot be
synthesized by the dehydrative condensation, become
straightforwardly available as open column chromatography-
stable compounds, being in stark contrast to the well-accepted
propensity of 2-pyridyl–B(OH)2 and –B(pin) to be
protodeborylated (vide infra).8,9a The diminished Lewis acidity

B(aam)
Ar1
B(OH)2
HCl aq.
-aam
Ar1
acidic deprotection
Scheme 1 Reported iterative SMC with Ar–B(aam).
(pin)BB(aam)
Pd2(dba)3CHCl3 (2.5 mol%)
XPhos (7.5 mol%)
Z
X
Z
B(aam)
KOAc (3 eq)
R
R
1,4-dioxane, 60 °C, 18 h
Z = C or N
O
HN
B
O
O
(pin)B B(aam)
=
B
HN
Scheme 2 Miyaura–Ishiyama reaction with (pin)B–B(aam).
of the B(aam) moiety, arising from its planar six-membered-ring
configuration as well as effective electron donation from the
neighboring nitrogen atoms, would be the key to the stability,
and the masked reactivity in SMC is also ascribable to the
diminishment. The endowed stabilizing effect by the aam-
introduction may provide another option for “2-pyridyl
problem”10 in organoboron chemistry, however, the above
acidic deprotection, of course, is not applicable to 2-pyridyl–
B(aam), because of the fast protodeborylation,9 and thus
development of direct SMC with Ar–B(aam), that addresses this
dilemma, should be of urgent importance. Herein we report
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima
University, Higashi-Hiroshima 739-8527, Japan
E-mail: yhiroto@hiroshima-u.ac.jp; Tel: +81-82-424-7724
† Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/x0xx00000x
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Table 1 Screening of reaction conditionsa
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DOI: 10.1039/C8CC10252J
Br
p-Tol
Pd(OAc)2 (5 mol %)
SPhos (10 mol %)
K3PO4 (7.5 eq)
MeO
N
B(aam)
p-Tol B(aam)
+
:
1,4-dioxaneH2O (51)
MW, 140 °C, 0.5 h
1a
OMe
1
OMe
1b
1
2a
Entry
Changes from standard conditions
None
60 °C, 6 h
Pd2(dba)3•CHCl3 (5 mol %), XPhos (10 mol %),
K3PO4 (7.5 eq)
PdCl2(dppf)•CH2Cl2 (2 mol %), K3PO4 (3 eq),
dry THF, 80 °C, 18 h
Pd2(dba)3•CHCl3 (5 mol %), XPhos (10 mol %), K2CO3 14e
(5 eq), Cu(OAc)2 (0.5 eq), DMF/IPA (4:1), 100 °C, 4 h
Pd(OAc)2 (3 mol %), PPh3 (6 mol %), KOH aq. (6 eq), 69
1,4-dioxane
Yield (%)b
88
1
2
3
89c,d,e
54
1.4 year later
4
5
6
4e
8.4
8.3
8.2
8.1
8.0
7.9
7.8
7.7
7.6
7.5
7.4
7.3
7.2
7.1
7.0
6.9
6.8
f1 (ppm)
Figure 1 Storability of 6-methoxy-2-pyridyl–B(aam).
(pin)BB(pin)
Pd2(dba)3CHCl3 (2.5 mol%)
XPhos (7.5 mol%)
aStandard conditions: 1b (0.150 mmol), aryl bromide (0.150 mmol), Pd(OAc)2
(7.50 μmol), SPhos (0.0150 mmol), K3PO4 (1.13 mmol), 1,4-dioxane (1.9 mL), H2O
(375 μL), microwave heating, 140 °C, 0.5 h. bNMR yield. cIsolated yield. d1b (0.225
mmol). eConventional heating.
MeO
N
Br
MeO
N
B(pin)
KOAc (3 eq)
1,4-dioxane, 60 °C, 18 h
NMR Yield 85%
Direct, acidic deprotection-free SMC of Ar–B(aam) has been
demonstrated to occur efficaciously by simply adding water to
a reaction medium. Thus, treatment of p-tolyl–B(aam) (1b) with
4-bromoanisole in 1,4-dioxane/H2O (5:1) solvent under
palladium catalysis [Pd(OAc)2–SPhos] turned out to afford a
biaryl (2a) in 88% yield (Table 1, Entry 1), being in contrast to
the previous two-step cross-coupling using Ar–B(aam), where
prior deprotection of a B(aam) moiety was conducted under
acidic conditions.1 The direct SMC also proceeded in similar
yield under conventional heating conditions (Entry 2), showing
that microwave irradiation is not always required for the
present reaction. The use of XPhos as a supporting ligand
resulted in a moderate yield (Entry 3), and the reaction
conducted in an anhydrous medium was found to be
unsuccessful, which indicates that the use of an aqueous
medium is a key to the successful cross-coupling (Entry 4).
Addition of copper (II) acetate as a transmetalation promoter in
an alcoholic medium, employed in SMC of Ar–B(MIDA),3b was
not effective (Entry 5), and the yield also decreased in the
reaction with a strong base (KOH) (Entry 6).
MeO
Ha
N
B(pin)
Hc
Ha/Hc
Hb
Hc/Ha
Hb
after aqueous work-up
.80
7.75
7.70
7.65
7.60
7.55
7.50
7.45
7.40
7.35
7.30
7.25
7.20
f1 (ppm)
7.15
7.10
7.05
7.00
6.95
6.90
6.85
6.80
6.75
6.70
6.65
6.
Scheme 3 Protodeborylation of 6-methoxy-2-pyridyl–B(pin).
that Ar–B(aam) facilely undergo direct, acidic deprotection-free
SMC just by adding water to the reaction medium.
With the optimized reaction conditions in hand, we next
investigated the direct SMC of 1b with various aryl bromides
(Table 2). Electron-rich and -deficient aryl bromides were
readily convertible into the respective biaryls (2a–2g) in high
yield within half an hour. Since a weak base (K3PO4) suffices for
In addition to the air- and moisture-stability of 2-pyridyl–
B(aam),6 they were found to be sufficiently durable as shown in
Figure 1: no trace decomposition of 6-methoxy-2-pyridyl–
B(aam) (1a) was observed in 1H NMR spectra even 1.4 year after
its synthesis without any special care (1a was stored in a vial at
ambient temperature).11 In marked contrast, its B(pin)-
counterpart, prepared by the Miyaura–Ishiyama reaction with
(pin)B–B(pin) (NMR yield 85%, calculated from a crude mixture),
instantly disappeared just by aqueous work-up (Scheme 3).
Moreover, half-life period of 6-methoxy-2-pyridyl–B(OH)2 was
reported to be about 3.5 mins (at pH = 6.86),9a demonstrating
that the exceptional stability and storability were given by of the
aam-introduction.
the smooth transformation,
a relatively base-sensitive
functional group including CO2Et, CN, Ac or CHO was tolerable
(2h–2k). In addition, heteroaryl bromides with 2-pyridyl, 5-
indolyl or 2-thienyl group could also participate in the reaction
to provide heterobiaryls (2l–2p).
It should be noted that the direct SMC turned out to be also
applicable to 2-pyridyl–B(aam), resulting in the formation of 2-
arylpyridines (2m, 2n, and 2q) in high yield (Table 3), which
provides an alternative approach for “2-pyridyl problem” in
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Table 2 Substrate scope on aryl halidesa
Pd(OAc)2 (5 mol %)
Table 4 Direct SMC of 2-(Het)Ar–B(aam)a
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DOI: 10.1039/C8CC10252J
Pd(OAc)2 (5 mol %)
SPhos (10 mol %)
K3PO4 (7.5 eq)
SPhos (10 mol %)
K3PO4 (7.5 eq)
Z
Z
B(aam)
p-Tol
1b
Ar Br
1
Ar p-Tol
+
:
p-Tol Br
+
:
1,4-dioxaneH2O (51)
MW, 140 °C, 0.5 h
1,4-dioxaneH2O (51)
MW, 140 °C, 0.5 h
1.5
1.5
1
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
S
O
p-Tol
p-Tol
2p: 78%
2r: 72%
O
O
OMe
TMS
OH
NH2
aIsolated yield. Conditions: 2-(Het)Ar–B(aam) (0.225 mmol), p-bromotoluene
(0.150 mmol), Pd(OAc)2 (7.50 μmol), SPhos (0.0150 mmol), K3PO4 (1.13 mmol), 1,4-
dioxane (1.9 mL), H2O (375 μL), microwave heating, 140 °C, 0.5 h.
2a: 88%b
2b: 99%
2c: 88%
2d: 69%
2e: 70%b
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-TolB(OH)2
p-AnisBr
Pd(OAc)2 (3 mol %)
SPhos (6 mol %)
K3PO4 (2 eq)
Pd(OAc)2 (5 mol %)
SPhos (10 mol %)
K3PO4 (7.5 eq)
B(aam)
B(aam)
p-Anis

CF3
NO2
COOEt
2h: quant.
CN
Ac
2f: 71%b
2g: 64%
2i: 95%b
2j: 85%
THF, 60 °C, 14 h
1,4-dioxane/H2O (5:1)
MW, 140 °C, 0.5 h

Br
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
3
84%
4
1.5 eq. of 3 was used.
86 %
N
S
Scheme 4 Iterative SMC with 4-bromophenyl–B(aam).
R
2l: R = H, 40 %
2m: R = OMe, 65%
2n: R = F, 68%
NH
2o: 45%
CHO
the present results can give another option for the iterative
cross-coupling, whose progress is totally controllable by the
absence/presence of water, as are the cases with an N-
methyliminodiacetic (MIDA) boronates.3,10d This was well
illustrated by the reaction of 4-bromophenyl–B(aam): its
C(aryl)–Br bond was chemoselectively convertible into C(aryl)–
C(aryl) bond by anhydrous SMC with p-tolylboronic acid, giving
3 in 84% yield (Scheme 4). The remaining C(aryl)–B(aam) bond
then underwent direct SMC with 4-bromoanisole under the
present conditions led to the formation of p-teraryl 4.
2k: 73%
2p: 60%
aIsolated yield. Conditions: 1b (0.225 mmol), aryl bromide (0.150 mmol),
Pd(OAc)2 (7.50 μmol), SPhos (0.0150 mmol), K3PO4 (1.13 mmol), 1,4-dioxane (1.9
mL), H2O (375 μL), microwave heating, 140 °C, 0.5 h. b1b (0.150 mmol).
Table 3 Direct SMC of 2-pyridyl–B(aam)a
Pd(OAc)2 (5 mol %)
SPhos (10 mol %)
K3PO4 (7.5 eq)
R
N
B(aam)
R
N
p-Tol
p-Tol Br
+
:
The deprotection-free procedure was found to also applicable
to rhodium-catalyzed 1,4-addition10c,13 to 2-cyclohexen-1-one,
and p-tolyl or 2-pyridyl moity was attached to its -position to
furnish 5a and 5b in 81% and 39% yields respectively (Table 5).
1,4-dioxaneH2O (51)
MW, 140 °C, 0.5 h
1
F
1.5
MeO
N
p-Tol
N
p-Tol
F3C
N
p-Tol
Table 5 Rhodium-catalyzed 1,4-addition of Ar–B(aam) to cyclohexenonea
O
O
2m: quant.
2n: 83%
2q: 81%
[RhCl(cod)]2 (3 mol %)
K3PO4 (1.5 eq)
aIsolated yield. Conditions: 2-pyridylB(aam) (0.225 mmol), p-bromotoluene
(0.150 mmol), Pd(OAc)2 (7.50 μmol), SPhos (0.0150 mmol), K3PO4 (1.13 mmol), 1,4-
dioxane (1.9 mL), H2O (375 μL), microwave heating, 140 °C, 0.5 h.
Ar B(aam)
+
:
1,4-dioxane/H2O (3:1)
MW, 140 °C, 0.5 h
Ar
1
2
cross-coupling process. Other 2-heteroarylboron compounds,
which tend to be protodeborylated, could efficiently be cross-
coupled by the aam-substitution; 2-thienyl– and 2-furyl–B(aam)
smoothly underwent the direct SMC to give 2p and 2r in 78%
and 72% yield respectively (Table 4).12 The successful cross-
coupling can obviously be ascribed to their protodeborylation-
resistant property as above, and also to in situ-release of cross-
coupling-active 2-heteroarylboronic acids at an appropriate
pace (cf. Scheme 5). In view of the fact that an Ar–B(aam) are
unreactive in the cross-coupling under anhydrous conditions,1
O
O
N
OMe
5a: 81%
5b: 39%b
aIsolated yield. Conditions: Ar–B(aam) (0.150 mmol), cyclohexenone (0.300
mmol), [RhCl(cod)]2 (4.50 μmol), K3PO4 (0.225 mmol), 1,4-dioxane (0.50 mL), H2O
(0.13 mL), microwave heating, 140 °C, 0.5 h. bH2O (27 μL).
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Takemoto and K. Takaki, Asian J. Org. Chem., 2014, 3, 1204;
(c) H. Yoshida, Y. Takemoto and K. TaDkaOkI:i,10C.1h0e3Vm9ie/.wCC8AorCtimCcle1m0O2un5lni2n.Je,
2015, 51, 6297; (d) I. Kageyuki, I. Osaka, K. Takaki and H.
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S. Kamio, I. Osaka and K. Takaki, Org. Chem. Front., 2017, 4,
1215; (f) H. Yoshida, S. Kamio, I. Osaka, Chem. Lett, 2018, 47,
957.
B(OH)2
1b
+
aam
88%
1,4-dioxaneH2O (51)
MW, 140 °C, 0.5 h
8
9
E. Tyrrell and P. Brookes, Synthesis, 2003, 469.
(a) P. A. Cox, A. G. Leach, A. D. Campbell and G. C. Lloyd-Jones,
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78%
Scheme 5 Aqueous treatment of 1b
A control experiment with 1b under the aqueous conditions 10 (a) G. A. Molander and B. Biolatto, J. Org. Chem., 2003, 68,
4302; (b) Y. Yamamoto, M. Takizawa, X. Q. Yu, N. Miyaura,
Angew. Chem. Int. Ed. 2008, 47, 928; (c) X. Q. Yu, Y. Yamamoto
and N. Miyaura, Synlett., 2009, 994; (d) G. R. Dick, E. M.
Woerly and M. D. Burke, Angew. Chem. Int. Ed. 2012, 51,
2667; (e) W. Ren, J. Li, D. Zou, Y. Wu and Y. Wu, Tetrahedron,
2012, 68, 1351; (f) K. Cheng, B. Zhao, S. Hu, X. M. Zhang and
C. Qi, Tetrahedron Lett., 2013, 54, 6211; (g) N. A. Isley, Y.
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gave a 78% yield of p-tolylboronic acid which would serve as an
actual boron reagent in the direct C–C bond-forming processes,
and the facile hydrolysis of the B(aam) moiety is consistent with
the previous Suginome’s result (Scheme 5).1
In conclusion, we have disclosed that direct SMC of Ar–
B(aam) smoothly proceeded under aqueous conditions without
the need for prior acidic deprotection. In addition to the
established procedure, the excellent stability of 2-pyridyl–
B(aam) toward protodeborylation provided a promising option
for 2-pyridyl problem in SMC. Further studies on direct,
catalytic carbon–carbon bond-forming reactions with Ar–
B(aam) are in progress.
11 The chemical shifts of N–H protons of aam (broad singlet) are
variable depending on the amount of a contaminated acid in
CDCl3.
12 Although we also tried to synthesize 2-pyrroyl– and ethynyl–
B(aam), they were found to be unavailable by the Burke’s or
our method. See: G. R. Dick, D. M. Knapp, E. P. Gillis and M.
D. Burke, Org. Lett., 2010, 10, 2314. See also ref. 6.
13 M. Sakai, H. Hayashi and N. Miyaura, Organometallics, 1997,
16, 4229.
This work was financially supported by JSPS KAKENHI Grant
Numbers JP16H01031 in Precisely Designed Catalysts with
Customized Scaffolding and JP17K05864.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
For boron-masking strategy with B(aam), see: (a) H. Ihara, M.
Koyanagi and M. Suginome, Org. Lett., 2011, 13, 2662; (b) M.
Koyanagi, N. Eichenauer, H. Ihara, T. Yamamoto and M.
Suginome, Chem. Lett., 2013, 42, 541.
For boron-masking strategy with B(dan), see: (a) H. Noguchi,
K. Hojo and M. Suginome, J. Am. Chem. Soc., 2007, 129, 758;
(b) H. Noguchi, T. Shioda, C. M. Chou and M. Suginome, Org.
Lett., 2008, 10, 377; (c) N. Iwadate and M. Suginome, J.
Organomet. Chem., 2009, 694, 1713; (d) N. Iwadate and M.
Suginome, Org. Lett., 2009, 11, 1899; (e) N. Iwadate and M.
Suginome, Chem. Lett., 2010, 39, 558. (f) N. Iwadate and M.
Suginome, J. Am. Chem. Soc., 2010, 132, 2548.
2
3
4
For boron-masking strategy with B(MIDA), see: (a) E. P. Gillis
and M. D. Burke, J. Am. Chem. Soc., 2007, 129, 6716; (b) D. M.
Knapp, E. P. Gillis and M. D. Burke, J. Am. Chem. Soc., 2009,
131, 6961; (c) E. P. Gillis and M. D. Burke, Aldrichimica Acta,
2009, 42, 17; (d) J. Li, A. S. Grillo and M. D. Burke, Acc. Chem.
Res., 2015, 48, 2297.
For boron-masking strategy with trifluoroborates, see: (a) G.
A. Molander and N. Ellis, Acc. Chem. Res., 2007, 40, 275; (b) S.
Darses and J. P. Genet, Chem. Rev., 2008, 108, 288.
T. Ishiyama, M. Murata and N. Miyaura, J. Org. Chem., 1995,
60, 7508.
S. Kamio, I. Kageyuki, I. Osaka, S. Hatano, M. Abe and H.
Yoshida, Chem. Commun., 2018, 54, 9290.
We have also reported on direct B(dan)-installation reactions
with (pin)B–B(dan). See: (a) H. Yoshida, Y. Takemoto and K.
Takaki, Chem. Commun., 2014, 50, 8299; (b) H. Yoshida, Y.
5
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