Ag(I)-promoted Suzuki-Miyaura cross-couplings of n-alkylboronic acids

Article abstract of DOI:10.1016/S0040-4039(01)01536-2

Ag(I) salts significantly enhance palladium-catalyzed Suzuki-Miyaura cross-couplings of n-alkylboronic acids with a wide variety of aryl and alkenyl halides/triflates.

Full text of DOI:10.1016/S0040-4039(01)01536-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7213–7215
Ag(I)-promoted Suzuki–Miyaura cross-couplings of
n-alkylboronic acids
Gang Zou, Y. Krishna Reddy and J. R. Falck*
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, Dallas,
TX 75390-9038, USA
Received 20 July 2001; revised 1 August 2001; accepted 10 August 2001
Abstract—Ag(I) salts significantly enhance palladium-catalyzed Suzuki–Miyaura cross-couplings of n-alkylboronic acids with a
wide variety of aryl and alkenyl halides/triflates. © 2001 Elsevier Science Ltd. All rights reserved.
The Suzuki–Miyaura cross-coupling reaction has
emerged as one of the premier methods for the creation
Some reaction parameters were briefly explored using
14
commercial n-butylboronic acid (1) and cis-alkenyl
iodide 2. The best yields of 3 were obtained with a
combination of Ag O and Pd(dppf)Cl in THF at 80°C
1
of carbonꢀcarbon bonds under mild conditions. Exten-
sive exploration of reaction parameters and catalysts in
2
15
2
2
recent years has significantly extended its scope. While
(Table 1, entry 1). The presence of additional base
was also required for optimum performance; generally,
powdered K CO was preferable to aqueous KOH. As
3
many types of organoboron compounds are suitable
donors, boronic acids are especially popular. The latter
are readily prepared, thermally stable, tolerant of
adventitious oxygen and water, and generate an innocu-
2
3
observed for 2, cross-coupling of cis-alkenyl bromide 4
proceeded with complete retention of configuration giv-
ing rise to 3 (entry 2), but in somewhat diminished
yield. Notably, even the sensitive homoallylic epoxide
4
ous by-product. Aryl- and alkenylboronic acids typi-
cally afford good yields of cross-coupled adduct with a
wide range of electrophiles, inter alia, chlorides, bro-
16
17
5
afforded a useful yield of adduct 6 (entry 3). In
5
6
7
mides, triflates, sulfonium salts, heteroaryl, and steri-
contrast, dimerization predominated with trans-alkenyl
iodide 7 and only a modest amount of silyl dec-5-enol
8
cally demanding aryl moieties.
In contrast,
n-alkylboronic acids are often refractory, resulting in
8
was produced (entry 4). Interestingly, aryl elec-
9
poor yields, even under forcing conditions. To improve
trophiles were well behaved regardless of the presence
of electron-rich or -deficient substituents. Aryl bromide
their reactivity, boronic acids are either (1) converted to
10
potassium trifluoroborates; (2) esterified and further
9
(entry 5), iodide 11 (entry 6), and triflate 12 (entry 7)
1
1
elaborated into ‘ate’ complexes or (3) complexed with
furnished good yields of 4-(n-butyl)anisole (10). Simi-
larly, ketone 14 and ester 16 were smoothly generated
from bromides 13 (entry 8) and 15 (entry 9), respec-
tively. Aryl and alkenyl chlorides, on the other hand,
were poor substrates and afforded comparatively little
1
2
highly toxic thallium salts.
However, we have
13
observed Ag(I) salts significantly enhance Suzuki–
Miyaura cross-couplings of n-alkylboronic acids and
we report herein the scope and limitations of this
modification (Eq. (1)).
2a
adduct regardless of reaction conditions.
E-X
RCH -B(OH)2
RCH -E
(1)
2
2
The transformation of terminal olefin 17 (entry 11),
ester 19 (entry 12), and silane 21 (entries 13 and 14)
into 18, 20, 22, and 23, respectively, demonstrated that
a variety of functional groups are well tolerated on the
boronic acid moiety. For the simplest case, i.e. methyl-
boronic acid (24), cross-coupling with cis-alkenyl iodide
Pd(dppf)Cl
2
+
Ag(I) , K CO
2
3
2
under the standard reaction conditions was sluggish
Keywords: Suzuki–Miyaura; alkylation; boron; coupling reactions;
palladium.
and only a trace of 25 was isolated. However, efficiency
was restored by the addition of n-PrOH to improve the
solubility of 24 in the reaction medium (entry 15).
*
Corresponding author. Tel.: 214-648-2406; fax: 214-648-6455;
e-mail: j.falck@utsouthwestern.edu
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01536-2

7
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G. Zou et al. / Tetrahedron Letters 42 (2001) 7213–7215
Table 1. Ag(I)-promoted Suzuki–Miyaura cross-couplings of n-alkylboronic acids
Entry
1
Boronic Acid
Electrophile
Adduct
Yield (%)
90
B(OH)2
I
OTBDPS
OTBDPS
2
4
3
3
1
78
2
3
1
1
OTBDPS
Br
O
O
84
I
5
7
6
I
4
5
1
1
38
80
OTBDPS
OCH3
OTBDPS
OCH3
8
Br
9
10
10
6
7
1
1
I
OCH3
80
92
11
TfO
OCH3
O
10
1
2
3
O
8
9
1
1
Br
Br
84
82
1
14
16
O
O
OEt
OEt
1
5
O
B(OH)2
11
15
77
1
7
18
20
MeO C
2
1
2
3
2
2
90
63
MeO C
B(OH)2
2
OTBDPS
19
Me Si
3
Me Si
B(OH)2
1
3
OTBDPS
21
22
O
1
4
21
14
2
80
80
Me Si
3
2
3
1
5
Me B(OH)2a
Me
OTBDPS
24
25
an-PrOH (10 equiv) added.
In summary, we describe a practical, high yield modifi-
cation of the Suzuki–Miyaura cross-coupling reaction
utilizing unactivated, primary alkyl groups under mild
conditions.
with 30% H O /10% aq. NaOH, and extracted thrice
2 2
with Et O. The combined ethereal extracts were con-
2
centrated in vacuo and the residue was purified via SiO2
chromatography (see Table 1).
General procedure: A suspension of boronic acid (0.27
mmol, 1.1 equiv.), organic electrophile (1.0 equiv.),
Pd(dppf)Cl (0.1 equiv.), powdered K CO (3 equiv.),
Acknowledgements
2
2
3
and Ag O (2.5 equiv.) in THF (5 mL) was stirred under
argon at 80°C in a sealed tube. After 6–10 h, the
mixture was cooled to room temperature, quenched
2
Financial support provided by the Robert A. Welch
Foundation, NIH (GM 31278, DK 38226) and an

G. Zou et al. / Tetrahedron Letters 42 (2001) 7213–7215
7215
unrestricted grant from Taisho Pharmaceutical Co.,
Ltd.
K.; Duan, J. J.-W.; Barbosa, J.; Hull, K. G.; Iwashima,
M.; Qiu, Y.; Spoors, P. G.; Bertounesque, E.; Salvatore,
B. A. J. Org. Chem. 1998, 63, 7596–7597.
1
4. Non-commercial boronic acids were prepared by addition
of the corresponding Grignard reagent to tri-(iso-pro-
pyl)borate with aqueous isolation or by olefinic hydrobo-
ration with catecholborane: see, Fend, Z.; Hellberg, M.
Tetrahedron Lett. 2000, 41, 5813–5816.
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3
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2
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13
(
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1
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3
l 7.65 (dt, J=1.8, 7.5 Hz, 1H), 7.56–7.60 (m, 1H), 7.29
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13
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3
27.2, 26.9, −1.78.