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15.2.7 Hayashi-Miyaura Coupling
The 1,4-addition (Michael addition) of alkenyl- and arylboronic acids to a,b-
unsaturated ketones catalyzed by Rh(acac)(CO)
2
and dppb was first reported
by Miyaura and co-workers in 1997.
89
Shortly after, Miyaura, Hayashi and
co-workers went on to describe the first asymmetric version with the
Rh(acac)(C
2
H
4
)
2
/BINAP catalytic system.
90
Compared with other 1,4-add-
itions, the Hayashi-Miyaura reaction has the following advantages: (a)
boronic acids display better oxygen and moisture stability than other or-
ganometallic reagents; (b) lack of 1,2-addition by-products; (c) both alkenyl
and arylboronic acids can be employed as nucleophiles; (d) a,b-unsaturated
ketones, esters, amides, phosphonates and nitro compounds can perform as
electrophiles; and (e) asymmetric induction can be accomplished through
the use of chiral ligands.
91
Nevertheless, owing to the relatively recent dis-
closure of this technology and the relatively high cost of Rh, very few ex-
amples on a large scale have been reported to date.
92
Numerous reviews on
the Rh-catalyzed Michael addition of organoboron reagents to activated
olefins have been published in recent years.
91,93
The medicinal chemistry group at Merck reported a Rh-catalyzed, asym-
metric Hayashi-Miyaura coupling en route to telcagepant (MK-0974; 65), a
calcitonin gene-related peptide receptor antagonist for the treatment of
migraine (Scheme 15.13).
92b
Initially, when the researchers applied typical
reaction conditions for the asymmetric Michael addition of 2,3-difluoro-
phenylboronic acid (63) to nitroolefin 62 [Rh(acac)(C
2
H
4
)
2
/(S)-BINAP (3
mol%) in dioxane-water (10:1) at 100 1C],
91,94
incomplete reaction was ob-
served due to the extensive decomposition of 63 (normally observed for
fluorophenylboronic acids). The decomposition of 63 could be minimized by
running the reaction at 45 1C but at the expense of further charges of catalyst
(10-20 mol%), which provided 64 in 80% yield and 93:7 dr. Further opti-
mization was focused on the use of additives to increase the reaction kin-
etics.
95
It was found that the reaction could be carried out with 3 mol%
i.
Rh(acac)(C
2
H
4
)
2
(3 mol%)
(
S
)-BINAP (3 mol%)
NaHCO
3
(0.5 equiv)
dioxane/H
2
O(10:1),35ºC,6h
O
BnO
B(OH)
2
O
2
N
O
BnO
N(Boc)
2
O
2
N
+
F
N(Boc)
2
ii. aqueous workup
iii. chromatography
F
F
62
63
(2.5 equi v)
64
(60 g)
93:7 dr
F
96%
O
NH
F
3
C
O
N
N
N
H
N
N
O
65
telcagepant
(MK-0974)
F
F
Scheme 15.13 Asymmetric Hayashi-Miyaura boronic acid addition en route to
telcagepant.
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