5
3. Conclusion
To illustrate the utility of Ir-catalyzed cross-coupling in the
preparation of drugs and some key intermediates, the synthetic
usage of this reaction was demonstrated by direct assembly of
one drug. Tafamidis26 is a transthyretin amyloid inhibitor
developed by Pfizer, which was approved by E.U. in 2011. In
2019, it was approved in Japan and the U.S. for the treatment of
transthyretin amyloid cardiomyopathy. Traditional synthesis
methods of key ester intermediates were showed as follows
(Scheme 3). The key intermediate 11 was cyclized in the
presence of p-TsOH·H2O in refluxing xylene, followed by
methylation with Me3SiCHN2 in benzene/MeOH affords the
desired benzoxazole methyl ester 14 (Route A).27 Alternatively,
methyl 1,3-benzoxazole-6-carboxylate (12) condensed with 1,3-
dichlorobenzene (13) using Pd(OAc)2, CuBr2, O2, K3PO4 and
pivalic acid in DMA at 140°C, giving ester 14 in 43% yield
(Route B).28 However, these routes suffered from high
temperature or many additives which limit large-scale industrial
applications. In our protocol (Route C), the key intermediate 16
could be readily cyclized in the presence of [Ir(cod)Cl]2 to afford
the desired product 14 in 52% yield. The coupling reaction was
run at medium temperature (100 °C), using 1% loading catalyst,
and giving target compound in moderate yield. The unreacted
starting material could be recycled and used again, which showed
potential application prospects in large-scale production.
In summary, we have developed an efficient irdium-catalyzed
intramolecular C-N and C-O/S cross-coupling reaction to
assemble
numerous
benzoxazoles,
benzothiazoles,
benzimidazoles, or benzofurans. Importantly, compared to Cu-
and Pd-catalyzed C-N or C-O bond formations, Ir-catalyzed
system could play a catalytic role with just 1 mol % catalyst
loading and conveniently produce desired compounds without
generating any debromination by-products. Simultaneously, a
concise and efficient synthesis of tafamidis was developed in 5-
gram scale. Applications of [Ir(cod)Cl]2 to other coupling
reactions, along with detailed mechanistic studies, are currently
underway in our laboratory.
Acknowledgments
This work was financially supported by Liaoning Provincial
Natural Science Foundation of China (No. 201602707).
References and notes
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To gain insight into the mechanism of the cross coupling
reactions with iridium as catalyst, we have selected one of 2-
haloarylamides and used the radical clock (RC) 1-allyloxy-2-
iodobenzene29 as substrate in the coupling reactions under
standard condition (Scheme 4). Result showed that RC did not
affect the reaction process, which implying the absence of radical
intermediates. This radical clock experiment indicated
[Ir(cod)Cl]2-catalyzed cross coupling reactions might suffer
conventional oxidative addition and reductive elimination
process.
2.
3.
4.
Scheme 4 Cross-coupling Reaction Using RC as Substrate
I
I
O
O
O
[Ir(cod)Cl]2, KOAc
DMSO
O
N
H
N
2c
RC
(80%)
1c
not observed
5.
6.
By an analogy with other Cu- and Co-catalyzed C-O or C-N
5,9
bond formations,
the plausible mechanism for the Iridium-
catalyzed cross-coupling reaction was as follows (Scheme 5). In
the presence of base, the initial coordination to iridium in b was
supported by the lack of reactivity of the halo substituents at
other positions in the ring under the iridium-catalyzed conditions.
Subsequently, an oxidative addition with dehalogenation
occurred to provide intermediate c, which could complete the
catalytic cycle by reductive elimination of the heterocycle.
7.
Scheme 5. Proposed Catalytic Cycle for the Iridium-
catalyzed C-N and C-O Cross-coupling Reactions
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R1
X
Y
X
N
Z
R2
+ :B
R1
N
R1
- H:B
W
WK+
R2
IrL
R2
a
reductive
elimination
K+
L
X
IrL
L = COD
Ir
W
W
R1
X = I, Br
R1
Y = NH, N
Z = ArNH, O
W = NAr, O
N
R2
N
R2
oxidative
addition
b
c
K+
KX
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