Angewandte
Communications
Chemie
a bioisostere of hydrogen to block oxidation at C-4 (the major
metabolism), and thus serves as a valuable fluorine-contain-
ing component in pharmaceutical design,[17] for example
Glanatec.[17d] For the purpose of molecular imaging by PET,
18F-isotopologues of fluoroisoquinoline would provide
a unique and non-invasive way to track in vivo behavior of
labeled drug candidates and their interactions with biological
targets. However, there are only limited methods for the
synthesis of fluoroisoquinolines with common theme focused
on the electrophilic fluorinating agents, including Select-
fluor[18] and N-fluorobenzenesulfonylimide (NFSI).[19] Apply-
ing these approaches for radiofluorination would require an
electrophilic fluorinating agent, nearly all of which are
generated from gaseous [18F]F2 and only available in a few
PET centers worldwide with specialized apparatus, and also
associated with serious shortcomings, i.e., unselective fluori-
nation and low specific activities. In order to obviate the need
for electrophilic fluorinating reagents during 18F-fluoroiso-
quinoline preparation, we report a new and efficient process
for synthesis of aryl(isoquinoline)iodonium salts by sequen-
tial silver-catalyzed amination of alkynes and exchange with
hypervalent iodine reagents (Scheme 1b). This approach
represents the first example of diaryliodonium salts prepared
from mesoionic carbene-metal [(mic)M] complex (2 or 3),
which eradicates the use of aryl halides in oxidation or metal
halide exchange conditions. Using concomitant isoprene
emission as the driving force, the “one-pot” cyclization
provides high yields for a wide range of aryl(isoquinoline)io-
donium salts and demonstrates their usefulness in the
(radio)fluorination of isoquinolines and synthesis of fluori-
nated natural product 18F-fluoroaspergillitine.
prepare diaryliodonium precursors for the synthesis of
[18F]fluoroisoquinolines.
Initial efforts were focused on the exploration of a concise
and general protocol to assemble diaryliodonium products
(Table 1). The imine 1a was readily synthesized in 90% yield
Table 1: Preparative conditions for aryl(isoquinoline)iodonium salts.[a]
Entry
Catalyst (mol%)
IIII reagent
Yield [%][b]
1
AgNO3 (20)
AgNO3 (20)
AgNO3 (20)
AgNO2 (20)
AgOTf (20)
Ag2CO3 (10)
AgNO3 (50)
AgNO3 (100)
AgNO3 (100)
AgNO3 (100)
AgNO3 (100)
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhIPy’2(OTf)2
PhI(OAc)2
80
78
27
74
79
79
86
95
2[c]
3[d]
4
5
6
7
8
9[e]
10[f]
11
30
78
98 (88)
PhI(O2CCF3)2
PhIPy2(OTf)2
[a] Reaction conditions: 1a (0.1 mmol), IIII reagent (0.12 mmol), reaction
was initiated at 08C then RT for 3 h. [b] 19F-NMR yields with CF3-DMA
(2,2,2-trifluoro-N,N-dimethylacetamide) as internal standard.
[c] 20 mol% Pyox. [d] 1 equiv of Li2CO3. [e] OAc as counter anion.
[f] O2CCF3 as counter anion; PhIPy’(OTf)2: Py’=4-methoxypyridine,
Pyox=(S)-4-isopropyl-2-(6-methylpyridin-2-yl)-4,5-dihydrooxazole.
via condensation reactions between the corresponding alde-
hyde and tert-butyl amine. Treatment of substrate 1a by
catalytic amount of AgNO3 (20 mol%) at 08C for 20 minutes,
followed by addition of PhIPy’2(OTf)2, provided product 4a in
80% yield (entry 1). Efforts towards optimization of this one-
pot method indicated that addition of Pyox ligand or base did
not effectively increase the reaction yields (entries 2 and 3).
Silver salts screening showed that AgNO3 is most effective
(entries 4–6). Increase of AgNO3 loading (to 1 equiv)
improved the yield to 95% (entries 7 and 8). When other
hypervalent iodine reagents, such as PhI(OAc)2 and PhI-
(OCOCF3)2, were employed, the desired product 4a was also
provided, yet in 30% yield using PhI(OAc)2, and 78% yield
using PhI(OCOCF3)2 (enties 9 and 10). When we switched
PhIPy’2(OTf)2 to PhIPy2(OTf)2, the reaction could avoid
contamination with an unknown impurity from AgPy’ com-
plex, and improve the yield to 98% by 19F-NMR spectrosco-
py. As a result, the final product 4a was obtained in 88%
isolated yield (entry 11). Finally, other transition metal
catalysts, such as Cu(CH3CN)4OTf, Pd(O2CCF3)2, PtCl2 and
AuCl3 which are used in the cyclization of alkyl-imine 1a in
the literatures,[20] were also investigated. However, none of
desired products 4a was detected. These observations reveal
the unique reactivity of [(mic)Ag] complex to hypervalent
iodine reagent.
Our mechanistic investigations[19d] (see Section 11 for
plausible mechanism in the Supporting Information, SI) on
the Ag-catalyzed amination of alkynes delineated an unusual
mesoionic carbene silver [(mic)2Ag] complex 3, which makes
the isoquinoline C-4 position accessible after the alkyne
cyclization. We found that when silver complex 3 was treated
with hypervalent iodine reagent PhIPy’2(OTf)2 (Py’ = p-
methoxypyridine), an unprecedented IIII adduct appeared in
nearly quantitative yield, which was subsequently character-
ized as 4a by X-ray crystallography (Scheme 2 and Section 14,
SI). This serendipitous discovery inspired us to speculate that
an apparent “umpolung” would occur at C-4 if nucleophiles,
for example fluoride ion, can be introduced to the newly
formed aryl(isoquinoline)iodonium(III) species to furnish the
synthesis of fluorinated isoquinoline instead of “18F” electro-
philes. Therefore, we adopted this one-pot tandem protocol
involving Ag-catalyzed amination of alkynes and exchange
with I(III) reagent to create a new and efficient approach to
The scope and practicality of this tandem alkynyl-imine
cyclization and hypervalent iodine exchange was investigated
and the results are summarized in Table 2. Alkynyl-imines
with a series of substituents (R) on the (hetero)aromatic ring,
Scheme 2. Hypothesis and formation of phenyl(isoquinoline)iodonium
salt.
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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