DiVersity-Oriented Synthesis of 3-Iodochromones
SCHEME 1. Synthesis of Alkynones
Recent work by our group and others has shown the
electrophilic cyclization of functionally substituted alkynes to
be an efficient way of generating benzo[b]thiophenes,10 ben-
zofurans,11 bicyclic â-lactams,12 cyclic carbonates,13 2,3-dihy-
dropyrroles and pyrroles,14 furans,15 furopyridines,16 indoles,17
isochromenes,18 isocoumarins and R-pyrones,19 isoquinolines
and naphthyridines,20 isoxazoles,21 naphthalenes,22 polycyclic
aromatics,23 and quinolines.24 Herein, we report an efficient
approach to various 3-iodochromones via ICl-induced cycliza-
tion (eq 1). These reactions are run under very mild neutral
reaction conditions, tolerate various functional groups, and
generally provide the iodochromone products in good to
excellent yields. Iodothiochromenones and iodoquinolinones are
also prepared by analogous ICl-induced cyclization. The iodide
products can be further elaborated to a wide range of function-
ally substituted chromones, furans, and polycyclic compounds
using subsequent palladium-catalyzed processes.
26
the resulted secondary alcohol by activated MnO2 (Scheme
1). Generally, the requisite alkynones are obtained in 66-98%
yields by these straightforward approaches (see the Supporting
Information for details).
To examine the feasibility of the iodocyclization of such
alkynones, we initially studied the reaction of 1-(2-methoxy-
phenyl)-3-phenylpropynone (1) and ICl. To our delight, the
3-iodochromone 2 was obtained in a 96% isolated yield after
stirring alkynone 1 (0.25 mmol) and 1.5 equiv of ICl in 3 mL
of CH2Cl2 at room temperature for only 10 min (Table 1, entry
1). It is noteworthy that no chromone 2 was obtained when the
weaker electrophile I2 was employed instead of ICl using CH2-
Cl2 as the solvent at room temperature for 6 h. The reaction is
still very efficient and provides the iodochromone 2 in a 99%
yield when run at -78 °C for 2 h (entry 2). It is noteworthy
that the reaction can be easily run on a multigram scale and the
iodochromone 2 is obtained in excellent yield without the use
of any column chromatography (see the Experimental Section
for details).
Results and Discussion
The 2-methoxyaryl-containing alkynones required for our
approach can be readily prepared in one or two steps by two
complementary methods: (1) the palladium/copper-catalyzed
Sonogashira coupling of an acid chloride with a terminal
acetylene at room temperature or 50 °C25 or (2) the addition of
a lithium acetylide to an aldehyde, followed by oxidation of
The scope of this reaction is quite general. Excellent yields
have been obtained when substituting the phenyl moiety of the
alkynone 1 by various electron-rich and ortho-substituted arenes
(entries 3-6). Also noteworthy is the fact that this chemistry
tolerates acetoxy (entry 7) and thiophene (entry 8) groups, and
the corresponding chromones are obtained in excellent yields.
However, none of the desired product was obtained when an
electron-poor 3-pyridyl group was introduced (entry 9).27 A 45%
isolated yield of chromone was obtained when a 3,5-bis-
(trifluoromethyl)phenyl group was employed (entry 10). This
reaction needed to be run at room temperature for a longer time.
A 3:1 ratio of regioisomeric side products arising from ICl
addition to the triple bond was also obtained from this reaction
in a 46% yield. It is likely that the introduction of more electron-
deficient aromatic rings on the distal end of the triple bond
destabilizes the expected carbocation-like iodonium intermedi-
ate, disfavoring cyclization and resulting in direct addition of
ICl across the triple bond (see the later mechanistic discussion).
A 96% isolated yield of iodochromone was obtained when a
1-cyclohexenyl group was introduced into the alkynone (entry
11). Alkyl-substituted alkynones are less reactive (entries 12-
14). Nonetheless, the desired products can be obtained in good
yields when the reactions are run under more dilute conditions
for a longer reaction time (entries 12 and 13). Unfortunately,
none of the desired product was obtained when the methoxy-
methyl-substituted alkynone 25 was employed, consistent with
destabilization of a polarized cationic intermediate (entry 14).
The TMS-substituted alkynone 27 afforded none of the desired
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possible that the ICl coordinates to the nitrogen moiety of the pyridine to
form a pyridinium salt first, which makes the pyridine ring even more
electron-deficient and unreactive.
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