D. Pappo et al.
many members of the coumestan family, other ethyl 2-ben-
zoylacetates having two ortho-substituents, such as ethyl 2-
(4-bromo-2,6-dimethoxybenzoyl)acetate and ethyl 2-(6-
bromo-2,4-dimethoxybenzoyl)acetate, which upon successful
coupling could provide an entry to wedelolactone natural
product,[17] were found to be inactive.
(Scheme 5) was detected in 75% yield by using NMR spec-
troscopy (FeCl3·ACTHUNTRGNE(UNG H2O)6/DTBP catalytic system), however it
was contaminated with Friedel–Crafts alkylation byproducts.
Although the coupling of phenols 2 and b-ketoesters 3
provides easy access to variety of coumestrol derivatives,
the reaction requires the use of the hazardous DTBP as the
oxidant.[11,12] Indeed, one of the weaknesses of many of the
CDC reactions is the need for organic oxidants that consti-
tute safety concerns, which are particularly troublesome for
future industrial applications. Since Li and co-workers re-
ported the first example of an iron-CDC reaction in 2007,[32]
most of the transformations developed subsequently have
required the use of organic oxidants such as DTBP
(tBuOOtBu),[33] TBHP (tBuOOH)[34] or 2,3-dichloro-5,6-di-
cyano-1,4-benzoqinone (DDQ).[1c,35] Exceptions are the al-
kylation reaction of 1,3-dicarbonyl compounds and benzylic
substrates in the presence of FeCl2, CuCl, and N-hydroxyph-
thalimide (NHPI) under an oxygen atmosphere[36] and Kat-
Scheme 5. FeCl3/O2 Oxidative coupling of b-ketoesters with phenols.
As a result, a pure compound 7 could only be obtained by
preparative-HPLC separation and in an unreported yield of
the isolated product.[11] Under our modified aerobic cou-
pling conditions benzofuran 7 was isolated in 55% yield.
Moreover, sensitive phenols, such as 2-methoxyphenol (3e,
Scheme 5), which had failed to react when DTBP was used
as the oxidant, now became a suitable partner; benzofuran 8
was obtained in 24% yield.
sukiꢁs FeACHTUNGTRENNUNG(salan) complex, which catalyzes enantioselective
aerobic oxidative cross-coupling reactions of naphthol deriv-
atives.[4,37]
The NHPI/O2 oxidation system was assumed to be a good
solution not only from the safety point of view, but also be-
cause it facilitates more environmentally friendly and eco-
nomical reactions and, in the case of phenol coupling reac-
tions, it should eliminate the Friedel–Crafts alkylation side
reaction that occurs with DTBP and TBHP. The oxidative
abilities of the NHPI/O2 system in hydrocarbon oxidations
has been studied extensively and reviewed,[38] and the ability
of that system to oxidize FeIII to FeIV species in CH oxida-
tion reactions has also been reported.[39] Therefore, it was
logical to explore that direction. Indeed, when ethyl 2-(2,4-
dimethoxybenzoyl)acetate (2c, 1 equiv) and 3-methoxyphe-
nol (3c, 1.3 equiv) were mixed in DCE at 1008C in the pres-
ence of FeCl3 (10 mol%) and NHPI (5 mol%) under an
oxygen atmosphere (O2 balloon), the reaction went to com-
pletion within 24 h, isolating the coupling product 6 in 61%
yield (Table 1, entry 1). Increasing the amount of NHPI to
20 mol% had a negative effect on the yield (53%, Table 1,
entry 2). Furthermore, when the reaction was performed in
the absence of NHPI, benzofuran 6 was isolated in a moder-
ate 63% yield (Table 1, entry 3), which indicates that NHPI
does not play a role in the reaction mechanism. The addi-
tion of 2,2’-bipyridine (5 mol%) to the reaction mixture
slowed down the process, and after 24 h only partial conver-
sion was observed (Table 1, entry 4). To simplify the method
even further, we performed the reaction under air atmos-
phere (open flask). Whereas the reaction in DCE was much
slower and required a longer reaction time (48 h), the reac-
tion in toluene went to completion in only 9 h. In both
cases, the desired coupling product 6 was isolated in 52%
yield. In addition, the modified conditions were examined
for the coupling of ethyl benzyloxyacetate (2a) with phenol
Encouraged by the success of our syntheses, we shifted
our attention to the synthesis of unnatural coumestrol ana-
logues suitable for a structure–activity relationship study.
Based on preliminary biology results (see below), 2-benzy-
loxyacetates 2c and 2d were chosen as the coupling partners
for building our library. These b-ketoesters were thus treat-
ed with a variety of phenol derivatives by using the FeCl3/bi-
pyridine/DTBP catalytic system (Table 2). The oxidative
coupling reaction of compounds 2c and 2d with phenols
bearing meta and para electron-neutral and electron-rich
substituents (3c–3i) afforded benzofurans 9–15 in moderate-
to-good yields (53–77%; Scheme 4 and Table 2, entries 1–7).
Electron-deficient phenols bearing p-Br (3j), p-F (3k) and
p-CF3 (3l) groups were also found to be good partners, and
benzofurans 16–18 were isolated in 65, 73, and 51% yields,
respectively. Less-activated phenols, such as 4-cyanophenol,
4-formylphenol and 4-(ethoxycarbonyl)phenol, failed to
react. For comparison reasons, our modified aerobic oxida-
tive coupling conditions were also examined affording the
desired products in moderate yields.
The conversion of benzofurans 9–18 and 19 to the corre-
sponding coumestrol analogues was performed in good-to-
excellent yields by using the deprotection–lactonization pro-
tocol developed for the synthesis of coumestrol (BBr3 in
CH2Cl2, then boiling ethanol). However, initial attempts to
convert benzofuran 18 bearing the trifluoromethyl group af-
forded the 9-ethoxycarbonyl-coumestrol derivative 29 in
84% yield, as a result of acid-catalyzed alcoholysis of the
acid-sensitive CF3 group.[40] Alternatively, when compound
18 was first deprotected with BBr3 (CH2Cl2, room tempera-
ture) and then heated at reflux in toluene in the presence of
a catalytic amount of triethylamine (50 mol%) for 30 min,
(3d). Previously, the corresponding benzofuran
7
&
4
&
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!
Kshirsagar, Umesh A.
