Palladium-catalyzed bisarylation of 3-alkylbenzofurans to 3-arylalkyl-2-arylbenzofurans on water: Tandem C(sp3)-H and C(sp2)-H activation reactions of 3-alkylbenzofurans

Article abstract of DOI:10.1039/c5cc04052c

A protocol involving facile sequential C(sp³)-H and C(sp²)-H activation reactions of 3-alkylbenzofurans catalyzed by Pd(OAc)₂ in the presence of pivalic acid, silver salt, and tricyclohexylphosphine 'on water' was developed. Aryl iodides were used as substrates in a tandem bisarylation reaction to generate 3-arylalkyl-2-arylbenzofurans in moderate to high yields at room temperature. The reaction revealed in this study is a rare example of consecutive C(sp³)-H and C(sp²)-H bond activation under mild reaction conditions.

Full text of DOI:10.1039/c5cc04052c

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Palladium-catalyzed bisarylation of
3-alkylbenzofurans to 3-arylalkyl-2-arylbenzofurans
on water: tandem C(sp3)–H and C(sp2)–H activation
reactions of 3-alkylbenzofurans†
Cite this:DOI: 10.1039/c5cc04052c
Received 19th May 2015,
Accepted 7th August 2015
Beom Shin Cho and Young Keun Chung*
DOI: 10.1039/c5cc04052c
www.rsc.org/chemcomm
A protocol involving facile sequential C(sp3)–H and C(sp2)–H acti- (on) water to give 3-arylalkyl-2-arylbenzofurans. Achieving the
vation reactions of 3-alkylbenzofurans catalyzed by Pd(OAc)2 in selective activation of a C(sp3)–H bond in the presence of a
the presence of pivalic acid, silver salt, and tricyclohexylphosphine competitive C(sp2)–H bond is considered to be a formidable
‘on water’ was developed. Aryl iodides were used as substrates in a challenge. To the best of our knowledge, the present study
tandem bisarylation reaction to generate 3-arylalkyl-2-arylbenzo- represents the first example of a metal-catalyzed difunctionali-
furans in moderate to high yields at room temperature. The reaction zation (bisarylation) of benzofuran via the activation of a C(sp3)–H
revealed in this study is a rare example of consecutive C(sp3)–H and bond and an aryl C(sp2)–H bond. Preliminary data for this novel
C(sp2)–H bond activation under mild reaction conditions.
finding are presented herein, where double activation of unacti-
vated C(sp3)–H and C(sp2)–H bonds in a single step is achieved on
Benzo[b]furan derivatives are an important class of biologically water. Thus, a mild and eco-friendly reaction for the bisarylation of
active oxygen-containing heterocyclic compounds.1 The 2-phenyl- 3-alkylbenzofuranes was discovered.
3-alkylbenzofuran moiety is found in biologically active natural
products exhibiting a broad range of biological and pharmaco-
logical activities.2–4 Natural products represent a significant source
of inspiration for the design of structural analogues with improved
pharmacological profiles.5 Thus, this desirable biological activity
(1)
of naturally occurring 2-phenyl-3-alkylbenzofurans stimulated our
interest in the synthesis of 2-aryl-3-alkylbenzofurans. Various
synthetically viable procedures have been used for the construction
Initially, the reaction of 3-methylbenzofuran (1) with iodo-
of 2,3-disubstituted benzofurans.6–10 The most common strategies benzene (2) to afford the C-2 arylated product, 3-methyl-2-phenyl-
utilized are transition-metal-catalyzed intra/intermolecular annula- benzofuran (3), ‘‘on water’’ was chosen as the model reaction in the
tions6 and modification of pre-functionalized benzofurans.7 Direct presence of Pd(OAc)2 (5 mol%), Ag2CO3 (1 mmol), and PivOH
arylation of 2- or 3-substituted benzofurans with aryl halides8,9 and (4 mmol) at 40 1C (eqn (1)).11 However, the reaction of 1 with 2
oxidative dehydrogenative cross-coupling reactions of benzofuran afforded a mixture of 3-methyl-2-phenylbenzofuran (3), 3-benzyl-2-
with benzene derivatives10 have also been documented. Concep- phenylbenzofuran (4),12 and 3-methyl-3-phenylbenzofuran-2(3H)-
tually, 2-aryl-3-alkylbenzofurans can be obtained from 2-arylbenzo- one (5)13 in 41%, 23%, and 28% yields, respectively. Although the
furans. However, C3-alkylation of 2-arylbenzofurans has not yet expected product 3 was obtained in 41% yield, a bisarylation
been reported. Moreover, no systematic study of the direct C2 product 4 was also isolated in 23% yield. Moreover, furanone 5,
arylation of 3-alkylbenzofurans with aryl halides has been another unexpected compound, was obtained in 28% yield. The
presented to date. Thus, we evaluated the direct C2 arylation observed formation of the bisarylation product 4 was very unusual
of 3-alkylbenzofurans and discovered the sequential C(sp3)–H because a tandem C(sp3)–H and C(sp2)–H activation reaction is
and C(sp2)–H activation (or a double C–H activation) of rare. Several years ago, tandem (sequential) sp3 C–H and sp2 C–H
3-alkylbenzofurans in the presence of a palladium catalyst in activations were reported by Sames and coworkers and by White
and coworkers.14 Encouraged by the above observation, the reac-
tion conditions for the bisarylation of benzofurans were optimized.
Screening of the amount of PivOH, Ag2CO3, Pd(OAc)2, and iodo-
Department of Chemistry, College of Natural Sciences, Seoul National University,
Seoul 151-747, Korea. E-mail: ykchung@snu.ac.kr
benzene was utilized to maximize the yield of 4 (see Table S1 in the
ESI†). From these optimization studies, a mixture of 1 mmol of
† Electronic supplementary information (ESI) available. CCDC 1045349. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c5cc04052c
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Table 1 Scope of iodobenzenesa
Fig. 1 X-ray structure of 16.
derivatives. However, a steric effect was observed in the reaction
with 2-tolyl iodides (11). In the case of 3-iodobenzonitrile, a mono-
arylation (C-2 arylated) product was observed predominantly.
The reaction can be extended to a naphtho[2,3-b]furan (15)
although the yield (34%) of bisarylation products was not high
(eqn (2)). The formation of a bisarylated product was confirmed
by an X-ray diffraction study (Fig. 1).15
(2)
a
1 (1 mmol), iodobenzene (2 mmol), Pd(OAc)2 (10 mol%), PCy3 (20 mol%),
Although cascade C–H activation reactions of simple aliphatic
substrates leading to complexity have rarely been observed,16
the sequential sp3 and sp2 double C–H activation reactions of
3-methylbenzofuran with iodobenzene derivatives were quite
common under the present reaction conditions. The bisarylation
Ag2CO3 (1.5 mmol), PivOH (1 mmol), and H2O (3 mL) at room temperature
for 40 h. Yields are of isolated products. Isolated yields of a pre-stirred
solution. PCy3 = tricyclohexylphosphine. PivOH = pivalic acid.
b
3-methylbenzofuran, 2 mmol iodobenzene, 10 mol% Pd(OAc)2, of other 3-alkylbenzofurans with iodobenzene was also investi-
20 mol% PCy3, 1.5 mmol Ag2CO3, and 1 mmol PivOH at room gated (Table 2). The reaction of 3-ethylbenzofuran yielded
temperature, and 40 h of reaction time provided the maximum 2-phenyl-3-(1-phenylethyl)benzofuran (18) and 3-ethyl-3-phenyl-
yield of 4 of 85% yield (a pre-stirred solution of Pd(OAc)2 and benzofuran-2(3H)-one (19) in 77% and 12% yields, respectively.
PCy3 was used as the catalyst). To confirm the advantages of Compared to the case of 3-methylbenzofuran, the yield of the
this catalyst system, Pd(OAc)2 was used as a homogeneous product derived from the sequential C(sp3)–H activation and
catalyst under the same conditions in different organic solvents, C(sp2)–H activation reactions declined slightly, presumably due
such as DMF (4: 2%; 5: 5%), dichloromethane (4: 29%; 5: 3%), to the steric hindrance. This reaction also exhibited excellent
toluene (4: 21%; 5: 5%), THF (4: 8%; 5: trace), and MeOH (4: 58%, site selectivity for the methylene group over the methyl group.
5: 3%). Thus, the activation of the C–H bond by the Pd catalyst Interestingly, the site selectivity observed herein was quite different
system was less efficient in organic solvents than on water under from that in alkyl arenes reported by Curto and Kozlowski.17 In the
the optimized conditions.
reaction of 3-n-butylbenzofuran with iodobenzene, 2-phenyl-3-(1-
After optimization of the reaction conditions, the substrate phenylbutyl)benzofuran (21), 3-n-butyl-3-phenylbenzofuran-2(3H)-
scope of the reaction was examined (Table 1). 3-Methylbenzofuran one (22), and 3-butylidene-2,3-dihydrobenzofuran (23) were isolated
was found to react smoothly with iodobenzene derivatives to in 61%, 3%, and 12% yields, respectively. The 3-benzylidene-2,3-
afford the bisarylated products in moderate to excellent yields. dihydrobenzofuran skeleton was previously reported in the base-
For the reaction with iodobenzene (4), 1-iodo-4-methylbenzene mediated cyclization of o-alkynylphenyl ether.18,19 The appearance
(5), or 1-iodo-3,5-dimethylbenzene (6), a pre-stirred solution of of the dihydrobenzofuran derivative may possibly be due to the
Pd(OAc)2 and PCy3 was used as catalyst system, resulting in high steric congestion at the butyl group. In contrast, the reaction of
yields (85%, 72%, and 90% yield, respectively) of the bisarylated 3-isopropylbenzofuran with iodobenzene yielded neither a doubly
products. However, the use of the pre-stirred catalytic solution did arylated product nor a lactone. Instead, 3-(dimethylmethylene)-2-
not produce the best yield for other aryl iodides (see the ESI†). phenyl-2,3-dihydrofuran (25) was isolated in 16% yield. The bisaryl-
Gratifyingly, a broad functional compatibility was observed ated product was not formed, presumably due to the steric
among the aryl iodides. Br and Cl substitutions (8, 9) were both congestion at the isopropyl group. In the reaction of 3-benzyl-
tolerated. p-Bromo(iodo)benzene was selectively phenylated at the benzofuran with iodobenzene, 3-benzylidene-2-phenyl-2,3-
iodo moiety. Electron-donating (5, 6, 7, 11, 12) as well as electron- dihydrobenzofuran (28) was isolated in 17% yield as one of the
withdrawing substituents (8, 9, 10, 13, 14) were tolerated under major isolable products. Moreover, 3-benzyl-2-phenylbenzofuran
the given reaction conditions. The yield of the reaction was not (4) and 3-benzhydryl-2-phenylbenzofuran (27) were both obtained
significantly affected by the electronic effects of the iodobenzene in 4% yield. 3-Benzylidene-2-phenyl-2,3-dihydrobenzofuran and
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Table 2 Bisarylation of 3-alkylbenzofuran derivativesa
bisarylated product (not shown here). Thus, the bisarylation
was highly sensitive to the electronic effect of the substituent
on the 6-position.
Control experiments were performed to gain insight into the
reaction mechanism (Scheme 1). When 3-methylbenzofuran
was reacted with 1 equiv. of iodobenzene, 4 was isolated in
45% yield based on 3-methylbenzofuran (90% based on iodo-
benzene) and 5 was isolated in 7% yield (Scheme 1a). Neither
3-benzylbenzofuran nor 3-methyl-2-phenylbenzofuran was observed.
Thus, it appears that the two reactions, the arylation reactions via
C(sp3)–H activation and C(sp2)–H activation, may occur almost
simultaneously. No reaction was observed for the use of 3-methyl-
2-phenylbenzofuran (3) (Scheme 1b). These observations sug-
gested that the formation of 3-benzyl-2-phenylbenzofuran from
3-methylbenzofuran did not occur via 3-methyl-2-phenylbenzo-
furan. Moreover, the C–H activations appeared to proceed by
a sequence initiated by C(sp3)–H activation and followed by
C(sp2)–H activation. Selective activation of the C(sp3)–H bond
over the C(sp2)–H bond was reported by Takemoto et al.,21
whereas in the Pd-catalyzed C(sp3)–H activation/amidation
reaction of carbamoyl chloride precursors, they observed selective
benzylic C(sp3)–H activation despite the presence of the C(sp2)–H
bond of naphthalene in the substrate. According to Fu’s mechanistic
study,22 the selective C(sp3)–H activation was due to the higher
acidity of the benzylic C(sp2)–H group in comparison to that of the
naphthalene C(sp2)-H group. Two deuterated compounds (1-D and
1-CD3) were prepared and their kinetic isotope effects (KIEs) were
Products
Starting material
R = Et (17)
R = nBu (20)
R = iPr (24)
R = Bn (26)
measured (Scheme 1c): the KIE values for k1/k1-D and k1/k1-CD were
3
a
1.2 and 1.1, respectively, suggesting that the C–H bond breaking
event was not rate-limiting.17,23 Moreover, a parallel experiment
with 1 and 1-CD3 revealed that the deuterated analogue proceeded
1.5 times slower, indicating that the C–H activation step might be
reversible (see the ESI†).
In conclusion, we have demonstrated that a consecutive bisaryla-
tion of 3-alkylbenzofurans occurs in the presence of Pd(OAc)2,
Ag2CO3, and PivOH on water at room temperature. The reaction
3-Alkylbenzofuran (1 mmol), 2 (2 mmol), Pd(OAc)2 (10 mol%), PCy3
(20 mol%), Ag2CO3 (1.5 mmol), PivOH (1 mmol), H2O (3 mL) at room
temperature for 40 h. Yields are of isolated products.
3-benzyl-2-phenylbenzofuran were both derived from mono-
arylation. 3-Benzhydryl-2-phenylbenzofuran was derived from
C(sp3)–H activation of the benzyl group and C(sp2)–H activation
of the furan moiety, although activation of methylene C(sp3)–H
bonds is quite rare.20 In addition to these products, several
intractable side-products were also formed. No lactone for-
mation was observed.
Thus, when the 3-position of benzofuran was substituted
with Me, Et, or nBu, the corresponding bisarylated product was
isolated as the major product, whereas substitution of this
position with iPr or Bn predominantly yielded the monoarylated
product. The differences in the reactivities may be related to the
feasibility of generating a p-allyl intermediate.
(3)
We studied the bisarylation of substituted 3-methylbenzofuran
under the optimized reaction conditions (eqn (3)). When a
3,6-dimethylbenzofuran (29) was utilized, the corresponding
bisarylated product (30) was isolated in 72% yield. However,
the use of 6-methoxy-3-methylbenzofurans failed to give the
Scheme 1 Control experiments.
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revealed in the study is a rare example of consecutive C(sp3)–H and
C(sp2)–H bond activation under mild reaction conditions. The mild
reaction conditions permit a broad set of functionalities in the aryl
iodide unit to be tolerated, and a variety of novel compounds were
successfully prepared in good yields. Thus, the one-pot, mild, and
eco-friendly process may provide a powerful synthetic tool to access
the synthesis of 3-arylalkyl-2-arylbenzofurans.
This work was supported by the National Research Founda-
tion of Korea (NRF) grant funded by the Korean government
(2014R1A5A1011165 and 2007-0093864). BSC is a recipient of
the BK21 plus Fellowship.
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