Palladium-catalyzed synthesis of benzofurans via C-H activation/oxidation tandem reaction and its application to the synthesis of decursivine and serotobenine

Article abstract of DOI:10.1039/c3cc49717h

A new palladium-catalyzed method for the synthesis of benzofurans by reaction of 2-hydroxystyrenes and iodobenzenes via a C-H activation/oxidation tandem reaction has been unprecedentedly discovered. By using this strategy, the overall synthetic efficienc

Full text of DOI:10.1039/c3cc49717h

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Palladium-catalyzed synthesis of benzofurans via
C–H activation/oxidation tandem reaction and its
application to the synthesis of decursivine and
serotobenine†
Cite this: Chem. Commun., 2014,
50, 3299
Received 23rd December 2013,
Accepted 24th January 2014
Lei Guo,a Fengying Zhang,a Weimin Hu,a Lei Lia and Yanxing Jia*ab
DOI: 10.1039/c3cc49717h
www.rsc.org/chemcomm
A new palladium-catalyzed method for the synthesis of benzofurans by
reaction of 2-hydroxystyrenes and iodobenzenes via a C–H activation/
oxidation tandem reaction has been unprecedentedly discovered. By
using this strategy, the overall synthetic efficiency of the synthesis of
decursivine and its analogues was indeed improved. Preliminary
mechanistic studies shed light into the possible mechanisms.
The development of short synthetic routes for the synthesis of
complex natural products remains a major topic in synthetic
organic chemistry, because they offer the best ways to achieve
overall efficiency. Ideally, the synthetic routes should also be
amenable to the preparation of diverse natural product analogues,
which are important for the discovery of new lead compounds
and for the study of complex biological systems.
Recently, we1 accomplished the highly efficient total synthesis
of decursivine, serotobenine (Fig. 1), and a variety of decursivine
analogues (4) by using the cascade Witkop photocyclization/
elimination/addition sequence (Scheme 1a).2–4 This approach is
very efficient for each target-molecule; however, considering the
overall synthetic efficiency, the synthesis of n different analogues
would require at least 4 Â n overall steps. To improve the overall
synthetic efficiency, we envisioned that the synthesis of natural
Scheme 1 Retrosynthetic analysis of decursivine and its analogues.
Fig. 1 Structures of decursivine and related alkaloids.
product decursivine, serotobenine, and multiple analogues can
be prepared via cyclization of a,b-unsaturated lactam 7. Com-
pound 7 could be obtained by Pd-catalyzed Heck reaction of the
common intermediate a,b-unsaturated lactam 9 with different
readily available aryl iodides 8 (Scheme 1b). In turn, the
key known intermediate 9 could be prepared in 40% overall
yield via a two-step procedure developed by us. If this strategy
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China.
E-mail: yxjia@bjmu.edu.cn; Tel: +86-10-82805166
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China
† Electronic supplementary information (ESI) available: Experimental details and
spectroscopic characterization. See DOI: 10.1039/c3cc49717h
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Table 1 Optimization of the reaction conditionsa
Scheme 2 Reduction of compound 13a.
Entry
Additive
Temp. (1C)
7a
Yieldb (%) 13a
14
amide and indole to the corresponding trans-dihydrobenzofuran
presented a considerable challenge. After a variety of trials, the
desired 4a could be obtained in 79% yield when 13a was reduced
with Sm and I2 in MeOH and DMA (Scheme 2).12
1c
2
TBAC
PPh3
PCy3ÁHBF4
PivOH
PCy3ÁHBF4
PivOH
—
R.T.
R.T.
100
100
—
—
—
—
17
28
23
40
27
24
37
24
3
4d
5d
6
100
100
—
—
60
25
20
34
After optimizing the reaction conditions for the formation of
benzofurans and its selective reduction, we turned our attention
to the synthesis of natural products decursivine and serotobenine
by employing this strategy (Scheme 3). Reaction of compound 9
with 8b provided the desired benzofuran 13b in 62% yield, which
was reduced with Sm and I2 to afford decursivine (1) in 78% yield.
Similarly, treatment of compound 9 with iodobenzene 8c provided
compound 13c in 43% yield. Subsequent reduction of 13c with
Sm and I2 followed by deprotection of benzyl group with Pd/C in
THF/MeOH yielded serotobenine (2). Thus, the linear sequence of
the synthesis of decursivine and serotobenine were shortened from
5 steps to 4 steps and from 8 steps to 5 steps from commercially
available starting material, respectively.1,2
Having successfully established the synthetic route, the synthesis
of natural product analogues using iodo-benzenes with different
electronic and steric properties were examined (Scheme 4). The
results indicated that the tandem reaction proceeded smoothly
with the electron-donating (13a–13c, 13e) and electron-neutral
iodobenzenes (13d), while the electron-withdrawing or steric
iodobenzenes were adverse to the tandem reaction (13f, 13g).
Reduction of these compounds could afford different analogues
of the natural product (4a, 4d–4f).
a
Reaction conditions: 9 (0.1 mmol), 8a (0.3 mmol), Pd(OAc)2 (0.01 mmol),
b
additive (0.03 mmol), K2CO3 (0.15 mmol) in DMA (2.0 mL). Isolated
yields. NaHCO3 (0.3 mmol) as base in CH3CN (2.0 mL). 0.3 mmol
PivOH was used.
c
d
could be realized, a total of (2 Â n À 2) overall step will be saved.
Moreover, the synthesis does not need any protecting step.
Herein, we report that during the course of our exploration
of this new strategy, we developed a new palladium-catalyzed
method for the synthesis of 2,3-diarylbenzofurans. We also
report studies on the mechanism of this transformation, which
suggest that the reaction proceeds via phenol directed alkenyl
C–H activation and unusual oxidation by iodobenzenes.
Initially, we explored the Pd-catalyzed cross-coupling reaction of
compound 9 by using p-iodoanisole 8a as a model substrate. Unfortu-
nately, the desired cross-coupling product 7a was not obtained under
standard Heck reaction conditions (Table 1, entries 1–2). Surprisingly,
the unexpected benzofurans 13a and 14 were isolated as the major
product, which were obviously oxidative products. In addition, the
combined yield of 13a and 14 was much higher than the amount of
Pd(OAc)2.5 After carefully analysis of the whole process, we thought
that 13a and 14 were resulted from oxidation of Pd(II), and p-iodo-
anisole 8a might act as a co-oxidant under palladium-catalyzed
conditions,6 so the formation of benzofuran 13a might be explained
by Pd-catalyzed Heck reaction/oxidative cyclization tandem sequence
although the detailed mechanism is still unknown. An extensive
literature search revealed that although preparation of benzofurans
by oxidative cyclization of 2-hydroxystyrenes using a variety of oxidants
have been reported,7 the use of aryl iodide as a co-oxidant under
palladium-catalyzed conditions has not been reported.8 We then
realized that this reaction might be a new method for the synthesis
of benzofurans that are found in natural products and molecules with
potent biological activities.5,7–10
We then examined the generality of this sequence in the syn-
thesis of 2,3-diarylbenzofurans (Scheme 5). When compound
15a was subjected to the aforementioned optimized reaction
conditions, unexpectedly, the desired benzofuran 16a was obtained
in only 5% yield and the Heck product 17a was obtained in 73%
yield as the sole Z isomer. The formation of sole Z isomer 17a is
We therefore optimized the reaction conditions for the synthesis
of 13a. The Heck reaction of 9 using PCy3ÁHBF4 as the ligand
provided 13a in 23% yield (Table 1, entry 3). Employment of
Fagnou’s condition in the presence of 3.0 equivalents of pivalic acid
provided 13a in 40% yield (Table 1, entry 4).11 Further optimization
of the reaction conditions was performed (see ESI†). Fortunately, we
obtained 13a in 60% yield under ligand-free conditions (entry 5).
The chemo-selective reduction of tetra-substituted double bond
in 13a within an aromatic system in the presence of activated Scheme 3 Synthesis of decursivine (1) and serotobenine (2).
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(1)
(2)
Scheme 4 Synthesis of natural product analogues.
Scheme 6 Kinetic isotope effect study.
in 86% yield (eqn (1)). Then olefin 17h was subjected to the
optimized reaction conditions, and it provided the desired
benzofuran 16h in 82% yield (eqn (2)). These results indicated
that the olefin 17 is the reaction intermediate of this tandem
reaction.
The key intermediate 17 was obtained as the sole Z isomer,
which suggested that the first Pd-catalyzed cross-coupling
was not a simple Heck reaction. Because Heck reaction would
usually give both the Z and the E isomer,13 it is unlikely that
high
Z selectivity would be achieved without chelation/
direction by the substrate. Recently, several groups reported
that phenol can be used as a directing group for C–H activa-
tion for the formation of C–C and C–O bond.14,15 Especially,
Iwasawa’s group recently described the first Pd-catalyzed direct
carboxylation of alkenyl C–H bonds of 2-hydroxystyrenes for
the synthesis of coumarins.15 We therefore expected that the
Z olefin 17 might be formed through the phenol directed C–H
activation.16 To gain further mechanistic insights, an isotope
effect study was conducted (Scheme 6). A kinetic isotope effect
(KIE, KH/KD) of 1.93 was obtained, indicating the probable
involvement of the breaking of olefin C–H bond as the rate-
determining step.
Scheme 5 Synthesis of 2,3-diarylbenzofurans.
interesting since it might be a reaction intermediate and could be
used to probe the possible mechanisms of this tandem reaction.
To our delight, by simply increasing the reaction temperature
to 160 1C (see ESI†), a variety of 2-hydroxystyrenes 15 bearing
electron-donating, electron-neutral, and weak electron-withdrawing
groups reacted smoothly with different electronic substituents to
provide the desired product 16 in good yields.
Because some experimental results are hard to understand,
we then sought the mechanistic understanding of this tandem
sequence. Reaction of 15c under our optimized reaction condi-
tions (160 1C) for 1 h afforded the olefin 17h (evidenced by NOESY)
(3)
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for elimination to give the desired products. The H–Pd–Ar species
27 undergoes reductive elimination to provide Pd(0) 19 and the
aromatic product 28.
In summary, we have developed a new palladium-catalyzed
C–H activation/oxidative cyclization tandem reaction for the
preparation of benzofurans. This new method enabled the expe-
dient synthesis of decursivine, serotobenine and their analogues
without any protecting group. Many interesting insights were
obtained during the mechanistic study and a rational mechanism
was proposed.
(4)
For oxidation of intermediate 17 to benzofuran 16, two control
experiments were performed. When iodobenzene was absent in
the reaction, it only provided benzofuran 16h in 9% yield due to
oxidation by Pd(OAc)2 (eqn (3)). In contrast, when compound 8r
was employed as the co-oxidant, the desired benzofuran 16r was
obtained in 86% yield and the high-boiling reduced product 18
was isolated in 73% yield (eqn (4)). Based on these results, we
conclude that the benzofurans 13 and 16 were produced by
oxidative cyclization of the intermediates 7 and 17, respectively.
Based on the previous studies and our current experimental
results, a mechanistic pathway is proposed (Scheme 7). Initially,
the oxidative addition of ArI 8 to Pd(0) 19 generates the Ar–Pd(II)–I
species 20, which could undergo ligand exchange with phenol to
provide the palladium intermediate 21. Intermediate 21 under-
goes alkenyl C–H activation to form intermediate 23 through a
six-membered palladacycle 22, which upon reductive elimination,
produces the cross-coupling Z isomer 24 and palladium(0) 19. The
isomer 24 coordinates with the Ar–Pd(II)–I species 20 to afford
the palladium aryl phenoxide complex 25. Intramolecular syn-
insertion of the alkene into the Pd–O bond would give the inter-
mediate 26,17 which subsequently undergoes syn-b-hydride
elimination to provide the desired benzofuran 16 and the
H–Pd–Ar species 27. For this oxidation, the alternative mechanism
in which the coordination of Ar–Pd(II)–I species 20 with olefin
occurs followed by anti-addition of phenolic hydroxyl group can
be ruled out since it should lead to products without cis-b-hydride
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Scheme 7 Proposed reaction mechanism.
3302 | Chem. Commun., 2014, 50, 3299--3302
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