Direct oxidative heck cyclizations: Intramolecular Fujiwara-Moritani arylations for the synthesis of functionalized benzofurans and dihydrobenzofurans

Article abstract of DOI:10.1002/anie.200461294

No extra functionalization step is required for palladium(II)-catalyzed oxidative carbocyclizations like that shown, which provide highly substituted benzofuran and dihydrobenzofuran derivatives by net dehydrogenation. The mechanism is similar to that of Heck cyclizations. Products containing quaternary carbon stereocenters can be obtained in diastereomerically pure form.

Full text of DOI:10.1002/anie.200461294

Communications
Pd-Catalyzed Cyclizations
Direct Oxidative Heck
Cyclizations: Intramolecular
Fujiwara–Moritani Arylations for
the Synthesis of Functionalized
Benzofurans and
Dihydrobenzofurans**
Haiming Zhang, Eric M. Ferreira, and
Brian M. Stoltz*
Over the past two and a half decades, the
intramolecular Heck reaction has proven to
be an integral process for the formation of
ꢀ
C C linkages in the synthesis of complex
molecules.[1] While the reaction provides
desirable products by the coupling of an aryl
or vinyl halide with an olefin by extrusion of
the hydrohalic acid, the overall process
involves two discrete functionalization
events: 1) halogenation of an aryl or vinyl
precursor and 2) palladium(0)-catalyzed
ꢀ
Scheme 1. a) A generalized Heck cyclization (note that the halide must be installed in a dis-
crete step). b) A generalized Fujiwara–Moritani/oxidative Heck cyclization. c) An example of
an indole annulation by oxidative arene–olefin cyclization.[8]
C C bond formation (Scheme 1a).
A
potentially more efficient process would
involve oxidative coupling of an unfunction-
alized arene directly with an olefin, thus
obviating the necessity for prehalogenation
of the substrate (Scheme 1b). Although the
intermolecular version of this reaction was
discovered in 1967 by Fujiwara and Mor-
itani,[2] subsequent studies have largely
focused on couplings of benzene with acti-
vated olefins (e.g., acrylate esters).[3] In fact,
the direct intramolecular oxidative arene/
olefin coupling (i.e., oxidative Heck cycliza-
tion[4]) has not been studied thoroughly.[5]
In the course of our efforts to develop
palladium(ii)-catalyzed dehydrogenation as
a general oxidation method,[6,7] we recently
Table 1: Screening of oxidants for the intramolecular oxidative Heck cyclization.[a]
Entry
Oxidant
[1 equiv]
Yield [%][b]
Entry
Oxidant
[1 equiv]
Yield [%][b]
1
2
3
4
O2 (1 atm)
benzoquinone
Cu(OAc)2
AgOAc
56
62
31
29
5
6
7
8
Tl(OCOCF3)3
K2S2O8
H2NC(S)NH2
PhCO3tBu
<10
30
<10
42
[a] All reactions were carried out with 0.10 mmol 1, 10 mol% Pd(OAc)2 (0.01 mmol), 40 mol%
described the catalytic oxidative cyclization ethyl nicotinate (0.04 mmol), and 0.10 mmol or 1 atm oxidant in 1.0 mL 4:1 tAmOH:AcOH
(0.1m in substrate). [b] Yield determined by gas chromatography.
of unsaturated indoles to give annulated
derivatives (Scheme 1c).[8] Our studies
determined that the indole cyclization
mechanism most likely involves initial arene palladation
with subsequent olefin insertion and b-hydrogen elimina-
[*] Dr. H. Zhang, E. M. Ferreira, Prof. B. M. Stoltz
tion.[9] Importantly, this mechanism is analogous to that of the
The Arnold and Mabel Beckman Laboratories of Chemical Synthesis
Division of Chemistry and Chemical Engineering
Heck cyclization, since a similar aryl–PdII species is believed
California Institute of Technology
1200 East California Boulevard, MC 164-30
Pasadena, CA 91125 (USA)
Fax: (+1)626-564-9297
E-mail: stoltz@caltech.edu
to be the key intermediate in both processes; however, the
ꢀ
new process is oxidative due to the initial C H bond
functionalization event and net dehydrogenation of the
substrate. Furthermore, since Pd0-mediated oxidative addi-
tion to electron-rich aryl halides is typically slower than that
to electron-poor arenes,[10] this direct oxidative process
(initiated by electrophilic palladation by PdII) is complemen-
tary to the Heck technology. We envisioned that electron-rich
arenes other than indoles could participate in such oxidative
cyclizations with unactivated olefins under similar catalysis.
[**] The authors wish to thank the NIH-NIGMS (R01 GM65961-01), the
NSF (predoctoral fellowship to E.M.F.), Johnson and Johnson,
Pfizer, Merck, Amgen, Research Corporation, Roche, GlaxoSmith-
Kline, and Eli Lilly for generous funding.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200461294
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Angewandte
Chemie
Table 2: Optimization studies for the intramolecular oxidative Heck
cyclization.[a]
Herein, we report a direct method for the synthesis of
benzofurans and dihydrobenzofurans by palladium-catalyzed
intramolecular Fujiwara–Moritani/oxidative Heck reac-
tions.[11,12]
In order to test the viability of applying the intramolecular
oxidative Heck cyclization to a nonindolic system, we
prepared allyl phenyl ether 1 by alkylation of the correspond-
ing phenol. Ether 1 was subjected to our optimized conditions
for the aforementioned indole cyclization in the presence of a
variety of stoichiometric oxidants (Table 1). We were grati-
fied to observe that in the presence of a range of oxidants,
ether 1 cyclized to give benzofuran 2 at 808C, presumably by
Entry
Ethyl nicotinate
[mol%]
NaOAc
[mol%]
T [8C]
t [h]
Yield [%][b]
1
2
3
4
5
6
7
8
40
20
10
0
20
20
20
20
–
–
–
80
80
80
80
80
80
100
120
24
24
24
24
24
24
12
12
62
66
59
55
70
74
ꢀ
palladium-catalyzed C C bond formation and b-hydride
–
elimination, followed by isomerization of the olefinic product
to the thermodynamically more stable benzofuran. As we
observed for indole cyclization, it was found that molecular
oxygen was a competent stoichiometric oxidant for the
cyclization 1!2. However, in the case at hand, benzoquinone
provided the highest yield of 2 (62% yield by GC) and thus
was used for further optimization.
100
20
20
20
80 (77)[c]
67
[a] All reactions were carried out with 0.10 mmol 1, 10 mol% Pd(OAc)2
(0.01 mmol), 0–40 mol% ethyl nicotinate (0–0.04 mmol), 0–0.10 mmol
NaOAc, and 0.10 mmol benzoquinone in 1.0 mL 4:1 tAmOH:AcOH
(0.1m in substrate). [b] Yield determined by gas chromatography.
[c] Yield of isolated product in parentheses.
Having found benzoquinone to be the optimal oxidant in
the cyclization 1!2, we examined the other parameters in the
process (Table 2).[13] It was found that a 1:2 ratio of Pd:ethyl
nicotinate was ideal (entries 1–4) and that inclusion of a
substoichiometric amount of NaOAc (20 mol%) provided
increased yields (entries 5 and 6). Finally, increasing the
temperature to 1008C led to optimal results, providing
benzofuran 2 in 77% yield after 12 h (entry 7).
Table 3: Oxidative benzofuran synthesis.[a]
Entry
Substrate
Product
t [h]
Yield [%][b]
1
2
3
R=Me
R=Et
R=n-C5H11
12
12
13
77
74
72
4
5
6
12
14
12
62
54
61
7
8
R=Me
R=Et
14
12
75
79
9
12
61
10
11
16
16
56[c]
52[c]
[a] All reactions were carried out with 0.50 mmol substrate, 10 mol% Pd(OAc)2 (0.05 mmol), 20 mol% ethyl nicotinate (0.10 mmol), 0.10 mmol
NaOAc, and 0.50 mmol benzoquinone in 5.0 mL 4:1 tAmOH:AcOH (0.1m in substrate) at 1008C. [b] Yield of isolated product. [c] Produced as a
single regioisomer.
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With a viable oxidative cyclization to produce benzofuran
proceeding by means of olefin activation, anti nucleophilic
attack of the arene on the Pd p complex, and syn b-hydride
elimination (Scheme 2, pathway A) can be differentiated
from one involving aryl-palladation, syn olefin insertion, and
syn b-hydride elimination (Scheme 2, pathway B). Under our
standard reaction conditions, ether 3 cyclized to produce a
diastereomerically pure product in 60% yield, which was
determined to be dihydrobenzofuran 5 by 1H NMR NOE
experiments.[15] The outcome of this mechanistic study
2 in hand, we set out to explore the generality of the
transformation. As shown in Table 3, the scope of the
oxidative benzofuran synthesis is quite broad, leading to
highly substituted products by selective ortho reactivity. The
methodology is currently limited to the use of electron-rich
arenes; however, the aryl subunit tolerates several alkoxy and
alkyl groups and substitution patterns. Likewise, the allylic
portion may be functionalized at both the proximal and distal
positions relative to the ether linkage with a variety of groups
(e.g. alkyl, aryl, functionalized alkyl).
ꢀ
suggests that pathway B is operative and that C H bond
functionalization precedes olefin insertion and b-hydride
We next investigated the feasibility of synthesizing elimination.[16] Additionally, this reaction demonstrates that
quaternary carbon-containing dihydrobenzofurans by
employing tri- and tetrasubstituted olefins in the process to
avoid olefin isomerization after the cyclization step. As shown
in Table 4, an array of highly functionalized dihydrobenzo-
furan derivatives can be synthesized in good yields with as
little as 5 mol% Pd(OAc)2 (Table 4, entry 2).[14]
In order to probe the mechanism of these carbocycliza-
tions, we prepared substrate 3 and subjected it to the oxidative
cyclization conditions (Scheme 2). Cyclization of this sub-
strate can distinguish between two mechanistically distinct
pathways (Scheme 2, A and B) by formation of diastereo-
meric products (i.e., either 4 or 5). Specifically, a mechanism
quaternary carbon stereocenters can be generated diastereo-
selectively, by chirality transfer, from a tertiary carbon center.
In summary, we have developed a method for intra-
II
ꢀ
molecular oxidative C C bond formation that relies on Pd
catalysis to access electron-rich, highly substituted benzo-
furan and dihydrobenzofuran derivatives. These oxidations
produce important heterocyclic ring systems[11] by direct C H
ꢀ
bond functionalization of the aromatic ring and cyclization
with unactivated olefins. Based on mechanistic insight (i.e. the
proposed intermediacy of an aryl PdII species), we have
illustrated the analogy of such oxidative carbocyclizations to
the corresponding intramolecular Heck reaction, and we thus
Table 4: Oxidative dihydrobenzofuran synthesis.[a]
Entry
Substrate
Product
t [h]
Yield [%][b]
1
R=H
R=Me
16
12
74
71
2[c]
3
30
58[d]
4
5
28
15
55
74[e]
6
7
n=1
n=0
24
18
80
78
8
9
R=H
R=Me
15
15
50
63
10
11
R=H
R=Me
15
15
60
66
[a] All reactions were carried out with 0.50 mmol substrate, 10 mol% Pd(OAc)2 (0.05 mmol), 20 mol% ethyl nicotinate (0.10 mmol), 0.10 mmol
NaOAc, and 0.50 mmol benzoquinone in 5.0 mL 4:1 tAmOH:AcOH (0.1m in substrate) at 1008C. [b] Yield of isolated product. [c] Performed with
5 mol% Pd(OAc)2 and 10 mol% ethyl nicotinate. [d] An inseparable mixture of roughly 66% product (E/Z=3:1) and 10% starting material was
isolated after 18 h. This mixture was subjected to another reaction with 5 mol% Pd(OAc)2, 10 mol% ethyl nicotinate, 20 mol% NaOAc, and 50 mol%
benzoquinone in 4:1 tAmOH:AcOH (0.1m) for 12 h after which only the E isomer was observed. The yield presented is the overall yield of isolated
product. [e] A 2.3:1 mixture of diastereomers was isolated with the major isomer shown.
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[2] a) I. Moritani, Y. Fujiwara, Tet-
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highly electron-rich arenes may be employed directly. In
certain cases, halogenated derivatives of such arenes may be
difficult to access selectively or may have undesirably low
reactivity toward Pd0 catalysts. While the method is currently
limited to the synthesis of five-membered ring ethers, the
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of complex molecules and the demonstration of its orthogon-
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scope; these remain primary goals of our laboratory.[17]
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[4] Recently, a number of catalytic intermolecular oxidative Heck
arylations have been reported. These protocols typically employ
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coupling partners and PdII catalysis. As in the typical Heck cases,
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[5] For
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Received: July 13, 2004
Keywords: benzofurans · homogeneous catalysis · oxidation ·
.
palladium
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ꢀ
[9] For recent reviews on Pd-catalyzed C H bond functionalization,
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[12] The Pd-mediated construction of benzofuran ring systems from
acyclic precusors has been an active area of research in recent
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[13] A screen of solvents and ligands was also conducted, but
provided no improvements. These parameters were investigated
extensively in our indole system.[8]
[14] Pd-promoted aryl Claisen rearrangements appear not to be
generally competitive, and no such products were isolated in any
of the reactions in Tables 3 and 4. Only one such case, involving
the reaction of a 1-allyloxynaphthalene derivative, has been
observed under our conditions.
[15] In addition to 5, a small amount of starting ether 3 was isolated.
No other isomeric products were observed in the reaction.
[16] A similar observation was made in our studies directed toward
the oxidative annulation of indoles.[8]
ꢀ
[17] We recently utilized an oxidative C C bond-forming reaction as
a key step for the total synthesis of the marine alkaloid
dragmacidin F, see: N. K. Garg, D. D. Caspi, B. M. Stoltz, J.
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