Direct assembly of 3,4-difunctionalized benzofurans and polycyclic benzofurans by phenol dearomatization and palladium-catalyzed domino reaction

Article abstract of DOI:10.1002/anie.201404155

A method to directly convert 2-alkynylphenols to 3,4-difunctionalized benzofurans and polycyclic benzofurans was developed. This protocol involves a hypervalent-iodine-mediated oxidative dearomatization to break the aromaticity of 2-alkynylphenols, and a

Full text of DOI:10.1002/anie.201404155

Angewandte
Chemie
DOI: 10.1002/anie.201404155
Synthetic Methods
Direct Assembly of 3,4-Difunctionalized Benzofurans and Polycyclic
Benzofurans by Phenol Dearomatization and Palladium-Catalyzed
Domino Reaction**
Zhaomeng Han, Liang Zhang, Zhiming Li,* and Renhua Fan*
Dedicated to Professor Li-Xin Dai on the occasion of his 90th birthday
Abstract: A method to directly convert 2-alkynylphenols to
3,4-difunctionalized benzofurans and polycyclic benzofurans
was developed. This protocol involves a hypervalent-iodine-
mediated oxidative dearomatization to break the aromaticity of
2-alkynylphenols, and a palladium-catalyzed domino reaction
to install two functional groups at the C3 and the C4 positions
and restore the aromaticity of benzofurans.
Scheme 1. Preparation of 3,4-difunctionalized benzofurans from
2-alkynylphenols.
the C3 and the C4 positions, and an aromatization to restore
the aromaticity.
T
he dearomatization of aromatic compounds provides
numerous possibilities for the construction of complex
molecules.[1] The main advantage of the dearomatization is
the possibility of converting an aromatic ring into a three-
dimensional molecule. Moreover, since dearomatization
offers unique strategic opportunities to circumvent the
inherent ortho/para selectivity of electron-rich aromatic
systems, the dearomatization strategy can also be used in
the synthesis of multi-functionalized aromatic compounds
that are difficult to prepare by electrophilic substitution
reactions.
(Diacetoxyiodo)benzene facilitated oxidative dearomati-
zation of 4-methyl-2-(2-phenylethynyl)phenol 1 in methanol.
The deleterious cyclization or oxidation of the sensitive
alkynyl group was not observed. The crude dearomatization
product was directly used to test the palladium-catalyzed
domino reaction with p-toluidine and ethyl acrylate. When
0.1 equivalents of PdCl2 were used together with 0.2 equiv-
alents of Ph3P, 4-amino-substituted 3-alkenylbenzofuran 2
was obtained in 7% yield. Its structure was confirmed by
single-crystal diffraction analysis.[13] A screening of solvents,
temperatures, and bases did not improve the yield beyond
10%, thus indicating that the reaction with palladium was
stoichiometric. Therefore, various oxidants were added to
promote the regeneration of catalytic PdII from Pd0 formed in
the Heck coupling. While the addition of 2 equivalents of
benzoquinone (BQ) improved the yield to 31% [Eq. (1)],
Among the family of benzofurans, 3,4-difunctionalized
benzofurans are attractive synthetic targets because of their
remarkable biological activities.[2] The synthetic challenge is
the selective functionalization of the C4 position of benzofur-
ans, which is not a preferred site for electrophilic substitution
reactions. 2-Alkynylphenols are the most commonly used
precursors to prepare benzofurans. A number of cyclization
or cascade cyclization/cross-coupling reactions of 2-alkynyl-
phenols have been developed.[3–12] However, these elegant
methods only enable the synthesis of benzofurans with
diverse substitutions on the five-membered ring. Herein, we
report a method that directly converts 2-alkynylphenols to
3,4-difunctionalized benzofurans (Scheme 1). This protocol
involves an oxidative dearomatization to break the aroma-
ticity of 2-alkynylphenols, a palladium-catalyzed domino
reaction to simultaneously install two functional groups at
compound 2 was not formed when Cu(OAc)2, CuCl2, AgOAc,
meta-chloroperbenzoic acid (m-CPBA), or PhI(OAc)2 were
added. The product formation was further optimized by
examining a variety of palladium salts and phosphine ligands.
When PdBr2 was used together with trifuran-2-ylphosphine,
the yield of compound 2 increased to 76%.[14]
[*] Z. Han, L. Zhang, Prof. Dr. Z. Li, Prof. Dr. R. Fan
Department of Chemistry, Fudan University
220 Handan Road, Shanghai, 200433 (China)
E-mail: zmli@fudan.edu.cn
After establishing the optimized reaction conditions, the
scope of this transformation was investigated (Table 1). For
rhfan@fudan.edu.cn
[**] We are grateful to the National Science Foundation of China
(21332009, 21102019), and the Shanghai Science and Technology
Committee (13431900103) for support of this research.
a
range of 2-alkynylphenols, the reactions proceeded
smoothly, leading to the corresponding 3,4-difunctionalized
benzofurans in moderate to good yields. In some cases, TsOH
was added to promote the aromatization, and PdCl2 was used
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404155.
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Table 1: Dearomatization and palladium-catalyzed domino reaction.
as nucleophile, the incorporation of the OCD3 group into
compound 29 was not observed. This result indicated that
compound 29 might be formed through a [1,2] transfer of the
methoxy group.
To understand the formation of product 2, 4-amino-
substituted benzofuran 28 was treated with ethyl acrylate
under the standard conditions. The formation of compound 2
was not observed. Meanwhile, the isolated non-aromatized
product 30 was completely converted to compound 2 when it
was treated with PdBr2 in ClCH2CH2Cl at reflux.
To gain more insight into the reaction, B3LYP density
functional theory (DFT) calculations were performed with
the Gaussian09 software package.[15] We initially evaluated
the role of the palladium catalyst. Palladium(II) might work
as a Lewis acid to coordinate with the carbonyl group of the
dearomatization product by a monodentate coordination
mode or with the carbonyl group and the triple bond by
a bidentate mode. Palladium(II) might also work as a p acid
to coordinate with the triple bond by a monodentate mode.
This activation might induce a cyclization to generate a furan-
like intermediate (see Scheme S1 in the Supporting Informa-
tion).[16] The computational results indicated that the furan-
like intermediate A is the most stable intermediate (Figure 1).
Entry
Product
Yield[a]
1
2: R1 =Ph
76
61
74
65
76
60
71
2[b]
3
3: R1 =4-MeC6H4
4: R1 =4-ClC6H4
5: R1 =nBu
4[c]
5
6: R1 =tBu
6
7: R1 =cyclopropyl
8: R1 =TMS
7[b,c]
8[b,c]
9
10
9: R2 =nBu
10: R2 =Ph
11: R2 =OMe
55
0
65
11[b]
12: R3 =Me
78
12
13
14
13: R4 =CN
63
62
0
14: R4 =CON(Me)2
15: R4 =Ph
15[b]
16[b,c]
17
16: R5 =Ph
61
72
72
82
42
61
65
71
60
0
17: R5 =4-iPrC6H4
18: R5 =4-nBuC6H4
19: R5 =4-MeOC6H4
20: R5 =3-MeOC6H4
21: R5 =4-FC6H4
22: R5 =4-ClC6H4
23: R5 =4-BrC6H4
24: R5 =2-IC6H4
25: R5 =Bn
18
19[b,c]
20
21[b,c]
22[b,c]
23[b,c]
24
25
26: R5 =nBu
0
Figure 1. Optimized structures of intermediate A. The numbers in
parenthesis are the NBO charges on atoms and the numbers in
square brackets are the condensed Fukui functions.
26
27: R6 =Me
64
[a] Reported yields are of the isolated products. [b] 4-Methylbenzene-
sulfonic acid (4 equiv) was added after 12 h. [c] PdCl2 was used instead
of PdBr2. Bn=benzyl, TMS=trimethylsilyl.
It is more than 5 kcalmolÀ1 more stable than other inter-
mediates. Therefore, palladium(II) acts as a p acid in the
initial step. Moreover, although there are two possible
reaction sites (C3 and C5) for the nucleophilic attack in the
structure of intermediate A, the natural bond orbital (NBO)
analysis showed that the C3 position is more positively
charged (À0.02) compared to the C5 position(À0.11). The
condensed Fukui function also predicted that the nucleophilic
attack will occur at the C3 position. These results are in line
with our experimental results.
We identified two possible reaction pathways from
intermediate A to the non-aromatized product to understand
the domino sequence. For clarity, only main stationary points
are shown in Figure 2, and the relative free energies are based
on the total free energy of intermediate A, p-toluidine, and
methyl acrylate. In one pathway (in black), intermediate A is
trapped by the electron-poor double bond of acrylate through
instead of PdBr2 to improve product yields. Electron-deficient
alkenes, such as acrylonitrile and N,N-dimethylacrylamide,
were also suitable reaction partners. When styrene was used,
the reaction only afforded 4-amino-substituted benzofuran
28. Various aromatic amines, including a secondary amine,
could be used as nucleophile to be introduced at the C4
position of benzofuran. When benzylamine or butan-1-amine
was used, no desired product was obtained, but a 4-methoxy-
substituted 3-alkenylbenzofuran 29 was isolated. This com-
pound was also the major product when diethyl malonate,
phenol, or thiophenol were used as nucleophile. Interestingly,
compound 29 was formed in a 63% yield in the absence of an
added nucleophile. When 1 equivalent of CD3OD was added
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three roles in the domino reaction: 1) as
a p acid to activate the triple bond of
2-alkynyl cyclohexadienones to induce the
cyclization, 2) as an organopalladium
intermediate to react with alkenes through
carbopalladation and b-H elimination, and
3) as a Lewis acid to promote the aroma-
tization.
When the electron-deficient alkene
was linked to the alkynyl group of the
substrate, this strategy could be used to
construct polycyclic benzofurans. For
example, under the standard conditions,
compound 31 was converted to tetracyclic
benzofuran 32 in a 62% yield [Eq. (2)]. An
intramolecular conjugated addition took
place instead of the Heck coupling, when
the acrylate moiety was changed to a vinyl
ketone or a 2-methylenemalonate moiety
(Scheme 3). It was supposed that a PdII
O-bound enolate might be formed after
Figure 2. Free-energy reaction profile (kcalmolÀ1) from intermediate A to the non-aromatized
product, calculated at the PCM(DCE) B3LYP/6-31G(d,p) with LANL2DZ (for Pd and Br)
level. TS=transition state.
syn insertion, thus affording intermediate D. Intermolecular
nucleophilic attack of the nitrogen of toluidine on the C3
position forms intermediate E. Subsequent syn b-H elimina-
tion gives rise to the non-aromatized product and releases
H2CO3 and HPdBr. In the alternative pathway (in red),
intermolecular nucleophilic attack occurs before the inser-
tion, thus leading to intermediate J. After releasing H2CO3,
intermediate K reacts with acrylate through insertion, fol-
lowed by b-H elimination to afford the non-aromatized
product and generate HPdBr. The potential energy surfaces
indicate that the rate-determining step for the first pathway is
the b-H elimination step (TSEF). For the second pathway, the
nucleophilic attack of p-toluidine is the rate-determining step
(TSAJ). The overall barrier for the first pathway is 39.3 kcal
molÀ1, while it is only 7.9 kcalmolÀ1 for the second one. This
means that the domino reaction favors the second pathway to
a large extent. On the basis of these results, a plausible
mechanism is depicted in Scheme 2. Palladium might play
the intramolecular insertion of organopalladium to the
double bond of vinyl ketone or 2-methylenemalonate. The
protonolysis of this intermediate might be more favorable
than the b-hydride elimination to give a conjugate addition
product.[17] In these palladium(II)-catalyzed reactions, the
addition of benzoquinone was not required. For most cases,
polycyclic benzofurans were produced in moderate to good
yields. The linkage between the alkynyl and the alkenyl group
could be a benzene ring or an alkyl chain. The reaction of
aromatic amines was found to tolerate a range of substituents
with different electronic demands on the aromatic rings,
involving electron-withdrawing and electron-donating
groups. When an unprotected aminophenol was employed,
Scheme 2. Plausible mechanism.
Scheme 3. Construction of polycyclic benzofuran derivatives.
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Angew. Chem. 2012, 124, 12834 – 12858; Angew. Chem. Int. Ed.
2012, 51, 12662 – 12686; h) Q. Ding, Y. Ye, R. Fan, Synthesis
2013, 1 – 13.
the reaction only afforded the N-arylated product. The
electron-rich indoles could serve as suitable reaction partners
in this process. With respect to other electron-rich aromatic
compounds, such as N,N-dimethylaniline, 1,2-dimethoxyben-
zene, and thiophene, the reactions were complex and the
desired products were not obtained.
With the aid of trifluoromethanesulfonic acid, compound
2 could be converted to compound 51 through an intra-
molecular Friedel–Crafts alkylation in a 94% yield [Eq. (3)].
Compound 51 has a dibenz[b,f]azepine core, which exists in
[2] a) W. Friedrichsen in Comprehensive Heterocyclic Chemistry II,
Vol. 2 (Eds.: C. W. Bird, A. R. Katritzky, C. W. Rees, E. F. V.
Scriven), Pergamon, London, 1996, pp. 368 – 378; b) Compre-
hensive Heterocyclic Chemistry II, Vol. 2 (Eds.: A. R. Katritzky,
C. W. Rees, E. F. V. Scriven), Pergamon, Oxford, UK, 1996,
pp. 259 – 321; c) X. L. Hou, Z. Yang, K. S. Yeung, H. N. C. Wong
in Progress in Heterocyclic Chemistry, Vol. 19 (Eds.: G. W.
Gribble, J. A. Joule), Elsevier, Oxford, 2008, pp. 176 – 207, and
previous volumes in the series.
[3] For recent reviews on the synthesis of benzofurans, see: a) S.
Cacchi, G. Fabrizi, A. Goggiomani, Heterocycles 2002, 56, 613 –
632; b) Y. Liao, Y. Hu, J. Wu, Q. Zhu, M. Donovan, R. Fathi, Z.
Yang, Curr. Med. Chem. 2003, 10, 2285 – 2316; c) G. Zeni, R. C.
Larock, Chem. Rev. 2004, 104, 2285 – 2309; d) I. Nakamura, Y.
Yamamoto, Chem. Rev. 2004, 104, 2127 – 2198; e) F. Alonso, I. P.
Beletskaya, M. Yus, Chem. Rev. 2004, 104, 3079 – 3160.
[4] For carbonylative annulation of 2-alkynylphenols, see: a) Y.
Nan, H. Miao, Z. Yang, Org. Lett. 2000, 2, 297 – 299; b) Y. Hu, Y.
Zhang, Org. Lett. 2001, 3, 1387 – 1390; c) Y. Hu, Y. Zhang, Z.
Yang, R. Fathi, J. Org. Chem. 2002, 67, 2365 – 2368; d) Y. Liao, J.
Smith, R. Fathi, Z. Yang, Org. Lett. 2005, 7, 2707 – 2709.
[5] For the synthesis of 2,3-functionalized benzofunans through 3-
zinciobenzofuran intermediates, see: a) M. Nakamura, L. Ilies, S.
Otsubo, E. Nakamura, Angew. Chem. 2006, 118, 958 – 961;
Angew. Chem. Int. Ed. 2006, 45, 944 – 947; b) M. Nakamura, L.
Ilies, S. Otsubo, E. Nakamura, Org. Lett. 2006, 8, 2803 – 2805;
c) H. Tsuji, C. Mitsui, L. Ilies, Y. Sato, E. Nakamura, J. Am.
Chem. Soc. 2007, 129, 11902 – 11903.
many natural products and medicinal compounds, such as
carbazepine and trileptal.[18]
In conclusion, we have developed a method to convert
2-alkynylphenols into 3,4-difunctionalized benzofurans and
polycyclic benzofurans. This protocol involves a hypervalent-
iodine-mediated oxidative dearomatization and a palladium-
catalyzed domino reaction. The application of this strategy to
the synthesis of natural products and investigations on a more
detailed mechanism are currently underway in our laboratory.
[6] For tandem cyclization/Heck coupling reactions, see: a) N.
Isono, M. Lautens, Org. Lett. 2009, 11, 1329 – 1331; b) C.
Martínez, R. lvarez, J. M. Aurrecoechea, Org. Lett. 2009, 11,
1083 – 1086; c) R. lvarez, C. Martínez, Y. Madich, J. G. Denis,
J. M. Aurrecoechea, . R. de Lera, Chem. Eur. J. 2010, 16,
12746 – 12753; d) C. Martínez, J. M. Aurrecoechea, Y. Madich,
J. G. Denis, A. R. de Lera, R. lvarez, Eur. J. Org. Chem. 2012,
99 – 106.
[7] For annulative electrophilic amination, see: a) N. Matsuda, K.
Hirano, T. Satoh, M. Miura, J. Org. Chem. 2012, 77, 617 – 625;
b) K. Hirano, T. Satoh, M. Miura, Org. Lett. 2011, 13, 2395 –
2397.
[8] For palladium-catalyzed cyclization and coupling with triflates
or halides, see: a) A. Arcadi, S. Cacchi, M. D. Rosario, G.
Fabrizi, F. Marinelli, J. Org. Chem. 1996, 61, 9280 – 9288; b) Y.
Hu, K. J. Nawoschik, Y. Liao, J. Ma, R. Fathi, Z. Yang, J. Org.
Chem. 2004, 69, 2235 – 2239.
Experimental Section
Representative procedure: PhI(OAc)2 (0.22 mmol) was added to
a solution of 4-methyl-2-(2-phenylethynyl)phenol 1 (0.2 mmol) in
MeOH (2.0 mL) at 258C. After 5 min, the reaction mixture was
concentrated in vacuo. The resulting crude product was mixed with
ethyl acrylate (0.4 mmol), p-toluidine (0.3 mmol), PdCl2 (0.02 mmol),
trifuran-2-ylphosphine (0.04 mmol), benzoquinone (0.4 mmol), and
K2CO3 (0.4 mmol) in ClCH2CH2Cl (2 mL). The reaction was stirred
under reflux. After the substrate was completely consumed (moni-
tored by TLC analysis), the reaction mixture was passed through
a short column of silica gel and then concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel (eluent: petroleum ether/ethyl acetate) to furnish the
desired compound 2.
[9] For palladium-catalyzed electrophilic annulation, see: a) Y.
Liang, S. Tang, X.-D. Zhang, L.-Q. Mao, Y.-X. Xie, J.-H. Li,
Org. Lett. 2006, 8, 3017 – 3020; b) H.-A. Du, X.-G. Zhang, R.-Y.
Tang, J.-H. Li, J. Org. Chem. 2009, 74, 7844 – 7848.
[10] For tandem cyclization/dehydrogenative coupling reactions, see:
H. Hachiya, K. Hirano, T. Satoh, M. Miura, Org. Lett. 2011, 13,
3076 – 3079.
[11] For carboalkoxylation of 1-alkynylphenyl ethers, see: a) A.
Arcadi, S. Cacchi, S. D. Giuseppe, G. Fabrizi, F. Marinelli, Org.
Lett. 2002, 4, 2409 – 2412; b) I. Nakamura, Y. Mizushima, Y.
Yamamoto, J. Am. Chem. Soc. 2005, 127, 15022 – 15023; c) A.
Fꢀrstner, P. W. Davies, J. Am. Chem. Soc. 2005, 127, 15024 –
15025; d) Z. Liang, S. Ma, J. Yu, R. Xu, J. Org. Chem. 2007, 72,
9219 – 9224; e) A. Fꢀrstner, E. K. Heilmann, P. W. Davies,
Angew. Chem. 2007, 119, 4844 – 4847; Angew. Chem. Int. Ed.
2007, 46, 4760 – 4763.
Received: April 9, 2014
Published online: && &&, &&&&
Keywords: benzofurans · dearomatization · domino reactions ·
.
multicomponent reactions · phenols
[1] For recent reviews on dearomatization, see: a) A. R. Pape, K. P.
Kaliappan, E. P. Kꢀndig, Chem. Rev. 2000, 100, 2917 – 2940;
b) D. Magdziak, S. J. Meek, T. R. R. Pettus, Chem. Rev. 2004,
104, 1383 – 1429; c) F. Lꢁpez Ortiz, M. J. Iglesias, I. Fernꢂndez,
C. M. Andffljar Sꢂnchez, G. R. Gꢁmez, Chem. Rev. 2007, 107,
1580 – 1691; d) S. Quideau, L. PouysØgu, D. Deffieux, Synlett
2008, 467 – 495; e) L. PouysØgu, D. Deffieux, S. Quideau,
Tetrahedron 2010, 66, 2235 – 2261; f) S. P. Roche, J. A. Porco, Jr.,
Angew. Chem. 2011, 123, 4154 – 4179; Angew. Chem. Int. Ed.
2011, 50, 4068 – 4093; g) C.-X. Zhuo, W. Zhang, S.-L. You,
[12] For the cyclization with allyl carbonate, see: S. Cacchi, G.
Fabrizi, L. Moro, Synlett 1998, 741 – 745.
4
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[13] CCDC 915522 (2) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[14] For the evaluation of conditions and catalysts, see Table S1 in the
Supporting Information.
[15] For computational details and references, see the Supporting
Information.
[16] a) T. Yao, X. Zhang, R. C. Larock, J. Am. Chem. Soc. 2004, 126,
11164 – 11165; b) T. Yao, X. Zhang, R. C. Larock, J. Org. Chem.
2005, 70, 7679 – 7685; c) Y. Xiao, J. Zhang, Angew. Chem. 2008,
120, 1929 – 1932; Angew. Chem. Int. Ed. 2008, 47, 1903 – 1906.
[17] For competition between conjugate addition and Heck-coupling
reaction, see: a) S. Cacchi, A. Arcadi, J. Org. Chem. 1983, 48,
4236 – 4240; b) T. Nishikata, Y. Yamamoto, N. Miyaura, Angew.
Chem. 2003, 115, 2874 – 2876; Angew. Chem. Int. Ed. 2003, 42,
2768 – 2770; c) A. L. Gottumukkala, J. G. de Vries, A. J. Min-
naard, Chem. Eur. J. 2011, 17, 3091 – 3095; d) Q. Peng, H. Yan, X.
Zhang, Y.-D. Wu, J. Org. Chem. 2012, 77, 7487 – 7496.
[18] a) R. G. Lande, Int. J. Psychiatry Clin. Pract. 2004, 8, 37 – 40;
b) N. Della Cꢂ, G. Maestri, M. Malacria, E. Derat, M. Catellani,
Angew. Chem. 2011, 123, 12465 – 12469; Angew. Chem. Int. Ed.
2011, 50, 12257 – 12261.
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Communications
Synthetic Methods
Z. Han, L. Zhang, Z. Li,*
R. Fan*
&&&& — &&&&
Direct Assembly of 3,4-Difunctionalized
Benzofurans and Polycyclic Benzofurans
by Phenol Dearomatization and
Destruction and reconstruction: The
combination of a hypervalent-iodine-
mediated oxidative dearomatization and
palladium-catalyzed domino reaction
provides a practical approach to 3,4-
difunctionalized benzofurans and poly-
cyclic benzofurans from 2-alkynylphenols.
Palladium-Catalyzed Domino Reaction
6
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