Phosphine-Catalyzed Domino β/γ-Additions of Benzofuranones with Allenoates: A Method for Unsymmetrical 3,3-Disubstituted Benzofuranones

Article abstract of DOI:10.1021/acs.orglett.7b01482

A phosphine-catalyzed domino process of benzofuranones with allenoates has been developed which furnishes highly functionalized unsymmetrical 3,3-disubstituted benzofuranones in synthetically useful yields. The mechanism for the transformation is a tandem β-umpolung/γ-umpolung process.

Full text of DOI:10.1021/acs.orglett.7b01482

Letter
pubs.acs.org/OrgLett
Phosphine-Catalyzed Domino β/γ-Additions of Benzofuranones with
Allenoates: A Method for Unsymmetrical 3,3-Disubstituted
Benzofuranones
Zhusheng Huang, Xiuqin Yang, Fulai Yang, Tao Lu, and Qingfa Zhou*
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China Pharmaceutical University, Nanjing 210009, P.
R. China
S
* Supporting Information
ABSTRACT: A phosphine-catalyzed domino process of
benzofuranones with allenoates has been developed which
furnishes highly functionalized unsymmetrical 3,3-disubstituted
benzofuranones in synthetically useful yields. The mechanism
for the transformation is a tandem β-umpolung/γ-umpolung
process.
3,3-Disubstituted benzofuranone is an important structural
motif found in many natural products, pharmaceuticals, and
biologically active compounds (Figure 1).1 It is also an
operational ease, and low cost.7 In this context, nucleophilic
phosphine-catalyzed γ-addition reactions have been extensively
investigated and were independently reported by the groups of
Trost and Lu in the 1990s.8 Then Kwon and co-workers and
Shi and co-workers simultaneously reported the phosphine-
catalyzed β-umpolung additions of ethyl 2-alkyl-2,3-butadie-
noate.9 Very recently, the Huang group and the Lu group
independently reported β-umpolung additions of hydrazones or
arylcyanoacetates to allenoates, which are very scarce examples
of phosphine-promoted β-umpolung additions.10 However, to
the best of our knowledge, the phosphine-mediated domino β-
and γ-addition reaction of allenoates has not been reported
until now. Herein, we describe the first phosphine-catalyzed
domino β- and γ-addition reaction of benzofuranones to
allenoates for the construction of highly functionalized
unsymmetrical 3,3-disubstituted benzofuranones.
At the outset of our study, we first chose 1a and 2a as the
standard substrates to search for suitable reaction conditions for
the synthesis 3a, and the results are shown in Table 1. The
reaction of 1a with 2a in the presence of PPh3 (5 mol %) in
CH2Cl2 at room temperature for 48 h afforded 3a as a white
solid in 65% yield (entry 1, Table 1), and the structure and
stereochemistry of compound 3 were characterized by a
combination of NMR spectroscopy, high-resolution mass
spectrometry (HRMS), and single-crystal X-ray diffraction.11
Increasing the PPh3 loading to 20 mol % gave a better result
(entry 3). However, the yield decreased obviously when more
catalyst loading was used, such as 50 or 100 mol % (entries 4
and 5). Subsequently, PPh2Et with relatively stronger
nucleophilicity was tested in the reaction, and it afforded the
product 3a in lower yield, but no product was obtained when
the stonger nucleophilic PPhEt2 or PBu3 was used as catalyst in
place of PPh3. Other nucleophilic bases, such as DBU, Et3N,
and DABCO, were also tested, and no product was formed.
Figure 1. Natural products containing benzofuranone rings.
important synthon that can undergo synthetically useful
transformations to other valuable heterocycles, such as aplysin,
isoaplysin, sesquiterpene, and isolaurinterol.2 Owing to its great
importance, there are a lot of methods developed for the
synthesis of diverse 3,3-disubstituted benzofuranones. These
methods mainly involved the condensation of 2-(2-
hydroxyphenyl)acetic acid derivatives;3 the cascade reaction
of α-hydroxy acid esters and phenols;4 transition-metal-
catalyzed inter- or intramolecular heteroannulation of pre-
functionalized substrates;5 and modification of the precon-
structed heterocyclic rings.6 Despite significant advances in the
synthesis of 3,3-disubstituted benzofuranones, synthesis of
unsymmetrical 3,3-disubstituted benzofuranone motifs from
readily accessible benzofuranones still remains a daunting
challenge. Notably, most of the above-mentioned methods
require tedious prefunctionalization steps or have limited
substrate scope, which severely restricts application in organic
and pharmaceutical synthesis. Therefore, developing a method
to build functionalized unsymmetrical 3,3-disubstituted benzo-
furanones in one step from readily available starting materials
with broad substrate scope would be highly appealing.
Recently, nucleophilic phosphine catalysis has become a
powerful tool in organic synthesis because of its high versatility,
Received: May 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Survey on Conditions for Formation of 3a
Scheme 1. Synthesis of Unsymmetrical 3,3-Disubstitued
a c
−
Benzofuranones
b
entry
base
PPh3
equiv
solvent
time (h)
yield (%)
1
0.05
0.10
0.20
0.50
1.00
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DMF
48
24
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
65
2
PPh3
PPh3
PPh3
PPh3
PPh2Et
PPhEt2
PBu3
DBU
Et3N
DABCO
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
72
3
95
4
79
5
74
6
40
7
NR
NR
trace
trace
trace
trace
97
8
9
10
11
12
13
14
15
16
17
toluene
MeCN
DMSO
THF
13
trace
61
Et2O
14
c
18
toluene
toluene
toluene
toluene
71
d
19
51
e
20
43
f
21
88
a
Typical conditions: base reagent was added to a stirred solution of 1a
(0.2 mmol) and 2a (0.44 mmol) in solvent (2.0 mL) under Ar
a
b
Typical conditions: PPh3 (0.04 mol, 10.5 mg) was added to a stirred
atmosphere and at room temperature. Isolated yield based on 1a.
c
d
solution of 1 (0.2 mmol) and 2 (0.44 mmol) in solvent (2.0 mL)
under Ar atmosphere and at room temperature. Isolated yield based
on 1. Based on the H NMR assay of the crude product.
The reaction was performed at 0 °C. The reaction was performed at
b
e
f
reflux. Using 0.2 mmol of 2a. Using 0.4 mmol of 2a.
c
1
Solvents were subsequently screened. Toluene was proved to
be the best solvent for the reaction. The temperature has a
great effect on the reaction. For example, both lowering the
reaction temperature to 0 °C and raising the temperature to
reflux led to a lower yield in toluene. Thus, we established the
optimal reaction conditions: 20 mol % of PPh3 as the catalyst in
toluene as the solvent at room temperature for the synthesis of
compound 3.
benzofuranones had no obvious effect on the yields. For
example, for substrates with a I or NO2 group attached on the
benzene ring, the corresponding products were obtained in
yields of 79% and 81%, respectively. A carbon−carbon double-
bond migration isomer was also observed when 5-iodobenzo-
furan-2(3H)-one was used as reactant. It is highlighted here
that a free OH group attached on the benzene ring also gave
the corresponding product 3j in a yield of 94% under our
reaction conditions. In addition, 5,7-dibromo- or 5,7-diiodo-
substituted benzofuranones also participated in the reaction and
gave the corresponding 3n and 3o in yields of 69% and 76%,
respectively. We also tested the feasibility of this reaction using
benzofuran-3(2H)-one. Treatment of benzofuran-3(2H)-one 4
with 2a under the present reaction conditions furnished double
γ-addition product 5 in 58% yield (Scheme 2).
Following the above optimized conditions, a range of
allenoates were first investigated to couple with benzofuranone
1a, and the results are outlined in Scheme 1.
The allenoates bearing various straight-chain alkyl units,
namely ethyl, methyl, normal-propyl and normal-butyl, gave the
products in good yields. The variation of ester group to
phenethyl and benzyl was well tolerated in the reactions and
gave the corresponding products in good yields. The nature of
the substituent on the benzene ring of the benzyl allenoate had
slight impact on the yields. For example, 4-methylbenzyl buta-
2,3-dienoate and 4-chlorobenzyl buta-2,3-dienoate gave the
products 3h and 3i in yields of 75% and 72%, respectively, and
they both afforded carbon−carbon double-bond migration
isomers 3h′ and 3i′. However, only a trace product was formed
when a bulk ester group in 1, such as tert-butyl, was introduced.
Examining substituted benzofuranones, we found that all tested
substituted benzofuranones were found to be applicable to this
reaction to give products 3 in good to excellent yields under the
optimized reaction conditions. The nature of the substituent on
The products of the domino process possess an all-carbon
quaternary center at the 3-position with a latent allyl group and
a vinyl group; these structures are not only interesting from a
biological point of view but also synthetically valuable. To
Scheme 2. Reaction of Benzofuran-3(2H)-one 4 with 2a
B
DOI: 10.1021/acs.orglett.7b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
demonstrate the synthetic potential of this catalytic system, the
gram-scale preparation of highly functionalized 3a was
investigated. The reaction of 10 mmol (1.34 g) of the starting
material (1a) proceeded smoothly, delivering the correspond-
ing product 3a (3.76 g) in a yield of 78% (Scheme 3), showing
BINAP was used in place of PPh3. The β-addition product 12
was treated with allenoate 2a, and the product 3a was formed
effectively. In addition, we found that the structure of lactones
is vital for the present process. For example, no reaction was
found when ethyl 2-phenylacetate 13 or ethyl 2-(4-
nitrophenyl)acetate 14 was used in place of benzofuran-
2(3H)-one compound 3a, while the O-β-addition product 16
was the sole product when the ethyl 2-(2-hydroxyphenyl)-
acetate 15 was used as the reaction partner.
Scheme 3. Gram-Scale and Synthetic Transformations
On the basis of our results and the previous studies, we
proposed a reasonable mechanism for these domino processes
(Scheme 5). In the presence of tertiary phosphine, the β-
Scheme 5. Proposed Mechanism for the Formation of 3
the reaction to be a practical tool for the synthesis of highly
functionalized unsymmetrical 3,3-disubstituted benzofuranones.
Treatment of product 3a with Et3N led to smooth carbon−
carbon double migrations and furnished a 3,3-vinyl-disubsti-
tuted benzofuranone 6. However, 3c was treated with Pd/C
under an atmosphere of H2 in MeOH at room temperature,
leading to a vinyl- and alkyl-substituted benzofuranone 7 in
95% yield. Interestingly, benzofuranone derivatives 8a and 8b
were obtained by treatment of 3a or 3c in toluene under reflux,
which could be formed by a Cope rearrangement. To our
surprise, a novel compound 9 was formed when 3a was
disposed with NaBH4 in MeOH.
To understand these domino processes, 3-phenylbenzofuran-
2(3H)-one 10 was synthesized and treated with allenoate 1a
under the above conditions (Scheme 4). The γ-addition
product 11 was formed, and no β-addition product was
found. This implied that the β-addition process may proceed
first, followed by the γ-addition process. Catching the β-
addition product is the key to understand the present process.
We found that only the β-addition product 12 was given when
phosphonium dienolate intermediate, formed though conjugate
addition of the phosphine to the allenoate, proceeds
subsequent transformation to give β-addition product first.10a
The β-addition product then reacts with another β-
phosphonium dienolate intermediate and proceeds through a
subsequent transformation to lead to the formation of γ-
addition product 3.8a
In conclusion, the first phosphine-catalyzed β/γ domino
process of allenoates with benzofuranones has been developed,
which shows an extra example on current phosphine chemistry
and a useful method for constructing functionalized unsym-
metrical 3,3-disubstituted benzofuranones. The potential utility
of this domino process indicates that the synthesized
unsymmetrical 3,3-disubstituted benzofuranones could be
transformed into other interesting heterocycles and performed
on a gram scale.
Scheme 4. Control Experiments
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01482.
Detailed experimental procedures, characterization data,
and 1H and 13C NMR spectra of key substrates and final
products (PDF)
X-ray data of 3a (CIF)
C
DOI: 10.1021/acs.orglett.7b01482
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 1987, 52, 5425. (h) Vedejs, E.; Wang, J. Org. Lett. 2000, 2,
1031. (i) Peris, G.; Vedejs, E. J. Org. Chem. 2008, 73, 1158. (j) Li, X.;
Xi, Z.; Luo, S.; Cheng, J.-P. Adv. Synth. Catal. 2010, 352, 1097.
(k) Wang, D.; Yang, Y.-L.; Jiang, J.-J.; Shi, M. Org. Biomol. Chem. 2012,
10, 7158. (l) Li, D.; Wang, L.; Yang, D.; Zhang, B.; Wang, R. ACS
Catal. 2015, 5, 7432. (m) Yang, C.; Zhang, E.-G.; Li, X.; Cheng, J.-P.
Angew. Chem. 2016, 128, 6616.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhouqingfa@cpu.edu.cn.
Notes
The authors declare no competing financial interest.
(7) (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(b) Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003, 2003, 317.
(c) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035.
(d) Lu, X.; Du, Y.; Lu, C. Pure Appl. Chem. 2005, 77, 1985. (e) Nair,
V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem.
Res. 2006, 39, 520. (f) Denmark, S. E.; Beutner, G. L. Angew. Chem.,
Int. Ed. 2008, 47, 1560. (g) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc.
Rev. 2008, 37, 1140. (h) Kwong, C. K.-W.; Fu, M. Y.; Lam, C. S.-L.;
Toy, P. H. Synthesis 2008, 2008, 2307. (i) Aroyan, C. E.; Dermenci, A.;
Miller, S. J. Tetrahedron 2009, 65, 4069. (j) Cowen, B. J.; Miller, S. J.
Chem. Soc. Rev. 2009, 38, 3102. (k) Marinetti, A.; Voituriez, A. Synlett
2010, 2010, 174. (l) Kolesinska, B. Cent. Eur. J. Chem. 2010, 8, 1147.
(m) Wang, Z.; Xu, X.; Kwon, O. Chem. Soc. Rev. 2014, 43, 2927.
(n) Xu, S.; He, Z. RSC Adv. 2013, 3, 16885. (o) Li, E.; Chang, M.;
Liang, L.; Huang, Y. Eur. J. Org. Chem. 2015, 2015, 710. (p) Chang,
M.; Wu, C.; Zheng, J.; Huang, Y. Chem. - Asian J. 2016, 11, 1512.
(q) Zhou, Q. F.; Chu, X. P.; Ge, F. F.; Wang, Y.; Lu, T. Adv. Synth.
Catal. 2013, 355, 2787. (r) Chen, Q.; Li, K.; Lu, T.; Zhou, Q. RSC
Adv. 2016, 6, 24792. (s) Huang, Z.; Chen, Q.; Yang, X.; Liu, Y.; Zhang,
L.; Lu, T.; Zhou, Q. Org. Chem. Front. 2017, 4, 967.
(8) (a) Trost, B. M.; Li, C. J. Am. Chem. Soc. 1994, 116, 3167.
(b) Trost, B. M.; Li, C. J. Am. Chem. Soc. 1994, 116, 10819. (c) Trost,
B. M.; Dake, G. R. J. Org. Chem. 1997, 62, 5670. (d) Zhang, C.; Lu, X.
Synlett 1995, 1995, 645. (e) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.;
Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631. (f) Chung, Y. K.; Fu,
G. C. Angew. Chem., Int. Ed. 2009, 48, 2225. (g) Smith, S. W.; Fu, G.
C. J. Am. Chem. Soc. 2009, 131, 14231. (h) Sinisi, R.; Sun, J.; Fu, G. C.
Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20652. (i) Sun, J.; Fu, G. C. J.
Am. Chem. Soc. 2010, 132, 4568. (j) Lundgren, R. J.; Wilsily, A.;
Marion, N.; Ma, C.; Chung, Y. K.; Fu, G. C. Angew. Chem., Int. Ed.
2013, 52, 2525. (k) Wang, T.; Yao, W.; Zhong, F.; Pang, G. H.; Lu, Y.
Angew. Chem., Int. Ed. 2014, 53, 2964.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grant Nos. 21102179 and
21572271), Qing Lan Project of Jiangsu Province.
REFERENCES
■
(1) For selected examples, see: (a) Onan, K. D.; Kelley, C. J.;
Patarapanich, C.; Leary, J. D.; Aladesanmi, A. J. J. Chem. Soc., Chem.
Commun. 1985, 121. (b) Shen, Z.; Falshaw, C. P.; Haslam, E.; Begley,
M. J. J. Chem. Soc., Chem. Commun. 1985, 1135. (c) Moody, C. J.;
Doyle, K. J.; Elliott, M. C.; Mowlem, T. J. J. Chem. Soc., Perkin Trans. 1
1997, 2413. (d) Miura, K.; Kikuzaki, H.; Nakatani, N. J. Agric. Food
Chem. 2002, 50, 1845. (e) Nicolaou, K. C.; Snyder, S. A.; Huang, X.-
H.; Simonsen, K. B.; Koumbis, A. E.; Bigot, A. J. Am. Chem. Soc. 2004,
126, 10162. (f) Piacente, S.; Montoro, P.; Oleszek, W.; Pizza, C. J. Nat.
Prod. 2004, 67, 882. (g) Balestrieri, C.; Felice, F.; Piacente, S.; Pizza,
C.; Montoro, P.; Oleszek, W.; Visciano, V.; Balestrieri, M. L. Biochem.
Pharmacol. 2006, 71, 1479. (h) Gu, Q.; Wang, R.-R.; Zhang, X.-M.;
Wang, Y.-H.; Zheng, Y.-T.; Zhou, J.; Chen, J.-J. Planta Med. 2007, 73,
279. (i) Fedorova, T. E.; Ivanova, S. Z.; Fedorov, S. V.; Babkin, V. A.
Chem. Nat. Compd. 2007, 43, 208. (j) Bassarello, C.; Bifulco, G.;
Montoro, P.; Skhirtladze, A.; Kemertelidze, E.; Pizza, C.; Piacente, S.
Tetrahedron 2007, 63, 148. (k) Lin, J.-Z.; Gerstenberger, B. S.;
Stessman, N. Y. T.; Konopelski, J. P. Org. Lett. 2008, 10, 3969. (l) Ge,
H.-M.; Zhu, C.-H.; Shi, D.-H.; Zhang, L.-D.; Xie, D.-Q.; Ng, S. W.;
Tan, R.-X. Chem. - Eur. J. 2008, 14, 376. (m) Wang, R.-R.; Gu, Q.;
Wang, Y.-H.; Zhang, X.-M.; Yang, L.-M.; Zhou, J.; Chen, J.-J.; Zheng,
Y.-T. J. Ethnopharmacol. 2008, 117, 249. (n) Wada, S.-I.; Hitomi, T.;
Tanaka, R. Helv. Chim. Acta 2009, 92, 1610. (o) Wada, S.; Hitomi, T.;
Tokuda, H.; Tanaka, R. Chem. Biodiversity 2010, 7, 2303. (p) Bai, L.;
Bao, H. Y.; Bau, T. Nat. Prod. Res. 2014, 28, 534.
(2) (a) Anacardio, R.; Arcadi, A.; D'Anniballe, G.; Marinelli, F.
Synthesis 1995, 1995, 831. (b) Ramachandran, P. V.; Chen, G.-M.;
Brown, H. C. Tetrahedron Lett. 1996, 37, 2205. (c) Harrowven, D. C.;
Lucas, M. C.; Howes, P. D. Tetrahedron 2001, 57, 791. (d) Srikrishna,
A.; Lakshmi, B. V. Tetrahedron Lett. 2005, 46, 7029. (e) Venkateswarlu,
S.; Panchagnula, G. K.; Guraiah, M. B.; Subbaraju, G. V. Tetrahedron
2005, 61, 3013.
(3) (a) Morrison, B. J.; Musgrave, O. C. Tetrahedron 2002, 58, 4255.
(b) Sharifi, A.; Abaee, M. S.; Mirzaei, M. Heterocycl. Commun. 2009,
15, 319. (c) Pertino, M. W.; Theoduloz, C.; Rodriguez, J. A.; Yanez,
T.; Lazo, V.; Schmeda-Hirschmann, G. J. Nat. Prod. 2010, 73, 639.
(4) Chen, L.; Zhou, F.; Shi, T.-D.; Zhou, J. J. Org. Chem. 2012, 77,
4354.
(9) (a) Martin, T. J.; Vakhshori, V. G.; Tran, Y. S.; Kwon, O. Org.
Lett. 2011, 13, 2586. (b) Guan, X.; Wei, Y.; Shi, M. Eur. J. Org. Chem.
2011, 2011, 2673.
(10) (a) Li, E.; Xie, P.; Yang, L.; Liang, L.; Huang, Y. Chem. - Asian J.
2013, 8, 603. (b) Gandi, V. R.; Lu, Y. Chem. Commun. 2015, 51,
16188.
(11) CCDC 1550564 contains the supplementary crystallographic
data for compound 3a. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(5) (a) D’Souza, D. M.; Rominger, F.; Muller, T. J. J. Angew. Chem.,
̈
Int. Ed. 2005, 44, 153. (b) D’Souza, D. M.; Kiel, D. M. A.; Herten, D.
P.; Rominger, F.; Muller, T. J. J. Chem. - Eur. J. 2008, 14, 529.
̈
(c) Matsuda, T.; Shigeno, M.; Murakami, M. Org. Lett. 2008, 10, 5219.
(d) Sue, D.; Kawabata, T.; Sasamori, T.; Tokitoh, N.; Tsubaki, K. Org.
Lett. 2010, 12, 256. (e) Yang, M.; Jiang, X.; Shi, W.-J.; Zhu, Q.-L.; Shi,
Z.-J. Org. Lett. 2013, 15, 690. (f) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin,
F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am.
Chem. Soc. 2013, 135, 1236.
(6) For selected examples, see: (a) Cariou, M.; Simonet, J.
Tetrahedron Lett. 1991, 32, 4913. (b) Hills, I. D.; Fu, G. C. Angew.
Chem., Int. Ed. 2003, 42, 3921. (c) Viswambharan, B.; Okimura, T.;
Suzuki, S.; Okamoto, S. J. Org. Chem. 2011, 76, 6678. (d) Wang, M.;
Zhang, Z.; Liu, S.; Xie, F.; Zhang, W. Chem. Commun. 2014, 50, 1227.
(e) Miller, J. A.; Matthews, R. S. J. Org. Chem. 1992, 57, 2514.
(f) Inagaki, M.; Matsumoto, S.; Tsuri, T. J. Org. Chem. 2003, 68, 1128.
(g) Black, T. H.; Arrivo, S. M.; Schumm, J. S.; Knobeloch, J. M. J. Org.
D
DOI: 10.1021/acs.orglett.7b01482
Org. Lett. XXXX, XXX, XXX−XXX