Synthesis of Spirofurooxindoles via Phenyliodine(III) Bis(trifluoroacetate) (PIFA)-Mediated Cascade Oxidative C?O and C?C Bond Formation

Article abstract of DOI:10.1002/adsc.201701635

Upon treatment with solely a hypervalent iodine reagent of phenyliodine(III) bis(trifluoroacetate) (PIFA), 3-(2-hydroxyphenyl)-3-oxo-N-phenyl propanamides and a series of its derivatives were conveniently converted to a class of undocumented spirofurooxindoles under mild conditions. Control experiments provided evidence that this spirocyclization process encompassed a cascade oxidative reactions involving the formation of a C?O bond prior to that of C?C bond. (Figure presented.).

Full text of DOI:10.1002/adsc.201701635

Title: Synthesis of Spirofurooxindoles via Phenyliodine(III)
Bis(trifluoroacetate) (PIFA)-Mediated Cascade Oxidative C–O
and C–C Bond Formation
Authors: Desong Sun, Xiaoyuan Zhao, Bobo Zhang, Ying Cong,
Xintong Wan, Mingmai Bao, Xue Zhao, Bing Li, Daisy Zhang-
Negrerie, and Yunfei Du
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701635
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10.1002/adsc.201701635
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Spirofurooxindoles via Phenyliodine(III)
Bis(trifluoroacetate) (PIFA)-Mediated Cascade Oxidative C–O
and C–C Bond Formation
Desong Sun,a Xiaoyuan Zhao,a Bobo Zhang,a Ying Cong,a Xintong Wan,a Mingmai
Bao,a Xue Zhao,a Bing Li,a Daisy Zhang-Negrerie,a and Yunfei Dua,b*
a Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and
Technology, Tianjin University, Tianjin 300072, China.
b Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.
Tel: +86-22-27404031; duyunfeier@tju.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Upon treatment with solely a hypervalent
iodine reagent of phenyliodine(III)
environmentally benign, and readily available,
hypervalent iodine reagents[6] have been referred
bis(trifluoroacetate) (PIFA), 3-(2-hydroxyphenyl)-3-
oxo-N-phenyl propanamides and a series of its
derivatives were conveniently converted to a class of
undocumented
spirofurooxindolesunder
mild
conditions. Control experiments provided evidence
that this spirocyclization process encompassed a
cascade oxidative reactions involving the formation of
a C–O bond prior to that of C–C bond.
Figure 1. Biologically active pharmaceutical
spirofuro-oxindoles.
Keywords: spirofurooxindole; cascade reaction;
hypervalent iodine oxidant; metal-free conditions;
spirocyclization
to as “green” oxidants, and have been vastly used in
oxidetive bond-forming reactions for the synthesis of
a
greatdiversity of heterocyclic compounds.[7]
Spirofurooxindole motifs constitute the core of a
wide range of biologically active natural products and
Although hypervalent iodine reagents have found
wide applications in C–C[8] and C–O bond-forming
reactions,[9] their involvement in cascade reactions
pharmaceutical
agents.[1]
For
examples,
spirofurooxindole A has been found to show
has
been seldomly
observed.[10]
In
this
significant inhibition of the growth of A549 lung
adenocarcinoma cells,[1a] orbicularisine
B
was
communication, we report a PIFA-mediated cascade
reaction involving oxidative C–O and C–C bond
formations, which led to the synthesis of a series of
spirofurooxidole compounds.
reported capable of excellent antibacterial
activities,[1b] and XEN907 C was discovered to be a
blocker of NaV1.7 for treatment of pain[1c] (Figure 1).
Accordingly, a number of useful synthetic methods
have been developed in pursuit of the construction of
this exclusive scaffold. Literature survey indicates
that the existing approaches mainly include N-
heterocyclic carbene (NHC) catalyzed annulations,[2]
In 2012, our group realized the synthesis of 3-
hydroxy-2-oxindoles via a PIFA-mediated, metal-free
cascade reaction, involving oxidative C(sp2)–C(sp3)
bond formation followed by an intermolecular
oxidative hydroxylation, of anilide derivatives
(Scheme 1a).[11] In 2009, Fan and coworkers reported
that o-acyl phenols could undergo tandem
acetoxylation and cyclization to afford α-acetoxy
benzofuranones (Scheme 1b).[12] Inspired by the
above works, we envisaged 3-(2-hydroxyphenyl-3-
oxo-N-phenyl) propanamide compounds 1, upon
treatment with a hypervalent iodine oxidant, to
undergo an intramolecular C(sp2)–C(sp3) bond
formation followed by an intramolecular C–O bond
intermolecular
cycloaddition
reactions,[3]
addition/cyclization sequences[4] and intramolecular
cyclizations.[5] Although these methods have their
own merit in the synthesis of each particular type of
spirofurooxindoles, there still is interest in developing
additional methods, especially those of metal-free
given the importance of this class of heterocyclic
compounds.
Due to many unique properties as nontoxic,
1
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10.1002/adsc.201701635
Advanced Synthesis & Catalysis
formation to give the spirofurooxindole products via
an oxoindole intermediate (Scheme 1c).
We chose substrate 1a, readily prepared from the
reaction of the commercially available 2’- hydroxyac-
Likewise, substrates bearing either an electron-
donating (–CH3) or -withdrawing (–Cl) R2 group,
regardless whether there was a R1 group or not, all
gave satisfactory yields (Table 2, entries 6-11). It’s
Table 1. Optimization of Reaction Conditionsa
Entry Oxidant
Catalyst
Solvent Time(min) Yield(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PhIO
PhIO
PIDA
PIDA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
PIFA
none
BF3·Et2O
none
BF3·Et2O
none
BF3·Et2O
TFA
none
none
none
none
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
THF
DMF
EtOAc
DCM
CHCl3
toluene
30
5
5
5
5
56
68
80
71
85
59
64
72
79
48
77
77
74
78
5
5
10
10
15
15
5
Scheme 1. Envisioned Synthesis of Spirofurooxindole
Based on Two Previous Works
none
none
none
5
5
etophenone and N-methylaniline in a straightforward
four-step process,[13] as the model substrate. Results
showed that the addition of PhIO to a solution of
substrate 1a in DCE at room temperature led to 2a in
a 56% yield after 30 min (Table 1, entry 1). Along
with the addition of a catalyst of BF3·Et2O (20 mol%)
the reaction time was drastically shortened to 5 min
and the yield was improved to 68% (Table 1, entry 2).
To our delight, by switching the oxidant to PIDA, 2a
was furnished with a much higher yield of 80% in an
equally short time of 5 min (Table 1, entry 3).
However, the yield was reduced to 71% in the
presence of the catalyst BF3·Et2O (20 mol%) (Table
1, entry 4). When the more potent oxidant, PIFA, was
used, the yield was further slightly improved to 85%
(Table 1, entry 5). However, the yield was greatly
reduced when BF3·Et2O was added (Table 1, entry 6).
Our attempt to further increase the yield by using
catalytic amount of TFA was proved to be futile
(Table 1, entry 7). Solvent-screening experiments
identified DCE as the most appropriate solvent for
this reaction among all the other solvents tested
including THF, DMF, CH3CN, EtOAc,DCM, CHCl3
and toluene. (Table 1, entries 8-14).
a
Reaction conditions: 1a (1 mmol), oxidant (2.2
b
equiv), additive (20 mol%) in solvent (4 mL).
Isolated yield.
worth noting that reactions of substrates bearing the –
F or dimethyl R1 group required longer time.
Unfortunately, reactions involving substrates bearing
a bromo group as R1 or R2 afforded products that
could not be isolated or characterized.
All substrates with a variety of hydrocarbon R3
groups, namely, methyl isopropyl, n-butyl and
phenyl, were all readily converted to the
corresponding desired products in good yields (Table
2, entries 12-14). Finally, when substrates with
methyl-protected hydroxyl group 1o and 1p were
subjected to the reaction conditions, the desired
product could be achieved as well, albeit in much
lower yields (Table 2, entries 15-16).
Although, initially, our understanding was that the
reaction underwent the intermolecular oxidative C–C
bond formation first, followed by the oxidative C–O
bond formation, our control experiments elucidated
another mechanistic pathway. Our first control
experiment was to treat, with 1.1 equiv of PIFA,
substrate 3, a modified 1a where the hydroxyl group
at ortho-position was removed. No desired new C–C
bond was formed. This result indicated that the
oxidative C–C bond formation was not as readily to
occur as expected. In our second control experiment,
substrate 5 was treated with 1.1 equiv. of PIFA. It was
found to furnish benzofuran 6. Our third control
experiment consisted of subjecting substrate 1a to 1.1
equiv. of PIFA in hopes to obtain a half-product with
either a C–C bond formed (such as 4) or C–O bond
formed. However, no such half-product was observed
Under the optimized conditions, a series of 3-(2-
hydroxy-phenyl)-N-methyl-3-oxo-N-phenylpropana-
mide derivatives were prepared with this newly
established method to investigate its scopes.
The substituent effect of R1 and R2 on the phenyl
rings, R3 on the N-atom, and R4 on the O-atom was
predominantly studied. Substrates bearing an
electron-donating (–Me, –di-Me, or –OMe) or
electron-withdrawing (–F) R1 groups were all
converted to the desired spirofurooxidole products in
satisfactory to good yields (Table 2, entries 1-5).
2
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10.1002/adsc.201701635
Advanced Synthesis & Catalysis
but 2a was formed in 43%. Switching to 1d where the
aniline moiety in 1a was replaced with a bulky 3,5-
dimethyaniline, an intermediate product of 7 was
formed in 5% yield, achieved through a C-O bond
forming in an intramolecular annulation reaction.
Treating intermediate 7 with 1.1 equiv of PIFA led to
Table 2. PIFA-Mediated Cascade Synthesis of Spirofurooxindolesa
b
aAll reactions were carried out at rt with 1 (1 mmol) and PIFA (2.2 mmol) in DCE (4 mL) under stir. Isolated
yield. cThe structure of 2m was confirmed by X-ray crystallography.[14]
the formation of spirofurooxindole 2d in 80% yield. electrophilic aromatic substitution reaction took place
These results together support the proposition that the
intramolecular oxidative C–O bond formation was
realized prior to that of the C–C bond formation in
this cascade reaction.
On the basis of a previous report,[12] we propose the
following mechanistic pathway, as depicted in
Scheme 3. First, the enol form 1a, K, nucleophically
attacked the iodine center of PIFA to give the C–I
intermediate L, along with release of one molecule of
trifluoroacetic acid. Intermediate L then underwent an
intramolecular cyclization, with the removal of one
molecule of PhI and trifluoroacetic acid to afford the
benzofuranone M. Intermediate N, the enol form of
M, reacted with the second molecule of PIFA and
gave the O-I intermediate O. An intramolecular
Scheme 2. Control Experiments
3
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10.1002/adsc.201701635
Advanced Synthesis & Catalysis
Petit, C. Moriou, O. Gros, A. Al-Mourabit, J. Nat. Prod.
2017, 80, 1693–1696; c) S. Chowdhury, M. Chafeev, S.
Liu, J. Sun, V. Raina, R. Chui, W. Young, R. Kwan, J.
Fu, J. A. Cadieux, Bioorg. Med. Chem. Lett. 2011, 21,
3676–3681; d) S. Buttachon, A. Chandrapatya, L.
Manoch, A. Silva, L. Gales, C. Bruyère, R. Kiss, A.
Kijjoa, Tetrahedron 2012, 68, 3253–3262; e) M. Ogata,
H. Matsumoto, S. Kida, S. Shimizu, K. Tawara, Y.
Kawmura, J. Med. Chem. 1987, 30, 1497–1502.
on the aniline ring, resulting in a new C–C bond along
with the formation of intermediate P, facilitated by
the departing of the leaving groups. Finally, with the
removal of a proton, P was converted to the title
spirofurooxindole compound 2a.
[2] a) J. Xu, S. Yuan, M. Miao, Z. Chen, J. Org. Chem.
2016, 81, 11454–11460; b) S. Mukherjee, S. Joseph, A.
Bhunia, R. G. Gonnade, S. R. Yetra, A. T. Biju, Org.
Biomol. Chem. 2017, 15, 2013–2019; c) X. Chen, K.
Chen, D. Sun, S. Ye, Chem. Sci. 2017, 8, 1936–1941;
d) J. Dugal-Tessier, E. A. O’Bryan, T. B. H. Schroeder,
D. T. Cohen, K. A. Scheidt, Angew. Chem., Int. Ed.
2012, 51, 4963–4967; e) Z. Jin, K. Jiang, Z. Fu, J.
Torres, P. Zheng, S. Yang, B. Song, Y. R. Chi, Chem. –
Eur. J. 2015, 21, 9360–9363; f) J. Li, B. Sahoo, C.
Daniliuc, F. Glorius, Angew. Chem., Int. Ed. 2014, 53,
10515–10519; g) V. Nair, S. Vellalath, M. Poonoth, R.
Mohan, E. Suresh, Org. Lett. 2006, 8, 507-509.
Scheme 3. Proposed Mechanism
[3] a) J. Li, Y. Liu, C. Li, X. Jia, Chem. – Eur. J. 2011, 17,
7409–7413; b) Z. Lian, M. Shi, Org. Biomol. Chem.
2012, 10, 8048–8050; c) L. Yang, P. Xie, E. Li, X. Li,
Y. Huang, R. Chen, Org. Biomol. Chem. 2012, 10,
7628–7634; d) A. Jose, A. J. Jayakrishnan, K. C. S.
Lakshmi, S. Varughese, V. Nair, Org. Biomol. Chem.
2015, 13, 3589–3592.
[4] a) L. Chen, Z. Wu, M. Zhang, D. Yue, X. Zhang, X.
Xu, W. Yuan, J. Org. Chem. 2015, 80, 12668–12675;
b) Z. Tang, Z. Liu, Y. An, R. Jiang, X. Zhang, C. Li, X.
Jia, J. Li, J. Org. Chem. 2016, 81, 9158–9166; (c) S.
Rana, A. Natarajan, Org. Biomol. Chem. 2013, 11,
244–247; c) J. Wu, X. Zhang, Y. Zhang, J. Xie, Org.
Biomol. Chem. 2015, 13, 4967–4975; d) Z. Lian, M.
Shi, Eur. J. Org. Chem. 2012, 3, 581–586; e) B. M.
Trost, K. Hirano, Org. Lett. 2012, 14, 2446–2449.
[5] a) K. S. Feldman, A. G. Karatjas, Org. Lett. 2004, 6,
2849–2852; b) Zhang, J.; Wang, R.; Li, D.; Zhao, L.
ACS Omega 2017, 2, 7022–7028; c) A. S. Kyei, K.
Tchabanenko, J. E. Baldwin, R. M. Adlington,
Tetrahedron Lett. 2004, 45, 8931–8934.
In conclusion, we have successfully designed and
developed a novel method for the construction of a
new class of spirofurooxindole molecules.[15] This
hypervalent iodine-mediated reaction undergoes a
cascade C–O and C–C bond formations under metal-
free and mild reaction conditions. Further studies on
converting the analogous O-aryl β-ketoester
substrates via the same method are undergoing in our
laboratory.
.
Experimental Section
General Procedure for the Preparation of
Spirofurooxindoles 2.
To a suspension of amide 1 (1.0 mmol) in DCE (4.0 mL)
was added PIFA (2.2 mmol) at room temperature. The
resulting mixture was kept at the same temperature until
TLC indicated that total consumption of amide 1. The
solvent was removed and the residue was purified by flash
column chromatography on silica gel (EA/PE = 1/9) to
afford the desired compound 2.
[6] a) L. Pouységu, D. Deffieux, S. Quideau, Tetrahedron
2010, 66, 2235–2261; b) R. M. Moriarty, O. Prakash,
Acc. Chem. Res. 1986, 19, 244-250; c) M. Uyanik, K.
Ishihara, Chem. Commun. 2009, 0, 2086–2099; d)T.
Dohi, A. Maruyama, N. Takenaga, K. Senami, Y.
Minamitsuji, H. Fujioka, S. B. Caemmerer, Y. Kita,
Angew. Chem. Int. Ed. 2008, 47, 3787–3790; e) T.
Wirth, U. H. Hirt, Synthesis 1999, 8, 1271–1287
Acknowledgements
[7] X. Zhang, Y. Cong, G. Lin, X. Guo, Y. Cao, K. Lei, Y.
Du, Chin. J. Org. Chem. 2016, 36, 2513–2529.
Y. Du acknowledges the National Natural Science Foundation of
China (#21472136) and the Tianjin Research Program of
[8] a) Y. Kita, T. Yakura, H. Tohma, K. Kikuchi, Y.
Tamura, Tetrahedron Lett. 1989, 30, 1119–1120; b) Y.
Tamura, T. Yakura, Y. Shirouchi, J. Haruta, Chem.
Pharm. Bull. 1986, 34, 1061–1066; c) S. R. Taylor, A.
T. Ung, S. G. Pyne, B. W. Skelton, A. H. White,
Tetrahedron 2007, 63, 11377–11385; d) T. Dohi, M.
Ito, I. Itani, N. Yamaoka, K. Morimoto, H. Fujioka, Y.
Kita, Org. Lett. 2011, 13, 6208–6211; e) M. Ito, H.
Application
Foundation
and
Advanced
Technology
(#15JCZDJC32900) for financial support.
References
[1] a) A. K. Franz, P. D. Dreyfuss, S. L. Schreiber, J. Am.
Chem. Soc. 2007, 129, 1020–1021; b) F. Goudou, P.
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201701635
Advanced Synthesis & Catalysis
Kubo, I. Itani, K. Morimoto, T. Dohi, Y. Kita, J. Am.
Chem. Soc. 2013, 135, 14078–14081.
[9] a) X. Wang, J. Gallardo-Donaire, R. Martin, Angew.
Chem., Int. Ed. 2014, 53, 11084–11087; b) Y. Ye, L.
Wang, R. Fan, J. Org. Chem. 2010, 75, 1760–1763; c)
Z. Yu, L. Ma, W. Yu, Synlett 2012, 23, 1534–1540; d)
J. A. Souto, P. Becker, Á. Iglesias, K. Muñiz, J. Am.
Chem. Soc. 2012, 134, 15505–15511.
[10] a) H. Fujioka, H. Komatsu, T. Nakamura, A. Miyoshi,
K. Hata, J. Ganesh, K. Murai, Y. Kita, Chem. Commun.
2010, 46, 4133–4135; b) K. Moriyama, K. Ishida, H.
Togo, Org. Lett. 2012, 14, 946–949; c) Y. Cao, X.
Zhang, G. Lin, D. Zhang-Negrerie, Y. Du, Org. Lett.
2016, 18, 5580–5583; d) B. Hu, Y. Cao, B. Zhang, D.
Zhang-Negrerie, Y. Du, Adv. Synth. Catal. 2017, 359,
2542–2548.
[11] J. Wang, Y. Yuan, R. Xiong, D. Zhang-Negrerie, Y.
Du, K. Zhao, Org. Lett. 2012, 14, 2210–2213.
[12] R. Fan, Y. Sun, Y. Ye, Org. Lett. 2009, 11, 5174–5177.
[13] a) W. Cheung, S. Zheng, W. Yu, G. Zhou, C. Che, Org.
Lett. 2003, 5, 2535–2538. b) J. Sun, D. Zhang-
Negrerie, Y. Du, Adv. Synth. Catal. 2016, 358, 2035–
2040. c) D. T. Witiak, S. K. Kim, A. K. Tehim, K. D.
Sternitzke, R. L. McCreery, S. U. Kim, D. R. Feller,
K. J. Romstedt, V. S. Kamanna, H. A. I. Newman, J.
Med. Chem. 1988, 31, 1437–1445. d) C. Allais, T.
Constantieux, J. Rodriguez, Chem. – Eur. J. 2009, 15,
Med. 12945–12948. e) C. H. Heathcock, R. Ratcliffe,
J. Am. Chem. Soc. 1971, 93, 1746–1757. f) N.
Bouider, W. Fhayli, Z. Ghandour, M. Boyer, K.
Harrouche, X. Florence, B. Pirotte, P. Lebrun, G.
Faury, S. Khelili, Bioorg. Med. Chem. 2015, 23,
1735–1746.
[14] CCDC 1812154 (2m) 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.
Formula:
C19H17N1O3, unit cell parameters: a = 9.5884(14) b =
15.108(2) c = 10.7433(17) P21/c
[15] In our previous work, we reported a PIFA-mediated
cascade annulation of 2-sulfonamide-N-phenyl
propiolamide leading to the construction of the similar
spirofurooxindole skeleton. However, after replacing
the amino moiety in the aniline ring with a –OH group,
the corresponding substrate failed to afford the similar
spirofurooxindole products, see: B. Zhang, X. Zhang,
B. Hu, D. Sun, S. Wang, D. Zhang-Negrerie, Y. Du,
Org. Lett. 2017, 19, 902–905.
5
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10.1002/adsc.201701635
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of Spirofurooxindoles via
Phenyliodine(III) Bis(trifluoroacetate) (PIFA)-
Mediated Cascade Oxidative C–O and C–C Bond
Formation
Adv. Synth. Catal. Year, Volume, Page – Page
Desong Sun,a Xiaoyuan Zhao,a Bobo Zhang,a Ying
Cong,a Xintong Wan,a Mingmai Bao,a Xue Zhao,a
Bing Li,a Daisy Zhang-Negrerie,a and Yunfei
Dua,b*
6
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