A novel entry to spirofurooxindoles involving tandem dearomatization of furan ring and intramolecular friedel- Crafts reaction

Article abstract of DOI:10.1002/adsc.201100034

A copper sulfate pentahydrate-catalyzed intramolecular Friedel-Crafts reaction using an oxocarbenium species derived from a furan ring as the alkylating agent was developed for the first time. By using this protocol, spirofurooxindoles 9 with multi-reactive sites were synthesized simply and concisely. In addition, selective hydrogenation of the endo-cyclic double bond and full hydrogenation of the endo and exo-cyclic double bonds of spirofurooxindoles 9 provided spirofurooxindoles 11 and 12, respectively. Copyright

Full text of DOI:10.1002/adsc.201100034

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DOI: 10.1002/adsc.201100034
A Novel Entry to Spirofurooxindoles Involving Tandem
Dearomatization of Furan Ring and Intramolecular Friedel–
Crafts Reaction
Biao-Lin Yin,a,* Jin-Qiang Lai,a Ze-Ren Zhang,a and Huan-Feng Jianga
a
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, Peopleꢀs
Republic of China
Fax : (+86)-20-8711-3735; phone: (+86)-20-8711-3735; e-mail: blyin@scut.edu.cn
Received: January 14, 2011; Revised: April 19, 2011; Published online: August 11, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100034.
Abstract: A copper sulfate pentahydrate-catalyzed
intramolecular Friedel–Crafts reaction using an
oxoACHTUNGTRENNUNGcarbenium species derived from a furan ring as
the alkylating agent was developed for the first
time. By using this protocol, spirofurooxindoles 9
with multi-reactive sites were synthesized simply
and concisely. In addition, selective hydrogenation
of the endo-cyclic double bond and full hydrogena-
tion of the endo and exo-cyclic double bonds of spi-
against the A431 human epidermoid carcinoma cell
line.[3] Spiro[isoxazolidine-3,3’-oxindoles] were dem-
onstrated to have significant cytostatic activity on the
human breast cancer cell line, MCF-7.[4] Spiro[furo-
2,3’-oxindoles] inhibited the growth of lung adenocar-
cinoma (A549) cells and hepatocellular carcinoma
(HepG2) cells.[5] Presently, the development of effi-
cient methods for the synthesis of novel heterocyclic
spiro-oxindoles and investigation of their bioactivities
are of great significance in organic and medicinal
chemistry.
rofurooxindoles 9 provided spirofuro
ACHTUNGTRENUNoNG xindoles 11
and 12, respectively.
To date, most of the documented methods for the
synthesis of heterocyclic spiro-oxindoles start with
substituted indoles (2a) or isatins (2b) containing ring
A, followed by the construction of the spiro-carbon
and formation of ring B (Pathway a, Figure 1).[6,7]
However, sometimes these methods suffer from inher-
ent drawbacks such as functional group compatibility,
Keywords: dearomatization; Friedel–Crafts reac-
tion; selective hydrogenation; spirofurooxindoles
The heterocyclic spirooxindoles 1 with diverse B harsh reaction conditions, multiple-step manipulation,
rings, of synthetic or natural origin, have attracted and poor availability of the starting material to diver-
much attention due to their significant biological ac- sify the molecular structure. It is highly desirable to
tivities.[1] For example, spiro[pyrrolidine-3,3’-oxin- develop simple and complementary methods for the
doles] have recently been found to be a novel inhibi- construction of the spiro-carbon of 1 and formation of
tor of the MDM2-p53 interaction.[2] Gelsedine-type ring
A
from readily available B-ring-containing
indole alkaloids showed strong cytotoxic effects amides 3 (Pathway b).[8]
Figure 1. Construction of the spiro-carbon of 1.
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Biao-Lin Yin et al.
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In our continuous efforts to search for bioactive Crafts reaction using oxocarbenium adjacent to an
spiro compounds, we have recently developed a gen- electron-withdrawing carbonyl group as an alkylation
eral and concise method for the construction of a li- agent has never been reported.
brary of spiroacetals (Scheme 1).[9,10] The synthetic
With the above-mentioned strategy in mind, we set
strategy involves: (i) the dearomatization of the five- out to synthesize precursor 7. As shown in Scheme 2,
membered aromtic ring of 4, which generates a carbo- 7 was prepared from a keto ester 10[11] in middle to
cation 5 when exposed to suitable acids; (ii) trapping good overall yields over 4 steps including hydrolysis,
of 5 with an intramolecular hydroxy group as a nucle- acetyl chlorination, amidation and reduction. To opti-
ophile to form spiroacetals; and (iii) further modifica- mize the reaction conditions for the cyclization of 7
tion of multiple reaction sites of 6 for diversity-orient- into 8, 7aa was used as the substrate under the influ-
ed synthesis (DOS). We envisaged that the diversifi- ence of various acids and the results were summarized
cation of the nucleophiles to trap carbocation 5 could in Table 1. Possibly due to the polymerization of the
produce a series of useful spiro-compounds with furan ring, strong Lewis acids such as TiCl4, SnCl4 and
structural novelty.
In this paper we wish to report a reaction in which
the carbocation 8, derived from 2-furancarboxamide
Table 1. Optimization of the reaction conditions for cycliza-
tion.[a]
7, is trapped by an intramolecular electron-rich
phenyl ring (Friedel–Crafts reaction). This protocol
would allow easy access to spirofurooxindoles 9. To
the best of our knowledge, such type of Friedel–
Entry Acid
Solvent Temp. Time Yield
[oC]
[h]
[%][b]
[c]
1
2
3
4
5
6
7
8
9
TiCl4
DCM À78
DCM À78
1
1
1
72
6
ND
ND
ND
25
[c]
SnCl4
BF3·Et2O[c]
CSA[c]
THF
À78
DCM r.t.
toluene r.t.
toluene 60
toluene 110
toluene 100
toluene 100
PTSA[c]
25
[c]
Yb
(OTf)3
2
ND[e]
NR[f]
62
[d]
CuSO4
12
18
5
CuSO4·5H2O[d]
CuSO4·5H2O[d]
and AcOH[c]
85
10
CuSO4·5H2O[d]
and AcOH[c]
toluene 110
1.5
78
[a]
[b]
[c]
[d]
[e]
[f]
All reactions were carried out on a 0.3 mmol scale.
Isolated yield.
0.1 equiv. was used.
1.5 equiv. were used.
ND: not detected.
Scheme 1. Intramolecular trapping of the carbocation de-
rived from a five-membered aromatic ring.
NR: no reaction.
Scheme 2. Synthesis of precursors 7 for cyclization.
1962
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A Novel Entry to Spirofurooxindoles Involving Tandem Dearomatization of Furan Ring
Table 2. Synthesis of spirofurooxindoles.[a]
BF3·Et2O led to very complicated reaction systems
(entries 1–3), although they have been frequently
used as catalysts for Friedel–Crafts reactions utilizing
acetals as alkylating agents. Weaker protonic or Lewis
acids such as CSA, PTSA, YbACTHNUTRGNEU(NG OTf)3, and CuSO4
were also screened (entries 4–7). To our delight, the
desired product 9aa was obtained in 62% yield when
CuSO4·5H2O (or CuSO4 with a small amount of H2O)
as a catalyst (entry 8). The structure of 9aa was con-
firmed by single-crystal X-ray data analysis (Figure 2).
Interestingly, under the same reaction conditions as in
entry 8, addition of a catalytic amount of AcOH im-
proved the yield remarkably to 85% (entry 9). Fur-
ther increases of the reaction temperature to 1108C
resulted in a lower yield (entry 10). Under the cataly-
sis of CuSO4·5H2O, AcOH might react with the hy-
droxy group of 7, forming the corresponding acetate.
The acetoxy group is a good leaving group which
helps to form carbocation 8.
To understand the generality of this reaction, we
subjected various 2-furylcarbinol amides 7 to provide
the spirofurooxindoles (9aa–9ed) under the same re-
action conditions as entry 9 in Table 1. The results are
summarized in Table 2. As expected, the electron
density of the phenyl ring of the anilines influenced
the yields remarkably. Higher electron density gener-
ally led to higher yields (9aa>9ab>9ac>9ad). The
failure with 9af might result from the low electron
density of its phenyl ring (entry 6). In entries 13–16
where the Ar group is 1-naphthyl, compounds 9ea–
9ed were obtained as a mixture of two isomers with a
ratio about 5:1. Products 9ea–9ed may be viewed as
trans-1,2-diarylethylenes where rotational isomerism
seems to exist.[12] Therefore, the isomers are probably
the rotamers about the naphthyl-CH= linkage. On the
basis of the ORTEP diagram of the major isomer of
9ed,[15] the structures of the two isomers are proposed
in Figure 3. It is worth noting that when the X group
Entry Ar
X
Time 9[b] Yield[c]
[h]
[%]
1
Ph
3,4,5-tri-MeO
3,5-di-MeO
3,4-di-MeO
3,5-di-Me
3-MeO
5
9aa 85
2
Ph
0.5
1.5
6
9ab 83
9ac 66
3
Ph
4
Ph
9ad 46
5
Ph
1
9ae 57 (3/1)[d]
6
Ph
H
16
1
9af
9ba 92
0
7
8
9
10
11
12
13
14
15
16
p-Cl-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-Cl-C6H4
p-NO2-C6H4 3,4,5-tri-MeO
p-MeO-C6H4 3,4,5-tri-MeO
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
3,4,5-tri-MeO
3,5-di-MeO
3,5-di-Me
3-MeO
1
9bb 89
5
5
3
9bd 60
9be 64 (4/1)[d]
9ca 85
7
2
9da 33
3,4,5-tri-MeO
3,5-di-MeO
3,4-di-MeO
3,5-di-Me
9ea 87ACHTUNGTRENNUNG
(5/1)[d]
1.5
1.5
5
9eb 80 (4.8/1)
9ec 91 (3.7/1)
9ed 71 (3/1)[d]
[a]
[b]
All reactions were carried out on a 0.3 mmol scale.
All compounds were fully characterized (see Supporting
Information).
Isolated yield.
Based on H NMR.
[c]
[d]
1
Figure 3. The structures of s-trans-9ed and s-cis-9ed.
was 3,4-dimethoxy, the cyclization occurred exclusive-
ly at the 6-position of the phenyl ring (entries 3, 15).
In contrast, when the X group was 3-methoxy, the
cyclization occurred predominately at the 6-position,
leading to two regioisomers, (entries 5 and 10).
To diversify the spirofurooxindoles scaffold, we
modified the endo and exo-cyclic double bonds of 9
(Scheme 3, Table 3). Selective hydrogenation of the
endo-cyclic double bond was achieved by reduction of
9 with NaBH4 (10 equiv.) in the presence of NiCl2
(1.5 equiv.) in DME-MeOH, yielding 11 with moder-
ate to good yields (60–75%). The substituted 2-meth-
ylenetetrahydrofuran ring of 11 is likely to adopt two
different conformations (the bent and twisted forms)
which may have a high barrier to pseudorotation.[13]
Figure 2. ORTEP diagram of 9aa.[15]
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Biao-Lin Yin et al.
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Scheme 3. Synthesis of spirofurooxindoles 12.
Table 3. Synthesis of spirofurooxindoles 11.[a]
Figure 4. ORTEP diagram of 11ea.[15]
role rings, to achieve molecular diversity of spirooxin-
doles and investigation of their bioactivities are under
way, and the results will be disclosed in due course.
Entry
9
Major product
Ratio[b]
Yield[c] [%]
1
2
3
4
5
6
7
8
9aa
11aa
11ab
11ad
11ba
11bb
11bd
11ea
11eb
1/0.35
1/0.37
1/0.43
1/0.31
1/0.71
1/0.85
1/0.35
1/0.41
70
60
65
71
63
75
70
68
9ab
9ad
9ba
9bb
9bd
9ea
Experimental Section
General Procedure for the Synthesis of Spirooxindole
9 from 7
The mixture of
7 (0.3 mmol), CuSO4·5H2O (112.5 mg,
Z-9eb
0.45 mmol), acetic acid (1.7 mL) and toluene (5 mL) was
stirred at 1008C until the disappearance of 7 according to
the TLC. The mixture then was cooled to room temperature
and the solid was filtered off. The removal of the organic
solvent provided the crude product which was purified by
flash chromatography to give 9.
[a]
All reactions were carried out on a 0.3 mmol scale.
The ratio of two conformational isomers is based on
1H NMR.
[b]
[c]
Isolated yield.
1
In the H NMR spectrum of 11, some proton signals,
such as the enol ether proton, are divided into two
parts. This is consistent with the existence of two con-
formations. The X-ray crystal structure of 11ea indi-
cates the non-coplanarity of the its naphthyl ring with
the enol ether (Figure 4).[14] A mixture of fully re-
duced products 12 was obtained upon palladium-cata-
lyzed hydrogenation, in favor of the cis isomer
(benzyl cis to carbonyl). The realative configuration
of 12aa was verified by NOESY experiments and
single-crystal X-ray data analysis (see Supporting In-
formation).[15]
General Procedure for the Synthesis of Spirooxindole
11 from 9
To a solution of 9 (0.2 mmol) in DME (2 mL) and anhy-
drous methanol (2 mL) was added NaBH4 (76.0 mg,
2 mmol), NiCl2 (38.1 mg, 0.3 mmol) in portions. The mixture
was stirred for 20 min until the starting material had disap-
peared according to the TLC. The organic solvents were re-
moved under reduced pressure, and then water (20 mL) was
added. The resulting mixture was extracted with ethyl ace-
tate (10 mLꢂ3). The combined organic layers were washed
with saturated brine (20 mL), dried over sodium sulfate, and
concentrated under reduced pressure to provide the crude
product. The crude mixture was purified using silica gel
flash chromatography to give the product 11.
In summary, three kinds of novel spirofurooxin-
doles (9, 11, 12) with structural diversity were pre-
pared using readily available furan derivatives as
starting material in a concise and effective way. The
key step involves an intramolecular Friedel–Crafts re-
action of the tethered electron-rich anilide with the
oxocarbenium derived from the furan ring. This pro-
tocol represents a potential and novel strategy for the
synthesis of new heterocyclic spirooxindoles. Further
studies on the trapping of 5, derived from the dearo-
General Procedure for the Synthesis of Spirooxindole
12 from Spirooxindole 9 or 11
To a round-bottom flask (50 mL) was added spirooxindole 9
or 11 (0.2 mmol), ethanol (15 mL) and Pd/C (10%, 42.6 mg).
Then the flask was purged with hydrogen (1 atm). The re-
sulting solution was stirred vigorously at room temperature
for 2 h. The reaction mixture was filtered through a short
matization of the corresponding thiophene and pyr- silica gel column. The organic solvent was removed under
1964
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Adv. Synth. Catal. 2011, 353, 1961 – 1965

A Novel Entry to Spirofurooxindoles Involving Tandem Dearomatization of Furan Ring
reduced pressure providing the crude product which was pu-
[8] Only a few examples are known using N-phenylamides
rified by flash chromatography to give the product 12.
as starting material to construct the spiro-carbon atom:
a) K. Jones, J. Wilkinson, J. Chem. Soc. Chem.
Commun. 1992, 1767–1769; b) L. E. Overman, M. D.
Rosen, Angew. Chem. 2000, 112, 4768–4771; Angew.
Chem. Int. Ed. 2000, 39, 4596–4599; c) A. S. Kyei, K.
Tchabanenko, J. E. Baldwin, R. M. Adlington, Tetrahe-
dron Lett. 2004, 45, 8931–8934; d) S. Jaegli, J. Dufour,
H.-L. Wei, T. Piou, X.-H. Duan, J.-P. Vors, L. Neuville,
J. P. Zhu, Org. Lett. 2010, 12, 4498–4450.
Acknowledgements
This work was support by Doctoral Fund of Ministry of Edu-
cation of China (200805611041), Fundamental Research
Funds for the Central Universities (2009M0241), the National
Natural Science Foundation of China (No. 21072062), and
the Natural Science Foundation of Guangdong Province,
China (10351064101000000). The authors are greatly indebt-
ed to Professor Yu-Lin Wu, Shanghai Institute of organic
Chemistry, the Chinese Academy of Sciences, and Professor
Fayang Qiu, Guangzhou Institute of Biomedicine & Health,
The Chinese Academy of Sciences, for their helpful discus-
sions about the stereochemistry.
[9] a) Y. Gao, W.-L. Wu, B. Ye, R. Zhou, Y.-L Wu, Tetrahe-
dron Lett. 1996, 37, 893–896; b) Y. Gao, W.-L. Wu, Y.-
L. Wu, B. Ye, R. Zhou, Tetrahedron 1998, 54, 12523–
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Yue, Y. Gao, W.-M. Wu, Y.-L. Wu, Synlett 2004, 306–
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1
[14] We also checked the H NMR spectrum of the crystal
in CDCl3, which was exactly the same as that before
crystallization.
[15] Crystallographic data for the structures of 9aa, s-trans-
9ed, 11ea and 12ea have been deposited with the Cam-
bridge Crystallographic Data Center as supplementary
publications number CCDC 822029, CCDC 822031,
CCDC 822030, and CCDC 822032, respectively. These
data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.ca-
m.ac.uk/data_request/cif or on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc. cam.ac.uk.
Adv. Synth. Catal. 2011, 353, 1961 – 1965
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1965