Triphenylphosphine-catalyzed [3+2] cycloaddition of allenoate and active olefins: Syntheses of spirooxindole derivatives

Article abstract of DOI:10.1055/s-0030-1261188

A series of spiro compounds was achieved by triphenylphosphine-catalyzed [3+2] cycloaddition between active methylenemalononitrile and ethyl 2,3-butadienoate. Careful investigation showed that the present method had high regioselectivity. The products have a spirooxindole skeleton, which is a motif common in many natural products and pharmaceutically active compounds. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1261188

2256
LETTER
Triphenylphosphine-Catalyzed [3+2] Cycloaddition of Allenoate and Active
Olefins: Syntheses of Spirooxindole Derivatives
Syntheses
of
S
h
pirooxindole
a
Derivative
n
s
yan Guo,a Rendong Wang,a Jian Li,a Chunju Li,a Hongmei Deng,c Xueshun Jia*a,b
a
Department of Chemistry, Shanghai University, Shanghai, 200444, P. R. of China
Fax +86(21)66132408; E-mail: xsjia@mail.shu.edu.cn
b
c
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, P. R. of China
Laboratory for Microstructures, Shanghai University, Shanghai, 200444, P. R. of China
Received 16 May 2011
this annulation strategy has been further applied to the to-
tal syntheses of natural products with biological activi-
ties.8
Abstract: A series of spiro compounds was achieved by triphe-
nylphosphine-catalyzed [3+2] cycloaddition between active meth-
ylenemalononitrile and ethyl 2,3-butadienoate. Careful
investigation showed that the present method had high regioselec-
tivity. The products have a spirooxindole skeleton, which is a motif
common in many natural products and pharmaceutically active
compounds.
PR3
X
CO2Et
X
CO2Et
[3+2]
EtO2C
R1
Key words: oxindoles, spirocycle, cycloaddition, allenoate, active
olefins
zwitterionic species
CO2Et
R2
X
PR3
Oxindole skeletons have been coined a privileged struc-
ture due to their common occurrence in natural products
and compounds of pharmaceutical significance.1 For in-
stance, medicines having this key structure have been
used as anti-Parkinson’s drug ropinirole and the growth
hormone secretagogues.2 Among these compounds,
spirooxindoles are particularly important due to their
unique structural complexity. Natural products such as al-
stonisine and horsfiline have been interesting synthetic
targets to synthetic chemists (Figure 1).3 Although con-
siderable progress has been described towards their syn-
theses, methods to efficiently construct this core structure
in a chemo- and regiocontrolled manner are still limited.4
X
[4+2]
CO2Et
R2
Scheme 1
Moreover, the asymmetric variants of such transforma-
tions have also been well disclosed by Zhao,9 Jacobsen,10
Miller,11 and Fu groups.12 Notably, using substituted allen-
oates, novel [4+2] annulations with imines, electron-
deficient olefins, and trifluoromethyl ketones have also
been reported by Kwon et al. (Scheme 1).13 Recently, we
have focused our attention on the syntheses of carbocycles
and potentially bioactive heterocycles.14 As a continua-
tion, herein we wish to report an efficient [3+2] cycload-
H
O
H
Me
N
dition
from
allenoates
and
various
active
methylenemalononitriles 1 to synthesize spirocyclic oxin-
Me
O
dole-butenolide derivatives (Scheme 2).
R
NH
Table 1 Optimization of Reaction Conditionsa
O
N
N
Me
H
Entry
Solvent
CH2Cl2
DCE
Yield (%)b
alstonisine (1)
horsfiline (2a, R = MeO)
coerulescine (2b, R = H)
1
2
3
4
5
6
60
56
73
41
31
59
Figure 1
Recently, the phosphine-catalyzed [3+2] cycloaddition of
allenoates with electron-deficient species such as olefins
and imines have been fully investigated, thereby provid-
ing access to functionalized five-membered carbo- and
heterocycles from readily available starting materials.5,6
Following the pioneering efforts of Lu and co-workers,7
toluene
MeCN
DMF
THF
a Reaction conditions: allenoate 2 (0.6 mmol), Ph3P (0.05 mmol),
methylenemalononitrile 1a (0.5 mmol), solvent (5 mL), air, r.t.
b Yields of product after silica gel chromatography.
SYNLETT 2011, No. 15, pp 2256–2258
Advanced online publication: 12.08.2011
x
x
.x
x
.2
0
1
1
DOI: 10.1055/s-0030-1261188; Art ID: W11711ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Syntheses of Spirooxindole Derivatives
2257
Table 2 Ph3P-Catalyzed [3+2] Cycloaddition of Allenoate 2 and
Activated Olefin 1a
NC
R4
CN
O
R
CO2Et
3
+
Entry
R
R1
R2
R3
R4
Time Product Yield
•
N
R5
(h)
(%)b
73
70
72
72
68
82
75
79
74
73
74
73
70
84
70
76
R2
2
R1
1
2
Me
Me
Me
Me
Me
Me
Me
Me
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
H
H
Br
H
H
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
5
3a
3b
3c
3d
3e
1a–p
Ph3P
H
H
6
toluene, r.t.
3
H
Cl
8
EtO2C
R4
4
H
F
4
R3
CN
CN
5
H
MeO
NO2
Me
H
5
O
R2
N
R5
6
H
13 3f
3g
13 3h
R1
7
Me
H
7
3a–p
8
Scheme 2
9
H
H
5
6
7
3i
In our initial experiments, methylenemalononitrile 1a was
employed as the model substrate to react with allenoate 2
(Table 1). A series of solvents were screened and toluene
was found to be the best choice (Table 1, entry 3). Reac-
tions in CH2Cl2, DCE, MeCN, DMF, and THF only led to
low conversions (Table 1, entries, 1, 2, 4–6). During this
process, the catalyst loading was also carefully examined
and 10% Ph3P were sufficient to catalyze the above-men-
tioned cyclization. With the optimized reaction conditions
10
11
12
13
14
H
H
3j
3k
H
Cl
H
F
10 3l
H
MeO
NO2
Me
H
9
3m
H
11 3n
in hand, we next explored the scope of the reaction. The 15
reaction of various substituted methylenemalononitrile 1
Me
H
8
3o
16
13 3p
bearing electron-withdrawing and electron-donating
groups on the aromatic rings with allenoate 2 was exam- a Reaction conditions: allenoate 2 (0.6 mmol), Ph3P (0.05 mmol), ac-
tivated alkene 1 (0.5 mmol), toluene (5 mL), r.t.
ined to afford the corresponding functionalized spirocy-
clic oxindoles, and the results are summarized in Table 2.
b Yields of products isolated after silica gel chromatography.
The transformations proceeded smoothly under optimized
conditions with satisfactory yields (Table 2, entries 1–8).
All new compounds were characterized by IR, 1H NMR,
13C NMR, HRMS, and elemental analysis, and the struc-
ture of compound 3b was confirmed by single-crystal X-
ray analysis (Figure 2).1,5 The reactions with N-benzyl-
protected olefins 1 were also carried out to establish the
scope and limitation (Table 2, entries 9–16). Furthermore,
halide, nitro, cyano, ester, amide, and methoxy groups
were all tolerated in the present reaction, which facilitate
their further functionalization.
The mechanism of this [3+2]-cycloaddition reaction has
not been unequivocally established, but one reasonable
possibility is proposed in Scheme 3. The beginning of the
cyclization involves the formation of zwitterionic species,
which exist as resonance-stabilized form A ¥ B.5 The in-
termediate then experienced Michael addition and in-
tramolecular annulation–elimination to give product 3.
In conclusion, we have described the synthesis of a series
of spirocyclic compounds by [3+2]-cycloaddition reac-
tion from readily available allenoates and active olefins in
an efficient and atom-economical manner.16 In the pres-
Figure 2
ence of catalytic amount of Ph3P, the present approach al-
Furthermore, the spirooxindole compounds have reactive
lows the syntheses of highly functionalized spirooxindole
carbon–carbon double bond, cyano, nitro, halide, and es-
derivatives with exclusive regioselectivity.
ter groups, which enable further modifications leading to
Synlett 2011, No. 15, 2256–2258 © Thieme Stuttgart · New York

2258
S. Guo et al.
LETTER
2008, 37, 1140. (d) Cowen, B. J.; Miller, S. J. Chem. Soc.
Rev. 2009, 38, 3102. (e) Marinetti, A.; Voituriez, A. Synlett
2010, 174.
CO2Et
Ph3P
CO2Et
CO2Et
•
PPh3
PPh3
(6) For relevant examples, see: (a) Zhang, C.; Lu, X. J. Org.
Chem. 1995, 60, 2906. (b) Xu, S.; Zhou, L.; Ma, R.; Song,
H.; He, Z. Chem. Eur. J. 2009, 15, 8698. (c) Henry, C. E.;
Kwon, O. Org. Lett. 2007, 9, 3069. (d) Dudding, T.; Kwon,
O.; Mercier, E. Org. Lett. 2006, 8, 3643. (e) Xia, Y.; Liang,
Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.;
Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 3470. (f) Wallace,
D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem. 2007, 72,
1051. (g) Lu, X.; Lu, Z.; Zhang, X. Tetrahedron 2006, 62,
457. (h) Sampath, M.; Loh, T.-P. Chem. Commun. 2009,
1568.
2
A
B
CN
Michael addition–
intramolecular cyclization
CN
1a
3a
N
Me
O
PPh3
EtO2C
C
(7) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906.
(8) (a) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (b) Wang,
J.-C.; Krische, M. J. Angew. Chem. Int. Ed. 2003, 42, 5855;
Angew. Chem. 2003, 115, 6035. (c) Pham, T. Q.; Pyne, S.
G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70,
6369.
Scheme 3
molecular diversity. Thus the present method has the po-
tential to be applied in medicinal and synthetic chemistry.
(9) Xiao, H.; Chai, Z.; Zheng, C.-W.; Yang, Y.-Q.; Liu, W.;
Zhang, J.-K.; Zhao, G. Angew. Chem. Int. Ed. 2010, 49,
4467; Angew. Chem. 2010, 122, 4569.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(10) Fang, Y.-Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
5660.
(11) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129,
10988.
(12) Wilson, J. E.; Fu, G. C. Angew. Chem. Int. Ed. 2006, 45,
1426; Angew. Chem. 2006, 118, 1454.
Acknowledgment
We thank the National Natural Science Foundation of China
(20872087, 21002061, 20902057), the State Key Laboratory of Ap-
plied Organic Chemistry, Lanzhou University, Leading Academic
Discipline Project of Shanghai Municipal Education Commission
(No: J50101), and the Graduate Innovation Fund of Shanghai Uni-
versity for financial support.
(13) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003,
125, 4716. (b) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 12234. (c) Tran, Y. S.; Kwon, O. Org. Lett. 2005,
7, 4289. (d) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 12632. (e) Wang, T.; Ye, S. Org. Lett. 2010, 12, 4168.
(14) (a) Li, J.; Liu, Y. J.; Li, C. J.; Jia, X. S. Adv. Synth. Catal.
2011, 353, 913. (b) Li, J.; Li, S. Y.; Li, C. J.; Liu, Y. J.; Jia,
X. S. Adv. Synth. Catal. 2010, 352, 336. (c) Zhao, Y. N.; Li,
J.; Li, C. J.; Yin, K.; Ye, D. Y.; Jia, X. S. Green Chem. 2010,
12, 1370.
(15) CCDC 763015 for compound 3b contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystal-
lographic Data Center via www.ccdc.cam.ac.uk/
data_request/cif.
References and Notes
(1) (a) Akai, S.; Tsujino, T.; Akiyamna, E.; Tanimoto, K.; Naka,
T.; Kita, Y. J. Org. Chem. 2004, 69, 2478. (b) Marti, C.;
Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (c) Zhang,
T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 193.
(2) (a) Gallagher, G.; Lavanchi, P. G.; Wilson, J. W.; Hieble, J.;
Demmarinis, R. M. J. Med. Chem. 1985, 28, 1533.
(b) Nagata, R.; Tokunaga, T.; Hume, W.; Umezone, T.;
Okazaki, U.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine,
J.; Seki, H.; Taiji, M.; Noguchi, H. J. Med. Chem. 2001, 44,
4641.
(3) (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36,
127. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int.
Ed. 2007, 46, 8748; Angew. Chem. 2007, 119, 8902.
(c) TrostB, M.; Jiang, C. Synthesis 2006, 369. (d) Lin, H.;
Danishefsky, S. J. Angew. Chem. Int. Ed. 2003, 42, 36;
Angew. Chem. 2003, 115, 38. (e) Zhou, F.; Liu, Y. L.; Zhou,
J. Adv. Synth. Catal. 2010, 352, 1381.
(16) Typical Experimental Procedure
Ph3P (10%) was added to a solution of alkene 1 (0.5 mmol)
and allenoate 2 (0.6 mmol) in 5 mL toluene at r.t. in the air.
The stirred mixture was allowed to react for given the time
in Table 2, and the process was monitored using TLC
detection. After completion of present reaction, the reaction
mixture was concentrated under vacuum. The residue was
purified by column chromatography on silica gel [silica:
200–300 mesh; eluant: PE–EtOAc] to afford the desired
product 3.
(4) For selected examples of total syntheses, see: (a) Greshock,
T. J.; Grubbs, A. W.; Tsukamoto, S.; Williams, R. M.
Angew. Chem. Int. Ed. 2007, 46, 2262; Angew. Chem. 2007,
119, 2312. (b) Grubbs, A. W.; Artman, G. D. I. I. I.;
Tsukamoto, S.; Williams, R. M. Angew. Chem. Int. Ed.
2007, 46, 2257; Angew. Chem. 2007, 119, 2307.
Selected Spectroscopic Data of Product 3
Compound 3a: White solid, mp 140.3–142.1 °C
(uncorrected). 1H NMR (500 MHz, CDCl3): d = 7.48–7.44
(m, 2 H), 7.16 (t, J = 7.5 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 1 H),
4.02–3.91 (m, 2 H), 3.80 (dd, J1 = 17.5 Hz, J2 = 2.0 Hz, 1 H),
3.48 (dd, J1 = 17.5 Hz, J2 = 3.0 Hz, 1 H), 3.30 (s, 3 H), 0.99
(t, J = 7.0 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = 171.7,
161.1, 144.6, 142.7, 136.5, 131.4, 125.5, 123.8, 123.5,
114.3, 112.9, 109.3, 64.8, 61.4, 43.5, 45.1, 27.1, 13.8. IR
(KBr): n = 3066, 2940, 2255, 1712, 1613, 1475. MS (ESI):
m/z = 322 [M + H+], 344 [M + Na+], 360 [M + K+]. HRMS
(MALDI): m/z calcd for C18H16N3O3+ [M + H]+: 322.1193;
found: 322.1186.
(c) Greshock, T. J.; Grubbs, A. W.; Jiao, P.; Wicklow, D. T.;
Gloer, J. B.; Williams, R. M. Angew. Chem. Int. Ed. 2008,
47, 3573; Angew. Chem. 2008, 120, 3629. (d) Trost, B. M.;
Cramer, N.; Bernsmann, H. J. Am. Chem. Soc. 2007, 129,
3086.
(5) For reviews on phosphine-catalyzed reactions, see: (a) Lu,
X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
(b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035. (c) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev.
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