Highly regio- and diastereoselective construction of spirocyclopenteneoxindoles through phosphine-catalyzed [3 + 2] annulation of Morita-Baylis-Hillman carbonates with isatylidene malononitriles

Article abstract of DOI:10.1021/ol201094f

Phosphine-catalyzed highly regio- and diastereoselective [3 + 2] annulation of Morita-Baylis-Hillman (MBH) carbonates with isatylidene malononitriles has been disclosed to give the corresponding spirocyclopenteneoxindoles in excellent yields under mild co

Full text of DOI:10.1021/ol201094f

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3348–3351
Highly Regio- and Diastereoselective
Construction of Spirocyclopenteneoxindoles
through Phosphine-Catalyzed [3 þ 2]
Annulation of MoritaꢀBaylisꢀHillman
Carbonates with Isatylidene Malononitriles
Hong-Ping Deng, Yin Wei, and Min Shi*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032 China
mshi@mail.sioc.ac.cn
Received April 26, 2011
ABSTRACT
Phosphine-catalyzed highly regio- and diastereoselective [3 þ 2] annulation of MoritaꢀBaylisꢀHillman (MBH) carbonates with isatylidene
malononitriles has been disclosed to give the corresponding spirocyclopenteneoxindoles in excellent yields under mild conditions. A plausible
reaction mechanism has also been proposed on the basis of previous literature.
MoritaꢀBaylisꢀHillman (MBH) acetates and carbo-
nates as synthetically useful synthons have attracted sig-
nificant attention from organic chemists.1 The transfor-
mations of MBH acetates and carbonates have been
directed toward the following three styles: substitution of
MBH acetates and carbonates at the β- or β0-position
withpronucleophiles(Scheme1, eqs1 and 2);2,3 annulation
of MBH acetates and carbonates with electron-deficient
olefins in the presence of tertiary phosphine (Scheme 1,
(3) Selected papers on the asymmetric substitution of MBH acetates
and carbonates by nucleophiles: (a) Du, Y.-S.; Han, X.-L.; Lu, X.-Y.
Tetrahedron Lett. 2004, 45, 4967. (b) van Steenis, D. J. V. C.; Marcelli,
T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. Adv.
Synth. Catal. 2007, 349, 281. (c) Jiang, K.; Peng, J.; Cui, H.-L.; Chen,
Y.-C. Chem. Commun. 2009, 45, 3955. (d) Cui, H.-L.; Peng, J.; Feng, X.;
Du, W.; Jiang, K.; Chen, Y.-C. Chem.;Eur. J. 2009, 15, 1574. (e) Cui,
H.-L.; Huang, J.-R.; Lei, J.; Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C.
Org. Lett. 2010, 12, 720. (f) Peng, J.; Huang, X.; Cui, H.-L.; Chen, Y.-C.
Org. Lett. 2010, 12, 4260. (g) Zhang, S.-J.; Cui, H.-L.; Jiang, K.; Li, R.;
Ding, Z.-Y.; Chen, Y.-C. Eur. J. Org. Chem. 2009, 5804. (h) Cui, H.-L.;
Feng, X.; Peng, J.; Lei, J.; Jiang, K.; Chen, Y.-C. Angew. Chem., Int. Ed.
2009, 48, 5737. (i) Hu, Z.-K.; Cui, H.-L.; Jiang, K.; Chen, Y.-C. Sci.
Chin. Ser. B-Chem. 2009, 52, 1309. (j) Feng, X.; Yuan, Y.-Q.; Cui, H.-L.;
Jiang, K.; Chen, Y.-C. Org. Biomol. Chem. 2009, 7, 3660. (k) Hong, L.;
Sun, W.-S.; Liu, C.-X.; Zhao, D.-P.; Wang, R. Chem. Commun. 2010, 46,
2856. (l) Sun, W.-S.; Hong, L.; Liu, C.-X.; Wang, R. Org. Lett. 2010, 12,
391. (m) Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetrahedron: Asymmetry
2007, 18, 1990. (n) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc.
2008, 130, 7202. (o) Ma, G.-N.; Cao, S.-H.; Shi, M. Tetrahedron:
Asymmetry 2009, 20, 1086. (p) Deng, H.-P.; Wei, Y.; Shi, M. Eur. J.
Org. Chem. 2011, 1956. (q) Yang, Y.-L.; Pei, C.-K.; Shi, M. Org. Biomol.
Chem. 2011, 9, 3349.
(1) For the latest reviews on MoritaꢀBaylisꢀHillman reactions, see:
(a) Dederck, V.; Mattinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1. (b)
Ma, G.-N.; Jiang, J.-J.; Shi, M.; Wei, Y. Chem. Commun. 2009, 45, 5496.
(c) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110,
5447.
(2) Selected papers on the substitution of MBH acetates and carbo-
nates by nucleophiles: (a) Im, Y. J.; Na, J. E.; Kim, J. N. Bull. Korean
Chem. Soc. 2003, 24, 511. (b) Im, Y. J.; Lee, C. G.; Kimb, H. R.; Kim,
J. N. Tetrahedron Lett. 2003, 44, 2987. (c) Lee, K. Y.; Gowrisankar, S.;
Kim, J. N. Bull. Korean Chem. Soc. 2004, 25, 413. (d) Park, D. Y.;
Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26, 1440. (e)
Lee, H. S.; Kim, S. J.; Kim, J. N. Bull. Korean Chem. Soc. 2006, 27, 1063.
(f) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Tetrahedron Lett. 2007, 48,
3105. (g) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org. Lett. 2004, 6,
1337. (h) Cho, C.-W.; Krische, M. J. Angew. Chem., Int. Ed. 2004, 43,
6689. (i) Park, H.; Cho, C.-W.; Krische, M. J. J. Org. Chem. 2006, 71,
7892. Also see: (j) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129,
12632. (k) Zhu, X.-F.; Henry, C.-E.; Kwon, O. J. Am. Chem. Soc. 2007,
129, 6722. (l) Mercier, E.; Fonovic, B.; Henry, C.; Kwon, O.; Dudding,
T. Tetrahedron Lett. 2007, 48, 3617. (m) Dudding, T.; Kwon, O.;
Mercier, E. Org. Lett. 2006, 8, 3643. (n) Tran, Y. S.; Kwon, O. Org.
Lett. 2005, 7, 4289.
r
10.1021/ol201094f
Published on Web 06/08/2011
2011 American Chemical Society

eq 3);4 dimerization of MBH acetates and carbonates
if R is an alkyl group in the presence of Lewis base
(Scheme 1, eq 4).5
The prenylated indole alkaloids containing a spirocy-
clopenteneoxindole scaffold isolated from both terrestrial
and marine fungi have attracted intense research efforts
owing to their complex molecular structures and range of
biological activities.8 Recently, our group has reported an
efficient method to construct this important structural motif
through annulation of isatin-derived electron-deficient al-
kenes with allenoate in the presence of phosphine.9 Herein,
we to disclose a phosphine-catalyzed highly regio- and dias-
tereoselective [3 þ 2] annulation of MBH carbonates with
isatylidene malononitriles to produce spirocyclopenteneox-
indoles in good yields under mild conditions (Scheme 2). It
should be also mentioned here that during our preparation of
this manuscript, Barbas and his co-workers have reported a
novel asymmetric [3 þ 2] cycloaddition of MBH carbonates
with methyleneindolinones in the presence of a chiral phos-
phine to give the corresponding spirocyclopentaneoxindoles,
which have different regioselectivities from ours, in good
yields and high ee values.10
Scheme 1. Transformations of MBH Acetates or Carbonates
Scheme 2. Phosphine-Catalyzed [3 þ 2] Annulations of Isatyli-
denes To Construct Spirocyclopenteneoxindoles
Among these transformations, annulation of MBH acet-
ates and carbonates with electron-deficient olefins is an ex-
tremely useful synthetic method to construct multifunctional
cyclic compounds because the in situ generated phosphorus
ylides from MBH acetates and carbonates in the presence of
tertiary phosphines are very reactive 1,3-dipoles in a variety
of annulations. In this aspect, Lu and co-workers first re-
ported a series of intra- and intermolecular [3 þ n] annula-
tions (n = 2, 4, 6) using MBH carbonates as 1,3-dipoles with
various electron-deficient olefins catalyzed by tertiary phos-
phine, affording the corresponding cycloadducts in good
yields and high regioselectivities under mild conditions.4aꢀf
More recently, Zhang, Huang, and He and co-workers have
also developed several MBH acetates and carbonates in-
volved [4 þ 1] annulations to give the annulation products in
high yields, respectively.6 Furthermore, Tang’s group uti-
lized spirobiindane-based chiral phosphines as catalysts to
provide the corresponding intramolecular [3 þ 2] annulation
products in good yields along with high ee values in 2010.7
We initially utilized 20 mol % of PPh3 as catalyst and
ethyl 2-((tert-butoxycarbonyloxy)(4-nitrophenyl)methyl)-
acrylate 1a (1.3 equiv) and 2-(1-benzyl-2-oxoindolin-3-
ylidene)malononitrile 2a (1.0 equiv) as substrates to
investigate the influence of solvents on this annulation reac-
tion. The results of these experiments are summarized in
Table 1. It was found that toluene is the best solvent in this
reaction, giving the corresponding annulation product 3a
in >99% yield along with >99:1 dr within 24 h (Table 1,
entries 1ꢀ6). The relative configuration of major product
(4) (a) Du, Y.-S.; Lu, X.-Y.; Zhang, C.-M. Angew. Chem., Int. Ed.
2003, 42, 1035. (b) Du, Y.-S.; Feng, J.-Q.; Lu, X.-Y. Org. Lett. 2005, 7,
1987. (c) Feng, J.-Q.; Lu, X.-Y.; Kong, A.-D.; Han, X.-L. Tetrahedron
2007, 63, 6035. (d) Zheng, S.-Q.; Lu, X.-Y. Org. Lett. 2008, 10, 4481. (e)
Zheng, S.-Q.; Lu, X.-Y. Tetrahedron Lett. 2009, 50, 4532. (f) Zheng,
S.-Q.; Lu, X.-Y. Org. Lett. 2009, 11, 3978. (g) Ye, L.-W.; Sun, X.-L.; Wang,
Q.-G.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951. (h) Zhou, R.; Wang,
J.-F.; Song, H.-B.; He, Z.-J. Org. Lett. 2011, 13, 580. (i) Cowen, B. J.; Miller,
J. S. Chem. Soc. Rev. 2009, 38,3102.(j)Wei,Y.;Shi,MAcc. Chem. Res. 2010,
43, 1005. (k) Marinetti, A.; Voituriez, A. Synlett 2010, 174.
(5) (a) Hoffmann, H. M. R.; Egger, U.; Poly, W. Angew. Chem., Int.
Ed. 1987, 26, 1015. (b) Poly, W.; Schomburg, D.; Hoffmann, H. M. R. J.
Org. Chem. 1988, 53, 3701. (c) Hoffmann, H. M. R.; Welchert, A.;
Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1990, 46, 5591. (d) Kim,
J. N.; Lee, H. J.; Lee, K. Y.; Gong, J. H. Synlett 2002, 173.
(8) Bond, R. F.; Boeyens, J. C. A.; Holzapfel, C. W.; Steyn, P. S. J.
Chem. Soc., Perkin Trans. 1 1979, 1751. (b) Williams, R. M.; Stocking,
E. M.; Sanz-Cevera, J. F. Top. Curr. Chem. 2000, 209, 97. (c) Williams,
R. M. Chem. Pharm. Bull. 2002, 50, 711. (d) Greshock, T. J.; Grubbs,
A. W.; Jiao, P.; Wicklow, D. T.; Gloer, J. B.; Williams, R. M. Angew.
Chem., Int. Ed. 2008, 47, 3573. (e) Miller, K. A.; Tsukamoto, S.;
Williams, R. M. Nat. Chem. 2009, 1, 63.
(6) (a) Chen, Z.-L.; Zhang, J.-L. Chem. Asian J. 2010, 5, 1542. (b) Xie,
P.-Z.; Huang, Y.; Chen, R.-Y. Org. Lett. 2010, 12, 3768. (c) Tian, J.-J.;
Zhou, R.; Sun, H.-Y.; Song, H.-B.; He, Z.-J. J. Org. Chem. 2011, 76,
2374.
(7) Wang, Q.-G.; Zhu, S.-F.; Ye, L.-W.; Zhou, C.-Y.; Sun, X.-L.;
Tang, Y.; Zhou, Q.-L. Adv. Synth. Catal. 2010, 352, 1914.
(9) (a) Zhang, X.-C.; Cao, S.-H.; Wei, Y.; Shi, M. Chem. Commun.
2011, 47, 1548. (b) Zhang, X.-C.; Cao, S.-H.; Wei, Y.; Shi, M. Org. Lett.
2011, 13, 1142.
(10) Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc.
2011, 133, 4672. The regiochemistry of the major product is different
from that of 3a.
Org. Lett., Vol. 13, No. 13, 2011
3349

1g as substrates afforded the desired products 3f and 3g
in 79% yield (dr = 8:1) and 94% yield (dr = 16:1),
respectively, after 72 h (Table 2, entries 6 and 7). How-
ever, we found that when dppb (10 mol %) instead of
PPh3 (20 mol %) was used as catalyst, the reactions also
proceeded efficiently, affording the cycloadducts 3gꢀk
in good yields along with good dr values within 24 h12
(Table 2, entries 7ꢀ11). Using MBH carbonate 1c as
substrate, we next examined its reactions with isatylidene
malononitriles 2bꢀg bearing different substituents on
their benzene rings or having different N-protecting
groups, and it was found that all of the reactions pro-
ceeded smoothly to produce the corresponding pro-
ducts 3lꢀq in excellent yields (88% f 99%) along with
good to excellent dr values (8:1 f 99:1) (Table 2, entries
12ꢀ17).
Table 1. Screening of Solvents and Catalysts
entry
cat
X
solvent
dra
7:1
yield (%) of 3ab
1
2
PPh3
20
20
20
20
20
20
20
10
20
20
20
10
5
CHCl3
toluene
DCM
88
>99
62
PPh3
>99:1
3:1
3
PPh3
4
PPh3
THF
7:1
88
5
PPh3
CH3CN
DMF
2:1
42
6
PPh3
1.5:1
14:1
49:1
3:1
38
7
PPh2Me
dppb
toluene
toluene
toluene
toluene
toluene
toluene
toluene
93
8
98
9
PPhMe2
PBu3
66
10
11
12c
13d
4:1
72
Table 2. Substrate Scope for [3 þ 2] Annulation of Isatylidene
DABCO
PPh3
Malononitrile Derivatives with MBH Carbonates
>99:1
>99:1
>99
>99
PPh3
a Determined by 1H NMR spectroscopic data of crude products.
b Yield was determined by 1H NMR spectroscopic data of crude
products using 1,3,5-trimethoxybenzene as a calibrated internal stan-
dard. c Reaction was carried out at room temperature for 30 h. d Reac-
tion was carried out at room temperature for 48 h.
entry
R1
R2
R3
dra
>99:1
yield (%) of 3b
was determined by X-ray crystal structure.11 Its ORTEP
drawing is shown in the Supporting Information, and the
corresponding CIF data are also presented in the Supporting
Information. The examination of other phosphines such as
PPh2Me, PPhMe2, dppb, or PBu3 and 1,4-diazabicyclic-
[2,2,2]octane (DABCO) revealed that PPh3 was the best
catalyst for this reaction and DABCO did not catalyze this
reaction (Table 1, entries 7ꢀ11). Reducing the employed
amounts of PPh3 to 10 or 5 mol % also gave 3a in 99%
yield and >99:1 dr upon prolonging the reaction time
(Table 1, entries 12 and 13).
1
2
3
4
5
6
7
8
9
1a, p-NO2C6H4 2a, H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
3a, >99 (86)
3b, 95 (89)c
3c, >99 (98)
3d, 92 (85)c
3e, 90 (81)f
1b, m-NO2C6H4
1c, p-CNC6H4
1d, p-BrC6H4
1e, p-ClC6H4
1f, o-ClC6H4
1g, C6H5
H
H
H
H
H
H
H
H
H
H
19:1
>99:1
12:1
10:1
8:1d, 4:1e 3f, 79d (73)c, 67e
16:1d, 23:1e 3g, 94d, 93e (84)c
1h, p-MeC6H4
1i, p-MeOC6H4
22:1e
19:1e
12:1e
2:1e
3h, 92e (86)c
3i, 94e (89)c
3j, 86e (81)c
3k, 69e (56)c
3l, 98 (97)c
3m, 99 (90)c
3n, 98 (90)c
3o, >99 (85)c
3p, 96 (89)c
3q, 88 (83)c
10 1j, H
11 1k, Me
12 p-CNC6H4
13 p-CNC6H4
14 p-CNC6H4
15 p-CNC6H4
16 p-CNC6H4
17 p-CNC6H4
2b, 5-Br Bn
2c, 5-Cl Bn
2d, 5-Me Bn
2e, 6-Br Bn
49:1
99:1
49:1
>99:1
Having identified the optimal reaction conditions, we
next set out to examine the scope and limitations of this
[3þ 2] annulation reaction, and the results are summarized in
Table 2. Using isatylidene malononitrile 2a as substrate, we
examined its reaction with MBH carbonates 1bꢀk derived
from various aromatic or aliphatic aldehydes and found that
the reactions of 2a with MBH carbonates 1bꢀe derived from
electron-deficient aromatic aldehydes proceeded smoothly
to give the corresponding products 3bꢀe in excellent
yields (90%f99%) along with high diastereoselectivities
(dr =10:1f99:1) (Table 2, entries 2ꢀ5). As for MBH
carbonate 1f having a chlorine substituent at the ortho-
position of the benzene ring, MBH carbonate 1g and MBH
carbonates 1h and 1i bearing an electron-donating group on
their benzene rings as well as MBH carbonates 1j and 1k
derived from aliphatic aldehydes, the reactions became
sluggish, presumably due to the steric or electronic effect,
respectively. For example, using MBH carbonates 1f and
H
H
2f, allylic 24:1
2g, Me 8:1
a Determined by1 H NMR spectroscopic data of crude products.
b Yield was determined by1H NMR spectroscopic data of crude pro-
ducts using 1,3,5-trimethoxybenzene as a calibrated internal standard.
c Isolated yield of the major product. d Reactions were performed for 72
h. e Reactions were carried out for 24 h in the presence of dppb (10 mol
%).
We have further explored the scope of isatylidenes 2 in
this phosphine-catalyzed annulation under standard con-
ditions and found that isatylidene cyanoacetate 2h could
also undergo this annulation reaction smoothly to give the
corresponding cycloadduct cis-5a in 78% isolated yield
along with a 4:1 dr (cis:trans) value (Scheme 3). The relative
configuration of the major diastereomer cis-5a has been also
determined by its X-ray crystal structure.13 Its ORTEP
drawing and the corresponding CIF data are presented in
(12) The dr value of 3j was the ratio of two regioisomers.
(13) The crystal data of cis-5a have been deposited in the CCDC with
no. 812838.
(11) The crystal data of 3a (major product) have been deposited in the
CCDC with no. 805747.
3350
Org. Lett., Vol. 13, No. 13, 2011

carbonate to take off carbon dioxide and t-BuOH, afford-
ing phosphorus ylide I. Then the nucleophilic attack of
phosphorus ylide I at the 3-position of isatylidene mal-
ononitrile with its C1-terminal produces intermediate II,
which undergoes Michael addition at the R-position of
phosphorus cation to generate intermediate III. The elim-
ination of PPh3 along with the double bond formation
furnishes the corresponding spirocyclopenteneoxindole
product and completes the catalytic cycle. The diastereos-
electivity of this reaction is perhaps controlled by steric
effects as a stepwise process.
Scheme 3. [3 þ 2] Annulation from MBH Carbonate 1a or MBH
Acetate 1l with Other Isatylidene Derivatives
Scheme 5. Plausible Reaction Mechanism
the Supporting Information. When isatylidene derivatives
2i (R1= R2 = CO2Et) and 2j (R1= NO2, R2 = H) were
used as substrates, no reaction occurred under the standard
conditions (Scheme 3). The reaction of MBH acetate 1l with
2a also proceeded smoothly to give the corresponding
cycloadduct 6a in 60% isolated yield along with 4:1 dr value
in toluene under reflux for 24 h (Scheme 3).
The chiral bifunctional thioureaꢀphosphine catalyst
TP, which was an effective catalyst for the asymmetric
allylic amination of MBH acetates,3p was also fairly
effective in the [3 þ 2] annulation of MBH carbonate 1c
with 2a in toluene at room temperature, giving the corre-
sponding major cycloadduct 3c in 92% isolated yield along
with 9:1 dr and 74% ee value (Scheme 4). The exploration
of more effective chiral phosphines is undergoing.
In summary, we have found and developed an interesting
phosphine-catalyzed highly regio- and diastereoselective
[3 þ 2] annulation of MBH carbonates with isatylidene
malononitriles, affording the corresponding functionalized
spirocyclopenteneoxindoles in good to excellent yields un-
der mild conditions. A plausible reaction mechanism has
also been proposed on the basis of previous literature and
our own investigations (Scheme 5). Efforts are in progress
toward the development of an asymmetric version of this
reaction and in the application of this new methodology to
synthesize interesting biologically active compounds.
Scheme 4. Asymmetric [3 þ 2] Annulation Catalyzed by Chiral
Bifunctional Thiourea-Phosphine Catalyst TP
Acknowledgment. We thank the National Basic Re-
search Program of China (973)-2010CB833302 and the
National Natural Science Foundation of China for finan-
cial support (21072206, 20472096, 20872162, 20672127,
20821002, and 20732008).
Supporting Information Available. Spectroscopic data
and NMR charts of the compounds shown in Tables 1
and 2, Scheme 3, X-ray crystal data of major diastereo-
mers 3a and cis-5a, as well as detailed descriptions of
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
On the basis of above experimental results and Lu’s
work,4c a plausible reaction mechanism has been outlined
in Scheme 4. PPh3 attacks from the β-position of MBH
Org. Lett., Vol. 13, No. 13, 2011
3351