Tertiary amine-catalyzed chemoselective and asymmetric [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones

Article abstract of DOI:10.1021/ol201776h

A chemo- and enantioselective [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones was catalyzed by a β-ICD O-MOM ether 1c, affording spirocyclic 2-oxindoles bearing an unusual cyclopentadiene motif in outstanding ee v

Full text of DOI:10.1021/ol201776h

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4584–4587
Tertiary Amine-Catalyzed Chemoselective
and Asymmetric [3 þ 2] Annulation of
MoritaꢀBaylisꢀHillman Carbonates of
Isatins with Propargyl Sulfones
Jing Peng,† Xin Huang,† Lin Jiang,† Hai-Lei Cui,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry, Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, China, and State Key Laboratory of Biotherapy,
West China Hospital, Sichuan University, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received July 3, 2011
ABSTRACT
A chemo- and enantioselective [3 þ 2] annulation of MoritaꢀBaylisꢀHillman carbonates of isatins with propargyl sulfones was catalyzed by a
β-ICD O-MOM ether 1c, affording spirocyclic 2-oxindoles bearing an unusual cyclopentadiene motif in outstanding ee values (up to >99%). More
electrophiles, such as N-phenylmaleimide, have been also utilized to deliver complex spirocyclic 2-oxindoles with good results.
The densely functionalized β-hydroxyl R-methylene car-
bonyl compounds, the so-called MoritaꢀBaylisꢀHillman
(MBH) products, have attracted much attention in syn-
thetic organic chemistry over the past decades.1 As much
effort has been devoted to the development of an enantio-
selective (aza) MBH reaction,2 recently, there has been an
increasing interest focused on the catalytic dynamic asym-
metric transformations of racemic MBH products. In
particular, great progress has been made in the asymmetric
allylic alkylation of MBH carbonates or acetates catalyzed
by either chiral Pd complexes3 or organic tertiary phos-
phines and amines.4,5 An asymmetric Michael additionꢀ
elimination pathway for MBH adducts has been also
reported but with very limited examples.6 On the other
hand, Lu and others have presented a series of phosphine
(4) For selected examples, see: (a) Cho, C.-W.; Krische, M. J. Angew.
Chem., Int. Ed. 2004, 43, 6689. (b) Du, Y.; Han, X.; Lu, X. Tetrahedron
Lett. 2004, 45, 4967. (c) 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. (d) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc.
2008, 130, 7202.
(5) For selected studies from this group, see: (a) Cui, H.-L.; Peng, J.;
Feng, X.; Du, W.; Jiang, K.; Chen, Y.-C. Chem.;Eur. J. 2009, 15, 1574.
(b) Cui, H.-L.; Feng, X.; Peng, J.; Jiang, K.; Chen, Y.-C. Angew. Chem.,
Int. Ed. 2009, 48, 5737. (c) Huang, J.-R; Cui, H.-L.; Lei, J.; Sun, X.-H.;
Chen, Y.-C. Chem. Commun. 2011, 47, 4784.
(6) (a) Ramachandran, P. V.; Madhi, S.; Bland-Berry, L.; Reddy,
M. V. R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005, 127, 13450. (b)
Chen, C.-G.; Hou, X.-L.; Pu, L. Org. Lett. 2009, 11, 2073. (c) Qiao, Z.;
Shafiq, Z.; Liu, L.; Yu, Z.-B.; Zheng, Q.-Y.; Wang, D.; Chen, Y.-J.
Angew. Chem., Int. Ed. 2010, 49, 7294. (d) Gendrineau, T.; Genet, J.-P;
Darses, S. Org. Lett. 2010, 12, 308.
(7) (a) Du, Y.; Lu, X.; Zhang, C. Angew. Chem., Int. Ed. 2003, 42,
1035. (b) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7, 1987. (c) Zheng, S.;
Lu, X. Org. Lett. 2008, 10, 4481. (d) Ye, L.-W.; Sun, X.-L.; Wang, Q.-G.;
Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 5951. (e) Basavaiah, D.; Roy,
S. Org. Lett. 2008, 10, 1819. (f) Zheng, S.; Lu, X. Org. Lett. 2009, 11,
3978. (g) Zhou, R.; Wang, J.; Song, H.; He, Z. Org. Lett. 2011, 13, 580.
† West China School of Pharmacy.
‡ West China Hospital.
(1) For reviews, see: (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811. (b) Declerck, V.; Martinez, J.; Lamaty, F.
Chem. Rev. 2009, 109, 1. (c) Singh, V.; Batra, S. Tetrahedron 2008, 64,
4511.
(2) For reviews, see: (a) Basavaiah, D.; Rao, K. V.; Reddy, R. J.
Chem. Soc. Rev. 2007, 36, 1581. (b) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem.
2007, 2905. (c) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int.
Ed. 2007, 46, 4614.
(3) (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 11262.
(b) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2002, 124,
11616. (c) Trost, B. M.; Thiel, O. R.; Tsui, H.-C. J. Am. Chem. Soc. 2003,
125, 13155. (d) Trost, B. M.; Tang, W.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 14785.
r
10.1021/ol201776h
Published on Web 08/04/2011
2011 American Chemical Society

(or sulfide)-catalyzed [3 þ 2], [3 þ 4], or [3 þ 6] annulation
reactions of MBH derivatives via allylic P (or S)-ylide
intermediates;7 unfortunately, the asymmetric variants
have been poorly developed,8 except for a notable chiral
bisphosphine-catalyzed [3 þ 2] example presented by
Barbas very recently.9 Therefore, the development of a
catalytic system that can realize the asymmetric annula-
tions of MBH derivatives to construct enantioenriched
carbo- or heterocycles would be highly desirable, especially
with more air-stable Lewis basic amines.
Recently, we reported an electrophilic process to deliver
2-oxindoles bearing C3-quaternary stereocenters through
asymmetric allylic alkylationof MBH carbonatesof isatins
(Scheme 1, approach a) by the catalysis of β-isocupreidine
1a (β-ICD; see Table 1).10 We envisioned that, as a result of
the highly electron-withdrawing ability of the 2-oxindole
motif, the vinylogous proton of the ammonium I would be
easily removed by the in situ generated tert-butoxy anion in
the absence of an additional acidic reagent, thus forming a
nucleophilic N-ylide II (approach b).11 Subsequently, an
asymmetric [3 þ 2] annulation to construct chiral five-
membered spirocyclic 2-oxindoles, which have been wit-
nessed in numerous biologically active materials,12 would
be achieved by the reaction with suitable activated unsa-
turated systems.13 It should be noted that tertiary amines
have been rarely applied in the transformations of MBH
adducts via allylic N-ylides even in a racemic manner.14
chalcone, etc., resulted in no success at room tempera-
ture,15 we were able to detect a spirocyclic 2-oxindole
product 4a incorporating a cyclopentadiene moiety when
a propargyl phenyl sulfone 3a was applied (3a easily
isomerizes to allenyl phenyl sulfone by base catalysis, which
should be the actual electrophile),16 albeit in very low yield
(Table 1, entry 1). Hence the expected [3 þ 2] annulation
occurred, followed by a domino isomerization sequence to
give the thermally more stable conjugated counterpart.
Nevertheless, sulfone 3a was consumed rapidly because of
its self-dimerization and other side reactions by nucleo-
philic amine catalysis.17,18 To our delight, we observed that
chiral β-ICD 1a exhibited a highly catalytic preference to
[3 þ 2] annulation pathway, though the yield was still
unsatisfying due to the sluggish conversion, while the
enantioselectivity was inspiring (entry 2).19 The reaction
˚
could be slightly enhanced by adding 4 A molecular sieves
(entry 3). We reasoned that the acidic hydroxyl group of β-
ICD 1a would affect the deprotonation of intermediate I to
generate active N-ylide II. Later it was very pleasing to find
that the desired reaction could be greatly accelerated by the
catalysis of β-isoquinidine 1b,20 and more importantly,
excellent enantioselectivity was obtained (entry 4).21 Sub-
sequently, a few modified β-ICD derivatives 1cꢀ1i in
consideration of steric and electronic features were further
prepared and tested (entries 5ꢀ11), and the best results in
regard to yield and ee were gained by applying a new β-
ICD O-MOM ether 1casthe catalyst(entry 5). Itshould be
noted that the catalytic efficacy was dramatically de-
creased when β-ICD O-triflate 1e and β-isocinchonine 1i
were used, indicating that the electron-rich characteristics
of Lewis bases are significant to the catalysis (entries 7 and
11). In addition, the annulation could proceed smoothly at
Scheme 1. Tertiary Amine-Catalyzed Asymmetric Transfor-
mations of MBH Carbonates Derived from Isatins
(13) For selected catalytic asymmetric reactions to construct chiral
spirocyclic 2-oxindoles, see: (a) Trost, B. M.; Cramer, N.; Silverman, S. M.
J. Am. Chem. Soc. 2007, 129, 12396. (b) Hojo, D.; Noguchi, K.; Hirano, M.;
Tanaka, K. Angew. Chem., Int. Ed. 2008, 47, 5820. (c) Chen, X.-H.; Wei, Q.;
Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (d)
Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song,
M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200. (e)
€
Antonchick, A. P.; Gerding-Reimers, C.; Catarinella, M.; Schurmann, M.;
Preut, H.; Ziegler, S.; Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735. (f)
Voituriez, A.; Pinto, N.; Neel, M.; Retailleau, P.; Marinetti, A. Chem.;Eur.
J. 2010, 16, 12541. (g) Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.; Shen, F.; Wang,
R. J. Am. Chem. Soc. 2010, 132, 15328.
(14) Viswambharan, B.; Selvakumar, K.; Madhavan, S.; Shanmugam,
P. Org. Lett. 2010, 12, 2108.
(15) For phosphine-catalyzed annulation of bromo derivatives of
MBH adducts of isatin in a racemic form, see: Selvakumar, K.;
Vaithiyanathan, V.; Shanmugam, P. Chem. Commun. 2010, 46, 2826.
(16) Liu, H.; Leow, D.; Huang, K.-W.; Tan, C.-H. J. Am. Chem. Soc.
2009, 131, 7212.
Although the initial screenings in the DABCO-catalyzed
reactions of MBH carbonate 2a with a few activated
olefins, such as methyl acrylate, vinyl phenyl sulfone, and
(17) (a) For a review, see: Back, T. G.; Clary, K. N.; Gao, D. Chem.
Rev. 2010, 110, 4498. (b) Cowen, B. J.; Saunders, L. B.; Miller, S. J. J.
Am. Chem. Soc. 2009, 131, 6105. (c) Denis, J.-B.; Masson, G.; Retailleau,
P.; Zhu, J. Angew. Chem., Int. Ed. 2011, 50, 5356.
(18) Propargyl phenyl sulfone 3a was also consumed rapidly in the
presence of a tertiary phosphine such as Ph3P.
(8) (a) 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. (b) Deng,
H.-P.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 3348.
(9) Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem. Soc.
2011, 133, 4672.
(10) Peng, J.; Huang, X.; Cui, H.-L.; Chen, Y.-C. Org. Lett. 2010, 12, 4260.
(11) For a review, see: Gaunt, M. J.; Johansson, C. C. C. Chem. Rev.
2007, 107, 5596.
(12) (a) Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature 2008, 455,
323. (b) Miller, K. A.; Tsukamoto, S.; Williams, R. M. Nat. Chem. 2009,
1, 63. (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. (d)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(19) Simple quinidine or (DHQD)2AQN showed no catalytic activ-
ity, while quinidine O-Me or quinine O-Me ether afforded poor results
(28%, 30% ee, or 36%, ꢀ46% ee, respectively).
€
€
(20) (a) Waldmann, H.; Khedkar, V.; Duckert, H.; Schurmann, M.;
Oppel, I. M.; Kumar, K. Angew. Chem., Int. Ed. 2008, 47, 6869. (b) For a
review, see: Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 7496.
(21) Other solvents(toluene, PhCF3, DCM, CHCl3, and 1,4-dioxane)
could be well tolerated (>80% yield, 85ꢀ90% ee).
Org. Lett., Vol. 13, No. 17, 2011
4585

Table 1. Screening Studies of [3 þ 2] Annulation of MBH
Carbonate 2a and Propargyl Phenyl Sulfone 3aa
Table 2. Substrate Scope in [3 þ 2] Annulation of MBH Car-
bonates 2 and Propargyl Phenyl Sulfone 3aa
temp
t
yieldb
(%)
eec
entry
R1
R2
(°C)
(h)
(%)
1
Boc
Me
H
H
0
24
24
12
12
12
24
24
24
24
24
24
12
4a, 84
4c, 87
4d, 94
4e, 93
4f, 88
4g, 72
4h, 74
4i, 63
4j, 81
4k, 83
4l, 71
4m, 82
99d
98
98
>99
96
95
97
97
97
97
91
96
2
0
3
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Me
5-Me
5-MeO
5,7-Me2
5-F
0
4
0
entry
cat.
yieldb (%)
eec (%)
5
0
6
rt
rt
rt
rt
rt
rt
0
1d
2d
3
DABCO
1a
<20
22
40
80
82
75
40
61
62
80
63
84
34
72
ꢀ
7
5-Cl
50
50
91
94
94
45
86
91
75
7
8
5-Br
1a
9
5-I
4
1b
1c
10
11
12
5-CF3O
7-F
5
6
1d
1e
5-Br
7
8
1f
a Reactions were performed with 0.12 mmol of 2, 0.1 mmol of 3a,
0.01 mmol of 1c, and 4 A MS (30 mg) in m-xylene (1 mL). b Yield of
9
1g
˚
isolated product. c Determined by HPLC on a chiral stationary phase.
d The absolute configuration of 4a was determined by X-ray analysis; see
the Supporting Information. The other products were assigned by
analogy.
10
11
12e
13f
14e,g
1h
1i
1c
99
94
99
1c
1c
substrates could provide beneficial effects on the annula-
tion process (entry 12 vs 8).
a Unless otherwise noted, reactions were performed with 0.12 mmol
˚
of 2a, 0.1 mmol of 3a, 0.01 mmol of catalyst, and 4 A MS (30 mg) in m-
xylene (1 mL) at rt under aerobic conditions. b Yield of isolated product
4a. c Determined by HPLC on a chiral stationary phase. d Without
adding 4 A MS. e At 0 °C. f 2b was used, and the data were related to
˚
Scheme 2. More Expansions of [3 þ 2] Annulationsa
4b. g At 0.5 mmol scale.
0 °C, and the enantiomerically pure product 4a was
isolated in high yield (entry 12). MBH acetate 2b exhibited
a much lower reactivity with sulfone 3a under the same
conditions, probably because the CH3CO2 anion could not
efficiently produce the reactive N-ylide on account of its
decreased basicity (entry 13). Finally, we tested the reac-
tion at a larger scale by the catalysis of 1c. The same
enantiopure product could be obtained with good yield
(entry 14).
Consequently, we investigated a number of MBH car-
bonates 2 derived from diverse isatins with propargyl
phenyl sulfone 3a by the catalysis of β-ICD O-MOM ether
1c. The results are summarized in Table 2. A N-methyl
protected 2-oxindole substrate showed the similar reactiv-
ity and enantiocontrol in the annulation reaction (Table 2,
entry 2). MBH carbonates bearing electron-donating sub-
stituents on the aryl ring exhibited better reactivity, and
excellent yields and enantioselectivity were obtained
(entries 3ꢀ5). On the other hand, a slower reaction rate
was observed for 2-oxindole substrates with electron-with-
drawing groups even at room temperature, but the ee
values were still remarkable (entries 6ꢀ11). Nevertheless,
the introduction of a N-methyl group in such a type of
a Unless otherwise noted, reactions were performed with 0.12 mmol
˚
of MBH carbonate, 0.1 mmol of electrophile, 0.01 mmol of 1c. and 4 A
MS (30 mg) in m-xylene (1 mL) at rt for 24 h. bAt 0 °C for 12 h. cFor 48 h.
We explored more propargyl sulfones and other electro-
philes in 1c-catalyzed [3 þ 2] annulations. A propargyl
2-pyridyl sulfone afforded excellent results (Scheme 2, 4n).
Nevertheless, the reaction became quite sluggish for a γ-
substituted propargyl sulfone even bearing a more elec-
tron-withdrawing benzothiazol-2-yl group, while the
4586
Org. Lett., Vol. 13, No. 17, 2011

enantioselectivity was still satisfactory (4o). Dimethyl but-
2-ynedioate reacted with MBH carbonate 2a smoothly,
and a multifunctional product5 was produced in high yield
and enantiopurity. On the other hand, some activated
olefins have been tested for the synthesis of 2-oxindoles
with a spiro cyclopentene structure.9 The reaction of
methyl (E)-4-oxo-4-phenyl-but-2-enoate and 2a proceeded
well at room temperature, but the diastereo- and enantios-
electivity of adduct 6 were moderate. Importantly,
N-phenylmaleimide could be efficiently utilized, and tetra-
cyclic heterocycles 7a and 7b were prepared with remark-
able dr and ee values. Nevertheless, other activated olefins,
such as nitroolefins, did not provide the desired cycload-
ducts under current catalytic conditions and remain to be
explored.
Scheme 3. Synthetic Transformations of Multifunctional Ad-
ducts
The multifunctional anulation adducts allow some syn-
thetic transformations with high chemo- and regioselec-
tivity. As outlined in Scheme 3, the Pd-catalyzed Suzuki or
Heck reaction could be smoothly conducted with halo-
substituted products 4i or 4j, thus delivering the further
functionalized spirocyclic oxindoles 8 and 9, respectively,
without affecting the cyclopentadiene moiety. More im-
portantly, we found that an R,β-unsaturated sulfone motif
exhibits higher electrophilicity, and a [2 þ 1] annulation
occurred with remarkable diastereoselectivity by employ-
ing CH3NO2 as a nucleophilic methylene transfer rea-
gent.22 The fused cyclopropane derivatives 10a and 10b
bearing three contiguous quaternary chiral centers were
efficiently constructed with retained enantiopurity.23
In conclusion, we have developed the first highly chemo-
and enantioselective [3 þ 2] annulation of Moritaꢀ
BaylisꢀHillman carbonates of isatins with propargyl sul-
fones by the catalysis of a chiral tertiary amine β-ICD
O-MOM ether (up to >99% ee). The reaction proceeds
via formal dipolar cycloaddition of in situ generated allylic
N-ylide and allenyl sulfone followed by a CdC bond
isomerization sequence, giving an efficient protocol to
construct spirocyclic2-oxindolesincorporating anunusual
cyclopentadiene motif. Moreover, the catalytic system has
been expanded to the synthesis of spirocyclic 2-oxindoles
with more structural diversity, which might be useful in
medicinal chemistry. Currently studies are actively under-
way to investigate the catalytic and synthetic utilities
reported in this work.
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation
of China (20972101 and 21021001) and National Basic
Research Program of China (973 Program) (2010CB-
833300).
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra and HPLC
chromatograms of the products, cif files of enantiopure
4a, 7b, and 10a. This material is available free of charge
via the Internet at http://pubs.acs.org.
(22) (a) Annen, K.; Hofmeister, H.; Laurent, H.; Seeger, A.; Weichert,
R. Chem. Ber. 1978, 111, 3094. (b) Ono, N.; Yanai, T.; Hamamoto, I.;
Kaminura, A.; Kaji, A. J. Org. Chem. 1985, 50, 2807.
(23) For reviews on cyclopropane compounds, see: (a) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. Rev. 2003, 103,
977. (b) Pellissier, H. Tetrahedron 2008, 64, 7041.
Org. Lett., Vol. 13, No. 17, 2011
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