Asymmetric michael addition of oxindoles to allenoate catalyzed by N-acyl aminophosphine: Construction of functionalized oxindoles with quaternary stereogenic center

Article abstract of DOI:10.1002/adsc.201300695

A novel reaction between ethyl allenoate and oxindoles that enables the asymmetric synthesis of 3,3-bisubstituted oxindoles with our previously established bifunctional N-acyl aminophosphine catalysts is reported. These products bearing a chiral quaternary carbon center at the C-3 position of the oxindoles may have potential significance in the synthesis of related structures. The best performance of these processes provides adducts with 92% yield and 94% ee.

Full text of DOI:10.1002/adsc.201300695

COMMUNICATIONS
DOI: 10.1002/adsc.201300695
Asymmetric Michael Addition of Oxindoles to Allenoate
Catalyzed by N-Acyl Aminophosphine: Construction of
Functionalized Oxindoles with Quaternary Stereogenic Center
Jinhao Chen,a Yuepeng Cai,a,* and Gang Zhaob,*
a
School of Chemistry and Environment, South China Normal University, Key Laboratory of the Energy Conversion and
Energy Storage Materials of Guangzhou City, Guangzhou 510006, China, and South China Normal University,
Guangzhou 510006, Peopleꢀs Repiblic of China
Fax : (+86)-20-8521-5865; phone: (+86)-20-3303-3475; e-mail: caiyp@scnu.edu.cn
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, 345 Lingling Road, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; phone: (+86)-21-5492-5182; e-mail: zhaog@mail.sioc.ac.cn
Received: August 1, 2013; Published online: January 8, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300695.
Abstract: A novel reaction between ethyl allenoate
and oxindoles that enables the asymmetric synthesis
of 3,3-bisubstituted oxindoles with our previously
established bifunctional N-acyl aminophosphine
catalysts is reported. These products bearing
a chiral quaternary carbon center at the C-3 posi-
tion of the oxindoles may have potential signifi-
cance in the synthesis of related structures. The best
performance of these processes provides adducts
with 92% yield and 94% ee.
Keywords: allenoates; asymmetric catalysis; chiral
phosphines; Michael addition; oxindoles
Figure 1. Oxindole structures in natural products.
Oxindoles are important structural skeletons preva-
lently occurring in many natural products and bioac-
tive molecules.[1] Especially those featuring a stereo-
The phosphine-catalyzed reactions with allenes
genic quaternary carbon center at the C-3 position have exhibited divergent reactivities derived from the
(Figure 1) have stimulated considerable research en- versatility of the zwitterionic intermediate, which
thusiasm due to the great substitution effect on the could act as a nucleophile or an electrophile, even
biological activities of these compounds. Therefore, combined with amphiphiles. When the activated p
the development of synthetic routes to construct a C- system acts as nucleophilic species, the reactions with
3 quaternary stereogenic center with control of the various types of electrophiles like electron-deficient
absolute configuration is of paramount importance. olefins,[4] imines,[5] or aldehydes[6] have been well
Recently, many powerful methods have been estab- documented in the literature. As shown in Scheme 1,
lished using 3-substituted oxindoles, oxindoles, isatins this strategy has also been applied in the synthesis of
or methyleneindolinones as the starting materials to spirocyclic oxindoles. On the other hand, upon proto-
construct chiral 3,3-disubstituted oxindole deriva- nation by a pronucleophile, the zwitterionic inter-
tives,[2] including a few examples of reactions with al- mediate could switch to an g-addition acceptor, which
lenes in the presence of chiral phosphines as nucleo- was first realized using allenoates by Lu in 1995[7] and
philic organocatalysts.[3]
further developed by Zhang and Fu in asymmetric
ways with a variety of nucleophiles (Scheme 1).[8] As
Adv. Synth. Catal. 2014, 356, 359 – 363
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
359

COMMUNICATIONS
Jinhao Chen et al.
Scheme 1. Cycloadditions and g-additions of allenoates.
Table 1. Screening of catalysts for the g addition.[a]
far as we know, no reaction has been discovered with
oxindoles through this pathway. Recently, our group
has focused on the development of novel and easily
accessible bifunctional N-acyl aminophosphine cata-
lysts from amino acids, which has unambiguously
proved valuable in all sorts of asymmetric cycloaddi-
tion reactions with allenoates.[9] As a follow-up of our
program to extend the application scope of these ver-
satile catalysts, herein, we present a highly enantiose-
lective g-addition of 3-substituted oxindoles to ethyl
allenoate catalyzed by bifunctional N-acyl aminophos-
phines to construct a quaternary stereogenic center
À
via C C bond formation reactions.
Initially, 3-phenyloxindole 1a was chosen as pronu-
cleophile in the g-addition with ethyl buta-2,3-dien-
oate 2 for evaluation by the catalysts 4a–4l (Table 1).
Four catalysts with different chiral backbones were
examined first. It was shown that the chiral backbones
of these catalysts have a great effect on the enantiose-
lectivity. The catalyst 4d, which could be synthesized
from phenylalanine in four steps, providing the
adduct 3a in 88% yield and 69% ee (Table 1, entry 4).
An enhanced hydrogen bonding interaction in the
catalyst reduced the enantioselecivity (Table 1,
entry 5). Subsequently, an examination of catalysts
4f–4l with different groups on the nitrogen was car-
ried out (Table 1, entries 6–12). Previous studies[9a,c]
have suggested that the hydrogen-bonding effects
tuned by these protecting groups played an important
role in the transition state with aminophosphine cata-
lysts.[10] Introduction of a trifluoromethyl group into
the catalyst 4f, which means a strong acidity on the
NH functionality, turned out to be detrimental to the
enantioselectivity, although an excellent yield was ob-
tained (Table 1, entry 6). On the other hand, the cata-
lyst 4l with a free amine provided a racemic product
(Table 1, entry 12). The reactions with other acetyl or
benzoyl amides also showed disadvantages in the re-
sults (Table 1). Further examinations on catalyst load-
ing and temperature did not give any more satisfacto-
ry results (Table 1, entries 13 and 14). We conceived
that replacement of the phenyl substituent by
Entry
R
Catalyst Time [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1a 4a
1a 4b
1a 4c
1a 4d
1a 4e
1a 4f
1a 4g
1a 4h
1a 4i
8
81
79
90
88
83
97
83
92
90
83
71
88
88
78
82
97
7
8
8
8
8
49
40
69
19
9
8
8
7
8
8
8
8
57
57
45
60
0
9
10
11
12
13
14
15
16
1a 4j
1a 4k
1a 4l
8
1a 4d[d]
1a 4d[e]
1b 4d
1b 4d[f]
24
72
8
60
65
80
88
15
[a]
Reactions were carried out with 1 (0.1 mmol, 1.0 equiv.)
and 2 (0.2 mmol, 2.0 equiv.) in the presence of catalyst 4
(20 mol%) in toluene (1.0 mL) at room temperature.
Yield of isolated products.
Determined by chiral HPLC analysis.
10 mol% of 4d was used.
[b]
[c]
[d]
[e]
[f]
The reaction was performed at 08C.
20 mol% of benzoic acid was added.
360
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 359 – 363

COMMUNICATIONS
Asymmetric Michael Addition of Oxindoles to Allenoate
Scheme 2. Enantioselective g-addition of 2 with oxindole 1.
a methyl group on the C-3 position of oxindole may lung additions proceeded smoothly with good yields
reduce the reactivity of the substrate, thus a better in most cases. The 3-methyloxindole 1b and allenoate
stereochemical control may be achieved. To our de- 2 underwent g addition with higher yield and enantio-
light, the desired addition product was isolated with selectivity in the presence of 20 mol% benzoic acid.
a significant improvement in enantioselectivity (from Allyl-substituted product 3d was obtained in 98%
69% ee to 80% ee, Table 1, entry 15). Thus, with 3- yield and 92% ee. The isatin derivative with an elon-
methyloxindole 1b as the new model substrate, the ef- gated aliphatic chain led to a slight drop in yield and
fects of solvents and additives were investigated (see ee (product 3e). Among all tested substrates, the 1-
the Supporting Information for details). The solvent propynyl-substituted ones 3f provided the best result
screening showed that toluene remained the reaction with 92% yield and 94% ee. Subsequently, differently
medium of first choice. In view of the previous re- substituted oxindoles in the benzene ring were also
ports that acidic additives may enhance the reaction surveyed. Most of them gave the corresponding prod-
efficiencies,[7,8b,11] we examined several additives in ucts with good yields and acceptable enantiopurities.
this reaction. Although the reaction required a pro- The 4-Cl substituted substrate gave its product in
longed time when benzoic acid was utilized as addi- a satisfactory yield albeit with an obvious drop in the
tive, the Michael adduct was attained with up to 97% enantioselectivity. The investigation on the nitrogen
yield and 88% ee.
protecting group proved that the oxindole with a Boc
Having identified the optimal reaction conditions, group was superior to that with a benzyl group in
we then explored the generality of the reaction re- terms of both yield and ee. The similar benzofuran
garding 3-substituted oxindoles (Scheme 2). As illus- substrates evaluated gave inferior results, which indi-
trated in Scheme 2, this catalyst system worked well cated that the stereochemical control takes advantage
with a range of oxindoles bearing phenyl, alkyl, and of the carbonyl group of the Boc. The absolute con-
ester groups. Generally, the enantioselective umpo- figuration of this g addition products was determined
Adv. Synth. Catal. 2014, 356, 359 – 363
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
361

COMMUNICATIONS
Jinhao Chen et al.
Scheme 3. A possible reaction mechanism.
by X-ray crystal structure analysis of 3l (see the Sup- development of related reactions and applications are
porting Information for details)[12]
underway and will be reported in due course.
.
A possible mechanism accounting for this g addi-
tion was proposed in Scheme 3. The zwitterionic inter-
mediate A acted as a Brønsted base to deprotonate Experimental Section
À
the active C-3 H of substrate 1 to generate anion B,
which attacked the g position of the phosphonium di- General Procedure
enolate intermediate to provide ylide C. After the
To a stirred solution of oxindole 1 (0.1 mmol, 1.0 equiv.),
proton transfer and elimination of phosphine catalyst,
the oxindole product 3 was obtained. The chirality
catalyst
4
(0.02 mmol, 0.2 equiv.) and benzyl acid
(0.02 mmol, 0.2 equiv.) in toluene (1.0 mL) was added ethyl
2,3-butadienoate (0.2 mmol, 2.0 equiv.) via syringe in one
portion. The reaction solution was stirred at room tempera-
ture and monitored by TLC. After the reaction was com-
plete, the mixture was directly purified by column chroma-
tography on silica gel (petroleum ether/EtOAc as the
eluent) to furnish the corresponding product 3.
À
transfer processes occurred in the C C bond-forming
step in which H-bonding and P O interaction might
À
play an important role to ensure a special spatial ar-
rangement. Based on the previous mechanistic pro-
posal in related reactions[4e,5d,7,10b,13] and our experi-
mental results, a plausible transition state was pro-
À
posed. The hydrogen-bonding interaction and P O at-
traction might facilitate formation of an ion pair
structure between the vinylphosphonium salt and the
anionic nucleophile; the benzyl of the dienolate might
block the Si face of the enolate and make the Re-face
attack more favourable.
Acknowledgements
Financial support from National Basic Research Program of
China (973 Program, 2010CB833300), the National Natural
Science Foundation of China (Nos. 21032006, 203900502,
20532040, 21290180), and the Science and Technology Com-
mission of Shanghai Municipality (11XD1406400) is ac-
knowledged.
In conclusion, we have developed a novel reaction
between allenoates and oxindoles that enables the
asymmetric synthesis of 3,3-bisubstituted oxindoles
with our previously established bifunctional N-acyl
aminophosphine catalysts. These processes which fea-
tured the construction of a chiral quaternary carbon
center at the C-3 position of oxindoles, may have po-
tential significance in the synthesis of related struc-
tures of natural occurring products and pharmacologi-
cally active molecules. Further studies regarding the
References
[1] a) H. Lin, S. J. Danishefsky, Angew. Chem. 2003, 115,
38–53; Angew. Chem. Int. Ed. 2003, 42, 36–51; b) R. M.
Williams, R. J. Cox, Acc. Chem. Res. 2003, 36, 127–139;
362
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 359 – 363

COMMUNICATIONS
Asymmetric Michael Addition of Oxindoles to Allenoate
c) K. Ding, Y. Lu, Z. Nikolovska-Coleska, S. Qiu, Y. S.
Ding, W. Gao, J. Stuckey, K. Krajewski, P. P. Roller, Y.
Tomita, D. A. Parrish, J. R. Deschamps, S. M. Wang, J.
Am. Chem. Soc. 2005, 127, 10130–10131; d) B. M. Trost,
M. K. Brennan, Synthesis 2009, 3003–3025; e) F. Zhou,
Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352, 1381–
1407.
5660–5661; h) R. P. Wurz, G. C. Fu, J. Am. Chem. Soc.
2005, 127, 12234–12235.
[6] a) X. F. Zhu, C. E. Henry, J. Wang, T. Dudding, O.
Kwon, Org. Lett. 2005, 7, 1387–1390; b) X. F. Zhu, A. P.
Schaffner, R. C. Li, O. Kwon, Org. Lett. 2005, 7, 2977–
2980; c) G. S. Creech, O. Kwon, Org. Lett. 2008, 10,
429–432.
[2] a) T. Bui, N. R. Candeias, C. F. Barbas III, J. Am.
Chem. Soc. 2010, 132, 5574–5575; b) N. Shibata, E.
Suzuki, T. Asahi, M. Shiro, J. Am. Chem. Soc. 2001,
123, 7001–7009; c) B. M. Trost, M. U. Frederiksen,
Angew. Chem. 2005, 117, 312–314; Angew. Chem. Int.
Ed. 2005, 44, 308–310; d) D. Wang, Y.-L. Yang, J.-J.
Jiang, M. Shi, Org. Biomol. Chem. 2012, 10, 7158–7166;
e) F. Zhou, M. Ding, Y. L. Liu, C. H. Wang, C. B. Ji,
Y. Y. Zhang, J. Zhou, Adv. Synth. Catal. 2011, 353,
2945–2952; f) M. Ding, F. Zhou, Y. L. Liu, C. H. Wang,
X. L. Zhao, J. Zhou, Chem. Sci. 2011, 2, 2035–2039;
g) F. Zhou, C. Tan, J. Tang, Y. Y. Zhang, W. M. Gao,
H. H. Wu, Y. H. Yu, J. Zhou, J. Am. Chem. Soc. 2013,
135, 10994–10997.
[7] a) C. M. Zhang, X. Y. Lu, Synlett 1995, 645–646.
[8] a) Y. K. Chung, G. C. Fu, Angew. Chem. 2009, 121,
2259–2261; Angew. Chem. Int. Ed. 2009, 48, 2225–2227;
b) Y. Fujiwara, J. Sun, G. C. Fu, Chem. Sci. 2011, 2,
2196–2198; c) R. J. Lundgren, A. Wilsily, N. Marion, C.
Ma, Y. K. Chung, G. C. Fu, Angew. Chem. 2013, 125,
2585–2588; Angew. Chem. Int. Ed. 2013, 52, 2525–2528;
d) R. Sinisi, J. Sun, G. C. Fu, Proc. Natl. Acad. Sci.
USA 2010, 107, 20652–20654; e) S. W. Smith, G. C. Fu,
J. Am. Chem. Soc. 2009, 131, 14231–14233; f) J. Sun,
G. C. Fu, J. Am. Chem. Soc. 2010, 132, 4568–4569.
[9] a) H. Xiao, Z. Chai, C. W. Zheng, Y. Q. Yang, W. Liu,
J. K. Zhang, G. Zhao, Angew. Chem. 2010, 122, 4569–
4572; Angew. Chem. Int. Ed. 2010, 49, 4467–4470; b) H.
Xiao, Z. Chai, H.-F. Wang, X.-W. Wang, D.-D. Cao, W.
Liu, Y.-P. Lu, Y.-Q. Yang, G. Zhao, Chem. Eur. J. 2011,
17, 10561–10564; c) H. Xiao, Z. Chai, D. Cao, H. Wang,
J. Chen, G. Zhao, Org. Biomol. Chem. 2012, 10, 3195–
3201.
[10] a) K. H. Jensen, M. S. Sigman, Angew. Chem. 2007,
119, 4832–4834; Angew. Chem. Int. Ed. 2007, 46, 4748–
4750; b) F. Zhong, X. Dou, X. Han, W. Yao, Q. Zhu, Y.
Meng, Y. Lu, Angew. Chem. 2013, 125, 977–981;
Angew. Chem. Int. Ed. 2013, 52, 943–947.
[11] a) B. M. Trost, C. J. Li, J. Am. Chem. Soc. 1994, 116,
10819–10820; b) B. M. Trost, G. R. Dake, J. Org. Chem.
1997, 62, 5670–5671.
[3] a) B. J. Cowen, S. J. Miller, Chem. Soc. Rev. 2009, 38,
3102–3116; b) A. Marinetti, A. Voituriez, Synlett 2010,
174–194.
[4] a) C. M. Zhang, X. Y. Lu, J. Org. Chem. 1995, 60, 2906–
2908; b) Y. S. Du, X. Y. Lu, Y. H. Yu, J. Org. Chem.
2002, 67, 8901–8905; c) X. Y. Lu, Z. Lu, X. M. Zhang,
Tetrahedron 2006, 62, 457–460; d) J. E. Wilson, G. C.
Fu, Angew. Chem. 2006, 118, 1454–1457; Angew. Chem.
Int. Ed. 2006, 45, 1426–1429; e) B. J. Cowen, S. J.
Miller, J. Am. Chem. Soc. 2007, 129, 10988–10989.
[5] a) Z. R. Xu, X. Y. Lu, J. Org. Chem. 1998, 63, 5031–
5041; b) Z. R. Xu, X. Y. Lu, Tetrahedron Lett. 1997, 38,
3461–3464; c) X. F. Zhu, C. E. Henry, O. Kwon, Tetra-
hedron 2005, 61, 6276–6282; d) X. F. Zhu, J. Lan, O.
Kwon, J. Am. Chem. Soc. 2003, 125, 4716–4717; e) L.
Jean, A. Marinetti, Tetrahedron Lett. 2006, 47, 2141–
2145; f) N. Fleury-Bregeot, L. Jean, P. Retailleau, A.
Marinetti, Tetrahedron 2007, 63, 11920–11927; g) Y.-Q.
Fang, E. N. Jacobsen, J. Am. Chem. Soc. 2008, 130,
[12] CCDC 941547 contains the supplementary crystallo-
graphic data for 3l. These data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[13] a) B. M. Trost, C. J. Li, J. Am. Chem. Soc. 1994, 116,
3167–3168.
Adv. Synth. Catal. 2014, 356, 359 – 363
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
363