Organocatalytic asymmetric allylic amination of Morita-Baylis-Hillman carbonates of isatins

Article abstract of DOI:10.3762/bjoc.8.139

The investigation of a Lewis base catalyzed asymmetric allylic amination of Morita-Baylis-Hillman carbonates derived from isatins afforded an electrophilic pathway to access multifunctional oxindoles bearing a C3-quaternary stereocenter, provided with good to excellent enantioselectivity (up to 94% ee) and in high yields (up to 97%).

Full text of DOI:10.3762/bjoc.8.139

Organocatalytic asymmetric allylic amination of
Morita–Baylis–Hillman carbonates of isatins
Hang Zhang, Shan-Jun Zhang, Qing-Qing Zhou, Lin Dong
and Ying-Chun Chen*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1241–1245.
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
doi:10.3762/bjoc.8.139
Received: 29 May 2012
Accepted: 09 July 2012
Published: 06 August 2012
Email:
Ying-Chun Chen* - ycchenhuaxi@yahoo.com.cn
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
* Corresponding author
Keywords:
allylic amination; asymmetric organocatalysis; Morita–Baylis–Hillman
carbonates; 2-oxindoles; quaternary chiral center
© 2012 Zhang et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The investigation of a Lewis base catalyzed asymmetric allylic amination of Morita–Baylis–Hillman carbonates derived from
isatins afforded an electrophilic pathway to access multifunctional oxindoles bearing a C3-quaternary stereocenter, provided with
good to excellent enantioselectivity (up to 94% ee) and in high yields (up to 97%).
Introduction
Chiral 3-amino-2-oxindoles are versatile and useful units for the Recently, we have developed the asymmetric allylic alkylation
preparation of natural products and drug candidates, such as the reactions [22] with Morita–Baylis–Hillman (MBH) carbonates
vasopressin VIb receptor antagonist SSR-149415 [1,2], the of isatins to obtain 2-oxindoles bearing a C3-quaternary chiral
potent gastrin/CCK-B receptor antagonist AG-041R [3], center, by the catalysis of chiral tertiary amines, β-iso-
chartelline C [4,5] and psychotrimine [6]. Therefore, the cupreidine (β-ICD) or its derivatives [23,24]. We envisaged that
development of asymmetric protocols to construct such chiral such a catalytic strategy should be applicable to the allylic
scaffolds has provoked wide interest. The application of amination of the corresponding MBH carbonates [25-28], as
3-substituted oxindoles as nucleophiles in the reactions with outlined in Scheme 1. Thus, multifunctional chiral 3-amino-2-
azodicarboxylates or nitrosobenzene provides a very simple and oxindoles could be obtained in a straightforward manner.
direct approach for the synthesis of optically active 3-amino-2-
oxindole derivatives [7], either by the catalysis of chiral metal Results and Discussion
complexes [8-10] or organic catalysts [11-15]. On the other Based on the above considerations, we initially investigated the
hand, the asymmetric addition to electrophilic imines of isatins reaction of MBH carbonate 2a and a diversity of nucleophilic
is also an attractive pathway, and a variety of examples have nitrogen sources by the catalysis of DABCO. No desired reac-
been presented [16-21].
tion occurred for phthalimide [25] or N-allyl p-toluenesulfon-
1241

Beilstein J. Org. Chem. 2012, 8, 1241–1245.
Scheme 1: Allylic amination of MBH carbonates of isatins to access 3-amino-2-oxindoles.
amide [27], which has been successfully applied in the asym- and O-benzyl groups [29] was applied in diethyl ether (Table 1,
metric amination of MBH carbonates derived from aryl alde- entry 1). Subsequently, an array of tertiary amines derived from
hydes. Pleasingly, the reaction took place smoothly to afford quinidine was explored to introduce chirality into the product.
product 4a when hydroxylamine 3a with N-benzyloxycarbonyl While poor enantioselectivity was obtained when β-iso-
Table 1: Screening studies of asymmetric allylic amination of MBH carbonate of isatin.a
entry
1
3
solvent
t (h)
yieldb (%)
eec (%)
1
DABCO
1a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3d
3d
3d
3d
3d
3d
3d
3d
3d
3d
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
DCE
PhCF3
m-xylene
PhF
12
12
12
12
12
12
12
24
12
24
24
24
24
18
12
12
12
12
24
4a, 86
4a, 83
4a, 80
4a, 85
4a, 85
4b, <10
4c, 80
4d, 85
4e, 53
4d, 88
4d, 78
4d, 90
4d, 88
4d, 74
4d, 93
4d, 97
4d, 83
4d, 93
4d, 92
–
2
17
37
52
58
–
3
1b
1c
4
5
1d
1d
1d
1d
1d
1e
6
7
72
83
72
77
72
74
85
74
86
82
85
88
91
8
9
10
11
12
13
14
15
16
17
18
19d
1f
1g
1h
1d
1d
1d
1d
1d
1h
PhCl
PhCl
aUnless otherwise noted, reactions were performed with 0.12 mmol of 2a, 0.1 mmol of 3, and 0.01 mmol 1 of in 0.5 mL solvent at room temperature.
bIsolated yield. cBased on chiral HPLC analysis. dAt 0 °C.
1242

Beilstein J. Org. Chem. 2012, 8, 1241–1245.
cupreidine 1a (β-ICD) or β-isoquinidine 1b was used (Table 1, when (S)-BINOL [32] was added, and even no reaction
entries 2 and 3), a moderate ee value was attained in the happened in the presence of other additives such as LiClO4 or
presence of O-MOM isocupreidine 1c (Table 1, entry 4) [30]. Ti(OiPr)4 [33].
Moreover, even a slightly higher enantiocontrol was
observed for a phenyl-substituted amine 1d (Table 1, entry 5) With the optimized conditions in hand, we explored a diversity
[31]. Consequently, we paid attention to the structural modifica- of MBH carbonates derived from isatins in the reactions with
tions on the nitrogen source. Very poor conversion was protected hydroxylamine 3d by the catalysis of chiral amine 1h
observed when N-Boc protected hydroxylamine 3b was applied in chlorobenzene at 0 °C. The results are summarized in
in the catalysis by 1d (Table 1, entry 6). To our gratification, Table 2. A series of MBH carbonates 2 bearing either electron-
dramatically improved enantioselectivity was obtained for 3c donating or -withdrawing substituents on the aromatic moiety of
bearing an O-TES group (Table 1, entry 7), and an even higher 2-oxindoles were well tolerated. A higher reactivity was gener-
ee value was gained for 3d with a bulkier O-TBS group, ally observed for MBH carbonates with electron-donating
although it exhibited lower reactivity (Table 1, entry 8). Never- substitutions, and excellent yields and enantioselectivity were
theless, inferior results were afforded for 3e with an O-TIPS obtained (Table 2, entries 2–4). On the other hand, MBH
group (Table 1, entry 9). Furthermore, we prepared more carbonates with electron-withdrawing groups exhibited a slower
isocupreidines with diverse aryl-substitutions and tested their reaction rate, but both good yields and ee values were still
catalytic efficacy in the reaction of MBH carbonate 2a and 3d. obtained (Table 2, entries 5–10).
Diminished enantioselectivity was delivered in the presence of
catalysts 1e–1g (Table 1, entries 10–12), but a slightly higher ee As outlined in Scheme 2, some synthetic transformations were
value could be obtained upon catalysis by 1h with a 4-tert- conducted with the multifunctional allylic amination product
butylphenyl group (Table 1, entry 13). In addition, a number of 4d. The N–O bond cleavage of 4d could be realized with Zn
solvents were investigated in the catalysis by 1d (Table 1, powder in acetic acid to produce compound 5, albeit in modest
entries 14–18), and chlorobenzene was found to be the optimal yield [34,35], whose absolute configuration has been deter-
selection (Table 1, entry 18). Finally, it was found that the reac- mined by X-ray analysis [36]. The removal of the O-TBS unit
tion still proceeded smoothly at 0 °C, and a high ee value could proceeded efficiently in the presence of hydrofluoric acid, and
be obtained in the catalysis by amine 1h, although a longer an intramolecular transesterification process of intermediate 6
reaction time was required to give a better yield (Table 1, happened to afford a spirocyclic oxindole 7 without loss of
entry 19). It should be noted that the reaction became sluggish enantiopurity [37].
Table 2: Substrate scope and limitations.a
entry
R
t (h)
yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
H (2a)
24
24
26
40
36
30
36
36
36
36
4d, 92
4f, 93
4g, 97
4h, 93
4i, 86
4j, 88
4k, 81
4l, 85
4m, 71
4n, 85
91
91
94
90
90
89
88
86
85
90
5-Me (2b)
5-MeO (2c)
5,7-Me2 (2d)
5-F (2e)
5-Cl (2f)
5-Br (2g)
5-I (2h)
5-CF3O (2i)
7-F (2j)
aReactions were performed with 0.12 mmol of 2, 0.1 mmol of 3d, and 0.01 mmol of 1h in 0.5 mL of chlorobenzene at 0 °C. bIsolated yield. cBased on
chiral HPLC analysis.
1243

Beilstein J. Org. Chem. 2012, 8, 1241–1245.
Scheme 2: Synthetic transformations of multifunctional product 4d.
3. Ochi, M.; Kawasaki, K.; Kataoka, H.; Uchio, Y.; Nishi, H.
Conclusion
Biochem. Biophys. Res. Commun. 2001, 283, 1118–1123.
doi:10.1006/bbrc.2001.4911
We have developed a highly enantioselective allylic amination
of Morita–Baylis–Hillman carbonates of isatins with
N-silyloxycarbamates by the catalysis of a modified β-ICD
derivative, which provides an electrophilic process to 3-amino-
2-oxindoles with a C3-quaternary chiral center. A range of
products with high molecular complexity were obtained with
good to excellent enantioselectivity (up to 94% ee) and high
yields (up to 97%). Currently, more studies on the catalytic
asymmetric transformations of MBH carbonates of isatins are
under way in our laboratory.
4. Chevolot, L.; Chevolot, A. M.; Gajhede, M.; Larsen, C.; Anthoni, U.;
Christophersen, C. J. Am. Chem. Soc. 1985, 107, 4542–4543.
doi:10.1021/ja00301a027
5. Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen, C.
J. Org. Chem. 1987, 52, 4709–4712. doi:10.1021/jo00230a010
6. Takayama, H.; Mori, I.; Kitajima, M.; Aimi, N.; Lajis, N. H. Org. Lett.
2004, 6, 2945–2948. doi:10.1021/ol048971x
7. Shen, K.; Liu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 327–334.
doi:10.1039/c1sc00544h
8. Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255–1257.
doi:10.1021/ja908906n
9. Yang, Z.; Wang, Z.; Bai, S.; Shen, K.; Chen, D.; Liu, X.; Lin, L.;
Feng, X. M. Chem.–Eur. J. 2010, 16, 6632–6637.
doi:10.1002/chem.201000126
Supporting Information
General experimental procedures, copies of 1H, 13C NMR
spectra and HPLC chromatograms for all new compounds,
crystal data and structure refinement for enantiopure 5.
10.Shen, K.; Liu, X.; Wang, G.; Lin, L.; Feng, X. Angew. Chem., Int. Ed.
2011, 50, 4684–4688. doi:10.1002/anie.201100758
11.Cheng, L.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Lett. 2009, 11,
3874–3877. doi:10.1021/ol901405r
Supporting Information File 1
12.Zhou, F.; Ding, M.; Liu, Y.-L.; Wang, C.-H.; Ji, C.-B.; Zhang, Y.-Y.;
Zhou, J. Adv. Synth. Catal. 2011, 353, 2945–2952.
doi:10.1002/adsc.201100379
General procedures and analytical data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-139-S1.pdf]
13.Bui, T.; Hernández Torres, G.; Milite, C.; Barbas, C. F., III. Org. Lett.
2010, 12, 5696–5699. doi:10.1021/ol102493q
14.Bui, T.; Borregan, M.; Barbas, C. F., III. J. Org. Chem. 2009, 74,
8935–8938. doi:10.1021/jo902039a
Acknowledgements
15.Qian, Z.-Q.; Zhou, F.; Du, T.-P.; Wang, B.-L.; Ding, M.; Zhao, X.-L.;
Zhou, J. Chem. Commun. 2009, 6753–6755. doi:10.1039/b915257a
16.Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A.
J. Org. Chem. 2009, 74, 4537–4541. doi:10.1021/jo900623c
17.Jung, H. H.; Buesking, A. W.; Ellman, J. A. Org. Lett. 2011, 13,
3912–3915. doi:10.1021/ol201438k
We are grateful for the financial support from the NSFC (grant
no. 21125206 and 21021001).
References
1. Bernard, K.; Bogliolo, S.; Ehrenfeld, J. Br. J. Pharmacol. 2005, 144,
18.Cao, Z.-Y.; Zhang, Y.; Ji, C.-B.; Zhou, J. Org. Lett. 2011, 13,
6398–6401. doi:10.1021/ol202705g
1037–1050. doi:10.1038/sj.bjp.0706103
2. Serradeil-Le Gal, C.; Derick, S.; Brossard, G.; Manning, M.;
Simiand, J.; Gaillard, R.; Griebel, G.; Guillon, G. Stress 2003, 6,
199–206. doi:10.1080/1025389032000114524
19.Guo, Q.-X.; Liu, Y.-W.; Li, X.-C.; Zhong, L.-Z.; Peng, Y.-G.
J. Org. Chem. 2012, 77, 3589–3594. doi:10.1021/jo202585w
1244

Beilstein J. Org. Chem. 2012, 8, 1241–1245.
20.Yan, W.; Wang, D.; Feng, J.; Li, P.; Wang, R. J. Org. Chem. 2012, 77,
3311–3317. doi:10.1021/jo300110a
License and Terms
21.Yan, W.; Wang, D.; Feng, J.; Li, P.; Zhao, D.; Wang, R. Org. Lett. 2012,
14, 2512–2515. doi:10.1021/ol3007953
This is an Open Access article under the terms of the
Creative Commons Attribution License
22.Liu, T.-Y.; Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101–4112.
doi:10.1039/c2cs35017c
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
23.Peng, J.; Huang, X.; Cui, H.-L.; Chen, Y.- C. Org. Lett. 2010, 12,
4260–4263. doi:10.1021/ol101668z
24.Huang, X.; Peng, J.; Dong, L.; Chen, Y.-C. Chem. Commun. 2012, 48,
2439–2441. doi:10.1039/c2cc17777c
25.Zhang, S.-J.; Cui, H.-L.; Jiang, K.; Li, R.; Ding, Z.-Y.; Chen, Y.-C.
Eur. J. Org. Chem. 2009, 5804–5809. doi:10.1002/ejoc.200900944
26.Lin, A.; Mao, H.; Zhu, X.; Ge, H.; Tan, R.; Zhu, C.; Cheng, Y.
Chem.–Eur. J. 2011, 17, 13676–13679. doi:10.1002/chem.201102522
27.Sun, W.; Ma, X.; Hong, L.; Wang, R. J. Org. Chem. 2011, 76,
7826–7833. doi:10.1021/jo2011522
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
28.Pei, C.-K.; Zhang, X.-C.; Shi, M. Eur. J. Org. Chem. 2011, 4479–4484.
doi:10.1002/ejoc.201100501
doi:10.3762/bjoc.8.139
29.Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc.
2006, 128, 9328–9329. doi:10.1021/ja063267s
30.Peng, J.; Huang, X.; Jiang, L.; Cui, H.-L.; Chen, Y.-C. Org. Lett. 2011,
13, 4584–4587. doi:10.1021/ol201776h
31.Waldmann, H.; Khedkar, V.; Dückert, H.; Schürmann, M.; Oppel, I. M.;
Kumar, K. Angew. Chem., Int. Ed. 2008, 47, 6869–6872.
doi:10.1002/anie.200802413
32.Cui, H.-L.; Peng, J.; Feng, X.; Du, W.; Jiang, K.; Chen, Y.-C.
Chem.–Eur. J. 2009, 15, 1574–1577. doi:10.1002/chem.200802534
33.Furukawa, T.; Kawazoe, J.; Zhang, W.; Nishimine, T.; Tokunaga, E.;
Matsumoto, T.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2011, 50,
9684–9688. doi:10.1002/anie.201103748
34.Hu, Z. K.; Cui, H. L.; Jiang, K.; Chen, Y. C. Sci. China, Ser. B: Chem.
2009, 52, 1309–1313. doi:10.1007/s11426-009-0187-8
35.Bentley, S. A.; Davies, S. G.; Lee, J. A.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E.; Toms, S. M. Tetrahedron 2010, 66, 4604–4620.
doi:10.1016/j.tet.2010.04.027
36.CCDC-888767 (5) contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
http://www.ccdc.cam.ac.uk/data_request/cif. The absolute configuration
of chiral products 4 in Table 2 could be assigned accordingly.
37.Benfatti, F.; Cardillo, G.; Contaldi, S.; Gentilucci, L.; Mosconi, E.;
Tolomelli, A.; Juaristi, E.; Reyes-Rangel, G. Tetrahedron 2009, 65,
2478–2483. doi:10.1016/j.tet.2009.01.071
1245