Base-catalyzed controllable reaction of 3-ylideneoxindoles with O-Boc hydroxycarbamates for the synthesis of amidoacrylates and spiroaziridine oxindoles

Article abstract of DOI:10.1039/c6ob00891g

A base-catalyzed divergent reaction of 3-ylideneoxindoles with O-Boc hydroxycarbamates has been developed to provide efficient access to various amidoacrylates and spiroaziridine oxindoles with generally high yields, which should be potentially useful in drug discovery.

Full text of DOI:10.1039/c6ob00891g

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Liu, S. Duan, R.
Zhang, Y. Liu, J. Chen and W. Xiao, Org. Biomol. Chem., 2016, DOI: 10.1039/C6OB00891G.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C6OB00891G
Journal Name
COMMUNICATION
B
ase-catalyzed controllable reaction of 3-ylideneoxindoles with
O-Boc hydroxycarbamates for the synthesis of amidoacrylates and
spiroaziridine oxindoles
Received 00th January 20xx,
Accepted 00th January 20xx
Yi-Yin Liu,a Shu-Wen Duan,a Rui Zhang,a Yun-Hang Liu,a Jia-Rong Chen*a and Wen-Jing Xiaoa
DOI: 10.1039/x0xx00000x
www.rsc.org/
A base-catalyzed divergent reaction of 3-ylideneoxindoles with O- from an organocatalytic asymmetric Mannich reaction of 3-
Boc hydroxycarbamates has been developed to provide an bromooxindoles with N-Ts-imines.14 It has also been recently
efficient access to various amidoacrylates and spiroaziridine reported by Marsini15a and Hajra15b respectively that the aza-Corey-
oxindoles with generally high yields, which should be potentially Chaykovsky aziridination reaction of isatin-derived chiral N-tert-
useful in drug discovery.
butanesulfinyl ketimines with in situ-generated sulfur ylides
provided a highly diastereoselective access to various optically
active spiroaziridine oxindoles. During the course of our study, the
group of Wang and Xu reported an elegant stoichiometric base-
mediated domino reaction of 3-methyleneindolinones with N-
Amidoacrylates and aziridines are two important classes of
versatile synthons with wide applications in organic synthesis.1,2 For
example, amidoacrylate derivatives are often employed as
dipolarophiles in 1,3-dipolar cycloaddition,3 dienophiles in Diels-
Alder reaction,4 electrophiles in Michael-type reactions,5 coupling
reagents in the Heck6 and Suzuki7 reactions, Friedel-Crafts
alkylation8 and other cycloaddition reactions.9 Employing these
tosyloxycarbamates, providing
a divergent approach for the
synthesis of various bispirooxindoles and spiroaziridine oxindoles by
tuning the substrate ratio (Scheme 1c).16 Despite these advances,
the development of new methods to construct diversely
functionalized amidoacrylates and aziridines with oxindole moiety is
still highly desirable for drug discovery and medicinal chemistry.
Base on our continuing interest in heterocycle synthesis,17 we
transformations,
a variety of synthetically and biologically
important nitrogen-containing compounds, such as unnatural
amino acids and heterocycles can be efficiently obtained.
Moreover, aziridines can also undergo
a diverse range of
recently achieved
a base-catalyzed divergent reaction of 3-
synthetically useful transformations, such as nucleophilic ring-
opening and ring-expansion because of the high strain energy of the
aziridine ring.10 Thus, a plethora of efficient protocols have been
developed for efficient construction of various structurally diverse
amidoacrylates and aziridines. In this context, however, the
incorporation of the privileged oxindole motif into the
amidoacrylate and aziridine scaffolds remains largely unexplored.11
As for the synthesis of amidoacrylates containing oxindole motif,
to our knowledge, only one report from the Becalli group described
an efficient route to access the α-dimethylamine-substituted
acrylate via a multi-step procedure (Scheme 1a).12 The group of
Loreto developed a direct aziridination of easily accessible 3-
ylideneoxindoles for facile synthesis of highly functionalized
spiroaziridine oxindoles (Scheme 1b).13 Peng disclosed an example
of enantioselective synthesis of spiroaziridine oxindole by
intramolecular SN2-cyclization of chiral Mannich products, obtained
methyleneindolinones with O-Boc hydroxycarbamates in
a
controllable manner (Scheme 1d). In contrast to Wang’s work, our
reaction gave the oxindole-containing acrylates and spiroaziridine
oxindoles in generally high yields by using suitable bases.
a. Key Laboratory of Pesticide & Chemical Biology, Ministry of Education; College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei
430079, China. E-mail: chenjiarong@mail.ccnu.edu.cn
Fax: +86 27 67862041; Tel: +86 27 67862041.
† Electronic Supplementary Information (ESI) available: Experimental procedures
and compound characterization data. For ESI and other electronic format, see DOI:
10.1039/x0xx00000x
Scheme 1 Reaction design with 3-methyleneindolinones
.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2015, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
View Article Online
DOI: 10.1039/C6OB00891G
COMMUNICATION
Journal Name
For instance, a series of N-free and N-substitued 3-ylideneoxindoles
with various electron-withdrawing, aryl and aliphatic groups on the
Inspired by the recent successful applications of the
hydroxycarbamate derivatives in aziridination reaction,18 we initially
investigated the reaction of 3-ylideneoxindole 1a with O-Boc
hydroxycarbamate 2a by evaluating various inorganic or organic
bases as the catalysts in CH2Cl2 as the solvent (Table 1).
Interestingly, in the most cases, the reaction proceeded smoothly to
give a mixture of unexpected amidoacrylate 3a and spiroaziridine
oxindole 4a with variable ratios (entries 1-6). For example, in the
presence 20 mol% of DABCO (triethylenediamine), the reaction
worked very well to give a 99% yield of 3a (entry 5); meanwhile,
the reaction with 20 mol% of TMG (tetramethylguanidine) as the
catalyst proceeded smoothly to furnish 4a in 75% yield (entry 6).
With these two organic bases identified, we then briefly examined
other commonly used solvents as well as reaction temperature to
further improve the reaction efficiency and yield. As for the
formation of product 3a, it was found that the combination of
DABCO and CH2Cl2 was still the best of choice, resulting in the best
isolated yield and chemoselectivity (entries 5 vs. 7-11). Moreover, a
combination of TMG with CH2Cl2 gave rise to the best results for the
Fig. 1 X-ray crystal structures of compounds 3a and 4a
.
nitrogen all turned out to be suitable for the reaction, giving the
corresponding products 3a-g with excellent yields (94-99%).
Moreover, the electronic property and substitution patterns of the
phenyl ring of 3-ylideneoxindoles have no obvious effect on the
reaction; and the corresponding products 3h-p were obtained in
quantitative yields. Notably, these Cl-, and Br-substituted
amidoacrylates 3h-l could be used for further transition metal-
catalyzed coupling, and the fluororine-containing products (i.e., 3m-
n and 3p) are of great biological interest. Replacement of the ester
moiety by the other carbonyl groups still furnished the expected
products (i.e., 3q-s) in high yields. As demonstrated in the synthesis
of 3t-u, variation of the carbamate also has no effect on the
reaction efficiency and chemoselectivity.
o
formation of 4a with up to 82% yield at 0 C (entries 12 vs. 13-17).
Notably, the structures of the products 3a and 4a were fully
characterized (see the ESI) and unambiguously confirmed by X-ray
single crystal analysis (Fig. 1).19
Table 1 Optimization studiesa
Table 2 Substrate scope for amidoacrylate synthesisa,b
3a
4a
Entry Base
Solvent Time (h)
Yieldb (%) Yieldb (%)
1
KOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
7
<5
<5
<5
33
99
<5
99
98
99
99
89
<5
<5
<5
<5
<5
<5
37
53
20
18
0
2
NaOH
K2CO3
Cs2CO3
7
3
7
4
15
24
0.25
72
96
5
DABCO CH2Cl2
TMG CH2Cl2
6
75
0
7
DABCO THF
DABCO Et2O
8
0
9
DABCO toluene 96
0
10
11
12c
13 c
14 c
15 c
16 c
17 c
DABCO DMF
26
0
DABCO DMSO
26
0
TMG
TMG
TMG
TMG
TMG
TMG
CH2Cl2
THF
2.5
2.5
2.5
2.5
2.5
2.5
82
64
77
68
57
56
Et2O
CH3CN
DMF
a
Conditions: reactions were performed with
1 (0.2 mmol), 2 (0.24
CHCl3
mmol), DABCO (0.04 mmol) and 1 mL of CH2Cl2. The solution was
a Unless noted, reactions were performed with 1a (0.2 mmol), 2a (0.24
mmol), base (20 mol%) in the solvent (1 mL) at room temperature.
b
stirred for 24 h at room temperature. Isolated yield after column
b
chromatography.
c
Isolated yield after column chromatography. Reactions were carried
out on a scale of 0.3 mmol in 5 mL of solvent at 0 oC.
Next, we explored the generality of the reaction for the synthesis
of synthetically and biologically important spiroaziridine oxindoles
using O-Boc hydroxycarbamate 2a (Table 3). As for the ester moiety
in the N-methyl-protected 3-ylideneoxindoles, the variation of the
ester moiety has very slight effects on the yields; and the
With the optimized reaction conditions established, we first
investigated the substrate scope for the synthesis of diversely
substituted amidoacrylates 3. As shown in Table 2, the reaction
tolerated a wide range of diversely substituted 3-ylideneoxindoles.
2 | J. Name., 2015, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 4
View Article Online
DOI: 10.1039/C6OB00891G
Journal Name
COMMUNICATION
corresponding products 4a-c were obtained in good yields. In
contrast, in the case of N-benzyl-protected 3-ylideneoxindoles, the
sterically more demanding ester group resulted in an increase of
the yield (i.e., 4d-e). Then, we continued to investigate the
influence of the electronic property and substitution patterns of the
aromatic ring on this aziridination reaction. A series of electron-
donating (Me, MeO) and electron-withdrawing (Br, Cl, F) functional
groups could be well incorporated into the C-4, C-5, C-6, and C-7
positions, producing the corresponding aziridines as single
diastereomers in generally high yields (90-99%). The excellent
diastereoselectivity observed in the aziridination can probably be
attributed to the high stereodirecting effect of Cbz (carbobenzyloxy)
group and the cyclic transition. The N-free 3-ylideneoxindole failed
to give the desired aziridination product (not shown).
Table 3 Substrate scope for the synthesis of spiroaziridine
oxindolesa,b
Scheme 2. Formation of bispirooxindole.
To gain some insights into the reaction mechanism, we
performed several more control experiments (Scheme 3). When
amidoacrylate 3a was subjected to the standard conditions, we did
not detect any spiroaziridine oxindole 4a, and 3a remained intact
(Scheme 3, eqn 1). Interestingly, subjectiong of the spiroaziridine
oxindole 4a to the standard conditions only gave rise to its
diastereomer 4a’ with moderate yields, which might be formed by
intermediate I via a base-catalyzed ring-opening process (Scheme 3,
eqn 2). It should be noted that the reaction of 3-ylideneoxindole 1a
with O-Boc hydroxycarbamate 2a using TMG as the base still lead to
the exclusive formation of 4a with comparable yield, even when the
reaction time was prolonged to 24 h. These observations indicated
that the products amidoacrylate 3a and spiroaziridine oxindole 4a
should be formed through different reaction pathways. Not
surprisingly, the spiroaziridine oxindole 4a should be formed by a
classical aziridination process.18
a
Conditions: reactions were performed with
1 (0.3 mmol), 2a (0.36
mmol), TMG (0.06 mmol) and 5 mL of CH2Cl2. The solution was
b
stirred for 15 min to 6 h at 0 oC. Isolated yield of the single
diastereomer after column chromatography.
In accordance with Wang’s observation, we also found that the
reaction of 1a and 2a with DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
as the catalyst could also lead to the formation of a 75% yield of
bispirooxindole 5 albeit with moderate diastereoselectivity, which
was confirmed by X-ray single crystal analysis (Scheme 2, eqn 1).19
Moreover, it was found that treatment of a mixture of 1a and 4a
with
a catalytic amount of DBU could also lead to the
bispirooxindole 5 in 60% yield, suggesting that 4a might be involved
as the key intermediate for bispirooxindole formation (Scheme 2,
eqn 2). Based on these results and Wang’s model,16 we then
postulated that the formation of bispirooxindole 5 should arise
from the base-catalyzed formal [3+2] cycloaddition of the initially
formed spiroaziridine oxindole 4a with another molecule of 3-
ylideneoxindole 1a through the intermediate I, which was formed
from ring-opening of the initially formed aziridine 4a by nucleophilic
attack of the tertiary amine catalyst (Scheme 2).
Scheme 3. Control experiments.
Although the detailed mechanism is not clear at this stage, we
proposed a possible mechanism for the formation of 3a (Scheme 4).
Initially, 3-ylideneoxindole 1a undergoes a base-catalyzed aza-
Michael addition with O-Boc hydroxycarbamate 2a to give the
intermediate 6,20 which further undergoes
a tertiary amine-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
View Article Online
DOI: 10.1039/C6OB00891G
COMMUNICATION
Journal Name
6
7
For selected examples, see: (a) A. Ritzén, B. Basu, A.
Wallberg and A. Frejd, Tetrahedron: Asymmetry, 1998,
3491; (b) F. D. Azambuja and C. R. D. Correia, Tetrahedron
Lett., 2011, 52, 42.
promoted elimination to furnish the imine 7. Then, the imine 7
isomerizes easily into the corresponding more stable amidoacrylate
3a. The tertiary amine catalyst would be regenerated through a
deprotonation process by the tert-butoxide anion for the next cycle.
9
,
For selected examples, see: (a) G. J. Roff, R. C. Lloyd and N.
J. Turner, J. Am. Chem. Soc., 2004, 126, 4098; (b) A. S.
Abreu, P. M. T. Ferreira, M. J. R. P. Queiroz, I. C. F. R.
Ferreira, R. C. Calhelha and L. M. Estevinho, Eur. J. Org.
Chem., 2005, 2951; (c) M.-J. R. P. Queiroz, E. M. S.
Castanheira, M. S. D. Carvalho, A. S. P. M. T. Abreu, Ferreira,
H. Karadeniz and A. Erdem, Tetrahedron, 2008, 64, 382.
For selected examples, see: (a) M. Righi, F. Bartoccini, S.
Lucarini and G. Piersanti, Tetrahedron, 2011, 67, 7923; (b)
M. E. Kieffer, L. M. Repka, S. E. Reisman, J. Am. Chem. Soc.,
2012, 134, 5131; (c) L. M. Repka and S. E. Reisman, J. Org.
Chem., 2013, 78, 12314.
For selected examples, see: (a) C. D. Gilmore, K. M. Allan
and B. M. Stoltz, J. Am. Chem. Soc., 2008, 130, 1558; (b) P.
M. T. Ferreira, E. M. S. Castanheira, L. S. Monteiro, G.
Pereira and H. Vilaca, Tetrahedron, 2010, 66, 8672; (c) A.
Ture, K. Rubina, E. Rozhkov and V. Kauss, Chem. Heterocycl.
Compd., 2011, 47, 838.
8
9
Scheme 4. Proposed catalytic cycle for the formation of 3a
.
In conclusion, we have developed a base-catalyzed
controllable and divergent reaction of 3-ylideneoxindoles with
O-Boc hydroxycarbamates under mild conditions. Employing
the simple organic bases, DABCO or TMG, as the catalysts, a
wide variety of highly functionalized amidoacrylates and 10 For recent examples, see: (a) D. C. Cruz, P. A. Murcia and K.
A. Jørgensen, Chem. Commun., 2012, 48, 6112; (b) K. S.
Halskov, T. Naicker, M. E. Jensen, K. A. Jørgensen, Chem.
Commun., 2013, 49, 6382; (c) J. L. Jat, M. P. Paudyal, H. Y.
Gao, Q. L. Xu, M. Yousufuddin, D. Devarajan, H. E. Daniel,
László Kürti and John R. Falck. Science, 2014, 343, 61.
spiroaziridine oxindoles were obtained in generally excellent
yields. The products should be potentially useful in drug
discovery. Studies on the application of these products and the
development of catalytic asymmetric versions to access chiral
aziridines and bispirooxindoles are currently underway in our 11 For recent reviews, see: (a) K. Shen, X.-H. Liu, L.-L. Lin and
X.-M. Feng, Chem. Sci., 2012, 3, 327; (b) G. S. Singh and Z. Y.
laboratory.
Desta, Chem. Rev., 2012, 112, 6104.
12 E. M. Beeealli and A. Marehesini, Tetrahedron, 1995, 51
2353.
13 For selected examples, see: (a) I. Ammetto, T. Gasperi, M.
A. Loreto, A. Migliorini, F. Palmarelli and P. A. Tardella. Eur.
J. Org. Chem., 2009, 6189; (b) T. Gasperi, M. A. Loreto, A.
Migliorini and C. Ventura, Eur. J. Org. Chem., 2011, 385.
We are grateful to the National Natural Science Foundation
of China (no. 21272087 and 21472058), the Youth Chen-Guang
Project of Wuhan (No. 2015070404010180) and the self-
determined research funds of CCNU (No. CCNU15A02009) for
support of this research.
,
14 J. Li, T. Du, G. Zhang and Y. Peng, Chem. Commun., 2013, 49
1330.
,
Notes and references
15 (a) M. A. Marsini, J. T. Reeves, J. N. Desrosiers, M. A.
Herbage, J. Savoie, Z. Li, K. R. Fandrick, C. A. Sader, B.
McKibben, D. A. Gao, J. Cui, N. C. Gonnella, H. Lee, X. Wei, F.
Roschangar, B. Z. Lu and C. H. Senanayake, Org. Lett., 2015,
17, 5614; (b) S. Hajra, S. M. Aziz, B. Jana, P. Mahish and D.
Das, Org. Lett., 2016, 18, 532.
1
For recent reviews on the chemistry of amidoacrylates, see:
(a) C. Bonauer, T. Walenzyk and B. Knonig, Synthesis, 2006,
1; (b) S. Kotha, V. B. Bandarugattu and N. G.Krishna,
Tetrahedron, 2014, 70, 5361.
2
For recent reviews on the chemistry of aziridines, see: (a) H.
C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
16 Q.-L. Wang, T. Cai, J. Zhou, F. Tian, X.-Y. Xu and L.-X. Wang,
Chem. Commun., 2015, 51, 10726.
Ed., 2001, 40, 2004; (b) X. E. Hu, Tetrahedron, 2004, 60
,
17 For selected examples, see: (a) F. Tan, L.-Q. Lu, Q.-Q. Yang,
W. Guo, Q. Bian, J.-R. Chen and W.-J. Xiao, Chem. Eur. J.,
2014, 20, 3415; (b) A. Boucherif, Q.-Q. Yang, Q. Wang, J.-R.
Chen, L.-Q. Lu and W.-J. Xiao, J. Org. Chem., 2014, 79, 3924;
(c) X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M.
Beauchemin and W.-J. Xiao, Angew. Chem. Int. Ed., 2014,
53, 12163; (d) Q.-H. Deng, J.-R. Chen, Q. Wei, Q.-Q. Zhao, L.-
Q. Lu and W.-J. Xiao, Chem. Commun., 2015, 51, 3537.
18 (a) J. Vesely, I. Ibrahem, G. L. Zhao, R. Rios and A. Córdova.
Angew. Chem. Int. Ed., 2007, 46, 778; (b) F. Pesciaioli, F. D.
Vincentiis, P. Galzerano, G. Bencivenni, G. Bartoli, A.
Mazzanti and P. Melchiorre. Angew. Chem. Int. Ed., 2008,
47, 8703.
2701; (c) M. Pineschi, Eur. J. Org. Chem., 2006, 4979; (d) G.
S. Singh, M. D’hooghe and N. D. Kimpe, Chem. Rev., 2007,
107, 2080; (e) R. Chawla, A. K. Singh and L. D. S. Yadav, RSC
Adv., 2013, 3, 11385; (f) G. Callebaut, T. Meiresonne, N. De
Kimpe and S. Mangelinckx, Chem. Rev., 2014, 114, 7954.
For selected examples, see: (a) A. Avenoza, J. H. Busto, N.
Canal, F. Corzana, J. M. Peregrina, M. P. Fernández and F.
Rodrìguez, J. Org. Chem., 2010, 75, 545; (b) Z. Wang, S. Luo,
S. Zhang, W. L. Yang, Y. Z. Liu, H. Li, X. Luo and W.-P. Deng,
Chem. Eur. J., 2013, 19, 6739.
For selected examples, see: (a) S. Kotha, A. K. Ghosh and M.
Behera, Indian J. Chem., 2002, 41B, 2330; (b) C. J. Moody, R.
A. Hughes, S. P. Thompson and L. Alcaraz, Chem. Commun.,
2002, 1760; (c) S. Kotha and A. K. Ghosh, Synthesis, 2004,
558.
For selected examples, see: (a) L. Navarre, R. Martinez, J. P.
Genet and S. Darses, J. Am. Chem. Soc., 2008, 130, 6159; (b)
T. Jousseaume, N. E. Wurz and F. Glorius, Angew. Chem.,
Int. Ed., 2011, 50, 1410; (c) B. M. K. Tong and S. Chiba, Org.
Lett., 2011, 13, 2948.
3
4
5
19 CCDC 1476290 (3a), 1476291 (4a), 1476292 (4a’), and
1476293 (5) contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
20 X.-F. Wang, L. Peng, J. An, C. Li, Q.-Q. Yang, L.-Q. Lu, F.-L. Gu
and W.-J. Xiao, Chem. Eur. J., 2011, 17, 6484.
4 | J. Name., 2015, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins