N-heterocyclic-carbene-catalyzed reaction of α-Bromo-α,β- unsaturated aldehyde or α,β-dibromoaldehyde with isatins: An efficient synthesis of spirocyclic oxindole-dihydropyranones

Article abstract of DOI:10.1002/chem.201202655

Smooth as isatin! A straightforward synthesis of spirocyclic oxindole-dihydropyranones through an N-heterocyclic-carbene-catalyzed [4+2] annulation of α-bromo-α,β-unsaturated aldehydes or α,β-dibromoaldehyde bearing γ-H with isatin derivatives under mild

Full text of DOI:10.1002/chem.201202655

DOI: 10.1002/chem.201202655
N-Heterocyclic-Carbene-Catalyzed Reaction of a-Bromo-a,b-Unsaturated
Aldehyde or a,b-Dibromoaldehyde with Isatins: An Efficient Synthesis of
Spirocyclic Oxindole–DihydroACTHNUTRGNEUpGN yranones
Changsheng Yao,*[a] Zhaoxin Xiao,[b] Rui Liu,[b] Tuanjie Li,[b] Weihui Jiao,[b] and
Chenxia Yu[b]
In past decades, extensive attentions have been paid to N-
heterocyclic carbene (NHCs)-catalyzed umpolung reactions,
for example, the benzoin condensation and the Stetter reac-
tion, due to their broad applications in organic synthesis.[1]
Some recent reports described the NHC-catalyzed redox-
type transformations of a-functionalized aldehydes bearing
reducible functionalities (internal redox reaction) or the oxi-
dation of aldehyde in the presence of oxidants (external
redox reaction).[1a,c,2] 5,6-Dihydropyran-2-one (a,b-unsatu-
Scheme 1. NHC-bonded vinyl enolate generated from a,b-unsaturated
rated d-lactone) is a privileged structure presented widely in
natural products and synthesized biological molecules.[3] Its
derivatives could be also used as versatile synthetic inter-
mediates.[4] So many efforts have been devoted to the devel-
opment of efficient approaches for its construction.[5] In
2011, Ye et al. disclosed a facile assembly of a,b-unsaturated
d-lactone from the formal [4+2] reaction of activated ke-
tones, for example, trifluoromethyl ketones and isatins, and
NHC-bonded vinyl enolate (A) generated from a,b-unsatu-
rated b-methylacyl chloride under basic conditions
(Scheme 1).[6] More recently, Chi et al. described an elegant
way to yield the same intermediate A through the oxidation
of enal bearing g-H presented by NHC (Scheme 2).[7] Our
previous communication showed that the reaction of 2-
bromo-2-enal and NHCs could give the Breslow intermedi-
ate B, which would be transformed into intermediates C
readily through an a3!d3 umpolung and debromination.[8a]
We speculated that the deprotonation of the intermediate C
at the g-position would give an intermediate (D) similar to
A effectively. The following reaction of D with activated ke-
b-methylacyl chloride.
Scheme 2. Formation of NHC-bonded vinyl enolate from oxidation of
enal bearing g-H.
tones would give rise to a,b-unsaturated d-lactones in the
absence of external oxidants (Scheme 3). Among the most
ubiquitous heterocycles in nature, indoles are common
structural motifs in many biologically active molecules and
pharmaceutical substances.[9] Also, the oxindole skeleton has
attracted much attention in the field of medicinal chemistry
[a] Prof. Dr. C. Yao
School of Chemistry and Engineering
Key Laboratory of Biotechnology for Medicinal Plant
Jiangsu Normal University
Xuzhou, Jiangsu 221116 (P.R. China)
Fax: (+86)516-83500365
E-mail: csyao@jsnu.edu.cn
[b] Z. Xiao, R. Liu, Prof. Dr. T. Li, W. Jiao, Prof. C. Yu
School of Chemistry and Engineering
Jiangsu Key Laboratory of Green Synthetic Chemistry
for Functional Materials, Jiangsu Normal University
Xuzhou Jiangsu 221116 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202655.
Scheme 3. An envisaged pathway to generate NHC-bonded vinyl enolate
from 2-bromo-2-enal with g-H.
456
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 456 – 459

COMMUNICATION
due to its biological significance and wide occurrence in nat-
ural products.[10] Its combination with pyran scaffolds should
arouse great interest in synthetic and medicinal chemists.[11]
Isatin derivatives are versatile building blocks to assemble
the spirocyclic frameworks.[12] To continue our work on the
NHC-catalyzed synthesis of dihydropyranones,[8a] herein we
shall report our preliminary results of an NHC-catalyzed re-
action of 2-bromo-2-enal bearing g-H with isatins, which
may afford spirocyclic oxindole-dihydropyranone derivatives
with potential biological activities (Scheme 4).
tBuOK were tested to evaluate the scope of the base, and it
was found that Cs2CO3 was the best among them, however
tBuOK could only give a poor yield of the desired product
(Table 1, entries 6 and 7). An investigation of the amount of
catalyst and base required indicated that 15 mol% of 4b
along with 115 mol% of Cs2CO3 was optimal to the reac-
tion. When the loading of the catalyst was decreased from
15 to 5 mol%, the yield of the desired product 3a reduced
(Table 1, entries 8–10); however, the use of 20 mol% of 4b
did not affect the yield notably (Table 1, entry 2). Subse-
quently, the solvent effect on the reaction was studied using
4b (15 mol%) and Cs2CO3 (115 mol%), and THF was
found to be the best solvent in terms of yield among THF,
toluene, and CH2Cl2 (Table 1, entries 10–12). An optimiza-
tion of the temperature revealed that 258C was preferable.
Under the optimized reaction conditions the reaction
scope was then briefly explored (Table 2). In the course of
the experiment, we found that electron-donating substitu-
Scheme 4. This work.
Table 2. Synthesis of spirocyclic oxindole–dihydropyranones.
The influences of various NHCs, bases, solvents, and dif-
ferent temperatures on the reaction of 1 and 2a were inves-
tigated to optimize the reaction conditions. As shown in
Table 1, initially, we screened the precatalyst by using differ-
ent imidazolium, thiazolium, and triazolium salts 4a--4e and
it was found that the best precatalyst for the synthesis of spi-
rocyclic product 3a was 4b (Table 1, entry 2). After that,
R1
R2
R3
Product
Yield
[%][a]
1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU), Cs2CO3 and
1
2
3
4
5
6
7
8
9
10
11
12
13
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Me
Et
Me
Allyl
Me
Et
H
H
OCF3
H
Me
Me
Me
Me
OMe
OMe
OMe
Cl
3a
3b
3c
3d
3e
3 f
3g
3h
3i
90
87
82
86
89
90
87
85
93
90
91
84
75
Table 1. Optimization of the reaction conditions.
Bn
Allyl
Me
Et
Bn
Me
Me
3j
3k
3l
Me
3m
[a] Yield of the isolated product.
Precat.
[(mol%)]
Solvent
Base
[(mol%)]
T
t
Yield
[%][a]
N.R[b]
86
ents on the aromatic ring of isatins needed a longer reaction
time, but which could provide a better yield of the product
relative to those with electron-withdrawing substituents. In
addition, different substituted groups on the N-atom of isa-
tins influenced the reactivity and the product yield; when
the methyl or ethyl group was replaced with allyl or benzyl
group, the reaction rate and yield were both slightly de-
creased.
An initial exploration of stereoselective synthesis of the
target compound 3 was performed due to the presence of a
pseudo-quaternary carbon in the final product. Unfortunate-
ly, when chiral precatalysts 4 f was applied to the reaction,
product 3a was obtained in 42% yield and with an enantio-
meric excess (ee) of 28%. In addition, the chemical yield
and enantioselectivity became worse when precatalyst 4g
G
G
A
[h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a (20)
4b (20)
4c (20)
4d (20)
4e (20)
4b (20)
4b (20)
4b (5)
4b (10)
4b (15)
4b (15)
4b (15)
4b (15)
4b (15)
4b (15)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
toluene
THF
THF
THF
Cs2CO3 (120)
Cs2CO3 (120)
Cs2CO3 (120)
Cs2CO3 (120)
Cs2CO3 (120)
tBuOK (120)
DBU (120)
Cs2CO3 (105)
Cs2CO3 (110)
Cs2CO3 (115)
Cs2CO3 (115)
Cs2CO3 (115)
Cs2CO3 (150)
Cs2CO3 (110)
Cs2CO3 (120)
25
25
25
25
25
25
25
25
25
25
25
25
0
24
8
10
24
12
24
18
15
12
8
10
9
22
6
16
N.R[b]
11
8
23
78
85
90
72
79
80
35
40
63
35
4.5
[a] Yield of the isolated product. [b] No reaction.
Chem. Eur. J. 2013, 19, 456 – 459
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
457

C. Yao et al.
Scheme 5. Asymmetric annulation catalyzed by chiral precatalysts.
was used (Scheme 5). It is clear that the level of chiral in-
duction is not yet ideal. We are currently designing new cat-
alysts to perfect this reaction from the standpoint of enan-
tioselectivity.
Our previous work demonstrated that a,b-dibromoalde-
hydes could readily give 2-bromo-2-enal under basic condi-
tions through dehydrogenbromination.[8a] So 2,3-dibromo-3-
methylbutanal 5 was used instead of 2-bromo-3-methylbut-
2-enal and the reaction worked well to give the same de-
sired product in a yield of 89% (Scheme 6).
Scheme 7. A proposed reaction mechanism.
Experimental Section
Typical procedure—NHC-catalyzed reaction of a-bromo-a,b-unsaturated
aldehydes or a,b-dibromoaldehyde with isatin derivatives: Precatalyst 4b
(51 mg, 0.15 mmol) (or 4 f (63 mg, 0.15 mmol) or 4g (57 mg, 0.15 mmol))
and Cs2CO3 (374 mg, for 2,3-dibromo-3-methylbutanal, 699 mg of Cs2CO3
was used) were weighed into an oven-dried 25 mL vial. THF (5 mL) was
added to the mixture. The resulting mixture was stirred at room tempera-
ture for 5 min followed by the addition of a solution of 2-bromo-2-enal
(or 2,3-dibromo-3-methylbutanal, 1 mmol), isatins 2 (1 mmol) in THF
(5 mL). The mixture was stirred at room temperature until completion
(monitored by TLC). After removal of the solvent under reduced pres-
sure, the crude product was purified by column chromatography (silica
gel, mixtures of ethyl acetate/petroleum ether, 1:1, v/v).
Scheme 6. N-Heterocyclic-carbene-catalyzed reaction of a,b-dibromoal-
dehyde with isatin derivatives.
A postulated reaction pathway for the formation of spiro-
cyclic product 3 is illustrated in Scheme 7. The Breslow in-
termediate B, generated by the reaction of 2-bromo-2-enal
with the NHC, was transformed into C through a3!d3 um-
polung and debromination. The acylazoliumion C was de-
protonated at the g-position to give the vinyl enolate D with
the aid of base. Next, intermediate D reacted with isatins 2,
maybe through a procedure similar to the Diels–Alder reac-
tion or a non-concerted nucleophilic addition reaction fol-
lowed by an intramolecular cyclization to afford target prod-
uct 3 and release the catalyst to complete the catalytic cycle.
In conclusion, we have developed an efficient NHC-cata-
lyzed [4+2] annulation of a-bromo-a,b-unsaturated alde-
hydes or a,b-dibromoaldehyde bearing g-H with isatin de-
rivatives under mild reaction conditions to prepare spirocy-
clic oxindole–dihydropyranones. This approach is particular-
ly attractive due to the concise construction, straightforward
procedure, avoidance of external oxidants, and the potential
utilization value of final products in molecular biology and
pharmacy. This strategy also extends the scope of NHC-cat-
alysis and provides a simple protocol for NHC-catalyzed
hetero-Diels–Alder reactions.
Acknowledgements
We are grateful for financial support by NSFC (No. 21242014), A Project
Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions the Major Basic Research Project of the
Natural Science Foundation of the Jiangsu Higher Education Institutions
(09 KJA430003), Natural Science Foundation of Xuzhou City
(XM12B074). The authors thank Prof. Changsheng Cao in Jiangsu
Normal University, China, for help regarding the synthesis of the precata-
lysts.
Keywords: annulation · carbenes · redox reaction · spiro
compounds · umpolung
[1] For reviews, please see: a) D. Enders, O. Niemeier, A. Henseler,
Chem. Rev. 2007, 107, 5606–5655; b) V. Nair, S. Vellalath, B. P.
Babu, Chem. Soc. Rev. 2008, 37, 2691–2698; c) J. L. Moore, T.
Rovis, Top. Curr. Chem. 2010, 291, 118–144; d) A. Grossmann, D.
Enders, Angew. Chem. Int. Ed. 2012, 51, 314–325; e) D. T. Cohen,
K. A. Scheidt, Chem. Sci. 2012, 3, 53–57; for recent advances, please
see: f) T. Ema, Y. Oue, K. Akihara, Y. Miyazaki, T. Sakai, Org. Lett.
458
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 456 – 459

Synthesis of Spirocyclic Oxindole–Dihydropyranones
COMMUNICATION
2009, 11, 4866–4869; g) S. P. Lathrop, T. Rovis, J. Am. Chem. Soc.
2009, 131, 13628–13630; h) D. Enders, A. Henseler, Adv. Synth.
Catal. 2009, 351, 1749–1752; i) D. A. DiRocco, K. M. Oberg, D. M.
Dalton, T. Rovis, J. Am. Chem. Soc. 2009, 131, 10872–10874; j) K.
Hirano, A. T. Biju, I. Piel, F. Glorius, J. Am. Chem. Soc. 2009, 131,
14190–14191; k) D. Enders, A. Grossmann, J. Fronert, G. Raabe,
Chem. Commun. 2010, 46, 6282–6284; l) Y. Shimakawa, T. Morika-
wa, S. Sakaguchi, Tetrahedron Lett. 2010, 51, 1786–1789; m) A. T.
Biju, N. E. Wurz, F. Glorius, J. Am. Chem. Soc. 2010, 132, 5970–
5971; n) F. G. Sun, X. L. Huang, S. Ye, J. Org. Chem. 2010, 75, 273–
276; o) T. Jousseaume, N. E. Wurz, F. Glorius, Angew. Chem. 2011,
123, 1446–1450; Angew. Chem. Int. Ed. 2011, 50, 1410–1414;
p) D. A. DiRocco, T. Rovis, Angew. Chem. Int. Ed. 2012, 51, 5904–
5906; q) M. Q. Jia, S. L. You, Chem. Commun. 2012, 48, 6363–6365;
r) A. Bhunia, S. R. Yetra, S. S. Bhojgude, A. T. Biju, Org. Lett. 2012,
14, 2830–2833.
48, 2639–2641; d) P. Kumar, M. Pandey, P. Gupta, D. D. Dhavale,
Org. Biomol. Chem. 2012, 10, 1820–1825; e) K. C. Majumdar, S.
Ganai, R. K. Nandi, K. Ray, Tetrahedron Lett. 2012, 53, 1553–1557;
f) Y. Huang, A. J. Minnaard, B. L. Feringa, Org. Biomol. Chem.
2012, 10, 29–31; g) H. Yeom, J. Koo, H. Park, Y. Wang, Y. Liang,
Z.-X. Yu, S. Shin, J. Am. Chem. Soc. 2012, 134, 208–211.
[6] L.-T. Shen, P.-L. Shao, S. Ye, Adv. Synth. Catal. 2011, 353, 1943–
1948.
[7] J. Mo, X. Chen, Y. R. Chi, J. Am. Chem. Soc. 2012, 134, 8810–8813.
[8] a) C. Yao, D. Wang, J. Lu, T. Li, W. Jiao, C. Yu, Chem. Eur. J. 2012,
18, 1914–1917; for other examples of NHC-catalyzed reactions of a-
bromoenal, see: b) F.-G. Sun, L.-H. Sun, S. Ye, Adv. Synth. Catal.
2011, 353, 3134–3138; c) B. Zhang, P. Feng, Y. Cui, N. Jiao, Chem.
Commun. 2012, 48, 7280–7282; d) X.-B. Wang, X.-L. Zou, G.-F. Du,
Z.-Y. Liu, B. Dai, Tetrahedron 2012, 68, 6498–6503.
[9] a) W. C. Sumpter, Chem. Rev. 1945, 37, 443–479; b) W. Gul, M. T.
Hamann, Life. Sci. 2005, 78, 442–453; c) L. Gupta, A. Talwar,
P. M. S. Chauhan, Curr. Med. Chem. 2007, 14, 1789–1803; d) A. J.
Kochanowska-Karamyan, M. T. Hamann, Chem. Rev. 2010, 110,
4489–4497; e) Y. Hou, L. Harinantenaina, Curr. Med. Chem. 2010,
17, 1191–1219; f) P. M. Pauletti, L. Silva Cintra, C. G. Braguine,
A. A. da Silva Filho, M. L. Andrade e Silva, W. R. Cunha, A. H. Ja-
nuario, Mar. Drugs 2010, 8, 1526–1549.
[10] a) Y. Kamano, H. Zhang, Y. Ichihara, H. Kizu, K. Komiyama, G. R.
Pettit, Tetrahedron Lett. 1995, 36, 2783–2784; b) A. Coste, F. Couty,
G. Evano, C. R. Chim. 2008, 11, 1544–1573; c) J. Xiao, W. West-
broek, O. Motabar, W. A. Lea, X. Hu, A. Velayati, W. Zheng, N.
Southall, A. M. Gustafson, E. Goldin, E. Sidransky, K. Liu, A. Si-
meonov, R. J. Tamargo, A. Ribes, L. Matalonga, M. Ferrer, J. J. Mar-
ugan, J. Med. Chem. 2012, 55, 7546–7559; d) H. Watanabe, M. Ono,
H. Kimura, K. Matsumura, M. Yoshimura, Y. Okamoto, M. Ihara,
R. Takahashi, H. Saji, Bioorg. Med. Chem. Lett. 2012, 22, 5700–
5703.
[2] a) E. M. Phillips, T. E. Reynolds, K. A. Scheidt, J. Am. Chem. Soc.
2008, 130, 2416–2417; b) M. He, J. W. Bode, J. Am. Chem. Soc.
2008, 130, 418–419; c) M. Rommel, T. Fukuzumi, J. W. Bode, J. Am.
Chem. Soc. 2008, 130, 17266–17267; d) J. Seayad, P. K. Patra, Y.
Zhang, J. Y. Ying, Org. Lett. 2008, 10, 953–956; e) J. Kaeobamrung,
J. W. Bode, Org. Lett. 2009, 11, 677–680; f) K. Thai, L. Wang, T.
Dudding, F. Bilodeau, M. Gravel, Org. Lett. 2010, 12, 5708–5711;
g) X. Fang, K. Jiang, C. Xing, L. Hao, Y. R. Chi, Angew. Chem.
2011, 123, 1950–1953; Angew. Chem. Int. Ed. 2011, 50, 1910–1913;
h) Z. Q. Rong, W. Zhang, G. Q. Yang, S. L. You, Curr. Org. Chem.
2011, 15, 3077–3090; i) H. U. Vora, P. Wheeler, T. Rovis, Adv. Synth.
Catal. 2012, 354, 1617–1639; j) C. E. I. Knappke, A. Imami, A. Jaco-
bi von Wangelin, ChemCatChem 2012, 4, 937–941; k) L. Yang, F.
Wang, P. J. Chua, Y. Lv, L. Zhong, G. Zhong, Org. Lett. 2012, 14,
2894–2897; l) T. Uno, T. Inokuma, Y. Takemoto, Chem. Commun.
2012, 48, 1901–1903; m) E. E. Finney, K. A. Ogawa, A. J. Boydston,
J. Am. Chem. Soc. 2012, 134, 12374–12377; n) S. E. Allen, J. Mahat-
thananchai, J. W. Bode, M. C. Kozlowski, J. Am. Chem. Soc. 2012,
134, 12098–12103.
[3] a) A. K. Banerjee, M. S. Laya, H. R. Mora, E. V. Cabrera, Curr.
Org. Chem. 2008, 12, 1050–1070; b) M. Ljungman, Chem. Rev. 2009,
109, 2929–2950; c) J.-Y. Wach, K. Gademann, Synlett 2012, 163–
170.
[4] F. Yoshimura, M. Torizuka, G. Mori, K. Tanino, Synlett 2012, 251–
254.
[5] a) C. Chen, J. Sun, F. Liu, K. Fung, P. Wu, Z. Huang, Tetrahedron
2012, 68, 2598–2606; b) T. Vijaya Kumar, K. Suresh Babu, J. Mad-
husudana Rao, Tetrahedron Lett. 2012, 53, 1823–1825; c) R. W.
Scott, C. Mazzetti, T. J. Simpson, C. L. Willis, Chem. Commun. 2012,
[11] a) M. P. Castaldi, D. M. Troast, J. A. Porco, Org. Lett. 2009, 11,
3362–3365; b) R. Shintani, S. Hayashi, M. Murakami, M. Takeda, T.
Hayashi, Org. Lett. 2009, 11, 3754–3756; c) J. Wang, E. A. Crane,
K. A. Scheidt, Org. Lett. 2011, 13, 3086–3089.
[12] For selected examples, please see: a) A. K. Franz, P. D. Dreyfuss,
S. L. Schreiber, J. Am. Chem. Soc. 2007, 129, 1020–1021; b) J. M.
Richter, Y. Ishihara, T. Masuda, B. W. Whitefield, T. Llamas, A.
Pohjakallio, P. S. Baran, J. Am. Chem. Soc. 2008, 130, 17938–17954;
For recent review, please see: G. S. Singh, Z. Y. Desta, Chem. Rev.
2012, 112, 6104–6155.
Received: July 26, 2012
Published online: December 7, 2012
Chem. Eur. J. 2013, 19, 456 – 459
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
459