N-heterocyclic carbene-catalyzed three-component domino reaction of alkynyl aldehydes with oxindoles

Article abstract of DOI:10.1021/ol300148f

A new and stereoselective synthetic approach to spirooxindole 4H-pran-2-one derivatives with three contiguous stereogenic centers has been developed via an NHC-catalyzed three-component domino reaction of alkynyl aldehydes with oxindoles. The reaction pro

Full text of DOI:10.1021/ol300148f

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1274–1277
N-Heterocyclic Carbene-Catalyzed
Three-Component Domino Reaction of
Alkynyl Aldehydes with Oxindoles
Ding Du,* Zhongyuan Hu, Jianlin Jin, Yingyan Lu, Weifang Tang, Bo Wang, and
Tao Lu*
State Key Laboratory of Natural Medicines, Department of Organic Chemistry, China
Pharmaceutical University, Nanjing, 210009, P. R. China
ddmn9999@cpu.edu.cn (Du); lut163@163.com (Lu)
Received January 19, 2012
ABSTRACT
A new and stereoselective synthetic approach to spirooxindole 4H-pran-2-one derivatives with three contiguous stereogenic centers has been
developed via an NHC-catalyzed three-component domino reaction of alkynyl aldehydes with oxindoles. The reaction proceeds smoothly in good
yields with good to high diastereoselectivities. These novel heterocyclic spirooxindoles may provide promising candidates for drug discovery.
Additionally, a possible mechanism for the entire reaction sequence is proposed.
The spirooxindoles are structurally interesting and fre-
quently present as important substructures in a broad
range of complex natural products, pharmaceuticals, and
synthetic heterocycles with highly pronounced biological
activities.1 A potentially promising subset of these bioac-
tive compounds is the oxa-spirooxindoles.2 As a particular
class of oxa-spirooxindoles, the spirooxindole 4H-pyran-
2-ones are characterized by a spiro fusion to the 4H-pyran-2-
one ring which is a valuable subunit of many bioactive
natural products3 at the 3-position of the oxindole core.
However, few investigations have been focused on the spiro-
oxindole 4H-pyran-2-ones, and versatile approaches to this
unique heterocyclic motif are considerably limited.4 Thus, the
search for general and efficient methods for the synthesis of
spirooxindole 4H-pyran-2-ones is highly desirable.
The highly efficient construction of complex skeletons of
molecules with potential biological activities by domino
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r
10.1021/ol300148f
Published on Web 02/21/2012
2012 American Chemical Society

reactions has drawn much attention over the past decade.5
In recent years, N-heterocyclic carbenes (NHCs) have also
evoked considerable interest because of their wide-ranging
utility as efficient organocatalysts in a large number of
umpolung transformations of different types of aldehdyes.6
However, few efforts have been focused on the R,β-unsatu-
rated ynals 1 (namely alkynyl aldehydes),7 which are an
important source of catalytically generated R,β-unsaturated
acyl azolium 2 (Scheme 1),8 a fascinating reactive inter-
mediate in a rapidly growing number of transformations
mediated by NHCs. Zeitler7a,b has reported the pioneering
work of an NHC-promoted stereoselective redox esterifica-
tion of alkynyl aldehydes 1 providing (E)-configurated
R,β-unsaturated carboxylic esters (Scheme 1, reaction a).
Bode7c and Xiao7d,e have recently described the NHC-
catalyzedreaction ofalkynylaldehydes1 with various enols
to give functionalized 3,4-dihydropyranones (Scheme 1,
reaction b). Inspired by these results and as part of our
ongoing program to explore efficient methodologies for
chemical transformations using NHCs as organocatalysts,9
we envisioned that the combination of alkynyl aldehydes 1
and oxindoles 3 in the presence of NHCs may produce
indole-fused dihydropyranones 4.10 Interestingly, instead
of the anticipated products 4, the spirooxindole 4H-pyran-
2-ones 5 with three contiguous stereogenic centers were
obtained in good yields with good to high diastereoselec-
tivities via a three-component domino process (Scheme 1,
reaction c).11 This strategy offered an efficient and stereo-
selective access to the construction of highly functionalized
spirooxindole 4H-pyran-2-ones which may provide pro-
mising candidates for drug discovery. Herein, we wish to
report our recent results.
Scheme 1. NHC-Catalyzed Reactions of Alkynyl Aldehydes 1
At the outset of our studies, a set of experiments were
carried out to evaluate and optimize the conditions for the
reaction of alkynyl aldehydes with oxindoles (Table 1).
Initially, we examined the model reaction of 3-phenylpro-
pioaldehyde 1a (3.0 equiv) with oxindole 3a (1.0 equiv) in
the presence of carbene precursors AÀF (entries 1À3).
NHCs derived from precursors AÀE proved unsuitable
for this reaction, leading to the formation of a large quantity
of Knoevenagel product 6a (entries 1 and 2). Surprisingly,
with 30 mol % of imidazolium salt F and 30 mol % of DBU
in THF, spirooxindole 4H-pyran-2-one 5a was obtained in
an 54% yield with modest diastereoselectivity which was
accompanied by <15% of isolated Knoevenagel product
6a (entry 3). The product 5a was constructed from one
molecule of 3a and two molecules of 1a via a three-compo-
nent domino process. Further screening of various bases
suggested t-BuOK was the optimal one (entries 4À8). The
attempts to decrease the catalyst loading led to decreased
yields and a prolonged reaction time (entries 9 and 10).
Moreover, the examination of several solvents such as
PhMe, DCE, DMF, and 1,4-dioxane also did not improve
the yield. Unfortunately, in all cases, the Knoevenagel
product 6a could not be suppressed completely. So, the
optimal reaction conditions were established as follows:
30 mol % of catalyst F and 30 mol % of t-BuOK in THF
for 2 h at 65 °C with an 60% yield and 85:15 dr (entry 8). The
structure and relative stereochemistry of the products were
established by spectroscopic analysis and further confirmed
by X-ray crystallography of 5a.12
(6) For selected reviews, see: (a) Enders, D.; Niemeier, O.; Henseler,
A. Chem. Rev. 2007, 107, 5606. (b) Marion, N.; Diez-Gonzalez, S.;
Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (c) Nair, V.;
Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (d) Biju,
A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011, 44, 1182. (e) Enders,
D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534.
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Adv. Synth. Catal. 2007, 349, 1851. (c) Kaeobamrung, J.; Mahatthanan-
chai, J.; Zheng, P.; Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810. (d)
Zhu, Z. Q.; Xiao, J. C. Adv. Synth. Catal. 2010, 352, 2455. (e) Zhu, Z.-Q.;
Zheng, X.-L.; Jiang, N.-F.; Wan, X.; Xiao, J.-C. Chem. Commun. 2011,
47, 8670. (f) Mahatthananchai, J.; Zheng, P.; Bode, J. W. Angew. Chem.,
Int. Ed. 2011, 50, 1673.
(8) For other NHC-catalyzed reactions involving R,β-unsaturated
acyl azolium 2, see: (a) Wanner, B.; Mahatthananchai, J.; Bode, J. W.
Org. Lett. 2011, 13, 5378. (b) Ryan, S. J.; Candish, L.; Lupton, D. W. J.
Am. Chem. Soc. 2011, 133, 4694. (c) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L.
€
Org. Lett. 2011, 13, 4080. (d) Biswas, A.; Sarkar, S. D.; Frohlich, R.;
Studer, A. Org. Lett. 2011, 13, 4966. (e) Sarkar, S. D.; Studer, A. Angew.
Chem., Int. Ed. 2010, 49, 9266. (f) Candish, L.; Lupton, D. W. Org. Lett.
2010, 12, 4836. (g) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am. Chem.
Soc. 2009, 131, 14176.
(9) (a) Du, D.; Wang, Z. Eur. J. Org. Chem. 2008, 4949. (b) Du, D.;
Li, L.; Wang, Z. J. Org. Chem. 2009, 74, 4379. (c) Li, L.; Du, D.; Ren, J.;
Wang, Z. Eur. J. Org. Chem. 2011, 614. (d) Du, D.; Lu, Y.; Jin, J.; Tang,
W.; Lu, T. Tetrahedron 2011, 67, 7557. (e) Du, D.; Hu, Z.; Tang, W.;
Wang, B.; Lu, T. Tetrahedron Lett. 2012, 53, 453.
With the optimized conditions in hand, the generality of
the reaction was explored (Table 2). We found that the
reaction could accommodate a broad range of substituted
oxindoles, although the Knoevenagel products were also
isolated in <15% yields in most cases (entries 1À13).
Oxindoles 3aÀd with different N-protecting groups had
(10) Lv, H.; Chen, X.-Y.; Sun, L.-h.; Ye, S. J. Org. Chem. 2010, 75,
6973.
(11) For other NHC-catalyzed synthesis of spirooxindoles, see: (a)
Wang, X.-N.; Zhang, Y.-Y.; Ye, S. Adv. Synth. Catal. 2010, 352, 1892.
(b) Sun, L.-H.; Shen, L.-T.; Ye, S. Chem. Commun. 2011, 47, 10136. (c)
Nair, V.; Vellalath, S.; Poonoth, M.; Mohan, R.; Suresh, E. Org. Lett.
2006, 8, 507. (d) Thomson, J. E.; Kyle, A. F.; Ling, K. B.; Smith, S. R.;
Slawin, A. M. Z.; Smith, A. D. Tetrahedron 2010, 66, 3801.
(12) See Supporting Information for details.
Org. Lett., Vol. 14, No. 5, 2012
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Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of the Reaction between Alkynyl Aldehydes 1
and Oxindoles 3a
a All reactions were performed by using 3.0 equiv of 1a (0.6 mmol),
˚
1.0 equiv of 3a (0.2 mmol), in the presence of 4 A MS (100 mg), 30 mol %
of a carbene precursor, and 30 mol % of a base in THF (3 mL) at 65 °C
under N2 for 2 h. b Isolated yield based on 3a. c Diastereomeric ratio
determined by H1 NMR of the crude product. d The reaction was carried
out with 20 mol % of F and 20 mol % of t-BuOK for 5 h, and 15% of 3a
was recovered . e The reaction was carried out with 30 mol % of F and
20 mol % of t-BuOK for 5 h, and 18% of 3a was recovered.
no significant impact on the yields and diastereoselectiv-
ities (entries 1À4). Remarkably, N-unprotected oxindole
3e could also give desired product 5e in a ratio of >95:5,
although the yield was lower and 22% of 3e was recovered
(entry 5). Oxindoles with electron-withdrawing groups (F,
Cl, Br) and an electron-donating group (Me) at the 4-, 5-,
6-, or 7-position worked equally well to afford the desired
products in good yields with good to high diastereoselec-
tivities (entries 6À13). Subsequently, a variety of alkynyl
aldehydes 1 were tested for this domino reaction with
oxindole 3g (entries 14À24). The reaction also proceeded
smoothly for alkynyl aldehydes 1bÀi with various substi-
tuents at different positions on the phenyl ring, affording
the corresponding products in good yields with good to
high diastereoselectivities except 3-Cl substituted substrate
1f and 2,3-disubstituted substrate 1i (entries 14À21). Un-
fortunately, in the case of 3-(1-naphthyl)propiolaldehyde
1j, no desired spirooxindole product was obtained, while
35% of Knoevenagel product was isolated and 38% of 3g
was recovered (entry 22). It was noteworthy that 3-hetero-
aromatic-substituted alkynyl aldehyde 1k was also sub-
jected to this process (entry 23). 3-Aliphatic-substituted
alkynyl aldehyde 1l was then examined, resulting in quan-
titativeformation of the Knoevenagel product withoutany
desired product (entry 24). Finally, this reaction pattern
was further applied to N-unprotected oxindole 3n (entries
a All reactions were performed by using 3.0 equiv of 1 (0.6 mmol), 1.0
equiv of 3 (0.2 mmol) in the presence of 30 mol % of F and 30 mol % of
t-BuOK in THF (3 mL) at 65 °C under N2 for 2 h. b Isolated yield based
on 3. c Diastereomeric ratios determined by H1 NMR of the crude pro-
ducts. d 22% of 3e was recovered. e 20% of 3g was recovered. f 38% of 3g
was recovered.
25and 26). Itwasfoundthat thereactionof 3nwithalkynyl
aldehydes 1a and 1e respectively gave the corresponding
products in significantly increased yields compared to
N-unprotected oxindole 3e.
To further explore the scope of the reaction, we paid
attention to the development of three-component couplings
with two different aldehydes (Scheme 2). We selected the
reaction of oxindole 3g with alkynyl aldehydes 1a and 1e to
examine the possibility of this three-component coupling. It
was interesting that, among four possible coupling products,
products 5g and 5q were obtained in 14% and 26% yields
respectively, while only one product 5y derived from the
cross-coupling of 3g with 1a and 1e was obtained in an 35%
yield (reaction a). The structure of 5y was established by
COSY, HSQC, and HMBC analysis.12 The reaction was
then tested by using oxindole 3g, alkynyl aldehyde 1a, and
4-chlorobenzaldehyde. Neverthless, only product 5g was
isolated in an 56% yield, and product 7 from the coupling of
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Org. Lett., Vol. 14, No. 5, 2012

Scheme 2. Three-Component Couplings with Two Different
Aldehydes
Scheme 4. Proposed Mechanism for NHC-Catalyzed Reaction
between Oxindoles and Alkynyl Aldehydes
3g with 1a and 4-cholorobenzaldehyde was not obtained,
perhaps due to the lower electrophilicity of 4-choloroben-
zaldehyde vs alkynyl aldehyde 1a (reaction b).
The resulting highly functionalized spirooxindoles offer
many opportunities for chemical transformations. For
example, the reduction of alkynyl group of 5a with
H2ÀPd/C gave hydrogenated product 8 in an 85% yield
(Scheme 3).
of the CtC;R1 group and the carbonyl of oxindole.
Another R1 group is relatively large, so it should also be in
an anti-orientation to the CtC;R1 group to avoid conflict
with the latter.
In conclusion, we have described an NHC-catalyzed
three-component domino reaction of oxindoles with alkynyl
aldehydes, which offers an effective and stereoselective
strategy for the synthesis of highly functionalized spiro-
oxindole 4H-pyran-2-ones with three contiguous stereogenic
centers from easily accessible materials. The unique struc-
ture of these products may be attractive for potential drug
discovery. Research on an enantioselective synthesis of this
protocol as well as exploration of novel NHC-catalyzed
reactions of alkynyl aldehydes is currently underway.
Scheme 3. Hydrogenation of Compound 5a
A mechanistic rationalization for this unexpected dom-
ino reaction is proposed as shown in Scheme 4. The
domino process initiates with the addition of NHC 9
generated upon deprotonation of carbene precursor F with
t-BuOK to alkynyl aldehydes 1, affording the Breslow
intermediate 10.7 After a subsequent redox reaction and
protonation with the acidic H-donor, oxindoles 3,
R,β-unsaturated acyl azolium 11, and intermediate 12 are
formed. The direct conjugate addition of 12 to 11 followed
by H-migration gives adduct 14, which subsequently un-
dergoes domino intermolecular aldol reaction with an-
other molecule of alkynyl aldehydes 1 and lactonization
to deliver products 5 and regenerates NHC 9 for the next
catalytic cycle. The stereochemistry of the products may be
rationalized by the chair-transition state 15 in the process of
lactonization. Steric hindrance leads to an anti-orientation
Acknowledgment. We thank the National Natural
Science Foundation of China (Nos. 21002124, 30973609),
Specialized Research Fund for the Doctoral Program of
Higher Education of China (No. 20100096120009), and the
Project Program of State Key Laboratory of Natural
Medicines of China Pharmaceutical University (No.
JKGQ201101) for financial support.
Supporting Information Available. Experimental pro-
cedures, compound characterization, and X-ray data for
5a (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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