Facile access to functionalized spiro[indoline-3,2′-pyrrole]-2, 5′-diones via post-Ugi domino Buchwald-Hartwig/Michael reaction

Article abstract of DOI:10.1021/ol5019079

A novel access to spiro[indoline-3,2′-pyrrole]-2,5′-diones is presented via a palladium-catalyzed post-Ugi cascade cyclization approach involving a Buchwald-Hartwig/Michael reaction sequence. The method allows the easy construction of a library of spirooxindoles in moderate to good yields starting from readily available precursors. In addition, alkynoic acids are replaced with α,β-unsaturated acids leading to variably substituted spirooxindoles.

Full text of DOI:10.1021/ol5019079

Letter
pubs.acs.org/OrgLett
Facile Access to Functionalized Spiro[indoline-3,2′-pyrrole]-2,5′-
diones via Post-Ugi Domino Buchwald−Hartwig/Michael Reaction
Nandini Sharma,‡ Zhenghua Li,‡ Upendra K. Sharma,* and Erik V. Van der Eycken*
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, B-3001 Leuven, Belgium
S
* Supporting Information
ABSTRACT: A novel access to spiro[indoline-3,2′-pyrrole]-2,5′-diones is presented via a palladium-catalyzed post-Ugi cascade
cyclization approach involving a Buchwald−Hartwig/Michael reaction sequence. The method allows the easy construction of a
library of spirooxindoles in moderate to good yields starting from readily available precursors. In addition, alkynoic acids are
replaced with α,β-unsaturated acids leading to variably substituted spirooxindoles.
most prevalent methods for the synthesis of the spirooxindole
socyanide based multicomponent reactions (IMCR) with
Isubsequent post-transformations have been extensively framework, while very few methods construct the indole unit
itself.7
demonstrated as a powerful method to access new and
privileged heterocyclic scaffolds.1 These reactions are partic-
Despite these remarkable advances, finding cost-effective and
sustainable synthetic methods to reproduce the structural
diversity and complexity of natural molecules would always be a
welcome addition. Encouraged by the numerous bioactivities of
spiro-oxindoles and in continuation of our endeavor toward the
diversity-oriented synthesis of bioactive heterocyclic molecules
using MCR reactions,2m−o,8 we were interested in designing a
new post-MCR strategy for the synthesis of novel spiroox-
indoles from readily available starting materials. We envisioned
that an efficient and concise one-pot post-Ugi modification
comprising a domino Buchwald−Hartwig/Michael reaction
sequence to obtain spiro[indoline-3,2′-pyrrole]-2,5′-diones
would be highly appealing (Scheme 1).
ularly appealing in terms of molecular diversity, simplicity, and
atom economy along with the ease of using readily available
starting materials. However, the post-IMCR transformations
are generally restricted to a single chemical reaction, thus
limiting the challenge of achieving a high level of structural
complexity. In this context, efforts to develop novel and
selective post-MCR transformations in a domino fashion will
significantly contribute to the advancement of diversity-
oriented synthesis as well as heterocyclic chemistry.2
The ability to access spirocyclic nitrogen-containing hetero-
cycles has always remained a great inspiration for organic
chemists because of their widespread prevalence in nature.3 In
particular, the pyrrolidinyl-spirooxindole framework is present
in a large number of bioactive, naturally occurring alkaloids
such as spiro-tryprostatin B, horsefiline, as well as various
medicinally relevant compounds (Figure 1).4 As a consequence,
efforts have been made to design and develop new methods for
the construction of novel synthetic spirooxindole-fused-hetero-
cycles.5 So far, domino or multicomponent reactions based on
the versatile reactivity of isatin derivatives5,6 have remained the
Scheme 1. Retrosynthetic Analysis for Spirooxindoles
To test our hypothesis, optimization efforts were initiated by
using the easily accessible N-(1-(2-bromophenyl)-2-(tert-
butylamino)-2-oxoethyl)-N-(4-methoxybenzyl)but-2-ynamide
(1a), obtained via Ugi reaction of o-bromobenzaldehyde, 4-
methoxybenzylamine, tert-butyl isocyanide, and 2-butynoic
Received: May 29, 2014
Published: July 16, 2014
Figure 1. Bioactive compounds containing a spirooxindole framework.
© 2014 American Chemical Society
3884
dx.doi.org/10.1021/ol5019079 | Org. Lett. 2014, 16, 3884−3887

Organic Letters
Letter
acid, as a substrate in the presence of a Pd catalyst under
various conditions (Table 1). A systematic study revealed that
promote this domino sequence effectively.11 It was also
observed that the reaction was occurring in a cascade manner
and in the absence of catalyst or ligand or base resulted in no
product yield (Table S2, Supporting Information).
a
Table 1. Optimization of Reaction Conditions
Further efforts to increase the yield by varying the reaction
time or temperature were not successful (entries 21−23). We
concluded that the best conditions are Pd(OAc)2 (5 mol %),
Xantphos (7.5 mol %), and Cs2CO3 (2 equiv) in toluene at 120
°C for 24 h, allowing the above domino reaction to occur
smoothly providing the spirooxindole 2a in 75% isolated yield
(Table 1, entry 3). With the optimized reaction conditions in
hand, we evaluated the scope and limitations of the process
(Table 2). Initially, the influence of the haloaldehyde subunit
Table 2. Scope of the Developed Domino Buchwald−
a
Hartwig/Michael Process
a
Reaction conditions: all reactions were performed with 1a (0.2
mmol), catalyst (5 mol %), ligand (7.5 mol %), and base (0.4 mmol)
b
in solvent (2.0 mL) at different temperatures for 24 h. Yields based
1
on H NMR. isolated yield in parentheses. nd = not detected.
the catalyst, the ligand, the base, and the temperature exerted a
remarkable influence on the yield of the products (Table 1).
Lower yields were obtained with K2CO3 and K3PO4 (entries 1
and 2) as compared to Cs2CO3 (entry 3), while replacement
with stronger bases such as t-BuONa or t-BuOLi resulted in no
reaction (entries 4 and 5). Also replacement of toluene with
more polar solvents displayed a diminished activity in terms of
yield (entries 6−9). Among the different Pd-catalyst tested,
Pd(OAc)2 was found to be the best (entries 3 and 10−13). The
choice of ligand is critical since only Xantphos was effective for
the aforementioned domino transformation, whereas well-
reported ligands for Buchwald−Hartwig amidation9 or N-
a
Reaction conditions: all reactions were performed with Ugi substrate
(0.2 mmol), Pd(OAc)2 (5 mol %), Xantphos (7.5 mol %) and Cs2CO3
(0.4 mmol) in toluene (2.0 mL) at 120 °C for 24 h. Isolated yield; nd
= not detected. PMB = p-methoxybenzyl.
b
on the reaction outcome was examined. Whereas the o-
iodobenzaldehyde afforded 2a in 80% yield, the o-chloroben-
zaldehyde led to a significant decrease in the reaction yield
(entries 1 and 2). As illustrated in Table 2, electron-donating or
electron-withdrawing groups on the aryl ring were well
tolerated. Also, substrates bearing ortho, meta, or para
substituents provided the corresponding products in moder-
10b
arylation of Ugi adducts like Me-Phos10a or P(o-tol)3 were
found to be ineffective (entries 19 and 20). Moreover, both
DPEphos and dppf, which are also bidentate ligands and have
similar bite angles as Xantphos, did not turn out to be that
active. This emphasizes the importance of the flexible
coordination environment of the Xantphos backbone to
3885
dx.doi.org/10.1021/ol5019079 | Org. Lett. 2014, 16, 3884−3887

Organic Letters
Letter
a
ate-to-good yields. The reaction worked well with aliphatic but
not with aromatic isonitriles (entry 12). In addition, the Ugi
adduct derived from propiolic acid failed to give the desired
spirocycle (entry 20).
Table 3. Control Experiments and Extended Scope
Mechanistically, two new chemical bonds are formed in the
present process, involving a Buchwald−Hartwig amidation (C−
N bond) and Michael addition (C−C bond) sequence.
Although it was reasonable to assume that two bonds were
formed sequentially and the aryl-amidation preceded the base-
catalyzed Michael addition, more convincing support was
sought. Our attempts to carry out the reactions in a sequential
manner, i.e., first the base-catalyzed Michael addition from the
active methine12 and then a Buchwald−Hartwig amidation or
reverse proved to be futile. Thus, the involvement of a
palladacycle in the intramolecular Michael addition13 could not
be ruled out with certainty. Moreover, our attempts to stop the
reaction after intermolecular N-arylation failed. Our assumption
that the second step of the reaction is simply a base-catalyzed
nucleophilic addition reaction was ascertained when 2-alkynoic
acid was replaced with benzoic acid or 2-fluorobenzoic acid,
resulting in the desired product in traces and 90% yield,
respectively (see the Supporting Information, Scheme S1).
Based on these observations and previous reports,10,12 we
hypothesized a reaction mechanism which is outlined in
Scheme 2. The first step is the oxidative addition of the Pd(0)
a
Reaction conditions: all reactions were performed with Ugi substrate
(0.2 mmol), Pd(OAc)2 (5 mol %), Xantphos (7.5 mol %), and
Cs2CO3 (0.4 mmol) in toluene (2.0 mL) at 120 °C for 24 h, dr ratio
determined on the basis of LC−MS analysis.
Scheme 2. Plausible Mechanism for the Domino Cyclization
In summary, we have devised a highly efficient methodology
for the synthesis of the spiro[indoline-3,2′-pyrrole]-2,5′-dione
framework via a Pd(0)-catalyzed domino Buchwald−Hartwig/
Michael reaction sequence. The protocol works equally well
when alkynoic acids are replaced with α,β-unsaturated acids
(such as cinnamic acids or atropic acid) leading to diversely
substituted spirooxindoles. The operational simplicity together
with the synthetic efficiency of the protocol will be beneficial
for academic and industrial research toward the synthesis of
druglike small molecules with enhanced structural diversity and
molecular complexity. Further studies on the reaction scope
and the expansion of the synthetic applications of the above
methodology are under current investigation.
catalyst to 1a leading to palladium complex A. Thereafter, the
base-catalyzed deprotonation of the amide and its co-ordination
to the Pd(II) species results in the formation of a six-membered
palladacycle B. This is followed by reductive elimination giving
intermediate C. The next step involves the base-catalyzed
Michael addition leading to the final product 2a. The activation
of this Csp3−H proton by base is well documented in the
literature regarding C-arylations.12a To further shed light on the
reaction mechanism, we performed a deuterium-labeling
experiment on the tandem Buchwald−Hartwig/Michael
addition sequence of the Ugi adduct 1a in the presence of
Pd(OAc)2, Xantphos, and Cs2CO3 with up to 3 equiv of
deuterated methanol in toluene. According to the NMR
spectra, the deuterium was located on the endocyclic double
bond of the pyrrole ring (Table 3, entry 1). Further, it was
ascertained that the use of 2-alkynoic acids was necessary to
ensure the occurrence of this domino reaction as substitution
with 3-alkynoic acid (Table 3, entry 2) failed to produce the
desired spirocycle. Furthermore, use of α,β-unsaturated acids
instead of 2-alkynoic acids resulted in good yields with
adequate diastereoselectivity (Table 3, entries 3 and 4).
ASSOCIATED CONTENT
* Supporting Information
Details of the experimental procedure as well as character-
ization data (1H and 13C NMR and HRMS) of Ugi adducts as
well as spirooxindoles. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: usharma81@gmail.com.
*E-mail: erik.vandereycken@chem.kuleuven.be.
Author Contributions
‡N.S. and Z.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the FWO [Fund for Scientific Research-Flanders
(Belgium)] and the Research Fund of the University of Leuven
■
3886
dx.doi.org/10.1021/ol5019079 | Org. Lett. 2014, 16, 3884−3887

Organic Letters
Letter
B. K.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2764−2765. (k) Liu,
Y.-K.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc.
2011, 133, 15212−15218. (l) Du, D.; Jiang, Y.; Xu, Q.; Shi, M. Adv.
Synth. Catal. 2013, 355, 2249−2256. (m) Shi, F.; Zhu, R.-Y.; Liang, X.;
Tu, S.-J. Adv. Synth. Catal. 2013, 355, 2447−2458. (n) Shi, F.; Tao, Z.-
L.; Luo, S.-W.; Tu, S.-J.; Gong, L.-Z. Chem.Eur. J. 2012, 18, 6885−
6894. (o) Chen, Q.; Liang, J.; Wang, S.; Wang, D.; Wang, R. Chem.
Commun. 2013, 49, 1657−1659. (p) Zhang, B.; Feng, P.; Sun, L.-H.;
Cui, Y.; Ye, S.; Jiao, N. Chem.Eur. J. 2012, 18, 9198−9203. (q) Han,
Y.; Wu, Q.; Sun, J.; Yan, C.-G. Tetrahedron 2012, 68, 8539−8544.
(r) Lv, H.; Tiwari, B.; Mo, J.; Xing, C.; Chi, Y. R. Org. Lett. 2012, 14,
5412−5415.
(KU Leuven) for financial support. N.S. and U.K.S. are grateful
to the University of Leuven for obtaining an F+ postdoctoral
fellowship. Z.L. is grateful to the China Scholarship Council
(CSC) for providing a doctoral fellowship. We also acknowl-
edge Ir. Bert Damarsin (KU Leuven) for HR-MS and Mr. Karel
Duerinckx (KU Leuven) for NMR analysis.
REFERENCES
■
(1) For reviews on multicomponent reactions, see: (a) Domling, A.
Chem. Rev. 2006, 106, 17−89. (b) Zhu, J.; Bienayme,
component Reactions; Wiley-VCH: Weinheim, 2005. (c) D’Souza, D.
̈
́
H. Multi-
(6) (a) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104−6155.
(b) Borad, M. A.; Bhoi, M. N.; Prajapati, N. P.; Patel, H. D. Synth.
Commun. 2014, 44, 897−922 and references cited therein.
M.; Muller, T. J. J. Chem. Soc. Rev. 2007, 36, 1095−1108.
̈
(2) For selected reviews on domino/cascade reactions, see: (a) Walji,
A. M.; MacMillan, D. W. C. Synlett 2007, 1477−1489. (b) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45,
7134−7186. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115−136.
(d) Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993−
3009. (e) Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth. Catal. 2011,
353, 809−841. For examples on domino-IMCR transformations, see:
(f) Cunny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126,
14475−14484. (g) Salcedo, A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008,
73, 3600−3603. (h) Salcedo, A.; Neuville, L.; Rondot, C.; Retailleau,
P.; Zhu, J. Org. Lett. 2008, 10, 857−860. (i) De Silva, R. A.; Santra, S.;
Andreana, P. R. Org. Lett. 2008, 10, 4541−4544. (j) Bararjanian, M.;
Balalaie, S.; Rominger, F.; Movassagh, B.; Bijanzadeh, H. R. J. Org.
Chem. 2010, 75, 2806−2812. (k) Santos, A. D.; El Kaïm, L.; Grimaud,
L.; Ronsseray, C. Beilstein J. Org. Chem. 2011, 7, 1310−1314. (l) El
Kaïm, L.; Grimaud, L.; Le Goff, X.-F.; Menes-Arzate, M.; Miranda, L.
D. Chem. Commun. 2011, 47, 8145−8147. (m) Vachhani, D. D.;
Kumar, A.; Modha, S. G.; Sharma, S. K.; Parmar, V. S.; Van der
Eycken, E. V. Eur. J. Org. Chem. 2013, 1223−1227. (n) Modha, S. G.;
Kumar, A.; Vachhani, D. D.; Jacobs, J.; Sharma, S. K.; Parmar, V. S.;
Meervelt, L. V.; Van der Eycken, E. V. Angew. Chem., Int. Ed. 2012, 51,
9572−9575. (o) Vachhani, D. D.; Galli, M.; Jacobs, J.; Meervelt, L. V.;
Van der Eycken, E. V. Chem. Commun. 2013, 49, 7171−7173l.
(p) Tyagi, V.; Khan, S.; Giri, A.; Gauniyal, H. M.; Sridhar, B.;
Chauhan, P. M. S. Org. Lett. 2012, 14, 3126−3129. (q) Xu, Z.; De
Moliner, F.; Cappelli, A. P.; Hulme, C. Org. Lett. 2013, 15, 2738−
2741. (r) Wang, X.; Xu, X.-P.; Wang, S.-Y.; Zhou, W.; Ji, S.-J. Org. Lett.
2013, 15, 4246−4249.
(7) For selected examples, see: (a) Piou, T.; Neuville, L.; Zhu, J.
Angew. Chem., Int. Ed. 2012, 51, 11561−11565. (b) Kamisaki, H.;
Nanjo, T.; Tsukano, C.; Takemoto, Y. Chem.Eur. J. 2011, 17, 626−
633. (c) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.; Neuville, L.; Zhu,
J. Chem.Eur. J. 2010, 16, 5863−5867. (d) Deppermann, N.;
Thomanek, H.; Prenzel, A. H. G. P.; Maison, W. J. Org. Chem. 2010,
75, 5994−6000 and references cited therein.
(8) For synthesis of heterocycles via post-MCR transformations from
our group, see: (a) Modha, S. G.; Vachhani, D. D.; Jacobs, J.; Van
Meervelt, L.; Van der Eycken, E. V. Chem. Commun. 2012, 48, 6550−
6552. (b) Modha, S. G.; Kumar, A.; Vachhani, D. D.; Sharma, S. K.;
Parmar, V. S.; Van der Eycken, E. V. Chem. Commun. 2012, 48,
10916−10918. (c) Kumar, A.; Li, Z.; Sharma, S. K.; Parmar, V. S.; Van
der Eycken, E. V. Org. Lett. 2013, 15, 1874−1877. (d) Kumar, A.; Li,
Z.; Sharma, S. K.; Parmar, V. S.; Van der Eycken, E. V. Chem. Commun.
2013, 49, 6803−6805.
(9) (a) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27−50.
(b) Noel, T.; Buchwald, S. L. Chem. Soc. Rev. 2011, 40, 5010−5029.
̈
(c) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027−3043.
(10) (a) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8,
4351−4354. (b) Kalinski, C.; Umkehrer, M.; Schmidt, J.; Ross, G.;
Kolb, J.; Burdack, C.; Hiller, W.; Hoffmann, S. D. Tetrahedron Lett.
2006, 47, 4683−4686.
(11) (a) Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.;
Dierkes, P. Chem. Rev. 2000, 100, 2741−2770. (b) Martinelli, J. R.;
Watson, D. A.; Freckmann, D. M. M.; Barder, T. E.; Buchwald, S. L. J.
Org. Chem. 2008, 73, 7102−7107.
(12) (a) Zhang, L.; Zhao, F.; Zheng, M.; Zhai, Y.; Liu, H. Chem.
Commun. 2013, 49, 2894−2896. (b) He, P.; Nie, Y.-B.; Wu, J.; Ding,
M.-W. Org. Biomol. Chem. 2011, 9, 1429−1436.
(13) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. Rev. 2005, 105,
2527−2571.
(3) (a) Rios, R. Chem. Soc. Rev. 2012, 41, 1060−1074. (b) D'yakonov,
V. A.; Trapeznikova, O. A.; de Meijere, A.; Dzhemilev, U. M. Chem.
Rev. 2014, 114, 5775−5814. (c) Dalpozzo, R.; Bartoli, G.; Bencivenni,
G. Chem. Soc. Rev. 2012, 41, 7247−7290.
(4) For selected reviews on spirooxindoles as a privileged scaffold,
see: (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127−139.
(b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209−2219.
(c) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36−51.
(d) Borschberg, H. J. Curr. Org. Chem. 2005, 15, 1465−1491.
(e) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748−8758. (f) Trost, B. M.; Brennan, M. K. Synthesis 2009, 3003−
3025. (g) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,
1381−1407. (h) Ball-Jones, N. R.; Badillo, J. J.; Franz, A. K. Org.
Biomol. Chem. 2012, 10, 5165−5181.
(5) For recent examples toward synthesis of various spirooxindole
derivatives, see: (a) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am.
Chem. Soc. 2007, 129, 12396−12397. (b) Albertshofer, K.; Tan, B.;
Barbas, C. F., III. Org. Lett. 2012, 14, 1834−1837. (c) Yang, H.-B.; Shi,
M. Org. Biomol. Chem. 2012, 10, 8236−8243. (d) Jiang, X.-X.; Cao, Y.-
M.; Wang, Y.-Q.; Liu, L.-P.; Shen, F.-F.; Wang, R. J. Am. Chem. Soc.
2010, 132, 15328−15333. (e) Sun, W.; Zhu, G.; Wu, C.; Hong, L.;
Wang, R. Chem.Eur. J. 2012, 18, 13959−13963. (f) Sun, W.; Zhu,
G.; Wu, C.; Hong, L.; Wang, R. Chem.Eur. J. 2012, 18, 6737−6741.
(g) Cao, Y.-M.; Jiang, X.-X.; Liu, L.-P.; Shen, F.-F.; Zhang, F.-T.;
Wang, R. Angew. Chem. 2011, 123, 9290−9293; Angew. Chem., Int. Ed.
2011, 50, 9124−9127. (h) Tan, B.; Candeias, N. R.; Barbas, C. F., III.
J. Am. Chem. Soc. 2011, 133, 4672−4675. (i) Peng, J.; Huang, X.; Jiang,
L.; Cui, H.-L.; Chen, Y.-C. Org. Lett. 2011, 13, 4584−4587. (j) Corkey,
3887
dx.doi.org/10.1021/ol5019079 | Org. Lett. 2014, 16, 3884−3887