Metal-free oxidative spirocyclization of hydroxymethylacrylamide with 1,3-dicarbonyl compounds: A new route to spirooxindoles

Article abstract of DOI:10.1021/ol402473m

A metal-free oxidative spirocyclization of hydroxymethylacrylamide with 1,3-dicarbonyl compounds is described. The reaction proceeds through tandem dual C-H functionalization and intramolecular dehydration, in which two new C-C bonds and one C-O bond were formed. This method affords a novel and straightforward access to various spirooxindoles under mild conditions.

Full text of DOI:10.1021/ol402473m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Metal-Free Oxidative Spirocyclization
of Hydroxymethylacrylamide with
1,3-Dicarbonyl Compounds: A New Route
to Spirooxindoles
Hua Wang, Li-Na Guo,* and Xin-Hua Duan*
Department of Chemistry, School of Science and MOE Key Laboratory for
Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong
University, Xi’an 710049, China
duanxh@mail.xjtu.edu.cn; guoln81@mail.xjtu.edu.cn
Received August 27, 2013
ABSTRACT
A metal-free oxidative spirocyclization of hydroxymethylacrylamide with 1,3-dicarbonyl compounds is described. The reaction proceeds through
tandem dual CꢀH functionalization and intramolecular dehydration, in which two new CꢀC bonds and one CꢀO bond were formed. This method
affords a novel and straightforward access to various spirooxindoles under mild conditions.
The heterocyclic spirooxindoles are of great interest in
organic synthesis due to their highly potential biological
activities as well as key precursors of natural alkaloids,
and clinical pharmaceuticals.1 Thus, numerous elegant
syntheticapproacheshavebeendevelopedfor the synthesis
of structurally diverse spirooxindoles.2 Among these
methods, the azaspirooxindoles have been extensively
investigated.2 In contrast, less attention has been paid to
the analogous oxaspirooxindoles. Recently, some efficient
strategies such as multicomponent reactions,3aꢀe RCM,3f
Prins cyclization,3g,h decarboxylative cyclization,3i and
vinylogous aldol reactions3j to six-membered oxaspiroox-
indoles have been reported, but all the methods were
limited to using the isatins and their derivatives as starting
materials. Up to now, a tandem bicyclization process for
the construction of six-membered oxaspirooxindoles has
neverbeenexploitedand, thus, remains achallengingissue.
(3) (a) Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron
2007, 63, 2057. (b) Zhu, S.-L.; Ji, S.-J.; Zhang, Y. Tetrahedron 2007, 63,
9365. (c) Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. J. Comb. Chem.
2009, 11, 341. (d) Li, Y.; Chen, H.; Shi, C.; Shi, D.; Ji, S. J. Comb. Chem.
2010, 12, 231. (e) Liang, B.; Kalidindi, S.; Porco, J. A., Jr.; Stephenson,
C. R. J. Org. Lett. 2010, 12, 572. (f) Alcaide, B.; Almendros, P.;
Rodrıguez-Acebes, R. J. Org. Chem. 2006, 71, 2346. (g) Castaldi,
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Wang, J.; Crane, E. A.; Scheidt, K. A. Org. Lett. 2011, 13, 3086. (i)
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Synlett 2010, 1128.
(4) (a) Jaegli, S.; Dufour, J.; Wei, H.-L.; Piou, T.; Duan, X.-H.; Vors,
J.-P.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498. (b) Wu, T.; Mu, X.;
Liu, G. Angew. Chem., Int. Ed. 2011, 50, 12578. (c) Mu, X.; Wu, T.;
Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878. (d)
Wei, W.-T.; Zhou, M.-B.; Fan, J.-H.; Liu, W.; Song, R.-J.; Liu, Y.; Hu,
M.; Xie, P.; Li, J.-H. Angew. Chem., Int. Ed. 2013, 52, 3638. (e) Li, Y.-M.;
Sun, M.; Wang, H.-L.; Tian, Q.-P.; Yang, S.-D. Angew. Chem., Int. Ed.
2013, 52, 3972. (f) Xie, J.; Xu, P.; Li, H.; Xue, Q.; Jin, H.; Cheng, Y.; Zhu,
C. Chem. Commun. 2013, 49, 5672. (g) Wei, X.-H.; Li, Y.-M.; Zhou,
A.-X.; Yang, T.-T.; Yang, S.-D. Org. Lett. 2013, 15, 4158.
(1) For reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. (b) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003,
42, 36. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748. For some recent examples, see: (d) Zhao, Y.; Liu, L.; Sun, W.;
Lu, J.; McEachern, D.; Li, X.; Yu, S.; Bernard, D.; Ochsenbein, P.;
Ferey, V.; Carry, J.-C.; Deschamps, J. R.; Sun, D.; Wang, S. J. Am.
Chem. Soc. 2013, 135, 7223. (e) Zhao, Y.; Yu, S.; Sun, W.; Liu, L.; Lu, J.;
McEachern, D.; Shargary, S.; Bernard, D.; Li, X.; Zhao, T.; Zou, P.;
Sun, D.; Wang, S. J. Med. Chem. 2013, 56, 5553. (f) Bertamino, A.;
Soprano, M.; Musella, S.; Rusciano, M. R.; Sala, M.; Vernieri, E.;
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r
10.1021/ol402473m
XXXX American Chemical Society

The catalytic difunctionalization of acrylamides via
direct CꢀH bond functionalization has attracted much
attention in the past few years and has been applied
successfully for the synthesis of various functionalized
oxindoles.2b,4 In particular, several metal-free oxidative
coupling/cyclization reactions were also discovered.5 Re-
lated elegant studies on radical cyclization strategies have
been previously reported for spirooxindoles by Murphy
and Curran.6aꢀc However, a tandem approach toward the
more complex spirooxindoles employing acrylamides and
its derivatives as a substrate with other reactants through
direct CꢀH bond functionalization has scarcely been
investigated.4a,6 As part of our continued interest in the
difunctionalization of acrylamides,7 we herein report the
metal-free oxidative spirocyclization of hydroxymethyla-
crylamide with 1,3-dicarbonyl compounds, providing an
efficient route to more valuable oxaspirooxindoles.8 This
new general approach allows the formation of two CꢀC
bonds and one CꢀO bond in one synthetic step (Table 1).
In our initial studies, 2-hydroxymethyl-N-methyl-N-
phenylacrylamide (1a) was treated with 1,3-cyclohexane-
dione (2a) in the presence of 1 equiv of K2S2O8 in CH2Cl2/
H2O (1:1) at 50 °C (Table 1, entry 1).7b Gratifyingly, the
desired spirooxindole 3a was obtained in 28% yield.
Among the solvents tested, CH3CN/H2O (1:1) was found
to be the best one (entry 5). Further screening of oxidants
revealed that K2S2O8 is better than (NH4)2S2O8 (entry 6),
whereas other oxidants gave none of the desired product
(entries 7 and 8). We were pleased to find that increasing
the amount of K2S2O8 up to 2 equiv improved the yield
from 70% to 90% (entry 9). It should be noted that 3a was
isolated in low yield in the absence of water (entry 10),
whereas addition of 18-crown-6 afforded a satisfying result
(entry 11).
Table 1. Optimization of the Reaction Conditionsa
oxidant
yield
(%)b
entry
(equiv)
solvent
1
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
(NH4)2S2O8 (1)
oxone (1)
CH2Cl2/H2O (1:1)
EtOAc/H2O (1:1)
DMF/H2O (1:1)
H2O
28
2
62
3
32
4
64 (86)c
70
5
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN
6
61
7
n.r.d
n.r.d
90
8
BQ (1)
9
K2S2O8 (2)
K2S2O8 (2)
K2S2O8 (2)
10
11
14
64e
CH3CN
a Reaction conditions: 1a (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2 equiv),
solvent (1 mL), oxidant (1 equiv), 50 °C, 28 h. b Yield of isolated product.
c The yield in parentheses using 2 equiv of K2S2O8. d n.r. = no reaction.
e 2 equiv of 18-crown-6 were added.
To explore the scope of the reaction, various hydroxy-
methylacrylamides 1 were first examined under the opti-
mized reaction conditions (Scheme 1). As shown in
Scheme 1, a range of acrylamides having different sub-
stituents on the aniline moieties underwent the desired
transformation smoothly to give the spirooxindoles 3bꢀi
(5) (a) Wu, T.; Zhang, H.; Liu, G. Tetrahedron 2012, 68, 5229. (b)
Zhou, M.-B.; Song, R.-J.; Ouyang, X.-H.; Liu, Y.; Wei, W.-T.; Deng,
G.-B.; Li, J.-H. Chem. Sci. 2013, 4, 2690. (c) Li, X.; Xu, X.; Hu, P.; Xiao,
X.; Zhou, C. J. Org. Chem. 2013, 78, 7343. (d) Matcha, K.; Narayan, R.;
Antonchick, A. P. Angew. Chem., Int. Ed. 2013, 52, 7985.
Figure 1. X-ray crystal structure of the spirooxindole 3f.
in good to high yields. It is worth noting that the reaction is
tolerant of many functional groups such as iodo, cyano,
and ester (3eꢀg). The ortho-methyl and fluoro substituted
substrates were also effective; therefore treatment of 1h
and 1i with 2a afforded the corresponding products 3h and
3i in 78% and 94% yields, respectively. For 2-hydroxy-
methyl-N-methyl-N-naphthylacrylamide 1j, the desired pro-
duct 3j was also formed albeit in low yield. Finally, changing
the protecting group on the N tether from the methyl
group to benzyl also gave the desired product 3k in 60%
yield. Unfortunately, we have not found a suitable method
to prepare the unprotected hydroxymethylacrylamide at
(6) (a) Lizos, D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1, 117.
ꢀ
ꢀ
(b) Gonzalez-Lopez de Turiso, F.; Curran, D. P. Org. Lett. 2005, 7, 151.
(c) Ueda, M.; Uenoyama, Y.; Terasoma, N.; Doi, S.; Kobayashi, S.;
Ryu, I.; Murphy, J. A. Beilstein J. Org. Chem. 2013, 9, 1340. For the
palladium-catalyzed domino process leading to spirooxindoles through
ortho-halo substituted anilide cyclization, see: (d) Ashimori, A.;
Overman, L. E. J. Org. Chem. 1992, 57, 4571. (e) D’Souza, D. M.;
€
Rominger, F.; Muller, T. J. J. Angew. Chem., Int. Ed. 2005, 44, 153. (f)
Ruck, R. T.; Huffman, M. A.; Kim, M. M.; Shevlin, M.; Kandur, W. V.;
Davies, I. W. Angew. Chem., Int. Ed. 2008, 47, 4711. (g) Jaegli, S.; Erb,
W.; Retailleau, P.; Vors, J.-P.; Neuville, L.; Zhu, J. Chem.;Eur. J. 2010,
16, 5863. (h) Piou, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2012,
51, 11561. For the metal-free oxidative domino process leading to
spirooxindoles through anilide cyclization, see: (i) Wang, J.; Yuan, Y.;
Xiong, R.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org. Lett. 2012, 14,
2210.
(7) (a) Meng, Y.; Guo, L.-N.; Wang, H.; Duan, X.-H. Chem. Com-
mun. 2013, 49, 7540. (b) Wang, H.; Guo, L.-N.; Duan, X.-H. Adv. Synth.
Catal. 2013, 355, 2222. (c) Zhou, S.-L.; Guo, L.-N.; Wang, H.; Duan,
X.-H. Chem.;Eur. J. 2013, 19, 12970.
(8) Jiang, X.; Sun, Y.; Yao, J.; Cao, Y.; Kai, M.; He, N.; Zhang, X.;
Wang, Y.; Wang, R. Adv. Synth. Catal. 2012, 354, 917.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Scope of Hydroxymethylacrylamidesa
Scheme 2. Scope of 1,3-Dicarbonyl Compoundsa,b
a Reaction conditions: 1 (0.2 mmol, 1 equiv), 2 (0.4 mmol, 2 equiv),
MeCN/H2O (1:1, 1 mL), K2S2O8 (2 equiv), 50 °C, 28 h. b The numbers in
parentheses are isolated yields for reactions performed in the presence of
10 mol % of AgNO3 and 2 equiv of K2S2O8.
in this tandem reaction (for details, see mechanism). Ethyl
acetoacetate was less effective, resulting in a 42% yield (4f).
Finally, hydroxymethylacrylamides having different groups
reacted with 2,4-pentanedione, producing the desired
a Reaction conditions: 1 (0.2 mmol, 1 equiv), 2a (0.4 mmol, 2 equiv),
MeCN/H2O (1:1, 1 mL), K2S2O8 (2 equiv), 50 °C, 28 h.
present. The structure of 3f was further unambiguously
confirmed by X-ray diffraction analysis (Figure 1).9
Next, the reactivities of different 1,3-dicarbonyl com-
pounds were investigated (Scheme 2). In addition to cyclic
β-diketone 2a, 5,5-dimethylcyclohexane-1,3-dione was
also a satisfying substrate for this transformation (4a).
Surprisingly, when 1,3-cyclopentanedione was used in-
stead of 1,3-cyclohexanedione under the standard condi-
tions, the desired product 4b was obtained in less than 5%
yield in addition to unidentified products; and most of the
acrylamide remained unreacted. It is important to note
that the phenyl group at the R-position of 1,3-dicarbonyl
compound strongly affected the efficiency of the spirocy-
clization reaction. Benzoylacetone 2d containing one phe-
nyl group gave the desired spirooxindole product 4d in
34% yield with high regioselectivity. Dibenzoylmethane 2e
bearing two phenyl groups led to the termination of the
bicyclization process, affording the oxindole 4e0 in 55%
isolated yield. This result suggested that the hydroxy-
methyl substituted oxindole might be the key intermediate
spirooxindoles 4c, 4gꢀi in 40%, 42%, 38%, and 30%
yield, respectively, due to low conversion. To our delight,
addition of 10 mol % AgNO3 provided cleaner reactions
and led to better yields when 2,4-pentanedione was used
as the substrate (4c, 4gꢀi). We presumed that the catalyst
is beneficial for the formation of the hydroxyl-containing
oxindoles, which are the key precursor of the spiro-
oxindoles.
(10) For reviews on the Mn(III)-mediated free-radical cyclization
reactions of 1,3-dicarbonyl compounds, see: (a) Iqbal, J.; Bhatia, B.;
Nayyar, N. K. Chem. Rev. 1994, 94, 519. (b) Snider, B. B. Chem. Rev.
1996, 96, 339.
(9) Crystallographic data for spirooxindole 3f have been deposited at
the Cambridge Crystallographic Date Centre (CCDC 953997).
(11) See Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

2a is depicted in Scheme 3. The deprotonation of 2a gives
radical I in the presence of K2S2O8, which then adds to 1a
to afford radical II. The radical II undergoes an intramo-
lecular cyclization to generate radical III,4dꢀg,5 followed by
oxidation of III into the corresponding carbocation, which
loses Hþ to produce the annulated oxindole IV.7b Finally,
intermediate IV undergoes an intramolecular dehydration
to afford spirooxindole 3a.
Scheme 3. Proposed Mechanism
In summary, we have developed a metal-free oxidative
spirocyclization of hydroxymethylacrylamide with 1,3-
dicarbonyl compounds via tandem sp3 CꢀH and sp2
CꢀH functionalization followed by intramolecular dehy-
dration. The process exhibits significant functional group
tolerance and atom economy and allows the synthesis of
structurally diverse functionalized spirooxindoles under
mild conditions. These simple and environmentally benign
processes would extend the potential application of valu-
able spirooxindole derivatives in synthetic and medicinal
chemistry.
A Mn(III)-mediated oxidative free radical cyclization
reaction of 1,3-dicarbonyl compounds and alkenes has
previously been described in the literature.10 Thus, the
reaction of 1a and 2a was conducted with stoichiometric
Mn(OAc)3 in HOAc/H2O, but afforded only a 21% yield
of 3a (eq 1).11 Furthermore, the reaction was also sup-
pressed when TEMPO, a radical-trapping reagent, was
added (eq 2). Thus, we speculated that the reaction
proceeded through free-radical substitution, which was
consistent with the mechanisms proposed in previous
reports.4dꢀg,5,7 A possible mechanism for the reaction of
hydroxymethylacrylamide 1a with 1,3-cyclohexanedione
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Nos. 21102111,
21102110) and the Fundamental Research Funds of the
Central Universities is greatly appreciated.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of new compounds. X-ray
data for 3f. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX