Efficient synthesis of spirooxindolyl oxazol-2(5: H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles

Article abstract of DOI:10.1039/c9ra07216k

A versatile synthesis of spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles is described. A wide range of spirooxindolyl oxazol-2(5H)-ones and other spirocyclic frameworks incorporating the oxazol-2(5H)-one unit can be readily prepared in good to high yields under the optimal conditions.

Full text of DOI:10.1039/c9ra07216k

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Efficient synthesis of spirooxindolyl oxazol-2(5H)-
ones via palladium(II)-catalyzed addition of
arylboronic acids to nitriles†
Cite this: RSC Adv., 2019, 9, 29424
a
a
a
b
a
*
*
Hao Song, Na Cheng, Li-Qin She, Yi Wu and Wei-Wei Liao
Received 22nd August 2019
Accepted 10th September 2019
A versatile synthesis of spirooxindolyl oxazol-2(5H)-ones via palladium(II)-catalyzed addition of arylboronic
acids to nitriles is described. A wide range of spirooxindolyl oxazol-2(5H)-ones and other spirocyclic
frameworks incorporating the oxazol-2(5H)-one unit can be readily prepared in good to high yields
under the optimal conditions.
DOI: 10.1039/c9ra07216k
rsc.li/rsc-advances
Rapid and efficient construction of pharmaceutical and bio- cation with cyclic ketones for the synthesis of spiro-4-oxazoli-
logically relevant compounds plays a very important role in dinones.11a In 2018, Alla and co-workers described a copper-
modern organic synthesis, and constitutes the original impetus catalyzed one-pot multicomponent protocol for the synthesis
for the development of various novel synthetic approaches. The of spiro(indoline-3,50-oxazolidine)-2,20-diones starting from
efficient construction of spirocyclic frameworks has been ketones, arylacetylenes and isocyanates.11b
a topic of great relevance in organic synthesis due to their
Recently, the transition-metal-catalyzed addition of organo-
inherent three-dimensional architectures and the pronounced boron reagents to nitriles has received remarkable progress,12
biological activities.1 In particular, the spirocyclic oxindoles since the elegant works on the addition of arylpalladium species
have emerged as attractive synthetic targets because of their to the cyano group reported by Larock and Lu et al.,13 in which
prevalence in numerous natural and unnatural products.2 nitriles served as C building blocks and provided aryl ketones.
Notably, the enhanced biological activities have been observed In virtue of palladium-catalyzed tandem addition of organo-
by the incorporation of a spiro ve-membered azaheterocyclic boron reagents to nitriles/cyclization protocol, this approach
ring at the C3 position of the oxindole core (Fig. 1).3 Thereby, enabled the combination of organoboron reagents and nitriles
a variety of synthetic methods have been developed to access to construct a diversity of nitrogen-containing heterocycles such
analogous compounds possessing such privileged structure as 2-aminobenzophenones, benzofurans, and indoles, in which
moieties.4
nitrile serves as C–N synthon instead and is incorporated into
As one of the important N–O heterocyclic compounds, oxa- heterocyclic frameworks in an atom-economical fashion.14
zolidinones and their derivatives have been widely used not only However, the development of transition-metal-catalyzed
as synthetic building blocks,5 but also as pharmaceuticals6 and tandem sequence involving the addition of organoboron
agrochemicals,7 owing to a diverse range of biological activi- reagents to nitriles to construct structural novel three-
ties.8 Although great contributions have been made to access dimensional architectures such as spirocyclic systems is still
these valuable scaffolds,9 the construction of structurally undeveloped.
diverse spirooxindolyl oxazol-2(5H)-ones, characterized by
We have recently developed both intramolecular and inter-
a spiro ring fusion at the C3 position of the oxindole core with molecular cyclization approaches to prepare indole and thio-
oxazol-2(5H)-one motif, has received less attention from phene fused polycyclic derivatives via Pd-catalyzed direct C–H
synthetic community,10 despite the fact that these spirocyclic bond addition to nitriles.15 Given the promising biological
heterocycles could be promising candidates possessing bio-
logical responses. In 2017, He and co-workers reported a formal
[3 + 2] cycloaddition reaction of in situ generated azaoxyallyl
aDepartment of Organic Chemistry, College of Chemistry, Jilin University, Changchun
130012, P. R. China. E-mail: wliao@jlu.edu.cn
bSchool of Pharmaceutical Science, Jilin University, Changchun 130012, P. R. China.
E-mail: wuyi19651007@163.com
† Electronic supplementary information (ESI) available. CCDC 1943540. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c9ra07216k
Fig. 1 Examples of spiro oxindoles containing natural products and
biological relevant compounds.
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activities of spirooxindoles-containing molecules in medicinal decreased yield (Table 1, entries 6 and 7). Subsequently, the
chemistry and our ongoing interest in the development of effi- effect of ligands was evaluated in the presence of Pd(acac)2. The
cient catalytic processes to prepare diverse aza-heterocyclic similar results were obtained when 4,40-dimethyl-2,20-bipyr-
frameworks, herein, we report an efficient synthetic approach idine (L2) and 1,10-phenanthroline (L4)were employed respec-
to prepare spirooxindolyl oxazol-2(5H)-ones via palladium(II)- tively, while 5,50-dimethyl-2,20-bipyridine (L3) gave the marginal
catalyzed addition of arylboronic acids to nitriles.
reducing yield of 3a (Table 1, entries 8–10). Notably, the similar
As functionalized nitriles, cyanohydrins which are readily efficiency can be observed in prolonged reaction time by using
prepared from ketones and aldehydes have demonstrated Pd(OAc)2, in which 91% yield can be obtained in the presence of
considerable synthetic potential as useful building blocks.16 We Pd(OAc)2 (5 mol%) and HOAc (5.0 equiv.) for 36 hours (Table 1,
chose the Pd(II)-catalyzed reaction of 3-cyano-1-methyl-2- entry 11). The obvious decline in the yield of product 3aa was
oxoindolin-3-yl ethyl carbonate 1a, which is readily prepared observed without HOAc (Table 1, entry 12), while HOAc cannot
from isatin and ethyl cyanoformate, and phenylboronic acid 2a promote this reaction alone (Table 1, entry 15). Both ligand and
as a model reaction for the optimization of the reaction Pd(II) catalyst proven to be essential to this transformation since
conditions (Table 1). Initially, we examined the reactions in no reaction happened without them (Table 1, entries 13 and 14).
various solvents in the presence of Pd(OAc)2 (10 mol%), 2,20- The attempt to reducing the amount of 2a resulted in the
bipyridine (L1: bpy) (12 mol%) and HOAc (10 equiv.) at 80 ꢀC. To decreased yield (Table 1, entry 16). Further survey on other
our delight, the desired spirooxindolyl oxazol-2(5H)-one 3aa was reaction parameters such as additives, reaction temperature
observed in range of solvents, in which low yield was obtained and concentration did not improve the chemical outcome of
in less polar solvent along with the small amount of byproduct this transformation (for details see the ESI†). In addition, the
4a (Table 1, entry 1), while moderate yields were obtained in reaction also was evaluated with Ni(II) catalyst system. However,
polar solvents in general (Table 1, entries 2–5). Replacing Ni(II)-catalyzed reaction gave the inferior to that of Pd(II) cata-
Pd(OAc)2 with Pd(acac)2 afforded the cyclized product 3aa in the lytic system (Table 1, entry 17), and delivered the desired
increased yield in NMP, while Pd(TFA)2 gave the slightly product 3aa in moderate yield under the optimized reaction
conditions (Ni(acac)2 (10 mol%) L2 (12 mol%) and MTBE) (for
details see the ESI†).
With the optimized reaction conditions in hand, the gener-
Table 1 Effects of reaction parametersa
ality of the Pd-catalyzed addition/cyclization sequence for the
preparation of spirooxindolyl oxazol-2(5H)-ones was evaluated
by employing various isatin based-O-ethoxycarbonyl cyanohy-
drins 1 and phenylboronic acid 2a rst (Scheme 1). Other than
N-methyl substrate 1a, cyanohydrin analogues 1 bearing
different N-substituents such as phenyl, benzyl, p-methox-
ybenzyl and p-nitrobenzyl can give the desired products 3ba–3ea
in high yields. The substitution pattern at the benzene ring of
t
(h)
cyanohydrins 1 has little inuence on the results, and high
Entry
Cat.
Ligand
Solvent
Yieldb (%)
yields could be obtained (3fa–3ia). In addition, the reactions
between substrates possessing both electron-donating (MeO
and Me) and electron-withdrawing (NO2, Br, Cl and I) substit-
uents at the benzene ring and phenylboronic acid 2a proceeded
well, and gave the corresponding products with excellent yields
(3ja–3oa). The structures of spirooxindolyl oxazol-2(5H)-ones
were unambiguously conrmed by the exemplication of X-ray
crystal structural analysis of product 3aa.17
Next, the substrate scope with respect to arylboronic acids
was also investigated, the results of which are summarized in
Scheme 2. Arylboronic acids bearing both electron-donating
(3ab–3ad) and electron-withdrawing substituents (3ae–3ag) at
the benzene ring were tolerated, affording the desired products
in good to high yields, exception for strong electron-
withdrawing substituent such as nitro group (3ah), which did
not react with 3-cyano-1-methyl-2-oxoindolin-3-yl ethyl
carbonate 1a. It is noteworthy that the reaction also proceeded
smoothly when a substituent was situated at the ortho position
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(OAc)2
Pd(OAc)2
—
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
L1
—
Toluene
THF
24
24
24
24
24
24
24
24
24
24
36
36
24
24
24
36
24
27
77
79
71
82
77
88
86
73
88
91
83
nd
nd
nd
79
67
DMF
DMSO
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
MTBE
9
10
11c,d
12c,e
13e
14e
15d
16c,d,f
17g
Pd(OAc)2
—
Pd(OAc)2
Ni(acac)2
—
L1
L2
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), catalyst (10 mol%),
ligand (12 mol%) and HOAc (10 equiv.) in solvent (1 mL) at 80 ꢀC.
b
d
c
Isolated yields. Pd(OAc)2 (5 mol%) and bpy (6 mol%) were used.
HOAc (5.0 equiv.) was used. Without HOAc. 2a (0.4 mmol) was of the arylboronic acid, albeit with the slightly decreased yield
e
f
g
used. Ni(acac)2 (10 mol%), L2 (12 mol%) and Cs2CO3 (20 mol%) in
MTBE (1 mL) at 110 ꢀC. L1: 2,20-bipyridine; L2: 4,40-dimethyl-2,20-
bipyridine; L3: 5,50-dimethyl-2,20-bipyridine; L4: 1,10-phenanthroline.
(3ai). As expected, meta- and di-substituted analogues afforded
products (3aj and 3ak) in high yields. Additionally, aryl boronic
acids with fused ring also gave their corresponding products
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optimized reaction conditions, while 9-phenanthreneboronic
acid gave spirooxindolyl product 3an in 83% yield. However,
hetero-aromatic boronic and alkyl boronic acid did not
provided any desired products (3ao–3ap).
In addition, besides spirooxindolyl oxazol-2(5H)-one frame-
works, this approach is also applicable to the construction of
other spirocyclic frameworks incorporating oxazol-2(5H)-one
unit via palladium-catalyzed tandem sequence (Scheme 3). For
example, treatment of 1-cyanocyclopentyl ethyl carbonate 5a
with 2a can furnish 4-phenyl-1-oxa-3-azaspiro[4.4]non-3-en-2-
one 6a in 84% yield, while six-membered-ring analogues deliv-
ered the corresponding six-membered ring fused spiro-products
(6b–6c) in high yields. Cyanohydrin 5d derived from 2-indanone
can also serve as a suitable substrate for this tandem sequence,
and provided the desired spiro-product 6d in 81% yield.
Finally, the synthetic utility of this Pd-catalyzed cyclization
was demonstrated (Scheme 4). The reduction of 3aa by using
BH3$SMe2 readily gave spirooxindolyl product 7 bearing the
oxazolidine unit in good yield with an excellent
diastereoselectivity.
On the basis of these results and other processes involving
the addition of arylpalladium species to nitrile,14,15 a plausible
mechanism was illustrated in Scheme 5. First, the trans-
metalation of arylboronic acid by Pd(II) catalyst A generates
arylpalladium species B. Then coordination of the nitrile
provides intermediate C, which undergoes a carbopalladation
of the cyano group to result in formation of the corresponding
ketimine Pd(II) complex D. The intramolecular cyclization of the
intermediate D to form palladium complex E which affords
product and regenerates the Pd(II) catalyst.
Scheme 1 Substrate scope for preparation of spirooxindolyl oxazol-
2(5H)-onesa. aReaction conditions: 1 (0.3 mmol), 2a (0.9 mmol),
Pd(OAc)2 (5 mol%), bpy (6 mol%), HOAc (5 equiv.) in NMP (1.5 mL) at
80 ꢀC for 36 h. Yields shown are of isolated products. PMB ¼ p-
methoxybenzyl; PNB ¼ p-nitrobenzyl.
with high yields. For examples, treatment of both a-naphthyl
and b-naphthyl boronic acids with 1a can deliver the corre-
sponding products (3al–3am) in high yields under the
In summary, we have demonstrated an efficient protocol for
the synthesis of spirooxindolyl oxazol-2(5H)-ones via Pd(II)-
catalyzed addition of arylboronic acids to nitriles. A diversity of
Scheme 3 Preparation of other spirocyclic frameworksa. aReaction
conditions: 5 (0.3 mmol), 2a (0.9 mmol), Pd(OAc)2 (5 mol%), bpy
(6 mol%), HOAc (5 equiv.) in NMP (1.5 mL) at 80 ꢀC for 36 h. Yields
shown are of isolated products.
Scheme 2 Substrate scope with respect to boronic acidsa. aReaction
conditions: 1a (0.3 mmol), 2 (0.9 mmol), Pd(OAc)2 (5 mol%), bpy
(6 mol%), HOAc (5 equiv.) in NMP (1.5 mL) at 80 ꢀC for 36 h. Yields
shown are of isolated products.
Scheme 4 Synthetic transformation.
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15328; (e) P. Zou, N. Zheng, S.-H. Yu and D.-X. Sun, J.
Pharm. Pharm. Sci., 2012, 15, 265.
4 For recent reviews, see: (a) G.-J. Mei and F. Shi, Chem.
Commun., 2018, 54, 6607; (b) G. M. Ziarani, R. Moradi and
N. Lashgari, Tetrahedron, 2018, 74, 1323; (c) L.-J. Yan and
Y.-C. Wang, ChemistrySelect, 2016, 1, 6948; (d) D. Cheng,
Y. Ishihara and C. F. Barbas, ACS Catal., 2014, 4, 743.
5 (a) D. J. Ager, I. Prakash, B. Tian and D. R. Schaad, Chem.
Rev., 1996, 96, 835; (b) L. Aurelio, R. T. C. Brownlee and
A. B. Hughes, Chem. Rev., 2004, 104, 5823.
6 K. Ando, T. Yamada and M. Shibuya, Heterocycles, 1989, 29,
2209.
7 A. Arnoldi, E. Betto, G. Farina and A. Griffini, Pestic. Sci.,
1982, 13, 670.
Scheme 5 Proposed mechanism.
8 (a) R. Somanathan, I. A. Rivero, G. I. Nunez and
L. H. Hellberg, Synth. Commun., 1994, 24, 1483; (b)
K. Michalska, I. Karpiuk and S. Tyski, Bioorg. Med. Chem.,
2013, 21, 577; (c) O. A. Phillips, E. E. Udo and R. Varghese,
Eur. J. Med. Chem., 2013, 66, 246; (d) X. Jiang, Y. Cao and
R. Wang, J. Am. Chem. Soc., 2010, 132, 15328; (e) T. Xue,
functionalized spirooxindolyl oxazol-2(5H)-ones can be
prepared in good to high yields under the optimal conditions.
Furthermore, by the virtue of this Pd-catalyzed sequence, other
ve- and six-membered ring fused spiro-oxazol-2(5H)-ones can
be readily prepared in good yields. Further studies on the
application of this synthetic method are currently under
investigation.
B. Guo and Y. Yang, Bioorg. Med. Chem. Lett., 2015, 25, 2203.
˚
¨
9 (a) S. K. Alamsetti, A. K. A. Persson and J.-E. Backvall, Org.
Lett., 2014, 16, 1434; (b) D.-Y. Li, H.-J. Chen and P.-N. Liu,
Adv. Synth. Catal., 2015, 357, 1193; (c) M. J. Gainer,
N. R. Bennett, Y. Takahashi and R. E. Looper, Angew.
Chem., Int. Ed., 2011, 50, 684; (d) H.-F. Jiang and
J.-W. Zhao, Tetrahedron Lett., 2009, 50, 60.
Conflicts of interest
There are no conicts to declare.
10 (a) T. Rajasekaran, B. Sridhar and B. V. S. Reddy,
Tetrahedron, 2016, 72, 2102; (b) T. Rajasekaran, G. Karthik
and B. V. S. Reddy, Org. Lett., 2013, 15, 1512; (c)
I. R. Siddiqui, P. Rai and M. A. Waseem, Tetrahedron Lett.,
2015, 56, 4367.
11 (a) P.-L. Shao, Z.-R. Li and Y. He, J. Org. Chem., 2017, 82,
10680; (b) G. R. Potuganti, D. R. Indukuri and M. Alla, J.
Org. Chem., 2018, 83, 15186.
Acknowledgements
The NSFC (No. 21772063) and the Open Project of State Key
Laboratory for Supramolecular Structure and Materials
(sklssm2019016) are acknowledged. This research was sup-
ported by China Scholarship Council.
12 (a) B.-W. Zhao and X.-Y. Lu, Org. Lett., 2006, 8, 5987; (b)
Y. C. Wong, K. Parthasarathy and C.-H. Cheng, Org. Lett.,
Notes and references
¨
˘
2010, 12, 1736; (c) S. Demir, M. Yigit and I. Ozdemir, J.
Organomet. Chem., 2013, 732, 21; (d) M. Yousuf, T. Das and
1 For recent reviews, see: (a) H. Guo, J.-W. Yang and R. Ramon,
Chem. Soc. Rev., 2018, 47, 5946; (b) X. Xie, C. Peng and
B. Han, Adv. Synth. Catal., 2018, 360, 194; (c) S. D. Griggs,
¨
S. Adhikari, New J. Chem., 2015, 39, 8763; (e) J. Savmarker,
J. Rydord and M. Larhed, Org. Lett., 2012, 14, 2394.
D. T. Tape and P. A. Clarke, Org. Biomol. Chem., 2018, 16, 13 (a) R. C. Larock, Q. Tian and A. A. Pletnv, J. Am. Chem. Soc.,
6620; (d) F. V. Singh, P. B. Kole, S. R Mangaonkar and
S. E. Shetgaonkar, Beilstein J. Org. Chem., 2018, 14, 1778; (e)
P.-W. Xu, J.-S. Yu and J. Zhou, ACS Catal., 2019, 9, 1820.
2 (a) E. V. Mercado-Marin, R. G. Berlinck and R. Sarpong,
1999, 121, 3238; (b) C. Zhou and R. C. Larock, J. Am. Chem.
Soc., 2004, 126, 2302; (c) C. Zhou and R. C. Larock, J. Org.
Chem., 2006, 71, 3551; (d) B.-W. Zhao and X.-Y. Lu,
Tetrahedron Lett., 2006, 47, 6765.
Nature, 2014, 509, 318; (b) Z. Bian, C. C. Marvin and 14 (a) K. Hu, J.-X. Chen and H.-Y. Wu, Green Chem., 2017, 19,
S. F. Martin, J. Am. Chem. Soc., 2014, 136, 14184; (c)
Z. Bian, C. C. Marvin and S. F. Martin, J. Am. Chem. Soc.,
2013, 135, 10886; (d) A. K. Gupta, M. Bharadwaj and
R. Mehrotra, Top. Curr. Chem., 2017, 375, 3; (e) Y.-T. Yang,
J.-F. Zhu and B. Yu, Curr. Med. Chem., 2018, 25, 2233.
1740; (b) L. Qi, J.-X. Chen and H.-Y. Wu, Org. Lett., 2017,
19, 218; (c) K. Hu, Q. Zhen and J.-X. Chen, Org. Lett., 2018,
20, 3083; (d) J.-H. Zhu, Y.-L. Shao and J.-X. Chen, Org.
Biomol. Chem., 2018, 16, 8596; (e) H.-H. Yu, X. Li and
L.-M. Shao, Chem. Commun., 2017, 53, 9745; (f) M. Yousuf
and S. Adhikari, Org. Lett., 2017, 19, 2214; (g) X.-C. Yang,
H.-H. Yu and L.-M. Shao, J. Org. Chem., 2018, 83, 9682.
3 (a) A. Jossang, P. Jossang, H. A. Hadi and B. Bodo, J. Org.
Chem., 1991, 56, 6527; (b) C. B. Cui, H. Kakeya and
H. Osada, Tetrahedron, 1996, 52, 12651; (c) M. Takasugi, 15 (a) T.-T. Wang, L. Zhao and W.-W. Liao, Org. Lett., 2016, 18,
K. Monde and A. Shirata, Chem. Lett., 1987, 16, 1631; (d)
X. Jiang, Y. Cao and R. Wang, J. Am. Chem. Soc., 2010, 132,
5002; (b) L. Zhao and W.-W. Liao, Org. Chem. Front., 2018, 5,
801; (c) T.-T. Wang, D. Zhang and W.-W. Liao, Chem.
This journal is © The Royal Society of Chemistry 2019
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Commun., 2018, 54, 2048; (d) D. Zhang, H. Song and
W.-W. Liao, Org. Lett., 2019, 21, 2745.
16 For reviews: (a) R. J. H. Gregory, Chem. Rev., 1999, 99, 3649;
examples: (c) A. Baeza, C. Najera and J. M. Sansano,
Synthesis, 2005, 2787; (d) Y. Ogura, M. Akakura and
K. Ishihara, Angew. Chem., Int. Ed., 2013, 52, 8299.
(b) M. North, Tetrahedron: Asymmetry, 2003, 14, 147; Selected 17 CCDC 1943540 (compound 3aa), see the ESI for details.†
29428 | RSC Adv., 2019, 9, 29424–29428
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