FeCl3-catalyzed stereoselective construction of spirooxindole tetrahydroquinolines via tandem 1,5-hydride transfer/ring closure

Article abstract of DOI:10.1021/ol301559k

An efficient FeCl₃-catalyzed stereoselective intramolecular tandem 1,5-hydride transfer/ring closure reaction was developed. The method allows for the formation of structurally diverse spirooxindole tetrahydroquinolines in high yields (up to 98%) with good to excellent levels of diastereoselectivity (up to 99:1 dr). The catalytic enantioselective variant of this process was also investigated preliminarily with a chiral BINOL-derived phosphoric acid.

Full text of DOI:10.1021/ol301559k

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
FeCl3‑Catalyzed Stereoselective
Construction of Spirooxindole
Tetrahydroquinolines via Tandem
1,5-Hydride Transfer/Ring Closure
Yan-Yan Han,†,‡ Wen-Yong Han,†,‡ Xue Hou,†,§ Xiao-Mei Zhang,† and
Wei-Cheng Yuan*,†
National Engineering Research Center of Chiral Drugs, Chengdu Institute of Organic
Chemistry, Chinese Academy of Sciences, Chengdu 610041, China, Graduate School of
Chinese Academy of Sciences, Beijing, 100049, China, and Center of Analysis and
Testing, Sichuan Academy of Agricultural Sciences, Chengdu 610066, China
yuanwc@cioc.ac.cn
Received June 6, 2012
ABSTRACT
An efficient FeCl3-catalyzed stereoselective intramolecular tandem 1,5-hydride transfer/ring closure reaction was developed. The method allows for the
formation of structurally diverse spirooxindole tetrahydroquinolines in high yields (up to 98%) with good to excellent levels of diastereoselectivity(upto99:1
dr). The catalytic enantioselective variant of this process was also investigated preliminarily with a chiral BINOL-derived phosphoric acid.
Because of their highly remarkable biological activities,
heterocyclic spiro compounds occupy a key place among
the various classes of organic molecules.1 Particularly,
spirocyclic-3,30-oxindoles have emerged as attractive syn-
thetic targets because of their prevalence in a number of
biologically active compounds and natural products.2
The defined three-dimensional spatial shape of spiroox-
indoles is an attractive target to complement the flat
heterocyclic compounds encountered in many drug dis-
covery programs, since it greatly influences the related
biological activity.2e In the past few years, many diverse
methods to access structure-diversity spirocyclic oxindoles
have been reported, including metal-based and organoca-
talytic methods.3 Undoubtedly, each of the developed
strategies results in a different class of spirocycle that
may show promise as biologically active compounds. In
this regard, new methods to afford spirocyclic oxindoles
† Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences
‡ Graduate School of Chinese Academy of Sciences.
§ Sichuan Academy of Agricultural Sciences
(1) (a) Chen, M.-H.; Pollard, P. P.; Patchett, A. A.; Cheng, K.; Wei,
L.; Chan, W. W.-S.; Butler, B.; Jacks, T. M.; Smith, R. G. Bioorg. Med.
Chem. Lett. 1999, 9, 1261. (b) Behera, R. K.; Behera, A. K.; Pradhan, R.;
Pati, A.; Patra, M. Synth. Commun. 2006, 36, 3729.
(2) For selected reviews, see: (a) Lin, H.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 36. (b) Williams, R. M.; Cox, R. J. Acc. Chem.
Res. 2003, 36, 127. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003,
2209. (d) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748. (e) Peddibhotla, S. Curr. Bioact. Compd. 2009, 5, 20. (f) Trost,
B. M.; Brennan, M. K. Synthesis 2009, 3003. (g) Badillo, J. J.; Hanhan,
N. V.; Franz, A. K. Curr. Opin. Drug Discovery Dev. 2010, 13, 758.
(h) Zhou, F.; Liu, Y. L.; Zhou, J. Adv. Synth. Catal. 2010, 352, 1381. For
selected examples, see: (i) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.;
Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.;
Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432.
(j) Shangary, S.; Wang, S. Annu. Rev. Pharmacol. Toxicol. 2009, 49, 223.
Scheme 1. Functionalization of C(sp3)ꢀH Bond via
1,5-Hydride Transfer/Ring Closure Sequence
r
10.1021/ol301559k
XXXX American Chemical Society

Table 1. Evaluation of Various Reaction Conditionsa
Scheme 2. Plan for the Construction of
Spiro[tetrahydroquinoline-3,30-oxindoles] via 1,5-Hydride
Transfer/Ring Closure Sequence
Lewis
yield
(%)c
entry
solvent
acid
x
time (h)
drb
1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
MeCN
Cu(OTf)2
FeCl3
30
30
30
30
30
30
20
10
5
3
3
91:9
92:8
91:9
91:9
91:9
91:9
92:8
93:7
ꢀ
95
2
94
3
Sc(OTf)3
Zn(OTf)2
Mg(ClO4)2
NiCl2
1
90
4
48
2
87
5
82
6
48
4
97
7
FeCl3
94
8
FeCl3
5
93
with structural diversity are highly desirable. More impor-
tant, such methods will probably provide a certain syn-
thetic platform for library-based medicinal evaluation of
the spirooxindoles and their analogues. However, to the
best of our knowledge, the methodology for the construc-
tion of a new class of spirooxindoles in which the oxindole
core is fused with a tetrahydroquinoline4 moiety at the
C3-position still remains elusive. Herein, we wish to report
a FeCl3-catalyzed protocol for the stereoselective synthesis
of spiro[tetrahydroquinoline-3,30-oxindoles] via a tandem
1,5-hydride transfer and subsequent ring closure reaction.
The functionalization of a C(sp3)ꢀH bond via intra-
molecular 1,5-hydride transfer/ring closure sequences
(Scheme 1) represents an important and creative goal in
synthetic organic chemistry.5 The intramolecular tandem
1,5-hydride transfer/ring closure sequence (Scheme 1) is
characterized by an internal redox process comprising a
1,5-hydride shift from the carbon atom (R to the nitrogen
9
FeCl3
48
5
trace
trace
trace
10
11
FeCl3
10
10
ꢀ
FeCl3
5
ꢀ
a Reaction conditions: 1a (0.11 mmol) in refluxing solvent (2.0 mL) with
the catalyst, its loading and the reaction time as indicated. b Diastereomeric
ratios were determined by 1H NMR spectra of purified product. Diaster-
eomers were inseparable by column chromatography. c Isolated yield.
atom) to the electrophilic position of the vinyl group
followed by a cyclization.6 Much effort has been exerted
to intensively study this tandem transformation and
employ it for the construction of tetrahydroquinoline
derivatives.6 Inspired by these related studies, and as part
of our research program on the development of synthetic
methods to access various spirocyclic oxindoles,7,8 we
speculated that a methodology, in which the initial cleavage
of a C(sp3)ꢀH bond in the context of a 1,5-hydride transfer
and subsequent ring closure utilizing corresponding
(3) For selected examples, see: (a) Antonchick, A. P.; Gerding-
Reimers, C.; Catarinella, M.; Schurmann, M.; Preut, H.; Ziegler, S.;
Rauh, D.; Waldmann, H. Nat. Chem. 2010, 2, 735. (b) Wei, Q.; Gong,
L.-Z. Org. Lett. 2010, 12, 1008. (c) Jiang, K.; Jia, Z.-J.; Yin, X.; Wu, L.;
Chen, Y.-C. Org. Lett. 2010, 12, 2766. (d) Jiang, K.; Jia, Z.-J.; Chen, S.;
Wu, L.; Chen, Y.-C. Chem.;Eur. J. 2010, 16, 2852. (e) Voituriez, A.;
Pinto, N.; Neel, M.; Retailleau, P.; Marinetti, A. Chem.;Eur. J. 2010,
16, 12541. (f) Jiang, X.; Cao, Y.; Wang, Y.; Liu, L.; Shen, F.; Wang, R.
J. Am. Chem. Soc. 2010, 132, 15328. (g) Tan, B.; Candeias, N. R.; Barbas,
C. F., III. Nat. Chem. 2011, 3, 473. (h) Peng, J.; Huang, X.; Jiang, L.; Cui,
H.-L.; Chen, Y.-C. Org. Lett. 2011, 13, 4584. (i) Tan, B.; Candeias, N. R.;
Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 4672. (j) Lan, Y.-B.;
Zhao, H.; Liu, Z.-M.; Liu, G.-G.; Tao, J.-C.; Wang, X.-W. Org. Lett.
2011, 13, 4866. (k) Jia, Z.-J.; Jiang, H.; Li, J.-L.; Gschwend, B.; Li, Q.-Z.;
Yin, X.; Grouleff, J.; Chen, Y.-C.; Jorgensen, K. A. J. Am. Chem. Soc.
2011, 133, 5053. (l) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem.,
Int. Ed. 2011, 50, 7837. (m) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Wang, R.
(6) For recent examples on the intramolecular 1,5-hydride transfer/
ring closure sequences, see: (a) Zhang, C.; Kanta De, C.; Mal, R.; Seidel,
D. J. Am. Chem. Soc. 2008, 130, 416. (b) Murarka, S.; Zhang, C.;
Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129. (c) Zhang, C.;
Murarka, S.; Seidel, D. J. Org. Chem. 2009, 74, 419. (d) Mori, K.;
Ohshima, Y.; Ehara, K.; Akiyama, T. Chem. Lett. 2009, 38, 524. (e)
McQuaid, K. M.; Long, J. Z.; Sames, D. Org. Lett. 2009, 11, 2972. (f)
Shikanai, D.; Murase, H.; Hata, T.; Urabe, H. J. Am. Chem. Soc. 2009,
131, 3166. (g) Yang, S.; Li, Z.; Jian, X.; He, C. Angew. Chem., Int. Ed.
2009, 48, 3999. (h) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131,
16525. (i) Pahadi, N. K.; Paley, M.; Jana, R.; Waetzig, S. R.; Tunge, J. A.
J. Am. Chem. Soc. 2009, 131, 16626. (j) Mori, K.; Kawasaki, T.; Sueoka,
S.; Akiyama, T. Org. Lett. 2010, 12, 1732. (k) Zhang, C.; Seidel, D.
J. Am. Chem. Soc. 2010, 132, 1798. (l) Deb, I.; Seidel, D. Tetrahedron
Lett. 2010, 51, 2945. (m) Jurberg, I. D.; Odabachian, Y.; Gagosz, F.
J. Am. Chem. Soc. 2010, 132, 3543. (n) Zhou, G.; Zhang, J. Chem.
Commun. 2010, 46, 6593. (o) Haibach, M. C.; Deb, I.; Kanta De, C.;
Seidel, D. J. Am. Chem. Soc. 2011, 133, 2100. (p) Zhang, C.; Das, D.;
Seidel, D. Chem. Sci. 2011, 2, 233. (q) Mori, K.; Sueoka, S.; Akiyama, T.
J. Am. Chem. Soc. 2011, 133, 2424. (r) Mori, K.; Ehara, K.; Kurihara,
K.; Akiyama, T. J. Am. Chem. Soc. 2011, 133, 6166. (s) Mori, K.;
Kawasaki, T.; Akiyama, T. Org. Lett. 2012, 14, 1436. (t) Vadola, P. A.;
Carrera, I.; Sames, D. J. Org. Chem. 201210.1021/jo300635m. (u) Chen,
L.; Zhang, L.; Lv, J.; Cheng, J.-P.; Luo, S. Chem.;Eur. J. 2012, 18, 8891.
(7) (a) Chen, W.-B.; Wu, Z.-J.; Hu, J.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2011, 13, 2472. (b) Han, Y.-Y.; Chen, W.-B.;
Han, W.-Y.; Wu, Z.-J.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2012, 14,
490. (c) Chen, W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Org. Lett. 2010, 12, 3132.
ꢀ
Angew. Chem., Int. Ed. 2011, 50, 9124. (n)Tan, B.;Hernandez-Torres, G.;
Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 12354. (o) Liu, Y.-K.;
Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011,
133, 15212. (p) Tan, B.; Zeng, X.; Leong, W. W. Y.; Shi, Z.; Barbas, C. F.,
III; Zhong, G. Chem.;Eur. J. 2012, 18, 63.
(4) For a leading review on the diverse array of biological activities of
tetrahydroquinolines, see: Katritzky, A. R.; Rachwal, S.; Rachwal, B.
Tetrahedron 1996, 52, 15031.
(5) For selected reviews, see: (a) Davies, H. M. L. Angew. Chem., Int.
Ed. 2006, 45, 6422. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem.
Rev. 2007, 107, 174. (c) Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069.
(d) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (e) Li, C.-J.
Acc. Chem. Res. 2009, 42, 335.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Scope of the Tandem 1,5-Hydride Transfer/Ring Closure Reactiona
a Reaction conditions: 1 (0.33 mmol) and FeCl3 (10 mol %) in ClCH2CH2Cl (6.0 mL) at 85 °C for the time as indicated. b Diastereomeric ratios were
1
determined by H NMR spectra of purified product. Diastereomers are inseparable by column chromatography. c Isolated yield. d The structure of
product 2e was characterized by X-ray crystallography.10
methyleneindolinone derivatives as substrates and Lewis
acids as catalysts, would ultimately lead to the formation of
a series of spirooxindole tetrahydroquinolines (Scheme 2).
Admittedly, if the above-mentioned strategy was suc-
cessfully realized, it will provide a highly attractive and
convergent approach toward the complex spiro[tetrahy-
droquinoline-3,30-oxindole] derivatives.
We commenced our investigation with compound 1a
as the substrate in 1,2-dichloroethane (DCE) for the
screening of various potential catalysts. As shown in
Table 1, with 30 mol % Cu(OTf)2, 1a could be smoothly
converted into the expected product 2a after 3 h in 95%
yield with 91:9 dr (Table 1, entry 1). To our delight, the
same reaction could complete even with inexpensive FeCl3
(30 mol %) after 3 h, affording 2a in 94% yield with 92:8 dr
(Table 1, entry 2). Additionally, we found that some other
Lewis acids, such as Sc(OTf)3, Zn(OTf)2, Mg(ClO4)2, and
NiCl2, also promoted the transformation of 1a to 2a well
with acceptable results (Table 1, entries 3ꢀ6). Therefore, in
light of multiple factors including the price of the catalyst,
(8) (a) Chen, W.-B.; Liao, Y.-H.; Du, X.-L.; Zhang, X.-M.; Yuan,
W.-C. Green Chem. 2009, 11, 1465. (b) Chen, W.-B.; Du, X.-L.; Cun,
L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441. (c) Liao,
Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Org. Lett. 2010, 12, 2896. (d) Liu, X.-L.; Liao, Y.-H.; Wu, Z.-J.; Cun,
L.-F.; Zhang, X.-M.; Yuan, W.-C. J. Org. Chem. 2010, 75, 4872. (e) Liu,
X.-L.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron Lett. 2011, 52, 903. (f)
Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. J. Org.
Chem. 2011, 76, 4008. (g) Han, Y.-Y.; Wu, Z.-J.; Chen, W.-B.; Du, X.-L.;
Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13, 5064. (h) Liao, Y.-H.;
Liu, X.-L.; Wu, Z.-J.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Chem.;
Eur. J. 2012, 18, 6679.
Org. Lett., Vol. XX, No. XX, XXXX
C

reactivity, and stereoselectivity, we decided to use FeCl3 as
the best catalyst for further investigation of other reaction
conditions. We were delighted to discover that the reaction
could proceed well in the presence of 20 or 10 mol % FeCl3
(Table 1, entries 7ꢀ8). Disappointedly, in the presence of
5mol%FeCl3, only a trace amount of 2a was obtained after
48 h (Table 1, entry 9). Additionally, a simple survey of
solvents revealed that DCE was significantly superior to
THF and acetonitrile (Table 1, entry 8 vs entries 10ꢀ11).
Therefore, these studies provided the optimal reaction con-
ditions: the reaction was conducted with 10 mol % FeCl3 as
the catalyst in refluxing DCE.
Scheme 3. Catalytic Asymmetric Variant of this Processa
a The relative configuration of the major isomer of 2a was determined
by NOE NMR,10 but the absolute configuration was not determined.
Having established the optimum reaction conditions,
we next examined the scope of the tandem transformation
with a series of substrates 1bꢀr (Table 2).9 First, an
unprotected methyleneindolinone derivative 1b as sub-
strate was investigated, it was found that the expect
intramolecular tandem 1,5-hydride transfer/ring closure
process proceeded smoothly, giving the corresponding
spirooxindole tetrahydroquinoline 2b in 96% yield with
97:3 diastereoselectivity ratio (Table 2, entry 1). Substitu-
tion on the oxindole aromatic ring was well tolerated
regardless of the electronic nature of the substituent,
leading to the desired ring-fused spirooxindole tetrahydro-
quinoline in high yield (92ꢀ98%) with high dr values
(Table 2, entries 2ꢀ4). The exact structure and relative
configuration of the major isomer of 2e was characterized
by single-crystal X-ray analysis.10 Nevertheless, the rela-
tive configuration of the major isomer of 2i could be
determined by NOE NMR experiment. Therefore, the
relative configurations, not absolute configurations, of
the major isomer of other products in this paper were
tentatively assigned by analogy. In addition, the reactions
with the piperidine derived substrates 1fꢀi showed very
good reactivity and stereoselectivity under the optimal
reaction conditions (Table 2, entries 5ꢀ8). The related
morpholine compound 1j, with an unprotected oxindole
core, also could rearrange efficiently to product 2j in 97%
yield and up to 99:1 dr with a longer reaction time (72 h,
Table 2, entry 9). However, some other morpholine-
derived substrates 1kꢀm, with a N-ethoxy carbonyl pro-
tected oxindole core, participated readily and delivered
the corresponding products 2kꢀm with satisfactory results
(Table 2, entries 10ꢀ12). We observed the tetrahydroiso-
quinoline 1n rapidly rearranged to 2n under the standard
conditions after 1 h in 89% yield with a 91:9 dr (Table 2,
entry 13). Gratifyingly, some other substrates 1oꢀr incor-
porating tetrahydroisoquinoline into the unprotected
oxindole core also smoothly rearranged to the expected
products even in no more than 30 min (Table 2, entries
14ꢀ17). Moreover, these cases demonstrate that various
amine donors, such as pyrrolidine, piperidine, morpholine,
and tetrahydroisoquinoline, are well-tolerated (Table 2).
We also attempted to develop a catalytic asymmetric
version of this process for access to enantioenriched spiroox-
indole tetrahydroquinolines. After a series of efforts, we found
that the use of some chiral ligands11 in combination with
various metal salts, including FeCl3, Cu(OTf)2, Sc(OTf)3,
Zn(OTf)2, Mg(ClO4)2, and NiCl2, gives rise to the product 2a
in very poor enantioselectivity (no more than 11% ee; results
not shown). However, to our delight, we discovered that a
promising result of the catalytic asymmetric process could be
obtained by using 20 mol % chiral BINOL-derived phos-
phoric acid12 to afford product 2a in 95% yield with 94:6 dr
and 54% ee (Scheme 3).13 Notably, this example indicates the
process is able to be realized without metal.
In conclusion, we have developed a highly stereo-
selective intramolecular tandem 1,5-hydride transfer/ring
closure reaction for the synthesis of a new class of spir-
ocyclic oxindole tetrahydroquinolines using FeCl3 as the
catalyst. Withthis tandem strategy, biologically interesting
and structurally diverse spirooxindole tetrahydroquinolines
are able to be smoothly obtained in excellent yield (up to
98%) and diastereoselectivity (up to 99:1 dr). A preliminary
experiment for the catalytic enantioselective variant of this
process with a chiral BINOL-derived phosphoric acid as the
catalyst12 could deliver the corresponding product in 95%
yield with 94:6 dr and 54% ee. Efforts to realize the highly
enantioselective version of this reaction and use this new
methodology to synthesize interesting biologically active
compounds are ongoing in our laboratory.
Acknowledgment. We are grateful for financial support
from the Western Light Talent Culture Project, and
Sichuan Youth Science and Technology Foundation. Dr.
Jie Yu (University of Science and Technology of China) is
acknowledged for helpful discussions.
(9) For the synthesis of substrates 1, see the Supporting Information.
(10) For details, see the Supporting Information.
(11) Chiral diamine, salen, diphosphine, and bisoxazoline ligands
were tested.
(12) For leading reviews of asymmetric catalysis using chiral phos-
phoric acids, see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b)
Terada, M. Chem. Commun. 2008, 4097. (c) Terada, M. Synthesis 2010,
1929. (d) Zamfir, A.; Schenker, S.; Freund, M.; Tsogoeva, S. B. Org.
Biomol. Chem. 2010, 8, 5262. (e) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem.
Res. 2011, 44, 1156.
Supporting Information Available. Experimental pro-
cedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(13) For the enantiomeric excess analysis of chiral 2a, see the
Supporting Information.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX