Asymmetric synthesis of spirocyclic oxindole-fused tetrahydrothiophenes via n,n-dioxide-nickel(ii) catalyzed domino reaction of 1,4-dithiane-2,5-diol with 3-alkenyloxindoles

Article abstract of DOI:10.1002/adsc.201400964

A highly efficient chiral N,N-dioxide-nickel(II) complex system has been developed to catalyze the domino thia-Michael/aldol reaction of 1,4-dithiane-2,5-diol with 3-alkenyloxindoles.A series of the desired spirocyclic oxindole-fused tetrahydrothiophenes was obtained in good yields with excellent ee and dr (up to 97% yield, 98% ee, >19:1 dr).Besides, based on the X-ray crystal structure of the catalyst as well as the absolute configuration of the product, a catalytic model was proposed to explain the stereocontrol process.

Full text of DOI:10.1002/adsc.201400964

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DOI: 10.1002/adsc.201400964
Asymmetric Synthesis of Spirocyclic Oxindole-Fused
Tetrahydrothiophenes via N,N’-Dioxide–Nickel(II) Catalyzed
Domino Reaction of 1,4-Dithiane-2,5-diol with
3-Alkenyloxindoles
Pengfei Zhou,a Yunfei Cai,a Lili Lin,a Xiangjin Lian,a Yong Xia,a Xiaohua Liu,a
and Xiaoming Fenga,b,*
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, Peopleꢀs Republic of China
Fax : (+86)-28-8541-8249; e-mail: xmfeng@scu.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, Peopleꢀs Republic of China
b
Received: October 6, 2014; Revised: November 13, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400964.
Abstract: A highly efficient chiral N,N’-dioxide–
nickel(II) complex system has been developed to
catalyze the domino thia-Michael/aldol reaction of
A spirocyclic oxindole moiety as the core structure
appears in many natural molecules.[8] As a result,
enormous efforts were devoted to building this scaf-
fold,[9] especially the chiral 3,3’-spirocyclic oxindoles
fused with a heterocycle structure. Several enantiose-
lectively synthetic approaches such as 1,3-dipolar cy-
cloaddition[11a,b] or NHC-catalyzed formal [3+2]annu-
lation,[10d,e,f] have been designed to synthesize spiro
oxa[10] and spiro aza[11] heterocycle oxindoles. Howev-
er, only few asymmetric routes to synthesize the spiro
tetrahydrothiophene oxindoles have been dis-
closed.[12,13] Xiaoꢀs group recently reported the first
domino thia-Michael/aldol reaction between 1,4-di-
thiane-2,5-diol and 3-alkenyloxindoles catalyzed by an
organo-Cinchona-based squaramide, delivering the
desired spirocyclic oxindole fused-tetrahydrothio-
phenes in a good result. However, the substrate scope
is limited to the strong electron-deficient ester group
1,4-dithiane-2,5-diol with 3-alkenyloxindoles.
A
series of the desired spirocyclic oxindole-fused tet-
rahydrothiophenes was obtained in good yields with
excellent ee and dr (up to 97% yield, 98% ee,
>19:1 dr). Besides, based on the X-ray crystal
structure of the catalyst as well as the absolute con-
figuration of the product, a catalytic model was pro-
posed to explain the stereocontrol process.
Keywords: asymmetric catalysis; N,N’-dioxide–
nickel complex; spirooxindoles; tetrahydrothio-
phenes
Among the various classes of organic sulfur com-
pounds, optically active polysubstituted tetrahydro-
thiophenes have attracted considerable attention in
the past decades, owing to their prevalence in natural
products with a large spectrum of biological activi-
ties.[1,2] Recently, many strategies have been devel-
oped for the synthesis of this structure.[2–4] For the
construction of chiral tetrahydrothiophenes, catalytic
asymmetric domino[5] thia-Michael/aldol and thia-Mi-
chael/Michael reactions between mercaptoacetalde-
hyde analogues and a,b-unsaturated compounds
belong to the most efficient and straightforward pro-
cesses. The Jørgensen[6] and Wang[7] groups have ap-
plied chiral diarylprolinol ethers as organocatalysts to
realize these reactions.
Scheme 1. Catalytic asymmetric thia-domino cyclization of
1,4-dithiane-2,5-diol with 3-alkenyloxindoles.
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Pengfei Zhou et al.
substituted 3-alkenyloxindoles, and the enantioselec- ed by organocatalysis and no Lewis acid as catalyst
had been reported. The possible reason might be that
the strong coordination ability of the sulfur atom to
the central metal might poison the catalyst when
a Lewis acid is used as catalyst.[14] Therefore, a highly
efficient Lewis acid able to catalyze an enantioselec-
tive thia-domino cyclization to synthesize the spirocy-
clic oxindole-fused tetrahydrothiophenes is still desir-
able and also a challenge. Herein, we have developed
a novel Ni(II)-catalyzed asymmetric domino thia-Mi-
chael/aldol reaction of 1,4-dithiane-2,5-diol with 3-al-
kenyloxindoles. In the presence of the chiral N,N’-di-
oxide–Ni(II) complex,[15] a broad spectrum of spirocy-
clic oxindole-fused tetrahydrothiophene compounds
was obtained in excellent results (56–97% yields, 90–
Figure 1. Chiral ligands evaluated in this study.
98% ee, 8:1 to >19:1 dr).
In our study, the domino reaction of 3-alkenyloxin-
dole 1a with 1,4-dithiane-2,5-diol 2 was chosen as the
tivities (<90% ee in most cases)[12] are also need to model reaction to probe the optimal reaction condi-
be further improved (Scheme 1).
tions. At the beginning, various metal salts coordinat-
On the other hand, the asymmetric thia-domino ed with N,N’-dioxide L-PiPh derived from (S)-pipe-
cyclization reactions mentioned above were dominat- colic acid were tested in CH2Cl2 at 358C (Figure 1).
Table 1. Optimization of the domino thia-Michael/aldol cycloaddition reaction.[a]
Entry
Ligand
Metal
Solvent
Yield [%][b]
ee [%][c]
dr[d]
1
2
3
4
L-PiPh
L-PiPh
L-PiPh
L-PiAd
L-PiMe2
L-PiEt2
L-PiPr2
L-PrPr2
L-RaPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
Yb(OTf)3
Sc(OTf)3
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
Ni(OTf)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
trace
46
52
63
74
82
90
71
78
80
79
90
89
13
90
–
–
49
24
14
30
83
93
77
80
40
40
94
94
20
931
1.5:1
4:1
>19:1
11.5:1
13.5:1
>19:1
>19:1
16:1
9:1
8:1
>19:1
>19:1
>19:1
>19:1
5
6
7[e]
8
9
10
11
12[e,f]
13[f,g]
14[h]
15[i]
[a]
Unless otherwise noted, all reactions were carried out with 1a (0.1 mmol), 2 (0.06 mmol) and L–metal (1:1, 10 mol%) in
solvent (0.5 mL) at 358C for 24 h.
[b]
[c]
[d]
[e]
[f]
Isolated yield of the major diastereoisomer by silica gel column chromatography.
Determined by HPLC analysis for the major diastereoisomer.
1
Determined by H NMR of crude product.
Substrate 1a consumed completely in 2 h.
Catalyst loading was 5 mol%.
Conducted at 258C for 16 h.
Using L-PiPr2–Ni(OTf)2 [L-PiPr2:Ni(OTf)2 =1:1.2, 5 mol%] as catalyst.
Catalyst loading was a mol%, substrate 1a was consumed completely in 8 h.
[g]
[h]
[i]
2
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Asymmetric Synthesis of Spirocyclic Oxindole-Fused Tetrahydrothiophenes
Table 2. Substrate scope of the domino thia-Michael/aldol cycloaddition reaction.[a]
Entry
R1
R2
R3
x
Time [h]
Yield [%][b]
ee [%][c]
dr[d]
1
2
3
4
5
6
7
8
H
H
H
H
H
H
COOMe
COOEt
COO-i-Pr
COO-t-Bu
COOPh
COOBn
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COOMe
COPh
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
10
10
10
10
10
10
10
10
10
5
2
2
2
2
2
2
3
3
3
2
2
2
2
2
2
2
36
36
16
16
36
36
14
16
14
2
90 (3a)
88 (3b)
92 (3c)
95 (3d)
88 (3e)
87 (3f)
95 (3g)
97 (3h)
92 (3i)
90 (3j)
90 (3k)
85 (3l)
97 (3m)
86 (3n)
84 (3o)
94 (3p)
80 (3q)
56 (3r)
93 (3s)
92 (3t)
77 (3u)
50 (3v)
84 (3w)
85 (3x)
80 (3y)
97 (3z)
94 (1S, 2R, 3R)
93 (1S, 2R, 3R)
93 (1S, 2R, 3R)
96 (1S, 2R, 3R)
92 (1S, 2R, 3R)
94 (1S, 2R, 3R)
94 (1S, 2R, 3R)
93 (1S, 2R, 3R)
93 (1S, 2R, 3R)
94 (1S, 2R, 3R)
94 (1S, 2R, 3R)
93 (1S, 2R, 3R)
95 (1S, 2R, 3R)
90 (1S, 2R, 3R)
90 (1S, 2R, 3R)
94
95
91
98
97
95
91
93
95
82
92
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
18:1
5-Me
5-MeO
5,7-Me2
5-F
5-Cl
5-Br
6-Cl
7-Br
7-F3C
H
H
H
H
H
H
H
H
H
9
10
11
12
13
14
15
16
17[e]
18[e]
19[e]
20[e]
21[e]
22[e]
23[e]
24[e]
25[e]
26
12.5:1
8.5:1
>19:1
13:1
8:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
11:1
Ph
4-MeC6H4
4-F3CC6H4
4-ClC6H4
2-naphthyl
3-thienyl
Me
t-Bu
n-decyl
COOEt
>19:1
13:1
>19:1
H
H
[a]
Unless otherwise noted, all reactions were carried out with 1 (0.1 mmol), 2 (0.06 mmol) and L-PiPr2–Ni(OTf)2 (1:1,
x mol%) in CH2Cl2 (0.5 mL) at 358C.
Isolated yield of the major diastereoisomer by silica gel column chromatography; 3i–3o isolated by silica gel column chro-
matography at 08C.
[b]
[c]
[d]
[e]
Determined by HPLC analysis for the major diastereoisomer.
1
Determined by H NMR of crude product.
Conducted with 1.0 equiv. of 2.
As presented in Table 1, when employing L-PiPh– tries 4–9). It was found that the amine substituents
Yb(OTf)3 as the chiral catalyst, only a trace amount had a great influence on the enantioselectivity and
of product was detected. The L-PiPh–Sc(OTf)3 com- diastereoselectivity. The ligand with an aromatic
plex delivered the corresponding cycloaddition prod- amine substituent was more promising than L-PiAd
uct 3a in 46% yield and 49% ee but with only 1.5:1 dr with an alkylamine substituent (Table 1, entry 3 vs.
(Table 1, entry 2). To our delight, the dr value could entry 4). On increasing the hindrance of the amide
be increased to 4:1 when employing the L-PiPh– from H to Me, Et and i-Pr, both the ee and dr values
Ni(OTf)2 complex as the catalyst although with a de- increased gradually from 24% ee, 4:1 dr to 93% ee,
crease of enantioselectivity (Table 1, entry 3). To fur- >19:1 dr (Table 1, entries 5–7 vs. entry 3). The ligands
ther improve the outcomes, a series of chiral N,N’-di- with other chiral backbone moieties had a negative
oxide ligands containing diverse amines and chiral influence on the stereoselectivity (Table 1, entries 8
backbone moieties was synthesized and complexed and 9). Investigation of other solvents did not give
with Ni(OTf)2 to catalyze the reaction (Table 1, en- rise to better results (Table 1, entries 10 and 11).
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Pleasingly, the catalyst loading could be reduced to
5 mol% without loss of yield, enantioselectivity and
diastereoselectivity (90% yield, 94% ee, >19:1 dr;
Table 1, entry 12). Decreasing the reaction tempera-
ture to 258C could give similar results but with longer
reaction times (Table 1, entry 13). Notably, when the
Ni(OTf)2 was in excess compared to the chiral N,N’-
dioxide ligand, the reaction was very sluggish. It was
speculated that the superfluous Ni(OTf)2 might com-
plex with sulfur atom of mercaptoacetaldehyde which
existed in the reaction system in the form of an equi-
librium with 1,4-dithiane-2,5-diol,[16] thus the coordi-
nated mercaptoacetadehyde could not take part in
the thia-domino cyclization.
Having established the optimal reaction conditions
(Table 1, entry 12), we next examined the generality
of this domino thia-Michael/aldol reaction (Table 2).
The steric hindrance of the ester group showed no ob-
vious influence on the reactivity and stereoselectivity
of the reaction, giving the corresponding cyclic ad-
ducts in good yields with excellent enantioselectivities
and diastereoselectivites (87–95% yields, 92–96% ee,
>19:1 dr; Table 2, entries 1–6). The electronic nature
or the position of substituents on the backbone of the
oxindole had a slight effect on the diastereoselectivity
but no effect on either yield or enantioselectivity (84–
97% yields, 90–95% ee, 8:1 to >19:1 dr; Table 2, en-
tries 7–15).[17] Excellent yield and enantioselectivity
were still maintained when the ester group was re-
placed by a benzoyl group (94% yield, 94% ee, >19:1
dr; Table 2, entry 16). Significantly, less reactive aryl-
substituted 3-alkenyloxindoles including fused- or het-
eroaromatic substituted ones as well as the alkyl-sub-
stituted ones 1w, 1x, 1y could also undergo this reac-
tion smoothly, affording the desired adducts in excel-
lent results (50–93% yields, 82–98% ee, 11:1 to >19:1
dr; Table 2, entries 17–25). Additionally, the N-
methyl-protected 3-alkenyloxindole was also well tol-
Figure 2. Proposed catalytic model and X-ray single crystal
structure of 3j.
Scheme 2. Scaled-up version of the domino thia-Michael/
erated (97% yield, 92% ee, >19:1 dr; Table 2, aldol cycloaddition reaction.
entry 24). Oxindoles without the benzyl protecting
group, such as (E)-methyl-2-(2-oxoindonlin-3-ylide-
ne)acetate, gave only 26% cycloaddition product with tioselectivity (>19:1 dr, 93% ee) even using 2 mol%
10% ee after 24 h.
catalyst loading. The enantiopure 3a could be ob-
The absolute configuration of cyclic adduct 3j was tained after one single recrystallization.
unambiguously determined by X-ray crystallographic
Based on the X-ray crystal structure of the cata-
analysis to be (C1S, C2R, C3R).[18] According to the lyst[19] as well as the absolute configuration of the
NMR analysis of the products and a comparison with products, a proposed catalytic model was provided to
the CD spectra of 3j, the absolute configurations of explain the observed stereocontrol. Both oxygen
other ester group-substituted 3-alkenyloxindole cyclo- atoms of the amide and N-oxide were complexed
addition products are also determined as (C1S, C2R, with the Ni atom in the complex. The carbonyl
C3R) (Figure 2).
oxygen atom of the 3-alkenyloxindole coordinated
To further evaluate the synthetic utility of the cata- with the nickel center and was stabilized by the p–p
lytic system, the reaction was conducted on a gram stack interactions between the two aromatic rings.
scale. As shown in Scheme 2, by treament of 3 mmol Meanwhile, the strong dipolar ability of N,N’-dioxide
1a and 1.8 mmol 2, the corresponding spirocyclic oxin- facilitated the nickel to coordinate with an oxygen
dole-fused tetrahydrothiophene 3a (1.01 g, 91% yield) atom better than a sulfur atom of the dissociated mer-
was obtained without any loss of diastereo- and enan- captoacetadehyde. Due to the fact that the Re-face of
4
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Asymmetric Synthesis of Spirocyclic Oxindole-Fused Tetrahydrothiophenes
oxindole was shielded by the neighboring 2,6-diiso- Acknowledgements
propylphenyl group of the N,N’-dioxide, the sulfur
We appreciate the National Natural Science Foundation of
atom attacked on the activated olefin at the Si-face
forming the C1S center followed by an intramolecular
aldol reaction via the chair-like transition state, af-
fording the C1S, C2R, C3R product.
China (Nos. 21432006, 21321061, 21372162) and National
Basic Research Program of China (973 Program: No.
2011CB808600) for financial support.
In summary, we have demonstrated an efficient
N,N’-dioxide–nickel(II) complex-catalyzed asymmet-
ric domino thia-Michael/aldol cycloaddition reaction,
which provided a practical access to the enantioen-
riched spirocyclic oxindole-fused tetrahydrothio-
phenes. A series of 3-alkenyloxindoles underwent this
reaction smoothly, affording the desired products in
good yields with excellent enantioselectivities and dia-
stereoselectivities (up to 97% yield, 98% ee, >19:1
dr). The reaction could be scaled-up to a gram scale
without loss of selectivity. Studies on further applica-
tions of this catalyst system to other asymmetric reac-
tions are underway.
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Typical Procedure for the Thia-Domino Cyclization
of 1,4-Dithiane-2,5-diol with 3-Alkenyloxindoles
An oven-dried test tube was charged with L-PiPr2
(0.005 mmol, 3.3 mg), Ni(OTf)2 (0.005 mmol, 1.8 mg) and 3-
alkenyloxindole 1a (0.1 mmol, 29.3 mg). The tube was then
sealed with a stopper. The vessel was briefly evacuated and
backfilled with nitrogen (repeated for three times) before
0.5 mL CH2Cl2 was added. After stirring at 358C for 10–
15 min, 1,4-dithiane-2,5-diol 2 ( 0.06 mmol, 9.1 mg) was
added to the tube. Then the reaction mixture was stirred at
the same temperature for 2 h. Finally the residue was puri-
fied by flash chromatography on silica gel (eluent: petrole-
um ether/EtOAc=3/1) to afford the desired product 3a as
white solid; yield: 90%, 94% ee, >19:1 dr. The enantiomeric
excess (ee) was determined by high-performance liquid
chromatography (HPLC) with Chiralcel AD-H, Chiralcel
IA. The diastereomeric ratio (dr) was determined by
1H NMR spectroscopy of crude product. Products 3j–3o
were purified by short silica gel column chromatography at
08C (eluent: DCM/EtOAc=25/1).
[4] For selected examples of synthesis of racemic tetrahy-
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Batory, C. E. Mclnnis, J. T. Njardarson, J. Am. Chem.
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Du, L. C. Ma, G. W. Li, M. L. Tao, W. Q. Zhang, Tetra-
hedron 2013, 69, 4749.
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Chem. Rev. 2014, 114, 2390; b) H. Pellissier, Chem.
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2012, 354, 237.
Typical Procedure for the Scaled-Up Reaction
An oven-dried 25-mL round-bottom flask was charged with
L-PiPr2
(0.06 mmol,
39.0 mg,
2 mol%),
Ni(OTf)2
(0.06 mmol, 21.6 mg, 2 mol%) and model substrate 1a
(3.0 mmol, 879.0 mg). The flask was then sealed with a stop-
per. The vessel was briefly evacuated and backfilled with ni-
trogen (repeated for three times) before 10.0 mL CH2Cl2
was added. After stirred at 358C for 10–15 min, 1,4-di-
thiane-2,5-diol 2 (1.8 mmol, 274.0 mg) was added. Then the
reaction mixture was stirred at the same temperature for an-
other 8 h before it was directly purified by flash chromatog-
raphy on silica gel (eluent: DCM/EtOAc=30/1) to afford
the desired product 3a; yield: 91%, 93% ee, >19:1 dr.
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the backbone of oxindole (3j–3o) would isomerize to
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with silica gel column chromatography; to avoid this
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eluent.
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6
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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
Asymmetric Synthesis of Spirocyclic Oxindole-Fused
Tetrahydrothiophenes via N,N’-Dioxide–Nickel(II)
Catalyzed Domino Reaction of 1,4-Dithiane-2,5-diol with 3-
Alkenyloxindoles
7
Adv. Synth. Catal. 2015, 357, 1 – 7
Pengfei Zhou, Yunfei Cai, Lili Lin, Xiangjin Lian,
Yong Xia, Xiaohua Liu, Xiaoming Feng*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!