Catalytic enantioselective cascade Michael/cyclization reaction of 3-isothiocyanato oxindoles with exocyclic α,β-unsaturated ketones: En route to 3,2′-pyrrolidinyl bispirooxindoles

Article abstract of DOI:10.1039/c6ob02187e

Cascade Michael/cyclization reactions between 3-isothiocyanato oxindoles and exocyclic α,β-unsaturated ketones are shown to proceed efficiently in the presence of a quinine-derived tertiary amino-squaramide catalyst and furnish 3,2′-pyrrolidinyl bispirooxindoles containing two spiro-quaternary and three contiguous stereocenters as a single diastereomer with excellent enantioselectivities (up to 99:1 er).

Full text of DOI:10.1039/c6ob02187e

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Catalytic enantioselective cascade Michael/cyclization reaction of
3-isothiocyanato oxindoles with exocyclic α,β-unsaturated
ketones en route to 3,2'-pyrrolidinyl bispirooxindoles
Received 00th January 20xx,
Accepted 00th January 20xx
Satavisha Kayal and Santanu Mukherjee*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Cascade Michael/cyclization reactions between 3-isothiocyanato oxindole bears the testimony of its excellent reactivity profile.
oxindoles and exocyclic α,β-unsaturated ketones are shown to Owing to the ambiphilic nature of 3-isothiocyanato oxindoles,
proceed efficiently in the presence of a quinine-derived tertiary reactions with a variety of π-electrophiles have led to highly
amino-squaramide catalyst and furnish 3,2'-pyrrolidinyl diastereo- and enantioselective synthesis of a wide range of
bispirooxindoles containing two spiro-quaternary and three densely functionalized spirooxindole derivatives.6 In fact, the
contiguous stereocenters as a single diastereomer with excellent same strategy has also been adopted for the catalytic
enantioselectivities (up to 99:1 er).
enantioselective synthesis of various bispirooxindole
derivatives.7,8
The growing popularity of spirocyclic compounds as potential
drugs as well as chiral ligands and catalysts has created a
demand for their enantioselective synthesis.1 Among various
spirocyclic cores, the spirooxindole framework containing a
pyrrolidine ring represents a very important class owing to
their rich bioactivities.2 In fact, the related bispirooxindole
scaffold has recently drawn considerable interest not only due
to its exclusive structural and stereochemical diversity but also
as a result of its presence in a number of bioactive molecules
(Figure 1).3
(A) State of the art:
NH
n
HN
HN
O
O
O
N
N
N
H
H
H
3,3'-pyrrolidinyl
spirooxindole
3,2'-pyrrolidinyl
spirooxindole
3,2'-pyrrolidinyl
bispirooxindole
many reports
less explored
rare
(B) This work:
S
cyclization
n
S
C
N
Michael addition/cyclization
cascade
n
O
HN
O
R
O
R
O
Michael
addition
N
R'
3,2'-pyrrolidinyl bispirooxindole
2 spiro-quaternary & 3 contiguous stereocenters
PG
N
R'
PG
Scheme 1 Catalytic enantioselective synthesis of bispirooxindoles
Despite these advancements, construction of differently
substituted and diversely functionalized spirooxindoles
containing multiple contiguous stereogenic centers continues
to be a formidable challenge. In addition, compared to the
large number of reports describing the enantioselective
synthesis of 3,3'-pyrrolidinyl spirooxindoles,9 3,2'-pyrrolidinyl
spirooxindoles are relatively less explored.10 Particularly the
catalytic enantioselective syntheses of 3,2'-pyrrolidinyl
bispirooxindoles are rather rare (Scheme 1A).7
Figure 1 Bioactive compounds bearing 3,2'-pyrrolidinyl bispirooxindole scaffold
Ever since the report by Yuan et al. in 2011,4
3-isothiocyanato oxindoles have been established as extremely
efficient and versatile synthon for the enantioselective
synthesis of spirooxindoles.5 The increasing number of
catalytic enantioselective reactions involving 3-isothiocyanato
As part of our ongoing research program directed toward
the enantioselective synthesis of spirocyclic compounds, we
became interested in developing an efficient route to
3,2'-pyrrolidinyl bispirooxindoles. We surmised that the
reaction between 3-isothiocyanato oxindole and an electron-
deficient exocyclic olefin would lead to the formation of
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012,
India. E-mail: sm@orgchem.iisc.ernet.in; Tel: +91-80-2293-2850; Fax: +91-80-2360-
0529.
†Electronic Supplementary Information (ESI) available: Experimental details,
See
characterization and analytical
DOI: 10.1039/x0xx00000x
data.
CCDC
1492583
(
3ao).
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Table 2 Substrate scopea
3,2'-pyrrolidinyl bispirooxindoles bearing two spiro-quaternary
and three contiguous stereocenters in a single step (Scheme
1B). While similar reactions of 3-isothiocyanato oxindole with
alkylidene heterocycles have been reported,7 to the best of
our knowledge, the same reaction with alkylidene carbocycles
has not been explored till date. Here we report the first
catalytic enantioselective cascade Michael/cyclization reaction
of 3-isothiocyanato oxindoles with exocyclic α,β-unsaturated
ketones.
R3
S
X
NCS
O
R1
IV (10 mol %)
HN
+
O
R1
O
R4
O
X
R4
CH2Cl2 (0.1 M)
25 °C
N
R3
R2
N
R2
1
2
3
(1.0 equiv)
(1.1 equiv)
>20:1 dr
(A)
R
t/h
Yield (%) er
Ph (3aa)
2-FC6H4 (3ab)
3-FC6H4 (3ac)
2
5
94
96
98:2
97:3
S
Table 1 Reaction optimizationa
HN
5
5
2
2
2
96
94
93
92
85
94
94
93
98:2
O
R
3ad
)
4-FC6H4
(
98:2
O
3-ClC6H4 (3ae)
4-BrC6H4 (3af)
4-MeC6H4 (3ag)
98:2
N
97:3
Bn
97.5:2.5
96:4
4-(i-Pr)C6H4 (3ah)
4-OMeC6H4 (3ai)
3,4-(OMe)2C6H3 (3aj)
4-CF3C6H4 (3ak)
3-NO2C6H4 (3al)
4-NO2C6H4 (3am)
C6F5 (3an)
2
2
2
94.5:5.5
95:5
5
2
3
2
1
3
3
5
2
88
97
92
95
94
86
97
94
97
99:1
98.5:1.5
98.5:1.5
96:4
2-Furyl (3ao)
2-Thienyl (3ap)
PhCH=CH (3aq)
i-Bu (3ar)
90:10 (97:3)
93:7
3ao
(CCDC 1492583)
95.5:4.5
83:17
Entry Cat.
Solvent
T/°C
t/hb
drc
erd
1
-
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
25
25
25
0
1
n.d.
-
H (3as)
98.5:1.5
2
I
1
10:1
6:1
29:71
83:17
85:15
75:25
78:22
77:23
97.5:2.5
98:2
(B)b
S
R
R = Cl (3at)
95% yield, 99:1 er
3
II
1
S
HN
4
II
3
4:1
O
Ph
R = Br (3au)
95% yield, 98.5:1.5 er
HN
5
II
–20
–60
25
25
25
25
25
25
25
25
3
9:1
O
O
Ph
N
6
II
48
1
>20:1
3:1
O
Bn
3ayc
R = F (3av)
96% yield, 98.5:1.5 er
N
7
III
IV
IV
IV
IV
IV
IV
IV
Bn
8
1
10:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
88% yield, 79:21 er
Br
9
1
S
S
S
OMe
O
10
11
12
13
14e
CHCl3
1
97.5:2.5
95:5
HN
HN
O
HN
O
O
PhCF3
1
Ph
Ph
Ph
O
O
2-MeTHF
TBME
1
96:4
O
N
N
N
1
95.5:4.5
97:3
Bn
Bn
3ax
Bn
CH2Cl2
1.5
3aw
3az
96% yield, 97.5:2.5 er
95% yield, 99:1 er
97% yield, 97:3 er
a Reactions were performed using 1.0 equiv of 1a and 1.1 equiv of 2a on a 0.05
(C)b
S
c
mmol scale. b Time required for complete consumption of 1a. Diastereomeric
R = Me (3ba)
94% yield, 98:2 er
S
ratio (dr) as determined by 1H NMR analysis of the crude reaction mixture; n.d. =
not determined. d Enantiomeric ratio (er) as determined by HPLC analysis using a
HN
O
HN
O
Me
R = n-Pr (3ca)
91% yield, 97:3 er
Ph
e
O
Ph
chiral stationary phase. Reaction using 5 mol % catalyst. TBME = tert-Butyl
O
N
methyl ether.
N
R
Me
R = PMB (3da)
96% yield, 97:3 er
3ea
94% yield, 97:3 er
In view of the success of bifunctional hydrogen bonding
catalysts11 in related cascade reactions of 3-isothiocyanato
oxindoles,5-7 we decided to commence our investigation with such
catalyst candidates. N-Benzyl-3-isothiocyanato oxindole 1a and
a
Reactions were performed on a 0.1 mmol scale. Yields correspond to the
isolated yield. Diastereomeric ratio (dr) was determined by 1H NMR analysis of
the crude reaction mixture and found to be >20:1 in all the cases. Enantiomeric
ratio (er) was determined by HPLC analysis using a chiral stationary phase. Values
b
(E)-β-benzylidene-α-indanone 2a were chosen as the model in the parenthesis indicate er of the product after a single recrystallization.
Reaction time = 2-3 h. c Reaction time = 24 h.
substrates, which were expected to undergo Michael
addition/cyclization cascade and generate
a bispirooxindole
diastereoselective (entry 3). Conducting the reaction at lower
temperature did not offer any beneficial effect on the
enantioselectivity of the reaction (entries 4-6). While similar
level of selectivities was observed with urea derivative III as
the catalyst (entry 7), the corresponding squaramide derivative
IV12 furnished the product with 10:1 dr and 97.5:2.5 er (entry
8). A survey of solvents revealed CH2Cl2 to be the optimum and
afforded the product as a single diastereomer with 98:2 er
(entry 9). The reaction could also be carried out using only 5
derivative containing two spiro-quaternary and three contiguous
stereogenic centers (Table 1). The said cascade reaction indeed
took place in toluene at 25 °C, in the absence of any catalyst, within
an hour to produce the desired bispirooxindole 3aa (entry 1). Under
identical reaction conditions, 10 mol % of Takemoto catalyst11e (I)
promoted the formation of 3aa with good diastereoselectivity but
with modest enantioselectivity (entry 2). Quinine-derived thiourea
II, in contrast, appeared to be more enantioselective but less
2 | J. Name., 2012, 00, 1-3
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mol % of IV, when the product was obtained with 97:3 er squaramide V, the pseudoenantiomer of catalyst IV. Under
(entry 14).
otherwise identical reaction conditions, ent-3aa was obtained in
The scope of the Michael addition/cyclization cascade reaction 96% yield and with 95.5:4.5 er.
was then evaluated under the optimized catalyst and reaction
Encouraged by the excellent yields and stereoselectivities
conditions (Table 1, entry 9). A variety of β-arylidene-α-indanones observed with a range of (E)-β-arylidene-α-indanones (Table 2-3),
(2a-n) with diverse steric and electronic character were well we wondered whether the exocyclic enones derived from
tolerated and the desired products (3aa-an) were obtained as a α-tetralone could be employed in the synthesis of bispirooxindole
single diastereomer in high yields and with good to excellent derivatives. To our delight, the β-arylidene-α-tetralones underwent
enantioselectivities (Table 2A). β-Heteroarylidene-α-indanones (2o- facile cascade Michael addition/cyclization reaction with
p) were also found to be suitable substrates and furnished the 3-isothiocyanato oxindole 1a under our optimized reaction
products (3ao-ap) in high yields and moderate to good en- conditions to deliver the desired bispirooxindoles (5aa-ac) as a
antioselectivities. α-Indanone-derived α,β,γ,δ-unsaturated ketone single diastereomer in high yields with good to high er (Scheme 3).
2q led to the formation of the desired product (3aq) in excellent
yield and high er along with exclusive regioselectivity. β-Alkylidene-
α-indanone (2r), however, turned out to be somewhat less reactive
and delivered the product (3ar) with significantly reduced er. We
were surprised to find that the product (3as) derived from
unsubstituted β-methylene-α-indanone (2s) was generated as a
single diastereomer with outstanding chemical and optical yield.
The same conditions were found to be suitable for different
β-arylidene-α-indanones (2t-x) having substituents on the aromatic
ring of α-indanone (Table 2B). In all these cases, the products were
Scheme
β-arylidene-α-tetralones
3
Enantioselective Michael addition/cyclization cascade with
formed, once again as a single diastereomer, in high yields with
excellent enantioselectivities. When (E)-2-benzylidenecyclopentan-
1-one (2y) was used as the substrate the corresponding product
The suitability of our protocol was then tested on a larger scale.
(3ay) was formed only with modest er. However, the product (3az) Thus, a reaction between 1a and 2a on a 1.0 mmol scale furnished
derived from (Z)-2-benzylidenebenzofuran-3-one was obtained in the product 3aa in 98% yield with the same level of diastereo- and
97% yield with 97:3 er.
enantioselectivity as observed in the smaller scale reaction (Scheme
Our protocol was found to be equally efficient for various 4).
3-isothiocyanato oxindoles (1b-d) with different N-substituents and
also for 1,5-dimethyl derivative (1e) (Table 2C). The limited
accessibility of 3-isothiocyanato oxindoles and their precursors
deterred the demonstration of further scope with respect to
differently substituted 3-isothiocyanato oxindoles. However, given
the high yields and enantioselectivities observed for a variety of
substrates, as shown in Table 2, similar outcome may be expected
for differently substituted 3-isothiocyanato oxindoles.
The relative and absolute configurations of 3ao were
established by the X-ray diffraction analysis of its single crystals
obtained from CHCl3 (Table 2A).13 Assuming an analogous catalytic
mechanism operates for the other substrates, the configurations of
the other products were assigned as the same.
Scheme 4 Large-scale experiment and functionalization of the product
We next directed our efforts to demonstrate the synthetic
utility of the resulting bispirooxindole derivatives. Methylation of
3aa with methyl iodide under mild conditions resulted in
bispirocyclic 2-methylthio-dihydropyrrole derivative 6 in 85% yield.
Treatment of 3aa with aqueous hydrogen peroxide under acidic
conditions furnished the pyrrolidinone derivative 7 in high yield.
Global reduction of 3aa with lithium aluminium hydride led to the
formation of bispiro[indoline-3,2'-pyrrolidine] 8 in 55% yield. The
stereochemistry at the newly formed stereocenter was established
through NMR spectroscopy.14 It must be noted that all these
transformations proceeded with complete stereochemical fidelity.
Scheme 2 Access to the enantiomeric bispirooxindole
As exemplified in Scheme 2, the enantiomeric product of this
cascade reaction could easily be prepared using quinidine-derived
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2014, 6696; (h) F. Tan, L.-Q. Lu, Q.-Q. Yang, W. Guo, Q. Bian,
J.-R. Chen and W.-J. Xiao, Chem.–Eur. J., 2014, 20, 3415; (i)
X.-L. Liu, W.-Y. Han, X.-M. Zhang and W.-C. Yuan, Org. Lett.,
2013, 15, 1246; (j) Y. Jiang, C.-K. Pei, D. Du, X.-G. Li, Y.-N. He,
Q. Xu and M. Shi, Eur. J. Org. Chem., 2013, 7895; (k) S. Kato,
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Angew. Chem., Int. Ed., 2012, 51, 7007.
The presence of a secondary amine functionality in a rigid
stereogenic framework in 8 intrigued us to test its catalytic
potential. Preliminary experiments revealed that 8 can indeed act
as a catalyst for reactions proceeding via iminium activation.14
However, both diastereo- and enantioselectivities remain modest at
this stage. Our future efforts would focus on the structural
modifications and functional diversifications of 8 to improve its
catalytic activity and selectivity.
7
8
(a) W.-Y. Han, S.-W. Li, Z.-J. Wu, X.-M. Zhang and W.-C. Yuan,
Chem.–Eur. J., 2013, 19, 5551; (b) H. Wu, L.-L. Zhang, Z.-Q.
In conclusion, a cascade Michael addition/cyclization reaction
has been developed for the highly enantioselective synthesis of
3,2′-pyrrolidinyl bispirooxindole derivatives. This cascade reaction
between 3-isothiocyanato oxindoles and exocyclic α,β-unsaturated
ketones is catalyzed by a quinine-derived bifunctional tertiary
amino-squaramide catalyst. The products containing three
contiguous stereogenic centers are obtained exclusively as a single
diastereomer generally in excellent yields and enantioselectivities.
This research work is funded by the CSIR [Grant No.
02(0207)/14/EMR-II] and SERB [Grant No. SB/S1/OC-63/2013]. S.K.
thanks the CSIR for a doctoral fellowship. We wish to thank Mr.
Prodip Howlader (Department of Inorganic and Physical Chemistry,
IISc, Bangalore) for his help with the X-ray structure analysis.
Tian, Y.-D. Huang and Y.-M. Wang, Chem.–Eur. J., 2013, 19
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Tan, H.-G. Cheng, B. Feng, Y.-Q. Zou, S.-W. Duan, J.-R. Chen
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selected
other
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routes
to
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3
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13 CCDC 1492583 contains the crystallographic data for 3ao
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
.
http://www.ccdc.cam.ac.uk/pages/Home.aspx
14 See the Supporting Information for details.
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