Synthesis of 3,3-disubstituted indoline-2-thiones catalysed by an N-heterocyclic carbene

Article abstract of DOI:10.1039/c4cc04047c

A catalytic method has been developed for construction of indoline-2-thiones containing an all-carbon quaternary centre at the C-3 position. Successive treatment of α,β-unsaturated aldehydes bearing an isothiocyanato moiety with an in situ generated N-heterocyclic carbene and an appropriate heteroatomic nucleophile provided the 3,3-disubstituted indoline derivatives in moderate to good yields. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc04047c

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Synthesis of 3,3-disubstituted indoline-2-thiones
catalysed by an N-heterocyclic carbene†
Cite this: Chem. Commun., 2014,
50, 8871
Hideo Ikota, Takayuki Ishida, Chihiro Tsukano and Yoshiji Takemoto*
Received 27th May 2014,
Accepted 15th June 2014
DOI: 10.1039/c4cc04047c
www.rsc.org/chemcomm
A catalytic method has been developed for construction of indoline-
2-thiones containing an all-carbon quaternary centre at the C-3
position. Successive treatment of a,b-unsaturated aldehydes bearing
an isothiocyanato moiety with an in situ generated N-heterocyclic
carbene and an appropriate heteroatomic nucleophile provided the
3,3-disubstituted indoline derivatives in moderate to good yields.
Scheme 1 Umpolung of enals by an NHC catalyst.
Umpolung strategies involving the use of N-heterocyclic carbenes
(NHC)1 have attracted considerable attention in the field of organic
synthesis since Breslow2 proposed a mechanism for the benzoin
condensation reaction in 1958 involving the use of a thiazolium
salt. Following this initial publication, a variety of other NHC-
catalysed reactions have been reported, including a Stetter
reaction,3 as well as reactions involving enolate generation,4 and
redox acylation.5 Homoenolate equivalents, which can be readily
prepared by the reaction of the corresponding a,b-unsaturated
aldehydes with an NHC catalyst, are well known to be unique
umpolung synthons that possess a nucleophilic b-carbon unit
(Scheme 1). The first synthetic applications of homoenolate
equivalents, in terms of their reaction with electrophilic species,
were reported independently by Bode6a and Glorius6b,c in 2004,
and a large number of related reactions have subsequently
been developed.7–10 Reports pertaining to the reaction of
b,b-disubstituted enals, however, have been limited in number
and only a few reactions have been explored, including the
asymmetric protonation of homoenolates, which was reported by
Scheidt11 and Ma’s synthesis of butenolide from b-chloroenal.12
Given that neither of these reactions leads to the formation of
an all-carbon quaternary centre, there still remains an urgent
need for the development of synthetic methods capable
of providing access to all-carbon quaternary centres from
b,b-disubstituted enals.
Indoline and its congeners represent the core structures of a large
number of natural products and biologically active compounds,13
and extensive research efforts have consequently been directed
towards the development of efficient synthetic methods for the
construction of these substructures.14 With this in mind, it was
envisaged that an NHC-catalysed process could be developed
for the synthesis of indoline-2-thione 4 from b,b-disubstituted
a,b-unsaturated aldehydes 2 bearing an isothiocyanato moiety,15
which could be readily derived from quinolines 1 according to the
method reported by Hull16 (Scheme 2). If the NHC catalyst reacted
predominantly with the formyl group of enal 2 instead of the
isothiocyanato moiety, then the resulting Breslow intermediate would
undergo successive C–C and S–C bond forming reactions with the
isothiocyanato moiety to give the desired 2H-thienoindolones 3
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan. E-mail: takemoto@pharm.kyoto-u.ac.jp;
Fax: +81-075-753-4569; Tel: +81-075-753-4528
† Electronic supplementary information (ESI) available. CCDC 992277. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc04047c
Scheme 2 Synthesis of 3,3-disubstituted indoline-2-thiones.
Chem. Commun., 2014, 50, 8871--8874 | 8871
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together with the generation of an all-carbon quaternary centre determined by X-ray crystallographic analysis.18 We then proceeded
at the C-3 position. Herein, we report the concise synthesis of to investigate the effect of different bases on the outcome of the
3,3-disubstituted indoline-2-thiones 4 from enal 2 via a tandem reaction (Table 1, entries 5–7). Although potassium or caesium
NHC-catalysed five-membered thiolactam formation/nucleo- carbonate furnished the desired product 3a, DBU was totally
philic ring opening reaction.
ineffective in this reaction. In any event, potassium tert-
We initially examined the NHC-catalysed cyclisation of enal 2a17 butoxide was superior to all of the other bases examined in
with several different NHC precursors A–D (Table 1). The reactions this study in terms of the chemical yield. Interestingly, the
were carried out in the presence of 10 mol% of each NHC precursor subsequent screening of solvents revealed that this reaction
and potassium tert-butoxide in toluene at 80 1C. The reactions proceeded only in aromatic hydrocarbon solvents such as
involving the use of triazolium salt A and imidazolinium salt B led toluene and benzene (Table 1, entries 8–11).
to the generation of quinoline 1a and the E/Z isomerisation of
Under these optimised conditions, the scope and limitations of
substrate 2a, but did not afford any of the desired product this reaction were investigated with respect to both the nucleo-
3a (Table 1, entries 1 and 2). However, imidazolium salts C philes (NuH) used for the ring-opening reaction and the sub-
(IMesÁHCl) and D (IPrÁHCl) promoted the desired reaction to stituents (R1 and R2) of the enals 2 (Table 2). As for the ring
give 2H-thienoindolone 3a as the major product (Table 1, opening of intermediate 3a, various nucleophiles such as aniline,
entries 3 and 4). Since 3a was not stable to silica gels, the methanol, and thiophenol could be used in the tandem reaction,
purification of the reaction mixture by column chromatography with the corresponding amide 4b, ester 4c, and thioester 4d
resulted in a poor isolated yield (16%), and the product ratios of products being formed in reasonable yields, respectively (Table 2,
3a/1a/2a reported in Table 1 were consequently evaluated by the entries 2–4). This reaction was also applicable to the synthesis
1H NMR analysis of the crude mixtures. The yield of 3a could be of Weinreb amide 4e by the reaction of 3a with a mixture of
estimated from the isolated yield of indoline-2-thione 4a, which N,O-dimethylhydroxylamine hydrochloride and triethylamine
was obtained by the subsequent addition of an appropriate (Table 2, entry 5). Along with the methyl group, various primary
nucleophile to the reaction mixture. Indeed, the tandem NHC- alkyl groups were also well tolerated as R1 substituents, including
catalyzed cyclization and ring-opening reaction of 2a and methyl- ethyl, homobenzyl and homoallyl groups, which gave the
amine in the presence of D provided the corresponding amide
4a in 75% yield, and the structure of 4a was unambiguously
Table 2 Scopes and limitations
Table 1 Optimization of conditions
Entry Substrate NuH
R1
R2
Product Yielda (%)
1
2a
2a
2a
2a
MeNH2
PhNH2
MeOH
PhSH
Me(MeO)NH Me
MeNH2
Me
Me
Me
Me
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
75
62
59
48
50
66
2b,c
3b,c
4c
5c,d 2a
6
2f
Et
7
8
2g
2h
MeNH2
MeNH2
H
H
4g
4h
67
78
Entry Catalyst Base
Solvent
3a : 1a : 2aa,b Yield of 4ac (%)
9
2i
2j
2k
MeNH2
MeNH2
MeNH2
iPr
tBu
Ph
H
H
H
4i
4j
4k
68
35
89
10e
11
1
2
3
4
A
B
C
D
KOtBu
KOtBu
KOtBu
KOtBu
Toluene 0 : 21 : 79
Toluene 0 : 6 : 94
Toluene 50 : 10 : 40
Toluene 90 : 5 : 5
—
—
—
75
12
2l
MeNH2
H
4l
60
5
6
7
D
D
D
K2CO3
Toluene 50 : 14 : 36
—
—
—
Cs2CO3 Toluene 80 : 15 : 5
DBU
13
14
15
16
17
2m
2n
2o
2p
2q
MeNH2
MeNH2
MeNH2
MeNH2
MeNH2
Me
Me
Me
Me
Me
Me
OMe 4n
NMe2 4o
Cl
Br
4m
73
75
44
43
55
Toluene 0 : 20 : 80
8
9
10
11
D
D
D
D
KOtBu
KOtBu
KOtBu
KOtBu
THF
1,2-DCE 0 : 0 : 100
DMF 0 : 63 : 37
Benzene 84 : 12 : 4
0 : 42 : 58
—
—
—
72
4p
4q
a
b
Isolated yield. Addition of NuH was carried out with 1.0 equivalent of
c
N,N-dimethyl-4-aminopyridine. Addition of NuH was carried out at room
a
d
Product ratios (3a :1a :2a) were determined by 1H NMR analysis of crude temperature. Addition of NuH was carried out with Me(MeO)NHÁHCl
b
c
e
materials. Recovered 2a contained an E-isomer. Isolated yield.
and Et3N. The reaction was performed at 100 1C.
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corresponding products 4f–h in 66, 67, and 78% yields, respectively
The proposed mechanism of the NHC-catalysed reaction
(Table 2, entries 6–8). Although the same reaction of 2i bearing an using catalyst D is shown in Scheme 3. The reaction would be
isopropyl group afforded the desired product 4i in 68% yield initiated by the formation of Breslow intermediate II, which
(Table 2, entry 9), the tert-butyl derivative 2j underwent the cyclisa- would be formed from enal 2 and the in situ generated NHC I.
tion quite slowly at 80 1C, and it was necessary to increase the Since intermediate II could be regarded as a homoenolate
reaction temperature to 100 1C to obtain thioamide 4j bearing two equivalent, the intramolecular C–C bond forming reaction
contiguous quaternary carbon centres, albeit in 35% yield (Table 2, between the b-carbon of the enal and the isothiocyanate carbon
entry 10). The b-arylated enals 2k and 2l were also applicable to the would proceed to give the enol intermediate III. It was assumed
tandem reaction, and reacted smoothly and without any difficulty that the transition state for the C–C bond-forming reaction
to give the corresponding products 4k and 4l in 89 and 60% yields, would be stabilised by a hydrogen-bonding interaction between
respectively (Table 2, entries 11 and 12). Notably, the latter adduct the aldehyde-derived hydroxyl moiety and the isothiocyanato
included two indole motifs, bearing different oxidation states. The moiety of intermediate II in a similar manner to that reported
effect of the R2 substituent on the aromatic ring was also examined, by Scheidt.4d,7d Following the tautomerisation from enol III to
and substrates 2m and 2n bearing electron-donating groups acylazolium salt IV, the nucleophilic substitution of the NHC by
(Me and MeO), on their aromatic ring reacted smoothly under the sulphur atom of the thioimidate anion would provide the
the optimised conditions to give the corresponding products 4m 2H-thienoindolone 3 together with the regeneration of catalyst I.
and 4n in 73% and 75% yields, respectively (Table 2, entries 13 The formation of quinoline 1 as a major by-product would
and 14). In contrast, enals 2o–q bearing either a dimethylamino be triggered by the nucleophilic addition of either a base or the
moiety or a halogen atom proved to be poor substrates for the NHC catalyst to the isothiocyanato moiety of 2, which would be
tandem reaction because of their poor solubility or low reactivity. followed by the intramolecular condensation of the resulting
As a result, only moderate yields of the desired products 4o, 4p, nitrogen anion with an aldehyde (V - VI - VII).
and 4q were observed, which were accompanied by the recovery of
the starting materials (Table 2, entries 15–17).
In conclusion, we have developed a novel tandem NHC-catalysed
2H-thienoindolone formation and nucleophilic ring-opening
reaction involving a,b-unsaturated aldehydes bearing an isothio-
cyanato moiety. This reaction allows for the concise synthesis of
various 3,3-disubstituted indoline-2-thiones containing all-carbon
quaternary centres at the C-3 position in moderate to good yields.
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘‘Advanced Molecular Transforma-
tions by Organocatalysts’’ from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) of Japan.
Notes and references
1 For selected reviews, see: (a) D. Enders and T. Balensiefer, Acc.
Chem. Res., 2004, 37, 534; (b) K. Zeitler, Angew. Chem., Int. Ed., 2005,
44, 7506; (c) D. Enders, O. Niemeier and A. Henseler, Chem. Rev.,
´
´
2007, 107, 5606; (d) N. Marion, S. Dıez-Gonzalez and S. P. Nolan,
Angew. Chem., Int. Ed., 2007, 46, 2988; (e) V. Nair, S. Vellalath and
B. P. Babu, Chem. Soc. Rev., 2008, 37, 2691; ( f ) V. Nair, R. S. Menon,
A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose and S. Vellalath, Chem. Soc.
Rev., 2011, 40, 5336; (g) X. Bugaut and F. Glorius, Chem. Soc. Rev.,
2012, 41, 3511; (h) X.-Y. Chen and S. Ye, Org. Biomol. Chem., 2013,
11, 7991; (i) S. J. Ryan, L. Candish and D. W. Lupton, Chem. Soc. Rev.,
2013, 42, 4906.
2 (a) R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719; (b) R. Breslow and
E. McNeils, J. Am. Chem. Soc., 1960, 82, 2394.
3 For selected examples of NHC-catalysed Stetter reactions, see:
(a) H. Stetter and H. Kuhlmann, Chem. Ber., 1976, 109, 2890;
(b) E. Ciganek, Synthesis, 1995, 1311; (c) D. Enders, K. Breuer,
J. Runsink and J. H. Teles, Helv. Chim. Acta, 1996, 79, 1899;
(d) M. S. Kerr, J. R. de Alaniz and T. Rovis, J. Am. Chem. Soc., 2002,
124, 10298; (e) J. Zhang, C. Xing, B. Tiwari and Y. R. Chi, J. Am. Chem.
Soc., 2013, 135, 8113.
4 For selected examples of NHC-catalysed enolate reactions, see:
(a) M. He, J. R. Struble and J. W. Bode, J. Am. Chem. Soc., 2006,
128, 8418; (b) J. Kaeobamrung, M. C. Kozlowski and J. W. Bode, Proc.
Natl. Acad. Sci. U. S. A., 2010, 107, 20661; (c) X. Fang, X. Chen and
Y. R. Chi, Org. Lett., 2011, 13, 4708; (d) E. O. McCusker and
K. A. Scheidt, Angew. Chem., Int. Ed., 2013, 52, 13616.
5 For the first examples of NHC-catalysed internal redox reactions,
see: (a) K. Y.-K. Chow and J. W. Bode, J. Am. Chem. Soc., 2004,
126, 8126; (b) N. T. Reynolds, J. R. de Alaniz and T. Rovis, J. Am.
Chem. Soc., 2004, 126, 9518For selected reviews, see: (c) H. U. Vora,
Scheme 3 Proposed reaction mechanism.
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P. Wheeler and T. Rovis, Adv. Synth. Catal., 2012, 354, 1617; 11 (a) B. E. Maki, A. Chan and K. A. Scheidt, Synthesis, 2008, 1306;
(d) J. Mahatthananchai and J. W. Bode, Acc. Chem. Res., 2014,
47, 696.
(b) B. E. Maki, E. V. Patterson, C. J. Cramer and K. A. Scheidt, Org.
Lett., 2009, 11, 3942.
6 (a) S. S. Sohn, E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004, 12 (a) Y. Wu, W. Yao, L. Pan, Y. Zhang and C. Ma, Org. Lett., 2010, 12, 640;
126, 14370; (b) C. Burstein and F. Glorius, Angew. Chem., Int. Ed., (b) W. Yao, M. Bian, G. Wang and C. Ma, Synthesis, 2011, 1998.
2004, 43, 6205; (c) C. Burstein, S. Tschan, X. Xie and F. Glorius, 13 For selected reviews on natural products containing indole and related
Synthesis, 2006, 2418.
skeletons, see: (a) J. S. Bindra, in The Alkaloids, ed. R. H. F. Manske,
Academic Press, New York, 1973, vol. 14, pp. 84–121; (b) M. Ishikura
and K. Yamada, Nat. Prod. Rep., 2009, 26, 803; (c) A. J. Kochanowska-
Karamyan and M. T. Hamann, Chem. Rev., 2010, 110, 4489.
7 For selected studies on [3+2] annulations, see: (a) M. He and J. W. Bode,
Org. Lett., 2005, 7, 3131; (b) V. Nair, S. Vellalath, M. Poonoth, R. Mohan
and E. Suresh, Org. Lett., 2006, 8, 507; (c) A. Chan and K. A. Scheidt,
J. Am. Chem. Soc., 2008, 130, 2740; (d) K. P. Jang, G. E. Hutson, 14 For reviews, see: (a) A. B. Dounay and L. E. Overman, Chem. Rev.,
R. C. Johnston, E. O. McCusker, P. H.-Y. Cheong and K. A. Scheidt,
J. Am. Chem. Soc., 2014, 136, 76.
2003, 103, 2945; (b) H. Lin and S. J. Danishefsky, Angew. Chem., Int.
Ed., 2003, 42, 36; (c) C. Marti and E. M. Carreira, Eur. J. Org. Chem.,
2003, 2209; (d) A. Steven and L. E. Overman, Angew. Chem., Int. Ed.,
2007, 46, 5488; (e) C. V. Galliford and K. A. Scheidt, Angew. Chem.,
Int. Ed., 2007, 46, 8748; ( f ) B. M. Trost and M. K. Brennan, Synthesis,
2009, 3003; (g) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal.,
2010, 352, 1381; (h) R. Dalpozzo, G. Bartoli and G. Bencivenni, Chem.
Soc. Rev., 2012, 41, 7247; (i) N. R. Ball-Jones, J. J. Badillo and
A. K. Franz, Org. Biomol. Chem., 2012, 10, 5165.
8 For selected studies on cyclopentenation reactions, see: (a) V. Nair,
S. Vellalath, M. Poonoth and E. Suresh, J. Am. Chem. Soc., 2006,
128, 8736; (b) V. Nair, B. P. Babu, S. Vellalath and E. Suresh, Chem.
Commun., 2008, 747; (c) B. Cardinal-David, D. E. A. Raup and
K. A. Scheidt, J. Am. Chem. Soc., 2010, 132, 5345; (d) W. W. Y. Leong,
X. Chen and Y. R. Chi, Green Chem., 2013, 15, 1505.
9 For examples of NHC-catalysed intramolecular b-nucleophilic addi-
tion of enals, see: (a) J. R. Struble and J. W. Bode, Tetrahedron, 2009, 15 For examples of NHC-catalysed reactions of ketene and nitroalkene with
65, 4957; (b) C. R. Sinu, D. V. M. Padmaja, U. P. Ranjini,
K. C. S. Lakshmi, E. Suresh and V. Nair, Org. Lett., 2013, 15, 68.
isothiocyanate, see: (a) C. Awasthi and L. D. S. Yadav, Synlett, 2010, 1783;
(b) X.-N. Wang, L.-T. Shen and S. Ye, Org. Lett., 2011, 13, 6382.
10 For selected studies on addition to nitroolefins, see: (a) V. Nair, 16 (a) R. Hull, J. Chem. Soc. C, 1968, 1777; (b) R. Hull, P. J. van den
C. R. Sinu, B. P. Babu, V. Varghese, A. Jose and E. Suresh, Org. Lett., Broek and M. L. Swain, J. Chem. Soc., Perkin Trans. 1, 1975, 922.
2009, 11, 5570; (b) B. Maji, L. Ji, S. Wang, S. Vedachalam, R. Ganguly 17 The stereochemistry of starting material 2a was confirmed as
and X.-W. Liu, Angew. Chem., Int. Ed., 2012, 51, 8276; (c) N. A. White,
D. A. DiRocco and T. Rovis, J. Am. Chem. Soc., 2013, 135, 8504.
(Z)-configuration by using 2D NMR experiments including NOESY.
18 CCDC 992277.
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