Efficient Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives by a One-Pot Asinger-Type Reaction

Abstract

A one-pot, three-component reaction has been developed and successfully employed for the synthesis of biologically relevant, highly functionalized spirooxindole-fused 3-thiazoline derivatives. Starting from ammonia, three mercapto carbonyl components and a series of substituted isatins, products were obtained in good yields (24 examples), by following a simple and rapid protocol. The obtained thiazolines proved to be optimal substrates for further transformations, including the three-component Ugi–Joullié reaction.

Thiazoline heterocycles are privileged motifs that are found in an array of biologically active natural products. For instance, they represent a relevant structural fragment of various cyclopeptide alkaloids extracted from different marine organisms, and they are endowed with a promising cytotoxic activity.[1] Compounds bearing thiazoline moieties have also been reported to exhibit a wide spectrum of biological effects, including antitubercular,[2] anti-inflammatory[3] [4] and antimicrobial[5] activity, boosting numerous synthetic and medicinal chemistry investigations.[6,7] Recently, many research groups have focused on the anticancer properties of thiazoline-based compounds, which range from cytotoxicity against various cell lines[8] to histone deacetylase inhibitory activity[9] and MDM2-p53 protein–protein interaction modulation.[10]

As part of our interest in the synthesis of spirooxindoles,[11] we looked into the biological significance of the thiazoline ring, aiming to introduce it as a spiro-fused heterocycle in our oxindole-based drug discovery programs.[12] The conjugation of privileged heterocycles into spiro structures is of special interest because it can provide compounds with great three-dimensionality, often with improved properties with respect to their interaction with biological systems, and such compounds may be more likely to be successfully developed as drugs.[13] Spirocyclic oxindoles have recently emerged as attractive targets because they have been demonstrated to have promising anticancer potential.[14] Among the class, there are natural products such as spirotryprostatins A and B[15] and synthetic spirooxindoles such as MI-888, which is currently in preclinical research for the treatment of human cancers.[16] A common characteristic of such bioactive compounds is the presence of various heterocyclic motifs, joined at C-3 of an oxindole core. This key structural element is the focus of huge interest for the development of rapid and efficient synthetic methods providing access to such spiro building blocks.

Table 1 Optimization of the One-Pot Reaction Conditions^a

Entry	Solvent	Concn [M]	Dehydr. agent	Ammonia source	Yield (%)b
1	MeOH	0.5	none	aq NH3	trace
2	toluene	0.5	3Å MS	NH3 (2 M in MeOH)	60
3	toluene	0.5	MgSO4	NH3 (2 M in MeOH)	66
4	toluene	0.3	MgSO4	NH3 (2 M in MeOH)	61
5	toluene	1.0	MgSO4	NH3 (2 M in MeOH)	88
6	CH2Cl2	1.0	MgSO4	NH3 (2 M in MeOH)	84

^a Reaction conditions: N-benzyl-isatin (1a; 0.25 mmol), NH₃ (0.5 mmol); then 1-mercaptopropan-2-one (2a; 0.3 mmol).

^b Isolated yield.

In the context of sulfur-containing compound synthesis, a number of methods have been developed for the preparation of spirooxindole-based 4-thiazolidinones, by reacting amines with isatins and mercaptoacetic acid under different conditions.[17] To our knowledge, no efforts have yet been made to synthesize spirooxindole-fused 3-thiazolines, which would represent more versatile intermediates because of the presence of the reactive C–N double bond.

Relying on our previous experience in multicomponent reactions (MCRs) applied to the synthesis of heterocyclic compounds,[18] we turned our attention to the Asinger sulfur-based MCR.[19] This method, which allows the synthesis of the thiazoline scaffold by treating a ketone with sulfur and ammonia, exhibits high atom efficiency. However, considerably more flexibility with respect to the original protocol is seen in the ‘resynthesis’, also discovered by Asinger; the reaction of preformed α-sulfanyl-ketones or aldehydes with ammonia and an oxo component, which greatly widens the scope of suitable substituents on the thiazoline ring.[20]

Table 2 Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives^a

Entry	Isatin 1	R1	R2	2	R3	3	Yield (%)b
1	1a	Bn	H	2a	Me	3a	88
2	1b	Me	H	2a	Me	3b	90
3	1c	Tr	H	2a	Me	3c	87
4	1d	H	H	2a	Me	3d	89
5	1e	allyl	H	2a	Me	3e	70
6	1f	p-MeOC6H4CH2	H	2a	Me	3f	62
7	1g	p-BrC6H4CH2	H	2a	Me	3g	69
8	1h	Bn	5-OMe	2a	Me	3h	70
9	1i	Bn	5-Br	2a	Me	3i	75
10	1j	Bn	5-F	2a	Me	3j	78
11	1k	Bn	5-Cl	2a	Me	3k	80
12	1l	Bn	5-NO2	2a	Me	3l	64
13	1m	Bn	6-Br	2a	Me	3m	65
14	1a	Bn	H	2b	H	3n	71
15	1b	Me	H	2b	H	3o	81
16	1c	Tr	H	2b	H	3p	62
17	1d	H	H	2b	H	3q	68
18	1n	Me	5-OMe	2b	H	3r	68
19	1o	Me	5-Br	2b	H	3s	66
20	1p	Me	5-F	2b	H	3t	71
21	1q	Me	5-Cl	2b	H	3u	70
22	1r	Me	6-Br	2b	H	3v	66
23	1a	Bn	H	2c	CO2Et	3w	65
24	1b	Me	H	2c	CO2Et	3x	61

^a Reaction conditions: isatin 1 (1 mmol), NH₃ (2 mmol); then compound 2 (1.1 mmol).

^b Isolated yield.

Herein, we report the first application of an Asinger-type reaction with isatin as the oxo component, allowing the synthesis of a large family of unprecedented 5′H-spiro[indoline-3,2′-thiazol]-2-one derivatives.

Initially, N-benzyl-isatin (1a) and 1-mercaptopropan-2-one (2a) were selected to optimize the reaction conditions (Table [1]). Since the reaction conducted by simultaneous addition of all components proved to be sluggish, probably due to the high instability of the isatin-derived NH-imine,[21] we introduced a period of 8 hours before adding the mercapto component, to maximize imine formation. Using aqueous ammonia solution in MeOH as solvent, after addition of 2a, the desired thiazoline 3a could be detected only in trace amounts (entry 1). Better results were obtained by employing 2 M ammonia solution in methanol and changing the solvent to toluene. The addition of a dehydrating agent proved to be beneficial, with MgSO₄ working better than molecular sieves (entries 2 and 3). Finally, lowering the substrate concentration lengthened the reaction time and reduced the conversion, whereas increasing the concentration gave a clean reaction, with a high isolated yield of 3a (entries 4 and 5). Finally, CH₂Cl₂ also proved to be a good solvent for the reaction, although thiazoline 3a was isolated in slightly lower yield (entry 6). Therefore, the optimized conditions for this one-pot reaction involved adding 2 M ammonia solution in methanol (0.5 mmol) to a toluene solution of 1a (0.25 mmol), allowing the reaction to proceed for 8 hours and then completing the reaction by addition of 2a (0.3 mmol). The whole process was carried out at room temperature and the imine conversion was complete after just 30 minutes from the addition of the mercapto component. A scale-up experiment, employing 1 mmol of isatin 1a, afforded the desired thiazoline 3a in the same time and yield as that obtained on a small scale.

With the optimized reaction conditions in hand, a variety substituted isatins 1a–r was next explored to investigate the substrate scope of this Asinger-type reaction. The generality was also evaluated with respect to the mercapto component 2a–c (Table [2]).

Working with 1-mercaptopropan-2-one (2a), the protecting group on the oxindole nitrogen atom was found to have a moderate effect on the reaction, with all compounds 3a–g obtained in satisfactory yields starting from isatins 1a–g (Table [2], entries 1–7). Notably, unprotected isatin 1d also afforded the corresponding thiazoline derivative 3d in very high yield, as a stable compound (entry 4).

Next, N-benzylisatins 1h–m, with various substituents on the aromatic ring, were explored. Good yields of the corresponding thiazolines were obtained in the presence of a variety of substituents, including an electron-donating group (entry 8), halogen substituents (entries 9–11 and 13) and a strongly electron-withdrawing group (entry 12) at either the 5- or 6-position on the oxindole aromatic ring. Finally, we investigated the Asinger-type reaction with two different mercaptocarbonyl compounds, namely 2-mercaptoacetaldehyde (2b; entries 14–22) and ethyl 3-mercapto-2-oxopropanoate (2c; entries 23 and 24). We were gratified to see that, with these components, the desired thiazolines could also be readily obtained, with yields up to 81% for the most reactive N-Me isatin 1b in reaction with 2b (entry 15).

Having established the scope of the method, we examined further transformations of the products obtained. The reaction of thiazoline 3a with m-chloroperbenzoic acid under the standard conditions gave sulfoxide 4 in quantitative yield, as a single diastereoisomer (as demonstrated by ¹H and ¹³C NMR spectroscopic analysis) whose relative stereochemistry was not further investigated. The latter compound could be then further oxidized to sulfone 5. When the reduction of 3a was performed under standard conditions, the expected thiazolidine 6 could be easily obtained as an inseparable 7:3 diastereoisomeric mixture. Notably, thiazoline 3n proved to be an optimal substrate for a subsequent multicomponent reaction (MCR), namely the Ugi–Joullié 3-CR, involving an isocyanide and a carboxylic acid as components, together with the cyclic imine. By reacting 3n with tert-butyl isocyanide and acetic acid, compound 7 was readily formed in high yield as a 4:1 mixture of 7a and 7b diastereoisomers, which could be readily separated by means of flash chromatography (Scheme [1]).

Diastereoisomers 7a and 7b were fully characterized by 1D and 2D NMR spectroscopic analyses. In particular, ­NOESY experiments allowed the 2′-4′-trans configuration for the major diastereoisomer 7a and the 2′-4′-cis configuration for the minor 7b to be determined. Diagnostic NOE interactions between H-4 of the oxindole nucleus and thiazolidine protons (assigned on the basis of the observed multiplicities and dihedral angle considerations) could be identified for both diastereoisomers. These interactions are indicated in Figure [1], together with the most relevant chemical shift values.

In conclusion, we have successfully developed the application of an Asinger-type reaction to isatin as the oxo component, allowing the synthesis of a large family of spiro­oxindole-fused 3-thiazoline derivatives.[22] The reaction conditions have been optimized and applied to a wide variety of substituted isatins. Exploitation of the attractive practical aspects of this method with regard to exploring the further reactivity of the derivatives for biological evaluation programs is underway.

• References and Notes

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• 18a Stucchi M, Cairati S, Cetin-Atalay R, Christodoulou MS, Grazioso G, Pescitelli G, Silvani A, Yildirime DC, Lesma G. Org. Biomol. Chem. 2015; 13: 4993
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• 18e Lesma G, Cecchi R, Crippa S, Giovanelli P, Meneghetti F, Musolino M, Sacchetti A, Silvani A. Org. Biomol. Chem. 2012; 10: 9004
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• 19a Liu Z.-Q. Curr. Org. Synth. 2015; 12: 20
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• 19b Brockmeyer F, van Gerven D, Saak W, Martens J. Synthesis 2014; 46: 1603
  Thieme ConnectSearch in Google Scholar
• 20 Keim W, Offermanns H. Angew. Chem. Int. Ed. 2007; 46: 6010
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• 21 Žari S, Kudrjashova M, Pehk T, Lopp M, Kanger T. Org. Lett. 2014; 16: 1740
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• 22 Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives 3a–x; General Procedure A (GP-A): To a solution of isatin 1a–r (1 mmol) in anhydrous toluene (1 mL, 1.0 M), MgSO₄ (3 mmol) and NH₃ (2 M in methanol, 2 mmol) were added. The solution was stirred for 8 h at r.t., then mercapto-derivative 2a–c was added (1.1 mmol). The resulting mixture was stirred for 30 min at the same temperature then diluted with CH₂Cl₂ (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (FC). Representative Analytical Data for 1-Benzyl-4′-methyl-5′H-spiro[indoline-3,2′-thiazol]-2-one (3a): Prepared according to GP-A using isatin 1a and mercaptoacetone 2a and purified by column chromatography (CH₂Cl₂–EtOAc, 19:1). Yield: 271 mg (88%); pale-orange foam. ¹H NMR (300 MHz, CDCl₃): δ = 7.36–7.24 (m, 6 H), 7.19 (br t, J = 7.7 Hz, 1 H), 7.04 (br t, J = 7.7 Hz, 1 H), 6.69 (br d, J = 7.8 Hz, 1 H), 4.94 (d, J = 15.7 Hz, 1 H), 4.84 (d, J = 15.7 Hz, 1 H), 4.43 (d, J = 15.8 Hz, 1 H), 4.27 (d, J = 15.8 Hz, 1 H), 2.32 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 175.3, 174.9, 142.4, 135.4, 130.2, 129.6, 128.9 (2C), 127.7, 127.3 (2C), 125.5, 123.5, 109.5, 88.2, 48.7, 44.2, 19.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₆N₂NaOS⁺: 331.0876; found: 331.0884.

• References and Notes

• 1a Luesch H, Yoshida WY, Moore RE, Paul VJ. Bioorg. Med. Chem. 2002; 10: 1973
  CrossrefPubMedSearch in Google Scholar
• 1b Luesch H, Yoshida WY, Moore RE, Paul VJ, Corbett TH. J. Am. Chem. Soc. 2001; 123: 5418
  CrossrefPubMedSearch in Google Scholar
• 2 Reddy DS, Hosamani KM, Devarajegowdab HC, Kurjogic MM. RSC Adv. 2015; 5: 64566
  CrossrefSearch in Google Scholar
• 3 Lynch DE, Hayer R, Beddows S, Howdle J, Thake CD. J. Heterocycl. Chem. 2006; 43: 191
  CrossrefSearch in Google Scholar
• 4 Pontiki E, Hadjipavlou-Litina D, Chaviara AT, Bolos CA. Bioorg. Med. Chem. Lett. 2006; 16: 2234
  CrossrefSearch in Google Scholar
• 5 Bonde CG, Gaikwad NJ. Bioorg. Med. Chem. 2004; 12: 2151
  CrossrefPubMedSearch in Google Scholar
• 6 Gaumont A.-C, Gulea M, Levillain J. Chem. Rev. 2009; 109: 1371
  CrossrefPubMedSearch in Google Scholar
• 7a Ino A, Murabayashi A. Tetrahedron 1999; 55: 10271
  CrossrefSearch in Google Scholar
• 7b Ino A, Hasegawa Y, Murabayashi A. Tetrahedron 1999; 55: 10283
  CrossrefSearch in Google Scholar
• 8 Altıntop MD, Kaplancıklı ZA, Çiftçi GA, Demirel R. Eur. J. Med. Chem. 2014; 74: 264
  CrossrefPubMedSearch in Google Scholar
• 9 Marson CM, Matthews CJ, Yiannaki E, Atkinson SJ, Soden PE, Shukla L, Lamadema N, Thomas NS. B. J. Med. Chem. 2013; 56: 6156
  CrossrefPubMedSearch in Google Scholar
• 10 Bertamino A, Soprano M, Musella S, Rusciano MR, Sala M, Vernieri E, Di Sarno V, Limatola A, Carotenuto A, Cosconati S, Grieco P, Novellino E, Illario M, Campiglia P, Gomez-Monterrey I. J. Med. Chem. 2013; 56: 5407
  CrossrefPubMedSearch in Google Scholar
• 11a Stucchi M, Lesma G, Meneghetti F, Rainoldi G, Sacchetti A, Silvani A. J. Org. Chem. 2016; 81: 1877
  CrossrefPubMedSearch in Google Scholar
• 11b Lesma G, Landoni N, Sacchetti A, Silvani A. Tetrahedron 2010; 66: 4474
  CrossrefSearch in Google Scholar
• 12a Lesma G, Meneghetti F, Sacchetti A, Stucchi M, Silvani A. Beilstein J. Org. Chem. 2014; 10: 1383
  CrossrefPubMedSearch in Google Scholar
• 12b Sacchetti A, Silvani A, Gatti FG, Lesma G, Pilati T, Trucchi B. Org. Biomol. Chem. 2011; 9: 5515
  CrossrefPubMedSearch in Google Scholar
• 12c Lesma G, Landoni N, Pilati T, Sacchetti A, Silvani A. J. Org. Chem. 2009; 74: 4537
  CrossrefPubMedSearch in Google Scholar
• 13a Yang C, Li J, Zhou R, Chen X, Gao Y, He Z. Org. Biomol. Chem. 2015; 13: 4869
  CrossrefPubMedSearch in Google Scholar
• 13b Zheng Y, Tice CM, Singh SB. Bioorg. Med. Chem. Lett. 2014; 24: 3673
  CrossrefSearch in Google Scholar
• 13c Tian Y, Nam S, Liu L, Yakushijin F, Yakushijin K, Buettner R, Liang W, Yang F, Ma Y, Horne D, Jove R. PLoS One 2012; e49306
• 14a Yu B, Yu D.-Q, Liu H.-M. Eur. J. Med. Chem. 2015; 97: 673
  CrossrefPubMedSearch in Google Scholar
• 14b Santos MM. M. Tetrahedron 2014; 70: 9735
  CrossrefSearch in Google Scholar
• 14c Singh GS, Desta ZY. Chem. Rev. 2012; 112: 6104
  CrossrefPubMedSearch in Google Scholar
• 15 Cui C.-B, Kakeya H, Osada H. Tetrahedron 1996; 52: 12651
  CrossrefSearch in Google Scholar
• 16 Zhao Y, Yu S, Sun W, Liu L, Lu J, McEachern D, Shargary S, Bernard D, Li X, Zhao T, Zou P, Sun D, Wang S. J. Med. Chem. 2013; 56: 5553
  CrossrefPubMedSearch in Google Scholar
• 17a Preetam A, Nath M. Tetrahedron Lett. 2016; 57: 1502
  CrossrefSearch in Google Scholar
• 17b Cheng P, Guo W, Chen P, Liu Y, Du X, Li C. Chem. Commun. 2016; 52: 3418
  Search in Google Scholar
• 17c Jain R, Sharma K, Kumar D. Helv. Chim. Acta 2013; 96: 414
  CrossrefSearch in Google Scholar
• 18a Stucchi M, Cairati S, Cetin-Atalay R, Christodoulou MS, Grazioso G, Pescitelli G, Silvani A, Yildirime DC, Lesma G. Org. Biomol. Chem. 2015; 13: 4993
  CrossrefPubMedSearch in Google Scholar
• 18b Stucchi M, Gmeiner P, Huebner H, Rainoldi G, Sacchetti A, Silvani A, Lesma G. ACS Med. Chem. Lett. 2015; 6: 882
  CrossrefPubMedSearch in Google Scholar
• 18c Lesma G, Bassanini I, Bortolozzi R, Colletto C, Bai R, Hamel E, Meneghetti F, Rainoldi G, Stucchi M, Sacchetti A, Silvani A, Viola G. Org. Biomol. Chem. 2015; 13: 11633
  CrossrefPubMedSearch in Google Scholar
• 18d Silvani A, Lesma G, Crippa S, Vece V. Tetrahedron 2014; 70: 3994
  CrossrefSearch in Google Scholar
• 18e Lesma G, Cecchi R, Crippa S, Giovanelli P, Meneghetti F, Musolino M, Sacchetti A, Silvani A. Org. Biomol. Chem. 2012; 10: 9004
  CrossrefPubMedSearch in Google Scholar
• 19a Liu Z.-Q. Curr. Org. Synth. 2015; 12: 20
  CrossrefSearch in Google Scholar
• 19b Brockmeyer F, van Gerven D, Saak W, Martens J. Synthesis 2014; 46: 1603
  Thieme ConnectSearch in Google Scholar
• 20 Keim W, Offermanns H. Angew. Chem. Int. Ed. 2007; 46: 6010
  CrossrefPubMedSearch in Google Scholar
• 21 Žari S, Kudrjashova M, Pehk T, Lopp M, Kanger T. Org. Lett. 2014; 16: 1740
  CrossrefPubMedSearch in Google Scholar
• 22 Synthesis of Spirooxindole-Fused 3-Thiazoline Derivatives 3a–x; General Procedure A (GP-A): To a solution of isatin 1a–r (1 mmol) in anhydrous toluene (1 mL, 1.0 M), MgSO₄ (3 mmol) and NH₃ (2 M in methanol, 2 mmol) were added. The solution was stirred for 8 h at r.t., then mercapto-derivative 2a–c was added (1.1 mmol). The resulting mixture was stirred for 30 min at the same temperature then diluted with CH₂Cl₂ (5 mL) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (FC). Representative Analytical Data for 1-Benzyl-4′-methyl-5′H-spiro[indoline-3,2′-thiazol]-2-one (3a): Prepared according to GP-A using isatin 1a and mercaptoacetone 2a and purified by column chromatography (CH₂Cl₂–EtOAc, 19:1). Yield: 271 mg (88%); pale-orange foam. ¹H NMR (300 MHz, CDCl₃): δ = 7.36–7.24 (m, 6 H), 7.19 (br t, J = 7.7 Hz, 1 H), 7.04 (br t, J = 7.7 Hz, 1 H), 6.69 (br d, J = 7.8 Hz, 1 H), 4.94 (d, J = 15.7 Hz, 1 H), 4.84 (d, J = 15.7 Hz, 1 H), 4.43 (d, J = 15.8 Hz, 1 H), 4.27 (d, J = 15.8 Hz, 1 H), 2.32 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 175.3, 174.9, 142.4, 135.4, 130.2, 129.6, 128.9 (2C), 127.7, 127.3 (2C), 125.5, 123.5, 109.5, 88.2, 48.7, 44.2, 19.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₈H₁₆N₂NaOS⁺: 331.0876; found: 331.0884.

• Supplementary Material