A novel self-terminated Prins strategy for the synthesis of tetrahydropyran-4-one derivatives and their behaviour in Fisher indole synthesis

Abstract

A novel self-terminated Prins strategy has been developed for the synthesis of 2-substituted tetrahydropyran-4-one derivatives through a condensation of 3-(phenylthio)but-3-en-1-ol with carbonyl compounds in the presence of 5 mol% of Sc(OTf)₃ under mild conditions. A few products were subsequently transformed into the corresponding indoles by Fisher-indole synthesis.

---

Introduction

Tetrahydropyrans of varied substitution pattern are embodied as an integral part of numerous biologically active natural products (Fig. 1).¹

Fig. 1 Examples of tetrahydropyranol containing natural products.

Generally, the tetrahydropyrans are prepared from aldol-type cyclizations,² hetero-Diels–Alder reactions,³ Japp–Maitland reactions,⁴ oxa-Michael reactions,⁵ and Petasis–Ferrier rearrangements.⁶ By employing these strategies, a wide range of tetrahydropyran-4-one substructures have been synthesized. The direct approach for the synthesis of tetrahydropyran-4-ones involves the cyclization of enol ethers and enol acetates with in situ generated oxocarbenium ions.^7–9 In addition, Prins cyclization has successfully been employed for the synthesis of tetrahydropyranols, which could subsequently be oxidized into the corresponding tetrahydropyranones.¹⁰ However, there have been no reports on the direct synthesis of tetrahydropyranones by the condensation of thiol functionalized homoallylic alcohol with aldehydes.

Results and discussions

Following our interest on Prins type cyclizations,¹¹ we herein report an efficient strategy for the direct synthesis of 2-substituted tetrahydropyran-4-ones by a self termination of Prins cyclization. The requisite precursor, 3-(phenylthio)but-3-en-1-ol (1) was prepared by treating homopropargyl alcohol with thiophenol in the presence of Pd(OAc)₂ in THF (Scheme 1).¹²

Scheme 1 Preparation of starting materials.

In a preliminary experiment, 3-(phenylthio)but-3-en-1-ol (1) was treated with benzaldehyde (2) in the presence of 5 mol% Sc(OTf)₃ in dichloromethane. Interestingly, the reaction proceeded well at room temperature and the corresponding 2-phenyl tetrahydropyran-4-one 3a was obtained in 87% yield (Scheme 2).

Scheme 2 Synthesis of 2-phenyltetrahydropyran-4-one.

The efficiency of other Lewis acids such as InCl₃, InBr₃, Yb(OTf)₃, TMSOTf and BF₃·OEt₂ was investigated and the results are presented in Table 1.

Table 1 Optimization of the reaction conditions

Entry	Catalyst^a	mol%	Solvent	Time (h)	Yield^b (%)
a Reactions were performed in 1 mmol scale.b Yield refers to pure product after chromatography.
a	Sc(OTf)3	5	DCM	6	87
b	Sc(OTf)3	5	THF	7	30
c	Sc(OTf)3	5	CH3CN	7	20
d	InCl3	10	DCM	8	25
e	InBr3	5	DCM	6	40
f	Yb(OTf)3	10	DCM	6	30
g	TMSOTf	5	DCM	7	35
h	BF3·OEt2	5	DCM	8	25

---

Among them, 5 mol% Sc(OTf)₃ was found to be the most effective in terms of conversion.

To our surprise, the most frequently used Lewis acids such as TMSOTf and BF₃·OEt₂ were also found to be less effective for this conversion. To know the effect of solvent, the reaction was performed in different solvents such as THF, acetonitrile and DCM. Of these, dichloromethane gave the best results.

These initial findings encouraged us to extend this process to other carbonyl compounds and the results are presented in Table 2. Interestingly, several aromatic aldehydes underwent a smooth Prins cyclization to furnish the respective substituted 2-tetrahydropyran-4-ones in good yields (entries a–g, i–k, o and p Table 2). Notably, the reaction was successful even with acid sensitive substrates like cinnamaldehyde and furfural (entries h & p, Table 2). In addition, the reaction also proceeded well with 4-hydroxybenzaldehyde without the protection of hydroxyl group (entry o, Table 2). The scope of this method was further illustrated with respect to aliphatic aldehydes such as n-valeraldehyde, isovaleraldehyde and n-hexanal (entries l–n, Table 2). In case of aliphatic aldehydes, the corresponding products were obtained relatively in lower yields than aromatic counter parts. In all the cases, the products were obtained in good to excellent yields. Finally, we examined the reactivity of ketones for example, cyclohexanone. To our delight, the corresponding spirotetrahydropyran-4-one was obtained in good yield (entry q, Table 2). However, other ketones such as 3-pentanone and acetophenone failed to give the desired product under the present reaction conditions.

Table 2 Synthesis of 2-substituted tetrahydropyran-2-one derivatives

Entry	Aldehyde	Product^a (3)	Time (h)	Yield^b (%)
a All products were characterized by NMR, IR and mass spectrometry.b Yield refers to pure products after chromatography.
a			7	87
b			6	85
c			6	80
d			7	78
e			7	80
f			7	86
g			8	82
h			7	72
i			8	70
j			8	67
k			8	76
l			7	72
m			7	75
n			7	65
o			8	58
p			6	75
q			7	70

---

Based on our previous observations,¹¹ we proposed a plausible reaction mechanism in Scheme 3. In the beginning, the aldehyde reacts with 3-(phenylthio)but-3-en-1-ol likely after activation with Sc(OTf)₃ to generate the oxocarbenium ion (A). A subsequent attack of the internal alkene followed by a neighbouring group participation of sulfide would generate the thia-carbenium ion (B). Up on hydrolysis of B would give the desired 2-substituted tetrahydropyran-4-one (3) along with thiophenol as a by-product.

Scheme 3 A plausible reaction pathway.

Next we were interested to demonstrate the use of tetrahydropyranones for indole synthesis. Indole derivatives are abundantly found in biologically active compounds and pharmaceuticals.¹³ For example, the core structure of type I is found in anti-inflammatory drug, etodolac.¹⁴ Indole type II was found to inhibit the NS5A polymerase.¹⁵ Furthermore, oxazinoindole type III exhibits potent antidepressant and antitumor properties (Fig. 2).¹⁶

Fig. 2 Biologically active indole derivatives.

Consequently, a few tetrahydropyran-4-ones were successfully converted into indole derivatives by means of Fischer indole synthesis (Table 3). Accordingly, treatment of 3 with phenylhydrazine (6) in the presence of acetic acid under reflux conditions afforded the indole derivative (7) as a major and dihydropyrazol (8) as a minor product (Table 3).

Table 3 Fischer indole synthesis

Entry	Substrate (3)	Major^a (7)	Minor^a (8)	Time (h)	Yield^b (%) 7 : 8
a All products were characterized by ^1H NMR, IR, and mass spectrometry.b Yield refers to pure products after chromatography.
a	3a			6	50 : 30
b	3c			5	45 : 35

---

The structure of 8c was confirmed by X-ray crystallography (Fig. 3).¹⁷

Fig. 3 ORTEP diagram of 8c.

Furthermore, compounds 3n and 3q were subjected to Fisher-indole reaction conditions, but the expected products were not obtained under the present reaction conditions. After the formation of hydrozone, the decomposition of the reaction mixture was observed.

Conclusion

In summary, we have developed a novel strategy for the direct synthesis of 2-substituted tetrahydropyran-4-one derivatives using a catalytic amount of Sc(OTf)₃ through a self termination of Prins cyclization. The synthetic utility of these tetrahydropyran-4-ones is exemplified by means of Fischer indole synthesis. This method is operationally simple and works with a diverse range of carbonyl compounds with broad substitution patterns.

Experimental

Typical procedure

To a mixture of 3-(phenylthio)but-3-en-1-ol (0.5 mmol) and aldehyde/ketone (0.6 mmol) in anhydrous DCM (5 mL) was added Sc(OTf)₃ (5 mol%) at 0 °C. The resulting mixture was allowed to stir at room temperature for the specified time. After completion, the reaction mixture was quenched with water and the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 × 5 mL). The combined organic phases were washed with brine, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The resulting crude mixture was purified by silica gel column chromatography (100–200 mesh) using ethyl acetate/hexane gradient mixture to afford the pure product 3.

Acknowledgements

S. Rehana Anjum thanks CSIR-SRF, New Delhi, India for the award of a senior research fellowship.

Notes and references

1. (a) A. B. Smith, R. J. Fox and T. M. Razler, Acc. Chem. Res., 2008, 41, 675; (b) P. A. Wender, B. A. Loy and A. J. Schrier, Isr. J. Chem., 2011, 51, 453; (c) K. S. Yeung and I. Paterson, Chem. Rev., 2005, 105, 4237; (d) K. Watanabe, J. Li, N. Veeraswamy, A. Ghosh and R. G. Carter, Org. Lett., 2016, 18, 1744.
2. S. Das, L. S. Li and S. C. Sinha, Org. Lett., 2004, 6, 123.
3. (a) M. Johannsen and K. A. Jorgensen, J. Org. Chem., 1995, 60, 5757; (b) S. E. Schaus, J. Branalt and E. N. Jacobsen, J. Org. Chem., 1998, 63, 403; (c) A. G. Dossetter, T. F. Jamison and E. N. Jacobsen, Angew. Chem., Int. Ed., 1999, 38, 2398; (d) C. F. Thompson, T. F. Jamison and E. N. Jacobsen, J. Am. Chem. Soc., 2001, 123, 9974; (e) M. Anada, T. Washio, N. Shimada, S. Kitagaki, M. Nakajima, M. Shiro and S. Hashimoto, Angew. Chem., Int. Ed., 2004, 43, 2664.
4. (a) F. R. Japp and W. Maitland, J. Chem. Soc., 1904, 85, 1473; (b) P. A. Clarke and W. H. C. Martin, Org. Lett., 2002, 4, 4527; (c) P. A. Clarke and W. H. C. Martin, Tetrahedron, 2005, 61, 5433.
5. (a) C. F. Nising and S. Brase, Chem. Soc. Rev., 2008, 37, 1218; (b) H. Kim and J. Hong, Org. Lett., 2010, 12, 2880; (c) S. Chandrasekhar, B. Roy, S. Pradhan and T. K. Ghosh, J. Org. Chem., 2012, 77, 9840; (d) H. Yao, J. Ren and R. Tong, Chem. Commun., 2013, 49, 193.
6. (a) N. A. Petasis and S. P. Lu, Tetrahedron Lett., 1996, 37, 141; (b) A. B. Smith, P. R. Verhoest, K. P. Minbiole and J. J. Lim, Org. Lett., 1999, 1, 909; (c) A. B. Smith, K. P. Minbiole, P. R. Verkoest and T. J. Beauchamp, Org. Lett., 1999, 1, 913.
7. (a) J. E. Dalgard and S. D. Rychnovsky, J. Am. Chem. Soc., 2004, 126, 15662; (b) J. E. Dalgard and S. D. Rychnovsky, Org. Lett., 2005, 7, 1589.
8. (a) G. S. Cockerill, P. Kocienski and R. J. Treadgold, J. Chem. Soc., Perkin Trans. 1, 1985, 2093; (b) W. J. Morris, D. W. Custar and K. A. Scheidt, Org. Lett., 2005, 7, 1113; (c) W. Tu and P. E. Floreancig, Angew. Chem., Int. Ed., 2009, 48, 4567; (d) C. Sun, Y. Zhang, P. Xiao, H. Li, X. Sun and Z. Song, Org. Lett., 2014, 16, 984.
9. (a) L. Liu and P. E. Floreancig, Org. Lett., 2010, 12, 4686; (b) H. H. Jung and P. E. Floreancig, Tetrahedron, 2009, 65, 10830; (c) G. R. Peh and P. E. Floreancig, Org. Lett., 2015, 17, 3750.
10. (a) C. Olier, M. Kaafarani, S. S. Gastaldi and M. P. Bertrand, Tetrahedron, 2010, 66, 413; (b) M. Pastor and I. M. Yus, Curr. Org. Chem., 2012, 16, 1277; (c) X. Han, G. R. Peh and P. E. Floreancig, Eur. J. Org. Chem., 2013, 1193; (d) K. Zheng, X. Liu, S. Qin, M. Xie, L. Lin, C. Hu and X. Feng, J. Am. Chem. Soc., 2012, 134, 17564.
11. (a) B. V. S. Reddy, S. Gopal Reddy, M. Durgaprasad, M. P. Bhadra and B. Sridhar, Org. Biomol. Chem., 2015, 13, 8729; (b) B. V. S. Reddy, V. Swathi, S. Manisha, M. PalBhadra, B. Sridhar, D. Satyanarayana and B. Jagadeesh, Org. Lett., 2014, 16, 6267; (c) B. V. S. Reddy, M. Durgaprasad and B. Sridhar, J. Org. Chem., 2015, 80, 653.
12. (a) H. Kuniyasu, A. Ogawa, K. Sato, I. Ryu, N. Kambe and N. Sonoda, J. Am. Chem. Soc., 1992, 114, 5902; (b) V. P. Aninkov, S. S. Zalesskiy, N. P. Orlov and I. P. Beletskaya, Russ. Chem. Bull., 2006, 55, 2109; (c) Y. Ichinose, K. Wakamatsu, K. Nozaki, J. L. Birbaum, K. Oshima and K. Utimoto, Chem. Lett., 1987, 1647.
13. (a) M. Lounasmaa and A. Tolvanen, Nat. Prod. Rep., 2000, 17, 175; (b) M. Somei and F. Yamada, Nat. Prod. Rep., 2005, 22, 73; (c) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105, 2873; (d) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106, 2875.
14. (a) S. Akai, H. Nemoto and M. Egi, Heterocycles, 2008, 76, 1537; (b) S. Vyas, P. Trivedi and S. C. Chaturvedi, Acta Pol. Pharm., 2009, 66, 201.
15. C. A. Coburn, B. J. Lavey, M. P. Dwyer, J. A. Kozlowski and S. B. Rosenblum, WO2012050848A1, 2012.
16. C. A. Demerson, G. Santroch, L. G. Humber and M. P. Charest, J. Med. Chem., 1975, 18, 577.
17. CCDC 1440304 contains supplementary crystallographic data for the structure 8c.

---

Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H and ¹³C NMR spectra of products. CCDC 1440304. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra11218h

---