Direct radical sulfonylation at α-C(sp3)-H of THF with sodium sulfinates in aqueous medium

Accepted Manuscript Direct radical sulfonylation at α-C(sp3)-H of THF with sodium sulfinates in aqueous medium Manjula Singh, Lal Dhar S. Yadav, Rana Krishna Pal Singh PII: DOI: Reference:

S0040-4039(19)30142-X https://doi.org/10.1016/j.tetlet.2019.02.021 TETL 50615

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Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

9 January 2019 8 February 2019 9 February 2019

Please cite this article as: Singh, M., Yadav, L.D.S., Singh, R.K.P., Direct radical sulfonylation at α-C(sp3)-H of THF with sodium sulfinates in aqueous medium, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet. 2019.02.021

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Direct radical sulfonylation at α-C(sp3)-H of THF with sodium sulfinates in aqueous medium Manjula Singh, Lal Dhar S. Yadav, Rana Krishna Pal Singh

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Tetrahedron Letters

Direct radical sulfonylation at α-C(sp3)-H of THF with sodium sulfinates in aqueous medium Manjula Singha, Lal Dhar S. Yadav*, Rana Krishna Pal Singha* a

Electrochemical laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India  Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533; E-mail address: [email protected] (L.D.S. Yadav) b

A RT I C L E I N F O

A BS T RA C T

Article history: Received Received in revised form Accepted Available online

A direct transition-metal-free, convenient and highly regioselective synthesis of 2-alkyl/aryl sulfonyl tetrahydrofurans (THFs) has been achieved from THF and sodium sulfinates using K2S2O8 as a mild oxidant. This one-pot simple protocol involves an efficient radical cross coupling reaction in aqueous medium utilizing K2S2O8 as an inexpensive and easy to handle radical surrogate at room temperature.

2009 Elsevier Ltd. All rights reserved Keywords: Radical reaction Sodium sulfinates Sulfonylation THF derivatives

The establishment of mild and efficient methods for C−S bonds formation has received considerable attention because these bonds are widely found in many important biological and pharmaceutical compounds.1 Nowadays free-radical-initiated sp3-hybridized C–H bond activation gets much importance because the α-C(sp3)-H bond in many stable compounds such as alcohols,2 ethers,3 amines,4 and 1,3-dicarbonyl compounds5 could be activated by the radical leading to the formation of a more usable C–X (X = C, O, N, S) bond. However, the selective activation of the inactive C(sp3)–H bonds in alkanes and ethers to form C–S bonds has been a challenging6 task owing to their low reactivity. The direct C−H functionalization is of great importance to organic chemistry due to its high efficiency and high atom-economy.7 Substituted tetrahydrofurans (THFs) are ubiquitous motifs present in biological, pharmaceutical and natural products and they are useful building blocks in organic synthesis.8 In general, substituted (THFs) are accessible through the α-C(sp3)−H functionalization of THF9 via Ni-catalyzed arylation of THF, 10 Fe(II)-catalyzed CDC reaction of THF with malonates,11 Cu- and Ir-catalyzed carbenoid insertion of ethyl diazoacetate into α-C–H of THF,12 Cr-promoted reaction of alcohols with THF,13 AIBN mediated alkenylation of THF with vinyl triflones,14 TBHPpromoted reaction of phenylacetylene with THF15 and BEt3and Me2Zn-mediated addition of THF with aldehydes and aldimines, respectively.16 α-Alkynyl cyclic ethers have been regioselectively prepared by the α-alkynylation of cyclic ethers.16–18 Brown and Ley have prepared α-alkynyl tetrahydrofuran from 2-arylsulfonyl furans by treatment with the corresponding organozinc agents.17 α-Alkynyl cyclic ethers have also been obtained through the α alkynylation of C(sp3)-H bonds in cyclic ethers with acetylenic triflones using peroxide or AIBN or under UV-

irradiation.18 In 1996, Malanga and coworkers have synthesized 2-phenyl sulfonyltetrahydrofuran by reacting 2,2dialkyl-1,3-dioxep-4-ene with phenylsulfinic acid (Scheme 1a).19 Ley and coworkers have reported the synthesis of 2phenylsulfonyltetrahydrofuran from 2,3-dihydrofuran and benzenesulphinic acid in dry dichloromethane at room temperature under argon (Scheme 1b).20 To the best of our knowledge, there is no report on the direct alkyl/aryl sulfonylation of THF in the literature. Recently, K2S2O8 has emerged as a suitable inorganic oxidant for a wide array of oxidative transformations under mild conditions.21 Owing to its low cost, easy handling, water solubility and workability at room temperature, K2S2O8 is advantageneous over organic peroxides. In view of the above discussion and our earlier studies on K2S2O8-mediated organic synthesis,22 we report herein a simple and efficient protocol to access α-alkyl/arylsulfonyl THF via K2S2O8mediated direct α-sulfonylation of THF with sodium sulfinates (Scheme 1c).

Scheme 1. Synthesis of 2-alkyl/arylsulfonyl tetrahydrofurans

2 Our investigation starts with the radical cross coupling reaction of equimolar tetrahydrofuran (THF, 1a) and sodium sulfinate 2a employing K2S2O8 (1.5 equiv) as a radical source in aqueous medium at rt under a nitrogen atmosphere to afford the product 3a in 87% yield (Table 1, entry 1). Encouraged by this excellent result, we proceeded to optimize the reaction conditions. Thus, we tested several solvents such as H2O, CH3CN, DCE, THF and DMF. Among these H2O was demonstrated to be the best solvent in terms of time and yield (Table 1, entry 1 vs 2-5). The optimum amount of K2S2O8 was found to be 1.5 equiv because the yield was considerably reduced on decreasing its amount from 1.5 to 1.0 equiv (Table 1, entry 1 vs 6), although on using 2.0 equiv of the oxidant, the yield remained unchanged (Table 1, entry 2 vs 7). The other oxidants like CAN (ceric ammonium nitrate), oxone, TBHP and DTBP were not as effective as K2S2O8 (Table 1 entry 2 vs 8-11). No reaction occurred in the absence of K2S2O8 (Table 1, entry 12). The reaction was quenched on addition of a radical scavenger 2,2,6,6tetramethylpiperidinyl-1-oxyl (TEMPO), indicating that a radical intermediate is involved in the reaction (Table 1, entry 13).

Table1 Optimization of reaction conditionsa

Entry

Solvent

Oxidant (1.5 equiv)

Time (h)

Yield (%) b

1

H2 O

K2S2O8 (1.5)

8

87

2

CH3CN

K2S2O8 (1.5)

12

79

3

DCE

K2S2O8 (1.5)

12

75

4

THF

K2S2O8 (1.5)

12

71

5

DMF

K2S2O8 (1.5)

12

62

6

H2 O

K2S2O8 (1.0)

8

69

7

H2 O

K2S2O8 (2.0)

8

87

8

H2 O

CAN (1.5)

12

73

9

H2 O

Oxone (1.5)

12

65

10

H2 O

TBHP (1.5)

12

56

11

H2 O

DTBP (1.5)

12

71

12

H2 O

8

n.d.c

13

H2 O

8

Tracesd

K2S2O8 (1.5)

\a

Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), oxidant (1-2 equiv), solvent (3 mL), stirred at rt for 8-12 h under an N 2 atmosphere. b Isolated yield of the pure product 3a. c Without oxidant the yield was not detected. d Reaction was quenched with TEMPO (4 equiv).

Under the optimized reaction conditions, we investigated the generality and scope of the present K 2S2O8-mediated synthesis of 2-alkyl/arylsulfonyl tetrahydrofurans 3.

THF 1 and a wide variety of sodium sulfinates 2 incorporating various functional groups such as CH3, OCH3, t-Bu, Ph, Cl, Br, CF3, and CN in their aromatic ring were used. The reaction showed splendid tolerance for both electron-donating and electron-withdrawing groups to produce the desired 2-alkyl/arylsulfonyl tetrahydrofurans 3 in good to excellent yields irrespective of their electronic properties (Table 2). Sodium sulfinates 2 bearing an electrondonating group in their aromatic ring appeared to react faster and afford slightly higher yields of the corresponding 2-alkyl/arylsulfonyl tetrahydrofurans 3 in comparision to those having an electron-withdrawing group (Table 2, 3bf vs 3g-p). Notably, aliphatic and alicyclic sulfinates also worked well under the present sulfonylation conditions (Table 2, 3q and 3r). This reaction was also effective with sixmembered pyran and/or acyclic ether and worked well (Table 2, 3s-u).

Table 2 Substrate scope for the synthesis of 2-alkyl/arylsulfonyl tetrahydrofurana

3 a

For experimental procedure, see ref. 23. b Yields of isolated pure compounds 3. c All compounds gave satisfactory spectral (1H NMR,13C NMR and HRMS) data. 2.

In accordance with our observations and the literature precedents,21, 22 a plausible mechanistic pathway is proposed in Scheme 2. First, the K2S2O8 homolyzes into two KSO•4 radicals, which abstract a hydrogen atom

from the α-(C-sp3)-H of THF (1a) to generate an αoxyalkyl radical A and oxidise sodium sulfinate 2a into a radical B via single electron transfer (SET). Subsequently, the radical A is coupled with B to produce the final product 3a.

3.

4. 5. 6.

7.

8.

Scheme 2. A plausible sulfonyltetrahydrofurans

mechanism for the formation of 2-alkyl/aryl-

In conclusion, we have developed an operationally simple, one-pot, efficient, transition-metal-free and highly regioselective synthetic method for 2-alkyl/arylsulfonyl tetrahydrofurans. This new protocol involves efficient radical sulfonylation at the α-C (sp3)-H bond of THF with sodium sulfinates using K2S2O8 as a mild oxidizing agent. Advantageously, the present efficient cross coupling reaction utilizes K2S2O8 as a readily available, inexpensive and easy to handle radical source in aqueous medium at room temperature.

9. 10. 11. 12.

Acknowledgments We sincerely thank the SAIF, Punjab University, Chandigarh, for providing spectra. M.S. is grateful to the UGC, New Delhi, for a research fellowship. References 1.

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4 19. C. Malanga, L. A. Aronica, L. Lardicci Synth. Commun. 26 (1996) 2317. 20. D. S. Brown, M. Bruno, R. J. Davenport, S. V. Ley Tetrahedron 45 (1989) 4293. 21. (a) S. Mandal, T. Bera, G. Dubey, J. Saha, J. K. Laha ACS Catal. 8 (2018) 5085; (b) A. Ilangovan, A. Polu, G. Satish Org. Chem. Front. 2 (2015) 1616; (c) D. Yang, K. Yan, W. Wei, G. Li, S. Lu, C. Zhao, L. Tian, H. Wang, J. Org. Chem. 80 (2015)11073; (d) X. Chen, X. Li, X.-L. Chen, L.-B. Qu, J.-Y. Sun, Z. D. Liu, W.-Z. Bi, Y.-Y. Xia H.-T. Wua, Y.-F. Zhao Chem. Commun. (2015) 3846; (e) J. Y. Wang, Q. Jiang, C. C. Guo Synth. Commun. 44 (2014) 3130; (f) H. Rao, P. Wang, J. Wang, Z. Li, X. Sun, Cao, S. RSC Adv. 4 (2014) 49165; (g) Q. Jiang, W. Shenga, C. Guo, Green Chem. 15 (2013) 2175; (h) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio, M. D. Bel, P. S. Baran J. Am. Chem. Soc. 133 (2011) 3292; (i) Z. Yang, X. Chen, S. Wang, J. Liu, K. Xie, A. Wang, Z. Tan J. Org. Chem. 77 (2012) 7086; (j) J. W. Lockner, D. D. Dixon, R. Risgaard, P. S. Baran Org. Lett. 13 (2011) 5628; (k) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio Y. Fujiwara, A. L. Sobel, P. S. Baran J. Am. Chem. Soc. 132 (2010) 13194. 22. (a) M. Singh, A. K. Yadav, L. D. S. Yadav, R. K. P. Singh Synlett. 29 (2018) 2306; (b) A. K. Singh, R. Chawla, L. D. S. Yadav, Tetrahedron Lett. 55 (2014) 4742; (c) A. K. Singh, R. Chawla, T. Keshari, V. K. Yadav, L. D. S. Yadav, Org. Biomol. Chem. 12 (2014) 8550; (d) R. Chawla, A. K. Singh, L. D .S. Yadav Eur. J. Org. Chem. (2014) 2032; (e) A. K. Singh, R. Chawla, L. D. S. Yadav, Tetrahedron Lett. 55 (2014) 2845. 23. General procedure for the synthesis of 2-alkyl/arylsulfonyl tetrahydrofurans 3: A mixture of tetrahydrofuran 1 (1.0 mmol), sodium sulfinate 2 (1.0 mmol), K2S2O8 (1.5 equiv), and H2O (3 mL) was taken in a flask and stirred at rt for 8-12 h (Table 2). After completion of the reaction (monitored by TLC), water (5 mL) was added and the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography using a mixture of hexane/ethyl acetate (4:1) as eluent to afford an analytically pure sample of product 3. All the compounds 3 were characterized by comparison of their spectral (1H NMR, 13C NMR and HRMS) data. Compound 3a: 1H NMR (400 MHz, CDCl3) δ: 7.56 (d, J = 7.2 Hz, 2H), 7.37-7.32 (m, 2H), 7.27-7.19 (m, 1H), 5.69-5.68 (m, 1H), 4.09-3.99 (m, 2H), 2.46-2.38 (m, 1H), 2.09-1.98 (m, 2H), 1.88-1.79 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 135.65, 130.98, 128.71, 126.69, 87.06, 67.18, 32.57, 24.77. HRMS (EI): calcd for C10H12O3S 212.0507, found 212.0504. Compound 3g: 1H NMR (400 MHz, CDCl3) δ: 7.47-7.36 (m, 4H), 5.63-5.59 (m, 1H), 4.06-3.97 (m, 2H), 2.39-2.36 (m, 1H), 2.05-1.89 (m, 3H); 13C NMR (100 MHz, CDCl3) δ: 134.93, 132.47, 131.74, 120.79, 87.03, 67.22, 32.54, 24.73. HRMS (EI): calcd for C10H11BrO3S 289.9612, found 289.9616. Compound 3n 1H NMR (400 MHz, CDCl3) δ: 7.74-7.69 (m, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.27-7.24 (m, 1H), 7.18-7.15 (m, 1H), 5.79-5.76 (m, 1H), 4.09-3.97 (m, 2H), 2.49-2.38 (m, 1H), 2.17-2.05 (m, 2H), 1.96-1.87 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 135.51, 133.99, 130.83, 129.53, 127.19, 127.18, 85.52, 76.49, 32.59, 24.78. HRMS (EI): calcd for C10H11ClO3S: 246.0117; found: 246.0113.

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Highlights Transition-metal-free one-pot approach to 2-alkyl/aryl THFs at rt. The direct radical sulfonylation at αC(sp3)-H of THF in aqueous medium. Sodium sulfinates as a radical source. K2S2O8 as a mild radical initiator.