Direct Substitution of Secondary and Tertiary Alcohols To Generate

Letter Cite This: Org. Lett. 2018, 20, 5353−5356

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Direct Substitution of Secondary and Tertiary Alcohols To Generate Sulfones under Catalyst- and Additive-Free Conditions Yanan Liu,† Peizhong Xie,*,† Zuolian Sun,† Xiangyang Wo,† Cuiqing Gao,‡ Weishan Fu,† and Teck-Peng Loh*,†,§

Org. Lett. 2018.20:5353-5356. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/08/18. For personal use only.

†

School of Chemistry and Molecular Engineering, Institute of Advanced Synthesis, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China ‡ Southern Modern Forestry Collaborative Innovation Center, College of Forestry, Nanjing Forestry University, Nanjing 210037, China § Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637371 S Supporting Information *

ABSTRACT: An environmentally benign protocol that affords propargylic sulfones containing highly congested carbon centers from easily accessible alcohols and sulfinic acids with water as the only byproduct is reported. The reaction proceeded via an in situ dehydrative cross-coupling process by taking advantage of the synergetic actions of multiple hydrogen bonds rather than relying on an external catalyst and/or additives to achieve high product distribution.

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of cathepsins,11 cancer Osaka thyroid modulators (Figure 1),12 and DNA cleaving agents.13,14 Unfortunately, the method-

he development of green and step- and atom-economic synthetic protocols by utilizing nontoxic, readily available, and environmentally benign feedstocks and reagents is one of the ultimate goals of organic synthesis.1 In this context, direct reactions of easily accessible alcohols as precursors that give water as the only byproduct is particularly attractive.2,3 Therefore, the replacement of activated organic sulfonates, esters, phosphates, and halides with easily accessible alcohols for carbon−carbon2 and carbon−heteroatom bond3 construction has attracted considerable attention in organic synthesis. However, the high activation barrier of C−OH bond scission (85−91 kcal mol−1) and the reactive proton of the alcohol pose great challenges for the direct application of such methods in organic synthesis.4 Recently, strong Brønsted acids,5 transition metals combined with well-defined promoters,2 and photoredox catalysts6 have been reported to activate C−OH bonds. In our continuing interest in developing green synthetic methods, we have realized powerful C−OH bond activation methods by taking advantage of the synergistic action of the multiple hydrogen bonds.7,8 Stimulated by the aforementioned investigation and the impressive research concerning asymmetric SN1-like reactions developed by Shenvi9a and Jacobsen,9b we embarked on an investigation of a green and effective method for the synthesis of propargylic sulfones, which are versatile building blocks in synthetic chemistry10 and recognized as a crucial structural moiety that is widely distributed in biologically and pharmaceutically active molecules,11−14 such as the inhibitors © 2018 American Chemical Society

Figure 1. Propargyl sulfone moieties in biologically active molecules.

ologies available for accessing this skeleton were quite limited.10a,15 Even for the most reliable protocol, multistep transformations involving hydroxyl group activation, substitution, oxidation, and harsh reaction conditions and tedious purification procedures were required (Scheme 1, top).10a Moreover, in most cases, the key step involving the C−S bond construction was carried out through an SN2 substitution process and was therefore limited to only primary and secondary alcohols, whereas tertiary propargyl alcohols were difficult to Received: July 20, 2018 Published: August 14, 2018 5353

DOI: 10.1021/acs.orglett.8b02188 Org. Lett. 2018, 20, 5353−5356

Letter

Organic Letters Scheme 1. Strategies for the Preparation of Propargylic Sulfones

Scheme 2. Direct Dehydrative Cross-Coupling Reaction of Propargyl Alcoholsa

access due to the competitive E1 elimination or rearrangement via carbocation intermediates.9 For synthetic efficiency and to address environmental concerns, developing a convenient and practical synthetic methodology is very attractive. Herein, we developed a regiospecific dehydrative cross-coupling reaction between sulfinic acids and propargyl alcohols to deliver a wide range of propargylic sulfones with highly congested carbon centers from easily available alcohols and sulfinic acids (Scheme 1, bottom). Initially, we selected the reaction of propargyl alcohols 1a and sulfinic acid 2a as the model. In aqueous media, propargyl sulfones 3a were obtained in lower yields with poor chemoselectivities (Supporting Information (SI), Table 1, entry 1). Screening of the solvents revealed that the yield and selectivity were sensitive to the solvent (SI, entries 2−5). Compared with aqueous media or alcohols, the organic solvents 1,4-dioxane and toluene offered improved results. CH3CN gave the best result in terms of yield and selectivity (SI, entry 5). Further investigation (Schemes 2−4, X-ray analysis of 3d and 3e) revealed that the propargylic alcohols participated in this process through in situ dehydrative cross-coupling of the C−OH bond instead of γselective activation. Under the optimized reaction conditions, the scope of this dehydrative cross-coupling reaction was examined using secondary propargylic alcohols (Scheme 2). The results show that the electronic properties and position of the substituent on the phenyl ring had little effect on the yields of the products (3a−3d). The phenolic hydroxyl group was also found to be tolerated in this reaction (3d). Extending the scope of this transformation to tertiary alcohols is attractive because the resulting propargyl sulfones are difficult to prepare by other methods. This is because, in addition to the steric hindrance, tertiary alcohols facilitate intramolecular elimination processes if they have an adjacent α-C−H bond.9a Notably, our method also worked with tertiary propargylic alcohols, and all the tested substrates proceeded in high yields with excellent α-selectivities. For instance, a methyl group on the tertiary alcohol was also found to be fully compatible with this method, regardless of the electron-withdrawing or electron-donating groups on the phenyl ring (3e−3l). Moreover, desired product 3m could also be obtained when the phenyl group was replaced by a ferrocenyl

a

Experimental conditions: 1 (0.3 mmol) and 2 (0.45 mmol) dissolved in CH3CN (2.0 mL) and then stirred at 30 °C for 12 h. Isolated yield. b At 30 °C for 18 h. cAt 30 °C for 5 h.

group. More sterically demanding alcohols were also accommodated with limited impact on the yield and regioselectivity (3n and 3o). The propargylic alcohols prepared from cyclic ketones or aliphatic ketones were also suitable substrates for this reaction (3p, 3q, and 3s). Under the optimized reaction conditions, desired product 3r could be obtained in moderate yield with excellent selectivity from 3-methyl-1,5-diphenylpenta-1,4-diyn-3-ol. Moreover, 3,5-diphenylpent-1-en-4-yn-3-ol is also tolerated in the reaction and gave desired product 3t, albeit in a lower yield. Next, we directed our effort to investigating the reactions of alcohols bearing a wide variety of alkynyl groups. As shown in Scheme 3, both electron-withdrawing and electron-donating groups on the phenyl ring were amenable to this protocol (3u− 3z). Moreover, alkynes bearing an aliphatic chain, even chains bearing a halogen substituent (3aa), and a cyclopropyl group (3ab) were also compatible. Remarkably, extending the scope of this transformation to terminal alkynes (3ac) was attractive because the resulting sulfones increase the possibilities for structural modification of the products and enhance their synthetic utility. The scope of sulfinic acids was then explored under identical conditions (Scheme 4). Owing to the lower reactivities and instability of alkyl sulfinic acids, it was still a challenging task to incorporate these groups into propargyl sulfones. In our developed method, both aromatic and aliphatic sulfinic acids can effectively react with 1,3-diphenylprop-2-yn-1-ol in sufficient yield and selectivity (3ag−3aj). Remarkably, both cyclic (3ai) and acyclic (3aj) alkyl sulfinic acids were suitable substrates in our reaction system and showed excellent performances. For tertiary propargylic alcohols, no negative 5354

DOI: 10.1021/acs.orglett.8b02188 Org. Lett. 2018, 20, 5353−5356

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Organic Letters

alkynes with an adjacent quaternary carbon center (3ac) can be conveniently modified by click chemistry to afford 5 in high yield (Scheme 5).

Scheme 3. Direct Dehydrative Cross-Coupling Reactions of Propargyl Alcohols Bearing Various Alkynesa

Scheme 5. Transformation of Propargylic Sulfones

The mechanism is not yet understood in detail, but the relevant observations are worth discussing. When we conducted the reaction of enantioenriched propargyl alcohol (R)-4-phenyl2-(p-tolyl)but-3-yn-2-ol (91% ee) with 2a under the optimized reaction conditions, corresponding product 3i was obtained as a racemic mixture (SI, control experiments). This result is identical to those of related solvolysis reactions with tertiary alcohol derivatives, which revealed that this transformation most likely proceeds via an SN1-like process.9 However, the unexpectedly high regioselectivity of this reaction, especially in the presence of steric hindrance, was inconsistent with the typical SN1 displacement process, which generally results in a carbocation rearrangement or E1 elimination9b with most counteranions even at −78 °C. In addition, no desired product 6 was obtained when the propargylic alcohols were replaced with 2-phenylpentan-2-ol. Although the SN1 process cannot be completely ruled out, to account for the mechanism, a more reasonable pathway was proposed, as shown in Scheme 6. Initially, the hydrogen bond

a

Experimental conditions: 1 (0.3 mmol) and 2 (0.45 mmol) dissolved in CH3CN (2.0 mL) and then stirred at 30 °C for 12 h. Isolated yield. b At 30 °C for 24 h.

Scheme 4. Direct Dehydrative Cross-Coupling Reactions of Sulfinic Acidsa

Scheme 6. Proposed Mechanism for the Dehydrative CrossCoupling Reaction

a Experimental conditions: 1 (0.3 mmol) and 2 (0.45 mmol) dissolved in CH3CN (2.0 mL) and then stirred at 30 °C for 12 h. Isolated yield.

between the sulfinic acid and propargylic alcohol promoted the formation of intermediate A. Then, a γ-selective attack occurred by an oxygen atom of the sulfinic acid with the formation of 4phenylpenta-2,3-dien-2-yl methanesulfinate B. This process was supported by DFT calculations at the B3LPY/6-31G+(d) level,16 which showed a bridged-ring transition state (TS1) with a free energy of 29.8 kcal mol−1. However, sulfinic esters B cannot be isolated under the reaction conditions. This might be attributable to the favored sigmatropic rearrangement process (B−C−D), which might proceed rapidly to give racemic 3 under the acidic conditions.17 In summary, we provide a simple, but practical method for the preparation of propargylic sulfones with high step and atom economy. The reaction occurred via a formal in situ direct dehydrative cross-coupling between sulfinic acids and prop-

results for either aryl and alkyl sulfinic acids were obtained (3ak−3ao). Gratifyingly, aryl sulfinic acids bearing both electron-withdrawing and electron-donating groups give positive results (3ap and 3aq). Moreover, bulkier substrates, such as naphthalene-1-sulfinic acid, butane-1-sulfinic acid, and 2phenylethanesulfinic acid, were also suitable for this process (3am, 3an, and 3ar). Propargylic sulfones are versatile building blocks in organic synthesis.10 For example, Bi and co-workers reported that benzofurans skeletons 4 can be obtained in excellent yields from propargylic sulfones 3d with the assistance of a silver salt.10c In our preliminary investigation, we found that even terminal 5355

DOI: 10.1021/acs.orglett.8b02188 Org. Lett. 2018, 20, 5353−5356

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Isley, N. A.; Lippincott, D. J.; Krause, N.; Lipshutz, B. H. Org. Lett. 2014, 16, 724. (4) (a) Smith, M. B.; March, J. March’s Advanced Organic Chemistry; Wiley: New York, 2001. (b) van Gemmeren, M.; Börjesson, M.; Tortajada, A.; Sun, S.-Z.; Okura, K.; Martin, R. Angew. Chem., Int. Ed. 2017, 56, 6558. (5) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011, 133, 3732. (6) (a) Jin, J.; MacMillan, D. W. C. Nature 2015, 525, 87. (b) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C. Nature 2015, 524, 330. (7) Xie, P.; Wang, J.; Fan, J.; Liu, Y.; Wo, X.; Loh, T.-P. Green Chem. 2017, 19, 2135. (8) (a) Xie, P.; Wang, J.; Liu, Y.; Fan, J.; Wo, X.; Fu, W.; Sun, Z.; Loh, T.-P. Nat. Commun. 2018, 9, 1321. (b) Geogheghan, K. J. Nat. Rev. Chem. 2018, 2, 3. (9) (a) Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Nature 2013, 501, 195. (b) Wendlandt, A. E.; Vangal, P.; Jacobsen, E. N. Nature 2018, 556, 447. (10) (a) García-Rubia, A.; Romero-Revilla, J. A.; Mauleón, P.; Gomez Arrayás, R.; Carretero, J. C. J. Am. Chem. Soc. 2015, 137, 6857. (b) Martzel, T.; Lohier, J.-F.; Gaumont, A.-C.; Briére, J.-F.; Perrio, S. Adv. Synth. Catal. 2017, 359, 96. (c) Liu, J.; Liu, Z.; Liao, P.; Bi, X. Org. Lett. 2014, 16, 6204. (d) Moure, A. L.; Mauleón, P.; Arrayás, R. G.; Carretero, J. C. Org. Lett. 2013, 15, 2054. (11) Oballa, R.; Bayly, C.; Truchon, J.-F.; Li, C. S.; Leger, S. U.S. Patent Appl. 0063013, 2010. (12) Bacon, E. M.; Balan, G.; Chou, C.-H.; Clark, C. T.; Kim, M.; Kirschberg, T. A.; Phillips, G.; Schroeder, S. D.; Aquires, N. H.; Stevens, K. L.; Taylor, J. G.; Watkins, W. J.; Wright, N. E.; Zipeel, S. M. PCT Int. Appl. WO 2017007689A1, 2017. (13) (a) Haruna, K.-i.; Kanezaki, H.; Tanabe, K.; Dai, W.-M.; Nishimoto, S.-i. Bioorg. Med. Chem. 2006, 14, 4427. (b) Haruna, K.-i.; Tanabe, K.; Ishii, A.; Min-Dai, W.; Hatta, H.; Nishimoto, S.-i. Bioorg. Med. Chem. 2003, 11, 5311. (c) McPhee, M. M.; Kerwin, S. M. Bioorg. Med. Chem. 2001, 9, 2809. (d) McPhee, M. M.; Kern, J. T.; Hoster, B. C.; Kerwin, S. M. Bioorg. Chem. 2000, 28, 98. (14) Muehlebach, M.; Lutz, W.; Wenger, J.; Finney, J.; Mathews, C. J.; Fawke, D. PCT Int. Appl. WO 2008110308A2, 2008. (15) (a) Liu, W.; Chen, Z.; Li, L.; Wang, H.; Li, C.-J. Chem. - Eur. J. 2016, 22, 5888. (b) Li, H.-H.; Dong, D.-J.; Jin, Y.-H.; Tian, S.-K. J. Org. Chem. 2009, 74, 9501. (c) Liu, C.-R.; Li, M.-B.; Cheng, D.-J.; Yang, C.F.; Tian, S.-K. Org. Lett. 2009, 11, 2543. (16) All DFT calculations were performed with the Gaussian 09 program package. For details, see the Supporting Information. (17) For the acid-catalyzed rearrangement from sulfinic esters to sulfones, see: Stirling, C. J. M. Chem. Commun. 1967, 131.

argylic alcohols by taking advantage of the intermolecular hydrogen bonding rather than relying on an external catalyst or a stoichiometric additive. A variety of propargyl sulfones could be prepared in high yields with excellent regioselectivities from a wide variety of alcohols and sulfinic acids. Moreover, this reaction proceeds at room temperature in an environmentally benign manner with water as the only byproduct.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02188. Experimental procedures, screening reaction conditions, NMR spectra of products, and DFT calculation results (PDF) Accession Codes

CCDC 1583940 and 1846174 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Teck-Peng Loh: 0000-0002-2936-337X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We greatly acknowledge financial support by the National Natural Science Foundation of China (21702108), the State Key Program of the National Natural Science Foundation of China (21432009), the Natural Science Foundation of Jiangsu Province, China (BK20160977), Nanjing Tech University, and the SCIAM Fellowship from Jiangsu National Synergetic Innovation Center for Advanced Material.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b02188 Org. Lett. 2018, 20, 5353−5356