SO2F2-Mediated Oxidative Dehydrogenation and Dehydration of

Article Cite This: J. Am. Chem. Soc. 2018, 140, 17666−17673

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SO2F2‑Mediated Oxidative Dehydrogenation and Dehydration of Alcohols to Alkynes Gao-Feng Zha,†,§ Wan-Yin Fang,†,§ You-Gui Li,‡ Jing Leng,† Xing Chen,† and Hua-Li Qin*,† †

State Key Laboratory of Silicate Materials for Architectures, and School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, P.R. China ‡ School of Chemistry and Chemical Engineering, Hefei University of Technology, 193 Tunxi Road, Hefei 230009, P.R. China

J. Am. Chem. Soc. 2018.140:17666-17673. Downloaded from pubs.acs.org by IOWA STATE UNIV on 01/17/19. For personal use only.

S Supporting Information *

ABSTRACT: Direct synthesis of alkynes from inexpensive, abundant alcohols was achieved in high yields (greater than 40 examples, up to 95% yield) through a SO2F2-promoted dehydration and dehydrogenation process. This straightforward transformation of sp3−sp3 (C−C) bonds to sp−sp (C≡C) bonds requires only inexpensive and readily available reagents (no transition metals) under mild conditions. The crude alkynes are sufficiently free of impurities to permit direct use in further transformations, as illustrated by regioselective Huisgen alkyne−azide cycloaddition reactions with PhN3 to give 1,4-substituted 1,2,3-traiazoles (16 examples, up to 92% yield) and Sonogashira couplings (10 examples, up to 77% yield).

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INTRODUCTION Alkyne is a privileged motif prevalent in pharmaceuticals, agrochemicals, natural products, catalyst architectures, ligands, and materials.1 It has been widely applied as one of the most versatile building blocks in the fields of organic chemistry,2 fuel science and technology,3 materials science,4 chemical biology,5 and drug discovery.5b,6 Alkynes also participate in a large number of important chemical transformations such as the “click” reaction (azide−alkyne 1,3-dipolar cycloaddition reactions),7 Sonogashira8 and Glaser couplings,9 Pauson− Khand carbonylation,10 metathesis,11 cycloaddition and cyclization reactions for the synthesis of aromatic and heterocyclic compounds,12 and aminations13 and often play key roles in natural product synthesis.14 Therefore, the development of novel and practical methods for construction of alkynes is extremely important. To date, numerous protocols have been reported such as Corey−Fuchs,15 Wittig/Horner− Emmons,16 and Gilbert−Seyferth reactions17 and their modifications.18 With the aim of developing powerful, sustainable, and costeffective methods for synthesis of alkynes, we became interested in the potential use of alcohols, inexpensive and abundant industrial chemicals, some of which can be obtained from renewable resources (biomass).19 Traditionally, alcohols have to be oxidized to aldehydes or ketones before subsequent conversion to alkynes (Scheme 1a−d). The alkynes synthesized by Corey−Fuchs reaction and modifications thereof15,18 add an additional carbon to the skeleton of the original carbonyl compounds (Scheme 1a). On the other hand, acetylenes obtained by elimination from vinyl sulfonates and halides promoted by strong bases maintain the same number of carbons (Scheme 1b).20 In addition to the above methods, 2-silylvinyltriflates derived from cyclic ketones were recently © 2018 American Chemical Society

Scheme 1. Strategies for Transformation of Alcohols to Alkynes

used to generate strained alkynes when treated with CsF;21 hydrazones derived from ketones were used to synthesize alkynes by Cu-catalyzed oxidation.22 Alternatively, alcohols can be transformed to alkynes via a three-step procedure (Scheme 1c): dehydration to alkene, 23 halogenation to vicinal dihalides,24 and subsequent elimination,25 which typically requires harsh conditions in every single step. Herein, we report a SO2F2-promoted direct dehydrative and dehydrogenative conversion of alcohols to alkynes under mild conditions without any transition metals (Scheme 1d). Received: September 17, 2018 Published: November 27, 2018 17666

DOI: 10.1021/jacs.8b10069 J. Am. Chem. Soc. 2018, 140, 17666−17673

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Journal of the American Chemical Society

enolate from the carbonyl group in situ for further reaction with SO2F2. This may be accompanied by undesirable side reactions. Third, DMSO is the ideal solvent for this reaction as it also serves as the oxidant in the first step. Therefore, all steps must proceed well in DMSO so that no intermediates need to be isolated and purified. However, DMSO has rarely been successfully used as the solvent for Swern-type oxidations because solvents of low polarity (for example, CH2Cl2) are essential to minimize the formation of methylthioalkyl ethers.28,29 The feasibility of the proposed reaction sequence was assessed using 2-(4-biphenyl)ethanol 1a as a representative substrate (Table 1; see Supporting Information for a more detailed account of optimization conditions). To our delight, 98% of 1a was consumed under SO2F2 atmosphere at room temperature when Et3N (2 equiv), the most commonly used base for Swern-type oxidation, was employed. The proposed βstyryl sulfurofluoridate (2a) was formed in nearly quantitative yield (96%, Table 1, entry 1). When the reaction was performed at 80 °C with 5 equiv of Et3N, a mixture of 2a (41% yield) and the proposed final product 4-ethynylbiphenyl (3a; 56% yield) resulted (Table 1, entry 2). Encouraged by these initial results, we turned our attention to inorganic bases, which have rarely been employed in Swern-type oxidation but have advantages over organic bases, such as low total organic carbon (TOC) in the waste and easy workup and purification. Excitingly, when K2CO3 (1.5 equiv) was used, 1a again cleanly converted to 2a in quantitative yield at room temperature (Table 1, entry 3). When the loading of K2CO3 was increased to 5.0 equiv and the reaction temperature was increased to 80 °C, after a period of 12 h, we were pleased to find that the main product was the desired alkyne 3a (73% yield, Table 1, entry 4). KF (5.0 equiv) was less effective (Table 1, entry 5). Our subsequent investigations focused on using two bases to maximize the formation of acetylene product while using K2CO3 for vinyl sulfurofluoridate generation. With both Bu4NF·3H2O and KF (3.0 equiv), a mixture of vinyl sulfurofluoridate 2a and alkyne 3a resulted after heating at 80 °C for 12 h (Table 1, entries 6 and 7). Gratifyingly, CsF

Developing efficient and practical methods using greener, cheaper, and more readily available substrates without unnecessary steps or energy waste has been a major target in modern sustainable chemistry.26 Besides alcohols as cheap and abundant reagent, SO2F2 is also an inexpensive (about 1$/ kg)27a and relatively inert starting material (stable up to 400 °C when dry), which has recently attracted significant attention as a reactive electrophile.27 We envisioned (Scheme 2) that SO2F2 would perform the role of an electrophilic Scheme 2. Proposed Direct Conversion of Alcohols to Alkynes Mediated by SO2F2

activator similar to oxalyl chloride under basic conditions, leading to oxidation of the alcohols to aldehydes or ketones by DMSO (Swern oxidation).28 Under the same basic conditions, the carbonyl intermediates would further react with SO2F2 to generate vinyl fluorosulfates, which will subsequently undergo fluorosulfonic ester elimination to give alkynes.20,21

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RESULTS AND DISCUSSION To achieve the direct transformation of alcohols to alkynes (Scheme 2), several challenges need to be addressed. First, SO2F2 has to be sufficiently reactive to activate DMSO for alcohol oxidation. However, Swern-type oxidations typically require low temperatures (−78 °C) to avoid deleterious Pummerer rearrangement and generation of highly reactive H2CS(+)−CH3 that consumes the starting alcohols in a nonproductive manner.29 Such low reaction temperatures will significantly decrease the reactivity of SO2F2. Second, a strong base is generally required to generate the corresponding

Table 1. Assessment of the Feasibility of Transformation of Alcohol 1a to Alkyne 3a and Optimization of Reaction Conditionsa

entry c

1 2 3c 4 5 6 7 8 9d 10d,e

base I (equiv) Et3N (2.0) Et3N (5.0) K2CO3 (1.5) K2CO3 (5.0) KF (5.0) K2CO3 (1.5) K2CO3(1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5)

base II (equiv)

conversion (1a, %)b

yield (2a, %)b

yield (3a, %)b

Bu4NF·3H2O (3.0) KF (3.0) CsF (3.0) CsF (3.0) CsF (3.0)

98 100 100 100 85 100 100 100 100 100

96 41 >99 1 20 30 35 0 0 0

0 56 0 73 59 49 59 84 90 95(88)

a Reaction conditions: 2-(4-biphenyl)ethanol (1a, 0.2 mmol), base I, DMSO (1.5 mL), and SO2F2 balloon, rt, 2 h; then 80 °C, 12 h. Base II was added just before the heating commenced, when applicable. bYields and conversion were determined by HPLC using 1a, 2a, or 3a as external standards (t1a = 4.0 min, λmax = 252 nm; t2a = 9.6, 10.6 min, λmax = 278, 276 nm; t3a = 7.6 min, λmax = 270 nm). cThe reaction was quenched before heating. dBefore base II was added, the reaction mixture was degassed under vacuum to remove the remaining SO2F2. eReaction was operated at 100 °C for 2 h.

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Journal of the American Chemical Society gave alkyne 3a in 84% yield with complete consumption of 2a (Table 1, entry 8). When the reaction mixture was degassed to remove excess SO2F2 before adding CsF, the yield of 3a was improved to 90%, indicating that the remaining SO2F2 hampered the conversion of 2a to 3a (Table 1, entry 9). Finally, increasing the reaction temperature to 100 °C increased the efficiency of the alkyne formation to provide 3a in 95% HPLC yield and 88% isolated yield (Table 1, entry 10), with this being the optimal set of conditions for the preparative runs described hereafter. As illustrated in Table 2, a variety of structurally and electronically diverse homobenzylic primary alcohols (2-

process well to provide their products 3k, 3m, and 3n in 58, 49, and 60% yield, respectively. The corresponding 1-naphthyl (1s) and 2-naphthyl (1t) analogues were also smoothly transformed into alkynes 3s and 3t in 83 and 60% yield, respectively. This method was also applicable to alcohols possessing heteroarenes to generate products 3ac, 3ad, and 3ae in 85, 89, and 49% isolated yield, respectively. Finally, substrate possessing two ethanol groups gave bisacetylene 3n in 40% yield. Homopropargyl (4a) and homoallylic (4b) alcohols also gave the conjugated alkynes 5a and 5b in 67 and 71% yield, respectively (Scheme 3).

Table 2. Scope of Dehydration and Dehydrogenation of 2Arylethanols to Arylalkynes

Scheme 3. Direct Dehydrative Dehydrogenation of Homopropargyl and Homoallylic Primary Alcohols to Alkynes

We subsequently examined direct conversion of aliphatic alcohols 6 to the corresponding alkynes 7. After extensive screening (see Supporting Information for details), we were pleased to find that vinyl sulfurofluoridates were generated from the aldehydes derived from alcohols 6a−e through DMSO-promoted oxidation by the use of a second base, DBU. The vinyl sulfurofluoridates were subsequently transformed to alkynes 7a−e through β-elimination promoted by CsF (Table 3; 47−76% yields). Notably the original triple bond functionality of 6d was well-tolerated during the process of transformation to 7d. Table 3. Direct Dehydrative Dehydrogenation of Aliphatic Alcohols to Alkynes

a

Reaction conditions: 2-arylethanol (1, 2.0 mmol), K2CO3 (415 mg, 3.0 mmol), DMSO (15 mL), and SO2F2 balloon, rt, 2 h; then CsF (914 mg, 6.0 mmol), 100 °C, 2 h. The yields were based on the amounts of isolated products. bEt3N (405 mg, 4.0 mmol) was used as the base in the first step, and DBU (1.22 g, 8 mmol) was used instead of CsF during the elimination process. c2,2′-(1,4-Phenylene)bis(ethan-1-ol) served as the starting material, and K2CO3 (830 mg, 6.0 mmol) and CsF (1.83 g, 12.0 mol) were used. dIsolated yield was 35%, and HPLC yield was 85% (due to the volatile properties of some low-boiling-point alkynes, their HPLC yields were typically much higher than the isolated yields).

a

Reaction conditions: alcohol (6, 1.0 mmol), K2CO3 (208 mg, 1.5 mmol), DMSO (7.5 mL), and SO2F2 balloon, rt, 12 h; then DBU (914 mg, 6.0 mmol), rt, 12 h; next was CsF (760 mg, 5 mmol) at 100 °C, 12 h. bThe yields were based on the amounts of isolated products.

arylethanols; 1) were successfully transformed to their corresponding phenylacetylenes (3) in moderate to excellent yields (35−95%) under the optimized conditions. Both electron-donating and electron-withdrawing aryl substituents were well-tolerated. It is worth noting that the thioether moiety in 1k, vinyl moiety in 1m, and acetenyl moiety in 1n, which are fragile to many oxidation conditions, tolerate the oxidative

Next, we extended the SO2F2-mediated direct dehydration/ dehydrogenation process to secondary alcohols. As illustrated in Table 4, secondary alcohols with adjacent methyl 8a or phenyl 8b groups were successfully converted to the corresponding disubstituted acetylenes 9a and 9b employing method A (Table 4, entries 1 and 2), albeit in lower yields (41 17668


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Journal of the American Chemical Society Table 4. Direct Dehydrative Dehydrogenation of Secondary Alcohols to Disubstituted Alkynes

a

Reaction conditions: alcohol (8, 1.0 mmol), K2CO3 (208 mg, 1.5 mmol), DMSO (7.5 mL), and SO2F2 balloon, rt, 2 h; then CsF (456 mg, 3.0 mmol), 100 °C, 2 h (method A); alcohol (8, 1.0 mmol), DBU (761 mg, 5 mmol), DMSO (7.5 mL), and SO2F2 balloon, rt, 5 h (method B). bThe yields were based on the amounts of isolated products.

and 35% yield, respectively). On the other hand, DBU alone (5.0 equiv) was sufficiently effective to promote the oxidation, enolization, and elimination for alcohols 8c−8i carrying a βsubstituted acylamino group, furnishing the corresponding alkynes 9c−9i in moderate yields, due to the competing formation of the analogous (E)-alkenes generated by strong

base-promoted dehydration of the starting alcohols in the presence of SO2F2.30 The direct dehydration and dehydrogenation method employs only inorganic reagents, thus producing alkyne solutions in DMSO of high purity. Hence, further transformations using the crude alkynes, resulting in a highly 17669


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Journal of the American Chemical Society efficient, step-economical, one-pot process, become feasible. Regioselective, Cu-catalyzed azide−alkyne 1,3-dipolar cycloaddition reaction to 1,4-disubstituted 1,2,3-triazoles7 (the “Huisgen alkyne−azide cycloaddition reaction”) is one of the most powerful and useful alkyne transformations in various research fields. After a considerable number of reported Huisgen alkyne−azide cycloaddition reaction conditions7 were evaluated, the procedure reported by Feringa,31 employing CuSO4·5H2O and PPh3 as ligand, provided 1,4-diaryl-1,2,3triazoles in moderate to excellent yields (53−92%; Table 5)

Table 6. Direct Transformation of 2-Arylethanols to Diarylalkynes by One-Pot Dehydrogenation/Dehydration and Sonogashira Couplinga

Table 5. Direct, Regioselective Transformation of 2Substituted Ethanols to 1,4-Diaryl-1,2,3-triazoles by OnePot Dehydration/Dehydrogenation and Huisgen Alkyne− Azide Cycloaddition Reactionsa a

Reaction conditions: 2-arylethanol (1, 1.0 mmol), K2CO3 (207 mg, 1.5 mmol), DMSO (8.0 mL) and SO2F2 balloon, rt, 2 h; then CsF (456 mg, 3.0 mmol), 100 °C, 2 h; [Pd(PPh3)Cl2] (35 mg, 5 mol %), CuI (19 mg, 10 mol %), iodobenzene (248 mg, 1.1 mmol), and Et3N (2.0 mL), rt, 12 h. The yields were based on the amount of isolated products.

substituents were tolerated well. 2-(1-Naphthyl)ethanol 1o also afforded the Sonogashira coupling product 11j in 77% yield. To demonstrate the utility of our developed SO2F2-mediated direct dehydration/dehydrogenation process in natural products, biologically active molecules, and drug synthesis, some extended work has been conducted. Excitingly, the synthesis of the drug Erlotinib (a tyrosine kinase inhibitor) from alcohol 12 in 1.0 mmol scale was accomplished through a two-step sequence of a nucleophilic addition and an oxidatively dehydrative dehydrogenation process in 52% overall yield. Furthermore, with the synthesis of a carbonic anhydrase (CA) inhibitor, the 1,4-substituted triazole 17 was also achieved33 using the developed “one-pot” process of oxidation, enolization, elimination, and 1,3-dipolar cycloaddition in 57% yield (Scheme 4).

a

Reaction conditions: 2-arylethanol (1, 1.0 mmol), K2CO3 (207 mg, 1.5 mmol), DMSO (8.0 mL), and SO2F2 balloon, rt, 2 h; then CsF (456 mg, 3.0 mmol), 100 °C, 2 h; next was H2O (8.0 mL), sodium ascorbate (20 mg, 10 mol %), CuSO4·5H2O (25 mg, 10 mol %), PPh3 (26 mg, 10 mol %), and PhN3(119 mg, 1.0 mmol), rt, 12 h. The yields were based on the amount of isolated products.

directly from primary homobenzylic alcohols without tedious isolation of any intermediates. Generally, homobenzylic primary alcohols carrying electron-rich substituents (OPh, OBn, Ph, Me) gave high yields (10a−e, 10f, 10i−k; 60−92%). Electron-withdrawing substituents on para positions generally led to lower yields, similarly to the trend observed in alkyne synthesis (Table 2). However, a m- or p-chloro substituent was well-tolerated (10g, 85%; 10h, 78%). Triazoles from 2heteroaryl ethanol and 2-(1-naphthyl)ethanol were also isolated in high yields (10k−n, 63−81%). Finally, the homopropargyl alcohol 4a and homoallylic alcohol 4b were also transformed into 1,2,3-triazole 10p and 10o in 79 and 53% yields, respectively. Another powerful and useful synthetic method using terminal alkynes is the Sonogashira reaction.8 To further demonstrate the usefulness of our method, a one-pot Sonogashira coupling following the protocol developed by Krause et al.32 using the crude alkynes obtained by direct dehydrogenation/dehydration of alcohols was successfully integrated into a one-pot procedure (Table 6). 2-Arylethanols possessing both electron-donating (OBn, OMe, Ph) and electron-withdrawing groups (Br, CN) afforded the unsymmetrical diarylalkynes 11a−i in 51−71% yields upon coupling with iodobenzene. Notably, Br (11d) and Cl (11g)

Scheme 4. Applications of the Developed Method for the Synthesis of Complicated Biologically Active Molecules

As illustrated in Scheme 5, a plausible mechanism involves the initial base-promoted formation of a fluorosulfate ester A from the corresponding alcohol and SO2F2. Subsequent SN2 displacement by DMSO acting as the nucleophile generates cationic intermediate C.34 The fate of C, being identical to the key intermediate in Swern-type oxidations, follows the latter 17670


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the bases were required to be added after preactivation of DMSO.

Scheme 5. Plausible Mechanism for Direct Dehydration and Dehydrogenation of Alcohols to Alkynes Mediated by SO2F2

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CONCLUSION In conclusion, a novel and practical method for direct dehydration/dehydrogenation of alcohols to alkynes under mild conditions was developed. This protocol employs cheap and readily available reagents, solvent, and inorganic bases without transition metals. Excess SO2F2 was used to activate DMSO for oxidative conversion of alcohols to alkenyl sulfurofluoridates under basic conditions at room temperature, which is the first report in the literature to the best of our knowledge. Direct access to 1,4-disubstituted-1,2,3-triazoles or diarylalkynes by one-pot Cu/phosphine-catalyzed regioselective Huisgen alkyne−azide cycloaddition reaction or Pdcatalyzed Sonogashira coupling, respectively, was enabled through the high purity of crude alkyne products. Further applications of this method for discovery of new drug candidates and functional materials are ongoing in our laboratory.

pathway, giving the sulfur ylide D upon deprotonation with the base. D undergoes intramolecular deprotonation−elimination of Me2S to provide the aldehyde (ketone) E. From E, the corresponding vinyl sulfurofluoridate 2 is successfully obtained from 1 equiv more of the base and SO2F2. Finally, base-assisted β-elimination furnishes the final alkyne 3 as the major product. However, the alkene B could also be observed as a byproduct when the fluorosulfate ester A undergoes β-elimination directly prior to SN2 displacement by DMSO. The proposed mechanism was examined by experimental studies, and the results revealed that, unlike the conventional Swern-type oxidations where the oxygens of aldehydes were adopted from the original alcohols, the oxygens of the oxidative enolates were provided by DMSO because the 18Olabeled arylethanol 1af generated enolate 2af with greater than 99% 16O-labeled purity (Scheme 6a). Further experiments

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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/jacs.8b10069. Experimental details (PDF)

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AUTHOR INFORMATION

Corresponding Author

Scheme 6. Mechanism Studies of the Oxidative Enolating Processa

*[email protected] ORCID

Gao-Feng Zha: 0000-0001-9240-8721 Hua-Li Qin: 0000-0002-6609-0083 Author Contributions §

G.-F.Z. and W.-Y.F. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Grant No. 21772150) and Wuhan University of Technology for their continuous encouragement toward the research and for financial support.

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REFERENCES

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a

Conditions: (a) oxidation of an 18O-labeled substrate; (b−f) control experiments for the roles of the base.

indicated that mixing of the reactants without K2CO3 (similar to Table 1, entry 3); mixing of the reactants before adding K2CO3 followed by removal of SO2F2; premixing SO2F2, K2CO3, and DMSO over 2 h, before removing SO2F2 and adding 1a; and premixing SO2F2 and DMSO over 2 h, followed by removing SO2F2, adding of 1a and K2CO3, resulted in very low yield of enolate 2a (Scheme 6c−f). These experiments further suggested that the current oxidative process, in which bases can be added without preactivation of DMSO, was different from the conventional Swern-type oxidations where 17671


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