Hydrofunctionalization of alkenols triggered by the addition of diverse radicals to unactivated alkenes and subsequent remote hydrogen atom translocation

Abstract

Diverse anti-Markovnikov hydrofunctionalization of alkenols triggered by the addition of S-, P-, and C-centered radicals to alkenes followed by intramolecular 1,5(6)-hydrogen atom transfer (HAT) with remote α-C–H bonds of alcohols has been developed. The strategy simultaneously realized the hydrofunctionalization of alkenes and remote alcohol oxidation. This mild and versatile method allows for direct access to valuable sulfonyl-, phosphonyl-, and malonate-substituted ketones or aldehydes from a wide range of alkenols.

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Introduction

The hydrofunctionalization of alkenes provides a facile access to a wide range of functionalized alkanes.¹ Among intensive research in this area, the radical-mediated alkene hydrofunctionalization initiated by the addition of radicals to alkenes followed by trapping of the incipient radical with a hydrogen donor represents an efficient and powerful tool for alkene hydrofunctionalization in an anti-Markovnikov manner.² The use of efficient hydrogen donors is critical for the realization of alkene hydrofunctionalization because of the high propensity of alkyl radical intermediates, particularly for linear alkene substrates, to undergo undesired competitive pathways such as 1,2-difunctionalization and β-hydrogen elimination.³ Compared with the well-established external hydrogen donors, intramolecular hydrogen delivery via 1,n-hydrogen atom transfer (HAT) for hydrofunctionalization of unactivated alkenes has recently attracted considerable attention due to its high regio-selectivity and concomitant remote C–H bond functionalization.⁴ In this respect, our group and others have independently reported the general and efficient hydrofluoroalkylation of alkenes with suitably positioned alcohols/ethers as internal hydrogen donors to afford a variety of fluoroalkyl-containing carbonyl products (Scheme 1a).⁵ However, the research on this chemistry was confined to fluoro-containing radical sources, which unnecessarily limited both the scope and the potential of this method for practical applications. Hence, the realization of hydrofunctionalization of alkenols via this strategy with diverse heteroatom- or carbon-centered radical sources is highly desirable.

Scheme 1 Hydrofunctionalization with diverse alkenols via 1,5(6)-HAT.

Organosulfones and organophosphorus compounds are common structural motifs widely displayed in agrochemicals, pharmaceuticals, and catalysts.⁶ They have also been employed as highly useful building blocks in organic synthesis. Recently, the direct functionalization of alkenes triggered by S-⁷ or P-centered⁸ radical addition to alkenes has emerged as a promising tool for the synthesis of functionalized organosulfones and organophosphorus compounds. Thus, much progress has been made in the development of sulfonylation and phosphonylation of activated olefins. However, the application of similar transformations to unactivated alkenes is more challenging,⁹ which is probably due to the unfavorable reversible generation of unstable radical intermediates.^8a,10 As our continuing interest in the functionalization of unactivated alkenes via the addition of radicals to unactivated alkenes followed by subsequent remote functional group translocation,¹¹ we describe herein a general and efficient protocol for hydrosulfonylation, hydrophosphonylation, and hydroalkylation of alkenols in the presence or absence of a gem-disubstituent effect via intramolecular 1,5(6)-HAT in a highly controlled site-selective manner. It generally provides valuable sulfonyl-, phosphonyl-, and malonate-functionalized carbonyl compounds in good yields (Scheme 1b).

Results and discussion

At first, we began our investigation by exploring the hydrosulfonylation reaction of linear alkenol 1A with p-toluenesulfinic acid 2a. Various oxidants were investigated and only K₂S₂O₈ gave the desired product 3Aa (entries 1–4, Table 1).^7e An inert atmosphere was slightly beneficial for the reaction (entry 5). Three equiv. of 2a together with two equiv. of K₂S₂O₈ were proven to be necessary for the full conversion of 1A and the good yield of 3Aa (entries 6–8). Switching the oxidant to (NH₄)₂S₂O₈ unexpectedly led to significantly diminished yield (entry 9). Co-solvent systems exhibited high reaction efficiency and resulted in a clear reaction mixture. Finally, we found that the reaction of 1A with p-toluenesulfinic acid (2a) proceeded smoothly by simply using the cheap K₂S₂O₈ (2 equiv.) as the oxidant in CH₃CN/H₂O (1 : 2) at 80 °C for 16 h, providing sulfonylated ketone 3Aa in 82% isolated yield.

Table 1 Reaction condition optimization for hydrosulfonylation^a

Entry	Oxidant (x equiv.)	2a (y equiv.)	Solvent (ratio)	Yield^b (%)
a Reaction conditions: 1A (0.2 mmol), 2a, solvent (2.0 mL) at 80 °C for 16 h under an argon atmosphere. b Determined by NMR spectroscopy using 1,3,5-trimethylbenzene as an internal standard. c p-Toluenesulfonylhydrazine was utilized. d Isolated yield.
1	Fe(NO3)3·9H2O (0.10), air	3.0	MeCN	Trace
2^c	TBAI (0.10), TBHP (3.0)	3.0	Dioxane/H2O (4/1)	Trace
3	Pyridine (4.0), air	5.0	DCE	NR
4	K2S2O8 (1.0), air	3.0	MeCN/H2O (1/2)	50%
5	K2S2O8 (1.0), argon	3.0	MeCN/H2O (1/2)	55%
6	K2S2O8 (2.0), argon	1.0	MeCN/H2O (1/2)	48%
7	K2S2O8 (2.0), argon	2.0	MeCN/H2O (1/2)	70%
8	K 2 S 2 O 8 (2.0), argon	3.0	MeCN/H 2 O (1/2)	82%
9	(NH4)2S2O8 (2.0), argon	3.0	MeCN/H2O (1/2)	35%

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With the optimal reaction conditions in hand, we set out to explore the scope with respect to various alkenols (Table 2). A range of linear alkenols bearing diversely functionalized aryl groups (electron-rich one: Me for 1B; electron-deficient ones: Cl for 1C–1E and Br for 1F) were found to be suitable substrates to give the corresponding products 3Ba–3Fa selectively in 48–80% yields. It should be noted that substrate 1I, with an isopropyl group in place of a phenyl one, also afforded the expected product 3Ia albeit with lower yield, thus clearly demonstrating that the current process was not limited to benzylic alcohol. Comparable to linear alkenyl alcohols, the aryl-tethered substrates 1J–1N were also applicable to this process, affording highly substituted Ts-containing aryl aldehydes 3Ja–3La and aryl ketones 3Ma–3Na in moderate to good yields. Notably, substrate 1N with a gem-disubstituted alkenyl group reacted efficiently to afford aryl ketone 3Na in 70% yield.

Table 2 Substrate scope of hydrosulfonylation^a,b

a Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), K₂S₂O₈ (0.4 mmol), CH₃CN (0.7 mL), H₂O (1.4 mL), 80 °C, 20 h. b Isolated yield.

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Inspired by the above successful results, we next focused our attention on other challenging heteroatom- and carbon-centered radicals. A phosphonyl radical was then selected as the heteroatom-centered radical to probe whether a similar radical process could be realized.^8,9 After systematic optimization of different reaction parameters (Table S1†), we were delighted to find that in the presence of 3.0 equiv. of AgOAc⁸ⁱ or 50 mol% of AgNO₃,^8d the reaction of alkenol substrates with 2.0 equiv. of Ph₂P(O)H (2b) in DMF at 100 °C afforded the corresponding phosphonylated ketones in good yields (Table 3). The reaction tolerated a variety of linear alkenols containing aryl groups with different substituents to yield products 4Ab–4Cb and 4Eb–4Hb in 47–90% yields. Similarly, the aryl-tethered substrates 1J and 1M exhibited high efficiency in this hydrophosphonylation reaction. Good reactivity was also observed for the gem-disubstituted alkene substrate 1N and aliphatic substrate 1O, thus illustrating the wide applicability of the current hydrophosphonylation reaction.

Table 3 Substrate scope of hydrophosphonylation^a,b

a Reaction conditions: 1 (0.2 mmol), 2b (0.4 mmol), AgOAc (0.6 mmol), DMF (2.0 mL), 100 °C, 12 h. b Isolated yield. c Forty percent of the starting material was recovered. d AgNO₃ (0.6 mmol) was used instead of AgOAc. e AgNO₃ (0.1 mmol) was used instead of AgOAc.

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In order to further expand the synthetic utility of this methodology, we next investigated the hydroalkylation of alkenols with C-centered radical precursors via the HAT strategy. Malonate, which is prone to undergoing oxidation to produce C-centered radicals, was then used to test our hypothesis.¹² After screening lots of reaction parameters (Table S2†), we optimized the reaction conditions of this hydroalkylation as follows: 3.0 equiv. of Mn(OAc)₃ as the oxidant and 2,2,2-trifluoroethanol as the solvent at 110 °C for 36 h.^12d The reaction of various substrates 1A, 1C, 1F, 1M, and 1O with malonate 2c as the radical precursor gave the desired malonate-substituted ketone products 5Ac, 5Cc, 5Fc, 5Mc, and 5Oc in moderate yields (Scheme 2).

Scheme 2 Substrate scope of hydroalkylation. Reaction conditions: 1 (0.2 mmol), 2c (0.3 mmol), Mn(OAc)₃·2H₂O (0.6 mmol), 2,2,2-trifluoroethanol (2.0 mL), 110 °C, 36 h.

Inspired by the above success in the 1,5-HAT process, we subsequently switched our attention to the use of alkenols 6 with one-carbon-longer chains to probe whether the more challenging 1,6-HAT obtained via a higher energy seven-membered cyclic transition state¹³ could be realized under the current reaction system. Gratifyingly, under the reaction conditions identical to those of the 1,5-HAT process (Tables 2, 3 and Scheme 2), remotely sulfonyl- (7Aa, 7Ba), phosphonyl- (7Ab, 7Cb), and malonate-substituted (7Ac, 7Bc) aldehydes/ketones were obtained in moderate to good yields from alkenyl alcohols 6A–6C (Table 4).

Table 4 Substrate scope of the 1,6-HAT process

a Reaction conditions: 6 (0.2 mmol), 2a (0.6 mmol), K₂S₂O₈ (0.4 mmol), CH₃CN (0.7 mL), H₂O (1.4 mL), 80 °C. b Reaction conditions: 6 (0.2 mmol), 2b (0.4 mmol), AgOAc (0.6 mmol), DMF (2.0 mL), 100 °C. c Reaction conditions: 6 (0.2 mmol), 2c (0.3 mmol), Mn(OAc)₃·2H₂O (0.6 mmol), 2,2,2-trifluoroethanol (2.0 mL), 110 °C. d Reaction conditions: 6 (0.2 mmol), 2b (0.4 mmol), AgNO₃ (0.6 mmol), DMF (2.0 mL), 100 °C.

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To gain insights into the reaction mechanism, several control experiments were performed. Firstly, the sulfonylation reaction was run under the standard conditions with the addition of radical scavengers such as benzoquinone (BQ) and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). The reactions were significantly inhibited by these reagents (Scheme 3, eqn (1)), indicating radical intermediates in the reaction. Secondly, the use of [D₁]-1A under the standard sulfonylation conditions led to the formation of [D₁]-3Aa with complete transposition of the α-D atom (Scheme 3, eqn (2)). Thirdly, no crossover products 3Aa or [D₁]-3Pa were detected when equal molar amounts of [D₁]-1A and 1P were used under the standard conditions, which excludes an intermolecular HAT process (Scheme 3, eqn (3)).

Scheme 3 Control experiments.

To illustrate the potential synthetic applicability of this protocol, 3Aa was prepared in large scale to indicate that no significant erosion in the reaction efficiency had occurred (Scheme 4, eqn (1)). The utility of our protocol was further demonstrated by cyclization of the obtained ketone 3Ma under basic conditions at room temperature to afford the α,β-unsaturated sulfone product 8 in 73% yield; 8 is a good Michael acceptor widely applied in biotransformation and organic synthesis (Scheme 4, eqn (2)).

Scheme 4 Large scale preparation and transformation.

Conclusions

In summary, we have successfully developed a general and efficient radical protocol for the concomitant diverse hydrofunctionalization of alkenes and oxidation of remote alcohols. It provides valuable sulfonyl-, phosphonyl-, and malonate-substituted ketones or aldehydes through ketyl radical intermediates via 1,5(6)-HAT triggered by addition of the corresponding S-, P-, and C-centered radicals to alkenes in an anti-Markovnikov manner. This mild and versatile method exhibits a broad substrate scope in regard to alkenols with or without gem-disubstituted tethering groups and tolerates a series of carbon- and heteroatom-centered radical precursors.

Experimental

General procedure for the radical hydrosulfonylation reaction system

To a flame-dried Schlenk tube equipped with a magnetic stir bar were added 1 (0.2 mmol), 2a (0.6 mmol), and K₂S₂O₈ (0.4 mmol). The tube was evacuated and backfilled with argon three times, and then MeCN (0.7 mL) and H₂O (1.4 mL) were added. The tube was stirred at 80 °C for 18 h and then H₂O (5 mL) was added. EtOAc was used to extract the product from the aqueous layer (3 × 20 mL). The combined organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated to afford the crude product, which was purified using flash column chromatography to afford the product 3.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

Financial support from the National Natural Science Foundation of China (No. 21722203, 21702093, and 21572096), the Shenzhen special funds for the development of biomedicine, Internet, new energy, and new material industries (No. JCYJ20170412152435366 and JCYJ20170307105638498), and the Shenzhen Nobel Prize Scientists Laboratory Project (No. C17213101) is greatly appreciated.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental section and characterization of compounds. See DOI: 10.1039/c8qo00734a

‡ These authors contributed equally to this work.

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