Hydroperfluoroalkylation of electron-deficient olefins with perfluoroalkyl iodides promoted by zinc/viologen

Abstract

The hydroperfluoroalkylation of electron-deficient olefins with perfluoroalkyl iodides promoted by a zinc/viologen system is described. Interestingly, no iodoperfluoroalkylation product was observed without the presence of radical H-donor.

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As the incorporation of a fluoroalkyl group into a drug candidate may result in profound modification of its physicochemical properties including increased lipophilicity and superior metabolic stability,¹ significant efforts have been directed towards the exploration of efficient methods for fluoroalkylation.² Although the use of perfluoroalkyl moieties as pharmacophores has been less investigated compared with other fluorinated functionalities such as trifluoromethyl and difluoromethyl groups,¹ the development of perfluoroalkylation strategies may open up avenues for further study on the biological potential of perfluoroalkyl groups. Therefore, a number of general and mild perfluoroalkylation approaches have been developed.³ As one of the most convenient and straightforward protocols, radical perfluoroalkylation has received a great deal of attention recently.^2d,3g,4 Since perfluoroalkyl radicals exhibit electrophilic reactivity, these species are reactive towards perfluoroalkylation of electron-rich substrates.⁵ However, radical perfluoroalkylation of electron-deficient olefins remains a largely ignored research area.

The readily commercially available source for perfluoroalkyl radical is perfluoroalkyl halide. The conversion of electron-deficient olefins with perfluoroalkyl halides usually results in haloperfluoroalkylation.⁶ In order to suppress the halogenation process, the addition of a radical hydrogen donor into the reaction system may be required.⁷ Interestingly, perfluoroalkylation without halogenation could also occur well promoted by an appropriate initiator, such as bimetal system,⁸ photocatalyst,⁹ and triethylborane.¹⁰ But these reactions suffer from narrow substrate scope, low yields, or the use of expensive initiator. On the basis that viologens¹¹ and arenes¹² have served as valuable electron-transfer reagents, we speculated that viologen should be able to be used in perfluoroalkylation of electron-deficient olefins via a single-electron-transfer process. In continuation of our research interest in the chemistry of fluoroalkylation,¹³ we have now investigated the hydroperfluoroalkylation of α,β-unsaturated ketones and esters with perfluoroalkyl iodides promoted by zinc/viologen system.

Our initial attempt at the hydroperfluoroalkylation of α,β-unsaturated ketone 1a with iodide 2a promoted by zinc powder and butyl viologen in DMF at 110 °C was successful to afford the desired product 3a, albeit in low yield (entry 1, Table 1). A brief survey of the reaction solvents (entries 1–6) revealed that chloroform was a suitable solvent (entry 5). Both zinc powder and viologen were necessary for this conversion, as evidenced by the results that no expected product was observed with the absence of either one (entries 7–8). Decreasing the loading of viologen led to the dramatic decrease in the yield (entries 9–10 vs. entry 5), but increasing its loading can't increase the yield (entry 11 vs. entry 5). Lower yields were obtained with lowering the reaction temperature (entries 12–14). 4 h of reaction time can guarantee the full conversion of substrate 1a. Shortening the reaction time to 2 h, the yield was decreased (entry 15 vs. entry 5). The transformation was not particular sensitive to water, and 38% yield could be obtained with the presence of 4 equiv. of water (entry 16). Refluxing the reaction mixture in a Schlenk tube under N₂ atmosphere gave the desired product only in 47% yield (entry 17).

Table 1 Screening reaction conditions^a

Entry	Solvent	X (equiv.)	Yield^b (%)
a Reaction conditions: the mixture of substrate 1a (0.1 mmol), perfluoroalkyl iodide 2a (0.3 mmol), zinc powder (0.6 mmol), dibutyl-4,4′-bipyridinium dibromide and solvent (1 mL) was stirred in a sealed tube at 110 °C for 4 h.b Isolated yields.c No zinc powder was used.d Reaction temperature was 50 °C.e Reaction temperature was 70 °C.f Reaction temperature was 90 °C.g Reaction time was 2 h.h H2O (4 equiv.) was used as an additive.i The reaction mixture was refluxed in a Schlenk tube under N2 atmosphere.
1	DMF	2	22
2	CH3CN	2	26
3	C2H5OH	2	19
4	THF	2	30
5	CHCl3	2	62
6	Cyclohexane	2	7
7^c	CHCl3	2	0
8	CHCl3	0	0
9	CHCl3	1	36
10	CHCl3	0.5	28
11	CHCl3	3	59
12^d	CHCl3	2	44
13^e	CHCl3	2	55
14^f	CHCl3	2	59
15^g	CHCl3	2	52
16^h	CHCl3	2	38
17^i	CHCl3	2	47

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With the optimal reaction conditions in hand (entry 5, Table 1), we then investigated the substrate scope for the hydroperfluoroalkylation of electron-deficient olefins promoted by zinc/viologen system. As shown in Table 2, the reactions occurred smoothly to give the desired products in moderate to good yields. It is noteworthy that no iodoperfluoroalkylation product was detected. The examination of electronic effects (entries 1–10) revealed that both weakly electron-withdrawing groups (entries 1–4) and electron-donating groups (entries 6–10) showed no side effect on the conversion of unsaturated aryl ketones. But a strong electron-withdrawing group led to a low yield (entry 5), which is because the substrate is reactive towards zinc powder. Besides perfluorobutyl iodide, other perfluoroalkyl iodides were also efficient radical source for this transformation (entries 11–12). The hydroperfluoroalkylation is not only applicable to α,β-unsaturated aryl ketones, but also to α,β-unsaturated aliphatic ketone (entry 13) and α,β-unsaturated ester (entry 14).

Table 2 Substrate scope for hydroperfluoroalkylation

Entry	R	RF	Yield^a (%)
a Isolated yields.
1	p-BrC6H4 (1a)	^nC4F9	3a, 62
2	o-BrC6H4 (1b)	^nC4F9	3b, 50
3	m-BrC6H4 (1c)	^nC4F9	3c, 54
4	p-ClC6H4 (1d)	^nC4F9	3d, 78
5	p-NO2C6H4 (1e)	^nC4F9	3e, 38
6	C6H4 (1f)	^nC4F9	3f, 71
7	p-PhC6H4 (1g)	^nC4F9	3g, 71
8	p-MeC6H4 (1h)	^nC4F9	3h, 74
9	p-MeOC6H4 (1i)	^nC4F9	3i, 64
10	β-Naphthyl (1j)	^nC4F9	3j, 64
11	p-BrC6H4 (1a)	^iC3F7	3k, 42
12	p-BrC6H4 (1a)	^nC6F13	3l, 54
13	Cyclohexyl (1m)	^nC4F9	3m, 76
14	p-PhCH2O (1n)	^nC4F9	3n, 80

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Since viologens are efficient electron-transfer reagents, it is reasonable to conceive that the hydroperfluoroalkylation proceeds via a single-electron-transfer process to generate perfluoroalkyl radical. The presence of the radical scavenger TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl] completely suppressed the desired transformation, further suggesting that the a radical process was involved (eqn (1), Scheme 1). In order to determine what the hydrogen source is for this hydroperfluoroalkylation reaction, more experimental evidences were collected. No deuterated product was detected by using CDCl₃ instead of CHCl₃ as the solvent for the conversion of naphthyl substrate 1j, implying that the hydrogen is not from the solvent. The use of D₂O (2 equiv.) as an additive under the optimal reaction conditions gave the desired product in 53% yield, with 61% deuterated at the α-position of the carbonyl group (eqn (2), Scheme 1), which means that H₂O is the source for the hydrogenation.

Scheme 1 Evidence for the elucidation of the reaction mechanism.

Based on the above results, we propose the reaction mechanism as shown in Scheme 2. The redox reaction of viologen with zinc powder generates Zn(I) and radical cation species A. The transfer of one electron from intermediate A to perfluoroalkyl iodide produces perfluoroalkyl radical and regenerates viologen. The attack of the perfluoroalkyl radical at the double bond in substrate gives intermediate B, which would be readily reduced by Zn(0) or Zn(I) to afford stable enolate C. It can't be ruled out that species B may also undergo iodine abstraction from perfluoroalkyl iodide to generate iodoperfluoroalkylation product D. In the presence of excessive zinc powder, the reduction of product D would occur easily to give enolate C. Protonation of enolate C by H₂O furnishes the final product.

Scheme 2 Plausible reaction mechanism.

The viologen can't be used in a catalytic amount because species A undergoes not only electron transfer to regenerate viologen, but also other conversions to afford side-products. For instance, the side product E formed by the combination of radical cation A with perfluorobutyl radical was detected by ESI† (Scheme 3).

Scheme 3 Side reaction of viologen.

Conclusions

In conclusion, we have described the hydroperfluoroalkylation of α,β-unsaturated ketones and esters with perfluoroalkyl iodides promoted by zinc/viologen system. It is noteworthy that no iodoperfluoroalkylation product was detected in this conversion. This zinc/viologen system-promoted hydroperfluoroalkylation strategy may find utilities in other research area.

Acknowledgements

This work was financially supported by the National Basic Research Program of China (2015CB931900, 2012CBA01200), the National Natural Science Foundation (21421002, 21472222, 21502214, 21542005, 21272152), the Chinese Academy of Sciences (XDA02020105, XDA02020106) and the Science and Technology Commission of Shanghai Municipality (15DZ1200102).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra11557h

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