Selective monofluorination of active methylene compounds: the important role of ZnCl₂ in inhibiting overfluorination

Abstract

In the presence of zinc chloride (ZnCl₂), active methylene compounds can be selectively monofluorinated at room temperature, and the undesired overfluorination (gem-difluorination) can be significantly diminished. The mechanistic study shows that ZnCl₂ plays an important role in selective monofluorination through its interaction with a Brønsted base to control the deprotonation of the starting methylene compounds over the corresponding monofluorinated products.

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Owing to their structural diversity and peculiar reactivity, active methylene compounds have found many applications in organic synthesis such as the Michael addition and aldol and Knoevenagel reactions.¹ On the other hand, compounds bearing a monofluoromethylene group (–CHF–) are important candidates in isostere-based drug design,² and these compounds can be usually prepared by an electrophilic C–H monofluorination of active methylene compounds. However, this reaction often suffers from overfluorination,^1b,3 resulting in a mixture of mono- and difluorinated products. In many cases, the similar polarity of the mono- and difluorinated products leads to difficulty in their separation (purification).^3b The general solution to this problem is that equal equivalents of a base and fluorination reagent (based on that of the active methylene compounds) are incorporated at low temperatures, but the efficiency of fluorination is often unsatisfactory.⁴ Other methods^3a,5 include the conversion of active methylenes to the corresponding enol ethers, and the latter species are selectively monofluorinated; however, this protocol is not amenable to methylene-containing sulfones. Fluorine-containing sulfones proved to be of great value in organic synthesis,⁶ especially in selective fluoroalkylation reactions.⁷ To the best of our knowledge, however, practical methods for the preparation of monofluorinated sulfones via selective fluorination of non-fluorinated sulfones are rare.⁸ In this communication, we wish to report a ZnCl₂-mediated selective monofluorination of active methylene compounds using an electrophilic fluorination reagent at room temperature.

At the onset of our investigation, we focused on the monofluorination of bis(phenylsulfonyl)methane (1a), since selective monofluorination of 1a can lead to a highly useful monofluoromethylation reagent 2a.^3b,9 Previously, efforts have been made by the Hu^9a and Shibata^9b groups through electrophilic fluorination to synthesize 2a; however, in both cases the formation of the difluorinated by-product 3a was observed.^9a,10 After a brief screening, we found that the employment of a bulky base was beneficial to minimize difluorination. Therefore, we chose sodium tert-butoxide (1.0 equiv.) as a base to react with 1a in THF at room temperature, and then 2.0 equiv. of SelectFluor was added. It turned out that a good yield of the monofluorinated 2a was obtained, with only a small amount of the difluorinated by-product 3a being observed by ¹⁹F NMR (Table 1, entry 1). However, when we increased the equivalents of the base to improve the conversion of the starting material 1a, the tendency of overfluorination unfortunately increased (Table 1, entries 2–4).

Table 1 Survey of reaction conditions

Entry	^tBuONa (equiv.)^a	ZnCl2 (equiv.)^a	2a (%)^b	2a (%)^b
a The equivalent is relative to that of 1a. b Determined by ^19F NMR analysis of the crude reaction mixture using PhCF3 as an internal standard.
1	1.0	—	73	2
2	1.2	—	71	3
3	1.5	—	61	19
4	1.8	—	60	22
5	1.8	1.0	79	3
6	1.8	1.5	57	—
7	1.8	1.8	45	—
8	2.2	1.5	91	7
9	2.2	1.8	79	—
10	2.5	2.2	94	3
11	2.5	2.5	91	1

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We presumed that the van der Waals radius of fluorine resembles that of hydrogen, leading to the difficulty in preventing overfluorination. Inspired by the monoiodination of methylene-containing sulfones reported by Imamoto,¹¹ we supposed that it could be possible to prepare the corresponding organozinc reagent¹² after deprotonation of active methylene compounds. Given the fact that the basicity of the organozinc reagent is relatively weak, over-deprotonation should be significantly inhibited. To test our hypothesis, 1.0 equiv. of anhydrous ZnCl₂ was added to the reaction mixture. We were satisfied to find that the monofluorinated product 2a was formed in 79% yield, with the difluorinated by-product 3a being formed in 3% yield (Table 1, entry 5). After further tuning the molar ratio between ^tBuONa and ZnCl₂ (entries 6–11), we found that an optimal yield (91%) of 2a was obtained when 2.5 equiv. of ^tBuONa and 2.5 equiv. of ZnCl₂ were employed (Table 1, entry 11).

Thereafter, we continued to examine the substrate scope of this new protocol of ZnCl₂-mediated monofluorination. Initially, we applied the optimized reaction conditions (as described in Table 1, entry 11) to other active methylene compounds such as 1b, 1c, and 1d; however, we quickly realized that the reaction is very sensitive to different substrates, and further optimizations are needed for different active methylene substrates.¹³ It is obvious that a significant change in the C–H acidity of 1 caused by different substituents results in a great influence in the degree of deprotonation of methylene compounds, and therefore, the alteration of the basicity of the reaction mixture could be crucial to the selectivity of deprotonation. We found that when substituents R¹ and R² on the methylene compound 1 are more electron-withdrawing, a decrease of the amount of ^tBuONa and/or an increase of that of ZnCl₂ could improve the selectivity of monofluorination.¹⁴ It should be mentioned that, by tuning the ratio between ^tBuONa and ZnCl₂, selective monofluorination was accomplished with a variety of structurally diverse active methylene compounds (Table 2). This ZnCl₂-mediated new method was also found to be amenable to other active methylene compounds without sulfonyl groups (see 2d, 2e, 2h and 2i). To verify the important role of ZnCl₂ in selective monofluorination of active methylene compounds, we chose some methylene-containing substrates (1b–1f) to be fluorinated in the absence of ZnCl₂: 1.0 equiv. sodium tert-butoxide was added to react with 1 in THF at room temperature, and then 2.0 equiv. of SelectFluor was added. In all cases, difluorinated by-products were observed by ¹⁹F NMR analysis. Moreover, for substrates 1d, 1e and 1f, these reactions suffered from overfluorination severely (Table 3).

Table 2 Electrophilic monofluorination of active methylene compounds 1 (R¹, R² = EWG)^a,b,c,d,e

a In all cases, the equivalents of ^tBuONa (x) and ZnCl₂ (y) are based on that of the corresponding starting material 1. b The yield of 2 refers to the isolated yield. c Unless otherwise mentioned, difluorinated products 3 were not observed by ¹⁹F NMR; when 3 was formed, the yield of 3 was determined by ¹⁹F NMR. d The range of pK_a values of C–H bonds among these methylene compounds 1 is between 11.4 and 17.2 in DMSO. e EWG = electron-withdrawing group.

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Table 3 Electrophilic fluorination of active methylene compounds 1 in the absence of ZnCl₂ (R¹, R² = EWG)^a,b

a The equivalent of ^tBuONa is based on that of the corresponding starting material 1. b The yield of 2 and 3 is determined by ¹⁹F NMR analysis of the crude reaction mixture using PhCF₃ as an internal standard.

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Inspired by the achievement of selective monofluorination with active methylene compounds 1, we extended the substrate scope of this reaction to relatively inactive methylene compounds 4 (see Table 4). Fluorinated benzothiazolyl sulfones have been reported as general synthons for the fluoro-Julia–Kocienski olefinations, and the resulting monofluoroalkene moiety can be used as a non-hydrolyzable mimetic of amide in the peptidomimetic unit of protease inhibitors.¹⁵ We envisaged that, for relatively inactive methylene compounds with the less acidic –CH₂– unit, a stronger base than tBuONa should be used. Therefore, lithium hexamethyldisilazide (LiHMDS) was chosen as a base for the reaction, and the amounts of base and ZnCl₂ were further optimized for each substrate 4 (for details of optimization, see ESI†). As shown in Table 4, a variety of relatively inactive methylene compounds can be selectively fluorinated to give the corresponding products 5; in all cases, no difluorinated by-products were observed.

Table 4 Electrophilic monofluorination of active methylene compounds 4 (R¹ = EWG, R² = phenyl, alkenyl)^a,b,c,d

a In all cases, the equivalents of LiHMDS (x) and ZnCl₂ (y) are based on that of starting materials 4. b The yield of 5 refers to the isolated yield. c In all cases, the difluorinated by-products are not observed. d The range of pK_a values of C–H bonds among these methylene compounds is between 17.7 and 23.4 in DMSO.

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To gain more insight into this ZnCl₂-mediated selective monofluorination, we carried out some experiments. First of all, we compared the tendency of deprotonation and fluorination between methylene compounds and the corresponding monofluorinated ones using (PhSO₂)₂CH₂ and (PhSO₂)₂CHF as model compounds. Equal equivalents of (PhSO₂)₂CH₂ and (PhSO₂)₂CHF were mixed in THF-d₈ in the presence of a substoichiometric amount of LiHMDS, and the mixture was characterized by ¹H NMR (1A, 1B, for details, see ESI†). It was found that (PhSO₂)₂CH₂ was more easily deprotonated than (PhSO₂)₂CHF, which was consistent with the theoretical calculation reported by Prakash and Olah.¹⁶ Secondly, we mixed equal equivalents of (PhSO₂)₂CH₂ and (PhSO₂)₂CHF in THF-d₈ in the presence of an excess amount of NaH, and thereafter, the reaction was quenched with a substoichiometric amount of N-fluorobisphenylsulfonimide (NFSI) (2A–2F, for details, see ESI†). It was found that (PhSO₂)₂CHF showed higher tendency for fluorination. According to these experimental results, the key to acquire the most monofluorinated product and inhibit the difluorination is to maximize the deprotonation of the methylene compound (PhSO₂)₂CH₂ and minimize the further deprotonation of the monofluorinated intermediate (PhSO₂)₂CHF. Thirdly, we added (PhSO₂)₂CH₂ to THF-d₈ under the optimized conditions (2.5 equiv. of ^tBuONa and 2.5 equiv. of ZnCl₂) (3A, 3B, for details, see ESI†). Unexpectedly, (PhSO₂)₂CH₂ was almost intact (i.e., the deprotonation hardly occurred), which was indicated by ¹H NMR.

As reported previously,¹⁷ mixing ^tBuONa with ZnCl₂ could generate the tert-butoxyzincate complex Na₂[Zn(O^tBu)₃]₂, whose basicity was too weak to deprotonate (PhSO₂)₂CH₂. Indeed, we observed a new species by ¹H NMR spectroscopy when ^tBuONa and ZnCl₂ were mixed (Fig. 1, 4B).

Fig. 1 Mechanistic study through ¹H NMR experiments.

Based on the aforementioned results, the selective monofluorination reaction is explained as depicted in Scheme 1. A trace amount of “(PhSO₂)₂CHZn” is generated in an equilibrium when (PhSO₂)₂CH₂ is added to the mixture of ^tBuONa and ZnCl₂ (through in situ formation of Na₂[Zn(O^tBu)₃]₂). Subsequently, SelectFluor is added to this mixture. “(PhSO₂)₂CHZn” is therefore fluorinated, which shifts the equilibrium to the side of “(PhSO₂)₂CHZn” (Scheme 1). Furthermore, for the reactions with different methylene substrates, ^tBuONa and ZnCl₂ should exist in proper ratios to prevent over-deprotonation and therefore overfluorination. It is obvious that the deprotonation of (PhSO₂)₂CHF by Na₂[Zn(O^tBu)₃]₂ is almost negligible. In the cases of relatively inactive methylene compounds (as shown in Table 4), we also presume that the reaction proceeds through a similar pathway in the presence of LiHMDS and ZnCl₂.¹⁸

Scheme 1 The equilibrium in the process of fluorination.

Conclusions

In conclusion, we have developed a highly selective and efficient monofluorination of methylene compounds with inhibition of undesired difluorination products. ZnCl₂ plays an important role in selective monofluorination through its interaction with a Brønsted base to control the deprotonation of the starting methylene compounds rather than the monofluorinated products. Given the mild reaction conditions and the ready availability of the reagents, this method has promising important applications in the synthesis of monofluoromethylene-containing compounds.

Acknowledgements

Support of our work by the National Basic Research Program of China (2012CB215500 and 2012CB821600), the National Natural Science Foundation of China (21372246 and 20825209), the Shanghai QMX program (13QH1402400), and the Chinese Academy of Sciences is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and the characterization data of new compounds. See DOI: 10.1039/c4qo00090k

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