DOI: 10.1002/chem.201405229

Communication

& Radical Reactions

Intermolecular Radical Carbofluorination of Non-activated Alkenes Stephanie Kindt and Markus R. Heinrich*[a] In memory of Hans Meerwein’s 135th birthday and the 75th anniversary of the Meerwein arylation

Abstract: The Meerwein arylation has recently become an even more powerful tool for the functionalization of alkenes. Besides the attachment of an aryl group, radical reactions of this type allow the introduction of several different heteroatoms and a broad variety of alkenes are meanwhile tolerated as substrates. Closing a long-standing gap of the methodology, this communication describes the first intermolecular Meerwein-type carbofluorination. In metal-free reactions, arylalkyl fluorides were obtained from arylhydrazines and alkenes with Selectfluor acting as oxidant and as radical fluorine source.

Since Hans Meerwein’s[1] first report in 1939 many variants of the Meerwein arylation have been developed (Scheme 1).[2] Besides the originally employed aryldiazonium salts (1, X = N2 + ), bromo- and iodobenzenes (1, X = Br, I) in particular have gained importance over the last few decades, and the diazonium salts themselves have just recently seen a remarkable revival in photocatalyzed versions.[3] Due to improved procedures, non-activated alkenes are now comparatively well tolerated substrates as activated alkenes (e.g. acrylates: 2, R =

Scheme 1. Carbofluorinations as an extension of the Meerwein arylation.

[a] S. Kindt, Prof. Dr. M. R. Heinrich Department fr Chemie und Pharmazie, Pharmazeutische Chemie Friedrich-Alexander-Universitt Erlangen-Nrnberg Schuhstraße 19, 91052 Erlangen (Germany) Fax: (+ 49) 9131-85-22585 E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405229. Chem. Eur. J. 2014, 20, 15344 – 15348

COOR’; styrene: 2, R = Ph), and the use of new radical scavengers has considerably broadened the range of functional groups or atoms Y. Regarding the variety of groups or atoms Y in the arylation products 3, many studies have recently focused on the development of carbooxygenation- (Y = OR)[4] or carboaminationtype (Y = NR2)[5] reactions. The first examples for intermolecular radical carbofluorinations,[6–8] which finally extend the scope of the Meerwein arylation to all halogens, are reported in this Communication. From a more general point of view, fluorination reactions of aliphatic, olefinic, and aromatic substrates represent a highly topical field of research with many groups being involved worldwide.[9, 10] Intra- as well as intermolecular carbofluorinations have also just recently been achieved, but so far only under transition-metal catalysis[11] or via ionic mechanisms.[12] Coming back to Meerwein arylations, the challenging aspect of a carbofluorination is to achieve a balanced interplay of the initial aryl radical addition to the alkene 2 and the selective fluorine transfer to the alkyl radical intermediate 4 to finally give the desired alkyl fluoride 5 (Scheme 1). Although these substeps have been studied individually,[13] and the radical fluorine transfer[14] to carbon-centered radicals is known to be feasible with reagents such as Selectfluor,[15] NFSI,[16a] NFPY,[16b] or NFTh,[16c] no combinations have yet been reported. Recent synthetic applications featuring radical fluorine transfer include decarboxylative fluorinations,[17] azido-,[18a] amino-,[18b] phosphono-,[18c] and hydrofluorinations,[19] as well as C H bond activations followed by fluorine transfer.[20] Owing to the strong oxidizing character of the above-mentioned radical fluorine transfer reagents and their inherent sensitivity to reductive conditions, we anticipated that arylhydrazines 6 could be suitable reactants for our purpose. Under oxidative conditions arylhydrazines are reliable sources of aryl radicals,[21, 22] and the oxidizing fluorinating reagent might thereby even play a double role in aryl radical generation and fluorine transfer. To investigate the feasibility of such a Meerwein-type carbofluorination, several series of experiments were carried out with 4-chlorophenylhydrazine (6 a), 3-buten-1-yl acetate (2 a), and Selectfluor (7) (Table 1). The first row of experiments (entries 1–6) showed that the arylhydrazine 6 a should be added slowly, over around 60 min, to 2 a and 7 in aqueous solutions of acetonitrile. This is beneficial since the required absence of oxygen (see below) would otherwise lead to increased concentrations of the aryldiazene 8,[23] and enable side reactions such as the addition of aryl radicals 9 to the diazene 8 to give azo compounds 10

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Communication Table 1. Radical carbofluorination: optimization of reaction conditions.

Entry 2 a:7 Conditions (CH3CN:H2O), temp., 6 a (added over…)[a] Yield[b] 5 a [%] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

12:5 12:5 12:5 12:5 12:5 12:5 12:5 12:5 12:5 3:5 24:5 12:3 12:5 12:5 12:5 12:5 12:5 12:5 12:5 12:5 12:5

(100:0), rt, 6 a (5 min) (100:0), rt, 6 a (60 min) (1:1), rt, 6 a (30 min) (1:1), rt, 6 a (120 min) (5:1), rt, 6 a (60 min) (8:1), rt, 6 a (120 min) (5:1), rt, 6 a (30 min) (5:1), rt, 6 a (120 min) (5:1), rt, 6 a (300 min) (5:1), rt, 6 a (60 min) (5:1), rt, 6 a (60 min) (5:1), rt, 6 a (60 min) (5:1), 40 8C, 6 a (60 min) (5:1), 0 8C, 6 a (60 min) (5:1), rt, 6 a (60 min), under air (5:1), rt, 6 a (120 min), K2CO3 (2.5 equiv) (5:1), rt, 6 a  HCl (60 min) (5:1), rt, 6 a (60 min), CF3COOH (3 equiv) (5:1), rt, 6 a (1200 min), CF3COOH (3 equiv) (5:1), rt, 6 a (60 min), CH3COOH (3 equiv) (5:1), rt, 6 a (60 min), CH3COOH (3 equiv), MnO2 (0.5 equiv) 12:5 (100:0), NFSI (5 equiv),[d] rt, 6 a (60 min) 12:5 (100:0), NFPY (5 equiv),[d] rt, 6 a (60 min)

5 20 31 30 46 38 42 46 40 19 44 32 33 28 23[c] 30 36 23 32 36 42 1 –

[a] Under argon unless otherwise noted. [b] Yield determined by 1H NMR spectroscopy using dimethyl terephthalate as internal standard. [c] Hydroperoxide 12 was obtained in 20 % yield; see also ref. [21e]. [d] NFSI or NFPY used instead of Selectfluor.

(Scheme 2).[24] Unlike in other reports,[18a] higher contents of water gave lower yields (entries 3, 4). Variations of the reaction time (entries 7–9) confirmed an ideal time span of 60 to 120 min for the addition of 6 a, and control reactions proved that the product 5 a is stable for six hours under the chosen conditions. Higher amounts of the alkene 2 a did not lead to an improvement (entry 11), whereas a reduction of the equivalents of either alkene 2 a (entry 10) or Selectfluor (7) resulted in remarkably decreased yields (entry 12). After having evaluated the influence of the reaction temperature (entries 13, 14), we turned to investigate the effect of

Scheme 2. Products and mechanistic steps in the carbofluorination reaction. Chem. Eur. J. 2014, 20, 15344 – 15348

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various additives (entries 15–21). Although the presence of oxygen could basically lead to improved yields due to a faster conversion of diazene 8 into aryl radicals 9, and thus less overoxidation of 8 to diazonium ions 11, the overall result is now significantly impaired by a formation of hydroperoxide 12 from alkyl radical intermediate 13 (Scheme 2).[21e] As the oxidation of the arylhydrazine by Selectfluor (7) leads to a formation of hydrogen fluoride, which might slow down the reaction through protonation of the hydrazine 6 a, the addition of potassium carbonate was evaluated, but showed no improvement (entry 16). The success of recently reported methods such as the azido-fluorination[18a] also led us to probe acidic conditions, but neither the use of 6 a as hydrochloride nor the addition of trifluoroacetic or acetic acid were able to give better yields (entries 17–21). A comparison of the results (entries 18–21) does however support the assumption that the arylhydrazine 6 a is more slowly oxidized in the presence of acids and longer reaction times (entry 19) or a co-oxidant (entry 21) are then required. Two control experiments with the alternative fluorinating agents NFSI[16a] and NFPY,[16b] which had so far been left aside due to the fact that these compounds might act as aryl radical scavengers themselves, led to only low yields of the desired product 5 a. With these optimized conditions we turned next to investigate the scope and limitations of the Meerwein-type carbofluorination. In a first series of experiments, the influence of the substituents on the arylhydrazine was evaluated (Table 2). The best result in this series was obtained with unsubstituted phenylhydrazine, which gave the carbofluorination product 5 b in 57 % yield. Yields in the range of 30–49 % were reached for arylalkyl fluorides 5 a and 5 c–m prepared from ring-methylated and ring-halogenated phenylhydrazines. Donor-substituted 4-methoxyphenylhydrazine furnished the fluorinated product 5 n in only 11 % yield, whereas electron-poor arylhydrazines, such as 2-pyridinylhydrazine, led to carbofluorination products 5 o–r again in better yields of 25–37 %.[25] In the second part of the study various alkenes were evaluated with regard to their applicability in carbofluorination reactions (Table 3). Whereas the exchange of butenyl for allyl acetate led to an only slightly decreased yield of product 5 s (c.f. 5 b, Table 2), which can be attributed to the now more reactive allylic position, the introduction of an additional methyl group resulted in a sharp drop to only 16 % for product 5 t. Since the aryl radical addition step to 1,1-disubstituted alkenes such as 3-methyl-3-buten-1-yl acetate is known to be fast, the large decrease in outcome for 5 t is certainly due to a less favorable fluorine-transfer to tertiary alkyl radicals. The successful experiments with 3-buten-1-ol to give 5 u–w ruled out a special effect exerted by the acetate group[26] and confirmed the preference for unsubstituted phenylhydrazine (c. f. Table 2). 5-Hexen-1-ol, 5-penten-2-one, and 4-pentenoic acid also gave the desired products 5 x–z, thereby indicating that also the polarity of the alkenes could have a strong influence on the product formation. The classical olefinic substrates used in Meerwein arylations, which are activated alkenes including acrylates, acrylonitriles, and styrenes,[2b] failed to give

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Communication Table 2. Radical carbofluorination: variation of the arylhydrazine.[a,b]

Table 3. Radical carbofluorination: variation of the alkene.[a,b]

[a] See Experimental Section for general procedure. [b] Yields after purification by column chromatography.

[a] See Experimental Section for general procedure. [b] Yields after purification by column chromatography.

the carbofluorination products 5 bb and 5 cc,[27] or produced them in only low yield as in the case of 5 aa (11 %). As the aryl radical addition to these alkenes is fast,[13] it again has to be an inefficient fluorine-transfer step that prevents product formation. The final experiment with diallylether (2 dd) was set up to gain insights into the kinetics of fluorine transfer to the so far preferred group of secondary alkyl radical intermediates, albeit 2 dd is not perfectly suited due to its high lipophilicity. Carbofluorination of 2 dd can thereby basically lead to the arylalkyl fluoride 5 dd, if the fluorine transfer proceeds rapidly, or to 14 a if the 5-exo-cyclization (kCycl = 9  106 m 1 s 1) occurs before fluorination.[28] The absence of 5 dd in the product mixture clearly indicated that the fluorine transfer to secondary alkyl radicals is not a very fast process under the chosen reaction conditions.[29] By presuming a minimal ratio of cyclized products 14 a and 14 b to non-cyclized 5 dd of 20:1, and an average concentration of Selectfluor of 0.7 mol L 1, these values and kCycl can be used to estimate an upper limit for the rate constant of the fluorine transfer of kFT = 6  105 m 1 s 1.[28] The ratio of the non-fluorinated compound 14 b and fluorinated 14 a moreover shows that the fluorine transfer to primary alkyl radicals is also not effective under the chosen conditions. Chem. Eur. J. 2014, 20, 15344 – 15348

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The fact that the estimated rate for fluorine transfer is low compared to halogen transfer[30] or related scavenging steps[2b] in known Meerwein arylations explains well why the carbofluorination principle is so far limited to non-activated alkenes 2 a and 2 s–z, as for such substrates oligomerization is also not fast and therefore less of a competing side-process. Moreover, these considerations could be a reason why no examples for this challenging reaction type have been reported so far. More generally, our study deepens the impression that the preference of radical fluorine transfer to different types of alkyl radicals largely depends on the actual process involved. Whereas some reports clearly favor benzylic radicals,[7, 20d] and others secondary or tertiary alkyl radicals,[17a, 20c] only the acidic conditions for the azidofluorination developed by Li and coworkers[18a] so far appear to be more versatile. Remarkably, the carbofluorination products 5 a–5 aa were obtained in high purity already after aqueous work-up, which indicates that most by-products are either insoluble in diethyl ether, easily removable by extraction, or volatile.[31] In accordance with this observation, we have identified diazonium ions[32] arising from over-oxidation of the phenyldiazene as byproducts (Scheme 2). Current studies therefore focus on a catalytic system that would more quickly convert the diazene further to aryl radicals to prevent this side reaction. In summary, we have reported the first examples for intermolecular Meerwein-type carbofluorination reactions. The metal-free procedure starting from arylhydrazines, among which only electron-rich derivatives were not tolerated, gave the best results for non-activated alkenes being converted to

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Communication secondary alkyl fluorides. In the reaction course Selectfluor is acting as an oxidant to generate aryl radicals and as a fluorine source in the final radical fluorine transfer step. Beneficially, fluorine-transfer to the highly reactive aryl radicals does not occur under the chosen conditions. Given the importance of fluorinated compounds in many fields of application, especially in medicinal chemistry[33] and 18F-radiopharmacy,[34] this methodology for the first time demonstrates the feasibility of a direct synthesis of b-arylalkyl fluorides, and thereby closes the long-standing gap among the halogens in Meerwein arylations.

Experimental Section

[10]

[11]

General procedure for carbofluorination reactions: To a stirred solution of Selectfluor (1.77 g, 5.00 mmol) and the alkene (12.0 mmol) in acetonitrile/water (5:1, 5 mL) at room temperature under an argon atmosphere, a solution of the arylhydrazine (1.00 mmol) in acetonitrile/water (5:1, 4 mL) was added dropwise over a period of 1 h. After 5 min the reaction mixture was diluted with diethyl ether (10 mL). The organic layer was washed with water (30 mL) and brine (30 mL) and dried over Na2SO4. The solvents were removed under reduced pressure and the products were purified by column chromatography on silica gel.

[12]

[13]

Acknowledgements

[14]

The authors would like to thank the Deutsche Forschungsgemeinschaft (DFG) for financial support within the projects HE 5413/2–2 and HE 5413/3–1.

[15]

Keywords: carbofluorination · Meerwein phenylhydrazines · radical reactions · Selectfluor

arylation

· [16]

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Chem. Eur. J. 2014, 20, 15344 – 15348

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[27] Oligomerization was observed as main side-reaction in the attempts with methyl acrylate (2 bb) and acrylonitrile (2 cc). [28] For the rate constant of the 5-exo cyclization of a 3-oxahex-5-en-1-yl radical, see: a) A. L. J. Beckwith, S. A. Glover, Aust. J. Chem. 1987, 40, 157 – 173; b) M. Newcomb in Radicals in Organic Synthesis (Eds.: P. Renaud, M. P. Sibi), Vol. 1, Wiley-VCH, Weinheim, 2001, p. 327. [29] For electronic effects in radical atom-transfer reactions, see: A. A. Zavitsas, J. Org. Chem. 2008, 73, 9022 – 9026. [30] C. L. Jenkins, J. K. Kochi, J. Am. Chem. Soc. 1972, 94, 856 – 865. [31] No aryl fluorides, pointing to direct fluorine-transfer from 7 to the aryl radical, could be detected in the reaction mixture before work-up. [32] The formation of diazonium ions could be proven through azo coupling reactions to b-naphthol. In the reaction course, the diazonium ions however appear to be largely present as adducts, since free diazonium ions would effectively lead to carbodiazenylation (see ref. [13]). [33] a) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886; b) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308 – 319; c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320 – 330. [34] a) For recent applications, see: I. S. R. Stenhagen, A. K. Kirjavainen, S. J. Forsback, C. G. Jørgensen, E. G. Robins, S. K. Luthra, O. Solin, V. Gouverneur, Chem. Commun. 2013, 49, 1386 – 1388; b) for a review, see: P. W. Miller, N. J. Long, R. Vilar, A. D. Gee, Angew. Chem. 2008, 120, 9136 – 9172; Angew. Chem. Int. Ed. 2008, 47, 8998 – 9033. Received: September 11, 2014 Published online on October 10, 2014

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 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Intermolecular radical carbofluorination of non-activated alkenes.

The Meerwein arylation has recently become an even more powerful tool for the functionalization of alkenes. Besides the attachment of an aryl group, r...
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