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Introducing a new radical trifluoromethylation reagent Azusa Sato, a Jianlin Han, b Taizo Ono, c Alicja Wzorek, d José Luis Aceña e and Vadim A. Soloshonok*ef

Received 00th January 2012, Accepted 00th January 2012

Dedicated to Professor Iwao Ojima on the occasion of his 70th birthday.

DOI: 10.1039/x0xx00000x www.rsc.org/

Perfluoro-3-ethyl-2,4-dimethyl-3-pentyl radical (PPFR) is a persistent radical stable at room temperature, but easily decomposes at 90 ºC to produce CF 3 radical which is able to react with a variety of aromatic compounds to afford the corresponding trifluoromethyl derivatives, usually as mixtures of regioisomers in good to excellent overall yields. The profound impact of fluorine on modern pharmaceutical industry is well recognized and has been the subject of numerous publications. 1 In particular, CF3-containing drug candidates usually show improved efficacy, enhanced membrane permeability and, most importantly, significantly higher stability towards oxidative degradation. 1,2 Consequently, in the recent years the development of trifluoromethylation methodology has been quite an intensive area of research. Approaches based on electrophilic, 3 nucleophilic 4 and radical5 supply of a trifluoromethyl group are presently well-established and offer an exciting wealth of methodological choices. The latter approach has received exceptional attention 6 as it can be conducted under operationally convenient conditions 7 and can be readily scaled up. 8 One may agree that all available sources of trifluoromethyl radical have been already completely exhausted 9-19 and the current research is mainly being focused on refining the reaction conditions and chemo/regio-selectivity. Therefore, the discovery and introduction of new reagents capable of generating CF 3 radical might be of high scientific and methodological significance. Here we introduce perfluoro-3-ethyl-2,4-dimethyl-3-pentyl radical (PPFR) 1 (Scheme 1) as a non-conventional source of trifluoromethyl radical and report preliminary data on its application for direct trifluoromethylation of unfunctionalized arenes. We demonstrate that the use of the benchtop stable

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PPFR 1 as trifluoromethylation reagent features several benefits, including controllable rate of CF3 radical release, totally metal-free one-step process under operationally convenient conditions, which, most likely, bodes well for PPFR 1 widespread, general application. F 3C

F

CF 3

F 3C F

F CF 3

F

PPFR 1

CF 3

T 1/2 90 ºC: 6.08 h 100 ºC: 1.83 h

F 3C

F

F3 C F

F CF 3 2

F

+

CF3

CF 3 3

Scheme 1 Structure and reactivity of persistent perfluoroalkyl radical PPFR 1

Persistent perfluoroalkyl radical PPFR 1 was first reported in 198520 and can be easily prepared by fluorination (F 2) of industrial perfluoropropylene trimer in good yields (up to ca. 90%). This procedure has been reproduced by us on a kilogram scale rendering compound 1 readily available on truly large scale. PPFR 1 is stable at room temperature in the open air and totally inert to the dimerization, O 2, halogens, aqueous acid or base, and its presence and concentration in a reaction mixture can be monitored simply by routine GC, like it is in the case of common organic compounds. However, at 80-120 ºC it undergoes β-scission releasing CF3 radical 3 and olefin 2 (Scheme 1). While this property has been known for quite some time, PPFR 1 was considered as merely a chemical curiosity and its applications remained unexplored. 21 Only very recently, the Ameduri group has reported a series of publications showing application of PPFR 1 to initiate various radical polymerization processes.22 On the other hand, opportunity to use PPFR 1 as a new radical trifluoromethylation reagent has

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never been considered. To explore this exciting synthetic prospect we decide first to study the trifluoromethylation of toluene. Under arbitrary conditions, using toluene as a reactant and a solvent, the mixture with PPFR 1 was heated at 90 ºC for 24 h. As shown in Table 1 (entry 1) the target products, CF3toluenes, were determined in the reaction mixture with a combined yield of 42%. Regardless of the relatively low yield, it was an important conceptual breakthrough as this result clearly demonstrated that PPFR 1 can perform as radical trifluoromethylating reagent. Table 1 Optimization of trifluoromethylation reaction using PPFR 1

PP FR 1 CF 3 solvent, N 2 9 0 ºC, 2 4 h

Entry 1 2 3 4 5d 6e 7e 8f

Toluene (equiv.) 20 1 1 1 1 1 1 1

Page 2 of 4

PPFR (equiv.) 1 2 3 3 3 2 3 3

Solvent none DCE DCE none DCE DCE DCE DCE

Yield (%)a 42c 59 94 65 56 88 90 0

Isomer ratio (p/m/o)b 2.5/1.0/2.2 2.4/1.0/1.7 3.0/1.0/1.5 2.6/1.0/1.3 3.0/1.0/1.5 2.3/1.0/1.2 3.0/1.0/1.5

a

Yields determined by 19F NMR analysis of the crude reaction mixtures and based on toluene. b Determined by integration in the 19F NMR spectrum. c Yield based on PPFR. d Reaction performed under O2 atmosphere. e 48 h reaction time. f 1 equiv. of TEMPO was added to the reaction mixture.

Encouraged by this exciting result, we tried next to optimize the reaction conditions. Application of 1,2-dichloroethane (DCE) as a solvent and using only one equivalent of toluene allowed us to enhance the yield to 59% (entry 2). Further improvement in the reaction outcome was achieved using 3 equivalent excess of reagent 1 (entry 3). In this case the target CF3-toluenes were obtained in excellent 94% yield. The use of solvent and inert (N 2) atmosphere were found to be essential for high yields as the reactions conducted without a solvent (entry 4) or in the presence of O 2 (entry 5) gave the products with noticeably reduced chemical yields. On the other hand, a lower excess (2 equiv.) of the reagent 1 and longer reaction time (48 h) gave rather promising results (entry 6) allowing preparation of the target trifluoromethylation products in very good 88% yield. By contrast, the attempt to improve the 94% yield (entry 3) by using longer reaction time was unsuccessful and the CF 3products were obtained with a bit lower chemical yield (entry 7). Finally, we demonstrated that in the presence of TEMPO (entry 8) the reaction did not take place at all, clearly indicating that the process under study is a radical trifluoromethylation. With the optimized reaction conditions in hand our next goal was the study of potential generality of reagent 1 for trifluoromethylation of various unfunctionalized arenes. Most successful and representative results are collected in Table 2. As discussed above, the best results in trifluoromethylation of toluene 4a (entry 1) were obtained using: 3 equivalents of reagent 1, DCE as a solvent, N2 atmosphere and stirring the

2 | J. Name., 2012, 00, 1-3

reaction mixture at 90 ºC for 24 h. All the reactions reported in Table 2 were conducted under these standard conditions to allow for comparison of the data obtained. Under these conditions the trifluoromethylation of benzene 4b (entry 2) occurred with excellent outcome allowing preparation of trifluoromethyl derivative 5b in excellent 93% yield. Similarly good results were obtained in a series of mono-alkyl-substituted benzenes (entries 3-8). Typically, the chemical yields in these trifluoromethylations were above 80%, occurring with moderate preference for o-substitution on the phenyl ring. It is interesting to note that the steric bulk of the alkyl group had no clear impact on neither reactivity nor substitution pattern. For example, trifluoromethylation of n-propyl benzene 4d gave a mixture of CF3-derivatives 5d in 84% yield and ratio of o-,m,p- as 1.7/1.0/1.6 (entry 4). On the other hand, significantly bulkier benzene 4e, containing iso-propyl group afforded 86% yield of a o-,m-,p- mixture of products 5e in 1.7/1.0/1.0 ratio (entry 5). Similar trends were observed in the reactions of benzenes 4f-h (entries 6-8) giving rise to CF3-products 5f-h in 83-86% yields and moderate preference for o-substitution. Radical trifluoromethylation of a series of di-alkyl-substituted benzenes 4i-l also gave rather excellent results (entries 9-12). For example, o-xylene 4i furnished two isomeric CF3-products 5i in a ratio of 1.3/1 and good 82% yield (entry 9). A bit lower yield of 75% was recorded in the trifluoromethylation of mxylene 4j, resulting in the formation of three isomeric derivatives 5j (entry 10). Synthetically very attractive outcome was obtained in the reaction of p-xylene 4k which gave a single product 5k (entry 11) in very good 81% yield. Interestingly, trifluoromethylation of p-t-Bu-toluene 4l proceeded with excellent chemical yield and reasonably good regio-selectivity. In this case two products 5l were obtained in a ratio of 2.9/1.0 with a preference for the less sterically constrained isomer (entry 12). Rather exceptional in this study result was observed in the trifluoromethylation of mesitylene 4m (entry 13) which gave a mixture of mono- and bis-trifluoromethylated products 5m in a ratio of 2.8 (mono)/1.0 (bis) and excellent (94%) chemical yield. This outcome suggested that reagent 1 may hold some more synthetic potential for performing bistrifluoromethylation of highly electron-rich arenes. Next we decided to study several examples of the trifluoromethylation of halogen-substituted arenes (entries 14-16). In sharp contrast with the alkyl-substituted arenes discussed above, reactions of chloro- 4n (entry 14) and bromobenzenes 4o (entry 15) occurred with noticeably lower chemical yields of 52 and 57% respectively. These results suggested that trifluoromethylation of benzenes containing electron-withdrawing substituents with reagent 1 may require particular optimization of the reaction conditions. Quite agreeably with possible electronic substituent effect on the chemical yields, the reaction of 2-bromo-1,3dimethylbenzene 4p gave products 5p (entry 16) with typically good for this study 89% yield. One may assume that in this case two methyl groups overpowered the negative effect of the bromine atom. Finally, we studied the trifluoromethylation of naphthalene 4r, which proceeded in rather good both yield and regio-selectivity for α-position (entry 17).

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CF3

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R

R

14 (n)

b c

DCE, N 2

Entry

90 ºC, 24 h

Substrate

Cl

5

Major product

1 (a)

c

a CF 3

b

2 (b)

CF 3

Yield (%)a

Isomer ratiob

94 (81)c

3.0/1.5/1.0 (2.7/1.4/1.0)c (a/b/c)

b c

Br

16 (p)

93 (87)c (81)d

52

2.0/1.8/1.0 (a/b/c)

3 (c)

73

c

a CF 3

b

4.2/3.1/1.0 (a/b/c)

a CF 3

57

1.5/1.3/1.0 (a/b/c)

89 (75)d

3.2/1.0 (4.0/1.0)d (a/b)

84 (70)c

6.8/1.0 (4.8/1.0)c (a/b)

Br b

Br

a CF 3

Cl

15 (o)

17 (q)

Et

2.8/1.0 (1.0/0)c (1.0/0)d (1.0/2.6)g (a/ab)

b

PPFR 1 (3 equiv)

4

94 (78)c (70)d (94)g

a CF3

Br

CF3 a b

Et a

4 (d)

c

a CF 3

b

n-Pr

80

1.7/1.6/1.0 (a/b/c)

84

1.7/1.0/1.0 (a/b/c)

n-Pr

5 (e)

c

a CF3

b

i -P r

i -Pr

6 (f)

c

a CF3

b

n-Bu

86

1.8/1.6/1.0 (a/b/c)

86

2.5/1.5/1.0 (a/b/c)

83 (81)e

1.7/1.0/0 (7.7/4.8/1.0)e (a/b/c)

82 (65)c (72)d

1.3/1.0 (1.4/1.0)c (2.0/1.0)d (a/b)

75 (76)c (77)d

4.2/3.1/1.0 (5.2/3.5/1.0)c (2.0/1.0/0)d (a/b/c)

n -Bu

7 (g)

b

a CF3

c

s-Bu

s-Bu

8 (h)

b

a CF 3

c

t -Bu

t-Bu

9 (i) a CF 3 b

10 (j)

c

a CF3

b

11 (k)

12 (l)

CF 3

t-Bu

t-Bu

b

a CF 3

81 (76)c (77)d 93 (78)d

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2.9/1.0 (5.0/1.0)d (a/b)

Yields determined by 19F NMR analysis of the crude reaction mixtures. b Determined by integration in the 19F NMR spectrum. c Data in parentheses reported in ref. 23. d Data in parentheses reported in ref. 16. e Data in parentheses reported in ref. 24. f A mixture of mono- and bistrifluoromethylated products (a:ab) was obtained. g Data in parentheses reported in ref. 25.

Considering the data presented in Table 2, one may agree that compound 1 works really well as a reagent for radical trifluoromethylation of unfunctionalized arenes. Notably, the chemical yields of the target products 5 are generally higher (entries 1, 2, 9-13, 16 and 17) as compared with the data reported for the known trifluoromethylation reagents. 16,23-25 In conclusion, this work has revealed that perfluoro-3-ethyl2,4-dimethyl-3-pentyl radical (PPFR) 1 (Scheme 1) can be successfully used as a new reagent for radical trifluoromethylation of unfunctionalized arenes. We demonstrate that the application of the reagent 1 offers some beneficial features, such as high chemical yields and operationally convenient conditions, underscoring its high synthetic potential. We thank IKERBASQUE, Basque Foundation for Science, and the Basque Government (SAIOTEK S-PE13UN098) for financial support.

Notes and references a

Department of Chemistry, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, 162-8666 Tokyo, Japan b School of Chemistry and Chemical Engineering, Nanjing University 210093 Nanjing, China c National Institute of Advanced Industrial Science and Technology (AIST), 2266-98 Anagahora, Shimoshidami, Moriyama, Nagoya, Aichi, 463-8560, Japan d Institute of Chemistry, Jan Kochanowski University in Kielce, Świętokrzyska 15G, 25-406 Kielce, Poland e Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain. Fax: +34 943-015270; Tel: +34 943-015177; E-mail: [email protected] e IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, 48013 Bilbao, Spain

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Table 2 Substrate scope of radical trifluoromethylation reaction using reagent 1

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COMMUNICATION Electronic Supplementary Information (ESI) available: Experimental

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Introducing a new radical trifluoromethylation reagent.

Perfluoro-3-ethyl-2,4-dimethyl-3-pentyl radical (PPFR) is a persistent radical stable at room temperature, but easily decomposes at 90 °C to produce a...
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A metal-free and cost-effective synthesis protocol has been initially proposed for the construction of CF3-containing oxindoles via the direct oxidative trifluoromethylation of activated alkenes with Langlois' reagent (CF3SO2Na). The present methodol

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide.
The trifluoromethylation of aryl iodides catalyzed by copper(I) salt with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide and Zn dust was accomplished. The catalytic reactions proceeded under mild reaction conditions, providi

Introducing a New Competency Into Nursing Practice.
As science advances, new competencies must be integrated into nursing practice to ensure the provision of safe, responsible, and accountable care. This article utilizes a model for integrating a new complex competency into nursing practice, using gen