Application of fluoroform in trifluoromethylation and diﬂuoromethylation reactions

Recent development in the trifluoromethylation and d iﬂuoromethylation of organic compounds employing ﬂ uoroform is reviewed. Eight approaches to trifluoromethylation and diﬂuoromethyl ation are summarized: (i) trifluoromethylation or diﬂuoromethylation of carbonyl compounds, (ii) trifluoromethylation of sulfonyl fluorides, (iii) trifluoromethylation of epoxides, (iv) nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds, (v) CuCF 3 derived from ﬂuoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, a renediazonium salts and alkynes, (vi) diﬂuoromethylation of alkynes, (vii) diﬂuoromethylation of phenols, thiophenols and heterocyclic compounds, and (viii) diﬂuoromethylation of nitriles.

On the basis of a large amount of research literature, [24][25][26] a proposed mechanism for trifluoromethylation and difluoromethylation reactions employing fluoroform is depicted in Scheme 1. Due to the weak acidity of HCF3, 27 in the presence of the strong bases, such as t-BuOK, [(Me2N)3PN]3PNCMe3, MeSOCH2K, n-BuLi and so on, fluoroform can produce the trifluoromethyl anion (CF3 -), which is a very important intermediate in trifluoromethylation reactions. 16The trifluoromethyl anion, as an unstable intermediate, can undergo decomposition to generate fluoride anion (F -) and difluorocarbene, 28 which can then react with substrates to afford difluoromethylated products.

Trifluoromethylation or difluoromethylation of carbonyl compounds
As early as 1998-2000, an effective nucleophilic trifluoromethylation of carbonyl compounds employing fluoroform as a CF3 source in the presence of a common base [t-BuOK, MeSOCH2K, electrogenerated or silicon-containing base] was developed by the research groups of Roques, Normant, Troupel and Langlois. 26,31- 34A series of aldehydes and ketones were tested for trifluoromethylation, and gave moderate to good yields of the target products 2 in most cases.products 2 in 0-81% yields (Scheme 2). 35When the chalcone containing a nitro group in the para position of the benzoyl group was employed for this transformation, however the target product 2 was not obtained. 35he other two research groups, such as Shibata and Mikami, both reported that in the effect of [(Me2N)3PN]3PNCMe3 as base, fluoroform was used for difluoromethylation reaction at lower temperature (-30 o C or -40 o C) or room temperature, and produced the compounds 2 in moderate to excellent yields (Shibata: 52-92% and 64-99%, Mikami: 48-99%, respectively). 24,36,37n addition, the carboxylic acid esters and halides 3 were also employed for trifluoromethylation by Mikami and co-workers (Scheme 3). 36It is very interesting that when benzoyl chloride and 1.2 equiv [(Me2N)3PN]3PNCMe3 were used for this transformation, the reaction time had no effect on the yield of the product 4 (72% yield).However, in the presence of 2.4 equiv.[(Me2N)3PN]3PNCMe3, as the reaction time was prolonged, the yield of the product 4 decreased gradually, while the yield of the product 5 gradually increased.A proposed catalytic cycle for the trifluoromethylation using fluoroform as a CF3 source in the presence of [(Me2N)3PN]3PNCMe3 and N(SiMe3)3, was described by Shibata and co-workers, 37 as shown in Scheme 4. The stabilized ion pair A, arising from the reaction between substrate 1 and fluoroform in the presence of [(Me2N)3PN]3PNCMe3, reacted with N(SiMe3)3 to produce the ion pair C and intermediate B, which underwent a process of removing TMS to afford the desired product 2 in the effect of TBAF.The fluoroform, as a weak acid, would suffer a deprotonation reaction in the presence of the ion pair C to produce the trifluoromethyl anion (CF3 -), which can react with compound 1 and H[[(Me2N)3PN]3PNCMe3] + also to give the stabilized ion pair A. In the entire reaction, H[[(Me2N)3PN]3PNCMe3] + should play an important role in the trifluoromethylation. 37 Arkivoc 2017, i, 67-83 A proposed catalytic cycle for the trifluoromethylation using fluoroform.
In 2013, Vugts and co-workers reported an efficient method for the synthesis of [ 18 F] trifluoromethylcontaining compounds 7 via a trifluoromethylation process using [ 18 F] fluoroform in the presence of t-BuOK as a base (Scheme 5). 38A series of aldehydes and ketones were found to undergo the desired transformations to give moderate to excellent yields of the corresponding products 7 in most cases.However, when the substrates 6 bearing an electron-withdrawing group such as 4-NO2 and 3-NO2 in the aromatic ring, only trace amounts of the desired products 7 were afforded under the action of a smaller amount of t-BuOK.
up to 99% Scheme 5.An efficient method for the synthesis of [ 18 F] trifluoromethyl containing compounds.

Trifluoromethylation of sulfonyl fluorides
In 2015, Shibata and co-workers developed an effective trifluoromethylation of sulfonyl fluorides 10 employing N(SiMe3)3 and excess HCF3, in the presence of a catalytic amount of [(Me2N)3PN]3PNCMe3 (Scheme 7). 37A series of sulfonyl fluorides 10a-g bearing an electron-withdrawing or electron-donating group located on the aromatic ring, underwent the desired transformations, and afforded the aryl triflones 11 in good to high yields (11a-g: 50-84%).Beyond that, the naphthyl-substituted sulfonyl fluorides 10h,i were also employed for the synthesis of aryl triflones, and give 60-78% yields of the the desired products 11h, i.

Trifluoromethylation of epoxides
In 2013, an organocatalysis approach to trifluoromethylation of epoxides with fluoroform at 40 ºC was developed by Mikami and co-workers (Scheme 8). 36The epoxides 12 or 14 containing not only electronwithdrawing but also electron-donating groups, afforded the internal or terminal trifluoromethylation products 13 or 15 in 37-69% yields.A suggested reaction mechanism, shown in Scheme 9, for the trifluoromethylation of epoxides was proposed by Mikami and co-workers. 36

Nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds
In 2012, Prakash and co-workers also reported a nucleophilic trifluoromethylation of silicon, boron, and sulfurbased compounds with HCF3 in the presence of KHMDS as base (Scheme 10). 35It was found that when CF3H was used for trifluoromethylation of silicon-based substrates 16, the desired products 17 were obtained in 42-80% yields.In the effect of KHMDS, the boron-based compounds 18 can react with fluoroform, then followed by 48% aqueous HF to afford CF3BF3K 19 in 53% or 66% yield.The trifluoromethanesulfonic acid (CF3SO3H) 20, a widely used and widely available organic acid, can be obtained in modest 18% conversion, in the presence of CF3H, S8, KHMDS, 30% H2O2 and H2SO4. 35Because of low conversion rate of this synthesis procedure, we think that this preparation method of trifluoromethanesulfonic acid is not going to be economically viable.Scheme 10.Nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds.

CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes
1][42][43][44][45] All these research groups showed that HCF3 can react with CuCl in the presence of t-BuOK and DMF, or zinc bis-2,2,6,6-tetramethylpiperidide (TMP)2Zn, 1,3dimethylpropyleneurea (DMPU) and phenanthroline to produce fluoroform-derived CuCF3, which was a good trifluoromethylating reagent for the trifluoromethylation, 5,46,47 and afforded the desired products 25-27 in moderate to excellent yields. 40 In 2014, a valuable method for the [ 18 F] trifluoromethylation of aryl iodides and aryl boronic acids in situ by use of HCF2 18 F as the precursor of CuCF2 18 F was described by Vugts and co-workers (Scheme 12). 48Under the optimized reaction conditions, a broad range of aryl iodides and aryl boronic acids can be converted successfully into the desired products 28 in moderate to excellent yields in many cases.From the experimental results, it can be seen that electronic effects seem to have no influence on the yields.However, the unprotected alcohol, carboxylic acid and amine did not perform well for the [ 18 F] trifluoromethylation reaction, and gave poor yields of the products 28k-m.When the substrates 28n, 28p, 28q and 29h were employed for the [ 18 F] trifluoromethylation, only 2-41% yields of the [ 18 F] trifluoromethyl arenes 30n, 30p, 30q and 30h were obtained.

Difluoromethylation of phenols, thiophenols and heterocyclic compounds
In 2013 and 2014, the conversion of a series of substrates such as phenols, thiophenols, imidazoles, benzotriazoles and hydroxypyridines into their difluoromethylated derivatives 34, 36 and 38, with fluoroform as a difluorocarbene source in the presence of KOH as base, was demonstrated by the research group of Dolbier (Scheme 14). 51,52They showed that the phenols and thiophenols 33 containing either electron withdrawing or electron donating groups, performed well under the conditions of synthetic methods A and B, and afforded the products 34 in moderate to excellent yields. 51Dolbier and co-workers found that, under the conditions of method B, difluoromethylation of heterocyclic compounds, such as imidazoles, benzimidazoles, indazoles and benzotriazoles (35) and hydroxypyridines (37), proved satisfactory, with moderate to good yields of the difluoromethylated products 36, 38 being obtained.

Difluoromethylation of nitriles
In 2015, Mikami and co-workers reported a valuable difluoromethylation of nitrile compounds with fluoroform as a CF2H source in the presence of nBuLi as base (Scheme 15). 53It was found that higher yields (40a-f: 75-96%) were generally observed for the substrates 39a-f containing either an electron withdrawing or electron donating group in the position of the benzene ring.However, when the acyclic or cyclic α-monoalkylated and vinylic substituted nitriles 39h-n were employed for the difluoromethylation reactions, the difluoromethylated products 40h-n were obtained in moderate yields (39-53%).

Conclusions
In summary, recent developments in trifluoromethylation and difluoromethylation by use of fluoroform are presented.In the presence of the strong bases, fluoroform can produce the trifluoromethyl anion, which is an unstable intermediate undergoing a decomposition reaction to generate difluorocarbene.Both the trifluoromethyl anion and difluorocarbene are very important intermediates in the trifluoromethylation or difluoromethylation reactions.In this review, we classified trifluoromethylation and difluoromethylation reactions under eight headings: (i) trifluoromethylation or difluoromethylation of carbonyl compounds, (ii) trifluoromethylation of sulfonyl fluorides, (iii) trifluoromethylation of epoxides, (iv) nucleophilic trifluoromethylation of silicon, boron, and sulfur-based compounds, (v) CuCF3 derived from fluoroform for the trifluoromethylation of aryl or heteroaryl halides, aryl boronic acids, arenediazonium salts and alkynes, (vi) difluoromethylation of alkynes, (vii) difluoromethylation of phenols, thiophenols and heterocyclic compounds, and (viii) difluoromethylation of nitriles.In most cases, the trifluoromethylated or difluoromethylated products were obtained in moderate to excellent yields.Compared with Umemoto's reagents, NaSO2CF3 and Togni's reagents, fluoroform is a non-toxic and harmless gas, and not easy to operate in the reactions.However, it can be converted to other stable CF3 reagents, such as CuCF3 and CF3SiMe3, which are relatively easy to operate in industrial production of the trifluoromethylated or difluoromethylated compounds.In spite of this, we also expect that the application of fluoroform in trifluoromethylation and difluoromethylation reactions will continue.
First of all, the [(Me2N)3PN]3PNCMe3 reacts with epoxides 12 at the terminal carbon to afford the intermediates A, which would undergo a hydrogen transfer process to produce methyl ketones B. Then the ketones B are attacked by trifluoromethyl anion (CF3 -), arising from the reaction between fluoroform and [(Me2N)3PN]3PNCMe3, to give the intermediates C, which finally form the observed products 13, by proton transfer from H[[(Me2N)3PN]3PNCMe3] + .