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Once Upon a Time Was the Langlois' Reagent
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
5
B.R. Langlois 1, 2 1 University of Lyon, Lyon, France; 2University Claude Bernard-Lyon 1, UMR 5246, Villeurbanne, France
Chapter Outline 1. Introduction 125 2. Origin of the Trifluoromethanesulfinate Salts and Their First Uses 127 3. Rebirth of the “Langlois’ Reagent” 131 4. Conclusions 135 Acknowledgments 135 References 136
1. Introduction Because of its unique properties, fluorine has become a “magic” element, and its introduction in various molecules is now considered as an essential tool to strongly modify several properties of a lot of compounds in different domains, from polymers, materials, and surfactants to pharmaceutical and agrochemical ingredients. Fluoro compounds are especially useful in the latter two areas since fluorine-containing substituents can deeply alter the chemical, physical, and biological properties of the compounds bearing them, which consequently gain a better metabolic stability and bioavailability.1 Fluorinated moieties act first by their electronic properties, which can be continuously regulated from F [the most electronegative element by induction (Pauling scale: 3.98)2a but electron donating by conjugation] to CF3, OCF3, and SCF3 (the strongest inductively electronwithdrawing groups). They also act by their hydrophobicity (related in some sense to the electronegativity of fluorine), which can be modulated to a rather large extent, as indicated by the HanscheLeo parameters PR3 (Table 5.1). Their hydrophobicity governs the bioavailability of the substrates bearing them. Among the fluorinated substituents, CF3, with an electronegativity of 3.5 (higher than that of Cl: 3.0),2b constitutes a good compromise for improving the hydrophobicity, and consequently, the bioavailability of substrates bearing it, without inducing too high an accumulation of these substrates in lipidic systems such as Modern Synthesis Processes and Reactivity of Fluorinated Compounds. http://dx.doi.org/10.1016/B978-0-12-803740-9.00005-6 Copyright © 2017 Elsevier Inc. All rights reserved.
126
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
HanscheLeo Parameters of Fluorinated Moieties and Hydrogenated Analogs (Logarithmic Scale)
Table 5.1
Moiety
PR (X [ H)
PR (X [ F)
0.00
þ0.14
CX3
þ0.56
þ0.88
OCX3
0.02
þ1.04
SCX3
þ0.61
þ1.44
SO2CX3
1.63
þ0.55
NHSO2CX3
1.18
þ0.92
X
PR > 0, hydrophobic substituent; PR < 0, hydrophilic substituent.
the nervous system. That is why, during the past 50 years, an incredibly large number of trifluoromethylated compounds have been proposed (and developed in many cases) as pharmaceuticals, anesthetics, “blood substitutes,” and agrochemicals.4 It must be pointed out that, in a large fraction of these bioactive ingredients, the CF3 group is linked to an aromatic or heteroaromatic nucleus. From the 1960s to the 1980s, trifluoromethylated aromatics (or heteroaromatics) were essentially obtained by a two-step synthesis from the corresponding methylated precursors, after radical chlorination and subsequent fluorination with SbF3 (Swarts’ reagent),5 anhydrous hydrogen fluoride,6,2b or tamed HF-containing mixtures, such as Et3N-3HF7 or HF/pyridine (Olah’s reagent).8 It must be pointed out that such a technique is quite exclusively restricted to aromatic substrates. Thus, to overcome this limitation, it rapidly appeared that it would be far better to have in hands specific reagents dedicated to the transfer of the CF3 group onto a larger panel of organic skeletons. For this purpose, three tools can be considered: generators (or equivalents) of the very unstable trifluoromethyl anion (CF3), equivalents of the putative trifluoromethyl cation (“þCF3”), or generators of the reasonably stable trifluoromethyl radical (CF3).9 The first successes were obtained with nucleophilic trifluoromethylating reagents (CF3 equivalents), first through the thermal decarboxylation of alkaline trifluoroacetates in the presence of cuprous iodide (a method that is, nevertheless, quite efficient only for the substitution of aryl or heteroaryl iodides),10 later improved by the action of the ternary system CF3CO2Me/CsCl/CuI on aromatic halides11 and the mild trifluoromethylation of carbonyl substrates with b-(trimethylsilyoxy)trifluoroacetamides/F.12 Then appeared the very popular RuppertePrakash reagent (CF3SiMe3),13 first used to add eCF3 to unsaturated electrophiles such as carbonyl compounds (as did Langlois et al. with fluoroform),14 the scope of which has been extended, year after year, to the substitutive carbon trifluoromethylation of nonactivated aliphatic or aromatic compounds, as well as the sulfur trifluoromethylation of thiocyanates leading to trifluoromethyl sulfides.15
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
127
Then appeared the electrophilic trifluoromethylating reagents (þCF3 equivalents), essentially Umemoto’s trifluoromethylsulfonium salts16 and Togni’s trifluoromethyliodonium salts,17 (may be inspired from the pioneering work of L.M. Yagupolskii with perfluoroalkyliodonium salts,18 but extensively extended to a very broad panel of substrates). As far as radical trifluoromethylation is concerned, many generations of the CF3 radical have been reported during the prehistory of fluorine chemistry, through photolysis of toxic precursors [Hg(CF3)2, Te(CF3)2] or putatively carcinogenic ones [CF3N ¼ NCF3, CF3N(NO)SO2R], single-electron reduction of highly reactive compounds [CF3C(O)CF3, (CF3CO2)2], or single-electron oxidation of trifluoroacetic acid at a very high potential. Trifluoromethyl iodide (CF3I) was considered at that time as the less unsatisfactory reagent for radical trifluoromethylation, despite its toxicity. Moreover, radical trifluoromethylation was considered for a long time to be insufficiently regioselective to be used for targeted syntheses, until the appearance of chemical libraries for which the simultaneous production of several isomers is beneficial, provided that these isomers could be separated. For these reasons, radical trifluoromethylation attracted less attention during the late 1990s and the first decade of the 21st century.
2. Origin of the Trifluoromethanesulfinate Salts and Their First Uses Nevertheless, it should be mentioned that great interest was accorded, from the mid1980s, to trifluoromethyl bromide (CF3Br), which is not toxic and was at that time commercially available, as a fire extinguisher, until the late 1990s, when its production was stopped because of its significant ozone-depleting effect. CF3Br can indeed be not only transformed into stabilized forms of the anion CF3 but can also be reduced, through a single-electron transfer, into Br and CF3, an electrophilic radical that can be trapped by nucleophilic substrates. In the early studiesdthose of C. Wakselman and M. Tordeux19a and L.M. Yagupolskii et al.19bdstrong and soft nucleophiles (thiolates20a,b or strongly delocalized carbanions20c) were used both to reduce CF3Br (in N,N-dimethylformamide and under a slight pressure) and then trap the resulting CF3 radical. Later, a collaboration was established between C. Wakselman’s group and B. Langlois’ group (from the Rhone-Poulenc Co. at that time) to find new singleelectron reducers of CF3Br, different from the nucleophilic substrates used to trap the generated CF3.19a It appeared that generators of the stable radical anion SO2 (Zn/SO2, HCO2Na/SO2, Na2S2O4) were the best candidates and were able to reduce CF3Br in the presence of substrates such as organic disulfides (leading to trifluoromethyl sulfides)21 or electron-rich aromatics,22 as shown in Scheme 5.1. Interestingly, it was observed that, in the absence of any substrate, CF3 was trapped by the persistent radical anion SO2 to provide a trifluoromethanesulfinate (“triflinate”) anion.23 This stable salt, after oxidation with hydrogen peroxide and acidification with sulfuric acid then oleum, opened a new and purely chemical route to triflic acid, which was ˇ
128
Modern Synthesis Processes and Reactivity of Fluorinated Compounds HCO2- /SO2
Zn/SO2
S2O42-
SO2.-
RSSR
SO2
CF3Br
RS-CF3 + RS.
Ar-H
CF3
Ar-CF3
SO2.-
Br-
F3C
O S
H2O2 O
CF3SO3-
H2SO4 oleum
CF3SO3H
Scheme 5.1 Generation and use of CF3 from CF3Br and SO2 .
previously obtained by Simmons’ electrochemical fluorination only. This synthesis has been industrially developed by Rhone-Poulenc Co.24 However, it was observed that only hydrogen peroxide was able to cleanly transform sodium triflinate (CF3SO2Na) into sodium triflate (CF3SO3Na). None of the other oxidizers that were tested (tert-butyl hydroperoxide and peroxide, cumyl hydroperoxide and peroxide, N2O4, cerium ammonium nitrate, sodium persulfate, and sodium hypochlorite) were able to transfer an oxygen atom onto CF3SO2Na. All of them led, at room temperature, to the same reaction: the cleavage of the carbonesulfur bond, the formation of sodium hydrogen sulfite and sulfate, as well as the evolution of sulfur dioxide and other gaseous products. Thus, it was suspected that they could act as single-electron oxidizers and transform the anion CF3 SO2 into the corresponding radical CF3 SO2 : , which is known to be very unstable25 and to collapse into SO2 and the trifluoromethyl radical CF3. tert-Butyl hydroperoxide appeared to be the most efficient oxidizer to get such a reaction (Scheme 5.2). ˇ
HSO3
HSO4 t-BuOOH
SO2
HO
CF3SO2
CF3SO2 unstable t-BuO CF3SO2
CF3 t-BuO
SO2
CF3SO2
HSO4 CF3
t
Scheme 5.2 Single-electron oxidation of CF3SO2Na by BuOOH.
To verify the involvement of CF3 during such an oxidation process, disulfides, known to trap efficiently this radical,21 were added to the medium. Indeed, trifluoromethyl sulfides were produced (Scheme 5.3),26 even from cystine and homocystine without any loss of enantioselectivity.26c Usually, no added catalyst was needed to get good results.27 Nevertheless, when the substrate contained electron-withdrawing moieties, the yield was improved by some MoO2(acac)2, known to facilitate the production of tBuO radicals.28 Thus, it could be deduced that these radicals oxidize the triflinate anion more efficiently than the hydroperoxide does.
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty” t-BuOOH (3-4 eq) MeCN/H2O/r.t. metal free
CF3SO2 + RS-SR (2-3 eq)
RS-CF3 + SO2 + RS
129 t-BuOOH
overoxidation
R = alkyl (100 %), c-hexyl (45 %), (-CH2)nCH(NHR')CO2Me [n = 1,2] (48-56 %) R = (CH2)2CO2Et [71 % (metal free) to 100 % (MoVI as catalyst)] R = (CH2)nCH(NHR')CO2Me (n= 1,2 ; R' = H2+, Ac) (37-56 %)
S
R
CF3
id.
SCF3 +
R
2
SR'
R
R' = H, CF3
Scheme 5.3 Oxidative sulfur trifluoromethylation with CF3SO2Na.
As it was observed that S and C trifluoromethylation coexisted during the reaction of aryl disulfides, the behavior of electron-rich aromatics was also examined. Indeed, CF3SO2Na and tert-butyl hydroperoxide were able to produce trifluoromethylated aromatics under very mild conditions, especially in the presence of Cu(II) catalysts (Scheme 5.4).29 This system was also able to trifluoromethylate pyrrole derivatives. CF3
CF3SO2Na (4 eq) t BuOOH (7 eq)
R2 R1
R1, R2 = H, OH, OMe, NHAc, CO2Me, Cln (21-90 %)
R2
Cu(OTf)2 (0.1 eq)
R1
idem N Ac
N Ac
CF3
(35 %)
Scheme 5.4 Oxidative trifluoromethylation of aromatics.
The behavior of 1,3-(dimethoxy)benzene, a very enriched substrate, indicated that this reaction can be carried out without any metallic catalyst, that Fe(III) improves the yield but without modifying the products ratio to any significant extent, and that Cu(II) is the most effective catalyst for enhancing the global yield and, in addition, minimizes the amount of bis-trifluoromethylated products (Scheme 5.5). The last of these effects is probably due to the better efficiency of Cu(II) to oxidize the intermediate trifluoromethylated cyclohexadienyl radical into the corresponding cation, as postulated in OMe
CF3SO2Na (4 eq) t BuOOH (7 eq) OMe
OMe
catalyst (0.1 eq)
Cata : none (yield: 58 %) Fe(NO3)3 (yield: 67 %) Cu(OTf)2 (yield: 90 %)
OMe CF3 F3C OMe
9 11 24
OMe F3C OMe
25 31 60
Scheme 5.5 Trifluoromethylation of (1,3-dimethoxy)benzene.
OMe CF3 F3C OMe
9 10 4
OMe CF3 14 15 3
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Scheme 5.6. Despite the fact that Cu(II) exhibits a lower oxidation potential than tertBuOOH, its better efficiency may be related to the fact that Cu(II) transfers an electron in an inner-sphere process, whereas tert-BuOOH does so in an outer-sphere process. Such hypotheses led the authors to qualify this reaction as a “pseudoelectrophilic” trifluoromethylation.
CF3SO2
t-BuOOH
H CF3
R CF3
H CF3
H
R
R Cu(II)
t-BuO SO2
CF3 H R
Cu(I) t-BuOOH
t-BuO CF3SO2
HO
Scheme 5.6 Postulated mechanism for the aromatic trifluoromethylation.
Our later experiments,30 as well as those of Smertenko et al.,31 concerning electrochemical oxidation of potassium triflinate in the presence of aromatic substrates corroborated this mechanism: when exactly 2 F/mole of substrate were used, no bis-trifluoromethylated product was produced. As it could be expected that such a mechanism, implying the oxidation of an intermediate trifluoromethylated radical, would be applied to other electron-rich unsaturated substrates, enol esters were submitted to the oxidative trifluoromethylation by sodium triflinate/tert-butyl hydroperoxide.32 As expected, a-(trifluoromethyl)ketones were obtained under very mild conditions (Scheme 5.7).33 This result was interpreted in a similar way as in Scheme 5.6. Interestingly, phenyl vinyl sulfide was also cleanly trifluoromethylated, provided that a nucleophile, such as methanol, was added to the medium. The role of methanol is to reduce the oxidation power of Cu(II) (and thus, avoid oxidation of the sulfide) and to trap the intermediate carbocation, which is too stabilized to evolve through deprotonation; in this way, a thioketal of 3,3,3trifluoropropionaldehyde was obtained (Scheme 5.7).34 O OAc R
R'
F3C
CF3SO2Na (1-4 eq) t-BuOOH (3-7 eq)
R
Cu(OTf)2 (0.1-0.25 eq) MeCN / r.t.
SPh CF SO Na / t-BuOOH 3 2 Cu(OTf)2 / MeCN / MeOH
R' + R
SPh
OMe + CF3 41 %
O
R'
66 %
CF3
CF3 SPh
53 %
OAc
O
OH
CF3
F3C
OH CF3 20 %
Scheme 5.7 Oxidative trifluoromethylation of enol esters and vinyl sulfides.
60 % O
O
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
131
As for the trifluoromethylation of less enriched unsaturated substrates, electrochemical oxidation of CF3SO2Na was a better tool: with 1.2e1.5 F/mole of substrate, that is, under conditions that prevented the oxidation of the intermediate trifluoromethylated radical and allowed its disproportionation, a mixture of saturated and unsaturated products were obtained.30 However, Langlois’ seminal results, which opened a promising methodology for the radical trifluoromethylation, were largely ignored for almost 15 years, perhaps because of the lack of availability of alkaline triflinates after the banishment of bromotrifluoromethane, although other environmentally benign sources of such salts have been reported during this period (Scheme 5.8).35e37
CF3CO2K + SO2 HCF3 PhCH2-S-CN
CF3SO2K + CO2
CF3SiMe3
CsF / SO2
1) HCCl3 / NaOH 2) Py, 10 HF
PhCH2-SO2-CF3
1) BrCH2CO2Et 2) K2CO3
Ref. 35
CF3SO2Cs
PhCH2-S-CF3
Ref. 36
H2O2
Ref. 37
AcOH
CF3SO2K + Ph
CO2Et
Scheme 5.8 Alternative syntheses of alkaline triflinates.
3. Rebirth of the “Langlois’ Reagent” Surprisingly, in mid-2011, Baran et al. published the trifluoromethylation of various nitrogen-containing heterocycles with sodium triflinate and tert-butyl hydroperoxide. They not only cited Langlois’ work from the 1990s but also, as perfect gentlemen, named CF3SO2Na the “Langlois’ reagent” (“an old reagent with a new use” sic).38 Indeed, the novelty was that they applied this reaction to a large panel of nitrogencontaining heterocycles (although they omitted to cite Langlois’ result on N-acetyl pyrrole) and observed its high tolerance toward various substituents as well as the ease with which it can be carried out. More importantly, they demonstrated that it is possible to trifluoromethylate sophisticated compounds in the last stages of a multistep synthesis. This greatly facilitates the preparation of libraries of potentially bioactive products. Concerning the technical aspect, Baran et al. carried out the reaction in a biphasic water/organic system, observed the influence of stirring on the yield and that of the organic solvent on the regioselectivity of trifluoromethylation, and claimed that no metallic catalyst was needed [a fact that Langlois et al. already reported while mentioning that Cu(II) improved the yield]. Since Baran’s work was commented in Nature39 and in different widely diffused journals [C&N News (December 2011), Royal Chemical Society News (August 2011), and the Scripps Institute advertisements], it quickly became popular. It was rapidly followed by M. Sanford et al. who published a substitutive trifluoromethylation
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
of aryl boronic acids with the “Langlois’ reagent.”40 Very soon thereafter, the use of CF3SO2M (M ¼ Na, K), associated with various oxidants, blossomed and gave rise to a broad family of radical or pseudoelectrophilic trifluoromethylations applied to a large variety of substrates.41 No less than 50 original articles appeared between 2012 and 2015! All these publications are summarized in the following schemes (Schemes 5.9e5.13), each of them being devoted to a type of substrate. For each article is given the main author, the year of publication, the claimed oxidant, and the reference. As it
CF3SO2Na
Ar-H Ar-N2
BF4
Shibata et al. (2013); PhI(OCOCF3)2; ref. 42 Itoh et al. (2013); hν / AQN-2-CO2H; ref. 43
Ar-CF3
[O]
CF3SO2Na
Qing et al. (2015); t-BuOOH / Cu(I) cat.; ref. 44
Ar-CF3
[O]
Scheme 5.9 Oxidative trifluoromethylation of aromatics. R2 R1
R2 CF3SO2Na [O] O
O
CF3SO2Na [O]
Het
R1
O
CF3 Het
CF3
Cao et al. (2014); Mn (OAc)3; ref. 45
O
Baran et al. (2011); t-BuOOH; ref. 38 Baran et al. (2013); t-BuOOH; ref. 46 Montesarchio et al. (2013); t-BuOOH; ref. 47 Molinski et al. (2014); t-BuOOH; ref. 48
Het
= nitrogen-heterocycle
Het
(CF3SO2)2Zn [O]
CF3 Het
Hajra et al. (2015); air / t-BuOOH cat. / Ag(I) cat., ref. 49 Baran et al. (2012); t-BuOOH; ref. 50 Baran et al. (2013); t-BuOOH; ref. 46 Blackmond et al. (2013); t-BuOOH, ref. 51 Baran et al. (2014); electrolysis; ref. 52
Scheme 5.10 Oxidative trifluoromethylation of heterocycles. Ar-B(OH)2 R-B(OH)2 R = aryl, vinyl
CF3SO2Na [O] CF3SO2Na [O]
CF3SO2Na R-BF3K [O] R = aryl, hetaryl, vinyl, alkynyl R
CO2H
CF3SO2Na [O]
Ar-CF3
Sandford et al. (2012); t-BuOOH / Cu(II) cat.; ref. 40
R-CF3
Beller et al. (2013); t-BuOOH / Cu(II)Ln cat.; ref. 53
R-CF3
Molander et al. (2013); t-BuOOH / Cu(I) cat.; ref. 54 Dubbaka et al. (2014); t-BuOOH / Cu(I) cat.; ref. 55
R
CF3
Liu et al. (2013); t-BuOOH / Cu(II) cat.; ref. 56 Duan et al. (2014); t-BuOOH / Cu(I) + Ag(I) cat.; ref. 57 Maiti et al. (2013); K2S2O8 / Fe(III) cat.; ref. 58 Liu et al. (2015); I2O5; ref. 59
Scheme 5.11 Substitutive trifluoromethylation of boronic acids, trifluoroborates, and acrylic acids.
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty” OAc
O
CF3SO2Na
Ar
Ar
[O] X
CF3
Duan et al. (2014); t-BuOOH / Cu(I) cat.; ref. 60
CF3
Lei et al. (2014); air / K2S2O8 cat.; ref. 61
O
CF3SO2Na
Ar
133
Ar
[O]
X = Cl, Br, NHAc, N3
Scheme 5.12 Oxidative trifluoromethylation of functionalized alkenes.62 H CF3SO2Na
Nicewicz et al. (2013); hν / photocat. / ArSH; ref. 63
[O] I
CF3
CF3SO2Na
Liu et al. (2014); I2O5; ref. 64
[O]
CF3 CF3
CF3SO2Na
Qing et al. (2015); t-BuOOH / Cu(I) (1 eq.); ref. 65
[O] H
CF3
O
CF3SO2Na
CF3
[O] H
O
CF3SO2Na
OH CF3 +
[O]
CF3
ONR1R2
CF3SO2Na
Luo et al. (2014); t-BuOOH / benzoquinone (1 eq.); ref. 67 Vicic et al. (2015); air / Mn(II) cat.; ref. 68
Qing et al. (2013); t-BuOOH / Cu(II) cat.; ref. 69
[O] R
Maiti et al. (2013); air / K2S2O8 cat. / Ag (I) cat.; ref. 66
O
CF3SO2Na [O]
R
CF3
Maiti et al. (2014); air / Ag (I) cat.; ref. 70
CF3
Scheme 5.13 Conjugated trifluoromethylation of nonfunctionalized alkenes and alkynes.
can be seen, a large panel of substrates have been used to prepare numerous and valuable products, but the principle of these reactions remains constant. Far more interesting is the variety of oxidant that have been experimented with, in a constant progression toward cheaper and environment-friendly reagents (vide infra). Radical trifluoromethylation with triflinate salts was also frequently used to induce cyclizations leading to potentially bioactive compounds, based on nitrogen- or oxygencontaining heterocycles. For this purpose, all the described oxidants have been
Lipshutz et al. (2014); t-BuOOH / Cu (II) cat.; ref. 71
R1
R3
R3 N R2
CF3SO2Na O
[O]
R1
N R2
Lei et al. (2014); t-BuOOH / Cu (I) cat.; ref. 72 CF3 O
Wang et al. (2014); K2S2O8; ref. 73 Tan et al. (2014); (NH4)2S2O8; Ag(I) cat.; ref. 74 Fu et al. (2014); PhI(OAc)2; ref. 75 Liu et al. (2014); I2O5; ref. 76
Scheme 5.14 Cyclizing trifluoromethylations leading to oxindoles.
134
Modern Synthesis Processes and Reactivity of Fluorinated Compounds Ar
Ar
R1 R1
N R2
Ar
O O
R1 N H
R3
NR
O
Mai, Xiao et al. (2014); K2S2O8 / Ag(I) cat.; ref. 77
O
CF3
Liu, Liang et al. (2015); t-BuOOH / Cu (I) cat.; ref. 78
Z O R1 Z = O, NR R3
CF3SO2Na [O]
R2
Ar
O R2
N
[O]
[O]
N
Fu et al. (2014); PhI(OAc)2; ref. 79
I
CF3SO2Na
R2 CF3SO2Na
CF3
R1
Ar
Ar
R1
N R2
Ar [O]
Z
R1
[O]
O
CF3SO2Na
Ar
CF3
CF3SO2Na
Liu et al. (2014); I2O5; ref. 76
CF3
N R
R2 R1
Zhang et al. (2015); t-BuOOH / Ag (I) cat.; ref. 80 N
CF3
Scheme 5.15 Cyclizing trifluoromethylations leading to various heterocycles.
employed. Trifluoromethylated oxindoles constituted the main target (Scheme 5.14), although other five-membered or six-membered cycles were prepared (Scheme 5.15). Apart from all the possibilities afforded by triflinate salts to carry out various trifluoromethylations, an analogous breakthrough must be emphasized: the use of zinc difluoromethanesulfinate (HCF2SO2)2Zn, reported for the first time by Baran et al., as well as Blackmond et al., to carry out radical difluoromethylation upon heterocycles, especially those containing nitrogen (Scheme 5.16).46,50e52,81 Later, this CHF2SO2Cl
Zn° / H2O
(CHF2SO2)2Zn
CHF2SO2Cl (2-4 eq) t-BuOOH (3-6 eq) N TFA (1 eq) (and other DCM:H2O / rt N-heterocycles) R
R
85 % CHF2
N
30–90 %
Scheme 5.16 Preparation of (HCF2SO2)2Zn and its use for radical difluormethylation.
difluoromethylation was applied to acrylic acids56 and for the synthesis of difluoromethylated oxindoles.74 Apart from the fact that (HCF2SO2)2Zn (zinc “diflinate”) can be easily prepared from difluoromethanesulfonyl chloride and is now commercially available,81 the interest in such a reaction is the fact that the difluoromethyl moiety has become more and more popular as a replacement for or complement to the trifluoromethyl one, for, at least, three reasons. The first is that, although interestingly stable, it is less stable than CF3. The second one is that, while remaining a highly hydrophobic group, its hydrophobicity is lower than that of CF3. Thus, for these two reasons, difluoromethylated compounds are less persistent in situ than their trifluoromethylated analogs, for example, in the soil (for
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
135
agrochemicals) or in lipidic systems (for pharmaceuticals), which gives it a serious advantage. The third reason is that CHF2 being less electrophilic than CF3, the regioselectivity of attack of these two radicals can differ, as it was nicely illustrated by Baran Et OH MeO
more electrophilic
CF3
N
CHF2 less electrophilic
Scheme 5.17 Difference in regioselectivities for CF3 and CHF2.
et al. on dihydroquinine and varenicline (Scheme 5.17).81 The interest in such a finding could allow us to name (HCF2SO2)2Zn as the “BaraneBlackmond reagent”!
4. Conclusions In conclusion, radical trifluoromethylation with trifluoromethanesulfinate salts under oxidative conditions, first discovered by Langlois’ et al. in the early 1990s, remained relatively little known until the very beginning of the 2010s decade when Baran et al., as well as Blackmond et al. brought it back to life, named sodium triflinate the “Langlois’ reagent,” and opened new perspectives for mild, easy, robust, and cheap syntheses of trifluoromethylated products, even sophisticated ones that could be of interest for bioactive specialties. Simultaneously, Baran et al., as well as Blackmond et al., also developed a similar method to graft difluoromethyl moieties on organic substrates from zinc difluoromethanesulfinate, which could have a bright future.82 Surprisingly, the rebirth of the Langlois’ reagent received a wide echo in the chemical community and induced an important blossom of publications. Although the principle remained the one postulated by Langlois et al. in 1991e92, important improvements were brought to the methodology, especially concerning the nature of the single-electron oxidant. Although until now, tert-butyl hydroperoxide, usually associated with copper or silver salts as catalysts, remains the most employed oxidant, more stable and cheaper reagents such as K2S2O8 and I2O5 are emerging. However, the breakthrough came from the possibility, published in 2015, to use air as oxidizer and various salts (K2S2O8) or metallic cations, especially Mn(II), as catalysts.61,66,68,70
Acknowledgments The author warmly acknowledges Dr. Thierry Billard and Dr. Fabien Toulgoat for helping him very efficiently during the elaboration of this chapter and carefully checking all the articles published between 2010 and 2015.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
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f. Zhang, C. P.; Chen, Q. Y.; Guo, Y.; Xiao, J. C.; Gu, Y. C. Chem. Soc. Rev. 2012, 41, 4536e4559. g. Ma, J. A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975e996. h. Landelle, G.; Panossian, A.; Pazenok, S.; Vors, J. P.; Leroux, F. R. Beilstein J. Org. Chem. 2013, 9, 2476e2536. i. Liu, X.; Xu, C.; Wang, M.; Liu, Q. Chem. Rev. 2015, 115, 683e730. j. Macé, Y.; Magnier, E. Eur. J. Org. Chem. 2012, 2479e2494. a. Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981, 1719. b. Carr, G. E.; Chambers, R. D.; Holmes, T. F.; Parker, D. G. J. Chem. Soc. Perkin Trans. I 1988, 921. Langlois, B. R.; Roques, N. J. Fluorine Chem. 2007, 128, 1318. Joubert, J.; Christophe, C.; Roussel, S.; Billard, T.; Langlois, B. R. Angew. Chem. Int. Ed. 2003, 42, 3133. a. Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393. b. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757e786. c. Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A. Science December 7, 2012, 338, 1324e1327. Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848e8856. a. Billard, T.; Large, S.; Langlois, B. R. Tetrahedron Lett. 1997, 38, 65e68. b. Bouchu, M. N.; Large, S.; Steng, M.; Langlois, B. R.; Praly, J. P. J. Carbohydrate Res. 1998, 314 (1e2), 37e45. c. Granger, C. E.; Félix, C. P.; Parrot-Lopez, H. P.; Langlois, B. R. Tetrahedron Lett. 2000, 41, 9257e9260. a. Umemoto, T.; Ishihara, S. Tetrahedron Lett. 1990, 31, 3579. b. ibid J. Am. Chem. Soc. 1993, 115, 2156. c. Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692. Eisenberger, R.; Gischig, S.; Togni, A. Chem. Eur. J. 2006, 12, 2579. Yagupolskii, L. M.; Maletina, I. I.; Kondratenko, N. V.; Orda, V. V. Synthesis 1978, 835. a. Wakselman, C.; Tordeux, M. In The Roots of Organic Development; Desmurs, J. R., Ratton, S., Eds.; Industrial Chemistry Library; Elsevier: Amsterdam, 1996, Vol. 8. b. Ignatev, N. V.; Boiko, V. N.; Yagupolskii, L. M. Zh. Org. Khim. 1985, 21, 653. a. Wakselman, C.; Tordeux, M. J. Chem. Soc. Chem. Commun. 1984, 793. b. Wakselman, C.; Tordeux, M. J. Org. Chem. 1985, 50, 4047. c. Bey, P.; Vevert, J. P. Tetrahedron Lett. 1978, 14, 1215. a. Wakselman, C.; Tordeux, M.; Clavel, J. L.; Langlois, B. J. Chem. Soc. Chem. Commun. 1991, 993e994. b. Clavel, J. L.; Langlois, B.; Wakselman, C.; Tordeux, M. Phosphorus Sulfur Silicon 1991, 59, 3691e3694. c. Clavel, J. L.; Langlois, B.; Nantermet, R.; Tordeux, M.; Wakselman, C. J. Chem. Soc. Perkin Trans. I 1992, 3371e3375. d. Clavel, J.L.; Langlois, B.; Nantermet, R.; Tordeux, M.; Wakselman, C. Eur. Patent 374,061 (1990) (to Rhone-Poulenc Co.). Chem. Abstr., 114, 5483. a. Tordeux, M.; Langlois, B.; Wakselman, C. J. Chem. Soc. Perkin Trans. I 1990, 2293e2299. b. Tordeux, M.; Wakselman, C.; Langlois, B. Eur. Patent 298,803 (1989) (to RhonePoulenc Co.). Chem. Abstr., 111, 173730. ˇ
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23. Tordeux, M.; Langlois, B.; Wakselman, C. J. Org. Chem. 1989, 54, 2452e2453. 24. a. Tordeux, M.; Langlois, B.; Wakselman, C. Eur. Patent 278,822 (1988) (to Rhone-Poulenc Co.). Chem. Abstr., 110, 94514.b. Tordeux, M.; Langlois, B.; Wakselman, C. French Patent 2,593,808 (1987) (to Rhone-Poulenc Co.). Chem. Abstr., 108, 166975.c. Forat, G.; Langlois, B.; Lorieau, P.; Poppei, J. Eur. Patent 396,458 (1990) (to Rhone-Poulenc Co.). Chem. Abstr., 114, 121482. 25. Gonbeau, D.; Guimon, M. F.; Duplantier, S.; Ollivier, J.; Pfister-Guillouzo, G. Chem. Phys. 1989, 135, 85e89. 26. a. Clavel, J. L.; Langlois, B.; Laurent, E.; Roidot, N. Phosphorus Sulfur Silicon 1991, 59, 169e172. b. Langlois, B.; Montegre, D.; Roidot, N. J. Fluorine Chem. 1994, 68, 63e66. c. Clavel, J.L.; Langlois, B.; Laurent, E.; Roidot, N. Eur. Patent 458,684 (1991) & U.S. 5,565,689 (1996) (to Rhone-Poulenc Co.). Chem. Abstr., 116, 127821. 27. Since sodium triflinate was produced in a glass-lined apparatus by a catalyst-free process, it was supposed to be free of any metallic impurity. Thus, we assumed that it was directly oxidized by the hydroperoxide. 28. a. Sharpless, K. B.; Verhoeven, T. R. Aldrichim Acta 1979, 12, 63. b. Kochi, J. K. Free Radicals; Wiley: New York, 1973; p 591. 29. Langlois, B.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1991, 32, 7525e7528. 30. Tommasino, J. B.; Brondex, A.; Médebielle, M.; Thomalla, M.; Langlois, B. R. Synlett 2002, 10, 1697e1699. 31. Smertenko, E. A.; Datsenko, S. D.; Ignatev, N. V. Russ. J. Electrochem. 1998, 34, 46. 32. Langlois, B.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1992, 33, 1291e1294. 33. Enol ethers were not appropriate substrates since they were too sensitive to tert-butyl hydroperoxide. 34. Langlois, B.; Billard, T.; Guérin, S.; Large, S.; Roidot-Pérol, N. Phosphorus Sulfur Silicon 1999, 153e154, 323e324. 35. Forat, G.; Mas, J.M.; Saint-Jalmes, L. Eur. Patent 735,023 (1996) (to Rhone-Poulenc Co.). 36. Singh, R. P.; Shreeve, J. M. Chem. Commun. 2002, 1818e1819. 37. Langlois, B.; Billard, T.; Mulatier, J. C.; Yézéguélian, C. J. Fluorine Chem. 2007, 128, 851e856. 38. a. Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 14411. b. Br€uckl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2012, 45, 826e839. 39. Parsons, A. T.; Buchwald, S. L. Nature December 08 , 2011, 480 (7376), 184e185. 40. Ye, Y.; K€unzi, S. A.; Sandford, M. S. Org. Lett. 2012, 14, 4979e4981. 41. As far as t-BuOOH is concerned as oxidant, it must be noticed that, except Baran et al. and some medicinal chemists, most of the scientists used a metallic catalyst, essentially Cu(II). 42. Yang, Y. D.; Iwamoto, K.; Tokunaga, E.; Shibata, N. Chem. Commun. 2013, 49, 5510e5512. 43. Cui, L.; Matusaki, Y.; Tada, N.; Miura, T.; Uno, B.; Itoh, A. Adv. Synth. Catal. 2013, 355, 2203e2207. 44. Zhang, K.; Xu, X. H.; Qing, F. L. J. Org. Chem. 2015, 80, 7658e7665. 45. Cao, X. H.; Pan, X.; Zhou, P. J.; Zou, J. P.; Taiwo Asekun, O. Chem. Commun. 2014, 50, 3359e3362. 46. O’Hara, F.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2013, 135, 12122e12134. ˇ
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47. Musumeci, D.; Irace, C.; Santamaria, R.; Montesarchio, D. Med. Chem. Commun. 2013, 4, 1405e1410. 48. Paige Stout, E.; Choi, M. Y.; Castro, J. E.; Molinski, T. F. J. Med. Chem. 2014, 57, 5085e5093. 49. Monir, K.; Kumar Bagdi, A.; Ghosh, M.; Hajra, A. J. Org. Chem. 2015, 80, 1332e1337. 50. Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Daa Funder, E.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herlé, B.; Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature December 6, 2012, 492, 95e99. 51. Baxter, R. D.; Blackmond, D. G. Tetrahedron 2013, 69, 5604e5608. 52. O’Brien, A. G.; Maruyama, A.; Inokuma, Y.; Fujita, M.; Baran, P. S.; Blackmond, D. G. Angew. Chem. Int. Ed. 2014, 53, 11868e11871. 53. Li, Y.; Wu, L.; Neumann, H.; Beller, M. Chem. Commun. 2013, 49, 2628e2630. 54. Presset, M.; Oehlrich, D.; Rombouts, F.; Molander, G. A. J. Org. Chem. 2013, 78, 12837e12843. 55. a. Dubbaka, S. R.; Salla, M.; Bolisetti, R.; Nizalapur, S. RSC Adv. 2014, 4, 6496e6499. b. Dubbaka, S. R.; Nizalapur, S.; Atthunuri, A. R.; Salla, M.; Mathew, T. Tetrahedron 2014, 70, 2118e2121. 56. Li, Z.; Cui, Z.; Liu, Z. Q. Org. Lett. 2013, 15, 406e409. 57. Yin, J.; Li, Y.; Zhang, R.; Jin, K.; Duan, C. Synthesis 2014, 46, 607e612. 58. Patra, T.; Deb, A.; Manna, S.; Sharma, U.; Maiti, D. Eur. J. Org. Chem. 2013, 5247e5250. 59. Shang, X. J.; Li, Z.; Liu, Z. Q. Tetrahedron Lett. 2015, 56, 233e235. 60. Lu, Y.; Li, Y.; Zhang, R.; Jin, K.; Duan, C. J. Fluorine Chem. 2014, 161, 128e133. 61. Lu, Q.; Liu, C.; Huang, Z.; Ma, Y.; Zhang, J.; Lei, A. Chem. Commun. 2014, 50, 14101e14104. 62. The work described in reference 60 is almost a pure pliagiarism of Langlois’ method (Ref. 32) since the only difference is the exclusive use of a-(hetero)aryl-enol acetates as substrates instead of aliphatic or cycloaliphatic enol acetates. 63. Wilger, D. J.; Gesmundo, N. J.; Nicewicz, D. A. Chem. Sci. 2013, 4, 3160e3165. 64. Hang, Z.; Li, Z.; Liu, Z. Q. Org. Lett. 2014, 16, 3648e3651. 65. Yang, B.; Xu, X. H.; Qing, F. L. Org. Lett. 2015, 17, 1906e1909. 66. Deb, A.; Manna, S.; Modak, A.; Patra, T.; Maity, S.; Maiti, D. Angew. Chem. Int. Ed. 2013, 52, 9747e9750. 67. Luo, H. Q.; Zhang, Z. P.; Dong, W.; Luo, X. Z. Synlett 2014, 25, 1307e1311. 68. Yang, Y.; Liu, Y.; Jiang, Y.; Zhang, Y.; Vicic, D. A. J. Org. Chem. 2015, 80, 6639e6648. 69. Jiang, X. Y.; Qing, F. L. Angew. Chem. Int. Ed. 2013, 52, 14177e14180. 70. Maji, A.; Hazra, A.; Maiti, D. Org. Lett. 2014, 16, 4524e4527. 71. Yang, F.; Klumphu, P.; Liang, Y. M.; Lipshutz, B. H. Chem. Commun. 2014, 50, 936e938. 72. Lu, Q.; Liu, C.; Peng, P.; Liu, Z.; Fu, L.; Huang, J.; Lei, A. Asian J. Org. Chem. 2014, 3, 273e276. 73. Wei, W.; Wen, J.; Yang, D.; Liu, X.; Guo, M.; Dong, R.; Wang, H. J. Org. Chem. 2014, 79, 4225e4230. 74. Liu, J.; Zhuang, S.; Gui, Q.; Chen, X.; Yang, Z.; Tan, Z. Eur. J. Org. Chem. 2014, 3196e3202. 75. Shi, L.; Yang, X.; Wang, Y.; Yang, H.; Fu, H. Adv. Synth. Catal. 2014, 356, 1021e1028. 76. Zhang, L.; Li, Z.; Liu, Z. Q. Org. Lett. 2014, 16, 3688e3691. 77. Mai, W. P.; Wang, J. T.; Yang, L. R.; Yuan, J. W.; Xiao, Y. M.; Mao, P.; Qu, L. B. Org. Lett. 2014, 16, 204e207.
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78. Hua, H. L.; He, Y. T.; Qiu, Y. F.; Li, Y. X.; Song, B.; Gao, P.; Song, X. R.; Guo, D. H.; Liu, X. Y.; Liang, Y. M. Chem. Eur. J. 2015, 21, 1468e1473. 79. Yu, J.; Yang, H.; Fu, H. Adv. Synth. Catal. 2014, 356, 3669e3675. 80. Liu, Y. R.; Tu, H. Y.; Zhang, X. G. Synthesis 2015, 47. A-G. 81. Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494e1497. 82. a. Rewcastle, G. W.; et al. J. Med. Chem. 2011, 54, 7105e7126. b. Meanwell, N. A. J. Med. Chem. 2011, 54, 2529e2591. and references therein. c. Furuya, T.; Kuttruff, C.; Ritter, T. Curr. Opin. Drug Disc. Dev. 2008, 11, 803e819.
5
B.R. Langlois 1, 2 1 University of Lyon, Lyon, France; 2University Claude Bernard-Lyon 1, UMR 5246, Villeurbanne, France
Chapter Outline 1. Introduction 125 2. Origin of the Trifluoromethanesulfinate Salts and Their First Uses 127 3. Rebirth of the “Langlois’ Reagent” 131 4. Conclusions 135 Acknowledgments 135 References 136
1. Introduction Because of its unique properties, fluorine has become a “magic” element, and its introduction in various molecules is now considered as an essential tool to strongly modify several properties of a lot of compounds in different domains, from polymers, materials, and surfactants to pharmaceutical and agrochemical ingredients. Fluoro compounds are especially useful in the latter two areas since fluorine-containing substituents can deeply alter the chemical, physical, and biological properties of the compounds bearing them, which consequently gain a better metabolic stability and bioavailability.1 Fluorinated moieties act first by their electronic properties, which can be continuously regulated from F [the most electronegative element by induction (Pauling scale: 3.98)2a but electron donating by conjugation] to CF3, OCF3, and SCF3 (the strongest inductively electronwithdrawing groups). They also act by their hydrophobicity (related in some sense to the electronegativity of fluorine), which can be modulated to a rather large extent, as indicated by the HanscheLeo parameters PR3 (Table 5.1). Their hydrophobicity governs the bioavailability of the substrates bearing them. Among the fluorinated substituents, CF3, with an electronegativity of 3.5 (higher than that of Cl: 3.0),2b constitutes a good compromise for improving the hydrophobicity, and consequently, the bioavailability of substrates bearing it, without inducing too high an accumulation of these substrates in lipidic systems such as Modern Synthesis Processes and Reactivity of Fluorinated Compounds. http://dx.doi.org/10.1016/B978-0-12-803740-9.00005-6 Copyright © 2017 Elsevier Inc. All rights reserved.
126
Modern Synthesis Processes and Reactivity of Fluorinated Compounds
HanscheLeo Parameters of Fluorinated Moieties and Hydrogenated Analogs (Logarithmic Scale)
Table 5.1
Moiety
PR (X [ H)
PR (X [ F)
0.00
þ0.14
CX3
þ0.56
þ0.88
OCX3
0.02
þ1.04
SCX3
þ0.61
þ1.44
SO2CX3
1.63
þ0.55
NHSO2CX3
1.18
þ0.92
X
PR > 0, hydrophobic substituent; PR < 0, hydrophilic substituent.
the nervous system. That is why, during the past 50 years, an incredibly large number of trifluoromethylated compounds have been proposed (and developed in many cases) as pharmaceuticals, anesthetics, “blood substitutes,” and agrochemicals.4 It must be pointed out that, in a large fraction of these bioactive ingredients, the CF3 group is linked to an aromatic or heteroaromatic nucleus. From the 1960s to the 1980s, trifluoromethylated aromatics (or heteroaromatics) were essentially obtained by a two-step synthesis from the corresponding methylated precursors, after radical chlorination and subsequent fluorination with SbF3 (Swarts’ reagent),5 anhydrous hydrogen fluoride,6,2b or tamed HF-containing mixtures, such as Et3N-3HF7 or HF/pyridine (Olah’s reagent).8 It must be pointed out that such a technique is quite exclusively restricted to aromatic substrates. Thus, to overcome this limitation, it rapidly appeared that it would be far better to have in hands specific reagents dedicated to the transfer of the CF3 group onto a larger panel of organic skeletons. For this purpose, three tools can be considered: generators (or equivalents) of the very unstable trifluoromethyl anion (CF3), equivalents of the putative trifluoromethyl cation (“þCF3”), or generators of the reasonably stable trifluoromethyl radical (CF3).9 The first successes were obtained with nucleophilic trifluoromethylating reagents (CF3 equivalents), first through the thermal decarboxylation of alkaline trifluoroacetates in the presence of cuprous iodide (a method that is, nevertheless, quite efficient only for the substitution of aryl or heteroaryl iodides),10 later improved by the action of the ternary system CF3CO2Me/CsCl/CuI on aromatic halides11 and the mild trifluoromethylation of carbonyl substrates with b-(trimethylsilyoxy)trifluoroacetamides/F.12 Then appeared the very popular RuppertePrakash reagent (CF3SiMe3),13 first used to add eCF3 to unsaturated electrophiles such as carbonyl compounds (as did Langlois et al. with fluoroform),14 the scope of which has been extended, year after year, to the substitutive carbon trifluoromethylation of nonactivated aliphatic or aromatic compounds, as well as the sulfur trifluoromethylation of thiocyanates leading to trifluoromethyl sulfides.15
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
127
Then appeared the electrophilic trifluoromethylating reagents (þCF3 equivalents), essentially Umemoto’s trifluoromethylsulfonium salts16 and Togni’s trifluoromethyliodonium salts,17 (may be inspired from the pioneering work of L.M. Yagupolskii with perfluoroalkyliodonium salts,18 but extensively extended to a very broad panel of substrates). As far as radical trifluoromethylation is concerned, many generations of the CF3 radical have been reported during the prehistory of fluorine chemistry, through photolysis of toxic precursors [Hg(CF3)2, Te(CF3)2] or putatively carcinogenic ones [CF3N ¼ NCF3, CF3N(NO)SO2R], single-electron reduction of highly reactive compounds [CF3C(O)CF3, (CF3CO2)2], or single-electron oxidation of trifluoroacetic acid at a very high potential. Trifluoromethyl iodide (CF3I) was considered at that time as the less unsatisfactory reagent for radical trifluoromethylation, despite its toxicity. Moreover, radical trifluoromethylation was considered for a long time to be insufficiently regioselective to be used for targeted syntheses, until the appearance of chemical libraries for which the simultaneous production of several isomers is beneficial, provided that these isomers could be separated. For these reasons, radical trifluoromethylation attracted less attention during the late 1990s and the first decade of the 21st century.
2. Origin of the Trifluoromethanesulfinate Salts and Their First Uses Nevertheless, it should be mentioned that great interest was accorded, from the mid1980s, to trifluoromethyl bromide (CF3Br), which is not toxic and was at that time commercially available, as a fire extinguisher, until the late 1990s, when its production was stopped because of its significant ozone-depleting effect. CF3Br can indeed be not only transformed into stabilized forms of the anion CF3 but can also be reduced, through a single-electron transfer, into Br and CF3, an electrophilic radical that can be trapped by nucleophilic substrates. In the early studiesdthose of C. Wakselman and M. Tordeux19a and L.M. Yagupolskii et al.19bdstrong and soft nucleophiles (thiolates20a,b or strongly delocalized carbanions20c) were used both to reduce CF3Br (in N,N-dimethylformamide and under a slight pressure) and then trap the resulting CF3 radical. Later, a collaboration was established between C. Wakselman’s group and B. Langlois’ group (from the Rhone-Poulenc Co. at that time) to find new singleelectron reducers of CF3Br, different from the nucleophilic substrates used to trap the generated CF3.19a It appeared that generators of the stable radical anion SO2 (Zn/SO2, HCO2Na/SO2, Na2S2O4) were the best candidates and were able to reduce CF3Br in the presence of substrates such as organic disulfides (leading to trifluoromethyl sulfides)21 or electron-rich aromatics,22 as shown in Scheme 5.1. Interestingly, it was observed that, in the absence of any substrate, CF3 was trapped by the persistent radical anion SO2 to provide a trifluoromethanesulfinate (“triflinate”) anion.23 This stable salt, after oxidation with hydrogen peroxide and acidification with sulfuric acid then oleum, opened a new and purely chemical route to triflic acid, which was ˇ
128
Modern Synthesis Processes and Reactivity of Fluorinated Compounds HCO2- /SO2
Zn/SO2
S2O42-
SO2.-
RSSR
SO2
CF3Br
RS-CF3 + RS.
Ar-H
CF3
Ar-CF3
SO2.-
Br-
F3C
O S
H2O2 O
CF3SO3-
H2SO4 oleum
CF3SO3H
Scheme 5.1 Generation and use of CF3 from CF3Br and SO2 .
previously obtained by Simmons’ electrochemical fluorination only. This synthesis has been industrially developed by Rhone-Poulenc Co.24 However, it was observed that only hydrogen peroxide was able to cleanly transform sodium triflinate (CF3SO2Na) into sodium triflate (CF3SO3Na). None of the other oxidizers that were tested (tert-butyl hydroperoxide and peroxide, cumyl hydroperoxide and peroxide, N2O4, cerium ammonium nitrate, sodium persulfate, and sodium hypochlorite) were able to transfer an oxygen atom onto CF3SO2Na. All of them led, at room temperature, to the same reaction: the cleavage of the carbonesulfur bond, the formation of sodium hydrogen sulfite and sulfate, as well as the evolution of sulfur dioxide and other gaseous products. Thus, it was suspected that they could act as single-electron oxidizers and transform the anion CF3 SO2 into the corresponding radical CF3 SO2 : , which is known to be very unstable25 and to collapse into SO2 and the trifluoromethyl radical CF3. tert-Butyl hydroperoxide appeared to be the most efficient oxidizer to get such a reaction (Scheme 5.2). ˇ
HSO3
HSO4 t-BuOOH
SO2
HO
CF3SO2
CF3SO2 unstable t-BuO CF3SO2
CF3 t-BuO
SO2
CF3SO2
HSO4 CF3
t
Scheme 5.2 Single-electron oxidation of CF3SO2Na by BuOOH.
To verify the involvement of CF3 during such an oxidation process, disulfides, known to trap efficiently this radical,21 were added to the medium. Indeed, trifluoromethyl sulfides were produced (Scheme 5.3),26 even from cystine and homocystine without any loss of enantioselectivity.26c Usually, no added catalyst was needed to get good results.27 Nevertheless, when the substrate contained electron-withdrawing moieties, the yield was improved by some MoO2(acac)2, known to facilitate the production of tBuO radicals.28 Thus, it could be deduced that these radicals oxidize the triflinate anion more efficiently than the hydroperoxide does.
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty” t-BuOOH (3-4 eq) MeCN/H2O/r.t. metal free
CF3SO2 + RS-SR (2-3 eq)
RS-CF3 + SO2 + RS
129 t-BuOOH
overoxidation
R = alkyl (100 %), c-hexyl (45 %), (-CH2)nCH(NHR')CO2Me [n = 1,2] (48-56 %) R = (CH2)2CO2Et [71 % (metal free) to 100 % (MoVI as catalyst)] R = (CH2)nCH(NHR')CO2Me (n= 1,2 ; R' = H2+, Ac) (37-56 %)
S
R
CF3
id.
SCF3 +
R
2
SR'
R
R' = H, CF3
Scheme 5.3 Oxidative sulfur trifluoromethylation with CF3SO2Na.
As it was observed that S and C trifluoromethylation coexisted during the reaction of aryl disulfides, the behavior of electron-rich aromatics was also examined. Indeed, CF3SO2Na and tert-butyl hydroperoxide were able to produce trifluoromethylated aromatics under very mild conditions, especially in the presence of Cu(II) catalysts (Scheme 5.4).29 This system was also able to trifluoromethylate pyrrole derivatives. CF3
CF3SO2Na (4 eq) t BuOOH (7 eq)
R2 R1
R1, R2 = H, OH, OMe, NHAc, CO2Me, Cln (21-90 %)
R2
Cu(OTf)2 (0.1 eq)
R1
idem N Ac
N Ac
CF3
(35 %)
Scheme 5.4 Oxidative trifluoromethylation of aromatics.
The behavior of 1,3-(dimethoxy)benzene, a very enriched substrate, indicated that this reaction can be carried out without any metallic catalyst, that Fe(III) improves the yield but without modifying the products ratio to any significant extent, and that Cu(II) is the most effective catalyst for enhancing the global yield and, in addition, minimizes the amount of bis-trifluoromethylated products (Scheme 5.5). The last of these effects is probably due to the better efficiency of Cu(II) to oxidize the intermediate trifluoromethylated cyclohexadienyl radical into the corresponding cation, as postulated in OMe
CF3SO2Na (4 eq) t BuOOH (7 eq) OMe
OMe
catalyst (0.1 eq)
Cata : none (yield: 58 %) Fe(NO3)3 (yield: 67 %) Cu(OTf)2 (yield: 90 %)
OMe CF3 F3C OMe
9 11 24
OMe F3C OMe
25 31 60
Scheme 5.5 Trifluoromethylation of (1,3-dimethoxy)benzene.
OMe CF3 F3C OMe
9 10 4
OMe CF3 14 15 3
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
Scheme 5.6. Despite the fact that Cu(II) exhibits a lower oxidation potential than tertBuOOH, its better efficiency may be related to the fact that Cu(II) transfers an electron in an inner-sphere process, whereas tert-BuOOH does so in an outer-sphere process. Such hypotheses led the authors to qualify this reaction as a “pseudoelectrophilic” trifluoromethylation.
CF3SO2
t-BuOOH
H CF3
R CF3
H CF3
H
R
R Cu(II)
t-BuO SO2
CF3 H R
Cu(I) t-BuOOH
t-BuO CF3SO2
HO
Scheme 5.6 Postulated mechanism for the aromatic trifluoromethylation.
Our later experiments,30 as well as those of Smertenko et al.,31 concerning electrochemical oxidation of potassium triflinate in the presence of aromatic substrates corroborated this mechanism: when exactly 2 F/mole of substrate were used, no bis-trifluoromethylated product was produced. As it could be expected that such a mechanism, implying the oxidation of an intermediate trifluoromethylated radical, would be applied to other electron-rich unsaturated substrates, enol esters were submitted to the oxidative trifluoromethylation by sodium triflinate/tert-butyl hydroperoxide.32 As expected, a-(trifluoromethyl)ketones were obtained under very mild conditions (Scheme 5.7).33 This result was interpreted in a similar way as in Scheme 5.6. Interestingly, phenyl vinyl sulfide was also cleanly trifluoromethylated, provided that a nucleophile, such as methanol, was added to the medium. The role of methanol is to reduce the oxidation power of Cu(II) (and thus, avoid oxidation of the sulfide) and to trap the intermediate carbocation, which is too stabilized to evolve through deprotonation; in this way, a thioketal of 3,3,3trifluoropropionaldehyde was obtained (Scheme 5.7).34 O OAc R
R'
F3C
CF3SO2Na (1-4 eq) t-BuOOH (3-7 eq)
R
Cu(OTf)2 (0.1-0.25 eq) MeCN / r.t.
SPh CF SO Na / t-BuOOH 3 2 Cu(OTf)2 / MeCN / MeOH
R' + R
SPh
OMe + CF3 41 %
O
R'
66 %
CF3
CF3 SPh
53 %
OAc
O
OH
CF3
F3C
OH CF3 20 %
Scheme 5.7 Oxidative trifluoromethylation of enol esters and vinyl sulfides.
60 % O
O
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
131
As for the trifluoromethylation of less enriched unsaturated substrates, electrochemical oxidation of CF3SO2Na was a better tool: with 1.2e1.5 F/mole of substrate, that is, under conditions that prevented the oxidation of the intermediate trifluoromethylated radical and allowed its disproportionation, a mixture of saturated and unsaturated products were obtained.30 However, Langlois’ seminal results, which opened a promising methodology for the radical trifluoromethylation, were largely ignored for almost 15 years, perhaps because of the lack of availability of alkaline triflinates after the banishment of bromotrifluoromethane, although other environmentally benign sources of such salts have been reported during this period (Scheme 5.8).35e37
CF3CO2K + SO2 HCF3 PhCH2-S-CN
CF3SO2K + CO2
CF3SiMe3
CsF / SO2
1) HCCl3 / NaOH 2) Py, 10 HF
PhCH2-SO2-CF3
1) BrCH2CO2Et 2) K2CO3
Ref. 35
CF3SO2Cs
PhCH2-S-CF3
Ref. 36
H2O2
Ref. 37
AcOH
CF3SO2K + Ph
CO2Et
Scheme 5.8 Alternative syntheses of alkaline triflinates.
3. Rebirth of the “Langlois’ Reagent” Surprisingly, in mid-2011, Baran et al. published the trifluoromethylation of various nitrogen-containing heterocycles with sodium triflinate and tert-butyl hydroperoxide. They not only cited Langlois’ work from the 1990s but also, as perfect gentlemen, named CF3SO2Na the “Langlois’ reagent” (“an old reagent with a new use” sic).38 Indeed, the novelty was that they applied this reaction to a large panel of nitrogencontaining heterocycles (although they omitted to cite Langlois’ result on N-acetyl pyrrole) and observed its high tolerance toward various substituents as well as the ease with which it can be carried out. More importantly, they demonstrated that it is possible to trifluoromethylate sophisticated compounds in the last stages of a multistep synthesis. This greatly facilitates the preparation of libraries of potentially bioactive products. Concerning the technical aspect, Baran et al. carried out the reaction in a biphasic water/organic system, observed the influence of stirring on the yield and that of the organic solvent on the regioselectivity of trifluoromethylation, and claimed that no metallic catalyst was needed [a fact that Langlois et al. already reported while mentioning that Cu(II) improved the yield]. Since Baran’s work was commented in Nature39 and in different widely diffused journals [C&N News (December 2011), Royal Chemical Society News (August 2011), and the Scripps Institute advertisements], it quickly became popular. It was rapidly followed by M. Sanford et al. who published a substitutive trifluoromethylation
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
of aryl boronic acids with the “Langlois’ reagent.”40 Very soon thereafter, the use of CF3SO2M (M ¼ Na, K), associated with various oxidants, blossomed and gave rise to a broad family of radical or pseudoelectrophilic trifluoromethylations applied to a large variety of substrates.41 No less than 50 original articles appeared between 2012 and 2015! All these publications are summarized in the following schemes (Schemes 5.9e5.13), each of them being devoted to a type of substrate. For each article is given the main author, the year of publication, the claimed oxidant, and the reference. As it
CF3SO2Na
Ar-H Ar-N2
BF4
Shibata et al. (2013); PhI(OCOCF3)2; ref. 42 Itoh et al. (2013); hν / AQN-2-CO2H; ref. 43
Ar-CF3
[O]
CF3SO2Na
Qing et al. (2015); t-BuOOH / Cu(I) cat.; ref. 44
Ar-CF3
[O]
Scheme 5.9 Oxidative trifluoromethylation of aromatics. R2 R1
R2 CF3SO2Na [O] O
O
CF3SO2Na [O]
Het
R1
O
CF3 Het
CF3
Cao et al. (2014); Mn (OAc)3; ref. 45
O
Baran et al. (2011); t-BuOOH; ref. 38 Baran et al. (2013); t-BuOOH; ref. 46 Montesarchio et al. (2013); t-BuOOH; ref. 47 Molinski et al. (2014); t-BuOOH; ref. 48
Het
= nitrogen-heterocycle
Het
(CF3SO2)2Zn [O]
CF3 Het
Hajra et al. (2015); air / t-BuOOH cat. / Ag(I) cat., ref. 49 Baran et al. (2012); t-BuOOH; ref. 50 Baran et al. (2013); t-BuOOH; ref. 46 Blackmond et al. (2013); t-BuOOH, ref. 51 Baran et al. (2014); electrolysis; ref. 52
Scheme 5.10 Oxidative trifluoromethylation of heterocycles. Ar-B(OH)2 R-B(OH)2 R = aryl, vinyl
CF3SO2Na [O] CF3SO2Na [O]
CF3SO2Na R-BF3K [O] R = aryl, hetaryl, vinyl, alkynyl R
CO2H
CF3SO2Na [O]
Ar-CF3
Sandford et al. (2012); t-BuOOH / Cu(II) cat.; ref. 40
R-CF3
Beller et al. (2013); t-BuOOH / Cu(II)Ln cat.; ref. 53
R-CF3
Molander et al. (2013); t-BuOOH / Cu(I) cat.; ref. 54 Dubbaka et al. (2014); t-BuOOH / Cu(I) cat.; ref. 55
R
CF3
Liu et al. (2013); t-BuOOH / Cu(II) cat.; ref. 56 Duan et al. (2014); t-BuOOH / Cu(I) + Ag(I) cat.; ref. 57 Maiti et al. (2013); K2S2O8 / Fe(III) cat.; ref. 58 Liu et al. (2015); I2O5; ref. 59
Scheme 5.11 Substitutive trifluoromethylation of boronic acids, trifluoroborates, and acrylic acids.
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty” OAc
O
CF3SO2Na
Ar
Ar
[O] X
CF3
Duan et al. (2014); t-BuOOH / Cu(I) cat.; ref. 60
CF3
Lei et al. (2014); air / K2S2O8 cat.; ref. 61
O
CF3SO2Na
Ar
133
Ar
[O]
X = Cl, Br, NHAc, N3
Scheme 5.12 Oxidative trifluoromethylation of functionalized alkenes.62 H CF3SO2Na
Nicewicz et al. (2013); hν / photocat. / ArSH; ref. 63
[O] I
CF3
CF3SO2Na
Liu et al. (2014); I2O5; ref. 64
[O]
CF3 CF3
CF3SO2Na
Qing et al. (2015); t-BuOOH / Cu(I) (1 eq.); ref. 65
[O] H
CF3
O
CF3SO2Na
CF3
[O] H
O
CF3SO2Na
OH CF3 +
[O]
CF3
ONR1R2
CF3SO2Na
Luo et al. (2014); t-BuOOH / benzoquinone (1 eq.); ref. 67 Vicic et al. (2015); air / Mn(II) cat.; ref. 68
Qing et al. (2013); t-BuOOH / Cu(II) cat.; ref. 69
[O] R
Maiti et al. (2013); air / K2S2O8 cat. / Ag (I) cat.; ref. 66
O
CF3SO2Na [O]
R
CF3
Maiti et al. (2014); air / Ag (I) cat.; ref. 70
CF3
Scheme 5.13 Conjugated trifluoromethylation of nonfunctionalized alkenes and alkynes.
can be seen, a large panel of substrates have been used to prepare numerous and valuable products, but the principle of these reactions remains constant. Far more interesting is the variety of oxidant that have been experimented with, in a constant progression toward cheaper and environment-friendly reagents (vide infra). Radical trifluoromethylation with triflinate salts was also frequently used to induce cyclizations leading to potentially bioactive compounds, based on nitrogen- or oxygencontaining heterocycles. For this purpose, all the described oxidants have been
Lipshutz et al. (2014); t-BuOOH / Cu (II) cat.; ref. 71
R1
R3
R3 N R2
CF3SO2Na O
[O]
R1
N R2
Lei et al. (2014); t-BuOOH / Cu (I) cat.; ref. 72 CF3 O
Wang et al. (2014); K2S2O8; ref. 73 Tan et al. (2014); (NH4)2S2O8; Ag(I) cat.; ref. 74 Fu et al. (2014); PhI(OAc)2; ref. 75 Liu et al. (2014); I2O5; ref. 76
Scheme 5.14 Cyclizing trifluoromethylations leading to oxindoles.
134
Modern Synthesis Processes and Reactivity of Fluorinated Compounds Ar
Ar
R1 R1
N R2
Ar
O O
R1 N H
R3
NR
O
Mai, Xiao et al. (2014); K2S2O8 / Ag(I) cat.; ref. 77
O
CF3
Liu, Liang et al. (2015); t-BuOOH / Cu (I) cat.; ref. 78
Z O R1 Z = O, NR R3
CF3SO2Na [O]
R2
Ar
O R2
N
[O]
[O]
N
Fu et al. (2014); PhI(OAc)2; ref. 79
I
CF3SO2Na
R2 CF3SO2Na
CF3
R1
Ar
Ar
R1
N R2
Ar [O]
Z
R1
[O]
O
CF3SO2Na
Ar
CF3
CF3SO2Na
Liu et al. (2014); I2O5; ref. 76
CF3
N R
R2 R1
Zhang et al. (2015); t-BuOOH / Ag (I) cat.; ref. 80 N
CF3
Scheme 5.15 Cyclizing trifluoromethylations leading to various heterocycles.
employed. Trifluoromethylated oxindoles constituted the main target (Scheme 5.14), although other five-membered or six-membered cycles were prepared (Scheme 5.15). Apart from all the possibilities afforded by triflinate salts to carry out various trifluoromethylations, an analogous breakthrough must be emphasized: the use of zinc difluoromethanesulfinate (HCF2SO2)2Zn, reported for the first time by Baran et al., as well as Blackmond et al., to carry out radical difluoromethylation upon heterocycles, especially those containing nitrogen (Scheme 5.16).46,50e52,81 Later, this CHF2SO2Cl
Zn° / H2O
(CHF2SO2)2Zn
CHF2SO2Cl (2-4 eq) t-BuOOH (3-6 eq) N TFA (1 eq) (and other DCM:H2O / rt N-heterocycles) R
R
85 % CHF2
N
30–90 %
Scheme 5.16 Preparation of (HCF2SO2)2Zn and its use for radical difluormethylation.
difluoromethylation was applied to acrylic acids56 and for the synthesis of difluoromethylated oxindoles.74 Apart from the fact that (HCF2SO2)2Zn (zinc “diflinate”) can be easily prepared from difluoromethanesulfonyl chloride and is now commercially available,81 the interest in such a reaction is the fact that the difluoromethyl moiety has become more and more popular as a replacement for or complement to the trifluoromethyl one, for, at least, three reasons. The first is that, although interestingly stable, it is less stable than CF3. The second one is that, while remaining a highly hydrophobic group, its hydrophobicity is lower than that of CF3. Thus, for these two reasons, difluoromethylated compounds are less persistent in situ than their trifluoromethylated analogs, for example, in the soil (for
Once Upon a Time Was the Langlois’ Reagent: a “Sleeping Beauty”
135
agrochemicals) or in lipidic systems (for pharmaceuticals), which gives it a serious advantage. The third reason is that CHF2 being less electrophilic than CF3, the regioselectivity of attack of these two radicals can differ, as it was nicely illustrated by Baran Et OH MeO
more electrophilic
CF3
N
CHF2 less electrophilic
Scheme 5.17 Difference in regioselectivities for CF3 and CHF2.
et al. on dihydroquinine and varenicline (Scheme 5.17).81 The interest in such a finding could allow us to name (HCF2SO2)2Zn as the “BaraneBlackmond reagent”!
4. Conclusions In conclusion, radical trifluoromethylation with trifluoromethanesulfinate salts under oxidative conditions, first discovered by Langlois’ et al. in the early 1990s, remained relatively little known until the very beginning of the 2010s decade when Baran et al., as well as Blackmond et al. brought it back to life, named sodium triflinate the “Langlois’ reagent,” and opened new perspectives for mild, easy, robust, and cheap syntheses of trifluoromethylated products, even sophisticated ones that could be of interest for bioactive specialties. Simultaneously, Baran et al., as well as Blackmond et al., also developed a similar method to graft difluoromethyl moieties on organic substrates from zinc difluoromethanesulfinate, which could have a bright future.82 Surprisingly, the rebirth of the Langlois’ reagent received a wide echo in the chemical community and induced an important blossom of publications. Although the principle remained the one postulated by Langlois et al. in 1991e92, important improvements were brought to the methodology, especially concerning the nature of the single-electron oxidant. Although until now, tert-butyl hydroperoxide, usually associated with copper or silver salts as catalysts, remains the most employed oxidant, more stable and cheaper reagents such as K2S2O8 and I2O5 are emerging. However, the breakthrough came from the possibility, published in 2015, to use air as oxidizer and various salts (K2S2O8) or metallic cations, especially Mn(II), as catalysts.61,66,68,70
Acknowledgments The author warmly acknowledges Dr. Thierry Billard and Dr. Fabien Toulgoat for helping him very efficiently during the elaboration of this chapter and carefully checking all the articles published between 2010 and 2015.
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Modern Synthesis Processes and Reactivity of Fluorinated Compounds
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