Trifluoromethylation of aryl and heteroaryl halides with fluoroform-derived CuCF3: Scope, limitations, and mechanistic features

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Triﬂuoromethylation of Aryl and Heteroaryl Halides with Fluoroform-

Derived CuCF₃: Scope, Limitations, and Mechanistic Features

Anton Lishchynskyi, Maxim A. Novikov, Eddy Martin, Eduardo C. Escudero-Adan, Petr Novak,

́

and Vladimir V. Grushin*

Institute of Chemical Research of Catalonia (ICIQ), Tarragona 43007, Spain

S

* Supporting Information

ABSTRACT: Fluoroform-derived CuCF₃recently discovered in our group

exhibits remarkably high reactivity toward aryl and heteroaryl halides,

performing best in the absence of extra ligands. A broad variety of

iodoarenes undergo smooth triﬂuoromethylation with the “ligandless”

CuCF₃at 23−50 °C to give the corresponding benzotriﬂuorides in nearly

quantitative yield. A number of much less reactive aromatic bromides also

have been triﬂuoromethylated, including pyridine, pyrimidine, pyrazine, and

thiazole derivatives as well as aryl bromides bearing electron-withdrawing

groups and/or ortho substituents. Only the most electrophilic chloroarenes can be triﬂuoromethylated, e.g., 2-chloronicotinic

acid. Exceptionally high chemoselectivity of the reactions (no side-formation of arenes, biaryls, and C₂F₅derivatives) has allowed

for the isolation of a large number of triﬂuoromethylated products in high yield on a gram scale (up to 20 mmol). The CuCF₃

reagent is destabilized by CuX coproduced in the reaction, the magnitude of the eﬀect paralleling the Lewis acidity of CuX: CuCl

> CuBr > CuI. While S_NAr and S_RN1 mechanisms are not operational, there is a well-pronounced ortho eﬀect, i.e., the enhanced

reactivity of ortho-substituted aryl halides 2-RC₆H₄X toward CuCF₃. Intriguingly, this ortho-eﬀect is observed for R = NO₂,

COOH, CHO, COOEt, COCH₃, OCH₃, and even CH₃, but not for R = CN. The ﬂuoroform-derived CuCF₃reagent and its

reactions with haloarenes provide an unmatched combination of reactivity, selectivity, and low cost.

Chen,⁹Fuchikami,¹⁰and others.^2,11,12The most notable recent

INTRODUCTION

■

developments include the ﬁrst aromatic C−CF₃bond formation

at Pd,¹³the synthesis of well-deﬁned Cu(I) triﬂuoromethylating

reagents,¹⁴the ﬁrst catalytic triﬂuoromethylation reactions of

haloarenes using Cu¹⁵and Pd¹⁶complexes, and oxidative

triﬂuoromethylation of aryl boronic acids and boronates.¹⁷

Triﬂuoromethylated aromatic and heteroaromatic compounds

are key building blocks and intermediates in the production of

numerous pharmaceuticals, agrochemicals, and specialty materi-

als.^1,2Aromatic derivatives bearing a CF₃group are currently

manufactured by a two-step process that involves exhaustive

radical chlorination of a methyl group on the ring, followed by

Swarts-type Cl/F exchange with HF (eq 1).³The stoichiometry

of this reaction sequence shows that to produce 1 equiv of the

desired product, 3 equiv of each Cl₂and HF are needed and 6

equiv of HCl (chlorine waste) is cogenerated. Being environ-

mentally hazardous, this process also suﬀers from low functional

group tolerance because of the involvement of highly reactive

Cl₂, HF, and HCl. Even simple alkyl, alkoxy, acyl, amino,

carboalkoxy, etc. groups cannot survive the reaction conditions.

The method is also inapplicable to many heteroaromatic

substrates.

In spite of the substantial progress in the area, there have been

no reports on a potentially industrially viable method that could

replace the currently used technology (eq 1). A key reason for

this is the high cost of the CF₃reagents (primarily CF₃SiMe₃

and CF₃SiEt₃) and ligands employed in the Ar−CF₃coupling

reactions.²Much less expensive, easily accessible sources of the

CF₃group are needed for aromatic and other triﬂuoro-

methylation reactions. Furthermore, these reactions should

occur eﬃciently and selectively in the absence of cost-

prohibitive ligands. It is also noteworthy that, in general, aryl

halides are preferred over the corresponding boronic acids as the

latter is usually prepared from the former.

An alternative to the two-step process shown in eq 1 would be

the selective introduction of the CF₃group into the desired

position on the aromatic or heteroaromatic ring (eq 2). The ﬁrst

example of such a transformation, the reductive coupling of aryl

halides with perﬂuoroalkyl iodides in the presence of Cu metal,

was reported by McLoughlin and Thrower⁴in the 1960s. Since

then, the area has progressed considerably, largely by the work

of the groups of Kumadaki,⁵Yagupolskii,⁶Kondo,⁷Burton,⁸

Fluoroform (triﬂuoromethane, CHF₃, HFC-23) has long

been recognized as the most readily available, cheap, and atom-

economical CF₃source.^2,18−22A side product of Teﬂon

manufacturing, ﬂuoroform is generated in an amount of over

Received: July 1, 2013

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Scheme 1

Scheme 2

20000 t per annum. While being nontoxic and ozone-friendly,

CHF₃is a potent greenhouse gas^23,24(bp = −82 °C) with a 264-

year atmospheric lifetime and a global warming potential over

10⁴that of CO₂. Therefore, the CHF₃side-product should be

either destroyed in what is a costly incineration process, or,

much more preferably, used as a feedstock for manufacturing

ﬂuorochemicals.²³Chemoselective activation of ﬂuoroform,

however, is a nontrivial challenge.

operations aimed at utilization of the side-produced ﬂuoroform

(see above). Shibata and co-workers²⁸reported CHF₃

deprotonation with Schwesinger’s phosphazene base t-Bu-P4²⁹

in THF. While being methodologically interesting, this

reaction²⁸employs stoichiometric quantities of costly t-Bu-P4

and still requires a low temperature (−30 °C) to proceed

smoothly. An example of aromatic triﬂuoromethylation via a

multistep procedure using the deprotonation methodology has

been reported (Scheme 2).^20bThe reaction of CHF₃with

dimsyl potassium in DMF at −25 to −40 °C gave HA that was

converted to its Cu analogue and eventually to CuCF₃that

eﬀected the triﬂuoromethylation of p-iodoanisole in 10−40%

yield.

The traditional strategy to use CHF₃, a weak acid (pK_a= 27 in

water),²⁵in synthesis is based on deprotonation with strong

alkali metal¹⁸⁻²²or electrogenerated²⁶organic bases. These

reactions are conventionally conducted at low temperatures in

−

DMF in order to minimize the facile decomposition of the CF₃

carbanionic species to diﬂuorocarbene. Under such conditions,

the CF₃adds across the CO bond of DMF to give the

A methodologically diﬀerent approach to activation of

ﬂuoroform was proposed by Folleas et al. in 2000.^20bIn their

report, they wrote: “Our first attempts to generate trifluoromethyl

metal with M = Cu and Zn from fluoroform were based on the

metallation concept with basic organocopper and organozinc

derivatives in order to directly obtain the trifluoromethyl copper

or zinc derivatives. However, whatever the organometallic used

((nBu)₂CuLi, (nBu)₂CuCNLi₂, (nBu)₃CuCNLi₃, tert-

Bu₂CuCNLi₂, Et₂Zn, (nBu)₃ZnLi, AllylZnBr,...) in different

conditions (heating, sonication, in pressurised flask) or different

solvents (Et₂O, THF, HMPA) no trace of the corresponding

trifluoromethyl organometallic was detected”.^20bThis quote

provides an indication of the scale of the challenge that was

overcome only over a decade later when two groups discovered

the ﬁrst reactions of direct zincation and cupration of

ﬂuoroform.

−

corresponding hemiaminolate (HA) that serves as a “reservoir”

of the CF₃nucleophile. Although unstable at room temperature,

this hemiaminolate decomposes only slowly if kept cold (hours

at −20 °C).^20bA summary of selected well-known triﬂuoro-

methylation reactions using this methodology is presented in

Scheme 1. Most recently, it was demonstrated by two

groups^27,28that similar transformations can be performed in

solvents other than DMF, such as THF, ether, and toluene.

Using the Roques−Russell^18,19CHF₃/KN(SiMe₃)₂system,

Prakash et al.²⁷prepared R₃SiCF₃(42−80% yield) and

CF₃SO₃H (18% yield) from R₃SiCl and S₈, respectively. To

eliminate the need for DMF, however, these reactions must be

conducted at a much lower temperature (−78 °C), making the

deprotonation methodology even less suitable for larger scale

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In 2011, Popov, Lindeman, and Daugulis^12breported the

zincation of R_fH (R_f= perﬂuoroalkyl), while our group^2,30

disclosed the ﬁrst reaction of direct cupration of ﬂuoroform. The

Daugulis method^12bemploying zinc bis-2,2,6,6-tetramethylpi-

peridide is useful for higher R_fH. For triﬂuoromethylation

reactions, however (R_f= CF₃), the method is less eﬃcient

because of α-ﬂuoride elimination leading to C₂F₅derivatives at

the elevated temperatures required for CF₃transfer to Cu in

order to utilize the originally produced Zn(CF₃)₂.

RESULTS

■

Of all haloarenes, aryl iodides are most reactive in a broad

variety of Cu-promoted/catalyzed coupling reactions, triﬂuoro-

methylation being no exception.^{2,4−12,14,15}Both structurally

2

undeﬁned CuCF₃and its adequately characterized derivatives

[(NHC)CuCF₃],¹⁴[(phen)CuCF₃],^12c[(Ph₃P)₃CuCF₃],^12d

[(Ph₃P)(phen)CuCF₃],^12dand [(bathophen)CuCF₃]^12ehave

been shown to triﬂuoromethylate various iodoarenes quite

eﬃciently. In contrast, only a very limited number of Cu-

promoted triﬂuoromethylation reactions of more cost-attractive

yet much less reactive bromoarenes have been reported.^2,12c

The lower reactivity of the Ar−Br bond toward Cu(I) is often

insuﬃcient to achieve satisfactory conversions and yields in Cu-

promoted triﬂuoromethylation reactions. Examples of triﬂuoro-

methylation of the least reactive aryl chlorides are extremely

rare.²

Our method³⁰is based on a novel ate complex reagent,

[K(DMF)][(t-BuO)₂Cu], that is formed quantitatively upon

treatment of CuCl with 2 equiv of t-BuOK. This dialkox-

ycuprate, generated in situ or preisolated, reacts with CHF₃at

room temperature and atmospheric pressure within minutes to

give rise to CuCF₃in >90% yield. Stabilization of the thus

produced triﬂuoromethyl copper(I) with a source of HF such as

Et₃N·3HF (TREAT HF) furnishes the reagent that is stable at

room temperature for days.³⁰

We have recently demonstrated that our CuCF₃reagent can

be used for high-yielding triﬂuoromethylation reactions of

various substrates, including transition metal complexes,³⁰

arylboronic acids,³¹and α-haloketones³²(Scheme 3).³³We

Triﬂuoromethylation of Aryl Iodides. The vast majority

of previously reported Cu-mediated/catalyzed triﬂuoro-

methylation reactions of aromatic electrophiles occur eﬃciently

only in the presence of a speciﬁcally added ligand,²most

commonly phenanthroline. In contrast, our ﬂuoroform-derived

CuCF₃is reactive toward iodoarenes in the absence of any

added ligands.³⁰Moreover, it was found in the current work that

adding various ligands, including phenanthroline, tertiary

phosphines, and pyridine to our CuCF₃reagent not only did

not have a beneﬁcial eﬀect on the triﬂuoromethylation reaction,

but often resulted in diminished reactivity and lower selectivity

and yield.

Scheme 3

Prior to the stabilization³⁰with TREAT HF³⁴(see above),

ﬂuoroform-derived CuCF₃reacted with iodobenzene and other

simple iodoarenes at as low as room temperature to give the

corresponding benzotriﬂuorides. This Ar−CF₃coupling was

complicated, however, by the competing alkoxylation reaction

leading to tert-butyl ethers, t-BuOAr (Scheme 4). The

stabilization with TREAT HF not only gave a much more

robust CuCF₃reagent but also suppressed altogether the

undesired alkoxylation, apparently due to neutralization of the

tert-butoxide formally present in the originally produced CuCF₃

solution. Furthermore, it was found that performing the reaction

in the presence of 0.2 equiv of extra TREAT HF had a beneﬁcial

eﬀect on both the conversion and yield.

To make the triﬂuoromethylation reaction potentially

practicable, it was critical to ﬁnd conditions for high conversion

(≥95%) of the iodoarene substrate with a minimal amount of

the CuCF₃reagent. The results of our eﬀort toward this goal are

summarized in Table 1. Note that in most of the previous

studies,²either the ArI substrate or the CF₃source had to be

used in considerable excess in order to obtain the desired

benzotriﬂuoride products in good yield.

have also preliminarily communicated³⁰triﬂuoromethylation of

a handful of iodoarenes under nonoptimized conditions to

demonstrate a proof of concept. Herein, we report the ﬁrst

systematic, detailed study of triﬂuoromethylation of aryl and

heteroaryl iodides, bromides, and chlorides with the new easily

accessible, low-cost ﬂuoroform-derived CuCF₃reagent.

As can be seen from Table 1, a broad variety of aryl iodides

could be eﬃciently triﬂuoromethylated in up to 99% yield at

>99% conversion with only 1.1−2.0 equiv of CuCF₃. To our

Scheme 4

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Table 1. Triﬂuoromethylation of Aryl and Heteroaryl Iodides with Fluoroform-Derived CuCF₃

D

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Table 1. continued

a

b

c

d

e

Determined by GC−MS. Determined by ¹⁹F NMR. 1,4-(CF₃)₂C₆H₄(4%) was produced. 1,2-(CF₃)₂C₆H₄(9%) was produced. 1,2-(CF₃)₂C₆H₄

f

(3%) was produced. Thiophene (7%, GC−MS) was produced.

delight, almost none of these reactions gave rise to arenes,

biaryls, and pentaﬂuoroethyl derivatives that are commonly side-

produced in Cu-mediated triﬂuoromethylation of aryl halides.²

The only exception was the reaction of 2-iodothiophene 1u that

produced 7% of thiophene as a side product.

procedure describing in suﬃcient detail not only reaction

conditions but also the way a targeted benzotriﬂuoride was

isolated pure on a ≥0.5 g scale and adequately characterized.

The particularly meticulous Cottet−Schlosser³⁵procedures for

the preparation of multigram quantities of some triﬂuoromethy-

lated naphthalenes and pyridines from the corresponding iodo

derivatives are truly exceptional in terms of both high quality

and considerable reaction scale. In the current work, isolation of

pure products in high yield was demonstrated for a number of

reactions (Table 1), and in several cases these were performed

on a 10−11-mmol scale to give, for example, 2b (1.71 g; 88%),

2d (1.53 g; 87%), 2k (2.09 g; 96%), 2l (1.62 g; 94%), and 2q

(1.53 g; 81%). In one 20-mmol scale-up, nearly 4 g of pure 1-

triﬂuoromethylnaphthalene 2p was prepared (98% yield).

Triﬂuoromethylation of Aryl Bromides and Chlorides.

While being less costly and more readily available, bromo- and

chloroarenes are considerably less reactive toward Cu(I)

coupling partners than their iodo congeners.³⁶Triﬂuoromethy-

lation of bromoarenes with copper reagents is an extremely

challenging and rare transformation²that usually occurs only

with electron-deﬁcient substrates even in the presence of

stabilizing ligands such as NHC^14band phen.^12cA handful of

publications mention isolated yields of triﬂuoromethylated

aromatics produced from the corresponding aryl bromides

(see Table 3 in ref 2). None of these reports, however, includes a

particular procedure for triﬂuoromethylation of an aryl bromide

and isolation and adequate characterization of the product. Only

Most of the optimization work was performed on 1b, a more

challenging substrate bearing a strongly electron-donating

methoxy group in the para-position. For electron-deﬁcient

(1k−o,q) and most of the ortho-substituted (1d,e,p,q)

iodoarenes, nearly quantitative conversions could be achieved

within 24 h at room temperature. o-Iodobenzamide (1q) was

particularly reactive, undergoing triﬂuoromethylation of the C−

I bond in >99% conversion within 15 min at 23 °C with only 1.1

equiv of CuCF₃(entry 34). This enhanced reactivity likely

reﬂects the ortho-eﬀect that is discussed below. For less reactive

aryl iodides bearing electron-donating groups in the meta or

para positions, heating at 50 °C for additional 18−24 h was

required in order to achieve >95% conversion. Various

substituents on the ring were easily tolerated, including not

only simple alkyls but also OMe, CO₂R, CN, NO₂, Ac, CHO,

CONH₂, and Br. The latter, however, was noticed to undergo

partial displacement in the reaction, albeit to a minor extent (3−

9%; entries 35−37).

While there have been a number of reports on Cu-promoted

triﬂuoromethylation of aryl halides,^{2,4−12,14,15}the products have

been seldom isolated but rather identiﬁed and quantiﬁed by ¹⁹

F

NMR and/or GC techniques. It is hard to ﬁnd a literature

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one article³⁷provides such procedures for the synthesis of four

triﬂuoromethylated heterocycles from the corresponding

bromides, 2,4-dimethoxy-5-(triﬂuoromethyl)pyrimidine, 2,4-

dimethoxy-6-(triﬂuoromethyl)pyrimidine, 3′,5′-di-O-acetyl-8-

(triﬂuoromethyl)-2′-deoxyadenosine, and 2′,3′,5′-tri-O-acetyl-

8-(triﬂuoromethyl)inosine in 42, 31, 64, and 42% yield,

respectively. To reach these yields, 11−25 equiv of CF₃I and

20−39 equiv of Cu in HMPA were used.

corresponding triﬂuoromethylated derivatives in only ca. 10−

30% yield. This reactivity pattern accords with the nearly

quantitative yields of 2-triﬂuoromethylpyrimidine 4n (95%) and

2,5-bis(triﬂuoromethyl)pyrazine 4p (94%), yet only 24% yield

of 4-triﬂuoromethylpyrimidine 4o from the corresponding

mono- and dibromo substrates (entries 15−17). Remarkably,

a CH₃group in an adjacent position (2 or 4) of the 3-

brominated pyridine ring enhanced noticeably the reactivity of

the C−Br bond (3l and 3m vs 3k). 2-Bromothiazole 3q and its

5-nitro derivative 3r were triﬂuoromethylated in only ca. 20%

yield under such conditions, apparently because of decom-

position by the reagent. In order to reach higher yields of 4q

(35%) and 4r (55%), only 1 equiv of CuCF₃stabilized with 0.33

equiv of TREAT HF should be used (entries 18 and 19). 4-

Bromopyridine, commercially available as its hydrochloride, was

triﬂuoromethylated in 74% yield (entry 20). In this case, 3 equiv

of CuCF₃were needed because, like other strong acids (HBr),³²

the HCl present in the starting material partially decomposes

the organocopper reagent.

We have preliminarily communicated³⁰the formation of 2-

triﬂuoromethylpyridine in 30% ¹⁹F NMR yield from the

reaction of 2-bromopyridine (3a) with ﬂuoroform-derived

CuCF₃used as a limiting reagent. In this work, we ﬁrst focused

on 3a as a substrate because triﬂuoromethylated pyridines, while

being particularly important in the preparation of biologically

active compounds, cannot be eﬃciently made from the

corresponding picolines (eq 1) without chlorination of the

pyridine ring.

Optimization of the reaction of 2-bromopyridine with the

CuCF₃reagent led to an increase in the yield of the desired

product, 2-triﬂuoromethylpyridine (4a), to 90% at full

conversion (eq 3). Herein, we present only a succinct summary

of the optimization studies that included over 60 runs. First, it

was established that, like in the case of iodoarenes (see above),

the reaction beneﬁts from additional amounts of TREAT HF.

The best yields were obtained using CuCF₃stabilized with 1.6

equiv of HF in the form of TREAT HF. Lower yields were

observed with Py(HF)_nas the stabilizer. At 50−60 °C, yields of

up to 60% at 75% conversion and 80% at >90% conversion

could be obtained with 1.0 and 1.5 equiv of CuCF₃, respectively.

To reach full conversion, however, 2.0 equiv of CuCF₃appeared

to be needed. While adding the copper reagent in two portions

resulted in further improvements, the best yield of 4a was

obtained when the copper reagent solution was added slowly,

over a period of 6 h, to 3a at 80 °C and the mixture was then

agitated for additional 2 h (eq 3). A number of additives were

tested. Neither [Bu₄N]⁺I⁻nor NEt₃(1 equiv) had a noticeable

eﬀect on the reaction, although in the presence of 10 equiv of

NEt₃, 4a was formed in a slightly higher yield. On deliberate

addition of water (1.5 equiv), the yield of 4a dropped

considerably because of decomposition of the CuCF₃reagent.

Electron-rich bromoarenes are known²to react with various

CuCF₃species only at elevated temperatures that also cause

quick decomposition of the copper reagent. As a result, the

yields of the triﬂuoromethylated products are low. More reactive

aryl bromides bearing electron-withdrawing groups on the ring

can be triﬂuoromethylated in much higher yields (Table 2,

entries 21−33). Like in the above-described triﬂuoro-

methylation of iodoarenes, the reactions of aryl bromides were

not complicated by side processes leading to arenes, biaryls, and

pentaﬂuoroethyl derivatives.³⁹In sharp contrast, the CuCF₃

generated in the widely known Cu−CF₂Br₂−DMAC system has

been reported⁴⁰to produce mainly biaryls on attempted

triﬂuoromethylation of aryl bromides and iodides.

The previously observed⁴⁰and recently reviewed^11epromot-

ing eﬀect of a nitro group in the ortho position was also seen in

the reactions of isomeric nitrobromobenzenes 3t−v with

ﬂuoroform-derived CuCF₃. o-Nitrobromobenzene 3t under-

went remarkably fast and clean triﬂuoromethylation to give o-

nitrobenzotriﬂuoride quantitatively within 18 h at room

temperature with only 1.3 equiv of CuCF₃. In contrast, the

reactions of the meta (3u) and para (3v) isomers required

longer times at 50−80 °C and a larger excess of CuCF₃, while

furnishing the corresponding products 4u and 4v in only 22%

and 60% yield, respectively. The ortho and para isomers of

bromobenzonitrile, however, exhibited identical moderate

reactivity toward CuCF₃(entries 25 and 26).

Strikingly, carbonyl-containing groups COOMe, COOH,

CHO, and COMe ortho to the bromine atom had a

tremendously strong accelerating eﬀect on the triﬂuoro-

methylation (entries 27−33). Unmatched reactivity was

observed for the acids 3z, 3aa, and 3ee that underwent

complete triﬂuoromethylation with only 1.1 equiv of CuCF₃

within 10−15 min at room temperature.⁴¹Although 2-

bromobenzaldehyde 3cc (entry 31), 2-bromoacetophenone

3dd (entry 32), and methyl 2-bromobenzoate 3y (entry 27)

were slightly less reactive, the corresponding triﬂuoromethy-

lated products 4cc, 4dd, and 4y were still obtained in 83, 96, and

98% yield, respectively. A number of aryl and heteroaryl

bromides were triﬂuoromethylated on a preparative 1−10 mmol

scale, and the corresponding products (4f,g,i,j,t,y,z,aa,dd) were

successfully isolated pure in high yield (Table 2).

After successful optimization of the synthesis of 4a from 3a,

we proceeded to explore triﬂuoromethylation reactions of a

broad variety of heteroaryl and aryl bromides (Table 2).³⁸All

isomeric monomethylated 2-bromopyridines 3b−e were tri-

ﬂuoromethylated in 73−88% yield at 91−99% conversion after

33 h at 50 °C (entries 2−5). In these experiments, the CuCF₃

reagent was added in two portions, 1 equiv at the beginning of

the reaction and 1 equiv 15 h later, after which the reaction was

continued for additional 18 h. More reactive 2-bromoquinoline

3f underwent smooth triﬂuoromethylation under milder

conditions, 23−50 °C, to give 2-triﬂuoromethylquinoline 4f in

up to 91% yield at >98% conversion (entries 6 and 7). 2-

Bromopyridines bearing electron-deﬁcient substituents,

CO₂Me, CHO, and NO₂, were even more reactive, undergoing

triﬂuoromethylation in 88−98% yield at >99% conversion with

only 1.5 equiv of CuCF₃after 12−15 h at room temperature

(entries 8−11). As expected, the intrinsically less electrophilic 3-

bromopyridines reacted more sluggishly to give rise to the

Chloroarenes are even more challenging substrates⁴²for

carbon−halogen bond activation, particularly with copper.³⁶

Unsurprisingly, 2-chloro-3-picoline and 2-chloro-pyridine-3-

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Table 2. Triﬂuoromethylation of Aryl and Heteroaryl Bromides with Fluoroform-Derived CuCF₃Stabilized with TREAT HF

(0.53 equiv)

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Table 2. continued

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Table 2. continued

a

b

c

Determined by GC−MS. Determined by ¹⁹F NMR. CuCF₃in DMF was added during 6 h, and then the reaction was continued for an additional

d

e

f

g

h

2 h. 18 h at 23 °C, then 18 h at 50 °C. ND = not determined. CuCF₃without extra TREAT HF. 24 h at 23 °C, then 15 h at 50 °C. CuCF₃in

DMF was added during 12 h, and then the reaction was continued for an additional 6 h. In the form of hydrochloride. 24 h at 23 °C, then 24 h at

i

j

k

l

50 °C. CuCF₃in DMF was added during 4 h, and then the reaction was continued for an additional 2 h. Approximately 10% of the corresponding

m

phenol was side-produced (¹H NMR). The isolated yields are given for pure products. Approximately 2% of benzaldehyde was side-produced

(GC−MS).

carbonitrile failed to react with CuCF₃and even more electron-

deﬁcient 5-nitro-2-chloro-3-picoline (5e) was triﬂuoro-

methylated in only ca. 20% yield. The above-described ortho-

eﬀect was observed in the reactions of CuCF₃with 2-

chloronicotinic acid (5a), its ethyl ester (5b), 2-chlorobenzoic

acid (5c), and 2,3-dichloronitrobenzene (5d) that gave the

corresponding triﬂuoromethyl derivatives in 30−60% yield

(Scheme 5). Remarkably, the reaction of 2-chloronicotinic acid

Scheme 5

Figure 1. ORTEP drawing of [Cu₂(μ-O₂CC₆H₄CF₃-2)₄(DMF)₂] with

thermal ellipsoids drawn to the 50% probability level and all H atoms

omitted for clarity. [Symmetry code: −x + 1, −y + 1, −z].

5a occurred at as low as room temperature, thereby attesting to

the strong ortho-eﬀect of the carboxylic acid functionality. This

triﬂuoromethylation reaction was performed on a 5 mmol scale

and the product, 2-triﬂuoromethylnicotinic acid 6a, was isolated

in 58% yield.

If the reaction mixtures from the triﬂuoromethylation of 2-

bromobenzoic acid and 2-chloronicotinic acid were not worked

up quickly but rather allowed to stand at room temperature

under argon for several hours (overnight), green-blue crystals

and copper metal slowly precipitated out. X-ray analysis of these

crystals revealed the structures [Cu₂(μ-O₂CAr)₄(DMF)₂] (Ar =

2-CF₃C₆H₄, 2-CF₃C₅H₃N), as shown in Figures 1 and 2.

Apparently, the Cu(I) byproduct of the reactions slowly

disproportionated in the presence of the triﬂuoromethylated

acid produced in the reaction to give Cu(0) and the stable

Cu(II) dimer. A number of paddlewheel dinuclear Cu(II)

carboxylates of the type [Cu₂(μ-O₂CR)₄(L)₂] where L is a

monodentate ligand such as H₂O, THF, DMF, Py, etc. have

been reported in the literature.^43,44

CuX Byproduct Eﬀect. Copper-mediated coupling reac-

tions of aryl halides sometimes display interesting features that

are not always mechanistically understood.^36,45In the course of

our studies, we found an unpredicted eﬀect of the CuX (X = I,

Br, Cl) byproduct of the triﬂuoromethylation reaction on the

CuCF₃reagent during the process. A series of experiments

indicated that the triﬂuoromethylation of 2-bromopyridine was

not aﬀected in any way when it was performed in the presence of

Figure 2. ORTEP drawing of [Cu₂(μ-3-O₂CC₅H₃NCF₃-2)₄(DMF)₂]

with thermal ellipsoids drawn to the 50% probability level and all H

atoms omitted for clarity. [Symmetry code: −x + 1, −y + 2, −z].

1 equiv of the deliberately added product, 2-(triﬂuoromethyl)-

pyridine. In contrast, CuBr, the reaction byproduct, was found

to destabilize the CuCF₃reagent, causing its partial decom-

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position.⁴⁶In line with these observations, dilution of the

reaction mixture with additional DMF led to an increase in

stability of the CuCF₃, while also slowing down the triﬂuoro-

methylation. This negative eﬀect of CuBr on the stability of

CuCF₃was unexpected. It is noteworthy that the reaction

medium contains triethylamine that comes from the TREAT

HF stabilizer and that is known⁴⁷to react with CuX (X = Cl, Br,

I) to give cubane-type complexes [Cu₄(NEt₃)₄X₄]. Indeed,

[Cu₄(NEt₃)₄Br₄] was isolated from the room-temperature

reaction of 3g and structurally characterized (Figure 3).⁴⁸

However, complexes of the type [Cu₄(NEt₃)₄X₄] are quite

labile,⁴⁷easily releasing CuX under the reaction conditions.

Scheme 6

characterized cuprous biﬂuoride complexes have been recently

reported.⁵⁰

To distinguish between the two conceptually distinct

mechanisms shown in Scheme 6, we studied the decomposition

of CuCF₃during its reaction with 4-iodoﬂuorobenzene in the

presence of deliberately added CuI, CuBr, and CuCl. These

experiments demonstrated that (i) larger quantities of CuCl

cause more decomposition (Table 3) and (ii) the ability of CuX

Table 3. Triﬂuoromethylation of 4-FC₆H₄I (1 equiv) with

Fluoroform-Derived CuCF₃(1.5 equiv) in DMF in the

Presence of Various Amounts of CuCl at 100 °C (0.5 h)

Figure 3. ORTEP drawing of [Cu₄(NEt₃)₄Br₄] with thermal ellipsoids

drawn to the 50% probability level and all H atoms omitted for clarity.

[Symmetry codes: (A) −x + 2, y, z + 2; (B) −x + 2, −y−2, z; (C) x, −y

+ 2, −z + 2].

CuCl (equiv)

¹⁹F NMR yield of 4-FC₆H₄CF₃(%)

0

85

82

69

34

0.1

0.5

1.0

Two distinct mechanisms might be operational in the CuX-

induced decomposition of CuCF₃(Scheme 6). One (pathway

A) involves coordination (nucleophilic attack) of the halide of

CuX to the Cu atom of the ligand-deﬁcient CuCF₃, prompting

the formation of an X bridge between the two metals. This

dinuclear intermediate then undergoes α-ﬂuoride elimination

that is facilitated by hydrogen bonding to the leaving ﬂuoride

ion. In the other mechanism (pathway B), CuX acts as a Lewis

acid rather than a nucleophile. Lewis acids are well-known⁴⁹to

promote α-ﬂuoride elimination from CF₃metal derivatives.

Although strong coordination of the copper atom of CuX to a

ﬂuorine atom of the CF₃ligand is unlikely, it cannot be ruled

out. A more likely possibility is HF-mediated interaction as

shown in Scheme 6 (pathway B). The proposed structures

presented in Scheme 6 are aimed only at portraying the general

concept of the two mechanistic possibilities and, in all

likelihood, are far from the real, probably very complex, strongly

H-bonded system involving DMF, HF, t-BuOH, and Et₃N (see

below). One way or another, the decomposition of the CuCF₃

species involves α-ﬂuoride elimination with subsequent facile⁴⁹

nucleophilic displacement of the ﬂuorines of the diﬂuorocarbene

ligand with t-butoxy groups. Bis(tert-butoxy)carbene Cu(I)

complexes have been isolated from partially decomposed

CuCF₃solutions and structurally characterized.³⁰Pertaining to

the F−H−F-Cu(I) species proposed in Scheme 6, structurally

Table 4. Triﬂuoromethylation of 4-FC₆H₄I (1.5 equiv) with

Fluoroform-Derived CuCF₃(1 equiv) in DMF in the

Presence of CuX (1 equiv) at 80 °C (12 h)

CuX

¹⁹F NMR yield of 4-FC₆H₄CF₃(%)

CuCl

CuBr

CuI

25

39

62

to decompose CuCF₃increases in the order X = I < Br < Cl

(Table 4), which correlates with the Lewis acidity⁵¹rather than

nucleophilicity of Cu(I) halides. Furthermore, if pathway A was

operational, nucleophiles with a strong aﬃnity for Cu(I), such as

iodide, might also make CuCF₃more prone to α-ﬂuoride

elimination. That, however, was not observed. On addition of 1

equiv of [Bu₄N]⁺I⁻to Et₃N·3HF-stabilized CuCF₃in DMF, the

population of the mono-CF₃Cu species (¹⁹F NMR: δ = ca. −26

ppm) decreased and that of [Cu(CF₃)₂]⁻(¹⁹F NMR: δ = ca.

−31 ppm) increased with no change in the overall integral

intensity of the sum of the two CF₃resonances. This

observation indicated that a fraction of the CuCF₃was

converted to CuI, likely in the form of [Cu₄(NEt₃)₄I₄] (see

above), and [Cu(CF₃)₂]⁻via I/CF₃ligand exchange and CF₃

redistribution. Importantly however, the treatment with

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[Bu₄N]⁺I⁻resulted in overall higher stability of the CuCF₃

species and their lower reactivity toward haloarenes. It has been

reported^14bthat [Cu(CF₃)₂]⁻is less reactive toward ArX than

mono-CF₃Cu(I) complexes. As follows from the above, the

side-decomposition of CuCF₃during the triﬂuoromethylation of

ArX is controlled primarily by the Lewis acidity of the Cu(I)

halide byproduct rather than by its donating ability.

The above-described results show that as the triﬂuoro-

methylation of ArX occurs, CuX is released that destabilizes

CuCF₃. The latter is consequently involved in two competing

processes, (i) the desired triﬂuoromethylation of the ArX

substrate and (ii) undesired decomposition that competes more

eﬃciently toward the end of the reaction when the

concentration of the ArX is lower and that of the by-produced

CuX is higher.

coupling is usually regiospeciﬁc.²Our triﬂuoromethylation

reactions are no exception, i.e. the substitution occurs

exclusively at the halogen site. Much more surprising, and

pleasantly so, is the remarkable chemoselectivity of the reactions

of aryl halides with ﬂuoroform-derived CuCF₃. These reactions

are not complicated by the side formation of biaryls, arenes, and

C₂F₅and higher R_fderivatives that are conventionally produced

in many reported analogous transformations.²The higher

perﬂuoroalkyl side products emerge from the generation of

diﬂuorocarbene that inserts into the Cu−CF₃bond to give

Cu(CF₂)_nCF₃(n > 0) which then ﬂuoroalkylates the substrate.

Separation of the coformed Ar(CF₂)_nCF₃from the desired

triﬂoromethylated compound is extremely diﬃcult, if not

impossible. This problem is nonexistent in the reactions of

ﬂuoroform-derived CuCF₃.

Mechanistic Considerations and the Ortho-Eﬀect. As

the Ar−CF₃coupling occurs, CuX is coproduced, that

destabilizes the CuCF₃reagent, acting as a Lewis acid. This

side reaction can be minimized, however, by performing the

triﬂuoromethylation at a higher dilution. The S_RN1 and S_NAr

routes that may govern⁵³some Cu-promoted or catalyzed

transformations of haloarenes are unlikely involved in our

triﬂuoromethylation reactions. The lack of formation of arenes

and biaryls as side-products indicates that S_RN1 may not be

operational to a considerable extent. Moreover, the formation of

only small quantities of the bis-triﬂuoromethylated products

from p- and o-BrC₆H₄I 1r and 1s (Table 1) is inconsistent with

the S_RN1 mechanism.^54,55An independent competition experi-

ment was performed to determine that p-nitroiodobenzene is

only 22 times more reactive toward the CuCF₃than

iodobenzene. This small diﬀerence in reactivity rules out the

classical S_NAr pathway.^56,57

DISCUSSION

■

Reactivity of Fluoroform-Derived CuCF₃and Selectiv-

ity of Its Coupling with Aryl Halides. The ﬂuoroform-

derived CuCF₃is highly reactive toward aryl halides. A

comparison of the data described above with those reported

in the literature suggests that our CuCF₃is one of the most, if

not the most, reactive copper-based species/systems for

triﬂuoromethylation of haloarenes. Under optimized conditions,

the triﬂuoromethylation reactions of aryl iodides occur in

excellent, usually nearly quantitative yield and selectivity at as

low as 23−50 °C (Table 1). Although more cost-attractive

bromoarenes are much less reactive, we have succeeded in

triﬂuoromethylating an unprecedented number of various aryl

and heteroaryl bromides with our CuCF₃in modest to excellent

yield (Table 2). Scale-up experiments and isolation of the

desired pure products on a gram scale attest to the synthetic

value of the ﬂuoroform-derived CuCF₃reagent.

The enhanced reactivity of many ortho-substituted haloarene

substrates toward the CuCF₃observed in the current work is

characteristic of Cu-mediated/catalyzed aromatic substitution

reactions in general. This so-called ortho-eﬀect,⁵⁸originally

discovered by Ullmann himself⁵⁹110 years ago and recognized

by others⁶⁰in the 1930s, was thoroughly studied⁶¹by the

methods of physical organic chemistry in the 1960s and

reviewed in the 1970s.⁶²⁻⁶⁴The accelerating eﬀect of the nitro

group in the ortho position reported by Clark⁴⁰for the Cl/CF₃

exchange (see above) is yet another example of the general

reactivity pattern that has received little study and virtually no

understanding in the chemistry of aromatic triﬂuoro-

methylation. Clark also reported that this eﬀect was absent in

the case of cyano-substituted chloroarenes and therefore

concluded that “the correct transition state geometry” was

required for the ortho-eﬀect to take place (Figure 4). Only weak

activation of the C−Cl bond was observed in Clark’s work for

carbonyl-containing ortho-functionalities CHO, COMe, and

CO₂Me.

Importantly, the triﬂuoromethylation reactions with ﬂuoro-

form-derived CuCF₃readily occur in the absence of additional

ligands. Moreover, deliberately adding ligands such as

phenanthroline, tertiary phosphines, and pyridine at the

beginning of the reaction does not result in improvement but

rather the opposite. As can be seen from eq 4, after the cupration

of ﬂuoroform in DMF and stabilization with 1 equiv of HF in

the form of Et₃N·3HF (TREAT HF), the resultant solution

formally contains ca. 1 equiv of “CuCF₃”, 2 equiv of t-BuOH,

and ¹/₃equiv of Et₃N. With additional TREAT HF used in this

work (see above), the solution comprises of DMF, t-BuOH,

Et₃N, and HF that most likely form a 3D hydrogen-bonded

network. The Cu(I) center in this seemingly simple yet very

complex environment must be stabilized by weak ligation to the

donor atoms of DMF, t-BuOH, NEt₃, and, possibly,⁵⁰even HF.

The exceptional reactivity of the CuCF₃in such a medium

suggests that limited coordinative saturation of the Cu center is

imperative for binding to the aromatic substrate as a key step of

the overall transformation. This conclusion is supported by the

previously observed^12dwell-pronounced inhibition of the

aromatic triﬂuoromethylation with [(Ph₃P)₃CuCF₃] by extra

phosphine R₃P (R = Ph, n-Bu, t-Bu).

The ortho-eﬀect could not be explored for ArX (X = Br, I) in

Clark’s studies because bromoarenes and iodoarenes produced

In addition to being highly reactive, the ﬂuoroform-derived

CuCF₃triﬂuoromethylates haloarenes in a remarkably selective

manner. Unlike radical triﬂuoromethylation of aromatic C−H

bonds that lacks positional selectivity,⁵²Cu-mediated Ar−CF₃

Figure 4. Proposed⁴⁰“correct” (o-NO₂) and “incorrect” (o-CN)

geometries of the transitions states in Cu-promoted triﬂuoro-

methylation of ortho-substituted chloroarenes.

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biaryls rather than CF₃derivatives on treatment with CuCF₃

generated from Cu and CF₂Br₂in DMAC.⁴⁰In our work, the

ortho-eﬀect was observed for both aryl iodides and bromides. In

accord with Clark’s data, o-bromonitrobenzene was considerably

more reactive than its meta and para isomers (Table 2, entries

21−23), while o- and p-bromobenzonitriles exhibited similar

reactivity toward CuCF₃.

irreversible poly triﬂuoromethylation of the Pd(II) center.^13,67

Finally, the enhanced reactivity of Pd complexes bearing a CF₃

ligand toward transmetalation¹³can lead to a quick loss of

catalytic activity. The reaction between [L_nPd(Ar)(X)] and

[L_nPd(CF₃)(Ar)] involved in the catalytic loop (Scheme 7)

produces catalytically inactive [L_nPd(CF₃)(X)] and [L_nPd-

(Ar)₂]. This pathway for catalyst deactivation via trans-

metalation has been conﬁrmed experimentally^13aand discussed

in more detail in our previous reports.^13d,68

Cupration vs Deprotonation for Fluoroform Activa-

tion. There is a fundamental diﬀerence between the long

known^{18−22,26−28}deprotonation methodology and our new

cupration reaction for activation and utilization of ﬂuoroform.

One would be mistaken to view these two as similar processes,

despite the fact that the F₃C−H bond is cleaved in both cases.

The mechanism of the reaction of ﬂuoroform with strong bases

evidently involves deprotonation that leads to CF₃⁻carbanionic

species that easily eliminate ﬂuoride to produce diﬂuorocarbene.

As discussed in the Introduction, to avoid this decomposition,

the deprotonation reactions must be run at a low temperature.

The cupration reaction is not mediated by free CF₃⁻but rather

leads directly to the formation of the covalent Cu−CF₃bond.³⁰

As a result, the cupration can be carried out at room temperature

without the risk of CF₂formation.

Another clear demonstration of the diﬀerence between the

two methodologies is the vastly distinct reactivity of the CF₃

species produced by the two types of reactions. The

triﬂuoromethyl anion generated on deprotonation of ﬂuoroform

readily adds to the CO bond,^{18−22,26−28}whereas the CuCF₃is

unreactive toward carbonyl functionalities, as can be clearly seen

from the above-described results and our previous publica-

tions.³⁰⁻³²A particularly convincing manifestation of this point

is the regiospeciﬁc triﬂuoromethylation of the carbon−halogen

bond of α-haloketones that is eﬀected by the CuCF₃reagent³²

but is inconceivable for the deprotonation methods. Obviously,

the direct cupration of ﬂuoroform and its deprotonation

constitute two distinct synthetic methodologies that comple-

ment each other rather than compete.⁶⁹

The strong ortho-eﬀect of the carbonyl-containing sub-

stituents COOMe, COOH, CHO, and COMe found in our

studies could be accounted for by coordination of the oxygen

atoms of these groups to the Cu atom that would facilitate the

reaction in the same manner as the nitro group (Figure 4). As o-

iodoanisole 1d is more reactive toward CuCF₃than its meta

(1c) and para (1b) isomers (Table 1), the methoxy group also

exhibits the ortho eﬀect. Furthermore, even a methyl group

ortho to the carbon−halogen bond promotes the triﬂuoro-

methylation. In the 3-bromopyridine series, the reactivity of the

C−Br bond is noticeably enhanced by the CH₃group in the 2 or

4 position (Table 2, 3l and 3m vs 3k; entries 12−14). We have

also established and quantiﬁed the ortho-eﬀect of the methyl

group for the benzene series by measuring the rate constant

ratio k_R/k_H= 3.5 for the reactions of ortho-bromotoluene (R =

2-CH₃) and bromobenzene with CuCF₃. While one might

picture, with some stretch of imagination, the proposed

chelation (Figure 4) for the methoxy group, it is hard to see

how this mechanism can account for the activating eﬀect of the

methyl group that is neither an electron-acceptor⁶⁵nor a lone

electron pair donor. This minor, yet real reaction rate

enhancement by the methyl substituent points to the general

complexity of the ortho-eﬀect that is currently being studied in

our laboratories.

Palladium Catalysis. An obvious idea to overcome the

problem of the intrinsically low reactivity of less activated aryl

bromides and especially chlorides toward CuCF₃would be to

apply palladium catalysis. As proposed in Scheme 7, the catalytic

Scheme 7

CONCLUSIONS

■

Fluoroform-derived CuCF₃has been found to exhibit

remarkably high reactivity toward aryl and heteroaryl halides,

performing most eﬃciently in the absence of any added ligands.

With a broad variety of iodoarene substrates, these reactions

occur under mild conditions (23−50 °C) and exhibit high

chemoselectivity to furnish the desired triﬂuoromethylated

products in consistently high, most often nearly quantitative

yield (86−99%). Vastly less reactive aryl and heteroaryl

bromides can be triﬂuoromethylated as well. Although the

scope is narrower in this case, a considerable number of

brominated pyridine, pyrimidine, pyrazine, and thiazole

derivatives as well as aryl bromides bearing electron-with-

drawing groups and/or ortho substituents have been triﬂuoro-

methylated in up to 99% yield. Triﬂuoromethylation of the

aromatic C−Cl bond has been demonstrated only for the most

electrophilic substrates such as 2-chloronicotinic acid (60%

yield).

loop would then include Ar−X bond activation via oxidative

addition to Pd(0) (step 1), followed by transmetalation with

CuCF₃(step 2), and Ar−CF₃reductive elimination (step 3). We

have performed a number of experiments toward the develop-

ment of such a process, albeit only limited turnover numbers

have been achieved.⁶⁶There are at least a few major problems

with the catalytic loop presented in Scheme 7. One is the

extremely diﬃcult Ar−CF₃reductive elimination from Pd(II).

Since the discovery of the ﬁrst example of this transformation

with Xantphos in 2006,¹³only BrettPhos and RuPhos have been

found¹⁶to eﬀect this type of coupling, in spite of high research

activity in the area. Another serious impediment to Pd-catalyzed

triﬂuoromethylation of aryl halides with CuCF₃is facile transfer

of the stabilizing phosphine ligand on Pd to Cu and the

Another key feature of the aromatic triﬂuoromethylation

reactions with ﬂuoroform-derived CuCF₃is their exceptionally

high chemoselectivity. The side-formation of biaryls and C₂F₅

derivatives that is characteristic of many reported analogous

transformations is not observed in the reactions of ﬂuoroform-

derived CuCF₃. Consequently, nearly 20 triﬂuoromethylated

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brought out of the glovebox, and kept at room temperature for 24 h and

then at 50 °C (oil bath) for 18 h. Quantitative ¹⁹F NMR analysis of the

reaction mixture indicated that 2a was produced in 96% yield (<0.01

equiv of CuCF₃remained in solution). After dilution with ether (2 mL)

and washing with water (5 mL), the organic layer was ﬁltered through a

short silica gel plug and analyzed by GC−MS to determine the

conversion of 1a (>99%). Characterization of 2a in reaction solution:

m/z = 146 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −61.9 (s).^13a

1-Methoxy-4-(triﬂuoromethyl)benzene (2b). To 1-iodo-4-

methoxybenzene (1b; purity 98%; 2.63 g; 11 mmol) was added

under argon at room temperature CuCF₃in DMF (0.38 M; 58 mL; 2

equiv) containing an extra 0.2 equiv of TREAT HF, and the mixture

was stirred for 24 h at room temperature and then for 24 h at 50 °C.

Ether (100 mL), water (300 mL) and aqueous NH₃(33%; 8 mL) were

added at agitation in air. The organic layer was separated and the

aqueous layer was washed with ether (2 × 50 mL). The combined ether

solutions were washed with brine (2 × 100 mL), dried over MgSO₄,

ﬁltered, and evaporated (25 °C; 100 mbar). The residue was dissolved

in pentane, the solution was ﬁltered through a short silica gel column,

and evaporated (25 °C; 50 mbar) to give 2b as a slightly yellowish oil

aromatic compounds have been isolated pure in high yield on a

gram scale (up to 20 mmol) from the reactions of various ArX

with ﬂuoroform-derived CuCF₃.

Additional studies have revealed that (i) the by-produced

Cu(I) halide destabilizes the CuCF₃reagent, the magnitude of

the eﬀect varying directly with the Lewis acidity of the copper

halide byproduct CuCl > CuBr > CuI; (ii) classical S_NAr and

S

_RN1 mechanisms are unlikely operational; and (iii) the

reactions exhibit an ortho eﬀect, i.e. the enhanced reactivity of

o-substituted aryl halides 2-RC₆H₄X toward CuCF₃. Interest-

ingly, this ortho-eﬀect is observed for R = NO₂, COOH, CHO,

COOEt, COCH₃, OCH₃, and even CH₃, but not for R = CN.

The nature of the ortho-eﬀect and the mechanism of the

reaction of CuCF₃with aryl halides are currently being studied

in our laboratories.

The ﬂuoroform-derived CuCF₃reagent and its reactions with

haloarenes provide an unmatched combination of reactivity,

selectivity, and low cost. This set of properties along with the

established substrate scope and reactivity patterns revealed in

our studies oﬀer opportunities for practicable developments of

the method. Such developments, in turn, may allow us “to kill

two birds with one stone” by utilizing the environmentally

hazardous ﬂuoroform waste streams as a chemical feedstock for

making valuable ﬂuorinated compounds.

1

(1.71 g; 88%). m/z = 176 (GC−MS; EI). H NMR (CDCl₃, 400

MHz): δ = 7.63 − 7.50 (m, 2H), 7.03−6.92 (m, 2H), 3.85 (s, 3H). ¹³C

5

NMR (CDCl₃, 100 MHz): δ = 162.2 (q, J_C−F= 1.2 Hz), 127.0 (q,

³J_C−F= 3.8 Hz), 124.7 (q, ¹J_C−F= 271.0 Hz), 123.0 (q, ²J_C−F= 32.7 Hz),

114.1, 55.5. ¹⁹F NMR (CDCl₃, 376 MHz): δ = −61.6 (s).^12c

1-Methoxy-3-(triﬂuoromethyl)benzene (2c). In a glovebox, to

1-iodo-3-methoxybenzene (1c; purity 98%; 16.5 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃containing an extra

0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 18 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2c

was produced in 96% yield (0.04 equiv of CuCF₃remained unreacted).

After dilution with ether (2 mL) and extraction with water (5 mL), the

organic layer was ﬁltered through a short silica gel plug and analyzed by

GC−MS to determine the conversion of 1c (99%). Characterization of

2c in the reaction solution: m/z = 176 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −61.9 (s).³¹

EXPERIMENTAL SECTION

■

Anhydrous DMF was stored over freshly calcined 4 Å molecular sieves

in a glovebox. NMR spectra were recorded on 400 and 500 MHz NMR

spectrometers. Quantitative ¹⁹F NMR analyses were carried out with

D1 = 5 s.

Preparation of CuCF₃from Fluoroform. Fluoroform-derived

CuCF₃reagents in DMF were prepared and stabilized with TREAT HF

(1 equiv HF per Cu) following the literature procedure.³⁰A summary

of particular reagent solutions used in this work is presented in Table

S1 of the Supporting Information. The reaction on a 0.1 mol scale was

carried out as follows. In a glovebox, CuCl (purity 99%; 10 g; 100

mmol) was added to a solution of t-BuOK (purity 97%; 23.6 g; 204

mmol) in DMF (170 mL), and the reaction mixture was vigorously

stirred for 30 min at room temperature. The precipitated KCl was

ﬁltered oﬀ and washed on the ﬁlter with DMF (30 mL). The combined

ﬁltrate and the washings were placed in a 12-oz Fischer−Porter vessel

equipped with a pressure gauge, a needle valve, and a Teﬂon-coated

magnetic stir-bar. The vessel was sealed, brought out, and evacuated on

a vacuum line to ca. 1 mmHg, as previously described.³⁰At vigorous

stirring and additional cooling in an ice bath (to prevent overheating),

ﬂuoroform was introduced at ca. 50 psi over approximately 5 min until

gas absorption ceased. A solution of TREAT HF (ca. 37% HF; 5.5 mL;

33 mmol) in DMF (15 mL) was then added at agitation under argon.

The vessel was brought back to the glovebox and the solution of CuCF₃

(232−233 mL) together with the suspended KF produced in the

stabilization step was transferred to a glass bottle for storage. For the

determination of the yield of CuCF₃and its concentration, to an aliquot

of the solution (1 mL) was added 1,3-bis(triﬂuoromethyl)benzene as

an internal standard (20 μL; 0.129 mmol), and the resultant sample was

analyzed by ¹⁹F NMR.

CuCF₃reagents with extra TREAT HF (0.2 mol of extra TREAT HF

per mol of stabilized CuCF₃) were prepared as follows. To a portion of

the solid free supernatant of the stabilized CuCF₃reagent (120 mL)

was added, with vigorous stirring, TREAT HF (1.7 mL, 10.2 mmol).

After ca. 1 h, the clear CuCF₃solution over the produced and settled

solid was used for triﬂuoromethylation reactions immediately or stored

at −30 °C in the glovebox for further use.

(Triﬂuoromethyl)benzene (2a). In a glovebox, to iodobenzene

(1a; purity >99%; 14 μL; 0.125 mmol) in an NMR tube was added at

room temperature CuCF₃containing an extra 0.2 equiv of TREAT HF

(0.37 M; 0.51 mL; 1.5 equiv) and 1,3-bis(triﬂuoromethyl)benzene

(internal standard; 9.7 μL). The NMR tube was sealed with a septum,

1-Methoxy-2-(triﬂuoromethyl)benzene (2d). To 1-iodo-2-

methoxybenzene (1d; purity 98%; 1.33 mL; 10 mmol) was added

under argon at room temperature CuCF₃in DMF (0.37 M; 40.5 mL;

1.5 equiv) containing an extra 0.2 equiv of TREAT HF, and the mixture

was stirred for 24 h at room temperature and then for 18 h at 50 °C.

Ether (100 mL), water (200 mL), and aqueous NH₃(33%; 5 mL) were

added at agitation in air. The organic layer was separated and the

aqueous layer was washed with ether (2 × 50 mL). The combined ether

solutions were washed with brine (2 × 100 mL), dried over MgSO₄,

ﬁltered, and evaporated (25 °C; 100 mbar). The residue was ﬁltered

through a short silica gel plug in pentane and the ﬁltrate was evaporated

(25 °C; 50 mbar) to give 2d as a colorless oil (1.53 g; 87%). m/z = 176

(GC−MS; EI). ¹H NMR (CDCl₃, 400 MHz): δ = 7.61−7.54 (m, 1H),

7.53−7.46 (m, 1H), 7.05−6.97 (m, 2H), 3.91 (s, 3H). ¹³C NMR

(CDCl₃, 100 MHz): δ = 157.7, 133.5, 127.1 (q, ³J_C−F= 5.3 Hz), 124.1

(q, ¹J_C−F= 272.0 Hz), 120.1, 118.8 (q, ²J_C−F= 30.7 Hz), 112.1, 55.7. ¹⁹

NMR (CDCl₃, 376 MHz): δ = −62.5 (s).⁷⁰

F

2,4-Dimethoxy-1-(triﬂuoromethyl)benzene (2e). To 1-iodo-

2,4-dimethoxybenzene (1e; purity 97%; 1.63 g; 6 mmol) was added

under argon at room temperature CuCF₃in DMF (0.37 M; 24 mL; 1.5

equiv) containing an extra 0.2 equiv of TREAT HF, and the mixture

was stirred for 72 h at room temperature. Ether (60 mL), water (120

mL), and aqueous NH₃(33%; 3 mL) were added at agitation in air. The

organic layer was separated and the aqueous layer was washed with

ether (2 × 30 mL). The combined ether solutions were washed with

brine (2 × 60 mL), dried over MgSO₄, ﬁltered, and evaporated (25 °C,

50 mbar). A solution of the residue in pentane was ﬁltered through a

short silica gel plug and evaporated (25 °C, 20 mbar) to give 2e as a

1

slightly yellowish oil (1.20 g; 97%). m/z = 206 (GC−MS; EI). H

NMR (CDCl₃, 400 MHz): δ = 7.47 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 2.0

Hz, 1H), 6.48 (dd, J = 8.6, 2.0 Hz, 1H), 3.87 (s, 3H), 3.83 (s, 3H). ¹³C

M

dx.doi.org/10.1021/jo401423h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

NMR (CDCl₃, 100 MHz): δ = 163.9, 159.0 (q, ³J_C−F= 1.6 Hz), 128.3

(q, ³J_C−F= 5.3 Hz), 124.2 (q, ¹J_C−F= 270.9 Hz), 111.6 (q, ²J_C−F= 31.3

Hz), 103.9, 99.4, 55.8, 55.5. ¹⁹F NMR (CDCl₃, 376 MHz): δ = −61.3

(s).^17l

organic layer was ﬁltered through a short silica gel plug and analyzed by

GC−MS to determine the conversion (99%). Characterization of 2j in

reaction solution: m/z = 202 (GC−MS; EI); ¹⁹F NMR (unlocked): δ =

−61.5 (s).^17a

1-Methyl-4-(triﬂuoromethyl)benzene (2f). In a glovebox, to 1-

iodo-4-methylbenzene (1f; purity 99%; 27 mg; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.66 mL; 2 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 24 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2f

was produced in 93% yield (<0.01 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with

water (5 mL), the organic layer was ﬁltered through a short silica gel

plug and analyzed by GC−MS to determine the conversion (>99%).

Characterization of 2f in reaction solution: m/z = 160 (GC−MS; EI);

¹⁹F NMR (unlocked): δ = −61.5 (s).⁷⁰

1-Methyl-3-(triﬂuoromethyl)benzene (2g). In a glovebox, to 1-

iodo-3-methylbenzene (1g; purity 99%; 16 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.66 mL; 2 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 24 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2g

was produced in 99% yield (<0.01 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with

water (5 mL), the organic layer was ﬁltered through a short silica gel

plug and analyzed by GC−MS to determine the conversion (>99%).

Characterization of 2g in reaction solution: m/z = 160 (GC−MS; EI);

¹⁹F NMR (unlocked): δ = −61.8 (s).⁷⁰

1-Methyl-2-(triﬂuoromethyl)benzene (2h). In a glovebox, to 1-

iodo-2-methylbenzene (1h; purity 98%; 16 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 18 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2

h was produced in 94% yield (<0.05 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>99%). Character-

ization of 2h in reaction solution: m/z = 160 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −60.7 (s).⁷⁰

2,4-Dimethyl-1-(triﬂuoromethyl)benzene (2i). In a glovebox, to

1-iodo-2,4-dimethylbenzene (1i; purity 97%; 18 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 18 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2i

was produced in 97% yield (0.07 equiv of CuCF₃remained unreacted).

After dilution with ether (2 mL) and extraction with water (5 mL), the

organic layer was ﬁltered through a short silica gel plug and analyzed by

GC−MS to determine the conversion (>99%). Characterization of 2i

in reaction solution: m/z = 174 (GC−MS; EI); ¹⁹F NMR (unlocked): δ

= −60.2 (s).⁷¹

Ethyl 4-(Triﬂuoromethyl)benzoate (2k). To ethyl 4-iodoben-

zoate (1k; purity 97%; 1.71 mL; 10 mmol) was added under argon at

room temperature CuCF₃in DMF (0.37 M; 40.5 mL; 1.5 equiv)

containing an extra 0.2 equiv of TREAT HF, and the mixture was

stirred for 24 h at room temperature and then for 18 h at 50 °C. Ether

(100 mL), water (200 mL), and aqueous NH₃(33%; 5 mL) were added

at agitation in air. The organic layer was separated and the aqueous

layer was washed with ether (2 × 50 mL). The combined ether

solutions were washed with brine (2 × 100 mL), dried over MgSO₄,

ﬁltered, and evaporated (25 °C; 100 mbar). A solution of the residue in

pentane was ﬁltered through a short silica gel plug and evaporated (25

°C; 20 mbar) to give 2k as a yellowish oil (2.09 g; 96%). m/z = 218

(GC−MS; EI). ¹H NMR (CDCl₃, 400 MHz): δ = 8.20−8.12 (m, 2H),

7.74−7.66 (m, 2H), 4.42 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

¹³C NMR (CDCl₃, 100 MHz): δ = 165.3, 134.3 (q, ²J_C−F= 32.7 Hz),

133.8, 130.0, 125.3, 123.8 (q, ¹J_C−F= 272.6 Hz), 61.5, 14.2. ¹⁹F NMR

(CDCl₃, 376 MHz): δ = −63.2 (s).^12c

4-(Triﬂuoromethyl)benzonitrile (2l). To 4-iodobenzonitrile (1l;

purity 99%; 2.31 g; 10 mmol) was added under argon at room

temperature CuCF₃in DMF (0.37 M; 40.5 mL; 1.5 equiv) containing

an extra 0.2 equiv of TREAT HF, and the mixture was stirred for 24 h at

room temperature and then for 18 h at 50 °C. Ether (100 mL), water

(200 mL), and aqueous NH₃(33%; 5 mL) were added at agitation in

air. The organic layer was separated and the aqueous layer was washed

with ether (2 × 50 mL). The combined ether solutions were washed

with brine (2 × 100 mL), dried over MgSO₄, ﬁltered, and evaporated

(25 °C, 50 mbar). The residue was dissolved in pentane/dichloro-

methane (2:1 v/v) and the solution was ﬁltered through a short silica

gel plug. The ﬁltrate was evaporated (25 °C, 10 mbar) to aﬀord 2l as a

1

light tan solid (1.62 g, 94%). m/z = 171 (GC−MS; EI). H NMR

(CDCl₃, 500 MHz): δ = 7.81 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.4 Hz,

2

2H). ¹³C NMR (CDCl₃, 126 MHz): δ = 134.2 (q, J_C−F= 33.3 Hz),

3

1

132.6, 126.0 (q, J_C−F= 3.8 Hz), 123.0 (q, J_C−F= 272.8 Hz), 117.3,

116.0 (q, J_C−F= 1.5 Hz). ¹⁹F NMR (CDCl₃, 471 MHz): δ = −63.6

5

(s).⁷⁰

1-Nitro-4-(triﬂuoromethyl)benzene (2m). To 1-iodo-4-nitro-

benzene (1m; purity 98%; 1.27 g; 5 mmol) was added under argon at

room temperature CuCF₃in DMF (0.38 M; 20 mL; 1.5 equiv)

containing an extra 0.2 equiv of TREAT HF, and the mixture was

stirred for 24 h at room temperature. Ether (50 mL), water (100 mL),

and aqueous NH₃(33%; 3 mL) were added at agitation in air. The

organic layer was separated and the aqueous layer was washed with

ether (2 × 25 mL). The combined ether solutions were washed with

brine (2 × 50 mL), dried over MgSO₄, ﬁltered, and evaporated (40 °C,

50 mbar). The residue was dissolved in pentane/dichloromethane (2:1

v/v) and the solution was ﬁltered through a short silica gel plug.

Evaporation of the ﬁltrate (40 °C; 5 mbar; partial sublimation of the

product was observed) gave 2m as a white solid (0.80 g; 83%). m/z =

191 (GC−MS; EI). ¹H NMR (CDCl₃, 400 MHz): δ = 8.37−8.31 (m,

2H), 7.86−7.80 (m, 2H). ¹³C NMR (CDCl₃, 100 MHz): δ = 150.2,

136.1 (q, ²J_C−F= 33.3 Hz), 126.9 (q, ³J_C−F= 3.7 Hz), 124.2, 123.1 (q,

¹J_C−F= 273.0 Hz). ¹⁹F NMR (CDCl₃, 376 MHz): δ = −63.5 (s).⁷⁰

1-(4-(Triﬂuoromethyl)phenyl)ethanone (2n). In a glovebox, to

1-(4-iodophenyl)ethanone (1n; purity 98%; 31 mg; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 18 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that

2n was produced in 95% yield (0.1 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and washing with water (5

mL), the organic phase was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>99%). Character-

ization of 2n in reaction solution: m/z = 188 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −62.2 (s).^17a

1-(tert-Butyl)-4-(triﬂuoromethyl)benzene (2j). In a glovebox, to

1-(tert-butyl)-4-iodobenzene (1j; purity 95%; 22 μL; 0.125 mmol) in

an NMR tube was added at room temperature CuCF₃in DMF

containing an extra 0.2 equiv of TREAT HF (0.38 M; 0.66 mL; 2 equiv)

and 1,3-bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The

NMR tube was sealed with a septum, brought out of the glovebox, and

kept at room temperature for 24 h and then at 50 °C (oil bath) for 24 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2j

was produced in 95% yield (0.05 equiv of CuCF₃remained unreacted).

After dilution with ether (2 mL) and extraction with water (5 mL), the

N

dx.doi.org/10.1021/jo401423h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

3-(Triﬂuoromethyl)benzaldehyde (2o). In a glovebox, to 3-

iodobenzaldehyde (1o; purity 95%; 30 mg; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF containing an

extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 18 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that

2o was produced in 99% yield (0.07 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>99%). Character-

ization of 2o in reaction solution: m/z = 174 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −62.2 (s). Lit.⁷²

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 24 h.

Quantitative ¹⁹F NMR analysis indicated that 2s was produced in 95%

yield. The solution also contained 3% of 1,2-(CF₃)₂C₆H₄and unreacted

CuCF₃(<0.01 equiv). After dilution with ether (2 mL) and extraction

with water (5 mL), the organic layer was ﬁltered through a short silica

gel plug and analyzed by GC−MS to determine the conversion

(>99%). Characterization of 2s in reaction solution: m/z = 224, 226

(GC−MS; EI); ¹⁹F NMR (unlocked): δ = −61.6 (s).⁷⁴

3-(Triﬂuoromethyl)pyridine (2t). In a glovebox, to 3-iodopyr-

idine (1t; purity 98%; 26 mg; 0.125 mmol) in an NMR tube was added

at room temperature CuCF₃in DMF containing an extra 0.2 equiv of

TREAT HF (0.38 M; 0.66 mL; 2 equiv) and 1,3-bis(triﬂuoromethyl)-

benzene (internal standard; 9.7 μL). The NMR tube was sealed with a

septum, brought out of the glovebox, and kept at room temperature for

24 h and then at 50 °C (oil bath) for 24 h. Quantitative ¹⁹F NMR

analysis of the reaction mixture indicated that 2t was produced in 86%

yield (<0.01 equiv of CuCF₃remained unreacted). After dilution with

ether (2 mL) and extraction with water (5 mL), the organic layer was

ﬁltered through a short silica gel plug and analyzed by GC−MS to

determine the conversion (96%). Characterization of 2t in reaction

solution: m/z = 147 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −61.7

(s).⁷⁰

2-(Triﬂuoromethyl)thiophene (2u). In a glovebox, to 2-

iodothiophene (1u; purity 98%; 14 μL; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF containing an

extra 0.2 equiv of TREAT HF (0.37 M; 0.51 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

50 °C (oil bath) for 18 h. Quantitative ¹⁹F NMR analysis indicated that

2u was produced in 87% yield (<0.05 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>99%). Thiophene

(7%) was also detected. Characterization of 2u in reaction solution: m/

z = 152 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −54.1 (s).⁷⁰

2-(Triﬂuoromethyl)pyridine (4a). To a solution of 2-bromopyr-

idine (3a; 24 μL; 0.25 mmol) in DMF (0.25 mL) placed in an oil bath

at 80 °C under argon, was added via a syringe pump over a period of 6 h

a solution of CuCF₃in DMF (0.37 M; 1.35 mL; 2 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for

additional 2 h at the same temperature. After the reaction mixture was

allowed to cool to room temperature, ether (5 mL) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 19.4 μL) were added

at agitation in air. The resultant suspension was ﬁltered. Quantitative

¹⁹F NMR analysis of the ﬁltrate indicated that 4a was produced in 90%

yield. After washing with water (5 mL), the organic layer was ﬁltered

through a short silica gel plug and analyzed by GC−MS to determine

the conversion of 3a (>99%). Characterization of 4a in reaction

solution: m/z = 147 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −67.2

(s).⁴⁰

1-(Triﬂuoromethyl)naphthalene (2p). To 1-iodonaphthalene

(1p; purity >98%; 3.0 mL; 20 mmol) was added under argon at

room temperature CuCF₃in DMF (0.37 M; 81 mL; 1.5 equiv)

containing an extra 0.2 equiv of TREAT HF, and the mixture was

stirred for 24 h at room temperature and then for 18 h at 50 °C. Ether

(100 mL), water (400 mL) and aqueous NH₃(33%; 10 mL) were

added at agitation in air. The organic layer was separated and the

aqueous layer was washed with ether (2 × 50 mL). The combined ether

solutions were washed with brine (2 × 100 mL), dried over MgSO₄,

ﬁltered, and evaporated (25 °C; 50 mbar). The residue was dissolved in

pentane and the solution was ﬁltered through a short silica gel plug.

Evaporation of the ﬁltrate (25 °C; 10 mbar) gave 2p as a colorless oil

(3.9 g; 98%). m/z = 196 (GC−MS; EI). ¹H NMR (CDCl₃, 400 MHz):

δ = 8.37−8.27 (m, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.98−7.90 (m, 2H),

7.73−7.63 (m, 1H), 7.66−7.57 (m, 1H), 7.56−7.46 (m, 1H). ¹³C NMR

(CDCl₃, 126 MHz): δ = 134.1, 132.9, 129.1 (q, ⁴J_C−F= 1.2 Hz), 128.9,

2

1

127.8, 126.7, 126.2 (q, J_C−F= 29.9 Hz), 125.0 (q, J_C−F= 273.4 Hz),

124.8 (q, J_C−F= 6.0 Hz), 124.4 (q, J_C−F= 2.3 Hz), 124.2. ¹⁹F NMR

3

(CDCl₃, 376 MHz): δ = −59.7 (s).⁷⁰

2-(Triﬂuoromethyl)benzamide (2q). To 2-iodobenzamide (1q;

purity 98%; 2.52 g; 10 mmol) was added under argon at room

temperature CuCF₃in DMF (0.37 M; 30 mL; 1.1 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for 15 min at

room temperature. Ether (150 mL), water (150 mL), and aqueous NH₃

(33%; 5 mL) were added at agitation in air. The organic layer was

separated and the aqueous layer was washed with ether (2 × 150 mL).

The combined ether solutions were washed with brine (50 mL), dried

over MgSO₄, ﬁltered, and evaporated (40 °C, 20 mbar). The residue

was crystallized from acetone/hexane (ca. 1:10 v/v) to give 2q as a

white solid (1.53 g; 81%). m/z = 189 (GC−MS; EI). ¹H NMR

(acetone-d₆, 400 MHz): δ = 7.78−7.73 (m, 1H), 7.72−7.66 (m, 1H),

7.66−7.62 (m, 1H), 7.62−7.57 (m, 1H), 7.31 (bs, 1H), 7.02 (bs, 1H).

¹³C NMR (acetone-d₆, 100 MHz): δ = 170.1, 137.8 (q, ³J_C−F= 2.1 Hz),

4

2

133.0 (q, J_C−F= 1.1 Hz), 130.4, 129.2, 127.6 (q, J_C−F= 31.8 Hz),

3

1

127.1 (q, J_C−F= 5.1 Hz), 124.9 (q, J_C−F= 273.0 Hz). ¹⁹F NMR

(acetone-d₆, 376 MHz): δ = −59.7 (s). Anal. Calcd for C₈H₆F₃NO: C,

50.8; H, 3.2; N, 7.4. Found: C, 50.7; H, 3.2; N, 7.5. Lit.⁷³

1-Bromo-4-(triﬂuoromethyl)benzene (2r). In a glovebox, to 1-

bromo-4-iodobenzene (1r; purity 98%; 36 mg; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 18 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that 2r

was produced in 96% yield. The solution also contained ca. 4% of 1,4-

(CF₃)₂C₆H₄and 0.05 equiv of unreacted CuCF₃. After dilution with

ether (2 mL) and extraction with water (5 mL), the organic layer was

ﬁltered through a short silica gel plug and analyzed by GC−MS to

determine the conversion (>99%). Characterization of 2r in reaction

solution: m/z = 224, 226 (GC−MS; EI); ¹⁹F NMR (unlocked): δ =

−61.9 (s).⁷⁰

3-Methyl-2-(triﬂuoromethyl)pyridine (4b). In a glovebox, to 2-

bromo-3-methylpyridine (3b; purity 95%; 15 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.39 M; 0.32 mL; 1 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 50 °C (oil bath) for 15 h. After another portion of CuCF₃(1 equiv)

was added via syringe, the mixture was heated at 50 °C for additional 18

h. Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that

4b was produced in 88% yield (<0.01 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and washing with water (5

mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>99%). Character-

ization of 4b in reaction solution: m/z = 161 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −64.3 (s). Lit.⁷⁵

1-Bromo-2-(triﬂuoromethyl)benzene (2s). In a glovebox, to 1-

bromo-2-iodobenzene (1s; purity 95%; 16 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.38 M; 0.43 mL; 1.3 equiv) and 1,3-

4-Methyl-2-(triﬂuoromethyl)pyridine (4c). In a glovebox, to 2-

bromo-4-methylpyridine (3c; purity 97%; 14 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

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an extra 0.2 equiv of TREAT HF (0.39 M; 0.32 mL; 1 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 50 °C (oil bath) for 15 h. Another portion of CuCF₃(1 equiv) was

then added via syringe and the mixture was heated at 50 °C for

additional 18 h. Quantitative ¹⁹F NMR analysis indicated that 4c was

produced in 80% yield (<0.01 equiv of CuCF₃remained unreacted).

After dilution with ether (2 mL) and extraction with water (5 mL), the

organic layer was ﬁltered through a short silica gel plug and analyzed by

GC−MS to determine the conversion (98%). Characterization of 4c in

reaction solution: m/z = 161 (GC−MS; EI); ¹⁹F NMR (unlocked): δ =

−67.2 (s). Lit.⁷⁵

5-Methyl-2-(triﬂuoromethyl)pyridine (4d). In a glovebox, to 2-

bromo-5-methylpyridine (3d; purity 98%; 22 mg; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.39 M; 0.32 mL; 1 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 50 °C (oil bath) for 15 h. Another portion of CuCF₃(1 equiv) was

then added via syringe and the mixture was heated at 50 °C for

additional 18 h. Quantitative ¹⁹F NMR analysis of the reaction mixture

indicated that 4d was produced in 77% yield (<0.01 equiv of CuCF₃

remained unreacted). After dilution with ether (2 mL) and extraction

with water (5 mL), the organic layer was ﬁltered through a short silica

gel plug and analyzed by GC−MS to determine the conversion (96%).

Characterization of 4d in reaction solution: m/z = 161 (GC−MS; EI);

¹⁹F NMR (unlocked): δ = −66.8 (s). Lit.⁷⁵

6-Methyl-2-(triﬂuoromethyl)pyridine (4e). In a glovebox, to 2-

bromo-6-methylpyridine (3e; purity 98%; 14.5 μL; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.39 M; 0.32 mL; 1 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 50 °C (oil bath) for 15 h. Another portion of CuCF₃(1 equiv) was

then added via syringe and the mixture was heated at 50 °C for

additional 18 h. Quantitative ¹⁹F NMR analysis indicated that 4e was

produced in 73% yield (<0.01 equiv of CuCF₃remained unreacted).

After dilution with ether (2 mL) and extraction with water (5 mL), the

organic layer was ﬁltered through a short silica gel plug and analyzed by

GC−MS to determine the conversion (91%). Characterization of 4e in

reaction solution: m/z = 161 (GC−MS; EI); ¹⁹F NMR (unlocked): δ =

−67.3 (s). Lit.⁷⁵

2-(Triﬂuoromethyl)quinolone (4f). To 2-bromoquinoline (3f;

purity 95%; 1.095 g; 5 mmol) was added under argon at room

temperature CuCF₃in DMF (0.37 M; 27 mL; 2 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for 48 h at

room temperature. Ether (50 mL), water (150 mL), and aqueous NH₃

(33%; 5 mL) were added at agitation in air. The organic layer was

separated and the aqueous layer was washed with ether (2 × 50 mL).

The combined ether solutions were washed with brine (50 mL), dried

over MgSO₄, ﬁltered, and evaporated (40 °C, 50 mbar). The residue

was dissolved in pentane/dichloromethane (5:1 v/v), the solution was

ﬁltered through a short silica gel plug, and evaporated (40 °C; 10 mbar)

to give 4f as a yellowish solid (0.79 g; 80%). m/z = 197 (GC−MS; EI).

¹H NMR (CDCl₃, 400 MHz): δ = 8.27 (d, J = 8.5 Hz, 1H), 8.19 (d, J =

8.5 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.77 (ddd, J = 8.5, 6.9, 1.5 Hz,

1H), 7.68 (d, J = 8.5 Hz, 1H), 7.62 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H). ¹³C

NMR (CDCl₃, 100 MHz): δ = 147.9 (q, ²J_C−F= 34.6 Hz), 147.2, 138.2,

130.9, 130.1, 128.9, 128.6, 127.8, 121.7 (q, ¹J_C−F= 275.2 Hz), 116.8 (q,

³J_C−F= 2.1 Hz). ¹⁹F NMR (CDCl₃, 376 MHz): δ = −67.5 (s).^15a

Methyl 2-(Triﬂuoromethyl)nicotinate (4g). To methyl 2-

bromonicotinate (3g; purity 97%; 668 mg; 3 mmol) was added

under argon at room temperature CuCF₃in DMF (0.37 M; 12 mL; 1.5

equiv) containing an extra 0.2 equiv of TREAT HF, and the mixture

was stirred for 12 h at room temperature. Ether (60 mL), water (120

mL), and aqueous NH₃(33%; 2 mL) were added at agitation in air. The

organic layer was separated and the aqueous layer was washed with

ether (2 × 30 mL). The combined ether solutions were washed with

brine (120 mL), dried over MgSO₄, ﬁltered, and evaporated (25 °C,

100 mbar). The residue was dissolved in pentane/dichloromethane

(1:3 v/v), the solution was ﬁltered through a short silica gel plug, and

evaporated (25 °C; 10 mbar) to give 4g as a colorless oil (0.56 g; 91%).

m/z = 205 (GC−MS; EI). ¹H NMR (CDCl₃, 400 MHz): δ = 8.74 (dd,

J = 4.8, 1.3 Hz, 1H), 8.12−7.99 (m, 1H), 7.54 (dd, J = 7.9, 4.8 Hz, 1H),

3.91 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz): δ = 165.8, 150.9, 145.6 (q,

²J_C−F= 35.2 Hz), 138.3, 127.8 (q, ³J_C−F= 1.1 Hz), 126.1, 121.1 (q, ¹J_C−F

= 275.0 Hz), 53.2. ¹⁹F NMR (CDCl₃, 376 MHz): δ = −64.9 (s). Anal.

Calcd for C₈H₆F₃NO₂: C, 46.8; H, 3.0; N, 6.8. Found: C, 46.9; H, 3.1;

N, 6.9.

2-(Triﬂuoromethyl)nicotinaldehyde (4h). In a glovebox, to 2-

bromonicotinaldehyde (3h; 23 mg; 0.125 mmol) in an NMR tube was

added at room temperature CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 12 h. Quantitative ¹⁹F NMR analysis of the

reaction mixture indicated that 4h was produced in 94% yield (0.1

equiv of CuCF₃remained unreacted). After dilution with ether (2 mL)

and extraction with water (5 mL), the organic layer was ﬁltered through

a short silica gel plug and analyzed by GC−MS to determine the

conversion (>99%). Characterization of 4h in reaction solution: m/z =

175 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −60.0 (s). Lit.⁷⁶

5-Nitro-2-(triﬂuoromethyl)pyridine (4i). To 2-bromo-5-nitro-

pyridine (3i; 1.218 g; 6 mmol) was added under argon at room

temperature CuCF₃in DMF (0.38 M; 24 mL; 1.5 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for 24 h at

room temperature. Ether (50 mL), water (150 mL), and aqueous NH₃

(33%; 5 mL) were added at agitation in air. The organic layer was

separated and the aqueous layer was washed with ether (2 × 50 mL).

The combined ether solutions were washed with brine (50 mL), dried

over MgSO₄, ﬁltered, and evaporated (25 °C; 100 mbar). The residue

was dissolved in pentane/dichloromethane (4:1 v/v) and the solution

was ﬁltered through a short silica gel plug and evaporated (25 °C, 10

mbar) to give 4i as a yellowish solid (1.05 g; 91%). m/z = 192 (GC−

MS; EI). ¹H NMR (CDCl₃, 400 MHz): δ = 9.52 (d, J = 2.3 Hz, 1H),

8.69 (ddd, J = 8.6, 2.5, 0.8 Hz, 1H), 7.94 (dd, J = 8.5, 0.7 Hz, 1H). ¹³C

NMR (CDCl₃, 100 MHz): δ = 152.8 (q, ²J_C−F= 35.9 Hz), 145.6, 145.5,

133.1, 121.4 (q, ³J_C−F= 2.7 Hz), 120.6 (q, ¹J_C−F= 275.0 Hz). ¹⁹F NMR

(CDCl₃, 376 MHz): δ = −68.3 (s).⁴⁰Anal. Calcd for C₆H₃F₃N₂O₂: C,

37.5; H, 1.6; N, 14.6. Found: C, 37.7; H, 1.6; N, 14.6.

3-Methyl-5-nitro-2-(triﬂuoromethyl)pyridine (4j). To 2-

bromo-3-methyl-5-nitropyridine (3j; 651 mg; 3 mmol) was added

under argon at room temperature CuCF₃in DMF (0.37 M; 12 mL; 1.5

equiv) containing an extra 0.2 equiv of TREAT HF, and the mixture

was stirred for 24 h at room temperature. Ether (60 mL), water (120

mL), and aqueous NH₃(33%; 2 mL) were added at agitation in air. The

organic layer was separated and the aqueous layer was washed with

ether (2 × 30 mL). The combined ether solutions were washed with

brine (60 mL), dried over MgSO₄, ﬁltered, and evaporated (25 °C, 100

mbar). The residue was dissolved in pentane/dichloromethane (1:4 v/

v) and the solution was ﬁltered through a short silica gel plug and

evaporated (25 °C, 10 mbar) to give 4j as a yellowish oil (0.57 g; 92%).

m/z = 206 (GC−MS; EI). ¹H NMR (CDCl₃, 400 MHz): δ = 9.25 (d, J

= 2.4 Hz, 1H), 8.47−8.42 (m, 1H), 2.68−2.61 (m, 3H). ¹³C NMR

(CDCl₃, 100 MHz): δ = 150.6 (q, ²J_C−F= 34.0 Hz), 145.3, 141.5, 135.2,

134.5, 121.4 (q, ¹J_C−F= 276.2 Hz), 18.2 (q, ³J_C−F= 2.7 Hz). ¹⁹F NMR

5

(CDCl₃, 376 MHz): δ = −65.9 (q, J_H−F= 1.6 Hz). Anal. Calcd for

C₇H₅F₃N₂O₂: C, 40.8; H, 2.5; N, 13.6. Found: C, 41.2; H, 2.6; N, 13.6.

3-(Triﬂuoromethyl)pyridine (4k). In a glovebox, to 3-bromopyr-

idine (3k; 12 μL; 0.125 mmol) in an NMR tube was added at room

temperature CuCF₃in DMF containing an extra 0.2 equiv of TREAT

HF (0.37 M; 0.51 mL; 1.5 equiv) and 1,3-bis(triﬂuoromethyl)benzene

(internal standard; 9.7 μL). The NMR tube was sealed with a septum,

brought out of the glovebox, and heated at 60 °C for 15 h. Quantitative

¹⁹F NMR analysis indicated that 4k was produced in 8% yield (<0.01

equiv of CuCF₃remained unreacted). After dilution with ether (2 mL)

and extraction with water (5 mL), the organic layer was ﬁltered through

a short silica gel plug and analyzed by GC−MS to estimate the

conversion (<20%). Characterization of 4k in reaction solution: m/z =

147 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −61.7 (s).⁷⁰

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2-Methyl-3-(triﬂuoromethyl)pyridine (4l). In a glovebox, to 3-

bromo-2-methylpyridine (3l; 14 μL; 0.125 mmol) in an NMR tube was

added at room temperature CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.37 M; 0.51 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 60 °C for 15 h. Quantitative ¹⁹F NMR analysis indicated that 4l was

produced in 20% yield (<0.01 equiv of CuCF₃remained unreacted).

After dilution with ether (2 mL) and extraction with water (5 mL), the

organic layer was ﬁltered through a short silica gel plug and analyzed by

GC−MS to determine the conversion (30%). Characterization of 4l in

reaction solution: m/z = 161 (GC−MS; EI); ¹⁹F NMR (unlocked): δ =

−61.5 (s).

4-Methyl-3-(triﬂuoromethyl)pyridine (4m). In a glovebox, to 3-

bromo-4-methylpyridine (3m; 14 μL; 0.125 mmol) in an NMR tube

was added at room temperature CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.37 M; 0.51 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 60 °C for 15 h. Quantitative ¹⁹F NMR analysis of the reaction

mixture indicated that 4m was produced in 17% yield (<0.01 equiv of

CuCF₃remained unreacted). After dilution with ether (2 mL) and

extraction with water (5 mL), the organic layer was ﬁltered through a

short silica gel plug and analyzed by GC−MS to determine the

conversion (35%). Characterization of 4m in reaction solution: m/z =

161 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −60.5 (s).

2-(Triﬂuoromethyl)pyrimidine (4n). In a glovebox, to 2-

bromopyrimidine (3n; purity 98%; 20 mg; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF containing an

extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 18 h. Quantitative ¹⁹F NMR analysis indicated

that 4n was produced in 95% yield (0.2 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (99%). Character-

ization of 4n in reaction solution: m/z = 148 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −69.8 (s).⁴⁰

5-(Triﬂuoromethyl)pyrimidine (4o). In a glovebox, to 5-

bromopyrimidine (3o; purity 98%; 20 mg; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF (0.37 M; 0.51

mL; 1.5 equiv) and 1,3-bis(triﬂuoromethyl)benzene (internal standard;

9.7 μL). The NMR tube was sealed with a septum, brought out of the

glovebox, and heated at 50 °C (oil bath) for 18 h. Quantitative ¹⁹F

NMR analysis of the reaction mixture indicated that 4o was produced

in 24% yield (<0.01 equiv of CuCF₃remained unreacted). Character-

ization of 4o in reaction solution: m/z = 148 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −61.8 (s).

2,5-Bis(triﬂuoromethyl)pyrazine (4p). In a glovebox, to 2,5-

dibromopyrazine (3p; 30 mg; 0.125 mmol) in an NMR tube was added

at room temperature CuCF₃in DMF containing an extra 0.2 equiv of

TREAT HF (0.36 M; 1.0 mL; 3 equiv) and 1,3-bis(triﬂuoromethyl)-

benzene (internal standard; 9.7 μL). The NMR tube was sealed with a

septum, brought out of the glovebox, and kept at room temperature for

24 h. Quantitative ¹⁹F NMR analysis of the reaction mixture indicated

that 4p was produced in 94% yield (0.25 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>99%). Character-

ization of 4p in reaction solution: m/z = 216 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −67.1 (s).

2-(Triﬂuoromethyl)thiazole (4q). In a glovebox, to 2-bromothia-

zole (3q, 11 μL, 0.125 mmol) in an NMR tube was added at room

temperature CuCF₃in DMF (0.37 M; 0.34 mL; 1 equiv) and 2-

(triﬂuoromethyl)pyridine 4a (internal standard; 14 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 15 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that

4q was produced in 35% yield (<0.01 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (>80%). Character-

ization of 4q in reaction solution: m/z = 153 (GC−MS; EI); ¹⁹F NMR

(unlocked): δ = −60.0 (s).

5-Nitro-2-(triﬂuoromethyl)thiazole (4r). To a solution of 2-

bromo-5-nitrothiazole (3r; purity 98%; 79 mg; 0.37 mmol) in DMF

(0.2 mL) under argon, at 50 °C, was added via a syringe pump, over 12

h CuCF₃in DMF (0.37 M; 1 mL; 1 equiv), and the mixture was stirred

for additional 6 h at this temperature. After cooling to room

temperature, ether (5 mL) and 2-(triﬂuoromethyl)pyridine 4a (internal

standard; 43 μL) were added at agitation in air. The resultant

suspension was ﬁltered and analyzed by ¹⁹F NMR to determine the

yield of 4r (55%). GC−MS analysis showed >99% conversion of 3r.

Characterization of 4r in reaction solution: m/z = 198 (GC−MS; EI);

¹⁹F NMR (unlocked): δ = −61.9 (s).

4-(Triﬂuoromethyl)pyridine (4s). In a glovebox, to 4-bromopyr-

idine hydrochloride (3s; 25 mg; 0.125 mmol) in an NMR tube was

added at room temperature CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.37 M; 1.0 mL; 3 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 15 h.

Quantitative ¹⁹F NMR analysis indicated that 4s was produced in 74%

yield (<0.01 equiv of CuCF₃remained unreacted). After dilution with

ether (2 mL) and extraction with water (5 mL), the organic layer was

ﬁltered through a short silica gel plug and analyzed by GC−MS to

determine the conversion (85%). Characterization of 4s in reaction

solution: m/z = 147 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −64.0

(s). Lit.⁷⁷

1-Nitro-2-(triﬂuoromethyl)benzene (4t). To 1-bromo-2-nitro-

benzene (3t; 2.06 g; 10 mmol) was added under argon at room

temperature CuCF₃in DMF (0.37 M; 35 mL; 1.3 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for 12 h at

room temperature and then for 6 h at 50 °C. Ether (50 mL), water (250

mL), and aqueous NH₃(33%; 5 mL) were added at agitation in air. The

organic layer was separated and the aqueous layer was washed with

ether (2 × 50 mL). The combined ether solutions were washed with

brine (2 × 50 mL), dried over MgSO₄, ﬁltered, and evaporated (25 °C,

100 mbar). The residue was dissolved in pentane/dichloromethane

(4:1 v/v) and the solution was ﬁltered through a short silica gel plug

and evaporated (25 °C, 10 mbar) to give 4t as a yellowish solid (1.685

g; 88%). m/z = 191 (GC−MS; EI). ¹H NMR (CDCl₃, 500 MHz): δ =

7.93−7.85 (m, 1H), 7.88−7.81 (m, 1H), 7.78−7.70 (m, 2H). ¹³C NMR

(CDCl₃, 126 MHz): δ = 148.1, 133.4, 132.8, 127.9 (q, ³J_C−F= 5.2 Hz),

2

1

124.9, 123.2 (q, J_C−F= 33.9 Hz), 122.2 (q, J_C−F= 273.0 Hz). ¹⁹F

NMR (CDCl₃, 471 MHz): δ = −60.1 (s).⁴⁰

1-Nitro-3-(triﬂuoromethyl)benzene (4u). In a glovebox, to 1-

bromo-3-nitrobenzene (3u; 25 mg; 0.125 mmol) in an NMR tube was

added at room temperature CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 24 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that

4u was produced in 22% yield (<0.05 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to estimate the conversion (ca. 20%).

Characterization of 4u in reaction solution: m/z = 191 (GC−MS;

EI); ¹⁹F NMR (unlocked): δ = −62.6 (s).^17a

1-Nitro-4-(triﬂuoromethyl)benzene (4v). To a stirring solution

of 1-bromo-4-nitrobenzene (3v; 51 mg; 0.25 mmol) in DMF (0.25

mL) under argon at 80 °C (oil bath) was added, via a syringe pump

over a period of 4 h, CuCF₃in DMF containing an extra 0.2 equiv of

TREAT HF (0.36 M; 1.39 mL; 2 equiv). After the addition was

ﬁnished, the mixture was stirred at 80 °C for additional 2 h. The

reaction mixture was allowed to cool to room temperature and treated

with ether (5 mL) and 1,3-bis(triﬂuoromethyl)benzene (internal

standard, 19.4 μL) at agitation in air. The resultant suspension was

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dx.doi.org/10.1021/jo401423h | J. Org. Chem. XXXX, XXX, XXX−XXX

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ﬁltered. Quantitative ¹⁹F NMR analysis of the ﬁltrate indicated that 4v

was produced in 60% yield. After washing with water (5 mL) and

subsequent ﬁltration through a short silica gel plug, the organic phase

was analyzed by GC−MS to determine the conversion (61%).

Characterization of 4v in reaction solution: m/z = 191 (GC−MS;

EI); ¹⁹F NMR (unlocked): δ = −62.2 (s).⁷⁰

5-Bromo-2-(triﬂuoromethyl)benzoic acid (4aa). To 2,5-dibro-

mobenzoic acid (3aa; purity 96%; 2.92 g; 10 mmol) was added under

argon at room temperature CuCF₃in DMF (0.37 M; 30 mL; 1.1 equiv)

containing an extra 0.2 equiv of TREAT HF, and the mixture was

stirred for 10 min at room temperature. Ether (100 mL) and aqueous

HCl (2N; 150 mL) were added at agitation in air. The organic layer was

separated and the aqueous layer was washed with ether (2 × 50 mL).

The combined ether solutions were washed with brine (2 × 50 mL),

dried over MgSO₄, and ﬁltered. A small amount of silica gel was added

to the ﬁltrate and the solvent was removed under reduced pressure. The

residue was placed onto a short silica gel column and washed with

EtOAc/hexane (1:4 v/v). Evaporation of the eluate gave 4aa as a white

2-(Triﬂuoromethyl)benzonitrile (4w). In a glovebox, to 2-

bromobenzonitrile (3w; purity 98%; 23 mg; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.36 M; 0.52 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 72 h. Quantitative ¹⁹F NMR analysis of the

reaction mixture indicated that 4w was produced in 30% yield (0.65

equiv of CuCF₃remained unreacted). After dilution with ether (2 mL)

and extraction with water (5 mL), the organic layer was ﬁltered through

a short silica gel plug and analyzed by GC−MS to determine the

conversion (ca. 27%). Characterization of 4w in reaction solution: m/z

= 171 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −61.1 (s). Lit.⁷³

4-(Triﬂuoromethyl)benzonitrile (4x). In a glovebox, to 4-

bromobenzonitrile (3x; purity 98%; 23 mg; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF containing an

extra 0.2 equiv of TREAT HF (0.36 M; 0.52 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 72 h. Quantitative ¹⁹F NMR analysis of the

reaction mixture indicated that 4x was produced in 31% yield (0.55

equiv of CuCF₃remained unreacted). After dilution with ether (2 mL)

and extraction with water (5 mL), the organic layer was ﬁltered through

a short silica gel plug and analyzed by GC−MS to determine the

conversion (ca. 27%). Characterization of 4x in reaction solution: m/z

= 171 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −62.6 (s).⁷⁰

Methyl 2-(Triﬂuoromethyl)benzoate (4y). To methyl 2-

bromobenzoate (3y; purity 98% 1.43 mL; 10 mmol) was added

under argon at room temperature CuCF₃in DMF (0.37 M, 54 mL, 2

equiv) containing an extra 0.2 equiv of TREAT HF, and the mixture

was stirred for 24 h at room temperature and then for 24 h at 50 °C.

Ether (100 mL), water (300 mL), and aqueous NH₃(33%; 10 mL)

were added at agitation in air. The organic layer was separated and the

aqueous layer was washed with ether (2 × 50 mL). The combined ether

solutions were washed with brine (2 × 100 mL), dried over MgSO₄,

ﬁltered, and evaporated (25 °C; 100 mbar). The residue was dissolved

in pentane/dichloromethane (4:1 v/v) and the solution was ﬁltered

through a short silica gel plug and evaporated (25 °C; 10 mbar) to give

4y as a slightly yellowish oil (1.94 g; 95%). m/z = 204 (GC−MS; EI).

¹H NMR (CDCl₃, 400 MHz): δ = 7.82−7.75 (m, 1H), 7.77−7.71 (m,

1H), 7.65−7.57 (m, 2H), 3.94 (s, 3H). ¹³C NMR (CDCl₃, 100 MHz):

δ = 167.0, 131.7 (q, ⁴J_C−F= 0.8 Hz), 131.1, 131.0 (q, ³J_C−F= 2.4 Hz),

130.0, 128.5 (q, ²J_C−F= 32.4 Hz), 126.5 (q, ³J_C−F= 5.4 Hz), 123.4 (q,

¹J_C−F= 273.1 Hz), 52.4. ¹⁹F NMR (CDCl₃, 376 MHz): δ = −59.9 (q,

⁵J_H−F= 1.6 Hz).⁷⁰

1

solid (2.20 g; 82%). H NMR (acetone-d₆, 400 MHz): δ = 8.09−8.04

(m, 1H), 8.00−7.92 (m, 1H), 7.81 (d, J = 8.5 Hz, 1H), 4.50−2.00 (bs,

1H). ¹³C NMR (acetone-d₆, 126 MHz): δ = 166.7, 135.1, 134.0, 133.9,

129.2 (q, ³J_C−F= 5.4 Hz), 128.0 (q, ²J_C−F= 33.0 Hz), 126.8, 124.0 (q,

¹J_C−F= 273.0 Hz). ¹⁹F NMR (acetone-d₆, 376 MHz): δ = −60.1 (s).

Lit.⁷⁹

5-Methoxy-2-(triﬂuoromethyl)benzoic Acid (4bb). In a glove-

box, to 2-bromo-5-methoxybenzoic acid (3bb; 25 mg; 0.125 mmol) in

an NMR tube was added at room temperature CuCF₃in DMF

containing an extra 0.2 equiv of TREAT HF (0.38 M; 0.36 mL; 1.1

equiv) and 1,3-bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL).

The NMR tube was sealed with a septum, brought out of the glovebox,

and kept at room temperature. Quantitative ¹⁹F NMR analysis of the

reaction mixture after 12 min indicated that 4bb was produced in 79%

yield (0.11 equiv of CuCF₃remained unreacted). Characterization of

4bb in reaction solution: ¹⁹F NMR (unlocked): δ = −57.1 (s). Lit.⁷⁹

2-(Triﬂuoromethyl)benzaldehyde (4cc). In a glovebox, to 2-

bromobenzaldehyde (3cc; purity 98%; 15 μL; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF containing an

extra 0.2 equiv of TREAT HF (0.37 M; 0.68 mL; 2 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 24 h and then at 50 °C (oil bath) for 24 h.

Quantitative ¹⁹F NMR analysis of the reaction mixture indicated that

4cc was produced in 83% yield (<0.01 equiv of CuCF₃remained

unreacted). After dilution with ether (2 mL) and extraction with water

(5 mL), the organic layer was ﬁltered through a short silica gel plug and

analyzed by GC−MS to determine the conversion (96%). Benzalde-

hyde (ca. 2%) was also detected. Characterization of 4cc in reaction

solution: m/z = 174 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −55.0

(s).⁴⁰

1-(2-(Triﬂuoromethyl)phenyl)ethanone (4dd). To 1-(2-

bromophenyl)ethanone (3dd; 1.36 mL; 10 mmol) was added under

argon at room temperature CuCF₃in DMF (0.37 M; 35 mL; 1.3 equiv)

containing an extra 0.2 equiv of TREAT HF, and the mixture was

stirred for 12 h at room temperature and then for 6 h at 50 °C. Ether

(50 mL), water (250 mL), and aqueous NH₃(33%; 5 mL) were added

at agitation in air. The organic layer was separated and the aqueous

layer was washed with ether (2 × 50 mL). The combined ether

solutions were washed with brine (2 × 50 mL), dried over MgSO₄,

ﬁltered, and evaporated (25 °C, 100 mbar). The residue was dissolved

in pentane/dichloromethane (2:1 v/v) and the solution was ﬁltered

through a short silica gel plug and evaporated (25 °C; 10 mbar) to give

2-(Triﬂuoromethyl)benzoic Acid (4z). To 2-bromobenzoic acid

(3z; purity 97%; 207 mg; 1 mmol) was added under argon at room

temperature CuCF₃in DMF (0.38 M; 2.9 mL; 1.1 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for 15 min at

room temperature. Ether (20 mL) and aqueous HCl (2N; 30 mL) were

added at agitation in air. The organic layer was separated and the

aqueous layer was washed with ether (2 × 10 mL). The combined ether

solutions were washed with brine (2 × 10 mL), dried over MgSO₄, and

ﬁltered. A small amount of silica gel was added to the ﬁltrate and the

solvent was removed under reduced pressure. The residue was placed

onto a short silica gel column and washed with EtOAc/hexane (1:4 v/

v). Evaporation of the eluate gave 4z as a white solid (147 mg; 77%).

m/z = 190 (GC−MS; EI). ¹H NMR (acetone-d₆, 400 MHz): δ = 7.94−

7.87 (m, 1H), 7.88−7.82 (m, 1H), 7.82−7.72 (m, 2H), 5.50−2.00 (bs,

1H). ¹³C NMR (acetone-d₆, 100 MHz): δ = 167.9, 133.2 (q, ⁴J_C−F= 1.1

Hz), 132.7 (q, ³J_C−F= 2.2 Hz), 132.2, 131.1, 128.8 (q, ²J_C−F= 32.2 Hz),

1

4dd as a yellowish oil (1.74 g; 92%). m/z = 188 (GC−MS; EI). H

NMR (CDCl₃, 500 MHz): δ = 7.74−7.67 (m, 1H), 7.64−7.57 (m, 1H),

7.58−7.51 (m, 1H), 7.45 (d, J = 7.5 Hz, 1H), 2.58 (d, J = 3.3 Hz, 3H).

3

¹³C NMR (CDCl₃, 100 MHz): δ = 201.7, 140.3 (q, J_C−F= 1.9 Hz),

4

2

131.9 (q, J_C−F= 0.8 Hz), 130.1, 127.1, 126.6 (q, J_C−F= 32.3 Hz),

126.6 (q, ³J_C−F= 5.1 Hz), 123.7 (q, ¹J_C−F= 273.4 Hz), 30.3 (q, ⁴J_C−F

=

1.6 Hz). ¹⁹F NMR (CDCl₃, 471 MHz): δ = −58.2 (s).⁴⁰

2-(Triﬂuoromethyl)terephthalic Acid (4ee). In a glovebox, to 2-

bromoterephthalic acid (3ee; purity 98%; 31 mg; 0.125 mmol) in an

NMR tube was added at room temperature CuCF₃in DMF containing

an extra 0.2 equiv of TREAT HF (0.37 M; 0.37 mL; 1.1 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature. Quantitative ¹⁹F NMR analysis of the reaction

mixture after 20 min indicated that 4ee was produced in 60% yield (0.1

3

1

127.5 (q, J_C−F= 5.5 Hz), 124.6 (q, J_C−F= 272.6 Hz). ¹⁹F NMR

(acetone-d₆, 376 MHz): δ = −59.9 (s). Lit.⁷⁸

R

dx.doi.org/10.1021/jo401423h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

equiv of CuCF₃remained unreacted). Characterization of 4ee in

reaction solution: ¹⁹F NMR (unlocked): δ = −58.7 (s).⁸⁰

CuCF₃(0.33 M; 0.3 mL). The NMR tube was sealed with a septum,

brought out, and kept at 100 °C (oil bath) for 30 min. Quantitative ¹⁹F

NMR analysis of the reaction mixture indicated that 1-ﬂuoro-4-

(triﬂuoromethyl)benzene was produced in 85% yield (<0.01 equiv of

CuCF₃remained unreacted). This experiment was then repeated in the

presence of various quantities of CuCl: 1 mg (0.01 mmol), 5 mg (0.05

mmol), and 10 mg (0.1 mmol). The yields of 1-ﬂuoro-4-

(triﬂuoromethyl)benzene are listed in Table 3.

Reactions with Various CuX (X = Cl, Br, I). Inside a glovebox, to

CuCl (21 mg; 0.2 mmol) in an NMR tube were added, at room

temperature, CuCF₃(0.33 M; 0.6 mL) and 1-ﬂuoro-4-iodobenzene

(purity 99%; 35 μL; 0.3 mmol). The NMR tube was sealed with a

septum, brought out of the glovebox, and kept at room temperature for

55 min and then at 80 °C (oil bath) for 12 h. Quantitative ¹⁹F NMR

analysis of the reaction mixture indicated that 1-ﬂuoro-4-

(triﬂuoromethyl)benzene was produced in 25% yield (<0.01 equiv of

CuCF₃remained unreacted). This experiment was repeated with CuBr

(32 mg; 0.2 mmol) and then with CuI (38 mg; 0.2 mmol) in place of

CuCl. The results of these experiments are presented in Table 4.

2-(Triﬂuoromethyl)nicotinic Acid (6a). To 2-chloronicotinic acid

(5a; purity 99%; 796 mg; 5 mmol) was added under argon at room

temperature CuCF₃in DMF (0.37 M; 20 mL; 1.5 equiv) containing an

extra 0.2 equiv of TREAT HF, and the mixture was stirred for 48 h at

room temperature. Ether (100 mL) and aqueous HCl (2N; 100 mL)

were added at agitation in air. The organic layer was separated and the

aqueous layer was washed with ether (3 × 50 mL). The combined ether

solutions were washed with brine (50 mL), dried over MgSO₄, ﬁltered,

and evaporated. The residue was crystallized from isopropanol/hexane

to give 6a as a white solid (556 mg; 58%). ¹H NMR (acetone-d₆, 400

MHz): δ = 8.86 (d, J = 4.1 Hz, 1H), 8.35−8.27 (m, 1H), 7.82 (dd, J =

7.9, 4.7 Hz, 1H), 4.00−2.00 (bs, 1H). ¹³C NMR (acetone-d₆, 100

MHz): δ = 166.7, 151.7, 145.4 (q, ²J_C−F= 34.8 Hz), 139.2, 129.4, 127.7,

1

122.4 (q, J_C−F= 274.2 Hz). ¹⁹F NMR (acetone-d₆, 376 MHz): δ =

−65.0 (s).⁸¹

Ethyl 2-(Triﬂuoromethyl)nicotinate (6b). In a glovebox, to ethyl

2-chloronicotinate (5b; 19 μL; 0.125 mmol) in an NMR tube was

added at room temperature CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.37 M; 0.68 mL; 2 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and heated

at 60 °C for 4.5 h. Quantitative ¹⁹F NMR analysis of the reaction

mixture indicated that 6b was produced in 30% yield (0.35 equiv of

CuCF₃remained unreacted). After dilution with ether (2 mL) and

extraction with water (5 mL), the organic layer was ﬁltered through a

short silica gel plug and analyzed by GC−MS to estimate the

conversion at 70%. Characterization of 6b in reaction solution: m/z =

219 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −63.4 (s). Lit.⁸²

2-(Triﬂuoromethyl)benzoic Acid (6c). In a glovebox, to 2-

chlorobenzoic acid (5c; purity 98%; 20 mg; 0.125 mmol) in an NMR

tube was added at room temperature CuCF₃in DMF containing an

extra 0.2 equiv of TREAT HF (0.38 M; 0.49 mL; 1.5 equiv) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The NMR

tube was sealed with a septum, brought out of the glovebox, and kept at

room temperature for 60 h. Quantitative ¹⁹F NMR analysis of the

reaction mixture indicated that 6c was produced in 35% yield (0.03

equiv of CuCF₃remained unreacted). Characterization of 6c in

reaction solution: ¹⁹F NMR (unlocked): δ = −58.5 (s). Lit.⁷⁸

ASSOCIATED CONTENT

* Supporting Information

NMR spectra (PDF) and full details of crystallographic studies

(CIF). This material is available free of charge via the Internet at

http://pubs.acs.org.

■

S

AUTHOR INFORMATION

Corresponding Author

*E-mail: vgrushin@iciq.es.

■

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank Fedor M. Miloserdov and Andrey I. Konovalov for

discussions. The ICIQ Foundation, Consolider Ingenio 2010

(Grant No. CSD2006-0003), and The Spanish Government

(Grant No. CTQ2011-25418) are acknowledged for support of

this work.

1-Chloro-3-nitro-2-(triﬂuoromethyl)benzene (6d). To a sol-

ution of 1,2-dichloro-3-nitrobenzene (5d; purity 97%; 25 mg; 0.125

mmol) in DMF (0.13 mL) under argon, at 80 °C, was added over a

period of 4 h (syringe pump) CuCF₃in DMF containing an extra 0.2

equiv of TREAT HF (0.38 M, 1.64 mL, 5 equiv) and the mixture was

stirred for one more h at this temperature. The reaction mixture was

then cooled to room temperature. Ether (5 mL) and 1,3-

bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL) were added

at agitation in air and the solution was ﬁltered and analyzed by ¹⁹F

NMR to determine the yield of 6d (58%). GC−MS analysis showed

92% conversion of 5d and the presence of 1-chloro-3-nitrobenzene (ca.

20%). Characterization of 6d in reaction solution: m/z = 226 (GC−

MS; EI); ¹⁹F NMR (unlocked): δ = −57.5 (s).⁴⁰

3-Methyl-5-nitro-2-(triﬂuoromethyl)pyridine (6e). In a glove-

box, to 2-chloro-3-methyl-5-nitropyridine (5e; 22 mg; 0.125 mmol) in

an NMR tube was added at room temperature CuCF₃in DMF

containing an extra 0.2 equiv of TREAT HF (0.37 M; 0.68 mL; 2 equiv)

and 1,3-bis(triﬂuoromethyl)benzene (internal standard; 9.7 μL). The

NMR tube was sealed with a septum, brought out of the glovebox, and

heated at 60 °C for 4.5 h. Quantitative ¹⁹F NMR analysis of the reaction

mixture indicated that 6e was produced in 20% yield, with 0.25 equiv of

CuCF₃still being present. After dilution with ether (2 mL) and

extraction with water (5 mL), the organic layer was ﬁltered through a

short silica gel plug and analyzed by GC−MS to determine the

conversion (56%) and indicate the formation of 2-ﬂuoro-3-methyl-5-

nitropyridine (ca. 20%). Characterization of 6e in reaction solution: m/

z = 206 (GC−MS; EI); ¹⁹F NMR (unlocked): δ = −64.6 (s).

Reactions with Various Quantities of CuCl. Inside a glovebox, to

a solution of 1-ﬂuoro-4-iodobenzene (purity 99%; 7.4 μL; 0.06 mmol)

in DMF (0.3 mL) in an NMR tube was added at room temperature

REFERENCES

■

(1) (a) For selected monographs, see: Hudlicky, M. Chemistry of

Organic Fluorine Compounds; Ellis Horwood: New York, 1976.

(b) Banks, R. E. Organoﬂuorine Chemicals and Their Industrial

Applications; Ellis Horwood: West Sussex, U.K., 1979. (c) Filler, R.;

Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Kodansha-

Elsevier: New York, 1982. (d) Clark, J. H.; Wails, D.; Bastock, T. W.

Aromatic Fluorination; CRC Press: Boca Raton, FL, 1996. (e) Kirsch, P.

Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.

(f) Uneyama, K. Organoﬂuorine Chemistry; Blackwell: Oxford, U.K.,

2006. (g) Ojima, I. Fluorine in Medicinal Chemistry and Chemical

Biology; Wiley-Blackwell: Chichester, U.K., 2009. (h) Petrov, V. A.

Fluorinated Heterocyclic Compounds. Synthesis, Chemistry and Applica-

tions; Wiley: Hoboken, NJ, 2009.

(2) For a recent comprehensive review, see: Tomashenko, O. A.;

Grushin, V. V. Chem. Rev. 2011, 111, 4475.

(3) Filler, R. Adv. Fluorine Chem. 1970, 6, 1.

(4) (a) McLoughlin, V. C. R.; Thrower, J. U.S. Patent 3408411, 1968.

(b) McLoughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.

(5) (a) Kobayashi, Y.; Kumadaki, I. Tetrahedron Lett. 1969, 4095. (b)

For a recent account of Kumadaki’s work, see: Sato, K.; Tarui, A.;

Omote, M.; Ando, A.; Kumadaki, I. Synthesis 2010, 1865.

(6) Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. Synthesis

1980, 932.

(7) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981,

1719.

(8) (a) Wiemers, D. M.; Burton, D. J. J. Am. Chem. Soc. 1986, 108,

832. (b) MacNeil, J. G.; Burton, D. J. J. Fluorine Chem. 1991, 55, 225.

S

dx.doi.org/10.1021/jo401423h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Featured Article

(9) Chen, Q.; Wu, S. J. Chem. Soc., Chem. Commun. 1989, 705.

(10) Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91.

(11) For reviews, see: (a) Burton, D. J.; Yang, Z. Y. Tetrahedron 1992,

48, 189. (b) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,

6555. (c) Burton, D. J.; Lu, L. Top. Curr. Chem. 1997, 193, 45.

(d) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (e) Roy, S.;

Gregg, B. T.; Gribble, G. W.; Le, V.-D.; Roy, S. Tetrahedron 2011, 67,

2161. (f) Qing, F.-L.; Zheng, F. Synlett 2011, 1052.

(12) For most recent reports not covered in the review article cited in

ref 2, see: (a) Zhang, C. P.; Wang, Z. L.; Chen, Q. Y.; Zhang, C. T.; Gu,

Y. C.; Xiao, J. C. Angew. Chem., Int. Ed. 2011, 50, 1896. (b) Popov, I.;

Lindeman, S.; Daugulis, O. J. Am. Chem. Soc. 2011, 133, 9286.

(c) Morimoto, H.; Tsubogo, T.; Litvinas, N. D.; Hartwig, J. F. Angew.

(23) Han, W.; Li, Y.; Tang, H.; Liu, H. J. Fluorine Chem. 2012, 140, 7.

(24) Miller, B. R.; Rigby, M.; Kuijpers, L. J. M.; Krummel, P. B.; Steele,

L. P.; Leist, M.; Fraser, P. J.; McCulloch, A.; Harth, C.; Salameh, P.;

Muhle, J.; Weiss, R. F.; Prinn, R. G.; Wang, R. H. J.; O’Doherty, S.;

̈

Greally, B. R.; Simmonds, P. G. Atmos. Chem. Phys. 2010, 10, 7875.

(25) Symons, E. A.; Clermont, M. J. J. Am. Chem. Soc. 1981, 103, 3127.

(26) (a) Shono, T.; Ishifune, M.; Okada, T.; Kashimura, S. J. Org.

Chem. 1991, 56, 2. (b) Barhdadi, R.; Troupel, M.; Perichon, M. Chem.

Commun. 1998, 1251.

(27) Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A.

Science 2012, 338, 1324.

(28) Kawai, H.; Yuan, Z.; Tokunaga, E.; Shibata, N. Org. Biomol.

Chem. 2013, 11, 1446.

(29) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987,

́

Chem., Int. Ed. 2011, 50, 3793. (d) Tomashenko, O. A.; Escudero-Adan,

E. C.; Martínez Belmonte, M.; Grushin, V. V. Angew. Chem., Int. Ed.

2011, 50, 7655. (e) Weng, Z.; Lee, R.; Jia, W.; Yuan, Y.; Wang, W.;

Feng, X.; Huang, K.-W. Organometallics 2011, 30, 3229. (f) Li, Y.;

Chen, T.; Wang, H.; Zhang, R.; Jin, K.; Wang, X.; Duan, C. Synlett

2011, 1713. (g) Kondo, H.; Oishi, M.; Fujikawa, K.; Amii, H. Adv.

Synth. Catal. 2011, 353, 1247. (h) Kremlev, M. M.; Mushta, A. I.; Tyrra,

26, 1167.

(30) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.;

Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901.

(31) Novak

2012, 51, 7767.

(32) Novak, P.; Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc.

́

, P.; Lishchynskyi, A.; Grushin, V. V. Angew. Chem., Int. Ed.

́

W.; Yagupolskii, Y. L.; Naumann, D.; Moller, A. J. Fluorine Chem. 2012,

̈

2012, 134, 16167.

133, 67. (i) Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A.

PCT Int. Appl. WO 2012/148772, 2012. (j) Schareina, T.; Wu, X.-F.;

Zapf, A.; Cotte, A.; Gotta, M.; Beller, M. Top. Catal. 2012, 55, 426.

(k) Mulder, J. A.; Frutos, R. P.; Patel, N. D.; Qu, B.; Sun, X.; Tampone,

T. G.; Gao, J.; Sarvestani, M.; Eriksson, M. C.; Haddad, N.; Shen, S.;

Song, J. J.; Senanayake, C. H. Org. Process Res. Dev. 2013, 17, 940.

(l) Dai, J. J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z.-J.; Lu, X.; Liu, L.; Fu,

Y. J. Am. Chem. Soc. 2013, 135, 8436. (m) Wang, X.; Xu, Y.; Mo, F.; Ji,

G.; Qiu, D.; Feng, J.; Ye, Y.; Zhang, S.; Zhang, Y.; Wang, J. J. Am. Chem.

(33) It was recently stated²⁷that our synthetic methods based on the

cupration reaction of ﬂuoroform³⁰⁻³²“require excess of CF₃H [2 to 3

equivalent (equiv)] and have limited scope”. In fact, no excess of

ﬂuoroform is required for our reactions. As for the scope, we invite the

reader to judge on that using our data both reported previously³⁰⁻³²

and obtained in this work.

(34) For general reviews of TREAT HF, see: (a) McClinton, M. A.

Aldrichimica Acta 1995, 28, 31. (b) Haufe, G. J. Prakt. Chem. 1996, 338,

99.

(35) (a) Cottet, F.; Castagnetti, E.; Schlosser, M. Synthesis 2005, 798.

(b) Cottet, F.; Schlosser, M. Tetrahedron 2004, 60, 11869. (c) Cottet,

F.; Schlosser, M. Eur. J. Org. Chem. 2004, 3793.

(36) For selected reviews, see: (a) Rao, H.; Fu, H. Synlett 2011, 745.

(b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.

(c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.

(d) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (e) Beletskaya, I. P.;

Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337. (f) Ley, S.;

Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (g) Hassan, J.;

Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,

1359.

Soc. 2013, 135, 10330. (n) Danoun, G.; Bayarmagnai, B.; Grunberg, M.

̈

F.; Gooßen, L. J. Angew. Chem., Int. Ed. 2013, 52, 7972.

(13) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,

12644. (b) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,

4632. (c) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (d) Bakhmutov,

́ ́

V. I.; Bozoglian, F.; Gomez, K.; Gonzalez, G.; Grushin, V. V.;

Macgregor, S. A.; Martin, E.; Miloserdov, F. M.; Novikov, M. A.;

Panetier, J. A.; Romashov, L. V. Organometallics 2012, 31, 1315.

(14) (a) Dubinina, G. G.; Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc.

2008, 130, 8600. (b) Dubinina, G. G.; Ogikubo, J.; Vicic, D. A.

Organometallics 2008, 27, 6233.

(15) (a) Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909.

(b) Inoue, M.; Araki, K. Jpn. Patent JP 2009-234921, 2009.

(16) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;

Buchwald, S. L. Science 2010, 328, 1679.

(37) Kobayashi, Y.; Yamamoto, K.; Asai, T.; Nakano, M.; Kumadaki, I.

J. Chem. Soc., Perkin Trans. 1 1980, 2755.

(38) In order to eliminate confusion, products 2t, 2m, and 2l in Table

1 are presented in Table 2 as 4k, 4v, and 4x, respectively.

(39) A small amount of benzaldehyde (ca. 2%) was produced in the

reaction of 3cc (GC−MS; see Table 2).

(40) Clark, J. H.; Denness, J. E.; McClinton, M. A.; Wynd, A. J. J.

Fluorine Chem. 1990, 50, 411.

(41) (a) Tetrabromoterephthalic acid readily reacted with ﬂuoro-

form-derived CuCF₃to give a complex mixture of triﬂuoromethylated

products. Tetrakis(triﬂuoromethyl)terephthalic acid that has not been

reported (SciFinder, as of June 3, 2013) is expected^41bto be a strong

acid that could decompose the CuCF₃reagent and might be highly

reactive and unstable. (b) Kuett, A.; Movchun, V.; Rodima, T.;

Dansauer, T.; Rusanov, E. B.; Leito, I.; Kaljurand, I.; Koppel, J.; Pihl, V.;

Koppel, I.; Ovsjannikov, G.; Toom, L.; Mishima, M.; Medebielle, M.;

(17) (a) Chu, L.; Qing, F. L. Org. Lett. 2010, 12, 5060. (b) Senecal, T.

D.; Parsons, A.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174. (c) Xu, J.;

Luo, D.-F.; Xiao, B.; Liu, Z.-J.; Gong, T.-J.; Fu, Y.; Liu, L. Chem.

Commun. 2011, 47, 4300. (d) Zhang, C.-P.; Cai, J.; Zhou, C.-B.; Wang,

X.-P.; Zheng, X.; Guc, Y.-C.; Xiao, J.-C. Chem. Commun. 2011, 47,

9516. (e) Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342. (f) Khan, B. A.;

Buba, A. E.; Gooßen, L. J. Chem.Eur. J. 2012, 18, 1577. (g) Jiang, X.;

Chu, L.; Qing, F.-L. J. Org. Chem. 2012, 77, 1251. (h) Litvinas, N. D.;

Fier, P. S.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51, 536. (i) Liu,

T.; Shao, X.; Wu, Y.; Shen, Q. Angew. Chem., Int. Ed. 2012, 51, 540.

(j) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034. (k) Ye, Y.;

Kunzi, S. A.; Sanford, M. S. Org. Lett. 2012, 14, 4979. (l) Li, Y.; Wu, L.;

̈

Neumann, H.; Beller, M. Chem. Commun. 2013, 49, 2628.

(18) (a) Roques, N.; Russell, J. PCT Int. Appl. WO 97/19038, 1997.

(b) Roques, N.; Russell, J. U. S. Patent 6355849, 2002.

(19) Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771.

(20) (a) Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L.

Tetrahedron Lett. 1998, 39, 2973. (b) Folleas, B.; Marek, I.; Normant, J.-

F.; Saint-Jalmes, L. Tetrahedron 2000, 56, 275.

Lork, E.; Roschenthaler, G.-V.; Koppel, I. A.; Kolomeitsev, A. A. J. Org.

Chem. 2008, 73, 2607.

̈

(42) For reviews, see: (a) Grushin, V. V.; Alper, H. Chem. Rev. 1994,

94, 1047. (b) Grushin, V. V.; Alper, H. Top. Organomet. Chem. 1999, 3,

193. (c) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.

(d) Bedford, R. B.; Cazin, C. S. J.; Holder, D. Coord. Chem. Rev. 2004,

248, 2283.

(21) Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65,

8848.

(43) For an X-ray structure of the simplest analogue [Cu₂(μ-

OAc)₄(DMF)₂], see: Rao, V. M.; Sathyanarayana, D. N.; Manohar, H. J.

Chem. Soc., Dalton Trans. 1983, 2167.

(22) (a) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101.

(b) Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848.

(c) Langlois, B. R.; Billard, T. ACS Symp. Ser. 2005, 911, 57.

T

dx.doi.org/10.1021/jo401423h | J. Org. Chem. XXXX, XXX, XXX−XXX

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(44) For the non-triﬂuoromethylated analogue [Cu₂(μ-

O₂CPh)₄(DMF)₂], see: Del Sesto, R. E.; Arif, A. M.; Miller, J. S.

Inorg. Chem. 2000, 39, 4894.

(45) For most recent critical reviews of mechanisms of Cu-mediated/

catalyzed coupling reactions of aryl halides, see: (a) Beletskaya, I. P.;

(67) Naumann, D.; Kirij, N. V.; Maggiarosa, N.; Tyrra, W.;

Yagupolskii, Y. L.; Wickleder, M. S. Z. Anorg. Allg. Chem. 2004, 630,

746.

(68) Algarra, A. G.; Grushin, V. V.; Macgregor, S. A. Organometallics

2012, 31, 1467.

(69) While it might be too early to assess the industrial feasibility of

the two technologies, the necessity to perform the deprotonation at low

temperatures would raise the production cost considerably. Apart from

the energy issue, the most expensive chemical employed in the

cupration process is potassium tert-butoxide,³⁰whereas the arguably

most eﬃcient base to deprotonate ﬂuoroform is potassium

bis(trimethylsilyl)amide (KHMDS).^18,19,27The current bulk (1 t)

prices per mol for KHMDS (as a 1.0 M solution in toluene) and t-

BuOK (pure solid), as quoted by a supplier on a highly competitive

Asian market, are approximately $36.70 and $1.80, respectively. This

diﬀerence in prices by far overwhelms the gain from the replacement of

the originally employed DMF^18,19with less costly solvents such as

toluene and THF.²⁷

̀

Cheprakov, A. V. Organometallics 2012, 31, 7753. (b) Lefevre, G.;

Franc, G.; Tlili, A.; Adamo, C.; Taillefer, M.; Ciofini, I.; Jutand, A.

Organometallics 2012, 31, 7694. (c) Sperotto, E.; van Klink, G. P. M.;

van Koten, G.; de Vries, J. G. Dalton Trans. 2010, 39, 10338.

(46) Independent experiments showed that the thermal decom-

position of the CuCF₃reagent is promoted by its products.

(47) Yoke, J. T., III; Weiss, J. F.; Tollin, G. Inorg. Chem. 1963, 2, 1210.

(48) Structural characterization of the chloro analogue

[Cu₄(NEt₃)₄Cl₄] has been reported: Dyason, J. C.; Healy, P. C.;

Engelhardt, L. M.; Pakawatchai, C.; Patrick, V. A.; Raston, C. L.; White,

A. H. J. Chem. Soc., Dalton Trans. 1985, 831.

(49) For reviews, see: (a) Brothers, P. J.; Roper, W. R. Chem. Rev.

1988, 88, 1293. (b) Torrens, H. Coord. Chem. Rev. 2005, 249, 1957.

(c) Hughes, R. P. Eur. J. Inorg. Chem. 2009, 4591.

(50) Vergote, T.; Nahra, F.; Welle, A.; Luhmer, M.; Wouters, J.;

Mager, N.; Riant, O.; Leyssens, T. Chem.Eur. J. 2012, 18, 793.

(51) (a) For a general review of Lewis acidity of metal halides, see:

Satchell, D. P. N.; Satchell, R. S. Chem. Rev. 1969, 69, 251. (b) Ahrland,

(70) Knauber, T.; Arikan, F.; Roschenthaler, G.-V.; Gooßen, L. J.

̈

Chem.Eur. J. 2011, 17, 2689.

(71) Ye, Y.; Lee, S. H.; Sanford, M. S. Org. Lett. 2011, 13, 5464.

(72) Gilman, H.; Tolman, L.; Yeoman, F.; Woods, L. A.; Shirley, D.

A.; Avakian, S. J. Am. Chem. Soc. 1946, 68, 426.

(73) Yagupol’skii, L. M.; Man’ko, N. I. Zh. Obshch. Khim. 1953, 23,

988.

S.; Blauenstein, P.; Tagesson, B.; Tuhtar, D. Acta Chem. Scand. A 1980,

̈

A34, 265. (c) Ahrland, S.; Nilsson, K.; Tagesson, B. Acta Chem. Scand. A

1983, A37, 193. (d) Johnsson, M.; Persson, I. Inorg. Chim. Acta 1987,

127, 43. (e) Lewandowski, A. J. Chem. Soc., Faraday Trans. 1 1988, 84,

4013. (f) Ahrland, S. Pure Appl. Chem. 1990, 62, 2077.

(74) Naumann, D.; Kischkewitz, J. J. Fluorine Chem. 1990, 47, 283.

(75) Janz, G. J.; Monahan, A. R. J. Org. Chem. 1965, 30, 1249.

(76) Ashimori, A.; Ono, T.; Uchida, T.; Ohtaki, Y.; Fukaya, C.;

Watanabe, M.; Yokoyama, K. Chem. Pharm. Bull. 1990, 38, 2446.

(77) Raasch, M. S. J. Org. Chem. 1962, 27, 1406.

(78) An, G.; Ahn, H.; De Castro, K. A.; Rhee, H. Synthesis 2010, 477.

(79) Yagupol’skii, L. M.; Belinskaya, R. V. Zh. Obshch. Khim. 1963, 33,

2358.

(80) Kuwabara, M.; Murakami, A.; Fukunishi, K.; Nomura, M.;

Yamanaka, H. J. Fluorine Chem. 1989, 42, 105.

(81) Schlosser, M.; Marull, M. Eur. J. Org. Chem. 2003, 1569.

(82) Kiss, L. E.; Ferreira, H. S.; Learmonth, D. A. Org. Lett. 2008, 10,

1835.

(52) (a) Radical triﬂuoromethylation of aromatic C−H bonds has

long been known^52b,cto suﬀer from low positional selectivity. For

reviews of radical perﬂuoroalkylations, see refs 52d and 52e. (b) Tiers,

G. V. D. J. Am. Chem. Soc. 1960, 82, 5513. (c) Drysdale, J. J.; Coffman,

D. D. J. Am. Chem. Soc. 1960, 82, 5111. (d) Dolbier, W. R., Jr. Chem.

Rev. 1996, 96, 1557. (e) Studer, A. Angew. Chem., Int. Ed. 2012, 51,

8950.

(53) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am. Chem.

Soc. 2010, 132, 6205 and references cited therein.

(54) (a) Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413. (b) Rossi, R. A.;

de Rossi, R. H. Aromatic Substitution by the S_RN1 Mechanism; American

Chemical Society: Washington, D.C., 1983. (c) van Leeuwen, M.;

McKillop, A. J. Chem. Soc., Perkin Trans. 1 1993, 2433.

(55) Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496.

(56) (a) Miller, J. Aromatic Nucleophilic Substitution; Elsevier: London,

1968. (b) Terrier, F. Nucleophilic Aromatic Displacement: The Inﬂuence

of the Nitro Group; VCH: New York, 1991.

(57) Lindley, J. Tetrahedron 1984, 40, 1433 and references cited

therein.

(58) (a) Not to be confused with other ortho-eﬀects^58bincluding

those in S_NAr⁵⁶and polar reactions of diaryliodonium salts.^58c

(b) Exner, O.; Bohm, S. Curr. Org. Chem 2006, 10, 763. (c) Grushin,

̈

V. V. Acc. Chem. Res. 1992, 25, 529.

(59) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382.

(60) Vorozhtsov, N. N., Jr.; Kobelev, V. A. Zh. Obshch. Khim. 1939, 9,

1043.

(61) (a) Vainshtein, F. M.; Tomilenko, E. I.; Shilov, E. A. Dokl. Akad.

Nauk SSSR 1966, 170, 1077. (b) Vainshtein, F. M.; Tomilenko, E. I.;

Shilov, E. A. Kinet. Katal. 1969, 10, 777. (c) Lisitsyn, V. N.; Shestakov,

V. A.; Sycheva, E. D. Zh. Vses. Khim. O-va im. D. I. Mendeleeva 1969, 14,

117. (d) Castro, C. E.; Havlin, R.; Honwad, V. K.; Malte, A.; Moje, S. J.

Am. Chem. Soc. 1969, 91, 6464. (e) Drozd, V. N.; Trifonova, O. I. Zh.

Org. Khim. 1970, 6, 2493.

(62) Shein, S. M.; Litvak, V. V. Zh. Vses. Khim. O-va im. D. I.

Mendeleeva 1976, 21, 274 and references cited therein.

(63) Bruggink, A.; McKillop, A. Tetrahedron 1975, 31, 2607.

(64) Regrettably, a highly informative review article⁶²on the ortho-

eﬀect is still available only in Russian.

(65) Hansch, H.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.

(66) Grushin, V.; Zanardi, A. PCT Int. Appl. WO 2012/113726, 2012.

U

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Trifluoromethylation of aryl and heteroaryl halides with fluoroform-derived CuCF3: Scope, limitations, and mechanistic features

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