Copper-mediated deoxygenative trifluoromethylation of benzylic xanthates: Generation of a C-CF3 bond from an O-based electrophile

Article abstract of DOI:10.1002/chem.201302328

The conversion of an alcohol-based functional group, into a trifluoromethyl analogue is a desirable transformation. However, few methods are capable of converting O-based electrophiles into trifluoromethanes. The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto's reagent as the source of CF₃ to form C-CF₃ bonds is described. The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the C-CF₃ bond forms by reaction of the substrate with in situ generated CuCF₃ and CuOTf. Further evidence suggests that the reaction could proceed via a radical cation intermediate. Highly compatible and useful: The copper-mediated trifluoromethylation of benzylic xanthates using Umemoto's reagent as the source of CF₃ to form C-CF₃ bonds is described (see scheme). The method is compatible with an array of benzylic xanthates bearing useful functional groups. A preliminary mechanistic investigation suggests that the C-CF₃ bond forms by reaction of the substrate with in situ generated CuCF₃ and CuOTf. Copyright

Full text of DOI:10.1002/chem.201302328

FULL PAPER
Trifluoromethylation
L. Zhu, S. Liu, J. T. Douglas,
R. A. Altman* ................ &&&& — &&&&
Copper-Mediated Deoxygenative
Trifluoromethylation of Benzylic
Highly compatible and useful: The
copper-mediated trifluoromethylation
of benzylic xanthates using Umemotoꢀs
reagent as the source of CF3 to form
with an array of benzylic xanthates
bearing useful functional groups. A
preliminary mechanistic investigation
À
Xanthates: Generation of C CF3
Bond from an O-Based Electrophile
À
suggests that the C CF3 bond forms by
À
C CF3 bonds is described (see
reaction of the substrate with in situ
generated CuCF3 and CuOTf.
scheme). The method is compatible
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DOI: 10.1002/chem.201302328
Copper-Mediated Deoxygenative Trifluoromethylation of Benzylic
À
Xanthates: Generation of C CF3 Bond from an O-Based Electrophile
Lingui Zhu,[a] Shasha Liu,[a] Justin T. Douglas,[b] and Ryan A. Altman*[a]
Abstract: The conversion of an alco-
hol-based functional group, into a tri-
fluoromethyl analogue is a desirable
transformation. However, few methods
are capable of converting O-based
electrophiles into trifluoromethanes.
The copper-mediated trifluoromethyla-
tion of benzylic xanthates using Ume-
motoꢀs reagent as the source of CF3 to
benzylic xanthates bearing useful func-
tional groups. A preliminary mechanis-
À
form C CF3 bonds is described. The
À
method is compatible with an array of
tic investigation suggests that the C
CF3 bond forms by reaction of the sub-
strate with in situ generated CuCF3
and CuOTf. Further evidence suggests
that the reaction could proceed via a
radical cation intermediate.
Keywords: copper · fluorine · radi-
cal cation · synthetic methods · tri-
fluoromethylation
Introduction
ethers,[12,13] or fluorides,[14] (Scheme 1). However, all these
À
transformations of xanthates only form C F bonds. In con-
The incorporation of trifluoromethyl groups (CF3) into or-
ganic molecules imparts profound changes in physical,
chemical, and biological properties of molecules.[1] Due to
high electronegativity, lipophilicity, and metabolic stability
of the trifluoromethyl group, trifluoromethylated com-
pounds have been widely employed in the fields of pharma-
ceuticals, agrochemicals and materials science.[1,2] Accord-
ingly, various protocols for the introduction of CF3 into or-
ganic molecules have increasingly emerged.[2a,3–5] Specifical-
ly, transition-metal-catalyzed or -mediated trifluoromethyla-
tion reactions have made remarkable progress.[3–5] For
trast, we describe a copper-mediated deoxygenative trifluor-
À
omethylation of benzylic xanthates to form C CF3 bond,
and an accompanying mechanistic study.
example, Pd-catalyzed trifluoromethylation of C
(sp2)-halides
2
À
and C
(sp ) H bonds,[4] and Cu-mediated or Cu-catalyzed tri-
fluoromethylation of halides, boronic acids and terminal al-
kynes[3g,5] provide access to compounds containing C
A
2
À
À
CF3 and C(sp) CF3 bonds. However, few examples exist of
À
the generation of C CF3 bonds from O-based electro-
philes.[6]
Scheme 1. Transformations of xanthates into fluorinated compounds.
The conversion of an alcohol-based functional group into
a trifluoromethyl analogue is a desirable transformation. Al-
cohols can be readily converted into xanthates,[7] which are
typically employed to generate radical intermediates.[8–11]
Besides forming radical intermediates, xanthates can also be
converted to useful fluorinated functional groups such as di-
Results and Discussion
3
À
To develop a C
N
fluoro(thiomethyl)methyl
ethers,[12]
trifluoromethyl
conditions and trifluoromethylating reagents were scouted
for the conversion of benzylic xanthate 1a into trifluorome-
thylated product 3a. The combination of Togniꢀs reagent 2c
(Scheme 2), catalytic CuI and 1,10-phenanthroline (1,10-
phen) afforded trifluoromethylated product 3a in 23%
yield. However, the use of other CuI or CuII salts, radical ini-
tiators, and alternate ligands decreased the yield of 3a.
Encouraged by recently reported copper-mediated tri-
fluoromethylation reactions of heteroaryl iodides and benzyl
bromides,[5c,d] we explored the use of copper powder to pro-
mote the reaction (for more details see Supporting Informa-
[a] Dr. L. Zhu, Dr. S. Liu, Prof. Dr. R. A. Altman
Department of Medicinal Chemistry
University of Kansas, Lawrence, KS 66045 (USA)
Fax : (+1)785-864-5326
E-mail: raaltman@ku.edu
[b] Dr. J. T. Douglas
Nuclear Magnetic Resonance Laboratory
University of Kansas, Lawrence, KS 66045 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302328.
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Trifluoromethylation of Benzylic Xanthates
FULL PAPER
Table 1. Effects of trifluoromethylating reagents and stoichiometry of re-
agents.[a]
+
Entry
“CF3
”
1/2/Cu0
Yield [%][b]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
1:2:3
1:2:3
1:2:3
1:2:3
1:2:2
1:2:4
1:3:3
1:3:4
1:3.5:4.5
1:4:5
60 (57)[c]
56
39
7
43
47
64
78
79
84[d]
Scheme 2. Initial screening of the trifluoromethylation of xanthates in-
volved reactions of CuI and 1,10-phen.
tion). Treatment of 1a with Umemotoꢀs reagent 2a and Cu0
in DMA provided an increased yield of 42%. Subsequent
screening of alternate solvents revealed that polar aprotic
solvents, such as DMA, NMP, DMSO, and CH3CN, facilitat-
ed the reaction, while no product was formed in non-polar
and ethereal solvents. The use of CH3CN at 608C afforded
3a in the reasonable yield (57%). Further optimization of
the reaction involved screening of the fluorinating reagents,
and stoichiometry of the reagents (Table 1). For the Cu0-
mediated trifluoromethylation reaction of 1a, Umemotoꢀs S-
trifluoromethyl dibenzothiophenium-based reagents 2a and
b outperformed Togniꢀs I-trifluoromethyl benziodoxole re-
agents 2c and d (entries 1–4), and triflate 2a was selected
for conducting all subsequent work. Increasing the stoichi-
ometry of Cu0, while maintaining the stoichiometry of 2a
constant, provided a lower yield of product 3a (entries 3, 5
and 6). However, simultaneously increasing both the equiva-
lents of 2a and Cu0 elevated the yield of 3a to 78–79% (en-
tries 8–9). Although an improved yield was obtained upon
increasing the ratio to 1:4:5 (84%, entry 10), the cost of re-
agents (relative to this modest improvement in yield) dis-
couraged use of such stoichiometry. In addition, the use of
N-, or P-type ligands decreased the yield of product 3a (for
more details of all screening reactions see Supporting Infor-
mation).
With the optimized reaction conditions in hand, the scope
of the Cu0-mediated deoxygenative trifluoromethylation of
xanthates was examined (Table 2). For substrates derived
from primary benzylic alcohols, xanthates with strong elec-
tron-withdrawing substituents (3i–l), as well as weak elec-
tron-withdrawing and -donating substituents (3a–f) provided
good yields of products. Even in the presence of reducing
Cu0, an aryl bromide remained intact. For ortho-substituted
xanthates 1q and 1r containing conjugated double bonds,
the trifluoromethylation reaction didn’t affect the neighbor-
ing alkenes. Reactions of xanthates containing heteroaro-
matic rings such as pyridine and benzothiophene afforded
the trifluoromethylated products in good yields (3s, 3u).
However, the reaction of a quinoline-based substrate 1t pro-
vided a lower yield of 3t. Trifluoromethylation of benzyl
xanthates bearing methoxy or dimethylamino on the o- or
p-position was generally unsuccessful. For these substrates,
the xanthate readily rearranged into the dithiocarbonate,
presumably under the Lewis acidic conditions resulting from
9
10
[a] Reaction conditions: 1a (1.0 equiv), 2, Cu0, anhydrous CH3CN (c=
0.1m), 608C, 9 h, under an atmosphere of N2. [b] Yields were determined
by 19F NMR analysis using benzotrifluoride as an internal standard.
[c] The reaction time for the yield in parenthesis was 11 h. [d] 20% of 2a
remained by 19F NMR analysis.
the reaction of Cu0 with 2a.[15] In many cases, this rearrange-
ment actually prohibited the preparation of xanthates from
electron-rich benzylic alcohols.[16] However, trifluoromethy-
lated product 3g could be obtained in 13% yield.
Xanthates derived from secondary benzylic alcohols also
underwent the trifluoromethylation reaction (Table 3), but
required slightly more Cu0 and 2a than xanthates derived
from primary alcohols. Trifluoromethylated products were
generated in lower yields than their respective non-branched
counterparts (5a vs 3a and 5b vs 3j), which may be attribut-
ed to the sensitivity of some a-branched benzylic xanthates
to Lewis acid (CuOTf).[15] For secondary benzylic xanthates
that tolerated the reaction conditions, trifluoromethylation
proceeded smoothly in moderate to good yields (5c, 5d and
5g). As steric hindrance a to the xanthate increased, the
yields decreased (5d–f). For certain reactions, the separation
of the dibenzothiophene byproduct from the trifluoromethy-
lated product was challenging (3o, 3p and 5g). For these
select cases, treatment of the reaction mixture with m-
CPBA allowed the oxidized dibenzothiophene to be separat-
ed by column chromatography in lower yields than suggest-
ed by 19F NMR spectroscopy.
Preliminary investigations established that both CuCF3
and in situ generated CuOTf were crucial for activating the
xanthate substrate (Scheme 3). No reaction was observed
when xanthate 1a was treated either with Cu0 in the absence
2a [Eq. (1)], or with 2a in the absence of Cu0 [Eq. (2)]. In
both cases, the majority of the starting material was recov-
ered. However, treatment of xanthate 1a with CuOTf pro-
vided dithiocarbonate 6 as the sole major product, potential-
ly by
a Lewis acid-mediated cationic rearrangement
[Eq. (3)].[15a,b] Treatment of 1a with 2.0 equiv CuCF3
(formed by reaction of CuI and TMSCF3 in the presence of
CsF)[5k] provided product 3a in 20% 19F NMR yield
[Eq. (4)], while the addition of CuOTf (2.0 equiv) to the re-
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R. A. Altman et al.
Table 2. Cu0-mediated trifluoromethylation of benzylic xanthates 1.[a,b]
Scheme 3. A) Substrate 1a was stable in the presence of Cu0 or 2a, but
was activated by CuOTf. B) Treatment of 1a with CuCF3 provided 3a,
but the yield of 3a increased in the presence of added CuOTf. C) A plau-
sible mechanism involves reduction of 2a to form CuCF3 and CuOTf.[5c]
Both Cu-based species are involved in trifluoromethylation.
[a] Reaction conditions: 1a–u (1.0 equiv), 2a (3.0 equiv), Cu0 (4.0 equiv),
anhydrous CH3CN (c=0.1m), 608C, 9 h, under an atmosphere of N2.
[b] Yields were determined by 19F NMR analysis using benzotrifluoride
as an internal standard (average of two runs) and the figures in parenthe-
sis refer to the isolated yields after purification (average of two runs).
[c] Isolated yield after using m-CPBA to facilitate separation of dibenzo-
thiophene.
agents with 1a [Eq. (6)]. In this sequence, CuOTf, presuma-
bly activates the xanthate towards trifluoromethylation.
Further experiments detected both radical and cationic
character for the interaction between 1a and CuCF3/CuOTf
(Scheme 4). Xanthates undergo reactions that proceed by
radical, SN2, SNi and SN1 pathways (A).[8–10,14–16] In order to
distinguish between these mechanisms, enantiomerically
pure xanthate (S)-4g was prepared from commercially avail-
able (S)-1-phenylethane-1,2-diol (99% ee). Trifluoromethy-
lation of (S)-4g, and subsequent desilylation provided
known alcohol (Æ)-7 [Eq. (7)].[17] Thus, pathways proceeding
by net SN2 (anticipated stereoinversion) or SNi (anticipated
stereoretention) reactivity were discounted, and further evi-
dence was sought to distinguish between radical and SN1
mechanisms. Using a series of p-substituted benzylic xan-
thates, a Hammett plot was constructed in order to establish
the relationship between electronic structure of the sub-
strate and the rate of trifluoromethylation using the CuCF3/
action mixture increased the yield of product 3a to 43%
[Eq. (5)]. Based on these results a plausible mechanism in-
volves reaction of Cu0 with 2a to generate CuOTf and
CuCF3,[5c] followed by reaction of this combination of re-
Table 3. Cu0-mediated trifluoromethylation of racemic a-branched ben-
zylic xanthates 4.[a,b]
CuOTf system (see Figure 1 in Supporting Information). A
+
linear free energy correlation of log
N
=À1.82Æ0.03, r2 =0.977) indicated that the trifluoromethy-
lation between CuCF3/CuOTf system and xanthates devel-
ops positive charge at the benzylic position near the transi-
tion state.[18a,19] Moreover, a weaker correlation between log-
[a] Reaction conditions: (Æ)-4a–g (1.0 equiv), 2a (4.0 equiv), Cu0
(5.4 equiv), anhydrous CH3CN (c=0.1m), 608C, 9 h, under an atmos-
phere of N2. [b] Yields were determined by 19F NMR analysis using ben-
zotrifluoride as an internal standard (average of two runs) and the figures
in parentheses refer to the isolated yields after purification (average of
two runs). [c] The reaction was run at 408C. [d] Isolated yield after using
m-CPBA to facilitate separation of dibenzothiophene.
(kX/kH) and sp (1 =À2.06Æ0.03, r2 =0.964) and a scattered
C
plot of logACTHUNGTRENNUNG
À
homolytic cleavage of the C O bond to generate neutral
radicals.[18–20] Although the value of 1 + is negative, the mag-
nitude is less than many SN1-type reactions of benzylic elec-
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Trifluoromethylation of Benzylic Xanthates
FULL PAPER
trophiles.[21] This could be attributed to the weak Lewis
acidic nature of CuOTf, which generates weak positive
charge at benzylic position in the transition state.[15a,b,22] Al-
ternatively, the small negative value for 1 + could be attrib-
uted to a pathway involving a benzylic radical cation inter-
mediate.[23] The reaction of 1a with a pregenerated combina-
tion of CuCF3/CuOTf was inhibited in the presence of sever-
al radical scavengers, including 1,4-dinitrobenzene, hydro-
quinone, and 2,2,6,6-tetramethyl-1-piperidinyloxy [TEMPO,
Eq. (9)]. Combined, these results establish both radical and
cationic character in the trifluoromethylation process.
Based on the above results and previous re-
ports,[5c,14–16,19–23] we propose a plausible mechanism for Cu0-
mediated deoxygenative trifluoromethylation of benzylic
xanthates using Umemotoꢀs reagent 2a (Scheme 5). Reduc-
tion of 2a by Cu0 in situ provides CuCF3 in addition to
CuOTf.[5c] This combination of reagents reacts with xanthate
(8) to afford the trifluoromethylated product (9) via a pro-
Scheme 5. Possible pathways for the interaction of CuCF3 with xanthates.
posed cationic radical intermediate (11). In this sequence,
CuOTf serves as an activating agent for the xanthate (10).
Conclusion
In summary, a Cu0-mediated deoxygenative trifluoromethy-
lation of benzylic xanthates using Umemotoꢀs reagent as the
source of CF3 has been developed. The protocol provides
access to a wide variety of trifluoroethylarenes bearing sen-
sitive functional groups in moderate to good yields in two
steps from widely available benzylic and heterobenzylic al-
cohols. The xanthates bearing p-donating substituents at the
2- or 4-position were not generally compatible with the tri-
fluoromethylation process, likely because of the sensitivity
of these compounds to heat and Lewis acidic conditions. A
preliminary mechanistic investigation suggests that the tri-
fluoromethylation process involves a radical cation inter-
mediate. Further, this mechanism might be relevant to other
trifluoromethylation reactions of electrophiles that employ
stoichiometric CuCF3.[5d,24] We anticipate that the insight
gained will accelerate the development of more atom-eco-
nomical trifluoromethylation reactions, as well as alternate
reactions of xanthate electrophiles.
Experimental Section
General procedure for the preparation of benzylic xanthates 1a–u
(except for 1r) and 4a–g:[6] Under an atmosphere of nitrogen, a solution
of alcohol (1.0 equiv) in anhydrous THF (2–4 mL) was added at 08C to a
suspension of NaH (60% dispersion in mineral oil, 2.5 equiv) and imida-
zole (5–8% equiv) in anhydrous THF (generally c=0.5m). The mixture
was stirred at room temperature for 30 min and H2 gas was released. CS2
(2.5 equiv) was added, and the resulting mixture was stirred at room tem-
perature for 0.5–1 h. MeI (2.5 equiv) was added, and the mixture was stir-
red at room temperature until the reaction was completed as monitored
by TLC (usually about 1 h). The reaction was cooled to 08C, and
quenched with a saturated aqueous solution of ammonium chloride. The
organic layer was separated, and the aqueous layer was extracted with
ethyl acetate thrice. The combined organic layers were washed with
brine, and dried over Na2SO4. After concentration under vacuum, the
residue was purified by flash column chromatography using 0–5% ethyl
Scheme 4. A) Possible pathways for the interaction of CuCF3 with xan-
thates. B) Racemization of (S)-4g discounts SN2 and SNi reaction path-
+
ways. C) A linear free energy correlation of log
N
lishes the build-up of cationic charge at the benzylic position at the tran-
sition state. See Supporting Information for more details. D) Reaction of
1a was inhibited by multiple radical scavengers.
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R. A. Altman et al.
acetate/hexane or dichloromethane/hexane as the eluent to afford xan-
thates 1a–u (except for 1r) and 4a–g.
[4] For recent Pd-catalyzed trifluoromethylation, see: a) X. Wang, L.
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General procedure for the trifluoromethylation of benzylic xanthates 1a–
u: Under an atmosphere of nitrogen, anhydrous CH3CN (c=0.1m) was
added to a sealed vial equipped with xanthate 1a–u (1.0 equiv), Umemo-
toꢀs reagent (3.0 equiv), copper powder (4.0 equiv) and a stir bar at room
temperature (when xanthate was oil, it was added as a solution in
CH3CN). Subsequently, the mixture was stirred at 608C for 9 h, and then
cooled to room temperature. Benzotrifluoride (1.0 equiv) was added as
an internal standard, and the resulting mixture was stirred at room tem-
perature for 5 min. After standing for 5 min, an aliquot of the upper
clear solution was removed, and subjected to 19F NMR analysis to deter-
mine the yield of product 3a–u. The NMR aliquot was returned to the
crude reaction mixture, and the solvent was removed in vacuo and the
residue was purified using RediSep Rf Silica cartridge on a Teledyne
ISCO CombiFlash Purification System (0–5% EtOAc/hexane as eluent)
to provide the corresponding product.
General procedure for the trifluoromethylation of racemic a-branched
xanthates 4a–g: Under an atmosphere of nitrogen, anhydrous CH3CN
(c=0.1m) was added to a sealed vial equipped with xanthate 4a–g
(1.0 equiv), Umemotoꢀs reagent (4.0 equiv), copper powder (5.4 equiv)
and a stir bar at room temperature (when xanthate was oil, it was added
as a solution in CH3CN). Subsequently, the mixture was stirred at 608C
for 9 h and then cooled to room temperature. Benzotrifluoride
(1.0 equiv) was added as an internal standard and the resulting mixture
was stirred at room temperature for 5 min. After standing for 5 min, an
aliquot of the upper clear solution was remove and subjected to
19F NMR analysis to determine the yield of product 5a–g. For product
5a, 5b, and 5d–g, the NMR aliquot was returned to the crude reaction
mixture, and the solvent was removed in vacuo and the residue was puri-
fied by flash chromatography (0–5% EtOAc/hexane as eluent) to pro-
vide the corresponding product.
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We thank the donors of the American Chemical Society Petroleum Re-
search Fund (52073-DNI1) for partial support of this research. Further fi-
nancial support from the University of Kansas Office of the Provost, De-
partment of Medicinal Chemistry, and General Research Fund (2302264)
is gratefully acknowledged. We thank Professor Jon A. Tunge for helpful
discussion and an astute reviewer for constructive suggestions.
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Received: June 18, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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