Aqueous Benzylic C-H Trifluoromethylation for Late-Stage Functionalization

Article abstract of DOI:10.1021/jacs.8b08547

The installation of trifluoromethyl groups has become an essential step across a number of industries such as agrochemicals, drug discovery, and materials. Consequently, the rapid introduction of this critical functional group in a predictable fashion would benefit current practitioners in those fields. This communication describes a mild trifluoromethylation of benzylic C-H bonds with high selectivity for the least hindered hydrogen atom. The reaction provides monotrifluoromethylation and proceeds in an environmentally friendly acetone/water solvent system. The method can be used to install benzylic trifluoromethyl groups on highly functionalized drug molecules.

Full text of DOI:10.1021/jacs.8b08547

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Aqueous Benzylic C−H Trifluoromethylation for Late-Stage
Functionalization
Shuo Guo, Deyaa I. AbuSalim, and Silas P. Cook*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405-7102, United States
S
* Supporting Information
ABSTRACT: The installation of trifluoromethyl groups
has become an essential step across a number of industries
such as agrochemicals, drug discovery, and materials.
Consequently, the rapid introduction of this critical
functional group in a predictable fashion would benefit
current practitioners in those fields. This communication
describes a mild trifluoromethylation of benzylic C−H
bonds with high selectivity for the least hindered
hydrogen atom. The reaction provides monotrifluorome-
thylation and proceeds in an environmentally friendly
acetone/water solvent system. The method can be used to
install benzylic trifluoromethyl groups on highly function-
alized drug molecules.
Figure 1. The switch from aromatic bromination (a) to benzylic
bromination (b) requires relatively minor changes to the reaction
conditions. The modern switch from aromatic trifluoromethylation (c)
to benzylic trifluoromethylation (d) has yet to be realized.
acile installation of the trifluoromethyl group remains a
Fcritical goal for organic synthesis. The unusual and often
desirable properties of the trifluoromethyl group (e.g., high
electronegativity and Teflon-like stability) have propelled this
moiety into the structures of a striking number of drugs, drug-
candidates, agrochemicals, and materials.1 Ever since the
McLoughlin−Thrower reaction,2 chemists have searched for
easily implemented couplings to install the trifluoromethyl
group.3 Excitingly, a number of recent reports describe novel
trifluoromethylating reagents that offer the potential for new
opportunities to trifluoromethylate organic molecules. The wide
availability of the Ruppert−Prakash,4 Togni,5 Umemoto,6
Langlois,7 Grushin,8 Chen,9 Shibata,10 Baran11 and other
reagents12 have provided chemists with numerous useful
trifluoromethyl synthons with unique properties. Evaluating
such reagents under traditional reaction conditions should
enable rapid access to new chemical matter.
For aromatic trifluoromethylation, methods have primarily
focused on metal-mediated couplings related to the McLough-
lin−Thrower2,13 or radical addition to electron-deficient
aromatic system to supplant individual Csp2−H bonds (Figure
1c).11,14 The introduction of aliphatic trifluoromethyl groups has
lagged by comparison.3b,e,15 For example, while fluoroform is
reasonably acidic (pKa = 28),16 the simple SN2 reaction to install
aliphatic trifluoromethyl groups remains troublesome due to the
rapid decomposition of the CF3 anion to fluoride and
difluorocarbene.17 Recent work has demonstrated that the use
ofradicalsgeneratedfromaliphaticcarboxylicacids,18 esters,19 or
halides20 offers a more convenient path to aliphatic trifluor-
omethylation compared to metal-mediated coupling.15b A more
direct approach would be to target Csp3−H bonds for
trifluoromethylation without the use of preinstalled functional
groups,21 a variant of which was published by Liu and co-workers
during the preparation of this work.22
Classic halogenation chemistry uses subtle changes in reaction
conditions to select for aromatic or benzylic functionalization
(Figure 1a,b). While the halogenation of alkenes and aromatics
was known in the 19th century (Figure 1a), it was the Wohl−
Ziegler reaction that revolutionized our thinking on how subtle
changesinreagentsandconditionscanhaveadrasticeffectonthe
outcome of halogenation chemistry (Figure 1b).23 Mysterious at
the time, the divergent selectivity stemmed from the unknown,
but critical, mechanistic switch from two-electron to radical
chemistry. Based on this classic work, we were curious whether
some modern trifluormethylating reagents might be capable of
quenching benzylic radicals generated directly from C−H bonds
(Figure 1d).
To start our investigations, we evaluated a variety of mild
peroxides for their ability to generate benzylic radicals from
toluene (1a). We found ammonium persulfate forms the
TEMPO inclusion product and bibenzyl in modest yield (eq
1). Based on a number of recent reports on copper-catalyzed
benzylic C−H functionalization,24 we reasoned that one of the
newly introduced CuCF3 complexes 2a−2c might work in
Received: August 9, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b08547
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Journal of the American Chemical Society
Communication
synergy with benzylic radical formation.8,12 To test this
hypothesis, ammonium persulfate and Grushin’s reagent (2a)
were heated to 50 °C in the presence of toluene (Table 1, entry
a
Table 2. Substrate Scope for Trifluoromethylation
a
Table 1. Optimization of Pertinent Reaction Parameters
a
Unless otherwise noted, all the reactions were run with 1a (0.6
b
mmol) and 2a (0.3 mmol) in 3.0 mL of solvent for 18 h. Yields were
determined by 19F NMR spectroscopy with 1-chloro-4-fluorobenzene
as the internal standard.
3). Interestingly, 6% of the desired product 3a formed in the
reaction. Since UV light facilitates radical C−H halogenation,23a
weexposedthereactiontoa365nmLEDbulb(Table1, entry4),
which dramatically increased the yield to 58%. A variety of strong
acids proved beneficial, with trifluoroacetic acid being the most
convenient and high yielding (Table 1, entry 5). The presence of
acid may facilitate the homolysis of Grushin’s reagent (2a)
through the protonation of the bipy ligand. No product formed
under a variety of reaction conditions with copper complex 2b
(Table 1, entry 7), but complex 2c did provide detectable 4%
yield (Table 1, entry 8). Based on the observation that aromatic
trifluoromethylation was a competing pathway (Figure 1a), we
reasoned that the CF3 radical byproduct from Grushin’s reagent
(2a) was consuming 1a. Consequently, we sought a mild radical
quenching agent that would be degenerate with benzyl radical.
After evaluating a series of silanes (see Supporting Information),
we found both triisopropylsilane and t-butyldimethylsilane
dramatically increased the yield (Table 1, entries 1, 5, 9−10)
while suppressing aromatic trifluoromethylation (Figure 1a).
Consequently, the direct trifluoromethylation of toluene (1a)
could be conducted in near quantitative yield based on 2a with
equimolar ammonium persulfate/triisopropylsilane and 8 equiv
of TFA25 in acetone/water solvent system (Table 1, entry 1).
After establishing the optimal reaction conditions for the
trifluoromethylation of toluene, we next evaluated a range of
benzylic C−H bonds (Table 2). Interestingly, the reaction did
not track the reactivity expected of benzylic C−H radical
abstraction.23a That is to say, the reaction showed a clear
a
All reactions were run on 0.3 mmol scale with 1a (0.6 mmol) and 2a
(0.3 mmol) in 3.0 mL of solvent for 18 h unless otherwise noted.
b
Isolated yield. Yield determined by 19F NMR spectroscopy with 1-
c
bromo-4-fluorobenzene as the internal standard. 2.0 equiv of
tBuMe2SiH instead of 3.0 equiv of iPr3SiH, and 4.0 equiv of
(NH4)2S2O8 were used. Cy = cyclohexyl, Phth = phthalimido.
dependence on the steric environment of the benzylic C−H
bond, whereby primary benzylic C−H bonds reacted faster and
in higher yield than secondary benzylic C−H bonds (Table 2a vs
2b). Moreover, tertiary benzylic or tertiary unactivated C−H
bonds showed no trifluoromethylation under our standard
reaction conditions. This surprising result allows practitioners to
reliably and selectively target specific benzylic C−H bonds in
more complicated systems. Moreover, the reaction offers a
monoselective trifluoromethylation, with excess Grushin’s
reagent (2a) providing only minimal ditrifluoromethylation.
Even in cases with multiple, identical benzylic C−H sites, the
B
DOI: 10.1021/jacs.8b08547
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Journal of the American Chemical Society
Communication
monotrifluoromethylationcouldbeachievedinhighyield(Table
2a, 3f−3h). The reaction tolerated a range of functional groups,
including halides (3c, 3o, 3s, and 3cc), pseudohalides (3b),
ketones (3i, 3aa−3cc, and 3ee), esters (3y and 3bb), amides
(3j−3r, 3z, and 3dd), aliphatic nitriles (3x), phthalimides (3v
and 3w), pyridines (3q and 3t), pyrimidines (3u) and silanes
(3e). Moreover,substrates1couldbeusedasthelimitingreagent
withonly10−15%lossinyield(1.5equiv2a), ifthesubstrateisof
particular value. Interestingly, there were occasions where
seemingly valid substrates (simple primary or secondary benzylic
C−H bonds with similar structural features) failed to undergo
trifluoromethylation (see SI). Consequently, a greater mecha-
nistic understanding was needed to reliably target requisite C−H
bonds.
mechanistic understanding arose through key mechanistic
experiments (Figure 3). The UV light serves multiple roles,
Figure 3. Mechanistic details.
To understand the observed C−H selectivity, we probed the
underlying mechanism for trifluoromethylation of primary,
secondary, and tertiary benzylic C−H bonds (Figure 2).
facilitating persulfate cleavage and homolysis of 2a to form the
active Cu(II) species (4) and CF3 radical (Figure 3).20 While
both sulfate radical anionandsilyl radicalcouldform the benzylic
radical (1-rad), H-atom abstraction with sulfate is −12.9 kcal/
mol more favorable thermodynamically than with silyl radical
(see SI). We were intrigued by the production of significant
quantities of fluoroform in the reaction. Examination of
deuterated toluene (d8−1a), silane, and water revealed
CDCF3 forms from the reaction of CF3 radical with silane (see
SI). Theseexperimentsexplaintheunderlyingmechanismforthe
ability of silane to suppress aromatic trifluoromethylation
(Figure 1c), through the quenching of CF3 radical (see SI).
Subsequent steps remain favorable whether the Cu(II) species is
unligated, complexed with bpy, or the aqua complex 5 (see SI).
SincetheCu(II)formsinacidicwater, aquacomplex5represents
the most relevant intermediate along the reaction coordinate.
Since 1-rad recombination with the Cu(CF3)2 (4) is only ∼4
kcal/mol, weruledouttheouterspheremechanism(i.e., where1-
radabstractsaCF3 directly),whichwouldrequirea>61kcal/mol
transition state (see SI). Finally, the reductive elimination
continues through a low 10.5−21.8 kcal/mol barrier (depending
on ligationstate, see SI)toformdesiredproduct 3and unreactive
6 (cf. 2c in Table 1).
The primary kinetic isotope effect (KIE) of kH/kD = 2.8
observed for the intermolecular, same-flask competition of
toluene (1a) and toluene-d8 (d8-1a) suggests that the C−H
bond-cleavage step or a prior step is rate determining (see SI).26
In combination with the kH/kD = 4.2 for the intramolecular KIE
ofmono-CD3 p-xylene(d3−1f), thehomolysisofpersulfateat23
°C under 365 nm light offers the most likely rate-determining
step for the overall reaction. While similar to radical
halogenation,27 the facility with which the benzylic radical is
quenched with trifluoromethylcopper reagent 4 is remarkable.
The clear advantage of this reaction is the ability to predictably
incorporate the trifluoromethyl group at benzylic sites of
elaborated molecules. To test this methodology, we subjected
several biologically relevant small molecules trifluoromethyla-
tion (Scheme 1). Trifluoromethylation of protected 4-methyl-
phenylglycine, meclizine, or celecoxib provided novel, undis-
closed CF3 analogs in all cases. Clearly, the method should find
immediate use for the facile trifluoromethylation of important
molecules.
Figure 2. Computed energy profile of C−H selectivity. Bipyridine-
ligated Cu illustrated here possessed the highest energy barriers relative
to water- or unligated Cu.
Experimentally, we observed that tertiary benzylic substrates
react to produce benzylic hydroxylation and styrene (see SI),
providing evidence for the formation of a tertiary benzylic radical
that is slow to recombine with Cu(II). To better understand this
observation, we calculated the relative energies for the reaction
coordinate of primary (1p), secondary (1s), and tertiary (1t)
radicals. While the recombination with bipyCu(CF3)2 (4) is
thermodynamically favorable for primary (1p) and secondary
(1s) by −4.2 and −4.0 kcal/mol, respectively, the lowest energy
cumenyl-copper(III) species (5t) was +5.6 kcal/mol less stable
than 1t. This thermodynamically uphill radical Cu−C recombi-
nation is surprising, but reflects the unfavorable steric hindrance
in 5t. Moreover, the rate-determining reductive elimination is
definitively higher for tertiary 5t-TS but not so unfavorable as to
subvert the overall reaction at 23 °C. Consequently, the
energetically uphill recombination of the tertiary radicals with
Cu(II) (4) allows unfavorable side reactions (e.g., oxidation/
elimination to form styrene) before productive reductive
elimination can occur.
In summary, we developed a mild method for the
trifluoromethylation of unhindered benzylic C−H bonds. The
method tolerates a wide range of functional groups and basic
heterocycles and can be used in the late-stage trifluoromethy-
lation of bioactive molecules. Moreover, the reaction proceeds in
While we constructed this reaction through analogy to the
Wohl−Ziegler reaction, a detailed picture for our current
C
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Journal of the American Chemical Society
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b08547.
Experimental details and spectroscopic data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*sicook@indiana.edu
ORCID
Deyaa I. AbuSalim: 0000-0003-0813-0486
Silas P. Cook: 0000-0002-3363-4259
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge funds from Indiana University in partial
support of this work. We also gratefully acknowledge the NSF
CAREER Award (CHE-1254783), NIH (GM121668) and the
NSF MRI CHE-1726633. Eli Lilly & Co. and Amgen supported
thisworkthroughtheLillyGranteeAwardandtheAmgenYoung
Investigator Award.
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