Fundamental studies and development of nickel-catalyzed trifluoromethylthiolation of aryl chlorides: Active catalytic species and key roles of ligand and traceless MeCN additive revealed

Article abstract of DOI:10.1021/jacs.5b00538

A catalytic protocol to convert aryl and heteroaryl chlorides to the corresponding trifluoromethyl sulfides is reported herein. It relies on a relatively inexpensive Ni(cod)₂/dppf (cod = 1,5-cyclooctadiene; dppf = 1,1′-bis(diphenylphosphino)ferrocene) catalyst system and the readily accessible coupling reagent (Me₄N)SCF₃. Our computational and experimental mechanistic data are consistent with a Ni⁽⁰⁾/Ni^(II) cycle and inconsistent with Ni^(I) as the reactive species. The relevant intermediates were prepared, characterized by X-ray crystallography, and tested for their catalytic competence. This revealed that a monomeric tricoordinate Ni^(I) complex is favored for dppf and Cl whose role was unambiguously assigned as being an off-cycle catalyst deactivation product. Only bidentate ligands with wide bite angles (e.g., dppf) are effective. These bulky ligands render the catalyst resting state as [(P-P)Ni(cod)]. The latter is more reactive than Ni(P-P)₂, which was found to be the resting state for ligands with smaller bite angles and suffers from an initial high-energy dissociation of one ligand prior to oxidative addition, rendering the system unreactive. The key to effective catalysis is hence the presence of a labile auxiliary ligand in the catalyst resting state. For more challenging substrates, high conversions were achieved via the employment of MeCN as a traceless additive. Mechanistic data suggest that its beneficial role lies in decreasing the energetic span, therefore accelerating product formation. Finally, the methodology has been applied to synthetic targets of pharmaceutical relevance.

Full text of DOI:10.1021/jacs.5b00538

Article
pubs.acs.org/JACS
Fundamental Studies and Development of Nickel-Catalyzed
Trifluoromethylthiolation of Aryl Chlorides: Active Catalytic Species
and Key Roles of Ligand and Traceless MeCN Additive Revealed
Guoyin Yin, Indrek Kalvet, Ulli Englert, and Franziska Schoenebeck*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A catalytic protocol to convert aryl and
heteroaryl chlorides to the corresponding trifluoromethyl
sulfides is reported herein. It relies on a relatively inexpensive
Ni(cod)2/dppf (cod = 1,5-cyclooctadiene; dppf = 1,1′-
bis(diphenylphosphino)ferrocene) catalyst system and the
readily accessible coupling reagent (Me4N)SCF3. Our
computational and experimental mechanistic data are con-
sistent with a Ni(0)/Ni(II) cycle and inconsistent with Ni(I) as
the reactive species. The relevant intermediates were prepared,
characterized by X-ray crystallography, and tested for their
catalytic competence. This revealed that a monomeric
tricoordinate Ni(I) complex is favored for dppf and Cl whose role was unambiguously assigned as being an off-cycle catalyst
deactivation product. Only bidentate ligands with wide bite angles (e.g., dppf) are effective. These bulky ligands render the
catalyst resting state as [(P−P)Ni(cod)]. The latter is more reactive than Ni(P−P)2, which was found to be the resting state for
ligands with smaller bite angles and suffers from an initial high-energy dissociation of one ligand prior to oxidative addition,
rendering the system unreactive. The key to effective catalysis is hence the presence of a labile auxiliary ligand in the catalyst
resting state. For more challenging substrates, high conversions were achieved via the employment of MeCN as a traceless
additive. Mechanistic data suggest that its beneficial role lies in decreasing the energetic span, therefore accelerating product
formation. Finally, the methodology has been applied to synthetic targets of pharmaceutical relevance.
However, for nickel there is little understanding of precise
ligand effects on the elemental catalytic steps. Moreover, an
additional crucial challenge is nickel’s propensity to exist in and
interchange readily between various oxidation states.2d,6 In this
context, several reports have implicated Ni(I) species as
intermediates,7,8 either via Ni(I)/Ni(III) catalysis or by in situ
generation through comproportionation or electron transfer
events. Another possibility is the side reaction of key catalytic
Ni(II) intermediates to give Ni(I) with concomitant formation of
biaryl (see Figure 1).2d,9
Modulation of the ligand sphere at Ni centers therefore not
only may impact the reactivities and selectivities of the
elementary catalytic steps but also likely influences the favored
oxidation state. For the development of general and efficient
Ni-catalyzed processes, there is hence a greater need to
carefully balance these competing effects. Gaining fundamental
understanding of these phenomena is therefore of utmost
importance.
INTRODUCTION
■
Catalysis is an integral and indispensable discipline in modern
academic and industrial chemistry. Specifically, metal-based
processes have enabled numerous processes and revolutionized
the synthetic repertoire.1 Nowadays there is increasing
academic and industrial interest in more sustainable alternatives
to those transformations typically achieved by precious metals.
In this context, nickel is an attractive alternative to palladium,
not only because of its greater abundance and lower cost but
also its ability to react with bonds that generally would be inert
toward palladium or copper.2,3 However, despite promising
reactivity precedent, the field of Ni catalysis has generally
progressed more slowly over the past decades compared to Pd-
based methodology.4 This has been ascribed to the challenges
in steering Ni-based processes toward desired reactivities, as
summarized by Colacot and Snieckus:4
“...Thus, nickel remained the brutish older brother to palladium,
able to affect the coupling of a wider range of halide partners for
which palladium failed. However, repeatedly over the coming years,
palladium would usurp nickel because its reactivity could be
modulated through the use of ligands whilst still retaining its
improved selectivity...”
Specific Case Study. A representative case for the
divergent developments of Ni- and Pd-based catalysis is the
metal-catalyzed C−S bond formation of aryl chlorides. While
there are numerous precedents for Pd-based chemistry,10 the
Undoubtedly, modulation of the steric and electronic
properties of electron-donating ligands, particularly phosphines,
has had a tremendous impact in organometallic catalysis.5
Received: January 16, 2015
© XXXX American Chemical Society
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RESULTS AND DISCUSSION
■
While no protocol exists for coupling of aryl chlorides to give
ArSCF3, Zhang and Vicic17b described an elegant Ni(cod)2/
bipyridine-catalyzed coupling protocol of aryl iodides and
bromides to give ArSCF3. This method proved to be ineffective
for the coupling of ArCl however. We hypothesized that Ni(0)
catalysts in conjunction with N ligands (e.g., bipyridine) may be
unreactive with aryl chlorides because these systems frequently
react via electron transfer processes involving radical inter-
mediates.7c−e,8a,f By contrast, we envisaged that the use of
phosphine ligands might create a much more reactive catalysis
system that may proceed via Ni(0)/Ni(II) catalysis (see Figure 1
and later discussion).
Identification of an Effective Catalytic System. We
Figure 1. Possible Ni(0)/Ni(II) or Ni(I)/Ni(III) catalytic cycles and key
challenges for the development of Ni catalysis.
initially subjected 1-chloro-4-methoxybenzene 1 and the readily
20
accessible reagent (Me4N)SCF3 to various test reactions, in
which we explored the effect of the ligand, precatalyst, solvent,
and temperature. To our delight, conversion of ArCl 1 to
ArSCF3 was seen when Ni(cod)2 was employed as the
precatalyst in conjunction with a wide-bite-angle ligand
(xantphos, dppf, or binap) in toluene.21 In stark contrast,
ligands with smaller bite angles (e.g., dppe) or monodentate
ligands were completely ineffective (see Figure 3). Additional
information can be found in Table S1 in the Supporting
Information.
coupling of aryl chlorides to give the corresponding aryl sulfides
via Ni catalysis is essentially undeveloped.11 This might be due
to the ability of Ni catalysts to cleave aromatic C−S bonds,12
which highlights a possible additional challenge for reaction
development.
As part of our ongoing mechanistic and methodological
program in organometallic chemistry13 and also with respect to
the generation of fluorine-containing compounds,14 we chose
the challenge of C−SCF3 bond formation as a platform for
fundamental studies of the effects of ligands and additives on
the key catalytic steps in Ni catalysis. The overall aim was to
develop the first trifluoromethylthiolation of aryl chlorides
(Figure 2).
Figure 2. Chosen challenge for fundamental studies of Ni catalysis.
Because of the high lipophilicity of the SCF3 moiety, which
influences membrane permeability and bioavailability, aryl
trifluoromethyl sulfides (ArSCF3) are important compounds
in pharmaceutical and agrochemical research,15 and there is
considerable interest in the development of straightforward and
general methods to introduce SCF3 groups into molecules.16
The direct cross-coupling of abundant and stable aryl halide
precursors would be highly attractive in this context. However,
the current repertoire of metal-catalyzed coupling method-
ologies is limited to coupling of aryl bromides and iodides,
which has been accomplished via Pd, Ni, and Cu catalysis.17 To
date there is no general and catalytic method available to
convert aryl chlorides to ArSCF3.18,19 However, in view of the
lower expense and greater availability of aryl chlorides
compared with aryl bromides and iodides, the coupling of
C−Cl would be inherently more attractive.
We herein describe the development of a mild and efficient
protocol for the conversion of aryl and heteroaryl chlorides to
the corresponding trifluoromethyl sulfides catalyzed by Ni-
(cod)2/dppf (cod = 1,5-cyclooctadiene; dppf = 1,1′-bis-
(diphenylphosphino)ferrocene). Mechanistic (experimental
and computational) studies of the favored reaction pathways,
insights into the crucial roles of the ligand and additive, and
applications to drug molecules are presented.
Figure 3. Effect of the ligand on the Ni-catalyzed SCF3 coupling of
ArCl. Yields of ArSCF3 are given. See Table S1 in the Supporting
Information for additional data.
While no detailed mechanistic information on Ni-catalyzed
C−S bond formations is available, the ineffectiveness of
monodentate ligands parallels observations previously made
in Pd-based C−S coupling reactions. It has been assumed that
monodentate ligands may be displaced from the Pd center by
nucleophilic RS− anions.10d While this hypothesis would in
principle account for the different conversions with mono- and
bidentate ligands, it does not account for the fact that only
wide-bite-angle ligands are effective under our Ni-catalyzed
coupling conditions. Wide-bite-angle ligands are generally more
labile and susceptible to displacement by nucleophiles than
ligands with smaller bite angles.22 To gain more insight, we
embarked on detailed mechanistic studies.
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Elucidation of the Favored Reaction Pathway: Ni(0) or
Ni(I) and Coordination Sphere of the Active Ni Species?
We subsequently undertook comparative mechanistic studies
with the ligands dppf (which had given high conversion in our
initial assessments in Figure 3) and 1,2-bis-
(diphenylphosphino)ethane (dppe) as a small-bite-angle
representative that had not given conversion (see Figure 3).
When we added dppf to Ni(cod)2 in a 1:1 metal to ligand ratio
in toluene, we observed the exclusive formation of [(dppf)Ni-
converted to Ni(I) with concomitant formation of biaryl. For Ar
= 2-MePh, the stable Ni(II) complex 3 was reported by
Buchwald and co-workers.23 By contrast, for Ar = Ph, upon
oxidative addition of Ni(cod)2/dppf to PhCl we isolated a Ni(I)
monomer and Ph−Ph. The novel complex [(dppf)Ni(I)(Cl)]
(4) was fully characterized by X-ray crystallography (Figure 4).
While three-coordinate transition-metal complexes are gen-
erally considered to be rare,24b there have been previous
encounters of monomeric Ni(I) complexes.24,25
1
(cod)] as judged by H and 31P NMR analyses and X-ray
We subsequently tested for the ability of Ni(II) complex 3 to
(i) produce ArSCF3 under stoichiometric conditions and (ii)
act as a precatalyst in the Ni-catalyzed trifluoromethylthiolation
of aryl chlorides. Scheme 1 presents the results. Ni(II) complex 3
crystallography (see Figure 4). By contrast, for dppe the
Scheme 1. Test of the Catalytic Competence of Ni(I) versus
26
Ni(II)
indeed proved to be both a competent intermediate and
precatalyst, supporting that Ni(0)/Ni(II) catalysis is operative. In
contrast, the Ni(I) complex 4 proved catalytically inactive (see
Scheme 1 bottom).27 These results strongly indicate that the
SCF3 coupling proceeds via Ni(0)/Ni(II) catalysis.
Figure 4. Different Ni(0) species formed with dppf and dppe and X-ray
structures of [(dppf)Ni(I)(Cl)] (4) and [(dppf)Ni(0)(cod)] .
analogous experiment gave rise to the cod-free complex
[(dppe)2Ni(0)]. Examination of the actual Ni(cod)2/dppf-
catalyzed SCF3 coupling of 1 (as shown in Figure 3) revealed
that [(dppf)Ni(cod)] was also the resting state of the catalytic
reaction. These observations highlight the different propensities
of the ligands to bind to Ni(0) and to displace the auxiliary cod
ligand. Because of the greater steric demand of dppf, the
favored state involves a single dppf ligand in the Ni sphere with
additional stabilization by the relatively small cod ligand. For
the smaller dppe, two ligands can readily be accommodated in
the coordination sphere. This has a significant impact on the
activity of the catalyst, as we will show later.
Having elucidated the favored resting state of the Ni(cod)2/
dppf catalytic system, we subsequently explored the likely
mechanism by which the catalysis proceeds. While a pathway
involving the Ni(0) and Ni(II) oxidation states constitutes one
mechanistic possibility, several previous reports have proposed
Ni(I) as an active catalytic species (Figure 1),7,8 most recently
by Martin and co-workers for the cleavage of aromatic C−O
bonds.7h To investigate this, we embarked on the preparation
of the key [(dppf)Ni(II)(Cl)(Ar)] and Ni(I) complexes to test
for their catalytic competence. The choice of “Ar” significantly
impacts the stability of the Ni(II) complex, which may be
Origin of the Ligand Effect: A Computational Study.
To understand why wide-bite-angle ligands are privileged in the
Ni-catalyzed trifluoromethylthiolation of aryl chlorides, we
undertook computational studies28 of the oxidative addition
and reductive elimination steps for the Ni(0)/Ni(II) coupling
cycle.29 We compared the reaction profiles for the wide-bite-
angle (=effective) ligand dppf versus the smaller-bite-angle
(=ineffective) ligand dppe. Our calculations employed the
B3LYP functional and the mixed basis set 6-31G(d) and
LANL2DZ (for Ni, Fe) for geometry optimizations. Energies
were obtained via single-point CPCM calculations (with
toluene as solvent) at the M06L/6-311++G(d,p) (with
LANL2DZ for Ni, Fe) level.30 The results are given in Figures
5 and 6. For the effective Ni(cod)2/dppf catalysis system, we
calculated the oxidative addition of [(dppf)Ni(0)(cod)] to
chlorobenzene with concomitant loss of a cod ligand (see
Figure 5). The activation free energy barrier (ΔG⧧) for this step
was calculated to be 24.4 kcal/mol, and this process was
predicted to be roughly thermoneutral overall. The reductive
elimination of PhSCF3 from [(dppf)Ni(II)(SCF3)(Ph)] was
calculated to be slightly more facile, proceeding with ΔG⧧ =
16.4 kcal/mol. The recoordination of the auxiliary cod ligand is
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Figure 5. Free energy barriers for the oxidative addition and reductive elimination of the SCF3 coupling of PhCl employing the (effective) dppf
ligand, calculated at the CPCM (toluene) M06L/6-311++G(d,p)//B3LYP/6-31G(d) [with LANL2DZ for Ni, Fe] level.
Figure 6. Free energy barriers for the oxidative addition and reductive elimination of the SCF3 coupling of PhCl employing the (ineffective) dppe
ligand, calculated at the CPCM (toluene) M06L/6-311++G(d,p)//B3LYP/6-31G(d) [with LANL2DZ for Ni] level.
crucial to stabilize the otherwise highly reactive [(dppf)Ni(0)]
species.
Exploration of Scope. Encouraged by these mechanistic
insights, we continued our developments with dppf as the
ligand and explored the scope of the Ni(cod)2/dppf catalytic
system.
Employing mild reaction conditions (45 °C) in toluene
allowed the coupling of electron-rich and electron-deficient aryl
chlorides with (Me4N)SCF3, yielding the corresponding
ArSCF3 compounds in good to excellent yields (see Table 1).
The bicyclic aromatic substrate 1-chloronaphthalene (entry 13)
also gave its trifluoromethylthiolated counterpart in high yield.
Dichloroarenes (entries 14 and 15) gave predominantly the
bis(SCF3) products under these conditions in mixtures with the
monofunctionalized arenes.
For heterocyclic arenes, which play an important role in
medicinal and agrochemical research, trifluoromethylthiolation
was successfully accomplished for a number of examples (see
Table 2). Quinoxaline, thiophene, and acridine derivatives
afforded the corresponding trifluoromethyl sulfides in good to
excellent yields. Notably, benzyl- and tert-butoxycarbonyl
(Boc)-protected indoles were well-tolerated under these
conditions.
While the protocol allowed the successful SCF3 coupling of a
number of aryl chlorides, some substrates gave rise to higher
conversions than others under these conditions. Intrigued by
these observations and with a view to increasing the substrate
scope, we subsequently undertook additional mechanistic
studies.
Performing the analogous calculations for [(dppe)2Ni(0)]
gave significantly larger activation free energy barriers for
oxidative addition to PhCl and reductive elimination of PhSCF3
(see Figure 6). These findings are in line with the experimental
observations. No conversion to ArSCF3 was seen under
Ni(cod)2/dppe conditions. The larger barrier in the oxidative
addition step (ΔG⧧ = 43.4 kcal/mol) is primarily due to the
energy penalty associated with the dissociation of one dppe
ligand from [(dppe)2Ni(0)] (ΔGrxn = 33.1 kcal/mol). In the
case of dppf, a weaker-binding cod ligand needs to be displaced
from [(dppf)Ni(0)(cod)] to enable the subsequent oxidative
addition.
Although phosphine ligands with smaller bite angles
generally render the metal center more nucleophilic (and
hence more reactive toward oxidative addition), the large ligand
dissociation energy associated with dppe outweighs this. On the
other hand, the observation of a ca. 7 kcal/mol higher barrier
for reductive elimination in the case of dppe is in accord with
commonly accepted bite-angle trends, i.e., wide-bite-angle
ligands generally lead to more facile reductive elimination.
These findings highlight the importance of the presence of a
weakly binding auxiliary ligand (e.g., cod) in the catalyst. They
further explain several previous reactivity observations of
L2Ni(0) complexes (with L = bidentate ligand) being ineffective
catalysts.31
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Table 1. Scope of the Ni(0)-Catalyzed SCF3 Coupling of
ArCl
Table 2. Scope of the Ni(0)-Catalyzed
Trifluoromethylthiolation of Heteroaryl Chlorides
a
a
a
Conditions: Ni(cod)2 (11.1 mg, 0.04 mmol), dppf (22.2 mg, 0.04
mmol), ArCl (0.4 mmol), (Me4N)SCF3 (0.6 mmol, 102 mg), toluene
b
(2 mL). Isolated yields are shown. The yield was determined by 19F
c
NMR analysis against PhCF3. The datum in parentheses corresponds
to the yield of the reaction with 15 mol % Ni(cod)2 and 15 mol %
dppf.
a
Conditions: Ni(cod)2 (11.1 mg, 0.04 mmol), dppf (22.2 mg, 0.04
mmol), ArCl (0.4 mmol), (Me4N)SCF3 (0.6 mmol, 102 mg), toluene
b
(2 mL). Isolated yields are shown. The yield was determined by 19F
c
NMR analysis against PhCF3. The datum in parentheses corresponds
to the yield of the reaction with 15 mol % Ni(cod)2 and 15 mol %
d
dppf. A 7% yield of the monosubstituted product was also observed
e
by GC−MS. A 20% yield of the monosubstituted product was also
f
obtained. Ni/dppf (0.08 mmol) and (Me4N)SCF3 (1.2 mmol) were
used.
Increase in Substrate Scope and Application to
Synthetic Targets of Pharmaceutical Relevance: Benefi-
cial Effect of MeCN Additive. Our above computational and
resting-state analyses highlighted that ligand binding was a
critical reactivity-controlling factor. As the mixture of Ni(cod)2
and dppf (1:1 ratio) produced [(dppf)Ni(cod)] along with 1
equiv of free cod ligand (see Figure 4), we were concerned that
the additional equivalent of cod may impede the SCF3-coupling
reactivity. To gain deeper insight, we monitored the Ni-
catalyzed trifluoromethylthiolation of p-methoxyaryl chloride 1
over time (see Figure 7), comparing the effectiveness of
[(dppf)Ni(cod)] (yellow) with Ni(cod)2/dppf (red). Indeed,
the excess equivalent of cod that is present under conditions in
which [(dppf)Ni(cod)] is generated in situ significantly affects
the reaction rate and overall efficiency. While this suggests that
the isolated [(dppf)Ni(cod)] catalyst should be used to achieve
high conversions of more challenging aryl chlorides, a protocol
in which the catalyst is generated in situ from commercially
available components would still pose advantages in terms of
operational simplicity. Thus, with the objective to potentially
Figure 7. Time courses for the conversion of 1 to 2 using (i) the
standard Ni(cod)2/(dppf) system (red), which forms [(dppf)-
Ni(0)(cod)] + cod in situ; (ii) [(dppf)Ni(0)(cod)] (yellow); and (iii)
Ni(cod)2/(dppf) in the presence of MeCN (1.0 equiv relative to 1)
(green).
generate a more reactive catalyst system in situ, we
subsequently studied the effect of additives. The key require-
ment for the additive is that it should bind less strongly to Ni(0)
than cod, therefore furnishing a more reactive catalyst.
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It has previously been established that Ni(0) can bind nitrile
compounds in an η2 fashion to the cyano group.3e,32 Such Ni(0)
complexes in turn were also shown to be robust and efficient
(pre)catalysts.9b,32b However, in terms of synthetic applicability
of the protocol as well as atom economy and minimization of
waste, the stoichiometric addition of an aromatic nitrile is not
very desirable. We therefore explored the effect of acetonitrile,
which could simply be used as a traceless additive (i.e., a
cosolvent). Pleasingly, excellent conversion with substrate 1
(see Figure 7) and an overall higher reaction rate than with the
isolated or in situ-generated [(dppf)Ni(cod)] catalyst were
seen. We subsequently subjected a number of challenging aryl
chloride substrates to Ni(cod)2/dppf catalysis conditions in the
presence of MeCN. Table 3 shows the results. Addition of
Scheme 2. Application of the Ni(cod)2/dppf/MeCN SCF3-
Coupling Protocol to Pharmaceutically Relevant Molecules
Table 3. Effect of MeCN Additive on the Ni(0)-Catalyzed
a
SCF3 Coupling of ArCl
tion protocol. The corresponding SCF3-substituted product
was isolated in a pleasing 71% yield. Moreover, we also
succeeded in the trifluoromethylthiolation of fenofibrate, a drug
against cardiovascular disease, highlighting the scope and
applicability of this methodology in a pharmaceutical context.
Effect of MeCN: Mechanistic Insights Gained with
Computation and Experiment. To gain deeper insight into
the accelerating effect of MeCN, we initially assessed whether
nitrile additives other than MeCN would be similarly active.
Thus, we studied the SCF3 coupling of 1,2-dimethyl-4-
chlorobenzene (5) under Ni(cod)2/dppf catalysis in toluene
and added a variety of nitriles that differed in their steric and/or
electronic properties (see Table 4). While all of the additives
explored had a beneficial effect on the reaction compared with
the additive-free conditions (entry 1), the electron-rich nitriles
led to higher conversions (e.g., compare entries 5, 10, and 12
with entries 7 and 8). It has previously been suggested that the
reactivity enhancement observed in the presence of a nitrile
could potentially be due to binding of the nitrile in the
oxidative addition step.8b While this would be consistent with
the greater effectiveness of the electron-rich (and potentially
more donating) nitriles, this theory appears to be inconsistent
with the lack of steric influence in the activity of the nitrile
additives (see entries 9 and 10). In line with this, all of our
attempts to computationally locate transition states that had
both dppf and MeCN bound led to dissociation of MeCN in all
of the cases examined.
a
Conditions: Ni(cod)2 (11.1 mg, 0.04 mmol), dppf (22.2 mg, 0.04
mmol), aryl chloride (0.4 mmol), (Me4N)SCF3 (0.6 mmol, 102 mg),
toluene (2 mL). Isolated yields are shown. CH3CN (20 μL) was
b
Thus, the effect of nitrile additives, particularly when
employed in excess, may lie in the displacement of cod ligands
from a Ni(0) precursor and generation of a more reactive nitrile-
bound (pre)catalyst.33 This assumption would be consistent
with the observation that the Ni(cod)2/dppf reaction in the
presence of nitrile was no longer impaired by the excess
equivalent of cod (compare the red and green lines in Figure
7).34
added.
MeCN proved to be advantageous in a number of cases (entries
1−4), with increases of up to 61% in the observed yield.
Moreover, the trifluoromethylthiolation of heterocyclic and
functionalized aromatic chlorides was achieved in good yields
(entries 5−7), showing compatibility with amide (entry 6) and
amine (entry 7) functional groups.
As a stern test of our newly developed methodology and the
advantageous acetonitrile effect, we also investigated the
trifluoromethylthiolation of a few drug molecules that contain
aromatic C−Cl sites. In this context, we first O-protected the
anti-inflammatory drug indomethacin (Scheme 2) and
subjected the product to our improved trifluoromethylthiola-
To examine this further, we studied the extent of cod
displacement from [(dppf)Ni(0)(cod)] in the presence of
1
MeCN (by 31P and H NMR; see Figure S3 in the Supporting
Information). Addition of 10 equiv of MeCN to 1 equiv of
[(dppf)Ni(0)(cod)] in C6D6 showed an increase in the amount
of free cod ligand by 10% shortly after addition. The fact that
complete displacement of the cod ligand by MeCN was not
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TZVP level of theory. (While this reactivity difference appears
to be substantial, it may likely be overestimated.35)
Table 4. Examination of the Effect of Different Nitrile
Additives on the Conversion of 5 to ArSCF3 6
a
However, the catalytic turnover and hence the reaction
progress depend on both the driving forces (i.e., the reaction
free energies, ΔGrxn) and activation barriers (ΔG⧧) of the
individual catalysis steps. Overall, the free energy difference
between the lowest and highest point of the reaction path
dictates the catalytic efficiency and reaction speed. This energy
difference has been coined as the “energetic span (δG°max)”.36,37
The more reactive nature of [(dppf)Ni(0)(MeCN)] means in
essence that the energy of [Ni(0)] is raised, which overall lowers
the energetic span and hence leads to higher turnover
frequencies (see Figure 8 for a qualitative drawing).
CONCLUSIONS
■
We have developed a mild and efficient Ni-catalyzed protocol
for the functionalization of aryl- and heteroaryl chlorides to give
the corresponding trifluoromethyl sulfides (ArSCF3). Several
electronically varied arenes, including quinoxaline, thiophene,
acridine, and indole derivatives as well as the pharmaceutically
relevant drugs indomethacin and fenofibrate, were converted to
their SCF3 counterparts in high yields. The method constitutes
a significant step forward within the field of catalytic
trifluoromethylthiolations of arenes (and Ni-catalyzed C−SR
bond formation more generally), as it substantially broadens
the current substrate scope while employing a relatively
inexpensive catalyst system. Extensive mechanistic studies
were performed to gain insight into the favored reaction
mechanism and ligand and additive effects. While the catalysis
was found to be consistent with a Ni(0)/Ni(II) cycle, the
corresponding Ni(I) complex proved to be catalytically
incompetent and instead constitutes a product of catalyst
deactivation. The employed phosphine ligand strongly
influences the overall catalytic activity via control of the ligand
sphere in the resting state. The small-bite-angle ligand dppe was
found to form [Ni(0)(dppe)2] as the resting state, while the
effective wide-bite-angle ligand dppf forms [(dppf)Ni(0)(cod)].
Computational studies revealed that the initial ligand
dissociation step to give “Ni(0)L” is the key difference in
catalytic performance. The dissociation of one dppe from
[Ni(0)(dppe)2] is associated with a much greater energy penalty
than the loss of cod from [(dppf)Ni(0)(cod)], rendering the
latter a much more reactive system. Further studies showed that
the addition of MeCN as traceless additive to Ni(0)(cod)2/dppf
leads to increased catalytic activity and hence greater substrate
scope. Computational and experimental data suggest that the
a
Conditions: Ni(cod)2 (11.1 mg, 0.04 mmol), dppf (22.2 mg, 0.04
mmol), ArCl (0.4 mmol), R−CN (0.4 mmol), (Me4N)SCF3 (0.6
mmol, 102 mg), toluene (2 mL). Conversions were determined by
calibrated GC−MS. Yields obtained from isolation are given in
parentheses.
obtained suggests that the MeCN is more weakly coordinating
than cod (as required for efficient catalysis), indicating that
different Ni(0) species may in fact be reversibly equilibrated in
the reaction mixture, i.e. [(dppf)Ni(0)(cod)] with [(dppf)-
Ni(0)(MeCN)]. The weaker coordinating ability of MeCN
implies that MeCN is also more readily dissociated from [Ni(0)]
prior to oxidative addition, rendering the [Ni(0)] catalysis
system more reactive. In line with this, our calculations of the
oxidative addition of [(dppf)Ni(0)(MeCN)] to PhCl predict a 9
kcal/mol lower activation free energy barrier than for
[(dppf)Ni(0)(cod)] at the CPCM (toluene) M06L/def2-
Figure 8. Schematic representation of the energetic span δGm°ax and turnover for the catalysis by (left) [(dppf)Ni(cod] and (right)
[(dppf)Ni(MeCN)].
G
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Journal of the American Chemical Society
Article
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ASSOCIATED CONTENT
■
S
* Supporting Information
Details of experimental procedures, spectroscopic data,
computational information, Cartesian coordinates of calculated
species, and complete ref 28 (as SI ref 4). This material is
available free of charge via the Internet at http://pubs.acs.org.
2013, 135, 1997−2009. (i) Breitenfeld, J.; Wodrich, M. D.; Hu, X.
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AUTHOR INFORMATION
■
T.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2013, 135, 1221−1224.
(e) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
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Corresponding Author
*franziska.schoenebeck@rwth-aachen.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank the MIWF NRW and the RWTH Aachen University
for financial support. The authors gratefully acknowledge the
computing time granted by the JARA-HPC “Vergabegremium”
and provided on the JARA-HPC partition’s part of the RWTH
Bull Cluster in Aachen (Grant JARA0091).
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