Comparative profiling of well-defined copper reagents and precursors for the trifluoromethylation of aryl iodides

Article abstract of DOI:10.3762/bjoc.13.225

A number of copper reagents were compared for their effectiveness in trifluoromethylating 4-iodobiphenyl, 4-iodotoluene, and 2-iodotoluene. Yields over time were plotted in order to refine our understanding of each reagent performance, identify any bottlenecks, and provide more insight into the rates of the reactions. Interestingly, differences in reactivity were observed when a welldefined [LCuCF₃] complex was employed directly or generated in situ from precursors by published reports. Relative reactivities were also found to highly dependent on the nature of the iodoarenes.

Full text of DOI:10.3762/bjoc.13.225

Comparative profiling of well-defined copper reagents and
precursors for the trifluoromethylation of aryl iodides
Peter T. Kaplan, Jessica A. Lloyd, Mason T. Chin and David A. Vicic*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2297–2303.
Department of Chemistry, Lehigh University, 6 E. Packer Ave.,
Bethlehem, PA 18015, USA
doi:10.3762/bjoc.13.225
Received: 28 June 2017
Accepted: 07 October 2017
Published: 30 October 2017
Email:
David A. Vicic* - vicic@lehigh.edu
* Corresponding author
This article is part of the Thematic Series "Organo-fluorine chemistry IV".
Guest Editor: D. O'Hagan
§ Phone: 1-610-758-3466, Fax: 1-610-758-6536
Keywords:
benchmarking; copper; fluorine; fluoroalkylation; trifluoromethylation
© 2017 Kaplan et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A number of copper reagents were compared for their effectiveness in trifluoromethylating 4-iodobiphenyl, 4-iodotoluene, and
2-iodotoluene. Yields over time were plotted in order to refine our understanding of each reagent performance, identify any bottle-
necks, and provide more insight into the rates of the reactions. Interestingly, differences in reactivity were observed when a well-
defined [LCuCF3] complex was employed directly or generated in situ from precursors by published reports. Relative reactivities
were also found to highly dependent on the nature of the iodoarenes.
Introduction
Selectively fluorinated molecules that bear the trifluoromethyl aryl iodides and have a low substrate scope, low turn-over
group have great importance in the life sciences and materials values, and/or involve decarboxylation reactions at high temper-
fields as well as discovery chemistry in general [1-3]. Conse- atures. Stoichiometric trifluoromethylating agents are therefore
quently, transition-metal-catalyzed methods for preparing aro- more commonly used in benchtop trifluoromethylation chem-
matic trifluoromethyl compounds from readily available aryl istry. Ancillary ligands (L) are known to play a large role in the
halides are an area that has seen rapid growth in the past ten reactivity of such [LnCu–CF3] reagents, and recent work has
years. Copper is one of the most successfully used metals for focused on developing new ligands that not only allow for
mediating the trifluoromethylation of aryl halides, and the better control of reactivity but also provide stability to facilitate
active form of the reagents is typically a copper(I) complex meaningful comparative studies, such as structural and electro-
bearing a trifluoromethyl ligand, i.e., [LnCu–CF3]. Sporadic ex- chemical ones [2]. N-Heterocyclic carbene (NHC) complexes of
amples of trifluoromethylation ‘catalysis’ using copper have copper such as A1 (Scheme 1) were the first well-defined and
been observed [4-9], but these reactions typically only work for structurally characterized copper–CF3 complexes that display
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Scheme 1: Reagents and precursors used for trifluoromethylation reactions.
activity for the trifluoromethylation of aryl halides [10,11]. plex was employed directly or generated in situ by published
[(SIMes)CuCF3] (1, SIMes = 1,3-bis(2,4,6-trimethylphenyl)- reports. If so, it will be informative to know the extent of differ-
4,5-dihydroimidazol-2-ylidene), which is in equilibrium with ences in reagent performance over time.
[(SIMes)2Cu][Cu(CF3)2] (2), can either be used directly or pre-
pared in situ through the reaction of [(SIMes)Cu(O-t-Bu)] (3)
with Me3SiCF3 (Scheme 2) [10]. Phenanthroline complexes of
copper B1 were reported shortly after the NHC counterparts
[5,12] and have reached much success in chemical synthesis
due to the ease of preparation and the low cost of the phenan-
throline ancillary ligand. [(phen)CuCF3] can now be purchased
commercially, or prepared in situ by a variety of methods in-
cluding the reaction of [Cu(O-t-Bu)]4 with Me3SiCF3 and phen
(B2, Scheme 1) [12] or by reaction of [(MeO)3BCF3] with CuI
and phen (B3, Scheme 1) [8]. The compound [(PPh3)3CuCF3]
has been for a long time [13], however, its trifluoromethylating
Scheme 2: Preparation of [(SIMes)2Cu][Cu(CF3)2].
ability and structure determination was not reported until 2011.
Trifluoromethylations with [(PPh3)3CuCF3] are only efficient
Results and Discussion
when the reactions are performed in neat aryl iodode [14]. Less
Because the phenanthroline-based system described as B1
(Scheme 1) is the most widely used reagent for trifluoromethyl-
ations, we modeled our “standard” comparative conditions simi-
lar to those reported by Hartwig in 2011 [12]. These conditions
involve reacting 4-iodo-1,1’-biphenyl with a [Cu–CF3] source
at 50 °C in DMF (Scheme 3). Somewhat more diluted reaction
conditions relative to the published procedure were used to
ensure homogeneity for all the different complexes described in
Scheme 1. Conversions to 4-(trifluoromethyl)-1,1’-biphenyl
were then monitored by gas chromatography relative to a cali-
brated internal standard. Experiments were performed in tripli-
side-products and higher yields are observed for trifluoro-
methylations with [(PPh3)3CuCF3] when dtbpy (dtbpy = 4,4′-di-
tert-butylbipyridine) is added to reaction mixtures (C1) to
presumably generate a dtbpy complex of CuCF3 [14]. Finally,
conditions that generate “ligandless” [CuCF3] (D1, for exam-
ple) are also amenable for the trifluoromethylation of aryl
iodides [15], but it is unclear how the reactivity profile of the
ligandless complex compares to systems A–C described in
Scheme 1. An important issue is that only single time point
yields have been reported for systems B–D, and the significant-
ly different reaction conditions employed for each system have
made it impossible to truly compare reagent performance based
on the available literature data. For this reason, we sought to run
trifluoromethylation reactions with systems A–D under both
identical and the reported optimal reaction conditions in order
to track how yields change over time for each reagent for com-
parative studies. We also sought to explore whether there were
differences in reactivity when a well-defined [LCuCF3] com-
Scheme 3: General protocol for reactions described in Figure 1.
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cate, and the average yields over time are plotted graphically in optimized solvent conditions to explore the effect of the solvent
Figure 1.
on the lower performing systems in Figure 1 [10,14]. The
results are shown in Figure 2 and highlight the fact that the sol-
vent plays a key role in reagent performance, even for reason-
ably comparable LCuCF3 complexes. The system C1 shows
high yields at early reaction times, but then suffers a severe
leveling out effect after approximately ten hours. Based on the
data, it is tempting to suggest that system C1 might be worthy
of a thorough mechanistic analysis, as if one can fully under-
stand why the reagent suffers a rapid deactivation then a perfor-
mance improvement may be possible. System A1, on the other
hand, displays sluggish reactivity at early reaction times, but
steadily produces 4-(trifluoromethyl)-1,1’-biphenyl in
yields that are slightly higher than C1 after 30 hours.
[(SIMes)Cu(CF3)], generated in situ from [(SIMes)Cu(O-t-Bu)]
and TMSCF3 (A2) afforded the highest yields at extended reac-
tion times. It is interesting to note here, for the trifluoromethyla-
tion of 4-iodobiphenyl with SIMes copper complexes under the
reported literature conditions, that the better performer was not
the isolated and well-defined LCu–CF3 complex, but instead the
LCu–CF3 complex generated in situ from the copper tert-
butoxide precursor. This trend in reactivity mirrors that which
was observed for the phen-based systems B1 and B2 in
Figure 1. The reported optimized conditions for A1 and A2,
however, involve using copper as the limiting agent with a five-
Figure 1: Yields of 4-(trifluoromethyl)-1,1’-biphenyl over time for the
systems described in Scheme 1. These runs represent “standard”
conditions described in Scheme 3 and the Experimental section. Yields
were monitored by gas chromatography relative to a calibrated internal
standard.
As shown in Figure 1, conditions where the [(phen)CuCF3] was fold excess of aryl halide [4]. Therefore, while yields of the
generated in situ (B2) provided the best yields of 4-(trifluoro- SIMes-based systems can provide good yields of product, the
methyl)-1,1’-biphenyl after 24 hours, with yields and conver- phen-based systems remain far more practical. Ligandless
sion of aryl iodide (data not shown) both near 65%. When com-
mercially purchased [(phen)CuCF3] (B1) was used, yields up to
the five hour mark were comparable to those of B2, but were
≈15% lower after the full 24 hours. Yields of product were
50%, with consumption of biphenyl iodide at 62%. Importantly,
traditional single time point yields would not be able to high-
light the loss of activity at the longer reaction times. The related
phen system B3, which uses K[(MeO)3BCF3] as the trifluoro-
methyl source, performed significantly lower than B1 and B2
and gave a final overall yield of 31%. Consumption of the
biphenyl iodide was found to be 51%. The data is intriguing
because systems B1, B2, and B3 are all expected to involve
[(phen)CuCF3] as the active trifluoromethylating agent, yet
there are clear differences in reactivities for only slight changes
in chemical components in the reaction mixtures. For the same
conditions in DMF at 50 °C, A1, C1, and D1 all performed
poorly relative to [(phen)CuCF3] and gave product yields less
than 10% (Figure 1).
Figure 2: Yields of 4-(trifluoromethyl)-1,1’-biphenyl over time for the
systems described in Scheme 1. Conditions for C1: [(PPh3)3Cu(CF3)]
+ dtbpy: toluene, 80 °C. Conditions for A1: [(SIMes)Cu(CF3)] and A2
([(SIMes)Cu(O-t-Bu)] + TMSCF3: DMI/benzene (1.5:7.5), 50 °C.
DMI = 1,3-dimethyl-2-imidazolidinone. Conditions for B2:
We then compared B2, the highest performing [(phen)CuCF3]
system in DMF, to the performance of isolated A1 and in
[(Cu(O-t-Bu)]4 + phen +TMSCF3: DMF, 50 °C. Yields were monitored
by gas chromatography relative to a calibrated internal standard.
situ generated (A2) [(SIMes)CuCF3] as well as to the
[(PPh3)3CuCF3 + dtbpy] combination (C1) under their reported
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CuCF3 was also tested under the reported optimized reaction noted a detection limit of approximately 2% with our NMR
conditions [15], but in our hands the protocol afforded CHCF3 spectrometer, so we believe this induction period with the elec-
as the major fluorine-containing product.
tron-rich substrates is real and not stemming from the different
analytical method used for determining yields for Figure 2 and
Because our group has developed the NHC-based copper Figure 3. Why an induction period is observed for the
reagents for trifluoromethylation reactions [10,11], we were iodotoluenes but not for the iodobiphenyl substrate is still not
interested in comparing the effects of electronics and sterics of well-understood and is currently under investigation.
the aryl halides using the NHC-based systems A1 and A2 with
the phen system B2. First, in order to explore reactivities with Reactions were then run with 2-iodotoluene in order to gauge
more electron rich aryl iodides, we investigated the use of steric effects in the trifluoromethylation reactions. It should be
4-iodotoluene as a substrate for trifluoromethylation reactions. noted here that the promoting effect of ortho substituents in tri-
Because the product 1-methyl-4-(trifluoromethyl)benzene had fluoromethylation reactions is well-known. For example, the
similar retention times as the solvents in the gas chromatogra- rate of trifluoromethylation of o-MeC6H4Br was found to be
phy analyses, we monitored the reactions of the iodotoluenes by 3.5 times faster than that for bromobenzene by CuCF3 in DMF
quantitative 19F NMR spectroscopy. Using the same solvent [16]. Figure 4 describes the results of the trifluoromethylations
systems employed for the reactions in Figure 2, conversions of 2-iodotoluene with systems A1, A2, and B2. For this
were measured over a 22 hour period (Figure 3). In this iodoarene substrate, the phen- and the NHC-based copper
case, [(SIMes)Cu(CF3)] performed just as well as the reagents performed nearly equally well at almost all time
[(phen)Cu(CF3)] generated in situ at the 22 hour mark. Howev- periods. The well-defined and isolated A1 again showed a
er, the yield versus time plot revealed that the phen-based noticeable induction period, whereas the induction period for
reagent was clearly better at early reaction times. The plots A2 was short.
revealed other interesting information. For the electron-rich aryl
iodides, the reactivity difference for the SIMes copper com-
plexes was opposite from what was observed previously in
Figure 2. Here, the isolated and well-defined [(SIMes)Cu(CF3)]
outperformed the in situ-generated counterpart, although at the
five hour mark both performed equally well. Single time point
yields would not have been able to identify the leveling out of
reactivity of A2 for the more electron-rich aryl halide. More-
over, an induction period was observed for both A1 and A2. We
Figure 4: Reaction of 2-iodotoluene with systems A1, A2, and B2 to
produce 1-methyl-2-(trifluoromethyl)benzene. Conditions for B2: DMF,
50 °C. Conditions for A1 and A2: DMI/benzene (1.5:7.5), 50 °C. Yields
were calculated by 19F NMR spectroscopy versus an internal standard.
Conclusion
In summary, we have determined that in DMF the best tri-
fluoromethylating agent was generated in situ using the [Cu(O-
t-Bu)]4/Me3SiCF3/phen combination. However, when opti-
mized solvents were employed, other metal complexes and pre-
cursors approached and even exceeded the [(phen)Cu(CF3)]
system, albeit with much higher metal loadings. In order to
Figure 3: Reaction of 1-iodo-4-methylbenzene with systems A1, A2,
and B2 to produce 1-methyl-4-(trifluoromethyl)benzene. Conditions for
B2: DMF, 50 °C. Conditions for A1 and A2: DMI/benzene (1.5:7.5),
rigorously assess future trifluoromethylating agents and mini-
mize issues of reproducibility, we encourage others to provide
50 °C. Yields were calculated by 19F NMR spectroscopy versus an
internal standard.
comparative data (yields versus time) for any newly developed
trifluoromethylation reaction with a well-established reagent
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using identical reaction vessels and performed by the same treated with a best fit curve generated by the Origin 9.0.0
experimentalist. The work shown here reveals the importance of program. The exponential fit with function ExpGro1 was
comparing trifluoromethylation reactions using a number of dif- selected for all data.
ferent variables (solvent, sterics, and electronics) in order to
adequately describe a catalyst’s performance for the commu- U p d a t e d p r o c e d u r e f o r t h e p r e p a r a t i o n o f
nity. Explicit benchmarking in catalysis science is rarely re- [(SIMes)2Cu][Cu(CF3)2] (2): A solution of [(SIMes)Cu(O-t-
ported in the literature (less than 500 mentions in approxi- Bu)] (220 mg, 0.50 mmol) and CF3Si(CH3)3 (0.110 mL,
mately 1 × 106 articles describing catalytic phenomena) [17], 0.74 mmol) in 6.0 mL THF was stirred at room temperature.
and as methodologies for trifluoromethylation reactions The conversion to product was monitored by 19F NMR spec-
continue to develop it will be important to have protocols for troscopy, and after 1.5 h the volatiles were evaporated on a high
assessing new reagents.
vacuum line. The white residue was filtered and washed twice
with 5 mL toluene and then twice with 5 mL of pentane. The
yield of [(SIMes)2Cu][Cu(CF3)2] was 81%. The spectroscopic
data matched literature values [10]. 1H NMR (25 °C, CD2Cl2)
Experimental
General
[(Phen)Cu(CF3)] was purchased from Aspira Scientific (Lot δ 1.84 (s, 12H), 2.39 (s, 6H), 3.80 (s, 4H), 6.89 (s, 4H);
#40C906, 90% purity) and used without further purification. All 19F NMR (25 °C, CD2Cl2) δ −31.33 (s, 3F).
other copper reagents were prepared according to reported pro-
cedures and were verified by 1H NMR and 19F NMR for purity. Updated procedure for the preparation of [(SIMes)Cu(O-t-
Copper salt precursors were purchased from Sigma-Aldrich. Bu)] (3): A suspension of [(SIMes)CuCl] (330 mg, 0.81 mmol)
Trimethyl(trifluoromethyl)silane (99% purity) was purchased and t-BuONa (78 mg, 0.81 mmol) in 6.0 mL THF was stirred
from SynQuest Labs, Inc. and used without further purification. for 2 h at room temperature and then filtered through a pad of
All other chemicals were verified by 1H NMR for purity and Celite. The Celite was washed two times with 4 mL of THF.
used without further purification. Purity of reagents used, CuCl The solvents were then removed on a high vacuum line, and the
(97%), KF (≥99%), 1,10-phenanthroline (≥99%), NaO-t-Bu resulting light yellow residue was dissolved in benzene and then
(98%), KO-t-Bu (98%), K2CO3 (≥99%), undecane (≥99%), filtered again through a pad of Celite. The Celite was washed
fluorobenzene (≥99%), 4-iodobiphenyl (97%), 4-iodotoluene two times with 4 mL of benzene, and the filtrate was evaporat-
(97%), 2-iodotoluene (97%), and 4,4′-di-tert-butyl-2,2′- ed on a high vacuum line. The resulting white solid was washed
dipyridyl (98%). All solvents were purified by passing through with pentane, filtered, and dried. Yield 92%. The spectroscopic
activated alumina and/or copper in a solvent purification system data matched literature values [10]. 1H NMR (C6D6) δ 1.31
supplied by Pure Process Technology or purchased anhydrous (s, 9H), 2.12 (s, 6H), 2.14 (s, 12H), 3.01 (s, 4H), 6.73 (s, 4H).
from Fisher Scientific (toluene, acetonitrile, DMF, and DMI).
The quantitative analyses were accomplished using a Shimadzu General procedure for the standard conditions of trifluoro-
GC-2010 Plus Gas Chromatograph and flame ionization methylation of 4-iodobiphenyl (systems A1, B1, and C1 in
detector (FID). A Rxi-5ms (fused silica), low-polarity phase, Figure 1). To a 20 mL vial was added copper trifluoromethyl
crossbond diphenyl dimethyl polysiloxane, 15.0 m length reagent (0.28 mmol) in 5.4 mL of DMF. In the case of
column was used. Parameters were: injection volume of 4.0 µL, [(PPh3)3CuCF3] [14], 77.2 mg (0.28 mmol) of dtbpy was also
25:1 split ratio, linear velocity of 57.0 cm/s, total flow of added. Then 67.1 mg (0.23 mmol) of 4-iodobiphenyl and
65.3 mL/min, and temperature program starting at 40 °C held 60.5 µL (0.28 mmol) of undecane as internal standard, were
for one minute, followed by a temperature ramp of 20.0 °C per added to the vial. The solution was then allowed to stir for five
minute to the final temperature of 250 °C which was held for minutes. Then 0.6 mL aliquots were taken and transferred into
4 minutes. All peaks were well separated. All manipulations 5 mL air-tight ampules fitted with a stirring bar. The ampules
were performed using standard Schlenk and high vacuum tech- were sealed and placed in an oil bath at 50 °C. The reactions
niques or were performed in a nitrogen filled glovebox. The were removed from the oil bath at various time intervals and
quantitative NMR analyses were accomplished using a Bruker quenched with 0.6 mL of methanol in air. Aliquots of each solu-
Ascend 400 MHz spectrometer by 19F NMR spectra referenced tion were injected into a GC-FID and the reactions were moni-
to internal standard of fluorobenzene. Solution 1H NMR spec- tored for the formation of the 4-trifluoromethylbiphenyl
tra were recorded at ambient temperature on a Bruker Ascend product.
400 MHz spectrometer and referenced to residual proton sol-
vent signals. 19F NMR spectra were recorded on the Bruker General procedure for the standard conditions of trifluoro-
Ascend NMR spectrometer operating at 376 MHz and refer- methylation of 4-iodobiphenyl using in situ generated
enced to trifluorotoluene set at δ −63.7. All graphical data were reagents (systems B2, B3, and D1 in Figure 1). The prepara-
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tion of each reagent (B2, B3, and D1) is described below. After benzene (1.5:7.5) with 60.5 µL (0.29 mmol) of undecane, as
preparation of the reagent, 60.50 µL (0.2851 mmol) of unde- internal standard. After the solution was allowed to stir for five
cane was added as internal standard. Each solution was allowed minutes, 0.6 mL aliquots were taken and transferred into 5 mL
to stir for five minutes, and then 0.60 mL aliquots were taken air-tight ampules. The ampules were sealed and placed in an oil
and transferred into 5 mL air-tight resealable ampules. The bath at 50 °C. The reactions were removed from the oil bath at
ampules were sealed and placed in an oil bath at 50 °C and the various time intervals and quenched with 0.6 mL of methanol in
solutions were stirred. The reactions were removed from the oil air. Aliquots of each solution were injected into a GC-FID and
bath at various time intervals and quenched with 0.6 mL of the reactions were monitored for the formation of the 4-tri-
methanol in air. Aliquots of each solution were injected into a fluoromethylbiphenyl product.
GC-FID and the reactions were monitored for the formation of
the 4-trifluoromethylbiphenyl product.
Reaction conditions employing [(PPh3)3CuCF3] (system
C1): A vial was charged with 0.31 mmol of 4-iodobiphenyl,
Generation of B2 in Figure 1: For the generation of 264 mg (0.29 mmol) of (PPh3)3CuCF3, and 85.0 mg
(phen)CuCF3 in situ, a vial was charged with 28.4 mg (0.32 mmol) of dtbpy in 5.4 mL of toluene with 60.5 µL
(0.28 mmol) of CuCl, 32.3 mg (0.28 mmol) of KO-t-Bu, and (0.29 mmol) of undecane, as internal standard. After the solu-
51.5 mg (0.28 mmol) of 1,10-phenanthroline in 5.4 mL of tion was allowed to stir for five minutes, 0.6 mL aliquots were
DMF. The solution was stirred for 0.5 h before the addition of taken and transferred into 5 mL air-tight ampules. The ampules
0.042 mL (0.28 mmol) of (Me)3SiCF3. The solution was stirred were sealed and placed in an oil bath at 80 °C. The reactions
for an additional hour before the introduction of 0.23 mmol of were removed from the oil bath at various time intervals and
4-iodobiphenyl.
quenched with 0.6 mL of methanol in air. Aliquots of each solu-
tion were injected into a GC-FID and the reactions were moni-
Generation of B3 in Figure 1: A vial was charged with tored for the formation of the 4-trifluoromethylbiphenyl
0.232 mmol of 4-iodobiphenyl, 53.6 mg (0.28 mmol) of CuI, product.
60.5 mg (0.28 mmol) of [K][B(OMe3)(CF3)] [8], and 51.5 mg
(0.28 mmol) of 1,10-phenanthroline in 5.4 mL of DMF.
General procedure for the
trifluoromethylation of 2-iodotoluene and
Generation of D1 in Figure 1: A vial was charged with
4-iodotoluene (system A1, A2 and B2 in
(0.23 mmol) of 4-iodobiphenyl, 53.6 mg (0.28 mmol) of CuI,
16.7 mg (0.28 mmol) of KF, and 0.042 mL (0.28 mmol) of Figure 3 and Figure 4)
(Me)3SiCF3 in 5.4 mL of DMF as solvent.
Reaction conditions employing [(SIMes)2Cu][Cu(CF3)2]
(system A1): A vial was charged with 270 mg (1.20 mmol) of
2-iodotoluene or 4-iodotoluene and 105 mg (0.12 mmol) of
[(SIMes)2Cu][Cu(CF3)2] in 5.4 mL of DMI/benzene (1.5:7.5)
with 90.0 µL (0.95 mmol) of fluorobenzene, as internal stan-
dard. After the solution was allowed to stir for five minutes,
0.6 mL aliquots were taken and transferred into 5 mL air-tight
ampules. The ampules were sealed and placed in an oil bath at
50 °C. The reactions were removed from the oil bath at various
time intervals and quenched with 0.6 mL of methanol in air.
Each aliquot was monitored by 19F NMR spectroscopy for for-
mation of the respective 2-trifluoromethyltoluene or 4-trifluoro-
methyltoluene product.
General procedure for the ‘best’ conditions of
trifluoromethylation of 4-iodobiphenyl
(systems A1, A2, and C1 in Figure 2)
Reaction conditions employing [(SIMes)2Cu][Cu(CF3)2]
(system A1): A vial was charged with 1.15 mmol of 4-iodobi-
phenyl and 105 mg (0.12 mmol) of [(SIMes)2Cu][Cu(CF3)2] in
5.4 mL of DMI/benzene (1.5:7.5) with 60.5 µL (0.29 mmol) of
undecane, as internal standard. After the solution was allowed
to stir for five minutes, 0.6 mL aliquots were taken and trans-
ferred into 5 mL air-tight ampules. The ampules were sealed
and placed in an oil bath at 50 °C. The reactions were removed
from the oil bath at various time intervals and quenched with
0.6 mL of methanol in air. Aliquots of each solution were
injected into a GC-FID and the reactions were monitored for the
formation of the 4-trifluoromethylbiphenyl product.
Reaction conditions employing [(SIMes)Cu(O-t-Bu)] +
TMSCF3 (system A2): A vial was charged with 270 mg
(1.20 mmol) of 2-iodotoluene or 4-iodotoluene, 106 mg
(0.24 mmol) of [(SIMes)Cu(O-t-Bu)] and 0.053 mL
Reaction conditions employing [(SIMes)Cu(O-t-Bu)] + (0.36 mmol) of (Me)3SiCF3 in 5.4 mL of DMI/benzene
TMSCF3 (system A2): A vial was charged with 1.15 mmol of (1.5:7.5) with 90.0 µL (0.95 mmol) of fluorobenzene, as
4-iodobiphenyl, 106 mg (0.24 mmol) of [(SIMes)Cu(O-t-Bu)] internal standard. After the solution was allowed to stir for five
and 0.053 mL (0.359 mmol) of (Me)3SiCF3 in 5.4 mL of DMI/ minutes, 0.60 mL aliquots were taken and transferred into 5 mL
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Beilstein J. Org. Chem. 2017, 13, 2297–2303.
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air-tight ampules. The ampules were sealed and placed in an oil
bath at 50 °C. The reactions were removed from the oil bath at
various time intervals and quenched with 0.6 mL of methanol in
air. Each aliquot was monitored by 19F NMR spectroscopy for
formation of the respective 2-trifluoromethyltoluene or 4-tri-
fluoromethyltoluene product.
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Reaction conditions employing [(phen)Cu(O-t-Bu)]4 +
TMSCF3 (system B2): For the generation of (phen)CuCF3 in
situ, a vial was charged with 28.4 mg (0.28 mmol) of CuCl,
32.3 mg (0.28 mmol) of KO-t-Bu, and 51.5 mg (0.28 mmol) of
1,10-phenanthroline. To the vial, 5.4 mL of DMF was added.
The solution was stirred for 0.5 h before the addition of
0.042 mL (0.28 mmol) of Me3SiCF3. The solution was stirred
for an additional hour before the introduction of 52.1 mg
(0.23 mmol) of 2-iodotoluene or 4-iodotoluene and 90.0 µL
(0.95 mmol) of fluorobenzene, as internal standard. After the
solution was allowed to stir for five minutes, 0.60 mL aliquots
were taken and transferred into 5 mL air-tight ampules. The
ampules were sealed and placed in an oil bath at 50 °C. The
reactions were removed from the oil bath at various time inter-
vals and quenched with 0.6 mL of methanol in air. Each aliquot
was monitored by 19F NMR spectroscopy for formation of the
respective 2-trifluoromethyltoluene or 4-trifluoromethyltoluene
product.
15.Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91–94.
doi:10.1016/S0040-4039(00)71226-3
16.Konovalov, A. I.; Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc.
2014, 136, 13410–13425. doi:10.1021/ja507564p
17.Bligaard, T.; Bullock, R. M.; Campbell, C. T.; Chen, J. G.; Gates, B. C.;
Gorte, R. J.; Jones, C. W.; Jones, W. D.; Kitchin, J. R.; Scott, S. L.
ACS Catal. 2016, 6, 2590–2602. doi:10.1021/acscatal.6b00183
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Acknowledgements
(http://www.beilstein-journals.org/bjoc)
D.A.V. thanks the Office of Basic Energy Sciences of the U.S.
Department of Energy (DE-SC0009363) for support of this
work.
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.13.225
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