Synthesis, reactivity, and catalytic applications of isolable (NHC)Cu(CHF2) complexes

Article abstract of DOI:10.1021/acs.organomet.7b00025

Difluoromethyl copper complexes have been proposed as key intermediates in a variety of Cu-catalyzed difluoromethylation reactions. However, studies of these putative intermediates have been impeded by the low stability of these [Cu(CHF₂)] species. This report describes the synthesis of isolable N-heterocyclic carbene ligated copper(I) difluoromethyl complexes. The stoichiometric reactions of these complexes with aryl electrophiles (i.e., diaryliodonium salts, aryl iodides, and aryl bromides) are described. In addition, Nheterocyclic carbene copper(I) species are demonstrated to serve as catalysts for the cross-coupling of aryl iodides with (difluoromethyl)trimethylsilane to afford difluoromethyl arene products.

Full text of DOI:10.1021/acs.organomet.7b00025

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Communication
pubs.acs.org/Organometallics
Synthesis, Reactivity, and Catalytic Applications of Isolable
(NHC)Cu(CHF2) Complexes
James R. Bour,† Stavros K. Kariofillis,† and Melanie S. Sanford*
University of Michigan, Department of Chemistry, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: Difluoromethyl copper complexes have been
proposed as key intermediates in a variety of Cu-catalyzed
difluoromethylation reactions. However, studies of these
putative intermediates have been impeded by the low stability
of these [Cu(CHF2)] species. This report describes the
synthesis of isolable N-heterocyclic carbene ligated copper(I)
difluoromethyl complexes. The stoichiometric reactions of
these complexes with aryl electrophiles (i.e., diaryliodonium salts, aryl iodides, and aryl bromides) are described. In addition, N-
heterocyclic carbene copper(I) species are demonstrated to serve as catalysts for the cross-coupling of aryl iodides with
(difluoromethyl)trimethylsilane to afford difluoromethyl arene products.
ifluoromethyl substituents are increasingly common
decomposes rapidly at temperatures above −30 °C to generate
1
Dcomponents of pharmaceuticals and agrochemicals. As a mixture of tetrafluoroethane and cis-difluoroethylene. These
such, there is significant demand for synthetic methods that
enable the formation of carbon−CHF2 bonds. Recent reports
have described Pd-,2 Ni-,3 and Cu-catalyzed4 and/or -medi-
ated5,6 processes for the cross-coupling of aryl electrophiles
with nucleophilic “CHF2” reagents. The Cu-based systems are
the oldest and arguably most common of these methods, yet
little is known about the organometallic chemistry of the
intermediates formed in these reactions. These transformations
are believed to proceed via the initial formation of a
(L)Cu(CHF2) intermediate A (Scheme 1, path i), followed
by the reaction of this (L)Cu(CHF2) species with an aryl
electrophile (Scheme 1, path ii),
byproducts implicate a bimolecular decomposition pathway,
which could potentially be mitigated by the incorporation of
sterically bulky ligands such as N-heterocyclic carbenes
(NHCs). Notably, Vicic has used an analogous approach to
stabilize and isolate related (NHC)Cu(CF3) complexes.8
We report herein the synthesis of the first examples of
isolable (NHC)Cu(CHF2) complexes. We show that, with an
appropriate choice of NHC, these complexes are stable for at
least 24 h in solution at room temperature, suggesting that
bimolecular decomposition pathways are relatively slow.
Furthermore, we demonstrate that these complexes react
stoichiometrically with diaryliodonium salts and aryl iodides
to afford difluoromethylated aromatics. These stoichiometric
studies are then used as a foundation for the development of an
(NHC)CuX-catalyzed cross-coupling of aryl iodides with
(difluoromethyl)trimethylsilane (TMSCHF2).
We initially targeted the preparation of a series of
(NHC)Cu(CHF2) complexes bearing different NHC ligands.
Our synthetic procedure was borrowed from Shen’s approach
to related (NHC)Ag(CHF2) compounds.5e The appropriate
(NHC)CuCl9 precursor was dissolved in THF, followed by the
sequential addition of 2 equiv of NaOtBu and then 2.1 equiv of
TMSCHF2 (Scheme 2). With the relatively small NHC ligand
iPr (1,3-diisopropylimidazol-2-ylidene),10 this sequence re-
sulted in the rapid formation of cis-difluoroethylene and
tetrafluoroethane. No 19F NMR signals consistent with
(iPr)Cu(CHF2) (2-iPr) were detected. We hypothesize that
2-iPr forms transiently under these conditions but undergoes
rapid bimolecular decomposition by analogy to Burton’s
compounds.7,11
Despite the importance of intermediate A in this catalytic
cycle, little is known about the fundamental chemistry of
[Cu(CHF2)] complexes. Early reports by Burton7a,c and later
Brauer7b showed that the reaction of Cd(X)(CHF2) with CuI
affords a [Cu(CHF2)] species that can be detected by 19F NMR
spectroscopy at −50 °C. However, this [Cu(CHF2)] complex
Scheme 1. General Catalytic Cycle for the Cu-Catalyzed
Difluoromethylation of Aryl Halides
Received: January 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.7b00025
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Communication
angles 175.6 and 178.2°, respectively). The Cu−CHF2 bond
distance in 2-IPr (1.928 Å) is shorter than that of 2-SIPr
(1.970 Å).13 However, the NHC−Cu bond lengths of 2-IPr
and 2-SIPr are nearly identical at 1.902 and 1.895 Å,
respectively. Furthermore, the steric protection offered to the
Cu center as determined by their buried volumes is also similar
(48.1% versus 49.4% for 2-IPr and 2-SIPr, respectively).14
Overall, these complexes represent the first isolated examples of
copper(I) complexes bearing a CHF2 ligand.15
Scheme 2. General Synthetic Procedure for
(NHC)Cu(CHF2) Complexes
The reactions of [Cu(CHF2)] intermediates with aryl
electrophiles are proposed as a key step in Cu-catalyzed
difluoromethylation reactions (Scheme 1, step ii). The isolation
of stable mononuclear (NHC)Cu(CHF2) complexes allowed
us to directly investigate the feasibility of this transformation.
We initially examined the reactions of 2-IPr and 2-SIPr with
the aryl electrophile bis(4-cyanophenyl)iodonium tetrafluor-
oborate16 in toluene. After 20 h at room temperature 2-IPr and
2-SIPr were fully consumed, and the formation of 4-
(difluoromethyl)benzonitrile was observed in 44 and 57%
yields, respectively, as determined by 19F NMR spectroscopy.
Benzonitrile was also detected in the crude reaction mixtures by
GCMS.5a
In contrast, no reaction was observed between 2-IPr or 2-
SIPr and 4-iodobenzonitrile at room temperature under
analogous conditions. However, when these reaction mixtures
were heated to 90 °C for 20 h, 4-(difluoromethyl)benzonitrile
was formed in >98% and 33% yields, respectively, as
determined by 19F NMR spectroscopy (Table 1). Unreacted
To address this issue, we next utilized the larger NHC ligand
IMes (IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-yli-
dene).10 Subjecting (IMes)CuCl (1-IMes) to the reaction
conditions resulted in the appearance of a 19F NMR resonance
at −121 ppm, which is consistent with the formation of
(IMes)Cu(CHF2) (2-IMes). However, the 19F NMR yield of
this species never exceeded 10%, and significant decomposition
was observed over the course of the reaction. As such, we were
unable to isolate pure samples of 2-IMes.
However, subjecting (IPr)CuCl (1-IPr), which contains the
even larger IPr (1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-
imidazol-2-ylidene) ligand,10 to the same conditions resulted in
the formation of a new 19F NMR resonance at −119 ppm. This
resonance is consistent with that expected for (IPr)Cu(CHF2)
(2-IPr), and this species was stable in solution over at least 24 h
at room temperature. Complex 2-IPr was isolated in 51% yield
via filtration of the reaction mixture and subsequent
precipitation from a minimum volume of THF. The closely
related complex (SIPr)Cu(CHF2) (2-SIPr; SIPr = 1,3-bis(2,6-
diisopropylphenyl)imidazolidin-2-ylidene)10 was prepared and
isolated in 82% yield via a closely related procedure.
Table 1. Reactions of 2-IPr and 2-SIPr with Aryl
a
Electrophiles
1
Complexes 2-IPr and 2-SIPr were characterized by H, 13C,
entry
[Cu]
X
temp (°C)
yield (%)
and 19F NMR spectroscopy. The NMR spectral data for both 2-
IPr and 2-SIPr in THF are consistent with neutral monomeric
species of general structure (NHC)Cu(CHF2) rather than the
ion pair [(NHC)2Cu][Cu(CHF2)2].12 For example, 13C/19F
HMBC experiments show strong correlations between the
metal-bound NHC carbons and the fluorine atoms of the CHF2
ligand. Furthermore, the chemical shifts of the 19F NMR
resonances of 2-IPr and 2-SIPr do not exhibit a concentration
dependence, as would be expected for a rapidly equilibrating
mixture of (NHC)Cu(CHF2) and [(NHC)2Cu][Cu(CHF2)2].
X-ray crystal structures of 2-IPr and 2-SIPr are shown in
Figure 1. Both solid-state structures show neutral monomeric
copper(I) complexes with linear geometries (C−Cu−CHF2
1
2
3
4
5
6
2-IPr
[I-(4-CN-C6H4)](BF4)
23
44
57
2-SIPr
2-IPr
I
90
>98
33
2-SIPr
2-IPr
Br
5
b
2-SIPr
nd
a
Reactions conducted on a 0.8 μmol scale at 0.02 M concentration.
b
Yields were determined by 19F NMR spectroscopy. nd = not
detected.
iodoarene was detected by GCMS in the crude reaction mixture
with 2-SIPr, suggesting that unproductive decomposition of
this Cu complex is competitive with productive iodoarene
difluoromethylation under these conditions. Complex 2-IPr
also reacted slowly with 4-bromobenzonitrile at 90 °C,
affording 4-(difluoromethyl)benzonitrile in 5% yield after 20
h. In contrast, 2-SIPr afforded none of the difluoromethylated
product under analogous conditions.17 No Cu intermediates
were detected by NMR spectroscopy in any of these
transformations. These reactivity trends parallel the relative
oxidizing strengths of the aryl electrophiles, suggesting that
oxidative addition is the slow step in this sequence. Notably,
Vicic demonstrated an analogous reactivity trend for related
(NHC)Cu(CF3) compounds.8
Figure 1. ORTEP drawings of 2-IPr (left) and 2-SIPr (right).
Thermal ellipsoids are drawn at 50% probability.
B
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We next examined the stoichiometric reactions of 2-IPr with
a broader range of electronically and sterically varied aryl
iodides. As shown in Table 2, electron-deficient aryl iodides
As summarized in Table 3, a variety of electron-rich, -neutral,
and -deficient aryl iodides underwent catalytic difluoromethy-
Table 3. Substrate Scope of IPrCuCl-Catalyzed
Difluoromethylation
a b
,
a
Table 2. Stoichiometric Reactions of 2-IPr with ArI
a
Reactions conducted on a 1 μmol scale at 0.02 M concentration.
b
c
Yields determined by 19F NMR spectroscopy. Reaction run at 120
°C.
generally reacted to afford high yields of the corresponding
ArCHF2 products 3a−e over 20 h at 90 °C in toluene. In
contrast, electron-rich aryl iodides reacted to afford ArCHF2 in
lower yields, and these substrates often required more forcing
reaction conditions (120 °C). In systems where the yield of
ArCHF2 was moderate/low, unreacted ArI was typically
observed by GC/MS at the end of the reaction, and traces of
cis-difluoroethylene were detected by 19F NMR spectroscopy.
These results suggest that the decomposition of 2-IPr can be
competitive with productive difluoromethylation when oxida-
tive addition is slow. Importantly, the higher reactivity of
electron-deficient aryl iodides is further consistent with the
electrophile trends seen in Table 1.
The stoichiometric reactions in Scheme 2 and Table 1
constitute the sequence of steps required for the catalytic cross-
coupling of aryl iodides with TMSCHF2. As such, we next
explored the use of (IPr)CuCl as a precatalyst for the
difluoromethylation of ArI. The relatively electron neutral
substrate 4-iodobiphenyl was selected for initial optimization,
with commercially available TMSCHF2 as the nucleophilic
source of CHF2. Initial efforts focused on the direct merger of
the transmetalation conditions developed in the synthesis of 2-
IPr with the difluoromethylation conditions in Table 2.
However, tert-butoxide bases proved to be too reactive at the
high temperatures required for oxidative addition and thus
yielded intractable heterogeneous mixtures upon workup. We
hypothesized that fluoride salts, which are also commonly used
to promote transmetalation from fluoroalkyl silicon reagent-
s,5a−c,6,18 might be more compatible with the reaction
conditions. After surveying various fluoride salts and solvents
(Table S2 in the Supporting Information), we found that the
combination of 10 mol % of (IPr)CuCl, 1 equiv of 4-
iodobiphenyl, 2 equiv of TMSCHF2, and 3 equiv of CsF in a 3/
1 dioxane to toluene mixture at 120 °C afforded a 72% isolated
yield of the difluoromethylated product 3f.19,20 Notably, this is
just the second reported example of a Cu-catalyzed
difluoromethylation.4
a
All reactions were conducted on a 0.31 mmol scale in a 3:1 dioxane:
toluene mixture (0.125 M). Yields were determined by 19F NMR
spectroscopy against an internal standard. Isolated yields are shown in
parentheses. nd = not detected.
lation under these standard reaction conditions. The good to
excellent yields obtained with electron-rich aryl iodides are
particularly noteworthy, as these were challenging substrates in
Mikami’s CuI-catalyzed difluoromethylation method.4 We
hypothesize that the IPr ligand provides sufficient stabilization
of the copper center to tolerate the high temperatures required
for oxidative addition with these electron-rich substrates.21
A
current limitation of our method is poor tolerance of carbonyl-
containing aryl iodides. Substrates bearing ketones and
aldehydes afforded mixtures of products, with addition of
CHF2 into the carbonyl moiety serving as the major side
reaction. However, acetal-protected carbonyls were compatible
with these conditions; for example, product 3n was formed in
58% isolated yield.
In summary, this communication describes the synthesis,
characterization, and reactivity of the first isolated examples of
difluoromethyl copper(I) complexes. Copper(I) compounds
bearing the bulky IPr ligand were found to exhibit high stability
in solution at room temperature. We demonstrate that
(IPr)Cu(CHF2) reacts stoichiometrically with a variety of aryl
electrophiles to afford difluoromethylated arenes. Furthermore,
we show that these stoichiometric studies can be translated to
develop an (IPr)CuCl-catalyzed difluoromethylation of aryl
iodides that is particularly effective for electron-rich aromatic
substrates.
C
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Communication
(10) Clavier, H.; Nolan, S. P. Chem. Commun. 2010, 46, 841−861.
(11) Notably, the saturated trifluoromethyl variant of 2-iPr is known
to be stable and isolable. See ref 8a.
(12) Related trifluoromethyl complexes were shown to exist as an
equilibrium mixture of (NHC)Cu(CF3) and [(NHC)2Cu][Cu(CF3)2]
in THF under analogous conditions. See ref 8b for complete details.
(13) Interestingly, this difference is not reflected in the analogous
(IPr)Ag(CHF2) and (SIPr)Ag(CHF2) compounds reported by Shen.
These silver compounds exhibit nearly identical Ag−CHF2 bond
lengths of 2.090 and 2.092 Å, respectively. See ref 5e.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.7b00025.
■
S
Experimental details, optimization tables, and complete
characterization data for all new compounds (PDF)
Crystallographic data (CIF)
Cartesian coordinates for calculated structures (XYZ)
(14) Determined from the X-ray structures of 2-IPr and 2-SIPr using
SambVca: A Web Application for the Calculation of the Buried
Volume of N-Heterocyclic Carbene Ligands. See: (a) Poater, A.;
Cosenza, B.; Correa, A.; Giudice, S.; Ragone, F.; Scarano, V.; Cavallo,
L. Eur. J. Inorg. Chem. 2009, 2009, 1759−1766. (b) Poater, A.; Ragone,
F.; Giudice, S.; Costabile, C.; Dorta, R.; Nolan, S. P.; Cavallo, L.
Organometallics 2008, 27, 2679−2681.
AUTHOR INFORMATION
Corresponding Author
*E-mail for M.S.S.: mssanfor@umich.edu.
ORCID
■
(15) The CuIII difluoromethyl complex [CuIII(CHF2)4]− has been
isolated and structurally characterized. See ref 7b for full details.
(16) For a related reaction of a Cu−CF3 complex with a
diaryliodonium salt, see: Pandey, V. K.; Anbarasan, P. RSC Adv.
2016, 6, 18525−18529.
Melanie S. Sanford: 0000-0001-9342-9436
Author Contributions
†J.R.B. and S.K.K. contributed equally to this work.
Notes
The authors declare no competing financial interest.
(17) Decomposition of 2-IPr and 2-SIPr appears to outcompete
productive difluoromethylation at these temperatures. Analysis of the
reaction mixtures by 19F NMR spectroscopy showed complete
consumption of 2-IPr and 2-SIPr, while unreacted 4-bromobenzoni-
trile was detected in both reactions by GCMS.
(18) (a) Cho, E.-J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D.
A.; Buchwald, S. L. Science 2010, 328, 1679−1681. (b) Maleckis, A.;
Sanford, M. S. Organometallics 2011, 30, 6617−6627.
(19) For optimization details see Table S3 in the Supporting
Information.
(20) Analysis of the crude reaction mixture revealed the presence of
some unreacted TMSCHF2 (detected by 19F NMR spectroscopy). In
addition, unreacted 4-iodobiphenyl was isolated from the reaction in
13% yield.
(21) The low concentration of 2-IPr and high concentration of ArI
during catalysis both likely serve to slow the competing decomposition
of 2-IPr that is observed during the stoichiometric reactions with
electron-rich aryl iodides.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
Grant CHE-1111563. We gratefully acknowledge Dr. Jeff
Kampf (University of Michigan) for X-ray crystallographic
analysis of complexes of 2-IPr and 2-SIPr, as well as funding
from NSF Grant CHE-0840456 for X-ray instrumentation. We
also thank Prof. Chip Nataro for helpful discussions. J.R.B.
thanks the NSF for a graduate fellowship, and S.K.K. thanks the
NSF for an REU summer fellowship.
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DOI: 10.1021/acs.organomet.7b00025
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