Synthesis of L-Au(I)-CF2H Complexes and Their Application as Transmetalation Shuttles to the Difluoromethylation of Aryl Iodides

Article abstract of DOI:10.1021/acs.organomet.1c00305

We describe herein two alternative protocols to efficiently prepare difluoromethylgold(I) complexes bearing ancillary ligands with different electronic and steric properties. LAu-OX (X = H andt-Bu) species, formed in the presence of base, have been identified as intermediate complexes involved in these transformations. The application of these compounds as “CF₂H transmetalation shuttles” from gold to palladium has been demonstrated in a Pd-catalyzed difluoromethylation reaction of aryl iodides, in which the Au-to-Pd transfer of “CF₂H” is feasible under stoichiometric conditions. These findings will pave the way for catalytic manifolds in gold chemistry.

Full text of DOI:10.1021/acs.organomet.1c00305

pubs.acs.org/Organometallics
Communication
Synthesis of L−Au(I)−CF2H Complexes and Their Application as
Transmetalation Shuttles to the Difluoromethylation of Aryl Iodides
Patricia García-Domínguez*
Cite This: https://doi.org/10.1021/acs.organomet.1c00305
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: We describe herein two alternative protocols to
efficiently prepare difluoromethylgold(I) complexes bearing
ancillary ligands with different electronic and steric properties.
LAu−OX (X = H and t-Bu) species, formed in the presence of
base, have been identified as intermediate complexes involved in
these transformations. The application of these compounds as
“CF2H transmetalation shuttles” from gold to palladium has been
demonstrated in a Pd-catalyzed difluoromethylation reaction of
aryl iodides, in which the Au-to-Pd transfer of “CF2H” is feasible
under stoichiometric conditions. These findings will pave the way
for catalytic manifolds in gold chemistry.
F2H-containing compounds have found applications in
from organosiloxanes to Au (I)10 and the transmetalation of
ethynyl groups from trimethylsilanes to gold complexes11 have
been reported. Furthermore, an early report from the beginning
of this century described the preparation of trifluoromethylgold
complexes by stoichiometric transmetalation with silanes.12
Difluoromethylgold(III) complex cis-[Au(PCy3)(4-F-C6H4)-
(CF2H)(Cl)] has been recently prepared; nevertheless, the use
of (SIPr)Ag(CF2H) complex as starting material is required for
C
several disciplines such as drug discovery,1 agrochemistry,2
and PET imaging technology.3 In medicinal chemistry, the
difluoromethyl group exhibits valuable properties, since it is a
bioisostere of the hydroxyl and thiol groups and can act as a
metabolically stable hydrogen bond donor. Consequently, in the
past few years, an increasing number of synthesis methodologies
aimed at incorporating these moieties in a direct and selective
manner into structurally diverse carbon skeletons have been
developed.4 Transition metal promoted difluoromethylation has
emerged as an alternative to overcome the challenging
installation of a difluoromethyl group onto (hetero)aromatic
rings.5 Ideal strategies are represented by single-metal-catalyzed
difluoromethylation reactions performed on easily accessible
(hetero)aryl halides and/or with inexpensive industrial raw
materials as “CF2H” source, although these processes are scant.6
Most often, nucleophilic organometallic M−CF2H compounds
have been used for this purpose. (NHC)Ag(CF2H) complexes
were among the first bench-stable organometallic compounds of
this type to be prepared and broadly used.5f,i,7 Later, Sanford and
co-workers were able to isolate and characterize analogous
(NHC)Cu(CF2H) complexes, and they further explored their
reactivity with aryl electrophiles, both in stoichiometric and
catalytic fashions.5d Very recently, isolable [(L)Pd(CF2H)X]
complexes have also been synthesized, and the stoichiometric
transfer of the CF2H substituent to arenes was studied.5l Given
the parallel reactivity exhibited by the coinage metals in many
instances,8 we wondered whether analogous L−Au−CF2H
complexes could be prepared by selecting the appropriate
ancillary ligands on gold. Notably, gold-catalyzed photoredox
reactions have been employed to form Csp2−CF2R bonds.9
In recent years, direct Si-to-Au(I) transmetalation has been
achieved. A fluoride-free transmetalation of organic fragments
the synthesis.13 Remarkably, Fu
̈
rstner and co-workers have
recently reported the challenging spectroscopic and chemical
characterization of a highly reactive gold difluorocarbenoid
complex.14 Prompted by all these evidence we set out to explore
the Si-to-Au(I) transmetalation process for the preparation of
L−Au(I)−CF2H complexes, employing the commercially
available TMSCF2H as difluoromethylating agent. Herein we
describe the synthesis and characterization of so far unknown
L−Au(I)−CF2H complexes and their applicability in the
palladium-catalyzed difluoromethylation of aryl iodides.
We began our investigation with the synthesis of a series of
Au(I) chloride complexes bearing a variety of ancillary ligands
(L),15 which are known to play a paramount role in modulating
the reactivity of the complexes (Figure 1). Electron-poor, -rich,
and -neutral phosphines (1a−12a), triphenyl phosphite (8a),
and electron-rich N-heterocyclic carbene ligands (NHC) that
Received: May 22, 2021
https://doi.org/10.1021/acs.organomet.1c00305
© XXXX American Chemical Society
Organometallics XXXX, XXX, XXX−XXX
A

Organometallics
pubs.acs.org/Organometallics
Communication
product 14b was formed in trace amounts, as revealed by its
diagnostic signals in the 1H NMR and 19F NMR spectra (Table
1, entry 4). Since the low yields obtained could be traced back to
experimental errors during the addition of the base due to the
small scale of the reaction, in the subsequent experiments the
amount of both the base and TMSCF2H were increased to 500
mol %. Fine-tuning of the experimental conditions for the
workup and the handling of the gold complexes (see Supporting
Information) led to almost full conversion to the product using
IPrAuCl (13a) (Table 1, entry 6) and to full conversion for
SIPrAuCl (14a) (Table 1, entry 5). Purification of both gold
complexes by column chromatography, precipitation, or
crystallization to give accurate isolated yields was not possible.
Due to this drawback, we turned our attention to quantitative
NMR for the determination of reaction yields with the addition
of an internal standard. Dibromomethane was selected for this
purpose and allowed to determine the yield for the IPrAu−
CF2H (13b) (92%) and SIPrAu−CF2H (14b) (quantitative)
gold complexes.
Next, we moved to the phosphine gold(I) complexes.
Unfortunately, when the conditions developed for the
preparation of (NHC)Au−CF2H were tested on the electron-
rich [tris(p-methoxyphenyl)phosphine]gold(I) chloride (1a),
the desired product was obtained in trace amounts (Table 1,
entry 7). Gratifyingly, the use of 200 mol % of NaOtBu and 500
mol % of TMSCF2H delivered desired compound 1b in
excellent yield (Table 1, entry 8).
With two set of conditions in hand (conditions A and B) the
full scope of this transformation was evaluated (Scheme 1).
Additional gold(I) complexes bearing electron-rich phosphines
could be converted into their corresponding Au−CF2H
complexes in yields ranging from very good to excellent (4b,
5b, 6b, and 7b). The neutral triphenylphosphinegold(I)
chloride (9a) was likewise a suitable substrate for this
transformation, since corresponding Au−CF2H complex 9b
could be generated in an excellent yield. To further expand the
scope for NHC−Au complexes, analogues 15b and 16b were
prepared following protocol A. To our delight, we were able to
obtain suitable crystals for single-crystal X-ray diffraction
analysis, which unambiguously confirmed the identity of
compounds 6b, 7b, 13b, and 14b. Surprisingly, the more
challenging electron-deficient (p-CF3−Ph)3PAu-CF2H (10b)
and (p-F-Ph)3PAu-CF2H (11b) complexes could be synthesized
in good and excellent yields, respectively (for scope limitations,
see the Supporting Information).17
Gold(I) complex 10c was obtained as a byproduct in the
formation of 10b. To shed light on the origin of this compound
and the general mechanism for the formation of the LAu−CF2H
complexes, the experiments outlined in Scheme 2 were
performed. A TSMCF2H-free experiment with JohnPhosAu−
Cl 7a in the presence of NaOH (eq 1, Scheme 2) revealed the
partial conversion of the starting gold complex to gold(I)
hydroxide 7c and, very likely, to triaurated oxonium cation 7d,18
after 3 h of reaction. The fact that 7a, 7c, and 7d were present in
the crude mixture almost in the same ratio after 14 h of reaction
seems to indicate the establishment of an equilibrium between
the three species, which is eventually shifted to the right when
the difluoromethylating agent is present in the reaction media to
react with 7c and furnish product 7b. Similar results could be
extrapolated to the NaOtBu base (see the Supporting
Information for further details). The analogous control
experiment with 10a led to the isolation of 10c in 75% yield
(eq 2). Secondary phosphine oxide−gold(I) complex19 10d and
Figure 1. Starting [LAuCl] complexes.
could stabilize Au(I)−fluoroalkyl complexes (13a−16a)16 were
included in this study.
The Si-to-Au “transmetalation” experiments aimed to
determine the “matching transmetalation couples” from the
pool of gold(I) chloride derivatives and the commercially
available TMSCF2H. The optimization of the reaction
conditions began with the treatment of all the starting gold(I)
complexes with 200 mol % of the nucleophilic difluoromethylat-
ing agent in THF for 3 h without other additives. As expected, no
formation of the product was observed for any of them (Table 1,
Table 1. Optimization of the Reaction Conditions for the Si-
to-Au Transmetalation
TMSCF2H
(mol %)
a b
,
entry [LAu-Cl]
base (mol %)
yield
1
2
1a−16a
1a−16a
200
200
c
NaOAc, CsOAc, CsF,
c
NaF, n-Bu4NF
c
(200)
3
4
5
14a
14a
14a
200
200
500
NaOtBu (200)
NaOH (200)
NaOH (500)
trace amounts
quantitative
(conditions A)
d
6
13a
500
NaOH (500)
92%
(conditions A)
trace amounts
7
8
1a
1a
500
500
NaOH (500)
NaOtBu (200)
94%
(conditions B)
a
b
1
Reaction scale: 0.030−0.040 mmol. Yield calculated by H NMR
c
using CH2Br2 as internal standard. Complex 1a was used. MeOH or
CH3CN were used as cosolvents. Concentration: [0.03M].
d
entry 1). The use of bases such as acetates or fluorides did not
allow to obtain the desired CF2H−gold(I) complexes (Table 1,
entry 2). Next, we focused our attention on NHC−Au(I)
complex 14a with the aim of investigating the effect of other
bases in the reaction outcome. On the basis of the protocols
employed in the synthesis of the analogous silver(I)7b and
copper(I)5d complexes, NaOtBu was the first base selected.
Unfortunately, the addition of 200 mol % of this additive led to
the recovery of the starting complex (Table 1, entry 3).
Nevertheless, when the same amount of NaOH was used,
B
https://doi.org/10.1021/acs.organomet.1c00305
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Communication
Scheme 1. Scope for LAu−CF2H Complexes
Scheme 2. Mechanistic Proposal for the LAu−CF2H
Formation (eq 1) and the Base-Promoted P-to-Au Transfer
of an Aryl Ring (eq 2): Detection of Intermediate Species
stoichiometric Au−Pd transmetalation20 of the difluoromethyl
moiety. Although this transformation has already been achieved
with a single palladium21 or copper5d catalysts or with a
bimetallic Ag−Pd system,7a the results obtained in these studies
will hopefully contribute to a better understanding of the
unexploited Au−M bimetallic catalytic processes, since as
demonstrated in previous reports in the literature, the
transmetalation is a key step in the catalytic cycle.22
4-Iodobiphenyl (17a) and (p-OMe-Ph)3PAu-CF2H (1b)
were selected as model systems to study the desired trans-
formation. Reactions were performed with freshly prepared Au-
CF2H crude mixtures; therefore, the yields were calculated over
the two-step sequence. Starting from the general conditions
depicted Table 2, palladium catalysts with different bidentate
Table 2. Optimization of the Reaction Conditions for the
a
Au−Pd Transmetalation
a
Conditions A: TMSCF2H (500 mol %), NaOH (500 mol %), THF
b
[0.05M], r.t., 3 h. Conditions B: TMSCF2H (500 mol %), NaOtBu
yield
(200 mol %), THF [0.05M], r.t., 3 h. Reaction scale: 0.030−0.040
mmol. Yield calculated by 1H NMR using CH2Br2 as internal
standard. The ORTEP diagrams are represented with the ellipsoids
drawn at 30% probability level.
b
entry
1
[Pd], ligand
solvent
1,4-dioxane
(2 steps)
Pd2(dba)3 or Pd(dba)2
Xantphos
Pd(dba)2, Xantphos
Pd(dba)2, Xantphos
Pd2(dba)3 or Pd(dba)2
Xantphos
20%
2
3
4
toluene
MeOH/toluene(1:1)
18%
3%
1,4-dioxane/toluene (1:1) 30% (27%)
its anionic form, 10e, were obtained as byproducts of this
reaction, as confirmed by 31P NMR and HR-ESI of the crude
mixture. According to these results and the conclusions drawn
from the previous control experiments, a metathesis reaction
between starting gold(I) complex 10a and gold(I) hydroxide
species 10f is proposed as a plausible pathway for this
transformation, to our knowledge unreported in the literature.
Very likely, this process occurs through a concerted transition
state and might represent a potential catalyst decomposition
pathway in gold-catalyzed reactions.
a
b
Reaction scale: 0.030−0.040 mmol. Yields calculated by 19F NMR
(200 mol % of 2-chloro-4-fluorotoluene as internal standard). Isolated
yields are given in brackets. Each entry was repeated twice or three
times; the highest yields obtained are shown.
ligands were screened (for further details, see the Supporting
Information). Pd2(dba)3 or Pd(dba)2 in combination with
Xantphos ligand turned out to be the most appropriate catalytic
system, which afforded desired product 17b in a 20% combined
yield over 2 steps, after 24 h of reaction time in 1,4-dioxane at
100 °C (entry 1, Table 2). Lower temperatures or shorter
To evaluate the applicability of the synthesized gold
complexes as difluoromethylating reagents, we set out to explore
a Pd-catalyzed difluoromethylation of aryl iodides by means of a
C
https://doi.org/10.1021/acs.organomet.1c00305
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Communication
reaction times led to a decrease in the yield (data not shown).
Likewise, the use of toluene or a binary mixture of MeOH and
toluene as solvents did not improve the outcome of the reaction
(entries 2 and 3). However, a 1:1 solvent mixture of 1,4-dioxane
and toluene provided the product in 30% yield (entry 4).
To test whether these optimal conditions could be
extrapolated to other gold(I)-CF2H complexes, we examined
the scope of the reaction on the entire series (Scheme 3).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.organomet.1c00305.
■
sı
Detailed experimental procedures and spectral data for all
compounds (PDF)
Accession Codes
CCDC 2073749−2073754, 2073756, and 2073757 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
Scheme 3. Scope for the Au−Pd Transmetalation
AUTHOR INFORMATION
Corresponding Author
■
Patricia García-Domínguez − CINBIO, Universidade de Vigo,
Departamento de Química Orgánica, 36310 Vigo, Spain;
orcid.org/0000-0003-0522-4823; Email: patrigarcia@
uvigo.es
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.organomet.1c00305
a
Using a 1b/21a ratio of 1.5:1 afforded the product in 35% yield.
Notes
The author declares no competing financial interest.
NHC−Au−CF2H complexes 13b, 14b, and 15b were first
assayed, but only traces of product were obtained. Despite the
fact that (p-CF3-Ph)Au−CF2H (10b) afforded traces of the
transmetalation product, the electron-poor (p-F-Ph)3PAu−
CF2H (11b) furnished 17b in 14% yield over the two steps.
Gold complexes bearing electron-rich phosphines such as 4b,
5b, 6b, and 7b under the same reaction conditions delivered the
desired product in yields ranging from 10 to 20%. Finally, the use
of neutral Ph3PAu−CF2H (9b) afforded the product in a
significant 25% combined yield. Next, the scope on the aryl
iodide was evaluated. Aryl iodides bearing electron-donating
groups in the para-position were not suitable for this
transformation, as shown by the detection of difluoromethylated
product 18b in trace amounts. However, the presence of
electron-withdrawing groups was beneficial for the reaction as
demonstrated by the preparation of the CF2H-aryl derivatives
20b and 21b in 33 and 38% yield, respectively, which represent
the best results achieved for this transformation. Given the low
yields reported in the literature for the single-step Au−Pd
transmetalation of alkyl groups,23 we consider these yields
calculated over the two-step sequence to be significant.
In summary, we have reported two efficient methods for the
preparation of the first examples of difluoromethyl gold(I)
complexes containing a variety of ancillary ligands. LAu−OX (X
= H and t-Bu) species have been identified as intermediate
complexes in these transformations. In addition, we have shown
their application as a “CF2H transmetalation shuttles”24 in a Pd-
catalyzed difluoromethylation reaction of aryl iodides, in which
the Au-to-Pd transfer of “CF2H” is possible in a stoichiometric
manner. Meaningful yields for the overall Si-to-Au(I)-to-Pd
process have been achieved with gold(I) complexes bound to
phosphines with opposite electronic properties, which broadens
the application of these transformations to substrates with
different electronic demands. Given the versatility of gold(I) as a
transmetalating partner,24,25 these new Au(I)−CF2H complexes
represent potential candidates for further synthesis applications.
ACKNOWLEDGMENTS
■
The author thanks the Spanish MINECO (SAF2016-77620-R-
FEDER and BIO2016-78057-R) and Xunta de Galicia
(Consolidación GRC ED431C 2017/61 from DXPCTSUG;
ED-431G/02-FEDER “Unha maneira de facer Europa” to
CINBIO, a Galician Research Center 2016−2019; POS-B/
2016/007-PR) for financial support. The author is very grateful
to Profs. Angel R. de Lera and Rosana Alvarez for support and
enlightening discussions on this project. The author thanks Dr.
Berta Covelo for the X-ray crystal structure determination of all
compounds (X-ray Diffraction Facility-CACTI).
REFERENCES
(1) (a) Wang, J.; Sánchez-Roselló, M.; Acen
■
̃
a, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the
Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−
2506. (b) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;
̃
Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-
Containing Pharmaceuticals, Compounds Currently in Phase II−III
Clinical Trials of Major Pharmaceutical Companies: New Structural
Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422−518.
(c) Inoue, M.; Sumii, Y.; Shibata, N. Contribution of Organofluorine
Compounds to Pharmaceuticals. ACS Omega 2020, 5, 10633−10640.
(2) (a) Page, M. J.; Ma, Y.; Qi, H.; Healy, E.; Trolinger, J.
Determination of Thiazopyr and Its Metabolite in Florida Groundwater
Using Graphatized Carbon Solid Phase Extraction and Liquid
Chromatographic Determination. J. Agric. Food Chem. 1997, 45,
3095−3099. (b) Chen, X.; Dong, F.; Xu, J.; Liu, X.; Wu, X.; Zheng, Y.
Effective Monitoring of Fluxapyroxad and Its Three Biologically Active
Metabolites in Vegetables, Fruits, and Cereals by Optimized
QuEChERS Treatment Based on UPLC-MS/MS. J. Agric. Food
Chem. 2016, 64, 8935−8943.
(3) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine
in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (b) Trump,
L.; Lemos, A.; Lallemand, B.; Pasau, P.; Mercier, J.; Lemaire, C.; Luxen,
D
https://doi.org/10.1021/acs.organomet.1c00305
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Communication
A.; Genicot, C. Late-Stage 18F-Difluoromethyl Labeling of N-
Heteroaromatics with High Molar Activity for PET Imaging. Angew.
Chem., Int. Ed. 2019, 58, 13149−13154.
Metal-Catalyzed Carboxylation Reactions with Carbon Dioxide. Angew.
Chem., Int. Ed. 2018, 57, 15948−15982. (d) Díaz-Requejo, M. M.;
Pérez, P. J. Coinage Metal Catalyzed C−H Bond Functionalization of
Hydrocarbons. Chem. Rev. 2008, 108, 3379−3394.
(9) Xie, J.; Zhang, T.; Chen, F.; Mehrkens, N.; Rominger, F.; Rudolph,
M.; Hashmi, A. S. K. Gold-Catalyzed Highly Selective Photoredox
C(sp2)−H Difluoroalkylation and Perfluoroalkylation of Hydrazones.
Angew. Chem., Int. Ed. 2016, 55, 2934−2938.
(10) (a) Dupuy, S.; Slawin, A. M. Z.; Nolan, S. P. The Fluoride-Free
Transmetalation of Organosilanes to Gold. Chem. - Eur. J. 2012, 18,
14923−14928. (b) Falivene, L.; Nelson, D. J.; Dupuy, S.; Nolan, S. P.;
Poater, A.; Cavallo, L. Mechanism of the Transmetalation of
Organosilanes to Gold. ChemistryOpen 2016, 5, 60−64.
(11) Klauke, K.; Werner, S.; Mohr, F. Ethynyl Complexes of Gold(I)
Formed by Transmetallation Using Tin(IV) or Silicon(IV) Com-
pounds. Eur. J. Inorg. Chem. 2018, 2018, 1053−1056.
(12) Usui, Y.; Noma, J.; Hirano, M.; Komiya, S. C-Si bond cleavage of
trihalomethyltrimethylsilane by alkoxo- and aryloxogold or -copper
complexes. Inorg. Chim. Acta 2000, 309, 151−154.
(4) For selected reviews, see (a) Rong, J.; Ni, C.; Hu, J. Metal-
Catalyzed Direct Difluoromethylation Reactions. Asian J. Org. Chem.
2017, 6, 139−152. (b) Yerien, D. E.; Barata-Vallejo, S.; Postigo, A.
Difluoromethylation Reactions of Organic Compounds. Chem. - Eur. J.
2017, 23, 14676−14701. (c) Dilman, A. D.; Levin, V. V.
Difluorocarbene as a Building Block for Consecutive Bond-Forming
Reactions. Acc. Chem. Res. 2018, 51, 1272−1280. (d) Barata-Vallejo, S.;
Postigo, A. Photocatalytic Difluoromethylation Reactions of Aromatic
Compounds and Aliphatic Multiple C−C Bonds. Molecules 2019, 24,
4483. (e) Levi, N.; Amir, D.; Gershonov, E.; Zafrani, Y. Recent Progress
on the Synthesis of CF2H-Containing Derivatives. Synthesis 2019, 51,
4549−4567. (f) Carvalho, D. R.; Christian, A. H. Modern approaches
towards the synthesis of geminal difluoroalkyl groups. Org. Biomol.
Chem. 2021, 19, 947−964.
(5) (a) Fier, P. S.; Hartwig, J. F. Copper-Mediated Difluoromethy-
lation of Aryl and Vinyl Iodides. J. Am. Chem. Soc. 2012, 134, 5524−
5527. (b) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.;
Masood, K.; Swabeck, J. K.; Olah, G. A. Copper-Mediated
Difluoromethylation of (Hetero)aryl Iodides and β-Styryl Halides
with Tributyl(difluoromethyl)stannane. Angew. Chem., Int. Ed. 2012,
51, 12090−12094. (c) Xu, L.; Vicic, D. A. Direct Difluoromethylation
of Aryl Halides via Base Metal Catalysis at Room Temperature. J. Am.
Chem. Soc. 2016, 138, 2536−2539. (d) Bour, J. R.; Kariofillis, S. K.;
Sanford, M. S. Synthesis, Reactivity, and Catalytic Applications of
Isolable (NHC)Cu(CHF2) Complexes. Organometallics 2017, 36,
1220−1223. (e) Zhu, S.-Q.; Xu, X.-H.; Qing, F.-L. Silver-mediated
oxidative C-H difluoromethylation of phenanthridines and 1,10-
phenanthrolines. Chem. Commun. 2017, 53, 11484−11487. (f) Lu,
C.; Gu, Y.; Wu, J.; Gu, Y.; Shen, Q. Palladium-catalyzed
difluoromethylation of heteroaryl chlorides, bromides and iodides.
Chem. Sci. 2017, 8, 4848−4852. (g) Zhu, S. Q.; Liu, Y. L.; Li, H.; Xu, X.
H.; Qing, F. L. Direct and Regioselective C-H Oxidative Difluor-
omethylation of Heteroarenes. J. Am. Chem. Soc. 2018, 140, 11613−
11617. (h) Xu, C.; Guo, W. H.; He, X.; Guo, Y. L.; Zhang, X. Y.; Zhang,
X. Difluoromethylation of (hetero)aryl chlorides with chlorodifluoro-
methane catalyzed by nickel. Nat. Commun. 2018, 9, 1170. (i) Lu, C.;
Lu, H.; Wu, J.; Shen, H. C.; Hu, T.; Gu, Y.; Shen, Q. Palladium-
Catalyzed Difluoromethylation of Aryl Chlorides and Triflates and Its
Applications in the Preparation of Difluoromethylated Derivatives of
Drug/Agrochemical Molecules. J. Org. Chem. 2018, 83, 1077−1083.
(j) Miao, W.; Zhao, Y.; Ni, C.; Gao, B.; Zhang, W.; Hu, J. Iron-
Catalyzed Difluoromethylation of Arylzincs with Difluoromethyl 2-
Pyridyl Sulfone. J. Am. Chem. Soc. 2018, 140, 880−883. (k) Motohashi,
H.; Mikami, K. Nickel-Catalyzed Aromatic Cross-Coupling Difluor-
omethylation of Grignard Reagents with Difluoroiodomethane. Org.
Lett. 2018, 20, 5340−5343. (l) Zhao, H.; Herbert, S.; Kinzel, T.; Zhang,
W.; Shen, Q. Two Ligands Transfer from Ag to Pd: En Route to
(SIPr)Pd(CF2H)(X) and Its Application in One-Pot C−H Borylation/
Difluoromethylation. J. Org. Chem. 2020, 85, 3596−3604.
(13) Liu, S.; Kang, K.; Liu, S.; Wang, D.; Wei, P.; Lan, Y.; Shen, Q. The
Difluoromethylated Organogold(III) Complex cis-[Au(PCy3)(4-F-
C6H4)(CF2H)(Cl)]: Preparation, Characterization, and Its C(sp2)−
CF2H Reductive Elimination. Organometallics 2018, 37, 3901−3908.
̈
(14) Tskhovrebov, A. G.; Lingnau, J. B.; Furstner, A. Gold
Difluorocarbenoid Complexes: Spectroscopic and Chemical Profiling.
Angew. Chem., Int. Ed. 2019, 58, 8834−8838.
(15) (a) Collado, A.; Gomez-Suarez, A.; Martin, A. R.; Slawin, A. M.
Z.; Nolan, S. P. Straightforward synthesis of [Au(NHC)X] (NHC = N-
heterocyclic carbene, X = Cl, Br, I) complexes. Chem. Commun. 2013,
49, 5541−5543. (b) Mauleón, P.; Zeldin, R. M.; González, A. Z.; Toste,
F. D. Ligand-Controlled Access to [4 + 2] and [4 + 3] Cycloadditions in
Gold-Catalyzed Reactions of Allene-Dienes. J. Am. Chem. Soc. 2009,
131, 6348−6349. (c) Nunokawa, K.; Onaka, S.; Tatematsu, T.; Ito, M.;
Sakai, J. Substituent effects on aurophilicity and π−π interaction in
crystals of arylphosphine−Au(I) derivatives. Synthesis and X-ray
structural studies of compounds (CX3C6H4)3P-Au-X and
{(CF3)2C6H3}3P-Au-X. Inorg. Chim. Acta 2001, 322, 56−64.
(16) Blaya, M.; Bautista, D.; Gil-Rubio, J.; Vicente, J. Synthesis of
Au(I) Trifluoromethyl Complexes. Oxidation to Au(III) and Reductive
Elimination of Halotrifluoromethanes. Organometallics 2014, 33,
6358−6368.
(17) R3PAuCF2H complexes 7b and 10b were the most stable
products, since isolation of the pure products after column
chromatography was possible for each of them. The remaining
R3PAuCF2H complexes showed different decomposition rates in
solution, but they were stable enough to be characterized. NHC−Au−
CF2H were generally more unstable in solution than their phosphine
counterparts. IPrAu−CF2H (13b) and SIPrAu−CF2H (14b) were
more or less stable as solids (in the crude mixtures).
(18) Zhdanko, A.; Ströbele, M.; Maier, M. E. Coordination Chemistry
of Gold Catalysts in Solution: A Detailed NMR Study. Chem. - Eur. J.
2012, 18, 14732−14744.
(19) Schröder, F.; Tugny, C.; Salanouve, E.; Clavier, H.; Giordano, L.;
(6) Feng, Z.; Min, Q. Q.; Fu, X. P.; An, L.; Zhang, X.
Chlorodifluoromethane-triggered formation of difluoromethylated
arenes catalysed by palladium. Nat. Chem. 2017, 9, 918−923.
̀
Moraleda, D.; Gimbert, Y.; Mouries-Mansuy, V.; Goddard, J.-P.;
Fensterbank, L. Secondary Phosphine Oxide−Gold(I) Complexes and
Their First Application in Catalysis. Organometallics 2014, 33, 4051−
4056.
(7) (a) Gu, Y.; Leng, X.; Shen, Q. Cooperative dual palladium/silver
catalyst for direct difluoromethylation of aryl bromides and iodides.
Nat. Commun. 2014, 5, 5405. (b) Gu, Y.; Chang, D.; Leng, X.; Gu, Y.;
Shen, Q. Well-Defined, Shelf-Stable (NHC)Ag(CF2H) Complexes for
Difluoromethylation. Organometallics 2015, 34, 3065−3071.
(c) Chang, D.; Gu, Y.; Shen, Q. Pd-Catalyzed Difluoromethylation of
Vinyl Bromides, Triflates, Tosylates, and Nonaflates. Chem. - Eur. J.
2015, 21, 6074−6078.
(20) For gold to palladium transmetalation in palladium-catalyzed
reactions, see (a) Shi, Y.; Ramgren, S. D.; Blum, S. A. Palladium-
Catalyzed Carboauration of Alkynes and Palladium/Gold Cross-
Coupling. Organometallics 2009, 28, 1275−1277. (b) Hashmi, A. S.
K.; Lothschutz, C.; Döpp, R.; Rudolph, M.; Ramamurthi, T. D.;
̈
Rominger, F. Gold and Palladium Combined for Cross-Coupling.
Angew. Chem., Int. Ed. 2009, 48, 8243−8246. (c) Shi, Y.; Roth, K. E.;
Ramgren, S. D.; Blum, S. A. Catalyzed Catalysis Using Carbophilic
Lewis Acidic Gold and Lewis Basic Palladium: Synthesis of Substituted
Butenolides and Isocoumarins. J. Am. Chem. Soc. 2009, 131, 18022−
(8) (a) Panda, B.; Sarkar, T. K. On the catalytic duo PdCl2(PPh3)2/
AuCl(PPh3) that cannot effect a Sonogashira-type reaction: a
correction. Tetrahedron Lett. 2010, 51, 301−305. (b) Boogaerts, I. I.
F.; Nolan, S. P. Direct C-H carboxylation with complexes of the coinage
metals. Chem. Commun. 2011, 47, 3021−3024. (c) Tortajada, A.; Juliá-
Hernández, F.; Börjesson, M.; Moragas, T.; Martin, R. Transition-
18023. (d) Hashmi, A. S. K.; Döpp, R.; Lothschutz, C.; Rudolph, M.;
̈
Riedel, D.; Rominger, F. Scope and Limitations of Palladium-Catalyzed
E
https://doi.org/10.1021/acs.organomet.1c00305
Organometallics XXXX, XXX, XXX−XXX

Organometallics
pubs.acs.org/Organometallics
Communication
Cross-Coupling Reactions with Organogold Compounds. Adv. Synth.
tz, C.;
Catal. 2010, 352, 1307−1314. (e) Hashmi, A. S. K.; Lothschu
̈
Döpp, R.; Ackermann, M.; De Buck Becker, J.; Rudolph, M.; Scholz, C.;
Rominger, F. On Homogeneous Gold/Palladium Catalytic Systems.
Adv. Synth. Catal. 2012, 354, 133−147.
(21) Ferguson, D. M.; Malapit, C. A.; Bour, J. R.; Sanford, M. S.
Palladium-Catalyzed Difluoromethylation of Aryl Chlorides and
Bromides with TMSCF2H. J. Org. Chem. 2019, 84, 3735−3740.
(22) García-Domínguez, P.; Nevado, C. Au−Pd Bimetallic Catalysis:
The Importance of Anionic Ligands in Catalyst Speciation. J. Am. Chem.
Soc. 2016, 138, 3266−3269.
(23) (a) Pena-López, M.; Ayán-Varela, M.; Sarandeses, L. A.; Pérez
̃
Sestelo, J. Palladium-Catalyzed Cross-Coupling Reactions of
Organogold(I) Reagents with Organic Electrophiles. Chem. - Eur. J.
2010, 16, 9905−9909. (b) Hansmann, M. M.; Pernpointner, M.; Döpp,
R.; Hashmi, A. S. K. A Theoretical DFT-Based and Experimental Study
of the Transmetalation Step in Au/Pd-Mediated Cross-Coupling
Reactions. Chem. - Eur. J. 2013, 19, 15290−15303. (c) Carrasco, D.;
Pérez-Temprano, M. H.; Casares, J. A.; Espinet, P. Cross Alkyl−Aryl
versus Homo Aryl−Aryl Coupling in Palladium-Catalyzed Coupling of
Alkyl−Gold(I) and Aryl−Halide. Organometallics 2014, 33, 3540−
3545.
(24) Hirner, J. J.; Shi, Y.; Blum, S. A. Organogold Reactivity with
Palladium, Nickel, and Rhodium: Transmetalation, Cross-Coupling,
and Dual Catalysis. Acc. Chem. Res. 2011, 44, 603−613.
(25) (a) Hashmi, A. S. K.; Molinari, L. Effective Transmetalation from
Gold to Iron or Ruthenium. Organometallics 2011, 30, 3457−3460.
(b) Cornell, T. P.; Shi, Y.; Blum, S. A. Synthesis of Alkenylgold(I)
Compounds via Sequential Hydrozirconation and Zirconium to Gold
Transmetalation. Organometallics 2012, 31, 5990−5993. (c) Alonso, J.
̀
M.; Munoz, M. P. Platinum and Gold Catalysis: a la Carte
̃
Hydroamination of Terminal Activated Allenes with Azoles. Org. Lett.
2019, 21, 7639−7644.
F
https://doi.org/10.1021/acs.organomet.1c00305
Organometallics XXXX, XXX, XXX−XXX