Well-defined CuC2F5 complexes and pentafluoroethylation of acid chlorides

Article abstract of DOI:10.1002/anie.201500341

Four new well-defined Cu^I complexes bearing a C₂F₅ ligand have been prepared and fully characterized: [(Ph₃P)₂CuC₂F₅] (2), [(bpy)CuC₂F₅] (3), [(Ph₃P)Cu(phen)C₂F₅] (4), and [(IPr)CuC₂F₅] (5). X-ray structures of all four have been determined, showing that the C₂F₅-ligated Cu atom can be di- (5), tri- (2 and 3), and tetracoordinate (4). The mixed phen-PPh₃ complex 4 is a highly efficient fluoroalkylating agent for a broad variety of acid chlorides. This high-yielding transformation represents the first general method for the synthesis of RCOC₂F₅ from the corresponding RCOCl. Four well-defined CuC₂F₅ complexes have been prepared and fully characterized, with [(phen)Cu(PPh₃)C₂F₅] (phen=1,10-phenanthroline) proving to be a remarkably efficient fluoroalkylating agent for a broad variety of acid chlorides (see scheme). The procedure represents the first general method for the one-step conversion of RCOCl into valuable pentafluoroethyl ketones.

Full text of DOI:10.1002/anie.201500341

Angewandte
Chemie
DOI: 10.1002/anie.201500341
Pentafluoroethylation Very Important Paper
Well-Defined CuC2F5 Complexes and Pentafluoroethylation of Acid
Chlorides**
Liubov I. Panferova, Fedor M. Miloserdov, Anton Lishchynskyi, Marta Martꢀnez Belmonte,
Jordi Benet-Buchholz, and Vladimir V. Grushin*
Abstract: Four new well-defined CuI complexes bearing a C2F5
ligand have been prepared and fully characterized:
[(Ph3P)2CuC2F5] (2), [(bpy)CuC2F5] (3), [(Ph3P)Cu-
(phen)C2F5] (4), and [(IPr*)CuC2F5] (5). X-ray structures of
all four have been determined, showing that the C2F5-ligated
Cu atom can be di- (5), tri- (2 and 3), and tetracoordinate (4).
The mixed phen-PPh3 complex 4 is a highly efficient fluo-
roalkylating agent for a broad variety of acid chlorides. This
high-yielding transformation represents the first general
method for the synthesis of RCOC2F5 from the corresponding
RCOCl.
14% yield by the thermal decomposition of a CuCF3 deriv-
ative. The Hartwig group[8] have prepared [(phen)Cu(C2F5)]
(phen = 1,10-phenanthroline) for pentafluoroethylation of
(hetero)aryl pinacolboronates and (hetero)aryl bromides.
This complex has been isolated and shown[8a] to equilibrate
with [(phen)2Cu]+[Cu(C2F5)2]À in solution. Two of us[9] have
developed the cupration of C2F5H with [K(DMF)]-
[(tBuO)2Cu], leading to [K(DMF)2][(tBuO)Cu(C2F5)] (1),
whose structure has been established by single-crystal dif-
fraction. There have been no reports of efficient pentafluoro-
ethylation reactions with a structurally defined C2F5CuI
complex. Herein we describe the first study targeting the
synthesis and full characterization of pentafluoroethyl deriv-
atives of copper. We also demonstrate the previously
unknown pentafluoroethylation of acid chlorides with one
of the new well-defined C2F5CuI complexes. This new, broad-
scope transformation is highly efficient and selective, afford-
ing ketones of the type RCOC2F5 in up to 95% yield.
D
erivatives of CuI bearing a CF3 ligand play a central role in
the development of trifluoromethylation methods for the
synthesis of biologically active compounds and specialty
materials.[1] The so-called “CuCF3”, referred to as “an elusive
and complex species” by Wiemers and Burton,[2] is partic-
ularly widely used in synthesis. However, CuCF3 is not a well-
defined compound but rather a variety of species of the
general formula [LnCuCF3], where L is a weakly bound ligand
or a solvent molecule.[3] Fully characterized CF3CuI com-
plexes are very rare and only a handful of such compounds
have been reported.[4]
Complex 1 has been shown[9] to react with 4-IC6H4F to
give a mixture of 4-C2F5C6H4F and 4-tBuOC6H4F in a 1:1.2
molar ratio. The undesired tert-butoxylation could be sup-
À
pressed by the acidolysis of the Cu O bond in 1 with
Et3N·3HF (TREAT HF). This reaction produces so-called
“ligandless” CuC2F5, in which the CuI center is stabilized by
coordination with weakly bound DMF solvent molecules,
Et3N released from the TREAT HF, and tBuOH coproduced
in the cupration step (Scheme 1).[3,9,10] We reasoned that
Synthetic methodologies for the introduction of the C2F5
group into organic molecules are not nearly as developed as
trifluoromethylation methods.[5] Nonetheless, examples have
already been reported[6] of biologically active C2F5 derivatives
that outperform their CF3 congeners. For instance, some
valylprolylvalylpentafluoroethyl ketones have been found to
act as active inhibitors of human neutrophil elastase, whereas
the corresponding CF3 derivatives exhibit no activity.[6a]
Given the clear need for new pentafluoroethylation methods,
it is critical to study C2F5CuI complexes as fluoroalkylating
agents. Such well-defined complexes, however, are even
scarcer than those bearing the CF3 ligand. Daugulis and co-
workers[7] have determined the crystal structure of the highly
unstable [K(DMPU)3]+[Cu(C2F5)Cl]À that was formed in
Scheme 1. Preparation of [K(DMF)2][(tBuO)Cu(C2F5)] (1) and “ligand-
less CuC2F5”.[9]
replacing these weakly coordinated molecules with stronger
binding ligands might produce new isolable complexes of the
type LnCuC2F5 for full characterization and use in penta-
fluoroethylation reactions.
[*] L. I. Panferova, F. M. Miloserdov, Dr. A. Lishchynskyi,
Dr. M. Martꢀnez Belmonte, Dr. J. Benet-Buchholz, Prof. V. V. Grushin
Institute of Chemical Research of Catalonia (ICIQ)
Avgda. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
E-mail: vgrushin@iciq.es
The addition of triphenylphosphine (5 equiv) to ligandless
CuC2F5 in DMF (Scheme 1), followed by evaporation and
crystallization from benzene/hexane produced a PPh3 com-
plex. This complex was expected to be tetrahedral
[(Ph3P)3CuC2F5], akin to the previously characterized CF3
analogue [(Ph3P)3CuCF3].[4d] Unexpectedly, however, X-ray
diffraction showed that the Cu atom in the isolated product
[**] This work was supported by the ICIQ Foundation and the Spanish
Government (Grant CTQ 2011-25418 and Severo Ochoa Excellence
Accreditation 2014-2018 SEV-2013-0319). F.M.M. is thankful to the
Government of Spain (MINECO) for the FPI Ph.D. Scholarship
(BES-2012-054922).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500341.
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Figure 1. ORTEP drawing of [(Ph3P)2CuC2F5] (2) with all H atoms
omitted for clarity and thermal ellipsoids drawn at the 50% probability
level.
Figure 4. ORTEP drawing of [(IPr*)CuC2F5]·C6H5CH3 (5·C6H5CH3) with
the cocrystallized toluene molecule and all H atoms omitted for clarity
and thermal ellipsoids drawn at the 50% probability level.
[(Ph3P)2CuC2F5] (2) is ligated with only two rather than three
phosphines (Figure 1). Given the high lability of the PPh3
ligands in [(Ph3P)3CuCF3],[4d] the bulkier C2F5 group appa-
rently forces the third phosphine off the copper atom. A
similar strategy was used to prepare [(bpy)CuC2F5] (3; bpy =
2,2’-bipyridyl) and [(Ph3P)Cu(phen)C2F5] (4). Treatment of
ligandless CuC2F5 in DMF with bpy or both PPh3 and phen
furnished 3 and 4, which were also structurally characterized
(Figures 2 and 3).
NHC ligand, the corresponding imidazolium salt was treated
À
with basic 1 to prompt Cu NHC bond formation through
deprotonation. In this way, [(IPr*)CuC2F5] (5; IPr* = 1,3-
bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-yli-
dene) was prepared, isolated, and structurally characterized
as a 1:1 toluene solvate (Figure 4). Less bulky imidazolium
salts bearing tBu or 2,6-(iPr)2C6H3 groups on the N atoms
were found to react with 1 nonselectively, producing C2F5H
(19F NMR).
A different approach was used to complexes of the type
[(NHC)CuC2F5], where NHC is an N-heterocyclic carbene.
Rather than reacting ligandless CuC2F5 with a preformed
Both tricoordinate 2 and 3 are planar in the crystal. The Y-
shaped molecule of 2 (Figure 1) displays noticeably different
À
À
À
C Cu P bond angles (117.10(5)8 and 126.58(5)8) and Cu P
À
À
bond distances (2.2845(5) and 2.2585(6) ꢀ). With the N Cu
N angle of 80.0(2)8, the Y geometry of 3 is considerably more
À
À
distorted, as manifested by the C Cu N bond angles of
À
128.3(2)8 and 151.3(2)8 and Cu N bond distances of 2.089(5)
À
and 2.013(4) ꢀ. On average, the Cu C2F5 bond length in 2–5
(1.93–1.99 ꢀ) is longer than in the [Cu(C2F5)Cl]À anion
(1.916(9) ꢀ)[7] and 1 (1.892(5) ꢀ),[9] and more comparable
with the value of 1.982(8) ꢀ previously determined for the
structure of a CuIII complex [(Et2NCS2)Cu(C2F5)2].[11] In 4 and
5, the C2F5 group is disordered over two (78:22) and three
Figure 2. ORTEP drawing of [(bpy)CuC2F5] (3) with all H atoms omit-
ted for clarity and thermal ellipsoids drawn at the 50% probability
level.
À
À
(61:23:16) positions, respectively. The Cu CF2 CF3 bond
angles in 2–5 (111–1248) are similar to those previously
reported for the structures of [Cu(C2F5)Cl]À (116.8(5)8),[7]
1 (115.7(4)8),[9] and the CuIII complex [(Et2NCS2)Cu(C2F5)2]
(117.4(6)8).[11]
Of the four new C2F5CuI derivatives synthesized and
structurally characterized in the current study, only one (4) is
a coordinatively saturated 18e species. Unsurprisingly, 4 is the
most stable and easiest to isolate and purify CuC2F5 complex
reported herein. Furthermore, the synthesis of this compound
is scalable, as was demonstrated by the preparation of 3.52 g
(90% yield) of 4 of > 90% purity (19F NMR). Additional
purification by recrystallization from warm benzene/hexane
furnished analytically and spectroscopically pure 4 as well-
shaped red-orange crystals in 72% overall yield. Although 4 is
air-sensitive and should be handled in an inert atmosphere, it
is noticeably more robust than 16e tricoordinate 2 and 3. The
PPh3 complex 2 was prepared and isolated analytically pure in
Figure 3. ORTEP drawing of [(Ph3P)Cu(phen)C2F5] (4) with all H atoms
omitted for clarity and thermal ellipsoids drawn at the 50% probability
level.
2
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60% yield. The orange bpy complex 3 (59% yield, 95%
purity) is particularly air-sensitive and poorly stable, showing
signs of decomposition (darkening) within a few days even if
stored in an argon-filled glove-box. It is noteworthy that
highly air-sensitive 3 is the C2F5 congener of [(bpy)CuCF3], an
active complex[12] in the oxidative trifluoromethylation of
arylboronic acids.[13] The NHC complex 5 was isolated
spectroscopically pure in 68% yield. Recrystallization from
benzene/hexanes gave analytically pure 5. As mentioned
above, [(phen)CuC2F5] exists in equilibrium with
[(phen)2Cu]+[Cu(C2F5)2]À.[8] Similarly, solutions of 2, 3, and
4 were found to contain 8%, 11%, and 5% of [Cu(C2F5)2]À,
respectively (19F NMR). In contrast, the NHC complex 5 does
not equilibrate with [(IPr*)2Cu]+[Cu(C2F5)2]À in solution,
apparently due to the exceptional steric bulk of the IPr*
ligand.[14]
Figure 5. ORTEP drawing of [(Ph3P)Cu(phen)Cl]·C2H4Cl2 (6·C2H4Cl2)
with the cocrystallized molecule of 1,2-dichloroethane and all H atoms
omitted for clarity and thermal ellipsoids drawn at the 50% probability
level.
As mentioned above, pentafluoroethyl ketones are of
particular importance for the synthesis of biologically active
C2F5 derivatives. Readily available and inexpensive acid
chlorides RCOCl would be ideal precursors to RCOC2F5 by
precipitate of 6 was produced. The structure of 6 in the form
of a 1:1 1,2-dichloroethane solvate was established by X-ray
analysis (Figure 5).
À
pentafluoroethylation of the C Cl bond. However, the only
currently available one-step transformation of this type
proceeds via a ketene intermediate and is, therefore, inappli-
cable to a broad variety of acid chlorides devoid of H atoms in
the a position.[15] In general, C2F5CuI reagents seem promis-
Various acid chlorides 7 cleanly reacted with 4 (1 equiv) to
give the corresponding ketones 8 in high yield (Scheme 2).
The reaction proceeded smoothly with benzoic acid chlorides
bearing electron-withdrawing and electron-donating substitu-
ents in the ortho, meta, and para positions of the benzene ring
(7a–r) and 1-naphthoic acid chloride (7s). Both 2-furancar-
boxylic acid chloride (7t) and 2-thiophenecarboxylic acid
chloride (7u) underwent pentafluoroethylation in nearly
quantitative yield. The aliphatic (7v) and vinylic (7w)
derivatives were also converted into the corresponding
pentafluoroethyl ketones in 85% and 92% yield, respectively.
In all reactions, the conversion was close to quantitative.
Fluorine and chlorine atoms on the aromatic ring are well-
tolerated (8h–n), and so is bromine in the meta position (8p),
as manifested by the high yields (85–95%) of the correspond-
ing ketone products. In contrast, the reaction of 2-bromo-
benzoic acid chloride furnished the desired product (8o) in
only 61% yield, as a consequence of competing pentafluor-
À
ing for pentafluoroethylation of the RCO Cl bond. Neither
1 nor ligandless CuC2F5, however, could be used for this
transformation. First, complex 1 bearing C2F5 and tBuO
ligands on the Cu center both pentafluoroethylates and tert-
butoxylates electrophiles[9] (see above). Second, the tBuOH
by-product present in the ligandless CuC2F5 solutions
(Scheme 1) could esterify RCOCl, especially in the presence
of Cu. Finally, the DMF solvent can react with acid chlorides
+
À
=
to generate [RCOOCH NMe2] Cl , a Vilsmeyer–Haack-
type adduct that is reactive toward nucleophiles, alcohols
included.[16] In contrast, the well-defined pre-isolated C2F5CuI
complexes 2–5 in an inert solvent are devoid of these
problems. Therefore, we explored the possibility of using
them as pentafluoroethylating agents for acid chlorides. The
initial tests were performed with 4-FC6H4COCl as the
substrate to obtain additional information by 19F NMR
spectroscopic analysis of the reaction mixtures.
À
oethylation of the aromatic C Br bond. The so-called “ortho
effect”,[3,17] that is, the enhanced reactivity of halogen atoms
in the 2-position of the ring, evidently brought about the side
formation of 2-(C2F5)C6H4COC2F5 (15%) and 2-
(C2F5)C6H4COCl (10%) in the reaction of 2-BrC6H4COCl.
Likewise, the reaction of 4-IC6H4COCl, which contains
Exploratory experiments indicated that 4-FC6H4COCl
reacted with 1.05 equiv of 2 or 5 (THF, 658C) in a nonselective
manner to give 4-FC6H4COC2F5 in only about 5–25% yield
(19F NMR) at > 90% conversion. The bpy complex 3 was not
considered as a reagent because of its poor stability and
exceedingly facile oxidizability (see above). We were
delighted to find, however, that the mixed phen-PPh3 complex
4 smoothly pentafluoroethylated 4-FC6H4COCl in a highly
selective manner. To achieve high chemoselectivity and avoid
the formation of by-products, 4 used for the fluoroalkylation
should be thoroughly purified by recrystallization. THF was
a particularly convenient solvent for the reaction because the
Cu by-product, [(Ph3P)Cu(phen)Cl] (6), appeared to be
poorly soluble in THF and precipitated out as the penta-
fluoroethylation occurs. Only 1 equiv of 4 was needed to
reach > 95% conversion of 4-FC6H4COCl after 3 h at 658C.
During that time, the red color from 4 vanished and a yellow
À
an even more reactive Ar I bond, with 1 equiv of 4
gave rise to 4-IC6H4COC2F5, 4-(C2F5)C6H4COCl, and 4-
(C2F5)C6H4COC2F5 in an approximately 3:4:6 molar ratio.
With 2 equiv of 4, this reaction afforded the disubstituted
À
product (8q) in 72% yield. The aromatic C Cl (7l–n) and
À
certain C Br (7p) bonds staying intact in the reaction provide
an opportunity for further functionalization of the penta-
fluoroethylated products by a variety of metal-catalyzed
cross-coupling reactions. Such chloroarenes bearing the
strongly electron-withdrawing COC2F5 group on the ring
(8l–n) are electron-deficient and therefore “activated”
[18]
À
toward C Cl bond functionalization with transition metals.
Electron-withdrawing groups on the ring of substituted
benzoic acid chloride derivatives facilitate the reaction. The
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oxidative addition to occur. It is noteworthy that, like other
CuI perfluoroalkyl compounds,[1,4,7–10,12,13,17] 4 and its equilib-
rium partner [Cu(C2F5)2]À (see above) are unreactive toward
=
C O bonds. Therefore, no C2F5 addition to the carbonyl
group of the desired RCOC2F5 product takes place even if 4 is
used in excess for the reaction with RCOCl.
The aforementioned precipitation of 6 during the process
facilitates the workup of the reaction mixtures and isolation of
the desired product. On the other hand, the enhanced
volatility of pentafluoroethyl ketones can cause considerable
losses during their isolation, especially from reactions per-
formed on a small scale. Four less-volatile (GC) pentafluoro-
ethyl ketone products 8 f, 8n, 8p, and 8s were selected for the
synthesis on a larger scale and isolation. The reactions of 7 f,
7n, and 7s performed with 0.2 g of 4 (0.32 mmol) furnished
the corresponding desired isolated products in 68%, 72%,
and 82% yield, respectively. From a larger scale-up experi-
ment with 1 g of 4 (1.6 mmol), 8p was isolated in 93% yield.
The synthesis of 8p was chosen for the largest scale reaction
due to the presence on its molecule of the Br atom for further
functionalization, if desired.
In summary, four novel CuI complexes bearing C2F5
ligands have been prepared and characterized in solution
and in the solid state.[20] Depending on the nature of the
ligands, the C2F5-ligated Cu atom in these complexes can be
di-, tri-, or tetracoordinate. In contrast with tetrahedral
[(Ph3P)3CuCF3],[4d] its C2F5 analogue, [(Ph3P)2CuC2F5] (2), is
trigonal-planar Y-shaped, containing only two PPh3 ligands
per Cu. The mixed phen-PPh3 complex [(Ph3P)Cu(phen)C2F5]
(4) is a highly efficient fluoroalkylating agent for a broad
variety of acid chlorides. This high-yielding transformation
represents the first general method for the synthesis of
pentafluoroethyl ketones from the corresponding acid chlor-
ides in one step.
Scheme 2. Pentafluoroethylation of acid chlorides (0.4 mmol) with 4
(0.4 mmol) in THF (0.5–0.9 mL). The yields were determined by
19F NMR spectroscopy with 1,3-bis(trifluoromethyl)benzene as an
internal standard. For details, see the Supporting Information.
[a] 10 min at 238C. [b] With 0.5 equiv of 4-IC6H4COCl. [c] With
1.1 equiv of 7t.
Received: January 14, 2015
Published online: && &&, &&&&
Keywords: copper · fluorine · organometallic synthesis ·
pentafluoroethylation · pentafluoroethyl ketones
particularly electron-deficient pentafluorobenzoic acid chlo-
ride (7k) reacted with 4 within 10 min at room temperature to
give C6F5COC2F5 (8k) in 85% yield. A nitro group on the
ring, however, is not tolerated: meta- and para-nitrobenzoic
acid chlorides and 3,5-dinitrobenzoic acid chloride did not
yield the corresponding ketones upon treatment with 4.
Instead, these reactions gave rise to C2F5H as the main
product. A detailed study of this change in reactivity was
beyond the scope of the current work. It is conceivable,
however, that coordination of the NO2 group to the CuI
center[3] triggers single-electron transfer and the formation
.
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propose that, like the trifluoromethylation of aryl halides, the
pentafluoroethylation of RCOCl is governed by a nonradical
À
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À
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4
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Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Pentafluoroethylation
L. I. Panferova, F. M. Miloserdov,
A. Lishchynskyi, M. Martꢁnez Belmonte,
J. Benet-Buchholz,
Four well-defined CuC2F5 complexes have
been prepared and fully characterized,
with [(phen)Cu(PPh3)C2F5] (phen=1,10-
phenanthroline) proving to be a remark-
ably efficient fluoroalkylating agent for
a broad variety of acid chlorides (see
scheme). The developed procedure rep-
resents the first general method for the
one-step conversion of RCOCl into val-
uable pentafluoroethyl ketones.
V. V. Grushin*
&&&& — &&&&
Well-Defined CuC2F5 Complexes and
Pentafluoroethylation of Acid Chlorides
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!