Active trifluoromethylating agents from well-defined copper(I)-CF 3 complexes

Article abstract of DOI:10.1021/ja802946s

The first examples of isolable and structurally characterized Cu(I)-CF₃ complexes are reported. N-Heterocyclic carbene (NHC)-supported copper tert-butoxide complexes reacted with Me₃Si-CF₃ to afford new (NHC)Cu-CF₃ complexes whose structures were dependent on whether or not the C₄-C₅ positions of the five-membered NHC rings were saturated. In situ generated (SIiPr)Cu-CF₃ cleanly transferred its trifluoromethyl group to a number of organic halides under mild conditions. Copyright

Full text of DOI:10.1021/ja802946s

Published on Web 06/11/2008
Active Trifluoromethylating Agents from Well-Defined Copper(I)-CF
3
Complexes
†
‡
,†
Galyna G. Dubinina, Hideki Furutachi, and David A. Vicic*
Department of Chemistry, UniVersity of Hawaii, 2545 McCarthy Mall, Honolulu, Hawaii 96822, and the DiVision of
Material Sciences, Graduate School of Natural Science and Technology, Kanazawa UniVersity Kakuma-machi,
Kanazawa 920-1192, Japan
Received April 28, 2008; E-mail: vicic@hawaii.edu
Fluorocarbons are becoming increasingly important in the
1
–4
medicinal, materials, and agricultural fields.
The ability of
fluorinated molecules to modulate biological functions may not be
surprising at first glance, as fluorine ranks 13th on the most naturally
abundant elements list. However, only a handful of naturally
5
occurring fluoroorganic molecules have ever been reported. Thus,
the vast majority of organofluorine compounds are manmade.
Consequently, synthetic methodology to incorporate fluorine and
fluorous synthons must be improved in order to prepare sophisti-
cated fluoroorganic molecules on a practical scale. There is an
incredible commercial driving force for improving fluorination
reactions, as three of the top eight selling drugs in 2007 contained
Figure 1. ORTEP diagrams of 2 (left) and 6 (right). Ellipsoids are shown
at the 50% level. Selected bond lengths for 2 (Å): Cu(1)-C(2), 1.902(6);
Cu(1)-C(1), 1.967(6); C(3)-C(4), 1.356(7); Si(1)-C(3), 1.888(7). Selected
bond angles for 2 (deg): C(2)-N(2)-C(17), 125.5(2); C(2)-N(1)-C(5),
6
fluorine, including two out of the top three.
Cross-coupling procedures would greatly facilitate the construc-
tion of fluoroorganic molecules; however they have been slow to
develop. Fluoro-alkyl cross-coupling methods, in particular, are
severely lacking. This gap in synthetic methodology parallels the
fact that only recently have chemists been able to effect cross-
coupling reactions using simple alkyl electrophiles and alkyl
1
24.2(3); C(2)-Cu(1)-C(1), 176.71(11); C(3)-N(1)-C(5), 122.9(3);
C(4)-N(2)-C(17), 123.3(3). Selected bond lengths for 6 (Å): Cu(2)-C(12),
1.906(4); Cu(2)-C(11), 2.022(4). Selected bond angles for 6 (deg):
C(12)-Cu(2)-C(11), 176.72(17); N(3)-C(12)-Cu(2), 127.0(3); N(4)-
C(12)-Cu(2), 124.2(3); C(12)-N(4)-C(15), 124.5(3).
7
,8
I
20
nucleophiles.
for solvated Cu -CF at -50 °C; however, decomposition was
3
Copper, by far, has shown the most promise in trifluoromethy-
lation reactions. However, the copper reactions have been plagued
observed at higher temperatures. Importantly, Burton also noted
that the thermal instability and nature of the decomposition products
9
–12
I
by unreliability, the need to use extremely high temperatures,
demonstrated that solvated Cu -CF
3
is more complex (in terms of
1
3–17
toxic or expensive sources of the CF
3
group,
and competing
aggregation) than previously appreciated, and that control of
nuclearity can have significant consequences in the ability to control
Ullmann coupling and reduction of aryl halides that generally
provide lower yields of fluorinated product. Most of the copper
couplings reported to date also involved the generation of
20
fluoroalkylations. Here we report that the steric bulk of the carbene
ligand in 2 rigorously controls the nuclearity, even in solution, as
no evidence of dimers or higher aggregates are observed by NMR
3
“Cu-CF ” in situ, making it more difficult to understand and control
what was happening at the copper center. We therefore sought to
spectroscopy. The Cu-CF
slightly longer than the Cu-CH
previously reported (IPr)Cu-CH
Cu-Ccarbene bond length in 2 (1.902(6) Å) is also longer than that
for (IPr)Cu-CH (1.887(5) Å).
3
bond length of 1.967 (6) Å in 2 is
I
prepare a well-defined Cu -CF
3
complex in order to systematically
3
bond length of 1.913 (6) Å in the
3
complex. Moreover, the
2
1
study its reactivity with organic halides.
We found the procedure outlined in eq 1 to be the most successful
I
synthetic approach to a stable Cu -CF
3
complex. Surprisingly when
3
1
8
CF
3
3
-SiMe was added to the known NHC copper complex 1,
1
9
not only was the desired CF
C D
6 6
3
group attached to copper ( F NMR,
, δ -33.7) but the H NMR data also suggested incorporation
of the trimethylsilyl group into the major product. (A ∼80:20 ratio
of 2 to the unsilylated (IPr)Cu-CF was observed by NMR
1
3
spectroscopy). The crystal structure of 2 is shown in Figure 1, and
the X-ray data confirms that the NHC ring was indeed silylated at
the 4-position of the imidazole ring (eq 1). This remarkable
silylation reaction is akin to that observed by Arnold and co-
workers, who found that treatment of the neodymium complex 3
1
9
3
with I-SiMe led to the neodymium iodide dimer 4 (eq 2).
Complex 2, to our knowledge, is the first example of an isolable
copper(I)-trifluoromethyl complex. Burton reported NMR evidence
†
As a promising lead, reaction of 2 with Ph-I (neat) at room
temperature for 44 h led to Ph-CF in 33% yield based on copper.
University of Hawaii.
Kanazawa University Kakuma-machi.
‡
3
8
600 9 J. AM. CHEM. SOC. 2008, 130, 8600–8601
10.1021/ja802946s CCC: $40.75  2008 American Chemical Society

C O M M U N I C A T I O N S
2
3
24
Table 1. Trifluoromethylations Mediated by 5 in DMF
at room temperature or at 80 °C. For comparison, runs
employing the TMS-CF /Cu-I/KF system were performed under
25
b
Solvent Compared to Yields Using Cu-I and KF in Place of 5
3
the same conditions as our runs using complex 5 as a catalyst
precursor, and the results are provided in Table 1. Not only are the
yields higher with the well-defined SIiPr ligand (sometimes up to
four times higher), but they are also consistent for a variety of aryl
idodides. Catalytic conditions using 1 equiv of KOt-Bu to regenerate
complex 5 were ineffective, as KOt-Bu reacts with TMS-CF
3
at
a background rate which is too fast (CF H was determined to be
3
the main product under catalytic conditions). If a nucleophile can
be developed to preferentially transmetalate copper into a species
that reacts with TMS-CF
We have shown that ligand supported Cu-CF
3
, then catalysis may be possible at copper.
complexes are stable
3
enough that decomposition can be avoided over long reaction times.
In conclusion, we have shown that the first thermally stable and
well-defined LCu(I)-CF complexes can efficiently trifluorom-
3
ethylate organic halides under mild conditions. Ligand choice is
important, since it was shown that an unsaturated NHC may undergo
3
silylation in the presence of TMS-CF . The ligand effects also
demonstrate that copper can be rationally tuned with supporting
ligands to afford trifluoromethylating reagents that are more reliable
than any method reported to date. Further explorations in ligand
and reagent design may render catalytic reactions at copper possible.
a
b
:
a white precipitate was observed Yields were recorded after
19
1
12
h
and measured by
F NMR relative to 1,3-dimethyl-2-
fluorobenzene as an internal standard. Yields are based on copper as the
limiting reagent.
Acknowledgment. D.A.V. thanks the Office of Basic Energy
Sciences of the U.S. Department of Energy (DE-FG02-07ER15885)
for support of this work. H.F. thanks the Japanese Ministry for an
international exchange fellowship.
Upon heating, product formation is competitive with decomposition
to a brown solid and the formation of an LCu-CF
2
CF
Si-F as detected by F NMR spectroscopy. Similar
fluorocarbon chain elongation had been observed by Burton upon
3
species
1
9
and Me
3
I
20
Supporting Information Available: General experimental proce-
dures and crystallographic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
warming solvated Cu -CF
The presence of Me Si-F as a decomposition product in the
reaction of 2 with aryl halides suggests that the silylated carbene
ring is undesirable in trifluoromethylation reactions. With that in
mind, we targeted the use of carbene ligands containing a saturated
backbone, like SIiPr shown in complex 5 (eq 3). The SIiPr ligand
3
solutions.
3
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(
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3
25) Although no DMF-CF adducts were detected by F NMR, we cannot
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JA802946S
J. AM. CHEM. SOC. 9 VOL. 130, NO. 27, 2008 8601