Copper(I) Diphosphine Bifluoride Complexes as Efficient Preactivated Catalysts for Nucleophilic Addition on Unsaturated Functional Groups

Article abstract of DOI:10.1021/acs.oprd.9b00443

Herein we report the synthesis of a family of copper(I) diphosphine bifluoride complexes, their characterization, and their use as efficient preactivated catalysts for nucleophilic copper addition of pronucleophiles on unsaturations. Their use as mechanistic probes is also highlighted by the identification of two copper deuterides.

Full text of DOI:10.1021/acs.oprd.9b00443

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Communication
Copper(I) Diphosphine Bifluoride Complexes as Efficient
Preactivated Catalyst for Nucleophilic Addition on Insaturations
Corentin Rasson, and Olivier Riant
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00443 • Publication Date (Web): 06 Jan 2020
Downloaded from pubs.acs.org on January 6, 2020
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Copper(I) Diphosphine Bifluoride Complexes as
Efficient Preactivated Catalyst for Nucleophilic
Addition on Insaturations
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Corentin Rasson and Olivier Riant*
Institute of Condensed Matter and Nanosciences, Molecules, Solids and Reactivity
(
IMCN/MOST) – Université catholique de Louvain, Place Louis Pasteur 1, bte L4.01.02, 1348
Louvain-la-Neuve (Belgium)
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Table of Content
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ABSTRACT
Herein we report the synthesis of a family of copper(I) diphosphine bifluoride complexes their
characterization and their use as preactivated efficient catalyst for nucleophilic copper addition of
pronucleophiles on insaturations. Their use as mechanistical probe is also highlighted by the
identification of two copper deuterides.
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Key Words
Copper Complexes, Bifluoride, Asymmetric catalysis, Diphosphine, Vinylation
INTRODUCTION
During the last decades, nucleophilic copper(I) chemistry has emerged as an efficient tool for
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the addition of pronucleophiles via the formation of Cu-H I, Cu-Si II, Cu-B III or Cu-C IV
species and their reaction on various insaturations. One of the main prerequisite to perform a -
bond metathesis between a silylated or borylated pronucleophile and a copper(I) source (Cu-X) to
generate the active catalytic species is to have either an oxygen derivative or a fluoride ion as the
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X ligand (Scheme 1). According to the hard-soft acid-base theory , those “hard” ligands are
mismatched with the “soft” copper(I) cation which results in a more labile and reactive Cu-X bond.
Scheme 1. Formation of nucleophilic copper species from pronucleophiles and activated copper
sources
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However, despite the increasing number of publications on this topic, to this day, the classical
protocols to obtain a diphosphine/Cu-X catalyst all present some drawbacks either on a practical
point of view or to obtain well-defined species in solution. The first protocol consist in the
combination of a copper source Cu-Y where Y is softer such as CuCl, CuBr or CuCN, an
oxygenated base (MOMe, MOi-Pr, MOt-Bu) and a disphosphine to generate the catalyst
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diphosphine/Cu-OR (Scheme 2a). This protocol is probably the most used in the literature and is
compatible with most reaction conditions. However, the use an alkoxide base can be problematic
in the case of base sensitive substrates. For the second protocol an oxygenated copper(I) source
such as CuOAc, (CuOTf)
2
·C
6
H
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or CuOt-Bu are directly used with a diphosphine to obtain in situ
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the desired catalyst (Scheme 2b). Despite the simplicity of this system, the drawback is that this
procedure is not easily applicable in laboratory not equipped with a glovebox due to the air-
sensitivity of the copper sources. A third possibility is to start from a stable copper(II) source such
as Cu(OAc)
2
, Cu(OTf)
2
or CuF
2
·H
2
O and combine it with an excess of diphosphine to reduce the
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copper(II) to copper(I) and to coordinate it (Scheme 2c). The main problem with this protocol
resides in the formation of a phosphine oxide which have been proved to be an efficient ligand for
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copper and could therefore results in an undesired catalytic cycle. A less used method consist in
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the use of the bench-stable CuF(PPh
3
) ·2MeOH in combination with a diphosphine (Scheme
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2
d). However, it will generate an equilibrium between two active copper catalyst which can
results in two different reactivities. We previously reported the synthesis of a copper diphosphine
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polyfluoride complex as well as some NHC-copper bifluoride complexes. Both complexes
hinted at the possibility to synthesize well-defined copper complexes that could bypass the
problems encountered in the classical methods.
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Scheme 2. In situ preparation of activated copper catalysts and preparation of copper diphosphine
bifluoride
RESULTS AND DISCUSSION
Herein, we report the synthesis, characterization and reactivity of a family of copper(I)
diphosphine bifluoride complexes.
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As stated above, a copper diphosphine polyfluoride complex has already been synthesized.
However, the quality as well as the reactivity of the complex was greatly dependent of the quality
of the starting materials. We therefore devised a new reproducible synthesis (Scheme 3).
Scheme 3. Synthesis of copper(I) (R)-DTBM-Segphos bifluoride complex
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Starting from the mesityl copper(I) and reacting it with 1 equivalent of Et
3
N·3HF to obtain the
intermediate tetrakis(acetonitrile)copper(I) bifluoride 1 characterized by a broad singlet at 14.1
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ppm in H NMR in CD
3
CN and a broad singlet at 166 ppm in F NMR in CD CN. This solution
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was then treated with 1 equivalent of (R)-DTBM-Segphos L1 to obtain the corresponding complex
+
L1Cu in a quantitative yield after thorough drying. This complex is characterized by a broad
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singlet at 13.77 ppm in H NMR in CD
3
CN, a broad singlet at 166.8 ppm in F NMR in CD
3
CN
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and a broad singlet at 2.8 ppm in P NMR in CD
3
CN. Moreover, the F NMR of this complex in
CD
2
Cl
2
exhibits two different peaks, one at -140.7 ppm, corresponding to the distal fluorine atom
(Cu-F-H-F), and one at -191.3 ppm, referring to the proximal fluorine atom (Cu-F-H-F). These
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results are in agreement with those found for other transition-metal bifluorides and bifluoride
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19
salts in the literature. The fact that only one signal is visible in F NMR in CD
CD Cl shows that this complex can either exist under a cationic form in coordinating solvents or
under a neutral form in non-coordinating solvents.
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CN and two in
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Figure 1. X-Ray structure of L1Cu+. Selected bond lengths (Å) and angles (°): Cu-F(1) 1.915,
F(1)-F(2) 2.308, F(1)-F(2)-Cu 120.52
To gain more insight on the nature of the counteranion a TGA analysis was performed on a
+
sample of L1Cu and showed the loss of one HF molecule. By submitting this sample after TGA
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to a F NMR in CD
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Cl only one broad singlet was visible at -197.9 ppm corresponding to the
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proximal fluorine atom. This combination of analysis shows that the counteranion is indeed a
bifluoride. To further confirm this result, single crystals were grown in a toluene/hexane mixture
and X-Ray analysis confirmed the presence of two fluorine (Figure 1). The analysis showed that
the Cu-F bond (1.915 Å) is shorter than the one present in the crystal structure of
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CuF(PPh
3
)
3
·2MeOH (2.062 Å) which tends to indicate a covalent bond between the copper and
the fluoride atom. Moreover the F---F separation (2.308 Å) is slightly bigger than the ones typically
found in FHF salts (between 2.24 and 2.28 Å). Those informations prove that in this crystal
structure the copper complex is present under a neutral form with a copper-fluoride covalent bond
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and an HF molecule in its surrounding. The complex L1Cu was fully characterized and proved
to be highly air stable in the solid state for up to 3 years.
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The next step was to extend this new method to other diphosphine in order to build a library of
active copper complexes (Scheme 4). Various diphosphines were used such as atropoisomeric
diphosphine (L1 to L6’) or ligands with a ferrocene core (L7, L8 and L10). The synthesis prove
to be highly efficient as all complexes were obtained in quantitative yields with only the copper
bound to one ligand visible in NMR.
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Scheme 4. Exemplification of the synthesis with various diphosphine ligands
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Since only copper complexes with one diphosphine ligand were obtained, the synthesis of the
corresponding complexes with two ligands was envisioned using two equivalents of a diphosphine.
This proved to be impossible using L1 due to its steric hinderance and the use of the less bulky
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(
R)-Segphos L2 resulted in a mixture of the bis-coordinated copper (L2) Cu+, L2Cu+ and L2 in
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a 9:1:1 ratio. However, the use of smaller ligands gave only the desired complexes (Scheme 5).
Scheme 5. Formation of copper bis(diphosphine) bifluoride complexes
With these complexes readily prepared and characterized it was decided to test their reactivity
in catalytic transformation. The first reaction to be investigated was the enantioselective reduction
of ketones to the corresponding alcohols. This reaction has notably been studied by Lipshutz and
coworkers using various diphosphine including L1.17 For this reason we decided to reduce
prochiral ketones using the same reactions conditions but replacing the CuCl/NaOt-Bu/L1
+
catalytic cocktail by L1Cu (Scheme 6).
Scheme 6. Enantioselective hydrosilylation of ketones using L1Cu+
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+
L1Cu (1 mol%)
O
OH
PMHS (10 equiv)
R1
R2
Toluene, -78 °C
OH
R1
R2
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OH
OH
Me
Br
3a
75 %
6 % ee
3b 97 %
3c
96 %
95 % ee
9
96 % ee
OH
OH
OH
MeO
O N
2
3d
97 %
95 % ee
3e
97 %
59 % ee
3f
94 %
85 % ee
OH
OH
OH
*
Ph
3g
91 %
91 % ee
3h 96 %
3i
51 %
18 % ee
98 % ee
OH
*
Ph
3j
35 %
% ee
2
To our delight, the reaction occurred spontaneously without the requirement of an added
activating agent, proving the preactivated character of the bifluoride complexes. Moreover, the
reduction of acetophenone 2a in the corresponding alcohol 3a gave comparable results with the
ones previously described by the team of Lipshutz (75 % yield vs 73 % and 96 % ee in both
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cases). For the other alcohol no comparison with the literature could be made using L1 but all
aromatic ketones gave great yields and good to excellent enantiomeric excess. The selectivities
and ee can be explained by a previously described model.18
After these encouraging results a more challenging reaction was investigated by performing the
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enantioselective vinylation of aldehydes described by Shibasaki and coworkers. To our dismay
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applying the same conditions than the ones described but replacing the CuF /L1 system to the
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vinylation of benzaldehyde 4a gave close to no allylic alcohol 6a (Table 1, entry 1). Some tweaking
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of the reaction conditions were performed and best yield and enantiomeric excess were obtained
+
using 4 mol % of L1Cu at 60 °C (Table 1, entry 3). Contrary to the results obtained for the
reduction of ketones, for that example, the yield and ee were lower than the ones previously
reported (89 % yield vs 99 % and 91 % ee vs 94 %). This difference in results can be attributed to
the probable presence of phosphine oxides in the original reaction.
Table 1. Optimization for the enantioselective vinylation of 4a
Entry
x mol% Temp.
°C)
Yield
(%)
ee (%)a
(
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2
3
4
2
2
4
4
40
60
60
50
2
ND
92
24
89
39
91
90
[a] ee determined by chiral HPLC
Despite this difference in results, a small scope of the reaction was studied with the
aforementioned conditions on various aromatic aldehydes and good to excellent yields and
enantiomeric excess were obtained (Scheme 7). It is to be noted that replacing DMF by THF and
lowering the temperature to 50°C gave 6a in 91 % yield and 95 % ee.
Scheme 7. Scope of the enantioselective vinylation reaction
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O
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.L1Cu+ (4 mol%)
Si(OMe)3
DMF, 60 °C
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4
5 (2 equiv)
6
OH
OH
OH
Me
t-Bu
6
a
89 %
1 % ee
6b 63 %
6c
84 %
91 % ee
9
92 % ee
OH
OH
OH
Ph
Cl
Br
6d 92 %
4 % ee
6e
84 %
6f
71 %
94 % ee
9
97 % ee
+
+
To further explore the various complexes synthesized, L2Cu and L10Cu were respectively
tested in the enantioselective allylation of acetophenone 2a and benzaldehyde 4a using allylsilane
as a pronucleophile (Scheme 8).
Both complexes readily reacted withtout the use of activating agent or additive to restore the
catalytic cycle to the contrary of previously reported allylation reaction.19 However, the
transformation afforded the products with only average enantiomeric excess. This could still be
improved by a screening of complexes and reaction conditions.
Scheme 8. Enantioselective allylation of 2a and 4a
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Beside the use of these copper complexes as catalyst, they can also be used to study reaction
+
mechanism or reaction intermediates due to their well-defined character. L9Cu was therefore
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reacted with two equivalent of a deuterated silane to obtain the corresponding copper-deuteride
2
visible in H NMR at 0.61ppm (Scheme 9). The same chemical shift is observed when mixing the
deuterated Stryker’s reagent with one equivalent of dppbz. These results are in accordance with
the trimer [L9CuH]
isolated by Norton and coworkers.20 Moreover, the same reaction was
3
+
2
performed with L1Cu to observe the Cu-D with a chemical shift of 0.93 ppm in H NMR. This
result differs substantially from the report of Lipshutz who observed a shift attributed to L1CuH
1
21
at 2.55 ppm in H NMR. None of those results can be confirmed using either Stryker’s reagent
or its deuterated analogue due to the steric hindrance of L1 which does not allow its reaction with
+
the hexamer. However, given the well-defined character of L1Cu compared to the catalytic
+
cocktail used by Lipshutz and given the verified results obtained with L9Cu we are inclined to
+
think that the result obtained with L1Cu is correct.
Scheme 9. Identification of copper deuterides
CONCLUSION
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In conclusion, we have developed an efficient synthesis to obtain a wide library of copper(I)
diphosphine bifluoride complexes. These complexes were fully characterized and catalytic test
demonstrated them to be very efficient with no need of an additional activating agent. We also
identified two copper deuteride intermediates highlighting the utility of those complexes to
perform mechanistic studies.
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ASSOCIATED CONTENT
Supporting Information.
NMR and TGA for the determination of bifluoride counteranion, 1H, 19F and 31P spectra of
copper complexes, NMR description of copper complexes, 3, 6, 7 and 9 and GC and HPLC
chromatogram for enantioenriched 3, 6, 7 and 9. This material is available free of charge via the
Internet at http://pubs.acs.org.
Corresponding Author

Prof. Olivier Riant. Tel.: +32-10-478777; fax: +32-10-474168; e-mail:
olivier.riant@uclouvain.be
ACKNOWLEDGMENT
Financial support from the Université catholique de Louvain is gratefully acknowledged. We
warmly thank Laurent Collard for his help in determining the enantiomeric excess by HPLC and
Koen Robeyns for performing the X-Ray diffraction.
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For details see supporting information.
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