Catalytic Asymmetric Fluorination of Copper Carbene Complexes: Preparative Advances and a Mechanistic Rationale

Article abstract of DOI:10.1002/chem.202000081

The Cu-catalyzed reaction of substituted α-diazoesters with fluoride gives α-fluoroesters with ee values of up to 95 %, provided that chiral indane-derived bis(oxazoline) ligands are used that carry bulky benzyl substituents at the bridge and moderately bulky isopropyl groups on their core. The apparently homogeneous solution of CsF in C₆F₆/hexafluoroisopropanol (HFIP) is the best reaction medium, but CsF in the biphasic mixture CH₂Cl₂/HFIP also provides good results. DFT studies suggest that fluoride initially attacks the Cu- rather than the C-atom of the transient donor/acceptor carbene intermediate. This unusual step is followed by 1,2-fluoride shift; for this migratory insertion to occur, the carbene must rotate about the Cu?C bond to ensure orbital overlap. The directionality of this rotatory movement within the C₂-symmetric binding site determines the sense of induction. This model is in excellent accord with the absolute configuration of the resulting product as determined by X-ray diffraction using single crystals of this a priori wax-like material grown by capillary crystallization.

Full text of DOI:10.1002/chem.202000081

A Journal of
Accepted Article
Title: Catalytic Asymmetric Fluorination of Copper Carbene
Complexes: Preparative Advances and a Mechanistic Rationale
Authors: Alois Fürstner, Michael Buchsteiner, Luis Martinez-Rodriguez,
Paul Jerabek, Iago Pozo, Michael Patzer, Nils Nöthling, and
Christian W. Lehmann
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To be cited as: Chem. Eur. J. 10.1002/chem.202000081
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10.1002/chem.202000081
Chemistry - A European Journal
Catalytic Asymmetric Fluorination of Copper Carbene Complexes: Preparative Advances and a
Mechanistic Rationale
Michael Buchsteiner, Luis Martinez-Rodriguez, Paul Jerabek, Iago Pozo, Michael Patzer, Nils Nöthling,
Christian W. Lehmann, and Alois Fürstner*
Abstract: The Cu-catalyzed reaction of substituted -diazoesters with fluoride gives -fluoroesters with
ee’s of up to 95%, provided that chiral indane-derived bis(oxazoline) ligands are used that carry bulky
benzyl substituents at the bridge and moderately bulky isopropyl groups on their core. The apparently
homogeneous solution of CsF in C6F6/hexafluoroisopropanol (HFIP) is the best reaction medium, but CsF
in the biphasic mixture CH2Cl2/HFIP also provides good results. DFT studies suggest that fluoride initially
attacks the Cu- rather than the C-atom of the transient donor/acceptor carbene intermediate. This
unusual step is followed by 1,2-fluoride shift; for this migratory insertion to occur, the carbene must
rotate about the Cu-C bond to ensure orbital overlap. The directionality of this rotatory movement
within the C2-symmetric binding site determines the sense of induction. This model is in excellent accord
with the absolute configuration of the resulting product as determined by X-ray diffraction using single
crystals of this a priori wax-like material grown by capillary crystallization.
Introduction
The incorporation of fluorine into active pharmaceutical ingredients (API’s) or agrochemicals often
entails substantial advantages in chemical and/or biological terms.1 (Chiral) -fluoro carbonyl
compounds represent a privileged motif and are therefore prominently featured in API’s;1,2 at the same
*
M. Buchsteiner, Dr. L. Martinez-Rodriguez, Dr. P. Jerabek, I. Pozo, M. Patzer, N. Nöthling, Prof. C. W.
Lehmann, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
Dr. P. Jerabek:
Present Address: Helmholtz-Zentrum Geesthacht, Nanotechnology Department, 21502 Geesthacht
(Germany)
Supporting Information and the ORCID Identification number(s) for the author(s) of this article can be found
under #################
1
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10.1002/chem.202000081
Chemistry - A European Journal
time, they constitute valuable building blocks for further elaboration. Most methods for their synthesis
invoke the carbonyl compound as (masked) enolate or enamine; the price to pay is the need for an
electrophilic fluorine source as the reaction partner.3,4,5 The alternative approach of using an
“umpoled” substrate in combination with an ordinary fluoride salt is currently less developed, despite
potential chemical virtues and practical advantages.6,7,8
Scheme 1. Lead finding of a copper catalyzed formation of -fluoroesters
A recent report on the fluorination of highly electrophilic copper carbenes generated in situ provides
an interesting foray in this direction (Scheme 1).9,10 Specifically, it was shown that -diazoesters such
as 1a, on treatment with catalytic amounts of [Cu(MeCN)4]PF6 (or [Cu(OTf)]2PhMe) and L1 as the
preferred ligand, react with excess KF in a biphasic mixture comprised of hexafluoroisopropanol (HFIP)
and 1,2-dichloroethane (DCE) at 40°C to give the corresponding -fluoroester 2a in good yield. Despite
the excellent track record of chiral bis(oxazolines) (BOX) and related ligands in asymmetric
catalysis,11,12 however, only poor enantioselectivity ( 31% ee) was reached. Use of a monodentate
chiral phosphoramidite in lieu of L1 entailed higher optical purity (86% ee) at the expense of the
chemical yield, which dropped to only 12%.9
Results and Discussion
Reaction optimization and scope. As part of our studies into structure, bonding and reactivity of
organotransition metal carbene complexes,13,14,15,16,17,18 we sought to improve on these lead findings.
We were fully apprehensive that the small size of the fluoride ion constitutes a formidable and inherent
challenge for asymmetric catalysis; moreover, any uncatalyzed and hence racemic background
reaction had to be prevented.19 To this end, it was deemed imperative to find milder reaction
conditions and to carry out a broad ligand screening. The first goal was readily achieved in that the use
2
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of CsF instead of KF allowed the reaction to proceed at ambient temperature in the biphasic mixture
CH2Cl2/HFIPas a ligand-accelerated process.20 Of arguably higher relevance  even beyond the present
context  is the observation that mixtures of HFIP and hexafluorobenzene form an apparently
homogeneous phase capable of dissolving CsF, in which the -fluorination proceeds particularly
cleanly.
Not unexpectedly, the search for effective chiral ligands proved challenging, not least because clear-
cut structure/selectivity relationships were difficult to deduce from the acquired data (for the full list,
see the SI). As one consistent trend, however, it was noticed that standard BOX ligands led to clean
reactions. The poor chiral induction notwithstanding (cf. Scheme 1 and the SI),9 the ligand optimization
exercise remained largely focused on this privileged scaffold.11,12 Our efforts were guided by the notion
that efficient steering of the small incoming fluoride anion likely mandates a tight chiral binding site.
We conjectured that this goal might be reached by adjustment of the following three parameters: (i)
implementation of substituents at the methylene bridge to exert remote control,21,22 (ii) extension of
the lateral “walls” of the C2-symmetric ligand scaffold beyond the tert-butyl substituents in L1, and (iii)
increase of the size of the electrophilic partner by using bulkier -diazoesters.
Figure 1. Subset of the tested BOX-ligands; for the full list, see the SI
Variation of any of these factors alone did not grant success; gratifyingly though, they were found to
synergize. While the commercially available indane-based bis(oxazoline) L2 gave methyl ester 2a with
only 31% ee (Figure 1) and the corresponding tert-butyl ester 2b with equally disappointing 35% ee
3
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(Table 1, entries 1, 2), gem-disubstitution of the methylene bridge entailed some improvement. This
effect has ample precedent in the literature and is usually ascribed to a buttressing effect, the fine-
tuning of the ligand’s bite-angle, and suppression of enolization at this site.11,12 Although these factors
are likely relevant in the present context too, additional aspects seem to play an important role.
Specifically, introduction of a cycloheptyl or cyclopropyl group improved the ee to 45% and 54% for
product 2b, respectively (entries 3, 4). Equally good or even better results were obtained with ligands
such as L5-L9 carrying different benzyl substituents at this position, which furnished 2b with ee’s of up
to 75% (entries 5-9);23 moreover, the size of the ester group in the diazo compound had a marked
effect (cf. entries 11 and 12).
Table 1. Ligand screening and optimization of the reaction conditions
Entry
R
Medium[a]
Ligand
ee (%)[b] (yield)
1
2
3
4
5
6
7
8
Me
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
Me
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
L2
L2
L3
L4
L5
L6
L7
L8
31
35
54
45
66
61
59
75
71
16
52
73
76
66
71
52
9
L9
10
11
12
13
14
15
16
17
18
19
20
21
22
L10
L11
L11
L12
L13
L14
L15
L16
L17
L18
L19
L19
L19
72
70
81
85 (72% yield)[c]
87 (65% yield)[c,d]
89 (87% yield)[c]
[a] A: HFIP (10 equiv.), CH2Cl2; B: HFIP (10 equiv.), C6F6; [b] ee of the isolated pure compound; for details, see the
SI; [c] isolated yield of analytically pure product; [d] using [Cu(OtBu)]4 instead of [Cu(OTf)]2PhMe
4
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Next, we considered placement of substituents at strategic positions of the indane core or an extension
of the scaffold by annulation of additional aryl rings. Such modifications are rare,24,25 but it was hoped
that they might entail a narrower trajectory for the incoming fluoride anion. Screening of a number of
variants showed that bis(oxazoline) L19 carrying bulky p-tert-butyl substituted benzyl moieties at the
bridge and an only moderately big isopropyl substituent on the indane nucleus gave the best result
(for the full data set, see the SI). This particular ligand furnished -fluorophenylacetate 2b in 87% yield
with 89% ee when the reaction was carried out in HFIP/C6F6 as the optimal medium (entry 22). More
electron-deficient -diazocarbonyl derivatives performed even better, especially those carrying the
electron-withdrawing group at the para-position of the aryl ring (Figure 2); the corresponding products
were isolated in high yields with optical purities of up to 95% ee. Comparison of the results obtained
for products 4 and 5 illustrates the influence of the substitution pattern on the outcome; in this context
it is noteworthy that attempted formation of the corresponding ortho-chlorinated analogue failed due
to decomposition of the diazo ester precursor.
Figure 2. Chiral -fluoroester derivatives prepared by copper-catalyzed diazoester decomposition.
Reaction conditions: [Cu(OTf)]2PhMe (2.5 mol%), L19 (5 mol%), CsF (3.5 equiv.), RT, 12 h, HFIP (10
equiv.)/CH2Cl2 (blue) or HFIP (10 equiv.)/C6F6 (red)
Configurational Assignment via Capillary Crystallization. Since none of the resulting -fluorinated
esters shown in Figure 2 had previously been prepared in the literature in optically active form, we
5
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faced the need to rigorously establish the absolute configuration prior to any mechanistic discussion.26
To this end, a sample of 2b (89% ee) as the parent compound of this series was subjected to preparative
HPLC on a chiral stationary phase to remove the remaining minor enantiomer. Low temperature
differential scanning calorimetry showed that 2b (ee  99%) features a broad melting range close to
ambient temperature (ca. +3 to +22°C) and a remarkably strong hysteresis upon cooling (see the SI).
Therefore crystallization was expected to be non-trivial.
Figure 3. Structure of compound 2b in the solid state which allowed the absolute configuration of the
-fluorinated ester derivative to be determined; all hydrogen atoms  except the one on the (S)-
configured chiral center C7  are omitted for clarity
The challenge was met by capillary crystallization: the neat “liquid” sample was filled into a capillary,
which was tightly fused before being chilled in a stream of cold air; the resulting polycrystalline
material was then locally warmed to slightly above melting temperature. This cooling/warming cycle
led to single crystals suitable for X-ray diffraction. The capillary was transferred quickly to the
diffractometer; the collected data set afforded a statistically significant absolute structure parameter
and allowed the absolute configuration to be determined;27 to the best of our knowledge is this the
first example of its kind28 and bodes well for configurational assignments of other chiral liquid samples
in the future. As shown in Figure 3, the major isomer of the -fluoroester 2b ([훼]ퟐ푫ퟎ = +65.9) formed in
the copper catalyzed reaction with ligand L19 is (S)-configured. All other compounds shown in Figure
2 were assigned by analogy, based on the fact that they are invariably dextrorotatory.
Mechanistic Discussion. Despite numerous attempts, we failed to grow single crystals of the copper
precatalyst carrying the optimal ligand L19, most likely because of the greasy lateral substituents.
6
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Therefore, we resorted to solving the structure of the related complex derived from L3, which leads to
the same sense of induction in the fluorination reaction but to a lower ee of 54 % (Table 1, entry 3). In
contrast to the copious information on BOX complexes of CuII and other (Lewis-acidic) transition
metals,29 surprisingly few crystal structures of (chiral) [BOXCuI]X complexes are known in the
literature;30,31,32,33 actually, some of them are intricate dimeric or oligomeric arrays, which likely have
to disassemble before any catalytic reaction can take place.
Figure 4. Structure of complex [L3Cu(MeCN)]BF4 in the solid state; hydrogen atoms on the ligand
backbone are omitted for clarity
In contrast, complex [L3Cu(MeCN)]BF4 is a monomeric entity (Figure 4); the coordination geometry
about the Cu-center is distorted trigonal. The N1-Cu1-N2 bite-angle of 95.9(1)° is wider than that of
the few comparable cases in the literature,31 which likely reflects the influence of the bulky gem-
disubstitution at the bridge as well as the steric demand of the indane core. Although the crystal
structure provides only a static picture, it is noteworthy that the complex is not strictly C2-symmetric
in the solid state; specifically, the N3-Cu1-N1 (121.8(1)°) and the N3-Cu1-N2 (141.5°) angles are notably
uneven, as are the distances Cu1-N1 (2.004(2) Å) and Cu1-N2 (1.952(2) Å).31,34
7
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Figure 5. Graphical representation of relevant nOe contacts in [L11Cu(MeCN)]BF4, which indicate that
the substituted benzyl groups are, on average, “foreward” oriented on the NMR time scale
NMR investigations provided some insights into the role of the substituents at the bridge between the
oxazoline rings.34 NOESY spectra of complex [L11Cu(MeCN)]BF4 in CDCl3 show numerous cross peaks
between the protons of the substituted benzyl groups and those of the indane ring (Figure 5). The
benzyl substituents are hence “forward” oriented in at least one averaged conformer on the NMR
timescale; as such, they (temporarily) reside in vicinity of the incipient carbene, above and below the
catalytically active Cu-center. The crystal structure of a related BOXCu complex with pendant p-(tert-
butyl)benzyl substituents corroborates the notion that these seemingly remote substituents actually
shield the upper and lower face of the coordination plane.31,35
If one takes the ligated acetonitrile as a dummy for the carbene to be formed upon reaction of the Cu-
center with the -diazoester, attack onto the Re-face of the electrophilic C-atom seems most plausible
at first sight, which would entail formation of (R)-2b (compare Figures 5 and 6). Since (S)-2b, however,
has been shown to be the major product, a more involved scenario must be operative. Therefore, a
computational study was performed to gain a better understanding. Density functionals based on the
generalized gradient approximation (GGA) were chosen for the good balance between accuracy and
performance. The BP86 functional was found to reproduce the experimental structure of the copper
complex [L3Cu(MeCN)]BF4 particularly well and was therefore used throughout (for the
computational methods, see the SI).
8
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Figure 6. Computed ground state structure of the donor/acceptor copper carbene complex
[L3Cu=CPh(COOtBu)]BF4 formed from [L3Cu(MeCN)]BF4 and the diazoester 1b; illustration of the
uneven barriers for clockwise and counterclockwise rotation about the CuC bond
The plane defined by the trigonal donor/acceptor carbene center in [L3Cu=CPh(COOtBu)]BF4 is
orthogonal to the {N2Cu}-plane of the chiral catalyst (Figure 6);36 this arrangement is geometrically
favorable and, at the same time, arguably maximizes back-bonding from the filled metal d-orbital that
is most destabilized by the N,N-donor ligand into the empty carbene p-orbital. As one might expect for
a C2-symmetric ligand environment,34 the barriers for clockwise and counter-clockwise rotation about
the CuC bond are notably different. The appreciable barrier heights of 14 and 25 kcalmol-1,
respectively, imply that the carbene moiety does not freely rotate at ambient temperature at which
the reaction with fluoride does occur, but rather oscillates about the conformation of lowest energy.
Importantly, this swinging motion is directional and the amplitudes are uneven, in that clockwise
movement will prevail by large margins as it avoids a clash between the carbene’s substituents and
the rigid indane scaffold.37
In exploring possible trajectories for the attack of fluoride onto this complex, we were surprised to find
that the Cu-center rather than the electrophilic carbene C-atom constitutes the prime site of attack;
no transition state was found for direct C-F bond formation, despite considerable search efforts.38 The
incoming nucleophile approaches the metal center from above or below the coordination plane to
9
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form the copper fluoride complexes F@Cutop and F@Cubot, respectively. It is striking that top-side
attack is barrierless with a submerged transition state TSFCu ,39 provided that a continuum solvent
top
environment was used in the computations (Figure 7). In stark contrast, attack from the bottom face
shows an activation barrier of no less than 12.3 kcalmol-1 (see the SI). Qualitatively, this differential is
rather intuitive and very well in line with the conclusions previously drawn from the solid-state
structure of electrophilic donor/acceptor dirhodium carbenes:13 Any incoming nucleophile, especially
when charged, will avoid dipole repulsion with the lone-pairs of the ester O-atoms40 and hence
preferentially follow a Bürgi-Dunitz trajectory alongside the aryl substituent of the donor/acceptor
carbene.13,41
Figure 7. Reaction profile for nucleophilic attack of fluoride from the top-face of the Cu-carbene
complex [L3Cu=CPh(COOtBu)]BF4, followed by isomerization of F@Cutop into (S)- or (R)-2b; for the free
energy profile of the bottom-face approach, see the SI
Since the top-face approach wins out by far, only the fate of the resulting complex F@Cutop needs to
be considered at this point. Orbital alignment is necessary before the fluoride ligand can migrate from
copper to carbon,42,43 which, in turn, mandates that the carbene unit rotates about the CuC bond.
The transition state for clockwise rotation is 1.9 kcalmol-1 lower in energy (Figure 7); it leads to
10
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complex (R)-2b@Cu, which ultimately delivers (S)-2b upon protonation (note that the inversion is due
to the formalism of the CIP-rules). Although this computational result overestimates the level of
induction, it correctly predicts the sense of induction of the copper catalyzed -fluorination reaction.
Conclusion
The first highly enantioselective metal catalyzed addition of fluoride to -diazoesters is described,
featuring ee’s of up to 95%. To properly assess this result, one has to consider the inherent challenges
for asymmetric catalysis posed by this particular nucleophile, which had basically thwarted an earlier
attempt at rendering this transformation asymmetric.9 Interestingly, the reaction most likely proceeds
by initial attack of fluoride onto the Cu- rather than the C-atom of the electrophilic metal carbene
intermediate; a subsequent 1,2-fluoride shift then leads to product formation. For this migration to
happen, the carbene must rotate about the Cu-C bond to ensure the necessary orbital overlap; the
directionality of this rotatory motion, enacted by the C2-symmetric ligand environment, is the major
enantiodetermining factor. Further work on the structure and reactivity of transition metal carbene
complexes and the stereoselective preparation of organofluorine derivatives44 is underway in our
laboratory and will be reported in due course.
Experimental Section
All experimental details can be found in the Supporting Information. The material includes compound
characterization data, additional crystallographic information, the full list of ligands investigated, HPLC
traces, supporting computational data, and copies of spectra of new compounds.
Acknowledgements
Generous financial support by the Max-Planck-Society, the Alexander-von-Humboldt Foundation
(return scholarship to P. J.), and the Xunta de Galicia and European Union (European Social Fund,
predoctoral fellowship to I. P.) is gratefully acknowledged. We thank the analytical departments of our
Institute for excellent support.
11
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For the Table of Contents
Let’s work together: Even though bisoxazolines are privileged ligands in asymmetric catalysis, standard
representatives give poor ee’s in the copper catalyzed asymmetric fluorination of -diazoesters. The
outcome was greatly improved, however, upon gem-benzylation of the bridge, proper substitution of
the core, and optimization of the medium. The reaction follows an unusual course in that the incoming
fluoride first hits the metal rather than the C-atom of the transient copper carbene complex.
Keywords: Asymmetric Catalysis  Bisoxazoline Ligands  Carbene Complexes  Copper  DFT 
Organofluorine Compounds
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Parenthetically, we note that the configurational assignment of -fluoro--phenylacetic acid
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This phenomenon is particularly well precedented for reactions in which one partner is small
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Related migratory insertion reactions were proposed for different metals, including copper, cf.:
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