Molecular design exploiting a fluorine gauche effect as a stereoelectronic trigger

Article abstract of DOI:10.1002/ejoc.201301730

Acyclic conformational control often relies on destabilising noncovalent interactions to give rise to predictable conformer populations. Pertinent examples of such strategies include allylic strain (A^1,2 and A ^1,3) and syn-pentane interactions. However, the incorporation of fluorine vicinal to an electron-withdrawing group (F-C_β-C _α-X) can lead to predictable conformations as a consequence of stabilising hyperconjugative and/or electrostatic interactions. Herein, we describe the application of a fluorine gauche effect to predictably control torsional rotation in a class of fluorinated 4-(dimethylamino)pyridine (DMAP) analogues. Intramolecularisation, such as protonation or acylation, generates an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F-C_β-C_α-N⁺); this is the only rotatable sp³-sp³ bond. In so doing, this substrate binding triggers a conformational change akin to the induced fit process inherent to enzymatic systems. Herein, we validate this design approach to control molecular space. A number of X-ray structures are documented that display this gauche preference (φ_NCCF ≈ 60°). Preliminary catalysis experiments are disclosed together with a kinetic and reactivity analysis. The fluorine gauche effect was used to control torsional rotation in fluorinated dimethylamino pyridine (DMAP) analogues. Upon substrate binding an electropositive nitrogen centre vicinal to the fluorine atom at a molecular hinge (F-C_β-C_α-N⁺) triggers a conformational change akin to those induced in enzymatic systems. Catalysis experiments and kinetic and reactivity studies are disclosed. Copyright

Full text of DOI:10.1002/ejoc.201301730

FULL PAPER
DOI: 10.1002/ejoc.201301730
Molecular Design Exploiting a Fluorine gauche Effect as a Stereoelectronic
Trigger
Yannick P. Rey,[a,b] Lucie E. Zimmer,[b][‡] Christof Sparr,[b][‡] Eva-Maria Tanzer,[a,b][‡]
W. Bernd Schweizer,[b] Hans Martin Senn,*[c] Sami Lakhdar,*[d] and Ryan Gilmour*[a][‡‡]
Dedicated to Professor Ernst-Ulrich Würthwein on the occasion of his retirement
Keywords: Asymmetric catalysis / Conformation analysis / Host-guest systems / Chiral resolution / Kinetics
Acyclic conformational control often relies on destabilising
noncovalent interactions to give rise to predictable conformer
populations. Pertinent examples of such strategies include
allylic strain (A1,2 and A1,3) and syn-pentane interactions.
However, the incorporation of fluorine vicinal to an electron-
withdrawing group (F–Cβ–Cα–X) can lead to predictable con-
formations as a consequence of stabilising hyperconjugative
and/or electrostatic interactions. Herein, we describe the ap-
plication of a fluorine gauche effect to predictably control tor-
sional rotation in a class of fluorinated 4-(dimethylamino)pyr-
idine (DMAP) analogues. Intramolecularisation, such as pro-
tonation or acylation, generates an electropositive nitrogen
centre vicinal to the fluorine atom at a molecular hinge
(F–Cβ–Cα–N+); this is the only rotatable sp3–sp3 bond. In so
doing, this “substrate binding” triggers a conformational
change akin to the induced fit process inherent to enzymatic
systems. Herein, we validate this design approach to control
molecular space. A number of X-ray structures are documen-
ted that display this gauche preference (φNCCF ≈ 60°). Prelim-
inary catalysis experiments are disclosed together with a ki-
netic and reactivity analysis.
formational equilibria that exist between enzyme active site
conformers in response to substrate binding, we sought to
imitate this behaviour using small molecules. It was envis-
aged that a fluorine stereoelectronic effect,[3] when used in a
dynamic sense, might be exploited to elicit a conformational
response upon substrate binding. In view of our recent
work on β-fluoro iminium salts,[4] 4-(dimethylamino)pyr-
idine (DMAP) derivatives such as 1 were a logical platform
from which to explore this concept. It was envisaged that an
intramolecularisation event (Scheme 1, compounds 1Ǟ2)[5]
might induce a fluorine gauche effect, placing the fluorine
synclinal to the electropositive centre (F–Cβ–Cα–N+), al-
lowing for stabilising hyperconjugative (σC–H Ǟσ*C–F) and
electrostatic (N+···Fδ–) interactions.[3,6,7]
Introduction
Enzymes are often referred to as Nature’s catalysts owing
to their unparalleled proficiency in accelerating reactions by
several orders of magnitude.[1] Unsurprisingly, these biomo-
lecules remain the ultimate blueprint for catalyst design,
hence, it is often desirable to incorporate features inherent
to enzymatic processes in the development of functional
small molecules.[2] Whilst conformational flexibility is es-
sential for enzyme function Ϫ ranging from enabling facile
access of substrates, transition-state stabilisation and prod-
uct release Ϫ asymmetric induction requires a degree of
conformational rigidification. Inspired by the dynamic con-
[a] Organisch-Chemisches Institut, Westfälische Wilhelms-
Universität Münster,
Corrensstrasse 40, 48149 Münster, Germany
E-mail: ryan.gilmour@uni-muenster.de
www.uni-muenster.de/Chemie.oc/gilmour
[b] Department of Chemistry and Applied Biosciences, ETH
Zürich,
Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
[c] WestCHEM and School of Chemistry, University of Glasgow,
Glasgow G12 8QQ, Scotland, UK
[d] CNRS, UMR 6507, Laboratoire de Chimie Moléculaire et
Thio-organique, ENSICAEN,
6 Boulevard Maréchal Juin, Caen, France
[‡] These authors contributed equally to this work.
[‡‡] Excellence Cluster EXC 1003, Cells in Motion, Münster,
Germany
Scheme 1. Conformational design concept exploiting a stereoelec-
tronic trigger.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301730.
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Use of a Fluorine gauche Effect as a Stereoelectronic Trigger
Consequently, the substituents on the fluorine-bearing possible gauche arrangements (II; synclinal-exo and III; syn-
carbon would be positioned in a defined area of molecular clinal-endo) would both conceivably benefit from a stabilis-
space (φNCCF ≈ 60°); in this case, one group would be lo- ing electrostatic interaction with the pyrrolidine nitrogen,
cated above the pyridinium system. This may then form the and thus be partitioned by a smaller energetic barrier. How-
basis of a future enantioinduction strategy for catalysis in ever, based on the minimisation of unfavourable nonbond-
which a planar pyridine-bound electrophile would be effec- ing interactions, and the favourable alignment of the C–
tively shielded. Herein, we describe our efforts to emulate H donor and C–F acceptor orbitals (σC–H Ǟσ*C–F), it is
the “induced fit” concept in a small molecule system by reasonable to expect III to be the lowest-energy conformer.
exploiting a dynamic fluorine gauche effect as the principle This hypothesis was therefore explored by a computational
design element.
study to compare the energetics of bond rotation in the
Since the pioneering reports of DMAP catalysis by Litvi- nonfluorinated congener 3 relative to the diphenylfluoro-
nenko and Kirichenko,[8] and Steglich and Höfle,[9] signifi- methyl derivative 4. This would first establish the confor-
cant effort has been invested in developing enantioselective mational influence of the small fluorine substituent com-
variants. The first milestone towards achieving this goal ap- pared to hydrogen, and secondly allow for the influence of
peared three decades later when Vedejs and Chen demon- shielding group modification in species 4 (5; 4-tBu, 6; 4-Ph;
strated that a 2-substituted DMAP analogue could be used Figure 2) to be examined. This initial computational study
as a stoichiometric, chiral acylating reagent.[10] In the ensu- was then complemented by an X-ray diffraction crystallo-
ing years a number of innovative scaffolds have been devel- graphic study of the fluorinated scaffolds, which established
oped in which the σ planes of DMAP have been removed the gauche preference in the solid state and provided struc-
(Figure 1).[11–13] At present, generality in performance is en- tural insights into this novel class of fluorinated materials.
joyed by relatively few systems, with the most widely uti- The structural analysis was then extended to include the
lised being the planar chiral analogues developed by Fu and more sterically demanding 2-naphthyl derivative 7, and the
co-workers.[14] Common to all catalyst design strategies is 2-pyridyl derivative 8 for comparison. Finally, a preliminary
the introduction of substituents that break the inherent validation of this class of materials in a representative enan-
symmetry of the parent system. A particularly effective ap- tioselective transformation was performed together with a
proach has been to substitute the dimethylamino group for kinetic and reactivity analysis.
a chiral pyrrolidine moiety based on proline.
Cognisant of this fact, a process of catalyst design was
initiated. It was envisaged that a simple DMAP scaffold
based on (S)-2-(fluorodiphenylmethyl)pyrrolidine[4a,4b,4d,15]
(Scheme 2) might exhibit the postulated fluorine gauche ef-
fect upon formation of the corresponding pyridinium salt
by an intramolecularisation event, the simplest being pro-
tonation. Consequently, by rendering the pyrrolidino nitro-
gen more electropositive, one might reasonably expect pro-
nounced energy differences to be created in the three stag-
gered conformers separated by 120° (synclinal-endo, syn-
clinal-exo and anti; Scheme 2). Whilst the anti arrangement
(I) would likely be disfavoured on stereoelectronic grounds
Scheme 2. Controlling molecular space by conformational refine-
(enforced alignment of σC–N+ Ǟσ*C–F; Scheme 2), the two ment in a model, fluorinated DMAP system (2; R = Ph).
Figure 1. Selected, structurally diverse catalysts based on the DMAP scaffold.[11,12]
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H. M. Senn, S. Lakhdar, R. Gilmour et al.
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phenyl ring directly above the C–H vector. This CH–π inter-
action is worth about 10–15 kJmol–1 and therefore ac-
counts for the enhanced stability of II in 3 and 4.
Table 2. Relative energies (kJmol–1) and exocyclic torsion angles
φNCCF [°] of rotamers for cationic parent compound 9 and fluoro
derivatives 10–12.
Rotamer
9
10
X = F
Ar = Ph
11
X = F
Ar = 4-tBuPh
12
X = F
Ar = biPh
Figure 2. Target fluorinated DMAP structures for investigation.
X = H
Ar = Ph
ΔE[a] φNCCF ΔE[a] φNCCF ΔE[b] φNCCF ΔE[b] φNCCF
Results and Discussion
IIIa
IIIb
II
0
1.2
8
–58
–58
60
0
0.4
6
–57
–57
64
0
–1
6
–62
–59
66
0
6
–
–
–62
–62
–
Computational Conformational Analysis
I
8
–164
18
–171 11
–173
–
Initially, the three rotamers I, II and III (anti, synclinal-
exo and synclinal-endo, respectively) of 3 (X = H) and 4 (X
= F) were optimised by using density-functional theory at
the M05-2X/6-311+G(2df,p) level. This analysis revealed
that for the neutral nonfluorinated system 3, synclinal-exo
(II) is clearly preferred (–19 kJmol–1; here and throughout,
all energies are expressed relative to rotamer III), whilst syn-
clinal-endo (III) and anti (I) are equally stable (0 and
2 kJmol–1, respectively; see Table 1). Fluorine substitution
(4) has the effect of destabilising the preferred synclinal-exo
rotamer (II) relative to the others, thus bringing the three
rotamers energetically closer together whilst maintaining
the order sc-exo Ͻ sc-endo Յ anti. The synclinal-exo rota-
mers (II; Table 2) of 3 and 4 differ from all other structures
studied herein by a flip of the five-membered pyrrolidine
ring, such that C4 is now “above” the average ring plane
(i.e., on the same side as the 2-substituent) and the pseu-
doaxial hydrogen on C4 points “upwards”. In this confor-
mation, the hydrogen points directly towards the centre of
one of the phenyl rings, thus enabling a stabilising CH–π
interaction (H–ring centre distance of ca. 2.61 Å). The
φNCCF torsions in these structures are significantly smaller
(ca. 50°) than the ideal value of ca. 60°, which positions the
[a] M05-2X/6-311+G(2df,p). [b] BLYP-D/def2-TZVPP.
To compare the torsional preferences in the neutral
forms of the DMAP systems with their activated forms, a
study of N-acylpyridinium salts (1Ǟ2; Scheme 1) was per-
formed. For rotamers III, both stereoisomers of the acylpyr-
idinium salts (s-cis, a and s-trans, b) were considered for
completeness. In the cationic, nonfluorinated parent sys-
tems (9; X = H) the energetic ordering was found to be
synclinal-endo (III) Ͻ synclinal-exo (II) = anti (I) (Table 2).
As predicted by the simple stereoelectronic arguments sum-
marised in Scheme 2, installation of the fluorine atom (10;
X = F) significantly destabilises the anti conformer I rela-
tive to II and III, which are now favoured by 12 and
18 kJmol–1, respectively. Moreover, fluorination increases
the torsional barriers from ca. 17 to ca. 27 kJmol–1 for syn-
clinal-endo (III)Ǟsynclinal-exo (II), and from ca. 25 to
ca. 42 kJmol–1 for synclinal-endo (III)Ǟanti (I). This can
be seen from the torsional energy profiles in Figure 3.
Table 1. M05-2X relative energies (kJmol–1) and exocyclic torsion
angles φNCCF [°][a] of conformers for neutral parent compound 3
and fluorinated derivative 4.
Rotamer
3 (X = H)
φNCCF
4 (X = F)
φNCCF
ΔE
ΔE
III
II
I
0
–19
2
–56
47
–164
0
–7
6
–57
51
–170
Figure 3. M05-2X energy profiles for rotation about the exocyclic
C–C bond in the cations 9 and 10. Only the minima are stationary
points.
[a] Conformations about exocyclic N–C–C–X torsion, φNCCF: syn-
clinal-exo (ca. +60°), synclinal-endo (ca. –60°), anti (ca. 180°).
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Use of a Fluorine gauche Effect as a Stereoelectronic Trigger
Clearly, there is an electrostatic gauche effect worth about orientation of the pyridinium acetyl group in 9, 10 (unsub-
10–15 kJmol–1 that acts to lock the preferred conformation stituted phenyls) nor in 11 (4-tBu-phenyl) (see Table 2). In
about the exocyclic C–C bond into the synclinal-endo (III) the biphenyl system 12, however, the s-trans acetyl confor-
conformer in the fluorinated acylpyridinium species 10–12. mation is preferred by 6 kJmol–1 (reported values for 12
The synclinal-endo rotamers III of cations 9–12 addition- apply to the lower-energy atropisomer of each conformer).
ally profit from a cationic π–π interaction between the This can be rationalised by invoking a weak CH–π interac-
pyridinium system and one of the phenyl rings (displaced tion between the acetyl group and the distal phenyl group
parallel arrangement; e.g., for synclinal-endo-9/10, the dis- (H–ring centre distance of 3.04 Å for s-trans), which is only
tance between ring centres is 3.69/3.71 Å; ring planes are possible when the acetyl is s-trans oriented (Figure 4). The
tilted by 25°/25°). Analysis of the two isomers a and b of 4-tBuPh groups in 11 were found to have little influence on
rotamers III revealed that there was no preference for either torsional preference or acetyl orientation.
The superposition of all twelve synclinal-endo conformers
considered (Figure 5) shows the high similarity in shape of
the basic scaffold across the set of structures, irrespective of
substitution. The most prominent difference is seen between
the neutral systems 3 and 4 (blue sticks) and the cations 9–
12 (i.e., upon the transformation 1Ǟ2). Because of the
slightly stronger pyramidalisation at N1 in neutral systems
such as 3 and 4 (less sp2 character),[16] the pyridyl plane is
more strongly tilted with respect to the plane of the phenyl
group, with which it forms an approximately parallel dis-
placed stack.
Synthesis and Structural Analysis
Having validated the hypothesis that fluorine introduc-
tion increases the barrier to rotation around the N–Cα–Cβ–
F axis in pyridinium salts compared to the neutral systems,
the fluorinated scaffolds 4–7 were prepared so that X-ray
Figure 4. BLYP-D structure of s-trans-synclinal-endo-12.
crystallographic analysis could be conducted (Scheme 3). In
addition to the 4-amino systems bearing modified aryl
units, a single 2-amino derivative (8) was prepared for com-
parison owing to the structural rigidity of the 2-aminopyr-
idine motif, by virtue of the contributing mesomeric forms.
Scheme 3. Synthesis routes to compounds 3 and 5–8.
Figure 5. Superimposed optimised structures of the twelve syn-
clinal-endo conformers, aligned on the carbon atoms of the 2-meth-
We elected to prepare compounds 4–7 by base-induced
ylpyrrolidine scaffold. Compounds 9 and 10 are shown in licorice
coupling of the secondary amines 14–17, respectively, with
4-bromopyridine hydrochloride in dioxane at ambient tem-
representation, carbon is cyan; other structures as sticks: blue (3,
4), tan (11), red (12).
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perature (Scheme 3).[17] The syntheses of the secondary
amines 14–17 have been reported elsewhere.[4d] Despite the
preparative difficulties associated with coupling such steri-
cally demanding amines and the risk of HF elimination, it
was possible to isolate the desired 4-aminopyridine struc-
tures in modest yields (10–40%). Importantly, comparison
of the HPLC profiles of these compounds with racemic
samples confirmed that the reaction conditions did not
erode the optical purity of the compounds (14–17; 94–
99%ee). Compound 8 was prepared in a much higher-yield-
ing sequence starting with the coupling of l-proline (13)
and 2-chloropyridine (18).[18] Conversion of the product
carboxylic acid 19 into the methyl ester followed by double
addition of PhMgBr delivered carbinol 20 in 45% yield
(three steps). Finally, deoxyfluorination using diethylami-
nosulfur trifluoride (DAST) in CH2Cl2 delivered the target
structure 8 in 69% yield.
Scheme 5. Synthesis of 4–7.
Structures 4–7 were then protonated to trigger the con-
formational change of interest (1Ǟ2; Scheme 1), and
mimic the putative intermediate in acylation catalysis.[21]
This also facilitated the isolation of crystals suitable for X-
ray crystallographic analysis, allowing the NCCF torsion
angle (φ) to be determined in the solid state (Figures 6 and
7).
Due to the poor yields obtained in the couplings of sec-
ondary amines 14–17 with 4-bromopyridine hydrochloride,
a comparable reaction sequence was explored for the prepa-
ration of 4–7. Interestingly, all attempts to couple l-proline
13 and 4-chloropyridine proved fruitless, as did a multitude
of metal-catalysed amination conditions.[19] However, by
following the procedure reported by Klotz and co-workers,
it was possible to perform a scalable amination of 4-phen-
oxypyridine (21) with l-proline (13) from the melt
(180 °C).[20] The product 22 is amphoteric and could poten-
tially render further manipulation challenging. Still, methyl-
Figure 6. Salts 28–31 investigated by X-ray crystallography.
To this end, pyrrolidino pyridines 4–7 were converted
ation proved facile with MeOH and thionyl chloride at re- into 28·Sb2F11–, 29·Cl–, 30·Cl– and 31·Cl–, respectively (85–
flux, and the intermediate hydrochloride salt was neutral- 100% yield). Analysis of 28 revealed the expected synclinal-
ised by treatment with Amberlyst A21 (23; 98% over two endo conformation with a torsion angle of φNCCF = –64°
steps; Scheme 4).
(average of the protonated and neutral molecule).[22] It is
also interesting to note that the “flap of the envelope” was
found to be C3, which was placed 0.496 Å over the average
N1C2,4,5 plane.
Interestingly, the corresponding tert-butyl derivative 29
had two symmetry independent molecules in the asymmet-
ric unit, one featuring a synclinal-endo conformation (φNCCF
= –63.9°), and the second adopting the synclinal-exo con-
formation (φNCCF = 47.9°). For the synclinal-endo system,
the flap of the pyrrolidine envelope was established as C3,
located 0.441 Å over the N1C2,4,5 mean plane and trans to
the exocyclic group. The pyramidalisation of the pyrrolidine
nitrogen amounts to 0.045 Å in the direction to the exocy-
clic group.[23] In the case of 30, only the synclinal-endo con-
formation (φNCCF = –63.7°, –60.1°) was found in the two
Scheme 4. Synthesis of compound 23 from l-proline 13.[19]
Unfortunately, all attempts to add aryl Grignard reagents symmetry independent molecules occupying the asymmet-
to this substrate failed, prompting us to explore the use of ric unit, with one phenyl ring of the biphenyl residues being
more reactive aryllithium species. Although this delivered slightly twisted out of the plane.[24] By X-ray crystallo-
the products of interest (24–27, up to 69% yield), the harsh graphic analysis of the catalyst salt 31, two symmetry inde-
conditions led to racemisation in all cases, rendering this pendent molecules were found in the asymmetric unit, both
approach less attractive. The products could, however, be exhibiting the expected synclinal-endo conformation (φNCCF
separated by an additional preparative HPLC step. DAST- = –57.1°, –60.1°).[25]
mediated deoxyfluorination of 24, 26 and 27 installed the
The synclinal-endo conformation was preserved in the
requisite C–F bond and completed the synthetic sequence nonprotonated form of 2-amino pyridine derivative 8
(4, 6 and 7; up to 40% yield). Unfortunately, the 4-tBu de- (φNCCF = –58.9°). Furthermore, the pyrrolidine displayed
rivative 25 proved recalcitrant to fluorination and the start- an envelope conformation with C2, as the flap, located
ing material was recovered quantitatively (Scheme 5).
0.419 Å over the N1C3,4,5 mean plane.[26]
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Use of a Fluorine gauche Effect as a Stereoelectronic Trigger
acetic anhydride, in the presence of catalyst 4, delivered
the expected product 33 rapidly even at low temperatures
(–78 °C, 1.5 h).
Kinetic and Reactivity Analysis
To quantify the nucleophilic reactivity of the pyridine-
derived catalyst 4, reactions with benzhydrylium ions 34–38
were studied by using the linear free energy relationship
shown in Equation (1).[28]
logk2 (20 °C) = sN (E + N)
(1)
where parameters E and N refer to the strength of the elec-
trophile and the nucleophile, respectively, and the sN pa-
rameter characterises the sensitivity of the nucleophile to
variation of the electrophile (Table 3).
Table 3. Benzhydrylium ions 34–38 used as reference electrophiles
in this work.[a]
Figure 7. Analogues 8 and 28–31 investigated by X-ray crystal-
lography. The counterions have been removed for clarity. Thermal
ellipsoids shown at 50% probability level.[22–26]
Preliminary Catalysis Studies
Having validated our molecular design approach both
computationally (Table 1 and Table 2) and crystallographi-
cally (Figure 7), it was important to assess whether or not
the C2 substituent on the pyrrolidine ring eroded the nu-
cleophilicity of the pyridine nitrogen. This remains a major
challenge in the development of enantioselective variants of
this catalyst class.[11] To this end, the efficiency of the cata-
lyst in the kinetic resolution of 1-phenyl ethanol (32Ǟ33)
was studied (Scheme 6).[27] Gratifyingly, reaction of 32 with
[a] Values taken from reference.[28]
The rates of the reactions of the coloured benzhydrylium
tetrafluoroborates with 4 were followed photometrically un-
der pseudo-first-order conditions by using more than ten
equivalents of 4. Under these conditions, the concentrations
of pyridine 4 were effectively constant throughout the reac-
tion and resulted in an exponential decay of the benz-
hydrylium absorbances, from which the pseudo-first-order
rate constants kobs were derived. The slopes of the linear
plots of kobs vs. [4] gave the second-order rate constants k2
(Figure 8), which are listed in Table 4.
Scheme 6. Investigating the nucleophilicity of 4.
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Figure 8. Exponential decay of the absorbance of cation 36
(1.56ϫ10–5 m) during the reaction with 4 (4.50ϫ10–4 m) in CH2Cl2
at 20 °C. (Inset) Determination of the second-order rate constant
k2 from the dependence of kobs on the concentration of 4.
Table 4. Second-order rate constants for the reactions of 4 with
benzhydrylium tetrafluoroborates 34–38 in dichloromethane at
20 °C.[a]
Figure 9. Plot of logk2 vs. the electrophilicity parameters E of the
benzhydrylium ions. Correlation equation: logk2 = 0.75 E + 10.93.
Ar2CH+
k2(4) [m–1 s–1
]
k2(DMAP) [m–1 s–1 [a]
]
k2(DMAP)/k2(4)
Table 5. Equilibrium constants K [m–1] and second-order rate con-
stants for the reactions of 4 and DMAP with the benzhydrilium
ions 37 and 38 in CH2Cl2 at 20 °C.[a]
34
35
36
37
38
1.64ϫ105
5.58ϫ104
2.71ϫ104
6.63ϫ103
2.93ϫ103
–
–
1.35ϫ105
4.96ϫ104
9.84ϫ103
6.45ϫ103
2.42
1.83
1.48
2.20
[a] See ref.[28]
Plots of log(k2) against the electrophilicity parameter E
of the benzhydrilium ions are linear, as required by Equa-
tion (1) (Figure 9). The derived reactivity parameters N and
sN were extracted from the slope and the intercept on the
abscissa, respectively (N = 14.57 and sN = 0.75).
As shown in Table 4, the second-order rate constants for
the reactions of 4 with the benzhydrylium cations 37 and
38 are similar to those derived from the reactions of the
same electrophiles with DMAP, showing that the diphenyl-
fluoromethyl group does not affect the reactivity of the pyr-
idine nitrogen.
37
38
k2
K
k2
K
4
6.63ϫ103
3.60ϫ103
2.93ϫ103 4.37ϫ103
DMAP[a] 1.29ϫ104
5.85ϫ103
5.30ϫ103 5.70ϫ103
[a] Values taken from reference.[28]
Finally, the catalytic efficiency of this class of fluorinated
Because the reactions of 4 with electrophiles 37 and 38 DMAP analogues was investigated in a representative ki-
do not go to completion, the equilibrium constants for netic resolution process. To this end, a solution of phenyl
these reactions were measured by UV/Vis spectroscopy. By ethanol was treated with Ac2O in the presence of 4–7
assuming proportionality between the absorbances and the (Table 6). Although all four catalysts proved to be perfectly
concentrations of the benzhydrylium ions, the equilibrium competent in accelerating this reaction of interest, the levels
constants for the reactions can be determined from the ini- of enantioinduction were negligible. However, the instal-
tial absorbances (A0) of the benzhydrylium ions and the lation of a 4-tBu group gave a small but measurable
absorbances at equilibrium (A) according to Equation (2) enantioselectivity.
(Table 5).
This lack of enantioselectivity may be a consequence of
Table 5 shows that 4 and DMAP display similar reactiv- facile rotation around the acyl pyridinium (N–C) bond,
ity as well as comparable Lewis basicity (K). Consequently, which would expose both faces of the electrophile to 32.
it can be concluded that both the nucleophilicity as well as To investigate this, a five-membered carbocyclic ring was
Lewis basicity are preserved in scaffolds such as 4.
appended to the pyridine moiety to fix the geometry of the
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Eur. J. Org. Chem. 2014, 1202–1211

Use of a Fluorine gauche Effect as a Stereoelectronic Trigger
Table 6. The kinetic resolution of phenyl ethanol 32 by using cata-
lysts 4–7.[a]
Entry Catalyst
Conv. [%][b]
e.r. (32)
e.r. (33)
s
1
2
3
4
4
5
6
7
80[c]
72
57
50:50
50:50
1.00
64.0:36.0
56.0:44.0
55.0:45.0
55.5:44.5 1.56
54.5:45.5 1.33
52.5:47.5 1.21
64
Scheme 8. Palladium-catalysed amination of 45. Conversion deter-
mined by 19F NMR spectroscopy is reported for 46 and 48. The
isolated yield for 47 is reported.
[a] To a solution or a suspension of catalyst 4–7 (5.00 μmol) in n-
hexane (1.0 mL) were added DIPEA (12.7 μL, 75.0 μmol), (Ϯ)-1-
phenylethanol (12.1 μL, 100 μmol) and Ac2O (7.1 μL, 75.0 μmol).
[b] Conversion was determined from the ee of the alcohol and the
ee of the acetate. [c] Conversion was determined by integration of
the GC signals of the alcohol and the acetate (correcting for re-
sponse factors).
the racemate, the use of analogue 46 led to an enantiomeric
ratio of 33 of 70.5:29.5. Comparable performances were ob-
served with 47–49. This supports the notion that incorpora-
tion of the cyclopentenopyridine moiety improves enantio-
selectivity by introducing allylic strain simultaneously be-
tween the pyrrolidino-pyridine and the acyl pyridinium por-
tions of the molecule.
acyl pyridinium species as a consequence of allylic strain
(A1,3).[29] Concurrently, the now substituted C3 pyridyl moi-
ety would reinforce the desired conformation to avoid A1,3
strain between the two ring systems (Scheme 7, compound
44).
Table 7. Kinetic resolution of phenyl ethanol 32 by using catalysts
46–49.[a]
Entry Catalyst Conv. [%]
e.r. (32)
e.r. (33)
s
1
2
3
4
46
47
48
49
26
29
29
32
57.0:43.0
59.0:41.0
56.0:44.0
58.5:41.5
70.5:29.5
72.5:27.5
65.0:35.0
68.0:32.0
2.71
3.17
2.08
2.47
[a] To a solution or a suspension of catalyst 46–49 (5.00 μmol) in
n-hexane (1.0 mL) were added DIPEA (12.7 μL, 75.0 μmol), (Ϯ)-1-
phenylethanol (12.1 μL, 100 μmol) and Ac2O (7.1 μL, 75.0 μmol).
Conversion was determined from the ee of the alcohol and the ee
of the acetate.
Scheme 7. Exploiting 1,3-allylic strain (A1,3) to control the geome-
try of the transient acyl pyridinium species 44.
To this end, the sterically demanding secondary amine
Conclusions
15 was coupled with 4-chloro-2,3-cyclopentenopyridine (45)
[30]
under palladium catalysis to furnish 47 in good overall
In an effort to mimic the “induced fit” concept by using
yield (Scheme 8). A process of screening revealed that the small molecules, a series of chiral pyrrolidino pyridine ana-
N-heterocyclic carbene liberated from hydrochloride salt 50 logues bearing a β-fluoroamine moiety have been investi-
was an extremely competent ligand for this transforma- gated. Remote functionalisation of the pyridine unit renders
tion.[31] Moreover, despite the elevated temperatures of the this moiety electropositive, thus inducing a gauche effect as
coupling conditions, the desired product 47 (R = tBu), con- a consequence of charge transmission through the planar
taining the sensitive β-fluoroamine motif, was isolated in core. This effective form of acyclic conformational control
75% yield with only partial erosion of the optical purity around the only freely rotatable sp3–sp3 bond in the scaffold
(80%ee). These standard conditions were then repeated places the fluorine atom in a synclinal-endo arrangement
with the β-fluoroamines 14–17 to generate a small set of thus preorganising the structure. The substituents on the
catalysts for further screening (46–49; Scheme 8).[32]
fluorine-bearing carbon are strategically positioned to
To validate the importance of the cyclopentenopyridine shield one face of the pyridinium system, forming the basis
motif in the catalyst design, an initial comparison of cata- of an induction strategy for enantioselective reaction de-
lysts 46–49 with 4–7 was performed in the kinetic resolution sign. Efforts to refine the concept of stereoelectronic trig-
of phenyl ethanol (Table 7). An improvement was immedi- gers in molecular design are ongoing in this laboratory and
ately evident. Whereas catalyst 4 delivered product 33 as will be reported in due course.
Eur. J. Org. Chem. 2014, 1202–1211
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1209

H. M. Senn, S. Lakhdar, R. Gilmour et al.
FULL PAPER
count dispersive interactions, either through parameterisation or
an empirical correction, is essential for the systems studied. All
structures were fully optimised and stationary points obtained with
M05-2X were verified as minima by the absence of imaginary fre-
quencies. All energies reported are relative potential energies, ΔE,
which agree with free-energy differences, ΔG, within Ͻ 5 kJmol–1.
Experimental Section
Full experimental procedures are provided in the Supporting Infor-
mation.
General: All reactions using air- or moisture-sensitive compounds
were carried out in flame-dried and evacuated glassware under an
atmosphere of argon. Fluorination reactions were performed under
an atmosphere of argon in pre-dried Teflon vessels. Solvents for
these reactions were dried according to standard procedures or
were taken from the solvent drying system. All chemicals were rea-
gent grade and used as supplied unless otherwise stated. Solvents
for extractions and chromatography were technical grade and dis-
tilled prior to use. Extracts were dried with technical grade Na2SO4
or MgSO4. Analytical thin-layer chromatography (TLC) was per-
formed on precoated Merck silica gel 60 F254 plates (0.25 mm).
Visualisation was accomplished by using ultraviolet light (λ =
254 nm) or by dipping in cerium ammonium molybdate (CAM)
stain [(NH4)6Mo7O24·4H2O (50 g), Ce(SO4)2 (10 g) and H2SO4
(100 mL) in water (900 mL)] or ninhydrin stain, followed by heat-
ing. Flash column chromatography was carried out on Fluka silica
gel 60 (230–400 mesh). Concentration in vacuo was performed at
ca. 10 mbar and 40 °C, drying at ca. 10–2 mbar and room temp. 1H,
19F and 13C NMR spectra were recorded with a Bruker AVANCE
300 MHz, a Bruker DRX 400 MHz, a Bruker AV 400 MHz or an
Agilent DD2 600 MHz spectrometer at ambient temperature. Some
spectra were recorded by the Laboratory for Organic Chemistry
(ETH) NMR service with a Bruker AV 600 MHz, DRX 600 MHz
or DRX 500 MHz spectrometer at ambient temperature. Chemical
shifts (δ) are reported in ppm relative to the residual solvent. Cou-
pling constants (J) are reported in Hz. The multiplicities are re-
ported as: s = singlet, br. s = broad singlet, d = doublet, t = triplet,
q = quartet, m = multiplet. Melting points were measured with a
Büchi B540 melting-point apparatus and are uncorrected. IR spec-
tra were measured with a Perkin–Elmer Spectrum 100 FTIR spec-
trometer and reported in cm–1. The intensities of the bands are
reported as: w = weak, m = medium, s = strong. Optical rotations
were obtained with a JASCO P-2000 polarimeter. HPLC spectra
were recorded with an Agilent 1100 series (DAD, Agilent technol-
ogies 1200 series) by using Reprosil Chiral-OM (5 μm,
250ϫ4.6 mm) or CHIRALCEL OJ-H (5 μm, 250ϫ4.6 mm) col-
umns and n-hexane/isopropanol as the eluent. High-resolution
mass spectra (HR ESI and EI MS) were performed by the MS
service at the Laboratory for Organic Chemistry, ETH Zürich.
Supporting Information (see footnote on the first page of this arti-
cle): General methods and the synthesis of catalysts 4–8, racemic
catalysts 4, 6 and 7, second generation catalysts 46–49, general pro-
cedure for the kinetic resolution of 1-phenylethanol, and GC chro-
matograms, selected NMR spectra, kinetics measurements, and
supporting computational results.
Acknowledgments
The authors gratefully acknowledge generous financial support
from the Westfälische Wilhelms University, Münster, the Alfred
Werner Foundation (assistant professorship to R. G. 2008–2012),
the Swiss National Science Foundation (grant 200021_129498,
2009-2012, to E. M. T.), the ETH Zürich (L. E. Z. was an ETH
Fellow, 2010–1011; Independent Investigator Research Award to
R. G.), Novartis AG Basel and F. Hoffmann La Roche Basel (doc-
toral fellowships to C. S. 2009 and 2010, respectively). This work
was partly supported by the Deutsche Forschungsgemeinschaft
(DFG), DFG EXC 1003 “Cells in Motion - Cluster of Excellence,
Münster”, Germany and SFB 858. The authors thank Prof. Dr.
Herbert Mayr (LMU Munich) for his interest in this work.
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General Procedure for the Kinetic Resolution of Phenylethanol: To
a solution or a suspension of the catalyst (5.00 μmol) in n-hexane
(1.0 mL) were added DIPEA (12.7 μL, 75.0 μmol), (Ϯ)-1-phenyl-
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[25] Crystallographic data for 31. CCDC-932516 contains the sup-
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free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[26] Crystallographic data for 8. CCDC-932512 contains the sup-
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free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: November 18, 2013
Published Online: January 8, 2014
Eur. J. Org. Chem. 2014, 1202–1211
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1211