Modulating NHC catalysis with fluorine

Article abstract of DOI:10.3762/bjoc.9.316

Fluorination often confers a range of advantages in modulating the conformation and reactivity of small molecule organocatalysts. By strategically introducing fluorine substituents, as part of a β-fluoroamine motif, in a triazolium pre-catalyst, it was possible to modulate the behaviour of the corresponding N-heterocyclic carbene (NHC) with minimal steric alterations to the catalyst core. In this study, the effect of hydrogen to fluorine substitution was evaluated as part of a molecular editing study. X-ray crystallographic analyses of a number of derivatives are presented and the conformations are discussed. Upon deprotonation, the fluorinated triazolium salts generate catalytically active N-heterocyclic carbenes, which can then participate in the enantioselective Steglich rearrangement of oxazolyl carbonates to C-carboxyazlactones (e.r. up to 87.0:13.0).

Full text of DOI:10.3762/bjoc.9.316

Modulating NHC catalysis with fluorine
Yannick P. Rey1,2 and Ryan Gilmour*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2812–2820.
1Organisch-Chemisches Institut, Westfälische Wilhelms-Universität
Münster, Corrensstraße 40, 48149 Münster, Germany, 2Department
of Chemistry and Applied Biosciences, ETH Zürich,
doi:10.3762/bjoc.9.316
Received: 30 August 2013
Accepted: 08 November 2013
Published: 06 December 2013
Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland, and 3Excellence
Cluster EXC 1003, Cells in Motion, Münster, Germany
Email:
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Guest Editor: D. O'Hagan
Ryan Gilmour* - ryan.gilmour@uni-muenster.de
* Corresponding author
© 2013 Rey and Gilmour; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
catalysis; enantioselectivity; fluorine; gauche effect; organo-fluorine;
Steglich rearrangement
Abstract
Fluorination often confers a range of advantages in modulating the conformation and reactivity of small molecule organocatalysts.
By strategically introducing fluorine substituents, as part of a β-fluoroamine motif, in a triazolium pre-catalyst, it was possible to
modulate the behaviour of the corresponding N-heterocyclic carbene (NHC) with minimal steric alterations to the catalyst core. In
this study, the effect of hydrogen to fluorine substitution was evaluated as part of a molecular editing study. X-ray crystallographic
analyses of a number of derivatives are presented and the conformations are discussed. Upon deprotonation, the fluorinated
triazolium salts generate catalytically active N-heterocyclic carbenes, which can then participate in the enantioselective Steglich
rearrangement of oxazolyl carbonates to C-carboxyazlactones (e.r. up to 87.0:13.0).
Introduction
Molecular editing using fluorine is a powerful strategy to modu- substituents to adopt a gauche preference (ΦF–C–C–F ≈ 60°) can
late the conformation and reactivity of small molecule be rationalised by invoking two stabilising hyperconjugative
organocatalysts [1-3]. The negligible steric penalty associated interactions (σC–H→σC–F*). This conformational preference is
with H→F substitution, together with the polarised nature and conserved in numerous systems in which one of the fluorine
stability of aliphatic C–F bonds, render this unit attractive from atoms has been substituted by another electron withdrawing
the perspective of molecular design [4]. The low-lying anti- group (X(δ+); X(δ+)–Cα–Cβ–Fδ−). Often this modification leads
bonding orbital (σC–F*) can interact with an array of vicinal to the introduction of a stabilising electrostatic component, thus
substituents ranging from non-bonding electron pairs, such as in enhancing the interaction: this is exemplified by the pioneering
the case of the fluorine anomeric effect [5], to electron rich work of O’Hagan and co-workers [10-12].
sigma bonds (σ→σ*). The stereoelectronic gauche effect in 1,2-
difluoroethane is the most prominent example (1; Figure 1) In recent years, this laboratory has strategically employed the
[6-9]. The counterintuitive preference of vicinal fluorine aforementioned effects in the design of functional small mole-
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formation [18,22], assist in rationalising the behaviour of the
NHCs generated in situ.
Herein, the synthesis and catalytic efficiency of a series of fluo-
rinated, bicyclic triazolium salts 2 is disclosed. The effect of
molecular editing by hydrogen to fluorine substitution is evalu-
ated in the NHC-catalysed, enantioselective Steglich rearrange-
ment of oxazolyl carbonates 3 to C-carboxyazlactones 4 [29],
recently reported by Smith and co-workers [30-36].
Fluorination sites were selected based on their proximity to the
ring junction nitrogen of the triazolium system (Figure 2).
Consequently, two distinct β-fluoroamine sub-classes may be
generated. The first site positions the β-fluorine atom on a
freely rotatable (sp3–sp3) exo cyclic group (5, 6 and 7),
conceivably allowing for both synclinal-exo and synclinal-endo
conformations to be populated: this is consistent with the
recently reported fluorine–NHC gauche effect [22]. The second
fluorination site embeds the β-fluoroamine within the bicycle
Figure 1: Exploring the effect of fluorine incorporation in triazolium
pre-catalysts (2) for the enantioselective Steglich rearrangement of
oxazolyl carbonates to the respective C-carboxyazlactones (3→4).
cules [13-22], often for application in organocatalysis [1]. framework of the triazolium salt, thus restricting con-
Common to these studies has been the strategic incorporation of formational freedom (e.g. 8). This later scenario was inspired by
a fluoro substituent vicinal to a catalytically active amino group. the elegant work of Rovis and co-workers, which demonstrated
Subsequent generation of a (partial) positive charge at nitrogen that backbone fluorination of bicyclic NHCs improves enantio-
generates the requisite X–Cα–Cβ–Fδ− system (X = N+), thus selectivity in Stetter reactions of heterocyclic aldehydes with
providing a facile approach to controlling rotation around this nitroalkenes [37-40]. Finally, one hybrid system was prepared
bond (ΦXCCF ≈ 60°). In this study, the influence of fluorination containing both β-fluoroamine classes (7). The trifluoro-
on catalyst behaviour is extended to the study of triazolium salts methylated triazolium salt 9 and the non-fluorinated equivalent
such as 2, which can be converted to the respective N-hetero- 10 served as electronic and steric control catalysts for this
cyclic carbenes (NHCs) by simple deprotonation.
study.
Results and Discussion
Given the importance of NHCs in modern organic synthesis
[23-28] it was envisaged that these systems would be intriguing Pre-catalyst synthesis
candidates for investigation. Moreover, structural information The synthesis of a novel series of fluorinated triazolium salts
gleaned from the triazolium salt pre-catalysts regarding con- (7–10) is described, following our previous studies concerning
Figure 2: Target triazolium salts 5–10 for this study. The synclinal-endo conformation of 5 is shown [18]. Only the synclinal-exo arrangement of 6 and
7 is shown [22].
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the preparation of triazolium salts 5 and 6 [18,22]. The route to
target 7 began by treating N-Boc-trans-4-hydroxy-L-proline
methyl ester (11) with diethylaminosulfur trifluoride (DAST) in
CH2Cl2 to install the first fluoro substituent (12) with clean
configurational inversion (88%, Scheme 1).
Oxidation of the pyrrolidine to the corresponding lactam 13
using a Ru(III)/NaIO4 system proceeded smoothly, followed by
TFA-mediated Boc deprotection to yield 14 (75%, 2 steps).
Reduction of the methyl ester to the primary alcohol (15, 18%),
and subsequent protection as the TBDMS ether delivered the
cyclisation substrate 16 in good yield (92%). A three step, one
pot sequence consisting of methylation, treatment with phenyl-
hydrazine and subsequent cyclisation furnished the triazolium
salt 17 in 76% yield (3 steps). Finally, DAST-mediated
TBDMS deprotection/deoxyfluorination completed the syn-
thetic sequence to give 7 in 45% yield.
Scheme 2: Synthesis of the monofluorinated triazolium salt 8.
The pre-catalysts 9 and 10 required for control experiments
Synthesis of the monofluorinated pre-catalyst 8 (Scheme 2) were prepared by an analogous reaction sequence (Scheme 3).
commenced with an Appel reaction of alcohol 15 to prepare the Commercially available (S)-(+)-(trifluoromethyl)pyrrolidine 20
primary bromide 18. Owing to the potentially labile nature of was protected (21, quantitative), oxidised to the corresponding
the primary bromide, this material was used without further lactam (22, 38% over 2 steps) and processed to the target
purification in the next step. Reduction (H2, Pd/C) furnished the triazolium salt 9 (46%, 3 steps). The non-fluorinated catalyst 10
lactam 19 (21% over 2 steps) in preparation for the cyclisation (Scheme 3; lower) was prepared in a short synthesis starting
sequence. As previously described, successive treatment with from the primary bromide 23 [22]. Hydrogenolysis (24, 67%)
the Meerwein salt, phenylhydrazine and methyl orthoformate [41] and subsequent conversion to the triazolium salt completed
yielded the target triazolium salt 8 in 61% over 3 steps.
the short synthesis (52% over 3 steps).
Scheme 1: Synthesis of the difluorinated triazolium salt 7 starting from commercially available N-Boc-trans-4-hydroxy-L-proline methyl ester (11).
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X-Ray structural analysis of 5, 6 and 7
The X-ray crystal structures of triazolium salts 5, 6 and 7 were
then compared to examine the conformation of the β-fluo-
roamine motifs that were the major motivation for this study
(Figure 3) [42]. In previous analyses of (S)-2-(fluorodiphenyl-
methyl)pyrrolidine derivatives, the synclinal-endo con-
formation was almost exclusively observed in the solid state
[13,15,16,18,21,22]. This was also found to be the case in
triazolium salt 5 (ΦNCCF −54.0°), with the diphenylfluo-
romethyl group adopting a quasi-equatorial orientation, presum-
ably to minimise non-bonding interactions as a consequence of
the sterically demanding phenyl groups.
Deletion of these Ph units from the exocyclic group (6) resulted
in a switch to the synclinal-exo conformation (ΦNCCF +67.9°),
with the monofluoromethyl group occupying a quasi-axial
orientation. Interestingly, this synclinal-endo → synclinal-exo
switch is also observed in the corresponding pyrrolidino
systems [13,21]. The hybrid structure 7 containing both β-fluo-
roamine types again showed the synclinal-exo arrangement
(ΦNCCF +63.65°) as expected, although the fluorine group on
the ring system did little to alter the conformation when
compared with 5 and 6.
Having completed the synthesis of the fluorinated triazolium
salts (5–10) for this study, their effectiveness in catalysing the
Steglich rearrangement of an oxazolyl carbonate derivative (25)
Scheme 3: Synthesis of the trifluoromethylated and non-fluorinated
pre-catalysts 9 and 10 for control studies.
Figure 3: X-ray crystal structures of triazolium salts 5·BF4−, 6·BF4− and 7·BF4− [42]. The tetrafluoroborate counterions have been omitted for clarity.
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to the corresponding C-carboxyazlactone 26 was investigated Employing chlorobenzene did not improve conversion, or the
(Table 1). For this initial study, the monofluorinated triazolium enantiomeric ratio of the products (Table 1, entry 8). Having
salt 6 was arbitrarily chosen (10 mol %), with toluene being identified toluene as the solvent of choice, attention was turned
used as the reaction medium and KHMDS as the base [30]. to exploring the effect of the base. It was noted that neither
Gratifyingly, complete conversion was observed after 18 h and DBU (Table 1, entry 9) nor KOt-Bu (Table 1, entry 10) led to
with good levels of enantioselectivity (e.r. 80.5:19.5). Variation higher levels of enantioselectivity. A control reaction using
in the choice of solvent proved detrimental to both the conver- solid KHMDS, rather than the commercial 0.5 M solution in
sion and enantioselectivity (Table 1, entries 2–8). Chlorinated toluene, revealed a lower conversion but did not alter the enan-
solvents such as CH2Cl2 and CDCl3 (Table 1, entries 2 and 3) tiomeric ratio (Table 1, entry 11). However, a commensurate
led to losses in enantioselectivity, whilst THF completely performance was noted with Cs2CO3 (Table 1, entry 12, >99%,
suppressed the reaction (Table 1, entry 4, <1% conversion). e.r. 80.5:19.5). Alterations in reaction concentration had little
Intriguingly, switching from THF to Et2O (Table 1, entry 5) influence on the selectivity (Table 1, entries 13 and 14, 0.02 or
resulted in full conversion and gave appreciable enantio- 0.5 mol·L−1, e.r. 80.5:19.5 and 79.0:21.0, respectively).
selectivity (e.r. 74.0:26.0). This behaviour was also preserved However, catalyst loading did dramatically alter the selectivity
with 1,4-dioxane as solvent (e.r. 74.5:25.5, Table 1, entry 6). outcome (Table 1, entries 15–17). Given that similar enantio-
Hexane gave comparable levels of enantioinduction but with a selectivities were recorded in reactions using Cs2CO3 (cf.
marked decrease in conversion (38%, Table 1, entry 7). KHMDS), an analogous set of reactions were run for complete-
Table 1: Optimisation studies using triazolium salt 6.a,b
Entry
Solvent
Base
Conc. (mol·L−1)
Loading (mol %)
T (°C)
Conversion (%)b e.r.b
1
toluene
CH2Cl2
CDCl3
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
DBU
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
0.19
10
10
10
10
10
10
10
10
10
10
10
10
10
10
30
5
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
>99
89
80.5:19.5
2
59.0:41.0
70.0:30.0
—
3
39
4
THF
<1
5
Et2O
>99
95
74.0:26.0
74.5:25.5
79.0:21.0
71.5:28.5
79.5:20.5
78.5:21.5
79.0:21.0
80.5:19.5
80.5:19.5
79.0:21.0
66.5:33.5
80.5:19.5
—
6
1,4-dioxane
n-hexane
PhCl
7
38
8
65
9
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
67
10
11
12
13
14
15
16
17
18
19
20
21
KOt-Bu
14
KHMDS (solid) 0.19
66
Cs2CO3
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0.19
0.02
0.50
0.19
0.19
0.19
0.02
0.50
0.19
0.19
>99
97
>99
>99
63
1
<1
10
10
30
5
92
81.0:19.0
80.0:20.0
80.0:20.0
80.0:20.0
99
99
96
aRepresentative reaction protocol: To a suspension of 6 in the appropriate solvent was added the base indicated. The mixture was then stirred for
15 min before a solution of 25 (20.0 mg, 76.0 µmol) in toluene was added. The mixture was stirred for a further 18 h, after which time the solution was
concentrated in vacuo and filtered over a plug of silica gel (CH2Cl2 as eluent). The resulting solution was then concentrated in vacuo. bThe conver-
sion and enantiomeric ratio of the product were determined by HPLC on an Agilent 1260 series system using a reprocil chiral-OM 4.6 mm column.
Percent conversion was determined by integration of the starting material and product peaks, correcting for response factors.
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ness (Table 1, entries 18–21). Again, reactions using Cs2CO3 Having evaluated a series of parameters for the catalytic
were not sensitive to changes in concentration (Table 1, entries Steglich rearrangement using catalyst 6, efforts were then
18 and 19), but in contrast to reactions employing KHMDS, focussed on a logical process of molecular editing to clarify the
altering the catalyst loading did not result in an erosion of the effect of H→F substitution (Table 2). Once again, toluene was
enantioselectivity (Table 1, entries 20 and 21, e.r. 80.0:20.0).
employed as solvent, and reactions were run at rt for 18 h at a
Table 2: A catalyst molecular editing study.a,b
Entry
Catalyst
Base
Conversion (%)b
e.r.b
1
2
Cs2CO3
KHMDS
83
0
54.5:45.5c
n.d.
5
6
3
4
Cs2CO3
KHMDS
99
99
80.5:19.5
80.5:19.5
5
6
Cs2CO3
KHMDS
99
14
87.0:13.0
86.0:14.0
7
7
8
Cs2CO3
KHMDS
97
54
77.5:22.5
76.0:24.0
8
9
9
10
Cs2CO3
KHMDS
0
0
n.d.
n.d.
11
12
Cs2CO3
KHMDS
98
81
62.5:37.5
62.5:37.5
10
aRepresentative reaction protocol: A suspension of the catalyst (7.6 µmol) in toluene (200 µL) was treated with Cs2CO3 (2.5 mg, 7.6 µmol) and stirred
for 15 min. A solution of 25 (20.0 mg, 76.0 µmol) in toluene (200 µL) was then added. The mixture was stirred for a further 18 h, after which time the
solution was concentrated in vacuo and filtered over a plug of silica gel (CH2Cl2 as eluent). The resulting solution was then concentrated in vacuo.
bThe conversion and enantiomeric ratio of the product were determined by HPLC on an Agilent 1260 series system using a reprocil chiral-OM 4.6 mm
column. Percent conversion was determined by integration of the starting material and product peaks, correcting for response factors. cReversal in the
sense of enantioselectivity.
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concentration of 0.19 M. Due to the similar enantioselectivities
observed when using KHMDS and Cs2CO3 (Table 1), it was
deemed prudent to perform the study using both bases indepen-
dently. Initially, the bulky diphenylfluoromethyl-containing
triazolium salt 5 was subjected to the optimised conditions. It
was envisaged that one of the phenyl rings might assist in the
facial discrimination of the activated electrophile, as a conse-
quence of the fluorine gauche effect (ΦNCCF −54.0°, Figure 3).
However, the product C-carboxyazlactone 26 was isolated
essentially in racemic form (Table 2, entry 1, e.r. 54.5:45.5).
Despite the modest selectivity, the sense of induction was
inverted relative to what had been previously observed. Puzz-
lingly, reactions in the presence of KHMDS did not yield any of
the desired product (Table 2, entry 2). As previously estab-
lished, deletion of the phenyl rings resulted in a marked
improvement with both the conversion and enantioselectivity
reaching useful values (99%, e.r. 80.5:19.5, Table 2, entries 3
and 4). As had been reported by Rovis et al. for certain Stetter
reactions [37-40], fluorination of the bicycle framework (7)
augmented the catalyst performance (Table 2, entries 5 and 6).
In the presence of Cs2CO3 almost quantitative conversion was
noted together with the highest enantioselectivities of the study
Figure 4: An overview of the molecular editing approach to catalyst
development.
(up to e.r. 87.0:13.0). Again, a significant loss in conversion Experimental
was observed in reactions performed with KHMDS (Table 2, Full experimental data is provided in Supporting Information
entry 6, 14%). Deletion of the fluorine substituent on the exo File 1.
cyclic group (8) resulted in a notable drop in the enantiomeric
ratio (77.5:22.5, Table 2, entry 7), with reactions containing
Supporting Information
KHMDS reaching only 54% conversion. Finally, in the control
reaction with the trifluoromethyl-containing triazolium salt 9,
Supporting Information File 1
no conversion was observed irrespective of the base employed
(Table 2, entries 9 and 10). Deletion of both fluorine atoms
from the catalyst core (10) was accompanied by a drop in
enantioselectivity (e.r. 62.5:37.5), although the reactions did not
display the same sensitivity to changes in base (Table 2, entries
11 and 12).
Experimental part.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-316-S1.pdf]
Acknowledgements
We gratefully acknowledge generous financial support from the
WWU Münster, and the ETH Zürich (Independent Investigator
Research Award to R.G.). This work was partly supported by
the Deutsche Forschungsgemeinschaft, DFG EXC 1003 “Cells
in Motion – Cluster of Excellence, Münster”, Germany. We
thank Dr. S. Paul for performing preliminary catalysis experi-
ments (ETH Zürich dissertation 20370), Dr. E.-M. Tanzer for
preparing compound 25 (ETH dissertation number 20919), and
Dr. C. Daniliuc for determining the X-ray structure of
triazolium salt 7.
Conclusion
In conclusion, the ability of fluorine to modulate the catalytic
performance of N-heterocyclic carbenes in the Steglich
rearrangement of oxazolyl carbonates has been demonstrated. A
focussed molecular editing study (Figure 4) has revealed that
the introduction of a single fluorine atom on the exocyclic unit
leads to enhanced enantioselectivities (6 versus 10, e.r.
80.5:19.5 versus 62.5:37.5). Further augmentation can be
achieved by introduction of a second fluorine substituent on the
catalyst core (7; e.r. 87.0:13.0, 99% conversion). However, the
reinforcing role of these two fluorine substituents in orches-
trating enantioinduction requires clarification and will be the
subject of future investigations. What is apparent is that fluo-
rine incorporation can confer significant advantages in
(organo)catalyst optimisation and design.
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