Syntheses and Applications of (Thio)Urea-Containing Chiral Quaternary Ammonium Salt Catalysts

Article abstract of DOI:10.1002/ejoc.201301594

We herein report our efforts to obtain a new class of systematically modified bifunctional (thio)urea-containing quaternary ammonium salts based on easily obtainable chiral backbones. Among the different classes of catalysts that were successfully synthesized, those based on trans-1,2-cyclohexane diamine were found to be the most powerful for the asymmetric α-fluorination of β-keto esters. Selectivities up to 93:7 could be obtained by using only 2 mol-% of the optimized catalyst. The importance of the bifunctional nature of these catalysts was demonstrated by control experiments using simplified monofunctional catalyst analogues, which gave almost racemic product only.

Full text of DOI:10.1002/ejoc.201301594

FULL PAPER
DOI: 10.1002/ejoc.201301594
Syntheses and Applications of (Thio)Urea-Containing Chiral Quaternary
Ammonium Salt Catalysts
Johanna Novacek[a] and Mario Waser*[a]
Keywords: Phase-transfer catalysis / Hydrogen bonds / Chirality / Enantioselectivity / Fluorination
We herein report our efforts to obtain a new class of system-
atically modified bifunctional (thio)urea-containing quater-
nary ammonium salts based on easily obtainable chiral back-
bones. Among the different classes of catalysts that were suc-
cessfully synthesized, those based on trans-1,2-cyclohexane
diamine were found to be the most powerful for the asym-
metric α-fluorination of β-keto esters. Selectivities up to 93:7
could be obtained by using only 2 mol-% of the optimized
catalyst. The importance of the bifunctional nature of these
catalysts was demonstrated by control experiments using
simplified monofunctional catalyst analogues, which gave al-
most racemic product only.
applications of such catalysts are not common.[7–9] To the
best of our knowledge, only one example describing the
synthesis and application of a thiourea-containing cinchona
alkaloid PTC[7] and two reports concerning urea-containing
cinchona PTCs[8] have been published (Figure 1). As illus-
trated in these reports, one of the major challenges is the
synthesis of these catalysts,[7,8] thus explaining why only a
limited number of different catalysts have been described.
During the preparation of this manuscript, the Zhao group
reported an elegant strategy with which to access a diversi-
Introduction
The use of chiral ammonium salt phase-transfer catalysts
(PTCs) has contributed significantly to the field of asym-
metric catalysis.[1] Compared to others, this catalytic strat-
egy is outstanding because it represents the only generally
applicable catalytic principle that is capable of stereoselec-
tively activating such important nucleophiles as, for exam-
ple, enolates, cyanides, or peroxides in a noncovalent and
easy to handle fashion.[1] Besides monofunctional chiral
ammonium salt catalysts, the use of bifunctional derivatives
has proven to be a powerful strategy to facilitate reactions
where other methods clearly fail.[2] It is noteworthy that the
vast majority of such catalysts contain an additional hy-
droxyl group (phenolic or aliphatic) as the second coordina-
tion site,[2–4] whereas the incorporation of alternative cata-
lytically active motifs has so far been less exhaustively inves-
tigated.[2,5–10]
Among the commonly employed hydrogen-bonding do-
nors, (thio)ureas have been shown to be excellent catalysts
in numerous case studies.[11,12] The successful combination
of their high potential to activate and control the reactivity
of electrophiles combined with the unique nucleophile acti-
vation potential of quaternary ammonium salts should
therefore result in a remarkable bifunctional catalytic sys-
tem. Surprisingly, investigations concerning syntheses and
[a] Institute of Organic Chemistry, Johannes Kepler University
Linz,
Altenbergerstraße 69, 4040 Linz, Austria
E-mail: Mario.waser@jku.at
www.orc.jku.at/mwaser
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301594.
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH &
Co. KGaA. This is an open access article under the terms of
the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the
original work is properly cited.
Figure 1. Known (thio)urea-containing bifunctional ammonium
salt catalysts.[7–9]
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(Thio)Urea-Containing Chiral Quaternary Ammonium Salt Catalysts
fied library of α-amino acid based (thio)urea-containing amine intermediate, which could be methylated again) be-
quaternary ammonium salts that were found to be powerful cause the corresponding intermediates 7 were found to de-
catalysts for asymmetric aza-Henry reactions and the ad- compose to some extent under prolonged exposure to base
dition of thiols to imines (Figure 1).[9]
under the reaction conditions. In addition, dibenzylated
Spurred on by the potential of such bifunctional catalysts tert-amines could not be quaternated any more. Neverthe-
for asymmetric applications and the limited number of dif- less, we were able to obtain sufficient quantities of interme-
ferent catalyst systems available so far, we carried out a sys- diates 7 and, after Boc-deprotection, the final coupling with
tematic feasibility study focusing on the development of different isocyanates or isothiocyanates was found to be
flexible and functional-group tolerant synthetic routes to easily possible, thus giving a series of substituted bifunc-
access a carefully diversified library of (thio)urea-contain- tional ammonium salts 1a–o in a straightforward man-
ing catalysts based on different, easily available chiral scaf- ner.[16] Alternatively, it was also possible to introduce a pi-
folds as shown in Figure 2. Hereby, access to both antipo- peridine moiety first to give intermediate 8, which could
des of the catalysts will be possible, thus overcoming some then be used to access catalysts 1p–r analogously. In ad-
of the major limitations that are apparent when using the dition, we were also able to synthesize the pyridinium-con-
pseudoenantiomeric cinchona alkaloid catalysts.
taining catalyst 1s by employing the Zincke salt 10 to intro-
duce a pyridinium moiety in the first step.[17]
With a robust route to access a carefully diversified li-
brary of cyclohexanediamine-based catalysts 1 at hand, we
next employed the same strategy to access catalysts 2 and 3
(Scheme 2). It should be pointed out that the developed
strategy allows for the synthesis of a larger variety of dif-
ferent catalysts of type 2 and 3. However, for the first
screening in our asymmetric test reaction to determine the
best-suited chiral backbone, we initially just synthesized the
derivatives 2a and 3a shown in Scheme 2, because these
compounds allowed for a direct comparison with the analo-
gous cyclohexanediamine-based catalysts.
In addition to catalysts 1–3, which are based on a chiral
C2-linker, we were also interested in obtaining catalysts
with a chiral C4-linker. Based on our recent experience in
developing tartaric acid-derived organocatalysts,[21,22] we
investigated the synthesis of catalysts 4 starting from known
diamine 14[23] (Scheme 3). Due to the presence of an acid-
labile acetonide moiety, the Boc-protecting group was not
Figure 2. Targeted bifunctional ammonium salt catalysts.
Results and Discussion
Catalyst Syntheses
Recent reports described incorporation of the H-bonding tolerated herein. After some experimentation, the Alloc-
donor first, followed by a final quaternarization step.[7–9] group was found to be best-suited for our approach. The
However, this strategy only gave access to a limited number mono-protection step was found to be less selective than in
of modified catalysts, especially when using cinchona alka- the case of the Boc-procedure employed for the synthesis of
loids, because of possible side reactions of the nucleophilic 6 (see Scheme 1) and even when only 0.4 equiv. allyl chloro-
heteroatoms of the H-bonding donor with the alkylating formate was used, still around 15% di-alloc-protected di-
agent.[13] We have therefore focused on an alternative se- amine was formed. Nevertheless, we were able to obtain
quence proceeding through an early quaternarization, fol- intermediate 15 in reasonable quantities under these unopti-
lowed by late-stage incorporation of the H-bonding donor. mized conditions. Quaternarization was found to be signifi-
The main chiral backbone used for these studies was 1,2- cantly faster than in the syntheses of catalysts 1–3, giving
trans-cyclohexanediamine (5) (Scheme 1).[14] After mono- also access to dibenzylated ammonium salts, which can be
Boc-protection,[15] quaternarization could be achieved attributed to the lower steric hindrance in the tartaric acid-
either by treating 6 with an excess of methyliodide (to ob- derived system. After deprotection with NaBH4 under Pd-
tain trimethylammonium salt-based intermediates 7) or by catalysis, coupling with different isocyanates to obtain the
carrying out a reductive amination with different arylcar- urea-containing catalysts 4 was easily accomplished. Be-
baldehydes first, followed by methylation. It is worth noting cause it was found that urea-containing catalysts 1 were, in
that, whereas direct exhaustive methylation of 6 could be general, more powerful than thioureas in our test reaction
achieved easily, alkylation of the benzylated sec-amine in- (see Table 1), we initially only synthesized and screened the
termediates was found to be significantly slower (usually urea-containing ammonium salts 4 shown in Scheme 3.
resulting in around 30% of recovered tert-amine intermedi-
ate, which could be resubmitted to the methylation). Even
more interestingly, when methylating the naphthyl-methyl-
Catalytic Potential
containing intermediates en route to catalysts 1j–o, the yield
To evaluate the catalytic potential of the new bifunc-
dropped to around 30% (50–60% based on recovered tert- tional catalysts, the asymmetric α-fluorination of β-keto es-
Eur. J. Org. Chem. 2014, 802–809
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J. Novacek, M. Waser
FULL PAPER
Scheme 1. Syntheses of cyclohexanediamine-based catalysts 1 tested in asymmetric applications.[16] Reagents and conditions:[18] (a) Accord-
ing to ref.[19] (b) MeI (5 equiv.), K2CO3 (2 equiv.), CH3CN, room temp., 3 d, quant.; (c) R1CHO (1 equiv.), NaBH4 (1.5 equiv.), MeOH/
THF (1:1), room temp., 4 h; (d) MeI (excess), K2CO3 (2 equiv.), reflux, 3–5 d, 24–64% (two steps); (e) CF3COOH (10 equiv.) or HI (57%
in H2O, 10 equiv.), CH2Cl2, room temp., 2–16 h; (f) R2NCX (1–1.5 equiv.), K2CO3 (3 equiv.), CH2Cl2 or CH3CN, room temp., 8–18 h,
31–71% (two steps); (g) According to ref.[20] (h) Boc2O (1.2 equiv.), CH2Cl2, room temp., 20 h, 72%; (i) MeI (excess), K2CO3 (1 equiv.),
reflux, 3 d, 45%; (j) DMSO, 90 °C, 1 d; (k) CyNCO (1.5 equiv.), K2CO3 (1 equiv.), CH2Cl2, room temp., 18 h, 41% (two steps).
ters 17 was chosen as a test reaction.[24] This reaction has conditions for the fluorination of tert-butyl ester 17a using
been carried out in the past by using chiral PTCs with good NFSI (18) as the fluorinating agent is summarized in
to excellent selectivities.[25] Noteworthy, Maruoka et al. re- Table 1.[27] Initial screening was carried out by using cyclo-
ported the beneficial effect of bifunctional free-hydroxyl- hexanediamine-based catalysts 1. We first found that, for
containing binaphthyl-based catalysts for this reaction,[25b] this specific reaction, the urea-containing catalysts (such as
whereas the groups of Lu and Meng observed a detrimental 1a) performed better than the corresponding thioureas (e.g.,
effect of free-hydroxyl-groups when using cinchona alkaloid 1b) (entries 1 and 2). In addition, an electron-withdrawing
based PTCs.[25d] On the other hand, the use of chiral (thio)- group on the urea moiety was found to be beneficial, lead-
ureas has so far only been briefly investigated for this im- ing to a promising initial enantiomeric ratio (er) of 80:20
portant reaction,[26] thus making it a challenging test reac- under unoptimized conditions (entry 3). In all these initial
tion for our bifunctional catalysts.
experiments, full conversion of starting material within five
An overview of the most significant results obtained in a hours at 0 °C was observed (isolated yields of these small-
very detailed screening of different catalysts and reaction scale experiments were typically around 80%). It is note-
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(Thio)Urea-Containing Chiral Quaternary Ammonium Salt Catalysts
even less selective manner). The lower potential of thioureas
was proven again by using piperidinium-based catalyst 1q.
Interestingly, the tartaric acid-based catalyst 4b performed
only slightly less selectively than 1c (compare entries 3 and
11). Nevertheless, because catalysts 1 were found to be more
potent than those based on alternative chiral skeletons, fur-
ther testing and optimization was conducted by using this
chiral backbone. Catalyst 1c was then employed to screen
a variety of different liquid/liquid conditions (entries 12–
23). Thereby, we identified aqueous K3PO4 (0.5 m, 2 equiv.)
as the best-suited mild inorganic base (aqueous carbonates
performed similarly well, compare entries 3 and 15). The
reaction could be performed in a similarly selective manner
by using different amounts of catalysts (1–20 mol-% were
tested), thus showing the high potential of these catalysts
to control this fast reaction even using low catalyst loadings
(entries 16–18; using less than 1 mol-% resulted in reduced
selectivity). Among a variety of different solvents, m-xylene
was found to facilitate the highest selectivity.
Scheme 2. Catalysts 2 and 3 synthesized and tested herein.
Having identified the biphasic system m-xylene/aqueous
K3PO4 (0.5 m, 2 equiv.) to be the best suited, giving 19a
with 82:18 er by using catalyst 1c at 0 °C, a series of substi-
tuted catalysts 1 was then screened. As expected, thiourea-
containing 1d was found to be less selective (Table 1, en-
try 25), although this was less pronounced than in the pre-
vious experiments. Testing differently substituted ammo-
nium groups and different ureas, it was observed that in-
creasing the steric bulk on the ammonium moiety (for ex-
ample by using a naphthyl group) and using ester-contain-
ing aryl on the urea group, was beneficial (see entries 29
and 32). Accordingly, combining these structural features
in catalyst 1k was found to be particularly advantageous
(entry 33). The α-naphthyl group was found be slightly bet-
Scheme 3. Synthesis of catalysts 4 tested herein. Reagents and con-
ditions:[18] (a) According to Ref.[23] (b) allyl chloroformate
(0.4 equiv.), CH2Cl2, 0 °C, 16 h; (c) MeI (5 equiv.), K2CO3 ter-suited than a β-naphthyl for our purpose (entries 33 vs.
(2 equiv.), CH3CN, reflux, 3 d, 23% (two steps); (d) PhCHO
34). Attempts to further modify other parent systems were
(1 equiv.), NaBH4 (1.5 equiv.), MeOH/THF (1:1), room temp.,
less satisfactory (entries 35 and 36). More interestingly, the
16 h; (e) MeI (excess), K2CO3 (2 equiv.), reflux, 3 d, 11% (three
use of dibenzylated tartaric acid-based catalyst 4c resulted
in a significantly lower selectivity than using monoben-
zylated 4b (entries 36 vs. 11).
Further variation of catalysts 1 by introducing different
esters on the aryl group of the ureas showed that para-sub-
stitution leads to a slightly reduced selectivity (Table 1, en-
steps); (f) BnBr (2.5 equiv.), K2CO3 (2 equiv.), CH3CN, reflux,
16 h; (g) MeI (excess), K2CO3 (1 equiv.), reflux, 2 d, 22% (three
steps); (h) [Pd(PPh3)4] (5%), NaBH4 (3 equiv.), CH2Cl2/MeOH
(1:1), room temp., 2 h; (i) ArNCO (1 equiv.), K2CO3 (1.5 equiv.),
CH2Cl2, room temp., 20 h, 40–69% (two steps).
worthy that using just catalytic amounts of base (entry 4), tries 37 and 38). In contrast meta-disubstitution resulted in
the selectivity dropped significantly, accompanied with a the reasonably selective bifunctional ammonium salt cata-
slightly slower conversion rate. It also should be noted that lyst 1o (entry 39). The selectivity could be slightly improved
the racemic background reaction proceeds reasonably fast further by carrying out the reaction at –10 °C (entry 40),
without any catalyst under liquid/liquid and liquid/solid bi- whereas further reduction in temperature had no further
phasic conditions, thus illustrating the need for highly po- beneficial effect (entry 41).
tent catalysts to control this reaction.
The observed enantioselectivities in all these experiments
The use of a solid base gave 19a with slightly lower (also compared with the results obtained by using the oppo-
enantioselectivity (Table 1, entry 5). Testing the alternative site configured catalysts 1p–r and 4) are in accordance with
catalyst moieties 2 and 3, we found that neither could com- the proposed bifunctional activation model depicted in
pete with catalysts 1 (entries 6 and 7). Thus, no further Scheme 4. Whereas the ammonium group is supposed to
attempts to optimize and fine-tune these ammonium salts activate the enolate of the keto ester, the H-donor group is
were undertaken. Moreover, the pyridinium-containing cat- believed to coordinate the NFSI, thus leading to a highly
alyst 1s (entry 8) did not meet the potential of 1c (we also ordered transition state. Because of the need for a stoichio-
synthesized a pyridinium-based catalyst 1 containing an metric amount of base to obtain high selectivities (see
aryl-substituent on the urea-moiety that performed in an Table 1, entry 4) formation of the enolate and, accordingly,
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Table 1. Identification of the most active catalyst and the best-suited reaction conditions for the asymmetric α-fluorination of β-keto ester
17a.
Entry[a]
Cat. (%)
Solvent
Base (equiv.)
T (°C)
e.r.[b] (R/S)[c]
1
2
1a (5)
1b (5)
1c (5)
1c (5)
1c (5)
2a (5)
3a (5)
1s (5)
1q (5)
4a (5)
4b (5)
1c (5)
1c (5)
1c (5)
1c (5)
1c (20)
1c (2)
1c (1)
1c (2)
1c (2)
1c (2)
1c (2)
1c (2)
1c (2)
1d (2)
1p (2)
1g (2)
1e (2)
1f (2)
1h (2)
1i (2)
1j (2)
1k (2)
1l (2)
1r (2)
4c (2)
1m (2)
1n (2)
1o (2)
1o (2)
1o (2)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (0.05)
K2CO3 (s) (1.1)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
77:23
58:42
80:20
52:48
75:25
34:66
67:33
42:58
35:65
40:60
23:77
78:22
51:49
59:41
81:19
82:18
81:19
81:19
69:31
52:48
78:22
76:24
81:19
82:18
79:21
20:80
75:25
82:18
85:15
79:21
80:20
86:14
90:10
89:11
15:85
43:57
85:15
86:14
91:9
3
4[d]
5
6
7
8
9
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
K2CO3 (0.5 m) (1.1)
KOH (0.5 m) (1.1)
LiOH (0.5 m) (1.1)
K2HPO4 (0.5 m) (2)
K3PO4 (0.5 m) (1.1)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (0.5 m) (2)
K3PO4 (2 m) (2)
10
11
12
13
14
15[e]
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40[f],[g]
41[g]
toluene
toluene
CH2Cl2
cyclohexane
MTBE
fluorobenzene
mesitylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
m-xylene
0
0
0
0
0
0
–10
–20
92:8
88:12
K3PO4 (2 m) (2)
[a] All reactions were run for 5 h (ensuring complete conversion of 17a) using 18 (1.1 equiv.). Different concentrations in the range 0.05–
0.3 m did not affect conversion or selectivity. [b] Determined by HPLC analysis by using a chiral stationary phase. [c] Determined by
comparison of the optical rotation and the retention order with reported values.[25,26] [d] 70% conversion. [e] The use of 0.5 equiv. base
gave 73:27 er only. [f] Partial freezing of the aqueous layer when using 0.5 m K3PO4. [g] 12 h reaction time to ensure complete conversion.
ion pairing with the catalyst, seems crucial. To further prove 2 mol-% catalyst 1o and, in each experiment, complete con-
the necessity for both functional groups we also tested cata- version of the keto ester within 12 h was observed. As can
lyst 20, which lacks the H-bonding donor unit, and 21, con- be seen from the results shown in entries 1–5, the nature of
taining a tert-amine instead of the ammonium group, under the ester group has a pronounced effect on the observed
these reaction conditions and found that both gave 19a with enantioselectivity. The methyl and benzyl esters 17b and
rather low enantioselectivity.
17c, respectively, gave the corresponding products with
Finally, having identified the most active catalyst 1o and lower selectivities of 85:15. The cumyl ester 17d (which was
the best-suited reaction conditions for this transformation, recently found to give good selectivities in phase-transfer
a short screening of different β-keto esters was carried out catalyzed α-alkynylation reactions of β-keto esters[28]) also
(Table 2). All reactions were carried out at –10 °C by using performed slightly less selectively (the corresponding prod-
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(Thio)Urea-Containing Chiral Quaternary Ammonium Salt Catalysts
uct was also found to be rather sensitive towards hydrolysis
and decarboxylation). On the other hand, the sterically
more demanding adamantyl ester 17e gave product 19e with
a reasonably high enantiomeric ratio of 93:7 (entry 5). The
same tendency was also observed when using indanone de-
rivatives 22, 24, and 26. In each case, the adamantyl esters
led to slightly more selectivity than the corresponding tert-
butyl esters (entries 6–11). Tetralone-based ester 28 could
also be successfully employed albeit with a slightly lower
selectivity than 17a, which is also consistent with reports by
others.[25b] Finally, the cyclopentanone-based ester 30 could
also be employed with similar selectivity (entry 13).
Conclusions
We succeeded in introducing a novel class of bifunctional
(thio)urea-containing quaternary ammonium salts based on
easily obtainable chiral backbones. The developed modular
synthetic approach allowed us to access a carefully diversi-
fied library of different catalysts. Among the different
classes tested herein, those ammonium salts based on trans-
1,2-cyclohexane diamine were found to be the most power-
ful catalysts for the asymmetric α-fluorination of β-keto es-
ters. By using the optimized catalyst 1o, selectivities up to
93:7 could be obtained by using 2 mol-% catalyst. The im-
portance of the bifunctional nature of these catalysts was
clearly demonstrated by control experiments using simpli-
fied monofunctional catalyst analogues, which gave almost
racemic product only. Further investigations to obtain even
more powerful catalysts and to elucidate the application
scope of these catalysts for other transformation, as well as
studies concerning the actual activation mode, are ongoing
and will be reported in due course.
Scheme 4. Proposed activation mode of these bifunctional catalysts
and control experiments performed by using the simplified catalysts
20 and 21.
Table 2. Application scope.[a]
Experimental Section
1
General Information: H and 13C NMR spectra were recorded with
a Bruker Avance III 300 MHz spectrometer and with a Bruker
Avance III 700 MHz spectrometer with a TCI cryoprobe; all NMR
spectra were referenced to the solvent peak. High-resolution mass
spectra were obtained with an Agilent 6520 Q-TOF mass spectrom-
eter with an ESI source and an Agilent G1607A coaxial sprayer.
All analyses were made in the positive ionization mode. Purine (m/z
121.050873 [M + H]+) and 1,2,3,4,5,6-hexakis(2,2,3,3-tetrafluoro-
propoxy)-1,3,5,2,4,6-triazatriphosphinane (m/z 922.009798 [M +
H]+) were used for internal mass calibration. IR spectra were re-
corded with a Shimadzu IR Affinity-1 Fourier transform infrared
spectrometer. Optical rotations were recorded with a Perkin–Elmer
Polarimeter Model 241 MC and with a Schmidt and Haensch
Polarimeter Model UniPol L 1000. HPLC was performed with a
Dionex Summit HPLC system with
a
Chiralcel OD-H
(250ϫ4.6 mm), a Chiralcel OD-R (250ϫ4.6 mm, 10 μm), or a
Chiralpak AD-H (250ϫ4.6 mm, 5 μm) chiral stationary phase. All
chemicals were purchased from commercial suppliers and used
without further purification unless otherwise stated. All reactions
were performed under an Ar-atmosphere. Starting β-keto esters
were either purchased from commercial suppliers or prepared ac-
cording to reported methods.[25,29]
[a] All reactions were carried out by using 18 (1.1 equiv.) for 12 h
to ensure complete conversion. [b] Isolated yields. [c] Determined
by HPLC analysis by using a chiral stationary phase. [d] After a
single recrystallization from heptane/EtOAc. [e] The product par-
tially hydrolyzed and decarboxylated during column chromatog-
raphy. [f] Ad = adamantyl. [g] Using the ethyl ester.
Eur. J. Org. Chem. 2014, 802–809
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
807

J. Novacek, M. Waser
FULL PAPER
A detailed experimental section including all the procedures and
analytical data of catalysts and fluorination products as well as
copies of NMR spectra and HPLC chromatograms can be found
in the Supporting Information.
Aqueous K3PO4 (2 m, 2 equiv.) was added to a mixture of keto ester
and catalyst 1o (2 mol-%) in m-xylene (20 mL/mmol keto ester) and
the mixture was cooled to –10 °C. NFSI was added portionwise
over 2 h and the mixture was vigorously stirred for another 10 h at
–10 °C under an Ar atmosphere. The reaction was quenched by
addition of satd. NH4Cl and the mixture was extracted with
CH2Cl2. After drying over Na2SO4 and evaporation to dryness, the
product was purified by silica gel column chromatography (hept-
anes/EtOAc, 20:1) to give the products in the reported yields.
Synthesis of Catalyst 1o
Compound 7d (R1 = α-Np-CH2-). Step 1: 1-Naphthaldehyde
(780 mg, 5 mmol) was added to a solution of 6 (1.07 g, 5 mmol)
[prepared from the dihydrochloride of (S,S)-cyclohexanediamine
(5)[30] according to a published procedure[19]] in THF/MeOH (1:1,
20 mL) and the solution was stirred at room temp. for 2 h. After
the addition of NaBH4 (285 mg, 1.5 equiv.), stirring was continued
for another 2 h at room temp. The reaction was quenched by ad-
dition of H2O and extracted with H2O/Et2O. The organic phase
was washed with brine, dried with Na2SO4, and the solvents were
evaporated to dryness to obtain the crude product, which was used
directly without any purification. Step 2: A mixture of the crude
sec-amine (5 mmol) and K2CO3 (1.38 g, 2 equiv.) in methyl iodide
(10 mL) was stirred and heated at reflux for 3 d. Excess methyl
iodide was removed under reduced pressure and the product was
purified by column chromatography (silica gel; CH2Cl2/MeOH,
40:1Ǟ10:1) to obtain 7d in 37% yield (two steps) (25% recovered
tert-amine intermediate was also obtained that could be methylated
again). [α]2D3 = –5.2 (c = 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3,
298 K): δ = 1.25–1.38 (m, 1 H), 1.45 (s, 9 H), 1.58–1.77 (m, 3 H),
1.85–2.08 (m, 3 H), 2.52–2.64 (m, 1 H), 2.99 (s, 3 H), 3.14 (s, 3 H),
4.14–4.28 (m, 1 H), 5.07–5.20 (m, 1 H), 5.30 (d, J = 13.4 Hz, 1 H),
5.47 (d, J = 13.4 Hz, 1 H), 6.16 (d, J = 10.1 Hz, 1 H), 7.40–7.53
(m, 2 H), 7.54–7.63 (m, 1 H), 7.67 (d, J = 7.0 Hz, 1 H), 7.86 (d, J
= 8.0 Hz, 1 H), 7.94 (d, J = 8.3 Hz, 1 H), 8.22 (d, J = 8.2 Hz, 1
H) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ = 24.5, 24.6, 27.6,
28.4, 35.6, 48.8, 50.6, 51.6, 62.3, 76.5, 80.7, 123.3, 123.6, 125.0,
126.6, 128.1, 129.3, 132.0, 133.1, 134.0, 134.1, 155.6 ppm. IR (film):
Compound (R)-19a: Reacting 17a (112 mg, 0.48 mmol) with NFSI
(18) gave the title compound. Analytical data are in full accordance
with those reported.[25] Yield 95%; 92:8 er; [α]2D0 = +3.2 (c = 0.65,
CHCl3). 1H NMR (700 MHz, CDCl3, 298 K): δ = 1.41 (s, 9 H),
3.38 (dd, J = 22.8, 17.6 Hz, 1 H), 3.71 (dd, J = 17.6, 10.9 Hz, 1
H), 7.44 (t, J = 6.8 Hz, 1 H), 7.48 (d, J = 7.4 Hz, 1 H), 7.67 (t, J
= 7.6 Hz, 1 H), 7.81 (d, J = 7.7 Hz, 1 H) ppm. 13C NMR
(175 MHz, CDCl3, 298 K): δ = 27.9, 38.4 (d, J = 24.1 Hz), 84.2,
94.5 (d, J = 202.4 Hz), 125.5, 126.6, 128.6, 133.7, 136.6, 151.1 (d,
J = 3.5 Hz), 166.4 (d, J = 27.9 Hz), 195.9 (d, J = 17.9 Hz) ppm.
19F NMR (282 MHz, CDCl3, 298 K): δ = –164.0 (dd, J = 22.8,
10.9 Hz) ppm. IR (film): ν = 3003, 2981, 2936, 1753, 1717, 1607,
˜
1466, 1370, 1296, 1209, 1152, 1074, 924, 835, 746, 723 cm–1. HRMS
(ESI): m/z calcd. for C14H15FO3 [M + NH4]+ 268.13435; found
268.13488. The enantioselectivity was determined by HPLC analy-
sis {Chiralpak AD-H; hexane/iPrOH, 200:1; 0.75 mL/min; 10 °C;
tR = 25.0 [(S)-enantiomer], 32.2 [(R)-enantiomer] min}.
Supporting Information (see footnote on the first page of this arti-
cle): General information, syntheses of bifunctional ammonium
salts, asymmetric α-fluorination, copies of NMR spectra of key
intermediates and most relevant catalysts, copies of NMR spectra
of selected known compounds and of new fluorination products,
HPLC chromatograms (chiral stationary phase).
ν = 3439, 3244, 3005, 2976, 2936, 2864, 1697, 1508, 1489, 1456,
˜
1393, 1366, 1321, 1273, 1242, 1159, 1047, 1024, 870, 808, 783,
733 cm–1. HRMS (ESI): m/z calcd. for C24H35N2O2 [M+]
383.2699; found 383.2693.
+
Acknowledgments
Catalyst 1o. Step 1: A solution of quaternary ammonium salt 7d
(105 mg, 0.2 mmol) and trifluoroacetic acid (155 μL, 10 equiv.) in
CH2Cl2 (2 mL) was stirred at room temp. for 2 h. After evaporation
to dryness, the crude amine was directly subjected to the final cou-
pling step (the reaction could also be carried out by using aq. HI).
Step 2: A mixture of amine, 3,5-dimethoxycarbonyl isocyanate
(70 mg, 1.5 equiv.), and K2CO3 (83 mg, 3 equiv.) in CH2Cl2 (2 mL)
was stirred at room temp. for 18 h. After filtration and evaporation
to dryness, the crude product was purified by column chromatog-
raphy (CH2Cl2/MeOH, 50:1Ǟ10:1) to obtain catalyst 1o (74 mg,
57%; two steps) as a yellowish oil. [α]2D3 = –49.1 (c = 0.75, CH2Cl2).
1H NMR (300 MHz, CDCl3, 298 K): δ = 1.25–1.48 (m, 2 H), 1.62–
1.90 (m, 2 H), 1.91–2.08 (m, 2 H), 2.15–2.28 (m, 1 H), 2.58–2.70
(m, 1 H), 2.90 (s, 3 H), 3.17 (s, 3 H), 3.94 (s, 6 H), 4.45–4.70 (m, 2
H), 5.42 (d, J = 13.1 Hz, 1 H), 5.70 (d, J = 13.1 Hz, 1 H), 7.15 (t,
J = 7.6 Hz, 2 H), 7.24 (d, J = 7.8 Hz, 1 H), 7.45 (d, J = 7.1 Hz, 1
H), 7.66 (t, J = 8.6 Hz, 2 H), 7.97 (d, J = 9.7 Hz, 1 H), 8.08 (d, J
= 8.6 Hz, 1 H), 8.42 (t, J = 1.4 Hz, 1 H), 8.56 (d, J = 1.4 Hz, 2 H),
9.05 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3, 298 K): δ = 24.5,
25.0, 27.4, 36.1, 48.0, 50.6, 51.4, 52.4, 63.5, 77.3, 122.9, 123.2,
123.8, 124.6, 125.0, 126.4, 127.8, 129.0, 131.2, 131.7, 132.8, 133.6,
This work was supported by the Austrian Science Funds (FWF)
(project number P22508-N17). Financial support by the Federal
State Government of Oberösterreich (research fellowship to J. N.)
is gratefully acknowledged. We are grateful to Prof. Norbert Müller
for fruitful discussions and to Dr. Markus Himmelsbach and DI
Michael Reisinger for their support with HRMS analysis. The
NMR spectrometers were acquired in collaboration with the Uni-
versity of South Bohemia (CZ) with financial support from the
European Union (EU) through the EFRE INTERREG IV ETC-
AT-CZ program (project number M00146, RERI-uasb).
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808
www.eurjoc.org
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: October 24, 2013
Published Online: December 2, 2013
Eur. J. Org. Chem. 2014, 802–809
© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
809