Towards an Asymmetric Organocatalytic α-Azidation of β-Ketoesters

Article abstract of DOI:10.3390/molecules23051142

Detailed investigations concerning the organocatalytic (asymmetric) α-azidation of prochiral β-ketoesters were carried out. It was shown that the racemic version of such a reaction can either be carried out under oxidative conditions using TMSN₃

Full text of DOI:10.3390/molecules23051142

molecules
Article
Towards an Asymmetric Organocatalytic α-Azidation
of β-Ketoesters
ID
Maximilian Tiffner, Lotte Stockhammer , Johannes Schörgenhumer, Katharina Röser and
ID
Mario Waser *
Institute of Organic Chemistry, Johannes Kepler University Linz, Altenbergerstr. 69, 4040 Linz, Austria;
maximilian.tiffner@gmail.com (M.T.); lotte.stockhammer@gmail.com (L.S.); j.schoergenhumer@gmail.com (J.S.);
ka.roeser@aon.at (K.R.)
*
Correspondence: mario.waser@jku.at; Tel.: +43-732-2468-5411
Academic Editors: Laura Palombi and Antonio Massa
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 20 April 2018; Accepted: 10 May 2018; Published: 11 May 2018
Abstract: Detailed investigations concerning the organocatalytic (asymmetric)
α-azidation of
prochiral β-ketoesters were carried out. It was shown that the racemic version of such a reaction can
either be carried out under oxidative conditions using TMSN as the azide-source with quaternary
3
ammonium iodides as the catalysts, or by using hypervalent iodine-based electrophilic azide-transfer
reagents with different organocatalysts. In addition, the latter strategy could also be carried out
with modest enantioselectivities when using simple cinchona alkaloid catalysts, albeit with relatively
low yields.
Keywords: azides; organocatalysis; hypervalent iodine reagents; ammonium iodides; cinchona alkaloids
1
. Introduction
Organic azides are an important and versatile class of molecules, and their syntheses and
applications have attracted considerable interest [
compounds can serve as valuable building blocks for further transformations, e.g., the direct syntheses
of heterocycles by means of a 1,3-dipolar cycloaddition with alkynes [ ], or their straightforward
reduction to free amines [ ] (to mention only a few thoroughly investigated prominent applications
of azides). Keeping this high potential in mind, it is no surprise that a variety of strategies to introduce
azide functionalities in organic molecules have been reported [ 10]. The classical way of installing
an azide group is based on the displacement of leaving groups, e.g., halides, by nucleophilic azide
sources, like NaN or trimethylsilylazide (TMSN ) [11]. In addition, the recent years there has also been
1–10]. Their potential lies in the fact that these
3–5
6–8
1,7–
3
3
remarkable progress in using these nucleophilic azides under oxidative conditions, which allows for
−
the azidation of usually-nucleophilic species, e.g., enolates, by using bench-stable N3 reagents under
operationally simple conditions [12
iodine-based electrophilic azide-transfer reagents, e.g., compounds
of hypervalent iodine reagents for the transfer of different “uncommon” electrophiles has emerged
as a powerful method over the last few years [16 17] and the use of reagents and to facilitate the
-azidation of prochiral nucleophiles represents an impressive application of such reagents. Pioneering
reports by the groups of Gade [20] and Waser [19] have shown that -azidations of enolate species with
compounds and is possible, even in a highly asymmetric fashion under chiral iron catalysis [20].
It was recently shown that hypervalent iodine-based electrophile-transfer reagents can also be
successfully used for a variety of asymmetric -functionalization reactions of prochiral nucleophiles
under non-covalent organocatalysis (e.g., ion pairing catalysis, organobase catalysis, etc.) [17 21 24].
Surprisingly, however, the asymmetric -azidation of commonly-employed -ketoesters has, to the
–
15]. An alternative strategy is based on the use of hypervalent
1
and (Scheme 1) [16 20]. The use
2
–
,
1
2
α
α
1
2
α
,
–
α
β
3
Molecules 2018, 23, 1142; doi:10.3390/molecules23051142
www.mdpi.com/journal/molecules

Molecules 2018, 23, 1142
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best of our knowledge, not been systematically investigated using chiral non-covalent organocatalysis
so far. Based on our research focus on asymmetric -heterofunctionalization reactions [25 28],
as well as our interest in the use of hypervalent iodine reagents under organocatalytic conditions [24],
we have, therefore, now carried out detailed investigations of the -azidation of ketoesters with
using the chiral organocatalysts C1 C7 shown in
α
–
α
3
the electrophilic azide-transfer reagents
Scheme 1 [26,29–32].
1
and
2
–
Scheme 1. Targeted α-azidation of β-ketoesters 3 using the electrophilic azide-transfer reagents 1 and 2.
Another strategy that attracted our interest is the use of simple nucleophilic azide reagents, like
TMSN3 (
iodides to facilitate the
recent reports that showed that chiral ammonium iodides can be used for asymmetric oxidative
transformations [33], we also wanted to test if an enantioselective -azidation by using our bifunctional
5
), in combination with oxidizing agents in the presence of achiral ammonium or guanidinium
α
-azidation of carbonyl compounds [14 15]. Inspired by these studies and
,
α
ammonium iodide catalyst C1 in combination with TMSN and an oxidant may allow us to establish
3
an enantioselective protocol for the synthesis of azides 4 (Scheme 2).
Scheme 2. Targeted
α-azidation of β-ketoesters 3 using TMSN under oxidative conditions using the
3
chiral ammonium iodide catalyst C1.

Molecules 2018, 23, 1142
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2
. Results and Discussion
We started our investigations by carrying out the
α
-azidation of ketoester 3a with the hypervalent
iodine reagent
1 under a variety of conditions using different organocatalysts (Table 1 gives an
overview of the most significant results of a rather broad screening). First attempts were carried out
with our bifunctional ammonium salt catalyst C1 26 28] (entries 1–4). In all experiments where we
[
–
used either an inorganic or an organic base we were able to isolate the product 4a in good yields in
relatively short reaction times but, unfortunately, with no asymmetric induction. When we carried
out the reaction under base-free conditions instead (entry 2), the conversion dropped significantly
but, again, no enantioselectivity could be obtained. Unfortunately, we were also not able to achieve
any mentionable face-differentiation under ammonium salt catalysis by using other solvents, bases,
or catalyst derivatives and, thus, switched our focus on the easily-accessible chiral amines C2–C4
next (entries 5–16). The first experiment already showed that cinchonidine (C2) is able to control the
azidation, albeit the yield was rather low herein (entry 5). By increasing the catalyst loading to 40 mol%
(entry 6), the yield and the enantioselectivity could be increased but, unfortunately, the conversion
was still limited to around 50% (with 44% isolated yield). Neither prolonging the reaction time nor
carrying out the azidation at higher temperature (entry 7) allowed us to achieve a higher product
yield. One possible explanation for this reduced turnover could be that the formed iodobenzoic acid
(
generated by addition of the enolate to the azide) may form an ion pair with the cinchona alkaloid and,
thus, lead to catalyst deactivation. Thus, we tested the addition of inorganic bases, but the yield could
not be improved either (entry 8). Interestingly the reaction was significantly faster in the beginning
(
almost 50% conversion of the starting material after 90 min), but then stalled again, and the addition
of additional amounts of azidation reagent after that period did not increase the yield measurably
other bases were tested as well, but with the same outcome). The only way to improve the yield
1
(
somewhat was by using a stoichiometric amount of amine C2 (entries 9 and 10). By using a two-fold
excess of the azide-reagent 1 we observed a slightly higher yield with an identical enantiomeric ratio
(
entry 11) but, again, this could not be improved by longer reaction times (entry 12) or by adding
reagent portion-wise. At this point we decided to change the nature of the azidation agent and
used compound instead. We reasoned that the hereby-formed benzylic alcohol reaction product is
1
2
less likely to form an ion pair with the catalyst and should, thus, not result in catalyst deactivation.
Surprisingly, however, even with this system no higher yield was possible and, in contrast to the
use of 1, the e.r. dropped significantly (entry 13). Using reagent 1 again and changing the solvent
also had no positive effect on yield and/or e.r. (entries 14 and 15) and we, therefore, tested the other
cinchona derivatives C3 and C4 next (entries 16 and 17), but neither of them matched the performance
of C2 (pseudoenantiomeric systems performed more or less equally selective in favor of the other
enantiomer of 4a). Accordingly, as we stuck to yields around 40–50% and an enantiomeric ratio of
around 80:20 with catalyst C1, we finally tested a few other commonly-employed organocatalysts.
Unfortunately however, neither Takemoto’s catalyst C5 [31], nor Lambert’s base catalyst C6 [32] or
sparteine C7 performed anywhere as well as cinchonidine (C1) (compare entry 11 with entries 18–20)
and, thus, the result depicted in entry 11 (40% yield, e.r. = 80:20) was the best we could achieve by
using a reasonably low amount of 20 mol% catalyst.

Molecules 2018, 23, 1142
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Table 1. Screening and optimization of the α-azidation of 3a with hypervalent iodine-transfer reagents.
Entry 1
Cat.
N3+
Base
K CO (1.1 eq.)
Solv.
T ( C)
◦
t (h)
Yield 2 (%) e.r. (S:R) 3
1
2
3
4
5
6
7
8
9
C1 (10%)
C1 (10%)
C1 (10%)
C1 (10%)
C2 (20%)
C2 (40%)
C2 (40%)
C2 (40%)
C2 (100%)
C2 (100%)
C2 (20%)
C2 (20%)
C2 (20%)
C2 (20%)
C2 (20%)
C3 (20%)
C4 (20%)
C5 (20%)
C6 (20%)
C7 (20%)
1
1
1
1
1
1
1
1
1
1
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
(1.1 eq.)
1 (2 eq.)
1 (2 eq.)
2 (2 eq.)
1 (2 eq.)
1 (2 eq.)
1 (2 eq.)
1 (2 eq.)
1 (2 eq.)
1 (2 eq.)
1 (2 eq.)
toluene
toluene
MTBE
25
25
25
25
25
25
50
25
25
25
25
25
25
25
25
25
25
25
25
25
3
80
50
85
88
18
44
39
40
52
66
40
41
24
39
19
35
15
traces
7
56:44
55:45
55:45
52:48
65:35
80:20
67:33
77:23
81:19
67:33
80:20
80:20
56:44
75:25
55:45
63:37
58:42
n.d.
2
3
-
16
0.5
0.5
18
40
40
1.5
1.5
1.5
18
72
18
18
18
18
18
18
18
18
K CO (1.1 eq.)
2
3
DMAP (1.1 eq.)
MTBE
-
-
-
toluene
toluene
toluene
toluene
toluene
MTBE
toluene
toluene
toluene
K CO (1.1 eq.)
2
3
-
-
-
-
-
-
-
-
-
-
-
-
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
7
8
9
0
CH Cl
2
2
THF
toluene
toluene
toluene
toluene
toluene
54:46
46:54
28
1
All reactions were carried out on a 0.1 mmol scale; 2 Isolated yield; 3 Determined by HPLC using a chiral stationary
phase and assigned in analogy to the reported retention times [20,34].
After testing the azidation with the hypervalent iodine reagents
1
and
2
we next focused on the
reaction of
β-ketoester 3a with TMSN3 (5) under oxidative conditions in the presence of ammonium
iodide catalysts (Table 2). First experiments using H O and the chiral catalyst C1 showed that this
2
2
reaction can be carried out with good yield under these conditions (entry 1). It was also shown that
the ammonium iodide is necessary for this reaction (entry 2). Unfortunately, however, no asymmetric
induction could be achieved in these first experiments (entries 1 and 3). When changing the oxidant
(entries 4 and 5) the reaction progress was similarly fast but, again, the product could only be accessed
in almost racemic form and neither variations of the conditions nor of the chiral catalyst gave any
better results. Despite this lack in selectivity we were attracted by the simplicity of this procedure
and, thus, also quickly tested the easily-accessible achiral bifunctional ammonium iodide C8, which
catalyzed the racemic azidation of 3a very well under operationally simple conditions (entry 6).
Table 2. α-Azidation of 3a under oxidative conditions using TMSN (5).
3
Entry
Oxidant
H O (35%) (1.2 eq.)
Solvent
Cat.
Yield [%] 1
e.r. [S:R] 2
1
2
3
4
5
6
toluene
toluene
AcN
toluene
toluene
toluene
C1
-
C1
C1
C1
C8
81
0
86
76
80
84
55:45
-
53:47
54:46
52:48
-
2
2
H O (35%) (1.2 eq.)
2
2
H O (35%) (1.2 eq.)
2
2
t-BuOOH (1.2 eq.)
6 (1.2 eq.)
H O (35%) (1.2 eq.)
2
2
1
Isolated yield; 2 Determined by HPLC using a chiral stationary phase and assigned in analogy to the reported
retention times [20,34].

Molecules 2018, 23, 1142
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After this broad screening of different catalysts and conditions for the
α
-azidation of
β-ketoester
3
a
under organocatalytic conditions we finally evaluated the substrate scope by testing a few different
ketoesters under the asymmetric conditions with cinchonidine (C2) and azide-reagent according to
3
1 (
the conditions shown in entry 11 in Table 1), as well as using the racemic oxidative strategy (entry 6,
Table 2).
As can be seen in Scheme 3, in neither case the yield for the asymmetric reaction was
higher than 40%, illustrating the general difficulties already observed in the initial screening.
Somewhat surprisingly, the achieved enantioselectivity was rather strongly substituent influenced,
i.e., the adamantyl-ester 4c could be accessed with rather low selectivity only, which is in strong
contrast to recent observations in other transformations [24,26]. On the other hand, the racemic
protocol performed similarly well for all substrates without any further optimization, thus proving the
generality for this reaction.
Scheme 3. Application scope.
3
. Experimental Section
1H- and 13C-NMR spectra were recorded on a Bruker Avance III 300 MHz spectrometer and
were referenced at the solvent peak. High-resolution mass spectra were obtained using a Thermo
Fisher Scientific LTQ Orbitrap XL with an Ion Max API source. HPLC analyses were performed
by using a Dionex Summit HPLC system with the chiral stationary phases indicated in the specific
cases. All reactions were performed under an Ar atmosphere unless stated otherwise. Catalysts
C1
were either purchased from commercial suppliers or prepared as described previously [26
Hypervalent iodine-base reagents and were prepared as described recently [18 20]. Product 4
is a known compound and the analytical data match those reported previously [19 20 34]. Further
–
C7 were either commercial or prepared as described recently [32
,35]. Starting β-ketoesters 3
–
28].
1
2
–
,
,
experimental and analytical details (like NMR spectra and HPLC copies) can be found in the online
supporting information.
Catalyst C8: To a solution of 3,5-bis(trifluoromethyl)phenyl isothiocyanate (0.336 mL, 1.84 mmol) in
toluene (2 mL) was added N,N-dimethylethylenediamine (0.201 mL, 1.84 mmol). After stirring for 14 h

Molecules 2018, 23, 1142
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at room temperature the reaction mixture was directly subjected to column chromatography (silica
gel, CH Cl /MeOH, 20:1) to afford 625 mg (95%) of the known thiourea intermediate [36]. A mixture
2
2
of this thiourea (100 mg, 0.278 mmol) and benzylbromide (95 mg, 0.556 mmol) was stirred in 2 mL
of CH CN for 15 h at room temperature. The reaction mixture was directly subjected to column
3
1
chromatography (silica gel, CH Cl /MeOH, 10:1) to yield 148 mg (92%) of catalyst C8
.
H NMR
2
2
(
4
1
300 MHz, CDCl3)
.35–4.46 (m, 2H), 3.9 (t, J = 5.8 Hz, 2H), 3.26 (s, 6H). C NMR (75 MHz, CDCl3)
32.9, 131.4 (q, J = 34 Hz), 131.3, 125.9, 123.1 (q, J = 274 Hz), 123.0, 122.9, 117.9, 68.8, 63.5, 50.6, 38.2.
δ 9.83 (s, 1H), 8.72 (t, J = 5.7 Hz, 1H), 8.22 (s, 2H), 7.40–7.58 (m, 6H), 4.81 (s, 2H),
13
δ 181.7, 140.3,
+
+
HRMS-ESI): calcd for C H F N S (M) 450.1433, found 450.1439.
20
22
6
3
Azidation Conditions A — General procedure: The ketoester
were dissolved in toluene (3 mL). Benziodoxole (2 eq.) was added and the reaction mixture was
stirred for 18–40 h (no difference in yield). The mixture was filtered over Na SO and the solvent
3 (0.1 mmol) and catalyst C2 (20 mol%)
1
2
4
was evaporated and the product was purified by column chromatography (DCM/heptanes = 5/1,
silica gel 60).
Azidation Conditions B — General procedure: The ketoester
were dissolved in toluene (3 mL) under argon at 0 C. Then H O (35%, 1.2 eq.) and TMSN
3 (0.1 mmol) and catalyst C8 (10 mol%)
◦
2
2
3
(1.1 eq.) were added. The resulting mixture was stirred overnight. The mixture was filtered over
Na SO and the solvent was evaporated and the product was purified by column chromatography
2
4
(DCM/heptanes = 5/1, silica gel 60).
Product 4a: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]
1
H-NMR (CDCl , 300 MHz, 298 K), δ/ppm: 7.82 (d, J = 7.7 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.48–7.41
3
(
m, 2H), 3.64 (d, J = 17.2 Hz, 1H), 2.99 (d, J = 17.2 Hz, 1H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl3,
2
98 K):
δ
/ppm = 198.1, 167.4, 152.3, 136.4, 133.3, 128.4, 126.5, 84.6, 70.6, 38.7, 28.0; MS (ESI+): m/z
+
calcd for C H N O [M + H] : 274.12; found: 274.14. The enantioselectivity was determined by
HPLC analysis (Chiralcel OJ-H, hexane/i-PrOH = 3/1, 1.0 mL min , 10 C; t / min = 6.1 (major),
1
4
16
3
3
−
1
◦
R
1
0.0 (minor).
Product 4b: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]
1
H-NMR (CDCl , 300 MHz, 298 K), δ/ppm: 7.85 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.50–7.43
3
(
m, 2H), 7.33–7.22 (m, 5H), 3.67 (d, J = 17.4 Hz, 1H), 3.02 (d, J = 17.3 Hz, 1H), 1.81 (s, 3H), 1.77 (s, 3H);
1
3
C NMR (75 MHz, CDCl , 298 K):
δ
/ppm = 197.9, 166.7, 152.2, 144.5, 136.4, 133.4, 128.5, 128.4, 127.6,
3
+
1
26.5, 125.7, 124.3, 85.5, 70.7, 38.6, 28.7, 28.1; HRMS (ESI+): m/z calcd for C H N O [M + NH ] :
19
21
4
3
4
3
53.1608; found: 353.1610. The enantioselectivity was determined by HPLC analysis (Chiralcel OJ-H,
−
1
◦
hexane/i-PrOH = 3/1, 1.0 mL min , 10 C; tR/min = 11.3 (major), 15.4 (minor).
Product 4c: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]
1
H-NMR (CDCl , 300 MHz, 298 K), δ/ppm: 7.81 (d, J = 7.6 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.48–7.40
3
(
m, 2H), 3.64 (d, J = 17.2 Hz, 1H), 2.98 (d, J = 17.3 Hz, 1H), 2.15 (s, 3H), 2.08 (s, 6H), 1.63 (s, 6H);
13
C NMR (75 MHz, CDCl , 298 K):
4.7, 70.6, 41.3, 38.7, 36.1, 31.0; MS (ESI+): m/z calcd for C H N O [M + NH ] : 369.19; found:
δ
/ppm = 198.2, 167.1, 152.4, 136.3, 133.4, 128.4, 126.4, 125.6,
3
+
8
3
20
25
4
3
4
69.20. The enantioselectivity was determined by HPLC analysis (YMC CHIRALART Cellulose-SB,
−
1
◦
hexane/i-PrOH = 300/1, 1.0 mL min , 10 C; tR/min = 9.1 (minor), 12.1 (major).
Product 4d: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]

Molecules 2018, 23, 1142
7 of 9
1
H-NMR (CDCl , 300 MHz, 298 K),
δ
/ppm: 7.65 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.35
3
13
(t, J = 7.4 Hz, 1H), 3.52 (d, J = 17.3 Hz, 1H) , 2.87 (d, J = 17.3 Hz, 1H), 2.34 (s, 3H), 1.47 (s, 9H);
C
NMR (75 MHz, CDCl , 298 K):
δ
/ppm = 198.3, 167.6, 151.3, 136.9, 135.8, 133.1, 128.6, 123.0, 84.6,
3
+
70.5, 37.6, 28.0, 17.9; HRMS (ESI+): m/z calcd for C H N O [M + H] : 288.1343; found: 288.1345.
15
18
3
3
The enantioselectivity was determined by HPLC analysis (Chiralcel OD-H, hexane/i-PrOH = 300/1,
− ◦
.0 mLmin , 10 C; t /min = 9.9 (minor), 13.2 (major).
R
1
1
Product 4e: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]
1
H-NMR (CDCl , 300 MHz, 298 K),
δ
/ppm: 7.34 (d, J = 8.1 Hz, 1H), 7.28–7.20 (m, 2H), 3.85 (s, 3H),
3
3
.55 (d, J = 16.8 Hz, 1H) , 2.91 (d, J = 16.9 Hz, 1H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl , 298 K):
3
δ/ppm = 198.0, 167.5, 160.1, 145.3, 134.5, 127.2, 125.9, 106.5, 84.6, 71.3, 55.8, 38.1, 28.0; HRMS (ESI+):
+
m/z calcd for C H N O [M + H] : 304.1292; found: 304.1293. The enantioselectivity was determined
15
18
3
4
−
1
◦
by HPLC analysis (Chiralcel OD-H, hexane/i-PrOH = 300/1, 1.0 mL min , 10 C; t /min = 8.6
R
(minor), 10.0 (major).
Product 4f: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]
1
H-NMR (CDCl , 300 MHz, 298 K), δ/ppm: 7.70–7.63 (m, 2H), 7.58 (d, J = 8.1 Hz, 1H), 3.61
3
(
d, J = 17.5 Hz, 1H), 2.96 (d, J = 17.4 Hz, 1H), 1.46 (s, 9H); 13C NMR (75 MHz, CDCl , 298 K):
3
δ/ppm = 197.0, 167.0, 153.8, 132.2, 132.1, 132.0, 129.8, 126.7, 84.9, 70.5, 38.3, 28.0; MS (ESI+): m/z
+
calcd for C H BrN O [M + H] : 352.03; found: 352.04. The enantioselectivity was determined by
14
15
3
3
−
1
◦
HPLC analysis (Chiralpak AD-H, hexane/i-PrOH = 100/1, 0.5 mL min , 10 C; t /min = 19.7 (major),
R
2
2.5 (minor).
Product 4g: Obtained in the yields and with the selectivities given in Scheme 3 in the main manuscript.
Analytical data match those reported recently [19,20,34]
1
H-NMR (CDCl , 300 MHz, 298 K), δ/ppm: 7.87–7.80 (m, 1H), 7.14 (t, J = 8.5 Hz, 1H), 7.35 (t, J = 7.4 Hz,
3
13
1
H), 3.62 (d, J = 17.4 Hz, 1H) , 2.97 (d, J = 17.6 Hz, 1H), 1.46 (s, 9H); C NMR (75 MHz, CDCl , 298 K):
3
δ
/ppm = 196.3, 167.2, 168.1, 155.4, 129.7, 128.1, 116.9, 113.4, 84.9, 70.7, 38.5, 28.0; HRMS (ESI+): m/z
+
calcd for C H FN O [M + H] : 292.1092; found: 292.1093. The enantioselectivity was determined
by HPLC analysis (Chiralcel OJ-H, hexane/i-PrOH = 3/1, 1.0 mL min , 10 C; t /min = 6.2 (major),
1
4
15
3
3
−
1
◦
R
9
.0 (minor).
4
. Conclusions
In conclusion, we have carried out detailed investigations concerning the organocatalytic
asymmetric) -azidation of prochiral -ketoesters. It was shown that, in general, an asymmetric
(
α
β
procedure for such a reaction is possible by using simple cinchona alkaloid catalysts. Unfortunately,
however, these reactions were relatively low yielding and only modestly enantioselective (up to
e.r. = 83:17). On the other hand, a very simple racemic version for this α-azidation was developed by
using TMSN as the azide-source under oxidative conditions with quaternary ammonium iodides
3
as catalysts.
Supplementary Materials: NMR spectra and HPLC traces are available online.
Author Contributions: The experimental work and analyses were carried out by M.T., L.S., J.S., K.R., M.T.; M.W.
designed the experiments; and M.W. wrote the manuscript.
Acknowledgments: The NMR spectrometers used were acquired in collaboration with the University of South
Bohemia (CZ) with financial support from the European Union through the EFRE INTERREG IV ETC-AT-CZ
program (project M00146, “RERI-uasb”).
Conflicts of Interest: The authors declare no conflict of interest.

Molecules 2018, 23, 1142
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Sample Availability: Sample Availability: Not available.
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