Sequential Au/Cu Catalysis: A Two Catalyst One-Pot Protocol for the Enantioselective Synthesis of Oxazole α-Hydroxy Esters via Intramolecular Cyclization/Intermolecular Alder-Ene Reaction

Article abstract of DOI:10.1002/adsc.201800246

A convenient protocol for the enantioselective synthesis of oxazole α-hydroxy ester derivatives 4 from readily available propargylamides 1 and alkylglyoxylates 3 was developed. The first step of the one-pot procedure is the selective intramolecular in situ formation of an alkylideneoxazoline 2, which then in an intermolecular reaction is enantioselectively transformed to the oxazole α-hydroxy ester derivatives 4 in quantitative yield and good to excellent enantioselectivity via an asymmetric copper(II)-catalyzed Alder-ene reaction. (Figure presented.).

Full text of DOI:10.1002/adsc.201800246

Title: Sequential Au/Cu Catalysis: A Two Catalyst One-Pot Protocol for
the Enantioselective Synthesis of Oxazole α-Hydroxy Esters via
Intramolecular Cyclization/Intermolecular Alder-Ene Reaction
Authors: Kumara Nalivela, Matthias Rudolph, and A. Stephen K.
Hashmi
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800246
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
Sequential Au/Cu Catalysis: A Two Catalyst One-Pot Protocol for
the Enantioselective Synthesis of Oxazole α-Hydroxy Esters via
Intramolecular Cyclization/Intermolecular Alder-Ene Reaction
Kumara Swamy Nalivela, Matthias Rudolph, and A. Stephen K. Hashmi*
Heidelberg University, Organisch-Chemisches Institut, Im Neuenheimer Feld 270, 69120
Heidelberg, Germany
Abstract:
A convenient protocol for the enantioselective synthesis of oxazole α-hydroxy ester derivatives 4
from readily available propargylamides 1 and alkylglyoxylates 3 was developed. The first step of
the one-pot procedure is the selective intramolecular in situ formation of an alkylideneoxazoline
2, which then in an intermolecular reaction is enantioselectively transformed to the oxazole α-
hydroxy ester derivatives 4 in quantitative yield and good to excellent enantioselectivity via an
asymmetric copper(II)-catalyzed Alder-ene reaction.
Keywords: propargylamides, gold catalysis, alkylglyoxylate, oxazole α-hydroxy ester,
heterocycles
Introduction
Optically active α-hydroxy carbonyl moieties are a widespread motif in natural products and
have been frequently used as convenient building blocks in organic synthesis.[1] The Alder-ene
reaction is a powerful tool for the construction of carbon-carbon bonds and the development of
enantioselective versions of that reaction has very important practical implications.[2] In this
context, the groups of Mikami, Feng, Nakai, and Evans have reported catalytic enantioselective
Alder-ene reactions with glyoxylate esters.[3] However, enantioselective metal-catalyzed Alder-
ene reactions are relatively unexplored and the development of highly efficient catalysts still
remains a great challenge.[4] To the best of our knowledge, so far no reports on a sequential
enantioselective approach towards oxazole α-hydroxy esters 3 via an Alder-ene reaction have
been reported.
1
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10.1002/adsc.201800246
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The unsubstituted oxazole moiety,[5] as well as the corresponding 5-methyloxazole,[6] and
functionalized 5-methyloxazole derivatives[7] can be found in many naturally occurring products
that are pharmaceutically active. Many biologically active oxazole-containing natural products
were isolated from marine sources, nearly all of them containing the 2,4-disubstituted oxazole
ring system.[8] However, a variety of Streptomyces strains have produced examples of 5-
monosubstituted oxazoles with biological profiles ranging from herbicidal to antitumor activity,
which includes Conglobatin[9] (5), a member of the oxazolomycin family.[10]
Figure 1. Structure of natural product Conglobatin
The 2-(oxazol-5-yl)ethyloxy nucleus is a key structural feature of the biologically active marine
natural product Conglobatin 5. The synthesis of oxazoles in complex molecular environments
remains a challenge, in particular the construction of a stereogenic center in the β-position of the
oxazole moiety. Therefore we envisioned the enantioselective synthesis of oxazole α-hydroxy
esters 3 from easily available starting precursors.
In 2004, in the context of the early development[11] of gold catalysis,[12] our group reported the
conversion of N-propargylcarboxamides into 5-methyloxazoles by using 2 mol% gold(III)
chloride.[13] This method has since been applied in academic[14] and industrial research.[15] If less
Lewis-acidic gold(I) precursors were used, we were able to isolate the intermediate
alkylideneoxazolines, previously unknown compounds with a highly interesting reactivity
profile.[16] This transformation has found broad application in the screening for new gold
catalysts[17] as well as the development of new reaction methodologies like the reaction of
alkylideneoxazolines with very reactive nitrogen electrophiles (azodicarboxylates) for Alder-ene
reaction.[18] Herein, we report the sequential enantioselective syntheses of oxazole α-hydroxy
esters using gold catalysis in combination with a copper-catalyzed Alder-ene reaction.
2
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
Results and discussion
We have recently reported on the gold-catalyzed cycloisomerization of N-propargylamides to the
corresponding alkylideneoxazolines followed by aerobic oxidation to the corresponding
hydroperoxymethyl oxazoles.[19] Due to this air-sensitivity, we started our study of an Alder-ene
(carbonyl-ene) reaction with the direct treatment of the stable 3-nitro alkylideneoxazoline with
its exocyclic double bond with ethyl glyoxalate in the presence of specific Lewis acidic catalysts
in combination with different chiral ligands L1-L7 (Scheme 1).
Scheme 1: Structures of chiral ligands [L1 = (S)-(−)-1,1′-Bi(2-naphthol), L2 = (S,S)-2,6-Bis(4-isopropyl-
2-oxazolin-2-yl)pyridine, L3
Isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline],
oxazoline), L6 2,2′-Methylenebis[(4S)-4-phenyl-2-oxazoline], L7
Methylenebis[3a,8a-dihydro-8H-indeno[1,2-d]oxazole]].
=
(S,S)-2,6-Bis(4-phenyl-2-oxazolinyl)pyridine, L4
=
2,2′-
L5 (S,S)-2,2'-Isopropylidene-bis(4-phenyl-2-
=
=
=
(3aS,3′aS,8aR,8′aR)-2,2′-
3
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
As a model system, we examined the Alder-ene reaction of ethyl glyoxal 7 and
2
alkylideneoxazoline 6 promoted by (i-PrO)2TiCl2 in combination with chiral biaryl L1 (Table 1,
entry 1), which exhibited α-hydroxyl ester 8 in good yield but poor enantioselectivity (6% ee) .
To improve the enantioselectivity of the reaction, Cu(OTf)2 in combination with the often
applied box ligands3 was examined under different reaction conditions (Table 1, entries 2-13).
Pybox ligands (L2 and L3) gave no detectable enantioselectivity (0% ee) with L2, and only poor
enantioselectivity (5% ee) with L3, in addition, the reaction times turned out to be much longer
(entries 2-3). The initial attempt with 10 mol% of Cu(OTf)2 and the same amount of chiral box
ligand L4 = 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] at room temperature showed a
moderate enantioselectivity (26% ee) going along with very good yield (entry 4). Switching to
phebox ligand L5 = (S,S)-2,2'-isopropylidene-bis(4-phenyl-2-oxazoline) in combination with 10
mol% of Cu(OTf)2 at room temperature produced a good enantioselectivity 70% ee in reasonable
reaction time and high yield (89%; Table 1, entry 5). Attempts to reduce the catalyst loading
were successful and still acceptable reaction times were observed with half the amount of the
catalyst system without any change in enantioselectivity (Table 1, entry 6). Next, we performed
the reaction at 0 oC which led to a doubling of the reaction time, but the selectivity was improved
enantioselectivity (76% ee) in quantitative yield (Table 1, entry 7). Also the reaction at 0 oC with
5 mol% of Cu(OTf)2 and 6 mol% L5 in order to ensure a complete catalyst complex formation
showed no improvement of the enantioselectivity (Table 1, entry 8). Two more box ligands, L6
and L7, with the same catalyst (Cu(OTf)2) gave 69% ee (L6, Table 1, entry 9) and 33% ee (L7,
Table 1, entry 10). With the best ligand (L5) (Table 1, entry 11, 12, 13) we tried to further
decrease the reaction temperature in order to obtain a higher enantioselectivity. In a series of
o
o
o
o
reactions at -20 C, -10 C and -5 C (Table 1, entry 11, 12, 13) a reaction temperature of -5 C
turned out to be ideal as the reaction time of 12 h is still acceptable and the ee rose to 81%. For
even lower reaction temperatures no or only incomplete conversion was observed.
Table 1. Optimization of the Alder-Ene Reaction Conditions
4
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
eea
Entry Catalyst (mol%)
Ligand
(mol%)
T, oC
Time
Yield
1
2
3
(i-PrO)2TiCl2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
L1 (10)
L2 (10)
L3 (10)
25
25
25
2.0 h
48 h
48 h
73%
80%
75%
6%
0%
5%
4
5
Cu(OTf)2 (10)
Cu(OTf)2 (10)
L4 (10)
L5 (10)
25
25
2.5 h
2.0 h
79%
89%
26%
70%
6
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
Cu(OTf)2 (5)
L5 (5)
L5 (5)
L5 (6)
25
0
2.5 h
4.0 h
4.0 h
83%
81%
85%
71%
76%
64%
7
8
0
9
L6 (5)
0
4.0 h
83%
69%
10
11
12
L7 (5)
L5 (5)
0
4.0 h
24 h
81%
-
33%
NR
-20
L5 (5)
L5 (5)
-10
-5
24 h
-
Incomplete
81%
13
Cu(OTf)2 (5)
12.0 h
86%
a Enantioselectivity determined by chiral HPLC.
Table 2. Solvent Influence of the Alder-Ene Reaction
5
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Advanced Synthesis & Catalysis
eea
Entry
Solvent
Time
Yield
1
2
3
4
5
CH2Cl2
MeNO2
Toluene
THF
12 h
12 h
12 h
12 h
24 h
87%
82%
76%
79%
66%
81%
58%
48%
46%
21%
CH3CN
a Enantioselectivity determined by chiral HPLC.
With the optimized catalyst system, we performed a screening of some solvents (Table 2). The
Alder-ene reaction of 6 with 7 took place in all of the tested solvents (CH2Cl2, CH3NO2,
Toluene, THF, and CH3CN) but the best yield and the best ee value was obtained in CH2Cl2, thus
we kept this as an optimal solvent for the subsequent reaction (Table 2, entry 1).
With the optimized conditions in hand for the Alder-ene reaction, we tried the sequential and
enantioselective synthesis of the α–hydroxy ester 8 by a gold-catalyzed cycloisomerization of 3-
nitro-N-(prop-2-yn-1-yl)benzamide to the corresponding alkylideneoxazoline 6 followed by the
Alder-ene reaction using Cu(OTf)2 and L5. To our delight, the sequential process turned out to
be highly efficient and despite the presence of the gold catalyst the enantioselectivity still was
good (82% ee) and an 84% yield over the two reactions was excellent (Table 3, entry 2). The
challenge here is to avoid ligand exchange between the two metal centers.[20] The low affinity of
gold(I) for nitrogen ligands[21] and the much more pronounced affinity of gold(I) for phosphane
ligands,[22] in combination with the linear coordination at gold(I) not benefiting from a potential
6
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
chelate effect, which the copper complex benefits from the N,N-chelation, helped to avoid such
ligand exchange.
Table 3. One-pot Au/CuL5-catalysed sequential enantioselective synthesis of substituted oxazole α-
hydroxy esters (4) via an Alder-ene reaction.
Entry
Amides (1)
α-Hydroxy Esters (4)
T, oC Time Yield
-5 12 h 93%
ee a
48%
1
-5
12 h
84%
82%
2
7
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
-5
16
90%
86%
3
-5
12 h
80%
84%
4
-5
16 h
81%
70%
5
-5
12 h
78%
71%
6
8
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
-5
12 h
85%
78%
7
-5
12 h
88%
72%
8
-5
16 h
83%
0%
9
-5
16 h
81%
56%
10
9
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
-5
16 h
92%
70%
11
-5
24 h
90%
69%
12
13
14
-5
24 h
81%
0%
48 h
84%
28%
25
a
b
Enantioselectivity determined by chiral HPLC.
Reaction conditions: amide (1.0 mmol), and
Ph3PAuNTf2 (0.05 mmol) in CH2Cl2 (4 mL) at rt under N2 atmosphere for 18 h then cooled reaction
o
mixture to -5 C, was added ethyl or benzylglyoxylate (2.0 mmol) followed by addition of CuL5 (0.05
mmol) and stirred until completion of Alder-ene reaction.
10
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
The scope with respect to propargyl benzamides bearing diverse substituents on the arene ring
was examined, too (Table 3). An unsubstituted arene provided the desired α–hydroxy ester in
excellent yield 93% but only moderate enantioselectivity (48% ee; Table 3, entry 1). Electron-
withdrawing groups, such as CN or CF3 on either the para or meta position were also tolerated
yielding the desired products in excellent enantioselectivity (86% ee, 84% ee) and excellent
overall yields (Table 3, entries 3, 4). Halogen substituents (F or Cl either in para or meta position
on benzamides) (Table 3: entries 5 and 6) were also well tolerated and produced the desired
product in good enantioselectivity (70% ee, 71% ee) and excellent yields as well. A phenyl
group as substituent in meta position afforded the desired product in very good enantioselectivity
(78% ee) and excellent yield (Table 3, entry 7). An electron-donating methoxy group in the ortho
position of the arene led to a complete loss of optical excess, which might be due to a
coordination of the additional oxygen atom (Table 3, entry 9). Indeed the chiral induction could
be restored by placing a methyl group instead of the methoxy (72% ee, 88% yield) (Table 3,
entry 8). Electron-rich substituents such as n-BuO or 3,4-OMe, in both para and meta positions
were well tolerated, leading to the formation of the desired products in good enantioselectivity
(56% ee, 70% ee) and in excellent yield (Table 3, entries 10, 11). Electron-rich OMe groups in
meta and para position were well tolerated delivering the product in excellent yield 90% and
good enantioselectivity (69% ee) (Table 3, entry 12) when it was Alder-ene reaction with ethyl
glyoxalate. It is noteworthy that the Alder-ene reaction with benzyl glyoxalate delivered only
racemic product, which might be explained by the increased sterical demand of the benzyl group
(Table 3, entry 13). Notably, this one-pot bimetallic sequential catalysis was suitable for
furamide as well. For this starting material and the reaction had to be performed at room
temperature of which might in part explain the moderate enantioselectivity (28% ee). In addition,
the reaction time was much longer but the isolated yield of 84% was still very good (Table 3,
entry 14).
In summary, we have developed an efficient one-pot sequential reaction protocol for the
enantioselective synthesis of oxazole α-hydroxy esters 4. Based on the compatibility of the two
metals applied (gold and copper) no isolation of the intermediate oxazolines was necessary and
the possibility to circumvent an additional purification step together with the versatility and the
11
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
fairly mild conditions of the transformation, underlay the high synthetic value for synthetic
organic chemistry. One-pot sequential processes can avoid time-consuming and costly processes
for purification of various precursors which makes them highly attractive for the pharmaceutical
industry. The observation that phosphane ligands on gold(I) are compatible with an N,N-chelate
ligand on a second metal like copper is important for the future development of heterobimetallic
catalysis with gold.
Experimental Section
1. General methods:
All reactions were performed in oven-dried glassware under an atmosphere of nitrogen unless
otherwise stated. Reactions were monitored by thin-layer chromatographic analysis.
Anhydrous CH2Cl2 was obtained from Solvent dispenser. “Evaporation” refers to the removal of
solvent under reduced pressure using a rotory evaporator and then the removal of the last traces
of solvent under high vacuum. “Dried” refers to the drying of organic extracts over MgSO4.
Commercial substances were used without further purification. NMR spectra were recorded on
Bruker Avance 600, 500, 400 and 300 and Bruker ARX-250 spectrometers. Chemical shifts were
referenced to residual solvent protons. Signal multiplicity as follows: s (singlet), d (doublet), t
(triplet), q (quartet), qu (quintet), hept (heptate), m (multiplet). 13C assignment was achieved via
HSQC, HMBC and DEPT135 spectra. MS spectra were recorded on Finnigan MAT TSQ 700,
Vakkum Generators ZAB-2F and JEOL JMS-700 spectrometer. IR spectra were recorded on a
Bruker Vector 22. TLC analyses were performed using aluminum-backed silica gel TLC plates.
Compounds were detected under a 254 nm ultraviolet lamp if applicable, or by staining with an
acidified aqueous solution of ammonium molybdate, followed by development with a heat gun.
Flash column chromatography was performed using Aldrich silica gel (70 – 230 mesh) packed
by the slurry method. Melting points were obtained using a Gallenkamp MF-370 capillary tube
melting point apparatus and are uncorrected. Low-resolution mass spectra were obtained on a
Shimadzu GC mass spectrometer (EI). HRMS were obtained in lieu of elemental analysis.
Enantiomer excesses were determined by chiral HPLC analysis on Daicel Chiralcel AS-H/IB-H
T
in comparison with the authentic racemates. Optical rotations were reported as follows: [α] D (c:
g/100 mL, in CHCl3). Ultra-Kryomat cooler was used for maintaining a low temperature.
2. General procedures for propargylic amides and Au-Cu catalyzed enantioselective
synthesis of α–hydroxy esters:
General procedure (GP 1) - Synthesis of propargylic amines:
12
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
To a solution of propargylamine (1.0 eq with respect to the acid chloride) in anhydrous CH2Cl2,
Et3N (1.0 eq) was added and DMAP (2.0 mol%). The reaction mixture cooled to 0 °C, and then
acid chloride (1.0 eq) was added drop wise. After stirring for 15 min at 0°C continued stirring at
room temperature for 3 h. After completion, the reaction mixture diluted with water and then
extracted with CH2Cl2. The organic layer was dried over MgSO4, and the solvent removed in
vacuo. The crude product was purified by column chromatography or by recrystallization.
General procedure (GP 2) – Sequential synthesis of α-hydroxyl esters:
To a solution of propargylamine (50 mg, 1.0 eq) in dry CH2Cl2 (2.0 mL) was added Ph3PAuNTf2
(5.0 mol%) and the reaction mixture stirred at room temperature for 18 h in an inert atmosphere
(N2) to the dihydrooxazole formation reaction (monitored by TLC). Then the mixture was cooled
to – 5 oC, at which time ethyl or benzyl glyoxylate (2.0 eq with respect to propargylicamide) and
CuL5 (5.0 mol%) prepared green suspension (a dry flask was charged with Cu(OTf)2 (5.0
mol%), phebox ligand L5 (5.0 mol%), dry CH2Cl2 (2.0 mL) and stirred at room temperature for
4 h in an inert atmosphere (N2) then the solution was turned to green suspension) was added via a
syringe and continued stirring until Alder-Ene reaction being completed (monitored by TLC).
After completion of the reaction, the crude product was directly purified by flash column
chromatography.
3-Nitro-N-(prop-2-yn-1-yl)benzamide (1b)
Prepared according to GP1 using propargyl amine (0.29 g, 5.40 mmol), Et3N (0.54 g, 5.40
mmol), DMAP (0.013 g, 0.10 mmol), dry CH2Cl2 (12.0 mL) and 3-Nitrobenzoyl chloride (1.0 g,
5.40 mmol). The residue triturated with petroleum ether and filtered to afford the title compound
1b (1.05 g, 95%) as a pale yellow solid.
Rf = 0.46 (1 : 2, EtOAc/petrol); M.p = 146 – 148 oC; IR (neat, νmax/cm-1): 1529, 1579, 1649,
3299; 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.30 (dd, J = 0.9, 8.0 Hz, 1H), 8.12 (d, J = 7.6
Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 6.54 (bs, NH), 4.23 (dd, J = 2.4, 5.2 Hz, 2H), 2.25 (t, J = 2.4
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 164.7 (s), 148.2 (s), 135.3 (s), 133.3 (s), 130.0 (s),
126.4 (s), 121.9 (s), 78.8 (s), 72.4 (s), 30.1 (s). MS (70 eV): m/z (%): 204 (61) [M+]; HRMS (EI
(+), 70 eV): [C10H8N2O3]+ : calcd 204.0535, found 204.0570.
13
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
N-(prop-2-yn-1-yl)-3,5-bis(trifluoromethyl)benzamide (1d)
Prepared according to GP1 using propargylamine (0.20 g, 3.62 mmol), Et3N (0.36 g, 3.62),
DMAP (9.0 mg, 0.07 mmol), dry CH2Cl2 (12.0 mL) and 3,5-bis(trifluoromethyl)benzoyl chloride
(1.0 g, 3.62 mmol). The residue triturated with petroleum ether and filtered to afford the title
compound 1d (0.92 g, 86%) as a pale yellow solid.
Rf = 0.61 (1 : 2, EtOAc/petrol); M.p = 88 – 90 oC; IR (neat, νmax/cm-1): 1419, 1454, 1542, 1618,
1647, 3100, 3247; 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 2H), 7.93 (s, 1H), 6.88 (bs, NH), 4.21
(dd, J = 2.4, 5.2 Hz, 2H), 2.22 (t, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 163.4 (s),
134.7 (s), 131.4 (q, J = 34.0 Hz, 2C), 126.5 (d, J = 3.0 Hz, 2C), 124.3 (qu, J = 4.0 Hz), 123.1 (q,
J = 271.0 Hz, 2C), 77.6 (s), 71.3 (s), 29.0 (s); MS (70 eV): m/z (%): 295 (66) [M+], 241 (100)
[M+-C3H4N.], 213 (68) [C8H3F6]; HRMS (EI (+), 70 eV): [C12H7NOF6]+ : calcd 295.0432, found
295.0409.
(+)-Ethyl 2-hydroxy-3-(2-(3-nitrophenyl)oxazol-5-yl)propanoate (8)
Prepared according to GP2 from 3-nitro-N-(prop-2-yn-1-yl)benzamide 1b (0.05 g. 0.245 mmol),
ethyl glyoxylate (0.05 g, 0.49 mmol), dry CH2Cl2 (4.0 mL), Ph3PAuNTf2 (9.0 mg, 0.012 mmol),
Cu(OTf)2 (4.42 mg, 0.012 mmol) and (S,S)-2,2`-Isopropylidene-bis(4-phenyl-2-oxazoline) (4.10
mg, 0.012 mmol). Purification via flash column chromatography (1 : 2, EtOAc/petrol) afforded
the title compound 8 (0.063 g, 84%) as a colourless solid.
14
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
[] 20 +4.9 (c 1.0, CHCl3); >82% ee; HPLC DAICEL CHIRALCEL AS-H, n-hexane/2-propanol
D
(85:15), flow rate = 1.0 mL/min, area: 550.861 (minor) and 5642.49 (major), retention time: 23.7
min (minor) and 26.9 min (major); Rf = 0.39 (1 : 1, EtOAc/petrol); M.p = 75 – 77 oC; IR (neat,
νmax/cm-1): 3434, 3089, 1738, 1552, 1173, 715; 1H NMR (400 MHz, CD2Cl2): δ 8.24 – 8.15 (m,
3H), 7.57 (t, J = 10.4 Hz, 1H), 6.95 (s, 1H), 4.43 (q, J = 7.3 Hz, 1H), 4.19 (q, J = 9.5 Hz, 2H),
3.14 (qd, J = 9.3, 20.8 Hz, 2H), 3.03 (s, 1H), 1.22 (t, J = 9.5 Hz, 3H); 13C NMR (100 MHz,
CD2Cl2): δ 172.7 (s), 158.1 (s), 148.7 (s), 147.9 (s), 130.8 (s), 129.2 (s), 128.4 (s), 125.8 (s),
123.6 (s), 119.9 (s), 67.9 (s), 61.5 (s), 30.1 (s), 13.2 (s); MS (70 eV): m/z (%): 306.1 (40) [M+];
HRMS (EI (+), 70 eV): [C14H14N2O6]+ : calcd 306.0852, found 306.0823.
(+)-Ethyl 3-(2-(3,5-bis(trifluoromethyl)phenyl)oxazol-5-yl)-2-hydroxypropanoate (4c)
Prepared according to GP2 from N-(prop-2-yn-1-yl)-3,5-bis(trifluoromethyl)benzamide 1d (0.05
g. 0.169 mmol), ethyl glyoxylate (0.034 g, 0.338 mmol), dry CH2Cl2 (4.0 mL), Ph3PAuNTf2
(6.26 mg, 0.0084 mmol), Cu(OTf)2 (3.06 mg, 0.0084 mmol) and (S,S)-2,2`-Isopropylidene-bis(4-
phenyl-2-oxazoline) (2.83 mg, 0.0084 mmol). Purification via flash column chromatography (1 :
2, EtOAc/petrol) afforded the title compound 4c (53.0 mg, 80%) as a colourless solid.
[] 20 +5.2 (c 1.0, CHCl3); 84% ee; HPLC DAICEL CHIRALCEL AS-H, n-hexane/2-propanol
D
(90:10), flow rate = 0.7 mL/min, area: 354.249 (minor) and 3268.88 (major), retention time: 7.5
min (minor) and 8.0 min (major); Rf = 0.51 (1 : 1, EtOAc/petrol); M.p = 60 – 62 oC; IR (neat,
νmax/cm-1): 3430, 2988, 1740, 1621, 1553, 736; 1H NMR (400 MHz, CD2Cl2): δ 8.35 (s, 2H),
7.85 (s, 1H), 6.97 (s, 1H), 4.43 (t, J = 5.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.14 (qd, J = 6.4,
15.2 Hz, 2H), 3.10 (s, 1H), 1.19 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CD2Cl2): δ 173.8 (s),
158.7 (s), 150.3 (s), 132.4 (q, J = 33.5 Hz, 2C), 129.9 (s), 126.4 (d, J = 3.2 Hz), 124.8 (q, J =
271.0 Hz, 2C), 123.6 (qu, J = 3.7 Hz, 2C), 69.0 (s), 62.6 (s), 31.2 (s), 14.3 (s); MS (70 eV): m/z
(%): 397.0 (25) [M+]; HRMS (EI (+), 70 eV): [C16H13NO4F6]+ : calcd 397.0734, found 397.0738.
15
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10.1002/adsc.201800246
Advanced Synthesis & Catalysis
Acknowledgment. We thank the Alexander von Humboldt Foundation for generous funding
support for a postdoctoral research fellowship.
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