Transformation of Racemic Azlactones into Enantioenriched Dihydropyrroles and Lactones Enabled by Hydrogen-Bond Organocatalysis

Article abstract of DOI:10.1002/ejoc.201901052

Azlactones, a potent building block for the synthesis of complex molecules, have been explored in an organocatalytic Mannich reaction with protected imines. In this study, azlactones containing a propargyl substituent were employed for the first time in organocatalysis so far. The catalytically active species responsible for high enantioselectivity with substrate containing such a small linear substituent is assembled in situ from a bifunctional thiourea, prone to dimerization, and an organic acid, as evidenced by DOSY NMR. The resulting α,β-diamino acid derivatives were subjected to further derivatization: as an example, gold-catalyzed intramolecular hydroamination of alkynes gave chiral spirocyclic dihydropyrrole. Alternatively, related squaramide catalyst enabled a Mannich reaction of azlactones with N-aryl or alkyl glyoxylate imines. Reduction of these adducts gave access to 2,3-diaminobutyrolactones or 2,3-diamino-1,4-diol with a tertiary and a quaternary stereocenter.

Full text of DOI:10.1002/ejoc.201901052

A Journal of
Accepted Article
Title: Transformation of Racemic Azlactones into Enantioenriched
Dihydropyrroles and Lactones Enabled by Hydrogen-Bond
Organocatalysis
Authors: Matej Zabka, Adrian Kocian, Stanislav Bilka, Samuel
Andrejcak, and Radovan Sebesta
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901052
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10.1002/ejoc.201901052
European Journal of Organic Chemistry
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Transformation of Racemic Azlactones into Enantioenriched
Dihydropyrroles and Lactones Enabled by Hydrogen-Bond
Organocatalysis
Matej Žabka,[a] Adrián Kocian,[a] Stanislav Bilka,[a] Samuel Andrejčák,[a] and Radovan Šebesta*[a]
Abstract: Azlactones, a potent building block for the synthesis of
complex molecules, have been explored in an organocatalytic
Mannich reaction with protected imines. In this study, azlactones
containing a propargyl substituent were employed for the first time in
organocatalysis so far. The catalytically active species responsible
for high enantioselectivity with substrate containing such a small
linear substituent is assembled in situ from a bifunctional thiourea,
prone to dimerization, and an organic acid, as evidenced by DOSY
NMR. The resulting α,β-diamino acid derivatives were subjected to
further derivatization: as an example, gold-catalyzed intramolecular
hydroamination of alkynes gave chiral spirocyclic dihydropyrrole.
highly relevant due to their occurrence in natural products and
building blocks for synthesis.[8]
Hydrogen-bond donating organocatalysis, due to its flexibility
and broad functional group tolerance is among the most
versatile strategies for building complex chiral structures.[9] Here,
we present
organocatalysis
a
sequential use of hydrogen-bonding
and gold(I)-catalysis towards chiral
dihydropyrroles. Chiral lactones, on the other hand, were
synthesized by the reduction of a highly decorated 2,3-
diaminobutane-1,4-dicarboxylate
skeleton
(Scheme
1b).
Versatile functional groups, including an ester, a carboxylic acid,
or a protected amine, attached to these heterocycles with
quaternary and tertiary stereocenters can be used as handles
for further derivatization.
Alternatively, related squaramide catalyst enabled
reaction of azlactones with N-aryl or alkyl glyoxylate imines.
Reduction of these adducts gave access to 2,3-
a Mannich
diaminobutyrolactones or 2,3-diamino-1,4-diol with a tertiary and a
quaternary stereocenter.
Azlactones have served as valuable building blocks for
syntheses of numerous complex molecular scaffolds.[10] We and
others have described catalytic methods, starting from racemic
azlactones 1 and imines 2, for accessing enantiopure α,β-
diamino acid derivatives 3 (Scheme 1).[11] In this work, we set
out to explore the possibility of appending a propargyl moiety to
the azlactone, and then use the gold-catalyzed 5-exo-dig
Introduction
The
synthesis
of
polyfunctionalized,
enantioenriched
cyclization of intermediates
4
to afford the spirocyclic
heterocyclic molecules has been recently in high demand.[1]
Such heterocycles are found in current state-of-the-art
pharmaceuticals, drug candidates, and agrochemicals.[2]
Specifically, chiral pyrrolidines and lactones are found as core
skeletons in a number of bioactive compounds and natural
products, e.g. (-)-cucurbitine, an amino acid isolated from
pumpkin seeds, designed drug (2R,4R)-APDC, spirooligomer-
peptoid hybrids,[3] or paraconic acids – lichen metabolites with
antibiotic and antitumor properties (Scheme 1a). The most
promising synthetic approach to the heterocycles with multiple
stereogenic centers, with regards to cost, time and material used,
is the use of cascade catalytic reactions.[4] Various
organocatalytic domino strategies efficiently afforded highly
substituted pyrrolidines.[5] The combination of organocatalysis
with metal-catalyzed reactions proved useful in the assembling
of chiral pyrrolidines,[6] or pyrroles.[7] Additionally, stereoselective
catalytic synthesis of chiral butenolides and butyrolactones is
dihydropyrroles 5. Catalysis with gold(I) species,[12] or in
combination with organocatalysis, provides a suitable strategy
for such hydroamination,[13] which affords variously substituted
chiral pyrrolidines. Related spiro-cyclic pyrrolidines were
assembled via diverse catalytic domino transformations.[14]
[a]
Dr. M. Žabka, A. Kocian, S. Bilka, S. Andrejčák, Prof. Dr. R. Šebesta
Department of Organic Chemistry, Faculty of Natural Science
Comenius University in Bratislava
Mlynska dolina, Ilkovičova 6, 84215 Bratislava, Slovakia
E-mail: radovan.sebesta@uniba.sk
Homepage: www.radovansebesta.com
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. a) Chiral pyrrolidines and lactones in selected important
compounds; b) the context of this work.
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Results and Discussion
The synthesis of the starting azlactone 1a, with appended
propargyl residue, requires the amino acid propargylglycine as a
precursor. Considering its cost, we opted for a cheaper
alternative, i.e., the synthesis of propargyl azlactones from
diethyl aminomalonate (8) in four steps (Scheme 2). Acylation
with aroyl chloride gave amides 9, and subsequent enolate
alkylation with a suitable propargyl bromide furnished diesters
10. Basic ester hydrolysis and decarboxylation gave N-protected
propargylglycines 11, which were dehydrated upon the action of
EDC to give the required azlactones 1. This approach allowed
us to vary the aryl and alkyl-substituents easily.
Figure 1. (Organo)catalysts used in this work for the Mannich reaction.
We first screened typical catalysts reported for the Mannich
transformations of azlactones and related reactions. Catalysts
such as TMS-quinine C1, BINOL phosphoric acid silver salt C4,
dimeric squaramide C5, and iminophosphorane C6 (Figure 1)
delivered the required adduct but proved unsuccessful regarding
stereoselectivity, particularly enantioselectivity. However, using
the bifunctional thiourea catalysts C2 or C7, derived from
quinine, and the reaction conditions we reported previously for a
related transformation,[11a] we were able to obtain the required
adduct 4a (Scheme 3) in moderate diastereomeric and very
good enantiomeric purity of 92:8 e.r. (Table 1, entry 11).
Changing the acid co-catalyst or the reaction conditions in any
way did not lead to further improvement (Table 1, entries 13-15).
Scheme 2. Synthesis of propargyl-substituted azlactones 1a-c.
Initially, we screened hydrogen-bonding catalysts C1-C7 for the
organocatalytic Mannich reaction between azlactone 1a and
tosyl imine 2a (Figure 1, Scheme 3). The results of this
screening are summarized in Table 1.
Scheme 3. Initial screening of the hydrogen-bonding catalysts.
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10.1002/ejoc.201901052
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1
from the broad peaks in a 1D H spectrum of the free catalyst,
which become sharp upon the addition of the acid, along with
the significant downfield shift of the thiourea NH hydrogens to δ
9.5 – 11.5 ppm, indicating a relatively strong binding via H-bond.
The subsequent addition of the azlactone did not lead to any
change in the appearance of the spectrum of the catalyst-acid
complex. The structure of the quinine catalyst dimer has been
confirmed and studied previously by NMR.[15] An X-ray crystal
structure of C7 and m-chlorobenzoic acid has already been
reported, thus supporting our hypothesis.[16]
Table 1. Catalyst screening in the Mannich reaction.
Entry[a]
Catalyst/(loading mol%)
Yield
d.r.
e.r.
1
C1[b] (20)
C2 (5)
64
70
72
53
71
52
63
59
49
62
70
30f
79
80
55
2.7:1
2.0:1
1.1:1
3.0:1
3.0:1
3.3:1
2.4:1
2.9:1
2.8:1
2.4:1
3.6:1
1:1
55:45
91:9
2
3
C4 (10)
52:48
49:51
57:43
92:8
To get insights into the structure of the complex, we conducted
NMR studies of a 1:1 mixture of C7 and diphenyl phosphate in
CD2Cl2 at 180 K. To confirm the binding site of the thiourea host
4
C5 (10)
5
C6/10
and the acid guest, we conducted
experiment.[17]
a
2D 1H,31P-HMBC
6
C7 (10)
7
C7 (5)
89:11
92:8
However, we could not detect any polarization transfer from
thiourea protons (or other belonging to the catalyst) to
8
C7 (2.5)
2h
phosphate 31P nucleus via
J , most probably due to the
HP
formation of an ion pair at low temperature. The dielectric
constant of the solvent increases with decreasing temperature,
and subsequently, ion pairs are stabilized. At 300 K, again no
binding was observed using 2D NOESY or 1H,31P-HMBC. A
single sharp 31P and 19F peaks were observed, indicating the
formation of a single species. However, 1H,31P-HMBC showed at
least three other species at low intensity. Only exchange of the
phosphate OH hydrogen with the more acidic thiourea hydrogen
next to the aryl group was detected (EXSY, 500 ms mixing time).
Titrating a solution of C7 in either DCM or MeCN with benzoic
acid (1 – 10 equiv.) did not cause any change in the ECD
spectrum, particularly due to the low concentration required and
small association constants. To reinforce this observation,
anionic species such as acetate or phosphate, but not neutral
molecules, have been reported to bind to oligo(thio)urea
foldamers, as observed by the change of ECD signal, thus
suggesting very low concentration of the ion pair at room
temperature in our case.[18]
9
C7 (1)
86:14
58:42
92:8
10
11
12
13
14
15
C7[c] (10)
C7[d] (5)
C7[e] (10)
C7+PhB(OH)2 (10)
C7+TsOH (10)
C7+C3 (10)
-
2.7:1
2.5:1
3.1:1
90:10
91:9
90:10
[a] Azlactone (0.24 mmol), imine (0.2 mmol), catalyst (x mol %), PhCO2H (x
mol %), PhMe, rt, 18 h; [b] Et2O used as a solvent, without PhCO2H; [c] No
acidic additive; [d] PhCF3 used as a solvent; [e] Reaction conducted in a ball
mill; [f] conversion determined by 1H NMR.
Related 1D 1H NMR experiments with C3 instead of diphenyl
phosphate showed broad NH signals which became slightly
sharper upon cooling down to 240 K at δ 11.0 – 11.5 ppm and
two species were present according to 31P NMR. However, we
did not study this complex further due to significant signal
overlap in the aromatic region of the 1H NMR spectrum.
The hint at why the complex of chiral thiourea and the acid has
much higher selectivity comes from the studies of Seidel and co-
workers on conjugate base-stabilized carboxylic acids, exploiting
the intramolecular activation of carboxylic acids by thiourea
binding in asymmetric catalysis.[19] Similarly, the binding of
carboxylic acids to Takemoto’s bifunctional thiourea and its
impact on the catalyst conformation has been described using a
combination of VCD and computational methods.[20] In our case,
intermolecular binding of the carboxylic acid to thiourea
enhances the acidity of the carboxylic proton, which in turn
activates the imine towards the addition of the nucleophile. The
thiourea or the benzoic acid on their own are most probably not
acidic enough to activate such tosyl imines. The thiourea moiety
is thus relaying the chiral information across the bound benzoic
Catalyst C7 alone was not able to induce enantioselectivity
(Table 1, entry 10). An acidic additive such as benzoic acid was
required to improve the selectivity. A complex of thiourea C7 and
benzoic acid is presumed to be formed under the reaction
conditions. This assembling of the enantioselective catalytic
species was proved by a DOSY NMR study. A 1:1 mixture of C7
and benzoic acid in benzene-d6 gave rise to a new set of signals
in DOSY spectra. Both components have identical D value
(8.1x10-6 cm2/s), indicating the formation of a complex (Figure 2).
Moreover, the signals of a free benzoic acid and a free catalyst
were no longer present. Other organic acids, such as achiral
boronic and sulfonic or chiral phosphoric acid also induce the
same level of enantioselectivity (Table 1, entries 13 – 15). These
results indicate that the acidity of the acidic species does not
play a role in reaching high selectivity.
Based on these results, the acid most probably disrupts the
equilibrium between the monomeric and dimeric species of the
catalyst. The values of diffusion coefficients for the benzoic acid
and catalyst from separate samples are slightly higher than
predicted and arise due to the equilibria between monomeric
and dimeric forms of both species. Another evidence comes
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10.1002/ejoc.201901052
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acid to the imine. This agrees with our previously calculated
transition state at the Hartree-Fock level of theory.[11a]
and alkyl-group on the azlactone and the imine protecting and
aryl groups. Three other alkynyl-appended adducts 4b-d are
depicted in Figure 3.
Figure 3. Additional propargyl Mannich products 4b-d obtained with
corresponding azlactones and sulfonyl imines.
With the products of the organocatalytic reaction in hand, we
focused on the gold-catalyzed hydroamination reaction. We
screened both neutral and cationic phosphine-gold complexes
C9-C12. The set of screened complexes involved bulky
phosphine ligands, such as Echavarren´s catalyst C11 or C12
(Scheme 4a). Gold-catalyzed hydroamination of compound 4a
afforded, after a full conversion, a mixture of products 5a-c
(Scheme 4b). Interestingly, an addition of 10 mol% of p-TsOH
inhibited the reaction. From the inspection of 1H NMR spectra of
the crude mixture, we could rule out the presence of 5b.
However, other derivatives were detected. From this mixture, we
could isolate as a pure material only the spirocyclic 2,3-dihydro-
1H-pyrrole derivative 5a. Result of Au-catalyzed spiro-cyclization
are summarized in Table 2.
Figure 2. a) Overlaid DOSY NMR spectra of benzoic acid (green), free
catalyst C7 with its dimer (blue), and a 1:1 mixture of C7 and benzoic acid,
resulting in complex formation (red) with its 1D 1H trace, in benzene-d6 at 298
K, referenced to benzene (2.2x10-5 cm2/s) and TMS; b) proposed structure of
the complex C7·PhCO2H.
The moderate diastereoselectivity slightly diminishes the
practical value of the Mannich reaction with chiral thioureas. This
erosion in selectivity might arise from a background reaction with
the catalyst. According to the HF calculation, the mutual
arrangement of the azlactone and the imine in the TS is
synclinal, shown in Figure S1 (see Supporting Information),
allowing for the H-bond network between the catalyst and the
substrates to develop and give the observed diastereomer. The
other possible synclinal arrangement, with the imine rotated by
180°, leading to the other diastereomer, would result in repulsion
between the azlactone alkyl group and the aryl group of the
imine and is arguably disfavored. The same would be true for
one of the antiperiplanar arrangements. However, the
antiperiplanar approach leading to the minor diastereomer is still
possible, and probably relevant in the reaction. As no H-bond
network with the chiral catalyst can develop for this arrangement,
the resulting minor diastereomer is racemic, in agreement with
the experiment.
Scheme 4. a) Gold(I) catalysts used in this work; b) The hydroamination
reaction; relative energies calculated at M06-2X/TZVP//B3LYP-D3(BJ)/SV(P)
level.
With the experimental conditions established to deliver product
4a in reasonably high enantiomeric purity, we then varied aryl-
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Spiro-dihydropyrrole 5a could then be converted to different
chiral pyrrolidine derivatives. For example, using sodium
borohydride in a mixture of methanol and diethyl ether, we
obtained dihydropyrrole 12 in quantitative yield without the need
for further purification (Scheme 5). However, the products are
labile and acid sensitive.
Table 2. Gold-catalyzed spiro-cyclization.
Entry
Catalyst/(loading mol%)[a]
Combined
yield of 5 (%)[b]
Isolated 5a
(% of the
mixture)
Attempts to conduct the Mannich reaction and the
hydroamination in one-pot process were not reproducible. The
gold(I)-catalyzed hydroaminations of 4b and 4c did not proceed
at all under the conditions used for 4a, whereas heating the
mixture resulted in the decomposition of the starting material.
To enhance the scope of the reaction and access other
heterocyclic structures, azlactones 1a, d, e were reacted with
glyoxylate imines 2c-e. Interestingly, a different catalyst was
necessary to obtain the corresponding Mannich adducts 6 in
high yields and enantiomeric purities (Scheme 6). Catalyst
screening revealed that squaramide C8, structurally related to
thiourea catalyst C7, was the most active and selective catalyst
affording the product 6a in 83% yield and 98.5:1.5 e.r. For more
details on the catalyst screening, see the Supporting information.
Substitution pattern can be altered both on the imine as well as
on the azlactone.
1
2
3
4
5
6
7
8
C9 (10 mol%)
0
-
C9 (10 mol%), reflux
C9 (10 mol%), PhMe/DCM 1:1
C11 (10 mol%)
0
-
0
-
33
60
39
50
54
45
60
100
C10 (10 mol%)
C10 (5 mol%)
C10 (10 mol%)
C12 (10 mol%), AgNTf2 (10
mol%)
78
0
[a] Catalyst (10 mol %), DCM (0.2 M in 4a), rt, 2 h; [b] DCM (0.03 M in 4a), 18
h.
We have probed the reaction conditions using the most effective
organocatalyst, squaramide C8 (see Supporting information for
more details on reaction optimization). Toluene was the best
solvent for this reaction (Table S1, entry 1). Neither the use of
other solvents such as DCM, hexane, tBuOMe, THF, nor various
additives (PhCO2H, Et3N, HFIP) had any positive effects.
Lowering reaction temperature to 0°C led to adduct 6a with the
highest enantiomer purity (99.5:0.5 e.r., Table S1, entry 2).
Adducts 6a-h were obtained in yield ranging 34-89%, with
diastereomeric ratios between medium 3.7:1 to excellent 22:1.
Enantiomeric purities ranged from 53 to 97% ee with smaller
values for methyl substituted azlactone and high values for i-
propyl substituted azlactones, again hinting at the importance of
the amine protecting group size.[11a] Propargyl substituted
azlactone also delivered corresponding addition products 6f-h in
high enantiomeric purities.
The major product 5a is a stable isomer also according to the
DFT
calculations
(M06-2X/TZVP//B3LYP-D3(BJ)/SV(P)).
NOESY and other 2D NMR methods (DQF-COSY) confirmed its
structure (Scheme 5a). The relative and absolute configuration
of 5a was determined by comparison of calculated and
experimental CD spectra; see Supporting information for details.
Scheme 5. a) Key NOESY interactions in spirocyclic dihydropyrrole 5a, and its
reduction with sodium borohydride; b) intensity normalized experimental and
DFT calculated (M06-2X/def2-TZVP) CD of 5a.
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configurations of the Mannich adducts 6a-h were assigned
based on the configuration of lactone 7. The absolute
configuration of adduct 6b was determined by comparison of
DFT calculated and experimental ECD spectra (see Supporting
information).
Scheme 7. Reductive opening/lactonization and complete reduction of
Mannich adduct 6a.
Conclusions
We have demonstrated that organocatalytic Mannich reaction of
azlactones to imines can serve as a useful starting point for the
synthesis of valuable chiral spiro-pyrrolidines and lactones.
Cinchona-derived thiourea catalyst efficiently catalyzed the
Mannich addition of propargyl substituted azlactones to imines.
The selective catalytic species is assembled from the thiourea,
prone to dimerization, and benzoic acid, as confirmed by DOSY
NMR. Our experiments confirmed that the intrinsic acidity of the
additive does not play any role, but only in the complex formed
there is a functionality acidic enough to activate the imines
towards a nucleophilic attack. However, the intermolecular
binding of thiourea to the species such as carboxylic or
phosphoric acids remains elusive for structural analysis in this
context. The corresponding Mannich adduct then underwent Au-
catalyzed spiro-cyclization. On the other hand, glyoxylate imines
Scheme 6. a) The Mannich reaction of azlactones 1a, d, e with glyoxylate
imines 2c-e; b) structures of adducts 6a-e; c) comparison of DFT calculated
(PBE0/def2-SVP//ωB97XD/6-31G*) and experimental CD spectra for (S,R)-6b.
We have also performed Au-catalyzed hydroamination on
adduct 6f using AuNTf2.PPh3 complex. The reaction proceeded
with full conversion of the starting material within 2.5 h. Mass
spectral analysis confirmed the formation of a hydroamination
product (m/z 407.1), but pure compounds could not be isolated.
The mixture probably contained corresponding spiro-cyclic
pyrrolidine and piperidine products, which were however too
unstable for purification.
We attempted a reductive opening of the Mannich products.
Interestingly, using mild reducing agent NaBH4, we did not
isolate the expected hydroxy ester 13, but after a partial
reduction of the azlactone carbonyl, a transesterification with the
pending ethoxycarbonyl group afforded lactone 7. Its enantiomer
purity remained high (98:2 e.r.). Complete reduction of adduct
6a to diol 14 was achieved with NaBH4/CaCl2 (Scheme 7). The
relative configuration of lactone 7 was determined by NOESY
and 2D NMR methods (gHMBC, gHSQC). Relative
required
a cinchona-based squaramide catalyst to afford
products in high yield and enantiomeric purity. The reductive
opening of this type of Mannich adduct can lead to either chiral
lactones or amino diols depending on the choice of the reducing
agent. Thus, we have shown that a readily available substrate
can be transformed into a variety of complex heterocyclic
products by combining complementary types of catalysis or
post-functionalization. The work to expand the scope of the
transformations is underway.
Experimental Section
General Information
All reactions were carried out in oven-dried glassware under argon. The
commercially available chemicals were used without further purification.
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Solvents THF, toluene, TBME, and dioxane were distilled from
Na/benzophenone; pyridine from KOH; DCM, MeOH, Et3N, and MeCN
from CaH2 under argon. Thin layer chromatography was performed on
pre-coated aluminium-backed plates (Merck Kieselgel 60 F254) and
visualized by ultraviolet irradiation (254 nm), potassium permanganate,
or phosphomolybdic acid stains. Column and flash chromatography were
performed on silica gel with particle size 0.040-0.065 and 0.025 mm in
diameter. NMR spectra were acquired on Varian NMR System 600 and
300 spectrometers, running at 600 and 300 MHz for 1H, or 150 and 75
MHz for 13C, respectively. Chemical shifts (δ) are reported in ppm relative
to tetramethylsilane (TMS) as an internal standard or to the solvent
residual signal; CDCl3 (1H: 7.26 ppm, 13C: 77.00 ppm), CD2Cl2 (1H: 5.32
ppm), CD3OD (1H: 3.31 ppm, 13C: 49.00 ppm) or DMSO-d6 (1H: 2.50 ppm,
13C: 39.52 ppm), respectively. The following abbreviations are used to
103 – 107 °C (Et2O). The characterization data match those in the
literature.[29]
Diethyl 2-benzamido-2-(prop-2-yn-1-yl)malonate (10a): Representative
procedure A (modified procedure from the literature):[30] To a suspension
of diethyl 2-benzamidomalonate (9a, 5.30 g, 19.0 mmol)and Cs2CO3
(6.00 g, 18.4 mmol, 1 eq.) in MeCN (50 mL) was added dropwise
propargyl bromide ( w = 80 % solution in toluene, 4.10 g, 27.6 mmol, 1.5
eq.) and the solution was stirred at rt overnight. The mixture was then
filtered under reduced pressure, and the solvent was evaporated under
reduced pressure. The residue was again dissolved in EtOAc (60 mL)
and washed with water (60 mL). The organic was dried over Na2SO4 and
the solvent evaporated under reduced pressure. Purification by silica gel
column chromatography (hexanes/EtOAc 1:1) gave 10a (4.30 g, 71 %
1
1
indicate the multiplicity in H NMR spectra: s, singlet; br s, broad singlet;
yield) as a yellow oil. H NMR (600 MHz, CDCl3): δ 7.86 – 7.82 (m, 2H),
d, doublet; br d, broad doublet; dd, double doublet; ddd, double double
doublet; t, triplet; dt, double triplet; q, quartet; dq, double quartet; m,
multiplet. IR spectra were measured at Nikolet IS10 spectrometer using a
universal ATR crystal sampling plate. HPLC was performed on Daicel
Chiralpak AD-H and IA columns with UV detection at 240 nm. Optical
rotation measurements were performed on Jasco P-2000 polarimeter.
HRMS analyses were performed using a Thermo Scientific LTQ Orbitrap
with an ESI source in the positive ion mode. CD data were acquired on
Jasco J-815 spectrophotometer using a 10.0 mm cell length quartz
cuvette in the solvent stated. Data were collected in continuous scan
mode with a data pitch of 0.5 nm, a scanning speed of 100 nm min-1 and
4 accumulations. Sample temperature was regulated at 22 °C.
7.63 (br s, 1H), 7.56 – 7.52 (m, 1H), 7.50 – 7.42 (m, 2H), 4.37 – 4.26 (m,
4H), 3.41 (d, J = 2.6 Hz, 2H), 1.98 (t, J = 2.7 Hz, 1H), 1.28 (t, J = 7.1 Hz,
6H). 13C NMR (151 MHz, CDCl3): δ 166.7 (2x CO), 166.2 (CO), 133.3
(CqAr), 132.0 (CHAr), 128.6 (CHAr), 127.2 (CHAr), 78.2 (Cqsp), 71.5 (CHsp),
65.5 (Cq), 63.1 (CH2), 23.9 (CH2), 14.0 (CH3). IR (ATR): 3418, 3280,
2982, 1736, 1662, 1477, 1310, 1205, 710 cm-1. HRMS (ESI+): calcd. for
[C17H19NO5+H]+ ([M+H]+): m/z 318.1336, found 318.1324.
Diethyl
2-(4-methoxybenzamido)-2-(prop-2-yn-1-yl)malonate
(10b):
Following Representative procedure A, starting from diethyl 2-(4-
methoxybenzamido)malonate (9b, 570 mg, 1.84 mmol) and purification
by crystallization (hexanes/EtOAc) gave 10b (220 mg, 34 % yield) as
1
white needle crystals. H NMR (600 MHz, CDCl3) δ 7.85 – 7.79 (m, 2H),
Catalysts C1,[21] C3,[22] C4,[23] C5,[24] C6,[25] C7,[26] C8,[27] C11, and C12[28]
were prepared according to the corresponding literature procedures.
7.54 (br s, 1H), 6.97 – 6.90 (m, 2H), 4.35 – 4.23 (m, 4H), 3.86 (s, 3H),
3.40 (d, J = 2.6 Hz, 2H), 1.97 (t, J = 2.6 Hz, 1H), 1.27 (t, J = 7.1 Hz,
6H).13C NMR (151 MHz, CDCl3, MZ471):δ 167.1, 165.9, 162.9, 129.3,
125.7, 114.0, 78.5, 71.6, 65.7, 63.2, 55.7, 24.1, 14.2. IR (ATR): 3417,
3273, 2983, 1733, 1658, 1606, 1485, 1456, 1296, 1260, 1213, 1179,
1029, 1008, 855 cm-1. LR-MS: calcd. for [C18H21NO6+Na]+ ([M+Na]+): m/z
370.1, found 370.1. HRMS (HESI+): calcd. for [C18H21NO6+H]+ ([M+H]+):
m/z 348.1447, found 348.1442. Mp.: 69 – 73 °C (hexanes/EtOAc).
Synthesis of Propargyl azlactones
Diethyl 2-benzamidomalonate (9a): 2-Aminomalonate hydrochloride (8,
5.0 g, 23.6 mmol) was dissolved in pyridine (50 mL). The mixture was
cooled to 0 °C, and benzoylchloride (3.31 g, 23.6 mmol) was added
dropwise. The mixture was stirred overnight at rt, and the solvent was
evaporated under reduced pressure. The mixture was then partitioned
between water (50 mL) and TBME (50 mL). The layers were separated,
and the aqueous phase was extracted with TBME (2x 50 mL). The
combined organic extracts were dried over Na2SO4, filtered and
concentrated under reduced pressure to afford 9a (5.31 g, 81 % yield) as
Diethyl
2-benzamido-2-(3-phenylprop-2-yn-1-yl)malonate
(10c):
Following Representative procedure A, starting from diethyl 2-
benzamidomalonate (2a, 750 mg, 2.68 mmol) and (3-bromoprop-1-yn-1-
yl)benzene (784 mg, 4.02 mmol, 1.5 eq.),[31] followed by purification by
silica gel column chromatography (hexanes/EtOAc 2:1 – 1:1) gave 10c
(685 mg, 66 % yield) as a white solid. 1H NMR (600 MHz, CDCl3) δ7.89 –
7.81 (m, 2H), 7.70 (br s, 1H), 7.60 – 7.40 (m, 3H), 7.36 – 7.20 (m, 5H),
4.41 – 4.24 (m, 4H), 3.63 (s, 2H), 1.29 (t, J =7.1 Hz, 6H).IR (ATR): 3390,
2976, 1728, 1661, 1482, 1294, 1111, 1070, 762 cm-1. HRMS (ESI+):
calcd. for [C23H23NO5+Na]+ ([M+Na]+): m/z 416.1468, found 416.1460.
1
a white solid. H NMR (300 MHz, CDCl3): δ 7.95 – 7.75 (m, 2H), 7.66 –
7.38 (m, 3H), 7.19 (br d, J = 6.9 Hz, 1H), 5.37 (d, J = 6.8 Hz, 1H), 4.40 –
4.22 (m, 4H), 1.32 (t, J = 7.1 Hz, 6H). 13C NMR (151 MHz, CDCl3): δ
166.8 (CO), 166.4 (CO), 133.0 (CqAr), 132.1 (CHAr), 128.6 (CHAr), 127.3
(CHAr), 62.7 (CH2), 56.8 (CH), 14.00 (CH3). The characterization data
match those in the literature.[29]
Rac-2-Benzamidopent-4-ynoic acid (11a): Representative Procedure B
(modified literature procedure):[32] To a solution of ester 10a (4.30 g, 13.6
mmol) in MeOH/H2O (5:1, 250 mL) was added solid KOH (1.66 g, 29.6
mmol, 2.2 eq,) and the mixture was heated at reflux for 2 h and overnight
at rt. The solvent was then evaporated under reduced pressure and 2 M
aq. HCl was added until pH 1 was reached. The aqueous phase was
washed with EtOAc (2x 100 mL). The combined organic extracts were
dried over Na2SO4, filtered and concentrated under reduced pressure to
afford 11a (2.14 g, 72 % yield) as a white solid. 1H NMR (600 MHz,
CD3OD): δ7.90 – 7.81 (m, 2H), 7.57 – 7.51 (m, 1H), 7.50 – 7.41 (m, 2H),
4.74 (dd, J = 8.1, 5.1 Hz, 1H), 2.89 (ddd, J = 17.0, 5.1, 2.7 Hz, 1H), 2.81
(ddd, J = 17.0, 8.1, 2.7 Hz, 1H), 2.36 (t, J = 2.7 Hz, 1H).13C NMR (151
MHz, CDCl3):δ 173.5 (CO), 170.2 (CO), 135. (CqAr), 132.9 (CHAr), 129.6
(CHAr), 128.5 (CHAr), 80.4 (Cqsp), 72.0 (CHsp), 53.2 (CH), 22.2 (CH2). IR
(ATR): 3307, 3029 (broad), 2914, 1712, 1649, 1529, 1420, 1279, 930 cm-
Diethyl 2-(4-methoxybenzamido)malonate (9b): 2-Aminomalonate
hydrochloride (8, 1.01 g, 5.0 mmol) was dissolved in pyridine (10 mL),
cooled to 0 °C, and 4-methoxybenzoylchloride (0.85 g, 5.0 mmol) was
added dropwise. The mixture was stirred overnight at rt, and the solvent
was evaporated under reduced pressure. Water (40 mL) and EtOH (5
mL) were added to the residue and the solid was filtered. The solid was
recrystallized from Et2O to give 9b (570 mg) as a white solid. The
crystallization mother liquor was concentrated under reduced pressure
and
the
residue
purified
by
column
chromatography
(hexanes/EtOAc/MeOH 10:10:1) to give additional portion of 9b (260 mg,
60 % combined yield). 1H NMR (600 MHz, CDCl3):δ 7.84 – 7.78 (m, 2H),
7.02 (d, J = 6.6 Hz, 1H), 6.96 – 6.89 (m, 2H), 5.33 (d, J = 6.8 Hz, 1H),
4.32 and 4.29 (AB of ABX3, JAB = 10.8 Hz, Jx = 7.1 Hz), 3.86 (s, 3H), 1.32
(t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 166.6, 166.3, 162.7,
129.2, 125.3, 113.8, 62.6, 56.8, 55.4, 14.0. Mp: 103 – 104 °C (Et2O); lit.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901052
European Journal of Organic Chemistry
FULL PAPER
1. HRMS (ESI+): calcd. for [C12H11NO3+H]+ ([M+H]+): m/z 218.0812,
found 218.0806.
was used without any further purification. 1H NMR (600 MHz, CDCl3): δ
8.06 – 8.02 (m, 2H), 7.61 – 7.57 (m, 1H), 7.53 – 7.47 (m, 2H), 7.29 –
7.17 (m, 5H), 4.63 (t, J = 5.2 Hz, 1H), 3.19 (dd, J = 17.0, 5.1 Hz, 1H),
3.12 (dd, J = 17.0, 5.2 Hz, 1H).13C NMR (125 MHz, CDCl3): δ 176.8 (CO),
162.8 (Cq), 133.0 (CHAr), 131.7 (CHAr), 128.8 (CHAr), 128.1 (2xCHAr),
128.1 (CHAr), 125.6 (CqAr), 122.7 (CqAr), 83.8 (Cqsp), 82.6 (Cqsp), 64.5
(CH), 22.7 (CH2).IR (ATR): 3059, 2917, 1815, 1649, 1489, 1310, 1049,
950, 879 cm- 1. HRMS (ESI+): calcd. for [C18H13NO2+H]+ ([M+H]+): m/z
276.1019, found 276.1010.
Rac-2-(4-Methoxybenzamido)pent-4-ynoic
acid
(11b):
Following
Representative Procedure B, starting from ester 10b (910 mg, 2.62
mmol) gave 11b (588 mg, 91 % yield) as a white solid. 1H NMR (600
MHz, CD3OD): δ 7.89 – 7.78 (m, 2H), 7.04 – 6.94 (m, 2H), 4.72 (dd, J =
7.7, 5.4 Hz, 1H), 3.84 (s, 3H), 2.88 (ddd, J = 17.1, 5.4, 2.7 Hz, 1H), 2.80
(ddd, J = 17.0, 7.9, 2.8 Hz, 1H), 2.35 (t, J = 2.6 Hz, 1H).13C NMR (151
MHz, CD3OD):δ173.6(CO), 169.7 (CO), 164.2 (CqAr-OMe), 130.4 (CHar),
127.1 (CqAr), 114.8 (CHAr), 80.5 (Cqsp), 72.0 (CH3) 55.9 (CH), 53.1 (CH),
22.3 (CH2).IR (ATR): 3404, 3202, 2929 (broad), 2120, 1716, 1604, 1540,
1500, 1430, 1250, 1177, 1003, 841 cm-1. HRMS (ESI+): calcd. for
[C13H13NO4+H]+ ([M+H]+): m/z 248.0917, found 248.0908.
Synthesis of Alkylazlactones
Rac-4-Methyl-2-phenyloxazol-5(4H)-one (1d): Representative Procedure
D (modified procedure from the literature):[34] To a solution of rac-N-
benzoylalanine (1.45 g, 7.5 mmol) in DCM (60 mL), cooled to 0 °C, TFAA
(2.05 g, 1.36 mL, 9.75 mmol) was added in one portion. The reaction
mixture was stirred at 0 °C in an ice bath. After 30 min the ice bath was
removed, and mixture was stirred for 2h at rt. The mixture was then
washed with saturated aq. NaHCO3 (3x20mL), the organic layer was
dried over Na2SO4 and solvent evaporated under reduced pressure.
Purification by silica gel column chromatography (hexanes/EtOAc 5:1)
gave 1d (0.68 g, 52 % yield) as a white solid. 1H NMR (300 MHz, CDCl3):
δ 8.03 – 7.97 (m, 2H), 7.62 – 7.54 (m, 1H), 7.53 – 7.45 (m, 2H), 4.45 (q,
J = 7.6 Hz, 1H), 1.59 (d, J = 7.6 Hz, 3H). The characterization data match
the literature data.[34]
Rac-2-Benzamido-5-phenylpent-4-ynoic
acid
(11c):
Following
Representative Procedure B, starting from ester 10c (500 mg, 1.27
mmol) gave 11c (380 mg, quantitative yield) as a white solid. 1H NMR
(600 MHz, DMSO-d6): δ 8.82 (d, J = 7.9 Hz, 1H), 7.87 – 7.83 (m, 2H),
7.51 – 7.48 (m, 1H), 7.46 – 7.41 (m, 2H), 4.61 (ddd, J = 8.9, 8.0, 5.6 Hz,
1H), 2.97 (dd, J = 17.1, 5.6 Hz, 1H), 2.92 (dd, J = 17.0, 8.9 Hz, 1H). 13
C
NMR (151 MHz, DMSO-d6): δ 172.0 (CO), 166.5 (CO), 133.9 (CqAr),
132.5 – 130.6 (m, CHAr), 129.0 – 128.0 (m, CHAr), 127.6 – 127.3 (m,
CHAr), 122.9 (CqAr), 87.0 (Cqsp), 81.9 (Cqsp), 51.8 (CH), 21.8 (CH2).IR
(ATR): 3280, 2850 (broad), 2610, 1705, 1637, 1528, 1297, 754 cm-1.
HRMS (ESI+): calcd. for [C18H15NO3+H]+ ([M+H]+): m/z 294.1125, found
294.1115.
Rac-4-Isopropyl-2-phenyloxazol-5(4H)-one
(1e):
Following
Representative Procedure D, starting from rac-N-benzoylvaline (1.66 g,
7.5 mmol) and purification by silica gel column chromatography
(hexanes/EtOAc 5:1) gave 1e (1.16 g, 76% yield) as a white solid. 1H
NMR (300 MHz, CDCl3): δ 8.08 – 7.96 (m, 2H), 7.65 – 7.42 (m, 3H), 4.29
(d, J = 4.5 Hz, 1H), 2.48 – 2.30 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H), 1.02 (d,
J = 6.9 Hz, 3H). The characterization data match the literature data.[34]
Rac-2-Phenyl-4-(prop-2-yn-1-yl)oxazol-5(4H)-one (1a): Representative
Procedure C: To a suspension of carboxylic acid 11a (2.00 g, 9.2 mmol)
in DCM (50 mL), cooled to 0 °C, was added EDCI.HCl (2.07 g, 11.0
mmol, 1.2 eq.) in portions and the mixture was stirred at 0 °C for 10 min
and for 1 h at rt. The solvent was then evaporated under reduced
pressure, and the residue dissolved in TBME (50 mL). The organic phase
was washed with water (50 mL), dried over Na2SO4, filtered and
concentrated under reduced pressure to afford 1a (1.60 g, 87 % yield) as
a yellow solid. The material was recrystallized from pentane/DCM (3:1) at
-20 °C overnight and triturated with pentane to yield the product as yellow
needles. 1H NMR (600 MHz, CDCl3) δ 8.06 – 8.02 (m, 2H), 7.60 (t, J =
7.5 Hz, 1H), 7.53 – 7.48 (m, 2H), 4.56 (t, J = 5.3 Hz, 1H), 2.97 (ddd, J =
16.9, 5.1, 2.6 Hz, 1H), 2.89 (ddd, J = 16.9, 5.5, 2.6 Hz, 1H), 2.03 (t, J =
2.6 Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 176.6 (CO), 162.8 (Cq),
133.0 (CHAr), 128.8 (CHAr), 128.1 (CHAr), 125.5(CqAr), 77.3 (Cqsp), 71.7
(CHsp), 64.1 (CH), 21.6 (CH2).IR (ATR): 3287, 1810, 1650, 1449, 1304,
1050, 989, 941, 891 cm-1. HRMS (ESI+): calcd. for [C12H9NO2+H]+
([M+H]+): m/z 200.0706, found 200.0698. The characterization data
match those in the literature.[33]
Synthesis of Imines
Ethyl 2-((4-methoxyphenyl)imino)acetate (2c): Representative Procedure
E (modified procedure from the literature):[35] Anhydrous MgSO4 was
suspended in a solution of 4-methoxyaniline (0.985 g, 8.0 mmol) in DCM.
The solution of ethyl glyoxylate in toluene (50% w/w, 1.55 g, 8.0 mmol)
was added and the mixture was stirred at reflux for 3h. Then the mixture
was filtrated under reduced pressure through a short pad of celite. The
solids were washed with DCM (2x20mL) and the solvent was evaporated
under reduced pressure to afford 2c (1.66 g, quantitative yield) as a
yellow oil. The product was used without further purification. 1H NMR
(300 MHz, CDCl3):δ 7.93 (s, 1H), 7.45 – 7.31 (m, 2H), 7.00 – 6.88 (m,
2H), 4.40 (q, J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H). The
characterization data match the literature data.[35]
Rac-2-(4-Methoxyphenyl)-4-(prop-2-yn-1-yl)oxazol-5(4H)-one
(1b):
Following Representative Procedure C, starting from carboxylic acid 11b
(558 mg, 2.26 mmol), purification by crystallization (pentane/DCM 3:1)
gave 1b (130 mg, 25 % yield) as a white solid. 1H NMR (600 MHz,
CDCl3): δ 8.03 – 7.90 (m, 2H), 7.05 – 6.93 (m, 2H), 4.52 (t, J = 5.3 Hz,
1H), 3.88 (s, 3H), 2.94 (ddd, J = 16.9, 5.1, 2.6 Hz, 1H), 2.85 (ddd, J =
16.9, 5.5, 2.6 Hz, 1H), 2.02 (t, J = 2.6 Hz, 1H).13C NMR (125 MHz,
CDCl3): δ176.8 (CO), 163.4 (Cq), 162.5 (CqAr-OMe), 130.0 (CHAr), 117.8
(CqAr), 114.2 (CHAr), 77.6 (Cqsp), 71.6 (CH3), 64.1 (CHsp), 55.5 (CH), 21.7
(CH2).IR (ATR): 3269, 2971, 1805, 1646, 1606, 1511, 1420, 1316, 1262,
1053, 873 cm-1. HRMS (ESI+): calcd. for [C13H11NO3+H]+ ([M+H]+): m/z
230.0812, found 230.0804.
Ethyl 2-(dodecylimino)acetate (2d): Following Representative Procedure
E, starting from n-dodecylamine (1.48 g, 1.84 mL, 8.0 mmol), 2d (2.09 g,
97% yield) was obtained as a colorless oil. The product was used without
further purification. 1H NMR (300 MHz, CDCl3):δ 7.69 (t, J = 1.5 Hz, 1H),
4.35 (q, J = 7.1 Hz, 2H), 3.63 (td, J = 7.1, 1.4 Hz, 2H), 1.77 – 1.65 (m,
2H), 1.36 (t, J = 7.1 Hz, 3H), 1.33 – 1.18 (m, 18H), 0.88 (t, J = 6.7 Hz,
3H). The characterization data match the literature data.
Ethyl 2-(benzylimino)acetate (2e): Following Representative Procedure E,
starting from benzylamine (0.857g, 0.87mL, 8.0 mmol) to afford 2e (1.45g,
95% yield) as a colorless oil. The product was used without further
purification. 1H NMR (300 MHz, CDCl3):δ 7.72 (t, J = 1.6 Hz, 1H), 7.39 –
7.27 (m, 5H), 4.86 (d, J = 1.3 Hz, 2H), 4.34 (q, J = 7.1 Hz, 2H), 1.35 (t, J
= 7.1 Hz, 3H). The characterization data match the literature data.[35]
Rac-2-Phenyl-4-(3-phenylprop-2-yn-1-yl)oxazol-5(4H)-one
(1c):
Following Representative Procedure C, starting from carboxylic acid 11c
(505 mg, 1.72 mmol) gave 1c (276 mg, 58 % yield) as a yellow oil, which
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901052
European Journal of Organic Chemistry
FULL PAPER
Ethyl 2-(isopropylimino)acetate (2f): Following Representative Procedure
E, starting from isopropylamine (0.473 g, 0.69 mL, 8.0 mmol) to afford 2f
(1.45 g, 95% yield) as a colorless oil. The product was used without
further purification. H NMR (600 MHz, CDCl3): δ 7.72 (s, 1H), 4.35 (q, J
= 7.1 Hz, 2H), 3.6 (spt, J = 6.3 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H), 1.26 (d,
J = 6.3 Hz, 6H). The characterization data match the literature data.[36]
N-((S)-((R)-5-oxo-2-phenyl-4-(prop-2-yn-1-yl)-4,5-dihydrooxazol-4-
yl)(phenyl)methyl) methanesulfonamide (4b): Following General
Procedure A, purification by silica gel column chromatography
(hexanes/EtOAc 3:1 – 1:1) gave adduct 4b as a white solid. RF = 0.42
(hexanes/EtOAc 3:1). 1H NMR (600 MHz, DMSO-d6): δ 8.14 (d, J = 10.8
Hz, 1H), 8.10 – 8.03 (m, 2H), 7.78 – 7.70 (m, 1H), 7.70 – 7.60 (m, 3H),
1
A
7.48 – 7.38 (m, 3H), 4.87 (d, J = 10.8 Hz, 1H), 3.02 – 2.87 (m, 2H, CH2
+ NH), 2.32 (s, 3H), 2.09 (dd, J = 16.2, 3.3 Hz, 1H, CH2B). 13C NMR (151
MHz, CDCl3): δ 177.1 (CO), 161.5 (Cq), 135.7 (CqAr), 133.4 (CHAr),
129.11 (CHAr), 129.09 (CHAr), 128.7 (CHAr), 128.4 (CHAr), 128.3 (CHAr),
125.3 (CqAr), 77.4 (Cq), 76.6 (Cq), 74.5 (CH), 61.2 (CH), 41.1 (CH3), 24.7
(CH2). HRMS: calcd. for [C20H19N2O4S]+ ([M+H]+): m/z 383.1060, found
383.1055. HPLC: Daicel IA column, eluent = hexanes/ i-PrOH 85:15, flow
rate = 1.0 mL.min-1; tR (major) = 10.6 min; tR (minor) = 12.2 min.
Synthesis of Catalyst C2
To
styryl)quinuclidin-2-yl) methanamine[37] (40 mg, 0.10 mmol) in THF (5
mL), cooled to °C, was added a solution of 3,5-
a solution
of
(1S)-(6-methoxyquinolin-4-yl)((2S,4S,5S)-5-((E)-
0
bis(trifluoromethyl)phenylisothiocyanate (33 mg, 0.12 mmol, 1.2 eq.) in
THF (2 mL) and the solution was stirred at rt overnight. The crude
mixture was purified by silica gel column chromatography
(DCM/MeOH/Et3N 10:2:1) to give C2 (62 mg, 92 % yield) as a white solid.
4-Methyl-N-((S)-((R)-5-oxo-2-phenyl-4-(3-phenylprop-2-yn-1-yl)-4,5-
dihydrooxazol-4-yl)(phenyl)methyl)benzenesulfonamide (4c): Following
General Procedure A, purification by silica gel column chromatography
(hexanes/EtOAc 4:1 – 3:1) gave adduct 4c as a white solid. RF = 0.34
(hexanes/EtOAc 3:1). 1H NMR (600 MHz, CDCl3): δ 7.97 (dd, J = 8.0, 1.4
Hz, 2H), 7.63 – 7.56 (m, 1H), 7.49 – 7.43 (m, 4H), 7.22 – 7.10 (m, 10H),
7.01 (d, J = 8.0 Hz, 2H), 5.43 (d, J = 10.8 Hz, 1H), 4.86 (d, J = 10.8 Hz,
20
1
[α]D -15.8 (c 0.35, CHCl3). H NMR (600 MHz, CD3OD): δ 8.69 (d, J =
4.7 Hz, 1H), 8.11 (s, 2H), 7.95 (d, J = 9.2 Hz, 1H), 7.61 (dd, J = 7.9, 3.1
Hz, 2H), 7.57 – 7.51 (m, 1H), 7.47 – 7.43 (m, 1H), 7.32 (t, J = 5.9 Hz, 2H),
7.26 – 7.13 (m, 3H), 6.42 (d, J = 15.8 Hz, 1H), 6.29 (dd, J = 15.8, 8.0 Hz,
1H), 4.03 (s, 3H), 3.67 (s, 1H), 3.56 (dd, J = 17.2, 10.1 Hz, 1H), 3.41 (dd,
J = 13.9, 10.2 Hz, 1H), 2.95 – 2.84 (m, 2H), 2.57 (s, 1H), 1.79 – 1.69 (m,
3H), 1.63 – 1.55 (m, 1H), 0.98 – 0.92 (m, 1H). 13C NMR (151 MHz,
CD3OD): δ 182.5 (CqAr), 159.7 (CqAr), 148.3 (CHAr), 145.2 (CqAr), 143.0
(CqAr), 138.8 (CqAr), 133.8 (CHAr), 132.7 (q, JCF = 33.4 Hz,Cq),131.6
(CHAr), 131.2 (CHAr), 129.5 (CHAr), 128.1 (CHAr), 127.1 (CHAr), 125.6 (q,
JCF = 270.7 Hz,Cq),123.8 (CHAr), 123.6 (CHAr), 117.8 (CHAr), 104.2
(CHAr),61.7 (CH), 57.4 (CH2), 56.5 (CH3), 42.9 (CH2), 40.3 (CH),29.2
(CH), 28.5 (CH2), 27.8 (CH), 27.0 (CH2). HRMS (HESI+): calcd. for
[C35H32F6N4OS+H]+ ([M+H]+): m/z 671.2279, found 671.2273.
1H), 3.01 (d, J = 16.8 Hz, 1H), 2.63 (d, J = 16.7 Hz, 1H), 2.30 (s, 3H). 13
C
NMR (151 MHz, CDCl3): δ 177.4 (CO), 162.9 (Cq), 143.3 (CqAr), 136.8
(CqAr), 135.0 (CqAr), 133.2 (CHAr), 131.5 (CHAr), 129.2 (CHAr), 128.8
(CHAr), 128.40 (CHAr), 128.39 (CHAr), 128.3 (CHAr), 128.1 (CHAr), 128.0
(CHAr), 127.8 (CHAr), 127.1 (CHAr), 125.1 (CqAr), 122.5 (CqAr), 84.4 (Cqsp),
81.8 (Cqsp), 76.3 (Cq), 61.1 (CH), 27.0 (CH2), 21.4 (CH3). IR (ATR): 3276,
1820, 1650, 1597, 1325, 1292, 1163, 982, 900 cm-1. HRMS (ESI+): calcd.
for [C32H26N2O4S+H]+ ([M+H]+): m/z 536.1686, found 536.1675. MS2
(ESI+): [M-CO]+ calcd. m/z 507.1737 found 507.1725; [M-
PhCHNHSO2Tol+2H]+ calcd. m/z 276.1019, found 276.1014. HPLC:
Daicel IA column, eluent = hexanes/i-PrOH 90:10, flow rate = 1.0 mL.min-
1; t (major) = 22.2 min; t (minor) = 29.5 min.
Mannich Reaction of Propargyl azlactones
N-((S)-((R)-2-(4-methoxyphenyl)-5-oxo-4-(prop-2-yn-1-yl)-4,5-
dihydrooxazol-4-yl)(phenyl)methyl)-4-methylbenzenesulfonamide
General Procedure A: An oven-dried Schlenk tube was charged with
imine 2a-b (0.2 mmol), azlactone 1a-c (0.24 mmol, 1.2 equiv.), catalyst
(0.02 mmol, 10 mol-%) and acid co-catalyst (0.01 mmol, 10 mol-%) if not
stated otherwise. The solvent (1 mL) was then added. After stirring at
room temperature for 18 h, the solution was concentrated in vacuo, and
the residue was purified by silica gel column chromatography (eluent
hexanes/EtOAc) to afford the product.
(4d):
Following General Procedure A, purification by silica gel column
chromatography (hexanes/EtOAc 3:1 – 1:1) gave adduct 4d as a white
solid. 1H NMR (600 MHz, CDCl3): δ 7.94 – 7.88 (m, 2H), 7.85 – 7.76 (m,
1H), 7.44 – 7.39 (m, 2H), 7.13 – 7.06 (m, 5H), 7.03 – 6.97 (m, 2H), 6.97 –
6.91 (m, 2H), 5.38 (d, J = 11.2 Hz, 1H), 4.76 (d, J = 10.9 Hz, 1H), 3.87 (s,
3H), 2.76 (dd, J = 16.6, 2.6 Hz, 1H), 2.39 (dd, J = 16.7, 2.6 Hz, 1H), 2.29
(s, 3H), 1.91 (t, J = 2.6 Hz, 1H). ). 13C NMR (151 MHz, CDCl3): δ 177.4
(CO), 163.6 (Cq), 143.3 (CqAr), 136.7 (CqAr), 134.9 (CqAr), 130.3 (CHAr),
129.7 (CqAr), 129.2 (CHAr), 128.4 (CHAr), 128.3 (CHAr), 127.8 (CHAr),
127.1 (CHAr), 126.5 (CHAr), 117.2 (CqAr), 114.2 (CHAr), 76.6 (Cq), 75.9
(Cq), 72.2 (CHsp), 61.1 (CH), 55.5 (CH3), 25.8 (CH2), 21.4 (CH3). IR
(ATR): 3277, 1820, 1640, 1604, 1509, 1257, 1159, 978, 877 cm-1. HRMS
(HESI+): calcd. for [C27H24N2O5S+H]+ ([M+H]+): m/z 489.1479, found
489.1471. MS2 (ESI+): [M-CO]+ calcd. m/z 461.1530 found 461.1519; [M-
4-Methyl-N-((S)-((R)-5-oxo-2-phenyl-4-(prop-2-yn-1-yl)-4,5-
dihydrooxazol-4-yl)(phenyl)methyl) benzenesulfonamide (4a): Following
General Procedure A, purification by silica gel column chromatography
(hexanes/EtOAc 4:1 – 3:1) gave adduct 4a as a white solid. RF = 0.32
20
(hexanes/EtOAc 3:1). [α]D -27.4 (c 0.50, CHCl3). 1H NMR (600 MHz,
CDCl3): δ 7.95 – 7.90 (m, 2H), 7.58 – 7.54 (m, 1H), 7.45 (dd, J = 11.1,
4.3 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.15 – 7.05 (m, 5H), 6.97 (d, J = 8.1
Hz, 2H), 5.44 (d, J = 10.8, 1H), 4.77 (d, J = 10.9 Hz, 1H), 2.79 – 2.75 (m,
1H), 2.40 (dd, J = 16.8, 1.7 Hz, 1H), 2.28 (s, 3H), 1.92 (t, J = 2.5 Hz, 1H).
13C NMR (151 MHz, CDCl3): δ 177.2 (CO), 163.0 (Cq), 143.2 (CqAr),
136.6 (CqAr), 134.6 (CqAr), 133.2 (CqAr), 129.2 (CHAr), 128.7 (CHAr),
128.7 (CHAr), 128.3 (CHAr), 128.3 (CHAr), 127.9 (CHAr), 127.1 (CHAr),
125.0 (CHAr), 76.5 (CHsp), 76.0 (Cqsp), 72.2 (Cq), 61.1 (CH), 25.8 (CH2),
21.4 (CH3). IR (ATR): 3300, 3263, 1826, 1649, 1494, 1422, 1319, 1295,
1159, 976 cm-1. LR-MS: calcd. for [C26H22N2O4S+Na]+ ([M+Na]+): m/z
481.1, found 481.1. HRMS (HESI+): calcd. for [C26H22N2O4S+H]+
C7H7SO2]+
calcd.
m/z
333.1239,
found
333.1227;
[M-
PhCHNHSO2Tol+2H]+ calcd. m/z 230.0812, found 230.0805. HPLC:
Daicel IA column, eluent = hexanes/i-PrOH 85:15, flow rate = 1.0 mL.min-
1; tR (major) = 14.4 min; tR (minor) = 18.9 min.
Gold(I)-Catalyzed Reactions
(5R,6S)-8-Methyl-2,6-diphenyl-7-tosyl-3-oxa-1,7-diazaspiro[4.4]nona-1,8-
dien-4-one (5a): To a solution of 4a (50 mg, 0.11 mmol) in DCM (4 mL)
was added [Ph3PAuNTf2]2.PhMe (8.5 mg, 5 mol %) and the solution was
stirred at rt for 18 h. The mixture was then concentrated under reduced
pressure and the residue purified by silica gel column chromatography
(hexanes/EtOAc 3:1 – 2:1) to give 5a (25 mg, 50 % yield). [α]D20 -97.8 (c
([M+H]+): m/z 459.1379, found 459.1374. Mp.: 185
– 187 °C
(hexanes/EtOAc). HPLC: Daicel IA column, eluent = hexanes/i-PrOH
90:10, flow rate = 1.0 mL.min-1; tR (major) = 14.8 min; tR (minor) = 18.9
min.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901052
European Journal of Organic Chemistry
FULL PAPER
1
0.35, CHCl3). H NMR (600 MHz, CDCl3): δ 7.88 – 7.83 (m, 2H), 7.80 –
1.08 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 179.1, 169.8,
161.8, 153.2, 141.1, 133.0, 128.8, 128.1, 117.4, 115.6, 114.9, 114.7,
76.8, 72.1, 63.4, 62.1, 55.7, 22.2, 13.9. IR (ATR): 3371, 1742, 1647 cm-1.
HRMS (HESI+): calcd. for [C21H22N2O5+H]+ ([M+H]+): m/z 383.1607,
found 383.1610. [α]D -1.5 (c 1.0, CHCl3). HPLC: Chiralpak IA column,
hexanes/i-PrOH 85:15, flow rate = 1.0 mL.min-1; tR (minor) = 8.0 min; tR
7.70 (m, 2H), 7.63 – 7.56 (m, 1H), 7.51 – 7.43 (m, 2H), 7.39 (d, J = 8.3
Hz, 2H), 7.35 – 7.28 (m, 5H), 5.33 (s, 1H), 4.73 (pseudo q, J = 1.2 Hz,
1H), 2.51 (s, 3H), 2.34 (d, J = 1.1 Hz, 3H). 13C NMR (151 MHz, CDCl3):
δ 174.5 (CO), 160.8 (Cq), 148.5 (Cq), 144.4 (CqAr), 135.5 (CqAr), 134.7
(CqAr), 133.2 (CHAr), 129.9 (CHAr), 128.8 (CHAr), 128.7 (CqAr), 128.5
(CHAr), 128.1 (CHAr), 127.9 (CHAr), 126.7 (CHAr), 125.2 (CqAr), 106.8
(CH), 80.3 (Cq), 73.8 (CH), 21.7 (CH3), 16.1 (CH3). HRMS (HESI+): calcd.
for [C26H22N2O4S+H]+ ([M+H]+): m/z 459.1379, found 459.1372. HPLC:
Daicel IA column, eluent = hexanes/i-PrOH 85:15, flow rate = 1.0 mL.min-
1; tR (minor) = 12.5 min; tR (major) = 15.5 min.
20
(major) = 15.1 min.
Ethyl
(S)-2-(dodecylamino)-2-((R)-4-methyl-5-oxo-2-phenyl-4,5-
dihydrooxazol-4-yl)acetate (6c): Following General procedure B, starting
with 1d (99 mg, 0.57 mmol), 2d (152 mg, 0.54 mmol), C8 (36 mg, 0.057
mmol), Et3N (16 µL, 0.113 mmol) in dried PhMe (1.4 mL). Purification by
silica gel column chromatography (4:1) gave product 6c (86 mg, 34 %
yield) as s colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.03 – 7.99 (m, 2H),
7.57 (t, J = 7.4 Hz, 1H), 7.50 – 7.44 (m, 2H), 4.29 – 4.23 (m, 2H), 3.56 (s,
1H), 2.56 (ddd, J = 11.3, 8.0, 6.1 Hz, 1H), 2.40 (ddd, J = 11.4, 8.1, 6.3 Hz,
1H), 1.78 (br s, 1H), 1.57 (s, 3H), 1.41-1.13 (m, 23H), 0.88 (t, J = 6.7 Hz,
3H). 13C NMR (75 MHz, CDCl3): 179.3, 171.3, 161.6, 132.8, 128.7, 128.2,
125.8, 72.2, 66.0, 61.3, 48.5, 31.8, 29.8, 29.61, 29.57, 29.6, 29.5, 29.4,
29.3, 27.0, 22.6, 20.9, 14.3, 14.1. IR (ATR): 2922, 2852, 1735, 1651 cm-1.
HRMS (HESI+): calcd. for [C26H40N2O4+H]+ ([M+H]+): m/z 445.3066,
N-((2S,3R)-3-(hydroxymethyl)-5-methyl-2-phenyl-1-tosyl-2,3-dihydro-1H-
pyrrol-3-yl)benzamide (12). Azlactone 5a (25 mg, 0.055 mmol) was
dissolved in MeOH (1 mL) and Et2O (1 mL), and the mixture was cooled
to 0 °C. Solid NaBH4 (14 mg, 0.37 mmol, 7 eq.) was added and the
mixture was stirred at 0 °C for 10 min. The reaction was quenched by the
addition of sat. aq. NH4Cl (2 mL) and Et2O (5 mL). The layers were
separated, and the mixture was extracted with Et2O (2 x 5 mL). The
combined organic layers were dried over Na2SO4, filtered and the solvent
evaporated under reduced pressure (quantitative yield). The product can
be purified by silica gel column chromatography (hexanes/EtOAc 3:1 –
2:1) to give alcohol 12 (2 mg, 8 % yield) as a colorless oil (the product is
not stable to silica gel or acidic conditions). 1H NMR (300 MHz, CDCl3): δ
7.61 (d, J = 8.0 Hz, 2H), 7.58 – 7.48 (m, 4H), 7.48 – 7.19 (m, 6H), 6.94 (d,
J = 7.9 Hz, 2H), 5.66 (s, 1H), 5.46 (s, 1H), 5.19 (s, 1H, CH3C=CH), 3.90
(dd, J = 11.6, 3.7 Hz, 1H, CH2A), 2.99 (dd, J = 11.2, 5.9 Hz, 1H, CH2B),
2.37 (s, 3H, CH3C=CH), 1.98 (s, 3H, CH3C6H4), 1.54 – 1.48 (pseudo t, J
= 6.1 Hz, 1H, OH). 13C NMR (151 MHz, CDCl3): decomposes in CDCl3.
20
found 445.3060. [α]D -31.9 (c 1.0, CHCl3). HPLC: Chiralpak IA column,
eluent = hexanes/i-PrOH 90:10, flow rate = 1.0 mL.min-1; tR (major) = 3.7
min; tR (minor) = 8.3 min.
Ethyl
(S)-2-(benzylamino)-2-((R)-4-methyl-5-oxo-2-phenyl-4,5-
dihydrooxazol-4-yl)acetate (6d): Following General Procedure B, starting
with 1d (120 mg, 0.69 mmol), 2e (131 mg, 0.54 mmol), C8 (43 mg, 0.069
mmol) and Et3N (19 µL, 0.137 mmol) in PhMe (1.7 mL). Purification by
silica gel column chromatography (4:1) gave product 6d (113 mg, 45 %
1
Mannich Reaction of Alkylazlactones with Glyoxylate
Imines
yield) as s yellowish oil. H NMR (600 MHz, CDCl3): δ 8.01 (dd, J = 8.3,
1.1 Hz, 2H), 7.59 – 7.54 (m, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.32 – 7.21 (m,
5H), 4.24 (qd, J = 7.1, 1.4 Hz, 2H), 3.81 (d, J = 13.3 Hz, 1H), 3.64 (d, J =
13.3 Hz, 1H), 3.61 (s, 1H), 2.27 (bs, 1H), 1.57 (s, 3H), 1.28 (t, J = 7.2 Hz,
3H). 13C NMR (151 MHz, CDCl3): δ 179.1, 170.8, 161.6, 138.8, 132.8,
128.7, 128.4, 128.3, 128.2, 127.2, 125.7, 76.8, 72.1, 64.9, 61.4, 52.2,
21.0, 14.3. IR (ATR): 3330, 1733, 1649 cm-1. HRMS (HESI+): calcd. for
General Procedure B: An oven-dried Schlenk tube was charged with
azlactone 1d-e (1 equiv.), imine 2c-e (1 equiv.), catalyst (0.1 equiv.) and
Et3N (0.2 equiv.). PhMe was then added. After stirring at room
temperature for 18 h, the solution was diluted with EtOAc (2 mL) and
then concentrated in vacuo, and the residue was purified by silica gel
column chromatography (eluent hexanes/EtOAc) to afford the product.
20
[C21H22N2O4+H]+ ([M+H]+): m/z 367.1658, found 367.1650. [α]D +1.9 (c
1.0, CHCl3). HPLC: Chiralpak IA column, eluent = hexanes/iPrOH 90:10,
flow rate = 1.0 mL.min-1; tR (major) = 5.4 min; tR (minor) = 6.5 min.
Ethyl (2S)-2-((R)-4-isopropyl-5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)-2-
((4-methoxyphenyl)amino) acetate (6a): Following General Procedure B,
starting with 1e (129 mg, 0.7 mmol), 2c (142 mg, 0.7 mmol), C8 (44 mg,
0.07 mmol, 10 mol %), Et3N (19 µL, 0.14 mmol, 20 mol %) in PhMe (1.7
mL). Purification by silica gel column chromatography (4:1) gave product
Ethyl
(S)-2-(benzylamino)-2-((R)-4-isopropyl-5-oxo-2-phenyl-4,5-
dihydrooxazol-4-yl)acetate (6e): Following General Procedure B, starting
with 1e (148 mg, 0.72 mmol), 2e (139 mg, 0.72 mmol), C8 (46 mg, 0.072
mmol) and Et3N (20 µL, 0.146 mmol) in PhMe (1.8 mL). Purification by
silica gel column chromatography (4:1) gave product 6e (229 mg, 80 %
yield) as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ 8.05 – 7.98 (m,
2H), 7.61 – 7.53 (m, 1H), 7.51 – 7.42 (m, 2H), 7.30 (m, 5H), 4.16 (q, J =
7.1 Hz, 2H), 3.85 (dd, J = 12.9, 4.6 Hz, 2H), 3.65 (dd, J = 13.1, 6.6 Hz,
1H), 2.51 (septet, J = 6.8 Hz, 1H), 2.41 – 2.28 (m, 1H), 1.22 (t, J = 7.1 Hz,
3H), 1.05 (d, J = 6.9 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 178.3, 171.5, 161.8, 139.0, 132.7, 128.7, 128.5, 128.3, 128.1,
127.2, 125.7, 78.3, 62.7, 61.2, 52.0, 31.9, 16.9, 16.3, 14.2. IR (ATR):
3381, 2969, 1733, 1649 cm-1. HRMS (HESI+): calcd. for [C23H26N2O4+H]+
1
6a (156 mg, 58 % yield) as a colorless oil. H NMR (300 MHz, CDCl3): δ
8.03 (m, 2H), 7.64 – 7.55 (m, 1H), 7.54 – 7.45 (m, 2H), 6.80 – 6.72 (m,
4H), 4.60 (d, J = 11.5 Hz, 1H), 4.35 (d, J = 11.5 Hz, 1H), 4.08 (q, J = 7.1
Hz, 2H), 3.74 (s, 3H), 2.59 – 2.47 (m, 1H), 1.12 (t, J = 7.1 Hz, 3H), 1.07
(d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ
178.7, 170.5, 162.2, 153.6, 139.8, 133.0, 128.8, 128.2, 128.1, 125.5,
116.7, 114.8, 77.6, 61.5, 61.3, 55.6, 32.1, 17.1, 16.4, 14.0. HRMS
(HESI+): calcd. for [C23H26N2O5+H]+ ([M+H]+): m/z 411.1920, found
411.1916. HPLC: Chiralpak IA column, eluent = hexanes/ i-PrOH 85:15,
flow rate = 1.0 mL.min-1; tR (minor) = 6.3 min; tR (major) = 9.6 min.
([M+H]+): m/z 395.1971, found 395.1960. [α]D +41.2 (c 1.0, CHCl3).
20
HPLC: Chiralpak IA column, eluent = hexanes/i-PrOH 90:10, flow rate =
1.0 mL.min-1; tR (major) = 5.2 min; tR (minor) = 5.7 min.
Ethyl (S)-2-((-4-methoxyphenyl)amino)-2-((R)-4-methyl-5-oxo-2-phenyl-
4,5-dihydrooxazol-4-yl) acetate (6b): Following General procedure B,
starting with 1d (103 mg, 0.59 mmol), 2c (121 mg, 0.59 mmol), C8 (37
mg, 0.059 mmol), Et3N (16 µL, 0.117 mmol) in PhMe (1.5 mL).
Purification by silica gel column chromatography (4:1) gave product 6b
(177 mg, 79 % yield) as a yellowish oil. 1H NMR (300 MHz, CDCl3): δ
8.00 (m, 2H), 7.62 – 7.54 (m, 1H), 7.52 – 7.44 (m, 2H), 6.84 – 6.72 (m,
4H), 4.47- 4.32 (m, 2H), 4.11 – 3.97 (m, 2H), 3.75 (s, 3H), 1.67 (s, 3H),
Ethyl 2-((4-methoxyphenyl)amino)-2-(5-oxo-2-phenyl-4-(prop-2-yn-1-yl)-
4,5-dihydro-oxazol-4-yl)acetate (6f): Light Orange-yellow solid. Melting
point: 125 °C. Yield: 76 %. IR (ATR): 3290 (w, N-H); 1814 (s, C=O); 1738
(s, C=O); 1645 (s, C=N); 1512 (s, C=C(Ar)); 1449 (s, CH2); 1292 (m,
C(Ar)-N); 1243 (s, C-O); 1181 (m, C-N); 991 (s, C-H alkene); 700 (s,
C(Ar)-H) cm-1. 1H NMR (600 MHz, CDCl3): δ 8.07 (d, J = 7.4 Hz, 2H,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901052
European Journal of Organic Chemistry
FULL PAPER
major); 8.03 (d, 0.4H, minor); 7.61 (t, J = 7.5 Hz, 1H, major); 7.60 (t, 0.2H,
minor); 7.50 (t, J = 7.8 Hz, 2H, major); 7.49 (t, 0.4H, minor); 6.77 (s, 0.8H,
minor); 6.76 (s, 4H, major); 4.52 (d, 0.2H, minor); 4.45 (d, J = 11.4 Hz,
1H, major); 4.32 (d, 0.2H, minor); 4.24 (d, J = 11.4 Hz, 1H, major); 4.18-
4.12 (m, 2H, major); 4.08-4.00 (m, 0.4H, minor); 3.75 (s, 0.6H, minor);
3.73 (s, 3H, major); 3.21 (dd, 0.2H, minor); 3.09 (dd, 1H, J = 16.8, 2.5 Hz,
1H, major); 2.96 (dd, J = 16.8, 2.5 Hz, 1H, major); 2.95 (dd, 0.2H, minor);
2.02 (t, J = 2.3 Hz, 1H, major); 2.00 (t, 0.2H, minor); 1.18 (t, J = 7.1 Hz,
3H, major); 1.07 (t, 0.6H, minor) ppm. 13C NMR (151 MHz, CDCl3): δ
177.4 (major); 177.2 (minor); 169.8 (major); 168.6 (minor); 163.5 (major);
163.2 (minor); 154.2 (major); 153.7 (minor); 140.8 (minor); 139.8 (major);
133.5 (major); 133.4 (minor); 129.0 (minor); 129.0 (major); 128.7 (major);
128.5 (minor); 125.5 (minor); 125.4 (major); 117.6 (major); 116.2 (minor);
115.1 (minor); 114.9 (major); 77.0 (major); 77.0 (minor); 75.1 (minor);
74.5 (major); 72.6 (minor); 72.5 (major); 63.4 (major); 62.8 (minor); 62.4
(minor); 62.1 (major); 55.9 (minor); 55.8 (major); 26.2 (minor); 25.5
(major); 14.3 (major); 14.1 (minor) ppm. HRMS (HESI): m/z [M + H]+
borohydride (37 mg, 1 mmol). The mixture was stirred at 0 °C for 20 min
and at room temperature for 24 h. The reaction was quenched by the
addition of sat. aq. NH4Cl (2 mL) and the mixture was extracted with
DCM (3 x 10 mL). The combined organic layers were dried over Na2SO4,
filtered and the solvent evaporated under reduced pressure. The residue
was purified by silica gel column chromatography (hexanes/Et2O 1:1) to
1
give 7 (30 mg, 81 % yield) as a colorless oil. H NMR (300 MHz, CDCl3):
δ 7.72 – 7.62 (m, 2H, ArH), 7.63 – 7.54 (m, 1H, ArH), 7.47 (t, J = 7.7 Hz,
2H, ArH), 6.71 (s, 4H, -C6H4OMe), 6.18 (br s, 1H, CONH), 5.51 (br s,
1H,CHCO), 5.12 (d, J = 9.7 Hz, 1H, CH2AO), 4.46 (d, J = 9.7 Hz, 1H,
CH2BO), 3.86 – 3.74 (br s, 1H, NH), 3.71 (s, 3H, OCH3), 2.28 (septet, J =
6.9 Hz, 1H, CH(CH3)2), 1.11 (d, J = 6.9 Hz, 3H, CHCH3A), 1.04 (d, J = 6.9
Hz, 3H, CHCH3B). 13C NMR (75 MHz, CDCl3): δ 175.2 (CO lactone),
167.8 (CO amide), 153.4 (OCqPMP), 140.8 (NHCqPMP), 134.3 (CqPh),
132.2 (CHPh), 128.9 (CHPh), 126.8 (CHPh), 115.3 (CHPMP),115.1 (CHPMP),
66.8 (OCH2), 65.4 (Cq), 58.3 (CH), 55.7 (OCH3), 31.7 (CHMe2), 17.8
(CHMeA), 16.9 (CHMeB). HPLC: Chiralpak IA column, eluent = n-
hexane/i-PrOH 90:10, flow rate = 1.0 mL.min-1, 254 nm; tR(major
diastereomer): (major) = 7.9 min; tR (minor) = 10.4 min. tR (minor
diastereomer): (major) = 6.9 min; tR (minor) = 9.0 min.
20
calcd for C23H23N2O5: 407.1601; found: 407.1610. [α]D -18.7 (c 1.0,
CHCl3). HPLC: Chiralcel OD-H column, eluent = n-hexane/i-PrOH 90:10,
flow rate = 0.5 mL.min-1, 254 nm; tR(major diastereomer): (minor) = 21.9
min; tR (major) = 19.8 min. tR (minor diastereomer): (minor) = 26.4 min; tR
(major) = 24.0 min.
N-((2S,3R)-1-hydroxy-3-(hydroxymethyl)-2-((4-methoxyphenyl)amino)-4-
methylpentan-3-yl)benzamide (14). The round bottom flask was filled
with NaBH4 (23 mg, 0.61 mmol) and CaCl2 (27 mg, 0.24 mmol), diluted in
anh. THF (1.5 mL). Mixture was stirred for 8 hours at 67 °C. Then the
azlactone 6a (50 mg, 0.12 mmol) in anh. THF (1.5 mL) added and
mixture was stirred at room temperature for 18 h. Solution was acidified
with 5 mL of 10% NH4Cl, extracted with DCM (3x20 mL) and sat. solution
of NaHCO3 (20 mL), dried over Na2SO4 and solvent was evaporated
under reduced pressure. Purification by silica gel column
chromatography (hexanes/EtOAc 1:1) gave product 14 (21 mg, 47%
yield) as a colorless oil. 1H NMR (600 MHz, CDCl3): δ 8.09 (s, 1H), 7.85 –
7.82 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.49 – 7.43 (m, 2H), 6.86 – 6.75 (m,
4H), 4.08 (d, J = 11.6 Hz, 1H), 3.99 (s, 1H), 3.97 (s, 1H), 3.94 (d, J = 11.6
Hz, 1H), 3.75 (s, 3H), 3.70 (s, 1H), 3.65 (d, J = 3.4 Hz, 2H), 3.55 (d, J =
12.2 Hz, 1H), 3.07 (m, J = 13.9, 6.9 Hz, 1H), 1.00 (d, J = 6.8 Hz, 3H),
0.96 (d, J = 7.2 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ 168.30, 153.53,
138.85, 133.47, 131.05, 127.76, 126.13, 118.49, 113.84, 76.20, 75.99,
75.78, 65.39, 64.34, 61.73, 59.37, 56.40, 54.60, 27.62, 19.98, 16.19,
15.58, 13.17. HRMS: calcd. for [C21H28N2O4+H]+ ([M+H]+): m/z 373.2122,
found 373.2122.
Ethyl 2-(benzylamino)-2-(3-oxo-5-phenyl-2-(prop-2-yn-1-yl)-3,4-dihydro-
2H-pyrrol-2-yl)acetate (6g). Light Orange-yellow solid. Mp 91 °C. Yield:
77 %. IR (ATR): 3296 (w, N-H); 1819 (s, C=O); 1727 (s, C=O); 1648 (s,
C=N); 1451 (s, CH2); 1290 (m, C(Ar)-N); 986 (s, C-H alkene); 694 (s,
C(Ar)-H) cm-1. 1H NMR (600 MHz, CDCl3):δ (major diastereomer) 8.03 (d,
J = 7.4 Hz, 2H); 7.58 (t, J = 7.4 Hz, 1H); 7.47 (t, J = 7.7 Hz, 2H); 7.32-
7.23 (m, 5H); 4.22-4.16 (m, 2H); 3.83 (d, J = 13.1 Hz, 1H); 3.70-3.64 (m,
2H); 3.06 (dd, J = 16.8; 2.4 Hz, 1H); 2.85 (dd, J = 16.8; 2.4 Hz, 1H); 2.33
(bs, 1H); 1.95 (s, 1H); 1.25 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (151 MHz,
CDCl3): δ (major diastereomer) 177.1; 170.5; 162.9; 138.7; 133.0; 128.7;
2x 128.4; 128.3; 127.3; 125.4; 77.1; 74.7; 71.9; 63.9; 61.6; 52.2; 25.2;
14.2 ppm. HRMS (HESI): m/z [M + H]+ calcd for C23H23N2O4: 391.1652;
found: 391.1656. [α]D20 +11.2 (c 1.0, CHCl3). HPLC: Chiralpak IA column,
eluent = n-hexane/i-PrOH 90:10, flow rate = 0.5 mL.min-1 254 nm;
tR(major diastereomer): (minor) = 18.2 min; tR (major) = 16.2 min.
Ethyl
2-(isopropylamino)-2-(5-oxo-2-phenyl-4-(prop-2-yn-1-yl)-4,5-
dihydrooxazol-4-yl)acetate (6h): Light Orange-yellow solid. Mp 74 °C.
Yield: 66 %. IR (ATR): 3288 (w, N-H); 1820 (s, C=O); 1735 (s, C=O);
1648 (s, C=N); 1450 (s, CH2); 1241 (m, C-O); 1174 (s, C-N); 983 (s, C-H
1
alkene); 694 (s, C(Ar)-H) cm-1. H NMR (600 MHz, CDCl3):δ 8.05 (d, J =
Acknowledgments
7.2 Hz, 2H, major); 8.01 (d, 0.4H, minor); 7.59 (t, J = 7.7 Hz, 1H, major);
7.58 (t, 0.2H, minor); 7.49 (t, J = 7.7 Hz, 2H, major); 7.48 (t, 0.4H, minor);
4.23 (q, J = 7.1 Hz, 2H, major); 4.08-4.00 (m, 0.4H, minor); 3.74 (s, 1H,
major); 3.73 (s, 0.2H, minor); 3.34 (dd, 0.2H, minor); 3.04 (dd, J = 16.7;
2.6 Hz, 1H, major); 2.89 (dd, J = 16.8; 2.6 Hz, 1H, major); 2.86 (sept,
0.2H, minor); 2.79 (dd, 0.2H, minor); 2.73 (sept, J = 6.2 Hz, 1H, major);
1.97 (t, J = 2.6 Hz, 1H, major); 1.95 (t, 0.2H, minor); 1.91 (bs, 1H, major);
1.55 (bs, 0.2H, minor); 1.27 (t, J = 7.1 Hz, 3H, major); 1.26 (t, 0.6H,
minor); 1.12 (dd, 1.2H, minor); 0.99 (dd, J = 6.3; 2.5 Hz, 6H, major) ppm.
13C NMR (151 MHz, CDCl3):δ 177.9; 177.1; 171.2; 170.9; 162.7; 162.4;
2x133.0; 128.8; 128.7; 128.4; 128.2; 2x125.5; 77.5; 77.3; 75.1; 75.0;
72.0; 71.8; 62.8; 62.5; 61.8; 61.5; 48.3; 47.4; 26.1; 25.0; 2x23.6; 22.3;
21.8; 14.2; 13.9 ppm. HRMS (HESI): m/z [M + H]+ calcd for C19H23N2O4:
343.1652; found: 343.1652. [α]D20 +7.7 (c 1.0, CHCl3).
This work was supported by the Slovak Grant Agency VEGA,
grant no. VEGA 1/0414/16. We thank Professor Ruth M.
Gschwind for suggestions about DOSY and related NMR
experiments, and Dr. Juraj Filo for assistance with NMR
measurements. We thank Filip Beňovič for some preliminary
experiments.
Keywords: hydrogen-bond • organic catalysis • Mannich
reaction • hydroamination • dihydropyrroles
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Entry for the Table of Contents
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Asymmetric organocatalysis
Matej Žabka, Adrián Kocian, Stanislav
Bilka, Samuel Andrejčák, Radovan
Šebesta*
Page No. – Page No.
Racemic azlactones are transformed into valuable chiral heterocycles via
asymmetric organocatalytic Mannich reaction followed by Au-catalyzed cyclization
or reduction.
Transformation of Racemic
Azlactones into Enantioenriched
Dihydropyrroles and Lactones
Enabled by Hydrogen-Bond
Organocatalysis
*one or two words that highlight the emphasis of the paper or the field of the study
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