First article .ejoc.pdf

DOI: 10.1002/ejoc.202000015 Full Paper
Multicomponent Reactions
Four-Component One-Pot Process Involving Passerini Reaction
Followed by Aldol Addition and Transesterification
Muhammad Hasan,[a][‡]
Manzoor Zaman,[a][‡]
Anatoly A. Peshkov,*[b]
Niyaz Amire,[b]
Adil Les,[b]
Anton A. Nechaev,[c]
Yuqing Wang,[a]
Stepan Kashtanov,[d]
Erik V. Van der Eycken,[c,e]
Olga P. Pereshivko,[a,b]
and Vsevolod A. Peshkov*[a,b,f]
Abstract: A four-component one-pot transformation involving
the Passerini reaction, an aldol addition, and a transesterifica-
tion has been elaborated, providing an access to a library of
densely functionalized tartaric acid derivatives. Two modifica-
tions of the process have been explored. In the first modifica-
tion, carboxylic acids and isocyanides were treated with an ex-
cess of ethyl glyoxalate leading to the incorporation of two
Introduction
Multicomponent reactions (MCRs) are convergent processes
that involve the construction of relatively complex molecular
architectures by the simultaneous incorporation of three or
more building blocks originating from simple and often mono-
functional starting materials.[1]
Four-component Ugi[2,3]
and
three-component Passerini[4–6]
reactions that are built upon the
ability of organic isocyanides to react with activated imines and
carbonyl compounds are among the most used and well-
explored multicomponent processes.
Despite that the three-component Passerini reaction has
been discovered nearly four decades before its four-component
[a] College of Chemistry, Chemical Engineering and Materials Science,
Soochow University,
Dushu Lake Campus, Suzhou 215123, P.R. China,
E-mail: vsevolod@suda.edu.cn
[b] Department of Chemistry, School of Sciences and Humanities,
Nazarbayev University,
53 Kabanbay Batyr Ave, Block 7, Nur-Sultan 010000,
Republic of Kazakhstan,
E-mail: anatolypeshkov1990@gmail.com
vsevolod.peshkov@nu.edu.kz
[c] Laboratory of Organic & Microwave-Assisted Chemistry (LOMAC),
Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, B-3001 Leuven, Belgium
[d] Department of Chemistry,
Xi′an Jiaotong-Liverpool University,
Suzhou, 215123, P.R. China
[e] Peoples' Friendship University of Russia (RUDN University),
Miklukho-Maklaya street 6, Moscow, 117198, Russia
[f] The Environment and Resource Efficiency Cluster (EREC),
Nazarbayev University,
Nur-Sultan 010000, Republic of Kazakhstan
[‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000015.
Eur. J. Org. Chem. 0000, 0–0 © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
ethyl glyoxalate residues in the resulting post-Passerini prod-
ucts. The second modification involved the initial reaction of a
carboxylic acid, an aryl glyoxal and an isocyanide to form the
Passerini adduct. This was followed by the in situ addition of
ethyl glyoxalate to produce the second type of post-Passerini
products through aldol addition and transesterification.
Ugi counterpart, it has received substantially less attention from
the scientific community, probably due to its lower diversifica-
tion power and general efficiency. The standard Passerini reac-
tion involves the condensation of a carbonyl compound 1, a
carboxylic acid 2 and an isocyanide 3 to produce α-acyloxy
amide 4 (Scheme 1a).[4–6]
Furthermore, several modifications
have been developed, involving the replacement of the carbox-
ylic acid with N-hydroxamic acids,[7]
trimethylsilyl azide,[8]
phen-
ols,[9]
triphenylsilanol,[10]
hexafluoro-2-propanol[11]
and even ali-
phatic alcohols.[12]
The replacement of the carbonyl component
by an in situ generated ketene for the synthesis of captodative
olefins has also been documented.[13]
Many recent efforts have been directed towards the utiliza-
tion of Passerini adducts 4 in a variety of post-transforma-
tions,[14]
especially in those that lead to the construction of
potentially bioactive heterocyclic motifs.[15]
Recently, the group
of Van der Eycken has developed a one-pot synthesis of
butenolides 8 through the Passerini reaction of ethyl glyoxalate
(5), 3-substituted propiolic acids 6 and isocyanides 3 followed
by an enolization triggered cycloisomerization of the resulting
adducts 7 (Scheme 1b).[16]
The process benefits from the use of
ethyl glyoxalate (5) as a carbonyl component that introduces
an additional electron-withdrawing group into the adduct 7,
resulting in the formation of a 1,3-dicarbonyl moiety. Addition
of base triggers an intramolecular nucleophilic attack of a 1,3-
dicarbonyl nucleophile onto the activated triple bond complet-
ing the construction of the butenolide core of 8. Another im-
portant synthetic application of Passerini products is linked
with the migratory ability of the acyl group in the adducts 10
derived from N-protected α-amino aldehydes 9 as highlighted
in the Passerini/Amine-Deprotection/Acyl-Migration (PADAM)
protocol, producing complex peptide-like structures 11 featur-
ing an α-hydroxy-β-amino acid unit. The PADAM strategy has

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Scheme 1. Passerini reaction and post-Passerini transformations relevant to the present study.
been successfully utilized as a tool for a combinatorial synthesis
of peptidomimetics[17]
and in the total synthesis of the natural
cyclic peptide cyclotheonamide C.[18]
The transformation described in this paper has been discov-
ered accidently in the course of our work on Passerini reactions
with ethyl glyoxalate (5). When such reactions were conducted
using high temperature and low dilution in addition to ex-
pected Passerini adduct 12, the formation of another complex
product 14 featuring tartaric acid backbone[19]
was observed.
The tentative pathway towards 14 is shown in Scheme 1d. The
initially formed Passerini adduct 12 engages in an intermolec-
ular aldol addition with the second molecule of 5 producing
intermediate 13. The subsequent acyl transfer from tertiary to
secondary alcohol via an intramolecular transesterification
yields compound 14. The overall process can also be regarded
as an isocyanide-triggered benzoin-type condensation of two
molecules of ethyl glyoxalate (5). In this report, we present our
studies on optimization and scope of this novel pseudo-four-
component process involving Passerini reaction followed by
aldol addition and transesterification. Besides, we outline the
extension of this chemistry towards the truly four-component
one-pot process.
Eur. J. Org. Chem. 0000, 0–0 www.eurjoc.org © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2
Results and Discussion
We selected benzoic acid (2a) and tert-butyl isocyanide (3a) as
model substrates to investigate their reaction with ethyl
glyoxalate (5) under different conditions (Table 1). When the
reaction was conducted using excess of 2a and 3a in dichloro-
methane as solvent at room temperature, the Passerini adduct
12a was obtained in a good yield of 75 % as the sole reaction
product (entry 1). When ethyl glyoxalate (5) was taken in excess
and the reaction was conducted at the elevated temperature
of 50 °C or 70 °C, the yield of 12a dropped. This was partially
compensated by the formation of a minor amount of post-
Passerini adduct 14a (entries 2 and 3). Next, we found that the
yield of 14a could be improved by increasing the concentra-
tions of the reactants in the reaction media (entries 4 and 5).
Finally, the use of 1,2-dichloroethane as solvent led to some-
what better result in terms of attaining 14a compared to the
analogous reactions in dichloromethane and chloroform (entry
7 vs. entries 5 and 6). As a result, we were able to obtain the
desired post-Passerini adduct 14a in an isolated yield of 38 %
(entry 7). Further adjustments of the reaction time, the dilution
or reagents ratio could not substantially improve the outcome

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Table 1. Screening the reaction conditions for the synthesis of post-Passerini adduct 14a.[a]
Entry 5:2a:3a Conditions[b]
Yield[c]
12a 14a
1[d]
1:1.33:1.33 DCM (0.25 M), r.t., 24 h 75[e]
–
2 2.2:1:1 DCM (0.25 M), 50 °C, 24 h 54 8
3 2.2:1:1 DCM (0.25 M), 70 °C, 48 h 29 14
4 2.2:1:1 DCM (0.5 M), 70 °C, 96 h 7 29
5 2.2:1:1 DCM (1 M), 70 °C, 48 h – 40
6 2.2:1:1 CHCl3 (1 M), 70 °C, 48 h – 32
7 2.2:1:1 DCE (1 M), 70 °C, 48 h – 41 (38)[e]
8 2.2:1:1 DCE (1 M), 70 °C, 24 h 44 28
9[f]
2.2:1:1 DCE (1.5 M), 70 °C, 48 h – 35
10 2.2:1.2:1 DCE (1 M), 70 °C, 48 h 6 35
11 2.2:1:1.2 DCE (1 M), 70 °C, 72 h – 42
12 2.2:1:1.5 DCE (1 M), 70 °C, 48 h 34 22
[a] Unless otherwise specified, the reactions were run on a 0.5 mmol scale with respect to 2a and 3a. [b] All reactions were conducted in sealed vials. The
indicated temperatures of 50 °C and 70 °C refer to the temperature of an oil bath to which the reaction vial was immersed. [c] Determined by 1
H NMR using
3,4,5-trimethoxybenzaldehyde as internal standard. [d] Run on a 1.5 mmol scale with respect to 5. [e] Isolated yield. [f] Run on a 0.4 mmol scale with respect
to 2a and 3a.
of this transformation towards the formation of product 14a
(entries 8–12). It should also be noted that in addition to
screening the conditions for the formation of 14a directly from
2a, 3a and 5, we have succeeded with the preparation of 14a
by treatment of the Passerini adduct 12a with an excess of
ethyl glyoxalate (5).
Next, we decided to evaluate the scope of this Passerini reac-
tion/aldol addition/transesterification process under one-pot
settings (Scheme 2). Employing various aromatic and hetero-
aromatic acids in combination with tert-butyl isocyanide (3a)
and ethyl glyoxalate (5), a series of post-Passerini adducts 14a–
j could be successfully prepared with yields ranging from 26 %
to 64 %. In addition to that, we were able to obtain products
14k–n by reacting 3a and 5 with different aliphatic acids, trans-
cinnamic acid and phenyl propiolic acid. The use of n-butyl and
2-naphthyl isocyandes in the reactions with appropriate carbox-
ylic acid 2 and ethyl glyoxalate (5) yielded products 14o and
14p indicating that the process is emendable to the variation
of the isocyanide component. It should be stressed, that all the
tested reactions were not particularly diastereoselective deliver-
ing tartaric acid derivatives 14 as mixtures of diastereomers.
Nonetheless, for products 14b, 14c and 14n some amounts of
major diastereomer could be separated by the column chroma-
tography. Thus, the structure of the major diastereomer of 14c
could be established by the single-crystal X-ray diffraction anal-
ysis.[20]
Considering that the discovered one-pot process involved
the incorporation of two aldehyde molecules, we became keen
in exploring the possibility of a cross-condensation in order to
shift from a pseudo four-component to a truly four-component
mode. In order to do so we decided to introduce an aryl glyoxal
3
15 as an additional reaction component while the overall trans-
formation was attempted in a two-step one-pot fashion. Con-
ducting the model reaction of phenyl glyoxal (15a), benzoic
acid (2a) and tert-butyl isocyanide (3a) delivered Passerini ad-
duct 16a featuring inbuilt 1,3-dicarbonyl moiety. Then, the re-
action mixture was concentrated and the crude 16a was al-
lowed to react with ethyl glyoxalate (5) under elevated temper-
ature and lower dilution completing the assembly of the de-
sired post-Passerini adduct 17a via aldol addition and trans-
esterification. The influence of the solvent on the outcome of
this transformation is summarized in Table 2. In general, the
yield of 17a was found to be rather constant regardless what
solvent was used. However, in terms of diastereoselectivity
chloroform showed better results in comparison with dichloro-
methane and 1,2-dichloroethane.
Therefore, chloroform was selected as the solvent of choice
for the subsequent substrate scope study (Scheme 3). Although
the most of acquired products 17 were obtained as mixtures of
diastereomers, having higher diastereomeric ratio proved to be
beneficial for distinguishing the signals from two diastereomers
in the NMR spectra during the characterization.
The scope of this two-step four-component approach was
thoroughly explored using various aryl glyoxals 15, carboxylic
acids 2 and isocyanides 3 delivering post-Passerini adducts 17
in up to 98 % yield albeit as mixtures of diastereomers in the
majority of cases (Scheme 3). Nonetheless, likewise in the case
of post-Passerini adducts of the first type (Scheme 2, products
14b, 14c and 14n), we were able to separate the major dia-
stereomers for certain tartaric acid derivatives of the second
type (Scheme 3, products 17a, 17b, 17j and 17o). This allowed
to perform a single crystal XRD analysis for the major diastereo-

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Scheme 2. Scope of the one-pot process leading to the construction of post-Passerini adducts 14.[a]
[a] Unless otherwise specified, the reactions were run on
a 0.5 mmol scale with 5:2:3 = 2.2:1:1 in DCE (0.5 mL) in sealed vials at 70 °C for 48 h. The indicated temperature of 70 °C refers to the temperature of an oil
bath to which the reaction vial was immersed. The reported yields and dr values correspond to purified products. The dr values were calculated from 1
H
NMR spectra. [b] The reactions were run on a 0.5 mmol scale with 5:2:3 = 2.2:1:1.2 in DCE (0.5 mL) at 70 °C for 72 h. [c] The yield is for purified major
diastereomer.
Table 2. Screening the reaction conditions for the synthesis of post-Passerini adduct 17a.[a]
Solvent Yield of 17a[b]
dr[b]
DCM 83 2.3:1
CHCl3 82 3.9:1
DCE 84 3.1:1
[a] The reactions were run on a 0.5 mmol scale with respect to 15a, 2a and 3a in sealed vials. The indicated temperature of 70 °C refers to the temperature
of an oil bath to which the reaction vial was immersed. [b] Determined by 1
H NMR using 3,4,5-trimethoxybenzaldehyde as internal standard.
mer of 17b in order to establish its exact structure.[20]
It should
be noted that the average efficiency of the second cross-con-
densation mode was found to be higher than the first homo-
condensation approach.
Previously, we have demonstrated that the aryl glyoxal-de-
rived Ugi adducts can undergo an enolization triggered cycliza-
4
tion[21]
as well as a complexation with boron trifluoride diethyl
etherate.[22]
However, an attempt to react such Ugi adducts 19a
and 19b with ethyl glyoxalate (5) under the conditions similar
to those used in Scheme 3 met with failure. Specifically, we
were unable to obtain any addition products 20 and/or 21. In
both cases, the NMR analysis of crude reaction mixtures indi-

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Scheme 3. Scope of the one-pot process leading to the construction of post-Passerini adducts 17.[a]
[a] Unless otherwise specified, the reactions were run on
a 0.5 mmol scale in CHCl3. All reactions were conducted in sealed vials. The indicated temperature 70 °C refers to the temperature of an oil bath to which
the reaction vial was immersed. The reported yields and dr values correspond to purified products. The dr values were calculated from 1
H NMR spectra.
[b] The yield is for purified major diastereomer. [c] The reactions was conducted in DCE.
Scheme 4. Attempted addition of phenyl glyoxal-derived Ugi adducts 19 to ethyl glyoxalate (5).
cated the presence of significant amounts of unreacted Ugi ad-
ducts 19 (Scheme 4). Thus, it can be concluded that the scope
of the transformation studied in this paper is limited to the
Passerini adducts.
Conclusion
In summary, we have discovered and documented a novel four-
component one-pot transformation involving a Passerini reac-
tion, an aldol addition and a transesterification, aiming to
5
broaden the scope of the post-Passerini chemistry. The result-
ing products featuring tartaric acid backbone were assembled
with the participation of one molecule of carboxylic acid, one
molecule of isocyanide and two aldehyde molecules with the
first one being incorporated during the Passerini step and the
second during the subsequent aldol-type addition. The overall
process can be regarded as an isocyanide-triggered benzoin-
type condensation. Consequently, two modifications of the
process have been developed – a homo-condensation of ethyl
glyoxalate and a cross-condensation of aryl glyoxal with ethyl
glyoxalate.

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Experimental Section
General Remarks: Unless otherwise specified, starting materials
and solvents were purchased from commercial sources and used as
received. The solvents were not additionally dried and the reactions
were carried out under the air atmosphere. Aryl glyoxal hydrates
15 were purchased or synthesized following previously described
protocol[23]
The synthesis and characterization of Ugi adduct 19a
was described by us previously.[22]
NMR spectra were recorded us-
ing 400 MHz and 600 MHz Bruker Avance instruments. The 1
H and
13
C chemical shifts are reported relative to TMS using the residual
CDCl3 signal as internal reference. HRMS were performed on a
Bruker microTOF-Q III.
Procedure for the Synthesis of Passerini Adduct 12a: Benzoic
acid (2a, 244 mg, 2 mmol) was placed in screw cap vial charged
with magnetic bead followed by the addition of dichloromethane
(8 mL), ethyl glyoxylate (5, 153 mg, 1.5 mmol, added as 297 μL of
ca 50 % soln. in toluene), and tert-butyl isocyanide (3a, 226 mg,
2 mmol). The reaction mixture was sealed and stirred at room tem-
perature for 24 h. The resulting mixture was diluted with EtOAc and
concentrated with silica. Column chromatography with petroleum
ether/EtOAc (4:1) as eluent delivered desired Passerini adduct 12a.
1-(tert-Butylamino)-3-ethoxy-1,3-dioxopropan-2-yl Benzoate
(12a): Yield: 346 mg, 75 % (white powder, m.p. 92–95 °C); 1
H NMR
(400 MHz, CDCl3) δ = 8.14–8.06 (m, 2H), 7.66–7.57 (m, 1H), 7.54–
7.43 (m, 2H), 6.28 (bs, 1H), 5.57 (s, 1H), 4.41–4.24 (m, 2H), 1.40 (s,
9H), 1.32 (t, J = 7.1 Hz, 3H); 13
C NMR (100 MHz, CDCl3) δ = 166.4,
165.0, 162.1, 134.0, 130.1, 128.8, 128.6, 73.5, 62.7, 52.2, 28.7, 14.2;
HRMS (ESI): m/z [M + H]+
for C16H22NO5
+
, calcd. 308.1492, found
308.1498.
Synthesis of Post-Passerini Adducts 14. General Procedure A:
Carboxylic acid 2 (0.5 mmol) was placed in screw cap vial charged
with magnetic bead followed by the addition of 1,2-dichloroethane
(0.5 mL), ethyl glyoxylate (5, 102 mg, 1.1 mmol, added as 221 μL of
ca 50 % soln. in toluene), and isocyanide 3 (0.5 mmol). The reaction
mixture was sealed and stirred at 70 °C for 48 h. The resulting mix-
ture was diluted with EtOAc, washed with 1 M aqueous solution of
NaOH to remove unreacted acid, dried with anhydrous Na2SO4 and
concentrated with silica. Column chromatography with petroleum
ether/EtOAc (the ratio was adjusted according to the TLC of the
reaction mixture) as eluent delivered desired adduct 14. General
Procedure B: Carboxylic acid 2 (0.5 mmol) was placed in screw cap
vial charged with magnetic bead followed by the addition of 1,2-
dichloroethane (0.5 mL), ethyl glyoxylate (5, 102 mg, 1.1 mmol,
added as 221 μL of ca 50 % soln. in toluene), and isocyanide 3
(0.6 mmol). The reaction mixture was sealed and stirred at 70 °C for
72 h. The resulting mixture was diluted with EtOAc, washed with
1 M aqueous solution of NaOH to remove unreacted acid, dried with
anhydrous Na2SO4 and concentrated with silica. Column chroma-
tography with petroleum ether/EtOAc (the ratio was adjusted
according to the TLC of the reaction mixture) as eluent delivered
desired adduct 14.
Diethyl 3-(Benzoyloxy)-2-(tert-butylcarbamoyl)-2-hydroxy-
succinate (14a): Yield: 78 mg, 38 % (dr = 2.8:1, procedure A, white
powder); 1
H NMR (400 MHz, CDCl3) δ = 8.10–7.99 (m, 2H, major +
minor), 7.64–7.54 (m, 1H, major + minor), 7.49–7.40 (m, 2H, major
+ minor), 6.86 (bs, 1H, major + minor), 6.25 (s, 1H, major + minor),
4.78 (s, 0.26H, minor), 4.65 (s, 0.74H, major), 4.48–4.15 (m, 4H, major
+ minor), 1.40 (t, J = 7.2 Hz, 0.78H, minor), 1.39 (s, 6.66H, major),
1.26 (t, J = 7.1 Hz, 2.22H, major), 1.24 (t, J = 7.1 Hz, 0.78H, minor),
1.23 (s, 2.34H, minor), 1.13 (t, J = 7.1 Hz, 2.22H, major); 13
C NMR
(100 MHz, CDCl3) δ = 169.9 (minor), 169.7 (major), 166.4 (minor),
6
165.8 (major), 165.2 (minor), 165.0 (major), 163.8 (minor), 163.6 (ma-
jor), 133.74 (major), 133.69 (minor), 130.2 (minor), 130.0 (major),
128.94 (minor), 128.89 (major), 128.6 (major), 128.5 (minor), 80.3
(major), 79.9 (minor), 75.5 (major), 75.4 (minor), 64.1 (major), 64.0
(minor), 62.3 (minor), 62.2 (major), 52.0 (minor), 51.8 (major), 28.6
(major), 28.5 (minor), 14.3 (major), 14.11 (minor), 14.08 (minor),
14.03 (major); HRMS (ESI): m/z [M + H]+
for C20H28NO8
+
, calcd.
410.1809, found 410.1817.
Diethyl 2-(tert-Butylcarbamoyl)-3-((4-chlorobenzoyl)oxy)-2-
hydroxysuccinate (14b): Yield: 82 mg, 37 % (dr = 2.7:1, procedure
B, white powder) or 40 mg, 18 % (major diastereomer, procedure B,
white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.00 (d, J = 8.6 Hz,
0.54H, minor), 7.96 (d, J = 8.7 Hz, 1.46H, major), 7.45–7.38 (m, 2H,
major + minor), 6.86 (bs, 0.27H, minor), 6.85 (bs, 0.73H, major), 6.26–
6.21(m, 1H, major + minor), 4.76 (bs, 0.27H, minor), 4.64 (bs, 0.73H,
major), 4.48–4.14 (m, 4H, major + minor), 1.40 (t, J = 7.2 Hz, 0.81H,
minor), 1.39 (s, 6.57H, major), 1.26 (t, J = 7.1 Hz, 2.19H, major), 1.23
(t, J = 7.1 Hz, 0.81H, minor), 1.23 (s, 2.43H, minor), 1.13 (t, J = 7.1 Hz,
2.19H, major); 13
C NMR (100 MHz, CDCl3) δ = 169.8 (minor), 169.6
(major), 166.2 (minor), 165.6 (major), 164.3 (minor), 164.1 (major),
163.7 (minor), 163.5 (major), 140.3 (major), 140.2 (minor), 131.5 (mi-
nor), 131.4 (major), 129.0 (major), 128.9 (minor), 127.4 (minor), 127.3
(major), 80.2 (major), 79.8 (minor), 75.6 (major), 75.5 (minor), 64.1
(major + minor), 62.4 (minor), 62.3 (major), 52.0 (minor), 51.8 (ma-
jor), 28.53 (major), 28.45 (minor), 14.3 (major), 14.09 (minor), 14.06
(major + minor); 1
H NMR (400 MHz, CDCl3, major diastereomer) δ =
7.96 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.84 (bs, 1H), 6.23
(s, 1H), 4.63 (s, 1H), 4.34–4.16 (m, 4H), 1.39 (s, 9H), 1.26 (t, J = 7.1 Hz,
3H), 1.13 (t, J = 7.1 Hz, 3H); 13
C NMR (100 MHz, CDCl3, major dia-
stereomer) δ = 169.7, 165.7, 164.2, 163.5, 140.4, 131.4, 129.1, 127.4,
80.2, 75.7, 64.2, 62.3, 51.9, 28.6, 14.3, 14.1; HRMS (ESI): m/z [M + H]+
for C20H27ClNO8
+
, calcd. 444.1420, found 444.1438.
Diethyl 3-((4-Bromobenzoyl)oxy)-2-(tert-butylcarbamoyl)-2-
hydroxysuccinate (14c): Yield: 108 mg, 44 % (dr = 2.8:1, procedure
A, white powder) or 68 mg, 28 % (major diastereomer, procedure
A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 7.93 (d, J = 8.6 Hz,
0.52H, minor), 7.88 (d, J = 8.6 Hz, 1.48H, major), 7.62–7.56 (m, 2H,
major + minor), 6.86 (bs, 0.26H, minor), 6.84 (bs, 0.74H, major), 6.24
(s, 1H, major + minor), 4.76 (s, 0.26H, minor), 4.64 (s, 0.74H, major),
4.47–4.16 (m, 4H, major + minor), 1.40 (t, J = 7.2 Hz, 0.78H, minor),
1.39 (s, 6.66H, major), 1.26 (t, J = 7.1 Hz, 2.22H, major), 1.24 (t, J =
7.1 Hz, 0.78H, minor), 1.23 (s, 2.34H, minor), 1.13 (t, J = 7.1 Hz, 2.22H,
major); 13
C NMR (100 MHz, CDCl3) δ = 169.8 (minor), 169.6 (major),
166.2 (minor), 165.6 (major), 164.5 (minor), 164.3 (major), 163.7 (mi-
(major), 129.1 (major), 129.0 (minor), 127.9 (minor), 127.8 (major),
80.2 (major), 79.8 (minor), 75.7 (major), 75.5 (minor), 64.1 (major +
minor), 62.4 (minor), 62.3 (major), 52.0 (minor), 51.8 (major), 28.54
(major), 28.46 (minor), 14.3 (major), 14.10 (minor), 14.07 (major +
minor); 1
H NMR (400 MHz, CDCl3, major diastereomer) δ = 7.88 (d,
J = 8.6 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 6.84 (bs, 1H), 6.23 (s, 1H),
4.64 (s, 1H), 4.35–4.17 (m, 4H), 1.39 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H),
1.13 (t, J = 7.1 Hz, 3H); 13
C NMR (100 MHz, CDCl3, major diastereo-
mer) δ = 169.7, 165.6, 164.3, 163.5, 132.1, 131.5, 129.1, 127.8, 80.2,
75.7, 64.2, 62.3, 51.9, 28.6, 14.3, 14.1; HRMS (ESI): m/z [M + H]+
for
C20H27BrNO8
+
, calcd. 488.0915, found 488.0899.
Diethyl 3-((2-Bromobenzoyl)oxy)-2-(tert-butylcarbamoyl)-2-
hydroxysuccinate (14d): Yield: 86 mg, 35 % (dr = 3.5:1, procedure
A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 7.95–7.83 (m, 1H,
major + minor), 7.72–7.63 (m, 1H, major + minor), 7.42–7.31 (m, 2H,
major + minor), 6.83 (bs, 1H, major + minor), 6.29 (s, 0.78H, major),
6.27 (s, 0.22H, minor), 4.70 (s, 0.22H, minor), 4.55 (s, 0.78H, major),

Full Paper
4.48–4.16 (m, 4H, major + minor), 1.41 (t, J = 7.1 Hz, 0.66H, minor),
1.39 (s, 7.02H, major), 1.31–1.19 (m, 7.32H, major + minor); 13
C NMR
165.4 (major), 164.01 (minor), 164.00 (major), 163.6 (minor), 163.3
(major), 134.50 (major), 134.48 (minor), 133.2 (major), 133.1 (minor),
(major), 127.1 (minor), 122.3 (minor), 122.1 (major), 80.0 (major),
79.6 (minor), 75.7 (major), 75.4 (minor), 64.0 (major + minor), 62.3
(minor), 62.2 (major), 51.9 (minor), 51.7 (major), 28.4 (major), 28.3
(minor), 14.1 (major), 14.0 (minor), 13.92 (minor), 13.89 (major);
for C20H27BrNO8
+
488.0907.
Diethyl 3-((2-Bromo-4-fluorobenzoyl)oxy)-2-(tert-butylcarb-
amoyl)-2-hydroxysuccinate (14e): Yield: 131 mg, 52 % (dr = 3.4:1,
procedure A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.00–
7.87 (m, 1H, major + minor), 7.43–7.34 (m, 1H, major + minor), 7.10–
7.00 (m, 1H, major + minor), 6.81 (bs, 0.23H, minor), 6.80 (bs, 0.77H,
major), 6.25 (s, 0.77H, major), 6.22 (s, 0.23H, minor), 4.71 (s, 0.23H,
minor), 4.59 (s, 0.77H, major), 4.45–4.12 (m, 4H, major + minor), 1.36
(t, J = 7.2 Hz, 0.69H, minor), 1.35 (s, 6.93H, major), 1.27–1.13 (m,
7.38H, major + minor); 13
C NMR (100 MHz, CDCl3) δ = 169.6 (minor),
169.4 (major), 166.0 (minor), 165.5 (major), 164.28 (d, J = 258.3 Hz,
major), 164.27 (d, J = 258.0 Hz, minor), 163.7 (minor), 163.4 (major),
163.11 (minor), 163.09 (major), 134.13 (d, J = 9.5 Hz, major), 134.11
(d, J = 9.5 Hz, minor), 126.5 (d, J = 3.5 Hz, major), 126.4 (d, J =
3.5 Hz, minor), 123.9 (d, J = 10.0 Hz, minor), 123.7 (d, J = 10.1 Hz,
major), 122.2 (d, J = 24.7 Hz, major), 122.1 (d, J = 24.6 Hz, minor),
114.8 (d, J = 21.4 Hz, major), 114.6 (d, J = 21.2 Hz, minor), 80.1
(major), 79.7 (minor), 75.8 (major), 75.6 (minor), 64.1 (minor), 64.0
(major), 62.4 (minor), 62.3 (major), 52.0 (minor), 51.8 (major), 28.5
(major), 28.4 (minor), 14.2 (major), 14.04 (minor), 13.99 (minor),
13.97 (major); HRMS (ESI): m/z [M + H]+
for C20H26BrFNO8
+
, calcd.
506.0820, found 506.0736.
Diethyl 2-(tert-Butylcarbamoyl)-2-hydroxy-3-((4-methoxy-
benzoyl)oxy)succinate (14f): Yield: 99 mg, 45 % (dr = 2.4:1, proce-
dure B, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.02 (d, J =
8.9 Hz, 0.6H, minor), 7.98 (d, J = 8.9 Hz, 1.4H, major), 7.94–7.88 (m,
2H, major + minor), 6.86 (bs, 0.7H, major), 6.84 (bs, 0.3H, minor),
6.21 (s, 0.3H, minor), 6.21 (s, 0.7H, major), 4.80 (s, 0.3H, minor), 4.65
(s, 0.7H, major), 4.46–4.15 (m, 4H, major + minor), 3.86 (s, 3H, major
+ minor), 1.40 (t, J = 7.1 Hz, 0.9H, minor), 1.38 (s, 6.3H, major), 1.26
(t, J = 7.1 Hz, 2.1H, major), 1.23 (t, J = 7.1 Hz, 0.9H, minor), 1.23 (s,
2.7H, minor), 1.13 (t, J = 7.1 Hz, 2.1H, major); 13
C NMR (100 MHz,
CDCl3) δ = 169.9 (minor), 169.8 (major), 166.5 (minor), 166.0 (major),
(minor), 163.6 (major), 132.3 (minor), 132.2 (major), 121.23 (minor),
121.19 (major), 113.9 (major), 113.8 (minor), 80.3 (major), 79.8
(minor), 75.3 (major), 75.1 (minor), 64.1 (major), 64.0 (minor), 62.3
(minor), 62.1 (major), 55.59 (major), 55.58 (minor), 52.0 (minor), 51.8
(minor), 14.05 (major); HRMS (ESI): m/z [M + H]+
for C21H30NO9
+
,
calcd. 440.1915, found 440.1914.
Diethyl 3-((Benzo[d][1,3]dioxole-5-carbonyl)oxy)-2-(tert-butyl-
carbamoyl)-2-hydroxysuccinate (14g): Yield: 68 mg, 30 % (dr =
2.1:1, procedure A, white powder); 1
H NMR (400 MHz, CDCl3) δ =
7.67 (dd, J = 8.2, 1.2 Hz, 0.32H, minor), 7.62 (dd, J = 8.2, 1.5 Hz,
0.68H, major), 7.47 (d, J = 1.3 Hz, 0.32H, minor), 7.42 (d, J = 1.2 Hz,
0.68H, major), 6.89–6.78 (m, 2H, major + minor), 6.19 (s, 1H, major
+ minor), 6.02 (s, 2H, major + minor), 4.77 (bs, 0.32H, minor), 4.66
(bs, 0.68H, major), 4.46–4.13 (m, 4H, major + minor), 1.38 (t, J =
7.2 Hz, 0.96H, minor), 1.37 (s, 6.12H, major), 1.24 (t, J = 7.2 Hz, 2.04H,
major), 1.23 (s, 2.88H, minor), 1.22 (t, J = 7.0 Hz, 0.96H, minor), 1.13
7
(t, J = 7.1 Hz, 2.04H, major); 13
C NMR (100 MHz, CDCl3) δ = 169.8
(minor), 169.7 (major), 166.4 (minor), 165.9 (major), 164.5 (minor),
164.3 (major), 163.8 (minor), 163.6 (major), 152.34 (major), 152.30
(minor), 148.0 (major), 147.9 (minor), 126.3 (minor), 126.1 (major),
122.82 (minor), 122.78 (major), 109.9 (minor), 109.8 (major), 108.2
79.9 (minor), 75.4 (major), 75.3 (minor), 64.0 (major), 63.9 (minor),
62.3 (minor), 62.1 (major), 52.0 (minor), 51.8 (major), 28.53 (major),
28.45 (minor), 14.3 (major), 14.1 (minor), 14.0 (major + minor); HRMS
(ESI): m/z [M + H]+
for C21H28NO10
+
454.1708.
Diethyl 2-(tert-Butylcarbamoyl)-2-hydroxy-3-((2-(phenylamino)-
benzoyl)oxy)succinate (14h): Yield: 159 mg, 64 % (dr = 2:1, proce-
dure A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 9.25 (bs, 1H,
major + minor), 8.02 (dd, J = 8.1, 1.4 Hz, 0.33H, minor), 7.90 (dd, J =
8.1, 1.4 Hz, 0.67H, major), 7.39–7.27 (m, 3H, major + minor), 7.26–
7.18 (m, 3H, major + minor), 7.14–7.05 (m, 1H, major + minor), 6.88
(bs, 1H, major + minor), 6.76–7.65 (m, 1H, major + minor), 6.27 (s,
0.33H, minor), 6.22 (s, 0.67H, major), 4.73 (s, 0.33H, minor), 4.66 (s,
0.67H, major), 4.49–4.16 (m, 4H, major + minor), 1.40 (t, J = 7.2 Hz,
0.99H, minor), 1.39 (s, 6.03H, major), 1.31–1.22 (m, 5.97H, major +
minor), 1.18 (t, J = 7.1 Hz, 2.01H, major); 13
C NMR (100 MHz, CDCl3)
δ = 169.9 (minor), 169.8 (major), 166.8 (minor), 166.7 (major +
minor), 166.0 (major), 163.8 (minor), 163.6 (major), 148.7 (major),
148.6 (minor), 140.6 (minor), 140.5 (major), 135.0 (major), 134.9
(minor), 132.3 (minor), 131.9 (major), 129.50 (major), 129.49 (minor),
jor), 117.1 (minor), 114.1 (major), 114.0 (minor), 110.5 (minor), 110.4
(major), 64.1 (minor), 62.4 (minor), 62.2 (major), 52.0 (minor), 51.8
(minor), 14.06 (major); HRMS (ESI): m/z [M + H]+
for C26H33N2O8
+
,
calcd. 501.2231, found 501.2255.
Diethyl 2-(tert-Butylcarbamoyl)-2-hydroxy-3-((thiophene-2-
carbonyl)oxy)succinate (14i): Yield: 53 mg, 26 % (dr = 3:1, proce-
dure A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 7.86 (dd, J =
3.8, 1.2 Hz, 0.25H, minor), 7.82 (dd, J = 3.8, 1.2 Hz, 0.75H, major),
7.62–7.57 (m, 1H, major + minor), 7.13–7.06 (m, 1H, major + minor),
6.84 (bs, 1H, major + minor), 6.20 (s, 0.75H, major), 6.20 (s, 0.25H,
minor), 4.72 (s, 0.25H, minor), 4.61 (s, 0.75H, major), 4.46–4.14 (m,
4H, major + minor), 1.39 (t, J = 7.1 Hz, 0.75H, minor), 1.37 (s, 6.75H,
major), 1.25 (t, J = 7.1 Hz, 2.25H, major), 1.24 (s, 2.25H, minor), 1.23
(t, J = 7.1 Hz, 0.75H, minor), 1.15 (t, J = 7.1 Hz, 2.25H, major); 13
C
NMR (100 MHz, CDCl3) δ = 169.8 (minor), 169.5 (major), 166.3 (mi-
nor), 165.7 (major), 163.7 (minor), 163.5 (major), 160.7 (minor), 160.5
(major), 134.8 (minor), 134.6 (major), 133.62 (major), 133.56 (minor),
132.1 (major), 128.1 (major), 128.0 (minor), 80.2 (major), 79.8 (mi-
nor), 75.5 (major), 75.3 (minor), 64.13 (major), 64.06 (minor), 62.4
(minor), 14.3 (major), 14.10 (minor), 14.06 (minor), 14.0 (major);
for C18H26NO8S+
416.1378.
Diethyl 2-(tert-Butylcarbamoyl)-2-hydroxy-3-((5-methylfuran-2-
carbonyl)oxy)succinate (14j): Yield: 130 mg, 63 % (dr = 3.2:1, pro-
cedure A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 7.14 (d, J =
3.4 Hz, 0.24H, minor), 7.09 (d, J = 3.4 Hz, 0.76H, major), 6.82 (bs,
0.24H, minor), 6.81 (bs, 0.76H, major), 6.16 (s, 0.76H, major), 6.15 (s,
0.24H, minor), 6.12–6.06 (m, 1H, major + minor), 4.70 (s, 0.24H, mi-
nor), 4.59 (s, 0.76H, major), 4.44–4.09 (m, 4H, major + minor), 2.33
(s, 3H, major + minor), 1.36 (t, J = 7.2 Hz, 0.72H, minor), 1.34 (s,
6.84H, major), 1.23 (s, 2.16H, minor), 1.22 (t, J = 7.1 Hz, 2.28H, major),
1.20 (t, J = 7.1 Hz, 0.72H, minor), 1.13 (t, J = 7.1 Hz, 2.28H, major);

Full Paper
13
C NMR (100 MHz, CDCl3) δ = 169.6 (minor), 169.4 (major), 166.3
(minor), 165.6 (major), 163.6 (minor), 163.5 (major), 158.4 (major),
158.2 (minor), 156.94 (minor), 156.85 (major), 141.7 (minor), 141.6
80.2 (major), 79.7 (minor), 75.0 (major), 74.8 (minor), 64.0 (minor),
63.9 (major), 62.3 (minor), 62.1 (major), 51.9 (minor), 51.7 (major),
28.4 (major), 28.3 (minor), 14.2 (major), 14.07 (minor), 14.05 (major),
14.01 (minor), 13.98 (minor), 13.9 (major); HRMS (ESI): m/z [M + H]+
for C19H28NO9
+
, calcd. 414.1759, found 414.1764.
Diethyl 2-(tert-Butylcarbamoyl)-3-(hexanoyloxy)-2-hydroxy-
succinate (14k): Yield: 57 mg, 28 % (dr = 4.5:1, procedure B, color-
less oil); 1
H NMR (400 MHz, CDCl3) δ = 6.81 (bs, 0.18H, minor), 6.77
(bs, 0.82H, major), 6.04 (s, 0.18H, minor), 5.98 (s, 0.82H, major), 4.58
(s, 0.18H, minor), 4.50 (s, 0.82H, major), 4.42–4.12 (m, 4H, major +
minor), 2.50–2.26 (m, 2H, major + minor), 1.69–1.56 (m, 2H, major
+ minor), 1.39–1.19 (m, 19H, major + minor), 0.92–0.83 (m, 3H, ma-
jor + minor); 13
C NMR (100 MHz, CDCl3) δ = 172.22 (minor), 172.15
163.7 (minor), 163.6 (major), 80.0 (major), 79.8 (minor), 74.9 (major),
74.6 (minor), 64.1 (minor), 63.8 (major), 62.2 (minor), 62.1 (major),
51.83 (minor), 51.77 (major), 33.8 (major), 33.7 (minor), 31.3 (minor),
31.2 (major), 28.5 (major), 28.4 (minor), 24.51 (major), 24.47 (minor),
22.3 (major + minor), 14.2 (major), 14.1 (major + minor), 14.00 (mi-
nor), 13.95 (minor), 13.94 (major); HRMS (ESI): m/z [M + H]+
for
C19H34NO8
+
, calcd. 404.2279, found 404.2300.
Diethyl 2-(tert-Butylcarbamoyl)-2-hydroxy-3-((4-phenylbutan-
oyl)oxy)succinate (14l): Yield: 108 mg, 48 % (dr = 3.8:1, procedure
B, white powder); 1
H NMR (400 MHz, CDCl3) δ = 7.30–7.23 (m, 2H,
major + minor), 7.20–7.13 (m, 3H, major + minor), 6.81 (bs, 0.21H,
minor), 6.78 (bs, 0.79H, major), 6.06 (s, 0.21H, minor), 6.00 (s, 0.79H,
major), 4.60 (bs, 0.21H, minor), 4.54 (bs, 0.79H, major), 4.45–4.08 (m,
4H, major + minor), 2.72–2.60 (m, 2H, major + minor), 2.52–2.28 (m,
2H, major + minor), 2.05–1.88 (m, 2H, major + minor), 1.39–1.20 (m,
15H, major + minor); 13
C NMR (100 MHz, CDCl3, only the signals of
major diastereomer are listed) δ = 171.9, 169.5, 165.8, 163.6, 141.2,
128.6, 128.5, 126.1, 80.0, 75.0, 63.8, 62.1, 51.8, 34.9, 33.0, 28.5, 26.4,
14.2, 14.0; HRMS (ESI): m/z [M + H]+
for C23H34NO8
+
, calcd. 452.2279,
found 452.2279.
Diethyl 2-(tert-Butylcarbamoyl)-3-(cinnamoyloxy)-2-hydroxy-
succinate (14m): Yield: 94 mg, 43 % (dr = 3.7:1, procedure B, white
powder); 1
H NMR (400 MHz, CDCl3) δ = 7.76 (d, J = 16.0 Hz, 0.21H,
minor), 7.73 (d, J = 16.0 Hz, 0.79H, major), 7.56–7.47 (m, 2H, major
+ minor), 7.41–7.34 (m, 3H, major + minor), 6.84 (bs, 0.21H, minor),
6.83 (bs, 0.79H, major), 6.48 (d, J = 16.0 Hz, 0.21H, minor), 6.46 (d,
J = 16.0 Hz, 0.79H, major), 6.17 (s, 0.21H, minor), 6.15 (s, 0.79H,
major), 4.73 (s, 0.21H, minor), 4.62 (s, 0.79H, major), 4.46–4.15 (m,
4H, major + minor), 1.41–1.19 (m, 15H, major + minor); 13
C NMR
jor), 146.81 (major), 146.78 (minor), 134.2 (minor), 134.1 (major),
130.84 (major), 130.76 (minor), 129.0 (major +minor), 128.4 (major),
128.3 (minor), 116.4 (minor), 116.3 (major), 80.2 (major), 79.8 (mi-
nor), 75.1 (major), 74.9 (minor), 64.04 (minor), 63.96 (major), 62.3
(minor), 14.3 (major), 14.09 (major), 14.07 (minor), 14.0 (minor);
for C22H30NO8
+
436.1991.
Diethyl 2-(tert-Butylcarbamoyl)-2-hydroxy-3-((3-phenyl-
propioloyl)oxy)succinate (14n): Yield: 90 mg, 42 % (dr = 2.5:1, pro-
cedure A, colorless oil) or 38 mg, 18 % (major diastereomer, proce-
dure A, colorless oil); 1
H NMR (400 MHz, CDCl3, major diastereomer)
δ = 7.63–7.53 (m, 2H), 7.51–7.42 (m, 1H), 7.42–7.32 (m, 2H), 6.81 (bs,
8
1H), 6.18 (s, 1H), 4.53 (s, 1H), 4.50–4.39 (m, 1H), 4.35–4.18 (m, 3H),
1.37 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13
C NMR
(100 MHz, CDCl3, major diastereomer) δ = 169.1, 165.0, 163.3, 152.2,
133.2, 131.1, 128.7, 119.1, 88.5, 80.0, 79.5, 75.9, 64.1, 62.2, 28.4, 14.2,
14.0; HRMS (ESI): m/z [M + H]+
for C22H28NO8
+
, calcd. 434.1809,
found 434.1819.
Diethyl 2-(Butylcarbamoyl)-2-hydroxy-3-((4-methoxybenzoyl)-
oxy)succinate (14o): Yield: 90 mg, 41 % (dr = 1:1, procedure A,
colorless oil); 1
H NMR (400 MHz, CDCl3) δ = 8.00 (d, J = 9.0 Hz, 1H),
7.97 (d, J = 9.0 Hz, 1H), 7.07–6.96 (m, 1H), 6.91 (d, J = 8.9 Hz, 1H),
6.90 (d, J = 8.9 Hz, 1H), 6.27 (s, 0.5H), 6.25 (s, 0.5H), 4.73 (bs, 0.5H),
4.63 (bs, 0.5H), 4.49–4.10 (m, 4H), 3.86 (s, 1.5H), 3.85 (s, 1.5H), 3.35–
3.10 (m, 2H), 1.60–1.47 (m, 1H), 1.44–1.16 (m, 7.5H), 1.11 (t, J =
7.1 Hz, 1.5H), 0.93 (t, J = 7.3 Hz, 1.5), 0.76 (t, J = 7.3 Hz, 1.5H); 13
C
NMR (100 MHz, CDCl3) δ = 169.7, 169.5, 166.6, 165.9, 165.1, 164.84,
164.83, 164.6, 164.04, 163.98, 132.3, 132.2, 121.4, 121.2, 113.9, 113.8,
80.3, 80.0, 75.2, 75.1, 64.24, 64.19, 62.3, 62.1, 55.6, 39.92, 39.86,
31.53, 31.48, 20.2, 20.0, 14.2, 14.11, 14.06, 14.0, 13.8, 13.7; HRMS
(ESI): m/z [M + H]+
for C21H30NO9
+
, calcd. 440.1915, found 440.1909.
Diethyl 3-(Benzoyloxy)-2-hydroxy-2-(naphthalen-2-ylcarb-
amoyl)succinate (14p): Yield: 152 mg, 63 % (dr = 2.4:1, procedure
A, white powder); 1
H NMR (400 MHz, CDCl3) δ = 9.07 (bs, 0.29H,
minor), 9.01 (bs, 0.71H, major), 8.35 (d, J = 1.8 Hz, 0.71H, major),
8.19 (d, J = 1.8 Hz, 0.29H, minor), 8.10–8.02 (m, 1.42H, major), 8.02–
7.95 (m, 0.58H, minor), 7.86–7.69 (m, 3H, major + minor), 7.64–7.57
(m, 0.71H, major), 7.55–7.37 (m, 4.71H, major + minor), 7.33–7.27
(m, 0.58H, minor), 6.49 (s, 0.71H, major), 6.43 (s, 0.29H, minor), 4.93
(s, 0.71H, major), 4.92 (s, 0.29H, minor), 4.60–4.08 (m, 4H, major +
minor), 1.46 (t, J = 7.1 Hz, 0.87H, minor), 1.27 (t, J = 7.1 Hz, 0.87H,
minor), 1.15 (t, J = 7.1 Hz, 2.13H, major), 1.09 (t, J = 7.1 Hz, 2.13H,
major); 13
nor), 162.8 (major), 134.4, 134.0, 133.9, 133.8, 133.6, 131.1, 130.1,
129.11, 129.05, 128.9, 128.74, 128.72, 128.5, 127.93 (major), 127.86
(minor), 127.72 (major), 127.67 (minor), 126.80 (major), 126.76 (mi-
nor), 125.52 (minor), 125.48 (major), 119.6 (minor), 119.5 (major),
75.2 (minor), 64.9 (minor), 64.8 (major), 62.5 (minor), 62.4 (major),
14.15 (minor), 14.10 (minor), 14.05 (major), 14.04 (major), for certain
signals in the aromatic region there is no certainty to which dia-
stereomer they belong to; HRMS (ESI): m/z [M + H]+
for C26H26NO8
+
,
calcd. 480.1653, found 480.1642.
General Procedure for the Synthesis of Post-Passerini Adducts
17: Carboxylic acid 2 (0.5 mmol) and aryl glyoxal monohydrate
15·H2O (0.5 mmol) was placed in screw cap vial charged with mag-
netic bead followed by the addition of chloroform (2 mL) and iso-
cyanide 3 (0.5 mmol). The reaction mixture was sealed and stirred
at r.t. for 24 h. Upon completion of this time, the reaction vial was
open and the solvent was evaporated under the ambient condition
(reduced pressure could also be applied by placing the reaction vial
to a big round-bottom flask and attaching it to a rotary evaporator).
The obtained crude Passerini adduct 16 was dissolved in chloro-
form (0.5 mL) followed by addition of ethyl glyoxylate (5, 56 mg,
0.55 mmol, added as 110 μL of ca 50 % soln. in toluene). The reac-
tion mixture was sealed and stirred at 70 °C for 48 h. The resulting
mixture was diluted with EtOAc and concentrated with silica. Col-
umn chromatography with petroleum ether/EtOAc (the ratio was
adjusted according to the TLC of the reaction mixture) as eluent
delivered desired adduct 17.
3-Benzoyl-4-(tert-butylamino)-1-ethoxy-3-hydroxy-1,4-dioxo-
butan-2-yl Benzoate (17a): Yield: 168 mg, 76 % (dr = 5.6:1, triturat-
ing with hexane was applied after the column chromatography,

Full Paper
white powder) or 104 mg, 47 % (major diastereomer, white powder,
m.p. 132–134 °C); 1
H NMR (400 MHz, CDCl3) δ = 8.30–8.21 (m, 1.7H,
major), 8.21–8.15 (m, 0.3H, minor), 8.13–8.07 (m, 0.3H, minor), 7.85–
7.74 (m, 1.7H, major), 7.61–7.26 (m, 6H, major + minor), 6.99 (bs,
0.85H, major), 6.80 (bs, 0.15H, minor), 6.55 (s, 0.15H, minor), 6.46 (s,
0.85H, major), 5.75 (s, 0.85H, major), 5.69 (s, 0.15H, minor), 4.37–4.18
(m, 1.7H, major), 4.17–4.03 (m, 0.3H, minor), 1.36 (s, 7.65H, major),
1.28 (t, J = 7.1 Hz, 2.55H, major), 1.19 (s, 1.35H, minor), 1.04 (t, J =
7.2 Hz, 0.45H, minor); 13
C NMR (100 MHz, CDCl3) δ = 199.3 (minor),
jor), 165.0 (major), 164.7 (minor), 135.3 (minor), 134.0 (major), 133.9
130.5 (minor), 130.2 (minor), 129.9 (major), 128.9 (minor), 128.61
(major), 128.56 (minor), 128.5 (major), 128.40 (major), 128.36
(minor), 85.2 (minor), 84.7 (major), 76.6 (major), 76.5 (minor), 62.3
(minor), 14.3 (major), 13.9 (minor); 1
H NMR (400 MHz, CDCl3, major
diastereomer) δ = 8.30–8.21 (m, 2H), 7.84–7.76 (m, 2H), 7.55–7.45
(m, 2H), 7.42–7.29 (m, 4H), 6.97 (bs, 1H), 6.45 (s, 1H), 5.72 (s, 1H),
4.37–4.21 (m, 2H), 1.37 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H); 13
C NMR
134.1, 133.9, 133.6, 130.7, 129.9, 128.7, 128.5, 128.4, 84.8, 76.7, 62.3,
52.1, 28.5, 14.3; HRMS (ESI): m/z [M + H]+
for C24H28NO7
+
, calcd.
442.1860, found 442.1865.
3-(4-Bromobenzoyl)-4-(tert-Butylamino)-1-ethoxy-3-hydroxy-
1,4-dioxobutan-2-yl Benzoate (17b): Yield: 183 mg, 70 % (dr =
11:1, the reaction was conducted in DCE, white powder) or 128 mg,
49 % (major diastereomer, white powder); 1
H NMR (400 MHz, CDCl3,
major diastereomer) δ = 8.15 (d, J = 8.8 Hz, 2H), 7.86–7.76 (m, 2H),
7.56–7.48 (m, 3H), 7.40–7.30 (m, 2H), 6.96 (bs, 1H), 6.39 (s, 1H), 5.70
(s, 1H), 4.36–4.20 (m, 2H), 1.36 (s, 9H), 1.29 (t, J = 7.1 Hz, 3H); 13
C
NMR (150 MHz, CDCl3, major diastereomer) δ = 196.3, 165.9, 165.1,
164.8, 133.7, 132.5, 132.3, 131.9, 129.9, 129.7, 128.54, 128.51, 84.8,
76.6, 62.3, 52.2, 28.5, 14.3; HRMS (ESI): m/z [M + H]+
for
C24H27BrNO7
+
, calcd. 520.0965, found 520.0970.
4-(tert-Butylamino)-1-ethoxy-3-(4-fluorobenzoyl)-3-hydroxy-
1,4-dioxobutan-2-yl Benzoate (17c): Yield: 207 mg, 90 % (dr = 3:1,
triturating with hexane was applied after the column chromatogra-
phy, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.41–8.33 (m,
1.5H, major), 8.33–8.27 (m, 0.5H, minor), 8.13–8.07 (m, 0.5H, minor),
7.83–7.75 (m, 1.5H, major), 7.63–7.56 (m, 0.25H, minor), 7.54–7.42
(m, 1.25H, major + minor), 7.37–7.30 (m, 1.5H, major), 7.18–7.11 (m,
0.5H, minor), 7.09–7.02 (m, 1.5H, major), 6.99 (bs, 0.75H, major), 6.82
(bs, 0.25H, minor), 6.51 (s, 0.25H, minor), 6.43 (s, 0.75H, major), 5.74
(s, 0.75H, major), 5.70 (s, 0.25H, minor), 4.37–4.19 (m, 1.5H, major),
4.18–4.04 (m, 0.5H, minor), 1.37 (s, 6.75H, major), 1.29 (t, J = 7.1 Hz,
2.25H, major), 1.19 (s, 2.25H, minor), 1.06 (t, J = 7.1 Hz, 0.75H, minor);
13
C NMR (150 MHz, CDCl3) δ = 197.4 (minor), 195.2 (major), 167.1
(minor), 166.0 (d, J = 256.6 Hz, minor), 165.9 (major), 165.5 (d, J =
248.3 Hz, major), 165.4 (minor), 165.3 (minor), 165.1 (major), 165.0
(major), 133.9 (d, J = 9.5 Hz, major), 133.8 (d, minor, overlaps with
the neighbouring signal of major diastereomer), 133.64 (major),
133.59 (minor), 131.6 (d, J = 2.3 Hz, minor), 130.2 (minor), 130.1 (d,
J = 1.6 Hz, major), 129.8 (major), 128.8 (minor), 128.57 (minor),
128.53 (major), 128.45 (major), 115.7 (d, J = 22.0 Hz, major), 115.6
(d, J = 22.5 Hz, minor), 85.2 (minor), 84.7 (major), 76.6 (major), 76.5
(major), 28.3 (minor), 14.3 (major), 13.9 (minor); HRMS (ESI): m/z
[M + H]+
for C24H27FNO7
+
, calcd. 460.1766, found 460.1774.
4-(tert-Butylamino)-1-ethoxy-3-hydroxy-3-(4-methoxybenzoyl)-
1,4-dioxobutan-2-yl Benzoate (17d): Yield: 198 mg, 84 % (dr =
3.2:1, triturating with hexane was applied after the column chroma-
9
tography, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.41–8.32
(m, 2H, major + minor), 8.13–8.08 (m, 0.48H, minor), 7.81–7.74 (m,
1.52H, major), 7.62–7.55 (m, 0.24H, minor), 7.52–7.40 (m, 1.24H, ma-
jor + minor), 7.35–7.28 (m, 1.52H, major), 7.01 (bs, 0.76H, major),
6.95 (d, J = 9.0 Hz, 0.48H, minor), 6.92 (bs, 0.24H, minor), 6.84 (d,
J = 9.1 Hz, 1.52H, major), 6.53 (s, 1H, major + minor), 5.90 (s, 0.76H,
major), 5.79 (s, 0.24H, minor), 4.36–4.21 (m, 1.52H, major), 4.17–4.01
(m, 0.48H, minor), 3.88 (s, 0.72H, minor), 3.81 (s, 2.28H, major), 1.35
(s, 6.84H, major), 1.29 (t, J = 7.1 Hz, 2.28H, major), 1.19 (s, 2.16H,
minor), 1.04 (t, J = 7.1 Hz, 0.72H, minor); 13
C NMR (100 MHz, CDCl3)
δ = 196.1 (minor), 193.8 (major), 166.4 (minor), 166.0 (major), 165.5
164.1 (minor), 133.8 (major), 133.7 (minor), 133.6 (minor), 133.5 (ma-
jor), 130.2 (minor), 129.9 (major), 129.0 (minor), 128.7 (major), 128.5
(minor), 128.4 (major), 127.8 (minor), 126.0 (major), 113.8 (major),
113.7 (minor), 85.1 (minor), 84.6 (major), 76.71 (major), 76.67
(minor), 62.20 (minor), 62.15 (major), 55.64 (minor), 55.59 (major),
13.9 (minor); HRMS (ESI): m/z [M + H]+
for C25H30NO8
+
, calcd.
472.1966, found 472.1971.
4-(tert-Butylamino)-3-(4-(dimethylamino)benzoyl)-1-ethoxy-3-
hydroxy-1,4-dioxobutan-2-yl Benzoate (17e): Yield: 101 mg, 42 %
(dr = 3:1, triturating with hexane was applied after the column chro-
matography, yellow powder); 1
H NMR (400 MHz, CDCl3) δ = 8.39 (d,
J = 9.2 Hz, 0.5H, minor), 8.34 (d, J = 9.3 Hz, 1.5H, major), 8.14–8.09
(m, 0.5H, minor), 7.81–7.75 (m, 1.5H, major), 7.60–7.54 (m, 0.25H,
minor), 7.50–7.40 (m, 1.25H, major + minor), 7.34–7.27 (m, 1.5H,
major), 7.04 (bs, 0.25H, minor), 7.02 (bs, 0.75H, major), 6.67 (d, J =
9.2 Hz, 0.5H, minor), 6.62 (s, 0.75H, major), 6.57–6.51 (m, 1.75H,
major + minor), 6.17 (s, 0.75H, major), 6.01 (s, 0.25H, minor), 4.37–
4.21 (m, 1.5H, major), 4.16–3.99 (m, 0.5H, minor), 3.09 (s, 1.5H, mi-
nor), 3.01 (s, 4.5H, major), 1.34 (s, 6.75H, major), 1.30 (t, J = 7.1 Hz,
13
C NMR (100 MHz, CDCl3, only the signals of major diastereomer
are listed) δ = 191.1, 166.24, 166.19, 165.3, 154.1, 134.0, 133.3, 130.0,
129.1, 128.3, 126.6, 110.6, 84.2, 76.8, 62.0, 51.5, 40.0, 28.6, 14.4;
for C26H33N2O7
+
485.2262.
4-(tert-Butylamino)-1-ethoxy-3-hydroxy-1,4-dioxo-3-(4-(tri-
fluoromethyl)benzoyl)butan-2-yl Benzoate (17f): Yield: 174 mg,
68 % (dr = 7.3:1, triturating with hexane was applied after the col-
umn chromatography, white powder); 1
H NMR (400 MHz, CDCl3)
δ = 8.30 (d, J = 8.2 Hz, 1.76H, major), 8.23 (d, J = 8.1 Hz, 0.24H,
minor), 8.12–8.07 (m, 0.24H, minor), 7.86–7.79 (m, 1.76H, major),
7.73 (d, J = 8.3 Hz, 0.24H, minor), 7.67–7.57 (m, 1.88H, major +
minor), 7.56–7.43 (m, 1.12H, major + minor), 7.39–7.32 (m, 1.76H,
major), 6.94 (bs, 0.88H, major), 6.72 (bs, 0.12H, minor), 6.52 (s, 0.12H,
minor), 6.35 (s, 0.88H, major), 5.64 (s, 0.88H, major), 5.63 (s, 0.12H,
minor), 4.36–4.21 (m, 1.76H, major), 4.18–4.09 (m, 0.24H, minor),
1.38 (s, 7.92H, major), 1.29 (t, J = 7.1 Hz, 2.64H, major), 1.20 (s, 1.08H,
minor), 1.09 (t, J = 7.1 Hz, 0.36H, minor); 13
C NMR (100 MHz, CDCl3,
only the signals of major diastereomer are listed) δ = 197.4, 166.0,
165.1, 164.6, 137.2, 134.9 (q, J = 32.9 Hz), 133.8, 130.9, 129.9, 128.6,
125.4 (q, J = 3.7 Hz), 123.5 (q, J = 272.8 Hz), 84.8, 76.5, 62.4, 52.4,
28.5, 14.3; HRMS (ESI): m/z [M + H]+
for C25H27F3NO7
+
, calcd.
510.1734, found 510.1729.
butan-2-yl 4-Methylbenzoate (17g): Yield: 223 mg, 98 % (dr =
6.2:1, beige amorphous material); 1
H NMR (400 MHz, CDCl3) δ =
8.28–8.22 (m, 1.72H, major), 8.20–8.15 (m, 0.28H, minor), 7.98 (d, J =
8.1 Hz, 0.28H, minor), 7.68 (d, J = 8.2 Hz, 1.72H, major), 7.58–7.52
(m, 0.14H, minor), 7.50–7.41 (m, 1.14H, major + minor), 7.38–7.31

Full Paper
(m, 1.72H, major), 7.22 (d, J = 8.0 Hz, 0.28H, minor), 7.09 (d, J =
8.1 Hz, 1.72H, major), 7.00 (bs, 0.86H, major), 6.80 (bs, 0.14H, minor),
6.54 (s, 0.14H, minor), 6.45 (s, 0.86H, major), 5.76 (s, 0.86H, major),
5.69 (s, 0.14H, minor), 4.34–4.19 (m, 1.72H, major), 4.15–4.02 (m,
0.28H, minor), 2.38 (s, 0.42H, minor), 2.30 (s, 2.58H, major), 1.35 (s,
7.74H, major), 1.27 (t, J = 7.1 Hz, 2.58H, major), 1.18 (s, 1.26H, minor),
1.02 (t, J = 7.1 Hz, 0.42H, minor); 13
C NMR (100 MHz, CDCl3) δ =
(major), 135.2 (minor), 133.9 (major), 133.7 (major), 133.4 (minor),
130.6 (major), 130.4 (minor), 130.2 (minor), 129.8 (major), 129.2 (mi-
(major), 85.1 (minor), 84.7 (major), 76.4 (major), 76.3 (minor), 62.2
(minor), 21.8 (minor), 21.7 (major), 14.2 (major), 13.8 (minor); HRMS
(ESI): m/z [M + Na]+
for C25H29NO7Na+
478.1842.
butan-2-yl 2-Methylbenzoate (17h): Yield: 134 mg, 59 % (dr =
4.8:1, triturating with hexane was applied after the column chroma-
tography, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.29–8.24
(m, 1.66H, major), 8.23–8.18 (m, 0.34H, minor), 8.05–8.00 (m, 0.17H,
minor), 7.63–7.36 (m, 4H, major + minor), 7.35–7.29 (m, 0.83H, ma-
jor), 7.28–7.22 (m, 0.34H, minor), 7.17–7.06 (m, 1.66H, major), 6.95
(bs, 0.83H, major), 6.81 (bs, 0.17H, minor), 6.57 (s, 0.17H, minor), 6.49
(s, 0.83H, major), 5.68 (s, 0.83H, major), 5.64 (s, 0.17H, minor), 4.36–
4.22 (m, 1.66H, major), 4.18–4.04 (m, 0.34H, minor), 2.63 (s, 0.51H,
minor), 2.40 (s, 2.49H, major), 1.36 (s, 7.47H, major), 1.30 (t, J =
7.1 Hz, 2.49H, major), 1.22 (s, 1.53H, minor), 1.06 (t, J = 7.1 Hz, 0.51H,
minor); 13
166.5 (minor), 166.2 (major), 166.1 (minor), 166.0 (major), 165.1 (ma-
jor), 164.9 (minor), 141.1 (minor), 140.6 (major), 135.3 (minor), 134.0
131.8 (minor), 131.6 (major), 131.4 (minor), 130.8 (major), 130.7 (ma-
jor), 130.5 (minor), 128.5 (major), 128.4, 128.3, 128.2 (minor), 125.9
(major), 28.4 (minor), 21.9 (minor), 21.4 (major), 14.3 (major), 13.9
(minor); HRMS (ESI): m/z [M + H]+
for C25H30NO7
+
, calcd. 456.2017,
found 456.2010.
butan-2-yl 4-Iodobenzoate (17i): Yield: 165 mg, 58 % (dr = 18:1,
triturating with hexane was applied after the column chromatogra-
phy, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.27–8.21 (m,
1.9H, major), 8.20–8.15 (m, 0.1H, minor), 7.83 (d, J = 8.8 Hz, 0.1H,
minor), 7.79 (d, J = 8.8 Hz, 0.1H, minor), 7.69 (d, J = 8.6 Hz, 1.9H,
major), 7.62–7.55 (m, 0.05H, minor), 7.54–7.43 (m, 2.95H, major),
7.42–7.35 (m, 1.9H, major), 6.95 (bs, 0.95H, major), 6.78 (bs, 0.05H,
minor), 6.51 (s, 0.05H, minor), 6.43 (s, 0.95H, major), 5.72 (s, 0.95H,
major), 5.65 (s, 0.05H, minor), 4.36–4.20 (m, 1.9H, major), 4.17–4.03
(m, 0.1H, minor), 1.36 (s, 8.55H, major), 1.29 (t, J = 7.1 Hz, 2.85H,
major), 1.20 (s, 0.45H, minor), 1.04 (t, J = 7.1 Hz, 0.15H, minor); 13
C
NMR (100 MHz, CDCl3, only the signals of major diastereomer are
listed) δ = 197.0, 165.8, 164.9, 164.7, 137.8, 134.1, 133.9, 131.2, 130.7,
128.5, 128.1, 101.6, 84.7, 76.8, 62.3, 52.1, 28.5, 14.3; HRMS (ESI): m/z
[M + H]+
for C24H27INO7
+
, calcd. 568.0827, found 568.0832.
butan-2-yl 3-(Trifluoromethyl)benzoate (17j): Column chroma-
tography was conducted used pure dichloromethane as eluent;
yield: 38 mg, 15 % (major diastereomer, white powder, m.p. 80–
83 °C) + 189 mg, 74 % (dr = 1.7:1, white powder) = 227 mg, 89 %
(dr = 2.2:1); 1
H NMR (400 MHz, CDCl3, major diastereomer) δ = 8.31–
10
8.25 (m, 2H), 8.03–7.99 (m, 1H), 7.99–7.94 (m, 1H), 7.78–7.71 (m, 1H),
7.53–7.44 (m, 2H), 7.42–7.35 (m, 2H), 7.01 (bs, 1H), 6.45 (s, 1H), 5.77
(s, 1H), 4.37–4.22 (m, 2H), 1.37 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3, major diastereomer) δ = 197.1, 165.7, 164.9,
163.9, 134.2, 133.8, 133.0, 131.1 (q, J = 33.1 Hz), 130.7, 130.1 (q,
J = 3.5 Hz), 129.4, 129.2, 128.6, 126.8 (q, J = 3.7 Hz), 123.6 (q, J =
272.5 Hz), 84.6, 77.2, 62.4, 52.2, 28.5, 14.3; HRMS (ESI): m/z [M + H]+
for C25H27F3NO7
+
, calcd. 510.1734, found 510.1730.
butan-2-yl Isonicotinate (17k): Yield: 69 mg, 31 % (dr = 2.5:1, tritu-
rating with diethyl ether was applied after the column chromatog-
raphy, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.85–8.77 (m,
0.58H, minor), 8.70–8.62 (m, 1.42H, major), 8.30–8.22 (m, 1.42H, ma-
jor), 8.22–8.15 (m, 0.58H, minor), 7.93–7.88 (m, 0.58H, minor), 7.63–
7.33 (m, 4.42H, major + minor), 6.94 (bs, 0.71H, major), 6.79 (bs,
0.29H, minor), 6.54 (s, 0.29H, minor), 6.47 (s, 0.71H, major), 5.80 (bs,
0.71H, major), 5.69 (bs, 0.29H, minor), 4.40–4.20 (m, 1.42H, major),
4.19–4.04 (m, 0.58H, minor), 1.36 (s, 6.39H, major), 1.30 (t, J = 7.1 Hz,
13
C NMR (150 MHz, CDCl3) δ = 196.4 (major), 165.6 (minor), 165.5
nor), 134.3 (major), 133.8 (minor), 133.6 (major), 130.6 (major), 130.5
(minor), 128.6 (major), 128.5 (minor), 123.5 (minor), 123.2 (major),
85.0 (minor), 84.6 (major), 62.6 (minor), 62.5 (major), 52.53 (minor),
52.1 (major), 28.4 (major), 28.3 (minor), 14.3 (major), 13.8 (minor);
for C23H27N2O7
+
443.1813.
Ethyl 3-Benzoyl-4-(tert-butylamino)-3-hydroxy-2-(isobutyryl-
oxy)-4-oxobutanoate (17l): Yield: 80 mg, 39 % (dr = 12:1, triturat-
ing with pentane was applied after the column chromatography,
white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.32–8.27 (m, 1.84H),
8.23–8.18 (m, 0.16H), 7.61–7.53 (m, 1H), 7.49–7.40 (m, 2H), 6.92 (bs,
0.92H), 6.77 (bs, 0.08H), 6.35 (s, 0.08H), 6.30 (s, 0.92H), 5.62 (s, 0.92H),
5.55 (s, 0.08H), 4.32–4.19 (m, 1.84H), 4.12–4.01 (m, 0.16H), 2.74–2.63
(m, 0.08H), 2.42–2.31 (m, 0.92H), 1.34 (s, 8.28H), 1.30 (s, 0.72H), 1.28
(t, J = 7.2 Hz, 2.76H), 1.24 (d, J = 7.0 Hz, 0.24H), 1.21 (d, J = 7.0 Hz,
0.24H), 1.06 (t, J = 7.1 Hz, 0.24H), 0.96 (d, J = 7.0 Hz, 2.76H), 0.79 (d,
J = 7.0 Hz, 2.76H); 13
C NMR (100 MHz, CDCl3, only the signals of
major diastereomer are listed) δ = 196.3, 175.4, 166.0, 165.1, 134.1,
133.6, 130.9, 128.6, 84.7, 75.7, 62.1, 52.0, 33.6, 28.5, 18.50, 18.49,
14.3; HRMS (ESI): m/z [M + H]+
for C21H30INO7
+
, calcd. 408.2017,
found 408,2031.
butan-2-yl Cyclohexanecarboxylate (17m): Yield: 80 mg, 36 %
(dr = 23:1, triturating with pentane was applied after the column
chromatography, white powder); 1
H NMR (400 MHz, CDCl3, only the
signals of major diastereomer are listed) δ = 8.32–8.25 (m, 2H), 7.60–
7.52 (m, 1H), 7.48–7.40 (m, 2H), 6.91 (bs, 1H), 6.30 (s, 1H), 5.61 (s,
1H), 4.32–4.17 (m, 2H), 2.18–2.08 (m, 1H), 1.73–1.66 (m, 1H), 1.65–
1.58 (m, 1H), 1.56–1.47 (m, 2H), 1.47–1.39 (m, 1H), 1.34 (s, 9H), 1.28
(t, J = 7.2 Hz, 3H), 1.25–1.01 (m, 5H); 13
C NMR (100 MHz, CDCl3, only
the signals of major diastereomer are listed) δ = 196.3, 174.4, 166.1,
165.1, 134.1, 133.6, 130.9, 128.5, 84.7, 75.6, 62.1, 51.9, 42.5, 28.50,
28.49, 28.43, 25.6, 25.2, 25.1, 14.3; HRMS (ESI): m/z [M + H]+
for
C24H34INO7
+
, calcd. 448.2330, found 448.2333.
4-(Butylamino)-1-ethoxy-3-hydroxy-3-(4-methoxybenzoyl)-1,4-
dioxobutan-2-yl 4-Methoxybenzoate (17n): Yield: 202 mg, 81 %
(dr = 3.8:1, triturating with hexane was applied after the column
chromatography, white powder); 1
H NMR (400 MHz, CDCl3) δ = 8.40
(d, J = 8.9 Hz, 2H, major + minor), 8.04 (d, J = 8.7 Hz, 0.42H, minor),
7.73 (d, J = 8.8 Hz, 1.58H, major), 7.16 (bt, J = 5.7 Hz, 0.79H, major),

Full Paper
7.07 (bt, J = 6.0 Hz, 0.21H, minor), 6.97–6.89 (m, 0.84H, minor), 6.84
(d, J = 9.0 Hz, 1.58H, major), 6.79 (d, J = 8.8 Hz, 1.58H, major), 6.58
(s, 0.79H, major), 6.53 (s, 0.21H, minor), 5.92 (s, 0.79H, major), 5.80
(s, 0.21H, minor), 4.36–4.18 (m, 1.58H, major), 4.16–4.00 (m, 0.42H,
minor), 3.87 (s, 0.63H, minor), 3.86 (s, 0.63H, minor), 3.80 (s, 2.37H,
major), 3.79 (s, 2.37H, major), 3.38–3.09 (m, 2H, major + minor),
1.60–1.08 (m, 6.37H, major + minor), 1.03 (t, J = 7.1 Hz, 0.63H, mi-
nor), 0.90 (t, J = 7.3 Hz, 2.37H, major), 0.72 (t, J = 7.3 Hz, 0.63H,
minor); 13
166.7 (major), 166.44 (minor), 166.42 (minor), 166.0 (major), 165.1
(minor), 164.7 (major), 164.5 (major), 164.2 (minor), 164.0 (minor),
163.8 (major), 133.9 (major), 133.8 (minor), 132.3 (minor), 132.0 (ma-
jor), 127.4 (minor), 125.6 (major), 121.4 (minor), 121.0 (major),
113.84 (major), 113.81 (minor), 113.72 (minor), 113.67 (major), 85.2
(minor), 84.5 (major), 76.37 (major), 76.35 (minor), 62.1 (minor), 62.0
(major), 55.62 (minor), 55.57 (major + minor), 55.5 (major), 40.2 (mi-
nor), 40.0 (major), 31.44 (major), 31.42 (minor), 20.1 (major), 19.9
(minor), 14.2 (major), 13.84 (minor), 13.77 (major), 13.6 (minor);
HRMS (ESI): m/z [M + Na]+
for C26H31NO9Na+
524.1888.
3-Benzoyl-4-(butylamino)-1-ethoxy-3-hydroxy-1,4-dioxobutan-
2-yl 4-Bromobenzoate (17o): Yield: 138 mg, 53 % (major dia-
stereomer, the reaction was conducted in DCE, white powder); 1
H
NMR (400 MHz, CDCl3, major diastereomer) δ = 8.34–8.27 (m, 2H),
7.63 (d, J = 8.4 Hz, 2H), 7.55–7.48 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H),
7.42–7.34 (m, 2H), 7.11 (bt, J = 5.3 Hz, 1H), 6.53 (s, 1H), 5.75 (s, 1H),
4.36–4.18 (m, 2H), 3.39–3.21 (m, 2H), 1.59–1.45 (m, 2H), 1.40–1.29
(m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 0.91 (t, J = 7.3 Hz, 3H); 13
C NMR
134.4, 133.3, 131.8, 131.3, 130.9, 128.9, 128.6, 127.5, 84.7, 76.7, 62.3,
40.2, 31.4, 20.1, 14.2, 13.8. HRMS (ESI): m/z [M + Na]+
for
C24H26BrNO7Na+
, calcd. 542.0785, found 542.0773.
1-Ethoxy-3-(4-fluorobenzoyl)-3-hydroxy-4-(naphthalen-2-yl-
amino)-1,4-dioxobutan-2-yl 4-Bromobenzoate (17p): Yield:
188 mg, 62 % (dr = 4:1, triturating with hexane was applied after
the column chromatography, white powder); 1
H NMR (400 MHz,
CDCl3) δ = 9.15 (s, 0.8H, major), 9.08 (s, 0.2H, minor), 8.61–8.48 (m,
2H, major + minor), 8.26 (d, J = 1.9 Hz, 0.8H, major), 8.08 (d, J =
1.9 Hz, 0.2H, minor), 7.89 (d, J = 8.6 Hz, 0.4H, minor), 7.85–7.69 (m,
3H, major + minor), 7.66 (d, J = 8.6 Hz, 1.6H, major), 7.55–7.37 (m,
5H, major + minor), 7.24–7.17 (m, 0.4H, minor), 7.14–7.06 (m, 1.6H,
major), 6.75 (s, 0.8H, major), 6.70 (s, 0.2H, minor), 6.11 (s, 0.8H, ma-
jor), 6.02 (s, 0.2H, minor), 4.33 (dq, J = 10.7, 7.1 Hz, 0.8H, major),
4.26–4.07 (m, 1.2H, major + minor), 1.16 (t, J = 7.1 Hz, 2.4H, major),
1.10 (t, J = 7.1 Hz, 0.6H, minor); 13
C NMR (100 MHz, CDCl3) δ = 194.6
(minor), 193.0 (major), 166.6 (d, J = 258.4 Hz, major), 166.5 (d, J =
258.0 Hz, minor), 166.0 (minor), 165.3 (major), 164.8 (minor), 164.4
(minor), 164.3 (major), 164.2 (major), 134.38 (d, J = 9.8 Hz, minor),
134.36 (d, J = 9.7 Hz, major), 134.2 (major), 133.81 (major), 133.77
(minor), 133.7 (minor), 132.02 (minor), 131.97 (major), 131.6 (major),
131.3 (major), 131.23 (minor), 131.21 (minor), 130.5 (d, J = 3.1 Hz,
minor), 129.19 (major + minor), 129.16 (major), 129.13 (minor),
129.07 (d, J = 2.9 Hz, major), 127.9 (major), 127.82 (minor), 127.76
(major), 127.72 (minor), 127.67 (minor), 127.2 (major), 126.90 (mi-
nor), 126.88 (major), 125.8 (minor), 125.7 (major), 119.7 (major +
minor), 117.5 (minor), 117.2 (major), 116.1 (d, J = 21.9 Hz, major),
116.0 (d, J = 21.8 Hz, minor), 85.6 (minor), 85.1 (major), 76.5 (major),
76.4 (minor), 62.7 (minor), 62.5 (major), 14.1 (major), 13.9 (minor);
HRMS (ESI): m/z [M + Na]+
for C30H23BrFNO7Na+
, calcd. 630.0534,
found 630.0509.
Synthesis of N-(1-(tert-Butylamino)-1,3-dioxo-3-phenylpropan-
2-yl)-N-phenylbenzamide (19b): Phenylglyoxal monohydrate
11
(15a·H2O, 122 mg, 0.8 mmol) was dissolved in methanol (4 mL)
followed by the addition of benzoic acid (2a, 98 mg, 0.8 mmol),
aniline (18b, 75 mg, 0.8 mmol), and tert-butyl isocyanide (3a, 67 mg,
0.8 mmol). The resulting mixture was stirred at room temperature
for 24 hours. Upon completion of the reaction time, the mixture
was diluted with ethyl acetate and concentrated with silica. Column
chromatography with petroleum ether/ethyl acetate (9:1) as eluent
delivered 19b. Yield: 239 mg, 72 % (triturating with hexane was
applied after the column chromatography, white powder, m.p. 137–
139 °C, in CDCl3 observed as a 3:2 mixture of enol and keto forms);
1
H NMR (400 MHz, CDCl3) δ = 14.99 (s, 0.6H, enol), 7.90–7.85 (m,
0.8H, keto), 7.59–7.52 (m, 0.4H, keto), 7.47–7.04 (m, 12.6H, enol +
keto), 7.00–6.92 (m, 1.2H, enol), 6.81 (bs, 0.4H, keto), 6.24 (s, 0.4H,
keto), 5.77 (bs, 0.6H, enol), 1.28 (s, 5.4H, enol), 1.25 (s, 3.6H, keto);
13
C NMR (100 MHz, CDCl3) δ = 196.0, 171.2, 171.1, 170.5, 170.3,
164.9, 142.0, 141.8, 136.7, 136.1, 134.9, 133.7, 133.3, 130.7, 130.6,
130.1, 129.6, 129.0, 128.8, 128.62, 128.59, 128.5, 128.2, 127.8, 127.6,
127.5, 127.3, 126.2, 123.8, 108.9, 69.4, 52.1, 51.8, 28.8, 28.5; HRMS
(ESI, [M + H]+) for C26H27N2O3
+
calcd. 415.2016, found 415.2017.
Acknowledgments
This work was supported by the start-up fund from Soochow
University (grant Q410900714), National Natural Science Foun-
dation of China (grant 21650110445), Natural Science Founda-
tion of Jiangsu Province of China (grant BK20160310), the Prior-
ity Academic Program Development of Jiangsu Higher Educa-
tion Institutions (PAPD) and the project of scientific and techno-
logic infrastructure of Suzhou (grant SZS201708). M.H. and M.Z.
are grateful to the Chinese Scholarship Council (CSC) for provid-
ing doctoral scholarships. A.A.N. is grateful to the European
Community Mobility Programme “Erasmus Mundus Action 2,
Strand 1” for providing a doctoral scholarship. E.V.V.d.E. ac-
knowledges the support of RUDN University through the Pro-
gram 5-100.
Keywords: Aldol addition · Multicomponent reactions ·
Passerini reaction · Transesterification · Molecular diversity
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Received: January 5, 2020

Full Paper
Multicomponent Reactions
M. Hasan, M. Zaman,
A. A. Peshkov,* N. Amire, A. Les,
A. A. Nechaev, Y. Wang, S. Kashtanov,
E. V. Van der Eycken, O. P. Pereshivko,
V. A. Peshkov* .................................. 1–13
Four-Component One-Pot Process
A four-component one-pot transfor- regarded as an isocyanide-triggered
Involving Passerini Reaction Fol-
mation involving the Passerini reac- benzoin-type condensation. Conse-
lowed by Aldol Addition and Trans-
tion, an aldol addition, and a trans- quently, two modifications of the proc-
esterification
esterification has been elaborated, ess have been developed – a homo-
providing an access to a library of condensation of ethyl glyoxalate and a
densely functionalized tartaric acid cross-condensation of aryl glyoxal with
derivatives. The overall process can be ethyl glyoxalate.
DOI: 10.1002/ejoc.202000015
13

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