A Br?nsted acid-catalyzed multicomponent reaction for the synthesis of highly functionalized γ-lactam derivatives

Article abstract of DOI:10.3390/molecules24162951

Br?nsted acids catalyze a multicomponent reaction of benzaldehyde with amines and diethyl acetylenedicarboxylate to afford highly functionalized γ-lactam derivatives. The reaction consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.

Full text of DOI:10.3390/molecules24162951

molecules
Communication
A Brønsted Acid-Catalyzed Multicomponent Reaction
for the Synthesis of Highly Functionalized
γ-Lactam Derivatives
Xabier del Corte , Edorta Martinez de Marigorta , Francisco Palacios * and Javier Vicario *
Departamento de Química Orgánica I, Centro de Investigación y Estudios Avanzados “Lucio Lascaray”-
Facultad de Farmacia, University of the Basque Country, UPV/EHU Paseo de la Universidad 7,
01006 Vitoria-Gasteiz, Spain
* Correspondence: francisco.palacios@ehu.eus (F.P.); javier.vicario@ehu.eus (J.V.);
Tel.: +34-945-013103 (F.P.); +34-945-013087 (J.V.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editor: Gianfranco Favi
Received: 24 July 2019; Accepted: 11 August 2019; Published: 14 August 2019
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Brønsted acids catalyze a multicomponent reaction of benzaldehyde with amines and
diethyl acetylenedicarboxylate to afford highly functionalized γ-lactam derivatives. The reaction
consists of a Mannich reaction of an enamine to an imine, both generated in situ, promoted by a
phosphoric acid catalyst and a subsequent intramolecular cyclization. The hydrolysis of the cyclic
enamine substrate can provide enol derivatives and, moreover, a second attack of the amine on the
carboxylate can afford amide derivatives. An optimization of the reaction conditions is presented in
order to obtain selectively cyclic enamines that can afford the enol species after selective hydrolysis.
Keywords: γ-lactam; pyrrolidones; multicomponent reactions; organocatalysis
1. Introduction
Multicomponent reactions (MCRs) [1,2] are valuable processes where three or more substrates,
which are simultaneously (or almost) added, react in a single vessel to form a new structure that
contains substantial portions of all the starting materials. Strecker, Hantzsch, Biginelli, Passerini,
Gröbcke-Blackburn-Bienaym
that fit with this definition, and they are widely used in organic synthesis [
molecular diversity achieved in MCRs, they are now an essential tool in diversity-oriented synthesis [
with huge potential in the field of medicinal chemistry [ ]. Considering the relevance of the -lactam
ring (Figure 1) [ ] and the increasing demand of potentially active compounds in medicinal sciences,
MCR protocols were extensively used during the last decades for the synthesis of a wide number
of densely functionalized -lactam derivatives [ ]. In particular, 1,5-dihydro-2H-pyrrol-2-ones II
(Figure 1) are conjugated unsaturated -lactam substrates with huge potential as intermediates in
synthetic chemistry that also show assorted pharmacological activities [10–13].
é
, Kabachnik-Fields, or Ugi are some of the names of classical reactions
]. Due to the high degree of
],
1,2
3,4
5
,6
γ
I
7
γ
8,9
γ
Figure 1.
General structure of γ-lactams I, 1,5-dihydro-2H-pyrrol-2-ones II, 3-amino
1,5-dihydro-2H-pyrrol-2-ones II, and dithiopyrrolone antibiotics IV.
Molecules 2019, 24, 2951; doi:10.3390/molecules24162951
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2951
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Within this family of compounds, the structure of their 3-amino substituted derivatives III (Figure 1)
contains the enamine moiety and, in addition to their obvious applications as synthetic intermediates
in organic synthesis [14
antimicrobials with anti-biofilm activity, caspase-3 inhibitors, antipyretics, or analgesics [16–20]
Moreover, these cyclic -dehydro -diamino acid derivatives contain the essential structure
,15], their skeleton is also present in many new bioactive ingredients such as
.
α
α,β
of dithiopyrrolone antibiotics IV (Figure 1) [21] and are key intermediates for the synthesis of
Amaryllidaceae and Sceletium alkaloids [22,23].
Several MCR procedures for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones were
reported to date [
pyruvate , aldehydes
functionalized -lactam derivatives
amines with both ethyl pyruvate
and aldimine that undergo a subsequent Mannich reaction, followed by a cyclization reaction driven
by the formation of an internal amide bond in the resulting adduct 6 (Scheme 1).
8]. In particular, some years ago, we reported a three-component reaction of ethyl
1
2
, and amines
3
mediated by sulfuric acid that yields very efficiently highly
γ
7
[
24]. In this reaction, an initial simultaneous condensation of
3
1 and aldehydes 2 leads to the formation of intermediate enamine 4
5
Scheme 1. Three-component reaction of ethyl pyruvate 1, aldehydes 2, and amines 3.
Based on this report, some authors later described several modifications of this synthetic procedure,
and the uncatalyzed [25] or solvent-free [26] reaction, and the use of recyclable catalysts [27] were
reported in the last few years. Interestingly, it was also established that such reaction can be performed
under organocatalysis [28] and, taking the advantage of this fact, very recently, we achieved a highly
enantioselective version of this reaction using 1,10-bi-2-naphthol (BINOL)-derived chiral phosphoric
acids as catalysts [29].
A similar multicomponent process, where dialkyl acetylenedicarboxylates are used instead of ethyl
pyruvate, was also reported for the synthesis of 3-amino 1,5-dihydro-2H-pyrrol-2-ones. In this case,
the nucleophilic addition of aromatic amines to the activated alkyne gives rise to a deactivated enamine
intermediate and 0.5 equivalents of benzoic acid are required in order to promote the subsequent
Mannich reaction [30]. Activation of this process was also described by the use of molecular iodine [31
]
or graphene-oxide nanosheets under solvent-free conditions [32]. In this context, organocatalysis
is identified to be at the heart of greening of chemistry, because this branch of science is found to
reduce the environmental impact of chemical processes. Therefore, in view of the demonstrated
ability of phosphoric acids to catalyze the nucleophilic addition of pyruvate-derived enamines
imines , we thought that this activation could be extended to the enamines derived from dialkyl
acetylenedicarboxylates. Consequently, continuing with the interest of our research group in the
synthesis of nitrogenated heterocycles [33 36] and amino-acid derivatives [37 40], we report here the
4 to
5
–
–
use of phosphoric acids as catalysts in a three-component reaction of amines, benzaldehyde, and diethyl
acetylenedicarboxylate to afford densely functionalized γ-lactam derivatives.
2. Results
Based on our previous experience in MCRs for the synthesis of 3-amino
1,5-dihydro-2H-pyrrol-2-ones [11
a Brønsted acid catalyst in the three-component reaction of benzaldehyde
R = p-MeC6H4), and diethyl acetylenedicarboxylate
(Scheme 2). However, only the enamine and/or imine intermediates that result from the reaction of
amine substrate with benzaldehyde or alkyne were observed in the crude (Table 1, Entry 1).
,14], we firstly used BINOL-derived phosphoric acid
9
as
2, p-toluidine
3
(
8 using refluxing dichloromethane as solvent
3
2
8

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Considering that our previously reported three-component reaction of ethyl pyruvate, benzaldehyde,
and amines smoothly yields the corresponding 3-amino 1,5-dihydro-2H-pyrrol-2-ones, we thought
that the increased steric hindrance, together with the additional deactivation present in the enamine
intermediate when acetylenedicarboxylates
reason for the lack of reactivity in this case.
8 are used instead of pyruvate derivatives, may be the
Scheme 2. Three-component reaction of diethyl acetylenedicarboxilate 8, benzaldehyde 2, and amines 3.
Table 1. Three-component reaction of ethyl pyruvate 1, benzaldehyde 2, and amines 3.
T (◦C)
Yield (%) 1
10/11/12 2
Entry
R
2/3/8
Solvent
1
2
3
4
5
6
7
8
9
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeC6H4
p-MeOC6H4
p-MeOC6H4
Bn
1/2/1
1/2/1
1/2/1
1/2/1
1/2/3
1/2/1
1/2/1
1/2/1
1/4/1
1/2/1
CH2Cl2
THF
DME
MTBE
MTBE
Dioxane
Toluene
Toluene
Toluene
Toluene
40
65
85
55
55
101
110
110
110
110
0
0
0
72
0
81
77
76
76
58
n.d.
n.d.
n.d.
40/60/0
n.d.
80/0/20
95/0/5
70/0/30
70/0/30
100/0/0
10
1
2
Isolated total yield. Determined by 1H-NMR. n.d.—not determined.
Then, we tried to perform the reaction at higher temperature and, although the same results
were observed using tetrahydrofurane (THF) or dimethoxyethane (DME) as solvents (Table 1, Entries
2 and 3), the reaction in refluxing methyl tert-butylether (MTBE) proceeded in full conversion in a few
hours, affording the expected 3-amino 1,5-dihydro-2H-pyrrol-2-one 10a together with enol derivative
11a [41], which may result from the hydrolysis of enamine moiety in 10a (Table 1, Entry 4). The use
of an excess of ethyl pyruvate in the parent MCR with benzaldehyde and amines proved to be very
effective in reducing the reaction times and temperatures [29]; however, remarkably, when three
equivalents of acetylene derivative 8 were used, no formation of γ-lactam derivatives 10a or 11a was
observed due to the consumption of p-toluidine 3a (R = p-MeC6H4) by reaction with the excess of
diethyl acetylenedicarboxylate 8 (Table 1, Entry 5).
Better selectivity was observed when the reaction was performed using hot dioxane as solvent.
In this case, amino 1,5-dihydro-2H-pyrrol-2-one 10a was obtained together with a significant amount
of amide derivative 12a, which presumably results from the nucleophilic attack of amine on the ethyl
carboxylate moiety in compound 10a (Table 1, Entry 6). Finally, the selectivity of the reaction was further
improved using toluene as the reaction solvent, and only a small amount (5%) of amide derivative 12a
was obtained together with γ-lactam 10a (Table 1, Entry 7). Under the same conditions, the use of more
nucleophilic p-anisidine 3b (R = p-MeOC6H4) in the reaction yielded 1,5-dihydro-2H-pyrrol-2-one 10b
as the major product of the reaction although, in this case, together with a 30% of amide derivative 12b
(Table 1, Entry 8). In order to obtain exclusively amide substrate 12b, four equivalents of amine were
used under the same reaction conditions, but the same proportion of the products was observed (Table 1,

Molecules 2019, 24, 2951
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Entry 9). However, the use of benzylamine 3c (R = Bn) afforded exclusively 1,5-dihydro-2H-pyrrol-2-one
10c, and no formation of enol 11c or amide 12c was observed (Table 1, Entry 10). The selectivity in this
case could be explained by the lower steric crowding in the enamine moiety in benzylamine derivative
10c if compared to the aromatic derivatives 10a and 10b [42].
In view of the three compounds observed, the reaction mechanism could start with an initial
concomitant addition of amines
3 to acetylene carboxylate 8 and benzaldehyde 2 that affords enamine
13 and aldimine 14. Both species 13 and 14 can be observed by 1H-NMR. Then, a subsequent Mannich
reaction leads to the formation of adduct 15, which undergoes an intramolecular cyclization by the
formation of an internal amide bond between the amine and carboxylate moieties to afford enamine
type γ-lactam 10. Due to the presence of water and some remaining amine 3, the γ-lactam 10 may
afford enol type lactam 11 through hydrolysis of the enamine moiety or amide derivative 12, through
the displacement of ethanol by the amine (Scheme 3). This is supported by the fact that, using
high-boiling-point solvents, no enol derivative 11 is observed, which may be due to the instantaneous
evaporation of water at high reaction temperatures.
Scheme 3. Reaction mechanism for the three-component reaction of diethyl acetylenedicarboxylate
benzaldehyde 2, and amines 3.
8,
In our case, the three resulting γ-lactam structures 10, 11, and 12 could be separated in all the
cases by simple chromatography, and they were fully characterized on the basis of their spectroscopic
data. However, due to the structural resemblance between all the lactam derivatives, in order to
unambiguously determine the identity of the substrates of the reaction, a single crystal of enol 11a
was prepared, and its X-ray diffraction structure was obtained (Figure 2). Key features of the crystal
structure are the almost planar shape of the five-membered ring and the presence of a hydrogen bond
between the enol hydrogen and the carboxylate group in a six-membered ring configuration rather
than with the amide carboxylate, forming a five-membered ring.

Molecules 2019, 24, 2951
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Figure 2. X-ray structure of 11a. (blue ball, Nitrogen; gray ball, Carbon).
In order to set up the optimal conditions for the preparation of enol derivatives 11
,
we proposed the corresponding reactions starting from their parent 1,5-dihydro-2H-pyrrol-2-ones
10 (Scheme 4). Therefore, the hydrolysis of enamine moiety in 10 was performed by treatment
of 1,5-dihydro-2H-pyrrol-2-ones 10 in the presence of aqueous hydrochloric acid in refluxing THF.
Despite the strong acidic conditions, no trace of the products derived from the hydrolysis of ester of
amide groups are observed and enol derivatives 11 are obtained in quantitative yields.
Scheme 4. Preparation of enol derivatives 11 and deprotection of benzylamine derivative 10.
In addition, the treatment of benzylamine derivative γ-lactam 10 (R = Bn) with a catalytic amount
of palladium under hydrogen atmosphere during several days led to the exclusive deprotection of the
nitrogen at the enamine moiety in quantitative yield to afford lactam 16. Remarkably, the benzyl group
at the endocyclic nitrogen and the enamine double bond remained unaltered under those reaction
conditions. Although the reaction times are very long, this process can be sped up by the addition of
one equivalent of aqueous hydrochloric acid (Scheme 4).
Taking into account the typical activation accepted by phosphoric acid catalysts [43–45], we propose
a tentative transition state for the key Mannich reaction, where a dual activation of imine and enamine
species takes place by the simultaneous formation of two hydrogen bonds between the phosphoryl
oxygen and the acidic proton of the phosphoric acid group with the enamine proton and the iminic
nitrogen, respectively (Figure 3).
Figure 3. Transition state proposed for the Mannich reaction in the three-component reaction.

Molecules 2019, 24, 2951
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According to the transition state proposed, we may expect substantial enantiomeric excesses for
this reaction. However, when enantiomerically pure chiral phosphoric acids were used as catalysts,
very poor enantioselectivities were observed with a maximum enantiomeric excess of 5%. This may be
attributable to the high temperatures required for the reaction conditions because of the steric hindrance
present in the enamine substrate, together with the additional deactivation of the nucleophile due to
the presence of two carboxylate groups.
In conclusion, we report a Brønsted acid-catalyzed MCR procedure for the preparation of 3-amino
1,5-dihydro-2H-pyrrol-2-ones where diethyl acetylenedicarboxylate, amines, and benzaldehyde are
used as substrates. This is the first example of such a reaction using phosphoric acids as catalyst.
Moreover, we present nine highly functionalized γ-lactam derivatives, adding some molecular diversity
to the already published substrates. The hydrolysis process of 1,5-dihydro-2H-pyrrol-2-ones from
enamine substrates to the enol derivatives 11 was not previously reported.
3. Materials and Methods
General. Solvents for extraction and chromatography were technical grade. All solvents used
in reactions were freshly distilled from appropriate drying agents before use. All other reagents
were recrystallized or distilled as necessary. All reactions were performed under an atmosphere of
dry nitrogen. Analytical thin layer chromatography (TLC) was performed with silica gel 60 F254
plates. Visualization was accomplished by ultraviolet (UV) light. 1H-, 13C-, and 31P-NMR spectra
were recorded on a Varian Unity Plus (at 300 MHz, 75 MHz, and 120 MHz, respectively, Advanced
Research Facilities (SGIker), by the University of the Basque Country, Vitoria-Gasteiz, Spain) and on a
Bruker Avance 400 (at 400 MHz, 100 MHz, and 160 MHz, respectively, Advanced Research Facilities
(SGIker), by the University of the Basque Country, Vitoria-Gasteiz, Spain). Chemical shifts (
δ
) are
reported in ppm relative to residual CHCl3 (
δ
= 7.26 ppm for 1H, and
δ
= 77.16 ppm for 13C-NMR).
1
Coupling constants (J) are reported in Hertz. Data for H-NMR spectra are reported as follows:
chemical shift, multiplicity, coupling constant, integration. Multiplicity abbreviations are as follows:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, b = broad. 13C-NMR peak assignments
were supported by distortionless enhanced polarization transfer (DEPT). High-resolution mass spectra
(HRMS) were obtained by positive-ion electrospray ionization (ESI). Data are reported in the form m/z
(intensity relative to base = 100). Infrared spectra (IR) were taken in a Nicolet iS10 Termo Scientific
spectrometer as neat solids. Peaks are reported in cm−1. Copies of 1H- and 13C {1H} NMR spectra for
γ-lactams 10, 11, 12, and 16 are in Supplementary Materials.
Crystal structure determination for compound 11a. Intensity data were collected on an Agilent
Technologies Super-Nova diffractometer (Advanced Research Facilities (SGIker), by the University of
the Basque Country, Leioa, Spain), which was equipped with monochromated Cu ka radiation (λ =
1.54184 Å) and Atlas CCD detector. Measurement was carried out at 150.00 (10) K with the help of
an Oxford Cryostream 700 PLUS temperature device (Advanced Research Facilities (SGIker), by the
University of the Basque Country, Leioa, Spain). Data frames were processed (united cell determination,
analytical absorption correction with face indexing, intensity data integration, and correction for
Lorentz and polarization effects) using the Crysalis software package (Version 1.171.37.31, release
14-01-2014 CryAlis171.NET, compiled Jan 14 2014, 18:38:05, Advanced Research Facilities (SGIker),
by the University of the Basque Country, Leioa, Spain). The structure was solved using ShelXS (Sheldrick,
2008, Advanced Research Facilities (SGIker), by the University of the Basque Country, Leioa, Spain) [46
]
and refined by full-matrix least-squares with SHELXL-97 (Sheldrick, 2008, Advanced Research Facilities
(SGIker), by the University of the Basque Country, Leioa, Spain) [47]. Final geometrical calculations
were carried out with Mercury [48] and PLATON [49,50] as integrated in WinGX [51].
General procedure for the synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones 10. A solution
of benzaldehyde
2
(0.1 mL, 1 mmol), diethyl acetylenedicarboxylate
8 (0.16 mL, 1 mmol), amine 3
(2 mmol), phosphoric acid catalyst
9
(34.8 mg, 0.1 mmol), and anhydrous MgSO4 was stirred in toluene

Molecules 2019, 24, 2951
7 of 11
(5 mL) at 110 ◦C for 48 h. The volatiles were dried off at reduced pressure, and the crude residue was
purified by column chromatography (AcOEt/hexanes) to afford pure lactams 10.
Ethyl 5-oxo-2-phenyl-1-(p-tolyl)-4-(p-tolylamino)-2,5-dihydro-1H-pyrrole-3-carboxylate (10a).
The general procedure was followed, using p-toluidine (0.21 g, 2 mmol), affording 0.311 g (73%) of
10a as a white solid. Melting point (m.p.) (Et2O) 154–155 ◦C. 1H-NMR (400 MHz, CDCl3):
δ
8.17 (bs,
CHar), 7.12 (d, 3JHH = 8.3 Hz, 2H,
CHar), 7.03 (d, 3JHH = 8.3 Hz, 2H, 2
CHar), 5.77 (s, 1H, CHN),
4.01 (q, 3JHH = 7.1 Hz, 2H, CH2 OEt), 2.33 (s, 3H, CH3), 2.23 (s, 3H, CH3), 1.01 (t, 3JHH = 7.1 Hz, 3H,
CH3 OEt). 13C {1H} NMR (101 MHz, CDCl3)
164.7 (C=O ester), 164.1 (C=O amide), 142.7 (=Cquat),
137.2 (Cquat), 136.1 (Cquat), 135.5 (Cquat), 134.6 (Cquat), 134.2 (Cquat), 129.5 (2 CHar), 129.1 (2 CHar),
128.4 (2 CHar), 128.1 (CHar), 127.83 (2 CHar), 123.2 (2 CHar), 122.8 (2 CHar), 108.9 (=Cquat), 63.3
1H, NH), 7.34 (d, 3JHH = 8.5 Hz, 2H, 2
CHar), 7.08 (d, J = 8.5 Hz, 2H, 2
×
CHar), 7.26–7.21 (m, 5H, 5
×
2×
×
×
δ
×
×
×
×
×
×
(CHN), 60.2 (CH2 OEt), 21.1 (CH3), 21.0 (CH3), 14.0 (CH3 OEt). Fourier-transform IR (FTIR) (neat)
3289 (N–H), 1701 (C=O), 1679 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+
ν
:
max
426.1943, found 426.1950.
Ethyl 1-(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-
3-carboxylate (10b). The general procedure was followed, using p-anisidine (0.25 g, 2 mmol), affording
0.284 g (63%) of 10b as a yellow solid. m.p. (Et2O) 116–117 ◦C. 1H-NMR (300 MHz, CDCl3)
δ
8.20 (bs,
CHar), 7.15 (d, 3JHH = 8.9 Hz, 2H, 2
CHar), 6.74 (d, 3JHH = 9.1, 2H, 2
CHar), 5.69 (bs, 1H, CHN), 4.01
(q, 3JHH = 7.1, 2H, CH2 OEt), 3.80 (s, 3H, CH3O), 3.71 (s, 3H, CH3O), 1.02 (t, 3JHH = 7.1, 3H, CH3 OEt).
13C {1H} NMR (75 MHz, CDCl3)
164.9 (C=O ester), 163.9 (C=O amide, 157.5 (Cquat), 157.3 (Cquat),
143.4 (=Cquat), 137.3 (Cquat), 131.6 (Cquat), 129.7 (Cquat), 128.4 (2 CHar), 128.1 (CHar), 127.9 (2 CHar),
125.1 (2 CHar), 124.8 (2 CHar), 114.1 (2 CHar), 113.8 (2 CHar), 107.9 (=Cquat), 63.6 (CHN), 60.1
(CH2 OEt), 55.6 (CH3), 55.5(CH3), 14.1 (CH3 OEt). FTIR (neat) max: 3436 (N–H), 1704 (C=O), 1672
1H, NH), 7.29 (d, 3JHH = 9.1, 2H, 2
CHar), 6.85 (d, 3JHH = 8.9 Hz, 2H, 2
×
CHar), 7.24–7.18 (m, 5H, 5
×
×
×
×
δ
×
×
×
×
×
×
ν
(C=O), 1629 (C=C). HRMS (Q-TOF) m/z calculated for C22H15Br2N3O3 [M]+ 458.1842, found 458.1844.
Ethyl 1-benzyl-4-(benzylamino)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (10c).
The general procedure was followed, using benzylamine (0.21 g, 2 mmol), affording 0.234 g (58%) of
10c as a white solid. m.p. (Et2O) 106–108 ◦C. 1H-NMR (400 MHz, DMSO-d6)
7.34–7.21 (m, 8H, 7 Char + NH), 7.08 (m, 4H, 4
1H, CHN), 4.86 (d, 3JHH = 15.1 Hz, 1H, CH2 Bn), 3.96–3.81 (m, 2H, CH2 OEt), 3.65 (d, 3JHH = 15.1 Hz,
1H, CH2 Bn), 0.91 (t, 3JHH = 7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (101 MHz, DMSO-d6)
164.6 (C=O
ester), 163.5 (C=O amide, 145.3 (=Cquat), 139.8 (Cquat), 137.0 (Cquat), 136.2 (Cquat), 128.0 (2 CHar),
127.9 (2 CHar), 127.8 (2 CHar), 127.5 (CHar), 127.3 (2 CHar), 127.1 (2 CHar), 126.8 (CHar), 126.7
(2 CHar), 126.4 (CHar), 103.4 (=Cquat), 60.8 (CHN) , 58.4 (CH2 OEt), 45.3 (CH2 Bn), 43.4 (CH2 Bn),
δ
7.36 (m, 4H, 4
×
CHar),
×
×
CHar), 5.09 (d, 3JHH = 6.8 Hz, 2H, CH2 Bn), 4.95 (s,
δ
×
×
×
×
×
×
13.3 (CH3 OEt). FTIR (neat) νmax: 3430 (N–H), 1691 (C=O), 1665 (C=O) 1624 (C=C). HRMS (Q-TOF)
m/z calculated for C22H15F2N3O3 [M]+ 426.1943, found 426.1942.
General procedure for the hydrolysis of compounds 10. To 10 mL of a 3 M HCl/THF (1:1)
solution, compound 10 (0.5 mmol) was added; the mixture was heated to 75 ◦C and stirred overnight.
The reaction was monitored by TLC and, once it was finished, the mixture was concentrated under
reduced pressure to eliminate the THF, washed with 3 M NaOH (2
and extracted with ethyl acetate. The combined organic phases were dried with anhydrous Mg2SO4,
and the crude residue was crystalized in Et2O: pentane.
×
5 mL) and H2O (2
×
5mL),
Ethyl
4-hydroxy-5-oxo-2-phenyl-1-(p-tolyl)-2,5-dihydro-1H-pyrrole-3-carboxylate
(11a).
The general procedure was followed, affording 0.161 g (95%) of 11a as a white solid. m.p. (Et2O)
170–172 ◦C. 1H-NMR (300 MHz, CDCl3)
δ
9.19 (bs, 1H, OH), 7.38 (d, 3JHH = 8.2 Hz, 2H, 2
×
CHar),
3
3
7.32–7.25 (m, 5H, 5
×
CHar), 7.09 (d, JHH = 8.2 Hz, 2H, 2
×
CHar), 5.74 (s, 1H, CHN), 4.20 (q, JHH
=, 7.1 Hz, 2H, CH2 OEt) 2.26 (s, 3H), 1.20 (t, 3JHH = 7.1Hz, 3H, CH3 OEt). 13C {1H} NMR (75 MHz,
CDCl3)
129.6 (2
δ
165.0 (C=O ester), 162.9 (C=O amide), 156.4 (=Cquat), 135.7 (Cquat), 135.3 (Cquat), 133.7 (Cquat),
CHar), 128.6 (2 CHar), 128.5 (CHar), 127.6 (2 CHar), 122.4 (2 CHar), 113.1 (=Cquat), 61.8
×
×
×
×

Molecules 2019, 24, 2951
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(CHN), 61.2 (CH2 OEt), 20.9 (CH3), 14.0 (CH3 OEt). FTIR (neat)
ν
max: 3425 (O–H), 1704 (C=O), 1675
(C=O), 1643 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 337.1314, found 337.1319.
Ethyl 4-hydroxy-1-(4-methoxyphenyl)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate
(
11b). The general procedure was followed, affording 0.162 g (92%) of 11b as a white solid. m.p. (Et2O)
1
182 ◦C (dec.). H-NMR (300 MHz, CDCl3)
δ
9.05 (bs, 1H, OH), 7.30 (d, 3JHH = 8.9 Hz, 2H, 2
×
CHar),
3
3
7.24–7.16 (m, 5H, 5
×
CHar), 6.79 (d, JHH = 8.8 Hz, 2H, 2
×
CHar), 5.63 (s, 1H, CHN), 4.17 (q, JHH
= 7.1 Hz, 2H, CH2 OEt), 3.72 (s, 3H, CH3), 1.16 (t, JHH = 7.1 Hz, 3H, CH2 OEt). 13C {1H} NMR
δ
3
165.4 (C=O ester), 162.8 (C=O amide), 157.7 (Cquat), 157.1 (=Cquat), 135.3 (Cquat), 129.3 (Cquat), 128.7
(2 CHar), 128.6 (2 CHar), 127.7 (2 CHar), 124.5 (2 CHar), 120.5 (CHar), 114.4 (2 CHar), 113.0
max: 3431 (O–H), 1711
×
×
×
×
×
(=Cquat), 62.2 (CHN), 61.3 (CH2 OEt), 55.5 (CH3), 14.1 (CH3 OEt). FTIR (neat)
ν
(C=O), 1677 (C=O), 1653 (C=CH). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 353.1263, found
353.1268.
Ethyl
1-benzyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate
(11c).
The general procedure was followed, affording 0.157 g (94%) of 11c as a white solid. m.p.
◦
1
(Et2O) 178–179 C. H-NMR (300 MHz, CDCl3)
δ
9.11 (bs, 1H, OH), 7.39–7.33 (m, 3H, 3 CHar),
×
7.32–7.27 (m, 3H, 3× CHar), 7.15–7.08 (m, 4H, 4× CHar), 5.20 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn), 4.88 (s,
1H, CHN), 4.08 (q, 3JHH = 7.2, 2H, , CH2 OEt), 3.55 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn), 1.06 (t, 3JHH
=
7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (75 MHz, CDCl3)
136.43 (Cquat), 134.68 (Cquat), 128.97 (CH), 128.68 (CH), 128.02 (CH), 127.98 (CH), 113.37 (Cquat), 61.14
(CH2), 59.75 (CH), 44.11 (CH2), 13.97 (CH3). FTIR (neat) max: 3450 (N–H), 1735 (C=O), 1675 (C=O),
1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 337.1314, found 337.1333.
General procedure for the isolation of amides 12. A solution of benzaldehyde (0.1 mL, 1 mmol),
diethyl acetylenedicarboxylate (0.16 mL, 1 mmol), amine (2 mmol), phosphoric acid catalyst
δ 165.59 (Cquat), 163.59 (Cquat), 157.91 (Cquat),
ν
2
8
3
9
(34.8 mg, 0.1 mmol), and anhydrous MgSO4 was stirred in toluene (5 mL) at 110 ◦C for 48 h. The volatiles
were dried off at reduced pressure, and the crude residue was purified by column chromatography
(AcOEt/hexanes) to afford pure lactams 12.
5-oxo-2-phenyl-N,1-di-p-tolyl-4-(p-tolylamino)-2,5-dihydro-1H-pyrrole-3-carboxamide
The general procedure was followed, affording 0.02 g (4%) of 12a as a white solid. m.p. (Et2O)
226 ◦C (dec.). (300 MHz, CDCl3)
8.31 (bs, 1H, NH), 7.38–7.28 (m, 6H, 6 CHar), 7.11–7.04 (m, 7H,
CHar), 6.96 (d, 3JHH = 8.5 Hz, 2H, 2 CHar), 6.84 (d, 3JHH = 8.5 Hz, 2H, 2
CHar), 6.63 (bs, 1H,
NH), 5.85 (s, 1H, CHN), 2.28 (s, 3H,CH3), 2.25 (s, 3H, CH3), 2.24 (s, 3H, CH3). 13C {1H} NMR (75 MHz,
CDCl3) (75 MHz, CDCl3) 164.75 (C=O), 162.12 (C=O), 139.1 (=Cquat), 136.6 (Cquat), 136.1 (Cquat),
135.8 (Cquat), 134.8 (Cquat), 134.6 (Cquat), 133.9 (Cquat), 133.8 (Cquat), 129.7 (4
129.4 (2 CHar), 129.3 (CHar), 128.0 (2 CHar), 123.3 (2 CHar), 122.5 (2
(12a).
δ
×
7
×
×
×
δ
×
CHar), 129.5 (2
CHar), 119.8 (2
×
CHar),
CHar),
×
×
×
×
×
112.4 (=Cquat), 63.8 (CHN), 21.1 (CH3), 21.0 (CH3), 21.0 (CH3). FTIR (neat) νmax: 3309 (N–H), 3251
(N–H), 1685 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 487.22598, found
487.2255.
N,1-bis(4-methoxyphenyl)-4-((4-methoxyphenyl)amino)-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-
3-carboxamide (12b). The general procedure was followed, affording 0.07 g (13%) of 12b as a white
solid. m.p. (Et2O) 228–229 ◦C. 1H-NMR (400 MHz, CDCl3)
δ
8.46 (bs, 1H, NH), 7.37–7.28 (m, 5H, 5
×
CHar), 7.26–7.22 (m, 2H, 2
CHar), 6.82 (d, 3JHH = 8.9 Hz, 2H, 2
= 9.1 Hz, 2H, 2
3.72 (s, 3H, CH3). 13C {1H} NMR (101 MHz, CDCl3)
(Cquat), 156.5 (Cquat), 140.2 (=Cquat), 136.7 (Cquat), 131.6 (Cquat), 130.5 (Cquat), 129.5 (2
×
CHar), 7.17 (d, 3JHH = 8.8 Hz, 2H, 2
×
CHar), 6.90 (d, 3JHH = 9.1 Hz, 2H,
2
×
×
CHar), 6.78 (d, 3JHH = 9.1 Hz, 2H, 2
×
CHar), 6.71 (d, 3JHH
×
CHar), 6.56 (bs, 1H, NH), 5.76 (s, 1H, CHN), 3.74 (s, 3H, CH3), 3.73 (s, 3H, CH3),
164.6 (C=O), 162.4 (C=O), 157.8 (Cquat), 157.2
CHar), 129.3
CHar), 114.3 (2
CHar), 110.9 (=Cquat), 64.1 (CHN), 55.6 (CH3), 55.6 (CH3), 55.5 (CH3). FTIR (neat)
δ
×
(CHar), 128.0 (2
CHar), 114.1 (2
×
CHar), 125.4 (2
×
CHar), 124.5 (2
×
CHar), 121.5 (2
×
CHar), 114.3 (2
×
×
×
ν
max: 3344 (N–H), 3286 (N–H), 1662 (C=O), 1682 (C=O), 1632 (C=C). HRMS (Q-TOF) m/z calculated
for C27H26N2O3 [M]+ 535.2107, found 535.2105.

Molecules 2019, 24, 2951
9 of 11
Ethyl 4-amino-1-benzyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate (16). A mixture
of 10c (21.3 mg, 0.5 mmol), 10% palladium on carbon (276 mg, 0.025 mmol), and 37% HCl (0.05 mL,
0.5 mmol) in methanol (30 mL) was stirred for 10 h under hydrogen pressure at 70 psi. The reaction
mixture was filtered through Celite, and the filtered solution was treated with NaHCO3 until neutral
and extracted with dichloromethane (3
anhydrous MgSO4, and distilled off at reduced pressure; the residue was crystallized in Et2O/pentane
(1:2) to afford 0.163 g (97%) of 11c as a white solid. m.p. (Et2O) 139–142 ◦C. 1H-NMR (400 MHz, CDCl3)
×
15 mL). The combined organic fractions were dried with
δ
7.37–7.27 (m, 6H, 6
1H, CH2 Bn), 4.89 (s, 1H, CHN), 4.10–3.87 (m, 2H, CH2 OEt), 3.57 (d, 3JHH = 14.8 Hz, 1H, CH2 Bn),
1.05 (t, 3JHH = 7.1 Hz, 3H, CH3 OEt). 13C {1H} NMR (75 MHz, CDCl3)
165.5 (C=O ester), 165.0 (C=O
amide), 145.9 (=Cquat), 136.6 (Cquat), 136.6 (Cquat), 128.9 (2 CHar), 128.7 (2 CHar), 128.5 (2 CHar),
128.4 (CHar), 128.0 (2 CHar), 127.9 (CHar), 104.8 (=Cquat), 61.5 (CHN) , 59.8 (CH2 OEt), 44.2 (CH2
Bn), 14.2 (CH3 OEt). FTIR (neat) max: 3450 and 3319 (N–H2), 1685 (C=O), 1654 (C=O), 1643 (C=C).
HRMS (Q-TOF) m/z calculated for C27H26N2O3 [M]+ 336.1474, found 336.1476.
×
CHar), 7.18–7.05 (m, 4H, 4
×
CHar), 5.74 (bs, 2H, NH), 5.13 (d, 3JHH = 14.8 Hz,
δ
×
×
×
×
ν
Supplementary Materials: Copies of 1H- and 13C {1H} NMR spectra for
γ-lactams 10, 11, 12, and 16 are available
online. CCDC 1938640 contains the supplementary crystallographic data for this paper (compound 11a). The data
can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/structures
Author Contributions: Conceptualization, X.C., E.M.M, F.P. and J.V.; methodology, X.C.; software, X.C.; validation,
E.M.M and J.V.; formal analysis, X.C; investigation, X.C; resources, E.M.M., F.P. J.V.; data curation, X.C.;
writing—original draft preparation, J.V.; writing—review and editing, X.C, E.M.M., F.P., J.V.; visualization, E.M.M.,
F.P., J.V..; supervision, E.M.M. and J.V.; project administration, E.M.M. and J.V.; funding acquisition, F.P.
Funding: Financial support was provided by the Ministerio de Ciencia, Innovación, y Universidades
(RTI2018-101818-B-I00, MCIU/AEI/FEDER, UE), and Gobierno Vasco (GV, IT 992-16) is gratefully acknowledged.
X. del Corte thanks Gobierno Vasco for a predoctoral grant.
Acknowledgments: The authors thank the technical and human support provided by SGIker (UPV/EHU/
ERDF, EU).
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design of the
study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to
publish the results.
References
1.
Zhu, J.; Wang, Q.; Wang, M.-X. (Eds.) Multicomponent Reactions in Organic Synthesis; Wiley-VCH: Weinheim,
Germnay, 2015.
2.
3.
Müller, T.J. J in Science of Synthesis, Multicomponent Reactions, Vol 1 and 2; Thieme: Stutgart, Germnay, 2014.
Knapp, J.M.; Kurth, M.J.; Shaw, J.T.; Younai, A. Diversity-Oriented Synthesis; Trabocchi, A., Ed.; Willey: New
York, NY, USA, 2013; Volume 41, pp. 29–57.
4.
5.
6.
7.
8.
9.
Schreiber, S.L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 2000, 287,
1964–1969. [CrossRef] [PubMed]
de Moliner, F.; Kielland, N.; Lavilla, R.; Vendrell, M. Modern Synthetic Avenues for the Preparation of
Functional Fluorophores. Angew. Chem. Int. Ed. 2017, 56, 3758–3769. [CrossRef] [PubMed]
Hall, D.G.; Rybak, T.; Verdelet, T. Multicomponent Hetero-[4 + 2] Cycloaddition/Allylboration Reaction: From
Natural Product Synthesis to Drug Discovery. Acc. Chem. Res. 2016, 49, 2489–2500. [CrossRef] [PubMed]
Caruano, J.; Muccioli, G.G.; Robiette, R. Biologically active
γ-lactams: Synthesis and natural sources.
Org. Biomol. Chem. 2016, 14, 10134–10156. [CrossRef] [PubMed]
Martinez de Marigorta, E.; de los Santos, J.; Ochoa de Retana, A.M.; Vicario, J.; Palacios, F.
Multicomponent Reactions in the Synthesis of γ –Lactams. Synthesis 2018, 50, 4539–4554.
Martinez de Marigorta, E.; de los Santos, J.; Ochoa de Retana, A.M.; Vicario, J.; Palacios, F.
Multicomponent reactions (MCRs): A useful access to the synthesis of benzo-fused γ-lactams. Beilstein J.
Org. Chem. 2019, 150, 1065–1085. [CrossRef] [PubMed]
10. Kirpotina, L.N.; Schepetkin, I.A.; Khlebnikov, A.I.; Ruban, O.I.; Ge, Y.; Ye, R.D.; Kominsky, D.J.; Quinn, M.T.
4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-ones as N-formyl peptide receptor 1 (FPR1) antagonists.
Biochem. Pharmacol. 2017, 142, 120–132. [CrossRef]

Molecules 2019, 24, 2951
10 of 11
11. Ma, K.; Wang, P.; Fu, W.; Wan, X.; Zhou, L.; Chu, Y.; Ye, D. Rational design of 2-pyrrolinones as inhibitors of
HIV-1 integrase. Bioorg. Med. Chem. Lett. 2011, 21, 6724–6727. [CrossRef]
12. Zhuang, C.; Miao, Z.; Zhu, L.; Dong, G.; Guo, Z.; Wang, S.; Zhang, Y.; Wu, Y.; Yao, J.; Sheng, C.; et al.
Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors
of p53–MDM2 Protein–Protein Interaction. J. Med. Chem. 2012, 55, 9630–9642. [CrossRef]
13. Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.; Schaechtele, C.; Heidenreich, R.;
Roecken, M.; Schollmeyer, D.; Laufer, S. Design, Synthesis, and Biological Evaluation of Novel
3-Aryl-4-(1H-indole-3yl)-1,5-dihydro-2H-pyrrole-2-ones as Vascular Endothelial Growth Factor Receptor
(VEGF-R) Inhibitors. J. Med. Chem. 2008, 51, 3814–3824. [CrossRef]
14. Liu, Q.-J.; Wang, L.; Kang, Q.-K.; Zhang, X.P.; Tang, Y. Cy-SaBOX/Copper(II)-Catalyzed Highly Diastereo- and
Enantioselective Synthesis of Bicyclic N,O Acetals. Angew. Chem. Int. Ed. 2016, 55, 9220–9223. [CrossRef]
[PubMed]
15. Bures, J.; Armstrong, A.; Blackmond, D. Explaining Anomalies in Enamine Catalysis: “Downstream Species
as a New Paradigm for Stereocontrol G. Acc. Chem. Res. 2016, 49, 214–222. [CrossRef] [PubMed]
16. Khalaf, A.I.; Waigh, R.D.; Drummond, A.J.; Pringle, B.; McGroarty, I.; Skellern, G.G.; Suckling, C.J.
Distamycin Analogues with Enhanced Lipophilicity: Synthesis and Antimicrobial Activity. J. Med. Chem.
2004, 47, 2133–2156. [CrossRef] [PubMed]
17. Ye, Y.; Fang, F.; Li, Y. Synthesis and anti-biofilm activities of dihydro-pyrrol-2-one derivatives on Pseudomonas
aeruginosa. Bioorg. Med. Chem. Lett. 2015, 25, 597–601. [CrossRef] [PubMed]
18. Zhu, Q.; Gao, L.; Chen, Z.; Zheng, S.; Shu, H.; Li, J.; Jiang, H.; Liu, S. A novel class of small-molecule
caspase-3 inhibitors prepared by multicomponent reactions. Eur. J. Med. Chem. 2012, 54, 232–238. [CrossRef]
[PubMed]
19. Gein, V.L.;
biological
Popov, A.V.;
activity of
Kolla, V.E.;
Popova, N.A.;
Potemkin, K.D. Synthesis and
and
1,5-diaryl-3-arylamino-4-carboxymethyl-2,5-dihydro-2-pyrrolones
1,5-diaryl-4-carboxymethyltetrahydropyrrole-2, 3-diones. Pharm. Chem. J. 1993, 27, 343–346. [CrossRef]
20. Gein, V.L.;
activity
Popov, A.V.;
Kolla, V.E.;
Popova, N.A. Synthesis and biological
and
of
1,5-diaryl-3-alkylamino-4-carboxymethyl-2,5-dihydropyrrol-2-ones
1,5-diaryl-4-carboxymethyl-tetrahydropyrrol-2,3-diones. Pharmazie 1993, 8, 107–109.
21. Li, B.; Wever, W.J.; Walsh, C.T.; Bowers, A.A. Dithiolopyrrolones: Biosynthesis, synthesis, and activity of a
unique class of disulfide-containing antibiotics. Nat. Prod. Rep. 2014, 31, 905–923. [CrossRef] [PubMed]
22. Rigby, J.H.; Hughes, R.C.; Heeg, M.J.J. Endo-Selective Cyclization Pathways in the Intramolecular Heck
Reaction. Am. Chem. Soc. 1995, 117, 7834–7835. [CrossRef]
23. Lewis, J.R. Amaryllidaceae and Sceletium alkaloids. Nat. Prod. Rep. 1994, 11, 329–332. [CrossRef]
24. Palacios, F.; Vicario, J.; Aparicio, D. An efficient synthesis of achiral and chiral cyclic dehydro-
α
-amino acid
derivatives through nucleophilic addition of Amines to β,γ-unsaturated α-keto esters. Eur. J. Org. Chem.
2006, 2843–2850. [CrossRef]
25. Shaterian, H.R.; Ranjbar, M. Uncatalyzed synthesis of 3-amino-1,5-dihydro-2H-pyrrol-2-ones.
Res. Chem. Intermed. 2014, 40, 2059–2074. [CrossRef]
26. Niknam, K.; Mojikhalifeh, S. Synthesis of new 1,5-diaryl-3-(arylamino)-1H-pyrrol-2(5H)-ones under
catalyst-free and solvent-free conditions. Mol. Diver. 2014, 18, 111–117. [CrossRef] [PubMed]
27. Quian, J.; Yi, W.; Cai, C. Recyclable fluorous organocatalysts promoted three-component reactions of pyruvate,
aldehyde and amine at room temperature. Tetrahedron Lett. 2013, 54, 7100–7102. [CrossRef]
28. Li, X.; Deng, H.; Luo, S.; Cheng, J.-P. Organocatalytic Three-Component Reactions of Pyruvate, Aldehyde
and Aniline by Hydrogen-Bonding Catalysts. Eur. J. Org. Chem. 2008, 4350–4356. [CrossRef]
29. del Corte, X.; Maestro, A.; Vicario, J.; Martinez de Marigorta, E.; Palacios, F. Brönsted-Acid-Catalyzed
Asymmetric Three-Component Reaction of Amines, Aldehydes, and Pyruvate Derivatives.
Enantioselective Synthesis of Highly Functionalized
[CrossRef] [PubMed]
γ-Lactam Derivatives. Org. Lett. 2018, 20, 317–320.
30. Gao, H.; Sun, J.; Yan, C.-G. Synthesis of functionalized 2-pyrrolidinones via domino reactions of arylamines,
ethyl glyoxylate and acetylenedicarboxylates. Tetrahedron 2013, 69, 589–594. [CrossRef]
31. Khan, A.T.; Gosh, A.; Khan, M.M. One-pot four-component domino reaction for the synthesis of substituted
dihydro-2-oxypyrrole catalyzed by molecular iodine. Tetrahedron Lett. 2012, 53, 2622–2626. [CrossRef]

Molecules 2019, 24, 2951
11 of 11
32. Saha, M.; Das, A.R. Access of Diverse 2-Pyrrolidinone, 3,4,5-Substituted Furanone and 2-Oxo-dihydropyrroles
Applying Graphene Oxide Nanosheet: Unraveling of Solvent Selectivity. ChemistrySelect 2017, 2, 10249–10260.
[CrossRef]
33. Palacios, F.; Aparicio, D.; García, J.; Vicario, J.; Ezpeleta, J.M. Regioselective alkylation reactions of enamines
derived from phosphane oxides - Synthesis of phosphorus substituted enamino esters, δ-amino-phosphonates,
pyridone derivatives and pyrroles. Eur. J. Org. Chem. 2001, 3357–3365. [CrossRef]
34. Palacios, F.; Aparicio, D.; Vicario, J. Synthesis of quinolinylphosphane oxides and -phosphonates from
N-arylimines derived from phosphane oxides and phosphonates. Eur. J. Org. Chem. 2002, 4131–4136.
35. Palacios, F.; Vicario, J.; Aparicio, D. Aza-Diels-Alder reaction of α,β-unsaturated sulfinylimines derived from
α-amino acids with enolethers and enamines. Tetrahedron Lett. 2007, 48, 6747–6750. [CrossRef]
36. Palacios, F.; Vicario, J.; Aparicio, D. A diastereoselective aza-Diels-Alder reaction of N-aryl-1-azadienes
derived from α-amino acids with enamines. Tetrahedron Lett. 2011, 52, 4109–4111.
37. Palacios, F.; Vicario, J.; Aparicio, D. Efficient synthesis of 1-azadienes derived from
Regioselective preparation of -dehydroamino acids, vinylglycines, and -amino acids. J. Org. Chem.
2006, 71, 7690–7696. [CrossRef] [PubMed]
38. Vicario, J.; Ortiz, P.; Ezpeleta, J.M.; Palacios, F. Asymmetric Synthesis of Functionalized Tetrasubstituted
-Aminophosphonates through Enantioselective Aza-Henry Reaction of Phosphorylated Ketimines.
α-aminoesters.
α
α
α
J. Org. Chem. 2015, 80, 156–164. [CrossRef] [PubMed]
39. Vicario, J.; Ezpeleta, J.M.; Palacios, F. Asymmetric Cyanation of
α
-Ketiminophosphonates Catalyzed by
-Aminophosphonic Acid Derivatives
Cinchona Alkaloids: Enantioselective Synthesis of Tetrasubstituted
α
from Trisubstituted α-Aminophosphonates. Adv. Synth. & Catal. 2012, 354, 2641–2647.
40. Maestro, A.; Martinez de Marigorta, E.; Palacios, F.; Vicario, J. Enantioselective alpha-Aminophosphonate
Functionalization of Indole Ring through an Organocatalyzed Friedel-Crafts Reaction. J. Org. Chem. 2019
84, 1094–1102. [CrossRef] [PubMed]
,
41. Metten, B.; Kostermans, M.; Van Baelen, G.; Smet, M.; Dehaen, W. Synthesis of 5-aryl-2-oxopyrrole derivatives
as synthons for highly substituted pyrroles. Tetrahedron 2006, 62, 6018. [CrossRef]
42. Winstein-Holnes values: ABn = 1.68 kcal.mol-1 and APh = 2.80 kcal.mol-1. In Stereochemistry of Organic
Compounds; Eliel, E.L.; Wilen, S.H.; Mander, L.N. (Eds.) Wiley: New York, NY, USA, 1994.
43.
Ávila, E.P.; Justo, R.M.S.; Gonçalves, V.P.; Pereira, A.A.; Diniz, R.; Amarante, G.W. Chiral Brønsted
Acid-Catalyzed Stereoselective Mannich-Type Reaction of Azlactones with Aldimines. J. Org. Chem. 2015
,
80, 590–594. [CrossRef] [PubMed]
44. Shaoa, Y.-D.; Chengb, D.-J. Catalytic Asymmetric 1,2-Difunctionalization of Indolenines with
α-(Benzothiazol-2-ylsulfonyl) Carbonyl Compounds. Adv. Synth. Catal. 2017, 359, 2549–2556. [CrossRef]
45. Huang, Q.; Cheng, Y.; Yuan, H.; Chang, X.; Li, P.; Li, W. Organocatalytic enantioselective Mannich-type
addition of 5H-thiazol-4-ones to isatin-derived imines: Access to 3-substituted 3-amino-2-oxindoles featured
by vicinal sulfur-containing tetrasubstituted stereocenters. Org. Chem. Front. 2018, 5, 3226–3230. [CrossRef]
46. Sheldrick, G.M. A short history of SHELX. Acta Cryst. 2008, A64, 112–122. [CrossRef] [PubMed]
47. Sheldrick, G.M. Crystal Structure Refinement with SHELXL. Acta Cryst. 2015, C71, 3–8.
48. Macrae, C.F.; Bruno, I.J.; Chisholm, J.A.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.;
Taylor, R.; van de Streek, J.; Wood, P.A. Mercury CSD 2.0 – new features for the visualization and investigation
of crystal structures. J. Appl. Cryst. 2008, 41, 466–470. [CrossRef]
49. Spek, A.L. PLATON, A Multipurpose Crystallographic Tool; Utrecht University: Utrecht, The Netherlands, 2010.
50. Spek, A.L. Single-crystal structure validation with the program. PLATON J. Appl. Cryst. 2003, 36, 7–13.
[CrossRef]
51. Farrugia, L.J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Cryst. 1999, 32, 837–838.
[CrossRef]
Sample Availability: Samples of the compounds 10, 11, 12, and 16 are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).