First mechanosynthesis of piperlotines A, C, and derivatives through solvent-free Horner–Wadsworth–Emmons reaction

Article abstract of DOI:10.1080/00397911.2018.1550204

Piperlotines are natural products characterized by an α,β-unsaturated amide moiety. These compounds found wide applications in Medicinal Chemistry like antibacterials, cytotoxic agents, anticoagulants, among others. To date, diverse methods of synthesis have been reported for piperlotines, but involving the use of catalysts, hazard reagents, anhydrous media or coupling reagents. Thus, in this work, we developed a greener method of synthesis of piperlotines A, C, and derivatives, through mechanochemical activation under solvent-free conditions. The reaction of a β-amidophosphonate, K₂CO₃, and an aromatic aldehyde afforded target compounds in moderate to good yields (46–77%), in an open atmosphere by grinding. It is worth to mention that this mechanochemical process was under thermodynamic control because just E isomer was isolated for every reaction. Moreover, synthesized piperlotines have been predicted by means of chemoinformatic analysis as potential therapeutic agents for the treatment of arthritis or cancer.

Full text of DOI:10.1080/00397911.2018.1550204

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
First mechanosynthesis of piperlotines A,
C, and derivatives through solvent-free
Horner–Wadsworth–Emmons reaction
Oscar Abelardo Ramírez-Marroquín, Flavio Manzano-Pérez, Adolfo López-
Torres, Alejandro Hernández-López, Abimelek Cortés-Pacheco & Miguel
Angel Reyes-González
To cite this article: Oscar Abelardo Ramírez-Marroquín, Flavio Manzano-Pérez, Adolfo
López-Torres, Alejandro Hernández-López, Abimelek Cortés-Pacheco & Miguel Angel
Reyes-González (2019): First mechanosynthesis of piperlotines A, C, and derivatives
through solvent-free Horner–Wadsworth–Emmons reaction, Synthetic Communications, DOI:
10.1080/00397911.2018.1550204
To link to this article: https://doi.org/10.1080/00397911.2018.1550204
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https://doi.org/10.1080/00397911.2018.1550204
First mechanosynthesis of piperlotines A, C, and derivatives
through solvent-free Horner–Wadsworth–Emmons reaction
a
a
ꢀ
ꢀ
ꢀ
, Flavio Manzano-Perez ,
Oscar Abelardo Ramırez-Marroquın
a
b
a
ꢀ
ꢀ
ꢀ
ꢀ
Adolfo Lopez-Torres , Alejandro Hernandez-Lopez , Abimelek Cortes-Pacheco ,
c
ꢀ
and Miguel Angel Reyes-Gonzalez
a
b
ꢀ
Instituto de Quımica Aplicada, Universidad del Papaloapan, Tuxtepec, Mexico; Instituto de
c
ꢀ
ꢀ
Biotecnologıa, Universidad del Papaloapan, Tuxtepec, Mexico; Facultad de Ciencias Quımicas,
Universidad Autonoma de Nuevo Leon, San Nicolas de los Garza Nuevo Leon, Mexico
ꢀ
ꢀ
ꢀ
ꢀ
ABSTRACT
ARTICLE HISTORY
Received 31 October 2018
Piperlotines are natural products characterized by an a,b-unsaturated
amide moiety. These compounds found wide applications in
Medicinal Chemistry like antibacterials, cytotoxic agents, anticoagu-
lants, among others. To date, diverse methods of synthesis have
been reported for piperlotines, but involving the use of catalysts,
hazard reagents, anhydrous media or coupling reagents. Thus, in this
work, we developed a greener method of synthesis of piperlotines A,
C, and derivatives, through mechanochemical activation under solv-
ent-free conditions. The reaction of a b-amidophosphonate, K2CO3,
and an aromatic aldehyde afforded target compounds in moderate
to good yields (46–77%), in an open atmosphere by grinding. It is
worth to mention that this mechanochemical process was under
thermodynamic control because just E isomer was isolated for every
reaction. Moreover, synthesized piperlotines have been predicted by
means of chemoinformatic analysis as potential therapeutic agents
for the treatment of arthritis or cancer.
KEYWORDS
Green chemistry;
mechanochemistry;
Horner–Wadsworth–Emmo-
ns reaction; Piper
genus; arthritis
GRAPHICAL ABSTRACT
Introduction
Piperlotines are secondary metabolites isolated from Piper genus plants[1]. An example
of this is black pepper (Piper nigrum), that has very important applications in medicinal
chemistry like antibacterial[2–4], antiplatelet aggregation[5–7], cytotoxic[8–10], and biopesti-
cide activities[11]. Despite its broad pharmacological application, the most of studies on
ꢀ
ꢀ
ꢀ
Instituto de Quımica Aplicada, Universidad
CONTACT Oscar Abelardo Ramırez-Marroquın
oramirez@unpa.edu.mx
del Papaloapan, Tuxtepec 68301, Mexico.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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O. ABELARDO RAMIREZ-MARROQUIN ET AL.
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Figure 1. Some natural a,b-unsaturated amides present in Piper genus plants.
Piper species have been done using extracts or fractions from plants, instead of pure
compounds[12, 13]. Therefore, the structure-activity relationships are unknown or incom-
plete in most of cases.
Nonetheless, piperlotine A, piperlotine C, piperlotine D, and piperiline among others,
have been isolated from Piper genus species (Figure 1).
These natural products are characterized by an a,b-unsaturated amide moiety and
have been synthesized through solution-phase Horner–Wadsworth–Emmons (HWE)
reaction[14], catalyzed aminocarbonylation of alkynes[15], transamidation reaction[16]
,
amidation from cinnamic acids[17–21], in addition to others[22] (Scheme 1). In this
respect, to the best of our knowledge, piperlotines have not been prepared by means of
mechanochemical HWE reaction.
Mechanosynthesis is a greener approach to prepare a broad range of organic com-
pounds including drugs, secondary metabolites, catalysts, fine chemicals, etc., and it has
been gaining attention because of its interesting advantages over solution-phase synthe-
sis: solvents could be avoided, mechanochemical processes lower reaction times and
sometimes change selectivity[23, 24]. To the best of our knowledge, there are just few
reports on mechanochemical Wittig reaction[25–27] (limited to the synthesis of stilbenes)
and a smaller amount on mechanochemical HWE reactions[28, 29] limited to the synthe-
sis of a,b-unsaturated esters. In view of all above mentioned, in this work, we report
the first mechanosynthesis of piperlotines A, C, and derivatives through an operationally
simple and stereoselective HWE reaction, under solvent-free conditions by grinding
(Scheme 1).
Results and discussion
Synthesis
The key step in the synthesis of piperlotines is the stereoselective formation of alkene
group. Therefore, we envisaged the synthesis of target compounds 3a–i trough the
HWE reaction of an aromatic aldehyde and key b-amidophosphonate 2 under thermo-
dynamic control, by means of a highly stabilized carbanion. Phosphonate 2 could be

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Scheme 1. Syntheses of piperlotines previously reported and our green HWE approach.
easily prepared from N-(bromoacetyl)pyrrolidine 1 and triethyl phosphite through
Michaelis-Arbuzov reaction.
Hence, the reaction of pyrrolidine and bromoacetyl bromide provided N-(bromoace-
tyl)pyrrolidine 1 in 89% yield, without chromatographic purification. Next, treatment of
1 with triethyl phosphite under solvent-free conditions afforded key b-amidophospho-
nate 2 in 97% yield (Scheme 2).
Then, we carried out HWE process starting from classical reaction conditions: the
mixture of 2, NaH and p-anisaldehyde in anhydrous THF at 0 ꢀC afforded Piperlotine
A 3a in 53% yield; but just trace amount of product 3 h was obtained when using
p-nitrobenzaldehyde, observing a complex reaction mixture (Scheme 3).
Because of lack of selectivity, in addition to previous reports of HWE reactions in
non-anhydrous media using mild bases[30], we changed reaction conditions. This time,
the use of K2CO3 as base in reflux of CH3CN afforded desired a,b-unsaturated amides
3a–i in moderate to good yields (39–92%) and just E isomer was isolated in every reac-
tion (Table 1). It is worth to mention that E configuration prevails in the most of bio-
logically active a,b-unsaturated amides of Piper species[1]. Additionally, to the best of
our knowledge, derivative 3e has not been previously reported in the literature.

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O. ABELARDO RAMIREZ-MARROQUIN ET AL.
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Scheme 2. Synthesis of key intermediate 2.
Scheme 3. Classical HWE conditions for the synthesis of 3a and 3h.
Table 1. Synthesis of 3a–i trough solution-phase HWE reaction.
Entry
Product
Yield/%
1
2
3
4
5
6
7
8
9
9
3a, Ar ¼ 4-MeOC6H4
3b, Ar ¼ 3,5-(MeO)2C6H3
3c, Ar ¼ 3,4,5-(MeO)3C6H2
3d, Ar ¼ 4-(Me)2NC6H4
3e, Ar ¼ 4-MeSC6H4
3f, Ar ¼ cinnamoyl
3g, Ar ¼ 4-ClC6H4
60
77
56
49
46
61
39
92
70
70
3h, Ar ¼ 4-O2NC6H4
3i, Ar ¼ 4-F3CC6H4
3i, Ar ¼ 4-F3CC6H4
1
Configuration of obtained alkenes was unambiguously assigned through H NMR spec-
3
trometry; specifically in order to JH-H vinylic coupling constant of ꢁ15 Hz.
Encouraged with these results and according to preliminary observations (HWE reac-
tion of 2, an aldehyde and K2CO3 in CH3CN proceeded at room temperature), we
decided to carry out this HWE process at room temperature and avoiding CH3CN, a
carcinogenic solvent. In consequence, the reaction of b-amidophosphonate 2, K2CO3
and an aromatic aldehyde (solid or liquid) in absence of solvent was carried out in a
mortar and pestle by grinding, affording target products 3a–i in moderate to good
yields (46–77%). Astonishingly, shorter reaction times than reflux conditions were
observed (40–120 min vs. 4–6 h, respectively); thus, grinding process accelerated forma-
tion of desired compounds (Scheme 4).
In this context, it is important to mention that previously reported mechanochemical
HWE processes required 2–7 h in a ball mill to obtain desired products and use of solv-
ent or a resin[28, 29]. Under our solvent-free conditions, just E isomer was isolated in

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Scheme 4. Synthesis of 3a–i trough mechanochemical HWE reaction.
Figure 2. Resonance stabilization of carbanion 2.
every reaction, despite temperature change from previous reflux conditions. We suggest
that reaction is under thermodynamic control due to the high stability of b-amido-
phosphonate carbanion which is stabilized by resonance. Evidence in this respect is that
all mechanochemical HWE reactions were carried out under open atmosphere with a
relative humidity >50%, suggesting significant stability of carbanion 2 (Figure 2).
Among studied reactions, only compound 3d could not be obtained by grinding
(90% aldehyde was recovered). To date, we can preliminary argument electrodonating
effect of dimethylamino substituent is decreasing the reactivity of aldehyde, but further
research is needed to have a clear explanation.
Design and prediction of biological activity
In other instance, as part of our ongoing interest in developing anti-inflammatory
agents[31], we started from piperine, which is contained in black pepper and has been
recognized by its anti-inflammatory activity[32, 33]. Synthesized compounds 3a–i are
structurally related with piperine. Both are characterized by
a
conjugated
a,b-unsaturated amide with a substituted benzene ring (Figure 3).

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O. ABELARDO RAMIREZ-MARROQUIN ET AL.
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Figure 3. Rational design of novel anti-inflammatory agents.
Table 2. Prediction of pharmacological activity of products 3a–i.
Product
Activity
Paa:Pib
3a
3b
3c
3d
3e
3f
3g
3h
3i
MMP9 expression inhibitor
MMP9 expression inhibitor
MMP9 expression inhibitor
MMP9 expression inhibitor
Other activities
MMP9 expression inhibitor
Other activities
0.805 : 0.003
0.820 : 0.003
0.791 : 0.003
0.650 : 0.011
–
0.823 : 0.003
–
0.592 : 0.016
0.617 : 0.014
MMP9 expression inhibitor
MMP9 expression inhibitor
aPa: Probability to be active.
bPi: probability to be inactive.
Prediction values are normalized to 1 (being 1 the maximal probability to be active/inactive).
In addition to the structural relationship between piperine and 3a–i, these com-
pounds were predicted as matrix metalloproteinase-9 (MMP-9) expression inhibitors,
according to Prediction of Activity Spectra for Substances (PASS Online) database[34]
(Table 2). PASS Online predicts more than 7000 types of biological activity with an
average accuracy >95%[35] and has been used successfully to predict in vitro and in vivo
diverse pharmacological activities of new compounds[36–38]. It is known that MMP-9 is
mainly expressed in inflammatory cells during diseases as rheumatoid arthritis and can-
cer[39]. Furthermore, other studies demonstrated a relationship between high circulating
MMP-9 in those patients with osteoporosis[40]. In this respect, we considered synthe-
sized compounds 3a–i as potential therapeutic agents for treatment of rheumatoid arth-
ritis or cancer. Moreover, all synthesized amides 3a–i agreed with Lipinski’s rules, thus
would have good absorption (by passive diffusion) in biologic systems due to their
appropriate lipophilicity, molecular weight, and hydrogen-bonding capacity[41]
.
Consequently, compounds 3a–i emerged as promising bioactive compounds for the
treatment of some important diseases as arthritis or cancer. Lastly, all above discussed
opens an opportunity to scale HWE reaction of b-amidophosphonate 2 and aromatic
aldehydes under ball milling conditions in search of better yields and even shorter reac-
tion times for obtaining such valuable natural products and derivatives.

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Conclusions
In this work, we developed a practical and operationally simple method of mechanosyn-
thesis of natural products: Piperlotine A 3a, 3b, Piperlotine C 3c, and derivatives, which
have proved its pharmacological value in previous reports. The synthesis of compounds
3a–i was carried out through the HWE reaction as key step of synthesis under solvent-
free conditions and in an open atmosphere, yielding desired products in moderate to
good yields with short reaction times as compared with those reported. In this respect,
it is important to mention that reported yields were the best obtained under manual
grinding reactions. These yields correlated better with applied pressure than grinding
speed or reaction time. It is needed a study of this HWE process under controlled con-
ditions (i.e., in a ball mill) to ensure a better reproducibility.
In other instance, we did not need to use solvents or resins as in previous works.
Also, it is important to mention that this method tolerated well the introduction of elec-
trowithdrawing groups, electrodonating groups, and unsaturations in the utilized alde-
hydes, both in solid or liquid state. Additionally, our mechanochemical HWE reaction
afforded stereoselectively E isomer in shorter reaction times than solution-phase process.
It is worth to mentioning that an in-depth mechanochemical study of the synthesis of
biologically relevant a,b-unsaturated amides (including synthesized products 3a–i) and
its pharmacological applications are under current research and will be pub-
lished elsewhere.
Experimental
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All commercial materials were used as received from Sigma-AldrichV without further
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purification. Flash chromatography was performed using 230–400 mesh Silica Flash 60V
silica gel. Thin layer chromatography was performed with pre-coated TLC sheets of sil-
ica gel (60F254, Merck). NMR spectra were recorded in a Varian System instrument
1
(400 MHz for H, 100 MHz for 13C, and 161.9 MHz for 31P) and calibrated with CDCl3
as the solvent and TMS as the internal standard signal. Chemical shifts (d) are reported
in parts per million. Multiplicities are recorded like: s ¼ singlet, d ¼ doublet, t ¼ triplet,
dd ¼ doublet of doublets, td ¼ triplet of doublets, bs ¼ broad singlet, q ¼ quartet, and
m ¼ multiplet. Coupling constants (J) are given in Hz. High resolution mass spectra
(HRMS) were obtained by direct infusion in a Synapt G2-Si Q-TOF system (Waters)
equipped with an electrospray (ESI) probe, and the following conditions were used:
flow rate, 10 lL/min; ionization mode, positive; capillary voltage, 3000 V; cone voltage,
40 V; capillary temperature, 100 ꢀC; desolvation temperature, 200 ꢀC; desolvation gas
flow, 800 L/h, cone gas, 50 L/h; Nebulizer pressure; 6 Bar. Data were acquired in the MS
Full Scan mode and centroid mode. Spectra were corrected infusing simultaneously the
lockmass Leucine Enkephaline (556.2771). Data analysis was conducted using MassLynx
software version 4.1 (Waters).
Synthesis of N-(bromoacetyl)pyrrolidine (1)
To an ice bath, cooled solution of bromoacetyl bromide (1.2 mL, 2.78 g, 13.78 mmol) in
20 cm3 of CH2Cl2 was added dropwise via addition funnel a solution of pyrrolidine

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O. ABELARDO RAMIREZ-MARROQUIN ET AL.
8
(2.4 mL, 2.4 g, 28.75 mmol) in 30 cm3 of CH2Cl2, and the reaction mixture was stirred
overnight. Then, reaction mixture was quenched by the addition of 20 cm3of distilled
water and extracted with CH2Cl2 (3 ꢂ 20 cm3). Then, 30 cm3 of HCl 2.0 N was added to
the combined organic extracts. After partition, the final organic extract was dried over
Na2SO4, filtered, and evaporated under reduced pressure, yielding 2.416 g (92%) of a
1
white solid that melts at room temperature. H NMR (400 MHz, CDCl3): d ¼ 1.87–1.94
(m, 2H, CH2), 1.98–2.05 (m, 2H, CH2), 3.50 (t, J ¼ 6.9 Hz, 2H, CH2N), 3.54 (t,
J ¼ 6.8 Hz, 2H, CH2N), 3.82 (AB system, J ¼ 20.0 Hz, 2H, CH2Br) ppm; 13C NMR
(100 MHz, CDCl3) d ¼ 24.31 (CH2), 26.15 (CH2), 27.39 (CH2Br), 46.43 (CH2N), 47.06
(CH2N), 165.07 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C6H11BrNO
[M þ H] þ 192.0024, found 192.0095.
Synthesis of diethyl (2-oxo-2-(pyrrolidin-1-yl)ethyl)phosphonate (2, C10H20NO4P)
A mixture of 298 mg (1.55 mmol) of 1 and 543 mg (3.27 mmol) of triethyl phosphite
was stirred at 60 ꢀC for 4.5 h. Then, crude product was purified using flash chromatog-
raphy AcoEt:MeOH (90:10), yielding 377 mg (97%) of a pale yellow oil. 1H NMR
(400 MHz, CDCl3): d ¼ 1.34 (t, J ¼ 7.1 Hz, 6 H, CH3), 1.83–2.01 (m, 4 H, CH2–CH2),
3.01 (d, J ¼ 22.1 Hz, 2H, CH2P), 3.49 (td, J ¼ 6.9, 2.0 Hz, 2H, CH2N), 3.60 (t, J ¼ 6.8 Hz,
2H, CH2N), 4.11–4.26 (m, 4 H, (CH2O)2P) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 16.28
(d, J ¼ 6.4 Hz, CH3), 24.47, 25.99, 34.64 (d, J ¼ 133.6 Hz, CH2P), 47.00, 47.59, 62.63 (d,
J ¼ 6.4 Hz), 163.16 (d, J ¼ 5.7 Hz, C ¼ O) ppm; 31P NMR (161.9 MHz, CDCl3): d
22.01 ppm; HRMS [ESI]: m/z calculated for C10H21NO4P [M þ H]þ 250.1208,
found 250.1214.
General procedure for the synthesis of a,b-unsaturated amides 3a–i
Method A: A mixture of b-amidophosphonate 2 (1.0 equiv), K2CO3 (1.5 equiv) and the
corresponding aldehyde (1.1 equiv) was refluxed in 5 cm3 CH3CN during 4–6 h. After
this time, reaction mixture was filtered, eliminating excess of K2CO3, then concentrated
under reduced pressure and finally, crude product was purified using flash column
chromatography AcOEt 100%, yielding corresponding products 3a–i.
Method B: A mixture of b-amidophosphonate 2 (1.0 equiv), K2CO3 (1.5 equiv) and
the corresponding aldehyde (1.1 equiv) was grinded homogenously for 40–120 min in
periods of 10 min in a porcelain mortar and pestle. It was observed an optimum grind-
ing speed of 100 compressions/min. Then, reaction mixture was suspended in a min-
imum of CH2Cl2, filtered and concentrated under reduced pressure. The crude product
was purified using flash column chromatography AcOEt 100%, obtaining corresponding
compounds 3a–i.
(E)-3-(4-methoxyphenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (3a)
1
Yield: 67 mg (59%) as a white solid; m.p.: 115.8–116.1 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.86–1.93 (m, 2H, CH2–CH2), 1.97–2.03 (m, 2H, CH2–CH2), 3.59 (t, J ¼ 6.1 Hz, 2H,
CH2N), 3.62 (t, J ¼ 6.0 Hz, 2H, CH2N), 3.83 (s, 3 H, CH3O), 6.60 (d, J ¼ 15.5 Hz, 1 H,

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CH), 6.89 (AA’ BB’ system, J ¼ 8.8 Hz, 2H, Harom), 7.48 (AA’ BB’ system, J ¼ 8.7 Hz,
2H, Harom), 7.66 (d, J ¼ 15.5 Hz, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 24.55
(CH2–CH2), 26.33 (CH2–CH2), 46.18 (CH2N), 46.72 (CH2N), 55.52 (OCH3), 114.35,
116.65, 128.26, 129.54, 141.46, 160.94, 165.21 (C ¼ O) ppm; HRMS [ESI]: m/z calculated
for C14H18NO2 [M þ H]þ 232.1338, found 232.1335.
(E)-3-(3,5-dimethoxyphenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (3b)
1
Yield: 123 mg (77%) as a white solid; m.p.: 117.1–117.9 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.87–1.94 (m, 2H, CH2–CH2), 1.97–2.04 (m, 2H, CH2–CH2), 3.61 (dt, J ¼ 13.7,
6.8 Hz, 4 H, CH2N), 3.81 (bs, 6 H, CH3O), 6.46 (t, J ¼ 2. 2H z, 1 H, Harom), 6.67 (d,
J ¼ 2.4 Hz, 2H, Harom), 6.69 (d, J ¼ 15.7 Hz, 1 H, CH), 7.61 (d, J ¼ 15.4 Hz, 1 H, CH)
ppm; 13C NMR (100 MHz, CDCl3) d ¼ 24.53 (CH2–CH2), 26.33 (CH2–CH2), 46.26
(CH2N), 46.79 (CH2N), 55.60 (OCH3), 101.74, 106.06, 119.58, 137.48, 141.84, 161.13,
164.76 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C15H20NO3 [M þ H]þ 262.1443,
found 262.1439.
(E)-1-(pyrrolidin-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (3c)
1
Yield: 89 mg (48%) as a white solid; m.p.: 156.3–157.4 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.88–1.95 (m, 2H, CH2–CH2), 1.99–2.05 (m, 2H, CH2–CH2), 3.60 (t, J ¼ 6.9 Hz, 2H,
CH2N), 3.65 (t, J ¼ 6.8 Hz, 2H, CH2N), 3.87 (bs, 3 H, OCH3), 3.90 (bs, 3 H, OCH3), 6.62
(d, J ¼ 15.4 Hz, 1 H, CH), 6.75 (bs, 2H, Harom), 7.62 (d, J ¼ 15.4 Hz, 1 H, CH) ppm; 13C
NMR (100 MHz, CDCl3) d ¼ 24.53 (CH2–CH2), 26.32 (CH2–CH2), 46.26 (CH2N), 46.81
(CH2N), 56.37 (OCH3), 61.12 (OCH3), 105.25, 118.25, 131.09, 139.71, 141.96, 153.55,
164.83 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C16H22NO4 [M þ H]þ 292.1549,
found 292.1544
(E)-3-(4-(dimethylamino)phenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (3d)
1
Yield: 96 mg (49%) as a pale yellow solid (reflux conditions); m.p.: 151.9–152.9 ꢀC; H
NMR (400 MHz, CDCl3): d ¼ 1.85–1.92 (m, 2H, CH2–CH2), 1.96–2.02 (m, 2H,
CH2–CH2), 3.00 (s, 6 H, (CH3)2N), 3.58 (t, J ¼ 5.5 Hz, 2H, CH2N), 3.62 (t, J ¼ 5.5 Hz,
2H, CH2N), 6.52 (d, J ¼ 15.4 Hz, 1 H, CH), 6.67 (AA’ BB’ system, J ¼ 8.9 Hz, 2H,
H
arom), 7.43 (AA’ BB’ system, J ¼ 8.9 Hz, 2H, Harom), 7.64 (d, J ¼ 15.4 Hz, 1 H, CH)
ppm; 13C NMR (100 MHz, CDCl3) d ¼ 24.59 (CH2–CH2), 26.34 (CH2–CH2), 40.39
((CH3)2N), 46.13 (CH2N), 46.68 (CH2N), 112.06, 113.79, 123.45, 129.51, 142.24, 151.47,
165.79 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C15H21N2O [M þ H]þ 245.1654,
found 245.1651.
(E)-3-(4-(methylthio)phenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (3e, C14H17NOS)
1
Yield: 88 mg (57%) as a white solid; m.p.: 102.2–102.9 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.86–1.93 (m, 2H, CH2–CH2), 1.97–2.04 (m, 2H, CH2–CH2), 2.50 (s, 3 H, SCH3),
3.61 (dt, J ¼ 13.4, 6.8 Hz, 4 H, CH2N), 6.68 (d, J ¼ 15.5 Hz, 1 H, CH), 7.22 (AA’ BB’

ꢀ ꢀ
O. ABELARDO RAMIREZ-MARROQUIN ET AL.
10
system, J ¼ 8.4 Hz, 2H, Harom), 7.45 (AA’ BB’ system, J ¼ 8.6 Hz, 2H, Harom), 7.65 (d,
J ¼ 15.5 Hz, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 15.53 (SCH3), 24.54
(CH2–CH2), 26.34 (CH2–CH2), 46.24 (CH2N), 46.76 (CH2N), 118.08, 126.31, 128.39,
132.16, 140.89, 141.25, 164.95 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for
C14H18NOS [M þ H]þ 248.1109, found 248.1107.
(2E,4E)-5-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3f)
1
Yield: 63 mg (46%) as a white solid; m.p.: 122.5–123.7 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.85–1.92 (m, 2H, CH2–CH2), 1.95–2.02 (m, 2H, CH2–CH2), 3.56 (td, J ¼ 6.8,
3.3 Hz, 4 H, CH2N), 6.31 (d, J ¼ 14.7 Hz, 1 H, CH), 6.84–6.95 (m, 2H), 7.26–7.36 (m,
3H), 7.44–7.50 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 24.53 (CH2–CH2), 26.31
(CH2–CH2), 46.13 (CH2N)), 46.68 (CH2N), 122.36, 127.02, 127.13, 128.78, 128.90,
136.57, 139.14, 141.83, 165.01 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C15H18NO
[M þ H]þ 228.1388, found 228.1386.
(E)-3-(4-chlorophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (3g)
1
Yield: 101 mg (68%) as a white solid; m.p.: 154.1–155.4 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.88–1.94 (m, 2H, CH2–CH2), 1.98–2.05 (m, 2H, CH2–CH2), 3.59 (t, J ¼ 7. 2H z,
2H, CH2N), 3.63 (t, J ¼ 6.8 Hz, 2H, CH2N), 6.71 (d, J ¼ 15.5 Hz, 1 H, CH), 7.34 (AA’
BB’ system, J ¼ 8.5 Hz, 2H, Harom), 7.47(AA’ BB’ system, J ¼ 8.4 Hz, 2H, Harom), 7.65 (d,
J ¼ 15.5 Hz, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 24.53 (CH2–CH2), 26.33
(CH2–CH2), 46.29 (CH2N), 46.80 (CH2N), 119.53, 129.18, 129.20, 133.99, 135.48,
140.50, 164.58 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C13H15ClNO [M þ H]þ
236.0842, found 236.0840.
(E)-3-(4-nitrophenyl)-1-(pyrrolidin-1-yl)prop-2-en-1-one (3h)
1
Yield: 106 mg (71%) as a white solid; m.p.: 207.8–208.9 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.90–1.97 (m, 2H, CH2–CH2), 2.01–2.08 (m, 2H, CH2–CH2), 3.61 (t, J ¼ 6.9 Hz, 2H,
CH2N), 3.67 (t, J ¼ 6.8 Hz, 2H, CH2N), 6.88 (d, J ¼ 15.5 Hz, 1 H, CH), 7.68 (AA’ BB’
system, J ¼ 8.9 Hz, 2H, Harom), 7.73 (d, J ¼ 15.5 Hz, 1 H, CH), 8.23 (AA’ BB’ system,
J ¼ 8.9 Hz, 2H, Harom) ppm; 13C NMR (100 MHz, CDCl3) d ¼ 24.49 (CH2–CH2), 26.32
(CH2–CH2), 46.43 (CH2N), 46.89 (CH2N), 123.20, 124.27, 128.57, 139.16, 141.77,
148.19, 163.79 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C13H15N2O3 [M þ H]þ
247.1083, found 247.1079.
(E)-1-(pyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (3i)
1
Yield: 100 mg (60%) as a white solid; m.p.: 131.7–133.8 ꢀC; H NMR (400 MHz, CDCl3):
d ¼ 1.89–1.95 (m, 2H, CH2–CH2), 2.00–2.06 (m, 2H, CH2–CH2), 3.60 (t, J ¼ 6.9 Hz, 2H,
CH2N), 3.65 (t, J ¼ 6.8 Hz, 2H, CH2N) 6.81 (d, J ¼ 15.5 Hz, 1 H, CH), 7.62 (AA’BB’ sys-
tem, 4 H, Harom), 7.71 (d, J ¼ 15.5 Hz, 1 H, CH) ppm; 13C NMR (100 MHz, CDCl3)
d ¼ 24.51 (CH2–CH2), 26.33 (CH2–CH2), 46.37 (CH2N), 46.86 (CH2N), 121.44, 124.10

R
SYNTHETIC COMMUNICATIONSV
11
(q, J ¼ 270.7 Hz, CF3), 125.91 (q, J ¼ 3.8 Hz), 128.14, 131.23 (q, J ¼ 32.6 Hz), 138.92,
140.19, 164.26 (C ¼ O) ppm; HRMS [ESI]: m/z calculated for C14H15F3NO [M þ H]þ
270.1106, found 270.1101.
Funding
ꢀ
ꢀ
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The authors thank CONACyT and Secretarıa de Educacion Publica of Mexico for financial sup-
port via project INFRA-2015-01-252013 and F-PROMEP-39/Rev-04 SEP.
ORCID
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ꢀ
Oscar Abelardo Ramırez-Marroquın
http://orcid.org/0000-0003-4354-5468
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