Acceleration of the Eschenmoser coupling reaction by sonication: Efficient synthesis of enaminones

Article abstract of DOI:10.1039/c2ra22033d

Enaminones are commonly prepared by the Eschenmoser coupling reaction. The duration of the reaction is often long. Here, we describe how sonication can accelerate this reaction. The reaction conditions provide an efficient method for the coupling of prima

Full text of DOI:10.1039/c2ra22033d

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Acceleration of the Eschenmoser coupling reaction by
sonication: efficient synthesis of enaminones3
Cite this: RSC Advances, 2013, 3, 181
Naga Durgarao Koduri,a Bethany Hileman,a Justin D. Cox,a Halee Scott,a
Phuong Hoang,a Alexa Robbins,a Kyle Bowers,a Lemma Tsebaot,a Kun Miao,a
Maria Castaneda,a Michael Coffin,a Guan Wei,a Tim D. W. Claridge,b Kenneth
P. Robertsa and Syed Raziullah Hussaini*a
Received 3rd September 2012,
Accepted 8th October 2012
Enaminones are commonly prepared by the Eschenmoser coupling reaction. The duration of the reaction
is often long. Here, we describe how sonication can accelerate this reaction. The reaction conditions
provide an efficient method for the coupling of primary, secondary and tertiary thioamides with
a-bromocarbonyl compounds.
DOI: 10.1039/c2ra22033d
www.rsc.org/advances
reaction conditions.4 The Eschenmoser coupling reaction
conducted under heterogeneous conditions4,16,19 could benefit
Introduction
Enaminones are enamines of a 1,3-diketone, b-ketoester or
similar 1,3-difunctional reagents.1 Enaminones are important
building blocks in organic synthesis. They are used in the
synthesis of natural products2–4 and utilized in the develop-
ment of pharmaceuticals,5,6 peptidomimetics,7,8 ligands for
catalysis9,10 and chiral auxiliaries.11 Additionally, enaminones
form part of biologically active compounds. These include
compounds with anticonvulsive, anti-inflammatory, antitumor
and antibiotic activity.1,5 Enaminones can act either as
electrophiles or nucleophiles and have been used widely in
organic synthesis. A number of approaches are available for
the synthesis of these compounds1,2,12,13 and the development
of new and efficient methods remains an active area of
research.3,14,15
The Eschenmoser coupling reaction has been extensively
employed in the construction of enaminones.1,2,4,13 The
reaction couples a thioamide and an a-halocarbonyl com-
pound (Scheme 1). The reaction generally requires a base, can
be carried out with or without the need of a thiophile, and the
reaction is known to work well with a range of different
substrates.4
from sonication as sonication reduces the particle size and
provides better mass and heat transfer compared to conven-
tional heating.20 In this paper, the effects of sonication on
such heterogeneous Eschenmoser coupling reactions, and
how it addresses the common issue of long reaction times and
allows for the use of primary thioamides, are discussed.
Results and discussion
Usually, carbonate and bicarbonate bases have been used
when the Eschenmoser coupling reaction is conducted under
heterogeneous conditions. Both have been used in the
coupling of 1,3-dicarbonyl compounds with thioamides.4,16,19
Since the aim was to couple both mono- and di-carbonyl
compounds with the thioamides, the stronger base Na2CO3
was selected for the present study. The pKa of sodium
carbonate (y10) is close to the pKa of amine bases (y10)
that have been used successfully for the coupling of mono-
carbonyl halides with thioamides under non-heterogeneous
conditions.4
The Eschenmoser coupling reaction often requires a long
reaction time16–18 and primary thioamides are not acceptable
substrates as they tend to convert into nitriles under the
Synthesis of starting materials
The synthesis of thioamides 1 (Scheme 1) was carried out
using literature conditions.14,21 The synthesis of a-bromocar-
bonyl compounds 2 however, gave some unexpected chal-
aDepartment of Chemistry and Biochemistry, The University of Tulsa, Keplinger Hall,
800 South Tucker Drive, Tulsa, Oklahoma 74104, United States.
E-mail: syed-hussaini@utulsa.edu; Fax: +1-918-631-3404; Tel: +1- 918-631-3520
bDepartment of Chemistry, University of Oxford, 12 Mansfield Road, Oxford, OX1
3TA, United Kingdom
Electronic supplementary information (ESI) available: Experimental
3
procedures for benzylpyrrolidin-2-one, 1f, 2c, 3n, 3o, 9, 10, 3p and 11,
preparation of bath sonicated and probe sonicated Na2CO3 and related
experiments, particle distribution graphs and 1H and 13C NMR spectra of all the
relevant compounds. See DOI: 10.1039/c2ra22033d
Scheme 1 The Eschenmoser coupling reaction.
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lenges (Fig. 1). Attempts to prepare 2b by reacting ethyl
acetoacetate with NaH and Br2,22 TsOH and NBS,23 or NH4OAc
and NBS24 did not give a pure product. Efforts to purify the
product by flash chromatography also failed as 2b decom-
posed on the column. Finally, the use of bromodimethylsulfo-
nium bromide (BDMS)25 provided 2b in pure form. We did not
succeed in isolating 2c under solvent free conditions.26 The
bromide 2c was obtained in pure form by reacting ethyl
benzoylacetate with the in situ generated bromo ion (Br+)27 and
isolating the product by column chromatography. Synthesis of
2d by the reaction of NBS on Meldrum’s acid provided low
yields (5%) of pure product.28 A better yield of 2d (up to 95%)
was obtained by reacting Meldrum’s acid with Br2 and
NaOH.29 However, the purity of the product varied from
experiment to experiment. All of the other bromides were
obtained from commercial sources.
pounds. Greater acidity could make the conversion of 1A4
or 1A5 the rate determining step, resulting in the reactions of
tertiary thioamides being slower as greater steric hindrance
would pose greater energy requirements in the alkylation step
(1A4, Scheme 2).31 Nonetheless, in all of the reactions of
tertiary thioamides, good yields were obtained and the
reaction was suitable for acyclic (entry 1), cyclic (entries 2–6)
and acyclically positioned thiocarbonyl groups (entry 7). The
a-bromoketoesters are generally considered unsuitable cou-
pling partners for providing enaminones with primary
thioamides. They instead give thiozoles.32–34 Nevertheless, a
primary thioamide did give the coupled product with
a-bromodicarbonyls (entry 1), and both the a-bromodiester
and a-bromoketoesters were also viable coupling partners for
secondary and tertiary thioamides (entries 2–7).
The reaction of a-bromoketoesters with secondary thioa-
mides (entries 2–4) provided predominantly E diastereomers.
The E stereochemistry in such compounds provides better
hydrogen bonding between the N–H and the ketone oxygen
and lowers the energy of the product. The coupling of 1a and
2b (R4 = OEt, R5 = CH3) (entry 1) gave a single diastereomer 3b.
The stereochemistry of 3b was tentatively assigned as E on the
basis of the H-bonding argument. The stereochemistry in the
secondary enaminones was assigned by comparing the
chemical shifts of the N–H protons, and by comparing the
signals of the carbonyl ester groups in the IR of relevant
compounds. The coupling of 1e with 2c (entry 5) provided just
the E diastereomer 3j. Such selectivity has been observed
before.4,35,36 The reaction of 1g with 2c was less selective and
produced an inseparable mixture of diastereomers 3m in a
2.4 : 1 ratio.
Synthesis of enaminones with the help of an ultrasonic bath
Ultrasonic baths are usually available in organic laboratories.
They are the most economical and commercially available
sources of ultrasonic irradiation for the chemical laboratory.20
As such, they have the greatest potential to be used in organic
synthesis. This type of equipment was initially used for the
Eschenmoser coupling reaction. Both the primary and the
secondary thioamides provided the enaminones after only 2.5
h of sonication (Table 1, entries 1–4). In comparison, a low
product conversion was observed when the reaction was
refluxed for 2.5 h through conventional heating (entry 4).
The mechanism of the Eschenmoser coupling reaction
consists of two main steps (Scheme 2). The first step is the
S-alkylation of thioamides with an electrophile. In the second
step the resulting thioether gets deprotonated at the a-proton
which is captured by the iminium 6 or the imine 7 to form the
episulfide 8. The episulfide collapses, with or without the help
of a thiophile, to give enaminones 3. When monoesters are
used, tertiary thioamides tend to give higher yields of product
with shorter reaction times. This rate and yield enhancement
is explained as a result of a greater acidity of the side-chain
a-proton. The greater acidity is due to the presence of the
positive charge in the thioiminium salts 4. In the case of
secondary thioamides, the iminium nitrogen does not retain
its charge. Under reaction conditions, it loses its proton and is
converted to an imine 5.4,30
Synthesis of enaminones with the help of probe sonication
Ultrasonic probes are less common in organic laboratories
than ultrasonic baths, even though they are not very
expensive.37 Furthermore, they are considered standard
equipment for biochemistry and analytical chemistry labora-
tories. The ultrasonic probe provides much more acoustic
energy than an ultrasonic bath. With an ultrasonic bath, the
amount of energy that reaches the reaction is around 1–5 W
cm22, while an ultrasonic probe can provide several hundred
W cm22 to the reaction.20 We hypothesized that the reaction
time for the coupling of tertiary thioamides could be reduced
by providing more energy to the reaction. Thus, the use of an
ultrasonic probe for the coupling of tertiary thioamides was
explored. Table 1 (entries 5–7) shows that probe sonication
reduces reaction times from days to hours.
In contrast to the above reports, in this study the coupling
reaction of tertiary thioamides proved to be more challenging
than the coupling of secondary thioamides and required
longer reaction times (compare entries 1–4 with entries 5–7).
This could be attributed to the higher acidity of a-bromodi-
carbonyl compounds compared to a-monocarbonyl com-
Reasons for the acceleration in reaction rates
The ultrasonic energy accelerates reactions primarily as a
result of cavitation bubbles. These bubbles can act as micro-
reactors which generate temperatures of several thousand
degrees and pressures greater than one thousand atmo-
spheres.20 In heterogeneous liquid–solid ionic reactions,
cavitation bubbles can form at or near a solid surface. When
such a bubble collapses, a liquid jet is formed which is
targeted at the solid surface. The liquid jet disrupts interfacial
boundary layers, causing an increase in the amount of mass
and heat transfer to the surface. The collapse of bubbles can
Fig. 1 a-Bromocarbonyl compounds used in this study.
182 | RSC Adv., 2013, 3, 181–188
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Table 1 Eschenmoser coupling reaction with the help of an ultrasonic bath
Entry
1
Thioamide
Product
Yield (%)
Time allowed
3a R = OEt (90)
3b R = CH3 (60)
2.5 h
2.5 h
1a
3c R = OEt (98)
(27)a
3d R = CH3 (84)
2.5 h
2.5 h
2.5 h
2
3
1b
3e R = OEt (80)
3f R = CH3 (47)
2.5 h
2.5 h
1c
3g R = OEt (73)
(24)b
2.5 h
2.5 h
2.5 h
4
5
3h R = Ph (74 E/Z 2 : 1)c
1d
3i R = OEt (74)
(97)d
20 h
8.5 h
3.0 h
3j R = Ph (99)d
1e
3k (85)
46 h
7.0 h
7.0 h
(89)d
(67 conversion by NMR)d,e
6
1f
3l R = OEt (94)
(87)d
5.0 days
11.5 h
6.0 h
3m R = Ph (100 dr 2.4 : 1)c,d
7
1g
a
b
c
Reaction was carried out in the absence of base. Refluxed in a pressure vessel immersed in a 47 uC oil bath. Product was obtained as an
d
e
inseparable mixture of diastereomers. Probe sonication was used. Reaction was cooled by a (28 uC) condenser.
also generate shock waves. These shock waves can cause
pressure and temperature increases and other mechanical
effects.38 Additionally, cavitation has the ability to reduce the
size of particles, which can also improve the mass transfer to
the surface.20 So, which of these factors are more important
than others in the sonication promoted Eschenmoser coupling
reaction? We designed a few experiments to answer this
question.
form enaminones.4 Hence, it was important to ascertain the
impact of the use of a base in this transformation. When 1b
was sonicated in a water bath with 2a in the absence of a base,
only 27% of 3c was isolated after 2.5 h (Table 1 entry 2). The
rest of the material remained in the thioether form indicating
that without the base, sonication alone cannot complete this
transformation in 2.5 h and the use of the base accelerates the
conversion of 5 into enaminones (Scheme 2).
Since a-halodicarbonyl species can exist in the enol form,
they have the potential to react in the absence of a base to
Thioamide 1f was reacted next with 2a using probe
sonication (Table 1, entry 6). A short condenser (28 uC) was
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Scheme 2 Accepted mechanism of the Eschenmoser coupling reaction.
attached to cool the vapor. After 7 h of sonication, 67% of 1f
was converted to the enaminones 3k. Similar results were
obtained when the reaction was cooled from outside by
immersing the reaction vessel in a room temperature water
bath. In contrast, without a condenser, 100% conversion of 1f
and 89% isolated yield was obtained for 3k (Table 1, entry 6).
This suggests that high temperatures and pressures are
important factors and that mechanical effects are not solely
responsible for the rate enhancement.20
particles and an increased temperature are important factors
in the rate enhancement of this reaction.
Limitations and side reactions
When 2d was reacted with 1b, only a 24% yield of the
enaminone 3n was obtained (Scheme 3). It was observed that
bromide 2d reacts rapidly with 1b without the need for
sonication. Immediate heating of the reaction vessel and
effervescence were observed upon the addition of 2d to the
CH2Cl2 solution of 1b and Na2CO3. TLC analysis suggested the
complete disappearance of 1b within the amount of time it
took to check the TLC (,5 min.). The fast reactivity of 2d is
expected as it is sterically less hindered and more acidic than
the open chain bromoesters and ketones (for comparison: the
pKa of Meldrum’s acid is 7.339 while the pKa of ethyl
acetoacetate and diethyl malonate are 14.240 and 16.439
respectively). These attributes should enable 2d to alkylate
easily 1A5 and deprotonate and cyclize efficiently 5A8
(Scheme 2). The low yield is possibly due to the thermolysis
of the Meldrum’s acid moiety of the enaminones 3n. It is
Particle distribution analysis (Fig. 2, see also the ESI ) was
3
performed on commercial, water bath sonicated and probe
sonicated Na2CO3. It showed that the probe sonicated base
had the smallest mean volume diameter (MV) of particles (646
nm) and the narrowest range of particle size distribution (428–
1060 nm). The cleaning bath sonicated base had finer particles
and a smaller range of particle sizes (761–1450 nm) than the
commercial base (1232–5640 nm).
The bath sonicated base was used in the reaction of 1b with
2a. After stirring for 2.5 h at room temperature all of 1b was
converted to 3c, suggesting that reduction in particle size was
the only factor responsible for the rate increase (compare with
Table 1, entry 2). However, when probe sonicated Na2CO3
(sonicated for 8.5 h) was used to couple 1e and 2a, less than
50% conversion of 1e into product 3i was observed even after
8.5 h of stirring at room temperature (compare Table 1, entry
5). These results indicate that, for tertiary thioamides, a
reduced particle size of the base is not the sole reason for the
fast reaction. It seems that both a reduction in the size of
known that such enaminones can decompose readily.41
A
more controlled reaction and much better yield were possible
with Et3N.
The coupling reaction of 1c and 2c provided the single
diastereomer of the enaminone 3o as a minor product
(Scheme 4).42 On the basis of 1D and 2D NMR spectroscopy
and mass spectrometry, structure 9 was assigned to the major
product. The formation of 9 can be explained as a result of the
breaking of the episulfide bond and proton transfer.
Production of 9 in this reaction provides strong evidence for
the presence of an episulfide intermediate. Such intermediates
8 (Scheme 4) have never been isolated, but have been proposed
in the mechanism of the Eschenmoser reaction.
Fig. 2 Particle distribution analysis of sodium carbonate.
184 | RSC Adv., 2013, 3, 181–188
Scheme 3 Coupling conditions for the cyclic diester 2d.
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ical effects that are produced due to the rapid collapse of
bubbles in sonication, are also important in the coupling
process. In the future, the methodology will be expanded to
include the coupling of a-halomonoesters and thioamides.
The reaction will also be used in the synthesis of biologically
important enaminones and natural products.
Experimental
General
Scheme 4 Formation of the unexpected thiol.
1H and 13C NMR spectra were obtained using a Varian 400/54
(400 MHZ) spectrometer. The residual solvent signals were
used as references (CDCl3: dH = 7.26 ppm, dC = 77.16 ppm).
Infrared spectra were recorded on an Avatar 360 FT-IR. High
resolution mass spectra and liquid chromatography were
performed on a Thermo Scientific Exactive LC-MS instrument.
The instrument was operated in a positive ion electrospray
mode by Dr K. P. Roberts and J. Holland at the Department of
Chemistry and Biochemistry, The University of Tulsa.
Chromatographic separation was performed on this instru-
ment with Thermo Scientific Hypersil Gold HPLC Column (50
6 2.1 mm I.D.; particle size 1.9 mm) coupled to a UV detector.
Thin layer chromatography (TLC) was performed on 250 mm
glass or aluminium-backed silica gel plates. Visualization was
accomplished using short wavelength UV light (254 nm), an
iodine chamber, or basic aqueous KMnO4 solution. Flash
column chromatography was performed using Sorbent silica
gel 60 Å (40–63 mm). Petroleum ether refers to those fractions
that distil at 30–60 uC. Anhydrous Na2CO3 was purchased from
Fisher (LOT AD-9195-27). Unless specified, all chemical
reagents and solvents were obtained from commercial sources.
Aldrich’s Zerostat1 3 gun was used to neutralize static
electricity during the Na2CO3 weighing and transfer.
Sonication was conducted either by an ultrasonic bath (VWR,
model no. 97043-968) or probe sonicator (Sonics, Vibra cell,
model no. VC X 130) equipped with a standard probe (tip dia.
6mm, length 113 mm). The pulse settings were 7 s on and then
1 s off with a 100% amplitude.
The reaction of monocarbonyl halides was not successful
under standard reaction conditions. When 1d was reacted with
2e the reaction did not proceed beyond the thioether stage 10
after 2.5 h of bath sonication (Scheme 5). However, on probe
sonication, in the presence of the thiophile PPh3 and xylene as
a solvent, the reaction provided the enaminone 3p as a single
diastereomer after 11 h.43 In contrast, under these conditions,
coupling of less acidic 1b with 2f remained unsuccessful. Even
after 20 h of probe sonication, only thioether 11 could be
recovered.
General procedure A: synthesis of enaminones using an
ultrasonic bath
A solution of 1 (157 mmol) in 0.40 mL CH2Cl2 was added to a
test tube containing Na2CO3 (3.2 eq). Bromide 2 (2 eq) was
dissolved in 0.40 mL CH2Cl2 and added to the reaction vessel.
Each vial, which originally contained 1 and 2, was washed
twice with 0.10 mL CH2Cl2 and the contents were transferred
to the reaction mixture. The test tube was capped and
sonicated for the specified period of time (Table 1).
Scheme 5 Issues with the sulphide contraction of monocarbonyl thioethers.
Conclusions
General procedure B: synthesis of enaminones using probe
sonication
It has been shown that sonication can accelerate the
Eschenmoser coupling reaction. The method can be applied
to the efficient coupling of primary, secondary and tertiary
thioamides with a-bromodiesters and a-bromoketones. In the
case of secondary thioamides, the rate enhancement is mainly
due to the reduction in the size of Na2CO3 particles. For
tertiary thioamides, other factors, such as heat and mechan-
A solution of 1 (157 mmol) in 0.40 mL CH2Cl2 was added to a
test tube containing Na2CO3 (3.2 eq). Bromide 2 (2 eq) was
dissolved in 0.40 mL CH2Cl2 and added to the reaction vessel.
Each vial, which originally contained 1 and 2, was washed
twice with 0.10 mL CH2Cl2 and the contents were transferred
to the reaction mixture. The sonication probe was inserted
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1
into the reaction tube and the tube was covered with paraffin.
The reaction was sonicated for the specified period of time
(Table 1). During sonication, the solvent level was monitored.
If the level reduced to y0.40 mL, additional CH2Cl2 (0.80 mL)
was added to make up the difference in lost solvent.
1247, 1017, 1035, 798; H NMR (400 MHz, CDCl3) d: 11.59 (s,
br, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.63 (t, J = 7.6 Hz, 2H), 3.15 (t, J
= 8.0 Hz, 2H), 2.41 (s, 3H), 2.02 (t, J = 7.6, 8.0 Hz, 2H), 1.31 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 197.8, 174.7,
169.0, 99.0, 59.6, 48.0, 35.2, 30.9, 21.2, 14.6; HRMS (ESI+):
Calcd. for C10H15NO3 (M + H+): 198.1125, found 198.1115; m/z
(ESI+): 198 (M + H+, 100%), 152 (17%); HPLC, Rt = 6.02 min.
Diethyl 2-(1-amino-3-phenylpropylidene)malonate (3a)14
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1a14 (20.0
mg, 121 mmol) into crude 3a. Column chromatography
(CH2Cl2 then 10% ethyl acetate in CH2Cl2) provided pure 3a
(31.6 mg, 108 mmol, 90%) as yellow oil. Rf 0.23 (CH2Cl2). IR
(neat) nmax/cm21: 3416, 3314, 3028, 2981, 2936, 2904, 1664,
1614, 1526, 1497, 1454, 1366, 1253, 1072, 798; 1H NMR (400
MHz, CDCl3) d: 8.78 (s, broad, 1H), 7.31–7.26 (m, 2H), 7.23–
7.19 (m, 3H), 4.90 (s, broad, 1H), 4.23 (q, J = 7.2 Hz, 2H), 4.17
(q, J = 7.2 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.69 (t, J = 7.6 Hz,
2H), 1.30 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d: 168.9, 168.5, 165.8, 140.5, 128.8, 128.5,
126.6, 93.4, 60.6, 59.8, 37.1, 34.8, 14.4; HRMS (ESI+): Calcd. for
C16H21NO4 (M + H+): 292.1543, found 292.1544; m/z (ESI+): 292
(M + H+, 100%), 246 (38%); HPLC, Rt = 8.44 min.
Diethyl 2-(piperidine-2-ylidene)malonate (3e)14,19
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1c14 (30.0
mg, 173 mmol) into crude 3e. Column chromatography (17%,
then 20% ethyl acetate in hexanes) provided pure 3e (33.7 mg,
140 mmol, 80%). Rf 0.26 (hexanes : EtOAc 4 : 1). IR (neat) nmax
/
cm21: 3248, 2979, 1697, 1643, 1600, 1480, 1281, 1225, 1071; 1H
NMR (400 MHz, CDCl3) d: 10.08 (s, broad 1H), 4.18–4.11 (m,
4H), 3.35–3.32 (m, 2H), 2.64 (t, J = 6.4 Hz, 2H), 1.78–1.68 (m,
4H), 1.30–1.22 (m, 6H); 13C NMR (100 MHz, CDCl3) d: 169.5,
168.9, 165.7, 89.8, 60.2, 59.3, 41.6, 27.2, 21.8, 19.4, 14.5, 14.4;
HRMS (ESI+): Calcd. for C12H19NO4 (M + H+): 242.1386, found
242.1377; m/z (ESI+): 242 (M + H+) ; HPLC, Rt = 9.29 min.
(E)-Ethyl 3-oxo-2-(piperidine-2-ylidene)butanoate (3f)42
(E)-Ethyl 2-acetyl-3-amino-5-phenylpent-2-enoate (3b)
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1c14 (20.0
mg, 174 mmol) into crude 3f. Column chromatography (40%
ethyl acetate in petroleum ether) provided pure 3f (17.4 mg,
82.2 mmol, 47%) as a single diastereomer. Rf 0.31 (petroleum
ether : EtOAc 3 : 2). IR (neat) nmax/cm21: 3398, 2928, 2855,
1692, 1599, 1463, 1448, 1358, 1332, 1307, 1278, 1192, 1108,
1070, 1054, 1025; 1H NMR (400 MHz, CDCl3) d: 12.77 (s, br,
1H), 4.19 (q, J = 7.2 Hz, 2H), 3.40–3.38 (m, 2H), 2.70 (t, J = 6.2
Hz, 2H), 2.25 (s, 3H), 1.81–1.67 (m, 4H), 1.31 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) d: 195.4, 170.1, 168.7, 101.8, 60.1,
41.7, 27.8, 21.3, 19.2, 14.4; HRMS (ESI+): Calcd. for C11H17NO3
(M + H+): 212.1281, found 212.1270; m/z (ESI+): 212 (M + H+,
100%), 166 (16%); HPLC, Rt = 6.41min.
The reaction was performed according to the general procedure
A. It was sonicated for 2.5 h to convert 1a (20.0 mg, 121 mmol)
into crude 3b. Column chromatography (30% ethyl acetate in
CH2Cl2) provided pure 3b (19.0 mg, 72.5 mmol, 60%) as a single
diastereomer. Rf 0.36 (dichloromethane : EtOAc 7 : 3). IR (neat)
nmax/cm21: 3370, 2921, 2844, 1710, 1645, 1551, 1320, 1260, 1093,
913; 1H NMR (400 MHz, CDCl3) d: 7.32–7.27 (m, 2H), 7.25–7.20
(m, 3H), 4.31 (q, J = 7.2 Hz, 2H), 3.28 (t, J = 7.8 Hz, 2H), 3.10 (t, J =
7.8 Hz, 2H), 2.71 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.25 (s, broad,
2H); 13C NMR (100 MHz, CDCl3) d: 128.8, 35.7, 35.0, 29.8, 14.4;
HRMS (ESI+): Calculated for C15H19NO3, (M + H+): 262.1437
found 262.1438; m/z (ESI+) 262 (M + H+); HPLC, Rt = 9.29 min.
Diethyl 2-(pyrrolidin-2-ylidene)malonate (3c)14,42
(S)-5-(Di(ethoxycarbonyl)methylidene)-pyrrolidine-2-carboxylic
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1b14 (12.0
mg, 114 mmol) into crude 3c. Column chromatography (CH2Cl2
then ethyl acetate) provided pure 3c (25.4 mg, 112mmol, 98%).
Rf 0.37 (hexanes : EtOAc 3 : 2). IR (neat) nmax/cm21: 3317,
2980, 1685, 1643, 1577, 1437, 1366, 1334, 1247, 1084, 1038,
797; 1H NMR (400 MHz, CDCl3) d: 9.52 (s, broad 1H), 4.18 (q, J
= 7.2 Hz, 2H), 4.17 (q, J = 7.2 Hz, 2H), 3.58 (t, J = 7.2 Hz, 2H),
3.09 (t, J = 8.0 Hz, 2H), 2.02 (tt, J = 7.2, 8.0 Hz, 2H), 1.27 (t, J =
7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) d: 173.4, 170.1, 167.9,
87.4, 59.8, 59.7, 47.5, 34.3, 21.8, 14.5; HRMS (ESI+): Calcd. for
C11H17NO4 (M + H+): 228.1230, found 228.1220; m/z (ESI+): 228
(M + H+, 100%), 182 (79%); HPLC, Rt = 6.59 min.
acid ethyl ester (3g)44
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1d44 (30.0
mg, 173 mmol) into crude 3g. Column chromatography (40%
ethyl acetate in petroleum ether) provided pure 3g (37.5 mg,
125 mmol, 73%). Rf 0.59 (hexanes : EtOAc 3 : 2). IR (neat) nmax
/
cm21: 3316, 2981, 1743, 1691, 1652, 1570, 1441, 1417, 1367,
1247, 1077, 1036; 1H NMR (400 MHz, CDCl3) d: 9.62 (s, br 1H),
4.45 (dd, J = 6.0, 8.8 Hz, 1H), 4.23–4.14 (m, 6H), 3.21–3.06 (m,
2H), 2.34 (dddd, J = 7.2, 8.8, 8.8, 13.2 Hz, 1H), 2.16 (dddd, J =
6.0, 6.0, 9.2, 13.2 Hz, 1H), 1.31–1.22 (m, 9H); 13C NMR (100
MHz, CDCl3) d: 172.1, 171.2, 169.5, 167.5, 89.0, 60.9, 60.8, 59.9,
59.8, 33.2, 26.0, 14.4, 14.2; HRMS (ESI+): Calcd. for C14H21NO6
(M + H+): 300.1442, found 300.1417; m/z (ESI+): 300 (M + H+,
100%), 254 (42%), 225 (60%); HPLC, Rt = 6.99 min.
(E)-Ethyl 3-oxo-2-(pyrrolidin-2-ylidene)butanoate (3d)14,35
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1b14 (20.0
mg, 198 mmol) into crude 3d. Column chromatography (40%
ethyl acetate in petroleum ether) provided pure 3d (32.9 mg,
167mmol, 84%). Rf 0.31 (petroleum ether : EtOAc 3 : 2). IR
(neat) nmax/cm21: 3316, 2981, 1743, 1691, 1652, 1570, 1367,
(S)-Ethyl 5-(1-ethoxy-1,3-dioxo-3-phenylpropan-2-
ylidene)pyrrolidine-2-carboxylate (3h)
The reaction was performed according to the general
procedure A. It was sonicated for 2.5 h to convert 1d44 (30.0
186 | RSC Adv., 2013, 3, 181–188
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mg, 173 mmol) into crude 3h. Column chromatography
(columned packed in petroleum ether and run in 20%, then
30% ethyl acetate in petroleum ether) provided pure 3h (42.5
mg, 128mmol, 74%) as an inseparable mixture of diasteromers
in a ratio of 1 : 2 (Z: E). Rf 0.56 (petroleum ether : EtOAc 3 : 2).
IR (neat) nmax/cm21: 3314, 2981, 1742, 1685, 1593, 1573, 1537,
1230; 1H NMR (400 MHz, CDCl3) d: 10.98 (s, br, 1H, major),
9.48 (s, br, 1H, minor), 7.61 (d, J = 6.8 Hz, 1H), 7.46–7.31 (m,
4H), 4.55–4.43 (m, 1H), 4.23 (d, J = 7.2 Hz, 2H), 3.89–3.79 (m,
2H), 3.34–3.14 (m, 2H), 2.46–2.36 (m, 1H), 2.28–2.15 (m, 1H),
1.29 (t, J = 7.2 Hz, 3H), 0.73–0.70 (m, 3H); 13C NMR (100 MHz,
CDCl3) d: (major) 195.3, 173.4, 170.8, 169.1, 143.3, 129.8, 127.8,
126.9, 98.9, 62.0, 61.6, 59.6, 33.2, 25.5, 14.2, 13.5; (minor)
195.3, 172.2, 171.1, 169.7, 142.6, 130.9, 128.1, 127.8, 96.8, 62.0,
61.0, 59.4, 32.5, 26.2, 14.2, 13.5; HRMS (ESI+): Calcd. for
C18H21NO5 (M + H+): 332.1465, found 332.1492; m/z (ESI+) 332
(M + H+, 100%), 207 (56%), 172 (24%); HPLC, Rt = 7.87 min.
Diethyl 2-(benzylpyrrolidin-2-ylidene)malonate 3k
BY THE GENERAL PROCEDURE A. The reaction was performed
according to the general procedure A with a few changes.
During sonication, the solvent level was monitored. After 9 h
additional CH2Cl2 (1.00 mL) was added to make up the
difference in lost solvent. After 37 h of sonication, 1.10 eq. of
additional 2a was added. The reaction was sonicated for 46 h
in total to convert 1f (30.0 mg, 157 mmol) into crude 3k.
Column chromatography (20%, then 30% ethyl acetate in
petroleum ether) provided pure 3k (42.4 mg, 134 mmol, 85%).
BY THE GENERAL PROCEDURE B. The reaction was performed
according to the general procedure B. It was sonicated for 7 h
to convert 1f (30.0 mg, 157 mmol) into crude 3k. Column
chromatography (20%, then 30% ethyl acetate in petroleum
ether) provided pure 3k (44.5 mg, 140 mmol, 89%). Rf 0.56
(petroleum ether : EtOAc 3 : 2). IR (neat) nmax/cm21: 2979,
1
1684, 1570, 1454, 1364, 1234, 1190, 1147, 1091, 1048, 955; H
Diethyl 2-(methylpyrrolidin-2-ylidene)malonate (3i)14,36
NMR (400 MHz, CDCl3) d: 7.34–7.25 (m, 3H), 7.19–7.17 (m,
2H), 4.40 (s, 2H), 4.06 (q, J = 7.2 Hz, 4H), 3.31 (t, J = 7.2 Hz, 2H),
3.23 (t, J = 7.6 Hz, 2H), 1.92 (tt, J = 7.2, 7.6 Hz, 2H), 1.17 (t, J =
7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) d: 168.5, 165.0, 135.8,
128.8, 127.8, 127.7, 90.6, 60.1, 54.3, 52.6, 35.4, 20.8, 14.3;
HRMS (ESI+): Calcd. for C18H23NO4 (M + H+): 318.1700, found
318.1674; m/z (ESI+) 318 (M + H+, 100%), 272 (90%); HPLC, Rt =
7.85 min.
BY THE GENERAL PROCEDURE A. The reaction was performed
according to the general procedure A with a few changes. After
4 and 8 h of sonication, 0.74 eq. of additional 2a was added.
The reaction was sonicated for 20 h in total to convert 1e14 (500
mg, 434 mmol) into crude 3i. Column chromatography (20%
ethyl acetate in CH2Cl2) provided pure 3i (77.9 mg, 323 mmol,
74%).
Diethyl 2-(phenyl(piperidine-1-yl)methylene)malonate (3l)14,45
BY THE GENERAL PROCEDURE B. The reaction was performed
according to the general procedure B. It was sonicated for 8.5 h
to convert 1e14 (20.0 mg, 174 mmol) into crude 3i. Column
chromatography (40% ethyl acetate in petroleum ether)
provided pure 3i (40.5 mg, 168 mmol, 97%). Rf 0.22 (petroleum
ether : EtOAc 3 : 2). IR (neat) nmax/cm21: 2965, 2926, 2852,
BY THE GENERAL PROCEDURE A. The reaction was performed
according to the general procedure A. The reaction was
sonicated for 5 days in total to convert 1g14 (24.0 mg, 117
mmol) into crude 3l. Column chromatography (20%, then 33%
ethyl acetate in hexanes) provided pure 3l (36.6 mg, 110 mmol,
94%).
1
1680, 1574, 1450, 1366, 1286, 1223, 1189, 1069, 915; H NMR
(400 MHz, CDCl3) d: 4.14 (q, J = 7.2 Hz, 4H), 3.48 (t, J = 7.2 Hz,
2H), 3.13 (t, J = 7.6 Hz, 2H), 2.82 (s, 3H), 1.94 (tt, J = 7.2, 7.6 Hz,
2H), 1.24 (t, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) d:
168.3, 166.7, 89.2, 59.9, 57.2, 36.8, 35.1, 20.6, 14.4; HRMS
(ESI+): Calcd. for C12H19NO4 (M + H+): 242.1386, found
242.1375; m/z (ESI+) 242 (M + H+, 43%), 196 (100%); HPLC,
Rt = 6.33 min.
BY THE GENERAL PROCEDURE B. The reaction was performed
according to the general procedure B. It was sonicated for 11.5
h to convert 1g14 (20.0 mg, 97.4 mmol) into crude 3l. Column
chromatography (20%, then 30% ethyl acetate in petroleum
ether) provided pure 3l (28.3 mg, 85.4 mmol, 87%). Rf 0.26
(petroleum ether : EtOAc 3 : 2). IR (neat) nmax/cm21: 2925,
2854, 1690, 1524, 1446, 1365, 1291, 1253, 1222, 1155, 1113,
1
(E)-Ethyl 2-(methylpyrrolidin-2-ylidene)-3-oxo-3-
phenylpropanoate (3j)36
1078, 1027, 858, 765; H NMR (400 MHz, CDCl3) d: 7.45–7.42
(m, 3H), 7.39–7.35 (m, 2H), 3.98 (q, J = 7.2 Hz, 4H), 3.14–3.11
(m, br, 4H), 1.72–1.63 (m, br, 6H), 1.10 (t, J = 7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d: 169.0, 167.9, 138.1, 130.5, 129.8,
128.5, 98.4, 60.0, 52.7, 27.0, 23.9, 14.2; HRMS (ESI+): Calcd. for
C19H25NO4 (M + H+): 332.1856, found 332.1836; m/z (ESI+) 332
(M + H+, 53%), 286 (100%); HPLC, Rt = 8.68 min.
The reaction was performed according to the general
procedure B. It was sonicated for 3 h to convert 1e14 (20.0
mg, 174 mmol) into crude 3j. Column chromatography (40%
ethyl acetate in petroleum ether) provided pure 3j (47.1 mg,
172 mmol, 99%) as a single diastereomer. Rf 0.16 (petroleum
ether : EtOAc 3 : 2). IR (neat) nmax/cm21: 2925, 2854, 1682,
1615, 1598, 1558, 1447, 1408, 1364, 1316, 1285, 1233, 1173,
Ethyl 2-benzoyl-3-phenyl(piperidine-1-yl)acrylate (3m)
1
The reaction was performed according to the general
procedure B. It was sonicated for 6 h to convert 1g14 (20.0
mg, 97.4 mmol) into crude 3m. Column chromatography (40%
petroleum ether in CH2Cl2) provided pure 3m (35.4 mg, 97.4
mmol, 100%) as an inseparable mixture of diastereomers
1123, 1094, 1060, 910, 880, 827; H NMR (400 MHz, CDCl3) d:
7.73–7.69 (m, 2H), 7.43–7.39 (m, 1H), 7.37–7.33 (m, 2H), 3.82
(q, J = 7.2 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H), 3.25 (t, J = 7.6 Hz,
2H), 2.74 (s, 3H), 2.05 (tt, J = 7.2, 7.6 Hz, 2H), 0.70 (t, J = 7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) d: 194.0, 170.7, 169.3, 142.6,
130.8, 128.2, 127.9, 96.9, 59.3, 57.7, 38.9, 35.6, 20.7, 13.6;
HRMS (ESI+): Calcd. for C16H19NO3 (M+H)+: 274.1437, found
274.1425; m/z (ESI+) 274 (M + H+, 100%), 228 (83%), 105 (17%);
HPLC, Rt = 6.85 min.
(2.4 : 1). Rf 0.14 (petroleum ether : EtOAc 9 : 1). IR (neat) nmax
/
cm21: 2935, 2855, 1670, 1668, 1507, 1446, 1364, 1273, 1243,
1220, 1208, 1168, 1156, 1110, 1059, 1026, 1000, 904, 772, 761;
1H NMR (400 MHz, CDCl3) d: (Major) 7.77 (d, J = 7.6 Hz, 2H),
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RSC Advances
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7.37–7.28 (m, 8H), 4.20 (q, J = 7.2 Hz, 2H), 3.27–3.26 (m, 4H),
1.70–1.68 (m, 6H), 1.24 (t, J = 7.2 Hz, 3H); (Minor) 8.07 (d, J =
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364.1892; m/z (ESI+) 364 (M + H+); HPLC, Rt = 10.38 min.
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Acknowledgements
Financial support was provided by The University of Tulsa new
faculty Lab-startup funds. B.H. and H.S. gratefully acknowl-
edge both the TURC and the CSURP scholarship funds from
The University of Tulsa. The authors thank J. Holland for her
help with the spectroscopic measurements. This material is
based upon work supported by the National Science
Foundation under Grant No. (CHE-1048784).
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