Synthesis of 3-[(4-Nitrophenyl)thio]-Substituted 4-Methylene-1-pyrrolines from N-Propargylic β-Enaminones

Article abstract of DOI:10.1021/acs.joc.0c00109

A facile and efficient method for the synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-pyrrolines is described. When treated with 4-nitrobenzenesulfenyl chloride in refluxing acetonitrile, N-propargylic β-enaminones produced α-sulfenylated N

Full text of DOI:10.1021/acs.joc.0c00109

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Article
Synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-
methylene-1-pyrrolines from N-propargylic #-enaminones
Esra Korkmaz, and Metin Zora
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00109 • Publication Date (Web): 10 Mar 2020
Downloaded from pubs.acs.org on March 10, 2020
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Synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-
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pyrrolines from N-propargylic β-enaminones
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Esra Korkmaz and Metin Zora*
Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
Phone: (+90)-312-2103213; fax: (+90)-312-2103200; e-mail: zora@metu.edu.tr
TABLE OF CONTENTS / ABSTRACT GRAPHIC
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ABSTRACT
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A facile and efficient method for the synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-
pyrrolines is described. When treated with 4-nitrobenzenesulfenyl chloride in refluxing acetonitrile, N-
propargylic β-enaminones produced α-sulfenylated N-propargylic β-enaminones, which in the presence of
sodium hydride or cesium carbonate underwent nucleophilic cyclization to afford 4-methylene-3-[(4-
nitrophenyl)thio]-1-pyrrolines in good to high yields. It was shown for the first time that on N-propargylic β-
enaminone systems, α-sulfenylation dominates over the formation of thiirenium ion. This one-pot two-step
process was found to be general for a variety of N-propargylic β-enaminones and demonstrated good
tolerance to a diversity of aromatic and heteroaromatic groups with electron-withdrawing and electron-
donating substituents. This process is also applicable to the cyclization of internal alkyne-tethered N-
propargylic β-enaminones. The enrichment of 1-pyrroline core with an aryl sulfide moiety might exhibit
potential for the synthesis of molecules of pharmacological interest.
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Key Words: Pyrrole, 1-Pyrroline, N-Propargylic β-enaminone, Sulfenylation, Organosulfur compounds,
Nucleophilic cyclization.
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INTRODUCTION
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Pyrroles, as one of the most abundant and important class of heterocyclic compounds, appear
frequently in the structures of many natural products, bioactive compounds and functional molecules.1
Indeed, pyrroles are precious scaffolds for pharmaceutical and medicinal research,2 since they exhibit
remarkable biological properties such as analgesic, antiallergic, anticonvulsant, antidepressant, antidiabetic,
antihyperlipidemic, antiinflammatory, antimicrobial, antifungal, antiviral, cholesterol reducing and antitumor
properties.3 Among pyrrole derivatives, 1-pyrrolines (3,4-dihydro-2H-pyrroles) have received significant
attention since they have proven to be useful as privileged scaffolds in organic synthesis.4,5
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Organosulfur compounds have become increasingly important in last decades due to their impact on
biological and environmental areas. In fact, sulfur is essential for the growth and proliferation of all living
organisms and found in organic compounds as constituents of proteins, coenzymes and major cellular
metabolites.6 Moreover, owing to their relative ease of oxidation, organosulfur compounds protect against
oxygen toxicity and radiation damage.6 A large number of drugs, which are used for the treatment of
Alzheimer’s and Parkinson’s diseases,7 cancer,8 HIV,9 and immune and inflammatory diseases,10 contain
aryl sulfide moieties on their skeletons. In brief, integration of the sulfur atom into a potentially bioactive
molecule can enhance its reactivity and pharmacological properties. Accordingly, many studies have been
devoted to the development of new strategies for the introduction of a sulfur moiety into organic
compounds.11 In this regard, commercially available 4-nitrobenzenesulfenyl chloride (p-NO2-C6H4-S-Cl) has
emerged as a valuable reagent in organic synthesis since, upon treatment with functionally substituted
alkynes, it has provided a rapid entry to (4-nitrophenyl)thio-substituted carbocycles and heterocycles,
including benzo[b]thiophenes, indoles, isochromenes, isocoumarines, isoquinolines, naphthyridines,
phenanthrenes and α-pyrones,12 two examples of which are depicted in Scheme 1. In summary, electrophilic
sulfur reagents not only initiate the cyclization of functionally substituted alkynes but also introduce an aryl
sulfide moiety into final product.
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Scheme 1. Electrophilic cyclization of functionally substituted alkynes with 4-nitrobenzenesulfenyl chloride.
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We have anticipated that enrichment of 1-pyrroline core with an aryl sulfide moiety may provide the
molecules with pronounced or distinct biological activities. Although 1-pyrrolines are among the most
intensely investigated heterocycles, to the best of our knowledge, 3-[(4-nitrophenyl)thio]-substituted 1-
pyrrolines are very limited. In particular, 4-methylene-1-pyrrolines with a quaternary center at 3-position are
very rare and, to the best of our knowledge, there are only two studies in this regard (Scheme 2). Karunakar
and coworkers have described a gold-catalyzed reaction of N-propargylic β-enaminones with the in situ
generated arynes, which gave rise to the formation of 4-methylene-1-pyrroline derivatives containing an exo
double bond and a quaternary center (Scheme 2a).13 On the other hand, Zhao and coworkers have reported a
Ag-catalyzed reaction of allenoates with activated isocyanoacetates in the presence of a cinchona alkaloid-
based phosphine ligand, which provided 4-methylene-1-pyrroline derivatives possessing an exocyclic olefin
and multiple quaternary stereocenters (Scheme 2b).14 So the development of new efficient and atom
economical processes for the preparation of such heterocycles remains an important goal in synthetic organic
chemistry since they can provide a platform for biological studies.
Scheme 2. Approaches for the synthesis of 4-methylene-1-pyrrolines.
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Recently, N-propargylic β-enaminones have played very important roles in organic synthesis due to
the fact that they possess both electrophilic and nucleophilic reactive sites in their structures, which allows
the building of various heterocycles with enriched structural diversity,15 such as pyrroles,16-20 1-pyrrolines,13
pyridines,16,19,21 1,2-dihydropyridines,22 and 1,4-oxazepines.23 In this regard, we have developed new
strategies for the synthesis of propargyl-substituted pyrroles,24 spiro-2H-pyrroles,25 pyridines,26 1,4-
oxazepines27 and 1,4-thiazepines28 from the corresponding N-propargylic β-enaminones or β-enaminothiones.
We have also investigated the reaction of N-propargylic β-enaminone 1a with 4-nitrobenzenesulfenyl
chloride in the presence of base (Scheme 3). On the basis of previous studies,12 we have anticipated that this
reaction would first produce thiirenium ion 2a. Then its cyclization into 4-methylene-1-pyrroline 3a and/or
dihydropyridine 5a via pathway a or b would afford (4-nitrophenyl)thio-substituted pyrrole 4a and/or
pyridine 6a, respectively, upon isomerization and/or oxidation. Suprisingly, this reaction did not yield any of
the expected pyrrole 4a and/or pyridine 6a derivatives. Instead, it produced only 3-[(4-nitrophenyl)thio]-
substituted 4-methylene-1-pyrroline derivative 8a via intermediacy of α-sulfenylated β-enaminone 7a
(Scheme 3). To the best of our knowledge, N-propargylic β-enaminone 1a is the first example, in which
sulfenylation competed with the formation of thiirenium ion, upon treatment with electrophilic 4-
nitrobenzenesulfenyl chloride, the former being observed to be exclusively dominant. In other words, during
the course of the reaction, first α-sulfenylation of β-enaminone 1a occurs to give β-enaminone 7a, which
immediately undergoes nucleophilic cyclization in the presence of base to furnish 3-[(4-nitrophenyl)thio]-
substituted 4-methylene-1-pyrroline 8a. As part of a program to synthesize new heterocyclic and carbocyclic
compounds as potential pharmaceuticals and scaffolds,29 we have explored the reaction of N-propargylic β-
enaminones 1 with 4-nitrobenzenesulfenyl chloride in the presence of base, which provided potentially
bioactive 4-methylene-3-[(4-nitrophenyl)thio]-1-pyrrolines 8 in good to high yields. Herein, we report the
full details of this study.
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Scheme 3. Possible competitive reaction pathways of N-propargylic β-enaminones with 4-
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nitrobenzenesulfenyl chloride.
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RESULTS AND DISCUSSION
First we synthesized the requisite N-propargylic β-enaminone derivatives 1 and 10 according to our
previous studies (Scheme 4).26a,27a Conjugate addition of propargylamine to α,β-alkynic ketones 9 in
refluxing methanol afforded N-propargylic β-enaminones 1. We then subjected β-enaminones 1 to
Sonogashira coupling according to standard literature procedures.26a,27a The palladium-catalyzed reaction of
β-enaminones 1 with aryl iodides in the presence of CuI and (i-Pr)2NH at room temperature gave the arylated
β-enaminones 10 (Scheme 4). Overall, 24 derivatives of N-propargylic β-enaminones 1 and 10, including
aryl and thiophenyl groups with electron-donating and electron-withdrawing substituents, were synthesized.
Scheme 4. Synthesis of N-propargylic β-enaminones 1 and 10.
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We next investigated the reaction of N-propargylic β-enaminones 1 with 4-nitrobenzenesulfenyl
chloride. In order to test the reaction and optimize its conditions, we first examined the reaction of N-
propargylic β-enaminone 1a under various conditions as illustrated in Table 1. Initially, the reaction of 1a
with 4-nitrobenzenesulfenyl chloride was tested in one-pot manner by using 1.0 and 1.5 molar equivalents of
NaH and Cs2CO3 in CH3CN at reflux conditions, which afforded 4-methylene-3-[(4-nitrophenyl)thio]-1-
pyrroline 8a in 35-53% yields (Table 1, entries 1-4), without formation of (4-nitrophenyl)thio-substituted
pyrrole 4a and/or pyridine 6a. Then the same reaction was carried out in the absence of base. This reaction
produced α-sulfenylated β-enaminone 7a in 84% yield as a 3.5:1.0 mixture of two isomers (Table 1, entry 5).
Although the identities of isomers could not be determined, we achieved to isolate small amount of major
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isomer in pure state for characterization purpose (for its characterization data, and H and 13C{1H} NMR
spectra, see Experimental Section and Supporting Information, respectively). Notably, α-sulfenylation of β-
enaminone 1a with 4-nitrobenzenesulfenyl chloride occured in the absence of base as well. Subsequently, we
subjected the mixture of α-sulfenylated β-enaminone 7a to NaH-mediated nucleophilic cyclization, which
furnished 1-pyrroline 8a in 88% yield (Table 1, entry 5). Overall yield of 8a from N-propargylic β-
enaminone 1a was 74%. Then we carried out these reactions as one-pot two-step process without isolating
intermediate α-sulfenylated β-enaminone 7a. These one-pot two-step reactions were performed with 1.0, 1.5
and 2.0 molar equivalents of NaH and Cs2CO3 in CH3CN at 82 °C (Table 1, entries 6-11). Notably, best
yields (71 and 68%) of 1-pyrroline 8a were obtained with 1.0 equiv. of NaH and Cs2CO3 (Table 1, entries 6
and 9, respectively). Clearly, excess amount of base interfered with the reaction and decreased the yield of
products significantly. Although the yields (71 and 68%) obtained with one-pot two-step sequential
transformations are slightly lower than that (74%) with a two step reactions, we have chosen to make the
derivatization studies with one-pot two-step process in order to save time and chemicals. So the generality of
the reaction and the scope of the substrates were investigated under these conditions (i.e. with the conditions
in entries 6 and 9 of Table 1).
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Table 1. Optimization of the reaction conditions for the synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-
methylene-1-pyrrolines 8.a
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Entry
Base (equiv.)
NaH (1.0)
Yield of 8a (%)
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NaH (1.5)
Cs2CO3 (1.0)
Cs2CO3 (1.5)
Entry
Yield of 7a (%)b
Base (equiv.)
Yield of 8a (%)
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NaH (1.0)
NaH (1.0)
88 (74)c
71c
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not isolated
not isolated
not isolated
not isolated
not isolated
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NaH (1.5)
29c
13c
68c
35c
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NaH (2.0)
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Cs2CO3 (1.0)
Cs2CO3 (1.5)
Cs2CO3 (2.0)
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All reactions were carried out on a scale of 0.30 mmol of N-propargylic β-enaminone
1a in 5 mL of solvent under argon with the indicated conditions. For work-up and
purification, see Experimental Section.
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α-Sulfenylated β-enaminone 7a was isolated as a 3.5:1.0 mixture of two isomers.
Overall yield of 8a from N-propargylic β-enaminone 1a.
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As depicted in Table 2, a diverse range of 4-methylene-3-[(4-nitrophenyl)thio]-1-pyrrolines 8 was
synthesized by employing a variety of N-propargylic β-enaminone derivatives 1. Notably, all reactions
proceeded well and afforded corresponding 1-pyrrolines 8 in good to high yields (47-87%), except that 1-
pyrroline 8f with two nitro groups resulted in moderate yields (32-42%). Both NaH- and Cs2CO3-mediated
reactions provided 4-methylene-3-[(4-nitrophenyl)thio]-1-pyrrolines 8 in comparable yields. For instance,
the reactions with NaH yielded 1-pyrrolines 8 in 42-87% yields while those with Cs2CO3 afforded the same
products in 32-81% yields. The reaction of N-propargylic β-enaminone 1a with NaH was carried on a
relatively larger scale as well, which yielded 1-pyrroline 8a in 74% yield (Table 2), slightly higher than that
(71%) in a small scale, indicating the practical utility of the method as a synthetic tool. Furthermore,
reactions exhibited good tolerance for both elecron-donating and electron-withdrawing groups. Indeed, a
large number of drugs and drug candidates in clinical development include halogen atoms in their structures
since the formation of halogen bonds in ligand-target complexes is evaluated as a kind of intermolecular
interaction which favorably contributes to the stability of protein-ligand complexes.30 Hence fifteen
derivatives of halogen-containing 1-pyrrolines were synthesized in 47-87% yields (Table 2). Six of them
have been fluorine-bearing 1-pyrrolines, which formed in 57-76% yields. It is well known that incorporation
of fluorine into organic structures might lead to improvements in their pharmacological properties.31 Since
thiophenes are frequently utilized as building blocks and scaffolds in a diversity of pharmaceuticals,
agrochemicals and materials science,32 we also synthesized one derivative of 2-(thiophen-3-yl)-substituted 1-
pyrroline, 8l, in 80-81% yields (Table 2).
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Table 2. Synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-pyrrolines 8 via one-pot two-step
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process.a,b
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a
Reaction conditions: N-propargylic β-enaminothione 1 (0.30 mmol), 4-nitrobenzenesulfenyl chloride (0.36 mmol),
NaH (0.30 mmol) or Cs2CO3 (0.30 mmol) and CH3CN (5.0 mL) at 82 °C. For the full procedure including workup
and purification, see Experimental Section.
b
The yields obtained with NaH are shown in parentheses while those obtained with Cs2CO3 are depicted in square
brackets.
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When the reaction was performed on a 1.58 mmol scale of N-propargylic β-enaminothione 1 with NaH, 4-methylene-
1-pyrroline 8a was obtained in 74% yield (see Experimental Section).
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The synthesized products 8 exhibit some characteristic peaks in their H and 13C{1H} NMR spectra
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regarding the formation of a five-membered 1-pyrroline ring. For instance, in the H NMR spectrum of 1-
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pyrroline 8a, methylene hydrogens (CH2) resonate at 4.49 ppm as a singlet while exo vinylic hydrogens
(=CH2) appear at 4.93 and 5.16 ppm as the singlets. On the other hand, in the 13C NMR spectrum of 8a,
carbonyl carbon (C=O) resonates at 194.4 ppm. One of exo double bond carbons (=CH2) appears at 109.0
ppm while the other carbon (C=) peak comes at 147.6 ppm. The peak of sulfur-bonded carbon (CS) on the
ring appears at 120.0 ppm, but nitrogen bonded double bond carbon (C=N) peak (i.e., the imine carbon peak)
comes at 150.9 ppm. Finally, methylene carbon (CH2) resonates at 56.8 ppm.
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Mechanism proposed for the formation of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-
pyrrolines 8 via one-pot two-step process is given in Scheme 5. First, sulfenylation via vinylogous amido-
imido tautomerization produces α-sulfenylated β-enaminones 7. Then, abstraction of acidic amine hydrogen
with base initiates nucleophilic cyclization through resonance interaction, which yields vinyl anions 11 and
12 depending upon the identity of counter metal ions. Finally, protonation of vinyl anions 11 and 12 affords
4-methylene-3-[(4-nitrophenyl)thio]-1-pyrrolines 8 (Scheme 5).
Scheme 5. Proposed mechanism for the formation of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-
pyrrolines 8.
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We have also examined three examples of the reactions of N-propargylic β-enaminones that contain
internal alkyne functionality, such as 10 (Table 3). First, we carried out the reactions of β-enaminones 10
with 4-nitrobenzenesulfenyl chloride, which produced α-sulfenylated β-enaminones 13 in 76-85% yields as a
mixture of E/Z isomers (Table 3). Although the identities of isomers could not be assigned, we were able to
isolate small amounts of major isomers in pure state for characterization purpose (for their characterization
data, and 1H and 13C{1H} NMR spectra, see Experimental Section and Supporting Information, respectively).
Then we subjected α-sulfenylated β-enaminones 13 to NaH-mediated nucleophilic cyclization in refluxing
CH3CN, which afforded the expected 3-[(4-nitrophenyl)thio]-substituted 4-benzylidene-1-pyrrolines 14 in
64-83% yields. In principle, these reactions could produce 1-pyrrolines 14 as one major or exclusive
diastereomer, or a mixture of two diastereomers. However, we were able to isolate 1-pyrrolines 14 as single
diastereomers although the identities of these diastereomers could not be determined. If other diastereomers
formed, they possibly formed in very low yield and escaped from isolation.
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Table 3. Synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-benzylidene-1-pyrrolines 14 via two-step
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Reaction conditions: First step: N-propargylic β-enaminothione 10 (0.30 mmol) 4-
nitrobenzenesulfenyl chloride (0.36 mmol) and CH3CN (5.0 mL) at 82 °C. Second step: α-
sulfenylated N-propargylic β-enaminothione 13 (0.30 mmol), NaH (0.30 mmol) and CH3CN
(5.0 mL) at 82 °C. For the full procedure including workup and purification for each step, see
Experimental Section.
b
The ratio of isomers are shown in square brackets.
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We have developed a new general method for the synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-
methylene-1-pyrroline derivatives. Interestingly, the reaction of N-propargylic β-enaminones with 4-
nitrobenzenesulfenyl chloride in refluxing acetonitrile led to formation of α-sulfenylated N-propargylic β-
enaminones, instead of thiirenium ion formation. In the presence of base such as NaH and Cs2CO3, α-
sulfenylated N-propargylic β-enaminones furnished 4-methylene-3-[(4-nitrophenyl)thio]-1-pyrrolines in
good to high yields through nucleophilic cyclization. This one-pot two-step sequential transformation was
found to be general for a range of N-propargylic β-enaminones and allowed the presence of a variety of
aromatic and heteroaromatic groups with electron-withdrawing and electron-donating substituents.
Furthermore, this protocol could be extended to the internal alkyne-tethered N-propargylic β-enaminones.
More importantly, we have shown for the first time that on N-propargylic β-enaminone systems, α-
sulfenylation preponderates over the formation of thiirenium ion when treated with electrophilic 4-
nitrobenzenesulfenyl chloride. In conclusion, high reaction efficiency and wide reaction scope make this
process a fast and straightforward route to 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-pyrrolines,
which might be of use in designing new and novel molecular entities and/or structural leads.
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EXPERIMENTAL SECTION
General information. H and 13C{1H} NMR spectra were recorded at 400 and 100 MHz, respectively.
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Chemical shifts were given in parts per million (ppm) relative to CDCl3 (7.26 and 77.16 ppm in H and
13C{1H} NMR, respectively). Coupling constants (J) were given in Hertz (Hz), and spin multiplicities were
shown by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). DEPT 13C
NMR information is depicted in parentheses as C, CH, CH2 and CH3. Infrared spectra (IR) were obtained by
using attenuated total reflection (ATR). Band positions diagnostic for major functional groups were recorded
in reciprocal centimeters (cm-1). Mass spectra (MS) and high resolution mass spectra (HRMS) were obtained
by using Electrospray Ionization (ESI) with Micro-Tof; m/z values are reported (For each measurement, the
mass scale was recalibrated with sodium formate clusters, and samples were dissolved and measured in
MeOH or CH3CN). Melting points were determined on an automated instrument. Flash chromatography was
performed using thick-walled glass columns and “flash grade” silica gel (230-400 mesh). Thin layer
chromatography (TLC) was accomplished by using commercially prepared 0.25 mm silica gel and
visualization was effected with short wavelength UV lamp (254 nm). The relative proportions of solvents in
chromatography solvent mixtures refer to the volume:volume ratio. All commercially available reagents
were used directly without purification unless otherwise stated. All solvents used in reactions and
chromatography were distilled and/or dried properly for purity. The inert atmosphere was created by slight
positive pressure (ca. 0.1 psi) of argon. All glassware was dried in oven prior to use.
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α,β-Alkynic ketones 9 were prepared according to our previous studies, 26a,27a except that α,β-alkynic
ketones 9g,h,m,p and u were synthesized in this study. Accordingly, N-propargylic β-enaminones 1 and 10
were prepared according to our previous studies, 26a,27a except that N-propargylic β-enaminones 1g,h,m,p and
u were synthesized in this study.
General Procedure for the synthesis of α,β-alkynic ketones 9. To a stirred solution of the corresponding
aryloyl chloride (1.2 mmol) in THF (5.0 mL) at room temperature under argon was added PdCl2(PPh3)2 (14
mg, 0.02 mmol) and Et3N (122 mg, 1.2 mmol), respectively, and the mixture was stirred for 10 min. Then
CuI (4 mg, 0.02 mmol) was added and the reaction mixture was stirred for another 10 min. Subsequently,
terminal acetylene (1.0 mmol) was added over 15 min, and the resulting reaction mixture was stirred at room
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temperature for approximately 6 h (Note that the progress of the reaction was monitored by routine TLC for
the disappearance of terminal acetylene). After the reaction was complete, THF was removed on a rotary
evaporator. The obtained residue was dissolved in ethyl acetate (50 mL) and the solution was washed with
0.1 N HCl (10 mL) and subsequently with a saturated aqueous solution of NH4Cl (10 mL) in a separatory
funnel. After the phases were separated, organic phase was dried over MgSO4 and evaporated on a rotary
evaporator to give the crude product, which was purified by flash chromatography on silica gel using
hexane/ethyl acetate (19:1) as the eluent to afford the corresponding α,β-alkynic ketone 9.
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3-(3,4-Dichlorophenyl)-1-phenylprop-2-yn-1-one (9g). Benzoyl chloride (307 mg, 2.18 mmol),
PdCl2(PPh3)2 (28 mg, 0.04 mmol), Et3N (222 mg, 2.18 mmol), CuI (8 mg, 0.04 mmol) and 3,4-
dichlorophenylacetylene (311 mg, 1.82 mmol) were employed to afford 407 mg (82%) of the indicated
1
product as a light yellow solid (Rf = 0.65 in 4:1 hexane/ethyl acetate; mp 111.5–112.8 °C). H NMR (400
MHz, CDCl3) δ 8.10 (d, J = 7.4 Hz, 2H), 7.65 (s, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.48–7.38 (m, 4H); 13C{1H}
NMR (100 MHz, CDCl3) δ 177.2 (CO), 136.3 (C), 135.3 (C), 134.18 (CH), 134.16 (CH), 132.9 (C), 131.7
(CH), 130.6 (CH), 129.3 (CH), 128.5 (CH), 119.8 (C), 89.4 (C), 87.7 (C); IR (neat): 3057, 2196, 2022, 1632,
1595, 1577, 1448, 1374, 1313, 1295, 1250, 1208, 1124, 1013, 823, 688 cm-1; HRMS (ESI) m/z: [M + H]+
Calcd for C15H9Cl2O 275.0025; Found 275.0020.
3-[3,5-Bis(trifluoromethyl)phenyl]-1-phenylprop-2-yn-1-one (9h). Benzoyl chloride (246 mg, 1.75
mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol), Et3N (178 mg, 1.75 mmol), CuI (6 mg, 0.03 mmol) and 1-ethynyl-
3,5-bis(trifluoromethyl)benzene (348 mg, 1.46 mmol) were employed to afford 439 mg (88%) of the
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indicated product as a brown solid (Rf = 0.81 in 4:1 hexane/ethyl acetate; mp 65.1–66.5 °C). H NMR (400
MHz, CDCI3) δ 8.20 (dd, J = 8.3, 1.1 Hz, 2H), 8.10 (s, 2H), 7.97 (s, 1H), 7.67 (tt, J = 7.0, 1.2 Hz, 1H), 7.59-
7.50 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.2 (CO), 136.4 (C), 134.8 (CH), 132.8 (CH), 132.7 (q,
2J = 34.1 Hz, C-CF3), 129.7 (CH), 128.9 (CH), 124.1 (q, 3J = 6.2 Hz, CH), 122.82 (C), 122.79 (q, 1J = 272.9
Hz, CF3), 88.7 (C), 88.1 (C); IR (neat): 3097, 2211, 1638, 1451, 1378, 1316, 1275, 1126, 1034, 1017, 896,
846, 795, 681, 629 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C17H9F6O 343.0552; Found 343.0544.
1-(2-Iodophenyl)-3-phenylprop-2-yn-1-one (9m). 2-Iodobenzoyl chloride (483 mg, 1.81 mmol),
PdCl2(PPh3)2 (21 mg, 0.03 mmol), Et3N (184 mg, 1.81 mmol), CuI (6 mg, 0.03 mmol) and phenylacetylene
(154 mg, 1.51 mmol) were employed to afford 230 mg (46%) of the indicated product as yellow oil (Rf =
0.67 in 4:1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 8.14 (dd, J = 7.8, 1.6 Hz, 1H), 8.06 (dd, J =
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7.9, 0.9 Hz, 1H), 7.65 (dd, J = 8.3, 1.3 Hz, 2H), 7.54–7.37 (m, 4H), 7.21 (td, J = 7.7, 1.7 Hz, 1H); C{1H}
NMR (100 MHz, CDCl3) δ 178.2 (CO), 142.2 (CH), 139.6 (C), 133.5 (CH), 133.2 (CH), 133.1 (CH), 131.1
(CH), 128.8 (CH), 128.2 (CH), 120.1 (C), 94.5 (C), 92.9 (C), 87.3 (C); IR (neat): 3056, 2190, 1724, 1642,
1577, 1487, 1427, 1290, 1199, 1123, 1055, 1004, 991, 812, 731, 686 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd
for C15H10IO 332.9771; Found 332.9782.
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1-(2-Bromophenyl)-3-(4-chlorophenyl)prop-2-yn-1-one (9p). 2-Bromobenzoyl chloride (392 mg,
1.79 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol), Et3N (182 mg, 1.79 mmol), CuI (6 mg, 0.03 mmol) and 1-
chloro-4-ethynylbenzene (204 mg, 1.49 mmol) were employed to afford 405 mg (81%) of the indicated
product as a light brown solid (Rf = 0.65 in 4:1 hexane/ethyl acetate; mp 95.8–97 °C). 1H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.51 (d, J = 8.2 Hz, 2H), 7.45–7.37 (m, 2H), 7.33
(d, J = 8.1 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 177.1 (CO), 137.4 (C), 137.1 (C), 135.0 (CH), 134.3
(CH), 133.6 (CH), 132.8 (CH), 129.1 (CH), 127.5 (CH), 121.3 (C), 118.4 (C), 92.7 (C), 88.6 (C); IR (neat):
3081, 2196, 1646, 1582, 1480, 1298, 1200, 1085, 1011, 829, 775, 728, 666, 634 cm-1; HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H9BrClO 318.9520; Found 318.9532.
3-[4-(tert-Butyl)phenyl]-1-(4-chlorophenyl)prop-2-yn-1-one (9u). 4-Chlorobenzoyl chloride (354
mg, 2.02 mmol), PdCl2(PPh3)2 (21 mg, 0.03mmol), Et3N (206 mg, 2.02 mmol), CuI (6 mg, 0.03mmol) and 1-
(tert-butyl)-4-ethynylbenzene (266 mg, 1.68 mmol) were employed to afford 474 mg (95%) of the indicated
product as a yellow solid (Rf = 0.80 in 4:1 hexane/ethyl acetate; mp 104.3–105.9 °C). 1H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.39–7.32 (m, 4H), 1.23 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) δ 176.9 (CO), 155.0 (C), 140.8 (C), 135.7 (C), 133.3 (CH), 131.1 (CH), 129.2 (CH),
126.1 (CH), 117.1 (C), 94.6 (C), 86.8 (C), 35.4 (C), 31.3 (CH3); IR (neat): 2963, 2194, 2049, 2020, 1630,
1585, 1572, 1484, 1400, 1300, 1285, 1265, 1161, 1090, 1025, 1006, 838, 746, 675, 627 cm-1; HRMS (ESI)
m/z: [M + H]+ Calcd for C19H18ClO 297.1041; Found 297.1046.
General Procedure for the synthesis of N-propargylic β-enaminones 1. To a stirred solution of the
corresponding α,β-alkynic ketone 9 (1.0 mmol) in absolute MeOH (5 mL) at room temperature under argon
o
was added propargylamine (1.2 mmol), and the resulting mixture was heated at 65 C in an oil bath for
approximately 2 h (Note that the progress of the reaction was monitored by the routine TLC analysis for the
disappearance of α,β-alkynic ketone. After the reaction was over, the solvent was removed on a rotary
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evaporator, and ethyl acetate (50 mL) and a saturated aqueous solution of NaCl (50 mL) were added. After
the layers were separated, the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The combined
organic layers were dried over MgSO4 and evaporated on a rotary evaporator to give the crude product,
which was purified by flash chromatography on silica gel using hexane/ethyl acetate (9:1 followed by 4:1) as
the eluent to afford the corresponding N-propargylic β-enaminone 1.
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(Z)-3-(3,4-Dichlorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1g).
3-(3,4-
Dichlorophenyl)-1-phenylprop-2-yn-1-one (9g) (311 mg, 1.13 mmol) and propargylamine (75 mg, 1.36
mmol) were employed to afford 335 mg (90%) of the indicated product as a light yellow solid (Rf = 0.59 in
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4:1 hexane/ethyl acetate; mp 97.7–98.2 °C). H NMR (400 MHz, CDCl3) δ 11.17 (t, J = 6.5 Hz, 1H), 7.89
(dd, J = 8.2, 1.4 Hz, 2H), 7.62 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.49–7.39 (m, 3H), 7.35 (dd, J =
8.2, 2.0 Hz, 1H), 5.81 (s, 1H), 3.90 (dd, J = 6.4, 2.5 Hz, 2H), 2.33 (t, J = 2.5 Hz, 1H); C{1H} NMR (100
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MHz, CDCl3) δ 189.6 (CO), 163.0 (C), 139.6 (C), 134.9 (C), 134.4 (C), 133.3 (C), 131.4 (CH), 130.9 (CH),
130.0 (CH), 128.4 (CH), 127.3 (CH), 95.1 (CH), 79.6 (C), 72.9 (CH), 34.3 (CH2) (Note that two CH peaks
overlap on each other); IR (neat): 3244, 3061, 1575, 1541, 1460, 1321, 1297, 1241, 1149, 1074, 1024, 926,
897, 801, 740, 682 cm-1; HRMS (ESI) m/z: [M H]Calcd for C18H12Cl2NO 328.0301; Found 328.0313.
(Z)-3-[3,5-Bis(trifluoromethyl)phenyl]-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1h). 3-
[3,5-Bis(trifluoromethyl)phenyl]-1-phenylprop-2-yn-1-one (9h) (423 mg, 1.24 mmol) and propargylamine
(82 mg, 1.49 mmol) were employed to afford 350 mg (71%) of the indicated product as a light brown solid
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(Rf = 0.65 in 4:1 hexane/ethyl acetate; mp 111.6–112.3 °C). H NMR (400 MHz, CDCl3) δ 11.17 (t, J = 6.1
Hz, 1H), 8.02 (s, 3H), 7.90 (d, J = 7.0 Hz, 2H), 7.55–7.34 (m, 3H), 5.85 (s, 1H), 3.86 (dd, J = 6.6, 2.5 Hz,
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2H), 2.35 (t, J = 2.5 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 189.7 (CO), 161.7 (C), 139.0 (C), 136.8
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(C), 132.1 (q, J = 33.8 Hz, C-CF3), 131.4 (CH), 128.24 (CH), 128.16 (CH), 127.1 (CH), 123.3 (q, J = 4.6
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Hz, CH), 122.7 (q, J = 273.2 Hz, CF3), 95.4 (CH), 79.0 (C), 72.8 (CH), 34.0 (CH2); IR (neat): 3281, 2927,
1597, 1577, 1535, 1462, 1378, 1278, 1173, 1123, 1054, 1023, 903, 846, 752, 692, 673, 638 cm-1; HRMS
(ESI) m/z: [M + H]+ Calcd for C20H14F6NO 398.0974; Found 398.0985.
(Z)-1-(2-Iodophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1m). 1-(2-Iodophenyl)-
3-phenylprop-2-yn-1-one (9m) (202 mg, 0.61 mmol) and propargylamine (40 mg, 0.73 mmol) were
employed to afford 173 mg (73%) of the indicated product as light brown oil (Rf = 0.50 in 4:1 hexane/ethyl
acetate). 1H NMR (400 MHz, CDCl3) δ 11.07 (br s, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.52–7.37 (m, 6H), 7.32 (t,
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J = 7.5 Hz, 1H), 7.00 (td, J = 7.7, 1.7 Hz, 1H), 5.41 (s, 1H), 3.96 (dd, J = 6.4, 2.4 Hz, 2H), 2.33 (t, J = 2.4
Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.4 (CO), 165.8 (C), 146.4 (C), 139.9 (CH), 134.3 (C), 130.3
(CH), 130.0 (CH), 128.7 (CH), 128.4 (CH), 127.8 (CH), 97.7 (CH), 92.6 (C), 79.6 (C), 72.7 (CH), 34.3
(CH2) (Note that two CH peaks overlap on each other); IR (neat): 3286, 3054, 1557, 1481, 1315, 1144, 1075,
1010, 925, 870, 749, 698 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C18H15INO 388.0193; Found 388.0191.
(Z)-1-(2-Bromophenyl)-3-(4-chlorophenyl)-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1p). 1-(2-
Bromophenyl)-3-(4-chlorophenyl)prop-2-yn-1-one (9p) (396 mg, 1.18 mmol) and propargylamine (78 mg,
1.42 mmol) were employed to afford 426 mg (96%) of the indicated product as a brown solid (Rf = 0.45 in
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4:1 hexane/ethyl acetate; mp 82.3–83.6 °C). H NMR (400 MHz, CDCl3) δ 11.02 (br s, J = 6.6 Hz, 1H), 7.56
(dd, J = 8.0, 1.2 Hz, 1H), 7.46–7.40 (m, 5H), 7.30 (td, J = 7.5, 1.2 Hz, 1H), 7.19 (td, J = 7.7, 1.8 Hz, 1H),
5.44 (s, 1H), 3.94 (dd, J = 6.5, 2.5 Hz, 2H), 2.34 (t, J = 2.5 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
191.2 (CO), 164.4 (C), 142.8 (C), 136.2 (C), 133.4 (CH), 132.7 (C), 130.4 (CH), 129.3 (CH), 129.2 (CH),
129.0 (CH), 127.2 (CH), 119.4 (C), 98.5 (CH), 79.5 (C), 72.9 (CH), 34.3 (CH2); IR (neat): 3297, 3053, 1589,
1554, 1478, 1320, 1260, 1145, 1084, 1015, 831, 778, 753, 638 cm-1; HRMS (ESI) m/z: [M H]Calcd for
C18H12BrClNO 371.9796; Found 371.9798.
(Z)-3-[4-(tert-Butyl)phenyl]-1-(4-chlorophenyl)-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1u). 3-
[4-(tert-Butyl)phenyl]-1-(4-chlorophenyl)prop-2-yn-1-one (9u) (423 mg, 1.42 mmol) and propargylamine
(94 mg, 1.70 mmol) were employed to afford 492 mg (98%) of the indicated product as a reddish-orange
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solid (Rf = 0.71 in 4:1 hexane/ethyl acetate; mp 72.3–72.9 °C). H NMR (400 MHz,CDCl3) δ 11.36 (br s,
1H), 7.83 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H),
5.78 (s, 1H), 3.99 (dd, J = 6.3, 2.5 Hz, 2H), 2.33 (t, J = 2.5 Hz, 1H), 1.36 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 187.2 (CO), 166.2 (C), 153.1 (C), 138.2 (C), 136.8 (C), 131.5 (C), 128.4 (CH), 128.2 (CH), 127.4
(CH), 125.4 (CH), 94.0 (CH), 79.5 (C), 72.3 (CH), 34.7 (CH2), 34.2 (C), 31.0 (CH3); IR (neat): 3283, 2959,
1582, 1539, 1501, 1478, 1295, 1267, 1221, 1146, 1089, 1063, 1009, 839, 773, 672 cm-1; HRMS (ESI) m/z:
[M + H]+ Calcd for C22H23ClNO 352.1463; Found 352.1476.
General Procedure for the synthesis of 3-[(4-nitrophenyl)thio]-substituted 4-methylene-1-pyrrolines 8
(Table 2). To a stirred solution of N-propargylic β-enaminone
1 (0.30 mmol) in acetonitrile (5 mL) at
room temperature under argon was added 4-nitrobenzenesulfenyl chloride (0.36 mmol), and the
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β-enaminone was completely consumed as monitored by the routine TLC analysis. Reaction
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mixture was then allowed to cool to room temperature, and the base, NaH (60% dispersion in mineral
oil, 0.30 mmol) or Cs2CO3 (0.30 mmol), was added into flask. Afterward, the resulting mixture was
heated at reflux in an oil bath again. The reaction was continued until the in situ formed α-
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sulfenylated N-propargylic β-enaminone
7 was completely consumed as monitored by the routine
TLC analysis. After the reaction was over, solvent was removed on a rotary evaporator. The obtained
residue was dissolved in ethyl acetate (30 mL) and a saturated aqueous solution of NH4Cl (30 mL)
was added. After the layers were separated, the aqueous layer was extracted with ethyl acetate (2 x
30 mL). The combined organic layers were dried over MgSO4 and evaporated on a rotary evaporator
to give the crude product, which was purified by flash chromatography on silica gel using
hexane/ethyl acetate (9:1 followed by 4:1) as the eluent to afford the corresponding 4-methylene-1-
pyrroline derivative 8.
{3-Methylene-4-[(4-nitrophenyl)thio]-5-phenyl-3,4-dihydro-2H-pyrrol-4-yl}(phenyl)methanone
(8a). (Z)-1,3-Diphenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1a) (97 mg, 0.37 mmol), 4-
nitrobenzenesulfenyl chloride (88 mg, 0.44 mmol) and the base, NaH (60% dispersion in mineral oil, 15 mg,
0.37 mmol) or Cs2CO3 (121 mg, 0.37 mmol), were employed to afford 109 mg (71%) and 104 mg (68%) of
the indicated product with NaH and Cs2CO3, respectively, as an orange-brown solid (Rf = 0.38 in 4:1
hexane/ethyl acetate; mp 124.1-125 °C). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 9.1 Hz, 2H), 7.48 (d, J =
7.2 Hz, 2H), 7.21–6.95 (m, 5H), 6.92–6.76 (m, 5H), 5.16 (s, 1H), 4.93 (s, 1H), 4.49 (s, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 194.4 (CO), 150.9 (C), 147.6 (C), 142.7 (C), 137.4 (C), 136.9 (C), 135.4 (C), 132.2
(CH), 130.3 (CH), 129.6 (CH), 129.4 (CH), 128.4 (CH), 127.8 (CH), 124.9 (CH), 122.9 (CH), 120.0 (C),
109.0 (=CH2), 56.8 (CH2); IR (neat): 3098, 2919, 2848, 1733, 1527, 1505, 1485, 1445, 1335, 1311, 1269,
1235, 1166, 1096, 884, 783, 755, 715, 692 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H19N2O3S
415.1111; Found 415.1112.
When the reaction was carried out on a relatively larger scale by employing (Z)-1,3-diphenyl-3-(prop-
2-yn-1-ylamino)prop-2-en-1-one (1a) (413 mg, 1.58 mmol), 4-nitrobenzenesulfenyl chloride (377 mg, 1.89
mmol) and NaH (60% dispersion in mineral oil, 63 mg, 1.58 mmol) in acetonitrile (11 mL), the indicated
product (8a) was obtained in 484 mg (74%).
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{5-(3-Fluorophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-
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yl}(phenyl)methanone (8b). (Z)-3-(3-Fluorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1b) (96 mg, 0.34 mmol), 4-nitrobenzenesulfenyl chloride (82 mg, 0.41 mmol) and the base, NaH (60%
dispersion in mineral oil, 14 mg, 0.34 mmol) or Cs2CO3 (111 mg, 0.34 mmol), were employed to afford 83
mg (57%) and 88 mg (60%) of the indicated product with NaH and Cs2CO3, respectively, as a reddish-
orange solid (Rf = 0.21 in 4:1 hexane/ethyl acetate; mp 92.8-93.5 °C). 1H NMR (400 MHz, CDCl3) δ 7.91 (d,
J = 9.1 Hz, 2H), 7.52 (dd, J = 8.3, 1.2 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 7.08 (t, J = 7.7 Hz, 2H), 6.92–6.75
(m, 5H), 6.56 (tdd, J = 8.3, 2.7, 1.1 Hz, 1H), 5.19 (d, J = 1.0 Hz, 1H), 4.95 (s, 1H), 4.47 (s, 2H); 13C{1H}
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1
4
NMR (100 MHz, CDCl3) δ 193.8 (CO), 162.1 (d, J = 248.0 Hz, CF), 150.4 (C), 144.9 (d, J = 3.5 Hz, C),
3
3
142.7 (C), 137.4 (d, J = 7.4 Hz, C), 136.9 (C), 136.0 (C), 132.3 (CH), 129.8 (d, J = 8.2 Hz, CH), 129.0
4
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(CH), 127.7 (CH), 125.9 (d, J = 3.1 Hz, CH), 124.7 (CH), 122.5 (CH), 121.2 (C), 116.4 (d, J = 16.2 Hz,
CH), 116.2 (d, 2J = 14.7 Hz, CH), 109.3 (=CH2), 56.4 (CH2); IR (neat): 3067, 2165, 1738, 1613, 1591, 1538,
1494, 1265, 1239, 1215, 1174, 1138, 1096, 848, 815, 788, 753, 705, 686, 668 cm-1; HRMS (ESI) m/z: [M +
H]+ Calcd for C24H18FN2O3S 433.1017; Found 433.1023.
{5-(4-Chlorophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8c). (Z)-3-(4-Chlorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1c)
(93 mg, 0.31 mmol), 4-nitrobenzenesulfenyl chloride (74 mg, 0.37 mmol) and the base, NaH (60%
dispersion in mineral oil, 12 mg, 0.31 mmol) or Cs2CO3 (101 mg, 0.31 mmol), were employed to afford 84
mg (60%) and 71 mg (51%) of the indicated product with NaH and Cs2CO3, respectively, as an orange solid
1
(Rf = 0.22 in 4:1 hexane/ethyl acetate; mp 104.5-105.5 °C). H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 9.1
Hz, 2H), 7.57 (d, J = 7.1 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.7 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H),
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6.97–6.87 (m, 4H), 5.26 (s, 1H), 5.02 (s, 1H), 4.54 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 194.1 (CO)
150.7 (C), 145.8 (C), 143.0 (C), 137.2 (C), 136.4 (C), 135.6 (C), 134.0 (C), 132.6 (CH), 131.3 (CH), 129.4
(CH), 128.8 (CH), 128.1 (CH), 125.0 (CH), 123.0 (CH), 120.9 (C), 109.5 (=CH2), 56.8 (CH2); IR (neat):
3007, 2886, 2142, 2046, 2010, 1590, 1486, 1331, 1313, 1286, 1234, 1174, 1089, 1011, 857, 736, 717, 694
cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H18ClN2O3S 449.0721; Found 449.0715.
{5-(4-Bromophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8d). (Z)-3-(4-Bromophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1d) (90 mg, 0.26 mmol), 4-nitrobenzenesulfenyl chloride (62 mg, 0.31 mmol) and the base, NaH (60%
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dispersion in mineral oil, 10 mg, 0.26 mmol) or Cs2CO3 (85 mg, 0.26 mmol), were employed to afford 69 mg
(54%) and 65 mg (51%) of the indicated product with NaH and Cs2CO3, respectively, as a light orange oil
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(Rf = 0.25 in 4:1 hexane/ethyl acetate). H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 9.1 Hz, 2H), 7.57 (d, J =
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7.1 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.16 (t, J = 7.7 Hz, 2H), 7.09–6.99 (m, 4H), 6.94 (d, J = 9.2 Hz, 2H),
5.26 (s, 1H), 5.02 (s, 1H), 4.54 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.7 (CO), 150.4 (C), 145.5
(C), 142.7 (C), 136.9 (C), 136.1 (C), 134.1 (C), 132.3 (CH), 131.5 (CH), 131.2 (CH), 129.1 (CH), 127.8
(CH), 124.8 (CH), 123.7 (C), 122.7 (CH), 120.7 (C), 109.3 (=CH2), 56.6 (CH2); IR (neat): 2923, 2190, 1730,
1590, 1528, 1475, 1393, 1333, 1313, 1286, 1236, 1100, 1069, 1008, 855, 693 cm-1; HRMS (ESI) m/z: [M +
H]+ Calcd for C24H18BrN2O3S 493.0216; Found 493.0216.
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{3-Methylene-4-[(4-nitrophenyl)thio]-5-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8e). (Z)-1-Phenyl-3-(prop-2-yn-1-ylamino)-3-[4-(trifluoromethyl)phenyl]prop-2-en-
1-one (1e) (97 mg, 0.29 mmol), 4-nitrobenzenesulfenyl chloride (70 mg, 0.35 mmol) and the base, NaH
(60% dispersion in mineral oil, 12 mg, 0.29 mmol) or Cs2CO3 (95 mg, 0.29 mmol), were employed to afford
89 mg (64%) and 88 mg (63%) of the indicated product with NaH and Cs2CO3, respectively, as a yellow
solid (Rf = 0.22 in 4:1 hexane/ethyl acetate; mp 148.8-150.1 °C). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J =
9.1 Hz, 2H), 7.50 (d, J = 7.1 Hz, 2H), 7.25–7.17 (m, 3H), 7.15–7.03 (m, 4H), 6.88 (d, J = 9.1 Hz, 2H), 5.21
(d, J = 1.0 Hz, 1H), 4.97 (s, 1H), 4.48 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.6 (CO), 150.3 (C),
2
144.4 (C), 142.8 (C), 138.7 (C), 136.7 (C), 135.6 (C), 132.5 (CH), 130.8 (q, J = 32.6 Hz, C-CF3), 130.0
(CH), 129.1 (CH), 127.9 (CH), 125.1 (q, 3J = 8.1 Hz, CH), 124.9 (CH), 123.4 (q, 1J = 270.6 Hz, CF3), 122.6
(CH), 119.0 (C), 109.7 (=CH2), 56.5 (CH2); IR (neat): 2927, 2330, 2177, 1920, 1593, 1525, 1495, 1320,
1285, 1231, 1167, 1124, 1109, 1064, 718 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H18F3N2O3S
483.0985; Found 483.0985.
{3-Methylene-5-(4-nitrophenyl)-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8f). (Z)-3-(4-Nitrophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1f)
(98 mg, 0.32 mmol), 4-nitrobenzenesulfenyl chloride (76 mg, 0.38 mmol) and the base, NaH (60%
dispersion in mineral oil, 13 mg, 0.32 mmol) or Cs2CO3 (104 mg, 0.32 mmol), were employed to afford 62
mg (42%) and 47 mg (32%) of the indicated product with NaH and Cs2CO3, respectively, as a reddish orange
oil (Rf = 0.10 in 4:1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 9.1 Hz, 2H), 7.83 (d, J
= 8.9 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.38–7.34 (m, 3H), 7.21 (t, J = 7.7 Hz, 2H), 6.95 (d, J = 9.2 Hz, 2H),
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5.34 (d, J = 1.1 Hz, 1H), 5.08 (d, J = 1.0 Hz, 1H), 4.55 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 193.2
(CO), 150.1 (C), 147.3 (C), 143.0 (C), 142.5 (C), 141.4 (C), 136.4 (C), 135.0 (CH), 133.1 (C), 130.2 (CH),
129.3 (CH), 128.1 (CH), 125.0 (CH), 124.0 (C), 123.4 (CH), 122.6 (CH), 110.4 (=CH2), 56.4 (CH2); IR
(neat): 2915, 2848, 2236, 2179, 2011, 1942, 1613, 1589, 1337, 1282, 1232, 1103, 866, 727, 717 cm-1; HRMS
(ESI) m/z: [M + H]+ Calcd for C24H18N3O5S 460.0962; Found 460.0965.
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{5-(3,4-Dichlorophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8g). (Z)-3-(3,4-Dichlorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1g) (89 mg, 0.27 mmol), 4-nitrobenzenesulfenyl chloride (64 mg, 0.32 mmol) and the base, NaH (60%
dispersion in mineral oil, 11 mg, 0.27 mmol) or Cs2CO3 (88 mg, 0.27 mmol), were employed to afford 91 mg
(70%) and 96 mg (74%) of the indicated product with NaH base and Cs2CO3, respectively, as a yellowish-
brown solid (Rf = 0.29 in 4:1 hexane/ethyl acetate); mp 87.7-89.3 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (d,
J = 9.1 Hz, 2H), 7.56 (d, J = 7.1 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 9.9 Hz, 2H), 7.18 (t, J = 7.7
13
Hz, 2H), 7.00– 6.95 (m, 3H), 5.28 (d, J = 0.7 Hz, 1H), 5.03 (s, 1H), 4.52 (s, 2H); C{1H} NMR (100 MHz,
CDCl3) δ 193.6 (CO), 150.2 (C), 144.0 (C), 142.9 (C), 136.9 (C), 135.6 (C), 135.1 (C), 133.3 (C), 132.5 (C),
132.4 (CH), 131.4 (CH), 130.1 (CH), 128.9 (CH), 128.6 (CH), 127.8 (CH), 124.9 (CH), 122.8 (CH), 121.9
(C), 109.7 (=CH2), 56.6 (CH2); IR (neat): 3061, 2918, 1729, 1590, 1493, 1462, 1331, 1312, 1288, 1232,
1107, 1027, 849, 749, 700 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H17Cl2N2O3S 483.0331; Found
483.0332.
{5-(3,5-Bis(trifluoromethyl)phenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-
4-yl}(phenyl)methanone
(8h).
(Z)-3-[3,5-Bis(trifluoromethyl)phenyl]-1-phenyl-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (1h) (99 mg, 0.25 mmol), 4-nitrobenzenesulfenyl chloride (60 mg, 0.30 mmol) and
the base, NaH (60% dispersion in mineral oil, 10 mg, 0.25 mmol) or Cs2CO3 (82 mg, 0.25 mmol), were
employed to afford 87 mg (63%) and 104 mg (76%) of the indicated product with NaH and Cs2CO3,
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respectively, as a brownish-yellow solid (Rf = 0.44 in 4:1 hexane/ethyl acetate; mp 205.8-206.5 °C). H
NMR (400 MHz, CDCl3) δ 7.96 (d, J = 9.1 Hz, 2H), 7.50 (s, 2H), 7.43 (d, J = 7.1 Hz, 2H), 7.33 (s, 1H),
7.22–7.14 (m, 1H), 7.05 (t, J = 7.7 Hz, 2H), 6.92 (d, J = 9.1 Hz, 2H), 5.29 (s, 1H), 5.00 (s, 1H), 4.49 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 193.3 (CO), 150.0 (C), 143.3 (q, 2J = 29.2 Hz, C-CF3), 137.6 (C), 136.7
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(C), 134.9 (C), 132.7 (CH), 131.8 (C), 131.5 (C), 129.6 (q, J = 8.3 Hz, CH), 129.0 (CH), 127.9 (CH), 125.0
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(CH), 123.4 (CH), 122.9 (q, J = 272.9 Hz, CF3), 122.5 (q, 3J = 7.2 Hz, CH), 120.9 (C), 110.5 (=CH2), 57.0
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(CH2); IR (neat): 2349, 1974, 1608, 1545, 1517, 1381, 1342, 1278, 1222, 1172, 1122, 1029, 860, 845, 716,
699 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C26H17F6N2O3S 551.0859; Found 551.0860.
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{3-Methylene-4-[(4-nitrophenyl)thio]-5-(p-tolyl)-3,4-dihydro-2H-pyrrol-4-yl}(phenyl)methanone
(8i). (Z)-1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(p-tolyl)prop-2-en-1-one (1i) (101 mg, 0.37 mmol), 4-
nitrobenzenesulfenyl chloride (88 mg, 0.44 mmol) and the base, NaH (60% dispersion in mineral oil, 15 mg,
0.37 mmol) or Cs2CO3 (121 mg, 0.37 mmol), were employed to afford 115 mg (73%) and 98 mg (62%) of
the indicated product with NaH and Cs2CO3, respectively, as an orange-brown solid (Rf = 0.31 in 4:1
hexane/ethyl acetate; mp 164.7-165.5 °C). 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 9.1 Hz, 2H), 7.56 (d, J
= 7.2 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 7.09 (t, J = 7.7 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 9.1 Hz,
2H), 6.70 (d, J = 8.0 Hz, 2H), 5.22 (s, 1H), 5.00 (s, 1H), 4.56 (s, 2H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 194.1 (CO), 150.7 (C), 147.8 (C), 142.3 (C), 139.5 (C), 137.2 (C), 136.9 (C), 132.2 (C), 131.6
(CH), 130.0 (CH), 129.0 (CH), 128.8 (CH), 127.4 (CH), 124.5 (CH), 122.6 (CH), 118.9 (C), 108.4 (=CH2),
56.4 (CH2), 20.7 (CH3); IR (neat): 2349, 2155, 2051, 1993, 1974, 1733, 1612, 1591, 1531, 1494, 1342, 1313,
1239, 1100, 1037, 847, 818, 789, 711 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H21N2O3S 429.1267;
Found 429.1271.
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{5-[4-(tert-Butyl)phenyl]-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8j). (Z)-3-[4-(tert-Butyl)phenyl]-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1j) (95 mg, 0.30 mmol), 4-nitrobenzenesulfenyl chloride (72 mg, 0.36 mmol) and the base, NaH (60%
dispersion in mineral oil, 12 mg, 0.30 mmol) or Cs2CO3 (98 mg, 0.30 mmol), were employed to afford 88 mg
(62%) and 76 mg (54%) of the indicated product with NaH and Cs2CO3, respectively, as an orange solid (Rf
= 0.41 in 4:1 hexane/ethyl acetate; mp 190.7-191.5 °C). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.1 Hz,
2H), 7.46 (d, J = 7.1 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.06–6.99 (m, 4H), 6.97 (d, J = 9.2 Hz, 2H), 6.88 (d, J
= 8.5 Hz, 2H), 5.24 (s, 1H), 5.00 (s, 1H), 4.56 (s, 2H), 1.03 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ
194.2 (CO), 152.7 (C), 150.7 (C), 148.5 (C), 142.4 (C), 137.5 (C), 137.0 (C), 132.1 (C), 131.3 (CH), 130.0
(CH), 128.8 (CH), 127.3 (CH), 124.9 (CH), 124.6 (CH), 122.8 (CH), 119.2 (C), 108.4 (=CH2), 56.6 (CH2),
34.2 (C), 30.4 (CH3); IR (neat): 3097, 2946, 1603, 1511, 1489, 1437, 1332, 1310, 1291, 1264, 1225, 1162,
1097, 1027, 888, 858, 716, 696, 656 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C28H27N2O3S 471.1737;
Found 471.1746.
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yl}(phenyl)methanone (8k). (Z)-3-(4-Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1k) (86 mg, 0.29 mmol), 4-nitrobenzenesulfenyl chloride (70 mg, 0.35 mmol) and the base, NaH (60%
dispersion in mineral oil, 12 mg, 0.29 mmol) or Cs2CO3 (95 mg, 0.29 mmol), were employed to afford 73 mg
(57%) and 61 mg (47%) of the indicated product with NaH and Cs2CO3, respectively, as an orange solid (Rf
= 0.21 in 4:1 hexane/ethyl acetate; mp 88.7-89.2 °C). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.1 Hz, 2H),
7.54 (d, J = 7.1 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 7.10 (t, J = 7.6 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.95 (d, J
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= 9.2 Hz, 2H), 6.43 (d, J = 8.8 Hz, 2H), 5.23 (s, 1H), 4.99 (s, 1H), 4.55 (s, 2H), 3.57 (s, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 194.2 (CO), 160.2 (C), 150.9 (C), 148.1 (C), 142.5 (C), 137.4 (C), 137.1 (C), 131.8
(CH), 131.7 (CH), 129.0 (CH), 127.7 (C), 127.6 (CH), 124.6 (CH), 122.9 (CH), 118.2 (C), 113.6 (CH), 108.4
(=CH2), 56.8 (CH2), 54.9 (CH3); IR (neat): 2349, 2254, 2190, 2160, 2044, 1739, 1591, 1497, 1331, 1313,
1237, 1171, 1108, 1025, 848, 752, 709 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H21N2O4S 445.1217;
Found 445.1219.
{3-Methylene-4-[(4-nitrophenyl)thio]-5-(thiophen-3-yl)-3,4-dihydro-2H-pyrrol-4-
yl}(phenyl)methanone (8l). (Z)-1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(thiophen-3-yl)prop-2-en-1-one (1l)
(97 mg, 0.36 mmol), 4-nitrobenzenesulfenyl chloride (87 mg, 0.43 mmol) and the base, NaH (60%
dispersion in mineral oil, 14 mg, 0.36 mmol) or Cs2CO3 (117 mg, 0.36 mmol), were employed to afford 121
mg (80%) and 123 mg (81%) of the indicated product with NaH and Cs2CO3, respectively, as a reddish-
orange solid (Rf = 0.40 in 4:1 hexane/ethyl acetate; mp 76.1-77.5 °C). 1H NMR (400 MHz, CDCl3) δ 7.97 (d,
J = 9.1 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.30–7.20 (m, 2H), 7.14 (t, J = 7.6 Hz, 2H), 6.94 (d, J = 9.1 Hz,
2H), 6.81 (dd, J = 5.1, 3.0 Hz, 1H), 6.63 (dd, J = 5.1, 1.3 Hz, 1H), 5.23 (s, 1H), 4.98 (s, 1H), 4.50 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 193.8 (CO), 150.7 (C), 142.7 (C), 141.8 (C), 137.2 (C), 136.9 (C), 136.4
(C), 132.0 (CH), 129.0 (CH), 128.9 (CH), 127.8 (CH), 127.3 (CH), 126.3 (CH), 124.7 (CH), 122.4 (CH),
118.9 (C), 109.0 (=CH2), 56.5 (CH2); IR (neat): 3102, 2958, 2849, 1728, 1590, 1494, 1307, 1279, 1237,
1174, 1108, 837, 798, 749, 692 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C22H17N2O3S2 421.0675; Found
421.0681.
(2-Iodophenyl){3-methylene-4-[(4-nitrophenyl)thio]-5-phenyl-3,4-dihydro-2H-pyrrol-4-
yl}methanone (8m). (Z)-1-(2-Iodophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1m) (72 mg,
0.19 mmol), 4-nitrobenzenesulfenyl chloride (46 mg, 0.23 mmol) and the base, NaH (60% dispersion in
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mineral oil, 8 mg, 0.19 mmol) or Cs2CO3 (62 mg, 0.19 mmol), were employed to afford 65 mg (63%) and 48
mg (47 %) of the indicated product with NaH and Cs2CO3, respectively, as an orange-brown solid (Rf = 0.38
in 4:1 hexane/ethyl acetate; mp 97.7-99.2 °C). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.1 Hz, 2H), 7.48
(d, J = 7.9 Hz, 1H), 7.18–7.14 (m, 3H), 6.99–6.90 (m, 6H), 6.68 (td, J = 7.6, 1.7 Hz, 1H), 5.32 (s, 1H), 4.97
(s, 1H), 4.57 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.4 (CO), 152.3 (C), 150.7 (C), 143.4 (C), 143.3
(C), 139.6 (CH), 136.8 (C), 134.9 (C), 130.9 (CH), 130.6 (CH), 130.4 (CH), 129.8 (CH), 128.0 (CH), 126.8
(CH), 124.7 (CH), 124.5 (CH), 118.8 (C), 109.0 (=CH2), 94.4 (C), 57.3 (CH2); IR (neat): 2349, 2097, 2016,
1591, 1513, 1334, 1308, 1286, 1233, 1108, 1013, 853, 736, 697 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for
C24H18IN2O3S 541.0077; Found 541.0081.
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(2-Bromophenyl){3-methylene-4-[(4-nitrophenyl)thio]-5-phenyl-3,4-dihydro-2H-pyrrol-4-
yl}methanone (8n). (Z)-1-(2-Bromophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1n) (93 mg,
0.27 mmol), 4-nitrobenzenesulfenyl chloride (64 mg, 0.32 mmol) and the base, NaH (60% dispersion in
mineral oil, 11 mg, 0.27 mmol) or Cs2CO3 (88 mg, 0.27 mmol), were employed to afford 77 mg (58%) and
90 mg (67%) of the indicated product with NaH and Cs2CO3, respectively as an orange solid (Rf = 0.21 in 4:1
1
hexane/ethyl acetate; mp 149.7-150.2 °C). H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 9.4, 2.7 Hz, 2H),
7.19–7.11 (m, 4H), 6.99–6.89 (m, 6H), 6.85 (td, J = 7.7, 1.9 Hz, 1H), 5.30 (s, 1H), 4.97 (s, 1H), 4.54 (s, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 192.5 (CO), 152.7 (C), 151.0 (C), 143.6 (C), 140.6 (C), 137.2 (C), 135.0
(C), 133.1 (CH), 131.1 (CH), 131.0 (CH), 130.9 (CH), 130.1 (CH), 128.2 (CH), 126.4 (CH), 124.9 (CH),
124.7 (CH), 120.6 (C), 119.7 (C), 109.2 (=CH2), 57.6 (CH2); IR (neat): 3057, 2044, 1748, 1631, 1587, 1509,
1490, 1426, 1336, 1307, 1288, 1236, 1173, 1103, 1025, 895, 850, 739 cm-1; HRMS (ESI) m/z: [M + H]+
Calcd for C24H18BrN2O3S 493.0216; Found 493.0226.
(2-Bromophenyl){5-(3-fluorophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-
pyrrol-4-yl}methanone (8o). (Z)-1-(2-Bromophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-ylamino)prop-2-
en-1-one (1o) (107 mg, 0.30 mmol), 4-nitrobenzenesulfenyl chloride (72 mg, 0.36 mmol) and the base, NaH
(60% dispersion in mineral oil, 12 mg, 0.30 mmol) or Cs2CO3 (98 mg, 0.30 mmol), were employed to afford
89 mg (58%) and 107 mg (70%) of the indicated product with NaH and Cs2CO3, respectively, as a brown
solid (Rf = 0.29 in 4:1 hexane/ethyl acetate; mp 132.8-133.9 °C). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J =
9.0 Hz, 2H), 7.20 (d, J = 7.7 Hz, 2H), 7.03–6.88 (m, 6H), 6.84 (dt, J = 9.0, 2.1 Hz, 1H), 6.61 (td, J = 8.2, 2.6
13
Hz, 1H), 5.31 (s, 1H), 4.98 (s, 1H), 4.52 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 192.3 (CO), 161.9 (d,
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1J = 248.7 Hz, CF), 150.7 (C), 150.4 (d, J = 2.5 Hz, C), 143.8 (C), 140.4 (C), 137.2 (d, J = 7.7 Hz, C),
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136.7 (C), 133.2 (CH), 131.2 (CH), 131.0 (CH), 129.8 (d, J = 8.5 Hz, CH), 127.2 (d, J = 3.0 Hz, CH),
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126.6 (CH), 124.8 (2 x CH), 120.8 (C), 120.5 (C), 117.5 (d, J = 22.2 Hz, CH), 117.1 (d, 2J = 21.1 Hz, CH),
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109.6 (=CH2), 57.4 (CH2) (Note that two CH peaks overlap on each other); IR (neat): 3066, 2086, 2002,
1982, 1956, 1917, 1584, 1509, 1336, 1290, 1236, 1174, 1138, 1102, 812, 779, 706 cm-1; HRMS (ESI) m/z:
[M + H]+ Calcd for C24H17BrFN2O3S 511.0122; Found 511.0137.
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(2-Bromophenyl){5-(4-chlorophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-
pyrrol-4-yl}methanone (8p). (Z)-1-(2-Bromophenyl)-3-(4-chlorophenyl)-3-(prop-2-yn-1-ylamino)prop-2-
en-1-one (1p) (100 mg, 0.27 mmol), 4-nitrobenzenesulfenyl chloride (64 mg, 0.32 mmol) and the base, NaH
(60% dispersion in mineral oil, 11 mg, 0.27 mmol) or Cs2CO3 (88 mg, 0.27 mmol), were employed to afford
104 mg (73%) and 88 mg (62%) of the indicated product with NaH and Cs2CO3, respectively, as a yellowish-
brown solid (Rf = 0.19 in 4:1 hexane/ethyl acetate; mp 97.7-99.2 °C). 1H NMR (400 MHz, CDCl3) δ 7.95 (d,
J = 9.0 Hz, 2H), 7.17 (td, J = 8.5, 7.7, 1.6 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.03–6.93 (m, 4H), 6.87 (d, J =
13
8.4 Hz, 2H), 5.30 (s, 1H), 4.97 (s, 1H), 4.51 (s, 2H); C{1H} NMR (100 MHz, CDCl3) δ 191.8 (CO), 150.7
(C), 150.4 (C), 143.4 (C), 140.2 (C), 136.5 (C), 135.8 (C), 133.2 (C), 132.8 (CH), 131.8 (CH), 130.8 (CH),
130.7 (CH), 128.1 (CH), 126.3 (CH), 124.7 (CH), 124.5 (CH), 120.3 (C), 120.0 (C), 109.2 (=CH2), 57.2
(CH2); IR (neat): 2024, 1733, 1589, 1514, 1482, 1334, 1289, 1232, 1105, 1089, 1027, 1012, 853, 819, 736
cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H17BrClN2O3S 526.9826; Found 526.9816.
(2-Bromophenyl){3-methylene-4-[(4-nitrophenyl)thio]-5-[4-(trifluoromethyl)phenyl]-3,4-
dihydro-2H-pyrrol-4-yl}methanone
(8q).
(Z)-1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-[4-
(trifluoromethyl)phenyl]prop-2-en-1-one (1q) (87 mg, 0.21 mmol), 4-nitrobenzenesulfenyl chloride (50 mg,
0.25 mmol) and the base, NaH (60% dispersion in mineral oil, 8 mg, 0.21 mmol) or Cs2CO3 (68 mg, 0.21
mmol), were employed to afford 74 mg (63%) and 80 mg (68%) of the indicated product with NaH and
1
Cs2CO3, respectively, as a reddish-orange oil (Rf = 0.24 in 4:1 hexane/ethyl acetate). H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.20–7.11 (m, 4H), 7.00–6.95 (m, 3H), 6.89 (td,
J = 7.7, 1.7 Hz, 1H), 5.34 (s, 1H), 5.00 (s, 1H), 4.53 (s, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.0
(CO), 150.4 (C), 149.8 (C), 143.9 (C), 140.2 (C), 138.4 (C), 136.3 (C), 133.1 (CH), 131.6 (C), 131.3 (CH),
1
131.2 (CH), 131.0 (CH), 126.6 (CH), 125.0 (CH), 124.92 (CH), 124.90 (CH), 123.0 (q, J = 272.6 Hz, CF3),
121.7 (C), 120.5 (C), 109.9 (=CH2), 57.4 (CH2); IR (neat): 1966, 1942, 1731, 1590, 1492, 1321, 1231, 1163,
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1106, 1064, 1015, 852, 734, 630 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H17BrF3N2O3S 561.0090;
Found 561.0104.
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(2-Bromophenyl){5-(2-methoxyphenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-
pyrrol-4-yl}methanone (8r). (Z)-1-(2-Bromophenyl)-3-(2-methoxyphenyl)-3-(prop-2-yn-1-ylamino)prop-2-
en-1-one (1r) (99 mg, 0.27 mmol), 4-nitrobenzenesulfenyl chloride (64 mg, 0.32 mmol) and the base, NaH
(60% dispersion in mineral oil, 11 mg, 0.27 mmol) or Cs2CO3 (88 mg, 0.27 mmol), were employed to afford
111 mg (79%) and 74 mg (53%) of the indicated product with NaH and Cs2CO3, respectively, as a dark
brown solid (Rf = 0.19 in 4:1 hexane/ethyl acetate; mp 123.8-125.2 °C). 1H NMR (400 MHz, CDCl3) δ 7.89
(d, J = 9.1 Hz, 2H), 7.23 (dd, J = 7.5, 1.6 Hz, 1H), 7.13 (dd, J = 7.7, 2.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H),
6.92–6.83 (m, 3H), 6.63 (t, J = 7.5 Hz, 1H), 6.15 (d, J = 8.3 Hz, 1H), 5.30 (s, 1H), 5.00 (s, 1H), 4.49 (s, 2H),
3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.8 (CO), 155.7 (C), 150.1 (C), 149.7 (C), 143.2 (C),
140.9 (C), 137.8 (C), 132.8 (CH), 132.4 (CH), 131.7 (CH), 130.1 (CH), 129.2 (CH), 125.6 (CH), 124.1 (CH),
123.8 (CH), 123.5 (C), 120.14 (CH), 120.05 (C), 117.5 (C), 109.6 (=CH2), 108.1 (CH), 56.0 (CH2), 54.7
(CH3); IR (neat): 2832, 1732, 1582, 1506, 1485, 1459, 1335, 1292, 1240, 1179, 1131, 1025, 851, 746, 731,
703 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C25H20BrN2O4S 523.0322; Found 523.0332.
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(4-Chlorophenyl){3-methylene-4-[(4-nitrophenyl)thio]-5-phenyl-3,4-dihydro-2H-pyrrol-4-
yl}methanone (8s). (Z)-1-(4-Chlorophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1s) (96 mg,
0.33 mmol), 4-nitrobenzenesulfenyl chloride (80 mg, 0.40 mmol) and the base, NaH (60% dispersion in
mineral oil, 13 mg, 0.33 mmol) or Cs2CO3 (108 mg, 0.33 mmol), were employed to afford 129 mg (87%) and
105 mg (71%) of the indicated product with NaH and Cs2CO3, respectively, as a reddish-orange solid (Rf =
0.53 in 4:1 hexane/ethyl acetate; mp 84.3-85.7 °C). 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.0 Hz, 2H),
7.48 (d, J = 8.4 Hz, 2H), 7.15–6.92 (m, 9H), 5.28 (s, 1H), 5.02 (s, 1H), 4.55 (s, 2H); 13C{1H} NMR (100
MHz, CDCl3) δ 192.7 (CO), 150.6 (C), 145.3 (C), 142.7 (C), 138.0 (C), 136.3 (C), 135.7 (C), 135.1 (C),
130.4 (CH), 130.2 (CH), 129.6 (CH), 128.3 (CH), 127.8 (CH), 124.6 (CH), 123.0 (CH), 119.3 (C), 109.0
(=CH2), 56.8 (CH2); IR (neat): 3078, 2919, 1638, 1587, 1495, 1311, 1239, 1171, 1087, 1011, 911, 853, 767,
739, 696 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C24H18ClN2O3S 449.0721; Found 449.0734.
(4-Chlorophenyl){5-(3-fluorophenyl)-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-
pyrrol-4-yl}methanone (8t). (Z)-1-(4-Chlorophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-ylamino)prop-2-en-
1-one (1t) (94 mg, 0.30 mmol), 4-nitrobenzenesulfenyl chloride (72 mg, 0.36 mmol) and the base, NaH
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(60% dispersion in mineral oil, 12 mg, 0.30 mmol) or Cs2CO3 (98 mg, 0.30 mmol), were employed to afford
83 mg (59%) and 84 mg (60%) of the indicated product with NaH and Cs2CO3, respectively, as an orange
solid (Rf = 0.42 in 4:1 hexane/ethyl acetate; mp 87.7-89.2 °C). 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 9.1
Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.11 (d, J = 8.5 Hz, 2H), 6.98–6.90 (m, 4H), 6.85 (dt, J = 9.6, 1.8 Hz, 1H),
6.70 (ddt, J = 7.2, 4.7, 2.6 Hz, 1H), 5.28 (s, 1H), 5.03 (s, 1H), 4.53 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.4 (CO), 162.1 (d, 1J = 248.7 Hz, CF), 150.3 (C), 145.4 (C), 142.8 (C), 138.5 (C), 137.2 (d, 3J =
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7.3 Hz, C), 135.7 (C), 135.4 (C), 130.3 (CH), 130.0 (d, J = 8.2 Hz, CH), 128.0 (CH), 125.9 (d, 4J = 1.9 Hz,
3
2
CH), 124.7 (CH), 122.9 (CH), 120.5 (C), 116.5 (d, J = 22.1 Hz, 2 x CH), 109.5 (=CH2), 56.6 (CH2) (Note
that two CH peaks overlap on each other); IR (neat): 2909, 2145, 2079, 1737, 1584, 1484, 1331, 1310, 1290,
1234, 1216, 1170, 1086, 1011, 867, 850, 806, 744, 667 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for
C24H17ClFN2O3S 467.0627; Found 467.0639.
{5-[4-(tert-Butyl)phenyl]-3-methylene-4-[(4-nitrophenyl)thio]-3,4-dihydro-2H-pyrrol-4-yl}(4-
chlorophenyl)methanone
(8u).
(Z)-3-[4-(tert-Butyl)phenyl]-1-(4-chlorophenyl)-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (1u) (90 mg, 0.26 mmol), 4-nitrobenzenesulfenyl chloride (62 mg, 0.31 mmol) and
the base, NaH (60% dispersion in mineral oil, 10 mg, 0.26 mmol) or Cs2CO3 (85 mg, 0.26 mmol), were
employed to afford 87 mg (66%) and 101 mg (77%) of the indicated product with NaH and Cs2CO3,
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respectively, as a brownish-yellow solid (Rf = 0.50 in 4:1 hexane/ethyl acetate; mp: 194.8-195.4 °C). H
NMR (400 MHz, CDCl3) δ 7.97 (d, J = 9.1 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 7.04–6.93 (m, 6H), 6.90 (d, J =
8.4 Hz, 2H), 5.26 (s, 1H), 5.00 (s, 1H), 4.54 (s, 2H), 1.06 (s, 9H); C{1H} NMR (100 MHz, CDCl3) δ 193.2
13
(CO), 153.6 (C), 151.0 (C), 149.8 (C), 143.0 (C), 137.5 (C), 137.1 (C), 136.5 (C), 132.4 (C), 130.6 (CH),
130.5 (CH), 127.7 (CH), 125.4 (CH), 124.9 (CH), 123.6 (CH), 119.0 (C), 109.0 (=CH2), 57.3 (CH2), 34.6
(C), 30.8 (CH3); IR (neat): 2960, 2349, 2128, 1956, 1587, 1492, 1334, 1309, 1235, 1169, 1087, 1011, 838,
742, 694, 670 cm-1; HRMS (ESI) m/z: [M + H]+ Calcd for C28H26ClN2O3S 505.1347; Found 505.1358.
General Procedure for the synthesis of α-sulfenylated N-propargylic β-enaminones 7 and 13 (Tables 1
and 3). To a stirred solution of N-propargylic β-enaminone
1 or 10 (0.30 mmol) in acetonitrile (5 mL)
at room temperature under argon was added 4-nitrobenzenesulfenyl chloride (0.36 mmol) and the
resulting mixture was heated at reflux in an oil bath for approximately 3 h. The reaction was
continued until N-propargylic β-enaminone
1
or 10 was completely consumed as monitored by the
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