One-Pot Synthesis of 2-Acetyl-1 H-pyrroles from N-Propargylic β-Enaminones via Intermediacy of 1,4-Oxazepines

Article abstract of DOI:10.1021/acs.joc.1c00077

A one-pot two-step protocol for the synthesis of 2-acetyl-1H-pyrroles from N-propargylic β-enaminones was described. When treated with zinc chloride in refluxing chloroform, N-propargylic β-enaminones produced in situ 2-methylene-2,3-dihydro-1,4-oxazepines, which, upon further refluxing in methanol with zinc chloride, afforded 2-acetyl-1H-pyrroles. The process was found to be general for a wide variety of N-propargylic β-enaminones and yielded a diverse range of 2-acetyl-1H-pyrroles in good to high yields with large substrate scope and good functional group tolerance. This operationally easy method may provide a rapid access to functionalized 2-acetyl-1H-pyrroles of pharmacological interest.

Full text of DOI:10.1021/acs.joc.1c00077

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One-Pot Synthesis of 2‑Acetyl‑1H‑pyrroles from N‑Propargylic
β‑Enaminones via Intermediacy of 1,4-Oxazepines
Nilay Kanova, Buse Aysen Dundar, Yilmaz Kelgokmen, and Metin Zora*
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ABSTRACT: A one-pot two-step protocol for the synthesis of 2-acetyl-1H-
pyrroles from N-propargylic β-enaminones was described. When treated with
zinc chloride in refluxing chloroform, N-propargylic β-enaminones produced in
situ 2-methylene-2,3-dihydro-1,4-oxazepines, which, upon further refluxing in
methanol with zinc chloride, afforded 2-acetyl-1H-pyrroles. The process was
found to be general for a wide variety of N-propargylic β-enaminones and
yielded a diverse range of 2-acetyl-1H-pyrroles in good to high yields with large
substrate scope and good functional group tolerance. This operationally easy
method may provide a rapid access to functionalized 2-acetyl-1H-pyrroles of
pharmacological interest.
enaminones, representative examples of which are given in
Scheme 1a. Pioneering studies of Cacchi and Fabrizi and Saito
and Hanzawa opened the way for the synthesis of type 1 and 2
pyrrole derivatives, respectively.8 Later, other research groups
were also involved in the synthesis of such pyrrole derivatives.9
Besides, the Cheng research group reported a ring-closing
carbonyl-allene metathesis reaction of N-propargyl β-enami-
nones, which provided 2,4-disubstituted pyrroles, called as type
3, via the intermediacy of dihydropyrrole-fused oxetanes
(Scheme 1a, lower left).10 However, in one case, a minor
pyrrole product, called as type 4 here, was also isolated from
this reaction in 7% yield (Scheme 1a, lower right). Formation
of this byproduct was explained by the ring opening of the
oxetane intermediate via C−O bond cleavage.10 Owing to the
presence of a carbonyl group, 2-acetylpyrroles have great
potential for further functionalization to construct more
complex structures, but their synthesis from N-propargylic β-
enaminones requires an efficient and high-yielding protocol,
possibly via a new synthetic strategy.
INTRODUCTION
■
Pyrroles constitute one of the most important classes of
heterocyclic compounds found in numerous natural products,
pharmaceutical molecules, and functional materials.1 Indeed,
pyrroles are precious scaffolds for pharmaceutical and
medicinal research since they possess a broad spectrum of
pharmacological and biological properties, including analgesic,
antiallergic, anticonvulsant, antidepressant, antidiabetic, anti-
hyperlipidemic, anti-inflammatory, antimicrobial, antifungal,
antiviral, cholesterol-reducing, and antitumor properties.2
Admittedly, pyrroles have a profound effect on human health
since they are present in a wide range of natural products (e.g.,
hymenidin, dispacamide B and D, longamide A and B, and
spongiacidin B) and drugs (e.g., aloracetam, atorvastatin,
elopiprazole, isamoltane, and ketorolac) in order to battle a
large number of diseases and pathophysiological conditions.2,3
Over the years, numerous methods have been developed for
their synthesis, and new ones continue to appear since they are
crucial intermediates in the synthesis of various drugs and
natural products.4 Thus, in recent years, substantial attention
has been paid to develop new and effective methods for the
construction of highly functionalized pyrroles.4,5
Recently, the rapid assembly of heterocyclic molecules from
simple acyclic precursors in a one-pot process has attracted
considerable interest of organic chemists. In this regard, N-
propargylic β-enaminones have proven to be useful since their
cyclizations have become a powerful tool in building a broad
range of important heterocycles,6 including pyrroles, 1-
pyrrolines, pyridines, 1,2-dihydropyridines, 1,4-oxazepines,
and 1,4-thiazepines.7 With respect to the five-membered ring
formation, cyclization of N-propargylic β-enaminones mostly
afforded pyrrole derivatives. So far, according to the
substitution pattern, four kinds of pyrrole derivatives have
been obtained from the cyclizations of N-propargylic β-
Recently, Karunakar and co-workers have reported a gold-
catalyzed cyclization of N-propargylic β-enaminones, leading
to 2-methylene-2,3-dihydro-1,4-oxazepines (Scheme 1b).11 We
have demonstrated that when treated with zinc chloride in
halogenated solvents, N-propargylic β-enaminones also
afforded 2-methylene-2,3-dihydro-1,4-oxazepines via 7-exo-dig
cyclization with high efficiency and large functional group
Received: January 12, 2021
Published: April 19, 2021
https://doi.org/10.1021/acs.joc.1c00077
© 2021 American Chemical Society
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Scheme 1. Strategies for the Synthesis of Pyrroles and 1,4-Oxazepines
Scheme 2. Synthesis of N-Propargylic β-Enaminones and 1,4-Oxazepines
tolerance (Scheme 1b, lower left).12 However, with the same
reaction in the presence of molecular iodine, it yielded 2-
(iodomethylene)-2,3-dihydro-1,4-oxazepines (Scheme 1b,
lower right).13 Our continued interest in the synthesis of
new heterocyclic compounds as potential pharmaceuticals and
scaffolds has prompted us to investigate new reactivity patterns
of N-propargylic β-enaminones.14 During these studies, we
found an unprecedented method for the synthesis of type 4
pyrrole derivatives. When the zinc chloride-mediated reaction
of N-propargylic β-enaminones was carried out in a polar
protic solvent such as methanol, instead of a halogenated
solvent such as methylene chloride or chloroform, it led to the
formation of 3,5-disubstituted 2-acetylpyrrole [1-(1H-pyrrol-2-
yl)ethanone] derivatives in good to high yields (Scheme 1c).
To the best of our knowledge, the formation of 2-
acetylpyrroles by these reactions is without precedent. As
part of our ongoing program unveiling the reactivity pathways
of N-propargylic β-enaminones, we herein report a new and
novel method for the synthesis of 2-acetylpyrrole derivatives.
RESULTS AND DISCUSSION
■
As noted before, reactions of N-propargylic β-enaminones with
ZnCl2 in halogenated solvents produced 1,4-oxazepines
(Scheme 1b, lower left).12 By elementary considerations, it
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might be expected that 2-acetylpyrroles could arise from
intermediate 1,4-oxazepines formed previously during the
course of the reaction. Alternatively, 2-acetylpyrroles could
result directly from N-propargylic β-enaminones without the
intermediacy of 1,4-oxazepines. To contribute to a better
understanding of the formation of 2-acetylpyrroles from these
reactions, we have first prepared 20 derivatives of each of the
N-propargylic β-enaminones 2 and 1,4-oxazepines 3 from α,β-
alkynic ketones 1 according to our previous studies (Scheme
2)12,14a and then investigated their reactions (for details, see
the Experimental Section).
synthesize a diverse range of 2-acetylpyrroles 4. All reactions
proceeded well and afforded the expected pyrroles 4 in good to
high yields (63−88%). By employing these reactions, 20
derivatives of 2-acetylpyrroles 4 were prepared, 19 of which
were synthesized for the first time. Notably, a large variety of
aromatic and heteroaromatic groups with electron-donating
and electron-withdrawing substituents survived in these
reactions. Halogenated compounds form a large portion of
drugs and drug candidates in clinical development since
halogen bonds play important roles in the improvement of
drug−target binding affinity.15 Thus, we synthesized 11
derivatives of halogen-containing 2-acetylpyrroles, 4g−j, m,
n, and 4p−t, in 63−88% yields (Table 2), three of which were
fluorine-bearing 2-acetylpyrroles, 4g, h, and t, obtained in 76−
88% yields. Notably, in the pharmaceutical industry,
fluorinated drugs are quite popular since fluorination has a
positive effect on absorption, distribution, metabolism, and
excretion.16 In a wide range of pharmaceuticals, agrochemicals,
and materials science, thiophenes are often employed as
building blocks and scaffolds.17 Therefore, we synthesized
three derivatives of 5-(thiophen-3-yl)-substituted 2-acetylpyr-
roles, 4k, o, and q, in 67−85% yields (Table 2).
We next started to explore the reaction of 1,4-oxazepines in
protic polar solvents such as alcohols. For this purpose, the
reaction of 1,4-oxazepine 3a was first investigated under
different conditions, as shown in Table 1. Initially, compound
Table 1. Optimization of the Reaction Conditions for the
Synthesis of 2-Acetylpyrroles from 2-Methylene-2,3-
a
dihydro-1,4-oxazepines
Next, we turned our attention to one-pot synthesis of 2-
acetylpyrroles 4 from N-propargylic β-enaminones 2, as
illustrated in Table 3. Initially, N-propargylic β-enaminone
2a was treated overnight with 1.0 equiv of ZnCl2 in methanol
under reflux conditions, which furnished 2-acetylpyrrole 4a in
46% yield (Table 3, entry 1). Subsequently, the reaction was
repeated in the presence of 1.5 and 2.0 molar equivalents of
ZnCl2 (Table 3, entries 2 and 3). Use of excess ZnCl2 did not
increase the yield (51%) of pyrrole 4a considerably. Then, the
same reaction was performed in ethanol and propanol under
reflux conditions (Table 3, entries 4 and 5), but these reactions
also yielded pyrrole 4a in low to moderate yields (34−46%).
Presumably, in alcohols, intermediate 1,4-oxazepine 3a does
not form in high yields since our previous study has shown that
1,4-oxazepines are obtained in good to high yields when the
reactions were carried out in halogenated solvents such as
dichloromethane and chloroform.12 On the other hand, in
halogenated solvents, 1,4-oxazepines do not convert into 2-
acetylpyrroles. Hence, we have planned this synthesis as a one-
pot two-step process, as depicted in Table 3. First of all, on the
basis of our previous study,12 N-propargylic β-enaminone 2a
was refluxed in chloroform for 2 h with 1.0 equiv of ZnCl2,
which provided in situ formation of intermediate 1,4-oxazepine
3a in good to high yields. Then, chloroform was replaced with
methanol, and the resulting crude mixture was refluxed under
the conditions given in entries 6−9 of Table 3. In other words,
the second step of the process was optimized. When the crude
reaction mixture was just refluxed in methanol in the second
step, it yielded 2-acetylpyrrole 4a in 57% yield (Table 3, entry
6). Subsequently, in the second step, the crude reaction
mixture was treated with 0.5, 1.0, and 1.5 molar equivalents of
ZnCl2 (Table 3, entries 7−9), which yielded pyrrole 4a in 75−
85% yields. The highest yield (85%) of 4a from these one-pot
two-step reactions was achieved by employing 1.0 equiv of
ZnCl2 in the second step (Table 3, entry 8). Notably, the use
of excess ZnCl2 such as 1.5 equiv of ZnCl2 in the second step
somewhat lowered the yield (75%) of pyrrole 4a (Table 3,
entry 9). In all reactions of the one-pot two-step process,
intermediate 1,4-oxazepine 3a was not isolated. Derivatization
studies for one-pot two-step transformation were made
according to optimized conditions given in entry 8 of Table 3.
entry ZnCl2 (equiv)
1
solvent
temp (°C) time (h) yield of 4a (%)
MeOH
MeOH
MeOH
MeOH
EtOH
65
65
35.0
3.0
1.5
1.0
3.0
3.5
2.0
77
88
84
80
71
74
63
2
3
4
5
6
7
1.0
1.5
2.0
1.0
1.0
1.0
65
65
78
97
n-PrOH
n-BuOH
116
a
All reactions were carried out on a scale of 0.30 mmol of 1,4-
oxazepine 3a in 3 mL of solvent under argon under the indicated
conditions. For work-up and purification, see the Experimental
Section.
3a was refluxed in methanol, which produced 2-acetylpyrrole
4a in 77% yield (Table 1, entry 1). However, this reaction took
long time (35 h) for completion. Then, the same reaction was
performed in the presence of 1.0, 1.5, and 2.0 molar
equivalents of ZnCl2 (Table 1, entries 2−4). Clearly, the use
of ZnCl2 increased the yields of pyrrole 4a considerably (80−
88%) and shortened the reaction times significantly (1−3 h).
Although the use of excess ZnCl2, such as 1.5 and 2.0 equiv,
decreased the reaction times slightly, it lowered the yields of
pyrrole 4a to some extent. After these results, we decided to
continue the reaction with 1.0 equiv of ZnCl2. Subsequently,
we carried out the reaction in ethanol, propanol, and butanol
under reflux conditions (Table 1, entries 5−7). However, these
reactions yielded pyrrole 4a in relatively lower yields (63−
74%). Eventually, the highest yield (88%) of 2-acetylpyrrole 4a
from 1,4-oxazepine 3a was obtained with 1.0 equiv of ZnCl2
(i.e., under the conditions in entry 2 of Table 1). On the basis
of these reactions, we have concluded that formation of 2-
acetylpyrroles 4 from N-propargylic β-enaminones 2 is a
secondary process and occurs from the in situ-formed 1,4-
oxazepines 3 during an alcohol-mediated reaction as will be
discussed later.
Afterward, we investigated the generality and substrate scope
for this reaction, as depicted in Table 2. A variety of 2-
methylene-2,3-dihydro-1,4-oxazepines 3 was employed to
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a b
,
Table 2. Synthesis of 2-Acetylpyrroles from 2-Methylene-2,3-dihydro-1,4-oxazepines and N-Propargylic β-Enaminones
a
b
The yields of 2-acetylpyrroles 4 obtained from 2-methylene-2,3-dihydro-1,4-oxazepines 3 according to eq 1 are shown in parentheses. The yields
of 2-acetylpyrroles 4 resulted from N-propargylic β-enaminones 2 via a one-pot two-step process according to eq 2, without isolating intermediate
c
1,4-oxazepines 3, are given in square brackets. When the reaction was performed on a 1.60 mmol scale of N-propargylic β-enaminone 2a, 2-
acetylpyrrole 4a was obtained in 80% yield (see the Experimental Section).
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a b
,
Table 3. Optimization of the Reaction Conditions for the Synthesis of 2-Acetylpyrroles from N-Propargylic β-Enaminones
entry
ZnCl2 (equiv)
solvent
temp (°C)
time (h)
yield of 4a (%)
1
2
3
4
5
1.0
1.5
2.0
2.0
2.0
MeOH
MeOH
MeOH
EtOH
65
65
65
78
97
24.0
12.0
11.0
8.0
46
51
51
46
34
n-PrOH
5.0
b
entry
ZnCl2 (equiv)
time (h)
yield of 4a (%)
6
7
8
9
3.0
1.5
1.0
1.0
57
75
85
75
0.5
1.0
1.5
a
All reactions were carried out on a scale of 0.30 mmol of N-propargylic β-enaminone 2a in 3 mL of solvent under argon under the indicated
b
conditions. For work-up and purification, see the Experimental Section. The amount (equiv) of ZnCl2 used in the second step.
Scheme 3. Proposed Mechanism for the Formation of 2-Acetylpyrroles from N-Propargylic β-Enaminones
Subsequently, we explored the generality and substrate
scope for one-pot two-step synthesis of 2-acetylpyrroles 4, as
shown in Table 2. A diverse range of 2-acetylpyrroles 4 was
synthesized from N-propargylic β-enaminones 2 in good to
high yields (51−85%). It is noteworthy to mention that the
yields (51−85%) of the one-pot two-step process are quite
comparable with those (64−88%) obtained from 1,4-
oxazepines 3 (see Table 2 for comparison of the yields). In
fact, all reactions of one-pot two-step transformation
proceeded well and tolerated the presence of a wide variety
of aromatic and heteroaromatic groups with electron-donating
and electron-withdrawing substituents. The reaction of N-
propargylic β-enaminone 2a was performed on a relatively
larger scale as well, which yielded 2-acetylpyrrole 4a in 80%
yield (Table 2), slightly lower than that (85%) in a small scale,
indicating the practical utility of the method as a synthetic tool.
We synthesized 11 derivatives of halogen-bearing 2-acetylpyr-
roles, 4g−j, m, n, and 4p−t, in 62−78% yields (Table 2), three
of which were fluorine-containing 2-acetylpyrroles, 4g, h, and t,
obtained in 63−72% yields. We also synthesized three
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derivatives of 5-(thiophen-3-yl)-substituted 2-acetylpyrroles,
4k, o, and q, in 67−77% yields (Table 2). Overall, 20
derivatives of 2-acetylpyrroles 4 were synthesized, 19 of which
were prepared for the first time in this study.
molecule was observed. This strongly implies that deuterium
incorporation mostly occurs during the conversion of 1,4-
oxazepine 3a to 2-acetylpyrrole 4a.
In order to further prove the methanol involvement in the
reaction, particularly via conjugate addition, we performed
some control experiments with 1,4-oxazepine 3a, as depicted in
Table 4. First, the reaction of 3a with ZnCl2 was carried out in
acetic acid (Table 4, entry 1), in which the starting 1,4-
oxazepine 3a was recovered in 55% yield, along with some
unidentified decomposition products. However, a type 1
pyrrole derivative, namely, (4-methyl-2-phenyl-1H-pyrrol-3-
yl) (phenyl)methanone (14a), was also isolated from this
reaction but in very low yield (2%), which possibly resulted
from the reaction of 1,4-oxazepine 3a with trace H2O existing
in acetic acid. This is supported by the reaction conducted in a
1:1 mixture of acetic acid/water, which expectedly yielded
pyrrole 14a in high yield (71%), along with a small amount of
2-acetylpyrrole 4a (6%) (Table 4, entry 2). As anticipated, an
increasing amount of water raises the yield of type 1 pyrrole
derivative 14a. It is worth mentioning that during their
purification on silica gel in our previous study,12 6-alkyl-
substituted 2-methylene-2,3-dihydro-1,4-oxazepines generated
the corresponding type 1 pyrrole derivatives in low yields (9−
20%) as well, presumably via a similar mechanism. Notably,
the reaction in acetic acid did not produce any 2-acetylpyrrole
4a (Table 4, entry 1). This might be possibly due to the fact
that acetic acid is less nucleophilic and basic as compared to
methanol and water, as a result of resonance. In other words,
acetic acid may not give conjugate addition under reaction
conditions, and so it does not catalyze the formation of 2-
acetylpyrrole 4a. However, the reaction in a 1:1 mixture of
acetic acid/water produced 2-acetylpyrrole 4a in low yield
(6%) (Table 4, entry 2). This could possibly have occurred as
a byproduct from the reaction of 1,4-oxazepine 3a with water.
Subsequently, the same reaction with ZnCl2 was tried in a 1:1
mixture of tetrahydrofuran (THF)/H2O, which yielded pyrrole
14a in 26% yield, along with the starting 1,4-oxazepine 3a
recovered in 65% yield (Table 4, entry 3). When a few drops of
conc. HCl was used instead of ZnCl2, the same reaction
provided pyrrole 14a in low yield (9%) and most of the
starting 1,4-oxazepine 3a was isolated back (76%) (Table 4,
entry 4). Next, the reaction with ZnCl2 was carried out in a 1:1
mixture of ethylene glycol/THF, which afforded 2-acetylpyr-
role 4a in 10% yield along with a new product, a keto−ketal
derivative 15a, in 26% yield (Table 4, entry 5); the formation
of the latter provides useful information about the reaction
mechanism, as will be discussed later. Finally, the same
reaction in a 1:1 mixture of ethylene glycol/1,4-dioxane also
yielded the same products, 4a and 15a, but in 22 and 20%
yields, respectively (Table 4, entry 6).
The mechanism proposed for the formation of 2-
acetylpyrroles 4 is given in Scheme 3, partly based on our
previous study.12 First, the interaction of zinc chloride with the
alkyne moiety of 2 yields 5. Subsequent coordination of
carbonyl oxygen to zinc through vinylogous amido−imido
tautomerization generates intermediate 6, bringing the carbon-
yl and alkyne functionalities in close proximity. Then,
intramolecular 7-exo-dig cyclization occurs to produce vinyl-
zinc intermediate 7. Hydrolysis with HCl generated in situ
affords 1,4-oxazepine derivatives 3.12 The interaction of zinc
chloride with amine nitrogen of 3 produces 8, in which the
vinylogous imine functionality is activated. This enables
conjugate addition of methanol to give ketal 9. Then, ring
opening provides enol 10, which converts into more stable
enol 11. Subsequently, cyclization takes place to furnish
dihydropyrrole 12. Finally, methanol elimination through enol
13 affords 2-acetylpyrrole derivatives 4 (Scheme 3). It is
noteworthy to mention that hydrolysis or rearrangement of
1,4-oxazepines to pyrroles was rarely observed,12,18 but
formation of 2-acetylpyrroles from them is without a
precedent.
During the course of the reaction, 2-methylene-2,3-dihydro-
1,4-oxazepines 3 undergo a methanol-mediated rearrangement
to afford 2-acetylpyrroles 4, as shown in the proposed
mechanism (Scheme 3). To the best of our knowledge, this
is a very rare or previously unknown process. In order to
provide evidence for the methanol involvement in reaction, we
carried out the reaction of 1,4-oxazepine 3a with 1.0 equiv of
ZnCl2 in d4-methanol (CD3OD) at reflux for 3 h to see if there
is any deuterium (D) incorporation in the final 2-acetylpyrrole
product 4a. The reaction was very clean and generated the
partially deuterium-incorporated pyrrole derivative 4a−D
1
(Scheme 4). From the integration values of the H NMR
Scheme 4. Reaction of 2-Methylene-2,3-dihydro-1,4-
oxazepine 3a with Zinc Chloride in CD3OD
Like methanol, water catalyzes or mediates the reaction as
well, but its reaction produces a type 1 pyrrole derivative such
as 14a, instead of a type 4 pyrrole product such as 4a. The
mechanism proposed for the formation of pyrrole 14a is
depicted in Scheme 5. Similar to the mechanism with methanol
in Scheme 3, conjugate addition of water to 1,4-oxazepine 3a
in the presence of ZnCl2 or acid, followed by ring opening,
gives bisenol 16a, which then converts into keto−enol
intermediate 17a. Reaction with water differs at this stage
(16a to 17a in Scheme 5) from that with methanol (10 to 11
in Scheme 3), which causes the formation of different pyrrole
products. Afterward, cyclization via an aldol-type reaction
furnishes 1-pyrroline (3,4-dihydro-2H-pyrrole) 18a. Water
spectrum of the crude reaction mixture (4a−D), 46%
deuteration of the methyl group, 58% deuteration of the C−
H bond of the pyrrole ring, and 99% deuteration of the N−H
bond were determined (see the Supporting Information for 1H
and 13C NMR spectra of the crude reaction mixture). In
particular, the incorporation of deuterium into methyl and C−
H regions of the molecule clearly supports the proposed
mechanism. However, during the course of the reaction, if
formed, the nondeuterated 2-acetylpyrrole 4a can also undergo
the deuteration process. Thus, we examined the reaction of the
pure 2-acetylpyrrole 4a with 1.0 equiv of ZnCl2 in CD3OD at
reflux for 3 h, but in this reaction, a low level of deuterium
incorporation (4−6%) at the methyl and C−H sites of the
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Table 4. Control Experiments for the Formation of 2-Acetylpyrroles from 2-Methylene-2,3-dihydro-1,4-oxazepines
entry
Conditions
products (yield, %)
1
2
3
4
5
6
ZnCl2 (1.0 equiv), CH3CO2H, 80 °C, 5.5 h
3a (55%) + 14a (2%)
4a (6%) + 14a (71%)
3a (65%) + 14a (26%)
3a (76%) + 14a (9%)
4a (10%) + 15a (26%)
4a (22%) + 15a (20%)
ZnCl2 (1.0 equiv), CH3CO2H/H2O (1:1), 80 °C, 5.5 h
ZnCl2 (1.0 equiv), THF/H2O (1:1), 80 °C, 6.0 h
THF/H2O (3:1), conc. HCl (3 drops), 80 °C, 6.0 h
ZnCl2 (1.0 equiv), HOCH2CH2OH/THF (1:1), 80 °C, 6.0 h
ZnCl2 (1.0 equiv), HOCH2CH2OH/dioxane (1:1), 80 °C, 5.5 h
Scheme 5. Proposed Mechanism for the Formation of Pyrrole 14a from N-Propargylic β-Enaminones
elimination through the intermediacy of enol 19a provides 2H-
pyrrole 20a. Finally, isomerization affords 1H-pyrrole 14a
(Scheme 5).
Notably, from the reactions in ethylene glycol, a keto−ketal
derivative, 15a, was obtained in addition to 2-acetylpyrrole 4a.
The suggested mechanism for the formation of 15a is given in
Scheme 6. As in the mechanism with methanol (Scheme 3),
Alternatively, keto−ketal intermediate 22a with enamine
functionality can also directly hydrolyze to keto−ketal 15a
without the intermediacy of keto−ketal 23a. However, we were
unable to isolate aminoacetone (24a) from these reactions
since it is water-soluble and possibly went into the water phase
during the extraction.
In summary, the reactions in the presence of water and
ethylene glycol indirectly prove the involvement of methanol
in these reactions through conjugate addition. Notably, after
the conjugate addition of water, followed by the ring opening
of the ketal formed, the reaction pathway changes as compared
to that with methanol and the resulting keto−enol
intermediate undergoes an aldol-type reaction to afford a
different pyrrole product, 14a (i.e., a type 1 pyrrole), instead of
the expected 2-acetylpyrrole 4a (i.e., a type 4 pyrrole).
However, in the reactions with ethylene glycol, conjugate
addition occurs twice, which results in the formation of a
keto−ketal product, 15a. Overall, these cumulative results
support the involvement of methanol indirectly to catalyze or
mediate the reaction.
Scheme 6. Proposed Mechanism for the Formation of
Keto−Ketal 15a from N-Propargylic β-Enaminones
CONCLUSIONS
■
In summary, we have developed a robust one-pot procedure
for the synthesis of 2-acetylpyrroles from N-propargylic β-
enaminones via intermediacy of 1,4-oxazepines. The rearrange-
ment of intermediate 1,4-oxazepines to 2-acetylpyrroles was
proved by refluxing the isolated 1,4-oxazepines with zinc
chloride in methanol. Interestingly, 1,4-oxazepines undergo a
methanol-promoted tandem ring-opening/ring-closing reac-
tion to afford 2-acetylpyrroles. A diverse range of 2-
acetylpyrrole derivatives were separately synthesized from
both 2-methylene-2,3-dihydro-1,4-oxazepines and N-propar-
tandem conjugate addition of ethylene glycol to 1,4-oxazepine
3a and ring opening of the resulting ketal yield enol 21a.
Subsequently, second conjugate addition takes place to afford
keto−ketal intermediate 22a with enamine functionality, which
then converts into more stable keto−ketal derivative 23a with
imine functionality. At last, hydrolysis of compound 23a
through imine functionality affords the observed keto−ketal
derivative 15a and aminoacetone (24a) (Scheme 6).
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2-Methylene-7-phenyl-5-(m-tolyl)-2,3-dihydro-1,4-oxazepine
(3b). 1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-en-1-one
(2b) (385.5 mg, 1.4 mmol) and ZnCl2 (190.8 mg, 1.4 mmol) were
used to yield 285.3 mg (74%) of the indicated product as an orange
gylic β-enaminones in good to high yields. The reaction was
general for a variety of both 1,4-oxazepines and N-propargylic
β-enaminones and demonstrated good tolerance to a variety of
aromatic and heteroaromatic groups. We anticipate that the
high efficiency and wide reaction scope of the process could
make it potentially attractive for the library construction of 2-
acetylpyrroles in designing new and novel molecular entities
and/or structural leads.
1
oil (Rf = 0.48 in 4:1 hexane/ethyl acetate). H NMR (400 MHz,
CDCl3): δ 7.86−7.79 (m, 2H), 7.70 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H),
7.52−7.45 (m, 3H), 7.38−7.26 (m, 2H), 6.44 (s, 1H), 4.81 (s, 1H),
4.60 (s, 2H), 4.44 (d, J = 1.3 Hz, 1H), 2.45 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 167.1 (C), 158.7 (C), 158.2 (C), 139.7 (C), 138.0
(C), 135.1 (C), 130.7 (CH), 130.1 (CH), 128.5 (CH), 128.2 (CH),
127.9 (CH), 126.2 (CH), 124.6 (CH), 99.8 (CH), 93.8 (CH2), 55.4
(CH2), 21.4 (CH3). The spectral data were in agreement with those
reported previously for this compound.12
EXPERIMENTAL SECTION
■
General Information. 1H and 13C{1H} NMR spectra were
recorded at 400 and 100 MHz, respectively. Chemical shifts were
given in parts per million (ppm) relative to CDCl3 (7.26 and 77.16
2-Methylene-7-phenyl-5-(p-tolyl)-2,3-dihydro-1,4-oxazepine
(3c). 1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(p-tolyl)prop-2-en-1-one
(2c) (220.3 mg, 0.8 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were
used to yield 154.1 mg (70%) of the indicated product as a brownish
1
ppm in H and 13C{1H} NMR, respectively) or CD3OD (3.31 and
49.00 ppm in 1H 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), and m (multiplet). DEPT 13C NMR information is
depicted in parentheses as C, CH, CH2, and CH3. Infrared (IR)
spectra were obtained using attenuated total reflection. Band position
diagnostics for major functional groups were recorded in reciprocal
centimeters (cm−1). Mass spectra (MS) and high-resolution MS
(HRMS) were obtained 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 accom-
plished using commercially prepared 0.25 mm silica gel, and
visualization was done with a 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 using slight positive pressure (ca. 0.1 psi) of argon. All
glassware was dried in an oven prior to use.
1
solid (Rf = 0.48 in 4:1 hexane/ethyl acetate; mp 73.0−75.0 °C). H
NMR (400 MHz, CDCl3): δ 7.78−7.74 (m, 2H), 7.69 (d, J = 8.1 Hz,
2H), 7.46−7.41 (m, 3H), 7.21 (d, J = 8.0 Hz, 2H), 6.39 (s, 1H), 4.73
(s, 1H), 4.54 (s, 2H), 4.37 (d, J = 1.4 Hz, 1H), 2.39 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 166.7 (C), 158.6 (C), 158.3 (C), 140.0
(C), 136.9 (C), 135.1 (C), 130.0 (CH), 129.0 (CH), 128.5 (CH),
127.3 (CH), 126.2 (CH), 99.8 (CH), 93.5 (CH2), 55.3 (CH2), 21.3
(CH3). The spectral data were in agreement with those reported
previously for this compound.12
5-[4-(tert-Butyl)phenyl]-2-methylene-7-phenyl-2,3-dihydro-1,4-
oxazepine (3d). 3-[4-(tert-Butyl)phenyl]-1-phenyl-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (2d) (253.9 mg, 0.8 mmol) and ZnCl2
(109.0 mg, 0.8 mmol) were used to yield 223.8 mg (88%) of the
indicated product as a brownish-orange oil (Rf = 0.58 in 4:1 hexane/
1
ethyl acetate). H NMR (400 MHz, CDCl3): δ 7.89−7.75 (m, 4H),
7.52−7.43 (m, 5H), 6.47 (s, 1H), 4.79 (s, 1H), 4.60 (s, 2H), 4.42 (d,
J = 1.3 Hz, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 166.8
(C), 158.6 (C), 158.3 (C), 153.3 (C), 137.0 (C), 135.2 (C), 130.1
(CH), 128.6 (CH), 127.2 (CH), 126.3 (CH), 125.3 (CH), 99.9
(CH), 93.7 (CH2), 55.5 (CH2), 34.8 (C), 31.3 (CH3); IR (neat):
2960, 1654, 1622, 1573, 1493, 1448, 1361, 1313, 1291, 1261, 1192,
1106, 1061, 1019, 999, 946, 820, 763, 731, 683, 613 cm−1; MS (ESI,
m/z): 318.19 [M + H]+; HRMS (ESI): calcd for C22H24NO,
318.1852 [M + H]+; found, 318.1859.
N-Propargylic β-enaminones 2 and 1,4-oxazepines 3 were
synthesized from α,β-alkynic ketones 1 according to our previous
studies.12,14a
5-(4-Methoxyphenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-ox-
azepine (3e). 3-(4-Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (2e) (203.9 mg, 0.7 mmol) and ZnCl2
(95.4 mg, 0.7 mmol) were used to yield 146.8 mg (72%) of the
indicated product as a yellow solid (Rf = 0.21 in 4:1 hexane/ethyl
acetate; mp 112.0−113.5 °C). 1H NMR (400 MHz, CDCl3): δ 7.79−
7.73 (m, 4H), 7.46−7.40 (m, 3H), 6.92 (d, J = 8.7 Hz, 2H), 6.39 (s,
1H), 4.72 (s, 1H), 4.52 (s, 2H), 4.37 (d, J = 1.1 Hz, 1H), 3.84 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 166.1 (C), 161.1 (C), 158.54
(C), 158.49 (C), 135.1 (C), 132.2 (C), 130.0 (CH), 128.8 (CH),
128.5 (CH), 126.2 (CH), 113.5 (CH), 99.8 (CH), 93.3 (CH2), 55.2
(OCH3), 55.1 (CH2). The spectral data were in agreement with those
reported previously for this compound.12
General Procedure for the Synthesis of 2-Methylene-2,3-
dihydro-1,4-oxazepines. To a stirred solution of the corresponding
N-propargylic β-enaminone (1.0 mmol) in CHCl3 (10.0 mL) under
argon was added ZnCl2 (1.0 mmol). The resulting mixture was then
heated to reflux at 61 °C for approximately 2 h in an oil bath (note
that the progress of the reaction was monitored by routine TLC for
the disappearance of N-propargylic β-enaminone using hexane/ethyl
acetate (9:1) as the eluent). After the reaction was over, the solvent
was removed on a rotary evaporator, and ethyl acetate (40 mL) and a
saturated aqueous NH4Cl solution (15 mL) were added. After the
layers were separated, the aqueous phase was extracted with ethyl
acetate (2 × 35 mL) again. The combined organic phases 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 2-methylene-2,3-dihydro-1,4-oxazepines.
2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxazepine (3a). 1,3-
Diphenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (2a) (287.5 mg,
1.1 mmol) and ZnCl2 (149.9 mg, 1.1 mmol) were used to yield 273.2
mg (95%) of the indicated product as a brownish-orange solid (Rf =
N,N-Dimethyl-4-(2-methylene-7-phenyl-2,3-dihydro-1,4-oxaze-
pin-5-yl)aniline (3f). 3-(4-(Dimethylamino)phenyl)-1-phenyl-3-
(prop-2-yn-1-ylamino)prop-2-en-1-one (2f) (334.8 mg, 1.1 mmol)
and ZnCl2 (149.9 mg, 1.1 mmol) were used to yield 204.5 mg (61%)
of the indicated product as a brownish-yellow oil (Rf = 0.30 in 4:1
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ 7.80−7.75
(m, 2H), 7.74−7.69 (m, 2H), 7.49−7.40 (m, 3H), 6.70 (d, J = 8.9 Hz,
2H), 6.43 (s, 1H), 4.69 (s, 1H), 4.51 (s, 2H), 4.35 (d, J = 1.2 Hz,
1H), 3.01 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 166.5 (C), 159.0
(C), 158.5 (C), 151.8 (C), 135.5 (C), 130.0 (CH), 128.8 (CH),
128.6 (CH), 127.2 (C), 126.3 (CH), 111.5 (CH), 100.3 (CH), 93.2
(CH2), 54.8 (CH2), 40.3 (N(CH3)2). The spectral data were in
agreement with those reported previously for this compound.12
5-(3-Fluorophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxa-
zepine (3g). 3-(3-Fluorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)-
prop-2-en-1-one (2g) (251.4 mg, 0.9 mmol) and ZnCl2 (122.7 mg,
1
0.26 in 4:1 hexane/ethyl acetate; mp 94.2−95.9 °C). H NMR (400
MHz, CDCl3): δ 7.85−7.73 (m, 4H), 7.50−7.38 (m, 6H), 6.40 (s,
1H), 4.76 (s, 1H), 4.57 (s, 2H), 4.39 (d, J = 1.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 167.1 (C), 158.9 (C), 158.2 (C), 139.8 (C),
135.2 (C), 130.2 (CH), 130.0 (CH), 128.6 (CH), 128.4 (CH), 127.4
(CH), 126.3 (CH), 99.8 (CH), 93.9 (CH2), 55.6 (CH2). The spectral
data were in agreement with those reported previously for this
compound.12
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0.9 mmol) were used to yield 211.3 mg (84%) of the indicated
product as an orange solid (Rf = 0.45 in 4:1 hexane/ethyl acetate; mp
67.7−68.5 °C). 1H NMR (400 MHz, CDCl3): δ 7.79−7.74 (m, 2H),
7.59−7.56 (m, 1H), 7.55−7.51 (m, 1H), 7.47−7.41 (m, 3H), 7.37
(td, J = 8.0, 5.9 Hz, 1H), 7.13 (ddd, J = 8.3, 5.1, 1.8 Hz, 1H), 6.35 (s,
1H), 4.78 (s, 1H), 4.56 (s, 2H), 4.41 (d, J = 1.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3): δ 166.0 (C), 162.9 (d, 1J = 246.3 Hz, CF), 159.4
2-Methylene-5-phenyl-7-(p-tolyl)-2,3-dihydro-1,4-oxazepine (3l).
3-Phenyl-3-(prop-2-yn-1-ylamino)-1-(p-tolyl)prop-2-en-1-one (2l)
(220.3 mg, 0.8 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were used
to yield 140.6 mg (64%) of the indicated product as a yellow solid (Rf
= 0.42 in 4:1 hexane/ethyl acetate; mp 81.0−83.0 °C). 1H NMR (400
MHz, CDCl3): δ 7.87−7.81 (m, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.49−
7.43 (m, 3H), 7.27 (d, J = 8.1 Hz, 2H), 6.41 (s, 1H), 4.79 (s, 1H),
4.59 (s, 2H), 4.42 (d, J = 1.2 Hz, 1H), 2.44 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 167.1 (C), 159.0 (C), 158.2 (C), 140.4 (C), 139.9
(C), 132.3 (C), 130.0 (CH), 129.3 (CH), 128.3 (CH), 127.4 (CH),
126.2 (CH), 99.1 (CH), 93.7 (CH2), 55.5 (CH2), 21.4 (CH3); IR
(neat): 3106, 2995, 2837, 1657, 1626, 1588, 1569, 1509, 1445, 1359,
1312, 1292, 1261, 1193, 1113, 1076, 1055, 1028, 952, 926, 908, 882,
813, 765, 705, 692, 616 cm−1; MS (ESI, m/z): 276.14 [M + H]+;
HRMS (ESI): calcd for C19H18NO, 276.1383 [M + H]+; found,
276.1386.
3
(C), 158.0 (C), 142.1 (d, J = 7.1 Hz, C), 135.1 (C), 130.4 (CH),
3
4
130.0 (d, J = 8.0 Hz, CH), 128.7 (CH), 126.4 (CH), 123.2 (d, J =
2
2
2.6 Hz, CH), 117.0 (d, J = 21.6 Hz, CH), 114.5 (d, J = 22.7 Hz,
CH), 99.2 (CH), 94.4 (CH2), 55.6 (CH2). The spectral data were in
agreement with those reported previously for this compound.12
2-Methylene-7-phenyl-5-[4-(trifluoromethyl)phenyl]-2,3-dihy-
dro-1,4-oxazepine (3h). 1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(4-
(trifluoromethyl)phenyl)prop-2-en-1-one (2h) (230.5 mg, 0.7
mmol) and ZnCl2 (95.4 mg, 0.7 mmol) were used to yield 172.9
mg (75%) of the indicated product as a yellowish-orange solid (Rf =
5-(4-Chlorophenyl)-2-methylene-7-(p-tolyl)-2,3-dihydro-1,4-oxa-
zepine (3m). 3-(4-Chlorophenyl)-3-(prop-2-yn-1-ylamino)-1-(p-
tolyl)prop-2-en-1-one (2m) (247.8 mg, 0.8 mmol) and ZnCl2
(109.0 mg, 0.8 mmol) were used to yield 198.3 mg (80%) of the
indicated product as an orange solid (Rf = 0.50 in 4:1 hexane/ethyl
acetate; mp 115.4−116.0 °C). 1H NMR (400 MHz, CDCl3): δ 7.64−
7.60 (m, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.28−7.24 (m, 2H), 7.13 (d, J
= 8.1 Hz, 2H), 6.19 (s, 1H), 4.65 (s, 1H), 4.42 (s, 2H), 4.28 (d, J =
1.5 Hz, 1H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 166.1
(C), 159.5 (C), 158.1 (C), 140.7 (C), 138.3 (C), 136.1 (C), 132.2
(C), 129.4 (CH), 128.8 (CH), 128.6 (CH), 126.3 (CH), 98.5 (CH),
94.1 (CH2), 55.6 (CH2), 21.4 (CH3); IR (neat): 2961, 1650, 1583,
1488, 1409, 1366, 1312, 1260, 1196, 1088, 1060, 1011, 863, 843, 802,
727, 679 cm−1; MS (ESI, m/z): 310.10 [M + H]+; HRMS (ESI):
calcd for C19H17ClNO, 310.0993 [M + H]+; found, 310.0996.
5-(3,4-Dichlorophenyl)-2-methylene-7-(p-tolyl)-2,3-dihydro-1,4-
oxazepine (3n). 3-(3,4-Dichlorophenyl)-3-(prop-2-yn-1-ylamino)-1-
(p-tolyl)prop-2-en-1-one (2n) (275.4 mg, 0.8 mmol) and ZnCl2
(109.0 mg, 0.8 mmol) were used to yield 220.3 mg (80%) of the
indicated product as a yellow solid (Rf = 0.53 in 4:1 hexane/ethyl
1
0.67 in 4:1 hexane/ethyl acetate; mp 101.9−103.4 °C). H NMR
(400 MHz, CDCl3): δ 7.91 (d, J = 8.1 Hz, 2H), 7.79−7.33 (m, 2H),
7.67 (d, J = 8.2 Hz, 2H), 7.50−7.40 (m, 3H), 6.35 (s, 1H), 4.79 (s,
1H), 4.58 (s, 2H), 4.42 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3): δ 165.8 (C), 159.6 (C), 157.8 (C), 143.1 (C), 134.9 (C),
2
131.7 (q, J = 32.4 Hz, C), 130.4 (CH), 128.7 (CH), 127.8 (CH),
3
1
126.3 (CH), 125.3 (q, J = 3.7 Hz, CH), 124.1 (q, J = 272.2 Hz,
CF3), 98.9 (CH), 94.5 (CH2), 55.8 (CH2). The spectral data were in
agreement with those reported previously for this compound.12
5-(4-Chlorophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxa-
zepine (3i). 3-(4-Chlorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)-
prop-2-en-1-one (2i) (207.0 mg, 0.7 mmol) and ZnCl2 (95.4 mg, 0.7
mmol) were used to yield 175.9 mg (85%) of the indicated product as
a brown solid (Rf = 0.61 in 4:1 hexane/ethyl acetate; mp 112.9−114.8
°C). 1H NMR (400 MHz, CDCl3): δ 7.80−7.66 (m, 4H), 7.46−7.30
(m, 5H), 6.32 (s, 1H), 4.77 (s, 1H), 4.54 (s, 2H), 4.40 (s, 1H); 13C
NMR (100 MHz, CDCl3): δ 165.7 (C), 159.2 (C), 158.0 (C), 138.1
(C), 136.0 (C), 134.9 (C), 130.2 (CH), 128.7 (CH), 128.6 (CH),
128.4 (CH), 126.2 (CH), 99.1 (CH), 94.0 (CH2), 55.5 (CH2); IR
(neat): 2961, 1660, 1624, 1584, 1559, 1487, 1446, 1397, 1363, 1315,
1290, 1263, 1197, 1115, 1103, 1083, 1062, 1026, 1011, 944, 881, 855,
815, 760, 730, 688, 606 cm−1; MS (ESI, m/z): 296.08 [M + H]+;
HRMS (ESI): calcd for C18H15ClNO, 296.0837 [M + H]+; found,
296.0842.
1
acetate; mp 119.0−120.8 °C). H NMR (400 MHz, CDCl3): δ 7.82
(d, J = 2.0 Hz, 1H), 7.59−7.52 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H),
7.19−7.14 (m, 2H), 6.18 (s, 1H), 4.69 (s, 1H), 4.45 (s, 2H), 4.32 (d,
J = 1.5 Hz, 1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 164.9
(C), 159.9 (C), 157.8 (C), 140.8 (C), 139.8 (C), 134.1 (C), 132.7
(C), 132.0 (C), 130.3 (CH), 129.41 (CH), 129.39 (CH), 126.7
(CH), 126.3 (CH), 97.9 (CH), 94.4 (CH2), 55.7 (CH2), 21.5 (CH3);
IR (neat): 2915, 1655, 1579, 1469, 1372, 1317, 1264, 1233, 1191,
1062, 1027, 854, 809, 754, 717, 676, 644 cm−1; MS (ESI, m/z):
344.06 [M + H]+; HRMS (ESI): calcd for C19H16Cl2NO, 344.0604
[M + H]+; found, 344.0613.
5-(4-Bromophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxa-
zepine (3j). 3-(4-Bromophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)-
prop-2-en-1-one (2j) (204.1 mg, 0.6 mmol) and ZnCl2 (81.8 mg,
0.6 mmol) were used to yield 177.9 mg (87%) of the indicated
product as an orange solid (Rf = 0.42 in 4:1 hexane/ethyl acetate; mp
1
120.3−121.9 °C). H NMR (400 MHz, CDCl3): δ 7.81−7.74 (m,
2H), 7.69 (t, J = 7.8 Hz, 2H), 7.58−7.51 (m, 2H), 7.50−7.41 (m,
3H), 6.35 (s, 1H), 4.80 (s, 1H), 4.57 (s, 2H), 4.42 (s, 1H); 13C NMR
(100 MHz, CDCl3): δ 166.0 (C), 159.3 (C), 158.0 (C), 138.6 (C),
135.0 (C), 131.5 (CH), 130.3 (CH), 129.0 (CH), 128.6 (CH),
126.3(CH), 124.6 (C), 99.1 (CH), 94.2 (CH2), 55.6 (CH2); IR
(neat): 2960, 1661, 1623, 1585, 1557, 1483, 1446, 1393, 1363, 1315,
1297, 1262, 1197, 1114, 1102, 1068, 1025, 1008, 949, 883, 855, 826,
814, 760, 723, 688 cm−1; MS (ESI, m/z): 340.03 [M + H]+; HRMS
(ESI): calcd for C18H1579BrNO, 340.0332 [M + H]+; found,
340.0334.
2-Methylene-7-phenyl-5-(thiophen-3-yl)-2,3-dihydro-1,4-oxaze-
pine (3k). 1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(thiophen-3-yl)prop-
2-en-1-one (2k) (294.1 mg, 1.1 mmol) and ZnCl2 (149.9 mg, 1.1
mmol) were used to yield 241.1 mg (82%) of the indicated product as
a yellow solid (Rf = 0.42 in 4:1 hexane/ethyl acetate; mp 98.0−100.0
°C). 1H NMR (400 MHz, CDCl3): δ 7.81−7.75 (m, 2H), 7.70−7.67
(m, 1H), 7.60 (d, J = 5.0 Hz, 1H), 7.46 (s, 3H), 7.35−7.29 (m, 1H),
6.42 (s, 1H), 4.78 (s, 1H), 4.55 (s, 2H), 4.42 (s, 1H); 13C NMR (100
MHz, CDCl3): δ 162.1 (C), 158.3 (C), 158.0 (C), 142.7 (C), 135.0
(C), 130.1 (CH), 128.5 (CH), 126.7 (CH), 126.2 (CH), 125.9
(CH), 125.6 (CH), 99.3 (CH), 93.9 (CH2), 55.2 (CH2). The spectral
data were in agreement with those reported previously for this
compound.12
2-Methylene-5-(thiophen-3-yl)-7-(p-tolyl)-2,3-dihydro-1,4-oxaze-
pine (3o). 3-(Prop-2-yn-1-ylamino)-3-(thiophen-3-yl)-1-(p-tolyl)-
prop-2-en-1-one (2o) (225.1 mg, 0.8 mmol) and ZnCl2 (109.0 mg,
0.8 mmol) were used to yield 188.7 mg (84%) of the indicated
product as a yellow solid (Rf = 0.23 in 4:1 hexane/ethyl acetate; mp
88.0−90.1 °C). 1H NMR (400 MHz, CDCl3): δ 7.71−7.65 (m, 3H),
7.57 (dd, J = 5.1, 1.1 Hz, 1H), 7.35−7.31 (m, 1H), 7.26 (d, J = 8.0
Hz, 2H), 6.40 (s, 1H), 4.76 (s, 1H), 4.54 (s, 2H), 4.41 (d, J = 1.1 Hz,
1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 162.4 (C), 158.7
(C), 158.1 (C), 143.0 (C), 140.5 (C), 132.3 (C), 129.3 (CH), 126.9
(CH), 126.3 (CH), 125.9 (CH), 125.7 (CH), 98.8 (CH), 93.9
(CH2), 55.4 (CH2), 21.4 (CH3); IR (neat): 2196, 1623, 1580, 1409,
1345, 1312, 1266, 1200, 1182, 1110, 1059, 1017, 865, 805, 778, 753,
695, 654 cm−1; MS (ESI, m/z): 282.09 [M + H]+; HRMS (ESI):
calcd for C17H16NOS, 282.0947 [M + H]+; found, 282.0942.
7-(4-Chlorophenyl)-2-methylene-5-phenyl-2,3-dihydro-1,4-oxa-
zepine (3p). 1-(4-Chlorophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)-
prop-2-en-1-one (2p) (236.6 mg, 0.8 mmol) and ZnCl2 (109.0 mg,
0.8 mmol) were used to yield 197.9 mg (84%) of the indicated
product as a yellow solid (Rf = 0.42 in 4:1 hexane/ethyl acetate; mp
1
125.8−127.1 °C). H NMR (400 MHz, CDCl3): δ 7.83−7.75 (m,
2H), 7.72−7.63 (m, 2H), 7.47−7.35 (m, 5H), 6.35 (s, 1H), 4.75 (s,
1H), 4.54 (s, 2H), 4.40 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz,
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CDCl3): δ 166.7 (C), 158.0 (C), 157.6 (C), 139.6 (C), 136.1 (C),
133.5 (C), 130.0 (CH), 128.8 (CH), 128.3 (CH), 127.5 (CH), 127.3
(CH), 99.8 (CH), 94.1 (CH2), 55.4 (CH2); IR (neat): 2953, 2837,
1656, 1625, 1587, 1569, 1488, 1445, 1402, 1362, 1312, 1290, 1258,
1192, 1110, 1088, 1054, 1028, 1010, 885, 858, 820, 769, 714, 691,
601 cm−1; MS (ESI, m/z): 296.08 [M + H]+; HRMS (ESI): calcd for
C18H15ClNO, 296.0837 [M + H]+; found, 296.0842.
General Procedure for the Synthesis of 2-Acetyl-1H-
pyrroles from 1,4-Oxazepines. To a stirred solution of the
corresponding 2-methylene-2,3-dihydro-1,4-oxazepine (0.5 mmol) in
MeOH (5.0 mL) under argon was added ZnCl2 (0.5 mmol), and the
resulting mixture was then heated to reflux at 65 °C for approximately
2 h in an oil bath (the progress of the reaction was monitored by
routine TLC for the disappearance of 2-methylene-2,3-dihydro-1,4-
oxazepine using hexane/ethyl acetate/acetone (19:1:0.2) as the
eluent). After the reaction was over, the solvent was removed on a
rotary evaporator, and ethyl acetate (40 mL) and saturated aqueous
NH4Cl (15 mL) were added. After the layers were separated, the
aqueous phase was extracted with ethyl acetate (2 × 35 mL). The
combined organic phases were dried over MgSO4 and evaporated on
a rotary evaporator to give a 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 2-acetyl-
1H-pyrroles.
1-(3,5-Diphenyl-1H-pyrrol-2-yl)ethanone (4a). 2-Methylene-5,7-
diphenyl-2,3-dihydro-1,4-oxazepine (3a) (130.7 mg, 0.5 mmol) and
ZnCl2 (68.1 mg, 0.5 mmol) were used to yield 115.0 mg (88%) of the
indicated product as a beige solid (Rf = 0.26 in 4:1 hexane/ethyl
acetate; mp 147.0−149.0 °C). 1H NMR (400 MHz, CDCl3): δ 10.17
(s, 1H), 7.70 (d, J = 7.4 Hz, 2H), 7.52−7.38 (m, 7H), 7.33 (t, J = 7.3
Hz, 1H), 6.58 (d, J = 2.9 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 188.8 (CO), 136.7 (C), 136.4 (C), 134.6 (C), 130.9 (C),
129.8 (CH), 129.6 (C), 129.0 (CH), 128.3 (CH), 128.2 (CH), 127.7
(CH), 125.3 (CH), 110.9 (CH), 27.6 (CH3); IR (neat): 3251, 1612,
1597, 1492, 1461, 1438, 1356, 1291, 1269, 1184, 1075, 992, 956, 914,
826, 760, 703, 688, 671, 613 cm−1; MS (ESI, m/z): 262.12 [M + H]+;
HRMS (ESI): calcd for C18H16NO, 262.1226 [M + H]+; found,
262.1232. The spectral data were in agreement with those reported
previously for this compound.10
1-[3-Phenyl-5-(m-tolyl)-1H-pyrrol-2-yl]ethanone (4b). 2-Methyl-
ene-7-phenyl-5-(m-tolyl)-2,3-dihydro-1,4-oxazepine (3b) (137.7 mg,
0.5 mmol) and ZnCl2 (68.1 mg, 0.5 mmol) were used to yield 100.9
mg (73%) of the indicated product as an off-white solid (Rf = 0.38 in
4:1 hexane/ethyl acetate; mp 130.0−131.0 °C). 1H NMR (400 MHz,
CDCl3): δ 10.38 (s, 1H), 7.58−7.51 (m, 2H), 7.49−7.39 (m, 5H),
7.35−7.28 (m, 1H), 7.16 (d, J = 7.5 Hz, 1H), 6.59 (d, J = 2.9 Hz,
1H), 2.42 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
188.7 (CO), 138.6 (C), 136.9 (C), 136.4 (C), 134.6 (C), 130.8 (C),
129.8 (CH), 129.4 (C), 129.0 (CH), 128.9 (CH), 128.3 (CH), 127.6
(CH), 125.9 (CH), 122.5 (CH), 110.9 (CH), 27.6 (CH3), 21.5
(CH3); IR (neat): 3275, 3224, 1625, 1492, 1451, 1358, 1273, 1206,
1109, 994, 956, 909, 822, 786, 768, 694, 613 cm−1; MS (ESI, m/z):
276.14 [M + H]+; HRMS (ESI): calcd for C19H18NO, 276.1383 [M +
H]+; found, 276.1390.
1-[3-Phenyl-5-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4c). 2-Methyl-
ene-7-phenyl-5-(p-tolyl)-2,3-dihydro-1,4-oxazepine (3c) (110.1 mg,
0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were used to yield 87.1
mg (79%) of the indicated product as an off-white solid (Rf = 0.38 in
4:1 hexane/ethyl acetate; mp 164.5−165.9 °C). 1H NMR (400 MHz,
CDCl3): δ 10.02 (s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.48−7.38 (m,
5H), 7.23 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 2.9 Hz, 1H), 2.38 (s, 3H),
2.11 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 188.6 (CO), 138.3
(C), 136.9 (C), 136.5 (C), 134.6 (C), 129.8 (CH), 129.7 (C), 129.3
(CH), 128.3 (CH), 128.1 (CH), 127.7 (C), 125.2 (CH), 110.5
(CH), 27.6 (CH3), 21.3 (CH3); IR (neat): 3299, 3277, 1620, 1495,
1462, 1409, 1287, 1262, 1181, 1100, 1071, 1017, 952, 801, 766, 700,
634, 610 cm−1; MS (ESI, m/z): 276.14 [M + H]+; HRMS (ESI):
calcd for C19H18NO, 276.1383 [M + H]+; found, 276.1391.
7-(4-Chlorophenyl)-2-methylene-5-(thiophen-3-yl)-2,3-dihydro-
1,4-oxazepine (3q). 1-(4-Chlorophenyl)-3-(prop-2-yn-1-ylamino)-3-
(thiophen-3-yl)prop-2-en-1-one (2q) (241.5 mg, 0.8 mmol) and
ZnCl2 (109.0 mg, 0.8 mmol) were used to yield 210.6 mg (87%) of
the indicated product as a yellow solid (Rf = 0.32 in 4:1 hexane/ethyl
1
acetate; mp 121.0−122.9 °C). H NMR (400 MHz, CDCl3): δ 7.66
(d, J = 8.5 Hz, 3H), 7.55 (dd, J = 5.0, 1.1 Hz, 1H), 7.37 (d, J = 8.6 Hz,
2H), 7.31−7.28 (m, 1H), 6.35 (s, 1H), 4.74 (s, 1H), 4.51 (s, 2H),
4.40 (d, J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 161.8 (C),
157.8 (C), 157.1 (C), 142.5 (C), 136.0 (C), 133.4 (C), 128.7 (CH),
127.5 (CH), 126.7 (CH), 125.9 (CH), 125.6 (CH), 99.4 (CH), 94.1
(CH2), 55.1 (CH2). IR (neat): 3100, 3952, 2834, 1652, 1621, 1578,
1520, 1488, 1402, 1349, 1312, 1260, 1231, 1194, 1111, 1088, 1055,
1011, 874, 837, 818, 787, 693, 605 cm−1; MS (ESI, m/z): 302.04 [M
+ H]+; HRMS (ESI): calcd for C16H13ClNOS, 302.0401 [M + H]+;
found, 302.0410.
7-(4-Chlorophenyl)-2-methylene-5-(m-tolyl)-2,3-dihydro-1,4-ox-
azepine (3r). 1-(4-Chlorophenyl)-3-(prop-2-yn-1-ylamino)-3-(m-
tolyl)prop-2-en-1-one (2r) (247.8 mg, 0.8 mmol) and ZnCl2 (109.0
mg, 0.8 mmol) were used to yield 214.8 mg (87%) of the indicated
product as a pale-yellow solid (Rf = 0.42 in 4:1 hexane/ethyl acetate;
1
mp 89.0−91.0 °C). H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.7
Hz, 2H), 7.65 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.41 (d, J = 8.7 Hz,
2H), 7.35−7.25 (m, 2H), 6.38 (s, 1H), 4.77 (s, 1H), 4.57 (s, 2H),
4.42 (d, J = 1.4 Hz, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3):
δ 167.0 (C), 158.1 (C), 157.6 (C), 139.6 (C), 138.1 (C), 136.2 (C),
133.6 (C), 130.9 (CH), 128.8 (CH), 128.3 (CH), 127.9 (CH), 127.6
(CH), 124.6 (CH), 100.0 (CH), 94.1 (CH2), 55.5 (CH2), 21.5
(CH3); IR (neat): 3053, 2960, 1645, 1624, 1572, 1491, 1404, 1361,
1318, 1262, 1200, 1114, 1087, 1063, 1010, 908, 874, 934, 809, 779,
696, 668, 631, 607 cm−1; MS (ESI, m/z): 310.10 [M + H]+; HRMS
(ESI): calcd for C19H17ClNO, 310.0993 [M + H]+; found, 310.1000.
5-[4-(tert-Butyl)phenyl]-7-(4-chlorophenyl)-2-methylene-2,3-di-
hydro-1,4-oxazepine (3s). 3-(4-(tert-Butyl)phenyl)-1-(4-chlorophen-
yl)-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (2s) (246.3 mg, 0.7
mmol) and ZnCl2 (95.4 mg, 0.7 mmol) were used to yield 202.3
mg (82%) of the indicated product as an orange oil (Rf = 0.48 in 4:1
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ 7.77−7.70
(m, 4H), 7.47 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.41 (s,
1H), 4.76 (s, 1H), 4.57 (s, 2H), 4.41 (d, J = 1.3 Hz, 1H), 1.37 (s,
9H); 13C NMR (100 MHz, CDCl3): δ 166.6 (C), 158.2 (C), 157.5
(C), 153.4 (C), 136.9 (C), 136.1 (C), 133.7 (C), 128.8 (CH), 127.6
(CH), 127.2 (CH), 125.4 (CH), 100.0 (CH), 94.0 (CH2), 55.4
(CH2), 34.8 (C), 31.3 (CH3); IR (neat): 2960, 1737, 1654, 1623,
1581, 1489, 1405, 1361, 1313, 1260, 1192, 1092, 1059, 1012, 909,
813, 736, 682, 632 cm−1; MS (ESI, m/z): 352.15 [M + H]+; HRMS
(ESI): calcd for C22H23ClNO, 352.1463 [M + H]+; found, 352.1473.
7-(4-Chlorophenyl)-5-(3-fluorophenyl)-2-methylene-2,3-dihy-
dro-1,4-oxazepine (3t). 1-(4-Chlorophenyl)-3-(3-fluorophenyl)-3-
(prop-2-yn-1-ylamino)prop-2-en-1-one (2t) (219.6 mg, 0.7 mmol)
and ZnCl2 (95.4 mg, 0.7 mmol) were used to yield 163.0 mg (74%) of
the indicated product as an orange solid (Rf = 0.48 in 4:1 hexane/
1
ethyl acetate; mp 114.5.0−115.6 °C). H NMR (400 MHz, CDCl3):
δ 7.67 (d, J = 8.6 Hz, 2H), 7.55−7.47 (m, 2H), 7.40−7.32 (m, 3H),
7.15−7.07 (m, 1H), 6.30 (s, 1H), 4.76 (s, 1H), 4.54 (s, 2H), 4.40 (d,
J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 165.6 (C), 162.8
1-{5-[4-(tert-Butyl)phenyl]-3-phenyl-1H-pyrrol-2-yl}ethanone
(4d). 5-[4-(tert-Butyl)phenyl]-2-methylene-7-phenyl-2,3-dihydro-1,4-
oxazepine (3d) (127.0 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4
mmol) were used to yield 100.0 mg (79%) of the indicated product as
a white solid (Rf = 0.47 in 4:1 hexane/ethyl acetate; mp 168.0−169.0
1
3
(d, J = 246.6 Hz, CF), 158.1 (C), 157.8 (C), 141.9 (d, J = 7.1 Hz,
3
C), 136.4 (C), 133.4 (C), 129.9 (d, J = 8.1 Hz, CH), 128.9 (CH),
127.6 (CH), 123.1 (d, 4J = 2.6 Hz, CH), 117.0 (d, 2J = 21.6 Hz, CH),
1
°C). H NMR (400 MHz, CDCl3): δ 10.16 (s, 1H), 7.67 (d, J = 8.0
2
114.3 (d, J = 22.7 Hz, CH), 99.3 (CH), 94.5 (CH2), 55.6 (CH2).
Hz, 2H), 7.52−7.39 (m, 7H), 6.59 (d, J = 2.9 Hz, 1H), 2.16 (s, 3H),
1.39 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 188.6 (CO), 151.5
(C), 136.8 (C), 136.4 (C), 134.6 (C), 129.9 (CH), 129.3 (C), 128.3
The spectral data were in agreement with those reported previously
for this compound.12
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(CH), 128.1 (C), 127.7 (CH), 126.0 (CH), 125.0 (CH), 110.6
(CH), 34.8 (C), 31.3 (CH3), 27.6 (CH3); IR (neat): 3273, 2961,
1626, 1494, 1452, 1415, 1289, 1261, 992, 957, 821, 772, 699, 673,
610 cm−1; MS (ESI, m/z): 318.19 [M + H]+; HRMS (ESI): calcd for
C22H24NO, 318.1852 [M + H]+; found, 318.1861.
to yield 89.0 mg (75%) of the indicated product as an off-white solid
(Rf = 0.40 in 4:1 hexane/ethyl acetate; mp 173.3−175.1 °C). H
1
NMR (400 MHz, CDCl3): δ 10.57 (s, 1H), 7.69 (d, J = 8.5 Hz, 2H),
7.48−7.39 (m, 5H), 7.37 (d, J = 8.6 Hz, 2H), 6.55 (d, J = 2.9 Hz,
1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.0 (CO),
136.2 (C), 135.8 (C), 134.8 (C), 134.0 (C), 129.83 (CH), 129.80
(C), 129.5 (CH), 129.2 (CH), 128.4 (CH), 127.8 (C), 126.7 (CH),
111.2 (CH), 27.7 (CH3); IR (neat): 3286, 1621, 1488, 1462, 1411,
1355, 1284, 1261, 1086, 1013, 956, 832, 812, 765, 738, 702, 666, 611
cm−1; MS (ESI, m/z): 296.08 [M + H]+; HRMS (ESI): calcd. for
C18H15ClNO, 296.0837 [M + H]+; found, 296.0844.
1-[5-(4-Methoxyphenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4e).
5-(4-Methoxyphenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxaze-
pine (3e) (116.5 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were
used to yield 84.8 mg (73%) of the indicated product as a yellowish-
white solid (Rf = 0.25 in 4:1 hexane/ethyl acetate; mp 174.1−177.0
1
°C). H NMR (400 MHz, CDCl3): δ 10.15 (s, 1H), 7.66−7.62 (m,
2H), 7.46−7.37 (m, 5H), 6.97−6.92 (m, 2H), 6.47 (d, J = 3.0 Hz,
1H), 3.83 (s, 3H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
188.5 (CO), 159.8 (C), 136.9 (C), 136.5 (C), 134.8 (C), 129.8
(CH), 129.1 (C), 128.3 (CH), 127.7 (CH), 126.7 (CH), 123.6 (C),
114.5 (CH), 110.1 (CH), 55.4 (OCH3), 27.5 (CH3); IR (neat):
3274, 1612, 1599, 1495, 1463, 1440, 1421, 1387, 1294, 1275, 1245,
1175, 1103, 1071, 1027, 954, 824, 793, 765, 716, 699, 641, 608 cm−1;
MS (ESI, m/z): 292.13 [M + H]+; HRMS (ESI): calcd for
C19H18NO2, 292.1332 [M + H]+; found, 292.1340.
1-{5-[4-(Dimethylamino)phenyl]-3-phenyl-1H-pyrrol-2-yl}-
ethanone (4f). N,N-Dimethyl-4-(2-methylene-7-phenyl-2,3-dihydro-
1,4-oxazepin-5-yl)aniline (3f) (121.8 mg, 0.4 mmol) and ZnCl2 (54.5
mg, 0.4 mmol) were used to yield 78.0 mg (64%) of the indicated
product as a yellow solid (Rf = 0.22 in 4:1 hexane/ethyl acetate; mp
193.6−195.9 °C). 1H NMR (400 MHz, CDCl3): δ 9.88 (s, 1H), 7.56
(d, J = 8.9 Hz, 2H), 7.46−7.38 (m, 5H), 6.74 (d, J = 8.8 Hz, 2H),
6.44 (d, J = 3.0 Hz, 1H), 3.00 (s, 6H), 2.10 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 187.9 (CO), 150.4 (C), 137.8 (C), 136.7 (C), 135.0
(C), 129.8 (CH), 128.6 (C), 128.2 (CH), 127.6 (CH), 126.3 (CH),
118.7 (C), 112.4 (CH), 109.3 (CH), 40.4 (N(CH3)2), 27.4 (CH3);
IR (neat): 3303, 3276, 2802, 1594, 1498, 1463, 1411, 1383, 1353,
1272, 1209, 1184, 1102, 1069, 948, 819, 798, 766, 699, 676, 632, 612
cm−1; MS (ESI, m/z): 305.17 [M + H]+; HRMS (ESI): calcd for
C20H21N2O, 305.1648 [M + H]+; found, 305.1651.
1-[5-(4-Bromophenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4j). 5-
(4-Bromophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepine
(3j) (102.1 mg, 0.3 mmol) and ZnCl2 (40.9 mg, 0.3 mmol) were used
to yield 83.7 mg (82%) of the indicated product as an off-white solid
1
(Rf = 0.43 in 4:1 hexane/ethyl acetate; mp 184.0−186.0 °C). H
NMR (400 MHz, CDCl3): δ 10.43 (s, 1H), 7.68−7.58 (m, 2H),
7.58−5.51 (m, 2H), 7.50−7.35 (m, 5H), 6.57 (s, 1H), 2.13 (d, J = 4.7
Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 189.0 (CO), 136.1 (C),
135.7 (C), 134.7 (C), 132.1 (C), 129.88 (CH), 129.86 (C), 129.8
(CH), 128.4 (CH), 127.8 (CH), 126.9 (C), 122.2 (CH), 111.2
(CH), 27.7 (CH3); IR (neat): 3854, 3284, 2008, 1618, 1485, 1462,
1408, 1282, 1261, 1068, 1007, 955, 810, 769, 739, 705, 611 cm−1; MS
(ESI, m/z): 340.03 [M + H]+; HRMS (ESI): calcd for
C18H1579BrNO, 340.0332 [M + H]+; found, 340.0333.
1-[3-Phenyl-5-(thiophen-3-yl)-1H-pyrrol-2-yl]ethanone (4k). 2-
Methylene-7-phenyl-5-(thiophen-3-yl)-2,3-dihydro-1,4-oxazepine
(3k) (133.7 mg, 0.5 mmol) and ZnCl2 (68.1 mg, 0.5 mmol) were
used to yield 89.9 mg (67%) of the indicated product as a yellow solid
1
(Rf = 0.38 in 4:1 hexane/ethyl acetate; mp 173.9−176.0 °C). H
NMR (400 MHz, CDCl3): δ 10.32 (s, 1H), 7.72−7.65 (m, 1H),
7.55−7.33 (m, 7H), 6.51−6.40 (m, 1H), 2.11 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 188.8 (CO), 136.4 (C), 134.7 (C), 133.0 (C),
132.6 (C), 129.9 (CH), 128.9 (C), 128.4 (CH), 127.8 (CH), 126.7
(CH), 125.6 (CH), 120.9 (CH), 111.1 (CH), 27.6 (CH3); IR (neat):
3286, 3092, 1620, 1473, 1450, 1409, 1380, 1266, 1212, 1075, 1021,
992, 957, 851, 818, 788, 764, 705, 679, 606 cm−1; MS (ESI, m/z):
268.08 [M + H]+; HRMS (ESI): calcd for C16H14NOS, 268.0791 [M
+ H]+; found, 268.0795.
1-[5-(3-Fluorophenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4g). 5-
(3-Fluorophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepine
(3g) (111.8 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were
used to yield 85.0 mg (76%) of the indicated product as a white solid
1
(Rf = 0.38 in 4:1 hexane/ethyl acetate; mp 176.0−177.0 °C). H
1-[5-Phenyl-3-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4l). 2-Methyl-
ene-5-phenyl-7-(p-tolyl)-2,3-dihydro-1,4-oxazepine (3l) (110.1 mg,
0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were used to yield 89.1
mg (81%) of the indicated product as an off-white solid (Rf = 0.43 in
4:1 hexane/ethyl acetate; mp 148.7−150.1 °C). 1H NMR (400 MHz,
CDCl3): δ 10.20 (s, 1H), 7.76−7.68 (m, 2H), 7.45 (t, J = 7.6 Hz,
2H), 7.39−7.33 (m, 3H), 7.30−7.27 (m, 2H), 6.58 (d, J = 3.0 Hz,
1H), 2.46 (s, 3H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
188.8 (CO), 137.5 (C), 136.6 (C), 134.6 (C), 133.3 (C), 131.0 (C),
129.7 (CH), 129.6 (C), 129.0 (CH), 128.2 (CH), 125.3 (CH), 111.0
(CH), 27.6 (CH3), 21.3 (CH3) (note that two CH peaks overlap on
each other); IR (neat): 3281, 3227, 1624, 1497, 1460, 1438, 1358,
1289, 1268, 1106, 1021, 996, 955, 913, 839, 823, 806, 762, 690, 670,
637 cm−1; MS (ESI, m/z): 276.14 [M + H]+; HRMS (ESI): calcd for
C19H18NO, 276.1383 [M + H]+; found, 276.1389.
1-[5-(4-Chlorophenyl)-3-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4m).
5-(4-Chlorophenyl)-2-methylene-7-(p-tolyl)-2,3-dihydro-1,4-oxaze-
pine (3m) (123.9 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol)
were used to yield 78.1 mg (63%) of the indicated product as a white
solid (Rf = 0.58 in 4:1 hexane/ethyl acetate; mp 199.1−201.0 °C). 1H
NMR (400 MHz, CDCl3): δ 10.13 (s, 1H), 7.56−7.52 (m, 2H),
7.30−7.26 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.1 Hz,
2H), 6.42 (d, J = 3.0 Hz, 1H), 2.33 (s, 3H), 2.03 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 189.0 (CO), 137.7 (C), 135.5 (C), 134.8 (C),
134.0 (C), 133.1 (C), 129.8 (C), 129.7 (CH), 129.5 (C), 129.3
(CH), 129.1 (CH), 126.5 (CH), 111.2 (CH), 27.7 (CH3), 21.4
(CH3); IR (neat): 3290, 1631, 1493, 1443, 1356, 1284, 1260, 1181,
1087, 1011, 955, 831, 817, 799, 729, 656 cm−1; MS (ESI, m/z):
310.10 [M + H]+; HRMS (ESI): calcd for C19H17ClNO, 310.0993
[M + H]+; found, 310.1001.
NMR (400 MHz, CDCl3): δ 10.20 (s, 1H), 7.48−7.34 (m, 8H),
7.05−6.98 (m, 1H), 6.57 (d, J = 3.0 Hz, 1H), 2.12 (d, J = 0.9 Hz,
1
3H); 13C NMR (100 MHz, CDCl3): δ 189.2 (CO), 163.4 (d, J =
3
246.2 Hz, CF), 136.2 (C), 135.5 (C), 134.6 (C), 133.2 (d, J = 8.3
Hz, C), 130.6 (d, 3J = 8.5 Hz, CH), 129.92 (CH), 129.86 (C), 128.4
4
2
(CH), 127.9 (CH), 121.0 (d, J = 1.9 Hz, CH), 115.1 (d, J = 21.3
2
Hz, CH), 112.4 (d, J = 23.1 Hz, CH), 111.5 (CH), 27.7 (CH3); IR
(neat): 3301, 3288, 3062, 1628, 1489, 1454, 1434, 1414, 1357, 1271,
1206, 1176, 1107, 1076, 991, 977, 957, 892, 848, 814, 784, 766, 729,
704, 680, 613 cm−1; MS (ESI, m/z): 280.11 [M + H]+; HRMS (ESI):
calcd for C18H15FNO, 280.1132 [M + H]+; found, 280.1136.
1-{3-Phenyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrrol-2-yl}-
ethanone (4h). 2-Methylene-7-phenyl-5-[4-(trifluoromethyl)phenyl]-
2,3-dihydro-1,4-oxazepine (3h) (131.7 mg, 0.4 mmol) and ZnCl2
(54.5 mg, 0.4 mmol) were used to yield 115.4 mg (88%) of the
indicated product as a yellowish-white solid (Rf = 0.41 in 4:1 hexane/
1
ethyl acetate; mp 196.0−198.0 °C). H NMR (400 MHz, CDCl3): δ
10.00 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.3 Hz, 2H),
7.49−7.38 (m, 5H), 6.64 (d, J = 3.0 Hz, 1H), 2.12 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 189.3 (CO), 136.0 (C), 134.9 (C), 134.5 (C),
134.3 (C), 130.3 (C), 130.2 (q, 2J = 32.4 Hz, C), 129.9 (CH), 128.5
3
(CH), 128.0 (CH), 126.1 (q, J = 3.5 Hz, CH), 125.4 (CH), 124.2
1
(q, J = 272.0 Hz, CF3), 112.1 (CH), 27.8 (CH3); IR (neat): 3290,
1618, 1465, 1450, 1411, 1318, 1295, 1262, 1159, 1106, 1062, 1017,
957, 841, 815, 767, 704, 676, 626, 612 cm−1; MS (ESI, m/z): 330.11
[M + H]+; HRMS (ESI): calcd for C19H15F3NO, 330.1100 [M + H]+;
found, 330.1109.
1-[5-(4-Chlorophenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4i). 5-
(4-Chlorophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepine
(3i) (118.3 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were used
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1-[5-(3,4-Dichlorophenyl)-3-(p-tolyl)-1H-pyrrol-2-yl]ethanone
(4n). 5-(3,4-Dichlorophenyl)-2-methylene-7-(p-tolyl)-2,3-dihydro-
1,4-oxazepine (3n) (137.7 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4
mmol) were used to yield 95.0 mg (69%) of the indicated product as
a white solid (Rf = 0.50 in 4:1 hexane/ethyl acetate; mp 224.0−226.0
(C), 129.2 (CH), 129.0 (CH), 128.6 (CH), 125.9 (CH), 122.5
(CH), 110.8 (CH), 27.7 (CH3), 21.6 (CH3); IR (neat): 3303, 3220,
1624, 1440, 1270, 1086, 1016, 952, 905, 837, 808, 782, 726, 694, 634,
613 cm−1; MS (ESI, m/z): 310.10 [M + H]+; HRMS (ESI): calcd for
C19H17ClNO, 310.0993 [M + H]+; found, 310.1001.
1
°C). H NMR (400 MHz, CDCl3): δ 10.21 (s, 1H), 7.76 (d, J = 1.8
1-{5-[4-(tert-Butyl)phenyl]-3-(4-chlorophenyl)-1H-pyrrol-2-yl}-
ethanone (4s). 5-[4-(tert-Butyl)phenyl]-7-(4-chlorophenyl)-2-meth-
ylene-2,3-dihydro-1,4-oxazepine (3s) (105.6 mg, 0.3 mmol) and
ZnCl2 (40.9 mg, 0.3 mmol) were used to yield 82.4 mg (78%) of the
indicated product as an off-white solid (Rf = 0.46 in 4:1 hexane/ethyl
acetate; mp 222.0−224.0 °C). 1H NMR (400 MHz, CDCl3): δ 10.15
(s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.41 (d, J =
8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 6.51 (d, J = 3.0 Hz, 1H), 2.12
(s, 3H), 1.35 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 188.3 (CO),
151.7 (C), 137.0 (C), 134.9 (C), 133.8 (C), 133.1 (C), 131.2 (CH),
129.3 (C), 128.5 (CH), 127.9 (C), 126.0 (CH), 125.1 (CH), 110.5
(CH), 34.8 (C), 31.3 (CH3), 27.7 (CH3); IR (neat): 3279, 2947,
1619, 1491, 1460, 1413, 1358, 1290, 1259, 1185, 1085, 1016, 994,
954, 832, 812, 757, 723, 671, 634, 610 cm−1; MS (ESI, m/z): 352.15
[M + H]+; HRMS (ESI): calcd for C22H23ClNO, 352.1463 [M + H]+;
found, 352.1472.
Hz, 1H), 7.45−7.37 (m, 2H), 7.23 (pseudo d, J = 8.3 Hz, 2H), 7.18
(pseudo d, J = 8.3 Hz, 2H), 6.46 (d, J = 3.0 Hz, 1H), 2.35 (s, 3H),
2.07 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 189.0 (CO), 137.8
(C), 134.8 (C), 134.2 (C), 133.4 (C), 132.9 (C), 132.1 (C), 131.14
(C), 131.06 (CH), 130.2 (C), 129.7 (CH), 129.2 (CH), 127.1 (CH),
124.5 (CH), 111.8 (CH), 27.8 (CH3), 21.4 (CH3); IR (neat): 3271,
1617, 1485, 1442, 1417, 1359, 1281, 1180, 1134, 1107, 1027, 993,
954, 870, 814, 758, 697, 655 cm−1; MS (ESI, m/z): 344.06 [M + H]+;
HRMS (ESI): calcd for C19H16Cl2NO, 344.0604 [M + H]+; found,
344.0601.
1-[5-(Thiophen-3-yl)-3-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4o). 2-
Methylene-5-(thiophen-3-yl)-7-(p-tolyl)-2,3-dihydro-1,4-oxazepine
(3o) (112.5 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were
used to yield 93.2 mg (83%) of the indicated product as a yellow solid
1
(Rf = 0.37 in 4:1 hexane/ethyl acetate; mp 167.0−169.0 °C). H
NMR (400 MHz, CDCl3): δ 10.50 (s, 1H), 7.76−7.72 (m, 1H), 7.46
(dd, J = 5.0, 0.8 Hz, 1H), 7.39−7.32 (m, 3H), 7.27 (d, J = 7.9 Hz,
2H), 6.46 (d, J = 2.8 Hz, 1H), 2.45 (s, 3H), 2.17 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 188.9 (CO), 137.5 (C), 134.8 (C), 133.3 (C),
133.0 (C), 132.7 (CH), 129.7 (C), 129.1 (CH), 128.9 (C), 126.6
(CH), 125.7 (CH), 120.8 (CH), 111.1 (CH), 27.6 (CH3), 21.4
(CH3); IR (neat): 3286, 3100, 2917, 1667, 1573, 1486, 1369, 1277,
1178, 1132, 1058, 1016, 768, 653 cm−1; MS (ESI, m/z): 282.09 [M +
H]+; HRMS (ESI): calcd for C17H16NOS, 282.0947 [M + H]+; found,
282.0956.
1-[3-(4-Chlorophenyl)-5-(3-fluorophenyl)-1H-pyrrol-2-yl]-
ethanone (4t). 7-(4-Chlorophenyl)-5-(3-fluorophenyl)-2-methylene-
2,3-dihydro-1,4-oxazepine (3t) (94.1 mg, 0.3 mmol) and ZnCl2 (40.9
mg, 0.3 mmol) were used to yield 73.5 mg (78%) of the indicated
product as an off-white solid (Rf = 0.40 in 4:1 hexane/ethyl acetate;
mp 199.0−201.0 °C). 1H NMR (400 MHz, CDCl3): δ 10.42 (s, 1H),
7.51−7.44 (m, 2H), 7.44−7.39 (m, 2H), 7.39−7.34 (m, 3H), 7.05−
6.98 (m, 1H), 6.54 (d, J = 3.0 Hz, 1H), 2.13 (s, 3H); 13C NMR (100
1
MHz, CDCl3): δ 189.0 (CO), 163.4 (d, J = 246.0 Hz, CF), 135.7
(C), 134.6 (C), 134.0 (C), 133.1 (C), 133.0 (d, 3J = 8.2 Hz, C), 131.2
(CH), 130.7 (d, 3J = 8.4 Hz,CH), 129.9 (C), 128.7 (CH), 121.0 (d, 4J
= 2.5 Hz, CH), 115.19 (d, 2J = 21.3 Hz, CH), 112.38 (d, 2J = 23.2 Hz,
CH), 111.4 (CH), 27.8 (CH3); IR (neat): 3294, 3060, 1631, 1491,
1432, 1356, 1274, 1204, 1175, 1089, 1014, 977, 955, 887, 841, 805,
777, 737, 720, 683, 627 cm−1; MS (ESI, m/z): 314.08 [M + H]+;
HRMS (ESI): calcd for C18H14ClFNO, 314.0743 [M + H]+; found,
314.0752.
1-[3-(4-Chlorophenyl)-5-phenyl-1H-pyrrol-2-yl]ethanone (4p). 7-
(4-Chlorophenyl)-2-methylene-5-phenyl-2,3-dihydro-1,4-oxazepine
(3p) (118.3 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were
used to yield 91.1 mg (77%) of the indicated product as a yellowish-
white solid (Rf = 0.37 in 4:1 hexane/ethyl acetate; mp 173.0−174.0
1
°C). H NMR (400 MHz, CDCl3): δ 10.28 (s, 1H), 7.72−7.67 (m,
2H), 7.45−7.31 (m, 7H), 6.53 (d, J = 3.0 Hz, 1H), 2.11 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 188.5 (CO), 136.9 (C), 134.8 (C),
133.8 (C), 133.1 (C), 131.1 (CH), 130.7 (C), 129.5 (C), 129.1
(CH), 128.6 (CH), 128.4 (CH), 125.3 (CH), 110.8 (CH), 27.7
(CH3); IR (neat): 3282, 3227, 1623, 1488, 1460, 1433, 1396, 1359,
1289, 1267, 1086, 1016, 994, 953, 914, 837, 809, 759, 688, 671, 632,
610 cm−1; MS (ESI, m/z): 296.08 [M + H]+; HRMS (ESI): calcd for
C18H15ClNO, 296.0837 [M + H]+; found, 296.0842.
General Procedure for the Synthesis of 2-Acetyl-1H-
pyrroles from N-Propargylic β-Enaminones. To a stirred solution
of the corresponding N-propargylic β-enaminone (0.5 mmol) in
CHCl3 (5.0 mL) under argon was added ZnCl2 (0.5 mmol), and the
resulting mixture was heated to reflux at 61 °C for approximately 2 h
in an oil bath (the progress of the first step was monitored by routine
TLC for the disappearance of N-propargylic β-enaminone using
hexane/ethyl acetate (9:1) as the eluent). After the mixture was
allowed to cool to room temperature, the solvent was removed on a
rotary evaporator, and methanol (5 mL) and ZnCl2 (0.5 mmol) were
added. The resulting mixture was then refluxed with stirring at 65 °C
for approximately another 2 h under argon in an oil bath (the progress
of the second step was monitored by routine TLC for the
disappearance of 2-methylene-2,3-dihydro-1,4-oxazepine using hex-
ane/ethyl acetate/acetone (19:1:0.2) as the eluent). After the reaction
was over, the solvent was removed on a rotary evaporator, and ethyl
acetate (40 mL) and saturated aqueous NH4Cl (15 mL) were added.
After the layers were separated, the aqueous phase was extracted with
ethyl acetate (2 × 35 mL). The combined organic phases were dried
over MgSO4 and evaporated on a rotary evaporator to give a 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 2-acetyl-1H-pyrroles.
1-[3-(4-Chlorophenyl)-5-(thiophen-3-yl)-1H-pyrrol-2-yl]-
ethanone (4q). 7-(4-Chlorophenyl)-2-methylene-5-(thiophen-3-yl)-
2,3-dihydro-1,4-oxazepine (3q) (120.7 mg, 0.4 mmol) and ZnCl2
(54.5 mg, 0.4 mmol) were used to yield 102.9 mg (85%) of the
indicated product as a pale-yellow solid (Rf = 0.34 in 4:1 hexane/ethyl
acetate; mp 195.1−196.3 °C). 1H NMR (400 MHz, CDCl3): δ 10.35
(s, 1H), 7.69−7.66 (m, 1H), 7.44−7.33 (m, 6H), 6.42 (d, J = 2.9 Hz,
1H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 188.5 (CO),
134.8 (C), 133.9 (C), 133.2 (C), 132.4 (C), 131.2 (CH), 128.9 (C),
128.6 (CH), 126.8 (CH), 125.6 (CH), 121.0 (CH), 111.0 (CH),
27.7 (CH3) (note that two C peaks overlap on each other); IR (neat):
3310, 3217, 3088, 2349, 2027, 1617, 1533, 1492, 1467, 1446, 1377,
1266, 1216, 1086, 1015, 993, 973, 952, 854, 829, 782, 735, 672, 648,
635, 605 cm−1; MS (ESI, m/z): 302.04 [M + H]+; HRMS (ESI):
calcd for C16H13ClNOS, 302.0401 [M + H]+; found, 302.0409.
1-[3-(4-Chlorophenyl)-5-(m-tolyl)-1H-pyrrol-2-yl]ethanone (4r).
7-(4-Chlorophenyl)-2-methylene-5-(m-tolyl)-2,3-dihydro-1,4-oxaze-
pine (3r) (123.9 mg, 0.4 mmol) and ZnCl2 (54.5 mg, 0.4 mmol) were
used to yield 100.2 mg (81%) of the indicated product as an off-white
solid (Rf = 0.37 in 4:1 hexane/ethyl acetate; mp 178.8−179.6 °C). 1H
NMR (400 MHz, CDCl3): δ 10.14 (s, 1H), 7.51−7.46 (m, 2H), 7.41
(d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.31 (t, J = 7.6 Hz, 1H),
7.15 (d, J = 7.4 Hz, 1H), 6.53−6.50 (m, 1H), 2.40 (s, 3H), 2.11 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 188.4 (CO), 138.8 (C), 137.0
(C), 134.8 (C), 133.8 (C), 133.0 (C), 131.1 (CH), 130.6 (C), 129.4
1-(3,5-Diphenyl-1H-pyrrol-2-yl)ethanone (4a). 1,3-Diphenyl-3-
(prop-2-yn-1-ylamino)prop-2-en-1-one (2a) (130.7 mg, 0.5 mmol)
and ZnCl2 (136.3 mg, 1.0 mmol) were used to yield 111.1 mg (85%)
of the indicated product as a beige solid (Rf = 0.26 in 4:1 hexane/
ethyl acetate; mp 147.0−149.0 °C).
When the reaction was carried out on a relatively larger scale by
employing 1,3-diphenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(2a) (418.1 mg, 1.6 mmol) and ZnCl2 (436.1 mg, 3.2 mmol), the
indicated product (4a) was obtained in 334.5 mg (80%).
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1-[3-Phenyl-5-(m-tolyl)-1H-pyrrol-2-yl]ethanone (4b). 1-Phenyl-
3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-en-1-one (2b) (137.7 mg,
0.5 mmol) and ZnCl2 (136.3 mg, 1.0 mmol) were used to yield 100.7
mg (73%) of the indicated product as an off-white solid (Rf = 0.38 in
4:1 hexane/ethyl acetate; mp 130.0−131.0 °C).
1-[3-Phenyl-5-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4c). 1-Phenyl-3-
(prop-2-yn-1-ylamino)-3-(p-tolyl)prop-2-en-1-one (2c) (110.1 mg,
0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were used to yield 67.9
mg (62%) of the indicated product as an off-white solid (Rf = 0.38 in
4:1 hexane/ethyl acetate; mp 164.5−165.9 °C).
1-{5-[4-(tert-Butyl)phenyl]-3-phenyl-1H-pyrrol-2-yl}ethanone
(4d). 3-[4-(tert-Butyl)phenyl]-1-phenyl-3-(prop-2-yn-1-ylamino)-
prop-2-en-1-one (2d) (127.0 mg, 0.4 mmol) and ZnCl2 (109.0 mg,
0.8 mmol) were used to yield 108.5 mg (85%) of the indicated
product as a white solid (Rf = 0.47 in 4:1 hexane/ethyl acetate; mp
168.0−169.0 °C).
1-[5-(4-Methoxyphenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4e).
3-(4-Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-
one (2e) (145.7 mg, 0.5 mmol) and ZnCl2 (136.3 mg, 1.0 mmol)
were used to yield 96.4 mg (66%) of the indicated product as a
yellowish-white solid (Rf = 0.25 in 4:1 hexane/ethyl acetate; mp
174.1−177.0 °C).
1-{5-[4-(Dimethylamino)phenyl]-3-phenyl-1H-pyrrol-2-yl}-
ethanone (4f). 3-[4-(Dimethylamino)phenyl]-1-phenyl-3-(prop-2-
yn-1-ylamino)prop-2-en-1-one (2f) (152.2 mg, 0.5 mmol) and
ZnCl2 (136.3 mg, 1.0 mmol) were used to yield 77.7 mg (51%) of
the indicated product as a yellow solid (Rf = 0.22 in 4:1 hexane/ethyl
acetate; mp 193.6−195.9 °C).
1-[5-(3-Fluorophenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4g). 3-
(3-Fluorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(2g) (139.8 mg, 0.5 mmol) and ZnCl2 (136.3 mg, 1.0 mmol) were
used to yield 88.1 mg (63%) of the indicated product as a white solid
(Rf = 0.38 in 4:1 hexane/ethyl acetate; mp 176.0−177.0 °C).
1-{3-Phenyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrrol-2-yl}-
ethanone (4h). 1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(4-
(trifluoromethyl)phenyl)prop-2-en-1-one (2h) (131.7 mg, 0.4
mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were used to yield 91.0
mg (69%) of the indicated product as a yellowish-white solid (Rf =
0.41 in 4:1 hexane/ethyl acetate; mp 196.0−198.0 °C).
1-[5-(4-Chlorophenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4i). 3-
(4-Chlorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(2i) (118.3 mg, 0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were
used to yield 79.7 mg (67%) of the indicated product as an off-white
solid (Rf = 0.40 in 4:1 hexane/ethyl acetate; mp 173.3−175.1 °C).
1-[5-(4-Bromophenyl)-3-phenyl-1H-pyrrol-2-yl]ethanone (4j). 3-
(4-Bromophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(2j) (136.1 mg, 0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were
used to yield 102.3 mg (75%) of the indicated product as an off-white
solid (Rf = 0.43 in 4:1 hexane/ethyl acetate; mp 184.0−186.0 °C).
1-[3-Phenyl-5-(thiophen-3-yl)-1H-pyrrol-2-yl]ethanone (4k). 1-
Phenyl-3-(prop-2-yn-1-ylamino)-3-(thiophen-3-yl)prop-2-en-1-one
(2k) (133.7 mg, 0.5 mmol) and ZnCl2 (136.3 mg, 1.0 mmol) were
used to yield 101.7 mg (76%) of the indicated product as a yellow
solid (Rf = 0.38 in 4:1 hexane/ethyl acetate; mp 173.9−176.0 °C).
1-[5-Phenyl-3-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4l). 3-Phenyl-3-
(prop-2-yn-1-ylamino)-1-(p-tolyl)prop-2-en-1-one (2l) (110.1 mg,
0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were used to yield
58.9 mg (53%) of the indicated product as an off-white solid (Rf =
0.43 in 4:1 hexane/ethyl acetate; mp 148.7−150.1 °C).
1-[5-(Thiophen-3-yl)-3-(p-tolyl)-1H-pyrrol-2-yl]ethanone (4o). 3-
(Prop-2-yn-1-ylamino)-3-(thiophen-3-yl)-1-(p-tolyl)prop-2-en-1-one
(2o) (112.5 mg, 0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were
used to yield 75.3 mg (67%) of the indicated product as a yellow solid
(Rf = 0.37 in 4:1 hexane/ethyl acetate; mp 167.0−169.0 °C).
1-[3-(4-Chlorophenyl)-5-phenyl-1H-pyrrol-2-yl]ethanone (4p). 1-
(4-Chlorophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(2p) (118.3 mg, 0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were
used to yield 89.1 mg (75%) of the indicated product as a yellowish-
white solid (Rf = 0.37 in 4:1 hexane/ethyl acetate; mp 173.0−174.0
°C).
1-[3-(4-Chlorophenyl)-5-(thiophen-3-yl)-1H-pyrrol-2-yl]-
ethanone (4q). 1-(4-Chlorophenyl)-3-(prop-2-yn-1-ylamino)-3-(thi-
ophen-3-yl)prop-2-en-1-one (2q) (120.7 mg, 0.4 mmol) and ZnCl2
(109.0 mg, 0.8 mmol) were used to yield 93.3 mg (77%) of the
indicated product as a pale-yellow solid (Rf = 0.34 in 4:1 hexane/ethyl
acetate; mp 195.1−196.3 °C).
1-[3-(4-Chlorophenyl)-5-(m-tolyl)-1H-pyrrol-2-yl]ethanone (4r).
1-(4-Chlorophenyl)-3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-en-
1-one (2r) (123.9 mg, 0.4 mmol) and ZnCl2 (109.0 mg, 0.8 mmol)
were used to yield 88.3 mg (71%) of the indicated product as an off-
white solid (Rf = 0.37 in 4:1 hexane/ethyl acetate; mp 178.8−179.6
°C).
1-{5-[4-(tert-Butyl)phenyl]-3-(4-chlorophenyl)-1H-pyrrol-2-yl}-
ethanone (4s). 3-(4-(tert-Butyl)phenyl)-1-(4-chlorophenyl)-3-(prop-
2-yn-1-ylamino)prop-2-en-1-one (2s) (140.7 mg, 0.4 mmol) and
ZnCl2 (109.0 mg, 0.8 mmol) were used to yield 109.6 mg (78%) of
the indicated product as an off-white solid (Rf = 0.46 in 4:1 hexane/
ethyl acetate; mp 222.0−224.0 °C).
1-[3-(4-Chlorophenyl)-5-(3-fluorophenyl)-1H-pyrrol-2-yl]-
ethanone (4t). 1-(4-Chlorophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-
1-ylamino)prop-2-en-1-one (2t) (125.5 mg, 0.4 mmol) and ZnCl2
(109.0 mg, 0.8 mmol) were used to yield 90.7 mg (72%) of the
indicated product as an off-white solid (Rf = 0.40 in 4:1 hexane/ethyl
acetate; mp 199.0−201.0 °C).
Reaction of 2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-ox-
azepine (3a) with ZnCl2 in CD3OD. To a stirred solution of 2-
methylene-5,7-diphenyl-2,3-dihydro-1,4-oxazepine (3a) (104.0 mg,
0.4 mmol) in methanol-d4 (CD3OD) (4.0 mL) under argon was
added ZnCl2 (54.5 mg, 0.4 mmol), and the resulting mixture was then
heated to reflux at 65 °C for approximately 3 h in an oil bath. After
the reaction was over, it was allowed to cool to room temperature,
1
and H and 13C NMR spectra were taken directly from the crude
reaction mixture.
Deuterium-Incorporated 1-(3,5-Diphenyl-1H-pyrrol-2-yl)-
ethanone (4a−D). 1H NMR (400 MHz, CD3OD): δ 11.32 (s,
0.01H), 7.77 (d, J = 7.4 Hz, 2H), 7.46−7.36 (m, 7H), 7.36−7.30 (m,
1H), 6.58 (d, J = 2.2 Hz, 0.42H), 2.08−2.00 (m, 1.62H). From the
integration values, the level of deuterium incorporation (% D) was
determined as 46% at 2.08−2.00 ppm, 58% at 6.58 ppm, and 99% at
11.32 ppm; 13C NMR (100 MHz, CD3OD): δ 190.3 (CO), 138.8
(C), 137.9 (C), 136.6 (C), 132.4 (C), 130.8 (CH), 130.5 (C), 129.9
(CH), 129.2 (CH), 129.1 (CH), 128.6 (CH), 126.6 (CH), 111.8
(CH), 27.5 (t, JC−D = 19.7 Hz, CH3).
General Procedure for the Reactions of 2-Methylene-5,7-
diphenyl-2,3-dihydro-1,4-oxazepine (3a) (Table 4). To a stirred
solution of 1,4-oxazepine 3a (0.4 mmol) in 4.0 mL of the indicated
solvent or solvent mixture was added ZnCl2 (0.4 mmol), except that
in one case, three drops of conc. HCl were used instead of ZnCl2. The
resulting mixture was then heated at 80 °C for approximately 5.5−6.0
h in an oil bath. After the reaction was over, the solvent was removed
on a rotary evaporator, and ethyl acetate (40 mL) and saturated
aqueous NH4Cl (15 mL) were added. After the layers were separated,
the aqueous phase was extracted with ethyl acetate (2 × 20 mL). The
combined organic phases were dried over MgSO4 and evaporated on
a rotary evaporator to give a crude product, which was purified by
flash chromatography on silica gel using hexane/ethyl acetate (19:1,
9:1, and 4:1) as the eluent to afford the indicated products.
Reaction of 1,4-Oxazepine 3a with ZnCl2 in CH3CO2H (Table 4,
Entry 1). 2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxazepine (3a)
1-(5-(4-Chlorophenyl)-3-(p-tolyl)-1H-pyrrol-2-yl)ethanone (4m).
3-(4-Chlorophenyl)-1-(p-tolyl)prop-2-yn-1-one (2m) (123.9 mg, 0.4
mmol) and ZnCl2 (109.0 mg, 0.8 mmol) were used to yield 90.1 mg
(73%) of the indicated product as a white solid (Rf = 0.58 in 4:1
hexane/ethyl acetate; mp 199.1−201.0 °C).
1-(5-(3,4-Dichlorophenyl)-3-(p-tolyl)-1H-pyrrol-2-yl)ethanone
(4n). 3-(3,4-Dichlorophenyl)-3-(prop-2-yn-1-ylamino)-1-(p-tolyl)-
prop-2-en-1-one (2n) (137.7 mg, 0.4 mmol) and ZnCl2 (109.0 mg,
0.8 mmol) were used to yield 85.4 mg (62%) of the indicated product
as a white solid (Rf = 0.50 in 4:1 hexane/ethyl acetate; mp 224.0−
226.0 °C).
6301
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J. Org. Chem. 2021, 86, 6289−6304

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(104.0 mg, 0.4 mmol) and ZnCl2 (50.0 mg, 0.4 mmol) in CH3CO2H
(4 mL) were used. After chromatographic purification, two fractions
were isolated. The first fraction yielded 57.0 mg (55%) of the starting
material 1,4-oxazepine 3a as a brownish-orange solid (Rf = 0.26 in 4:1
hexane/ethyl acetate; mp 94.2−95.9 °C). The second fraction
afforded 2.0 mg (2%) of (4-methyl-2-phenyl-1H-pyrrol-3-yl)
(phenyl)methanone (14a) as a brownish-orange solid (Rf = 0.22 in
4:1 hexane/ethyl acetate; mp 118.5−120.0 °C).
1447, 1321, 1177, 1078, 1024, 1000, 947, 862, 809, 763, 699, 688,
603 cm−1; MS (ESI, m/z): 269.12 [M + H]+; HRMS (ESI): calcd for
C17H17O3, 269.1172 [M + H]+; found, 269.1178. The spectral data
were in agreement with those reported previously for this
compound.20
Reaction of 1,4-Oxazepine 3a with ZnCl2 in HOCH2CH2OH/1,4-
Dioxane (Table 4, Entry 6). 2-Methylene-5,7-diphenyl-2,3-dihydro-
1,4-oxazepine (3a) (100.0 mg, 0.4 mmol) and ZnCl2 (50.0 mg, 0.4
mmol) in a 1:1 mixture of HOCH2CH2OH/1,4-dioxane (4 mL) were
used. After chromatographic purification, two fractions were isolated.
The first fraction yielded 21.0 mg (20%) of 1-phenyl-2-(2-phenyl-1,3-
dioxolan-2-yl)ethanone (15a) as a purple oil (Rf = 0.34 in 4:1 hexane/
ethyl acetate). The second fraction afforded 22.0 mg (22%) of 1-(3,5-
diphenyl-1H-pyrrol-2-yl)ethanone (4a) as a beige solid (Rf = 0.26 in
4:1 hexane/ethyl acetate; mp 147.0−149.0 °C).
(4-Methyl-2-phenyl-1H-pyrrol-3-yl) (phenyl)methanone (14a).
1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 7.71−7.64 (m, 2H),
7.31 (d, J = 7.4 Hz, 1H), 7.21−7.16 (m, 4H), 7.12−7.09 (m, 3H),
6.65 (s, 1H), 2.19 (d, J = 0.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
δ 195.0 (CO), 139.6 (C), 136.4 (C), 132.4 (CH), 131.9 (CH), 129.9
(C), 128.3 (CH), 128.2 (CH), 127.8 (CH), 127.4 (CH), 122.4
(CH), 120.5 (C), 117.4 (C), 11.7 (CH3); IR (neat): 3161, 2945,
2852, 1733, 1716, 1588, 1569, 1488, 1455, 1424, 1400, 1352, 1286,
1236, 924, 898, 843, 772, 742, 694 cm−1; MS (ESI, m/z): 262.12 [M
+ H]+; HRMS (ESI): calcd for C18H16NO, 262.1226 [M + H]+;
found, 262.1232. The spectral data were in agreement with those
reported previously for this compound.19
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00077.
Reaction of 1,4-Oxazepine 3a with ZnCl2 in CH3CO2H/H2O
(Table 4, Entry 2). 2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxaze-
pine (3a) (85.0 mg, 0.33 mmol) and ZnCl2 (40.0 mg, 0.33 mmol) in
a 1:1 mixture of CH3CO2H/H2O (4 mL) were used. After
chromatographic purification, two fractions were isolated. The first
fraction afforded 5.4 mg (6%) of 1-(3,5-diphenyl-1H-pyrrol-2-
yl)ethanone (4a) as a beige solid (Rf = 0.26 in 4:1 hexane/ethyl
acetate; mp 147.0−149.0 °C). The second fraction yielded 60.4 mg
(71%) of (4-methyl-2-phenyl-1H-pyrrol-3-yl) (phenyl)methanone
(14a) as a brownish-orange solid (Rf = 0.22 in 4:1 hexane/ethyl
acetate; mp 118.5−120.0 °C).
Reaction of 1,4-Oxazepine 3a with ZnCl2 in THF/H2O (Table 4,
Entry 3). 2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxazepine (3a)
(132.0 mg, 0.51 mmol) and ZnCl2 (70.0 mg, 0.51 mmol) in a 1:1
mixture of THF/H2O (4 mL) were used. After chromatographic
purification, two fractions were isolated. The first fraction yielded 86.0
mg (65%) of the starting material 1,4-oxazepine 3a as a brownish-
orange solid (Rf = 0.26 in 4:1 hexane/ethyl acetate; mp 94.2−95.9
°C). The second fraction afforded 35.0 mg (26%) of (4-methyl-2-
phenyl-1H-pyrrol-3-yl) (phenyl)methanone (14a) as a brownish-
orange solid (Rf = 0.22 in 4:1 hexane/ethyl acetate; mp 118.5−120.0
°C).
Reaction of 1,4-Oxazepine 3a with Conc. HCl in THF/H2O (Table
4, Entry 4). 2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxazepine (3a)
(104.0 mg, 0.4 mmol) and three drops of conc. HCl in a 3:1 mixture
of THF/H2O (4 mL) were used. After chromatographic purification,
two fractions were isolated. The first fraction yielded 79.0 mg (76%)
of the starting material 1,4-oxazepine 3a as a brownish-orange solid
(Rf = 0.26 in 4:1 hexane/ethyl acetate; mp 94.2−95.9 °C). The
second fraction afforded 9.0 mg (9%) of (4-methyl-2-phenyl-1H-
pyrrol-3-yl) (phenyl)methanone (14a) as a brownish-orange solid (Rf
= 0.22 in 4:1 hexane/ethyl acetate; mp 118.5−120.0 °C).
1
Copies of H NMR and 13C{1H} NMR spectra for all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Metin Zora − Department of Chemistry, Middle East
Technical University, 06800 Ankara, Turkey; orcid.org/
0000-0001-7764-2288; Phone: (+90)-312-2103213;
Email: zora@metu.edu.tr; Fax: (+90)-312-2103200
Authors
Nilay Kanova − Department of Chemistry, Middle East
Technical University, 06800 Ankara, Turkey
Buse Aysen Dundar − Department of Chemistry, Middle East
Technical University, 06800 Ankara, Turkey
Yilmaz Kelgokmen − Department of Chemistry, Middle East
Technical University, 06800 Ankara, Turkey
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00077
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. James W. Herndon of New
Mexico State University (formerly at the University of
Maryland at College Park) on his birthday occasion. We
thank the Scientific and Technological Research Council of
Turkey (TUBITAK, grant no. 118Z428) and the Research
Fund of Middle East Technical University (METU, grant no.
GAP-103-2018-2770) for the financial support of this research.
We also thank Prof. Dr. Metin Balci for NMR discussion.
Reaction of 1,4-Oxazepine 3a with ZnCl2 in HOCH2CH2OH/THF
(Table 4, Entry 5). 2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxaze-
pine (3a) (101.0 mg, 0.39 mmol) and ZnCl2 (50.0 mg, 0.39 mmol) in
a 1:1 mixture of HOCH2CH2OH/THF (4 mL) were used. After
chromatographic purification, two fractions were isolated. The first
fraction yielded 35.0 mg (26%) of 1-phenyl-2-(2-phenyl-1,3-dioxolan-
2-yl)ethanone (15a) as a purple oil (Rf = 0.34 in 4:1 hexane/ethyl
acetate). The second fraction afforded 10.0 mg (10%) of 1-(3,5-
diphenyl-1H-pyrrol-2-yl)ethanone (4a) as a beige solid (Rf = 0.26 in
4:1 hexane/ethyl acetate; mp 147.0−149.0 °C).
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