Zinc Chloride Mediated Synthesis of 1,4-Oxazepines from N-Propargylic β-Enaminones

Article abstract of DOI:10.1002/ejoc.201701433

An efficient and general method for the synthesis of 1,4-oxazepines is described. When reacted with ZnCl₂ in DCM at 40 °C or CHCl₃ at 61 °C, N-propargylic β-enaminones undergo 7-exo-dig cyclization to afford 2-methylene-2,3-dihydro-1,4-oxazepines in good to high yields. This cyclization has been found to be general for a diverse range of N-propargylic β-enaminones, and proceeds with high efficiency and with broad functional group tolerance. The reactions in refluxing CHCl₃ produced 1,4-oxazepines in comparatively short reaction times and with better yields that those obtained in refluxing DCM. This operationally easy method may provide rapid access to a library of functionalized 1,4-oxazepine derivatives of pharmacological interest.

Full text of DOI:10.1002/ejoc.201701433

A Journal of
Accepted Article
Title: Zinc Chloride-Mediated Synthesis of 1,4-Oxazepines from N-
Propargylic β-Enaminones
Authors: Yilmaz Kelgokmen, Yasemin Cayan, and Metin Zora
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10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
Zinc Chloride-Mediated Synthesis of 1,4-Oxazepines from N-
Propargylic β-Enaminones
Yilmaz Kelgokmen,[a] Yasemin Cayan[a] and Metin Zora*[a]
Dedication ((optional))
Abstract: An efficient and general method for the synthesis of 1,4-
oxazepines is described. When reacted with ZnCl2 in DCM at 40 ºC
or CHCl3 at 61 ºC, N-propargylic β-enaminones undergo 7-exo-dig
cyclization to afford 2-methylene-2,3-dihydro-1,4-oxazepines in good
to high yields. This cyclization has been found to be general for a
diverse range of N-propargylic β-enaminones with high efficiency
and broad functional group tolerance. The reactions in refluxing
CHCl3 produced 1,4-oxazepines in comparatively shorter reaction
times and better yields as compared to those in refluxing DCM. This
operationally easy method may provide quick access to a library of
functionalized 1,4-oxazepine derivatives of pharmacological interest.
(Figure 1), the latter being used primarily in the treatment of
schizophrenia as well. For the synthesis of substituted 1,4-
oxazepines, many fruitful methods have been developed for
decades and new variants also continue to emerge since their
biological activity has made them a focus of medicinal chemistry
over the years.
R
CH3
N
N
CH3
N
O
N
N
O2N
Cl
O
O
Amoxapine (R = H)
Loxapine (R = CH3)
Sintamil
(Nitroxazepine)
Introduction
1,4-Oxazepines possess a unique position in the design and
synthesis of novel biologically active agents that exhibit
noteworthy medicinal activities.[1] In fact, 1,4-oxazepines have
been extensively studied in the last decades as an intriguing
class of heterocycles and still receive considerable attention for
their interesting biological and pharmaceutical activities.[2] The
most well-known examples of 1,4-oxazepines include half and
fully saturated (i.e. dihydro, tetrahydro and perhydro), benzo-,
dibenzo- and pyrido-fused, and/or oxo derivatives. 1,4-
Oxazepine derivatives have been reported to display a wide
Figure 1. Representative 1,4-oxazepine-containing drugs.
Noticeably, half and fully unsaturated monocyclic 1,4-
oxazepines are relatively less explored. In particular, the fully
unsaturated monocyclic derivatives are very rare. Indeed, very
few strategies to synthesize these scaffolds have been reported.
First examples of fully unsaturated monocyclic 1,4-oxazepines
were reported by the Tsuchiya research group in 1986.[ 26 ]
Photolysis
of
3-oxa-6-aza-tricyclo[3.2.0.02,4]hept-6-enes,
3
]
range of biological properties, including analgesic,[
prepared from pyridines via five steps, resulted in valence
isomerization with ring opening to afford 1,4-oxazepines
(Scheme 1a). It was mentioned that as a result of having an
antiaromatic ring system with 8-electrons, the obtained 1,4-
oxazepines were relatively unstable and readily decomposed
during isolation by column chromatography.[27] Loreau and Taran
have reported a method for the preparation of 2,3-dihydro-1,4-
antiallergic,[4] antibacterial,[5] anticonvulsant,[6] antidepressant,[7,8]
9
]
10
]
11 ]
antihistaminic,[8,
antiinflammatory,[
antipsychotic,[
anxiolytic,[12] antiulcer[13] and antitumor[14,15] activities. They have
also been often used as histamine H4 receptor (H4R) agonist,[16]
progesterone receptor agonists,[17] calcium antagonist,[18] PGE2
antagonist,[3]
non-nucleoside inhibitor of HIV-1 reverse
transcriptase[19] and PI3Ka selective inhibitor.[15] In addition, 1,4-
oxazepine derivatives have proven to be useful for the treatment
of various diseases, including allergic bronchitis,[20 ] bronchial
asthma,[20] breast cancer,[21] epilepsy and trigeminal neuralgia,[22]
and psychotic disorders.[11] Furthermore, 1,4-oxazepines are
frequently employed as building blocks and scaffolds for
pharmaceutical research since they are present in the structures
of a variety of drugs, including antidepressants Amoxapine[23]
and Sintamil (Nitroxazepine),[24] and antipsychotic Loxapine[25]
oxazepines via
a phosphine-mediated tandem aza Wittig
reaction of α,β-alkynic ketones with 2-azidoalcohols and
intramolecular cyclization (Scheme 1b).[28]
Recently, N-propargylic β-enaminones have been
recognized as valuable substrates in organic synthesis since,
when treated with proper reagents, they afford a variety of
29
]
30 ]
heterocycles,[
including pyrroles and pyridines.[
It is
noteworthy that mostly five- and six-membered heterocycles
resulted from the cyclizations of N-propargylic β-enaminones.
Although N-propargylic β-enaminones could serve as potential
precursors for the synthesis of seven-membered ring systems
such as 1,4-oxazepines, to our knowledge, very few reports
have appeared until now. Cheng and Cui have shown that under
strong basic conditions, N-propargylic β-enaminones have
produced in situ 1,4-oxazepines, which undergo a series of
rearrangements and concomitant reactions with heteroaromatic
nitrogen nucleophiles to afford N-heteroarene-substituted
pyridines (Scheme 1c).[ 31 ] When the reactions have been
[a]
Y. Kelgokmen, Y. Cayan, M. Zora
Department of Chemistry
Middle East Technical University
06800 Ankara, Turkey
E-mail: zora@metu.edu.tr
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
stopped after few minutes, the corresponding 1,4-oxazepine
derivatives could be isolated in low to good yields. By using
similar strategies, they have also described the synthesis of 2-
treated with molecular iodine in the presence of sodium
bicarbonate, N-propargylic β-enaminones undergo electrophilic
cyclization to afford iodo-substituted pyridines in good to high
yields with a broad range of functional group tolerability.[ 35 ]
Iodopyridines have been further elaborated to more complex
structures by metal-catalyzed coupling reactions such as
(1H-pyrrol-1-yl)pyridines,
2-alkoxy/2-sulfenylpyridines
and
dihydrofuro[2,3-b]pyridines from N-propargylic β-enaminones,
which proceed via the intermediacy of the corresponding 1,4-
oxazepines.[32] Karunakar and coworkers have reported a gold-
catalyzed intramolecular cyclization of N-propargylic β-
enaminones, leading to the formation of 2-methylene-2,3-
dihydro-1,4-oxazepine derivatives (Scheme 1d).[33] This method
has been recently applied to the synthesis of 3-methylene-3,4-
dihydrobenzo[b]oxepin-5-ones.[34]
36
]
Suzuki–Miyaura and Sonogashira reactions.[
We have
anticipated that other metal Lewis acids, particularly inexpensive
ones, could affect the intramolecular cyclization of N-propargylic
β-enaminones to generate seven-membered ring systems.
Recently, zinc Lewis acids and salts have proven to be valid
catalysts or mediators to accomplish a series of organic and
organometallic reactions, including aldol- and Mannich-type
reactions, cycloaddition, Michael addition, cross-coupling and
Henry reactions.[ 37 ] We have found that the reactions of N-
propargylic β-enaminones with zinc halides such as ZnCl2 afford
2-methylene-2,3-dihydro-1,4-oxazepines (Scheme 1e). Herein,
we report the results of this study.
(a) Tsuchiya's study (Ref. 26)
1
2
O
2
R
R
1
O
R
R
hv
N
N
Ph
Ph
(b) Loreau and Taran's study (Ref. 28)
1
1
3
R
R
R
Results and Discussion
O
3
HO
R
PBu
3
+
N
First, we synthesized the requisite N-propargylic β-enaminones
N
3
2
2
recent report.[35] Conjugate addition of
R
O
R
according to
a
propargylamine to α,β-alkynic ketones provided N-propargylic β-
enaminones in good to excellent yields (61-98%). In fact, we
prepared 21 kinds of N-propargylic β-enaminone derivatives, 16
of which have been synthesized for the first time (For identity of
R groups and yields, see Experimental Section).
(c) Cheng and Cui's study (Ref. 31)
2
R
2
2
R
CH
3
R
O
O
Nu-H
NaOH
CH
3
1
NH
R
N
1
1
N
Nu
R
R
With N-propargylic β-enaminones in hand, we next
investigated their Lewis acid promoted electrophilic cyclizations.
In order to test seven-membered ring formation and optimize its
conditions, we first studied the cyclization of N-propargylic β-
enaminone 1a with a variety of transition or post-transition metal
Lewis acids as depicted in Table 1. When the reaction was
performed with FeCl3, InCl3, NiCl2, PdCl2(PPh3)2, HfCl4 or AuCl
in refluxing DCM, no reaction was observed and the starting β-
enaminone 1a was recovered by some decomposition (Table 1,
Entries 1-6). However, the reaction with AuCl3 under same
conditions yielded 2-methylene-2,3-dihydro-1,4-oxazepine (2a)
in trace amount (Table 1, Entry 7). When the same reaction was
carried out in refluxing DCE, instead of DCM, 2a was isolated in
15% yield (Table 1, Entry 8). Subsequently, we tested the
reaction with equimolar amounts of ZnI2, ZnBr2 and ZnCl2 in
refluxing DCM, which afforded 2-methylene-2,3-dihydro-1,4-
oxazepine (2a) in 40, 85 and 95% yields, respectively (Table 1,
Entries 9-11), the latter giving the highest yield of 2a. Next we
determined the effective number of equivalents of ZnCl2 in the
reaction. When the reaction was performed in turn with 0.2, 0.5
and 1.5 equivalents of ZnCl2, it produced 1,4-oxazepine 2a in 22,
52 and 95% yields, respectively (Table 1, Entries 12-14).
Noticeably, the lower number of equivalents (0.2 and 0.5 equiv.)
of ZnCl2 significantly decreased the yield of 2a while a higher
number of equivalents (1.5 equiv) did not improve the yield.
Hence the reactions were carried out with 1.0 equiv of ZnCl2.
The same reaction was also tried in CHCl3 at 61 oC and DCE at
84 oC, which yielded 1,4-oxazepine 2a in 95 and 76% yields,
(d) Karunakar's study (Ref. 33)
2
R
2
R
O
N
O
AuCl
3
1
NH
R
AgSbF
6
1
R
(e) This study
2
R
2
R
O
O
NH
ZnCl
2
1
R
N
1
R
Scheme 1. Strategies for the synthesis of 1,4-oxazepines.
Cyclizations involving metal-catalyzed activation of alkynes
are mostly carried out by precious metals such as gold,
palladium, platinum or rhodium. Accordingly, the use of
inexpensive catalysts or mediators for such benefits attracts
great attention since they could provide economically better
alternatives and/or different reaction outcomes. 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. In this regard, we have recently shown that when
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10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
respectively (Table 1, Entries 15 and 16). Notably, the former
As depicted in Table 2, a diverse range of 2-methylene-
2,3-dihydro-1,4-oxazepines (2) were synthesized by employing a
variety of N-propargylic β-enaminones 1. Most of the cyclizations
proceeded efficiently in both conditions and afforded the
corresponding 1,4-oxazepines 2 in good to high yields (55-95%),
except that oxazepines 2b, 2f and 2l were obtained in moderate
yields (40-47%). Notably, in many cases, the cyclizations in
CHCl3 at 61 °C afforded the corresponding 1,4-oxazepines in
comparatively higher yields and shorter reaction times. However,
the cyclizations in DCM at 40 °C produced 1,4-oxazepines 2f, 2r,
2t and 2u in relatively better yields as compared to those in
CHCl3 at 61 °C. Two derivatives of 5-alkyl-substituted 1,4-
oxazepines, 2k, and 2l, were synthesized in 40-72% yields
(Table 2). It should be noted that along with 1,4-oxazepines 2k
and 2l, pyrrole derivatives 3k and 3l were also isolated,
respectively, from these reactions but in low yields (9-20%), the
structures of which are given in Figure 2. Interestingly, the
reaction not only produced 1,4-oxazepine 2a with the highest
o
yield (95%), as in case of DCM at 40 C (Table 1, Entry 11), but
it also reduced the reaction time from 9.0 to 1.5 h. Finally, the
reaction was carried out with Zn dust but no reaction occurred
(Table 1, Entry 17). In summary, the reactions performed with
1.0 equiv of ZnCl2 in refluxing DCM and CHCl3, i.e. the
conditions in entries 11 and 15 of Table 1, respectively, gave the
highest yield of 2a. Thus, the reactions were conducted under
both conditions. It is noteworthy that in most cases, the reactions
in refluxing CHCl3 provided 2-methylene-2,3-dihydro-1,4-
oxazepines (2) in relatively higher yields and shorter reaction
times as compared to those in refluxing DCM. However, in few
cases, the reactions in refluxing DCM gave comparatively better
yields of 2, as it will be discussed later. The results from a
systematic study are shown in Table 2.
1
Table 1. Optimization of the reaction conditions.[a]
analyses of the crude reaction mixtures by H NMR did not at all
reveal the formation of these pyrrole derivatives. We have,
however, found that under flash-chromatography conditions on
silica gel, 1,4-oxazepines 2k and 2l were not so stable that they
were converted into the corresponding pyrroles and/or
decomposed to some extent. For instance, when a pure amount
of 2k was rechromatographied under the same conditions on
silica gel, it produced pyrrole 3k in 9% yield while 72% of 2k was
recovered. The remaining 19% of 2k was presumably
decomposed during isolation. In brief, pyrroles 3k and 3l forms
via silica gel-catalyzed rearrangement as will be shown in the
proposed mechanism. It is noteworthy that the incorporation of
fluorine-bearing groups into organic compounds could result in
beneficial biological and medicinal properties.[ 38 ] Thus, five
derivatives of fluorine-containing 2-methylene-2,3-dihydro-1,4-
oxazepines, 2h, 2i, 2s, 2t and 2u, were synthesized in 77-92%
yields (Table 2). Briefly, this cyclization was found to be general
Ph
Lewis Acid
Solvent
Ph
O
O
Ph
NH
N
Temperature
Time
Ph
2a
1a
Entry
Lewis acid
(equivalent)
Solvent
Temp.
(oC)
Time
(h)
Yield
(%)[b][c]
1
FeCl3 (1.0)
InCl3 (0.05)
NiCl2 (1.0)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
DCE
DCM
40
40
40
40
40
40
40
84
40
40
40
40
40
40
61
84
40
5.0
11.5
3.0
NR
NR
NR
NR
NR
NR
trace
15
2
3
4
PdCl2(PPh3)2 (0.05)
HfCl4 (0.1)
7.0
5
7.0
for
a
diversity of N-propargylic β-enaminones
1
and
6
AuCl (0.05)
AuCl3 (0.05)
AuCl3 (0.05)
ZnI2 (1.0)
11.5
15.0
12.0
11.0
7.5
demonstrated good tolerance to a variety of substituents,
including electron-donating and electron-withdrawing groups.
A possible mechanism for the formation of 2-methylene-
2,3-dihydro-1,4-oxazepines 2 is outlined in Scheme 2. First,
interaction of zinc chloride with alkyne moiety of 1 gives 4, which
enhances the electrophilicity of alkyne unit. Subsequent
coordination of carbonyl oxygen to zinc through vinylogous
amido-imido tautomerization generates intermediate 5, bringing
the carbonyl and alkyne functionalities in close proximity. Then
intramolecular 7-exo-dig electrophilic cyclization takes place to
produce vinyl zinc intermediate 6. Finally, hydrolysis with HCl
generated in situ affords 1,4-oxazepine derivatives 2 (Scheme 2).
The mechanism proposed for the formation of pyrroles 3 is
depicted in Scheme 3. First, activation of vinylogous imine
functionality in 2 with silica gel generates intermediate 7, which
enables conjugate addition of water to give hemiketal 8. Ring
opening affords dienol intermediate 9, which, upon
tautomerization, converts into keto-enol derivative 10.
Subsequently, cyclization takes place to furnish aldol product 11.
Water elimination via intermediate 12 produces 2H-pyrrole 13.
Finally, isomerization affords pyrrole derivatives 3 (Scheme 3).
7
8
9
40
10
11
12
13
14
15
16
17
ZnBr2 (1.0)
ZnCl2 (1.0)
ZnCl2 (0.2)
ZnCl2 (0.5)
ZnCl2 (1.5)
ZnCl2 (1.0)
ZnCl2 (1.0)
Zn dust (1.0)
85
9.0
95
17.0
17.0
8.0
22
52
95
1.5
95
3.5
76
9.0
NR
[a] Reactions were carried out on a scale of 0.3 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.
[b] Isolated yield.
[c] NR = no reaction.
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10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
Table 2. Synthesis of 2-methylene-2,3-dihydro-1,4-oxazepine derivatives.[a][b]
R2
R2
ZnCl2
O
DCM, 40 oC
O
R1
NH
N
or
R1
CHCl3, 61 oC
2
1
O
O
O
O
O
O
O
N
N
N
N
N
N
N
OCH3
Br
CH3
2b
H3C
H3CO
(H3C)2N
2a
2c
2d
2e
2f
2g
(95%, 9.0 h)
[95%, 1.5 h]
(43%, 9.0 h)
[74%, 1.5 h]
(62%, 9.0 h)
[74%, 2.0 h]
(63%, 9.0 h)
[66%, 6.0 h]
(66%, 9.0 h)
[73%, 3.0 h]
(47%, 10.0 h)
[40%, 1.5 h]
(63%, 20.0 h)
[73%, 12.0 h]
Br
O
Br
O
O
N
O
N
O
N
O
N
O
N
N
N
O
N
O
H3C
S
CH3
F
F3C
2h
2i
2j
2k
2l
2m
(80%, 9.0 h)
[81%, 1.5 h]
2n
(86%, 9.0 h)
[90%, 2.0 h]
(80%, 9.0 h)
[82%, 2.0 h]
(74%, 9.0 h)
[84%, 2.0 h]
(59%, 24.0 h)[c]
[72%, 5.0 h][d]
(40%, 20.0 h)[e]
[40%, 9.0 h][f]
(55%, 9.0 h)
[95%, 1.5 h]
Cl
Br
O
Br
O
Br
O
Br
O
Br
O
Br
O
O
N
N
N
N
N
N
N
OCH3
Br
F
F
H3CO
F3C
H3C
2o
2p
2q
2r
2s
2t
2u
(70%, 9.0 h)
[90%, 2.0 h]
(81%, 15.0 h)
[88%, 6.0 h]
(70%, 9.0 h)
[90%, 2.5 h]
(77%, 9.0 h)
[68%, 5.0 h]
(79%, 9.0 h)
[86%, 1.5 h]
(92%, 9.0 h)
[91%, 3.0 h]
(89%, 9.0 h)
[77%, 3.0 h]
[a] Reaction conditions: N-propargylic β-enaminone 1 (0.30 mmol), ZnCl2 (0.30 mmol), DCM (5 mL) at 40 ºC or CHCl3 (5 mL) at 61 ºC, under
argon. For the full procedure including work-up and purification, see Experimental Section.
[b] Yields and reaction times in DCM at 40 ºC are shown in parentheses while those in CHCl3 at 61 ºC are depicted in square brackets. All
yields are of isolated products.
[c] Along with 2k, pyrrole 3k was also isolated in 14% yield from this reaction (see Figure 2 for its structure).
[d] Along with 2k, pyrrole 3k was also isolated in 9% yield from this reaction (see Figure 2 for its structure).
[e] Along with 2l, pyrrole 3l was also isolated in 20% yield from this reaction (see Figure 2 for its structure).
[f] Along with 2l, pyrrole 3l was also isolated in 12% yield from this reaction (see Figure 2 for its structure).
We have also examined one example of the reaction of N-
propargylic β-enaminone that contains internal alkyne
functionality, such as 14 (Scheme 4). Interestingly, the reaction
of β-enaminone 14 under both conditions did not produce any
1,4-oxazepine derivative such as 16, presumably to steric and/or
electronic effects; instead, it gave a pyridine derivative, 15, via 6-
endo-dig cyclization but in low yields (25-28%) (Scheme 4).
Since the formation of pyridines from N-propargylic β-
enaminones is well documented,[30,35] we have not investigated
their formation further.
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10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
Ph
Ph
O
O
O
Ph
ZnCl2
Ph
O
CH3
DCM, 40 oC
CH3
O
Ph
O
Ph
NH
or
N
N
H
Ph
N
15
CHCl3, 61 oC
N
H
Ph
N
Ph
16
14
H3C
3k
3l
(25%, 7.0 h)
[28%, 7.0 h]
Not Observed
O
Figure 2. Structures of pyrrole derivatives isolated along with 1,4-oxazepines.
Scheme 4. Formation of pyridines from internal alkyne-tethered N-propargylic
β-enaminone (Yields and reaction times in DCM are depicted in parentheses
while those in CHCl3 are shown in square brackets).
R2
Cl
Cl
R2
R2
O
O
Zn
O
ZnCl2
Zn
Cl
Conclusions
R1
NH
-HCl
R1
N
H
R1
N
In summary, we have developed a new robust method for the
synthesis of 1,4-oxazepines. When treated with ZnCl2 in
refluxing DCM or CHCl3, N-propargylic β-enaminones have
produced 2-methylene-2,3-dihydro-1,4-oxazepines in good to
high yields via electrophilic cyclization. Reaction has been found
to be general for a variety of N-propargylic β-enaminones and
tolerated a broad range of functional groups with electron-
donating and electron-withdrawing substituents. In most cases,
the reactions carried out in CHCl3 have provided 1,4-oxazepines
in higher yields and shorter reaction times. In conclusion, we
anticipate that the efficiency and operational simplicity of the
method could make it potentially attractive for the library
construction of 1,4-oxazepines, particularly in the area of
pharmaceuticals.
1
4
5
ZnCl
R2
R2
O
O
N
HCl
-ZnCl2
N
R1
R1
2
6
Scheme 2. Proposed mechanism for the synthesis of 2-methylene-2,3-
dihydro-1,4-oxazepines
H2O
R2
HO
R2
R2
O
O
O
"SiO2"
Experimental Section
-"SiO2"
N
H
General information. 1H and 13C NMR spectra were recorded at 400
and 100 MHz, respectively. Chemical shifts are reported in parts per
million (ppm) relative to CDCl3 (7.26 and 77.16 ppm in 1H and 13C NMR,
respectively). Coupling constants (J) are reported in Hertz (Hz), and spin
multiplicities are presented by the following symbols: s (singlet), br s
(broad singlet), d (doublet), t (triplet), q (quartet), m (multiplet). DEPT 13C
NMR information is given in parentheses as C, CH, CH2 and CH3.
Infrared spectra (IR) were recorded by using attenuated total reflection
(ATR). Band positions are reported 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). Flash chromatography was performed using thick-
walled glass columns and “flash grade” silica gel (230-400 mesh) or
aluminium oxide (neutral, 70-230 mesh). Thin layer chromatography
(TLC) was performed by using commercially prepared 0.25 mm silica gel
or aluminium oxide (neutral) plates 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.
N
N
R1
8
R1
SiO2
R1
2
7
R2
R2
O
OH HO
N
OH O
N
CH3
R2
OH
CH3
R1
R1
R1
N
11
10
9
O
O
OH
R2
R1
CH3
R2
R1
R2
R1
OH
CH3
CH3
-H2O
N
H
N
N
12
13
3
Scheme 3. Proposed mechanism for the formation of pyrroles.
α,β-Alkynic ketones were synthesized from commercially available
terminal alkynes and acyl chlorides according to standard
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
protocols.[30,35, 39 ] N-Propargylic β-enaminones 1 were synthesized by
conjugate addition of propargylamine to α,β-alkynic ketones according to
recent literature procedures.[30,35] N-Propargylic β-enaminone 14 was
MHz, CDCl3) δ 188.8 (C=O), 163.3 (C), 156.0 (C), 140.1 (C), 131.2 (CH),
130.7 (CH), 129.8 (CH), 128.1 (CH), 127.1 (CH), 123.6 (C), 120.9 (CH),
110.8 (CH), 94.0 (CH), 79.4 (C), 72.1 (CH), 55.5 (OCH3), 33.8 (CH2); IR
(neat): 3285, 2935, 1732, 1594, 1567, 1482, 1455, 1326, 1241, 1145,
1114, 1056, 1023, 808, 753, 692 cm-1; MS (ESI, m/z): 292.13 [M+H]+;
HRMS (ESI) calcd. for C19H18NO2: 292.1332 [M+H]+, found: 292.1341.
prepared from β-enaminone 1a and iodobenzene by
a coupling
procedure.[30,35]
General Procedure for the synthesis of N-propargylic β-enaminones
1. To a stirred solution of the corresponding α,β-alkynic ketone (2.5
mmol) in absolute MeOH (10 mL) was added propargylamine (3.0 mmol)
and the resulting mixture was heated at 65 oC for approximately 6 h
(Note that the progress of the reaction was monitored by routine TLC for
the disappearance of alkynic ketone). After the reaction was over, the
solvent was removed on a rotary evaporator, and ethyl acetate (50 mL)
and a saturated NaCl solution (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 β-
enaminone 1.
3-(4-Methoxyphenyl)-1-phenyl-3-(prop-2-ynylamino)prop-2-en-1-one
(1e). 3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one (590.7 mg, 2.5
mmol) and propargylamine (165.3 mg, 3.0 mmol) were employed to
afford 713.8 mg (98%) of the indicated product. 1H NMR (400 MHz,
CDCl3) δ 11.35 (br s, 1H), 7.94-7.87 (m, 2H), 7.48-7.37 (m, 5H), 7.02-
6.96 (m, 2H), 5.84 (s, 1H), 3.98 (dd, J = 6.3 and 2.5 Hz, 2H), 3.86 (s, 3H),
2.32 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 189.0 (C=O),
166.0 (C), 161.0 (C), 140.2 (C), 131.0 (CH), 129.6 (CH), 128.3 (CH),
127.3 (CH), 114.2 (CH), 94.7 (CH), 80.1 (C), 72.5 (CH), 55.5 (OCH3),
34.4 (CH2) (Note that two C peaks overlap on each other). The spectral
data were in agreement with those reported previously for this
compound.[35]
3-(4-(Dimethylamino)phenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-
2-en-1-one (1f). 3-(4-(Dimethylamino)phenyl)-1-phenylprop-2-yn-1-one
(623.3 mg, 2.5 mmol) and propargylamine (165.3 mg, 3.0 mmol) were
employed to afford 639.2 mg (84%) of the indicated product. 1H NMR
(400 MHz, CDCl3) δ 11.47 (br t, J = 5.5 Hz, 1H), 7.93 (dd, J = 7.6, 1.8 Hz,
2H), 7.48-7.35 (m, 5H), 6.72 (d, J = 8.8 Hz, 2H), 5.88 (s, 1H), 4.05 (dd, J
= 6.2, 2.4 Hz, 2H), 2.99 (s, 6H), 2.34 (t, J = 2.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 188.2 (C=O), 166.9 (C), 151.4 (C), 140.4 (C), 130.6 (CH),
129.2 (CH), 128.1 (CH), 127.0 (CH), 121.7 (C), 111.5 (CH), 94.0 (CH),
80.3 (C), 72.3 (CH), 40.1 (N(CH3)2), 34.4 (CH2); IR (neat): 3208, 2884,
2805, 2111, 1614, 1579, 1502, 1481, 1446, 1328, 1264, 1233, 1194,
1141, 1054, 928, 815, 797, 743, 729 cm-1; MS (ESI, m/z): 305.17 [M+H]+;
HRMS (ESI) calcd. for C20H21N2O: 305.1648 [M+H]+, found: 305.1653.
1,3-Diphenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1a).
1,3-
Diphenylprop-2-yn-1-one (515.6 mg, 2.5 mmol) and propargylamine
(165.3 mg, 3.0 mmol) were employed to afford 640.3 mg (98%) of the
indicated product. 1H NMR (400 MHz, CDCl3) δ 11.33 (br s, 1H), 7.95-
7.87 (m, 2H), 7.55-7.37 (m, 8H), 5.85 (br s, 1H), 3.95 (dd, J = 6.3, 2.5 Hz,
2H), 2.31 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 189.3 (C=O),
166.0 (C), 140.1 (C), 135.1 (C), 131.1 (CH), 130.0 (CH), 128.8 (CH),
128.4 (CH), 128.0 (CH), 127.3 (CH), 94.8 (CH), 79.9 (C), 72.6 (CH), 34.3
(CH2). The spectral data were in agreement with those reported
previously for this compound.[30,35]
1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-en-1-one (1b). 1-
Phenyl-3-m-tolylprop-2-yn-1-one
(550.7
mg,
2.5
mmol)
and
propargylamine (165.3 mg, 3.0 mmol) were employed to afford 653.9 mg
(95%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.40 (br t,
J = 6.0 Hz, 1H), 7.97-7.89 (m, 2H), 7.48-7.24 (m, 7H), 5.86 (s, 1H), 3.93
(dd, J = 6.3, 2.5 Hz, 2H), 2.41 (s, 3H), 2.35 (t, J = 2.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 188.8 (C=O), 165.9 (C), 139.8 (C), 138.4 (C), 134.6
(C), 130.8 (CH), 130.4 (CH), 128.4 (CH), 128.2 (CH), 128.1 (CH), 127.0
(CH), 124.7 (CH), 94.3 (CH), 79.8 (C), 72.4 (CH), 34.0 (CH2), 21.2 (CH3);
IR (neat): 3224, 3055, 2113, 1667, 1594, 1550, 1476, 1324, 1270, 1226,
1173, 1134, 1054, 1024, 789, 733 cm-1; MS (ESI, m/z): 276.14 [M+H]+;
HRMS (ESI) calcd. for C19H18NO: 276.1383 [M+H]+, found: 276.1380.
3-(2-Bromophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1g). 3-(2-Bromophenyl)-1-phenylprop-2-yn-1-one (712.8 mg, 2.5 mmol)
and propargylamine (165.3 mg, 3.0 mmol) were employed to afford 714.4
mg (84%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.19
(br s, 1H), 7.82-7.69 (m, 2H), 7.52-7.46 (m, 1H), 7.34-7.20 (m, 5H), 7.18-
7.12 (m, 1H), 5.62 (s, 1H), 3.78 (ddd, J = 17.7, 4.9, 2.5 Hz, 1H), 3.58
(ddd, J = 17.6, 7.1, 2.4 Hz, 1H), 2.14 (t, J = 2.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 189.2 (C=O), 163.2 (C), 139.6 (C), 135.5 (C), 132.9 (CH),
131.0 (CH), 130.8 (CH), 129.8 (CH), 128.2 (CH), 127.6 (CH), 127.1 (CH),
121.4 (CBr), 93.9 (CH), 79.0 (C), 72.6 (CH), 33.6 (CH2); IR (neat): 3291,
1732, 1595, 1572, 1549, 1462, 1322, 1306, 1254, 1145, 1054, 1024, 944,
853, 749 cm-1; MS (ESI, m/z): 340.03 [M+H]+; HRMS (ESI) calcd. for
C18H1579BrNO: 340.0332 [M+H]+, found: 340.0329.
1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(p-tolyl)prop-2-en-1-one (1c). 1-
Phenyl-3-p-tolylprop-2-yn-1-one
(550.7
mg,
2.5
mmol)
and
propargylamine (165.3 mg, 3.0 mmol) were employed to afford 633.3 mg
(92%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.40 (br t,
J = 5.6 Hz, 1H), 7.97-7.89 (m, 2H), 7.49-7.37 (m, 5H), 7.28 (d, J = 7.9 Hz,
2H), 5.87 (s, 1H), 3.96 (dd, J = 6.3, 2.5 Hz, 2H), 2.42 (s, 3H), 2.35 (t, J =
2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 188.9 (C=O), 166.1 (C), 140.0
(C), 131.9 (C), 130.9 (C), 129.3 (CH), 128.2 (CH), 127.7 (CH), 127.1
(CH), 94.5 (CH), 79.9 (C), 72.4 (CH), 34.1 (CH2), 21.3 (CH3) (Note that
two CH peaks overlap on each other). The spectral data were in
agreement with those reported previously for this compound.[35]
3-(3-Fluorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1h). 3-(3-Fluorophenyl)-1-phenylprop-2-yn-1-one (560.6 mg, 2.5 mmol)
and propargylamine (165.3 mg, 3.0 mmol) were employed to afford 628.4
mg (90%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.27
(br s, 1H), 7.98-7.88 (m, 2H), 7.55-7.39 (m, 4H), 7.33-7.14 (m, 3H), 5.86
(s, 1H), 3.95 (dd, J = 6.4, 2.5 Hz, 2H), 2.35 (t, J = 2.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 189.5 (C=O), 164.2 (C), 162.7 (d, 1J = 248.4 Hz, CF),
139.8 (C), 137.0 (d, 3J = 7.6 Hz, C), 131.3 (CH), 130.6 (d, 3J = 8.2 Hz,
CH), 128.4 (CH), 127.3 (CH), 123.8 (d, 4J = 3.1 Hz, CH), 116.9 (d, 2J =
21.0 Hz, CH), 115.2 (d, 2J = 22.7 Hz, CH), 94.8 (CH), 79.7 (C), 72.8 (CH),
34.3 (CH2); IR (neat): 3222, 1600, 1570, 1549, 1520, 1474, 1431, 1323,
1299, 1284, 1265, 1250, 1226, 1203, 1025, 1000, 965, 876, 788 cm-1;
MS (ESI, m/z): 280.11 [M+H]+; HRMS (ESI) calcd. for C18H15FNO:
280.1132 [M+H]+, found: 280.1134.
3-(2-Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-
one (1d). 3-(2-Methoxyphenyl)-1-phenylprop-2-yn-1-one (590.7 mg, 2.5
mmol) and propargylamine (165.3 mg, 3.0 mmol) were employed to
afford 582.7 mg (80%) of the indicated product. 1H NMR (400 MHz,
CDCl3) δ 11.51 (br s, 1H), 7.96-7.86 (m, 2H), 7.48-7.35 (m, 4H), 7.31 (dd,
J = 7.5, 1.4 Hz, 1H), 7.04 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H),
5.79 (s, 1H), 4.00-3.70 (m, 5H), 2.27 (t, J = 2.5 Hz, 1H); 13C NMR (100
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(4-(trifluoromethyl)phenyl)prop-
2-en-1-one (1i). 1-Phenyl-3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-one
(685.6 mg, 2.5 mmol) and propargylamine (165.3 mg, 3.0 mmol) were
employed to afford 666.9 mg (81%) of the indicated product. 1H NMR
(400 MHz, CDCl3) δ 11.27 (br t, J = 5.6 Hz, 1H), 7.90 (dd, J = 5.2, 3.2 Hz,
2H), 7.73 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 7.49-7.36 (m, 3H),
5.83 (s, 1H), 3.87 (dd, J = 6.4, 2.4 Hz, 2H), 2.33 (t, J = 2.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 189.4 (C=O), 164.0 (C), 139.6 (C), 138.4 (C),
131.8 (q, 2J = 32.7 Hz, C), 131.3 (CH), 128.4 (CH), 128.3 (CH), 127.2
(CH), 125.7 (q, 3J = 3.7 Hz, CH), 123.8 (q, 1J = 272.4 Hz, CF3), 94.9 (CH),
79.5 (C), 72.8 (CH), 34.2 (CH2); IR (neat): 3055, 2116, 1600, 1583, 1548,
1502, 1430, 1321, 1294, 1240, 1225, 1163, 1104, 1072, 1050, 1015, 925,
849, 737 cm-1; MS (ESI, m/z): 330.11 [M+H]+; HRMS (ESI) calcd. for
C19H15F3NO: 330.1100 [M+H]+, found: 330.1100.
m/z): 340.03 [M+H]+; HRMS (ESI) calcd. for C18H1579BrNO: 340.0332
[M+H]+, found: 340.0333.
1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-en-1-
one (1n). 1-(2-Bromophenyl)-3-(m-tolyl)prop-2-yn-1-one (747.9 mg, 2.5
mmol) and propargylamine (165.3 mg, 3.0 mmol) were employed to
afford 770.5 mg (87%) of the indicated product. 1H NMR (400 MHz,
CDCl3) δ 11.12 (br s, 1H), 7.57 (dd, J = 8.0, 1.0 Hz, 1H), 7.50-7.44 (m,
1H), 7.38-7.24 (m, 5H), 7.22-7.16 (m, 1H), 5.47 (s, 1H), 3.98 (dd, J = 6.4,
2.5 Hz, 2H), 2.40 (s, 3H), 2.36 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 190.9 (C=O), 166.1 (C), 143.0 (C), 138.5 (C), 134.2 (C), 133.3
(CH), 130.8 (CH), 130.2 (CH), 129.1 (CH), 128.5 (CH), 128.3 (CH), 127.1
(CH), 124.8 (CH), 119.4 (CBr), 98.1 (CH), 79.6 (C), 72.7 (CH), 34.3 (CH2),
21.4 (CH3); IR (neat): 3289, 1731, 1561, 1479, 1359, 1256, 1082, 1023,
758 cm-1; MS (ESI, m/z): 354.05 [M+H]+; HRMS (ESI) calcd. for
C19H1779BrNO: 354.0488 [M+H]+, found: 354.0490.
1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(thiophen-3-yl)prop-2-en-1-one
(1j). 1-Phenyl-3-(thiophen-3-yl)prop-2-yn-1-one (530.7 mg, 2.5 mmol)
and propargylamine (165.3 mg, 3.0 mmol) were employed to afford 628.3
mg (94%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.44
(br t, J = 6.1 Hz, 1H), 7.95-7.86 (m, 2H), 7.59 (dd, J = 2.9, 1.1 Hz, 1H),
7.46-7.32 (m, 4H), 7.24 (dd, J = 5.0, 1.0 Hz, 1H), 5.92 (s, 1H), 3.97 (dd, J
= 6.4, 2.4 Hz, 2H), 2.38 (t, J = 2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
188.5 (C=O), 160.3 (C), 139.6 (C), 135.1 (C), 130.7 (CH), 128.0 (CH),
127.0 (CH), 126.9 (CH), 126.5 (CH), 126.1 (CH), 93.9 (CH), 79.9 (C),
72.6 (CH), 33.9 (CH2). The spectral data were in agreement with those
reported previously for this compound.[35]
1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-(p-tolyl)prop-2-en-1-
one (1o). 1-(2-Bromophenyl)-3-(p-tolyl)prop-2-yn-1-one (747.9 mg, 2.5
mmol) and propargylamine (165.3 mg, 3.0 mmol) were employed to
afford 752.8 mg (85%) of the indicated product. 1H NMR (400 MHz,
CDCl3) δ 11.13 (br s, 1H), 7.58 (dd, J = 8.0, 0.9 Hz, 1H), 7.48 (dd, J = 7.6,
1.7 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.26
(d, J = 7.9 Hz, 2H), 7.20 (td, J = 7.7, 1.7 Hz, 1H), 5.48 (s, 1H), 4.00 (dd, J
= 6.4, 2.5 Hz, 2H), 2.41 (s, 3H), 2.36 (t, J = 2.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 190.9 (C=O), 166.1 (C), 143.2 (C), 140.3 (C), 133.4 (CH),
131.5 (C), 130.3 (CH), 129.4 (CH), 129.3 (CH), 127.9 (CH), 127.2 (CH),
119.5 (CBr), 98.3 (CH), 79.8 (C), 72.7 (CH), 34.4 (CH2), 21.4 (CH3); IR
(neat): 3280, 1586, 1571, 1492, 1310, 1256, 1046, 1080, 1021, 827, 791,
757 cm-1; MS (ESI, m/z): 354.05 [M+H]+; HRMS (ESI) calcd. for
C19H1779BrNO: 354.0488 [M+H]+, found: 354.0489.
1-Phenyl-3-(prop-2-yn-1-ylamino)hept-2-en-1-one (1k). 1-Phenylhept-
2-yn-1-one (465.7 mg, 2.5 mmol) and propargylamine (165.3 mg, 3.0
mmol) were employed to afford 555.1 mg (92%) of the indicated product.
1H NMR (400 MHz, CDCl3) δ 11.48 (br s, 1H), 7.89-7.83 (m, 2H), 7.46-
7.36 (m, 3H), 5.75 (s, 1H), 4.08 (dd, J = 6.2, 2.5 Hz, 2H), 2.42-2.35 (m,
2H), 2.32 (t, J = 2.5 Hz, 1H), 1.67-1.57 (m, 2H), 1.44 (sextet, J = 7.4 Hz,
2H), 0.96 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 188.8 (C=O),
168.2 (C), 140.4 (C), 130.7 (CH), 128.2 (CH), 127.1 (CH), 92.2 (CH),
79.2 (C), 72.5 (CH), 32.3 (CH2), 31.9 (CH2), 30.2 (CH2), 22.7 (CH2), 13.9
(CH3). The spectral data were in agreement with those reported
previously for this compound.[35]
1-(2-Bromophenyl)-3-(2-methoxyphenyl)-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one
methoxyphenyl)prop-2-yn-1-one
(1p).
(787.9
1-(2-Bromophenyl)-3-(2-
mg, 2.5 mmol) and
propargylamine (165.3 mg, 3.0 mmol) were employed to afford 703.5 mg
(76%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.21 (br s,
1H), 7.57 (dd, J = 8.0, 0.7 Hz, 1H), 7.49 (dd, J = 7.6, 1.7 Hz, 1H), 7.46-
7.40 (m, 1H), 7.35-7.27 (m, 2H), 7.19 (td, J = 7.7, 1.7 Hz, 1H), 7.03 (t, J =
7.2 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 5.40 (br s, 1H), 4.02-3.77 (m, 2H),
3.88 (s, 3H), 2.28 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 190.8
(C=O), 163.4 (C), 156.1 (C), 143.2 (C), 133.4 (CH), 131.5 (CH), 130.2
(CH), 130.0 (CH), 129.4 (CH), 127.1 (CH), 123.4 (C), 121.0 (CH), 119.6
(CBr), 111.0 (CH), 98.0 (CH), 79.3 (C), 72.3 (CH), 55.7 (OCH3), 34.1
(CH2); IR (neat): 3247, 2190, 1587, 1536, 1485, 1461, 1328, 1237, 1163,
1084, 1065, 1023, 796, 753 cm-1; MS (ESI, m/z): 370.04 [M+H]+; HRMS
(ESI) calcd. for C19H1779BrNO2: 370.0437 [M+H]+, found: 370.0440.
2-(5-Oxo-5-phenyl-3-(prop-2-yn-1-ylamino)pent-3-en-1-
yl)isoindoline-1,3-dione
(1l).
2-(5-Oxo-5-phenylpent-3-yn-1-
yl)isoindoline-1,3-dione (758.3 mg, 2.5 mmol) and propargylamine (165.3
mg, 3.0 mmol) were employed to afford 546.5 mg (61%) of the indicated
product. 1H NMR (400 MHz, CDCl3) δ 11.30 (br t, J = 5.8 Hz, 1H), 7.86-
7.72 (m, 4H), 7.70-7.61 (m, 2H), 7.43-7.29 (m, 3H), 5.76 (s, 1H), 4.21 (dd,
J = 6.2, 2.4 Hz, 2H), 4.03-3.87 (m, 2H), 2.85-2.70 (m, 2H), 2.35 (t, J = 2.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 189.0 (C=O), 167.9 (C), 162.8
(C=O), 139.7 (C), 134.1 (CH), 131.9 (CH), 130.9 (C), 128.2 (CH), 127.0
(CH), 123.4 (CH), 93.0 (CH), 79.2 (C), 72.8 (CH), 36.0 (CH2), 32.4 (CH2),
30.8 (CH2); IR (neat): 3260, 1775, 1713, 1594, 1580, 1392, 1337, 1247,
1188, 1098, 970, 753 cm-1; MS (ESI, m/z): 359.14 [M+H]+; HRMS (ESI)
calcd. for C22H19N2O3: 359.1390 [M+H]+, found: 359.1399.
1-(2-Bromophenyl)-3-(4-methoxyphenyl)-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one
methoxyphenyl)prop-2-yn-1-one
(1q).
(787.9
1-(2-Bromophenyl)-3-(4-
mg, 2.5 mmol) and
propargylamine (165.3 mg, 3.0 mmol) were employed to afford 703.5 mg
(76%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.11 (br s,
1H), 7.56 (dd, J = 8.0, 1.0 Hz, 1H), 7.50-7.41 (m, 3H), 7.30 (td, J = 7.5,
1.1 Hz, 1H), 7.21-7.15 (m, 1H), 6.98-6.92 (m, 2H), 5.45 (br s, 1H), 4.00
(dd, J = 6.4, 2.5 Hz, 2H), 3.83 (s, 3H), 2.34 (t, J = 2.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 190.8 (C=O), 165.9 (C), 161.1 (C), 143.3 (C), 133.4
(CH), 130.3 (CH), 129.6 (CH), 129.3 (CH), 127.2 (CH), 126.7 (C), 119.5
(CBr), 114.2 (CH), 98.3 (CH), 79.9 (C), 72.7 (CH), 55.5 (OCH3), 34.50
(CH2); IR (neat): 3286, 1587, 1558, 1490, 1323, 1296, 1247, 1174, 1083,
1021, 873, 759 cm-1; MS (ESI, m/z): 370.04 [M+H]+; HRMS (ESI) calcd.
for C19H1779BrNO2: 370.0437 [M+H]+, found: 370.0440.
1-(2-Bromophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1m). 1-(2-Bromophenyl)-3-phenylprop-2-yn-1-one (712.8 mg, 2.5 mmol)
and propargylamine (165.3 mg, 3.0 mmol) were employed to afford 740.0
mg (87%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.10
(br s, 1H), 7.56 (dd, J = 8.0, 1.0 Hz, 1H), 7.52-7.40 (m, 6H), 7.30 (td, J =
7.5, 1.1 Hz, 1H), 7.21-7.15 (m, 1H), 5.47 (s, 1H), 3.96 (dd, J = 6.4, 2.5 Hz,
2H), 2.33 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.1 (C=O),
165.8 (C), 143.1 (C), 134.4 (C), 133.4 (CH), 130.3 (CH), 130.1 (CH),
129.2 (CH), 128.8 (CH), 127.9 (CH), 127.2 (CH), 119.5 (CBr), 98.4 (CH),
79.6 (C), 72.8 (CH), 34.4 (CH2); IR (neat): 3290, 1731, 1588, 1560, 1483,
1461, 1427, 1317, 1244, 1145, 1082, 1023, 949, 751 cm-1; MS (ESI,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
1,3-Bis(2-bromophenyl)-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1r).
1,3-Bis(2-bromophenyl)prop-2-yn-1-one (910.1 mg, 2.5 mmol) and
propargylamine (165.3 mg, 3.0 mmol) were employed to afford 901.1 mg
(86%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.02 (br t,
J = 5.5 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.44
(dd, J = 7.6, 1.5 Hz, 1H), 7.39-7.31 (m, 2H), 7.30-7.23 (m, 2H), 7.15 (td, J
= 8.0, 1.6 Hz, 1H), 5.34 (s, 1H), 3.92 (ddd, J = 17.7, 5.0, 2.5 Hz, 1H),
3.72 (ddd, J = 17.7, 7.0, 2.4 Hz, 1H), 2.28 (t, J = 2.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 191.2 (C=O), 163.2 (C), 142.6 (C), 135.0 (C), 133.2
(CH), 132.8 (CH), 130.9 (CH), 130.3 (CH), 129.6 (CH), 129.0 (CH), 127.6
(CH), 127.0 (CH), 121.2 (CBr), 119.3 (CBr), 97.7 (CH), 78.6 (C), 72.8
(CH), 33.7 (CH2); IR (neat): 3291, 1704, 1586, 1548, 1457, 1426, 1355,
1255, 1074, 1023, 750 cm-1; MS (ESI, m/z): 417.94 and 419.94 [M+H]+;
HRMS (ESI) calcd. for C18H1479Br2NO: 417.9437 [M+H]+, found:
417.9442; calcd. for C18H1479Br81Br NO: 419.9417 [M+H]+, found:
419.9420.
General Procedure for the synthesis of 2-methylene-2,3-dihydro-1,4-
oxazepines (2) (Table 2). To a stirred solution of the corresponding N-
propargylic β-enaminone 1 (0.30 mmol) in DCM (5 mL) or in CHCl3 (5
mL) at room temperature under argon were added ZnCl2 (0.30 mmol).
The resulting mixture was then refluxed at 40 oC (DCM) or at 61 oC
(CHCl3) (Note that reaction was continued until N-propargylic β-
enaminone 1 was completely consumed as monitored by routine TLC).
After the reaction was over, the solvent was removed on a rotary
evaporator, and ethyl acetate (40 mL) and a saturated aqueous solution
of NH4Cl (15 mL) were 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 1,4-oxazepine derivative 2.
2-Methylene-5,7-diphenyl-2,3-dihydro-1,4-oxazepine
(2a).
1,3-
1-(2-Bromophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-ylamino)prop-
2-en-1-one (1s). 1-(2-Bromophenyl)-3-(3-fluorophenyl)prop-2-yn-1-one
(787.9 mg, 2.5 mmol) and propargylamine (165.3 mg, 3.0 mmol) were
employed to afford 850.7 mg (95%) of the indicated product. 1H NMR
(400 MHz, CDCl3) δ 11.01 (br s, 1H), 7.57 (dd, J = 8.0, 1.0 Hz, 1H), 7.48-
7.39 (m, 2H), 7.35-7.26 (m, 2H), 7.25-7.12 (m, 3H), 5.47 (s, 1H), 3.95 (dd,
J = 6.4, 2.5 Hz, 2H), 2.35 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 191.4 (C=O), 164.2 (C), 162.6 (d, 1J = 248.4 Hz, CF), 142.9 (C), 136.4
(d, 3J = 7.6 Hz, C), 133.5 (CH), 130.6 (d, 3J = 8.2 Hz, CH), 130.5 (CH),
129.3 (CH), 127.3 (CH), 123.8 (d, 4J = 3.1 Hz, CH), 119.5 (CBr), 117.1 (d,
2J = 21.0 Hz, CH), 115.3 (d, 2J = 22.9 Hz, CH), 98.5 (CH), 79.5 (C), 73.0
(CH), 34.4 (CH2); IR (neat): 3294, 1562, 1477, 1321, 1224, 1197, 1079,
1023, 872, 790, 758 cm-1; MS (ESI, m/z): 358.02 [M+H]+; HRMS (ESI)
calcd. for C18H1479BrFNO: 358.0237 [M+H]+, found: 358.0239.
Diphenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-one (1a) (78.4 mg, 0.30
mmol) and ZnCl2 (40.9 mg, 0.30 mmol) were employed to afford the
indicated product (74.5 mg (95%) in refluxing DCM; 74.5 mg (95%) in
refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.87-7.72 (m, 4H), 7.51-
7.38 (m, 6H), 6.41 (s, 1H), 4.76 (d, J = 1.4 Hz 1H), 4.57 (s, 2H), 4.40 (d, J
= 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 167.1 (C), 159.0 (C), 158.2
(C), 139.8 (C), 135.2 (C), 130.2 (CH), 130.1 (CH), 128.7 (CH), 128.4
(CH), 127.5 (CH), 126.4 (CH), 99.8 (CH), 94.0 (CH2), 55.6 (CH2); IR
(neat): 3104, 3059, 2994, 2955, 2837, 1656, 1627, 1587, 1570, 1491,
1446, 1361, 1313, 1290, 1260, 1230, 1191, 1176, 1110, 1076, 1055,
1027, 999, 946, 926, 882, 832, 804, 762 cm-1; MS (ESI, m/z): 262.12
[M+H]+; HRMS (ESI) calcd. for C18H16NO: 262.1226 [M+H]+, found:
262.1236. The spectral data were in agreement with those reported
previously for this compound.[33]
1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-(4-
2-Methylene-7-phenyl-5-(m-tolyl)-2,3-dihydro-1,4-oxazepine (2b). 1-
Phenyl-3-(prop-2-yn-1-ylamino)-3-(m-tolyl)prop-2-en-1-one (1b) (90.9 mg,
0.33 mmol) and ZnCl2 (45.0 mg, 0.33 mmol) were employed to afford the
indicated product (39.1 mg (43%) in refluxing DCM; 67.3 mg (74%) in
refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.84-7.77 (m, 2H), 7.67 (s,
1H), 7.61 (d, J = 7.5 Hz, 1H), 7.51-7.42 (m, 3H), 7.37-7.24 (m, 2H), 6.43
(s, 1H), 4.79 (d, J = 0.9 Hz, 1H), 4.59 (s, 2H), 4.42 (d, J = 1.5 Hz, 1H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.3 (C), 158.9 (C), 158.2
(C), 139.7 (C), 138.1 (C), 135.3 (C), 130.9 (CH), 130.2 (CH), 128.7 (CH),
128.3 (CH), 128.0 (CH), 126.4 (CH), 124.7 (CH), 99.9 (CH), 93.9 (CH2),
55.5 (CH2), 21.5 (CH3); IR (neat): 3056, 3026, 2920, 1707, 1657, 1622,
1596, 1546, 1491, 1447, 1373, 1315, 1260, 1198, 1067, 1044, 1024, 999,
907, 831, 787, 764 cm-1; MS (ESI, m/z): 276.14 [M+H]+; HRMS (ESI)
calcd. for C19H18NO: 276.1383 [M+H]+, found: 276.1394.
(trifluoromethyl)phenyl)prop-2-en-1-one (1t). 1-(2-Bromophenyl)-3-(4-
(trifluoromethyl)phenyl)prop-2-yn-1-one (882.8 mg, 2.5 mmol) and
propargylamine (165.3 mg, 3.0 mmol) were employed to afford 898.1 mg
(88%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.02 (br t,
J = 5.8 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 7.55
(dd, J = 8.0, 0.9 Hz, 1H), 7.45 (dd, J = 7.6, 1.7 Hz, 1H), 7.30 (td, J = 7.5,
1.0 Hz, 1H), 7.18 (td, J = 7.7, 1.7 Hz, 1H), 5.46 (s, 1H), 3.91 (dd, J = 6.5,
2.5 Hz, 2H), 2.35 (t, J = 2.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 191.3
(C=O), 163.8 (C), 142.6 (C), 137.9 (C), 133.4 (CH), 131.9 (q, 2J = 32.8
Hz, C), 130.5 (CH), 129.2 (CH), 128.4 (CH), 127.2 (CH), 125.7 (q, 3J =
1
3.7 Hz, CH), 123.7 (q, J = 272.4 Hz, CF3), 119.3 (CBr), 98.6 (CH), 79.3
(C), 73.0 (CH), 34.3 (CH2); IR (neat): 3297, 1587, 1561, 1319, 1167,
1125, 1063, 1018, 849, 740 cm-1; MS (ESI, m/z): 408.02 [M+H]+; HRMS
(ESI) calcd. for C19H1479BrF3NO: 408.0205 [M+H]+, found: 408.0206.
2-Methylene-7-phenyl-5-(p-tolyl)-2,3-dihydro-1,4-oxazepine (2c). 1-
Phenyl-3-(prop-2-yn-1-ylamino)-3-(p-tolyl)prop-2-en-1-one (1c) (88.1 mg,
0.32 mmol) and ZnCl2 (43.6 mg, 0.32 mmol) were employed to afford the
indicated product (54.6 mg (62%) in refluxing DCM; 65.2 mg (74%) in
refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.80-7.74 (m, 2H), 7.71 (d,
J = 8.2 Hz, 2H), 7.48-7.41 (m, 3H), 7.22 (d, J = 8.0 Hz, 2H), 6.40 (s, 1H),
4.75 (s, 1H), 4.55 (s, 2H), 4.39 (d, J = 1.5 Hz, 1H), 2.40 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 166.9 (C), 158.8 (C), 158.4 (C), 140.2 (C), 137.1 (C),
135.3 (C), 130.1 (CH), 129.1 (CH), 128.6 (CH), 127.4 (CH), 126.3 (CH),
100.0 (CH), 93.7 (CH2), 55.4 (CH2), 21.4 (CH3); IR (neat): 3112, 3055,
3025, 3000, 2962, 2836, 1659, 1624, 1584, 1561, 1508, 1492, 1446,
1362, 1316, 1292, 1264, 1229, 1198, 1179, 1109, 1063, 1028, 950, 882,
854, 812, 758 cm-1; MS (ESI, m/z): 276.14 [M+H]+; HRMS (ESI) calcd. for
C19H18NO: 276.1383 [M+H]+, found: 276.1386.
1-(4-Chlorophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-ylamino)prop-
2-en-1-one (1u). 1-(4-Chlorophenyl)-3-(3-fluorophenyl)prop-2-yn-1-one
(646.7 mg, 2.5 mmol) and propargylamine (165.3 mg, 3.0 mmol) were
employed to afford 713.8 mg (91%) of the indicated product. 1H NMR
(400 MHz, CDCl3) δ 11.27 (br s, 1H), 7.90-7.80 (m, 2H), 7.51-7.42 (m,
1H), 7.41-7.34 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.26-7.15 (m, 2H), 5.79
(s, 1H), 3.94 (dd, J = 6.2, 2.2 Hz, 2H), 2.35 (t, J = 2.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 187.9 (C=O), 164.6 (C), 162.7 (d, 1J = 248.5 Hz, CF),
138.1 (C), 137.4 (C), 136.8 (d, 3J = 7.8 Hz, C), 130.6 (d, 3J = 8.3 Hz, CH),
128.7 (CH), 128.6 (CH), 123.7 (d, 4J = 3.0 Hz, CH), 117.0 (d, 2J = 21.1
Hz, CH), 115.2 (d, 2J = 22.9 Hz, CH), 94.4 (CH), 79.5 (C), 72.9 (CH),
34.3 (CH2); IR (neat): 3232, 1570, 1545, 1473, 1325, 1282, 1265, 1231,
1092, 1065, 878, 764 cm-1; MS (ESI, m/z): 314.07 [M+H]+; HRMS (ESI)
calcd. for C18H14ClFNO: 314.0743 [M+H]+, found: 314.0746.
5-(2-Methoxyphenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-
oxazepine
(2d).
3-(2-Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
ylamino)prop-2-en-1-one (1d) (110.7 mg, 0.38 mmol) and ZnCl2 (51.8 mg,
0.38 mmol) were employed to afford the indicated product (69.7 mg
(63%) in refluxing DCM; 73.1 mg (66%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.75-7.69 (m, 2H), 7.51 (dd, J = 7.5, 1.8 Hz, 1H), 7.43-
7.34 (m, 4H), 7.03-6.97 (m, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.37 (s, 1H),
4.77 (d, J = 0.9 Hz, 1H), 4.56 (s, 2H), 4.40 (d, J = 1.3 Hz, 1H), 3.85 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 167.7 (C), 157.8 (C), 157.3 (C), 156.8
(C), 135.5 (C), 130.8 (CH), 130.3 (CH), 130.0 (CH), 128.6 (CH), 126.4
(CH), 120.9 (CH), 111.6 (CH), 102.6 (CH), 94.2 (CH2), 55.9 (OCH3), 55.7
(CH2) (Note that one C and one CH peak overlap on each other); IR
(neat): 3059, 2937, 2836, 1731, 1710, 1657, 1623, 1597, 1567, 1487,
1461, 1434, 1365, 1321, 1241, 1179, 1161, 1120, 1063, 1046, 1020, 904,
813, 751 cm-1; MS (ESI, m/z): 292.13 [M+H]+; HRMS (ESI) calcd. for
C19H18NO2: 292.1332 [M+H]+, found: 292.1345.
employed to afford the indicated product (76.9 mg (86%) in refluxing
DCM; 80.5 mg (90%) in refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ
7.79-7.74 (m, 2H), 7.59-7.56 (m, 1H), 7.55-7.51 (m, 1H), 7.48-7.41 (m,
3H), 7.37 (td, J = 8.0, 5.8 Hz, 1H), 7.13 (tdd, J = 8.3, 2.6, 0.8 Hz, 1H),
6.35 (s, 1H), 4.78 (d, J = 0.4 Hz, 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 = 246.2 Hz,
CF), 159.5 (C), 158.0 (C), 142.1 (d, 3J = 7.1 Hz, C), 135.1 (C), 130.4
(CH), 130.0 (d, 3J = 8.0 Hz, CH), 128.7 (CH), 126.4 (CH), 123.2 (d, 4J =
2.5 Hz, CH), 116.7 (d, 2J = 21.6 Hz, CH), 114.5 (d, 2J = 22.7 Hz, CH),
99.2 (CH), 94.4 (CH2), 55.6 (CH2). IR (neat): 3102, 2993, 2951, 2837,
1731, 1704, 1656, 1624, 1569, 1483, 1447, 1431, 1361, 1313, 1296,
1261, 1248, 1196, 1174, 1104, 1077, 1055, 874, 825, 790, 762 cm-1; MS
(ESI, m/z): 280.11 [M+H]+; HRMS (ESI) calcd. for C18H15FNO: 280.1132
[M+H]+, found: 280.1137.
5-(4-Methoxyphenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-
2-Methylene-7-phenyl-5-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1,4-
oxazepine
(2e).
3-(4-Methoxyphenyl)-1-phenyl-3-(prop-2-yn-1-
oxazepine
(2i).
1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(4-
ylamino)prop-2-en-1-one (1e) (131.1 mg, 0.45 mmol) and ZnCl2 (61.3 mg,
0.45 mmol) were employed to afford the indicated product (86.5 mg
(66%) in refluxing DCM; 95.7 mg (73%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.79-7.74 (m, 4H), 7.46-7.41 (m, 3H), 6.95-6.89 (m, 2H),
6.39 (s, 1H), 4.73 (d, J = 1.1 Hz, 1H), 4.53 (s, 2H), 4.38 (d, J = 1.5 Hz,
1H), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4 (C), 161.4 (C),
158.9 (C), 158.6 (C), 135.4 (C), 132.4 (C), 130.2 (CH), 129.1 (CH), 128.7
(CH), 126.4 (CH), 113.8 (CH), 99.9 (CH), 93.7 (CH2), 55.5 (OCH3), 55.3
(CH2); IR (neat): 3081, 3052, 2996, 2953, 2835, 1656, 1630, 1604, 1586,
1562, 1510, 1492, 1462, 1432, 1367, 1315, 1299, 1254, 1199, 1172,
1109, 1063, 1029, 999, 869, 856, 820, 762 cm-1; MS (ESI, m/z): 292.13
[M+H]+; HRMS (ESI) calcd. for C19H18NO2: 292.1332 [M+H]+, found:
292.1346.
(trifluoromethyl)phenyl)prop-2-en-1-one (1i) (98.8 mg, 0.30 mmol) and
ZnCl2 (40.9 mg, 0.30 mmol) were employed to afford the indicated
product (79.0 mg (80%) in refluxing DCM; 81.0 mg (82%) in refluxing
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.1 Hz, 2H), 7.80-7.74
(m, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.50-7.41 (m, 3H), 6.36 (s, 1H), 4.80 (d,
J = 1.1 Hz, 1H), 4.59 (s, 2H), 4.42 (d, J = 1.6 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 166.0 (C), 159.8 (C), 157.8 (C), 143.1 (C), 135.0 (C),
131.9 (q, 2J = 32.4 Hz, C), 130.5 (CH), 128.8 (CH), 127.9 (CH), 126.5
(CH), 125.4 (q, 3J = 3.7 Hz, CH), 124.2 (q, 1J = 272.2 Hz, CF3), 99.0 (CH),
94.7 (CH2), 55.8 (CH2); IR (neat): 3109, 3085, 3054, 3039, 1660, 1623,
1586, 1565, 1491, 1446, 1408, 1365, 1326, 1315, 1264, 1201, 1183,
1153, 1105, 1067, 1014, 947, 884, 861, 819, 759 cm-1; MS (ESI, m/z):
330.11 [M+H]+; HRMS (ESI) calcd. for C19H15F3NO: 330.1100 [M+H]+,
found: 330.1101.
N,N-Dimethyl-4-(2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepin-5-
yl)aniline (2f). 3-(4-(Dimethylamino)phenyl)-1-phenyl-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (1f) (91.3 mg, 0.30 mmol) and ZnCl2 (40.9 mg,
0.30 mmol) were employed to afford the indicated product (42.9 mg
(47%) in refluxing DCM; 36.5 mg (40%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.79-7.75 (m, 2H), 7.74-7.70 (m, 2H), 7.46-7.40 (m, 3H),
6.75-6.65 (m, 2H), 6.43 (s, 1H), 4.70 (d, J = 1.0 Hz, 1H), 4.51 (s, 2H),
4.37 (d, J = 1.4 Hz, 1H), 3.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
166.4 (C), 159.0 (C), 158.5 (C), 151.8 (C), 135.5 (C), 130.0 (CH), 128.7
(CH), 128.6 (CH), 127.2 (C), 126.3 (CH), 111.5 (CH), 100.3 (CH), 93.2
(CH2), 54.9 (CH2), 40.4 (N(CH3)2); IR (neat): 2891, 2828, 1737, 1646,
1629, 1606, 1578, 1548, 1523, 1490, 1447, 1357, 1317, 1267, 1189,
1107, 1059, 811, 758, 683 cm-1; MS (ESI, m/z): 305.17 [M+H]+; HRMS
(ESI) calcd. for C20H21N2O: 305.1648 [M+H]+, found: 305.1662.
2-Methylene-7-phenyl-5-(thiophen-3-yl)-2,3-dihydro-1,4-oxazepine
(2j). 1-Phenyl-3-(prop-2-yn-1-ylamino)-3-(thiophen-3-yl)prop-2-en-1-one
(1j) (82.9 mg, 0.31 mmol) and ZnCl2 (42.3 mg, 0.31 mmol) were
employed to afford the indicated product (61.3 mg (74%) in refluxing
DCM; 69.6 mg (84%) in refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ
7.81-7.72 (m, 2H), 7.68 (dd, J = 2.9, 1.2 Hz, 1H), 7.56 (dd, J = 5.1, 1.2
Hz, 1H), 7.48-7.40 (m, 3H), 7.31 (dd, J = 5.1, 3.0 Hz, 1H), 6.41 (s, 1H),
4.75 (br s, 1H), 4.53 (s, 2H), 4.40 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 162.3 (C), 158.6 (C), 158.1 (C), 142.9 (C), 135.2 (C), 130.2
(CH), 128.7 (CH), 126.9 (CH), 126.4 (CH), 126.0 (CH), 125.7 (CH), 99.5
(CH), 94.1 (CH2), 55.4 (CH2); IR (neat): 3098, 2989, 2954, 2832, 1656,
1626, 1577, 1492, 1448, 1352, 1312, 1283, 1261, 1194, 1110, 1057,
1028, 872, 764, 689 cm-1; MS (ESI, m/z): 268.08 [M+H]+; HRMS (ESI)
calcd. for C16H14NOS: 268.0791 [M+H]+, found: 268.0791.
5-(2-Bromophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepine
(2g). 3-(2-Bromophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-
one (1g) (112.3 mg, 0.33 mmol) and ZnCl2 (45.0 mg, 0.33 mmol) were
employed to afford the indicated product (70.7 mg (63%) in refluxing
DCM; 82.0 mg (73%) in refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ
7.78-7.67 (m, 2H), 7.60 (dd, J = 8.0, 1.0 Hz, 1H), 7.48-7.32 (m, 5H), 7.27-
7.20 (m, 1H), 6.13 (s, 1H), 4.84 (d, J = 1.0 Hz, 1H), 4.58 (s, 2H), 4.44 (d,
J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.6 (C), 157.9 (C),
157.2 (C), 142.0 (C), 135.0 (C), 133.2 (CH), 130.2 (CH), 130.2 (CH),
130.1 (CH), 128.6 (CH), 127.5 (CH), 126.4 (CH), 121.3 (CBr), 101.4 (CH),
95.2 (CH2), 56.1 (CH2); IR (neat): 3058, 1657, 1623, 1597, 1571, 1464,
1365, 1318, 1294, 1257, 1193, 1153, 1119, 1066, 1045, 1024, 848, 826,
757 cm-1; MS (ESI, m/z): 340.03 [M+H]+; HRMS (ESI) calcd. for
C18H1579BrNO: 340.0332 [M+H]+, found: 340.0330.
5-Butyl-2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepine (2k) and (2-
butyl-4-methyl-1H-pyrrol-3-yl)(phenyl)methanone (3k). 1-Phenyl-3-
(prop-2-yn-1-ylamino)hept-2-en-1-one (1k) (72.4 mg, 0.30 mmol) and
ZnCl2 (40.9 mg, 0.30 mmol) were employed. Chromatographic
purification of crude product on silica gel produced a mixture of two
compounds. The mixture was then rechromatographed on aluminium
oxide (neutral), which afforded two fractions. The product in the first
fraction was identified as 5-butyl-2-methylene-7-phenyl-2,3-dihydro-1,4-
oxazepine (2k) (42.7 mg (59%) in refluxing DCM; 52.1 mg (72%) in
refluxing CHCl3). The product in the second fraction was assigned as (2-
butyl-4-methyl-1H-pyrrol-3-yl)(phenyl)methanone (3k) (10.1 mg (14%) in
refluxing DCM; 6.5 mg (9%) in refluxing CHCl3).
2k: 1H NMR (400 MHz, CDCl3) δ 7.72-7.63 (m, 2H), 7.44-7.35 (m,
3H), 5.88 (s, 1H), 4.68 (d, J = 1.1 Hz, 1H), 4.31 (s, 3H), 2.43-2.34 (m, 2H),
1.60 (tt, J = 7.8, 6.5 Hz, 2H), 1.37 (sextet, J = 7.3 Hz, 2H), 0.92 (t, J = 7.3
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3 (C), 157.8 (C), 157.1 (C),
135.2 (C), 130.0 (CH), 128.6 (CH), 126.3 (CH), 100.9 (CH), 93.8 (CH2),
5-(3-Fluorophenyl)-2-methylene-7-phenyl-2,3-dihydro-1,4-oxazepine
(2h).
3-(3-Fluorophenyl)-1-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-
one (1h) (89.4 mg, 0.32 mmol) and ZnCl2 (43.6 mg, 0.32 mmol) were
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
55.2 (CH2), 40.3 (CH2), 29.9 (CH2), 22.5 (CH2), 14.1 (CH3); IR (neat):
3268, 2957, 2928, 2870, 1703, 1623, 1596, 1450, 1428, 1378, 1266,
1175, 1107, 1072, 1025, 767, 699 cm-1; MS (ESI, m/z): 242.15 [M+H]+;
HRMS (ESI) calcd. for C16H20NO: 242.1539 [M+H]+, found: 242.1541.
3k: 1H NMR (400 MHz, CDCl3) δ 8.45 (br s, 1H), 7.47-7.31 (m, 5H),
6.56 (dd, J = 2.2, 1.0 Hz, 1H), 2.39-2.31 (m, 2H), 2.26 (d, J = 0.8 Hz, 3H),
1.51-1.42 (m, 2H), 1.10 (sextet, J = 7.4 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 200.8 (C=O), 136.6 (C), 133.7 (C), 129.2
(CH), 128.6 (CH), 128.5 (CH), 122.2 (C), 121.8 (C), 117.0 (CH), 42.2
(CH2), 27.2 (CH2), 22.4 (CH2), 13.9 (CH3), 12.6 (CH3); IR (neat): 3467,
3194, 3056, 2954, 2928, 1708, 1679, 1622, 1450, 1421, 1402, 1340,
1281, 1060, 768, 696 cm-1; MS (ESI, m/z): 242.16 [M+H]+; HRMS (ESI)
calcd. for C16H20NO: 242.1539 [M+H]+, found: 242.1551.
7-(2-Bromophenyl)-2-methylene-5-(m-tolyl)-2,3-dihydro-1,4-
oxazepine (2n). 1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-(m-
tolyl)prop-2-en-1-one (1n) (77.9 mg, 0.22 mmol) and ZnCl2 (30.0 mg,
0.22 mmol) were employed to afford the indicated product (42.8 mg
(55%) in refluxing DCM; 74.0 mg (95%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.75-7.50 (m, 4H), 7.47-7.17 (m, 4H), 6.06 (s, 1H), 4.71 (s,
3H), 4.40 (s, 1H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9 (C),
159.5 (C), 158.9 (C), 139.1 (C), 138.2 (C), 137.8 (C), 133.5 (CH), 131.0
(CH), 130.9 (CH), 130.8 (CH), 128.3 (CH), 128.0 (CH), 127.5 (CH), 124.6
(CH), 122.1 (CBr), 104.8 (CH), 94.1 (CH2), 55.5 (CH2), 21.5 (CH3); IR
(neat): 3021, 2921, 2855, 1653, 1632, 1592, 1572, 1466, 1355, 1310,
1255, 1184, 1106, 1066, 1039, 1021, 951, 862, 831, 796, 757 cm-1; MS
(ESI, m/z): 354.05 [M+H]+; HRMS (ESI) calcd. for C19H1779BrNO:
354.0488 [M+H]+, found: 354.0495.
2-(2-Methylene-7-phenyl-2,3-dihydro-1,4-oxazepin-5-yl)isoindoline-
1,3-dione
(2l)
and
2-(2-(3-benzoyl-4-methyl-1H-pyrrol-2-
7-(2-Bromophenyl)-2-methylene-5-(p-tolyl)-2,3-dihydro-1,4-
yl)ethyl)isoindoline-1,3-dione (3l). 2-(5-Oxo-5-phenyl-3-(prop-2-yn-1-
ylamino)pent-3-en-1-yl)isoindoline-1,3-dione (1l) (75.1 mg, 0.21 mmol)
and ZnCl2 (28.6 mg, 0.21 mmol) were employed. Chromatographic
purification of crude product on silica gel produced a mixture of two
compounds. The mixture was then rechromatographed on aluminium
oxide (neutral), which afforded two fractions. The product in the first
fraction was identified as 2-(2-methylene-7-phenyl-2,3-dihydro-1,4-
oxazepin-5-yl)isoindoline-1,3-dione (2l) (30.0 mg (40%) in refluxing DCM;
30.0 mg (40%) in refluxing CHCl3). Second fraction produced a mixture of
1,4-oxazepine 2l and pyrrole 3l. Spectroscopic identification of pyrrole 3l
was made by peak picking of 1H NMR spectrum of the mixture (see
Figure S87 on page S45 of Supporting Information). The yield of pyrrole
3l was calculated by the integration of the related 1H NMR peaks of the
mixture, which was found to be 20% (equivalent to 15.0 mg) in refluxing
DCM and 12% (equivalent to 9.0 mg) in refluxing CHCl3.
oxazepine
(2o).
1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-3-(p-
tolyl)prop-2-en-1-one (1o) (102.7 mg, 0.29 mmol) and ZnCl2 (39.5 mg,
0.29 mmol) were employed to afford the indicated product (71.9 mg
(70%) in refluxing DCM; 92.4 mg (90%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.57 (dd,
J = 7.6, 1.5 Hz, 1H), 7.44-7.37 (m, 1H), 7.33-7.27 (m, 1H), 7.23 (d, J =
8.0 Hz, 2H), 6.06 (s, 1H), 4.70 (s, 3H), 4.40 (br s, 1H), 2.40 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.6 (C), 159.5 (C), 159.0 (C), 140.5 (C),
137.8 (C), 136.3 (C), 133.4 (CH), 130.9 (CH), 130.8 (CH), 129.2 (CH),
127.5 (CH), 127.4 (CH), 122.1 (CBr), 104.8 (CH), 94.0 (CH2), 55.4 (CH2),
21.5 (CH3); IR (neat): 2951, 2920, 2839, 1656, 1626, 1610, 1589, 1562,
1509, 1467, 1434, 1353, 1310, 1277, 1252, 1181, 1107, 1071, 1040,
1030, 861, 812, 754 cm-1; MS (ESI, m/z): 354.05 [M+H]+; HRMS (ESI)
calcd. for C19H1779BrNO: 354.0488 [M+H]+, found: 354.0489.
2l: 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ
7.83-7.79 (m, 2H), 7.69-7.65 (m, 2H), 7.65-7.62 (m, 2H), 7.41-7.34 (m,
3H), 5.87 (s, 1H), 4.67 (d, J = 1.0 Hz, 1H), 4.27 (s, 2H), 4.24 (d, J = 1.4
Hz, 1H), 4.02 (t, J = 7.3 Hz, 2H), 2.77 (t, J = 7.3 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 168.2 (C=O), 158.1 (C), 157.0 (C), 134.9 (C), 133.9 (CH),
132.6 (CH), 132.3 (C), 130.2 (C), 128.6 (CH), 126.4 (CH), 123.3 (CH),
100.4 (CH), 94.6 (CH2), 55.2 (CH2), 38.4 (CH2), 36.0 (CH2); IR (neat):
3393, 3180, 2917, 2848, 1764, 1698, 1644, 1596, 1468, 1419, 1400,
1362, 1319, 1258, 1091, 992, 829, 760, 718 cm-1; MS (ESI, m/z): 359.14
[M+H]+; HRMS (ESI) calcd. for C22H19N2O3: 359.1390 [M+H]+, found:
359.1400.
3l: 1H NMR (400 MHz, CDCl3) δ 8.28 (br s, 1H), in 7.84-7.75 (m,
2H), in 7.69-7.65 (m, 2H), in 7.41-7.34 (m, 5H), 6.55 (dd, J = 2.2, 1.0 Hz,
1H), 3.92 (t, J = 7.5 Hz, 2H), in 2.84-2.74 (m, 2H), 2.26 (d, J = 0.9 Hz,
3H). As mentioned above, pyrrole 3l could not be isolated in pure state
from flash column chromatography. That’s why; further characterization
of this compound could not be achieved.
7-(2-Bromophenyl)-5-(2-methoxyphenyl)-2-methylene-2,3-dihydro-
1,4-oxazepine (2p). 1-(2-Bromophenyl)-3-(2-methoxyphenyl)-3-(prop-2-
yn-1-ylamino)prop-2-en-1-one (1p) (74.0 mg, 0.20 mmol) and ZnCl2 (27.3
mg, 0.20 mmol) were employed to afford the indicated product (59.9 mg
(81%) in refluxing DCM; 65.1 mg (88%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.65 (dd, J = 7.9, 1.0 Hz, 1H), 7.55 (dd, J = 7.5, 1.7 Hz,
1H), 7.49 (dd, J = 7.6, 1.7 Hz, 1H), 7.41-7.33 (m, 2H), 7.30-7.25 (m, 1H),
7.01 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.02 (s, 1H), 4.71 (s,
2H), 4.70 (s, 1H), 4.38 (d, J = 1.3 Hz, 1H), 3.87 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 167.5 (C), 158.9 (C), 157.2 (C), 157.1 (C), 138.1 (C),
133.3 (CH), 130.83 (CH), 130.77 (CH), 130.7 (CH), 130.3 (CH), 129.6
(C) 127.4 (CH), 122.2 (CBr), 120.9 (CH), 111.4 (CH), 107.7 (CH), 93.8
(CH2), 55.9 (OCH3), 55.8 (CH2); IR (neat): 2962, 2831, 1656, 1630, 1591,
1569, 1486, 1465, 1433, 1360, 1313, 1300, 1253, 1189, 1162, 1113,
1076, 1027, 943, 872, 851, 832, 751 cm-1; MS (ESI, m/z): 370.04 [M+H]+;
HRMS (ESI) calcd. for C19H1779BrNO2: 370.0437 [M+H]+, found:
370.0440.
7-(2-Bromophenyl)-2-methylene-5-phenyl-2,3-dihydro-1,4-oxazepine
(2m). 1-(2-Bromophenyl)-3-phenyl-3-(prop-2-yn-1-ylamino)prop-2-en-1-
one (1m) (88.5 mg, 0.26 mmol) and ZnCl2 (35.4 mg, 0.26 mmol) were
employed to afford the indicated product (70.8 mg (80%) in refluxing
DCM; 71.7 mg (81%) in refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ
7.76-7.70 (m, 2H), 7.57 (dd, J = 8.0, 1.1 Hz, 1H), 7.46 (dd, J = 7.6, 1.7
Hz, 1H), 7.38-7.27 (m, 4H), 7.23-7.16 (m, 1H), 5.95 (s, 1H), 4.60 (s, 3H),
4.29 (d, J = 1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 166.8 (C), 159.7
(C), 158.9 (C), 139.2 (C), 137.9 (C), 133.5 (CH), 130.9 (CH), 130.8 (CH),
130.3 (CH), 128.5 (CH), 127.54 (CH), 127.47 (CH), 122.1 (CBr), 104.7
(CH), 94.2 (CH2), 55.6 (CH2); IR (neat): 3246, 3055, 2966, 2841, 1655,
1629, 1587, 1563, 1485, 1464, 1434, 1360, 1313, 1253, 1189, 1180,
1114, 1077, 1064, 1025, 953, 857, 831, 755 cm-1; MS (ESI, m/z): 340.03
[M+H]+; HRMS (ESI) calcd. for C18H1579BrNO: 340.0332 [M+H]+, found:
340.0332.
7-(2-Bromophenyl)-5-(4-methoxyphenyl)-2-methylene-2,3-dihydro-
1,4-oxazepine (2q). 1-(2-Bromophenyl)-3-(4-methoxyphenyl)-3-(prop-2-
yn-1-ylamino)prop-2-en-1-one (1q) (74.0 mg, 0.20 mmol) and ZnCl2 (27.3
mg, 0.20 mmol) were employed to afford the indicated product (51.8 mg
(70%) in refluxing DCM; 66.6 mg (90%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.84-7.77 (m, 2H), 7.67 (dd, J = 8.0, 0.9 Hz, 1H), 7.56 (dd,
J = 7.6, 1.7 Hz, 1H), 7.40 (td, J = 7.5, 1.0 Hz, 1H), 7.33-7.27 (m, 1H),
6.97-6.90 (m, 2H), 6.05 (s, 1H), 4.68 (s, 3H), 4.38 (d, J = 0.8 Hz, 1H),
3.85 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9 (C), 161.4 (C), 159.33
(C), 159.30 (C), 137.9 (C), 133.4 (CH), 131.9 (C), 130.87 (CH), 130.83
(CH), 129.0 (CH), 127.5 (CH), 122.1 (CBr), 113.7 (CH), 104.8 (CH), 93.7
(CH2), 55.4 (OCH3), 55.3 (CH2); IR (neat): 2993, 2952, 2835, 1656, 1627,
1603, 1587, 1569, 1510, 1492, 1461, 1361, 1312, 1192, 1168, 1107,
1072, 1028, 1000, 945, 855, 821, 759 cm-1; MS (ESI, m/z): 370.04
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701433
European Journal of Organic Chemistry
FULL PAPER
[M+H]+; HRMS (ESI) calcd. for C19H1779BrNO2: 370.0437 [M+H]+, found:
370.0442.
MHz, CDCl3) δ 165.8 (C), 162.9 (d, 1J = 246.3 Hz, CF), 158.4 (C), 157.8
(C), 141.9 (d, 3J = 7.1 Hz, C), 136.5 (C), 133.5 (C), 130.0 (d, 3J = 8.1 Hz,
CH), 128.9 (CH), 127.7 (CH), 123.2 (d, 4J = 2.6 Hz, CH), 117.10 (d, 2J =
21.5 Hz, CH), 114.5 (d, 2J = 22.7 Hz, CH), 99.3 (CH), 94.7 (CH2), 55.5
(CH2); IR (neat): 3297, 2997, 1657, 1623, 1591, 1573, 1484, 1439, 1402,
1362, 1314, 1259, 1178, 1090, 1055, 1010, 984, 881, 819, 783 cm-1; MS
(ESI, m/z): 314.08 [M+H]+; HRMS (ESI) calcd. for C18H14ClFNO:
314.0743 [M+H]+, found: 314.0750.
5,7-Bis(2-bromophenyl)-2-methylene-2,3-dihydro-1,4-oxazepine (2r).
1,3-Bis(2-bromophenyl)-3-(prop-2-yn-1-ylamino)prop-2-en-1-one
(1r)
(83.8 mg, 0.20 mmol) and ZnCl2 (27.3 mg, 0.20 mmol) were employed to
afford the indicated product (64.5 mg (77%) in refluxing DCM; 57.0 mg
(68%) in refluxing CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.9,
0.9 Hz, 1H), 7.60 (dd, J = 8.0, 0.8 Hz, 1H), 7.54 (dd, J = 7.6, 1.7 Hz, 1H),
7.45 (dd, J = 7.6, 1.7 Hz, 1H), 7.36 (td, J = 7.5, 1.2 Hz, 2H), 7.31-7.21 (m,
Synthesis of 1,3-diphenyl-3-((3-phenylprop-2-yn-1-yl)amino)prop-2-
2H), 5.78 (s, 1H), 4.79 (s, 1H), 4.72 (s, 2H), 4.43 (d, J = 1.5 Hz, 1H); 13
C
en-1-one (14). To
a
stirred solution of 1,3-diphenyl-3-(prop-2-
NMR (100 MHz, CDCl3) δ 168.6 (C), 158.7 (C), 158.1 (C), 141.4 (C),
137.6 (C), 133.4 (CH), 133.2 (CH), 130.9 (CH), 130.6 (CH), 130.4 (CH),
130.2 (CH), 127.6 (CH), 127.5 (CH), 122.1 (CBr), 121.3 (CBr), 106.3
(CH), 95.1 (CH2), 56.1 (CH2); IR (neat): 3055, 2973, 1656, 1629, 1589,
1577, 1562, 1466, 1428, 1360, 1316, 1300, 1247, 1190, 1117, 1075,
1024, 943, 854, 828, 753 cm-1; MS (ESI, m/z): 417.94 and 419.94
[M+H]+; HRMS (ESI) calcd. for C18H1479Br2NO: 417.9437 [M+H]+, found:
417.9432; calcd. for C18H1479Br81Br NO: 419.9417 [M+H]+, found:
419.9417.
ynylamino)prop-2-en-1-one (1a) (156.9 mg, 0.6 mmol) in DMF (0.15 mL)
at room temperature under argon was added (i-Pr)2NH (1.2 mL),
PdCl2(PPh3)2 (8.6 mg, 0.012 mmol) and CuI (2.3 mg, 0.012 mmol) in turn
and the reaction mixture was stirred for 10 min. Iodobenzene (190.4 mg,
0.93 mmol) was then added and the resulting mixture was stirred at room
temperature for approximately 3-5 h (Note that stirring was continued
until β-enaminone 1a was completely consumed as monitored by routine
TLC). After the reaction was over, ethyl acetate (18 mL) was added, and
the resulting solution was washed with 0.1
N HCl (4 mL) and
subsequently with a saturated NH4Cl solution (4 mL) in a separatory
funnel. After the layers 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 (9:1 followed by 4:1) as the eluent to afford 178.2
mg (88%) of the indicated product. 1H NMR (400 MHz, CDCl3) δ 11.42
(br s, 1H), 7.96-7.87 (m, 2H), 7.57-7.52 (m, 2H), 7.51-7.47 (m, 3H), 7.46-
7.38 (m, 5H), 7.35-7.28 (m, 3H), 5.87 (s, 1H), 4.18 (d, J = 6.2 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 189.0 (C=O), 165.9 (C), 140.1 (C), 135.1
(C), 131.7 (CH), 130.9 (CH), 129.8 (CH), 128.7 (CH), 128.4 (CH), 128.3
(CH), 128.2 (CH), 127.9 (CH), 127.2 (CH), 122.6 (C), 94.6 (CH), 85.2 (C),
84.2 (C), 35.0 (CH2). The spectral data were in agreement with those
reported previously for this compound.[35]
7-(2-Bromophenyl)-5-(3-fluorophenyl)-2-methylene-2,3-dihydro-1,4-
oxazepine (2s). 1-(2-Bromophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (1s) (96.7 mg, 0.27 mmol) and ZnCl2 (36.8 mg,
0.27 mmol) were employed to afford the indicated product (76.4 mg
(79%) in refluxing DCM; 83.2 mg (86%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.57 (dd, J = 8.0, 1.1 Hz, 1H), 7.53-7.48 (m, 1H), 7.48-
7.42 (m, 2H), 7.34-7.25 (m, 2H), 7.24-7.17 (m, 1H), 7.07-7.01 (m, 1H),
5.90 (s, 1H), 4.62 (d, J = 1.4 Hz, 1H), 4.60 (s, 2H), 4.31 (d, J = 1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 165.7 (C), 162.9 (d, 1J = 246.2 Hz,
CF), 160.2 (C), 158.5 (C), 141.3 (d, 3J = 7.7 Hz, C), 137.6 (C), 133.5
(CH), 131.1 (CH), 130.8 (CH), 130.0 (d, 3J = 8.1 Hz, CH), 127.6 (CH),
123.2 (d, 4J = 2.5 Hz, CH), 122.0 (CBr), 117.21 (d, 2J = 21.4 Hz, CH),
114.4 (d, 2J = 22.8 Hz, CH), 104.1 (CH), 94.7 (CH2), 55.5 (CH2); IR
(neat): 3063, 2959, 1657, 1625, 1571, 1484, 1468, 1439, 1359, 1309,
1297, 1277, 1258, 1241, 1194, 1161, 1110, 1072, 1042, 1027, 1010, 981,
945, 897, 857, 786, 756 cm-1; MS (ESI, m/z): 358.02 [M+H]+; HRMS
(ESI) calcd. for C18H1479BrFNO: 358.0237 [M+H]+, found: 358.0242.
Reaction of N-propargylic β-enaminone 14 with ZnCl2. To a stirred
solution of 1,3-diphenyl-3-((3-phenylprop-2-yn-1-yl)amino)prop-2-en-1-
one (14) (57.4 mg, 0.17 mmol) in DCM (3 mL) or in CHCl3 (3 mL) at room
temperature under argon were added ZnCl2 (23.2 mg, 0.17 mmol). The
resulting mixture was then refluxed at 40 oC (DCM) or at 61 oC (CHCl3)
(Note that reaction was continued until N-propargylic β-enaminone 14
was completely consumed as monitored by routine TLC). After the
reaction was over, the solvent was removed on a rotary evaporator, and
ethyl acetate (25 mL) and a saturated aqueous solution of NH4Cl (10 mL)
were added. After the layers were separated, the aqueous layer was
extracted with ethyl acetate (2 x 20 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 14.3 mg (25%) in refluxing DCM and 16.0 mg (28%) in refluxing
CHCl3 of (2,4-diphenylpyridin-3-yl)(phenyl)methanone (15). 1H NMR (400
MHz, CDCl3) δ 8.87 (d, J = 5.1 Hz, 1H), 7.59-7.54 (m, 2H), 7.54-7.49 (m,
7-(2-Bromophenyl)-2-methylene-5-(4-(trifluoromethyl)phenyl)-2,3-
dihydro-1,4-oxazepine (2t). 1-(2-Bromophenyl)-3-(prop-2-yn-1-ylamino)-
3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (1t) (93.9 mg, 0.23 mmol)
and ZnCl2 (31.4 mg, 0.23 mmol) were employed to afford the indicated
product (86.4 mg (92%) in refluxing DCM; 85.4 mg (91%) in refluxing
CHCl3). 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.2 Hz, 2H), 7.68 (d, J
= 8.1 Hz, 3H), 7.57 (dd, J = 7.6, 1.7 Hz, 1H), 7.41 (td, J = 7.5, 1.1 Hz, 1H),
7.32 (td, J = 7.7, 1.7 Hz, 1H), 6.03 (s, 1H), 4.75 (s, 1H), 4.74 (s, 2H), 4.43
(d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 165.6 (C), 160.2 (C),
158.5 (C), 142.5 (C), 137.6 (C), 133.5 (CH), 131.9 (q, 2J = 32.5 Hz, C),
131.1 (CH), 130.7 (CH), 127.8 (CH), 127.6 (CH), 125.4 (q, 3J = 3.7 Hz,
CH), 124.1 (q, 1J = 272.3 Hz, CF3), 122.0 (CBr), 104.0 (CH), 94.8 (CH2),
55.8 (CH2); IR (neat): 3054, 2985, 1650, 1632, 1595, 1571, 1467, 1443,
1408, 1359, 1320, 1256, 1185, 1173, 1119, 1105, 1071, 1062, 1029,
1013, 954, 853, 767 cm-1; MS (ESI, m/z): 408.02 [M+H]+; HRMS (ESI)
calcd. for C19H1479BrF3NO: 408.0205 [M+H]+, found: 408.0213.
2H), 7.39 (d, J = 5.0 Hz, 1H), 7.39-7.34 (m, 1H), 7.30-7.19 (m, 10H); 13
C
NMR (100 MHz, CDCl3) δ 197.3 (C=O), 157.2 (C), 149.9 (CH), 149.3 (C),
139.6 (C), 137.9 (C), 137.7 (C), 133.7 (C), 133.3 (CH), 129.4 (CH), 129.3
(CH), 128.8 (CH), 128.7 (CH), 128.5 (2 x CH), 128.4 (CH), 128.3 (CH),
123.2 (CH); IR (neat): 3054, 1663, 1595, 1538, 1492, 1441, 1384, 1293,
1248, 1178, 1155, 1026, 921, 858, 753, 695 cm-1; MS (ESI, m/z): 336.14
[M+H]+; HRMS (ESI) calcd. for C24H18NO: 336.1383 [M+H]+, found:
336.1398. The spectral data were in agreement with those reported
previously for this compound.[40]
7-(4-Chlorophenyl)-5-(3-fluorophenyl)-2-methylene-2,3-dihydro-1,4-
oxazepine (2u). 1-(4-Chlorophenyl)-3-(3-fluorophenyl)-3-(prop-2-yn-1-
ylamino)prop-2-en-1-one (1u) (72.2 mg, 0.23 mmol) and ZnCl2 (31.4 mg,
0.23 mmol) were employed to afford the indicated product (64.3 mg
(89%) in refluxing DCM; 55.6 mg (77%) in refluxing CHCl3). 1H NMR (400
MHz, CDCl3) δ 7.73-7.66 (m, 2H), 7.55 (dd, J = 7.8, 1.0 Hz, 1H), 7.53-
7.48 (m, 1H), 7.44-7.33 (m, 3H), 7.17-7.09 (m, 1H), 6.31 (s, 1H), 4.77 (d,
J = 1.2 Hz, 1H), 4.55 (s, 2H), 4.41 (d, J = 1.6 Hz, 1H); 13C NMR (100
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10.1002/ejoc.201701433
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We thank the Scientific and Technological Research Council of
Turkey (TUBITAK, Grant No. 114Z811) and the Research Fund
of Middle East Technical University (METU, Grant No. BAP-
2011-07-02-00-01) for financial support of this research.
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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A new robust method is described
for the synthesis of 2-methylene-2,3-
dihydro-1,4-oxazepines via ZnCl2-
mediated cyclization of N-propargylic
β-enaminones
1,4-Oxazepines
R2
R2
ZnCl2
Yilmaz Kelgokmen, Yasemin Cayan,
Metin Zora*
O
DCM, 40 o
C
O
R1
NH
or
N
CHCl3, 61 o
C
R1
Page No. – Page No.
21 examples
Zinc Chloride-Mediated Synthesis of
1,4-Oxazepines from N-Propargylic
β-Enaminones
R1 = aryl, heteroaryl, alkyl
R2 = aryl
up to 95% yield
*one or two words that highlight the emphasis of the paper or the field of the study
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