Copper-catalyzed domino reaction between terminal alkynes, isocyanates, and oxiranes: An atom-economic route to morpholine derivatives

Article abstract of DOI:10.1002/jhet.3756

In situ generated copper acetylides react with isocyanates and oxiranes to form a decent range of morpholine derivatives. The reactions proceeded with acceptable yields and excellent regioselectivity. The presence of oxygen and moisture completely inhibit

Full text of DOI:10.1002/jhet.3756

Received: 3 August 2019
DOI: 10.1002/jhet.3756
Revised: 9 September 2019
Accepted: 11 September 2019
A R T I C L E
Copper‐catalyzed domino reaction between terminal
alkynes, isocyanates, and oxiranes: An atom‐economic route
to morpholine derivatives
1
1
2
Vahid Beigi‐Somar | Seyed Saied Homami
| Majid Ghazanfarpour‐Darjani
|
3
Amirhossein Monzavi
1
Department of Applied Chemistry,
Abstract
Faculty of Science, South Tehran Branch,
Islamic Azad University, Tehran, Iran
In situ generated copper acetylides react with isocyanates and oxiranes to form
a decent range of morpholine derivatives. The reactions proceeded with accept-
able yields and excellent regioselectivity. The presence of oxygen and moisture
completely inhibited the reaction. The scope of the reaction is wide and the
reactions involve consecutive C–C, C–N, and C–O bond formations.
2
Department of Chemistry, Buinzahra
Branch, Islamic Azad University,
Buinzahra, Iran
3
Department of Polymer and Textile
Engineering, South Tehran Branch,
Islamic Azad University, Tehran, Iran
Correspondence
Seyed Saied Homami, Department of
Applied Chemistry, Faculty of Science,
South Tehran Branch, Islamic Azad
University, Tehran, Iran.
Email: s_homami@azad.ac.ir
Funding information
Islamic Azad University, South Tehran
1
| INTRODUCTION
situ metalation of terminal acetylenes and their reactions
with various electrophiles attracted considerable atten-
[
11–14]
Reactions involving electrophilic cyclization across C–C
triple bonds are known as reliable and valuable strategy
for synthesis of a diverse range of heterocyclic com-
tions.
These reports revealed that copper acetylides
could easily attack on carbonyls, imines, and even unsat-
urated carbonyl acceptors in mild reaction conditions and
a benign solvent. Commencing from these reports, a
number of reports involving nucleophilic additions of
copper acetylides on C=N and C=O in the presence of
an appropriate third partner electrophile have been
[1,2]
pounds.
Along this line, those reactions involving
domino nucleophilic addition–electrophilic cyclization
catalysis in copper have preeminence.
per salts presents the advantages of being inexpensive,
easy to handle, and insensitive, suitable for performing
even in aqueous conditions. The role of copper is multi-
faceted in these reactions. Initially π–electrons of triple
[3–6]
The use of cop-
[
15–18]
appeared.
Particularly in this regard is the use of
heterocumulenes and three‐membered heterocycles in
reaction with metal acetylides which opened up a possi-
bility for expedient synthesis of a wide range of heterocy-
bond coordinated to copper salt, lowering the pK of
a
alkyne proton to some extent in which easily removed
clic compounds from the readily available starting
[7,8]
[19–24]
by common bases.
In electrophilic cyclization, coordi-
materials.
The reactions represent a meaningful
nation of copper salts with the triple bond electrons led to
develop a large partial positive charge ready for the 6‐
step forward in leveraging the less‐explored copper
acetylide–heterocumulene coupling, both in terms of
employing more practical catalysts and in incorporating
an appropriate partner to access synthetically important
endo,
cyclizations.
6‐exo,
and
kinetically
favored
5‐exo
[
9,10]
Pioneered by Carreira in the 2000s, in
140
© 2019 Wiley Periodicals, Inc.
wileyonlinelibrary.com/journal/jhet
J Heterocyclic Chem. 2020;57:140–150~.

BEIGI‐SOMAR ET AL.
141
a
targets. On the other hand, Patel and coworkers
have reported regioselective ring opening of
TABLE 1 Optimization of reaction conditions
three‐membered
isothiocyanates.
heterocycles
with
aroyl
[25,26]
Morpholine skeletons are common in pharmaceuticals
and natural products and numerous synthetic approaches
to access morpholine derivatives have been reported in lit-
Entry Catalyst
Base
Solvent Yield of 4 (%)
[27–29]
erature.
To our knowledge no report on nucleophilic
1
2
3
4
5
6
7
8
9
1
CuI
DIPEA
DBU
Dioxane 37
Dioxane 69
additions of copper acetylides on isocyanate has been
reported in literature. Accordingly, we became encouraged
to examine if isocyanate underwent nucleophilic additions
with copper acetylides. Along this line, we report herein,
regioselective ring opening of oxiranes with propargylic
amide adduct derived from copper acetylides and isocya-
nates, leading to the formations of morpholine skeletons
through a 6‐exo cyclization mode (Scheme 1).
CuI
CuI
DABCO Dioxane 31
CuI
Et
3
N
Dioxane 21
Dioxane 47
CuI
Cs CO
2 3
CuI
t.BuOLi Dioxane 25
t.BuOK Dioxane 79
CuI
CuI
t.BuOK DMF
t.BuOK PEG‐400 NR
t.BuOK MeCN 62
t.BuOK Toluene 72
t.BuOK THF 55
38
b
CuI
0
CuI
2
| PLACEHOLDER TEXTRESULTS
AND DISCUSSION
11
CuI
12
13
14
15
CuI
An initial study on feasibility of the proposed reaction has
been performed using phenyl acetylene (1a), phenyl iso-
cyanate (2a), and 2‐ethyloxirane (3a) in the presence of
CuCl
CuBr.SMe
t.BuOK Dioxane 41
t.BuOK Dioxane 68
t.BuOK Dioxane 24
2
2
Cu O
CuI as the catalyst and (i‐Pr) EtN as the base in MeCN.
2
After the mixture being stirred at 105°C for 18 h, the
desired compound 4a was obtained only in traces
amounts together with phenylcarbamic acid (derived
from the hydrolysis of isocyanate) in 63% yield. Grate-
fully, performing the reaction with 3 Å molecular sieves
not only completely suppress the formation of
phenylcarbamic acid but also increased the yield of 4a
to 23%. To further develop the reaction parameters, we
examined the reaction with various bases, solvents, and
catalyst and the results are shown in Table 1. In initial
effort, the reaction was performed with various organic
and inorganic bases and t.BuOK gave superior result
16
3 4 6
Cu (CH CN) PF t.BuOK Dioxane 80
1
1
1
2
7
8
9
0
CuOTf
Cu (OTf)
Cu (OAc)
t.BuOK Dioxane 37
t.BuOK Dioxane 40
t.BuOK Dioxane 53
t.BuOK Dioxane 62
t.BuOK Dioxane 19
2
2
Cu (BF
AgOAc
‐
4 2
)
21
2
2
2
2
3
4
t.BuOK Dioxane Traces
CuI
‐
Dioxane
‐
CuI
t.BuOK
‐
Traces
a
Reaction conditions: 1a (1.2 mmol), 2a (1.0 mmol), 3a (1.5 mmol), catalyst
0.1 mmol), 250 mg of ground 3 Å molecular sieves, base (1.5 mmol), and sol-
(
(
entries 1–7). Of the solvents, dioxane has been found to
be the most effective choice for the reaction (entries 8–
2). It is worth mentioning that, PEG‐400 (a known sol-
vent (4.0 mL) at 105°C for 18 h.
b
No reaction.
1
[30]
vent in activation of oxiranes ) was not suitable here
entry 9). A catalyst survey indicated that the outcome
of the reaction had great dependence to catalyst of choice
entries 13–20). However, the oxidation state of copper
did not have appreciable effect on reaction yield (entry
7 vs. 18). The desired compound 4a was formed only in
(
is not catalyzed by silver salts (entry 21). The reaction
did not afford the targeted product 4a in the absence of
catalyst (entry 22). The reaction did not proceed at all
without t.BuOK, indicating the vital role of base in this
transformation (entry 23). Only a trace amount of the
product 4a was obtained under the neat condition (entry
(
1
low yield with AgOAc, suggesting the proposed reaction
24). Interestingly and in contrast of the previous reports,
the reaction exhibited excellent chemoselectivity and no
products arising from the direct attack of copper acetylide
on 3a are detected in crude reaction mixture analy-
[
21,31]
sis.
Based on the spectroscopic analyses, all of the
SCHEME 1 Catalytic synthesis of morpholine derivatives.
reactions proceeded through a 6‐exo cyclization path.

142
BEIGI‐SOMAR ET AL.
When the temperature was decreased to 80°C, the yield of
a dropped to 51% (not shown in Table 1). Additionally,
decreasing the loading of the catalyst and base resulted
in diminished yields (not shown in Table 1).
oxiranes 3j–3 m afforded the benzylic‐attacked products
4j–4 m, exclusively. Importantly, the reactions with aro-
matic oxiranes also afforded comparatively higher yields
than those of alkyl oxiranes. Interestingly, the tolerance
for bromide moiety on the aromatic oxirane 3 m offers
an opportunity for subsequent cross‐coupling reactions,
giving further advantage to the present protocol from a
synthetic point of view. This result indicated that π–
electrons of the phenyl group of the oxirane might
involve in reaction progress through coordination to the
copper catalyst.
The reaction generality was also examined with vari-
ous alkynes and isocyanates (Table 3). A modest increase
in the yields of the products 4n and 4o occurred upon
using alkyl‐substituted isocyanates 2b and 2c. The pres-
ence of electron‐realizing groups such as p‐Me and p‐
methoxy on the phenyl ring of isocyanate afforded the
targeted products 4q and 4r in 87 and 92% yields, com-
pared to phenyl isocyanate 4p, 80%. The reactivity of
electron‐rich alkyne 1c was also tested with electron‐
neutral and electron‐deficient aryl isocyanates 2a and
2f, providing the corresponding products 4 s and 4 t in
4
We next investigated the behavior of various oxiranes
under the optimized reaction conditions (Table 2). Simple
ethyl‐linked oxirane 3a afforded expected product 4a in
acceptable yield. It is worth mentioning that sterically
encumbered oxiranes likes 3b and 3c reacted with only
marginally decreased reaction yields. The proposed reac-
tion is consistent with the presence of an ester as motif
on oxirane, giving the desired products 4d and 4e with
moderate yields. Oxiranes bearing an additional oxygen
atom (an etheric group) likes 3f and 3 g afforded excellent
yields of products 4f and 4 g, most likely due to a better
coordination ability compared to that of other oxiranes.
The reaction was found to tolerate cyclic oxirane 3 h.
Benzyl‐linked oxirane 3i was also effective in this trans-
formation and gave the desired product 4i in 79% yield.
The regioselectivity in ring opening of oxirane completely
switched upon using aromatic oxiranes under an other-
wise identical reaction conditions, as aryl‐substituted
a
TABLE 2 Scope of oxirane
a
For all entries: 1a (1.2 mmol), 2a (1.0 mmol), 3 (1.5 mmol), CuI (0.1 mmol), t.BuOK (1.5 mmol), and 250 mg of ground 3 Å molecular sieves, in dry dioxane
(
4.0 mL) at 105°C for 18 h.

BEIGI‐SOMAR ET AL.
143
a
TABLE 3 Scope of alkyne and isocyanate
a
For all entries except stated otherwise: 1 (1.2 mmol), 2 (1.0 mmol), 3n (1.5 mmol), CuI (0.1 mmol), t.BuOK (1.5 mmol), and 250 mg of ground 3 Å molecular
sieves, in dry dioxane (4.0 mL) at 105°C for 18 h.
b
At 120°C for 22 h.
7
8% and 21% yields, respectively. These results demon-
instead the desired product 4a was obtained in 78% yield.
This data demonstrated that copper catalyst is involved in
formation of compound 6, presumably through electro-
philic activation of oxirane. This proposal is supported
by the fact that oxiranes bearing an etheric group, which
could be act as an additional coordination site, reacted
with higher yields (see Table 2, entries 6 and 7). Finally,
the successes of electrophilic cyclization of alkynol 6 to
morpholine skeleton 4a had great dependence on the
presence of copper catalyst as only a traces amount of
4a was achieved in the absence of copper (Scheme 3, c).
strated that the reaction outcome depends highly on elec-
tronic properties of phenyl isocyanates.
To further explore the reaction pathway chiral oxirane
f' was treated with phenyl isocyanate (2a) and ethyl oxi-
3
rane (3a). This result indicated that the domino ring
opening/cyclization reaction proceeded with racemiza-
tion at the chiral carbon in the presence of phenyl oxi-
rane (Scheme 2).
To get insight on the detail of the reaction pathway,
the reaction was conducted in stepwise manner and the
results are shown in Scheme 1. Initially, phenyl acetylene
was reacted with phenyl isocyanate to form the expected
propargylic amide 5. The study indicated that the pres-
ence of copper salt and an inert atmosphere are necessary
to furnish the transformation in acceptable yield
Based on the above finding and commencing from pre-
vious reports, the following reaction pathway is proposed
(
Scheme 4). Coordination of copper catalyst with phenyl
acetylene in the presence of t.BuOK gave copper acetylide
. The nucleophilic attack of in situ generated copper
7
(Scheme 3, a). For ring opening of oxirane with
acetylide to the sp‐carbon of isocyanate yielded the
propargylic adduct 9 which further reacted with activated
oxirane (species 10) to form the ring opened‐intermediate
propargylic amide 5, it would be interesting to see if cop-
per salt is involved in reaction progress. To check this, the
reaction was conducted with and without copper catalyst
under an inert atmosphere and air (Scheme 3, b). Com-
pound 6 could be isolated only in 18% yield without of
catalyst while, no formation of the ring‐opened interme-
diate 6 take place with copper salt and t.BuOK and
11. The electrophilic cyclization of 11 by the action of
copper salt afforded the expected 6‐exo intermediate 12
which further transferred to the compound 4a by
protonolysis with t.BuOH.
In this report, we have developed a novel catalytic
reaction to form a range of morpholine derivatives from
the commercially available substrates. Control experi-
ments were performed to propose a more sophisticated
reaction pathway. To furnish the transformation with
good success, it is necessary to work under the conditions
where oxygen and moisture are rigorously excluded. The
SCHEME 2 Enantiopure 2‐phenyloxirane reaction.

144
BEIGI‐SOMAR ET AL.
SCHEME 3 Control experiments.
SCHEME 4 Proposed mechanism.
effects of electronic and steric variations of substrates on
reaction outcome have been examined. The regioselec-
tivity in ring opening of oxiranes is switched upon using
aryl‐oxiranes however, in all cases the reactions
proceeded in regioselective manner and only one
regioisomer is detected in crude reaction mixture
analysis.
with the calculated values. Silica gel 60 (particle size
63–200 μm or 40–100 mesh) was used for column chro-
matography (Merck, item number 7734–3). TLC analy-
ses were performed on commercial glass plates bearing
a 0.25‐mm layer of Merck Silica gel 60 (Merck, item
number 116835).
3
.1 | General procedure for the
3
| PLACEHOLDER
preparation of compounds 4
TEXTEXPERIMENTAL
A Schlenk tube (25 mL) equipped with a magnetic stir
bar was charged with terminal alkyne (1.2 mmol), isocy-
anate (1.0 mmol), CuI (0.1 mmol), t.BuOK (1.5 mmol),
250 mg of ground 3 Å molecular sieves, and dioxane
(4.0 mL). The tube was evacuated and backfilled with
argon (three times). The mixture was stirred at 105°C
for 1 h and oxirane (1.5 mmol) was then added under
an inert atmosphere. Subsequently, the mixture was
stirred for 18 h at 105°C. After cooling to room tempera-
ture, the mixture was passed through silica gel pad and
concentrated under reduced pressure. The resulting resi-
due was purified with column chromatography on silica
gel (eluent gradient of EtOAc/hexane, see spectroscopic
analysis section) to give the products 4 in the yields listed
in Tables 2 and 3.
All reactions were carried out in Schlenk tube (25 mL)
under an Ar atmosphere. All the reagents, catalysts,
and additives were obtained from commercial sources.
All the solvents were purchased from PALAENERGY
Pure Chemical Industries, and were dried and degassed
before use. Melting points were measured with
Electrothermal‐9100 apparatus. IR spectra were deter-
1
13
mined on a Nicolet 6700 spectrometer. H and
NMR spectra were recorded with Bruker DRX‐500
C
AVANCE instrument; in CDCl at 500 and 125 MHz,
3
resp; δ in ppm, J in Hz. Mass spectra were determined
on a EIMS (70 eV): Finnigan‐MAT‐8430 mass spectrom-
eter, in m/z. Elemental analyses were performed with a
Heraeus Rapid analyzer. The results agreed favorably

BEIGI‐SOMAR ET AL.
145
2
3
3
.2 | Preparation of compounds 5
CH), 4.15 (1 H, dd, J = 15.1 Hz, J = 5.0 Hz, CH),
.78–4.84 (1 H, m, CH), 6.52 (1 H, s, CH), 7.04 (1 H, t,
4
3
A Schlenk tube (25 mL) equipped with a magnetic stir bar
was charged with terminal alkyne (0.3 mmol), isocyanate
J = 7.4 Hz, CH), 7.26–7.33 (3 H, m, 3 CH), 7.44 (2 H,
3
3
t, J = 7.4 Hz, 2 CH), 7.66 (2 H, d, J = 7.4 Hz, 2
3
13
(0.25 mmol), CuI (0.3 mmol), t.BuOK (0.4 mmol), 50 mg
CH), 7.78 (2 H, d, J = 7.2 Hz, 2 CH). C NMR
(125.7 MHz, CDCl ): δ = 11.8 (Me), 34.2 (CH ), 61.8
of ground 3 Å molecular sieves, and dioxane (1.0 mL).
The tube was evacuated and backfilled with argon (three
times). The mixture was stirred at 105°C for 5 h under an
inert atmosphere. After cooling to room temperature, the
mixture was passed through silica gel pad and concen-
trated under reduced pressure. The resulting residue
was purified with column chromatography on silica gel
3
C
2
(CH ), 80.8 (CH), 112.8 (CH), 126.3 (2 CH), 126.9
(CH), 127.4 (CH), 128.9 (2 CH), 129.5 (2 CH), 130.2 (2
CH), 133.1 (C), 145.5 (C), 148.9 (C), 165.3 (C). EI‐MS
(70 eV): m/z (%) = 293 (M , 1), 264 (11), 186 (43), 98
(87), 91 (36), 77 (100). Anal. Calcd (%) for C H NO
2
(293.37): C, 77.79, H, 6.53, N, 4.77. Found: C, 77. 93,
H, 6.71, N, 4.90.
2
+
19
19
(eluent gradient of EtOAc/hexane, see spectroscopic anal-
ysis section) to give the product 5.
3
.6 | 2‐Benzylidene‐6‐isopropyl‐4‐
phenylmorpholin‐3‐one (4b)
3.3 | Preparation of compounds 6
The crude product was purified by column chromatogra-
A tube (25 mL) equipped with a magnetic stir bar was
charged with compound (0.5 mmol), t.BuOK
0.7 mmol), 150 mg of ground 3 Å molecular sieves, and
dioxane (2.5 mL). The tube was evacuated and backfilled
with argon (three times). The mixture was then stirred for
phy (SiO ; Hexane/EtOAc 5/1, R : 0.36) affording 0.23 g
5
2
f
(
1
75%) of 4b; Colorless oil. IR (KBr): v = 3029, 2962,
(
1
641, 1534, 1267, 1154. H NMR (500.1 MHz, CDCl ):
3
3
δH = 1.12 (6 H, d, J = 5.0 8 Hz, 2 Me), 2.47–2.53 (1 H,
m, CH), 3.97 (1 H, dd, J = 14.6 Hz, J = 5.8 Hz, CH),
4
2
3
1
2 h at 105°C. After cooling to room temperature, the
2
3
.11 (1 H, dd, J = 14.6 Hz, J = 10.9 Hz, CH), 4.56–
mixture was passed through silica gel pad and concen-
trated under reduced pressure. The resulting residue
was purified with column chromatography on silica gel
4
.61 (1 H, m, CH), 6.62 (1 H, s, CH), 7.01 (1 H, t,
3
3
J = 7.2 Hz, CH), 7.29 (2 H, t, J = 7.2 Hz, 2 CH), 7.38
3
3
(
1 H, t, J = 7.7 Hz, CH), 7.46 (2 H, t, J = 7.7 Hz, 2
(eluent gradient of EtOAc/hexane, see spectroscopic anal-
3
CH), 7.61 (2 H, d, J = 7.6 Hz, 2 CH), 7.80 (2 H, d,
ysis section) to give the products 4a.
3
13
J = 7.2 Hz, 2 CH). C NMR (125.7 MHz, CDCl3):
δC = 19.8 (2 Me), 36.7 (CH), 60.1 (CH ), 83.4 (CH),
114.1 (CH), 126.8 (2 CH), 127.3 (CH), 127.9 (CH), 129.2
2
3.4 | Conversion 6 to 4a
(
1
1
2 CH), 129.9 (2 CH), 131.4 (2 CH), 134.2 (C), 142.5 (C),
46.8 (C), 166.1 (C). EI‐MS (70 eV): m/z (%) = 307 (M ,
), 263 (17), 186 (35), 98 (86), 82 (71), 77 (100). Anal.
+
A Schlenk tube (25 mL) equipped with a magnetic stir
bar was charged with compound 6 (0.5 mmol), CuI
(
(
0.05 mmol), t.BuOK (0.7 mmol), and dioxane
2.0 mL). The mixture was stirred for 3 h at 105°C. After
Calcd (%) for C H NO (307.39): C, 78.15; H, 6.89, N,
20
21
2
4.56. Found: C, 78.32; H, 7.06, N, 4.72.
cooling to room temperature, the mixture was passed
through silica gel pad and concentrated under reduced
pressure. The resulting residue was purified with col-
umn chromatography on silica gel (eluent gradient of
EtOAc/hexane, see spectroscopic analysis section) to
give the products 6.
3
.7 | 2‐Benzylidene‐6‐(tert‐butyl)‐4‐
phenylmorpholin‐3‐one (4c)
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 5/1, R : 0.51) affording 0.24 g
2
f
(
74%) of 4c; Colorless oil. IR (KBr): v = 3046, 2947,
1
3
.5 | 2‐Benzylidene‐6‐ethyl‐4‐
1662, 1543, 1462, 1254, 1104. H NMR (500.1 MHz,
CDCl ): δ = 0.98 (9 H, s, 3 Me), 3.89 (1 H, dd,
phenylmorpholin‐3‐one (4a)
3
H
2
3
J = 13.9 Hz, J = 5.4 Hz, CH), 4.14 (1 H, dd,
J = 13.9 Hz, J = 10.7 Hz, CH), 4.39 (1 H, dd,
2
3
3
3
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 4/1, R : 0.41) affording 0.23 g
J = 10.7, 5.4 Hz, CH), 6.54 (1 H, s, CH), 6.94 (1 H, t,
2
f
3
(
1
79%) of 4a; Colorless oil. IR (KBr): v = 3018, 2867,
J = 7.6 Hz, CH), 7.31 (2 H, t, J = 7.6 Hz, 2 CH), 7.35
1
3
3
659, 1461, 1312, 1066. H NMR (500.1 MHz, CDCl ):
(1 H, t, J = 7.3 Hz, CH), 7.44 (2 H, t, J = 7.3 Hz, 2
3
3
3
δH = 1.04 (3 H, d, J = 6.4 Hz, Me), 1.79–1.85 (2 H,
m, 2 CH), 3.98 (1 H, dd, J = 15.1 Hz, J = 10.6 Hz,
CH), 7.64 (2 H, d, J = 7.3 Hz, 2 CH), 7.82 (2 H, d,
2
3
3
13
J = 7.6 Hz, 2 CH). C NMR (125.7 MHz, CDCl3):

146
BEIGI‐SOMAR ET AL.
δC = 30.3 (3 Me), 35.1 (C), 58.7 (CH ), 96.0 (C), 113.6
3.10 | 2‐Benzylidene‐6‐
2
(CH), 126.3 (2 CH), 127.0 (CH), 128.1 (CH), 128.7 (2
(isopropoxymethyl)‐4‐phenylmorpholin‐3‐
CH), 129.1 (2 CH), 130.2 (2 CH), 133.8 (C), 144.7 (C),
one (4f)
+
1
49.1 (C), 166.7 (C). EI‐MS (70 eV): m/z (%) = 321 (M ,
1
), 264 (28), 186 (44), 145 (31), 98 (87), 77 (100), 57 (72).
The crude product was purified by column chromatogra-
Anal. Calcd (%) for C H NO (321.42): C, 78.47; H,
phy (SiO
; Hexane/EtOAc 5/1, R : 0.32) affording 0.31 g
2 f
20
21
2
7
.21, N, 4.36. Found: C, 78.69; H, 7.42, N, 4.52.
(93%) of 4f; Colorless oil. IR (KBr): v = 3019, 2978,
1
1
657, 1467, 1312, 1267, 1076. H NMR (500.1 MHz,
3
CDCl ): δ = 1.22 (6 H, d, J = 6.6 Hz, 2 Me), 3.71 (1
3
H
3
.8 | Methyl‐6‐benzylidene‐2‐methyl‐5‐
2
3
H, dd, J = 13.5 Hz, J = 9.7 Hz, CH), 3.75 (1 H, dd,
oxo‐4‐phenylmorpholine‐2‐carboxylate (4d)
2
3
J = 13.5 Hz, J = 5.4 Hz, CH), 3.87–3.92 (1 H, m, CH),
2
3
4
.04 (1 H, dd, J = 12.9 Hz, J = 9.7 Hz, CH), 4.16 (1 H,
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 4/1, R : 0.19) affording 0.20 g
2
3
dd, J = 12.9 Hz, J = 5.7 Hz, CH), 4.65–4.70 (1 H, m,
CH), 6.61 (1 H, s, CH), 7.04 (1 H, t, J = 7.6 Hz, CH),
2
f
3
(58%) of 4d; Colorless oil. IR (KBr): v = 3033, 2972,
3
7.31 (2 H, t, J = 7.6 Hz, 2 CH), 7.35–7.44 (3 H, m, 3
1
1
735, 1660, 1534, 1311, 1082. H NMR (500.1 MHz,
3
CH), 7.65 (2 H, d, J = 7.6 Hz, 2 CH), 7.80 (2 H, d,
CDCl ): δ = 1.65 (3 H, s, Me), 3.79 (3 H, s, OMe), 4.56
3
H
2
3
13
J = 7.9 Hz, 2 CH).
C NMR (125.7 MHz, CDCl3):
2
(1 H, d, J = 12.2 Hz, CH), 4.71 (1 H, d, J = 12.2 Hz,
δC = 21.8 (2 Me), 59.2 (CH ), 69.6 (CH ), 78.1 (CH),
3
2
2
CH), 6.63 (1 H, s, CH), 6.96 (1 H, t, J = 7.8 Hz, CH),
82.5 (CH), 116.1 (CH), 127.0 (2 CH), 127.4 (CH), 127.9
3
7
.29 (2 H, t, J = 7.8 Hz, 2 CH), 7.37 (1 H, t,
(
(
(
CH), 128.2 (2 CH), 129.2 (2 CH), 130.4 (2 CH), 134.5
3
3
J = 7.0 Hz, CH), 7.47 (2 H, t, J = 7.0 Hz, 2 CH), 7.67
C), 144.3 (C), 149.3 (C), 166.8 (C). EI‐MS (70 eV): m/z
3
3
(2 H, d, J = 7.0 Hz, 2 CH), 7.76 (2 H, d, J = 7.8 Hz, 2
+
%) = 337 (M , 1), 322 (8), 278 (17), 202 (48), 111 (83),
13
CH). C NMR (125.7 MHz, CDCl ): δ = 24.1 (Me),
5
CH), 126.8 (CH), 127.7 (CH), 128.9 (2 CH), 129.6 (2
CH), 129.9 (2 CH), 134.1 (C), 145.1 (C), 150.6 (C), 165.8
3
C
98 (47), 91 (39), 77 (100). Anal. Calcd (%) for
5.7 (OMe), 67.3 (CH ), 92.8 (C), 119.7 (CH), 126.5 (2
2
C H NO (337.42): C, 74.75; H, 6.87, N, 4.15. Found:
21
23
3
C, 74.92; H, 6.95, N, 4.34.
+
(C), 174.1 (C). EI‐MS (70 eV): m/z (%) = 337 (M , 3),
3
22 (9), 245 (49), 156 (62), 98 (86), 77 (100). Anal. Calcd
(
%) for C H NO (337.38): C, 71.20; H, 5.68, N, 4.15.
20
19
4
3
.11 | 2‐Benzylidene‐6‐(phenoxymethyl)‐4‐
Found: C, 71.38; H, 5.51, N, 4.32.
phenylmorpholin‐3‐one (4 g)
3
.9 | Methyl‐6‐benzylidene‐5‐oxo‐4‐
The crude product was purified by column chromatogra-
phenylmorpholine‐2‐carboxylate (4e)
phy (SiO
; Hexane/EtOAc 4/1, R : 0.32) affording 0.35 g
2 f
(
95%) of 4 g; Colorless oil. IR (KBr): v = 3025, 2961,
1
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 3/1, R : 0.18) affording 0.21 g
1649, 1469, 1324, 1189, 951. H NMR (500.1 MHz,
CDCl ): δ = 4.05 (1 H, dd, J = 12.9 Hz, J = 8.9 Hz,
3 H
CH), 4.14 (1 H, dd, J = 12.9 Hz, J = 5.5 Hz, CH), 4.42
2
3
2
f
2
3
(64%) of 4e; Colorless oil. IR (KBr): v = 3036, 2960,
1
2
3
1
739, 1651, 1278, 1153. H NMR (500.1 MHz, CDCl ):
(1 H, dd, J = 11.7 Hz, J = 9.2 Hz, CH), 4.55 (1 H, dd,
3
2
2
3
δ
= 3.73 (3 H, s, OMe), 4.60 (1 H, d, J = 12.9 Hz,
J = 11.7 Hz, J = 5.1 Hz, CH), 4.78–4.83 (1 H, m, CH),
H
3
2
3
J = 10.1 Hz, CH), 4.74 (1 H, d, J = 12.9 Hz,
J = 5.6 Hz, CH), 5.15–5.21 (1 H, m, CH), 6.69 (1 H, s,
6.58 (1 H, s, CH), 6.89 (2 H, d, J = 7.5 Hz, 2 CH), 6.98–
7.04 (2 H, m, 2 CH), 7.24 (2 H, t, J = 7.5 Hz, 2 CH),
3
3
3
3
CH), 7.04 (1 H, t, J = 7.4 Hz, CH), 7.28 (2 H, t,
7.29 (2 H, t, J = 7.1 Hz, 2 CH), 7.35 (1 H, t,
3
3
3
3
J = 7.4 Hz, 2 CH), 7.39 (1 H, t, J = 7.6 Hz, CH), 7.44
J = 7.8 Hz, CH), 7.46 (2 H, t, J = 7.8 Hz, 2 CH), 7.63
3
3
3
3
(2 H, t, J = 7.6 Hz, 2 CH), 7.63 (2 H, d, J = 7.06 Hz, 2
(2 H, d, J = 7.8 Hz, 2 CH), 7.76 (2 H, d, J = 7.1 Hz, 2
CH). C NMR (125.7 MHz, CDCl ): δ = 58.7 (CH2),
3
13
13
CH), 7.79 (2 H, d, J = 7.4 Hz, 2 CH). C NMR
3
C
(
125.7 MHz, CDCl ): δ = 55.1 (OMe), 59.8 (CH ), 89.1
68.1 (CH ), 81.7 (CH), 114.1 (2 CH), 115.3 (CH), 121.6
3
C
2
2
(
1
1
CH), 118.1 (CH), 126.9 (2 CH), 127.3 (CH), 128.1 (CH),
28.4 (2 CH), 129.1 (2 CH), 129.5 (2 CH), 134.3 (C),
(CH), 126.9 (2 CH), 127.3 (CH), 128.0 (CH), 128.4 (2
CH), 128.7 (2 CH), 129.6 (2 CH), 130.3 (2 CH), 134.2
(C), 144.5 (C), 149.2 (C), 160.5 (C), 166.1 (C). EI‐MS
44.7 (C), 148.9 (C), 166.1 (C), 172.9 (C). EI‐MS (70 eV):
+
+
m/z (%) = 323 (M , 2), 292 (7), 264 (26), 188 (58), 153
(70 eV): m/z (%) = 371 (M , 1), 278 (22), 202 (37), 111
(
42), 98 (83), 91 (32), 77 (100). Anal. Calcd (%) for
(63), 98 (84), 93 (63), 77 (100). Anal. Calcd (%) for
C H NO (371.44): C, 77.61; H, 5.70, N, 3.77. Found:
C H NO (323.35): C, 70.58; H, 5.30, N, 4.33. Found:
19
17
4
24 21
3
C, 70.74; H, 5.49, N, 4.51.
C, 77.82; H, 5.90, N, 3.92.

BEIGI‐SOMAR ET AL.
147
2
3
2
.12 | 2‐Benzylidene‐4‐phenylhexahydro‐
H‐benzo[b][1,4]oxazin‐3(4H)‐one (4 h)
(500.1 MHz, CDCl ): δ = 4.79 (1 H, dd, J = 13.5 Hz,
3 H
3
2
J = 5.3 Hz, CH), 4.97 (1 H, dd, J = 13.5 Hz,
J = 9.2 Hz, CH), 5.33–5.37 (1 H, m, CH), 6.64 (1 H, s,
CH), 7.05 (1 H, t, J = 7.8 Hz, CH), 7.26 (1 H, t,
J = 7.3 Hz, CH), 7.30–7.49 (9 H, m, 9 CH), 7.66 (2 H,
d, J = 7.3 Hz, 2 CH), 7.82 (2 H, d, J = 7.8 Hz, 2 CH).
C NMR (125.7 MHz, CDCl ): δ = 70.1 (CH), 81.9
3
3
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 6/1, R : 0.34) affording 0.27 g
3
2
f
3
3
(84%) of 4 h; Colorless solid, m.p: 111–113°C. IR (KBr):
1
13
v = 3016, 2951, 1653, 1476, 1234, 1156. H NMR
3
C
(
500.1 MHz, CDCl ): δ = 1.38–2.02 (8 H, m, 8 CH),
.88 (1 H, ddd, J = 6.1 Hz, CH), 4.29 (1 H, ddd,
J = 6.5 Hz, CH), 6.61 (1 H, s, CH), 7.02 (1 H, t,
(CH ), 115.2 (CH), 125.5 (CH), 125.9 (2 CH), 126.4
3
H
2
3
3
(CH), 126.8 (2 CH), 127.4 (CH), 128.3 (2 CH), 129.2 (2
CH), 129.8 (2 CH), 130.1 (2 CH), 130.5 (2 CH), 134.1
(C), 140.3 (C), 144.2 (C), 150.7 (C), 166.2 (C). EI‐MS
3
3
J = 7.7 Hz, CH), 7.24–7.46 (5 H, m, 5 CH), 7.65 (2 H,
3
3
+
d, J = 7.1 Hz, 2 CH), 7.80 (2 H, d, J = 7.7 Hz, 2 CH).
(70 eV): m/z (%) = 341 (M , 1), 264 (23), 188 (41), 173
1
3
C NMR (125.7 MHz, CDCl ): δC = 27.1 (CH ), 28.5
(46), 98 (81), 91 (37), 77 (100). Anal. Calcd (%) for
C H NO (341.41): C, 80.92; H, 5.61, N, 4.10. Found:
3
2
(
CH ), 30.6 (CH ), 35.2 (CH ), 67.1 (CH), 88.3 (CH),
2 2 2
23 19
2
1
13.2 (CH), 126.5 (2 CH), 127.0 (CH), 128.3 (CH), 128.9
C, 81.15; H, 5.80, N, 4.28.
(
2 CH), 129.7 (2 CH), 130.3 (2 CH), 135.1 (C), 141.2 (C),
+
1
1
7
7
46.0 (C), 167.3 (C). EI‐MS (70 eV): m/z (%) = 319 (M ,
), 290 (19), 212 (31), 188 (57), 116 (34), 98 (83), 91 (33),
7 (100). Anal. Calcd (%) for C H NO (319.40): C,
3
.15 | 2‐Benzylidene‐4‐phenyl‐5‐(o‐tolyl)
morpholin‐3‐one (4 k)
21
21
2
8.97; H, 6.63, N, 4.39. Found: C, 79.16; H, 6.82, N, 4.54.
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 3/1, R : 0.41) affording 0.18 g
2
f
3
.13 | 6‐Benzyl‐2‐benzylidene‐4‐
(52%) of 4 k; Colorless solid, m.p: 64–66°C. IR (KBr): v
= 3042, 2981, 1655, 1532, 1468, 1316, 1162, 1021. H
1
phenylmorpholin‐3‐one (4i)
NMR (500.1 MHz, CDCl ): δ = 2.32 (3 H, s, Me), 4.61
3
H
2
3
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 5/1, R : 0.34) affording 0.28 g
(1 H, dd, J = 13.1 Hz, J = 5.0 Hz, CH), 4.73 (1 H, dd,
J = 13.1 Hz, J = 10.3 Hz, CH), 5.13–5.18 (1 H, m,
CH), 6.58 (1 H, s, CH), 6.90 (1 H, d, J = 7.3 Hz, CH),
6.97 (1 H, t, J = 7.0 Hz, CH), 7.18 (1 H, t, J = 7.5 Hz,
CH), 7.22 (1 H, t, J = 7.5 Hz, CH), 7.25–7.36 (4 H, m, 4
CH), 7.47 (2 H, t, J = 7.8 Hz, 2 CH), 7.61 (2 H, d,
J = 7.8 Hz, 2 CH), 7.79 (2 H, d, J = 7.5 Hz, 2 CH).
2
3
2
f
3
(79%) of 4i; Colorless solid, m.p: 56–58°C. IR (KBr): v =
1
3
3
3
041, 2972, 1652, 1438, 1279, 1161, 1023.
H
3
NMR (500.1 MHz, CDCl ): δ = 2.93 (1 H, dd,
3
H
2
3
3
2
3
J = 12.3 Hz, J = 5.1 Hz, CH), 3.11 (1 H, dd, J = 12.3 Hz,
J = 9.5 Hz, CH), 4.03 (1 H, dd, J = 11.9 Hz, J = 9.6 Hz,
2
3
3
3
13
C
2
3
CH), 4.18 (1 H, dd, J = 11.9 Hz, J = 5.2 Hz, CH), 4.71–
.77 (1 H, m, CH), 6.53 (1 H, s, CH), 6.99 (1 H, t,
NMR (125.7 MHz, CDCl ): δ = 21.7 (Me), 68.3 (CH),
3
C
4
79.2 (CH ), 115.7 (CH), 122.1 (CH), 124.3 (CH), 126.1
2
3
J = 7.6 Hz, CH), 7.16–7.35 (8 H, m, 8 CH), 7.42 (2 H, t,
J = 7.1 Hz, 2 CH), 7.65 (2 H, d, J = 7.1 Hz, 2 CH),
(CH), 127.0 (2 CH), 127.8 (CH), 128.0 (CH), 128.5 (2
CH), 128.9 (2 CH), 129.2 (2 CH), 131.1 (CH), 133.4 (C),
136.8 (C), 140.1 (C), 143.4 (C), 149.5 (C), 166.7 (C). EI‐
3
3
3
13
7
.79 (2 H, d, J = 7.6 Hz, 2 CH). C NMR (125.7 MHz,
+
CDCl ): δ = 42.9 (CH ), 60.3 (CH ), 83.5 (CH), 116.5
MS (70 eV): m/z (%) = 355 (M , 1), 264 (16), 188 (37),
3
C
2
2
(
CH), 125.8 (CH), 126.9 (CH), 127.1 (2 CH), 127.8 (CH),
159 (60), 98 (85), 91 (34), 77 (100). Anal. Calcd (%) for
C H NO (355.44): C, 80.10; H, 5.96, N, 3.94. Found:
C, 80.27; H, 6.12, N, 4.12.
1
1
1
28.1 (2 CH), 128.5 (2 CH), 129.1 (2 CH), 129.4 (2 CH),
30.7 (2 CH), 134.6 (C), 138.25 (C), 144.7 (C), 149.2 (C),
24
21
2
+
66.7 (C). EI‐MS (70 eV): m/z (%) = 355 (M , 1), 264
(
11), 188 (63), 98 (81), 91 (89), 77 (100). Anal. Calcd (%)
3
.16 | 2‐Benzylidene‐4‐phenyl‐5‐(p‐tolyl)
for C H NO (355.44): C, 81.10; H, 5.96, N, 3.94. Found:
C, 81.28; H, 6.15, N, 4.14.
24
21
2
morpholin‐3‐one (4 l)
The crude product was purified by column chromatogra-
3
.14 | 2‐Benzylidene‐4,5‐
phy (SiO
; Hexane/EtOAc 3/1, R : 0.38) affording 0.33 g
2 f
diphenylmorpholin‐3‐one (4j)
(93%) of 4 l; Colorless solid, m.p: 101–103°C. IR (KBr): v
1
=
3036, 2979, 1662, 1441, 1267, 1165, 1032. H NMR
The crude product was purified by column chromatogra-
(500.1 MHz, CDCl ): δ = 2.24 (3 H, s, Me), 4.64 (1 H,
3
H
2
3
phy (SiO ; Hexane/EtOAc 3/1, R : 0.29) affording 0.32 g
dd, J = 12.0 Hz, J = 5.3 Hz, CH), 4.70 (1 H, dd,
2
f
2
3
(
3
93%) of 4j; Colorless solid, m.p: 89–91°C. IR (KBr): v =
018, 2981, 1658, 1517, 1462, `1278, 1034. H NMR
J = 12.0 Hz, J = 8.9 Hz, CH), 5.01–5.05 (1 H, m, CH),
1
3
6.56 (1 H, s, CH), 6.97 (1 H, t, J = 7.7 Hz, CH), 7.14 (2

148
BEIGI‐SOMAR ET AL.
3
3
H, d, J = 7.2 Hz, 2 CH), 7.25 (2 H, d, J = 7.2 Hz, CH),
(CH), 114.2 (CH), 127.3 (CH), 128.2 (2 CH), 129.7 (2
3
7
.28–7.40 (5 H, m, 5 CH), 7.63 (2 H, d, J = 7.7 Hz, 2
CH), 7.80 (2 H, d, J = 7.1 Hz, 2 CH). C NMR
CH), 134.8 (C), 150.1 (C), 167.8 (C). EI‐MS (70 eV): m/z
3
13
+
(%) = 245 (M , 1), 230 (9), 202 (17), 126 (34), 112 (63),
(
125.7 MHz, CDCl ): δ = 23.5 (Me), 66.1 (CH), 79.3
98 (84), 77 (100). Anal. Calcd (%) for C H NO
2
3
C
15 19
(
CH ), 115.2 (CH), 126.3 (2 CH), 127.1 (CH), 127.5 (2
(245.32): C, 73.44, H, 7.81, N, 5.71. Found: C, 73. 62, H,
7.95, N, 5.87.
2
CH), 127.9 (CH), 128.2 (2 CH), 128.9 (2 CH), 129.3 (2
CH), 130.8 (2 CH), 133.1 (C), 138.5 (C), 139.8 (C), 141.3
(
(
(
C), 147.2 (C), 166.2 (C). EI‐MS (70 eV): m/z (%) = 355
M , 2), 278 (9), 188 (36), 175 (57), 98 (87), 91 (42), 77
+
3.19 | 2‐Benzylidene‐4‐cyclohexyl‐6‐
methylmorpholin‐3‐one (4o)
100). Anal. Calcd (%) for C H NO (355.44): C, 80.10;
24
21
2
H, 5.96, N, 3.94. Found: C, 79.98; H, 5.82, N, 3.99.
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 5/1, R : 0.35) affording 0.24 g
2
f
3
.17 | 2‐Benzylidene‐5‐(4‐bromophenyl)‐4‐
(84%) of 4o; Colorless solid, m.p: 82–84°C. IR (KBr): v =
1
phenylmorpholin‐3‐one (4 m)
3021, 2935, 1652, 1435, 1311, 1178, 1054. H NMR
3
(
500.1 MHz, CDCl ): δ = 1.27 (3 H, d, J = 6.3 Hz,
3
H
The crude product was purified by column chromatogra-
Me), 1.35–1.87 (10 H, m, 5 CH ), 3.52 (1 H, dd,
2
2
2
3
phy (SiO ; Hexane/EtOAc 3/1, R : 0.16) affording 0.39 g
J = 13.2 Hz, J = 10.1 Hz, CH), 3.65 (1 H, dd,
2
f
3
(
(
94%) of 4 m; Colorless solid, m.p: 100–102°C. IR
KBr): v = 3036, 2982, 1658, 1436, 1312, 1163, 1042. H
J = 13.2 Hz, J = 5.1 Hz, CH), 3.77–3.82 (1 H, m, CH),
1
4.61–4.67 (1 H, m, CH), 6.49 (1 H, s, CH), 7.32 (1 H, t,
3
3
NMR (500.1 MHz, CDCl ): δ = 4.81 (1 H, dd,
J = 7.8 Hz, CH), 7.48 (2 H, t, J = 7.8 Hz, 2 CH), 7.67
3
H
2
2
3
3
13
J = 13.4 Hz, J = 5.6 Hz, CH), 4.96 (1 H, dd,
J = 13.4 Hz, J = 9.5 Hz, CH), 5.22–5.26 (1 H, m,
CH), 6.64 (1 H, s, CH), 6.92 (1 H, t, J = 7.3 Hz, CH),
.19 (2 H, d, J = 7.6 Hz, 2 CH), 7.31 (2 H, t,
J = 7.3 Hz, CH), 7.37 (1 H, t, J = 7.8 Hz, CH), 7.45
2 H, d, J = 7.8 Hz, 2 CH), 7.66 (2 H, d, J = 7.8 Hz, 2
CH), 7.78 (2 H, d, J = 7.3 Hz, 2 CH), 7.91 (2 H, d,
J = 7.6 Hz, 2 CH). C NMR (125.7 MHz, CDCl3):
δ = 69.3 (CH), 80.1 (CH ), 115.7 (CH), 120.4 (C), 126.8
(2 H, d, J = 7.8 Hz, 2 CH). C NMR (125.7 MHz,
CDCl ): δ = 20.1 (Me), 24.1 (CH ), 27.3 (CH ), 29.4
3
3
C
2
2
3
(CH ), 30.8 (CH ), 36.6 (CH ), 53.5 (CH ), 66.8 (CH),
2 2 2 2
79.1 (CH), 115.5 (CH), 126.8 (CH), 128.7 (2 CH), 129.5
3
7
3
3
(2 CH), 134.1 (C), 150.6 (C), 168.6 (C). EI‐MS (70 eV):
3
3
+
(
m/z (%) = 285 (M , 3), 270 (12), 181 (34), 112 (47), 98
3
(83), 83 (71), 77 (100). Anal. Calcd (%) for C H NO
2
18
23
3
13
(285.39): C, 75.76, H, 8.12, N, 4.91. Found: C, 75. 91, H,
8.28, N, 5.12.
C
2
(2 CH), 127.3 (CH), 127.7 (2 CH), 128.5 (CH), 128.9 (2
CH), 129.7 (2 CH), 130.5 (2 CH), 132.7 (2 CH), 133.6
3
.20 | 6‐Methyl‐2‐(4‐methylbenzylidene)‐
(
(
3
C), 140.1 (C), 143.5 (C), 149.1 (C), 166.7 (C). EI‐MS
+
+
4‐phenylmorpholin‐3‐one (4p)
70 eV): m/z (%) = 421 (M , 4), 419 (M , 4), 332 (9),
30 (9), 254 (32), 252 (32), 175 (57), 98 (87), 91 (28), 77
100). Anal. Calcd (%) for C H BrNO (420.31): C,
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 5/1, R : 0.36) affording 0.23 g
(
23
18
2
2
f
6
5.73; H, 4.32, N, 3.33. Found: C, 65.90; H, 4.50, N, 3.51.
(
80%) of 4p; Colorless solid, m.p: 81–83°C. IR (KBr): v =
1
3
018, 2971, 1647, 1445, 1278, 1106, 1032. H NMR
(500.1 MHz, CDCl ): δ = 1.33 (3 H, s, Me), 2.58 (3 H,
s, Me), 4.01 (1 H, dd, J = 12.8 Hz, J = 10.1 Hz, CH),
3
.18 | 2‐Benzylidene‐4‐isopropyl‐6‐
3
H
2
3
methylmorpholin‐3‐one (4n)
2
3
4.14 (1 H, dd, J = 12.8 Hz, J = 4.9 Hz, CH), 4.67–4.73
The crude product was purified by column chromatogra-
(1 H, m, CH), 6.61 (1 H, s, CH), 7.01 (1 H, t,
3
3
phy (SiO ; Hexane/EtOAc 6/1, R : 0.34) affording 0.21 g
J = 7.4 Hz, CH), 7.30 (2 H, t, J = 7.4 Hz, 2 CH), 7.46
2
f
3
3
(
1
83%) of 4n; Colorless oil. IR (KBr): v = 3011, 2935,
(2 H, d, J = 7.8 Hz, 2 CH), 7.65 (2 H, d, J = 7.8 Hz, 2
1
3
13
651, 1542, 1471, 1255, 1067. H NMR (500.1 MHz,
CH), 7.79 (2 H, d, J = 7.4 Hz, 2 CH). C NMR
(125.7 MHz, CDCl ): δ = 21.2 (Me), 24.3 (Me), 68.8
3
CDCl ): δ = 1.23 (6 H, d, J = 6.1 Hz, 2 Me), 1.34 (3
3
H
3
C
3
2
H, d, J = 6.2 Hz, Me), 3.41 (1 H, dd, J = 11.7 Hz,
(CH ), 80.1 (CH), 115.1 (CH), 127.3 (2 CH), 127.8 (CH),
2
3
2
J = 10.0 Hz, CH), 3.58 (1 H, dd, J = 11.7 Hz,
129.1 (2 CH), 129.9 (2 CH), 130.7 (2 CH), 131.4 (C),
3
J = 5.3 Hz, CH), 3.99–4.04 (1 H, m, CH), 4.56–4.61 (1
139.2 (C), 144.7 (C), 150.1 (C), 165.8 (C). EI‐MS (70 eV):
3
+
H, m, CH), 6.43 (1 H, s, CH), 7.30 (1 H, t, J = 7.6 Hz,
m/z (%) = 293 (M , 2), 278 (13), 202 (27), 175 (49), 112
3
CH), 7.45 (2 H, t, J = 7.6 Hz, 2 CH), 7.62 (2 H, d,
(62), 98 (87), 91 (34), 77 (100). Anal. Calcd (%) for
C H NO (293.37): C, 77.79; H, 6.53, N, 4.77. Found:
3
13
J = 7.6 Hz, 2 CH). C NMR (125.7 MHz, CDCl3):
δ = 20.3 (Me), 22.5 (2 Me), 51.1 (CH ), 60.6 (CH), 79.3
19
19
2
C, 77.96; H, 6.74, N, 4.93.
C
2

BEIGI‐SOMAR ET AL.
149
1
3
4
.21 | 6‐Methyl‐2‐(4‐methylbenzylidene)‐
‐(p‐tolyl)morpholin‐3‐one (4q)
v = 3042, 2972, 1655, 1472, 1243, 1032. H NMR
(500.1 MHz, CDCl ): δ = 1.35 (3 H, s, Me), 3.84 (3 H,
s, OMe), 3.95 (1 H, dd, J = 12.0 Hz, J = 9.3 Hz, CH),
3
H
2
3
2
3
The crude product was purified by column chromatogra-
4.06 (1 H, dd, J = 12.0 Hz, J = 4.9 Hz, CH), 4.50–4.56
phy (SiO ; Hexane/EtOAc 5/1, R : 0.44) affording 0.27 g
(1 H, m, CH), 6.50 (1 H, s, CH), 7.03 (1 H, t,
2
f
3
3
(
3
87%) of 4q; Colorless solid, m.p: 84–86°C. IR (KBr): v =
034, 2972, 1657, 1543, 1455, 1267, 1152, 1032. H NMR
J = 7.7 Hz, CH), 7.12 (2 H, d, J = 7.5 Hz, 2 CH), 7.38
1
3
3
(2 H, t, J = 7.7 Hz, 2 CH), 7.61 (2 H, d, J = 7.5 Hz, 2
3
13
(
500.1 MHz, CDCl ): δH = 1.35 (3 H, s, Me), 2.39 (3 H,
CH), 7.70 (2 H, d, J = 7.7 Hz, 2 CH). C NMR
(125.7 MHz, CDCl ): δ = 21.8 (Me), 56.1 (OMe), 65.6
3
2
s, Me), 2.51 (3 H, s, Me), 3.93 (1 H, dd, J = 12.1 Hz,
3
C
3
2
J = 10.0 Hz, CH), 4.04 (1 H, dd, J = 12.1 Hz,
(CH ), 79.1 (CH), 114.1 (2 CH), 115.3 (CH), 125.1 (C),
2
3
J = 5.2 Hz, CH), 4.46–4.51 (1 H, m, CH), 6.53 (1 H, s,
127.3 (2 CH), 128.1 (2 CH), 129.6 (2 CH), 133.9 (2 CH),
3
CH), 7.11 (2 H, d, J = 7.6 Hz, 2 CH), 7.28 (2 H, d,
142.1 (C), 149.8 (C), 160.1 (C), 166.1 (C). EI‐MS (70 eV):
3
3
+
J = 7.4 Hz, 2 CH), 7.43 (2 H, d, J = 7.1 Hz, 2 CH),
m/z (%) = 309 (M , 1), 295 (8), 218 (34), 175 (51), 122
3
13
7
.61 (2 H, d, J = 7.1 Hz, 2 CH). C NMR (125.7 MHz,
(88), 98 (80), 91 (34), 77 (100). Anal. Calcd (%) for
C H NO (309.37): C, 73.77; H, 6.19, N, 4.53. Found:
CDCl ): δ = 20.1 (Me), 22.3 (Me), 24.3 (Me), 67.1
3
C
19 19
3
(
CH ), 79.6 (CH), 115.3 (CH), 127.9 (2 CH), 129.3 (2
C, 73.94; H, 6.37, N, 4.68.
2
CH), 129.6 (2 CH), 130.9 (C), 135.1 (2 CH), 135.1 (C),
1
38.6 (C), 141.3 (C), 149.4 (C), 166.1 (C). EI‐MS (70 eV):
+
3.24 | 2‐(4‐Methoxybenzylidene)‐6‐methyl‐
m/z (%) = 307 (M , 3), 292 (18), 189 (42), 162 (28), 98
87), 91 (34), 91 (34), 77 (100). Anal. Calcd (%) for
C H NO (307.39): C, 78.15; H, 6.89, N, 4.56. Found:
4
‐(4‐nitrophenyl)morpholin‐3‐one (4 t)
(
20
21
2
The crude product was purified by column chromatogra-
C, 78.32; H, 6.71, N, 4.73.
phy (SiO ; Hexane/EtOAc 1/1, R : 0.38) affording 0.07 g
2
f
(
21%) of 4 t; Colorless solid, m.p: 176–178°C. IR (KBr): v
1
3
.22 | 4‐(4‐Methoxyphenyl)‐6‐methyl‐2‐(4‐
= 3028, 2988, 1653, 1552, 1467, 1345, 1211, 1165. H
NMR (500.1 MHz, CDCl ): δ = 1.32 (3 H, s, Me), 3.90
3 H, s, OMe), 4.07 (1 H, dd, J = 13.5 Hz, J = 9.8 Hz,
methylbenzylidene)morpholin‐3‐one (4r)
3
H
2
3
(
2
3
The crude product was purified by column chromatogra-
CH), 4.19 (1 H, dd, J = 13.5 Hz, J = 5.5 Hz, CH),
4.58–4.63 (1 H, m, CH), 6.54 (1 H, s, CH), 7.13 (2 H, d,
phy (SiO ; Hexane/EtOAc 6/1, R : 0.31) affording 0.30 g
2
f
3
3
(
=
92%) of 4r; Colorless solid, m.p: 98–100°C. IR (KBr): v
3033, 2973, 1651, 1452, 1311, 1252, 1087. H NMR
J = 7.4 Hz, 2 CH), 7.47 (2 H, d, J = 7.8 Hz, 2 CH),
1
3
7.71 (2 H, d, J = 7.4 Hz, 2 CH), 8.17 (2 H, d,
3
13
(
500.1 MHz, CDCl ): δH = 1.31 (3 H, s, Me), 2.52 (3 H,
J = 7.8 Hz, 2 CH). C NMR (125.7 MHz, CDCl3):
δ = 21.2 (Me), 56.8 (OMe), 67.1 (CH ), 80.9 (CH), 114.7
3
2
s, Me), 3.89 (3 H, s, OMe), 3.83 (1 H, dd, J = 13.6 Hz,
C
2
3
2
J = 11.5 Hz, CH), 3.94 (1 H, dd, J = 13.6 Hz,
(2 CH), 116.9 (CH), 124.9 (2 CH), 125.7 (C), 131.8 (2
CH), 133.7 (2 CH), 144.7 (C), 149.8 (C), 150.3 (C), 160.1
3
J = 5.3 Hz, CH), 4.53–4.59 (1 H, m, CH), 6.59 (1 H, s,
3
+
CH), 6.90 (2 H, d, J = 7.8 Hz, 2 CH), 7.43 (2 H, d,
(C), 166.7 (C). EI‐MS (70 eV): m/z (%) = 354 (M , 1),
3
3
J = 7.2 Hz, 2 CH), 7.65 (2 H, d, J = 7.2 Hz, 2 CH),
340 (11), 219 (37), 146 (28), 122 (67), 98 (83), 91 (34), 77
3
13
7
.98 (2 H, d, J = 7.8 Hz, 2 CH). C NMR (125.7 MHz,
(100). Anal. Calcd (%) for C H N O (354.36): C, 64.40;
19
18 2 5
CDCl ): δ = 20.7 (Me), 24.2 (Me), 56.1 (OMe), 63.8
H, 5.12, N, 7.91. Found: C, 64.59; H, 5.31, N, 7.78.
3
C
(
CH ), 76.3 (CH), 114.1 (2 CH), 116.2 (CH), 124.1 (2
2
CH), 129.1 (2 CH), 129.8 (2 CH), 131.3 (C), 137.1 (C),
3
.25 | N,3‐diphenylpropiolamide (5)
1
39.4 (C), 149.6 (C), 159.7 (C), 165.3 (C). EI‐MS (70 eV):
+
m/z (%) = 323 (M , 3), 308 (9), 205 (19), 203 (38), 107
70), 98 (87), 91 (34), 77 (100). Anal. Calcd (%) for
C H NO (323.39): C, 74.28; H, 6.55, N, 4.33. Found:
The crude product was purified by column chromatogra-
phy (SiO ; Hexane/EtOAc 2/1, R : 0.38) affording 0.20 g
(
2
f
20
21
3
(
92%) of 5; Colorless solid, m. p: 81–81°C. IR (KBr): v =
C, 74.45; H, 6.68, N, 4.50.
1
3341, 3043, 2971, 1658, 1532, 1467, 1231. H NMR
3
(
500.1 MHz, Acetone‐d ): δ = 7.11 (1 H, t, J = 7.8 Hz,
6
H
3
3
4
.23 | 2‐(4‐Methoxybenzylidene)‐6‐methyl‐
‐phenylmorpholin‐3‐one (4 s)
CH), 7.29 (2 H, t, J = 7.8 Hz, 2 CH), 7.38–7.44 (3 H, m,
3
3 CH), 7.54 (2 H, d, J = 7.9 Hz, 2 CH), 7.65 (2 H, d,
3
13
J = 7.8 Hz, 2 CH), 8.35 (1 H, br s, NH). C NMR
(125.7 MHz, CDCl ): δ = 83.5 (C), 98.8 (C), 120.3 (C),
The crude product was purified by column chromatogra-
3
C
phy (SiO ; Hexane/EtOAc 7/1, R : 0.25) affording 0.24 g
123.9 (2 CH), 127.1 (CH), 127.9 (CH), 129.1 (2 CH),
2
f
(78%) of 4 s; Colorless solid, m.p: 116–118°C. IR (KBr):
130.8 (2 CH), 133.4 (2 CH), 138.5 (C), 148.2 (C). EI‐MS

150
BEIGI‐SOMAR ET AL.
+
(
70 eV): m/z (%) = 221 (M , 1), 144 (46), 129 (21), 101
[5] N. T. Patil, V. S. Raut, J. Org. Chem. 2010, 75, 6961.
(
8
76), 77 (100). Anal. Calcd (%) for C H NO (221.26): C,
1.43, H, 5.01, N, 6.33. Found: C, 81. 60, H, 5.18, N, 6.48.
[6] G. R. Potuganti, D. R. Indukuri, J. B. Nanubolu, M. Alla, J. Org.
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[
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7] M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952.
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Chem. 2006, 51.
3
.26 | N‐(2‐hydroxybutyl)‐N,3‐
diphenylpropiolamide (6)
[
9] P. G. Cozzi, R. Hilgraf, N. Zimmermann, Eur. J. Org. Chem
2
004, 4095.
The crude product was purified by column chromatogra-
[
[
10] F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodleman,
phy (SiO ; Hexane/EtOAc 4/1, R : 0.29) affording 0.07 g
2
f
K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127, 210.
(
2
23%) of 6; Colorless oil. IR (KBr): v = 3432, 3031, 2967,
11] D. E. Frantz, R. Fa¨ssler, C. S. Tomooka, E. M. Carreira, Acc.
Chem. Res. 2000, 33, 373.
1
256, 1653, 1532, 1432, 1221, 1092.
H
NMR
3
(500.1 MHz, CDCl ): δH = 0.91 (3 H, d, J = 5.8 Hz,
3
[12] N. K. Anand, E. M. Carreira, J. Am. Chem. Soc. 2001, 123, 9687.
Me), 1.55–1.63 (2 H, m, 2 CH), 3.74 (1 H, dd,
[
[
[
[
[
13] D. Boyall, D. E. Frantz, E. M. Carreira, Org. Lett. 2002, 4, 2605.
14] T. F. Knöpfel, E. M. Carreira, J. Am. Chem. Soc. 2003, 125, 6054.
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16] L. Zani, C. Bolm, Chem. Commun. 2006, 4263.
2
2
3
J = 12.3 Hz, J = 9.0 Hz, CH), 4.01 (1 H, dd,
3
J = 12.3 Hz, J = 5.2 Hz, CH), 4.26–4.32 (1 H, m, CH),
3
4
(
.74 (1 H, br s, OH), 6.92 (1 H, t, J = 7.2 Hz, CH), 7.29
3
3
2 H, t, J = 7.2 Hz, 2 CH), 7.40 (2 H, t, J = 7.8 Hz, 2
CH), 7.51 (1 H, t, J = 7.9 Hz, CH), 7.59 (2 H, d,
J = 7.8 Hz, 2 CH), 7.81 (2 H, d, J = 7.2 Hz, 2 CH).
17] X. Xu, J. Gao, D. Cheng, J. Li, G. Qiang, H. Guoa, Adv. Synth.
Catal 2008, 350, 61.
3
3
3
13
C
[18] A. Ranjan, A. Mandal, S. G. Yerande, D. H. Dethe, Chem.
NMR (125.7 MHz, CDCl ): δ = 11.2 (Me), 32.6 (CH ),
3
C
2
Commun. 2015, 51, 14215.
5
9.3 (CH ), 73.1 (CH), 90.1 (C), 98.2 (C), 119.4 (C), 126.9
2
[19] A. Ranjan, R. Yerande, P. B. Wakchaure, S. g. Yerande, D. H.
(2 CH), 126.9 (CH), 127.1 (CH), 127.9 (CH), 129.2 (2
Dethe, Org. Lett. 2014, 16, 5788.
CH), 130.5 (2 CH), 132.9 (2 CH), 140.9 (C), 145.9 (C).
EI‐MS (70 eV): m/z (%) = 293 (M , 1), 264 (8), 220 (31),
[
20] M. Ghazanfarpour‐Darjani, M. Babapour‐Kooshalshahi, S. M.
Mousavi‐Safavi, J. Akbari‐Neyestani, M. Khalaj, Synlett 2016,
27, 259.
+
1
29 (73), 92 (80), 77 (100). Anal. Calcd (%) for
C H NO (293.37): C, 77.79, H, 6.53, N, 4.77. Found:
[21] A. Samzadeh‐Kermani, J. Sulfur. Chem 2019, 40, 554. https://
19
19
2
doi.org/10.1080/17415993.2019.1631316
C, 77. 62, H, 6.42, N, 4.86.
[
22] A. Samzadeh‐Kermani, J. Heterocyclic Chem. 2019, 56, 450.
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[
ACKNOWLEDGMENTS
56, 2202. https://doi.org/10.1002/jhet.3614
[
[
24] A. Samzadeh‐Kermani, Tetrahedron 2016, 72, 5301.
The authors wish to state their thanks to Islamic Azad Uni-
versity (South Tehran Branch), for supporting this work.
25] A. Dahiya, W. Ali, B. K. Patel, ACS Sustainable Chem. Eng.
2018, 6, 4272.
[26] A. Modi, W. Ali, B. K. Patel, Org. Lett. 2017, 19, 432.
ORCID
[27] M. K. Jackl, L. Legnani, B. Morandi, J. F. Bode, Org. Lett. 2017,
1
9, 4696.
Seyed Saied Homami
380
Majid Ghazanfarpour‐Darjani
002-1175-599X
Amirhossein Monzavi
056
https://orcid.org/0000-0001-6914-
[
[
[
28] Y. Y. Lau, H. Zhai, L. L. Schafer, J. Org. Chem. 2016, 81, 8696.
29] Z. Lu, S. S. Stahl, Org. Lett. 2012, 14, 1234.
6
https://orcid.org/0000-
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0
2007, 72, 9822.
https://orcid.org/0000-0003-1880-
[
31] A. Varmazyar, A. Nozad Goli‐Kand, S. Sedaghat, M. Khalaj, S.
6
Arab‐Salmanabadi, J. Heterocyclic Chem. 2019, 56, 1850.
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