Copper-catalyzed oxidative synthesis of 2-oxo-acetamidines from one-pot three-component reaction of aryl methyl ketones, secondary amines and anilines

Article abstract of DOI:10.1016/j.tet.2018.08.021

Some novel 2-oxo-acetamidines were synthesized via one-pot three-component reaction of acetophenones, secondary amines and anilines in presence of CuI as catalyst. The reaction involved in a oxidation process of C (sp³)–H bonds of acetophenones

Full text of DOI:10.1016/j.tet.2018.08.021

Accepted Manuscript
Copper-catalyzed oxidative synthesis of 2-oxo-acetamidines from one-pot three-
component reaction of aryl methyl ketones, secondary amines and anilines
Leema Dutta, Pulak J. Bhuyan
PII:
S0040-4020(18)30974-8
10.1016/j.tet.2018.08.021
TET 29741
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 May 2018
Revised Date: 20 July 2018
Accepted Date: 14 August 2018
Please cite this article as: Dutta L, Bhuyan PJ, Copper-catalyzed oxidative synthesis of 2-oxo-
acetamidines from one-pot three-component reaction of aryl methyl ketones, secondary amines and
anilines, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.021.
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ACCEPTED MANUSCRIPT
As we Graphical Abstract
Copper-catalyzed oxidative synthesis of
Leave this area blank for abstract info.
2-oxo-acetamidines from one-pot three-component
reaction of aryl methyl ketones, secondary amines and anilines
Leema Dutta and Pulak J Bhuyan*
Applied Organic Chemistry Group, CSIR-North East Institute of Science and Technology, Jorhat-785006, Assam, India.

Tetrahedron
1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Copper-catalyzed oxidative synthesis of 2-oxo-acetamidines from one-pot
three-component reaction of aryl methyl ketones, secondary amines and
anilines
Leema Dutta and Pulak J Bhuyan*
Applied Organic Chemistry Group, CSIR-North East Institute of Science and Technology, Jorhat-785006, Assam, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Some novel 2-oxo-acetamidines were synthesized via one-pot three-component reaction
of acetophenones, secondary amines and anilines in presence of CuI as catalyst. The
reaction involved in a oxidation process of C(sp3)-H bonds of acetophenones in presence
of air followed by aminations, and products were obtained in good to excellent yields
(70-82%) in simple work-up procedure.
Available online
Keywords:
Acetophenones,
Amines,
2015 Elsevier Ltd. All rights reserved
.
2-oxo-acetamidines,
Copper iodide
1. Introduction
molecules possessing α-amino carbonyl moiety are
shown in figure 1 (V, VI).
Organic synthesis aims in building new valuable
structures/C-C or C-heteroatom bond. Now a days,
researchers find α-amination of C=O group as an
interesting area due to the ability of such linkage as
versatile scaffold to approach a diverse spectrum of
complex molecular scaffolds.1 In organic research area,
amidines are considered as important functional groups
for their structural similarity with guanidines and as they
can form water soluble salts.2 Amidines/2-oxo-
acetamidines constitute the core functional group of
diverse drugs and pharmaceutical which is reviewed in
the book series “Progress in Medicinal Chemistry”.3 A
few of such amidine bearing drugs are shown in figure 1
(I, II, III, IV). Compounds containing N-arylamidines
also serves as active molecule in the treatment of
inflammation and pain.4
Considering the importance of amidines/2-oxo-
acetamidines and α-amino ketones, lot of efforts has
been diverted towards the development of method for
the preparation of these compounds. The synthesis of
amidines, particularly 2-oxo-acetamidines usually
involves the construction of a carbon-nitrogen double
bond and a carbon-nitrogen single bond whereas the
synthesis of α-amino ketones involves the construction
of a carbon-nitrogen single bond. In the present times,
significant progress has been achieved in developing
Carbonyls bearing α-amino group are widely considered
among pharmaceutically active compounds and
bioactive molecules.5 α-Amino ketones also serve as
important precursors to numerous natural products and
pharmaceutically relevant compounds.6 Some bioactive
_____
Corresponding author. Tel. +91-376-2370121; Fax. +91-
376-2370011; e-mail: pulak_jyoti@yahoo.com

2
Tetrahedron
ACCEPTED MANUSCRIPT
various functionalization of C-H bonds adjacent to a
carbonyl group by utilizing different methodology.7 In
this regard, although, the formation of C-C bonds has
been reported largely, but the cleavage of a C(sp3)-H
bonds adjacent to the carbonyl group leading to C-N
bond formation has rarely been studied. The literature
survey revealed a number of reports for the preparation
of amidines/2-oxo-acetamidines from the reaction of
carbonyl compounds and amines under various catalytic
and reaction conditions all of which involved in a
carbon-nitrogen single as well as double bond formation
process. However, all these methods have some
limitations in terms of the reaction conditions, substrate
scope and the catalyst used. In 2012, Ning Jiao and his
group reported the synthesis of 2-oxo-acetamidines
utilizing aryl-acetaldehydes with primary amines in
presence of copper bromide as catalyst.8 But the reaction
α-amino-carbonyl compounds using copper catalyst.
Another method for the synthesis of 2-oxo-acetamidines
was reported by C. Hulme by utilizing aryl glyoxal with
amines and anilines in presence of CsCO3 as base.10
However, the reaction used only nitrogen bearing
heterocyclic compounds for N-1 addition and the
o
reaction was performed at 110 C. Recently, Jiannan
11
Xiang
reported the synthesis of 2-oxo-acetamidines
via a copper catalyzed oxidative cross coupling of
amines with α-amino carbonyl compounds. But, the
reaction required the use of excess base and took long
reaction time at 60 oC. Considering the importance of 2-
oxo-acetamidines and our continued work on the
synthesis of heterocyclic compounds of biological
importance,12 in the present paper, we report the
synthesis of some new 2-oxo-acetamidines 4 from aryl
methyl ketones 1, secondary amines 2 and aryl amines 3
using CuI as oxidant, which involved in a oxidation
process of C(sp3)-H bond followed by the formation of a
carbon-nitrogen double bond and a carbon-nitrogen
single bond (Scheme 1). During the reaction process,
small amount of α-amino ketones 5 also formed which
is also an important class of compounds.
Previous work:
1. Ning Jiao et.al.
O
R2
N
CuBr (5 mol%)
Pyridine (2 equiv)
R2
R1
O
+
H2N
R1
toluene (2.5 mL)
60oC, O2
NH
R2
R1=R2=aryl
2. Huang et.al.
O
Cu(OAc)2.H2O
Et3N
2. Results and discussion
O
H
N
HN
R1
R2
+
N
R1
R2
Synthesis of 2-oxo-acetamidines 4 and α-amino ketones 5
CH2Cl2, Air, r.t.
N
3. Christopher Hulme et.al.
O
R1NH2
N
Na2SO4,
R
R1
110 oC MW
R
COCHO
+
N
Cs2CO3,
air (DCE)
N
H
O
4. Jiannan Xiang et.al.
N
R1
R2
NHR3
or R1
O
R3
O
Cu(OAc)2.H2O
H2N
H
N
or
O
R2
N
R1
R2 +
or TBHP, DCE
60oC, N2, 12h
N
H
N
R1
R2
HN
The study was initiated by conducting the reaction of
acetophenone 1a (1mmol), morpholine 2a (3 mmol) and
aniline 3a (1 mmol) in the presence of CuI as catalyst
using toluene as solvent at 50 oC under oxygen
atmosphere (Scheme 2). In fact, CuI was utilized earlier
for oxidation of C(Sp3)H bond in a method of
preparation of α-ketoamides from the reaction of aryl
methyl ketones and secondary amines in presence of an
oxygen atmosphere.13 It was expected that utilization of
anilines with aryl methyl ketones and secondary amines
in the presence of CuI as catalyst in a similar reaction
protocol will produce predominantly our desired 2-oxo-
acetamidines derivative 4a. But, after the completion of
N
R3
Our work:
H
N
O
Ar/
N
O
O
CuI
N
+
Ar
2
Ar
Ar
Air,r.t
+
N
O
Ar/ NH2
1
3
4 (70-82%)
5 (10-13%)
Scheme 1
has the limitation of substrate scope as they used only
aryl acetaldehydes and aromatic amines in the reaction
process. Moreover, the reaction required the use of two
equivalents of pyridine and took long reaction time. In
2016, G-H. Huang and his group9 described the
synthesis of 2-oxo-acetamidines via α-amination of

Tetrahedron
3
ACCEPTED MANUSCRIPT
the reaction, as checked by TLC and further analyzed
Table 2: Scope of the product 4 with respect to 1 and 3
with the help of column chromatography, we found that
the reaction produced the desired compound 4a only in
28 % yield and the α-amino ketone 5a in 62% yield
(Table 1, Entry 1). Then we optimized the temperature
of the reaction by performing the reaction at various
temperatures. It was very interesting to note that the
yield of the product 4a increases with the decrease of
the undesired compound 5a with the lowering of
reaction temperature, and 25 oC is found to be sufficient
O
O
Cl
N
N
N
O
N
O
O
4a (75%, 6h)
4b (77%, 6 h)
N
O
I
N
N
N
F
O
O
4d (76%, 7 h)
O
4c (74%, 7 h)
O
N
O
N
NO2
N
O
Table 1: Optimisation of temperature, catalyst and
Amines 2a & 3a
N
O
4e (78%, 7 h)
O
4f (72%, 8.5 h)
Ent. Comp. 2a
Comp.
3a
T
Cat. Yd.4a Yd. 5a
(%)
oC
mol%
(%)
O
N
N
N
1a 3 mmol 1 mmol 50 20 28
2a 3 mmol 1 mmol 40 20 30
3a 3 mmol 1 mmol 25 20 33
4 a 2 mmol 1 mmol 25 20 35
5 a 1.5 mmol 1 mmol 25 20 74
6a 1 mmol 1 mmol 25 20 60
7a 1.5 mmol 1 mmol 25 15 75
8b 1.5 mmol 1 mmol 25 15 75
9b 1.5 mmol 1 mmol 25 10 75
10a 1.5 mmol 1 mmol 70 10 25
11 a 1.5 mmol 1 mmol 20 10 60
62
N
Br
50
42
40
17
14
13
13
12
65
20
O
O
4g (73%, 6.5 h)
4h (82%, 6 h)
O
O
N
N
N
N
Br
Cl
4i (80%, 6.5 h)
O
O
4j (80%, 6 h)
O
O
N
N
N
N
O
MeO
O
4k (74%, 8 h)
4l (73%, 8 h)
O
N
O
b
a
N
Ent = Entry
;
= oxygen ballon
;
=
air;
Comp. = Compound;
N
O
T = Temperature; Cat. = Catalyst; Yd. = Yield.
N
O2N
MeO
4m (72%, 9 h)
to produce maximum yield of the product 4a (Table 1,
O
4n (81%, 6.5 h)
Entry 7). On the other hand increase in the reaction
temperature above 50 C decreases the yield of the
O
O
N
o
N
N
N
desired compound 4a (Table 1, Entry 10), and lowering
F
F
o
the temperature to 20 C lowers the yield of both the
4p (76%, 7.5 h) O
OH
O
4o (79%, 6.5 h)
O
compound 4a & 5a (Table 1, Entry 11). Hence, all other
O
N
reactions were carried out at 25 oC. It was also observed
N
N
O
o
NC
N
O
that when the reaction was carried out at 25 C
O
additional oxygen is not required and atmospheric
oxygen is sufficient to produce the product in maximum
yield (Table 1, Entry 8). To explore the utility of oxygen
in the reaction, we also performed the reaction in an
inert atmosphere. But, as expected, it did not proceed to
afford our desired product. Then we optimized the load
of the catalyst, and 10 mol% of CuI was found to be
sufficient for the reaction process at optimized reaction
temperature (Table 1, Entry 9). The reaction was also
studied taking different molar ratio of morpholine 2a
and aniline 3a. Equimolar amounts of both morpholine
2a and aniline 3a produced only 60% of the desired
compound 4a and 14% of the compound 5a (Table 1,
Entry 6). With the increase in the amount of morpholine
with respect to aniline, the
4v (74%, 7 h)
N
4u (73%, 7 h)
N
O
4w (70%, 8 h)
Table 3: Scope of the product 4 with respect to 2

4
Tetrahedron
ACCEPTED MANUSCRIPT
yield of the desired product 4a also increases. Finally,
1.5 equivalent of morpholine and 1.0 equivalent of
aniline were found to be the best for the formation of the
desired product 4a in high yield (Table 1, Entry 5 & 9).
with the application aliphatic primary amine in place of
aniline as it produced only a small amount of the
compound 5 only which was not desirable.
In general, we observed that irrespective of the
substitution pattern on the substrate 1, 2 and 3 all the
reactions afforded satisfactory yield of the products.
However, the reactions were smooth and products were
obtained in higher yield in case of the aryl methyl
ketones possessing electron withdrawing group at the
aromatic ring.
After optimization of the reaction conditions 1.0
equivalent of acetophenone 1a, 1.5 equivalent of
morpholine 2a and 1.0 equivalent of aniline 3a were
treated in the presence of CuI (10 mol%) as catalyst
o
using toluene as solvent at room temperature (25 C)
under stirring conditions. Progress of the reaction was
monitored by thin layer chromatographic study. After
completion of the reaction, the compounds formed were
separated and purified with the help of column
chromatography. The spectroscopic and analytical data
confirmed the formation of 2-oxo-acetamide 4a and
ketoamide 5a in 75% and 12% isolated yield
respectively. The generality of the reaction was
established by synthesizing the compounds 4a-w and
5a-w by using various substituted acetophenones 1,
secondary amine 2 and anilines 3 (Table 2, 3 and 4) and
characterizing them. The reaction was not satisfactory
Mechanism for the formation of 4 and 5
O
H
N
+
O
2a
1a
-H2O
CuI + O2
O
N
O
N
CuII + O2
-.
O
H
O
H
B
A
CuI
O
Table 4: Formation of compound 5
H
N
N
O
O
O
O
O
O
H
N
N
H
O
O
N
O
O
Path a
Br
5a (12%), 5b-g=10-13%
5h (11%), 5i=10%
O
C
H2O
O
O
O
O
NH2
O
N
N
OH
H+
O
Me
O
OH
O
5k (13%)
Cl
5j (10%)
3a
path b
O
O
O
O
N
N
N
H
O
O
O
NH
O
O
N
O2N
H
MeO
5n (10%)
N
O
5l (10%), 5m=11%
OH
O
N
O
G
O
CuI/O2
O
D
N
H2O
O
O
O
F
H
5q (10%)
5o (10 %), 5p=12%
N
O
O
N
NH
O
O
N
N
5a
O
E
O
O
5r (12%)
5s (10%)
O
O=O
(Air)
OH
O
O
O
O
N
N
O
N
NH
O
N
O
5t (10%)
O
5u (12%)
O
N
O
H
O
O
H2O2
O
4a
F
N
O
Scheme 3
N
On the basis of above results and previous studies,13,14
we proposed the probable mechanistic pathway for the
O
O
NC
5v (13%)
5w (11%)

Tetrahedron
5
ACCEPTED MANUSCRIPT
formation of 4a and 5a as shown in scheme 3. Initially,
4. Experimental
an enamine A was generated from acetophenone 1a and
morpholine 2a. This enamine interacted with the
superoxide radical (O2 ) and Cu (II) which was formed
General information: All chemicals were purchased
from Merck and Aldrich chemical companies. The
reagents and solvents were used without drying. The IR
spectra were recorded on Perkin Elmer system 2000
.-
through the aerial oxidation of CuI in the presence of
morpholine, to produce aminodioxetane B. Then, B
underwent ring opening and gave the phenylglyoxal.
The formation of phenylglyoxal was detected in TLC
study of the reaction mixture during the reaction
process. This in situ generated phenyl glyoxal reacted
with morpholine to form the intermediate 2-oxo
iminium ion C. It was followed by the reaction with
aniline 3a that produced the intermediate D and then E
which on interaction with air formed the intermediate F.
Finally, this intermediate F underwent intramolecular
rearrangement and afforded the required product 4a by
losing one molecule of hydrogen peroxide (path a). On
the other hand the addition of morpholine reacted with
phenylglyoxal also to form hemiaminal intermediate G
(path b) which on oxidation by air and copper iodide
resulted the formation of side product 5a. From the
effect of temperature in the reaction process it could be
concluded that higher temperature favored the path b
and hence the formation of compound 5. On the other
1
FTIR spectrometer. H NMR and 13C NMR Spectra
were recorded on Bruker AV500 Avance–III 500 MHz
and 125 MHz FT NMR in CDCl3 using TMS as an
internal standard. NMR chemical shifts were measured
relative to the signals of residual CDCl3 at δH 7.26 ppm,
δC 76.65-77.16 ppm and δH 1.5 ppm (water
contamination). Mass spectra were recorded in Waters
Xevo G2-XS QT of mass spectrometer. Analytical thin
layer chromatography (TLC) was performed using E-
Merck aluminium-backed silica gel plates coated with
0.2 mm thickness of silica gel. Melting points
(uncorrected) were determined in open capillary tubes
on a Buchi B-540 apparatus.
General procedure for the synthesis of 4 and 5:
Aryl methyl ketone
g, 1 mmol), secondary amine
1.5 mmol), aryl amine (Aniline, 0.093 g, 1 mmol)
1
(Methyl phenyl ketone, 0.120
2
(Morpholine, 0.131g
3
and CuI (10 mol %) were taken in a 25 mL round
bottomed flask. To this added 2 mL of toluene and
o
hand, room temperature (25 C) is sufficient for the
o
the reaction mixture was stirred at 25 C until the
formation of arylglyoxal and to produce the desired
product 4 through path a. In case of aliphatic primary
amines the localized lone pair of electrons of the
secondary amine of the intermediate type E might have
disfavored the oxidation step, and hence the product 4
was not formed. We also studied the reaction using
arylglyoxal in place of acetophenone in a similar
reaction condition and observed the formation of the
products 4 and 5 as expected which further supported
the proposed mechanism.
completion of the reaction (as confirmed by TLC).
Then, the reaction mixture was concentrated under
reduced pressure to give a crude product which was
purified by column chromatography (silica gel 100-
200#, hexane/ EtOAc, 9:1) to yield the compounds
4a and 5a. Similarly, compounds 4a-w and 5a-w
were synthesized by using various substituted
acetophenones
1, secondary amine 2 and anilines 3
and characterized.
4a. (Z)-2-morpholino-1-phenyl-2-(phenylimino)etha-
3. Conclusion
none: Yield: 220 mg, 75%; Yellow solid, m.p. 131.9-
1
133.8 °C; Rf = 0.21 (EtOAc/Hexane = 2:8); H NMR
In conclusion, we have developed a new synthetic
method for the preparation of 2-oxo-acetamidines from
one-pot three-component reactions of acetophenones,
secondary amines and anilines in the presence of CuI as
catalyst and air as oxidizing agent. The reaction
occurred via oxidation of C(sp3)-H bonds of aryl methyl
ketones followed by double amination process. The
reaction protocol involved a simple and cheap catalyst,
readily available starting materials and mild reaction
conditions that gave a new and highly attractive
approach towards acetamidines. The small amount of α-
amino ketones which were formed during the reaction
process is also an important class of compounds.
(500 MHz, CDCl3) δ 7.81 (dt, J = 8.4, 1.5 Hz, 2H), 7.56
– 7.51 (m, 1H), 7.43 – 7.37 (m, 2H), 7.04 – 6.98 (m,2H),
6.78 (tt, J = 7.6, 1.2 Hz, 1H), 6.73 – 6.68 (m, 2H), 3.76
(s, 4H), 3.53 (s, 4H); 13C NMR (126 MHz, CDCl3) δ
193.98, 156.00, 148.02, 134.51, 134.33, 129.11, 128.80,
128.30, 122.44, 122.11, 66.48; IR (cm-1): 3586, 2920,
2854, 1775, 1606, 1597, 1497, 503; HRMS (M+H)+
calcd for C18H18N2O2= 295.1447, found = 295.1448.
4b. (Z)-2-((2-chlorophenyl)imino)-2-morpholino-1-
phenylethanone: Yield: 252 mg, 77%; Yellow solid,
m.p. 121.6-122.6 °C; Rf = 0.41 (EtOAc/Hexane = 2:8);
1H NMR (500 MHz, CDCl3) δ 7.88 – 7.83 (m, 2H), 7.55

6
Tetrahedron
ACCEPTED MANUSCRIPT
(ddd, J = 8.7, 2.5, 1.3 Hz, 1H), 7.45 – 7.38 (m, 2H), 7.11
194.68, 156.35, 155.07, 141.14, 134.26, 133.77, 129.10,
128.83, 122.94, 113.64, 66.48, 55.12; IR (cm-1): 3415,
2924, 2085, 1689, 1643, 1179, 763; HRMS (M+H)+
calcd for C19H20N2O3= 325.1552, found = 325.1554.
(dd, J = 7.9, 1.4 Hz, 1H), 6.92 (td, J = 7.7, 1.4 Hz, 1H),
13
6.76 – 6.65 (m, 2H), 3.78 (s, 8H); C NMR (126 MHz,
CDCl3) δ 193.12, 155.93, 144.87, 134.76, 133.75,
129.18, 129.01, 128.79, 126.96, 126.66, 123.39, 123.31,
66.51; IR (cm-1): 3414, 2922, 2851, 2100, 1679, 1600,
4g.
(Z)-2-morpholino-1-phenyl-2-(p-tolylimino)-
ethanone: Yield: 224.2 mg, 73%; Yellow solid; m.p.
769;
329.1057, found = 329.1055.
HRMS (M+H)+ calcd for C18H17ClN2O2=
1
124-126 °C °C; Rf = 0.55 (EtOAc/Hexane= 2:8); H
NMR (500 MHz, CDCl3) δ 7.85 – 7.80 (m, 2H), 7.54 (t,
J = 7.3 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 6.81 (d, J = 8.3
Hz, 2H), 6.60 (d, J = 8.2 Hz, 2H), 3.75 (s, 4H), 3.52 (s,
4H), 2.12 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
194.29, 156.03, 145.23, 134.49, 134.33, 131.73, 129.14,
128.95, 128.81, 121.88, 66.48, 20.56; IR (cm-1): 3429,
2966, 2854, 2098, 1682, 1450, 1211, 1177; HRMS
(M+H)+ calcd for C19H20N2O2= 309.1603, found =
309.1606
4c.
(Z)-2-((2-iodophenyl)imino)-2-morpholino-1-
phenylethanone: Yield: 310 mg, 74%; Yellow solid;
m.p. 106.8-108.9 °C; Rf = 0.54 (EtOAc/Hexane = 2:8);
1H NMR (500 MHz, CDCl3) δ 7.91 – 7.85 (m, 2H), 7.60
– 7.52 (m, 2H), 7.43 – 7.39 (m, 2H), 7.02 – 6.98 (m,
1H), 6.67 (dd, J = 7.9, 1.5 Hz, 1H), 6.52 – 6.47 (m, 1H),
3.80 (s, 8H); 13C NMR (126 MHz, CDCl3) δ 193.21,
155.33, 148.28, 138.32, 134.79, 133.77, 129.13, 128.82,
128.39, 123.93, 121.48, 95.29, 66.64; IR (cm-1): 3412,
2920, 2853, 2101, 1678, 1609, 505; HRMS (M+H)+
calcd for C18H17N2O2I= 421.0413, found = 421.0416.
4h.
(Z)-1-(4-bromophenyl)-2-morpholino-2-
(phenylimino)ethanone: Yield: 304.3 mg, 82%; yellow
solid, m.p. 139.2-141.4 °C.; Rf = 0.36 (EtOAc/Hexane=
2:8), 1H NMR (500 MHz, CDCl3) δ 7.70 – 7.63 (m, 2H),
7.59 – 7.50 (m, 2H), 7.08 – 6.99 (m, 2H), 6.81 (dd, J =
10.6, 4.2 Hz, 1H), 6.68 (dd, J = 8.4, 1.1 Hz, 2H), 3.76 (s,
4H), 3.52 (s, 4H).13C NMR (126 MHz, CDCl3) δ 193.08,
155.50, 147.76, 133.00, 132.26, 130.44, 130.08, 128.44,
122.65, 122.02, 66.45; IR (cm-1): 3340, 2949, 2922,
1679, 1609, 1266, 1116, 751; HRMS (M+H) + calcd for
C18H17BrN2O2= 373.0552, found = 373.0554
4d.
(Z)-2-((4-fluorophenyl)imino)-2-morpholino-1-
phenylethanone: Yield: 236.5 mg, 76%; Yellow solid,
1
m.p. 136-137 °C ; Rf = 0.18 (EtOAc/Hexane = 2:8); H
NMR (500 MHz, CDCl3) δ 7.86 – 7.77 (m, 2H), 7.56
(dd, J = 10.6, 4.3 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 6.78
– 6.62 (m, 4H), 3.77 (s, 4H), 3.54 (s, 4H); 13C NMR
(126 MHz, CDCl3) δ 193.98, 157.69, 156.52, 144.11,
134.71, 134.16, 129.07, 128.92, 123.24, 123.17, 115.03,
114.85, 66.46; IR (cm-1): 3419, 2922, 2850, 1680, 1610,
1451, 1219, 510; HRMS (M+H)+ calcd for
C18H17N2O2F= 313.1352, found = 313.1356
4i.
(Z)-1-(4-bromophenyl)-2-morpholino-2-(p-
tolylimino)ethanone: Yield: 307.8 mg, 80%; Yellow
solid, m.p. 130.2-131.9 °C; Rf = 0.32 (EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.70 – 7.64 (m, 2H),
7.57 – 7.52 (m, 2H), 6.83 (d, J = 8.0 Hz, 2H), 6.61 –
6.56 (m, 2H), 3.75 (s, 4H), 3.49 (s, 4H), 2.14 (s, J = 6.6
Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 193.43, 155.52,
145.04, 133.01, 132.26, 131.95, 130.48, 130.02, 129.08,
121.79, 66.45, 20.58; IR (cm-1): 3398, 2950, 2854,
1680, 1609, 1213, 1116, 505; HRMS (M+H) + calcd for
C19H19N2O2Br= 387.0708, found = 387.0706
4e.
(Z)-2-morpholino-2-((3-nitrophenyl)imino)-1-
phenylethanone: Yield: 264.1mg, 78%; Yellow solid;
m.p. 113.4-114.8°C; Rf = 0.42 (EtOAc/Hexane = 2:8);
1H NMR (500 MHz, CDCl3) δ 7.80 (dd, J = 8.4, 1.2 Hz,
2H), 7.64 (ddd, J = 8.1, 2.2, 0.9 Hz, 1H), 7.60 – 7.53 (m,
2H), 7.44 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 8.1 Hz, 1H),
7.01 (ddd, J = 7.9, 2.1, 1.0 Hz, 1H), 3.81 (s, 4H), 3.32
13
(s, 4H); C NMR (126 MHz, CDCl3) δ 192.69, 156.59,
149.66, 148.12, 135.14, 133.87, 129.17, 129.04, 128.96,
128.38, 117.17, 66.42; IR (cm-1): 3425, 2354, 2100,
1678, 1455, 1116, 769, 521; HRMS (M+H)+ calcd for
C18H17N3O4= 340.1297, found = 340.1299.
4j.
(phenylimino)ethanone: Yield: 262.5 mg, 80%;
Yellow solid, m.p. 145-146.3 °C; Rf 0.24
(Z)-1-(4-chlorophenyl)-2-morpholino-2-
=
1
(EtOAc/Hexane= 2:8); H NMR (500 MHz, CDCl3) δ
7.77 – 7.71 (m, 2H), 7.40 – 7.34 (m, 2H), 7.06 – 7.00
(m, 2H), 6.84 – 6.77 (m, 1H), 6.73 – 6.66 (m, 2H), 3.76
(s, 4H), 3.52 (s,4H);13C NMR (126 MHz, CDCl3) δ
192.84, 155.56, 147.79, 141.14, 132.62, 130.42, 129.27,
128.43, 122.63, 122.02, 66.45; IR (cm-1): 3412, 2923,
2855, 2108, 1663, 1598, 984; HRMS (M+H) + calcd for
C18H17N2O2Cl= 329.1057, found = 329.1055
4f. (Z)-2-((3-methoxyphenyl)imino)-2-morpholino-1-
phenylethanone: Yield: 232 mg, 72%; Yellow solid;
1
m.p. 87-88°C; Rf = 0.61 (EtOAc/Hexane = 2:8); H
NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 8.3, 1.2 Hz,
2H), 7.56 – 7.52 (m, 1H), 7.41 (t, J = 7.8 Hz, 2H), 6.68
– 6.62 (m, 2H), 6.60 – 6.55 (m, 2H), 3.76 (s, 4H), 3.64
(s, 3H), 3.49 (s, 4H); 13C NMR (126 MHz, CDCl3) δ

Tetrahedron
7
ACCEPTED MANUSCRIPT
(Z)-2-morpholino-2-(phenylimino)-1-(p-
4k.
= 8.6, 5.4 Hz, 2H), 7.04 (dt, J = 15.6, 8.1 Hz, 4H), 6.79
(t, J = 7.3 Hz, 1H), 6.69 (d, J = 7.6 Hz, 2H), 3.77 (s,
4H), 3.53 (s, 4H); 13C NMR (126 MHz, CDCl3) δ
192.32, 167.39, 165.34, 155.72, 147.90, 131.97, 131.89,
130.85, 128.39, 122.57, 122.02, 116.27, 116.09, 66.47;
IR (cm-1): 3361, 2921, 2853, 1675, 1598, 983, 615;
tolyl)ethanone: Yield: 227.2 mg, 74%; yellow solid,
m.p. 114.6-116.8 °C.; Rf = 0.35(EtOAc/Hexane= 2:8),
1H NMR (500 MHz, CDCl3) δ 7.74 – 7.67 (m, 2H), 7.23
– 7.16 (m, 2H), 7.05 – 6.98 (m, 2H), 6.78 (tt, J = 7.6, 1.1
Hz, 1H), 6.74 – 6.68 (m, 2H), 3.76 (s, 4H), 3.53 (s, 4H),
13
+
2.36 (s, 3H); C NMR (126 MHz, CDCl3) δ 193.47,
HRMS (M+H) calcd for C18H17N2O2F= 313.1352,
156.15, 148.16, 145.79, 131.97, 129.57, 129.29, 128.29,
found = 313.1353
122.36, 122.11,66.49, 21.74; IR (cm-1): 3006, 2944,
4p.
(Z)-1-(4-fluorophenyl)-2-morpholino-2-(p-
+
2883, 1773, 1663, 1598, 1226, 755; HRMS (M+H)
tolylimino)ethanone: Yield: 247 mg, 76%; Yellow
calcd for C19H20N2O2= 309.1603, found = 309.1605
solid; m.p.1112.5-113.8°C; Rf = 0.24 (EtOAc/Hexane=
1
4l.
(Z)-1-(4-methoxyphenyl)-2-morpholino-2-
2:8); H NMR (500 MHz, CDCl3) δ 7.84 (ddd, J = 8.2,
(phenylimino)ethanone: Yield: 236 mg, 73%; Yellow
solid; m.p. 109.4-111.7 °C; Rf = 0.38 (EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.81 (dd, J = 8.3,
1.2 Hz,2H), 7.56 – 7.52 (m, 1H), 7.41 (t, J = 7.8 Hz,
2H), 6.67 – 6.62 (m, 2H), 6.59 – 6.55 (m, 2H), 3.76 (s,
4H), 3.64 (s, 3H), 3.49 (s, 4H); 13C NMR (126 MHz,
CDCl3) δ 192.13, 164.57, 156.28, 148.28, 131.69,
128.30, 127.52, 122.34, 122.07, 114.11, 66.51, 55.45;
5.1, 2.5 Hz, 2H), 7.10 – 7.04 (m, 2H), 6.82 (d, J = 8.0
Hz, 2H), 6.61 – 6.57 (m, 2H), 3.76 (s, 4H), 3.51 (s, 4H),
2.13 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 192.69,
167.38, 165.33, 155.74, 145.18, 131.99, 131.91, 131.86,
130.86, 130.84, 129.03, 121.78, 116.27, 116.09, 66.47,
20.57; IR (cm-1): 3427, 2933, 2851, 2099, 1681, 1448,
+
1215, 965; HRMS (M+H) calcd for C19H19N2O2F=
327.1509, found = 327.1505
IR (cm-1): 3412, 2921, 2087, 1776, 1648, 1188, 765;
4q.
(Z)-1-phenyl-2-(phenylimino)-2-(pyrrolidin-1-
+
HRMS (M+H)
calcd for C19H20N2O3= 325.1552,
yl)ethanone: Yield: 191.2 mg, 69%; Yellow solid; m.p.
found = 325.1556.
1
179.1-180.2°C; Rf = 0.27(EtOAc/Hexane= 2:8); H
4m.
(Z)-1-(4-methoxyphenyl)-2-morpholino-2-(p-
NMR (500 MHz, CDCl3) δ 7.81 (d, J = 7.6 Hz, 2H),
7.51 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.7 Hz, 2H), 7.00 (t,
J = 7.7 Hz, 2H), 6.81 – 6.70 (m, 3H), 3.70 (s, 2H), 3.32
(s, 2H), 1.96 (d, J = 23.7 Hz, 4H); 13C NMR (126 MHz,
CDCl3) δ 194.44, 154.61,148.81, 134.23, 133.86,
129.29, 128.71, 128.20, 122.72, 122.04, 46.78; IR (cm-
1): 3422, 2923, 2354, 2100, 1645, 1515, 754, 662;
HRMS (M+H) + calcd for C18H18N2O= 279.1497, found
= 279.1494
tolylimino)ethanone: Yield: 236 mg, 70%; Yellow
solid; m.p.108.9-109.6°C; Rf = 0.39(EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.83 – 7.77 (m, 2H),
6.91 – 6.80 (m, 4H), 6.62 (d, J = 7.2 Hz, 2H), 3.84 (s,
13
3H), 3.75 (s, 4H), 3.52 (s, 4H), 2.13 (s, 3H); C NMR
(126 MHz, CDCl3) δ 192.49, 164.53, 156.29, 145.57,
131.69, 131.55, 128.95, 127.58, 121.81, 114.10, 66.51,
55.45, 20.5; IR (cm-1): 3411, 2921, 2086, 1775, 1649,
1191, 503; HRMS (M+H) calcd for C20H22N2O3=
339.1709, found = 339.1708
+
4r.
(Z)-1-phenyl-2-(phenylimino)-2-(piperidin-1-
yl)ethanone: Yield: 213 mg, 73%; Yellow solid; m.p.
1
4n.
(Z)-2-morpholino-1-(4-nitrophenyl)-2-
129.6-132.0°C; Rf = 0.35(EtOAc/Hexane= 2:8); H
(phenylimino)ethanone: Yield: 274 mg, 81%; Yellow
solid; m.p.138.0-139.0.6°C; Rf = 0.15 (EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 8.25 – 8.19 (m, 2H),
7.96 – 7.89 (m, 2H), 7.05 – 6.97 (m, 2H), 6.83 – 6.76
(m, 1H), 6.70 – 6.63 (m, 2H), 3.78 (s,4H), 3.53 (s, 4H);
13C NMR (126 MHz, CDCl3) δ 192.91, 154.99, 150.73,
147.31, 138.33, 129.94, 128.57, 124.02, 122.95, 122.02,
66.42. IR (cm-1): 3420, 2354, 2098, 1643, 1515, 1455,
1116, 770; HRMS (M+H)+ calcd for C18H17N3O4=
340.1297, found = 340.1295
NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 8.3, 1.1 Hz,
2H), 7.57 – 7.51 (m, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.01
(dd, J = 11.7, 4.1 Hz, 2H), 6.77 (td, J = 7.4, 1.0 Hz, 1H),
6.74 – 6.68 (m, 2H), 3.49 (s, 4H), 1.71 (s, 6H); 13C
NMR (126 MHz, CDCl3) δ 194.42, 155.95, 148.54,
134.59, 134.24, 129.11, 128.68, 128.19, 122.42, 121.99,
24.53; IR (cm-1): 3424, 2933, 2852, 2098, 1671, 1599,
+
1276, 973; HRMS (M+H)
calcd for C19H20N2O=
293.1654, found = 293.1656
4s.
(Z)-N,N-diethyl-2-oxo-N',2-diphenylacetimid-
4o.
(Z)-1-(4-fluorophenyl)-2-morpholino-2-
amide: Yield: 181.8 mg, 65%; Yellow solid; m.p. 88.0-
89.8°C; Rf = 0.63(EtOAc/Hexane= 2:8); H NMR (500
MHz, CDCl3) δ 7.78 (d, J = 7.1 Hz, 2H), 7.54 – 7.48 (m,
1H), 7.38 (t, J = 7.8 Hz, 2H), 7.00 – 6.95 (m, 2H), 6.71
1
(phenylimino)ethanone: Yield: 246.1 mg, 79 %;
Yellow solid; m.p.133.8-136.2°C; Rf = 0.21(EtOAc/
Hexane= 2:8); 1H NMR (500 MHz, CDCl3) δ 7.83 (dd, J

8
Tetrahedron
ACCEPTED MANUSCRIPT
(ddd, J = 11.5, 9.5, 4.2 Hz, 3H), 3.64 (d, J = 85.9 Hz,
2H), 3.15 (s, 2H), 1.36 (s, 3H), 1.11 (s, 3H); C NMR
(s, 4H), 3.46 (s, 4H), 2.44
(s,1H), 1.77 (s, 4H), 1.68
13
(d, J = 12.5 Hz, 1H), 1.30 (t, J = 9.9 Hz, 4H), 1.22 –
1.14 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 193.49,
156.19, 155.47, 148.16, 132.21, 129.38, 128.28, 127.35,
122.33, 122.13, 66.50, 44.66, 33.77, 26.50, 25.84; IR
(126 MHz, CDCl3) δ 193.98, 155.33, 148.78, 134.55,
134.11, 129.16, 128.60, 128.46, 128.11, 122.56, 121.78,
77.16, 76.90, 76.65, 29.59; IR (cm-1): 3431, 2094, 1648,
1632, 1224, 766; HRMS (M+H) + calcd for C18H20N2O=
281.1654, found = 281.1652
(cm-1): 3484, 2918, 2852, 1650, 1623, 1596, 1470;
+
HRMS (M+H)
calcd for C24H28N2O2= 377.2229,
found = 377.2226
4t. (Z)-2-(3,4-dihydroisoquinolin-2(1H)-yl)-1-phenyl-
2-(phenylimino)ethanone: Yield: 227 mg, 67%;
Yellow solid; m.p. 130.0-131.6°C; Rf = 0.45(EtOAc/
5a. 1-morpholino-2-phenylethane-1,2-dione: Yield:
26 mg, 12%; Yellow oil; Rf = 0.24 (EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.97 (dt, J = 8.5,
1.4 Hz, 1H), 7.67 (tdd, J = 7.1, 4.2, 2.9 Hz, 1H), 7.56 –
7.51 (m, 1H), 7.27 (s, 1H), 3.85 – 3.77 (m, 2H), 3.70 –
3.63 (m, 1H), 3.42 – 3.36 (m, 1H); 13C NMR (126 MHz,
CDCl3) δ 191.06, 165.35, 134.87, 132.91, 129.69,
129.57, 129.01, 66.63, 66.56, 46.15, 41.51; IR (cm-1):
3336, 2971, 2920, 2855, 1681, 1644, 11595, 1114;
HRMS (M+H) + calcd for C12H13NO3= 220.0974, found
= 220.0972.
1
Hexane= 2:8); H NMR (500 MHz, CDCl3) δ 7.82 (d, J
= 6.9 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.38 (t, J = 7.4
Hz, 2H), 7.24 – 7.12 (m, 4H), 7.01 (t, J = 7.7 Hz, 2H),
6.81 – 6.70 (m, 3H), 4.88 (s, 2H), 3.55 (s, 2H), 2.92 (s,
2H); 13C NMR (126 MHz, CDCl3) δ 194.04, 155.83,
148.30, 134.45, 132.82, 129.18, 128.79, 128.63, 128.27,
126.40, 122.37, 122.28; IR (cm-1): 3583, 3411, 2920,
+
2851, 1647, 1019, 503; HRMS (M+H) calcd for
C23H20N2O= 341.1654, found = 341.1656
4u.
(Z)-1-(2-hydroxyphenyl)-2-morpholino-2-
5h.
1-(4-bromophenyl)-2-morpholinoethane-1,2-
(phenylimino)ethanone: Yield: 226 mg, 73%; Yellow
dione: Yield: 32 mg, 11 %; Light Yellow solid; m.p.
126.0-126.5 °C; Rf = 0.12 (EtOAc/Hexane= 2:8); H
1
solid, m.p. 127.4-128.4°C; Rf = 0.60(EtOAc/Hexane=
1
2:8); H NMR (500 MHz, CDCl3) δ 11.30 (s, 1H), 7.61
NMR (500 MHz, CDCl3) δ 7.85 – 7.81 (m, 2H), 7.70 –
7.66 (m, 2H), 3.83 – 3.77 (m, 4H), 3.68 – 3.65 (m, 2H),
3.39 (dd, J = 6.1, 3.5 Hz, 2H); 13C NMR (126 MHz,
CDCl3) δ 189.82, 164.76, 132.41, 131.79, 131.56,
130.97, 130.45, 66.64, 66.55, 46.18, 41.60; IR (cm-1):
2970, 2921, 2856, 1680, 1644, 1596, 1114, 665; HRMS
(dd, J = 8.0, 1.6 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.05 (t, J
= 7.9 Hz, 2H), 6.92 – 6.81 (m, 3H), 6.72 (d, J = 7.4 Hz,
2H), 3.78 (s, 4H), 3.55 (s, 4H); 13C NMR (126 MHz,
CDCl3) δ 198.87, 162.36, 153.96, 147.74, 137.79,
132.04, 128.43, 122.72, 121.86, 119.59, 118.26, 118.10,
66.43; IR (cm-1): 3416, 2917, 2856, 1678, 1597, 1450,
+
(M+H) calcd for C12H12 Br NO3= 298.0079, found =
+
1220, 941; HRMS (M+H) calcd for C18H18N2O3=
298.0078.
311.1396, found = 311.1391.
5j. 1-(4-chlorophenyl)-2-morpholinoethane-1,2-dione
: Yield: 25.4 mg, 10 %; Yellow solid; m.p. 115.6.0-
116.4 °C; Rf = 0.30 (EtOAc/Hexane= 2:8); 1H NMR
(500 MHz, CDCl3) δ 7.94 – 7.90 (m, 2H), 7.52 – 7.49
(m, 2H), 3.82 – 3.77 (m, 4H), 3.68 – 3.65 (m, 2H), 3.40
4v.
(Z)-4-(2-morpholino-2-(phenylimino)acetyl)-
benzonitrile: Yield: 236 mg, 74%; Yellow solid; m.p.
103.5-109.5°C; Rf = 0.42(EtOAc/Hexane= 2:8); H
1
NMR (500 MHz, CDCl3) δ 7.89 – 7.83 (m, 2H), 7.70 –
7.66 (m, 2H), 7.01 (td, J = 7.5, 1.9 Hz, 2H), 6.82 – 6.77
(m, 1H), 6.65 (dd, J = 8.4, 1.1 Hz, 2H), 3.77 (s, 4H),
3.51 (s, 4H); 13C NMR (126 MHz, CDCl3) δ 193.08,
155.01, 147.36, 136.97, 132.61, 129.23, 128.54, 122.90,
122.01, 117.45, 117.42, 66.42; IR (cm-1): 3058, 2968,
13
– 3.37 (m, 2H); C NMR (126 MHz, CDCl3) δ 189.60,
164.80, 141.54, 131.33, 130.94, 129.41, 66.64, 66.54,
46.18, 41.60; IR (cm-1): 2918, 2850, 1674, 1628, 1587,
+
1466, 1216, 765; HRMS (M+H) calcd for C12H12 Cl
NO3= 254.0584, found = 254.0587.
2919, 2855, 2231, 1683, 1607, 1590, 1438,1267, 983;
5k. 1-morpholino-2-(p-tolyl)ethane-1,2-dione: Yield:
30.3 mg, 13 %; Colorless solid; m.p. 80.5-81.2°C; Rf =
0.27 (EtOAc/Hexane= 2:8); 1H NMR (500 MHz,
CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.0 Hz,
2H), 3.80 (d, J = 1.6 Hz, 4H), 3.67 – 3.63 (m, 2H), 3.37
+
.HRMS (M+H)
calcd for C19H17N3O2= 320.1399,
found = 320.1397
4w.
(Z)-1-(4-cyclohexylphenyl)-2-morpholino-2-
(phenylimino)ethanone: Yield: 263 mg, 70%; Yellow
solid; m.p. 133.2-136.1°C; Rf = 0.54(EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 7.1 Hz,
2H), 7.15 (d, J = 7.4 Hz, 2H), 6.95 (t, J = 7.2 Hz, 2H),
6.71 (t, J = 6.9 Hz, 1H), 6.64 (d, J = 8.1 Hz, 2H), 3.69
13
(dd, J = 6.1, 3.6 Hz, 2H), 2.45 (s, 3H); C NMR (126
MHz, CDCl3) δ 190.82, 165.57, 146.25, 130.48, 130.06,
129.74, 129.69, 129.07, 66.64, 66.57, 46.15, 41.45,
21.84; IR (cm-1): 3332, 2968, 2922, 2857, 1715, 1676,

Tetrahedron
9
ACCEPTED MANUSCRIPT
1650, 1444, 757; HRMS (M+H) calcd for C13H15
+
7.59 (m, 1H), 7.51 (dd, J = 10.7, 4.8 Hz, 2H), 7.28 (s,
1H), 3.71 (s, J = 5.0 Hz, 2H), 3.29 (dd, J = 6.3, 4.8 Hz,
2H), 1.70 (dd, J = 5.7, 2.7 Hz, 4H), 1.54 (d, J = 4.6 Hz,
2H).13C NMR (126 MHz, CDCl3) δ 191.89, 165.33,
134.60, 133.07, 129.45, 128.91, 46.92, 42.02, 26.07,
25.32, 24.24; IR (cm-1): 2964, 2881, 1683, 1627, 1552;
HRMS (M+H) + calcd for C13H15 NO2= 218.1181, found
= 218.1185.
NO3= 234.1130, found = 234.1137.
5l.
1-(4-methoxyphenyl)-2-morpholinoethane-1,2-
dione: Yield: 23.2 mg, 10 %; Yellow solid; m.p. 112.9-
113.4°C; Rf = 0.24 (EtOAc/Hexane= 2:8);1H NMR (500
MHz, CDCl3) δ 7.93 (dd, J = 9.3, 2.4 Hz ,2H), 7.27 (s,
1H), 6.99 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H), 3.80 (t, J =
4.6 Hz, 4H), 3.68 – 3.63 (m, 2H), 3.41 – 3.37 (m,
2H).13C NMR (126 MHz, CDCl3) δ 189.73, 165.70,
164.92, 132.07, 125.99, 114.32, 66.68, 66.59, 55.59,
46.19, 41.44; IR (cm-1): 2970, 2919, 2855, 1638, 1599,
5s. N,N-diethyl-2-oxo-2-phenylacetamide: Yield: 21
mg, 10 %; Gummy ; Rf = 0.33 (EtOAc/Hexane= 2:8); 1H
NMR (500 MHz, CDCl3) δ 7.97 – 7.93 (m, 2H), 7.66 –
7.62 (m, 1H), 7.51 (dd, J = 10.7, 4.8 Hz, 2H), 7.27 (s,
1H), 3.57 (q, J = 7.2 Hz, 2H), 3.25 (q, J = 7.1 Hz, 2H),
+
1507, 1443, 1264, 980; HRMS (M+H) calcd for
C13H15 NO3= 234.1130, found = 234.1137.
13
1.29 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); C
5n. 1-morpholino-2-(4-nitrophenyl)ethane-1,2-dione:
Yield: 26.5 mg, 10 %; Yellow solid; m.p. 140.0-
141.5°C; Rf = 0.18 (EtOAc/Hexane= 2:8); 1H NMR (500
MHz, CDCl3) δ 8.38 – 8.35 (m, 2H), 8.19 – 8.15 (m,
2H), 7.27 (s, 1H), 3.82 (s, 4H), 3.72 – 3.68 (m, 2H),
3.45 – 3.42 (m, 2H); 13C NMR (126 MHz, CDCl3) δ
188.56, 163.90, 151.06, 137.33, 130.74, 124.07, 66.63,
66.52, 46.24, 41.83; IR (cm-1): 2918, 2850, 1687, 1643,
NMR (126 MHz, CDCl3) δ 191.52, 166.63, 134.51,
133.09, 129.53, 128.87, 42.00, 38.67, 14.00, 12.74; IR
(cm-1): 3363, 2919, 2851, 1687, 1647, 1595, 1450;
HRMS (M+H) + calcd for C12H15 NO2= 206.1181, found
= 206.1180.
5t.
1-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenyl-
ethane-1,2-dione: Yield: 26.4 mg, 10 %; Colorless
solid; m.p. 105.8-107.2°C; Rf = 0.30 (EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.97 (ddd, J = 16.4,
8.3, 1.1 Hz, 2H), 7.69 – 7.61 (m, 1H), 7.51 (dt, J = 15.8,
7.8 Hz, 2H), 7.18 (ddd, J = 25.0, 15.2, 7.1 Hz, 4H), 4.73
(d, J = 187.2 Hz, 2H), 4.04 – 3.50 (m, 2H), 3.06 – 2.70
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 191.45, 191.30,
165.99, 165.68, 134.79, 134.75, 134.08, 133.31, 132.98,
132.91, 131.71, 131.43, 129.65, 129.64, 128.99, 128.96,
128.90, 128.73, 127.13, 126.79, 126.75, 126.60, 126.53,
126.00, 47.24, 43.43, 43.34, 39.26, 29.13, 28.17; IR
(cm-1): 3027, 2943, 2881, 2166, 1643, 1597, 1474, 1226,
720; HRMS (M+H)+calcd for C17H15 NO2= 266.1181,
found = 266.1182.
+
1524, 1347, 1208, 981; HRMS (M+H) calcd for
C12H12 N2O5= 265.0824, found = 265.0823.
5o. 1-(4-fluorophenyl)-2-morpholinoethane-1,2-dione
: Yield: 24 mg, 10 %; Light yellow solid; m.p. 86.2-
86.6°C; Rf = 0.21 (EtOAc/Hexane= 2:8); 1H NMR (500
MHz, CDCl3) δ 8.02 (d, J = 5.2 Hz, 2H), 7.20 (d, J = 3.1
Hz, 2H), 3.80 (s, 4H), 3.73 – 3.60 (m, 2H), 3.54 – 3.31
(m, 2H); 13C NMR (126 MHz, CDCl3) δ 189.39, 167.83,
165.78, 165.09, 132.60, 132.52, 129.63, 116.55, 116.38,
77.29, 77.04, 76.78, 66.75, 66.66, 46.31, 41.70; IR (cm-
1): 2958, 2923, 2852, 1682, 1638, 1597, 1506, 1442,
981; HRMS (M+H) + calcd for C12H12 NO3F= 238.0879,
found = 238.0876.
5u.
dione: Yield: 28 mg, 12 %; Colorless solid; m.p. 108.2-
109.4°C; Rf = 0.30 (EtOAc/Hexane= 2:8);
1H NMR
1-(2-hydroxyphenyl)-2-morpholinoethane-1,2-
5q.
1-phenyl-2-(pyrrolidin-1-yl)ethane-1,2-dione:
Yield: 20 mg, 10 %; Oily ; Rf = 0.18 (EtOAc/Hexane=
2:8); 1H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 7.3 Hz,
2H), 7.64 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H),
7.29 (s, 1H), 3.67 (dd, J = 14.5, 7.7 Hz, 2H), 3.42 (t, J =
6.4 Hz, 2H), 1.95 (dq, J = 9.4, 7.0 Hz, 4H); 13C NMR
(126 MHz, CDCl3) δ 191.51, 164.85, 134.56, 132.72,
129.77, 128.84, 46.57, 45.14, 25.78, 23.90; IR (cm-1):
3361, 2921, 2854, 1757, 1661, 1598, 1515, 754; HRMS
(M+H)+ calcd for C12H13 NO2= 204.1025, found =
204.1029.
(500 MHz, CDCl3) δ 11.26 (s, 1H), 7.60 – 7.54 (m, 2H),
7.06 – 7.02 (m, 1H), 6.97 (td, J = 7.7, 1.0 Hz, 1H), 3.83
– 3.77 (m, 4H), 3.70 – 3.66 (m, 2H), 3.43 – 3.39 (m,
2H);13C NMR (126 MHz, CDCl3) δ 195.92, 163.42,
163.24, 138.08, 131.88, 119.81, 118.59, 116.66, 66.58,
66.50, 46.27, 41.54; IR (cm-1): 3417, 2941, 2122, 1717,
1638, 1598, 1470, 1191; HRMS (M+H)+ calcd for
C12H13 NO4= 236.0923, found = 236.0924.
5v. 4-(2-morpholino-2-oxoacetyl)benzonitrile: Yield:
31.4 mg, 13 %; Colorless solid; m.p. 118.2-119.9°C; Rf
= 0.21 (EtOAc/Hexane= 2:8); 34B =1H NMR (500
MHz, CDCl3) δ 8.10 – 8.07 (m, 2H), 7.84 – 7.82 (m,
5r.
1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione:
Yield: 26.2 mg, 12 %; Yellow solid; m.p. 104.1-
104.8°C; Rf = 0..29 (EtOAc/Hexane= 2:8); H NMR
(500 MHz, CDCl3) δ 7.95 (d, J = 7.1 Hz, 2H), 7.67 –
1

10
Tetrahedron
ACCEPTED MANUSCRIPT
2H), 3.84 – 3.78 (m, 4H), 3.70 – 3.67 (m, 2H), 3.43 –
3.40 (m, 2H).13C NMR (126 MHz, CDCl3) δ 188.90,
163.99, 135.91, 132.70, 129.98, 117.81, 117.46, 66.63,
66.51, 46.21, 41.78; IR (cm-1): 3317, 2924, 2853, 1724,
1650, 1598, 1467, 1227; HRMS (M+H) calcd for
C13H12 N2O3= 245.0926 found = 245.0927.
4.
(a) Annedi, S. C.; Ramnauth, J.; Maddaford, S. P.;
Renton, P.; Rakhit, S.; Mladenova, G.; Dove, P.;
Silverman, S.; Andrews, J. S.; Felice, M. D.; Porreca, F.
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+
5w. 1-(4-cyclohexylphenyl)-2-morpholinoethane-1,2-
5.
Evans, R.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D.
W. C. J. Am. Chem. Soc. 2013, 135, 16074
dione: Yield: 33 mg, 11 %; Yellow oily; Rf = 0.27
1
(EtOAc/Hexane= 2:8); H NMR (500 MHz, CDCl3) δ
6. Concellón, J. M.; Rodríguez-Solla, H. Current Organic
Chemistry, 2008, 12, 524.
7.88 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 3.80
(s, 4H), 3.67 – 3.64 (m, 2H), 3.40 – 3.36 (m, 2H), 2.68 –
2.50 (m, 1H), 1.87 (d, J = 7.0 Hz, 4H), 1.77 (d, J = 12.3
7. (a) Zhao, L.; Basle, O.; Li, C-J. Proc. Natl. Acad. Sci.
USA, 2009, 106, 4106; (b) Zhang, G.; Zhang, Y.; Wang,
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78, 9450; (e) Rohlmann, R.; Stopka, T.; Richter, H.;
Mancheno, O. G. J. Org. Chem. 2013, 78, 6050; (f) Liu,
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13
Hz, 1H), 1.66 (s, 1H), 1.48 – 1.35 (m, 4H); C NMR
(126 MHz, CDCl3) δ 190.82, 165.62, 155.98, 130.77,
129.83, 127.57, 66.68, 66.58, 46.16, 44.81, 41.46, 33.85,
26.51, 25.83; IR (cm-1): 2970, 2924, 1938, 1719, 1463,
1208; HRMS (M+H) + calcd for C18H23NO3= 302.1756
found = 302.1757.
Acknowledgement
The authors thank Director, CSIR-NEIST, Jorhat for
providing the facility to carry out the work.
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