Synthesis of (3-aminophenyl)(morpholino)methanone from benzotrichloride as precursor

Article abstract of DOI:10.14233/ajchem.2016.19419

(3-Aminophenyl)(morpholino)methanone derivatives are key intermediates in the preparation of active pharmaceutical ingredients. In this synthesis benzotrichloride is selected as a precursor for the preparation of target molecule, the precursor is easily available raw material. The present synthesis consisting of four steps, in the first step we are nitrating the benzotrichloride to obtain the meta-nitrobenzoic acid, which on chlorinated with thionyl chloride to obtain meta nitro benzoyl chloride, which on condensing with morpholine, further reduction with iron and HCl for the formation of the target molecule.

Full text of DOI:10.14233/ajchem.2016.19419

Asian Journal of Chemistry; Vol. 28, No. 2 (2016), 441-443
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2016.19419
Synthesis of (3-Aminophenyl)(morpholino)methanone from Benzotrichloride as Precursor
*
CHANDRASEKHAR REDDY and I.V. KASI VISWANATH
Department of Chemistry, K.L. University, Vaddeswaram, Guntur-522 502, India
*Corresponding author: E-mail: viswanath_fed@kluniversity.in
Received: 19 June 2015; Accepted: 30 July 2015;
Published online: 3 November 2015;
AJC-17624
(
3-Aminophenyl)(morpholino)methanone derivatives are key intermediates in the preparation of active pharmaceutical ingredients. In
this synthesis benzotrichloride is selected as a precursor for the preparation of target molecule, the precursor is easily available raw
material. The present synthesis consisting of four steps, in the first step we are nitrating the benzotrichloride to obtain the meta-nitrobenzoic
acid, which on chlorinated with thionyl chloride to obtain meta nitro benzoyl chloride, which on condensing with morpholine, further
reduction with iron and HCl for the formation of the target molecule.
Keywords: Benzotrichloride, Thionyl chloride, Morpholine, Iron.
INTRODUCTION
EXPERIMENTAL
The generation of diverse compound libraries plays an
Synthesis of 3-nitrobenzoic acid(II) from benzotrichlo-
ride: In a four neck-round bottom flask equipped with a
condenser and thermopacket, charged benzotrichloride (0.1
mol) at room temperature, charged dichloromethane (5 V) at
room temperature, cooled to 15-20 °C, slowly added 90 %
nitric acid (0.15 mol) and sulphuric acid (0.3 mol) at 15-20 °C
for 1 h. The temperature, maintained at room temperature until
evolution of HCl gas is ceases, once evolution of HCl gas ceases
quench the reaction mass in ice water (200 mL), settled and
separated layers. The aqueous layer extracted with dichloro-
methane, combined total organic layer. The organic layer
is washed with sodium chloride solution until the solution of
sodium chloride is colourless, organic layer is dried over
sodium sulphate, concentrated organic layer under rotovapour,
3-nitrobenzoic acid a pale yellow crystalline powder obtained,
yield is 85 %, compound purified with column chromato-
graphy.
important role in the development of potential drug and
pesticide molecules [1], in addition to high flexibility, selectivity
and atom economy, multi component reactions are one of the
most powerful and convenient synthetic routes for building of
small library molecules.
The morpholine structural core is present in many bio-
active compounds [2], which have shown promising biological
properties, such as antidepressant, anticancer, antioxidant, anti-
inflammatory and fungicidal activities. Although a variety of
synthetic protocols for morpholine derivatives are reported [3],
most of them need to use elevated temperature, functionalized
pre-synthesized starting materials, and often suffer from draw-
backs such as poor yield and tedious work up process. Mean
while, there are less reports on the straight synthesis of morpho-
lines which may have potential biological value [4]. Therefore
the development of a straight forward high-yielding protocol
for the synthesis of morpholines at room temperature from
easily available raw materials is of our great interest [5,6].
Melting point: 139-141 °C. IR spectra (νmac, KBr pellet,
-1
cm ): 3086 (=C-H), 1692 (C=O), 1616 (C=C), 1530 (C=C),
(3-Aminophenyl) (morpholino) methanone is a key inter-
1478 (C=C); NMR-Data (500 MHz,CDCl ): 11.67 (1H, s),
3
mediate in the synthesis of API Intermediates and their deri-
vatives, earlier authors are reported similar moieties with their
own choice, exact literature for this molecule not available in
our known sources. Morpholine derivatives are using in the
preparation of tyrosine kinase inhibitors and other biologically
active agents [7,8] and the synthesis of (3-aminophenyl)
8.960 (1H, d), 8.49 (1H, dd), 8.47 (1H, dd), 7.737 (1H, dd).
GC-MS data (m/e): 167, 121, 93, 65.1, 28.1
Synthesis of 3-nitrobenzoyl chloride(III) from 3-nitro-
benzoic acid: In a 250 mL four-necked flask equipped with a
thermo pocket, condenser and a guard tube, charged 3-nitro
benzoic acid (0.1 mol) at 30 °C, charged with dichloromethane
(5 V) at 30 °C, slowly heated to 40 °C, slowly added thionyl
chloride (0.15 mol) at 40 °C for 1 h, maintained 2 h at 40-
(
morpholino) methanone from benzotrichloride presented in
the Scheme-I.

442 Reddy et al.
Asian J. Chem.
Cl
Cl
Cl
COOH
COCl
SOCl2
HNO3
+
3 HCl
+
HCl
H SO
2
4
NO2
NO2
III
II
I
H
N
Morpholine
O
O
O
O
N
O
N
+
H O
2
Fe/HCl
+
Morpholine
hydrochloride
NH2
NO2
V
IV
Scheme-I
4
5 °C, distilled out dichloromethane and thionyl chloride
Synthesis of (3-aminophenyl)(morpholino)methanone
(V): In a 250 mL 4 neck flask equipped with magnetic stirrer,
thermopocket, condenser and CaCl guard tube, charged
with vacuum, obtained 3-nitrobenzoyl chloride with 80 %
yield.
2
Boiling point: 275-278 °C; IR spectra (νmac, KBr pellet,
methanol (5 V) at 25 °C, charged morpholino(3-nitrophenyl)-
methanone (0.1 mol) at 25 °C, charged Fe (0.9 mol) at 25 °C,
slowly heated to 60-65 °C, conc. HCl (100 mL) added at 65 °C,
maintained 1 h at 65 °C, cooled to 30 °C, filtered the mass
through hyflow, washed hyflow bed with methanol, the
filtrate is basified with 10 % NaOH solution and extracted with
dichloromethane two times, washed dichloromethane with
water, separated the dichloromethane layer and concentrated
the dichloromethane layer with vacuum, purified the crude
compound with column chromatography, yield 70 %.
-1
cm ): 3090 (=C-H), 1766 (C=O), 1653 (C=C), 1614 (C=C),
1
8
1
585 (C=C); NMR data (500 MHz, CDCl ): 8.930 (1H, d),
3
.57 (1H, dd), 8.50 (1H, dd), 7.737 (dd); GC-MS data (m/e):
85, 150, 104, 76.0, 50.
Synthesis of morpholino(3-nitrophenyl)methanone
IV): In a 250 mL 4 neck flask equipped with magnetic stirrer,
(
thermo pocket, condenser and CaCl guard tube, charged
2
diethyl ether at 25 °C, charged 3-nitrobenzoyl chloride (0.1
mol) at 25 °C, slowly added morpholine (0.22 mol) at 25-
3
0 °C for 1 h, maintained 1 h at 30 °C for 1 h filtered morpho
Boiling point: 290-295 °C; IR spectra (νmac, KBr pellet,
cm ): 3334 (N-H), 3302 (N-H), 3080 (=C-H), 1760 (C=O),
1656 (C=C), 1614 (C=C), 1270 (C-N), 1225 (C-O); NMR data
-1
line hydrochloride salt, the filtrate is distilled out with vacuum,
obtained the crude morpholino(3-nitrophenyl)methanone with
80 % yield, the above product is purified with column chroma-
(500 MHz, CDCl ): 8.91 (1H, s), 8.57 (1H, dd), 8.47 (1H, dd),
3
tography.
7.64 (1H, dd), 4.0 (2H, s), 3.43 (4H, t), 3.71 (4H, t). GC-MS
data (m/e): 206, 120, 92, 65, 42, 28.
-1
Melting point: 85-88 °C; IR spectra (νmac, KBr pellet, cm ):
080 (=C-H), 1774 (C=O), 1643 (C=C), 1614 (C=C), 1582
3
RESULTS AND DISCUSSION
(
C=C), 1526 (C-N), 1382 (N-O). NMR data (500 MHz,
CDCl ): 8.930 (1H, d), 8.42 (1H, dd), 8.41 (1H, dd), 7.69 (1H,
dd), 3.41 (4H, t), 3.64 (4H, t). GC-MS data (m/e): 235, 205,
89, 150, 134, 104, 76, 56, 28.
3
The molecule is prepared from the benzotrichloride,
nitration of benzotrichloride gives 3-nitro benzoic acid, in this
reaction nitration and hydrolysis happening at one time, which
1

Vol. 28, No. 2 (2016)
Synthesis of (3-Aminophenyl)(morpholino)methanone from Benzotrichloride as Precursor 443
on treatment with thionyl chloride forming 3-nitrobenzoyl
chloride, which on treatment with morpholine forming the
subject molecule.
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Conclusion
(
3-Aminophenyl)(morpholino)methanone is prepared
from benzotrichloride, in nitration of benzotrichloride with
0 % nitric acid achieved 90-95 % selectivity of meta-nitro-
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8
8
0 % yield, morpholine is coupled with step 2 product achieved
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