Ultrasonicated synthesis of N-Benzyl-2,3-substituted morpholines, via the mitsunobu diol cyclisation

Article abstract of DOI:10.1155/2010/931015

A facile five step synthesis of N-benzyl-2,3-substituted morpholines (i-iii) was performed. The key steps were microwave assisted Friedel-crafts acylation and diol cyclization carried out via an ultra sonication of Mitsunobu reaction using DEAD (diethylaz

Full text of DOI:10.1155/2010/931015

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(4), 1184-1189
http://www.e-journals.net
Ultrasonicated Synthesis of N-Benzyl-2,3-substituted
Morpholines, via the Mitsunobu Diol Cyclisation
B. JAYACHANDRA REDDY and M. C. SOMASEKHARA REDDY*
Department of Basic Sciences,
G.P.R.Engg. College (Autonomous), Kurnool-518 002, (A.P), India.
som16@rediffmail.com
Received 21 September 2009; Revised 29 December 2009; Accepted 4 February 2010
Abstract: A facile five step synthesis of N-benzyl-2,3-substituted morpholines
(i-iii) was performed. The key steps were microwave assisted Friedel-crafts
acylation and diol cyclization carried out via an ultra sonication of Mitsunobu
reaction using DEAD (diethylazodicarboxylate), TPP in THF for 1 h. The
morpholine products were generated as diasteriomers (ii and iii) which has
been separated by the column chromatography to good yield. The structure of
compounds (i-iii) has been characterized by the spectral and chemical studies.
Keywords: Friedel crafts acylation, Morpholine, Sonicator, Mitsunobu reaction, DEAD.
Introduction
Various saturated nitrogen containing heterocycles often serves as structural fragments of
biological active compounds. In particular, morpholine derivatives have substance P antagonists
(SPA), prevention of postoperative nausea and vomiting (apripitant)1, antifungal activity
(amorolfin)2, antiulcerative3 and antidepressants (viloxazine)4.
Recently, microwave5, and ultrasonication6 assisted synthesis in organic chemistry is
quickly growing. Many organic reactions proceed much faster with higher yields under
microwave irradiation compared to conventional heating. It has long been know that
molecules undergo excitation with electromagnetic radiation is a technique for microwave
synthesis4 In the present work, at first, we aimed to examine the AlCl3 catalyzes the Friedel-
.
crafts acylation on H-imidazo[1,2-a]pyridine (8) efficiently under microwave irradiation in
solvent free conditions.
Ultrasonication reactions enhances the reaction rates up to a million times, believed to be
due small cavities (100 microns) which implode, creating tremendous heat and pressure, shock
waves, and particular accelerations. In this context, we became interested to developing general
and efficient synthetic methodology, a facile synthesis of morpholines (i-iii) has been carried out
by the mitsunobu diol cyclization7 under ultrasonication6 Mitsunobu demonstrated that the
zwitterionic adducts of triphenylphosphine (TPP) and diethyl or diisopropyl azodicarboxylate
(DEAD and DIAD) activate hydroxyl groups to SN2 substitution by various nucleophiles.

1185
M. C. S. REDDY et al.
Experimental
1-(2-Methylimidazo [1,2-b]pyridazin-3-yl)ethanone (3)
A mixture of pyridazine-3-amine (1) (10 g, 105.15 mmol) and 3-chloropentane-2,4-dione (2)
o
(21.2 g; 157.7 mmol) in ethanol (100 mL) was refluxed8 at 80 C for 24 h. The volatiles were
concentrated under reduced pressure. The crude material was purified through silica gel column
chromatography, eluted product with 80% ethylaceate/hexanes to afford 1-(2-methylimidazo[1,2-
1
b]pyridazin-3-yl) ethanone (3) (7.1g; 39% yield) as a solid. Mass (e/z): 176 (M+1). H NMR
(200 MHz, CDCl3): δ 8.49-8.46 (dd, J = 1.8, 2.6 Hz, 1H), 8.00-7.95 (dd, J = 1.6, 7.6 Hz, 1H), 7.25-
7.18 (m, 1H), 2.83 (s, 3H), 2.77 (s, 3H). Anal. Calcd. for C9H9N3O: C, 61.70; H, 5.18; O, 9.13.
2-Bromo-1-(2-methylimidazo[1,2-b]pyridazin-3-yl)ethanone (4)
To a 1-(2-methylimidazo[1,2-b]pyridazin-3-yl)ethanone (3) (1 g, 5.71 mmol) in a mixture of
diethyl ether (10 mL), dichloromethane (2 mL) and bromine (1.09 g, 6.85 mmol) was added
o
drop wise at 0 C. The reaction mixture9 was warmed to RT (Room temperature) and then
stirred for 2 h. The reaction mixture was diluted with diethyl ether (50 mL), filtered the
precipitated solids. The solids were washed with 10% ethanol/diethyl ether (20 mL), dried under
vacuum to afford 2-bromo-1-(2-methylimidazo[1,2-b]pyridazin-3-yl)ethanone (4) (850 mg;
58% yield) as a light white solid. Mass (e/z): 255 (M+1). 1H NMR (200 MHz, DMSO-d6): δ
8.79 (d, J = 3 Hz, 1H), 8.28-8.23 (dd, J = 7.8, 1.4 Hz, 1H), 7.56-7.49 (m, 1H), 4.95 (s, 2H), 2.64
(s, 3H). Anal. Calcd. for C9H8BrN3O: C, 42.54; H, 3.17; Br, 31.45; N, 16.54; O, 6.30.
Ethyl-2-(N-benzyl-N-(2-(2-methylimidazo[1,2-b]pyridazin-3-yl)-2-oxoethyl)amino)
acetate (6)
To a solution of 2-bromo-1-(2-methylimidazo[1,2-b]pyridazin-3-yl)ethanone (4) (2 g, 7.87
mmol) in acetonitrile (20 mL), N-benzyl glycine ethyl ester (5) (3.7 g, 19.67 mmol) was
added slowly at 0 oC. The reaction mixture was warmed to RT, and then stirred for 4 h. The
volatiles were concentrated under reduced pressure; the residue was diluted with ethyl
acetate and washed with water. The reaction mixture was dried (anhy. Na2SO4) concentrated
under reduced pressure. The residue was purified through silica gel column chromatography,
eluted product by using 20% ethyl acetate/hexanes to afford ethyl-2-(N-benzyl-N-(2-(2-
methylimidazo[1,2-b]pyridazin-3-yl)-2-oxoethyl)amino)acetate (6) (2.1 g, 72.9% yield) as a
1
syrup. Mass (e/z): 367 (M+1). H NMR (200 MHz, CDCl3): δ 8.41-8.38 (dd, J = 3.0, 1.6
Hz, 1H), 7.97-7.91 (dd, J = 7.6, 1.8 Hz, 1H), 7.34-7.14 (m, 6H), 4.47 (s, 2H), 4.21-4.10 (q,
2H), 4.05 (s, 2H), 2.76 (s, 3H), 1.25 (t, J = 6 Hz, 3H). Anal. Calcd. for C20H22N4O3: C,
65.56; H, 6.05; N, 15.29; O, 13.10.
2-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-(2-methylimidazo[1,2-b]pyridazin-3-yl)
ethanol (7)
To a solution of ethyl-2-(N-benzyl-N-(2-(2-methylimidazo[1,2-b]pyridazin-3-yl)-2-oxoethyl)
amino) acetate (6) (2 g, 5.46 mmol) in methanol (15 mL) was added NaBH4 (247 mg, 6.55
o
mmol) at 0 C, then iodine (27 mg, 0.108 mmol) was added at 0 oC. The reaction mixture was
warmed to RT and then stirred for 3 h. The volatiles were concentrated under reduced pressure,
then residue was diluted in ethyl acetate. The organic layer was separated, washed with water, dried
(anhy.Na2SO4) and concentrated under reduced pressure to afford 2-(N-benzyl-N-(2-
hydroxyethyl)amino)-1-(2-methylimidazo[1,2-b]pyridazin-3-yl)ethanol (7) (1.4 g, 79% yield) as
a syrup. Mass (e/z): 327 (M+1). 1H NMR (200 MHz, CDCl3): δ 8.18-8.15 (dd, J = 2.8, 1.6 Hz,
1H), 7.85-7.79 (dd, J = 7.6,1.6 Hz, 1H), 7.38-7.22 (m, 5H), 6.99-6.92 (m, 1H), 5.31-5.24 (m,
1H), 3.75-3.62 (m, 4H), 3.30-3.19 (m, 1H), 3.02-2.81 (m, 3H), 2.60-2.50 (m, 1H), 2.42 (s, 3H).
Anal. Calcd for C18H22N4O2: C, 66.24; H, 6.79; N, 17.17; O, 9.80.

Ultrasonicated Synthesis of N-Benzyl-2,3-substituted Morpholines
3-(4-Benzylmorpholin-2-yl)-2-methylimidazo[1,2-b]pyridazine (i)
1186
2-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-(2-methylimidazo[1,2-b]pyridazin-3-yl)ethanol (7)
(250 mg, 1.106 mmol) and TPP (376 mg, 1.437 mmol) in anhy.THF (5 mL) was ultra
sonicated for 15 min, then DEAD (288 mg, 1.659 mmol) was added drop wise to the
reaction mixture over the 5 min. After addition, reaction mixture was ultra sonicated for
45 min at RT. The volatiles were concentrated under reduced pressure, then the residue was
purified through silica gel column chromatography, eluted product with 70% ethyl
acetate/hexane afford 3-(4-benzylmorpholin-2-yl)-2-methylimidazo[1,2-b]pyridazine (i)
1
(134 mg, 57% yield) as syrup. Mass (e/z): 309 (M+1). H NMR (200 MHz, CDCl3): ): δ
8.29-8.26 (dd, J = 2.8, 1.8 Hz, 1H), 7.83-7.81 (dd, J = 7.2, 1.8 Hz, 1H), 7.38-7.22 (m, 5H),
6.99-6.92 (m, 1 H), 5.37-5.30 (dd, J = 7.6, 2.8 Hz, 1H), 4.07-3.81 (m, 2H,) 3.62 (s, 3 H),
2.92-2.74 (m, 3H), 2.59 (s, 3 H), 2.45-2.32 (m, 1H). Anal. Calcd for C18H20N4O: C, 70.11;
H, 6.54; N, 18.17; O, 5.19.
1-(H-Imidazo[1,2-a]pyridin-3-yl)propan-1-one (10)
A mixture of H-imidazo[1,2-a]pyridine (8) (500 mg, 4.23 mmol), propanoic anhydride (9)
(2.75 g, 21.18 mmol)and AlCl3 (1.12 g, 8.46 mmol) was irradiated in microwave10 for 20
o
min at 100 C. The crude was neutralized with sat. Na2CO3 and extracted product into ethyl
acetate (25 mL), dried (anhy. Na2SO4) and concentrated under reduced pressure. The crude
material was purified through silica gel column chromatography, eluted product with 2%
MeOH/DCM to afford 1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (10) (352 mg, 47.7%
yield) as a solid. Mass (e/z): 175 (M+1). 1H NMR (200 MHz, DMSO-d6): δ 8.56 (d, J = 6.6
Hz, 1 H), 8.63 (s, 1 H), 7.84 (d, J = 9.2 Hz, 1 H), 7.63 (t, J = 6.8 Hz, 1 H), 7.26 (t, J = 6.6
Hz, 1 H), 3.04-2.93 (q, 2 H), 1.15 (t, J = 7.4 Hz, 3 H). Anal. Calcd for C10H10N2O: C,
68.95; H, 5.79; N, 16.08; O, 9.18.
2-Bromo-1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-one (11)
Compound (11) was prepared according to the method describes for preparation of
1
compound (4), Pale brown Solid. Mass (e/z): 255 (M+1). H NMR (200 MHz, CDCl3): δ
9.82 (d, J = 6.6 Hz, 1 H), 9.24 (s, 1 H), 8.60 (d, J = 9.2 Hz, 1 H), 8.15 (t, J = 6.8 Hz, 1 H),
7.62 (t, J = 6.6 Hz, 1 H), 5.51-5.59 (q, 2 H), 2.01 (d, J = 7.4 Hz, 3 H). Anal. Calcd. for
C10H9BrN2O: C, 47.46; H, 5.79; N, 11.07; O, 6.32.
Ethyl 2-(N-(1-H-imidazo[1,2-a]pyridin-3-yl)-1-oxopropan-2-yl)-N-benzylamino)
acetate (13)
Compound (13) was prepared according to the method describes for preparation of
compound (6), Syrup. Mass (e/z): 255 (M+1). 1H NMR (200 MHz, CDCl3): δ 9.68 (d, J = 7
Hz, 1 H), 8.56 (s, 1 H), 7.76 (d, J = 9 Hz, 1 H), 7.46 (t, J = 7.8 Hz, 1 H), 7.34-7.26 (m, 5 H),
7.11 (t, J = 5.6 Hz, 1H), 4.21-4.07 (q, 2 H), 3.84 (d, J = 5.6 Hz, 1H), 3.81 (s, 3 H), 3.41 (s,
2H), 1.40 (d, J = 6.8 Hz, 3 H), 1.27 (t, J = 7 Hz, 3H). Anal. Calcd for C21H23N3O3: C, 69.02;
H, 6.34; N, 11.50; O, 13.13.
2-(N-Benzyl-N-(2-hydroxyethyl)amino)-1-(H-imidazo[1,2-a]propan-1-ol (14)
Compound (14) was prepared according to the method describes for preparation of
1
compound (7), Syrup. Mass (e/z): 326 (M+1). H NMR (200 MHz, CDCl3): δ 7.85 (d, J =
6.8 Hz, 1 H), 7.52-7.11 (m, 7 H), 7.18 (t, J = 6.8 Hz, 1 H), 6.61 (t, J = 6.8 Hz, 1H), 5.30 (br
s, 1H), 4.86 (t, J = 5 Hz, 1 H), 4.78 (d, J = 9.8 Hz, 1H), 3.97 (d, J = 13.4 Hz, 1H), 3.69-3.44
(m, 3H), 3.17-3.09 (m, 1H), 2.86-2.72 (m, 1H), 2.55-2.42 (m, 1H), 0.77 (d, J = 6.6 Hz, 3 H).
Anal. Calcd for C19H23N3O2: C, 70.13; H, 7.12; N, 12.91; O, 9.83.

1187
M. C. S. REDDY et al.
3-(4-Benzyl-3-methylmorpholin-2yl)H-imidazo[1,2-a]pyridine (ii and iii)
2-(N-benzyl-N-(2-hydroxyethyl)amino)-1-(H-imidazo[1,2-a]pyridin-3-yl)propan-1-ol (14) (500 mg,
1.53 mmol) and TPP (524 mg, 1.99 mmol) in anhy.THF (10 mL) was ultra sonicated
for 15 min, then DEAD6 (401 mg, 2.30 mmol) was added drop wise to the reaction mixture
over the 5 min. After addition, reaction mixture was ultra sonicated for 45 min at RT. The
volatiles were concentrated under reduced pressure, then the residue was purified through silica
gel column chromatography, eluted faster product with 40% ethyl acetate/hexane afford 3-
cis( )-4-benzyl-3-methylmorpholin-2yl)H-imidazo[1,2-a]pyridine (ii) (130 mg, 27.5% yield)
and slower product with 50% ethyl acetate/hexanes to afford 3-trans( )-4-benzyl-3-
methylmorpholin-2yl)H-imidazo[1,2-a]pyridine (iii) (160 mg, 33.8% yield ) as a syrup.
3-cis( )-4-Benzyl-3-methylmorpholin-2yl)H-imidazo[1,2-a]pyridine (ii)
Mass (e/z): 308 (M+1). added 1H NMR (200 MHz, DMSO-d6): δ 8.39 (d, J = 6.8 Hz, 1H), 7.73 (s,
1H), 7.57 (d, J = 9 Hz, 1 H), 7.44-7.212 (m, 6 H), 6.93 (t, J = 6.8 Hz, 1H), 5.21 (d, J = 3 Hz, 1H), 3.88
(d, J = 13.6 Hz, 1H), 3.71-3.45 (m, 2 H), 3.39 (d, J = 13.6 Hz, 1 H), 3.12-3.09 (m, 1H), 2.67-2.59 (m, 1
H), 1.06 (d, J = 6.6 Hz, 3 H). Anal. Calcd for C19H21N3O: C, 74.24; H, 6.89; N, 13.67; O, 5.20.
3-trans( )-4-Benzyl-3-methylmorpholin-2yl)H-imidazo[1,2-a]pyridine (iii)
Mass (e/z): 308 (M+1). 1H NMR (200 MHz, DMSO-d6): δ 8.51 (d, J = 6.8 Hz, 1H), 7.61 (s,
1H), 7.57 (d, J = 9 Hz, 1 H), 7.37-7.21 (m, 6 H), 6.93 (t, J = 6.8 Hz, 1H), 4.73 (d, J = 8.2 Hz,
1H), 4.08 (d, J = 13.4 Hz, 1H), 3.71-3.66 (m, 2 H), 3.27 (d, J = 13.4 Hz, 1 H), 3.00-2.92 (m,
1H), 2.65-2.59 (m, 1 H), 2.40-2.27 (m, 1 H), 1.08 (d, J = 6.6 Hz, 3 H). Anal. Calcd for
C19H21N3O: C, 74.24; H, 6.89; N, 13.67; O, 5.20.
Results and Discussion
All the three new compounds (i-iii) were synthesized. Cyclic keto compound (3) was prepared
by cyclization of 2-amino pyridine (1) with 3-chloropentane-2,4-dione (2) in ethanol under the
reflux for 24 h (ca. 39% yield). Bromination of (3) in ether/dichloromethane for 2 h at RT to
give α-bomo compound (4) (ca. 58% yield), then N-alkylation11 on N-benzyl glycine ester by
using excess amine (5) in THF at reflux for 12 h, in (ca. 70% yield). Sodium borohydride
mediated reduction using I2 catalytic12,13 yielded diole (7) in (ca. 65% yield). Then
ultrasonicated mitsunobu diole cyclization6,7 to give the morpholine derivative (i) using
DEAD, TPP, in THF (cat. 57% yield) according to Scheme 1.
O
O
NH2
N
N
(b)
NH
(a)
+
+
N
4
O
N
N
N
N
N
1
Cl
2
O
N
i
O
O
5
3
Br
N
N
N
N
N
N
N
N
N
(e)
(c)
(d)
O
O
OH
O
OH
N
N
O
6
7
Reagents & Conditions: (a) EtOH; rfx; 24 h (b) Br2; ether; DCM; 0oC-RT; 2 h (c) ACN; 0 oC-
RT; 2 h (d) NaBH4; I2; MeOH; RT; 3 h (e) DEAD; TPP; THF; Ultra sonicator; RT, 1 h
Scheme 1

Ultrasonicated Synthesis of N-Benzyl-2,3-substituted Morpholines
1188
A microwave synthesis10 of Friedel-crafts acylation5,14 on H-imidazo[1,2-a]pyridine (8)
o
by using AlCl3, propanoic anhydride (9) irradiating in microwave at 100 C for 20 min to
give acylated product (10) (in ca. 45% yield). Then, further 11, 13, 14 and morpholine
derivatives (ii-iii) were prepared as followed similar procedure of related analogue 4, 6, 7
and (i). The morpholine derivatives cis (ii) and trans (iii) separated by column
chromatography to afford in good yield according to Scheme 2.
O
O
O
N
N
N
H
N
(a)
(b)
+
+
N
O
9
O
N
N
O
O
8
10
11
12
Br
N
N
N
N
N
N
N
N
N
N
N
(c)
(e)
OH
(d)
+
O
O
OH
O
O
N
O
14
13
(rac-trans)
(rac-cis)
ii
iii
Reagents & Conditions: (a) AlCl3; microwave;100 oC; 20 min (b) Br2; ether; DCM; 0o C-RT; 2 h
(c) ACN; 0 oC-RT; 2 h (d) NaBH4; I2; MeOH; RT; 3 h (e) DEAD; TPP; THF; Ultra sonicator; 1 h
Scheme 2
Conclusion
The Mitsunobu diol cyclization in ultrasonicator has been given in good yields (cal. 57%)
comparatively the standard reaction conditions, where reaction proceeded in less time with
good yield. When the reaction carried out at standard reaction conditions using same reagents,
stirring in maganetic stirrer for 12 h, also not reached good yield (cal. 20 %) as comparative
with the same reaction in ultrasonicator for 1 h. However, due to the explosive hazards of
azodicarboxylates, we are not recommend that the sonication procedure for bigger scale (> 2 g)
unless precautions are taken to remove excessive heat buildup during the reaction.
The NMR analysis of ultrasonicated Mitsunobu diol cyclization showing diasteriomeric
mixture (ii and iii) suggests that it consist almost 1:1 ratio of cis/trans. In the NMR
spectra15,16 of cis (ii), the chemical shift of the C2-H falls in the expected range (C2-H at
5.21). The NMR of trans (iii) showed that the chemical shift of the C2-H was shifted up
field to 4.73 ppm. These shifts are consistent with the indicated structural assignments.
When the proton in cis exposed to shielding effect to heterocyclic ring. The coupling of C2-
H with neighboring proton and splitting as doublet, coupling constant (J)17,18 of cis (ii) 3 Hz
and trans (iii) 8.2 Hz. Comparatively of both coupling constants expected cis (ii) showing
less coupling constant than corresponding trans (iii).
Acknowledgment
The authors wish to thank Principal, Director and Management of G.P.R. Engg. College

1189
M. C. S. REDDY et al.
(Autonomous), Kurnool-518 002 (A.P.), India for their constant encouragement and help.
The authors are also thankful to Indian Institute of Chemical Technology (IICT), Hyderabad
for spectral analysis and Literature assistance.
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http://www.hindawi.com
Hindawi Publishing Corporation
http://www.hindawi.com
Volume 2014
Volume 2014
Volume 2014
Volume 2014
Volume 2014