Synthesis of N-(morpholinomethyl) benzamides as moclobemide analogs

Article abstract of DOI:10.1081/SCC-120003642

Syntheses of new morpholinomethylbenzamides 6 bearing both electron-withdrawing and electron-releasing groups at the aromatic ring are described. The strategy involved synthesis of hippuric acid ethyl esters 3, their hydrolysis to hippuric acids 4, subseq

Full text of DOI:10.1081/SCC-120003642

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SYNTHESIS OF N-(MORPHOLINOMETHYL) BENZAMIDES
AS MOCLOBEMIDE ANALOGS
Hernán Pessoa-Mahana a , Claudio I. Astudillo O. a & R. Araya-Maturana a
a Facultad de Ciencias Químicas y Farmacéuticas , Departamento de Química Orgánica y
Fisicoquímica , Universidad de Chile , Casilla 233, Santiago 1, Santiago, Chile
Published online: 17 Aug 2006.
To cite this article: Hernán Pessoa-Mahana , Claudio I. Astudillo O. & R. Araya-Maturana (2002) SYNTHESIS OF N-
(MORPHOLINOMETHYL) BENZAMIDES AS MOCLOBEMIDE ANALOGS, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 32:9, 1437-1445, DOI: 10.1081/SCC-120003642
To link to this article: http://dx.doi.org/10.1081/SCC-120003642
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SYNTHETIC COMMUNICATIONS, 32(9), 1437–1445 (2002)
SYNTHESIS OF
N-(MORPHOLINOMETHYL)
BENZAMIDES AS MOCLOBEMIDE
ANALOGS
*
Hernan Pessoa-Mahana, Claudio I. Astudillo O.,
and R. Araya-Maturana
Facultad de Ciencias Quımicas y Farmaceuticas, and
Departamento de Quımica Organica y Fisicoquımica,
Universidad de Chile, Casilla 233, Santiago 1, Chile
ABSTRACT
Syntheses of new morpholinomethylbenzamides 6 bearing
both electron-withdrawing and electron-releasing groups at
the aromatic ring are described. The strategy involved
synthesis of hippuric acid ethyl esters 3, their hydrolysis to
hippuric acids 4, subsequent oxidative decarboxylation to
acetate 5 and morpholine addition to provide 6.
Moclobemide, p-chloro-N-2-(morpholinoethyl) benzamide (1) is a
short acting, selective and reversible inhibitor of MAO-A,1,2 well tolerated,
widely available for clinical use, and an effective antidepressant.
Monoamine oxidase (MAO) is a flavoprotein of the mitochondrial outer
membranes of neuronal cells, involved in the biodegradation of aromatic
*Corresponding author. Fax: 56-2-6782868; E-mail: hpessoa@ll.ciq.uchile.cl
1437
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1438
PESSOA-MAHANA, ASTUDILLO, AND ARAYA-MATURANA
monoamines, including classical neurotransmitters such as serotonin,
adrenaline, and dopamine, playing a central role in several psychiatric
and neurological disorders.
A variety of moclobemide derivatives has been prepared, and studies
on structure-activity relationships reveal that both the morpholine and
phenyl rings are necessary for antidepressant activity.3,4 However effects
of changes in the aliphatic chain length on biological activity have not
been reported. We report herein new and facile syntheses of N-(morpholi-
nomethyl) benzamides as moclobemide analogs.
Several studies regarding the synthesis and reactivity of N-(morpho-
linomethyl) benzamides have been reported.5,6 Katritzky7 et al. examined
syntheses of monoacylaminals as constituent units of retro-peptide inter-
mediates for obtaining heterocycles.
The synthesis of our analogs started with the classical reaction of
substituted benzoyl chlorides 2(a–d) with glycine hydrochloride8,9 to
afford the ethyl esters of hippuric acids 3(a–d) (Scheme 1).
a
b
c
R1¼OCH3; R2¼H; R3¼OCH3; R4¼H
R1¼OCH3; R2¼NO2; R3¼OCH3 ; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼NO2
R1¼H; R2¼Cl; R3¼H; R4¼H
d
Scheme 1.

N-(MORPHOLINOMETHYL) BENZAMIDES
1439
Scheme 2.
The hippuric esters 3(a–d) were subsequently hydrolyzed with metha-
nolic-potassium hydroxide at room temperature, to afford the correspond-
ing hippuric acids 4(a–d) (Scheme 2). Special care must be taken with the
ester 3(d), to avoid competitive hydrolysis of the amide which was detected
as a side reaction (See Experimental).
The hippuric acids 4(a–d) were reacted with a mixture of anhydrous lead
tetraacetate and cupric acetate, in acetonitrile giving the acetates 5(a–d)10 in
good yield, (Table 1). This oxidative decarboxylation gave better yields using
acetonitrile rather than benzene; when compounds 4(a–d) were decarboxy-
lated in benzene,11 their solubilities were low with decreased yields.
In summary we have developed efficient syntheses which afford
N-(morpholinomethyl) benzamides. Further studies on applications of
these compounds will be reported.
EXPERIMENTAL
Melting points were determined on a hot-stage apparatus and are
uncorrected. The IR spectra were recorded, on a FT-IR Bruker IFS55
spectrophotometer for KBr disc and wave numbers are reported in cmÀ1
.
1
The H and 13C NMR spectra were performed on Bruker DRX-300 and
AM-200 spectrometers in CDCl3 or DMSO-d6. Chemical shifts were

1440
PESSOA-MAHANA, ASTUDILLO, AND ARAYA-MATURANA
Table 1.
Entry
Substrate
Product
Yield (%)
2-a
2-b
2-c
2-d
3-a
3-b
3-c
3-d
4-a
4-b
4-c
4-d
5-a
5-b
5-c
5-d
R1¼OCH3; R2¼H; R3¼OCH3; R4¼H
R1¼OCH3; R2¼NO2; R3¼OCH3; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼NO2
R1¼H; R2¼Cl; R3¼H; R4¼H
3-a
3-b
3-c
3-d
4-a
4-b
4-c
4-d
5-a
5-b
5-c
5-d
6-a
6-b
6-c
6-d
85
84
79
82
85
98
95
87
91
76
78
58
71
63
46
52
R1¼OCH3; R2¼H; R3¼OCH3; R4¼H
R1¼OCH3; R2¼NO2; R3¼OCH3; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼NO2
R1¼H; R2¼Cl; R3¼H; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼H
R1¼OCH3; R2¼NO2; R3¼OCH3; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼NO2
R1¼H; R2¼Cl; R3¼H; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼H
R1¼OCH3; R2¼NO2; R3¼OCH3; R4¼H
R1¼OCH3; R2¼H; R3¼OCH3; R4¼NO2
R1¼H; R2¼Cl; R3¼H; R4¼H
recorded in ppm (d) relative to TMSas internal standard. J values are given
in Hz. EIMSwere recorded on VB-12-250 spectrometer.
Microanalyses were carried out on a Fisons EA 1108 analizer. Silica
gel Merck 60 (70–230 mesh) and DC-alufolien 60 F254 were normally used
for column and TLC chromatography respectively.
GeneralProcedure for the Synthesis of
Hippuric Ester Derivatives (3)
To a solution of glycine ethyl ester hydrochloride (170 mg, 1.22 mmol),
triethylamine (333 mg, 0.45 ml 3.33 mmol) in dry THF (50 ml) at 0ꢀC,
benzoyl chloride derivative 2 (1.11 mmol) in THF (10 ml), was slowly
added under nitrogen atmosphere . The solution was stirred for 1 h at 0ꢀC
and then at room temperature. After 3 h water (100 ml) was added and the
mixture was extracted with chloroform (3 Â 50 ml). The combined extracts
were dried (Na2SO4) and evaporated under reduced pressure. The residue
was chromatographed on silica gel column (chloroform : ethyl acetate ¼
1 : 1) or crystallized to give 3.
2,5-Dimethoxy-hippuric acid ethylester (3-a): M.p. 82–83ꢀC; purified
by silica gel chromatography, (chloroform : ethyl acetate ¼ 1 : 1) Anal. calcd

N-(MORPHOLINOMETHYL) BENZAMIDES
1441
for C13H17NO5: C, 58.42; H, 6.37; N, 5.24. Found: C, 57.58; H, 6.55; N,
1
5.24. IR: 3349, 1755, 1643. H NMR (300 MHz, CDCl3) d: 1.33 (t, 3H,
J ¼ 7.1, OCH2CH3), 3.83 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.23–4.31
(m, 4H, OCH2CH3 and NH-CH2-CO), 6.95 (d, 1H, Jo ¼ 8.70, Ar-3-H),
7.04 (dd, 1H, Jo ¼ 8.70, Jm ¼ 3.40, Ar 4-H), 7.77 (d, 1H, Jm ¼ 3.40, Ar 6-H).
13C NMR (75 MHz CDCl3) d: 14.6, 42.5, 56.2, 57.0, 61.8, 113.5, 115.9,
120.1, 121.7, 152.5, 154.3, 165.5, 170.6.
ꢀ
2,5-Dimethoxy-4-nitro-hippuric acid ethylester (3-b): M.p. 151–152 C
(Ethanol); Anal calcd for C13H16N2O7: C, 50.0; H, 5.16; N, 8.97. Found: C,
49.79; H, 5.25; N, 9.02. IR: 3339, 1753, 1649. 1H NMR (200 MHz CDCl3) d:
1.32 (t, 3H, J ¼ 7.72, OCH2CH3), 3.97 (s, 3H, OCH3), 4.03 (s, 3H, OCH3),
4.21–4.28 (m, 4H, OCH2CH3 and NH-CH2), 7.50 (s, 1H, Ar 6-H), 8.00
(s, 1H, Ar 3-H), 8.56 (br.s, 1H, NH). 13C NMR (75 MHz CDCl3) d: 14.2,
42.2, 57.1, 57.1, 61.7, 109.2, 117.8, 125.7, 141.0, 147.1, 150.6, 163.1, 169.7;
EIMS m/z (%): 312 (Mþ, 8), 267 (2), 210 (100), 163 (24).
2,5-Dimethoxy-6-nitro-hippuric acid ethylester (3-c): M.p. 86–88ꢀC;
(Ethanol). Anal calcd for C13H16N2O7: C, 50.0; H, 5.16; N, 8.97. Found:
C, 49.51; H, 5.39; N, 8.88. IR: 3321, 1740, 1667. 1H NMR (300 MHz,
CDCl3) d: 1.23 (t, 3H, J ¼ 7.40, OCH2CH3), 3.77 (s, 3H, OCH3), 3.87 (s,
3H, OCH3), 4.11 (d, 2H, J ¼ 3.2, NH-CH2), 4.17 (q, 2H, J ¼ 7.40,
OCH2CH3), 7.00 (d, 1H, J ¼ 6.10, Ar 3-H), 7.10 (d,1H, J ¼ 6.10, Ar 4-H),
7.70 (s, 1H, NH). 13C NMR (75 MHz, CDCl3) d: 14.5, 42.3, 55.7, 57.6, 62.0,
114.7, 116.7, 117.1, 142.6, 145.9, 150.1, 162.0, 170.0.
4-Chloro-hippuric acid ethyl ester (3-d): M.p. 114.5–116ꢀC8; (purified
by column chromatography, chloroform : ethyl acetate ¼ 2 : 1) Anal. calcd
for C11H12O3NCl: C, 54.65; H, 4.96; N, 5.80. Found: C, 54.17; H, 5.06; N,
1
5.97. IR: 3268, 1747, 1647. H NMR (CDCl3, 300 MHz) d: 1.30 (t, 3H,
J ¼ 7.15, OCH2CH3), 4.20 (d, 2H, J ¼ 5.14, NH-CH2), 4.24 (q, 2H,
J ¼ 7.15, OCH2CH3), 6.86 (s, 1H, NH), 7.39 (d, 2H, J ¼ 13.3, Ar 3-H and
Ar 5-H), 7.74 (d, 2H, J ¼ 13.3, Ar 2-H and Ar 6-H). 13C NMR (75 MHz,
CDCl3) d: 14.2, 41.9, 61.8, (2 Â 128.6) (2 Â 128.8), 132.1, 138.1, 170.1, 173.8.
GeneralProcedure for the Synthesis of
Hippuric Acid Derivatives (4)
A solution of the ethyl ester 3 (1.90 mmol.) in KOH 0.5 N : EtOH (1 : 1
v/v), (40 ml) was stirred at room temperature for 3 h (except for the chloro
derivative (3-d) we use 30 min). The mixture was then diluted with water
(50 ml), acidified with HCl 0.1 M and extracted with ethyl acetate, (3 Â 50 ml).
Organic layers were dried (Na2SO4) and the solvent was evaporated under

1442
PESSOA-MAHANA, ASTUDILLO, AND ARAYA-MATURANA
vacuo. Purification was carried out by chromatographic techniques or
crystallization.
2,5-Dimethoxy-hippuric acid (4-a): M.p. 107–108ꢀC (White crystals,
column chromatographed, AcOEt). Anal calcd for: C11H13NO5: C, 55.23;
H, 5.44; N, 5.86. Found: C, 54.57; H, 5.61; N, 5.96. IR: 3300–2980, 1732,
1615. 1H NMR (300 MHz, CDCl3): d 3.81 (s, 3H, OCH3), 3.95 (s, 3H,
OCH3), 4.30 (d, 2H, J ¼ 4.8, -CH2-), 6.92 (d, 1H, Jo ¼ 9.0 Ar 3-H), 7.02
(d, d, 1H, Jo ¼ 9.0, Jm ¼ 3.0, Ar 4-H), 7.73 (d, 1H, Jm ¼ 3.0, Ar 6-H), 8.75
(br s, 1H, NH). 13C NMR (75 MHz, CDCl3) d: 42.4, 55.9, 56.7, 113.2, 115.6,
120.3, 120.7, 152.3, 154.0, 166.1, 173.3.
2,5-Dimethoxy-4-nitro-hippuric acid (4-b): Yellow crystals (Ethanol)
M.p. 197–197.5ꢀC; Anal calcd for C11H12N2O7: C, 46.48; H, 4.26; N, 9.86.
Found: C, 46.67; H, 4.44; N, 9.93. IR: 3379–2850, 3380, 1740, 1613. 1H NMR
(300 MHz, DMSO-d6) d: 3.90 (s, 3H, OCH3), 3.92 (s, 3H, OCH3), 4.00 (d, 2H,
J ¼ 5.7, -CH2-), 7.68 (s, 1H, Ar 6-H or Ar 3-H), 7.70 (s, 1H, Ar 3-H or Ar
6-H), 8.69 (t, 1H, J ¼ 5.7, NH), 12.7 (s, 1H, COOH); 13C NMR (75 MHz,
DMSO-d6) d: 42.1, 57.4, 57.5, 109.6, 116.6, 127.1, 141.2, 145.7, 150.9, 163.6,
171.4.
2,5-Dimethoxy-6-nitro-hippuric acid (4-c): M.p. 233–235ꢀC; Anal calcd
for: C11H12N2O7: C, 46.47; H, 4.26; N, 9.86. Found: C, 46.49; H, 4.57; N,
9.74. IR: 3450, 3350, 1766, 1638, 1532, 1375. 1H NMR (300 MHz DMSO-d6):
d 3.80 (s, 3H, OCH3), 3.90 (s, 3H, OCH3), 4.05 (d, 2H, J ¼ 5.3, -CH2-), 7.19 (d,
1H, J ¼ 9.3 Ar 3-H, or 4-H), 7.25 (d, 1H, J ¼ 9.3, Ar 4-H or 3-H), 8.30 (brt,
1H, NH). 13C NMR (75 MHz, DMSO-d6) d: 41.4, (2 Â 57.1), 115.3, 116.0
118.4, 140.2, 144.5, 150.2, 161.8, 170.6.
4-Chloro-hippuric acid (4-d): White pale crystals (Ethanol). M.p.
141.5–142.5ꢀC Anal. calcd for C9H8NClO3: C, 50.58; H, 3.74; N, 6.55.
Found: C, 50.88; H, 3.67; N, 6.42. IR: 3600–2850, 3338, 1746, 1685.
1H NMR (300 MHz, CDCl3): d ¼ 4.1 (s, 2H, -CH2-), 7.38 (d, 2H, J ¼ 8.35,
Ar 3-H, and 5-H), 7.83 (d, 2H, J ¼ 8.35, Ar 2-H, and Ar 6-H), 7.94 (br.d.,
1H, J ¼ 4.5, NH), 9.8–11.2 (br.s., 1H, COOH). 13C NMR (75 MHz, CDCl3):
d ¼ 39.7, (2 Â 128.4), (2 Â 128.8) 132.3, 137.4, 166.4, 171.7.
GeneralProcedure for the Synthesis of
N-(Acetoxymethyl) Benzamides (5)
To a solution of carboxylic acid 4 (0.574 mmol), in acetonitrile (40 ml)
was added a mixture of anhydrous lead tetraacetate (250 mg, 0.573 mmol)
and cupric acetate (104 mg, 0.573 mmol). The mixture was refluxed for 3 h.
The reaction mixture was then quenched with water (100 ml), and the result-
ing solution extracted with ethyl acetate (3 Â 50 ml), dried (Na2SO4), and

N-(MORPHOLINOMETHYL) BENZAMIDES
1443
concentrated in vacuo. The products were further purified by silica gel
column chromatography.
N-(Acetoxymethyl)-2,5-dimethoxybenzamide (5-a): Pale yellow oil
(column chromatographed, AcOEt). Anal calcd for: C12H15NO5: C, 56.90;
H, 5.97; N, 5.33. Found: C, 57.03; H, 6.29; N, 5.41. IR: 3380, 1733, 1669.
1H NMR (300 MHz, CDCl3): d 2.08 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.93 (s,
3H, OCH3), 3.84 (s, 3H, OCH3), 5.46 (d, 2H, J ¼ 7.18, -CH2-), 6.92 (d, 1H,
Jo ¼ 9.0, Ar 3-H), 7.03 (dd, 1H, Jo ¼ 9.0, Jm ¼ 2.90, Ar 4-H), 7.76 (d, 1H,
Jm ¼ 2.90, Ar 6-H), 8.95–9.05 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3)
d: 21.0, 55.8, 56.6, 64.7, 113.1, 115.9, 120.3, 120.9, 152.2, 153.9, 165.7, 171.8.
N-(Acetoxymethyl)-4-nitro-2, 5-dimethoxybenzamide (5-b): Yellow crys-
tals (column chromatographed, CHCl3/AcOEt ¼ 1 : 1). M.p. 123–124.5ꢀC.
Anal. calcd for C12H14N2O7: C, 48.43; H, 4.73; N, 9.39. Found: C, 48.36;
1
H, 4.85; N, 9.36. IR: 3386, 1747, 1668. H NMR (300 MHz,CDCl3) d: 2.10
(s, 3H, CH3), 3.98 (s, 3H, OCH3), 4.0 (s, 3H, OCH3), 5.46 (d, 2H, J ¼ 7.0,
NH-CH2-O), 7.49 (s, 1H, Ar 6-H), 8.00 (s, 1H, Ar 3-H), 8.93 (br.t, 1H, J ¼ 7.0,
NH). 13C NMR (75 MHz, CDCl3) d: 20.9, 57.1, 57.2, 64.5, 109.4, 118.1,
125.2, 141.2, 147.0, 150.7, 163.8, 171.7.
N-(Acetoxymethyl)-6-nitro-2, 5-dimethoxybenzamide (5-c): Yellow crys-
tals (column chromatographed: AcOEt/CHCl3 2 : 1). M.p. 124–125ꢀC. Anal
calcd. for C12H14N2O7: C, 48.32; H, 4.73; N, 9.39. Found: C, 49.09; H, 4.99;
N, 9.38. IR: 3357, 1726, 1680, 1539, 1370. 1H NMR (300 MHz, DMSO-d6): d
2.01 (s, 3H, CH3), 3.79 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 5.17 (d, 2H,
J ¼ 6.9, -CH2-), 7.30 (d, 1H, J ¼ 8.1, Ar 3-H, or 4-H), 7.37 (d, 1H, J ¼ 8.1,
Ar 4-H, or 3-H), 9.47 (br.t, 1H, J ¼ 6.9, NH). 13C NMR (75 MHz, DMSO-d6)
d: 21.1, 57.3, 57.7, 64.2, 116.6, 117.3, 119.9, 139.5, 144.8, 150.1, 163.6, 170.5.
N-(Acetoxymethyl)-4-chloro-benzamide (5-d): M.p. 218–219ꢀC White
crystals (column chromatographed AcOEt/CHCl3 ¼ 1 : 2) Anal. calcd for
C10H10NClO3: C, 52.74; H, 4.39; N, 6.15; Cl, 15.6. Found: C, 53.46; H,
4.50; N, 5.93. IR: 3328, 1737, 1652. 1H NMR (300 MHz, CDCl3): d ¼ 2.1 (s,
3H, CH3), 5.43 (d, 2H, J ¼ 7.2, CH2), 7.40 (br t, 1H, NH), 7.41 (d, 2H, J ¼ 8.1,
Ar 2-H, and Ar 6-H), 7.76 (d, 2H, J ¼ 8.1, Ar 3-H and Ar 5-H). 13C NMR
(75 MHz, CDCl3): d ¼ 20.9, 64.7, (2 Â 128.7), (2 Â 128.9), 131.5, 138.7,
166.4, 172.2.
GeneralProcedure for the Synthesis of
N-(Morpholinomethyl) Benzamides (6)
To a stirred solution of acetatebenzamide 5 (0.6 mmol) in acetonitrile
(20 ml), triethylamine (55.7 mg, 0.080 ml, 0.55 mmol) and Morpholine
(48.0 mg, 0.048 ml, 0.55 mmol) were added at 25ꢀC for 4 h. The mixture

1444
PESSOA-MAHANA, ASTUDILLO, AND ARAYA-MATURANA
was poured into ice-water and extracted with ethyl acetate (3 Â 50 ml). The
organic layers were washed with water and dried (Na2SO4). Removal of the
solvent afforded crude morpholine derivatives 6 which were purified by silica
gel column chromatography or crystallization.
2,5-Dimethoxy-N-(morpholinomethyl) benzamide (6-a): Pale yellow oil
(column chromatographed), AcOEt). Anal. calcd for C14H20N2O4: C, 59.99;
H, 7.19; N, 9.99. Found: C, 58.12; H, 7.25; N, 9.86. IR: 3391, 1658.
1H NMR (300 MHz, CDCl3): d 2.53 (t, 4H, J ¼ 4.7, Morpholine 2-H and
6-H, (N-CH2)), 3.61 (t, 4H, J ¼ 4.7, Morpholine 3-H and 5-H, (O-CH2)),
3.70 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.22 (d, 2H, J ¼ 6.30, NH-CH2-N),
6.83 (d, 1H, J ¼ 9.0, Ar 3-H), 6.90 (dd, 1H, Jo ¼ 9.0, Jm ¼ 3.20, Ar 4-H) 7.63
(d, 1H, Jm ¼ 3.20, Ar 6-H), 8.22 (br t, 1H, NH). 13C NMR (75 MHz, CDCl3)
d: (2 Â 50.1), 55.5, 56.3, 61.24, (2 Â 66.5), 112.7, 115.5, 119.2, 121.4, 151.5,
153.6, 165.5.
2,5-Dimethoxy-4-nitro–N-(morpholinomethyl) benzamide (6-b): Yellow
crystals (Ethanol). M.p. 116–118ꢀC. Anal. calcd for C14H19N3O6 : C, 51.69;
H, 5.89; N, 12.92. Found: C, 51.08; H, 5.98; N, 12.42. IR: 3383, 1669,
1
1511,1342. H NMR (300 MHz, CDCl3): d 2.63 (t, 4H, J ¼ 4.8, Morpholine
2-H and 6-H, (N-CH2)), 3.73 (t, 4H, J ¼ 4.8,Morpholine 3-H and 5-H,
(O-CH2)), 3.98 (s, 3H,OCH3), 4.0 (s, 3H, OCH3), 4.35 (d, 2H, J ¼ 6.50,
NH-CH2-N), 7.51 (s, 1H, Ar 6-H), 8.0 (s, 1H, Ar 3-H), 8.17 (s, broad,
1H, NH). 13C NMR (75 MHz, CDCl3) d: (2 Â 50.4), (2 Â 57.0), (2 Â 63.1),
66.8, 109.1, 118.0, 126.1, 140.7, 147.2, 150.3, 163.8.
2,5-Dimethoxy-6-nitro-N-(morpholinomethyl) benzamide (6-c): Pale
yellow crystals (Ethanol). M.p. 169–172ꢀC Anal. calcd for C14H19N3O6: C,
51.69; H, 5.89; N, 12.92. Found: C, 51.43; H, 5.80; N, 13.02. IR: 3400, 1669,
1535, 1367. 1H NMR (300 MHz, CDCl3): d 2.63 (t, 4H, J ¼ 4.7, (Morpholine
2-H and 6-H, (N-CH2)), 3.72 (t, 4H, J ¼ 4.7, (Morpholine 3-H and 5-H), (O-
CH2)), 3.88 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.29 (d, 2H, J ¼ 6.35,
-NCH2N-), 7.02 (brt, 1H, NH), 7.07 (d, 1H, J ¼ 9.24 Ar 6-H), 7.11 (d, 1H,
J ¼ 9.24, Ar 3-H). 13C NMR (75 MHz, CDCl3) d: (2 Â 50.3), 57.2, 57.3, 61.7,
(2 Â 66.9), 114.3, 115.9, 118.8, 142.0, 146.0, 151.0, 162.5.
4-Chloro-N-(morpholinomethyl) benzamide (6-d). Brown pale solid
(column chromatographed, CHCl3–AcOEt ¼ 1 : 2). M.p. 70.2–71.3ꢀC.
Anal. calcd for C12H15N2O2Cl: C, 56.58; H, 5.89; N, 11.00. Found: C,
56.37; H, 5.79; N, 10.78. IR: 3304, 1658, 1116. 1H NMR (300 MHz,
CDCl3): d ¼ 2.67 (t, 4H, J ¼ 4.4, Morpholine 2-H and 6-H, (N-CH2)), 3.73
(t, 4H, J ¼ 4.4, Morpholine 3-H and 5-H), (O-CH2)), 4.29 (d, 2H, J ¼ 6.1,
-CH2-), 7.41 (d, 2H, J ¼ 8.4, Ar 3-H and 5-H), 7.79 (d, 2H, J ¼ 8.4, Ar 2-H
and 6-H), 8.29 (br.s, 1H, NH). 13C NMR (75 MHz, CDCl3): d ¼ (2 Â 50.3),
61.5, (2 Â 66.0), (2 Â 128.6), (2 Â 128.8), 132.1, 138.0, 166.9.

N-(MORPHOLINOMETHYL) BENZAMIDES
ACKNOWLEDGMENTS
1445
We thanks to Facultad de Ciencias Quımicas y Farmaceuticas.
Universidad de Chile y al Centro de Instrumentacion CEPEDEQ, for
access to the instruments.
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Received in the USA May 14, 2001