Synthesis of diamides from 1,4-Benzodioxane-2-and isochroman-1-carboxylic acids

Article abstract of DOI:10.1134/S1070428012070147

1,4-Benzodioxane-2-carboxylic acid and isochroman-1-carboxylic acid were treated with thionyl chloride, and the resulting acid chlorides reacted with p-aminobenzoic acid in dioxane in the presence of pyridine to produce the corresponding amido acids. The

Full text of DOI:10.1134/S1070428012070147

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 7, pp. 972–976. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © S.O. Vartanyan, A.B. Sargsyan, A.S. Avakyan, E.A. Markaryan, T.O. Asatryan, 2012, published in Zhurnal Organicheskoi Khimii,
2012, Vol. 48, No. 7, pp. 976–979.
Synthesis of Diamides from 1,4-Benzodioxane-2-
and Isochroman-1-carboxylic Acids
S. O. Vartanyan, A. B. Sargsyan, A. S. Avakyan, E. A. Markaryan, and T. O. Asatryan
Scientific Technological Center of Organic and Pharmaceutical Chemistry, Mndzhoyan Institute of Fine Organic Chemistry,
National Academy of Sciences of Armenia, pr. Azatutyan 26, Yerevan, 0014 Armenia
e-mail: avagal@mail.ru
Received January 16, 2012
Abstract—1,4-Benzodioxane-2-carboxylic acid and isochroman-1-carboxylic acid were treated with thionyl
chloride, and the resulting acid chlorides reacted with p-aminobenzoic acid in dioxane in the presence of
pyridine to produce the corresponding amido acids. The latter were converted into acid chlorides which were
brought into reaction with various amines to obtain a number of new diamides.
DOI: 10.1134/S1070428012070147
Interest in derivatives of oxygen-containing hetero-
cycles, 1,4-benzodioxane and isochroman, is deter-
mined by their high and diverse pharmacological activ-
ity. With a view to reveal effective biologically active
substances in this series, over a number of years we
performed studies on the synthesis of new amines,
amino alcohols, amino amides, and diamides possess-
ing adrenolytic, sympatholytic, antiarrhythmic, and
antihypoxic properties [1]. While continuing studies in
this line we tried to synthesize new diamides contain-
ing both heterocyclic 1,4-benzodioxane or isochroman
fragment and pharmacophoric N-substituted p-amino-
benzoic acid fragment. The latter is present in mole-
cules of a number of drugs and is probably responsible
for their pharmacological properties. We proposed the
following scheme for the synthesis of such com-
pounds. 1,4-Benzodioxane-2-carboxylic acid (I) or
isochroman-1-carboxylic acid (II) was initially treated
with thionyl chloride to obtain the corresponding acid
chloride which then reacted with p-aminobenzoic acid
to afford key amido acids III and IV. When the reac-
tion was carried out in toluene at 105–110°C (reaction
time 6–8 h), insoluble dimeric products were formed.
Desired amido acids III and IV were obtained in 75–
80% yield by heating in dioxane at 65–70°C for 4–5 h.
Acids III and IV were then converted into acid chlo-
rides, and reactions of the latter with various amines
gave diamides Va–Vh and VIa–VIi (Scheme 1). The
best yields (55–70%) were obtained in anhydrous di-
oxane in the presence of pyridine. As amine compo-
Scheme 1.
O
(1) SOCl2
(2) HNRR'
COOH
O
O
O
O
NRR'
SOCl2
4-H2NC6H4COOH
Ht
OH
Ht
Cl
Ht
N
H
Ht
N
H
I, II
III, IV
V, VI
O
O
O
.
I, III, V, Ht =
; II, IV, VI, Ht =
V, R = H, R′ = i-Bu (a), 4-EtOC(O)C6H4 (b), 1,4-benzodioxan-2-ylmethyl (c), 1-phenylcyclopentylmethyl (d), 1-(1,4-benzodioxan-
2-yl)ethyl (e), 3-(morpholin-4-yl)propyl (f), 1,3,4-thiadiazol-2-yl (g); RR′N = morpholin-4-yl (h); VI, R = H, R′ = s-Bu (a),
4-EtOC(O)C6H4 (b), 1,4-benzodioxan-2-ylmethyl (c), 1-phenylcyclopentylmethyl (d), 3-Cl-4-MeC6H3 (e), 3,4-(MeO)2C6H3CH2CH2 (f),
isochroman-1-ylmethyl (g), pyridin-2-yl (h); RR′N = piperidin-1-yl (i).
972

SYNTHESIS OF DIAMIDES FROM 1,4-BENZODIOXANE-2- ...
973
nent we used alkyl-, aralkyl-, hetaryl-, and hetaryl-
alkyl-amines, cyclic amines, and substituted anilines
with a view to reveal the most efficient pharmaco-
phoric fragment in the molecules of the final products.
The structure and purity of the synthesized com-
pounds were confirmed by physicochemical methods
and thin-layer chromatography. Compounds Vb–Vd,
Vf, and VIc were tested for their activity against
calcium chloride-induced arrhythmia; however, no
pronounced antiarrhythmic effect was observed. Study
on pharmacological properties of the synthesized
compounds will be continued.
16.3, 4.4 Hz), 3.10 d.d.d (1H, CH2, J = 16.3, 8.5,
5.0 Hz), 3.92 d.d.d (1H, OCH2, J = 11.1, 8.5, 4.0 Hz),
4.30 d.t (1H, OCH2, J = 11.1, 4.9 Hz), 5.25 s (1H,
OCH), 7.10–7.20 m (3H) and 7.44 m (1H) (iso-
chroman), 7.77 m and 7.88 m (2H each, C6H4), 9.75 s
(1H, NH); 12.21 m (1H, OH). Found, %: C 57.00;
H 4.81; N 4.48. C17H15NO4. Calculated, %: C 57.28;
H 5.05; N 4.78.
Acid III and IV chlorides were synthesized by
heating a solution of 50 mmol of acid III or IV and
7.2 g (60.5 mmol) of thionyl chloride in 50 ml of anhy-
drous toluene for 10 h at 80–85°C. The mixture was
cooled, the unreacted acid was filtered off, the filtrate
was evaporated under reduced pressure, 30 ml of anhy-
drous toluene was added to the residue, and the mix-
ture was evaporated to dryness. Yield 78–80%. The
products were brought into reaction with amines with-
out additional purification.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
trometer from samples dispersed in mineral oil. The
1H NMR spectra were measured on a Varian Mercury-
300 instrument from solutions in DMSO-d6 using
tetramethylsilane as internal reference. The mass spec-
tra were run on an MKh-1321A mass spectrometer
with direct sample admission into the ion source. The
melting points were determined on a Boetius hot stage.
The progress of reactions and the purity of products
were monitored by TLC on Silufol UV-254 plates
using benzene–acetone (3:1) as eluent; development
with iodine vapor.
Diamides Va–Vh and VIa–VIi (general proce-
dure). A mixture of 40 mmol of acid III or IV chloride,
40 mmol of the corresponding amine, and 3.2 g
(40 mmol) of pyridine in 50–70 ml of anhydrous diox-
ane was heated for 10–12 h at 70–75°C. The mixture
was filtered, the filtrate was poured into 150–200 ml of
water, the mixture was left overnight, and the precip-
itate was filtered off, washed with dilute hydrochloric
acid (1:3), water, a 5% solution of NaOH, and water
again, dried in air, and recrystallized from alcohol.
1,4-Benzodioxane-2-carboxylic acid (I) and its
chloride were synthesized according to the procedure
reported in [2], and isochroman-1-carboxylic acid (II)
and its chloride were prepared as described in [3].
N-(4-Isobutylcarbamoylphenyl)-1,4-benzodiox-
ane-2-carboxamide (Va). Yield 74%, white crystals,
1
mp 164–165°C, Rf 0.35. H NMR spectrum, δ, ppm:
4-(1,4-Benzodioxan-2-ylcarbonylamino)benzoic
acid (III). Pyridine, 3.2 g (40 mmol), was added to
a solution of 6.7 g (50 mmol) of p-aminobenzoic acid
in 80 ml of anhydrous dioxane, a solution of 12.0 g
(40 mmol) of 1,4-benzodioxane-2-carbonyl chloride in
50 ml of anhydrous dioxane was then slowly added,
the mixture was heated for 4–5 h at 70°C, cooled, and
poured into 200 ml of water, and the precipitate was
filtered off, washed with hot water, and dried in air.
Yield 9.2 g (78%), mp 259–260°C (from EtOH),
Rf 0.54. IR spectrum, ν, cm–1: 3391 (NH), 2730–2550
(OH), 1683 (C=O, acid), 1610, 1593 (C=O, amide).
Found, %: C 64.00; H 4.50; N 4.58. C16H13NO5. Cal-
culated, %: C 64.21; H 4.35; N 4.68.
0.94 d (6H, CH3, J = 6.7 Hz), 1.88 d [1H, CH(CH3)2,
J = 6.7 Hz], 3.08 d.d (2H, CH2, J = 6.7, 6.0 Hz),
4.28 d.d (1H, OCH2, J = 11.4, 6.9 Hz), 4.47 d.d (1H,
OCH2, J = 11.4, 2.7 Hz), 4.83 d.d (1H, OCH, J = 6.9,
2.7 Hz), 6.78–6.88 m (3H) and 7.00 m (1H) (benzodi-
oxane), 7.70 m and 7.79 m (2H each, C6H4), 8.04 t
(1H, NHCH2, 6.0 Hz), 9.98 s (1H, NH). Found, %:
C 67.68; H 6.45; N 7.71. C20H22N2O4. Calculated, %:
C 67.80; H 6.21; N 7.91.
Ethyl 4-[4-(1,4-benzodioxan-2-ylcarbonylamino)-
benzoylamino]benzoate (Vb). Yield 75%, white crys-
1
tals, mp 212–213°C, Rf 0.37. H NMR spectrum, δ,
ppm: 1.39 t (3H, CH3, J = 7.1 Hz), 4.31 q (2H,
OCH2CH3, J = 7.1 Hz), 4.31 d.d (1H, OCH2, J = 11.4,
6.7 Hz), 4.48 d.d (1H, OCH2, J = 11.4, 2.7 Hz),
4.86 d.d (1H, OCH, J = 6.7, 2.7 Hz), 6.79–6.89 m (3H)
and 7.01 m (1H) (benzodioxane), 7.81 m and 7.97 m
(2H each, NC6H4CON), 7.92 s (4H, NC6H4COO),
4-(Isochroman-1-ylcarbonylamino)benzoic acid
(IV) was synthesized in a similar way. Yield 75%, light
brown crystals, mp 243–244°C (EtOH), Rf 0.61.
1H NMR spectrum, δ, ppm: 2.79 d.t (1H, CH2, J =
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 7 2012

VARTANYAN et al.
974
10.12 s (1H, NH), 10.19 s (1H, NH). Found, %:
C 67.46; H 4.71; N 6.00. C25H22N2O6. Calculated, %:
C 67.26; H 4.93; N 6.28.
OCH2, J = 11.5, 6.9 Hz), 4.46 d.d (1H, OCH2, J = 11.5,
2.8 Hz), 4.83 d.d (1H, OCH, J = 6.9, 2.8 Hz), 6.77–
6.89 m (3H) and 7.00 m (1H) (benzodioxane), 7.71 m
and 7.78 m (2H each, C6H4), 8.13 t (1H, NHCH2, J =
5.7 Hz), 10.01 s (1H, NH). Found, %: C 64.63; H 6.12;
N 9.49. C23H27N3O5. Calculated, %: C 64.94; H 6.35;
N 9.88.
N-[4-(1,3,4-Thiadiazol-2-ylcarbamoyl)phenyl]-
1,4-benzodioxane-2-carboxamide (Vg). Yield 61%,
white crystals, mp 167–168°C, Rf 0.40. 1H NMR spec-
trum, δ, ppm: 4.31 d.d (1H, OCH2, J = 11.4, 6.7 Hz),
4.47 d.d (1H, OCH2, J = 11.4, 2.7 Hz), 4.86 d.d (1H,
OCH, J = 6.7, 2.7 Hz), 6.79–6.89 m (3H) and 7.01 m
(1H) (benzodioxane), 7.83 m and 8.14 m (2H each,
C6H4), 8.93 s (1H, CHS), 10.15 s (1H, NH), 12.81 br
(1H, NH). Found, %: C 56.17; H 3.34; N 14.25.
C18H14N4O4S. Calculated, %: C 56.54; H 3.66;
N 14.66.
N-[4-(1,4-Benzodioxan-2-ylmethylcarbamoyl)-
phenyl]-1,4-benzodioxane-2-carboxamide (Vc).
Yield 74%, light gray crystals, mp 160–161°C, Rf 0.41.
1H NMR spectrum, δ, ppm: 3.51 d.t (1H, CH2, J =
13.7, 6.2 Hz), 3.63 d.t (1H, CH2, J = 13.7, 5.4 Hz),
3.96 d.d (1H, OCH2, J = 11.8, 7.6 Hz), 4.29 d.d (1H,
OCH2, J = 11.5, 6.9 Hz), 4.29–4.36 m (2H, OCH2,
OCH), 4.46 d.d (1H, OCH2, J = 11.5, 2.7 Hz), 4.84 d.d
(1H, OCH, J = 6.9, 2.7 Hz), 6.72–6.88 m (7H) and
7.00 m (1H) (benzodioxane), 7.73 m and 7.84 m (2H
each, C6H4), 8.46 d.d (1H, NHCH2, J = 6.2, 5.4 Hz),
10.02 s (1H, NHCO). Found, %: C 67.00; H 4.65;
N 6.00. C25H22N2O6. Calculated, %: C 67.26; H 4.93;
N 6.28.
N-[4-(1-Phenylcyclopentylmethylcarbamoyl)-
phenyl]-1,4-benzodioxane-2-carboxamide (Vd).
Yield 78%, white crystals, mp 120–121°C, Rf 0.42.
1H NMR spectrum, δ, ppm: 1.67 m (2H ), 1.81–1.93 m
(4H), and 1.99–2.10 m (2H, C5H8); 3.46 d (2H, NCH2,
J = 6.2 Hz), 4.28 d.d (1H, OCH2, J = 11.4, 6.9 Hz),
4.46 d.d (1H, OCH2, J = 11.4, 2.7 Hz), 4.82 d.d (1H,
OCH, J = 6.9, 2.7 Hz), 6.78–6.88 m (3H) and 7.00 m
(1H) (benzodioxane), 7.14 m (1H) and 7.24–7.33 m
(4H) (Ph), 7.33 t (1H, NHCH2, J = 6.2 Hz), 7.62–
7.70 m (4H, C6H4), 9.98 s (1H, NH). Found, %:
C 73.22; H 6.34; N 5.87. C28H28N2O4. Calculated, %:
C 73.68; H 6.14; N 6.14.
N-[4-(Morpholin-4-ylcarbonyl)phenyl]-1,4-ben-
zodioxane-2-carboxamide (Vh). Yield 75%, white
1
crystals, mp 214–216°C, Rf 0.55. H NMR spectrum,
δ, ppm: 3.50–3.57 m (4H) and 3.59–3.64 m (4H)
(OCH2CH2N), 4.29 d.d (1H, OCH2, J = 11.4, 6.8 Hz),
4.46 d.d (1H, OCH2, J = 11.4, 2.7 Hz), 4.84 d.d (1H,
OCH, J = 6.8, 2.7 Hz), 6.78–6.89 m (3H) and 7.01 m
(1H) (benzodioxane), 7.33 m and 7.74 m (2H each,
C6H4), 10.01 s (1H, NH). Found, %: C 65.44; H 5.73;
N 7.33. C20H20N2O5. Calculated, %: C 65.21; H 5.43;
N 7.61.
N-[4-(Butan-2-ylcarbamoyl)phenyl]isochroman-
1-carboxamide (VIa). Yield 67%, light brown crys-
tals, mp 162–163°C, Rf 0.30. Found, %: C 71.12;
H 6.51; N 7.55. m/z 352 [M]+. C21H24N2O3. Calculated,
%: C 71.59; H 6.82; N 7.95. M 352.43.
N-{4-[1-(1,4-Benzodioxan-2-yl)ethylcarbamoyl]-
phenyl}-1,4-benzodioxane-2-carboxamide (Ve).
Yield 67%, light brown crystals, mp 138–140°C,
1
Rf 0.38. H NMR spectrum, δ, ppm: 1.38 d (3H, CH3,
J = 6.6 Hz), 3.95 d.d (1H, OCH2, J = 11.3, 7.4 Hz),
4.10 m (1H, OCH2), 4.17–4.33 m (4H, OCH2, OCH),
4.47 d.d (1H, OCH2, J = 11.3, 2.2 Hz), 4.84 d.d (1H,
OCH, J = 6.8, 2.4 Hz), 6.71–6.88 m (7H) and 7.00 m
(1H) (benzodioxane), 7.73 m and 7.84 m (2H each,
C6H4), 8.16 d (1H, NHCH, J = 8.3 Hz), 10.03 s (1H,
NH). Found, %: C 67.54; H 5.43; N 5.82. C26H24N2O6.
Calculated, %: C 67.83; H 5.22; N 6.09.
N-{4-[3-(Morpholin-4-yl)propylcarbamoyl]-
phenyl}-1,4-benzodioxane-2-carboxamide (Vf).
Yield 72%, white crystals, mp 166–167°C, Rf 0.52.
1H NMR spectrum, δ, ppm: 1.71 q (2H, NHCH2CH2,
J = 6.9 Hz), 2.38 t (2H, NCH2, J = 6.9 Hz), 2.39 m
(4H, NCH2CH2O), 3.31 t.d (2H, NHCH2, J = 6.9,
5.7 Hz), 3.59 m (4H, OCH2CH2N), 4.28 d.d (1H,
Ethyl 4-[4-(isochroman-1-ylcarbonylamino)ben-
zoylamino]benzoate (VIb). Yield 67%, light brown
1
crystals, mp 172–173°C, Rf 0.28. H NMR spectrum,
δ, ppm: 1.39 t (3H, CH3, J = 7.1 Hz), 2.84 m and
3.10 m (1H each, CH2), 3.93 d.d.d (1H, OCH2, J =
11.2, 8.2, 3.8 Hz), 4.31 q (2H, OCH2CH3, J = 7.1 Hz),
4.31 m (1H, OCH2), 5.27 s (1H, OCH), 7.11–7.20 m
(3H) and 7.46 m (1H) (isochroman), 7.82 m and
7.95 m (2H each, NC6H4CON), 7.91 s (4H, NC6H4-
COO), 9.82 s (1H, NH), 10.16 s (1H, NH), Found, %:
C 70.75; H 5.33; N 6.12. C26H24N2O5. Calculated, %:
C 70.27; H 5.41; N 6.31.
N-[4-(1,4-Benzodioxan-2-ylmethylcarbamoyl)-
phenyl]isochroman-1-carboxamide (VIc). Yield
64%, white crystals, mp 157–158°C, Rf 0.35. 1H NMR
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SYNTHESIS OF DIAMIDES FROM 1,4-BENZODIOXANE-2- ...
975
spectrum, δ, ppm: 2.79 d.t (1H, CH2, J = 16.2, 4.4 Hz),
3.10 d.d.d (1H, CH2, J = 8.2, 8.6, 5.1 Hz), 3.51 d.t (1H,
NCH2, J = 13.8, 6.3 Hz), 3.63 d.t (1H, NCH2, J = 13.8,
5.4 Hz), 3.92 d.d.d (1H, OCH2, J = 11.2, 8.6, 4.0 Hz),
3.96 d.d (1H, OCH2, J = 11.9, 7.7 Hz), 4.27–4.37 m
(3H, OCH2, OCH), 5.26 s [1H, OCHC(O)], 6.71–
6.85 m (4H, benzodioxane), 7.10–7.21 m (3H) and
7.47 m (1H) (isochroman), 7.75 m and 7.83 m (2H
each, C6H4), 8.43 t (1H, NHCH2, J = 5.9 Hz), 9.69 s
(1H, NH). Found, %: C 69.92; H 5.12; N 6.00.
C26H24N2O5. Calculated, %: C 70.27; H 5.41; N 6.31.
(isochroman), 7.72 m and 7.76 m (2H each, C6H4),
8.09 t (1H, NHCH2, J = 5.7 Hz), 9.69 s (1H, NH).
Found, %: C 70.82; H 6.33; N 6.00. C27H28N2O5. Cal-
culated, %: C 70.43; H 6.09; N 6.09.
N-[4-(Isochroman-1-ylmethylcarbamoyl)phenyl]-
isochroman-1-carboxamide (VIg). Yield 73%, light
1
yellow crystals, mp 169–170°C, Rf 0.45. H NMR
spectrum, δ, ppm: 2.71–2.96 m (3H, CH2), 3.10 m (1H,
CH2), 3.43 d.d.d (1H, NCH2, J = 13.6, 9.1, 5.4 Hz),
3.75 d.d.d (1H, OCH2, J = 11.3, 7.7, 4.2 Hz),
3.87 d.d.d (1H, NCH2, J = 13.6, 5.7, 3.0 Hz), 3.92 m
(1H, OCH2), 4.12 d.t (1H, OCH2, J = 11.4, 5.0 Hz),
4.31 d.t (1H, OCH2, J = 11.1, 5.0 Hz), 4.88 d.d (1H,
OCHCH2, J = 9.1, 3.0 Hz), 5.25 s (1H, OCH); 7.06–
7.19 m (6H), 7.26 m (1H), and 7.46 m (1H) (isochro-
man); 7.73 m and 7.82 m (2H each, C6H4), 8.13 t (1H,
NHCH2, J = 5.7 Hz), 9.70 s (1H, NH). Found, %:
C 73.55; H 5.89; N 6.18. C27H26N2O4. Calculated, %:
C 73.30; H 5.88; N 6.33.
N-[4-(1-Phenylcyclopentylmethylcarbamoyl)-
phenyl]isochroman-1-carboxamide (VId). Yield
68%, light brown crystals, mp 139–140°C, Rf 0.37.
1H NMR spectrum, δ, ppm: 1.60–1.75 m (2H), 1.77–
1.94 m (4H), and 1.97–2.10 m (2H) (C5H8); 2.78 d.t
(1H, CH2, J = 16.3, 4.4 Hz), 3.09 d.d.d (1H, CH2, J =
16.3, 8.6, 5.0 Hz), 3.45 d (2H, NHCH2, J = 6.3 Hz),
3.91 d.d.d (1H, OCH2, J = 11.1, 8.6, 4.0 Hz), 4.30 d.t
(1H, OCH2, J = 11.1, 5.0 Hz), 5.24 s (1H, OCH), 7.10–
7.20 m (3H) and 7.44 m (1H) (isochroman), 7.15 t
(1H, NHCH2, J = 6.3 Hz), 7.23–7.33 m (5H, Ph),
7.61 m and 7.69 m (2H each, C6H4), 9.68 s (1H, NH).
Found, %: C 76.45; H 6.28; N 5.92. C29H30N2O3. Cal-
culated, %: C 76.65; H 6.61; N 6.17.
N-[4-(Pyridin-2-ylcarbamoyl)phenyl]isochro-
man-1-carboxamide (VIh). Yield 71%, gray crystals,
1
mp 183–184°C, Rf 0.51. H NMR spectrum, δ, ppm:
2.79 d.t (1H, CH2, J = 16.4, 4.4 Hz), 3.11 m (1H, CH2),
3.92 d.d.d (1H, OCH2, J = 11.2, 8.5, 4.0 Hz), 4.31 d.t
(1H, OCH2, J = 11.2, 5.0 Hz), 5.27 s (1H, OCH),
7.03 m (1H, Py), 7.11–7.21 m (3H) and 7.46 m (1H)
(isochroman), 7.72 m (1H, Py), 7.80 m and 8.00 m (2H
each, C6H4), 8.26–8.31 m (2H, Py), 9.76 s (1H, NH),
10.18 s (1H, NH). Found, %: C 70.54; H 5.27;
N 11.42. C22H19N3O3. Calculated, %: C 70.78; H 5.09;
N 11.26.
N-[4-(3-Chloro-4-methylphenylcarbamoyl)-
phenyl]isochroman-1-carboxamide (VIe). Yield
1
63%, gray crystals, mp 171–172°C, Rf 0.41. H NMR
spectrum, δ, ppm: 2.34 s (3H, CH3), 2.80 d.t (1H, CH2,
J = 16.3, 4.4 Hz), 3.11 d.d.d (1H, CH2, J = 16.3, 8.5,
5.1 Hz), 3.93 d.d.d (1H, OCH2, J = 11.1, 8.5, 4.0 Hz),
4.31 d.t (1H, OCH2, J = 11.1, 5.1 Hz), 5.27 s (1H,
OCH), 7.11–7.22 m (3H) and 7.47 m (1H) (isochro-
man), 7.16 d (1H, 5-H in C6H3, J = 8.3 Hz), 7.61 d.d
(1H, 6-H in C6H3, J = 8.3, 2.2 Hz), 7.90 d (1H, 2-H in
C6H3, J = 2.2 Hz), 7.81 m and 7.92 m (2H each, C6H4),
9.79 s (1H, NH), 9.94 s (1H, NH). Found, %: C 68.01;
H 4.68; N 6.17. C24H21ClN2O3. Calculated, %:
C 68.49; H 4.99; N 6.66.
N-[4-(Piperidin-1-ylcarbonyl)phenyl]isochro-
man-1-carboxamide (VIi). Yield 71%, light brown
1
crystals, mp 134–135°C, Rf 0.47. H NMR spectrum,
δ, ppm: 1.51–1.73 m (6H, 3-H, 4-H, 5-H, piperidine),
2.79 d.t (1H, CH2, J = 16.3, 4.4 Hz), 3.10 d.d.d (1H,
CH2, J = 16.3, 8.7, 5.1 Hz), 3.47 m (4H, NCH2, piper-
idine), 3.91 d.d.d (1H, OCH2, J = 11.1, 8.7, 4.1 Hz),
4.31 d.t (1H, OCH2, J = 11.1, 4.9 Hz), 5.24 s (1H,
OCH), 7.10–7.20 m (3H) and 7.44 m (1H) (isochro-
man), 7.26 m and 7.74 m (2H each, C6H4), 9.67 s
(1H, NH). Found, %: C 72.32; H 6.19; N 7.42. m/z 364
[M]+. C22H24N2O3. Calculated, %: C 72.53; H 6.59;
N 7.69. M. 364.44.
N-{4-[2-(3,4-Dimethoxyphenyl)ethylcarbamoyl]-
phenyl}isochroman-1-carboxamide (VIf). Yield
67%, light brown crystals, mp 97–98°C, Rf 0.33.
1H NMR spectrum, δ, ppm: 2.78 t (2H, C6H3CH2, J =
7.3 Hz), 2.78 m (1H, CH2), 3.10 d.d.d (1H, CH2, J =
16.0, 8.6, 5.0 Hz), 3.46 t.d (2H, NCH2, J = 7.3,
5.7 Hz), 3.75 s (3H, OCH3), 3.76 s (3H, OCH3),
3.91 d.d.d (1H, OCH2, J = 11.1, 8.4, 4.0 Hz), 4.30 d.t
(1H, OCH2, J = 11.1, 4.9 Hz), 5.25 s (1H, OCH), 6.69–
6.77 m (3H, C6H3), 7.10–7.20 m (3H) and 7.45 m (1H)
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