Synthesis of novel aryloxy propanoyl thiadiazoles as potential antihypertensive agents

Article abstract of DOI:10.1002/jccs.201000196

2-Amino-5-aryl/alkyl-1,3,4-thiadiazoles 3a-e were synthesized from aliphatic and aromatic acids and thiosemicarbazide. These 2-amino-5-aryl/alkyl- 1,3,4-thiadiazoles 3a-e were condensed with 2-(naphthalenyloxymethyl) oxirane 4a-b to prepare some naphthalenyloxy-propanol amine derivatives 5a-j. These compounds were synthesized as potential antihypertensive agents.

Full text of DOI:10.1002/jccs.201000196

Journal of the Chinese Chemical Society, 2010, 57, 1327-1330
1327
Synthesis of Novel Aryloxy Propanoyl Thiadiazoles as Potential
Antihypertensive Agents
Amarish B. Samel and Nandini R. Pai*
Department of Organic Chemistry, D.G. Ruparel College, Senapati Bapat Marg,
Mahim, Mumbai-400 016, India
2-Amino-5-aryl/alkyl-1,3,4-thiadiazoles 3a-e were synthesized from aliphatic and aromatic acids and
thiosemicarbazide. These 2-amino-5-aryl/alkyl-1,3,4-thiadiazoles 3a-e were condensed with 2-(naphtha-
lenyloxymethyl) oxirane 4a-b to prepare some naphthalenyloxy-propanol amine derivatives 5a-j. These
compounds were synthesized as potential antihypertensive agents.
Keywords: Aryloxy propanol amines; 1,3,4-Thiadiazoles; Antihypertensive.
INTRODUCTION
RESULTS AND DISCUSSION
Numerous compounds are known which exhibit b-re-
ceptor blocking activity and therefore are useful in the
treatment of heart and vascular diseases such as angina
pectoris, hypertension, vasoregulatoric neurasteni and
some form of arrhythmia. For example 1-phenoxy-2-hy-
droxy-3,5-butyl amino propane derivatives which exhibit
bradcardia and block isoproterenol activity.1 A series of
para-substituted phenoxy hydroxy propyl amines are thera-
peutically effective to block the b-receptors of heart tis-
sue.2 Also a number of propanol amine compounds exhibit
b-adrenergic blocking activity3 of which some derivatives
contain 1-naphthoxy substituent and the primary amino
group are substituted by one or two alkyl or aralkyl radi-
cals. An important conventional compound which contains
a 1-naphthoxy substituent is propanolol which is a strong
b-adrenergic blocking agent.
The synthesis involves reaction of aromatic/aliphatic
acids 1a-e with thiosemicarbazide 2, using sulfuric acid for
dehydrative cyclization to produce 2-amino-5-aryl/alkyl-
1,3,4-thiadiazoles 3a-e. These 2-amino-5-aryl/alkyl-1,3,4-
thiadiazoles 3a-e on further treatment with 2-(naphthalen-
yloxymethyl) oxirane prepared by condensing naphthols
with excess epichlorohydrin employing potassium carbon-
ate in acetone, this approach minimizes second additions to
the epoxides and promotes ring closure to the epoxide
when nucleophilic attack occurs at the epoxide rather than
at the halide-containing carbon12 4a-b yielded the desired
substituted aryloxy propanol amines 5a-j. The structures of
the intermediates 3a-e and 4a-b, as well as the final prod-
ucts 5a-j, were confirmed on the basis of both analytical
and spectroscopic data.
EXPERIMENTAL SECTION
1,3,4-Thiadiazole, is a versatile pharmacophore which
exhibits a wide variety of biological activities. A few of
them which are worthy of mention are diuretic,4,5 CNS de-
pressants,6,7 hypoglycemic,8,9 anti-inflammatory,10 anti-
microbial activities.11-13 and antihypertensive properties of
2-aryl-5-hydrazino-1,3,4-thiadiazoles.14
Melting points were determined in open capillaries
1
on a Thomas Hoover apparatus and are uncorrected. H
NMR spectra were recorded on a Bruker 300 UltrashieldTM
at 300 MHz. 13C were obtained on the same instrument at
75.5 MHz in CDCl3 solution with tetramethylsilane (1H
spectra) or CDCl3 (13C spectra) as an internal reference, un-
less otherwise stated. Chemical shifts are given in parts per
million (ppm). Splitting patterns are designated as follows:
s- singlet, d- doublet, t- triplet, q- quartet and m- multiplet.
HRMS were recorded on micromss Q-Tof microTM instru-
It was planned to suitably incorporate the aryloxy
propanol moiety into the 1,3,4-thiadiazole ring system and
to explore the possibilities of some altered biological ac-
tion. Hence, the following aryloxy propanol amine deriva-
tives were synthesized.
* Corresponding author. E-mail: nandini_pai@hotmail.com

1328 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Samel and Pai
Table 1. Different substituent’s R and Ar for compounds 5a-j
Scheme I
Compounds
R
Ar
-CH3
5a
-CH3
5b
5c
5d
-CH2CH3
-CH2CH3
Cl
5e
5f
Cl
CH3
CH3
5g
ment. The reactions were followed up on TLC plates (Sil-
ica gel 60 F254, Merck), visualizing the spots in ultraviolet
light.
5h
5i
General procedures
Preparation of 2-Amino-(5-aryl/alkyl)-1,3,4-thiadi-
azoles12 3a-e
To a round bottom flask (r.b.f.) was added carboxylic
acid 1 (0.01 mol), thiosemicarbazide 2 (0.012 mol) and
conc. H2SO4 (15 mL) slowly under cooling. The resultant
reaction mixture was heated on a water bath for 3 h, then
poured into crushed ice and neutralized with ammonia so-
lution cautiously. A yellow coloured solid separated out. It
was filtered off, washed with saturated sodium bicarbonate
solution and water. Then dried under suction and crystal-
lized from ethanol.12
5j
1559 (C=C of aromatic ring), 1039 (N-N), 724 (C-S-C)
cm-1; 1H NMR (DMSO-d6): 6.06 (bs, 2H, NH2), 7.56-7.83
(m, 4H, Ar); 13C NMR (75.5 MHz; DMSO-d6) 127.7,
128.2, 129.3, 135.6, 154.6, 168.9.
3d. Yield (51%), mp. 117-119 ºC; IR: 3354 (NH2),
1554 (C=C of aromatic ring), 1036 (N-N), 727 (C-S-C)
cm-1; 1H-NMR (DMSO-d6): 2.32 (s, 3H, Ar-CH3), 7.24 (d,
2H, Ar-H), 7.36 (s, 2H, NH2), 7.61 (d, 2H, Ar-H);13C NMR
(75.5 MHz; DMSO-d6) 20.8, 126.2, 128.2, 129.6, 139.2,
156.4, 168.1.
3a. Yield (48%), mp. 110-112 ºC; IR: 3345 (NH2),
1027 (N-N), 725 (C-S-C) cm-1; 1H NMR (DMSO-d6): 2.37
(s, 3H, Ar-CH3), 6.9 (s, 2H, NH2); 13C NMR (75.5 MHz;
DMSO-d6) 15.0, 153.8, 168.4.
3b. Yield (50%), mp. 200-203 ºC; IR: 3345 (NH2),
1027 (N-N), 725 (C-S-C) cm-1; 1H NMR (DMSO-d6): 1.08
(t, 3H, CH2-CH3), 2.66 (q, 2H, Ar-CH2-CH3), 6.9 (s, 2H);
13C NMR (75.5 MHz; DMSO-d6) 13.7, 23.0, 159.6, 168.0.
3c. Yield (45%), mp. 120-122 ºC; IR: 3365 (NH2),
3e. Yield (53%), mp. 112-114 ºC; IR: 3350 (NH2),
1565 (C=C of aromatic ring), 1030 (N-N), 730 (C-S-C)
cm-1; 1H NMR (DMSO-d6): 7.36-7.49 (m, 5H, Ar) 7.76 (s,
2H, NH2); 13C NMR (75.5 MHz; DMSO-d6) 126.2, 129.0,

Anti-hypertensive: Aryloxy Propanoyl Thiadiazoles
J. Chin. Chem. Soc., Vol. 57, No. 6, 2010 1329
129.5, 130.9, 156.3, 168.4.
calcd. for C16H17N3O2S 316.1120 found: 316.1112.
Preparation of 2-(naphthalenyloxymethyl) oxirane13
To a round bottom flask (r.b.f.) was added (0.1 mol)
napthol, (0.2 mol) potassium carbonate, and (0.4 mol)
epichlorohydrin in 250 mL of acetone and heated to reflux
for 12 h. The reaction medium was then filtered and evapo-
rated, leaving oil, which was taken up in toluene and suc-
cessively washed with water, 1.0 N sodium hydroxide, and
water. The toluene phase was dried with magnesium sulfate
and evaporated to provide clear oil, which was chromato-
graphed on a silica gel column employing chloroform as
the eluant.
4a. Yield (73%), mp. 55 ºC;15 1H NMR (300 MHz;
CDCl3) 2.71 (1H, dd, CHCH2O), 2.85 (1H, t, CHCH2O),
3.32-3.36 (1H, m, CH2CH(O)CH2), 3.94 (1H, dd,
CHCH2OAr), 4.23 (1H, dd, CHCH2OAr), 7.07 (1H, d,
1-H), 7.13 (1H, dd, 3-H), 7.28-7.33 (1H, m, 6-H), 7.37-
5b. Yield (51%), mp. 103-104 ºC; IR: 3265 (NH),
1266 (O-H), 1077 (C-O) cm-1; 1H NMR (CDCl3): 2.25 (s,
3H, Ar-CH3), 4.08-4.14 (m, 1H, CH2NHCH), 4.26-4.33
(m, 1H, CH2NHCH), 4.38-4.47 (m, 2H, CHCH2OAr),
4.48-4.54 (m, 1H, CH2CH(OH)CH2), 6.83 (d, 1H, 2-H),
7.34-7.51 (m, 4H, 3-H, 4-H, 6-H, 7-H), 7.78-7.81 (m, 1H,
5-H), 8.28-8.31 (m, 1H, 8-H), 13C NMR (75.5 MHz;
CDCl3) 15.6, 52.0, 67.9, 68.9, 103.5, 119.2, 120.7, 123.9,
124.2, 124.5, 125.1, 126.1, 133.1, 143.1, 152.9, 164.9;
HRMS calcd. for C16H17N3O2S 316.1120 found: 316.1132.
5c. Yield (45%), mp. 92-94 ºC; IR: 3245 (NH), 1245
1
(O-H), 1087 (C-O) cm-1; H NMR (CDCl3): 1.22 (t, 3H,
CH2-CH3), 2.53 (q, 2H, Ar-CH2-CH3), 4.03-4.09 (m, 1H,
CH2NHCH), 4.13-4.2 (m, 1H, CH2NHCH), 4.21-4.35 (m,
2H, CHCH2OAr), 4.39-4.46 (m, 1H, CH2CH(OH)CH2),
5.27 (bs, 1H), 7.14-7.19 (m, 2H, 1-H, 3-H), 7.30 (t, 1H,
6-H), 7.42 (t, 1H, 7-H), 7.69-7.76 (m, 3H, 4-H, 5-H, 8-H),
13C NMR (75.5 MHz; CDCl3) 10.6, 23.1, 51.3, 67.4, 68.3,
105.1, 117.2, 121.9, 124.6, 125.1, 125.8, 127.3, 127.6, 132.7,
148.8, 154.8, 164.16; HRMS calcd. for C17H19N3O2S
330.1276 found: 330.1267.
7.43 (1H, m, 7-H), 7.66-7.73 (3H, m, 4-H, 5-H, 8-H). 13
C
NMR (75.5 MHz; CDCl3) 44.7, 50.1, 68.7, 106.9, 118.8,
123.9, 126.5, 126.8, 127.7, 129.2, 129.6, 134.5, 156.5.
4b. Yield (61%); 1H NMR (300 MHz; CDCl3) 2.80
(dd, 1H, -CHCH2O), 2.92 (t, 1H -CHCH2O), 3.40-3.46 (m,
1H, CH2CH(O)CH2), 4.05 (dd, 1H, CHCH2OAr), 4.31 (dd,
1H, CHCH2OAr), 6.80 (d, 1H, 2-H), 7.26 (t, 1H, 3-H),
7.51-7.54 (m, 3H, 4-H, 6-H, 7-H), 7.74-7.82 (m, 1H, 5-H),
8.26-8.34 (m, 1H, 8-H). 13C NMR (75.5 MHz; CDCl3)
44.7, 50.2, 68.9, 105.0, 120.8, 122.0, 125.3, 125.6, 125.7,
126.5, 127.4, 134.5, 154.2.
5d. Yield (49%), mp. 72-74 ºC; IR: 3256 (NH), 1265
1
(O-H), 1088 (C-O) cm-1; H NMR (CDCl3): 1.07 (t, 3H,
CH2-CH3), 2.37 (q, 2H, Ar-CH2-CH3), 3.97-4.03 (m, 1H,
CH2NHCH), 4.13-4.18 (m, 1H, CH2NHCH), 4.29-4.38 (m,
2H, CHCH2OAr), 4.4-4.45 (m, 1H, CH2CH(OH)CH2),
6.69, (d, 1H, 2-H), 5.75 (bs, 1H), 7.26-7.39 (m, 4H, 3-H,
4-H, 6-H, 7-H), 7.66-7.7 (m, 1H, 5-H), 8.19-8.22 (m, 1H,
8-H), 13C NMR (75.5 MHz; CDCl3) 10.2, 22.7, 51.2, 67.3,
68.1, 102.83, 118.5, 120.1, 123.1, 123.5, 123.7, 124.3,
125.3, 132.4, 148.3, 152.2, 163.9; HRMS calcd. for
C17H19N3O2S 330.1276 found: 330.1277.
Condensation of 2-(naphthalenyloxymethyl) oxirane
(epoxide) with 2-Amino-(5-aryl/alkyl)-1,3,4-thiadi-
azoles (amine) 5a-j
To a round bottom flask (r.b.f.) was added (2.5 mmol)
epoxide, (2.75 mmol) amine, 0.1 g magnesium trisilicate
and dissolved in 20 mL 1:1 toluene : methanol mixture and
refluxed for 48 h. The reaction medium was then filtered
and evaporated, leaving a residue, which was chromato-
graphed on a silica gel column employing chloroform with
2% methanol as the eluant.
5e. Yield (48%), mp. 135-136 ºC; IR: 3255 (NH),
1255 (O-H), 1077 (C-O) cm-1; 1H NMR (CDCl3): 4.07-4.16
(m, 1H, CH2NHCH), 4.19-4.26 (m, 1H, CH2NHCH), 4.35-
4.49 (m, 3H, CHCH2OAr, CH2CH(OH)CH2), 5.72 (1H, br
s, CH2CH(OH)CH2), 6.76 (1H, br s CH2-NHC, D2O-ex-
change), 7.19-7.62 (m, 8H, 1-H, 3-H, 6-H, 7-H naphthyl,
2-H, 3-H, 5-H, 6-H chloro phenyl), 7.69-7.81 (m, 3H, 4-H,
5-H, 8-H naphthyl); 13C NMR (75.5 MHz; CDCl3) 53.4,
69.0, 70.1, 107.0, 118.7, 123.7, 126.4, 126.8, 126.9, 127.6,
128.5, 129.1, 129.4, 134.4, 136.2, 145.0, 156.5, 164.8;
HRMS calcd. for C21H18ClN3O2S 412.0887 found:
412.0880.
5a. Yield (50%), mp. 112-113 ºC; IR: 3255 (NH),
1265 (O-H), 1087 (C-O) cm-1; 1H NMR (CDCl3): 2.25 (s,
3H, Ar-CH3), 3.95-4.01 (m, 1H, CH2NHCH), 4.13-4.19
(m, 1H, CH2NHCH), 4.21-4.30 (m, 2H, CHCH2OAr),
4.31-4.36 (m, 1H, CH2CH(OH)CH2), 7.12-7.15, (m, 2H,
1-H, 3-H), 7.26 (t, 1H, 6-H), 7.36 (t, 1H, 7-H), 7.64-7.70
(m, 3H, 4-H, 5-H, 8-H), 13C NMR (75.5 MHz; CDCl3)
15.3, 51.6, 67.4, 68.6, 105.2, 117.3, 122.1, 124.7, 125.2,
126.0, 127.4, 127.7, 132.8, 142.7, 154.9, 164.5; HRMS
5f. Yield (50%), mp. 125-126 ºC; IR: 3265 (NH),
1275 (O-H), 1089 (C-O) cm-1; 1H NMR (CDCl3): 4.01-4.07

1330 J. Chin. Chem. Soc., Vol. 57, No. 6, 2010
Samel and Pai
(m, 1H, CH2NHCH), 4.21-4.28 (m, 1H, CH2NHCH), 4.40-
4.53 (m, 3H, CHCH2OAr, CH2CH(OH)CH2), 5.72 (1H, br
s, CH2 NHC, D2O-exchange), 6.48 (d, 1H, 2-H naphthyl),
7.17-7.65 (m, 8H, 3-H, 4-H, 6-H, 7-H naphthyl, 2-H, 3-H,
5-H, 6-H chloro phenyl), 7.71-7.74 (m, 1H, 5-H naphthy),
8.24-8.28 (m, 1H, 8-H naphthyl); 13C NMR (75.5 MHz;
CDCl3) 51.6, 67.0, 68.0, 102.9, 118.5, 119.9, 123.1, 123.4,
123.7, 124.3, 124.8, 125.3, 126.3, 127.0, 132.4, 134.1,
142.8, 152.1, 162.8; HRMS calcd. for C21H18ClN3O2S
412.0887 found: 412.0876.
1256 (O-H), 1077 (C-O) cm-1; 1H NMR (CDCl3): 3.98-4.05
(m, 1H, CH2NHCH), 4.15-4.25 (m, 1H, CH2NHCH), 4.37-
4.62 (m, 3H, CHCH2OAr, CH2CH(OH)CH2), 5.72 (1H, br
s, CH2 NHCH, D2O-exchange, disappear), 6.82 (d, 1H, 2-H
naphthyl), 7.21-7.60 (m, 9H, 3-H, 4-H, 6-H, 7-H naphthyl,
2-H, 3-H, 4-H, 5-H, 6-H phenyl), 7.85-7.87 (m, 1H, 5-H
naphthy), 8.24-8.26 (m, 1H, 8-H naphthyl); 13C NMR (75.5
MHz; CDCl3) 53.1, 68.7, 69.6, 104.5, 120.1, 121.6, 124.7,
125.1, 125.2, 125.3, 125.8, 126.9, 128.3, 129.4, 129.7,
134.0, 145.7, 153.7, 164.6; HRMS calcd. for C21H20N3O2S
378.1276 found: 378.1285.
5g. Yield (50%), mp. 132-133 ºC; IR: 3268 (NH),
1265 (O-H), 1078 (C-O) cm-1; 1H NMR (CDCl3): 2.35 (s,
3H, Ar-CH3), 4.07-4.13 (m, 1H, CH2NHCH), 4.21-4.26
(m, 1H, CH2NHCH), 4.34-4.41 (m, 1H, CHCH2OAr),
4.46-4.53 (m, 2H, CHCH2OAr, CH2CH(OH)CH2), 7.19-
7.45 (m, 8H, 1-H, 3-H, 6-H, 7-H naphthyl, 2-H, 3-H, 5-H,
6-H p-Tolyl), 7.69-7.76 (m, 3H, , 4-H, 5-H, 8-H naphthyl);
13C NMR (75.5 MHz; CDCl3) 21.4, 53.4, 69.2, 70.2, 106.9,
118.9, 123.7, 125.7, 126.3, 126.8, 127.3, 127.6, 129.1,
129.4, 129.6, 134.5, 140.7, 146.5, 156.5, 165.2; HRMS
calcd. for C22H21N3O2S 392.1433found: 392.1442.
CONCLUSION
We have synthesized 10 compounds as potential
antihypertensive agents based on structure activity rela-
tionship with propanalol.
ACKNOWLEDGEMENTS
The authors are thankful to BASF India Ltd. for pro-
viding analytical support.
5h. Yield (49%), mp. 120-121 ºC; IR: 3255 (NH),
1267 (O-H), 1084 (C-O) cm-1; 1H NMR (DMSO-d6): 2.35
(s, 3H, Ar-CH3), 4.2-4.3 (m, 2H, CH2NHCH), 4.5-4.65 (m,
3H, CHCH2OAr, CH2CH(OH)CH2), 5.92 (1H, br s,
CH2CH(OH)CH2, D2O-exchange), 6.99 (d, 1H, 2-H naph-
thyl), 7.33 (d, 2H, 3-H, 5-H p-Tolyl), 7.36-7.54 (m, 4H,
3-H, 4-H, 6-H, 7-H naphthyl), 7.64 (d, 2H, 2-H, 6-H p-tol-
yl), 7.87 (d, 1H, 5-H naphthy), 8.27 (d, 1H, 8-H naphthy),
10.43 (1H, br s, CH2 NHCH, D2O-exchange, disappear);
13C NMR (75.5 MHz; DMSO-d6) 20.9, 53.5, 66.7, 69.5,
105.2, 120.1, 121.7, 124.6, 124.7, 125.1, 126.1, 126.4,
126.5, 127.3, 129.9, 133.9, 142.4, 153.7, 153.9, 167.2;
HRMS calcd. for C22H21N3O2S 392.1433. found: 392.1441.
5i. Yield (45%), mp. 126-127 ºC; IR: 3275 (NH),
1277 (O-H), 1087 (C-O) cm-1; 1H NMR (CDCl3): 4.02-4.17
(m, 1H, CH2NHCH), 4.19-4.29 (m, 1H, CH2NHCH), 4.47-
4.53 (m, 1H, CHCH2OAr), 4.64-4.94 (m, 2H, CHCH2OAr,
CH2CH(OH)CH2), 5.92 (1H, br s, CH2 NHCH, D2O-ex-
change, disappear), 7.19-7.45 (m, 9H, 1-H, 3-H, 6-H, 7-H
naphthyl, 2-H, 3-H, 4-H, 5-H, 6-H phenyl), 7.69-7.76 (m,
3H, 4-H, 5-H, 8-H naphthyl); 13C NMR (75.5 MHz; CDCl3)
53.3, 69.0, 70.0, 106.8, 118.7, 123.6, 125.7, 126.2, 126.7,
127.5, 128.8, 128.9, 129.3, 129.8, 130.2, 134.35, 146.2,
156.4, 165.0; HRMS calcd. for C21H20N3O2S 378.1276
found: 378.1271.
Received May 27, 2010.
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5j. Yield (51%), mp. 113-114 ºC; IR: 3245 (NH),