Synthesis of 5-alkyl-2-amino-1,3,4-thiadiazoles and α,ω-bis(2- amino-1,3,4-thiadiazol-5-yl)alkanes in ionic liquids

Article abstract of DOI:10.1016/j.mencom.2011.11.013

Reaction of thiosemicarbazide with carboxylic acids, including N-substituted amino acids, in ionic liquids with H₂SO₄ as a catalyst affords 5-R-2-amino-1,3,4-thiadiazoles. On using alkanedicarboxylic acids, α,ω-bis(2-amino-1,3,4,-thiadiazol-5-yl)alkanes were obtained.

Full text of DOI:10.1016/j.mencom.2011.11.013

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 331–333
Synthesis of 5-alkyl-2-amino-1,3,4-thiadiazoles and
a,w-bis(2-amino-1,3,4-thiadiazol-5-yl)alkanes in ionic liquids
a
a
b
Margarita A. Epishina, Alexander S. Kulikov, Nikolai V. Ignat’ev,
b
a
Michael Schulte and Nina N. Makhova*
a
b
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: mnn@ioc.ac.ru
Ionic Liquid Research Laboratory, Merck KGaA, 64293 Darmstadt, Germany. E-mail: nikolai.ignatiev@merck.de
DOI: 10.1016/j.mencom.2011.11.013
Reaction of thiosemicarbazide with carboxylic acids, including N-substituted amino acids, in ionic liquids with H SO as a catalyst
2
4
affords 5-R-2-amino-1,3,4-thiadiazoles. On using alkanedicarboxylic acids, a,w-bis(2-amino-1,3,4,-thiadiazol-5-yl)alkanes were
obtained.
1
,3,4-Thiadiazole derivatives found application in medicine,
Furthermore, these reactions are suitable only for the synthesis of
monocyclic compounds. A synthesis of a,w-bis(2-amino-1,3,4-thia-
diazol-5-yl)alkanes 2 from dicarboxylic acids is based on multi-
step reactions, e.g., on refluxing of dihydrazides 3 of corre-
sponding diacids with KSCN in hydrochloric acid followed by
cyclization of the formed a,w-bis(thiosemicarbazid-4-yl)alkanes
4 into the target compounds 2 on treatment with an excess of
agriculture and in many technological areas such as manufac-
turing of dyes, lubricating formulations, optically active liquid
crystals, photographic materials, etc.1 A large number of
,2
1
,3,4-thiadiazole derivatives has been patented in the agricul-
3
4
tural field as herbicides, insecticides and fungicides. The
,3,4-thiadiazole ring is moiety of biologically active compounds
1
5
18
which possess antihypertensive, anticonvulsive and antituber-
culosis activities. 2-Amino derivatives occupy an important
conc. H SO , compounds 2 being characterized only by melting
2
4
6
points (Scheme 1).
place in the 1,3,4-thiadiazole series. One of the best-known
drugs based on 2-acetamido-5-sulfamido-1,3,4-thiadiazole, so-
called ‘acetazola’, is a carbonic anhydrase inhibitor. It is applied
This reaction, however, is not general and is applicable for
malonic and adipic acids only. 1,2-Bis(aminothiocarbamoyl)-
hydrazine is produced by heating of succinic acid dihydrazide
7
1
8
for therapy of many diseases such as epilepsy, glaucoma and
with KSCN. 1,2-Bis(2-amino-1,3,4-thiadiazol-5-yl)ethane 2b
8
congestive cardiac failure. 2-Amino-5-mercapto-1,3,4-thiadiazole
was synthesized under the action of thiosemicarbazide on bis-
9
19
derivatives are efficient radioprotective agents. 5-Alkyl-2-amino-
iminoether of succinic acid dihydrochloride 5 (Scheme 2).
1
,3,4-thiadiazoles display spasmolytic and anti-inflammatory
1
0
activities.
H
Cl H2N
EtO
NH2Cl
OEt
N
N
NH2
A synthesis of 2-amino-1,3,4-thiadiazoles 1 is based on cyclo-
(
CH2)2
+ 2 H N
2
condensation of carboxylic acids with thiosemicarbazide in the
S
1
1–13
5
acidic medium, mostly in conc. H SO , on heating.
In some
2
4
1
4
15
16
cases, POCl3, MeSO H in the presence of P O , PPA,
N
N
N
3
2
5
dichlorophosphate on polyethyleneglycole and acidic aluminum
oxide (with a simultaneous action of microwave radiation) are
used as acidic catalysts.17
(CH2)2
H2N
NH2
S
S
2
b
The above methods produce good results in many cases,
although they have certain disadvantages, in particular, a large
amount of inorganic salts is generated in neutralization of H SO
and other acidic catalysts, which results in adverse environmental
impact and creates troubles in the isolation of the final products.
Scheme 2
The goal of this research was to develop a new general method
for the preparation of both mono- (1) and bicyclic (2) 2-amino-
1,3,4-thiadiazole derivatives. As an approach to the solution of
that, we decided to carry out an interaction between carboxylic
acids and thiosemicarbazide in ionic liquids (ILs), which over
the past years have been widely employed as potential substitutes
of conventional solvents for a variety of chemical processes.
From a large pool of ILs at first of choice was 1-ethyl-3-methyl-
imidazolium hydrosulfate [emim][HSO ] since it is one of the
2
4
H
H
KSCN
HCl
N
(CH2)n
3
N
H2N
NH2
O
O
20–23
S
S
H
H
4
N
(CH2)n
N
most accessible and possesses acidic properties, so it can be
used both as a reaction medium and as an acidic catalyst.
Phenylacetic acid was selected as a starting object. However,
H2N
N
H
N
NH2
n = 1 or 4
H
O
O
4
its interaction with thiosemicarbazide in [emim][HSO ] even at
4
N
N
N
N
100°C did not bring about positive results. The target 2-amino-
5-phenyl-1,3,4-thiadiazole 1a was obtained in 87% yield after
adding several drops of conc. H SO to the reaction mixture and
(
CH2)n
H2N
NH2
S
S
2
4
2
stirring at 100°C for 5 h. These conditions proved appropriate for
Scheme 1
2011 Mendeleev Communications. All rights reserved.
preparing 2-amino-1,3,4-thiadiazoles 1b–g from other aliphatic
©
– 331 –

Mendeleev Commun., 2011, 21, 331–333
†
N
N
This procedure (see experimental, procedure 1), however, did
not allow regenerating and reuse of the IL. Therefore, we carried out
the same reactions in other ILs – 1-hexyl-1-methylimidazolium
and butylmethylpyrrolidinium trifluorotris(pentafluoroethyl)
H
N
NH2
i
RCOOH
+
2
H N
R
NH2
S
S
1
a–g
a R = PhCH (92%)
e R = MeS(CH ) CH(NHBz) (40%)
phosphates [hmim][F P(C F ) ] and [bmpyr][F P(C F ) ]
2
2 2
3
2
5 3
‡
3
2 5 3
b R = Pr (73%)
f
R = MeCH(NHBz) (96%)
g R = CH2(NHTs) (54%)
(
see experimental, procedure 2) with H SO as a catalyst. Thus,
i
2
4
c R = Pr (76%)
the target 2-amino-1,3,4-thiadiazoles 1a–g and 2a–d were formed
d R = CH NHBz (70%)
2
‡
in comparable yields. This procedure allowed regenerating ILs,
which were reused for the same reactions at least 3 times.
To conclude, a new, simple and general method was developed
for the preparation of both 5-substituted 2-amino-1,3,4-thia-
diazoles and a,w-bis(5-amino-1,3,4-thiadiazol-2-yl)alkanes. This
method was based on heating of mono- or dicarboxylic acids,
including N-protected a-amino acids, with thiosemicarbazide at
100°C in certain ILs with addition of H SO in a catalytic amount.
Scheme 3 Reagents and conditions: i, [emim][HSO ], [hmim][F P(C F ) ] or
4
3
2 5 3
[
bmpyr][F P(C F ) ], H SO (1–1.5 mol), 100°C, 5–6 h.
3
2
5 3
2
4
monocarboxylic acids (butyric and isobutyric acids), including
N-aroyl- or arylsulfonyl a-amino acids (Scheme 3), as well as for
synthesizing a,w-bis(2-amino-1,3,4-thiadiazol-5-yl)alkanes 2a–d
from aliphatic dicarboxylic acids – malonic, succinic, glutaric and
adipic (Scheme 4).
2
4
Some ILs have been regenerated and reused for the same reactions.
H
This work was supported by Merck KGaA.
N
NH2
HOOC (CH2)n COOH
+
H2N
S
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.11.013.
N
N
N
N
i
(
CH2)n
H2N
NH2
S
S
5
-Benzoylaminomethyl-1,3,4-thiadiazol-2-amine 1d: yield 70% (pro-
2
2
a n = 1 (41%)
b n = 2 (62%)
2c n = 3 (98%)
2d n = 4 (100%)
cedure 1), 77% (procedure 2), 75% (regenerated [hmim][F P(C F ) ]),
mp 218°C (lit.,24 216°C). H NMR, d: 4.58 (d, 2H, CH , J 8.4 Hz), 7.08
br.s, 2H, NH ), 7.48 (m, 3H, Ph, J 8.2 Hz), 7.88 (d, 2H, Ph, J 8.2 Hz),
.27 (t, 1H, NH, J 8.4 Hz). C NMR, d: 38.59 (CH ), 127.23, 128.40,
3
2 5 3
1
3
2
3
3
(
9
1
2
Scheme 4 Reagents and conditions: i, [emim][HSO ], [hmim][F P(C F ) ] or
4
3
2
5 3
3
13
2
[
bmpyr][F P(C F ) ], H SO (1–1.5 mol), 100°C, 5–6 h.
3
2
5 3
2
4
31.56, 133.59 (Ph), 156.55 (C CH ), 166.41, 169.36 (C–NH , C=O).
ring
2
2
–1
†
IR (n/cm ): 3312, 3120, 2932, 1628, 1600, 1580, 1528, 1512, 1484,
1424, 1344, 1312, 1264, 1180, 1152, 1068, 828, 720. MS, m/z (%): 234
All new compounds gave satisfactory elemental analyses and their struc-
tures were confirmed by IR, MS, H and C NMR spectra. IR spectra
were measured on a UR-20 spectrometer. H and C NMR spectra of
1
13
+
+
1
13
(M , 52), 129 (M – PhCO, 100), 105 (PhCO, 77), 76 (NH2CSNH2, 80).
-(1-Benzoylamino-3-methylthiopropyl)-1,3,4-thiadiazol-2-amine 1e:
5
compounds in DMSO-d were recorded on a Bruker AM300 spectrometer
6
1
1
13
yield 40% (procedure 1), 35% (procedure 2), mp 198–200°C. H NMR,
d: 2.02 (s, 3H, Me), 2.26 (m, 2H, CH C), 2.60 (m, 2H, CH S), 5.38 (q,
H, CH, J 8.6 Hz), 7.10 (br.s, 2H, NH ), 7.52 (m, 3H, Ph, J 8.0 Hz),
.92 (d, 2H, Ph, J 8.0 Hz), 9.04 (d, 1H, NH, J 8.6 Hz). C NMR, d:
4.71 (Me), 29.97 (CH C), 32.67 (CH S), 48.33 (CH), 127.47, 128.35,
31.56, 133.88 (Ph), 160.42 (C CH), 166.31, 168.90 (C–NH , C=O).
IR (n/cm ): 3268, 1640, 1580, 1516, 1492, 1436, 1316, 1264, 1216, 1192,
148, 1060, 968, 936, 864, 820, 804, 696. MS, m/z (%): 308 (M , 18),
(
300 MHz for H and 75.5 MHz for C). MS spectra were measured on a
Finnigan MAT INCOS-50 instrument. Melting points were measured on
a Gallenkamp instrument (Sanyo).
General procedure 1 for the synthesis of 5-substituted 2-amino-1,3,4-
thiadiazoles 1a–g and a,w-bis(5-amino-1,3,4-thiadiazol-2-yl)alkanes
2
2
3
3
1
7
1
1
2
3
3
13
2
2
2
a–d in [emim][HSO ]. Thiosemicarbazide (0.25 g, 2.74 mmol) was
ring
2
4
–1
added to 1 g of [emim][HSO ] (5 mmol) and this mixture was stirred for
5 min at 50°C. Then 3 mmol of a monocarboxylic acid or 1.5 mmol of
a dicarboxylic acid and 0.5 g (4.9 mmol) of 97% H SO were added, the
temperature was raised to 100°C and the reaction mixture was stirred for
–6 h in a reaction vessel supplied with condenser and protection from
moisture. The temperature was decreased to 20°C, 2 ml of water was
added, the reaction mixture was stirred for 15 min, then an aqueous
solution of ammonia was added to pH 7–8, stirring was continued for 1 h,
the precipitate was filtered off, washed with water and dried in air.
4
+
1
2
1
1
+
47 (M – MeSCH , 14), 234 (HetCH NHCOPh, 98), 129 (HetCH NH,
00), 105 (PhCO, 100), 77 (NH CSNH + 1, 89).
2
2
2
2
4
2
2
5-(Tosylaminomethyl)-1,3,4-thiadiazol-2-amine 1g: yield 54% (proce-
5
1
3
dure 1), mp 221°C. H NMR, d: 2.40 (s, 3H, Me), 4.12 (d, 2H, CH , J
.0 Hz), 7.15 (br.s, 2H, NH ), 7.42 (d, 2H, Ph, J 7.8 Hz), 7.72 (d, 2H,
Ph, J 7.8 Hz), 8.38 (t, 1H, NH, J 8.0 Hz). C NMR, d: 20.98 (Me),
1.71 (CH ), 126.56, 129.66, 137.30, 142.92 (Ph), 155.81 (C CH2),
169.60 (C–NH ). IR (n/cm ): 3480, 3368, 1595, 1524, 1496, 1420, 1380,
348, 1320, 1308, 1288, 1252, 1192, 1160, 1120, 1092, 1032, 968, 836,
12, 792, 704. MS, m/z (%): 284 (M , 1), 222 (18), 218 (7), 178 (13), 154
Ts – 1, 26), 129 (M – Ts, 56), 114 (M – TsNH, 50), 107 (77), 105 (99),
00 (NH Het, 77), 91 (100).
2
3
8
2
3
3
13
4
2
ring
–1
‡
General procedure 2 for the synthesis of 5-substituted 2-amino-1,3,4-
thiadiazoles 1a–g and a,w-bis(2-amino-1,3,4-thiadiazol-5-yl)alkanes
a–d in [hmim][F P(C F ) ] or [bmpyr][F P(C F ) ]. The carboxylic
2
1
8
(
1
+
2
3
2
5 3
3
2 5 3
+
+
acid (or N-protected a-amino acid) (2.2 mmol for monoacids or 1.1 mmol
for diacids) and 2 mmol of thiosemicarbazide were added to 1.5–2 g of
the corresponding IL and stirred for 5 min. Then 3.7 mmol of conc. H SO4
were added, the reaction mixture was heated to 100°C, stirred for 6 h at
this temperature and cooled to 20°C. The mixture of 5 ml of CH Cl :H O
1:1 v/v) was added to the reaction mixture, the organic layer was separated,
and the aqueous layer was extracted with CH Cl (6´2 ml). The organic
layer was washed with water, dried with MgSO , the solvent was evaporated,
2
1,2-Bis(5-amino-1,3,4-thiadiazol-2-yl)ethane 2b: yield 62% (proce-
2
19
1
dure 1), 63% (procedure 2), mp 290–293°C (lit., 2
d: 3.36 (s, 4H, 2CH2), 7.15 (s, 4H, 2NH2). C NMR, d: 28.94 (CH2), 156.38
(CringCH2), 168.57 (C–NH2). IR (n/cm ): 3240, 3096, 1656, 1556, 1444,
1424, 1400, 1372, 1360, 1224, 1172, 1152, 1052, 1016, 996, 688, 676. MS,
91–293°C). H NMR,
13
2
2
2
–1
(
2
2
+
m/z (%): 228 (M , 72), 153 (ring-CH2CH2CN – 1, 64), 114 (ring-CH2, 100).
4
the rest was dried under P O in a vacuum desiccator and the recovered
1,4-Bis(5-amino-1,3,4-thiadiazol-2-yl)butane 2d: yield 100% (procedure 1),
2
5
9
4% (procedure 2), mp 266–267°C (lit.,18 265–267°C). H NMR, d: 1.68
1
IL was reused in the next runs. Aqueous ammonia was added to the aqueous
layer to pH 7–8 and the reaction mixture was stirred for 1 h. Then the
precipitate formed was filtered off, washed with water and dried in air.
[br. s, 4H, CH2(CH2)2CH2], 2.80 [br.s, 4H, CH2(CH2)2CH2], 7.08 (s, 4H,
2NH2). 13C NMR, d: 28.16 [CH2(CH2)2CH2], 31.97 [CH2(CH2)2CH2],
–1
5
-Benzyl-1,3,4-thiadiazol-2-amine 1a: yield 92% (procedure 1), 80%
157.20 (CringCH2), 167.96 (C–NH2). IR (n/cm ): 3320, 3162, 1620, 1576,
1532, 1456, 1336, 1220, 1192, 1116, 1056, 688, 648, 632. MS, m/z (%): 256
(
procedure 2), 85% (procedure 2, regenerated [bmpyr][F P(C F ) ]),
3
2 5 3
16
1
(M , 4), 214 (M – NCNH2, 8), 199 (M+ – NCNHNH2, 9), 181 [ring-
+
+
mp 201–203°C (lit., 202–204°C). H NMR, d: 4.17 (s, 2H, CH ), 7.00
2
13
(
br.s, 2H, NH ), 7.27 (s, 5H, Ph). C NMR, d: 35.43 (CH ), 126.77, 128.49,
(CH ) CN – 1, 56], 141 [ring-(CH ) – 1, 100], 128 (ring-CH CH , 88), 115
2
2
2 4
2 3
2
2
–1
1
3
1
28.57, 137.98 (Ph), 157.50 (CringCH ), 168.77 (C–NH ). IR (n/cm ):
(ring-Me, 62), 99 (ring – 1, 48).
For characteristics of compounds 1b,c,f and 2a,c, see Online Supple-
mentary Materials.
2
2
320, 3104, 1632, 1612, 1520, 1504, 1452, 1424, 1368, 1328, 1216, 1148,
076, 1048, 920, 900, 748, 700.
–
332 –

Mendeleev Commun., 2011, 21, 331–333
12 V. K. Panday, S. Tusi, Z. Tusi, R. Raghbir, M. Dixit, M. N. Josh and
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Received: 15th June 2011; Com. 11/3740
–
333 –