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2 3-Bis5-alkyl-2-thiono-1 3 5-thiadiazin-3-yl Propionic AcidOne-Pot Domino Synthesis and Antimicrobial Activity.

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DOI 10.1002/ardp.200400906
38
Arch. Pharm. Chem. Life Sci. 2005, 338, 38−43
2,3-Bis(5-alkyl-2-thiono-1,3,5-thiadiazin-3-yl)
Propionic Acid: One-Pot Domino Synthesis and
Antimicrobial Activity
Serry A. A. El Bialya, Ali M. Abdelala, Abdel-Nasser El-Shorbagib, and
Samy M. M. Kheirac
a
Department of Pharmaceutical Organic Chemistry, University of Mansoura, Mansoura, Egypt
Department of Pharmaceutical Organic Chemistry Faculty of Pharmacy, Assiut University, Assiut, Egypt
c
Department of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
b
In a search for promising antibacterial and antifungal compounds, two new series of 2,3-bis(5-alkyl2-thiono-1,3,5-thiadiazin-3-yl)propionic acid 1 and their corresponding N,N-dimethylpropionamide 6
have been synthesized. The reaction of 2,3-diaminopropionate 3, carbon disulfide, formaldehyde, and
the appropriate alkyl amines furnished the title compound 1. N,N-dimethylpropionamides 6 were obtained by the reaction of 1 with dimethyl amine in the presence of POCl3. The newly prepared compounds were screened in vitro against certain strains of Gram-positive and Gram-negative bacteria
and compared with nalidixic acid and ciprofloxacin. Moreover, the title compounds were tested for
their antifungal activity in vitro against Candida albicans, phytopathogenic, Penicillum expansum and
Trichoderma hazianum, and aflatoxin-producing Aspergillus flavus. These compounds exhibit varied
activity against the tested pathogenic bacteria and remarkable inhibitory effects on growth or sporulation of some of the tested fungal species.
Keywords: Bis(2-thiono-tetrahydro-2H-1,3,5-thiadiazine); Domino reaction, Antibacterial and antifungal
activity
Received: June 15, 2004; Accepted: October 22, 2004 [FP906]
Introduction
structures for selective antifungal or dual antibacterial antifungal agents [19, 20].
The syntheses of novel molecules which resemble known
biologically active compounds by virtue of the presence of
pharmacophoric groups represent the main approach for
discovering highly potent active agents. There is a growing
and critical need for more potent antifungal agents because
of the increasing detection of systemic mycosis in patients
suffering from debilitating diseases such as neoplasia and in
long term parenteral nutrition [1]. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadizin-2-thione derivatives deserve great
interest for their biological and pharmacological activities,
especially for their potential antitumor and antifungal
properties [2-18]. It was reported that 1,2-bis(2-thiono-1,3,5thiadiazinan-3-yl)ethane displays a promising antibacterial
and antifungal activity through the production of isothiocyanate and dithiocarbamic acid. Therefore, and as a continuation of our research on five- and/or six-membered heterocycles which are separated by one or two carbon atoms, we
directed our interest towards the synthesis of new lead
The retrosynthetic analysis (Scheme 1) of 2,3-bis(2-thiono1,3,5-thiadiazinan-3-yl)propionic acid derivatives 1 revealed
that compound 1 could be obtained from intramolecular
addition of the secondary amine to the iminium salt in 5.
The formation of reacting species in the intermediate 5, iminium salt and S-amino-methyl, was achieved by the reaction of HCHO with the secondary amine and thiol groups
of compound 4 in acid medium, respectively [20]. By the
effect of acid, bis(dithiocarbamic acid) 4 was made accessible from the potassium bis(dithiocarbamate) 2 in acidic medium; potassium bis(dithiocarbamate) 2 which, in turn, was
obtained from the reaction of CS2 with the diamine 3.
Correspondence: Serry A. A. El Bialy, The University of Tokyo,
Graduate School of Science, Chemistry Department, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan. Phone: ⫹81 3 5841-4344,
Fax: ⫹81 3 5800-6891, e-mail: sbialy65@yahoo.com
In contrast to the stepwise formation of individual bonds
in the target molecules using multi-step transformation,
domino reactions can form several bonds in one sequence
without isolating the intermediates, changing the reaction
conditions, or adding reagent [21, 22]. Therefore, this type
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Results and discussion
Chemistry
Arch. Pharm. Chem. Life Sci. 2005, 338, 38−43
Bis(1,3,5-thiadiazin-3-yl) Propionic Acids
Scheme 1. The retrosynthetic analysis and the synthetic mechanism of 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadizin-2-thione.
of reactions would allow an ecologically and economically
favorable production [23].
Scheme 2. Synthesis of 2,3-bis(2-thiono-1,3,5-thiadiazinan3-yl)propanoic acids (1a⫺h) and their N,N-dimethyl propionamide derivatives (6a⫺h)
Practically, the synthesis of 2,3-bis(2-thiono-1,3,5-thiadiazinan-3-yl)propionic acid derivatives 1 was carried out
using a three-component domino reaction. Thus, according
to the retrosynthesis the process would be carried out by
reacting the free bis(dithiocarbamic acid) 4, formaldehyde,
and secondary amines to furnish the title compounds. Ethyl
2,3-diaminopropionate 3 [24⫺26] reacted with two equivalents of carbon disulfide in the presence of aqueous KOH
solution to give the corresponding bis(dithiocarbamate) 2
which was treated with a known excess of HCl to liberate
the free bis(dithiocarbamic acid) 4. In order to improve the
overall yield of reaction, it is advantageous to prepare the
bis(dithiocarbamate) 2 in the presence of sufficient amounts
Table 1. Physical data of 2,3-bis(2-thiono-1,3,5-thiadiazinan-3-yl)propanoic acids (1a⫺h) and their N,N-dimethyl propionamide
derivatives (6a⫺h). Elemental analyses were within 0.4 % of the calculated value.
Compound
No.
R
Molecular
Formula
Crystallization
Solvent†
Yield
[%]
M.P
[°C]
1a
1b
1c
1d
1e
1f
1g
1h
6a
6b
6c
6d
6e
6f
6g
6h
CH3
C2H5
C3H7
C4H9
Cyclo C6H11
C6H5CH2
4-FC6H4CH2
C6H5(CH2)2
CH3
C2H5
C3H7
C4H9
Cyclo C6H11
C6H5CH2
4-FC6H4CH2
C6H5(CH2)2
C11H18N4O2S4
C13H22N4O2S4
C15H26N4O2S4
C17H30N4O2S4
C21H34N4O2S4
C23H26N4O2S4
C23H24F2N4O2S4
C25H30N4O2S4
C13H23N5OS4
C15H27N5OS4
C17H23N5OS4
C19H35N5OS4
C23H39N5OS4
C25H31N5OS4
C25H29F2N5OS4
C27H26N5OS4
A
B
C
A⫺D
A⫺D
A⫺E
F
B
C
C⫺D
A⫺E
A⫺E
B
C
F⫺D
A⫺E
63
62
70
66
72
58
80
77
60
64
63
60
70
82
90
83
210⫺212
187⫺189
196⫺198
156⫺158
146⫺148
202⫺204
177⫺179
210⫺212
122⫺124
120⫺122
135⫺137
119⫺121
145⫺147
168⫺170
128⫺130
166⫺168
†
A: Ethanol, B: Acetic acid, C: Methanol, D: Water, E: Chloroform, F: Acetone.
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
39
40
El Bialy et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 38−43
Table 2. NMR data of 2,3-bis(2-thiono-1,3,5-thiadiazinan-3-yl)propanoic acids (1a⫺h) and their N,N-dimethyl propionamide
derivatives (6a⫺h).
No
R
N-R
CHCH2
4 & 4⬘-CH2
6 & 6⬘-CH2
1a
CH3
2.59 (s, 6H, 2 CH3)
4.15 (d, 2H, J ⫽ 6.8 Hz)
4.37 (t, 1H, J ⫽ 6.8 Hz)
4.37 (s, 4H)
4.42 (s, 4H)
1b
C2H5
1.32 (t, 6H, J ⫽ 7.3, 2 CH2)
2.74 (q, 4H, J ⫽ 7.3, 2 CH2)
4.12 (d, 2H, J ⫽ 6.8 Hz)
4.31 (t, 1H, J ⫽ 6.8 Hz)
4.29 (s, 4H)
4.35 (s, 4H)
1c
i-C3H7
1.19 (d, 6H, J ⫽ 6.8 Hz, 2CH3)
3.57 (m, 2H, 2 CH)
4.05 (d, 2H, J ⫽ 6.8 Hz)
4.30 (t, 1H, J ⫽ 6.8 Hz)
4.19 (s, 4H)
4.60 (s, 4H)
1d
C4H9
0.89 (t, 6H, 2CH3)
1.38-1.49 (m,8H, 2CH2CH2)
2.68 (t, 4H, 2CH2)
4.01 (d, 2H, J ⫽ 6.8 Hz)
4.27 (t, 1H, J ⫽ 6.8 Hz)
4.15 (s, 4H)
4.55 (s, 4H)
1e
cyclo-C6H11
1.40-2.32 (m, 20H, 2C6H11)
3.15-3.27 (m, 2H, 2CHcyc)
4.20 (d, 2H, J ⫽ 6.8 Hz)
4.36 (t, 1H, J ⫽ 6.8 Hz)
3.98 (s, 4H)
4.52 (s, 4H)
1f
C6H5CH2
4.20 (s, 4H, 2CH2C6H5)
7.59-7.65 (m, 10H, Ar-H).
4.14 (d, 2H, J ⫽ 6.8 Hz)
4.41 (t, 1H, J ⫽ 6.8 Hz)
4.46 (s, 4H)
4.67 (s, 4H)
1g
4-FC6H4CH2
4.42 (s, 4H, 2 CH2C6H4F)
6.98-7.08 (m, 4H, Ar-H)
7.45-7.56 (m, 4H, Ar-H)
4.27 (d, 2H, J ⫽ 6.8 Hz)
4.49 (t, 1H, J ⫽ 6.8 Hz)
4.48 (s, 4H)
4.69 (s, 4H)
1h
C6H5CH2CH2
3.23 (t, 4H, 2CH2C6H5)
3.86 (t, 4H, 2NCH2CH2C6H5)
7.25-7.52 (m, 10H, Ar-H)
4.15 (d, 2H, J ⫽ 6.8 Hz)
4.45 (t, 1H, J ⫽ 6.8 Hz)
4.56 (s, 4H)
4.61 (s, 4H)
6a
CH3
2.47 (s, 6H, 2 CH3)
4.31 (d, 2H, J ⫽ 6.8 Hz)
4.35 (t, 1H, J ⫽ 6.8 Hz)
4.41 (s, 4H)
4.40 (s, 4H)
6b
C2H5
1.37 (t, 6H, J ⫽ 7.3 , 2 CH2)
2.79 (q, 4H, J ⫽ 7.3, 2 CH2)
4.23 (d, 2H, J ⫽ 6.8 Hz)
4.41 (t, 1H, J ⫽ 6.8 Hz)
4.29 (s, 4H)
4.38 (s, 4H)
6c
i-C3H7
1.21 (d, 6H, J ⫽ 6.8 Hz, 2 CH3)
3.59 (m, 2H, 2 CH)
4.15 (d, 2H, J ⫽ 6.8 Hz)
4.37 (t, 1H, J ⫽ 6.8 Hz)
4.23 (s, 4H)
4.73 (s, 4H)
6d
C4H9
0.89 (t, 6H, 2CH3)
1.38-1.49 (m,8H, 2CH2CH2)
2.68 (t, 4H, 2CH2)
4.02 (d, 2H, J ⫽ 6.8 Hz)
4.47 (t, 1H, J ⫽ 6.8 Hz)
4.20 (s, 4H)
4.71 (s, 4H)
6e
cyclo-C6H11
1.58-2.42 (m, 20H, 2C6H11)
3.21-3.36 (m, 2H, 2CHcyc)
4.15 (d, 2H, J ⫽ 6.8 Hz)
4.40 (t, 1H, J ⫽ 6.8 Hz)
4,01 (s, 4H)
4.50 (s, 4H)
6f
C6H5CH2
4.27 (s, 4H, 2CH2C6H5)
7.65-7.81 (m, 10H, Ar-H)
4.23 (d, 2H, J ⫽ 6.8 Hz)
4.46 (t, 1H, J ⫽ 6.8 Hz)
4.52 (s, 4H)
4.74 (s, 4H)
6g
4-FC6H4CH2
4.43 (s, 4H, 2 CH2C6H4F)
7.17-7.28 (m, 4H, Ar-H)
7.65-7.86 (m, 4H, Ar-H)
4.42 (d, 2H, J ⫽ 6.8 Hz)
4.52 (t, 1H, J ⫽ 6.8 Hz)
4.49 (s, 4H)
4.82 (s, 4H)
6h
C6H5CH2CH2
3.23 (t, 4H, J ⫽ 7.6 Hz 2CH2C6H5)
3.88 (t, 4H, J ⫽ 7.6 Hz
2NCH2CH2C6H5)
7.25-7.52 (m, 10H, Ar-H)
4.32 (d, 2H, J ⫽ 6.8 Hz)
4.42(t, 1H, J ⫽ 6.8 Hz)
4.58 (s, 4H)
4.71 (s, 4H)
of a water-miscible solvent e.g. methanol or acetonitrile. For
further reaction, 4 mol of formaldehyde in aqueous solution
and 2.1 mol of primary amines as HCl salt were added and
the reaction mixture was stirred at room temperature. In
order to isolate the products, the solution was concentrated
and the residue was treated with alkali and taken up with
EtOAc from which the 2,3-bis(2-thiono-1,3,5-thiadiazinan3-yl)propionic acid derivatives 1 were obtained (Scheme 2).
The reaction of 1 with dimethyl amine in the presence of
POCl3 gave the corresponding propionamide derivatives 6
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
in high yield. Table 1 shows the physicochemical data of the
newly synthesized derivatives (1a⫺h, 6a⫺h).
Antibacterial activity
The antibacterial activity of the prepared compounds
was determined against certain strains of Grampositive (Staphylococcus aureus and Staphylococcus faecalis)
and Gram-negative bacteria (Escherichia Coli and Pseudo-
Table 3. The in vitro antimicrobial activity of the prepared compounds 1⫺6 and Ciprofloxacin at 1 µg/mL.
Minimum inhibitory concentration (MIC) [µg/mL]†
(mean ± S.E.M, n ⴝ 5)
Microorganisms tested‡
2
3
Compound
No.
1
65 ±0.9
77 ±0.6
46 ±2.1
96 ±0.1
80 ± 0.2
20 ± 2.5
9 ± 1.5
44 ± 0.2
50 ± 3.2
62 ± 1.5
85 ± 0.2
62 ± 0.8
98 ± 0.5
112 ± 1.5
62 ± 2.3
115 ± 0.4
0.4 ± 0.1
⫺
1a
1b
1c
1d
1e
1f
1g
1h
6a
6b
6c
6d
6e
6f
6g
6h
Ciprofloxacin
Control
†
‡
99 ± 2.4
112 ± 1.1
65 ± 0.3
43 ± 2.1
95 ± 0.8
18 ± 0.5
10 ± 5.0
30 ± 0.3
46 ± 0.8
39 ± 2.5
170 ± 3.0
44 ± 0.2
35 ± 0.6
210 ± 4.0
96 ± 0.8
202 ± 0.9
0.3 ± 0.005
⫺
45 ± 4.2
110 ± 1.5
95 ± 0.7
70 ± 0.3
19 ± 1.8
45 ± 4.5
15 ± 0.5
22 ± 0.7
75 ± 0.3
210 ± 3.7
115 ± 4.6
102 ± 3.5
114 ± 0.7
98 ± 0.9
15 ± 0.6
54 ± 0.5
0.8 ± 0.01
⫺
4
222 ± 0.1
210 ± 0.1
68 ± 4.5
95 ± 0.9
153 ± 0.5
35 ± 3.5
40 ± 4.2
16 ± 0.5
65 ± 2.5
120 ± 0.9
49 ± 0.1
156 ± 0.1
203 ± 0.7
200 ± 0.9
66 ± 4.1
116 ± 3.2
0.5 ± 0.05
⫺
Minimum inhibitory concentration (MIC), is the lowest concentration of the tested compounds that inhibits visible growth of the organism
after 24h at 37 °C.
The microorganisms tested: 1: Staphylococcus aureus ATCC 29213 (Gram-positive bacteria); 2: Staphylococcus faecalis VGH 84-87 (Grampositive bacteria); 3: Escherichia coli ATCC 25922 (Gram-negative bacteria); 4: Pseudomonas aeruginsa VGH 84-4 (Gram-negative bacteria).
Table 4. DNA gyrase inhibitory of the prepared compounds
compared with Nalidixic acid.
Compound
No.
IC50
[1 µg/mL]
Compound
No.
IC50
[1 µg/mL]
1a
1b
1c
1d
1e
1f
1g
1h
Nalidixic
acid
130
73
63
120
90
60
58
156
57
6a
6b
6c
6d
6e
6f
6g
6h
Nalidixic
acid
>200
68
88
180
102
135
70
95
57
monas aeruginosa) using the standard reference two-fold serial dilution method in Muller-Hinton agar [27]. The bactericidal activity generated by some of these compounds may
be attributed to the inhibition of bacterial DNA gyrase; this
enzyme is essential for the replication, transcription, and
repair of bacterial DNA because its inhibition keeps the
bacterial DNA in a supercoil state, thereby preventing bacterial replication.
The compounds (0.1 mg) were dissolved in propylene glycol
(1 mL) and subsequently diluted with phosphate buffer (pH
7.0) to 10 mL. One part of each solution obtained was added to nine parts (v/v) of molten agar (1 µg/mL) and cooled
to 50 °C. After thorough mixing, the mixture was poured
on a Petri dish. Incubation of the Petri dishes was carried
out using a Steers inoculator with an inoculum size of 107
colony forming units (cfu)/mL. The minimum inhibitory
concentration (MIC) was recorded after incubation at 37 °C
for 24 h. The antibacterial activity of the prepared compounds compared with Ciprofloxacin [28] is shown in
Table 3.
The obtained data reveal that compounds 1g and 1f show
high activity towards the tested microorganisms, while compounds 1h, and 1c show an encouraging activity. In case of
compounds 1a, 6a, 6b, and 6g showed low or remarkable
activity. In order to ascertain the mechanism of action, a
DNA gyrase inhibitory activity test was done (Table 4). This
experiment revealed that compounds 1g, 1f, 1c, 6b, 6g affect
the DNA gyrase enzyme, while compounds 1h and 6a do
not, because bacteria develop resistance for some of these
compounds (mutation). The compounds which have antibacterial activity but have no activity towards the DNA gyrase enzyme might act just by penetrating the bacterial cell
wall.
42
El Bialy et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 38−43
Table 5. Antifungal activity of the tested compounds (expressed as the diameter of the inhibition zone; average of three observations; inhibition zone in mm; disc diameter is 6 mm).
Compound
No.
(µmol/mL)
Concentration
µmol/mL
C.
albicans
100
100
100
100
50
100
50
25
100
50
25
100
100
50
25
100
50
25
100
100
100
100
100
50
100
100
50
⫺
15
9
18
18
25
10
8
32
25
15
10
29
20
10
25
25
17
7
⫺
⫺
⫺
28
8
15
8
10
⫺
1a
1b
1c
1d
1e
1f
1g
1h
6a
6b
6c
6d
6e
6f
6g
6h
Control
†
P.
T.
expansum
harzianum
Diameter of the inhibition zone [mm]
17
9
8
20
20
20
13
13
18
12
⫺
14
25
20
20
15
9
⫺
⫺
⫺
⫺
⫺
⫺
7
12
8
⫺
⫺†
13
17
14
⫺
12
⫺
⫺
18
18
5
12
⫺
⫺
⫺
12
⫺
⫺
15
20
⫺
⫺
17
⫺
12
25
7
⫺
A.
flavus
21
7
9
8
8
7
10
⫺
8
10
7
13
17
10
⫺
7
⫺
⫺
⫺
30
⫺
⫺
8
10
10
7
⫺
⫺
‘⫺’ no inhibition zone.
Antifungal activity
The newly synthesized compounds (1a⫺h and 6a⫺h) were
tested for their antifungal activity in vitro against the pathogenic fungi Candida albicans, phytopathogenic Penicillum
expansum and Trichoderma hazianum, and aflatoxin-producing Aspergillus flavus using the standard agar diffusion
method [29]. Table 5 shows the results of the antifungal
activity of the tested compounds expressed as the inhibition
zone in mm.
For each compound the test was carried out at concentrations of 100, 50, and 25 µmol/mL in DMSO. The results
clearly indicate that compound 1f (R ⫽ CH2C6H5) at 100
µmol/mL is the most active one with a broad spectrum activity against all tested species. Propionic acid derivatives
1c, 1d, 1e display broad and improved antifungal activity
against the tested fungal species and more than the propionamide analogues 6c, 6d, 6e. But the propionamide analogues
6a, 6g, 6h display broad and increased antifungal activity
against the tested fungal species if compared with propionic
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
acid derivatives 1a, 1g, 1h. The aromatic compounds (R ⫽
aromatic) at 100 µmol/mL are generally more active than
the aliphatic compounds (R ⫽ aliphatic). Compounds 1a,
1h, and 6a display a promising activity against C. albicans
and P. exponsum only. At a concentration of 50 µmol/mL,
1d, 1e, 1f, 1h, 6a, 6f, and 6h still show antifungal activity at
least against two types of tested species. Moreover,
compounds 1e, 1f, 1h, and 6a reveal promising antifungal
activity against C. albicans and P. exponsum at a concentration of 25 µmol/mL. In this respect, Ertan et al. reported
similar antifungal activities of 1,3,5-thiadiazine-2-thione derivatives [7].
The rest of compounds do not show activity at 50 and 25
µmol/mL. Conversely, some tested compounds allowed a
dense mycelial growth instead of inhibiting growth or
sporulation of the tested fungal species. This indicates that
fungi can utilize such compounds as carbon or nitrogen
sources. Similarily, it is reported that some pyrimidine derivatives (uracile, uridine, cytosine, cytidine, deoxycytidine,
and dihydrouracil) allowed mycelial growth, sporulation,
and nucleic acid synthesis [30] or could be utilized by some
fungal species as a sole nitrogen source [31].
Generally, we can conclude that the antifungal activity of
the newly synthesized derivatives is greatly affected by the
bulkiness of the side chain. In the presence of a free acid
moiety as substituent on the ethylene spacer connecting two
2-thioxo-1,3,5-thiadiazinane rings the antifungal activity
improved with bulky aromatic groups.
Acknowledgments
The authors would like to express their appreciations to
Dr. El-Sayed E. Habib for carrying out the DNA gyrase
inhibitory activity.
Experimental
General
Melting points in °C were recorded on a Fisher-Johns
apparatus (Fischer-Scientific, Pittsburgh, PA, USA) and were uncorrected. IR spectra (KBr disc) were recorded on a Schimadzu IR470 spectrometer (Shimadzu, Kyoto, Japan). 1H-NMR spectra were
recorded on a Varian EM-360 L NMR spectrometer (90 MHz)
(Varian Inc., Palo Alto, CA, USA). Chemical shifts are expressed
in δ-values (ppm) relative to TMS as internal standard and using
DMSO-d6 as solvent. Microanalytical data (C, N, H) agreed with
the proposed structures within 0.4 % of the theoretical values. Thin
layer chromatography was performed on percoated silica gel plates
(Kieselgel, 0.25 mm, 60G F 254, Merck, Darmstadt, Germany). A
developing solvent system of chloroform/methanol (8:2) was used
and the spots were detected by ultraviolet light.
Chemistry
Synthesis of 2,3-bis(5-alkyl-2-thiono-1,3,5-thiadiazinan-3-yl)propionic
acids (1aⴚh)
To a stirred solution of ethyl 2,3-diamino propionate 3 (11.8 g, 0.1
mol) in 100 mL MeOH, CS2 (13.2 g, 0.2 mol) and 50 % aqueous
KOH (39 mL, 0.3 mol) was added dropwise at 20 °C over a period
of 2 h. To this solution, 40 % HCHO (30 mL, 0.41 mol) in 100 mL
5N HCl-MeOH were added followed by the amine (0.2 mol). The
reaction mixture was stirred for further 3h at rt and concentrated
under reduced pressure. The residue was neutralized with 40 mL
50 % KOH and extracted twice with 250 mL AcOEt. The organic
layer was dried (Na2SO4) and recrystallized from the appropriate
solvent to give 1. Yields, melting points, physical data are given in
Table 1.
Synthesis of N,N-dimethyl-2,3-bis(5-alkyl-2-thiono-1,3,5-thiadiazinan-3-yl)propionamide (6aⴚh)
A mixture of 1a⫺h (0.01 mol), POCl3 (40 mL), and PCl5 (0.02 mol)
was heated under reflux for 2h. The excess of POCl3 was removed
under reduced pressure and the product was dissolved in CH2Cl2
(30 mL). Dimethylamine (0.88 g, 0.02 mol) was added dropwise to
the produced acid chloride in CH2Cl2. The reaction mixture was
stirred for 3 h at rt. The separated solid was filtered, washed with
H2O, dried, and crystallized. Yields, melting points, physical data
are given in Table 1.
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