Chemistry of Heterocyclic Compounds, Vol. 49, No. 4, July, 2013 (Russian Original Vol. 49, No.

4, April, 2013)

SYNTHESIS OF NEW 2-ALKYL-5-ARYLIMINO2,5-DIHYDROISOTHIAZOLE DERIVATIVES

I. Skrastia1*, A. Baran1, and D. Muceniece1
The cyclization of 2-substituted N-arylamides of 3-alkylaminobut-2-enethioic acid gave a series of new
2-alkyl-5-arylimino-2,5-dihydroisothiazole derivatives containing a benzoyl or ester group at position
4. A study was carried out on the course of this reaction in the presence of various oxidizing agents,
including halogens, N-bromosuccinimide, hydrogen peroxide. Some of the isothiazoles obtained in this
work exhibited cytotoxic activity against both normal and cancer cell lines.
Keywords: 2-alkyl-5-arylimino-2,5-dihydroisothiazoles, 2-substituted N-arylamides of 2-alkylaminobut2-enethioic acid, enamine-imine tautomerism, oxidative cyclization.
Isothiazole (1,2-thiazole) derivatives are known since the mid-1950's and have been intensively studied
since the 1960's as potent biocidal agents in medicine, industry, and agriculture [1-4]. Antiviral activity has
recently been discovered for analogous derivatives [5], including effect against the human immunodeficiency
virus [6], as well as anti-inflammatory and immunomodulation properties [7, 8]. These discoveries have
considerably reinvigorated the biological studies of isothiazole compounds. Nevertheless, there have been only
a few reports concerning the synthesis of partially hydrogenated isothiazoles, in particular 2,5-dihydroisothiazole derivatives [9].
The main method for the synthesis of 5-imino-2,5-dihydroisothiazoles is the oxidative cyclization of
readily available 3-aminoprop-2-enethioic acid amides. Oxidizing agents used for this reaction were bromine or
iodine [10-12], hydrogen peroxide [13], and diethyl azodicarboxylate (DEAD) [14, 15]. Other oxidizing agents
have also been employed [16, 17]. Nevertheless, the mechanism of this reaction has not been definitively
determined. The most likely reaction path involved an initial oxidation of the thioamide sulfur atom in the
starting compounds, followed by reaction of the sulfur-containing electrophilic species with the adjacent
nitrogen atom of the enamine fragment, leading to closure of the isothiazole ring [18]. When reagents such as
hydrogen peroxide, benzoyl peroxide, or Oxone (KHSO4K2SO42KHSO5) were used, another mechanism could
not be excluded, entailing epoxidation of the enamine double bond, opening of the oxirane ring with
participation of the thioamide group, and subsequent dehydration to give the desired 5-imino-2,5-dihydroisothiazole [19].
In the present work, we synthesized new 2-alkyl-5-arylimino-2,5-dihydroisothiazole derivatives 2a-k by
cyclization of the corresponding 2-substituted N-arylamides of 3-alkylaminobut-2-enethioic acid 1a-k and
studied the effect of various oxidizing agents on the yields of the desired products.
_______
*To whom correspondence should be addressed, e-mail: ingrida@osi.lv.
1

Latvian Institute of Organic Synthesis, 21 Aizkraukles St. Riga LV-1006, Latvia.

________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 669-681, April, 2013. Original
article submitted November 26, 2012.
624

0009-3122/13/4904-06242013 Springer Science+Business Media New York

O
Me
4

Alk

Hal2

N
1

Me

HHal

Alk

1ak

Alk

S
1

Bu

HHal

Hal
Ph

Me

A
O

O
Me

N
NH

Me

3 Me
(from 1)

2ak

1, 2 ad R = Ph; a Alk = Bu, R1 = 3,5-Me2; b Alk = Pr, R1 = 3,4-Cl2; c Alk = Pr, R1 = 4-OMe;
d Alk = Pr, R1 = 4-NO2; ei R = OBn; e Alk = Pr, R1 = H; f Alk = Pr, R1 = 4-F;
g Alk = Pr, R1 = 4-OEt; h Alk = Pr, R1 = 3,4-Me2; i Alk = Bn, R1 = 4-Me;
jk Alk = Me2N(CH2)3, R1 = 3-CF3; j R = OMe; k R = OEt

The starting compounds 1a-k were synthesized by a procedure described by Cie and Szneler [8]
involving the condensation of the corresponding aryl isothiocyanates and 3-alkylaminobut-2-en-1-ones or
3-alkylaminobut-2-enoic acid esters. Compounds 1a-k were obtained in high yields and readily isolated from
the reaction mixture. These products could be used immediately in the next step without additional purification.
The cyclization reaction was investigated in the presence of various oxidizing agents (Table 1).
Thioamide 1j was used as the model compound.
Our results for the cyclization of thioamide 1j showed that the greatest amount of the desired
condensation product 2j in the reaction mixture was obtained using molecular bromine, DEAD, or hydrogen
peroxide as the oxidizing agent under acidic conditions. In all cases, the reaction mixture contained many
unidentified minor products, but no benzothiazole side product was found among them. According to literature
data, a competing substitution reaction in the aromatic ring of intermediate A to give product 3 was more likely
in the case of activated N-arylamide derivatives [20-26].
TABLE 1. Cyclization of Thioamide 1j in the Presence of Various
Oxidizing Agents
Oxidizing agent
Br2
Oxone
NBS
(PhCO)2O2
H2O2
H2O2
DEAD

Conditions
CHCl3, 0C, 2 h, then room temp., 8 h
"
"
"
"
HCl (cat.), EtOH, room temp., 8 h
CHCl3, room temp., 8 h

Content of compound 2j*, %

68
20
18
3
0
50
60

_______
*Content of ester 2j was determined by GC/MS without isolation from the
reaction mixture.
These results provided the methodology for preparing a range of new 2-alkyl-5-arylimino-2,5-dihydroisothiazole derivatives 2a-k by cyclization of the corresponding thioamides 1a-k in the presence of
bromine or iodine as oxidizing agents. The yields of the desired products varied from moderate to high
(51-93%). In the case of derivative 2a, benzothiazole 3 was also formed in 11% yield along with the desired
isothiazole product. Benzothiazole 3 was isolated and characterized.
625

Structures of the starting thioamides 1a-k and the reaction products 2a-k and 3 were confirmed by
NMR spectroscopy and X-ray structural analysis. According to literature sources, the thioamides 1a-k may exist
as a mixture of E- and Z-isomers, as well as in various tautomeric forms, each of which having its own set of
1
H NMR signals due to the different extent of NH proton participation in intramolecular interactions [7, 8, 27].
Our data showed that these derivatives existed in dilute CDCl3 solutions predominantly as the most stabilized
(Z)-enamino-thioamide isomer, in which both protons at the nitrogen atoms participated in intramolecular
hydrogen bonding (the enamine NH proton interacted with the thiocarbonyl group, while the thioamide NH
proton interacted with either the keto or carboxyl group), which led to a downfield shift in the signals of these
protons (>10 ppm). The presence of the (E)-diastereomer was confirmed by the presence of a second, upfieldshifted set of signals, since the participation of the thioamide proton in hydrogen bonding was considerably
diminished in this case. The existence of these isomers in enamine form was indicated by satellite signals
adjacent to the main 1H NMR signals, due to 1H-15N coupling constant J = 85-90 Hz
In examining the effect of substituents on the (E)- and (Z)-isomer ratio, we found that the sterical
hindrance and electronic nature of the substituent at position 2 had the greatest effect. Thus, the methyl ester 1j
and ethyl ester 1k in CDCl3 had the enamino group almost entirely in (Z)-configuration (CSNH 11.04-11.17,
HNC= 12.65-12.77 ppm), while bulky benzyl esters 1e-i were a mixture of (Z)- and (E)-isomers in a ratio of 3-4:1
(CSNH 9.90-10.44, HNC= 11.55-12.09 ppm for the (Z)-isomer and CSNH 9.37-9.47 (s), HNC= 9.51-9.84 ppm (t)
for the (E)-isomer). There was less stabilization of the (Z)-isomers of these benzyl esters in comparison with
esters 1j,k, which led to an upfield shift of the corresponding signals and facilitated the formation of
(E)-isomers. In this case, the benzyloxycarbonyl group interacted with the two NH protons, which probably
accounted for the similar chemical shifts of these protons. It is interesting to note that no significant amount of
the imino form was found in the spectra of esters 1e-k due to significant stabilization of both enamino tautomers
by hydrogen bonding.
Another case was observed for 2-benzoyl derivatives 1a-d. As previously, the (Z)-enamino-thioamide
isomer was most stabilized (CSNH 10.09-11.17, HSC= 13.13-13.44 ppm). In case of the (E)-enamino isomer, the
thioamide group proton did not participate at all in intramolecular hydrogen bonding and its signal was
O.. .
H

Ph

Me

Me
Bu

11.46 ppm

5.67 ppm

Me

imino-thioamide
~20%
Ph

10.09 ppm

Me

Me
Bu
13.12 ppm

. . .O

O. . .
H

Bu

N
Me

. . .S

Me
(Z)-enamino-thioamide
~65%

Ph

12.70 ppm

9.00 ppm

Me

(E)-enamino-thioamide Me
~15%

shifted upfield to 9.00 ppm. The molecule was also stabilized by formation of the imino form, in which the
thioamide proton could interact with the carbonyl group of the benzoyl fragment and the hydrogen atom at the
tertiary carbon (N=CCH) was stabilized by adjacent electron-withdrawing groups. This hypothesis was
supported by spectral data (N=CCH 5.67, CSNH 11.46-11.48 ppm). Electronic factors also had a significant effect
626

in stabilizing the imino tautomer. Thus, derivatives 1a,c, which had electron-donating arylthioamide groups,
existed in CDCl3 solution as a mixtures of the (Z)-enamino, (E)-enamino, and imino forms in 65:20:15 (1a) and
75:15:10 (1c) ratio. On the other hand, thioamides 1b,d, containing electron-withdrawing chlorine (1b) or a
nitro group (1d), existed only as mixtures of (Z)-enamino and imino forms in various ratios. With increasing
concentration, only the signals for the imino-thioamide tautomers remained in the 1H NMR spectra of these
derivatives.

Fig. 1. Molecular structures of isothiazoles 2a (a) and 2k (b) with atoms represented by thermal vibration
ellipsoids of 50% probability. The hydrogen atoms are not shown.
A series of additional NMR experiments (1H, 13C, and 2D 1H-1H NOESY) was performed for compound
1b to obtain evidence supporting the above-mentioned conclusions. In particular, the presence of imino group
was indicated by satellite 1H-13C coupling signals with constant J = 160 Hz adjacent to the main 1H NMR signal
at 5.67 ppm, as well as a 13C NMR signal at 164.9 ppm (N=C), which was absent in the case of thioamides 1e-k.
627

The presence of a thioamide group stabilized by an intramolecular hydrogen bond with the NH group was
established by the presence of a 13C NMR signal at 187.5 ppm. Furthermore, the NOESY experiment confirmed
an interaction of the imino group proton with the ortho protons of the phenyl ring along with absence of an
interaction of the thioamide proton with other hydrogen atoms in this molecule. These results were in agreement
with the literature data for similar 2-phenyl [12], 2-acetyl [7], and 2-ethoxycarbonyl [8] amides of 3-aminobut2-enethioic acid, as well as for hydrazone-thioamide derivatives RNHN=C(Ph)CSNR1R2 [28].
The structures of the obtained dihydroisothiazoles were also in accordance with the 1H and 13C NMR
spectral data. Thus, the 1H NMR spectra of compounds 2a-k lacked signals for NH group protons. In
comparison with the spectral data of the starting thioamides 1a-k, the spectra of the cyclic products were
markedly simpler due to the impossibility of forming isomeric and tautomeric forms.
The 13C NMR signals for C-3 and C-5 atoms in the spectra of isothiazoles 2a,k were found at 154.1155.1 and 162.1-164.7 ppm, respectively. The ester group carbonyl in derivative 2k gave a 13C NMR signal near
164 ppm, while the keto group carbonyl in compound 2a gave a 13C NMR signal at 192.3 ppm. Furthermore, a
characteristic 13C-19F coupling was observed in the spectrum of isothiazole 2k.
An X-ray structural analysis of these products also confirmed the proposed structures (Fig. 1) with
(Z)-configuration for the imine double bond. The C=NC bond angle was in the range of 117.79-124.26, while the
C(1)=N(2) double bond length was 1.281-1.285 , and the adjacent groups occupied the sterically most favored
positions. Thus, the aromatic ring of the benzoyl substituent in isothiazole 2a was virtually perpendicular and the
dimethylphenyl ring formed an angle of 18.57-33.41 relative to the plane of the isothiazole ring. Furthermore, the
isothiazole ring itself was twisted about the C(1)C(2) bond axis. The dihedral angle between these limiting
positions was 20.730.13. In the absence of a bulky benzoyl fragment, the arylimino substituent in isothiazole 2k
was perpendicular to the plane of the five-membered ring with the corresponding dihedral angle 68.690.06.
Some of the 5-arylimino-2,5-dihydroisothiazoles 2a-k obtained in this work were screened for possible
cytotoxic activity. In particular, we studied the activity of derivatives 2b,g,k against HT-1080 (human
fibrosarcoma), MG-22A (murine hepatoma), and NIH 3T3 (normal murine embryonal fibroblast cells). The tests
were performed using standard MTT and CV methods, evaluating the IC50 values for each cell line.
Furthermore, the cells were studied for change in morphology and nitric oxide production.
TABLE 2. Cytotoxic Activity of Isothiazoles 2b,g,k*
HT-1080
Compound

2b
2g
2k

MG-22A

3T3

IC50, CV

IC50, MTT

NO, %

IC50, CV

IC50, MTT

NO, %

IC50

LD50

2
3
3

4
3
2

700
467
400

2
2
11

2
4
24

250
250
400

16
6
22

418
275
486

_______
*The IC50 values are given in g/ml and the LD50 values are given in mg/kg. The LD50 values were calculated from
the toxicity tests for 3T3 cells. According to the protocols of the Interagency Coordinating Committee on the
Validation of Alternative Methods and the National Toxicology Program of the Interagency Center for the
Evaluation of Alternative Toxicological Methods, the cytotoxic tests for 3T3 cells performed in vitro provided an
alternative to in vivo LD50 tests. The toxicity ranges of the compounds are divided as follows: LD50 25 mg/kg is
very toxic, LD50 < 25-200 mg/kg is toxic, LD50 < 200-2000 mg/kg is harmful, and LD50 > 2000 mg/kg is harmless.

628

TABLE 3. Physicochemical Characteristics of Compounds 1a-k and 2a-k

Compound

Empirical
formula

23H28N2OS

1b

20H20Cl2N2OS

1c

21H24N2O2S

1d

20H21N3O3S

1e

21H24N2O2S

1f

21H23FN2O2S

1g

23H28N2O3S

1h

23H28N2O2S

1i

26H26N2O2S

1j

18H24F3N3O2S

1k

19H26F3N3O2S

2a

23H26N2OS

2b

20H18Cl2N2OS

2c

21H22N2O2S

2d

20H19N3O3S

2e

21H22N2O2S

2f

21H21FN2O2S

2g

23H26N2O3S

2h

23H26N2O2S

2i

26H24N2O2S

2j

18H22F3N3O2S

2k

19H24F3N3O2S

C
72.50
72.59
59.05
58.97
68.43
68.45
62.38
62.64
68.47
68.45
65.27
65.26
66.91
66.96
69.70
69.66
72.24
72.53
53.72
53.59
54.43
54.66
73.11
72.98
59.04
59.26
68.77
68.83
62.90
62.98
68.72
68.83
65.57
65.60
67.15
67.29
69.70
70.02
72.67
72.87
53.92
53.85
54.98
54.93

Found, %

Calculated, %
H
N
7.30
7.42
4.89
4.95
6.50
6.56
5.47
5.52
6.53
6.56
6.02
6.00
6.74
6.84
7.04
7.12
6.00
6.09
5.97
6.00
6.07
6.28
6.92
6.92
4.44
4.48
5.98
6.05
4.95
5.02
5.95
6.05
5.36
5.51
6.33
6.38
6.58
6.64
5.51
5.64
5.63
5.52
5.83
5.82

7.34
7.36
6.80
6.88
7.55
7.60
10.93
10.96
7.54
7.60
7.27
7.25
6.72
6.79
7.04
7.06
6.42
6.51
10.29
10.41
9.91
10.06
7.32
7.40
6.75
6.91
7.51
7.64
10.90
11.02
7.59
7.64
7.23
7.29
6.81
6.82
7.15
7.10
6.50
6.54
10.24
10.47
9.98
10.11

Mp, C

Yield, %

Color

109-111

94

Bright-yellow

rxn 1-1

117-119

94

Bright-yellow

rxn 4-1

123-124

85

Bright-yellow

rxn 6-1

130-132

94

Orange

rxn 10-1

107-109

88

Bright-yellow

rxn 11-1

106-108

80

Bright-yellow

rxn 13-1

99-105

70

Bright-yellow

rxn 15-1

107-109

84

Bright-yellow

rxn 17-1

103-105

72

Light-yellow

rxn 19-1

112-114

66

Bright-yellow

rxn 22-1

89-91

91

Bright-yellow

rxn 24-1

99-100

58

Yellow

rxn 27-1

86-88

59

Yellow

rxn 29-1

79-81

70

Light-yellow

rxn 30-1

120-122

93

Orange

rxn 31-1

108-110

51

Yellow

rxn 32-1

101-103

57

Light-yellow

rxn 33-1

84-86

65

Light-yellow

rxn 34-1

87-88

69

Light-yellow

rxn 35-1

116-118

52

Light-yellow

rxn 36-1

124-126

74

Bright-yellow

rxn 37-1

103-104

89

Light-yellow

rxn 38-1

All these compounds demonstrated high cytotoxic activity against HT-1080 and MG-22A cancer cell
lines and may be classified as harmful substances according to the toxicity test with 3T3 cells. Isothiazole 2k
exhibited some selectivity against different cell lines, since the greatest cytotoxic effect was achieved against
HT-1080 cells and the weakest effect was found against MG-22A and 3T3 cells. Furthermore, all the
compounds increased NO generation by 400-700% in both cancer cell lines, which also indicated their toxic
effect. However, these compounds caused no morphological changes in the cells.
Thus, we obtained a series of new 2-alkyl-5-arylimino-2,5-dihydroisothiazole derivatives by cyclization
of the corresponding 2-substituted N-arylamides of 3-alkylaminobut-2-enethioic acid. We studied the effect of
various oxidizing agents, including halogens, N-bromosuccinimide, and hydrogen peroxide, on the yields of the
desired products. A preliminary cytotoxic activity screening against normal and malignant cell lines was
performed for several of these compounds.

629

EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Varian 400-MR instrument (400 and 100 MHz,
respectively) in CDCl3. The residual solvent protons served as internal standard (7.26 ppm for 1H nuclei and
77.0 ppm for 13C nuclei). The electrospray ionization mass spectra were recorded on a Waters Acquity UPLC
system with a Micromass QTOF mass spectrometer, using a 2.150-mm Waters XBridge C18 chromatography
column (3.5 m). The flow rate was 0.6 ml/min. Gradient elution was carried out with MeCN0.1% HCO2H in
water. Both positive and negative ions were recorded. The elemental analysis was carried out on a Carlo Erba
EA 1106 instrument. The melting points were determined on a Kofler bench. The purity of the products was
monitored by thin-layer chromatography on Merck silica gel 60 F254 plates. Reagents and solvents from Acros
and Alfa Aesar were used without further purification.
1
3
2
2-Benzoyl-3-butylaminobut-2-enethioic
Acid (3,5-Dimethylphenyl)amide (1a). A mixture of
25
3,5-dimethylphenyl isothiocyanate (13.06 g, 80 mmol) and 3-(butylamino)-1-phenylbut-2-en-1-one (17.38 g,
80 mmol) was dissolved in petroleum ether (15 ml). The resultant solution was stirred at room temperature for
24 h. The crystalline precipitate was filtered off and dried. 1 NMR spectrum, , ppm (J, Hz) ((Z)-isomer:
(E)-isomer:imine ratio = 65:20:15): 0.97 (0.45H, t, J = 7.3) and 0.99 (2.55H, t, J = 7.4, N(CH2)33); 1.42-1.57
(2H, m, N(CH2)2CH23); 1.60-1.68 (0.30H, m) and 1.68-1.77 (1.70H, m, NCH2CH2); 2.13 (1.95H, s), 2.17
(0.60H, s), and 2.47 (0.45H, s, =C(N)H3); 2.08 (0.90H, s), 2.26 (5.10H, s), and 2.30 (1.20H, s, Ar(CH3)2);
3.30-3.36 (0.30H, m) and 3.36-3.41 (1.70H, m, NHCH2); 5.67 (0.15H, s, N=CH (imine)); 6.04-6.08 (0.30H,
br. s, H Ar); 6.70-6.74 (0.15H, br. s, H Ar); 6.80-6.85 (1.3H, s) and 6.85-6.87 (0.4H, s, H-2,6 Ar); 6.90-6.92
(0.15H, m, H Ar); 7.13-7.24 (0.40H, m, H-3,5 Ph); 7.28-7.35 (0.65H, m, H-4 Ph); 7.35-7.45 (2.95H, m, H Ph,
H-4 Ar); 7.72-7.77 (1.30H, m) and 7.84-7.89 (0.40H, m, H-2,6 Ph); 9.00 (0.15H, br. s), 10.09 (0.20H, br. s), and
11.46 (0.65H, br. s, CSNH); 12.70 (0.20H, br. s) and 13.12 (0.65H, br. s, NHCH2).
Amides 1b-k (Table 3) were obtained analogously.
4
5
2-Benzoyl-3-propylaminobut-2-enethioic
Acid (3,4-Dichlorophenyl)amide (1b). 1 NMR spectrum,
, ppm (J, Hz) ((Z)-isomer:imine ratio = 66:34): 1.04 (1.02H, t, J = 7.4) and 1.10 (1.98H, t, J = 7.4,
8000 CH CH ); 1.64-1.75 (0.68H, m) and 1.73-1.84 (1.32H, m, CH CH ); 1.97 (1.98H, s) and 2.08 (1.02H, s,
2
2
3
2
2
3
=C(N)H3); 3.27-3.33 (0.68H, m) and 3.32-3.39 (1.32H, m, NHCH2); 5.67 (0.34H, s, N=CH (imine)); 7.08
(0.34H, dd, J = 8.5, J = 2.4, H-6 Ar); 7.20-7.26 (0.66H, m, H Ar); 7.34 (0.34H, d, J = 2.4, H-2 Ar); 7.34-7.51
(4.00H, m, H-2,5 Ar, H-3,5,4 Ph); 7.55-7.59 (0.66H, m, H Ar); 7.67-7.75 (1.32H, m) and 7.83-7.90 (0.68H, m,
H-2,6 Ph); 11.17 (0.7H, br. s) and 11.47 (0.3H, br. s, CSNH); 13.34 (0.7H, br. s, NHCH2).
6
7
8
2-Benzoyl-3-propylaminobut-2-enethioic
Acid (4-Methoxyphenyl)amide (1c). 1 NMR spectrum, , ppm
(J, Hz) ((Z)-isomer:(E)-isomer:imine ratio = 70:20:10): 1.04 (0.30H, t, J = 7.5) and 1.09 (2.70H, t, J = 7.5,
2CH23); 1.64-1.72 (0.20H, m) and 1.72-1.82 (1.80H, m, 2CH23); 2.13 (0.30H, s) and 2.48 (2.70H, s,
=C(N)H3); 3.27-3.32 (0.20H, m) and 3.32-3.38 (1.80H, m, NHCH2); 3.79 (0.30H, s) and 3.81 (2.70H, s, OCH3); 5.67
(0.10H, s, N=CH (imine)); 6.36-6.42 (0.30H, m, H Ar); 6.63-6.69 (0.30H, m, H Ar); 6.80-6.85 (1.50H, m, H Ar);
6.85-6.88 (0.20H, m, H Ar); 7.05-7.12 (1.50H, m, H Ar); 7.16-7.19 (0.20H, m, H Ar); 7.17-7.33 (0.75H, m, H-3,4,5
Ph); 7.35-7.46 (2.65H, m, H Ph); 7.72-7.78 (1.40H, m) and 7.84-7.88 (0.20H, m, H-2,6 Ph); 9.00 (0.10H, br. s), 10.09
(0.20H, br. s), and 11.47 (0.70H, br. s, CSNH); 12.65 (0.20H, br. s) and 13.14 (0.70H, br. s, CH2NH).
9
10
2-Benzoyl-3-propylaminobut-2-enethioic
Acid (4-Nitrophenyl)amide (1d). 1 NMR spectrum, ,
rxn 10-1
ppm (J, Hz) ((Z)-isomer:imine ratio = 7:93): 1.04 (2.79H, t, J = 7.4) and 1.11 (0.21H, t, J = 7.4, (CH2)23);
1.64-1.74 (0.14H, m) and 1.75-1.85 (1.86H, m, 2CH23); 2.08 (0.21H, s) and 2.18 (2.79H, s, =C(N)H3);
3.27-3.34 (0.14H, m) and 3.34-3.40 (1.86H, m, NHCH2); 5.67 (0.93H, s, N=CCH (imine)); 7.33-7.37 (1.86H,
m, H-2,6 Ar (imine)); 7.37-7.45 (3.14H, m, H-3,4,5 Ph, H-2,6 Ar (Z)); 7.68-7.75 (0.14H, m) and 7.83-7.89
(1.86H, m, H-2,6 Ph); 8.15-8.20 (0.14H, m) and 8.23-8.28 (1.86H, m, H-3,5 Ar); 11.48 (0.93H, br. s, CSNH
(imine)); 13.44 (0.07H, br. s, CH2NH).
11 12
2-Benzyloxycarbonyl-3-propylaminobut-2-enethioic Acid Phenylamide (1e). 1 NMR spectrum, ,
8001 ppm (J, Hz) (isomer ratio (Z):(E) = 4:1): 0.96 (0.60H, t, J = 7.3) and 1.04 (2.40H, t, J = 7.4, (CH2)23);
630

26

1.57-1.64 (0.40H, m) and 1.64-1.76 (1.60H, m, CH2CH23); 2.21 (0.60H, s) and 2.22 (2.40H, s, =C(N)H3);
3.183.24 (0.40H, m) and 3.25-3.32 (1.60H, m, NHCH2); 4.80-5.04 (0.40H, m) and 5.21 (1.60H, s, OCH2Ph);
6.886.95 (0.40H, m), 7.10-7.40 (8H, m) and 7.49-7.55 (1.60H, m, H Ph); 9.47 (0.20H, br. s) and 10.30 (0.80H,
br. s, CSNH); 9.60 (0.20H, br. s) and 11.78 (0.80H, br. s, NHCH2).
13
14
2-Benzyloxycarbonyl-3-propylaminobut-2-enethioic
Acid (4-Fluorophenyl)amide (1f). 1 NMR
spectrum, , ppm (J, Hz) (isomer ratio (Z):(E) = 4:1): 0.97 (0.60H, t, J = 7.4) and 1.04 (2.40H, t, J = 7.4,
(CH2)23); 1.56-1.65 (0.40H, m) and 1.65-1.76 (1.60H, m, 2CH23); 2.22 (3H, s, =C(N)H3); 3.18-3.25
(0.40H, m) and 3.27-3.30 (1.60H, m, NHCH2); 4.96 (0.40H, s) and 5.21 (1.60H, s, OCH2Ph); 6.81-6.87 (0.40H,
m); 7.00-7.07 (1.60H, m, H-3,5 Ph); 7.18-7.25 (0.40H, m) and 7.32-7.43 (6.60H, m, H Ph, H Ar); 9.37 (0.20H,
br. s) and 10.44 (0.80H, br. s, CSNH); 9.60 (0.20H, br. s) and 12.09 (0.80H, br. s, NHCH2).
15
16
2-Benzyloxycarbonyl-3-propylaminobut-2-enethioic Acid (4-Ethoxyphenyl)amide (1g). 1 NMR
spectrum, , ppm (J, Hz) (isomer ratio (Z):(E) = 4:1): 0.95 (0.60H, t, J = 7.5) and 1.03 (2.40H, t, J = 7.4,
(CH2)23); 1.41 (0.60H, t, J = 7.0) and 1.42 (2.40H, t, J = 7.0, OCH23); 1.53-1.63 (0.40H, m) and 1.63-1.74
(1.60H, m, CH2CH23); 2.18 (0.60H, s) and 2.22 (2.40H, s, =C(N)H3); 3.15-3.22 (0.40H, m) and 3.24-3.31
(1.60H, m, NHCH2); 3.97 (0.40H, q, J = 7.0) and 4.04 (1.60H, q, J = 7.0, OCH23); 4.93-5.02 (0.40H, m) and
5.20 (1.60H, s, OCH2Ph); 6.65-6.70 (0.40H, m, H Ar); 6.78-6.84 (0.40H, m, H Ar); 6.84-6.90 (1.60H, m, H Ar);
7.27-7.41 (6.60H, m, H Ph, H Ar); 9.40 (0.20H, br. s) and 10.08 (0.80H, br. s, CSNH); 9.51 (0.20H, t, J = 6.0)
and 11.62 (0.80H, br. s, NHCH2).
18
17
2-Benzyloxycarbonyl-3-propylaminobut-2-enethioic
Acid (3,4-Dimethylphenyl)amide (1h). 1 NMR
spectrum, , ppm (J, Hz) (isomer ratio (Z):(E) = 4:1): 0.96 (0.60H, t, J = 7.4) and 1.03 (2.40H, t, J = 7.4,
(CH2)23); 1.56-1.63 (0.40H, m) and 1.64-1.74 (1.60H, m, 2CH23); 2.10 (0.60H, s, Ar3); 2.19 (0.60H, s,
Ar3); 2.20 (0.60H, s, =C(N)H3); 2.22 (2.40H, s, =C(N)H3); 2.24 (2.40H, s, Ar3); 2.25 (2.40H, s, Ar3);
3.18-3.24 (0.40H, m) and 3.25-3.31 (1.60H, m, NHCH2); 4.89-5.00 (0.40H, m) and 5.20 (1.60H, s, OCH2Ph); 6.65
(0.20H, d, J = 1.7) and 7.20 (0.80H, d, J = 1.7, H-2 Ar); 6.67 (0.20H, dd, J = 8.1, J = 1.9) and 7.25 (0.80H, dd,
J = 8.1, J = 1.9, H-6 Ar); 6.94 (0.20H, d, J = 8.0) and 7.12 (0.80H, d, J = 8.0, H-5 Ar); 7.26-7.41 (5H, m, H Ph); 9.39
(0.20H, br. s) and 10.03 (0.80H, br. s, CSNH); 9.56 (0.20H, t, J = 4.9) and 11.55 (0.80H, br. s, NHCH2).
20
19
2-Benzyloxycarbonyl-3-benzylaminobut-2-enethioic
Acid (4-Methylphenyl)amide (1i). 1 NMR
spectrum, , ppm (J, Hz) (isomer ratio (Z):(E) = 3:1): 2.14 (0.75H, s) and 2.23 (2.25H, s, =C(N)H3); 2.33
8002 (0.75H, s) and 2.35 (2.25H, s, ArCH3); 4.45 (0.50H, d, J = 6.2) and 4.53 (1.50H, d, J = 5.9, NHCH2Ph);
4.95-5.05 (0.50H, m) and 5.20 (1.50H, s, OCH2Ph); 6.78-6.82 (0.50H, m, H Ar); 6.97-7.02 (0.50H, m, H Ar);
7.14-7.19 (1.50H, m, H Ar); 7.22-7.26 (0.50H, m, H Ph); 7.28-7.41 (11H, m, H Ph, H Ar); 9.44 (0.25H, br. s)
and 9.90 (0.75H, br. s, CSNH); 9.84 (0.25H, t, J = 6.0) and 11.63 (0.75H, br. s, NHCH2).
21
22
2-Methoxycarbonyl-3-(3-dimethylaminopropylamino)but-2-enethioic
acid (3-Trifluoromethyl1
phenyl)amide (1j). NMR spectrum, , ppm (J, Hz) (isomer ratio (E):(Z) = 5:95): 1.68-1.76 (0.10H, m) and
8003 1.78-1.91 (1.90H, m, NCH2CH2CH2); 2.22 (0.30H, s) and 2.23 (5.70H, s, N(CH3)2); 2.27 (3H, s, =C(N)H3);
2.33 (0.10H, t, J = 7.0) and 2.41 (1.90H, t, J = 6.7, CH2N(CH3)2); 3.23-3.30 (0.10H, m) and 3.37-3.51 (1.90H,
m, NHCH2(CH2)2); 3.76 (3H, br. s, OCH3); 7.38-7.55 (2H, m, H-2,5 Ar); 7.71-7.89 (2H, m, H-4,6 Ar); 8.55
(0.05H, br. s) and 11.04 (0.95H, br. s, CSNH); 12.65 (0.95H, br. s, NHCH2 (Z))*.
23
24
2-Ethoxycarbonyl-3-(3-dimethylaminopropylamino)but-2-enethioic Acid (3-Trifluoromethylphenyl)amide (1k). 1 NMR spectrum, , ppm (J, Hz) (isomer ratio (E):(Z) = 1:9): 1.25 (0.30H, t, J = 7.2) and 1.32
(2.70H, br. s, CH2CH3); 1.68-1.76 (0.20H, m) and 1.79-1.90 (1.80H, m, NCH2CH2CH2); 2.22 (0.60H, s) and
8004 2.23 (5.40H, s, N(CH
3)2); 2.29 (3H, s, =C(N)H3); 2.33 (0.20H, t, J = 7.1) and 2.41 (1.80H, t, J = 7.0,
CH2N(CH3)2); 3.23-3.29 (0.20H, m) and 3.39-3.50 (1.80H, m, NHCH2(CH2)2); 4.09 (0.20H, q, J = 7.2) and 4.23
(1.80H, br. s, OCH23); 7.38-7.55 (2H, m, H-2,5 Ar); 7.71-7.86 (2H, m, H-4,6 Ar); 8.56 (0.10H, br. s) and
11.17 (0.90H, br. s, CSNH); 12.77 (0.90H, br. s, NHCH2 (Z))*.
_______
*The signal of the (E)-isomer was not seen due to low intensity and broadening.
631

27

4-Benzoyl-2-butyl-3-methyl-5-(3,5-dimethylphenylimino)-2,5-dihydroisothiazole (2a). Pyridine

(4.2 ml, 52 mmol) was added to a solution of thioamide 1a (19.79 g, 52 mmol) in dry chloroform (250 ml). The
reaction mixture was cooled to 0-5C on an ice bath, and a solution of I2 (13.20 g, 52 mmol) in a minimum
39
amount of ethanol was slowly added dropwise with cooling over 3 h. The reaction
mixture was then stirred with
cooling for another 1 h. At the end of the reaction, the solvent was removed in vacuum, and methyl tert-butyl
ether (MTBE) was added to the residue. The crystalline precipitate was filtered off, washed with a small amount
of MTBE and water. The product was added to water (70 ml) and CH2Cl2 (30 ml). Then, 10% aqueous NaOH
(30 ml) was added, and the mixture was heated on a water bath for 1 h with stirring. The organic phase was
separated and the solvent was removed at reduced pressure. The crystalline precipitate was washed with water
on the filter, dried at room temperature, and recrystallized from MTBE. 1 NMR spectrum, , ppm (J, Hz): 0.97
(3, t, J = 7.4, (CH2)33); 1.32-1.44 (2H, m, (CH2)2CH23); 1.64-1.73 (2H, m, NCH2CH2); 2.25 (6H, s,
Ar(CH3)2); 2.37 (3H, s, 3-3); 3.63 (2H, t, J = 7.4, NCH2); 6.49 (2H, s, H-2,6 Ar); 6.66 (1H, s, H-4 Ar); 7.38-7.44
(2H, m, H-3,5 Ph); 7.45-7.51 (1H, m, H-4 Ph); 7.95-8.00 (2H, m H-2,6 Ph). 13C NMR spectrum, , ppm: 13.6;
14.2; 19.7; 21.3; 31.7; 48.3; 110.0; 114.4; 117.4; 125.4; 127.8; 129.8; 132.1; 138.9; 139.1; 154.1; 162.1; 162.5;
192.3. Mass spectrum, m/z (Irel, %): 379 [M+H]+ (100). After separation of the crystalline product 2a, the filtrate
was subjected to chromatography on a silica gel column using 1:2 MTBEpetroleum ether with 0.5% Et3N as
the eluent to give 3-butylamino-2-(5,7-dimethylbenzothiazol-2-yl)-1-phenylbut-2-en-1-one (3). Yield 2.22 g 28
(11%). Mp 124-126C. 1 NMR spectrum, , ppm (J, Hz): 1.00 (1.5H, t, J = 7.3) and 1.06 (1.5H, t, J = 7.4,
CH23); 1.46-1.57 (1H, m) and 1.57-1.67 (1H, m, CH23); 1.68-1.77 (2H, m) and 1.77-1.85 (1H, m,
CH2CH23); 1.90 (1.5H, s) and 2.09 (1.5H, s, =C(N)3); 2.36 (1.5H, s, CH3 Ar); 2.46 (1.5H, s, CH3 Ar); 2.47
(1.5H, s, CH3 Ar); 2.52 (1.5H, s, CH3 Ar); 3.39-3.47 (2H, m, CH2NH); 6.90 (0.5H, s) and 6.96 (0.5H, s, H-6 Ar);
7.08-7.15 (1.0H, m, H-3,5 Ph); 7.15-7.20 (0.5H, m) and 7.45-7.51 (0.5H, m, H-4 Ph); 7.35-7.45 (2.5H, m, H-2,3,5,6
Ph, H-4 Ar); 7.67 (0.5H, s, H-4 Ar); 7.69-7.74 (1H, m, H-2,6 Ph); 12.76 (0.5H, br. s) and 12.95 (0.5H, br. s, CH2NH).
Found, %: C 72.77; H 6.91; N 7.33. 23H26N2OS. Calculated, %: 72.98; 6.92; N 7.40.
Isothiazoles 2b-d were obtained analogously. Isothiazoles 2e-i were obtained using bromine in the
presence of pyridine. The syntheses of 2j,k were carried out analogously to the procedures for the preparation of
isothiazoles 2e-i without the addition of pyridine (Table 3).
29
4-Benzoyl-5-(3,4-dichlorophenylimino)-3-methyl-2-propyl-2,5-dihydroisothiazole (2b). 1 NMR
spectrum, , ppm (J, Hz): 1.00 (3, t, J = 7.4, (CH2)23); 1.71-1.82 (2H, m, 2CH23); 2.38 (3H, s,
3-3); 3.65 (2H, t, J = 7.3, NCH2); 6.71 (1H, dd, J = 8.5, J = 2.5, H-6 Ar); 6.95 (1H, d, J = 2.4, H-2 Ar); 7.30
(1H, d, J = 8.5, H-5 Ar); 7.39-7.46 (2H, m, H-3,5 Ph); 7.48-7.54 (1H, m, H-4 Ph); 7.90-7.95 (2H, m, H-2,6 Ph).
Mass spectrum, m/z (Irel, %): 405 [M+H]+ (100).
30
4-Benzoyl-5-(4-methoxyphenylimino)-3-methyl-2-propyl-2,5-dihydroisothiazole (2c). 1 NMR spectrum,
, ppm (J, Hz): 0.98 (3, t, J = 7.4, (CH2)23); 1.68-1.79 (2H, m, 2CH23); 2.36 (3H, s, 3-3); 3.60
(2H, t, J = 7.3, NCH2); 3.77 (3H, s, OCH3); 6.76-6.86 (4H, m, H Ar); 7.38-7.45 (2H, m, H-3,5 Ph); 7.45-7.52
(1H, m, H-4 Ph); 7.94-8.00 (2H, m, H-2,6 Ph). Mass spectrum, m/z (Irel, %): 367 [M+H]+ (100).
31 4-Benzoyl-3-methyl-5-(4-nitrophenylimino)-2-propyl-2,5-dihydroisothiazole (2d). 1 NMR spectrum, ,
ppm (J, Hz): 1.02 (3, t, J = 7.4, (CH2)23); 1.74-1.85 (2H, m, 2CH23); 2.41 (3H, s, 3-3); 3.71 (2H, t,
J = 7.3, NCH2); 6.88-6.93 (2H, m, H-2,6 Ar); 7.40-7.46 (2H, m, H-3,5 Ph); 7.50-7.56 (1H, m, H-4 Ph);
7.90-7.96 (2H, m, H-2,6 Ph); 8.10-8.15 (2H, m, H-3,5 Ar). Mass spectrum, m/z (Irel, %): 382 [M+H]+ (100).
32 3-Methyl-5-phenylimino-2-propyl-2,5-dihydroisothiazole-4-carboxylic Acid Benzyl Ester (2e). 1 NMR
spectrum, , ppm (J, Hz): 0.92 (3, t, J = 7.4, (CH2)23); 1.621.72 (2H, m, 2CH23); 2.53 (3H, s, 3-3); 3.55
(2H, t, J = 7.3, NCH2); 5.39 (2H, s, OCH2Ph); 7.04-7.12 (3H, m, H-2,4,6 Ph); 7.26-7.32 (1H, m, H-4 Bn); 7.33-7.39
(4H, m, H-3,5 Ph, H-3,5 Bn); 7.54-7.58 (2H, m, H-2,6 Bn). Mass spectrum, m/z (Irel, %): 367 [M+H]+ (100).
33 5-(4-Fluorophenylimino)-3-methyl-2-propyl-2,5-dihydroisothiazole-4-carboxylic Acid Benzyl Ester
(2f). 1 NMR spectrum, , ppm (J, Hz): 0.92 (3, t, J = 7.4, (CH2)23); 1.62-1.73 (2H, m, CH2CH23); 2.52 (3H,
s, 3-3); 3.55 (2H, t, J = 7.3, NCH2); 5.38 (2H, s, OCH2Ph); 7.04-7.12 (4H, m, H Ar); 7.26-7.32 (1H, m, H-4 Ph);
7.32-7.38 (2H, m, H-3,5 Ph); 7.51-7.55 (2H, m, H-2,6 Ph). Mass spectrum, m/z (Irel, %): 385 [M+H]+ (100).
632

34 5-(4-Ethoxyphenylimino)-3-methyl-2-propyl-2,5-dihydroisothiazole-4-carboxylic Acid Benzyl Ester

(2g). 1 NMR spectrum, , ppm (J, Hz): 0.91 (3, t, J = 7.4, (CH2)23); 1.42 (3, t, J = 7.0, OCH23); 1.611.72 (2H, m, CH2CH23); 2.51 (3H, s, 3-3); 3.54 (2H, t, J = 7.3, NCH2); 4.03 (2H, q, J = 7.0, OCH23);
5.38 (2H, s, OCH2Ph); 6.86-6.91 (2H, m, H Ar); 6.96-7.01 (2H, m, H Ar); 7.25-7.31 (1H, m, H-4 Ph); 7.32-7.38
(2H, m, H-3,5 Ph); 7.52-7.57 (2H, m, H-2,6 Ph). Mass spectrum, m/z (Irel, %): 411 [M+H]+ (100).
35 3-Methyl-5-(3,4-dimethylphenylimino)-2-propyl-2,5-dihydroisothiazole-4-carboxylic Acid Benzyl
Ester (2h). 1 NMR spectrum, , ppm (J, Hz): 0.91 (3, t, J = 7.4, (CH2)23); 1.61-1.72 (2H, m,
CH2CH23); 2.25 (6H, s, Ar(CH3)2); 2.52 (3H, s, 3-3); 3.54 (2H, t, J = 7.3, NCH2); 5.38 (2H, s, OCH2Ph);
6.81 (1H, dd, J = 7.9, J = 2.2, H-6 Ar); 6.86 (1H, d, J = 2.2, H-2 Ar); 7.10 (1H, d, J = 7.9, H-5 Ar); 7.25-7.31
(1H, m, H-4 Ph); 7.32-7.38 (2H, m, H-3,5 Ph); 7.527.58 (2H, m, H-2,6 Ph). Mass spectrum, m/z (Irel, %): 395
[M+H]+ (100).
36 2-Benzyl-3-methyl-5-(4-methylphenylimino)-2,5-dihydroisothiazole-4-carboxylic Acid Benzyl
Ester (2i). 1 NMR spectrum, , ppm (J, Hz): 2.32 (3H, s, ArCH3); 2.53 (3H, s, 3-3); 4.75 (2H, s, NCH2Ph);
5.39 (2H, s, OCH2Ph); 6.93-6.97 (2H, m, H Ar); 7.11-7.16 (4H, m, H Ar); 7.28-7.33 (2H, m, H-4 OBn,
H-4 NBn); 7.33-7.38 (4H, m, H-3,5 OBn, H-3,5 NBn); 7.53-7.57 (2H, m, H-2,6 OBn). Mass spectrum, m/z (Irel,
%): 429 [M+H]+ (100).
37 2-(3-Dimethylaminopropyl)-3-methyl-5-(3-trifluoromethylphenylimino)-2,5-dihydroisothiazole4-carboxylic Acid Methyl Ester (2j). 1 NMR spectrum, , ppm (J, Hz): 1.71-1.82 (2H, m, NCH2CH22);
2.17 (6H, s, N(CH3)2); 2.23 (2H, t, J = 6.4, CH2NMe2); 2.61 (3H, s, 3-3); 3.73 (2H, t, J = 6.9,
NCH2CH22); 3.89 (3H, s, OCH3); 7.17-7.22 (1H, m, H-4(6) Ar); 7.28-7.34 (2H, m, H-2,6(4) Ar); 7.43 (1H, t,
J = 7.9, H-5 Ar). Mass spectrum, m/z (Irel, %): 402 [M+H]+ (25).
38 2-(3-Dimethylaminopropyl)-3-methyl-5-(3-trifluoromethylphenylimino)-2,5-dihydroisothiazole4-carboxylic acid Ethyl Ester (2k). 1 NMR spectrum, , ppm (J, Hz): 1.38 (3H, t, J = 7.1, OCH2CH3);
1.72-1.80 (2H, m, NCH2CH22); 2.17 (6H, s, N(CH3)2); 2.22 (2H, t, J = 6.5, CH2NMe2); 2.58 (3H, s, 3-3);
3.72 (2H, t, J = 6.9, NCH2CH22); 4.37 (2H, q, J = 7.1, OCH2CH3); 7.17-7.22 (1H, m, H-4(6) Ar); 7.28-7.31
(2H, m, H-2,6(4) Ar); 7.42 (1H, t, J = 7.9, H-5 Ar). 13C NMR spectrum, , ppm (J, Hz): 14.4; 14.9; 27.4; 45.2;
46.2; 55.1; 60.3; 105.0; 117.6 (q, 3J = 3.7, C-2(4) Ar); 120.2 (q, 3J = 4.0, C-4(2) Ar); 123.8 (q, 5J = 1.0, C-6 Ar);
124.0 (q, 1J = 271.0, CF3); 130.1; 131.9 (q, 2J = 32.0, C-3 Ar); 155.1; 164.3; 164.4; 164.7. Mass spectrum, m/z
(Irel, %): 416 [M+H]+ (25).
Study of the Cytotoxic Properties of the Obtained Compounds. The in vitro cytotoxicity of
compounds 2b,g,k was determined by standard methods described by Arsenyan et al. [29]. The number of
surviving cells was determined colorimetrically using dyes tris-(4-dimethylaminophenyl)methyl chloride
(crystal violet, CV) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Nitric oxide
generation by the cells was determined as described by Fast et al. [30].
X-ray Structural Analysis of Dihydroisothiazoles 2a,k. Unit cell parameters for the monoclinic
crystals of compound 2a (C23H26N2OS) at 190 K were as follows: a 8.8407(3), b 14.8911(5), c 16.2409(7) ,
105.440(2), V 2060.91(13) 3, space group P21/c, Z 4, dcalc 1.220 g/cm3, 0.172 mm-1, F(000) 808. The unit
cell parameters for the monoclinic crystals of compound 2k (C19H24F3N3O2S) at 190 K were as follows: a
9.5387(3), b 14.9286(5), c 14.0287(4) , 94.960(2), V 1990.20(11) 3, space group P21/c, Z 4, dcalc 1.387
g/cm3, 0.210 mm-1, F(000) 872.
The unit cell parameters and intensities of 8912 reflections (4724 independent reflections, Rint 0.0732)
for compound 2a and 7681 reflections (4520 independent reflections, Rint 0.0394) for compound 2k were
measured on a Bruker-Nonius KappaCCD automatic diffractometer using MoK radiation, graphite
monochromator, measurements to 2max = 55 (Mo 0.71073 ). The structures of both compounds were solved
by the direct method using the SIR2004 software package [31] and refined using the SHELXL software package
[32] anisotropically for the non-hydrogen atoms. The positions of the hydrogen atoms were obtained
geometrically from electron density difference maps and refined using the "rider" model with Uiso = 1.5Ueq for
the methyl group and Uiso = 1.2Ueq for the other hydrogen atoms. The final probability factors were R1 0.598 and
633

wR2 0.1509 for the compound 2a; R1 0.0486 and wR2 0.1208 for the compound 2k. The complete
crystallographic data sets for compounds 2a,k were deposited at the Cambridge Crystallographic Data Center
(deposits CCDC 905607 for compound 2a and 905414 for compound 2k).
The authors express their gratitude to the Experimental Chemotherapeutic Group of the Medicinal
Chemistry Division of the Latvian Institute of Organic Chemistry for the study of cytotoxic activity and to
A. Mishnev for carrying out the X-ray structural investigation.

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