Novel synthesis of oxothiazolidine derivatives

Article abstract of DOI:10.1002/jhet.935

(Z)-Methyl 2-[3-(arylideneamino)-2-(arylidenehydrazono)-4-oxothiazolidin-5- ylidene]acetate prepared during the reaction between thiocarbonohydrazides and dimethyl acetylene dicarboxylate. Rational for there conversations involving the nucleophilic additi

Full text of DOI:10.1002/jhet.935

1054
Novel Synthesis of Oxothiazolidine Derivatives
Vol 49
a
a
a
*
Alaa A. Hassan, Yusria R. Ibrahim, Essmat M. El‐Sheref,
and Alan B. Brownb
aChemistry Department, Faculty of Science, Minia University, El‐Minia 61519, Egypt
bChemistry Department, Florida Institute of Technology, Melbourne, Florida, 32901
*
E-mail: alaahassan2001@yahoo.com
Received February 9, 2011
DOI 10.1002/jhet.935
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
(Z)‐Methyl 2‐[3‐(arylideneamino)‐2‐(arylidenehydrazono)‐4‐oxothiazolidin‐5‐ylidene]acetate prepared during
the reaction between thiocarbonohydrazides and dimethyl acetylene dicarboxylate. Rational for there conversa-
tions involving the nucleophilic addition on C/C triple bond of dimethyl acetylenedicarboxylate are presented.
J. Heterocyclic Chem., 49, 1054 (2012).
INTRODUCTION
Recently, it has been reported that, the reaction of diacyl
thiocarbohydrazides with DMAD (1) in refluxing ethanol
led to (4‐oxathiazolidine‐5‐ylidene)acetates [12], whereas
(Z)‐methyl‐2‐arylhydrazide‐4‐oxo‐3‐(propan‐2‐ylidenea-
mino)thiazolidine‐5‐ylidene)acetates formed during the re-
action of DMAD (1) with N‐[2‐(propan‐2‐ylidene)
hydrazinecarbonothioyl]arylhydrazides [12].
Thiazolidine‐4‐one ring systems are known to possess
antibacterial [13, 14], antituberculosis [15, 16], antiviral
[16, 17], anticancer [18–20], and antioxidant [21].
On the basis of aforementioned encouraged results,
we investigated the reaction of 1,5‐bis(substituted aryl‐
methylidene)thiocarbohydrazides 2a–d with dimethyl
acetylenedicarboxylate (1).
The pronounced reactivity of thioureas and thiosemi‐
carbazides toward dimethyl acetylenedicarboxylate (DMAD)
is well documented [1–7]. Different thiosemi‐carbazone deriva-
tives reacted with DMAD and diethyl acetylenedicarboxylate
(DEAD) by three different methods [8]: (a) in ethyl acetate
solvent at ambient temperature, (b) one‐pot synthesis under
microwave irradiation and solvent‐free conditions (three-
component reaction between thiosemicarbazide, aldehyde/
ketone, and DMAD or DEAD), (c) a microwave‐assisted syn-
thesis under solvent‐free condition, to obtain five‐membered
S,N‐heterocycles thiazolines [8]. The reaction of DMAD with
heterocyclic thioamides has been carried out and a number of
thiazoline derivatives have been reported [4]. Facial DMAD‐
mediated cyclization reactions of easily available thiosemi-
carbazones of formyl‐ and acetyl‐ferrocene and S‐methyl
derivatives affording biologically promising sulfur hetero-
cycles (thiazolone, thiazole, 1,3‐thiazine‐4‐one), carrying at
least one carbomethoxy group [9]. Cyclization of 1,5‐bis
(ferrocenylmethylidene)thio‐carbonohydrazide with DMAD
afforded diastereomeric dimethylthiazole‐4,5‐dicarboxylates
(cis and trans) [10].
RESULTS AND DISCUSSION
In methanol and reflux temperature, the thiocarbo
-hydrazides 2a–d reacted with DMAD (1) to give one single
product each in 75–95% yield (Scheme 1).
From elemental analyses and the mass spectra, a net re-
lease of methanol had occurred. The mass spectra showed
the following five fragments common to all products
[M+‐31], [M+‐Ar‐CH N], [M+‐Ar‐CH N NC], [M+‐Ar‐
CH N N C S], and [MeO2C CH C S].
On the other hand, the reaction of arenaldehyde thiose-
micarbazones with DMAD gave methyl [3‐aryl‐4‐oxo‐1‐
(phenylthiocarbamoyl)‐4,5‐dihydro‐1H‐pyrazol‐5‐ylidene]
ethanoate due to the azaenamine reactivity shown by thiose-
micarbazones and the availability of the methine proton [11].
In IR spectra, two carbonyl bands were seen in the
ranges 1715–1730 cm−1 and 1690–1705 cm−1 in addition
© 2012 HeteroCorporation

September 2012
Novel Synthesis of Oxothiazolidine Derivatives
1055
Scheme 1
Scheme 2
Scheme 3
to a band between 1625 and 1635 cm−1 was assigned to
C N vibration.
The H‐NMR spectra showed the presence of vinylic‐
1
CH between 6.85 and 7.00 ppm and methoxy protons at
about 3.85–3.90 ppm as two singlets. All the new com-
pounds synthesized contain a carbomethoxy methylidene
1
side chain ( CHCO2Me). In the H‐NMR signals, one of
CH N is downfield shifted (δH = 9.05–9.30 ppm) due to
the formation of hydrogen‐bond with lactam‐CO, the other
CH N showed one singlet at δH = 8.50–8.65 ppm due to the
anisotropy of the N (sp2) atom [22].
In all cases, the 13C‐NMR spectra have been obtained
showing six downfield lying lines at 165.41–166.48
(C O, ring), 164.33–165.35 (C O, ester), 160.25–163.26
(CH N), 156.31–160.24 (C‐2, C N), 140.29–141.65 (C‐5)
and 115.91–116.86 (vinyl‐CH).
Compounds 2a–d may react either with their sulfur
atom, N2 as nucleophilic sites. On the other hand, it has
been reported that the azomethine carbon and N2 of 2a–d
had taken part in the heterocyclization [11]. The methine
carbon of 2 had to act as a nucleophile in the sense of an
“umpolung” [11]. Thus, several options for interaction be-
tween 2a–d and DMAD (1) may be expected as will be
outlined later.
Scheme 4
If the reaction took place through N2 and azomethine‐
CH or N2 and SH of 2, the most likely isomeric products
would be 5 and 6, respectively (Scheme 2).
If N2 attached the triple bond of 1 followed by interamo-
lecular nucleophilic attack of N4 or SH at α‐ and β‐ester
group, the products 8 and 9 were observed (Scheme 3).
The products 3 and 11 could be isolated if the reaction
involve the participation of SH and N4, respectively
(Scheme 4).
The structures 6 and 8 can be immediately ruled out, no
signal is far enough down field for a C S. On the other
hand, compounds 5 and 9 have been already eliminated
Journal of Heterocyclic Chemistry
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A. A. Hassan, Y. R. Ibrahim, E. M. El-Sheref, and A. B. Brown
Vol 49
as C‐2″. The carbon resonating at δC = 140.68 does not give
any HMBC correlations, but is assigned as C‐3″ by analogy
with other structures [12].
The two p‐anisylidene units can be unambiguously differ-
entiated based on the coupling networks, except for C‐6,6′.
Each p‐anisylidene subunit is spectroscopically isolated, but
13C-NMR simulation predicts that C‐1 will resonate down-
field of C‐1′ (predicted δC = 163.7 vs. 154.7); therefore, the
downfield of the two (experimental δC = 164.99 vs. 160.23)
is assigned as C‐1 and the rest of the assignment follow.
CONCLUSIONS
The presented synthesis is provides insight into the reac-
tions between the electron donating thiocarbo‐hydrazides
2a–d and dimethyl acetylenedicarboxylate (1). Oxothiazoli-
dine derivatives 3a–d are formed from 2 and 1. The results
reported herein supplement the rich chemistry of dimethyl
acetylenedicarboxylate.
Figure 1.
based on the ring carbonyl 13C‐resonance, should occur
considerably down‐field to those which have been ob-
served. We will concentrate between the alternative struc-
tures 3 and 11. In each DMAD‐derived structure 3 and
11, C‐1″ is the lactam carbonyl, C‐2″ is the proton‐bearing
carbon and C‐3″ is the “quaternary” carbon (Fig. 1). The
spectra of compound 3c show two p‐anisyl units: one isolated
methoxy group and one isolated vinyl‐CH proton (Table 1).
The signals between δC = 166.48–156.79 ppm (Table 2)
must represent two C O, three C N, and two methoxy‐bearing
aryl carbons. Of the three sets of methoxy protons, the signals
at δH = 3.89 ppm is assigned as the ester methoxyl; this signal
EXPERIMENTAL
Melting points were determined with a Gallenkamp melting
point apparatus and were uncorrected. The IR spectra were
recorded with a Shimadzu 408 instrument using potassium bro-
1
mide pellets. The 400 MHz H‐ and 100 MHz 13C‐NMR were
measured in CDCl3 using Bruker AV 400 spectrometer. Chemical
shifts are expressed at δ (ppm) using tetramethylsilane (TMS) = 0.
The 13C‐NMR assignments (q = quaternary carbon atoms) were
made with aid of DEPT 135/90 spectra. Coupling constants are
gives HSQC correlation with the attached carbon at δC
=
1
stated in Hz; H‐coupled 13C spectra were measured using gated
52.53 ppm (Table 2) and HMBC correlation with the ester
carbonyl at δC = 166.48 ppm. The signal (δC = 161.32
ppm) giving HMBC correlation to H‐2″ (δH = 6.97 ppm) is
assigned as the lactam carbonyl C‐1″. Under gated decou-
pling, C‐1″ couples to H‐2″ with J = 5.4 Hz, a value which
require a three‐bond coupling not two‐bond coupling [23].
Thus, structure 11 can also be ruled out. The magnitude of
this coupling further argues that C‐1″ and H‐2″ are mutually
decoupling. Correlations were established using 1H‐1H COSY,
HMBC, and HSQC experiments. The mass spectra (70 eV, elec-
tron impact mode) were recorded on a Finnigan MAT instrument.
Elemental analyses were carried out at the Microanalytical Cen-
ter, Cairo University, Egypt.
Starting materials. Dimethyl acetylenedicarboxylate (DMAD,
1) was bought from Fluka. 1,5‐Bis(substituted arylmethylidene)‐
thiocarbohydrazide 2a–d were prepared according to the literatures
as 1,5‐bis(phenylmethylidene)thiocarbohydrazide 2a [24], 1,5‐bis
(4‐methylphenylmethylidene)thiocarbohydrazide 2b [25] 1,5‐bis
(4‐methoxyphenylmethylidene)thiocarbo‐hydrazide 2c [24], and
1,5‐bis(4‐chlorophenylmethylidene)‐thiocarbohydrazide 2d [24,26].
cis [23] as depicted in structure 3c. The carbon (δC
116.38 ppm) giving HSQC correlation to H‐2″ is assigned
=
Reactions
thiocarbohydrazide 2a–d and dimethyl ethynedicarboxylate
(1). mixture of 1,5‐bis(substituted arylmethylidene)
of
1,5‐bis(substituted
arylmethylidene)
Table 1
1H NMR data for compound 3c.
A
thiocarbohydrazide 2a–d (1 mmol) and dimethyl acetylenedi‐
carboxylate (1, 1 mmol) in methanol was refluxed for 30 min (for
compound 2a), 1 h (for compound 2b), 1.5 h (for compound 2c),
and 2 h (for compound 2d). The solvent was evaporated and the
obtained precipitate was recrystallized to give 3a–d.
1H NMR (CDCI3)
COSY
Assignment
9.06 (s; 1H)
8.49(s; 1H)
H‐1
H‐1′
H‐3
H‐3′
H‐4
H‐2″
H‐4′
C02CH3
H‐6
7.88 (d, J = 8.8; 2H)
7.78 (d, J = 8.8;2H)
6.99 (d, J = 9.3; 2H)
6.97 (s; 1H)
6.95 (d, J = 8.8; 2H)
3.893 (s; 3H)
6.99
6.95
7.88
(Z)‐Methyl 2‐[(Z)‐3‐((E)‐benzylideneamino)‐2‐((E)‐benzyl‐
idenehydrazono)‐4‐oxothiazolidin‐5‐ylidene]acetate (3a). This
compound was obtained as yellow crystals (ethanol) (85%), mp
166–168°C; IR: Ali‐CH 2960, CO 1725,1705, C N 1625, Ar‐C C
7.78
1
1605, 1590 cm−1; H‐NMR: δ 3.960 (s, 3H, CO2CH3), 7.0 (s, 1H,
3.887 (s; 3H)
3.87 (s; 3H)
vinyl‐CH, C‐2″), 7.45–7.60 (m, 6H, Ar‐H), 7.80–7.95 (m, 4H,
H‐6′
Ar‐H), 8.60 (s, 1H, C‐1′‐H), 9.30 (s, 1H, C‐1‐H); 13C‐NMR: δ
Journal of Heterocyclic Chemistry
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September 2012
Novel Synthesis of Oxothiazolidine Derivatives
1057
Table 2
13C NMR, HSQC, and HMBC data for compound 3c.
13CNMR (CDCI3)a
HSQC
HMBC
Assignment
166.48 (dq, Jd = 1.3, Jq = 4.0)
164.99 (dt, Jd = 166.6, Jt = 5.2)
163.26 (m)
162.36 (m)
161.32 (d, J = 5.4)
160.23 (dt, Jd = 163.5, Jt = 4.2)
156.79 (s)
140.68 (s)
131.02 (ddd, J = 160.9, 7.1, 4.2)
130.35 (ddd, J = 160.5, 7.3, 4.0)
126.55 (dt, Jd = Jt = 7.8)
125.20 (dt, Jd = Jt = 7.4)
116.38 (d, J = 172.6)
114.36 (dd, J = 161.2, 4.7)
114.27 (dd, J = 160.2, 4.8)
55.51 (q, J = 144.3), 55.45 (q, J = 144.4)
52.53 (q, J = 147.6)
3.893
CO2CH3
C‐1
C‐5
C‐5′
C‐1″
C‐1′
C ( ) N
C‐3″
C‐3
C‐3′
C‐2′
C‐2
C‐2″
C‐4
C‐4′
C‐6,6′
CO2CH3
9.06b
7.88, 3.887
7.78,3.87
6.97
8.49c
7.88
7.87
9.06, 7.88, 6.99
8.49, 7.78, 6.95
8.49, 6.95
9.06,6.99
6.97
6.99
6.95
3.887, 3.87
3.893
7.88, 6.99
7.78, 6.95
aCarbon multiplicities were measured via a gated decoupling experiment.
bDetected via one‐bond coupling in HMBC.
cDetected via one‐bond coupling in 1H‐coupled 13C spectrum.
52.61 (CO2CH3), 116.86 (vinyl‐CH), 128.65 (Ar‐CH), 128.80,
128.91, 129.07, 131.50, 132.57, 133.69 (Ar‐CH), 140.29 (C‐5
(3″)), 157.83 (C‐2, C N), 160.31 (CH N, C‐1′), 161.42 (C‐5, C‐1″),
162.43 (C OCH3, C‐5′), 163.35 (C OCH3, C‐5), 165.08 (CH N, C‐
1), 166.57 ppm (CO, ester); ms: m/z 392 (M+, 15), 288 (22), 230
(8), 146 (100), 116 (81), 90 (79), 77 (85), 72 (32), 59 (24). Anal.
Calcd. for C20H16N4O3S: C, 61.21; H, 4.11; N, 14.28; S, 8.17.
Found: C, 61.37; H, 4.03; N, 14.18; S, 8.32.
(Z)‐Methyl 2‐[(Z)‐3‐((E)‐(4‐methylbenzylidene)amino)‐2‐((E)‐
(4‐methylbenzylidene)hydrazono)‐4‐oxothiazolidin‐5‐ylidene]
acetate (3b). This compound was obtained as yellow crystals
(ethanol) (90%), mp 178–180°C; IR: Ali‐CH 2975, CO 1720,1690,
C N 1635, Ar‐C C 1600, 1585 cm−1; 1H‐NMR: δ 2.40 (s, 3H,
CH3), 3.90 (s, 3H, CO2CH3), 6.97 (s, 1H, vinyl‐CH, C‐2″), 7.30 (d,
J = 8.86, 2H, H‐4′), 7.33 (d, J = 9.34, 2H, H‐4), 7.81 (d, J = 8.86,
2H, H‐3′), 7.90 (d, J = 8.86, 2H, H‐3), 8.55 (s, 1H, C‐1′‐H), 9.18
(s, 1H, C‐1‐H); 13C‐NMR: δ 21.28 (CH3), 52.07 (CO2CH3), 116.09
(vinyl‐CH, C‐2″), 128.14 (Ar‐C), 128.61, 129.06, 129.14, 129.37,
129.86, 130.51 (Ar‐CH), 141.65 (C‐5 (C‐3″)), 156.31 (C‐2, C N),
160.27 (CH N, C‐1′), 161.38 (C‐1″), 162.37 (C‐5′), 163.31 (C‐5),
165.02 (C‐1), 166.53 ppm (CO, ester); ms: m/z 420 (M+, 19), 302
(27), 144 (11), 144 (100), 116 (61), 91 (42), 77 (36), 59 (35). Anal.
Calcd. for C22H20N4O3S: C, 62.84; H, 4.79; N, 13.32; S, 7.63.
Found: C, 63.02; H, 4.71; N, 13.49; S, 7.48.
1730,1705, C N 1630, Ar‐C C 1610, 1595 cm−1 1H‐NMR: δ
;
3.85 (s, 3H, CO2CH3), 6.85 (s, 1H, vinyl‐CH), 7.50–7.68
(m, 4H, Ar‐H), 7.76–7.92 (m, 4H, Ar‐H), 8.65 (s, 1H, C‐1′‐H),
9.30 (s, 1H, C‐1‐H); 13C‐NMR: δ 115.91 (vinyl‐CH), 128.87,
136.62 (Ar‐C), 129.18, 129.39, 129.82, 130.30, 130.56, 130.14
(Ar‐CH), 141.08 (C‐5 (3″)), 159.57 (C‐2, C N), 160.56 (CH N,
C‐1′), 161.69 (C‐1″), 165.21 (CH N, C‐1), 166.50 ppm
(CO, ester); ms: m/z 460/464 (M+, 12), 389 (21), 226 (32), 182
(73), 116 (100), 77 (64). Anal. Calcd. for C20H14Cl2N4O3S: C,
52.07; H, 3.06; Cl, 15.37; N, 12.14; S, 6.95. Found: C, 51.89;
H, 2.97; Cl, 15.48; N, 11.96; S, 7.08.
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(Z)‐Methyl 2‐[(Z)‐3‐((E)‐(4‐methoxybenzylidene)amino)‐2‐((E)‐
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This compound was obtained as yellow crystals
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1
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. A. Hassan, Y. R. Ibrahim, E. M. El-Sheref, and A. B. Brown
Vol 49
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet