Synthesis of 3-substituted 5-arylidene-1-methyl-2-Thiohydantoins under microwave irradiation

Article abstract of DOI:10.3987/com-02-9452

A mono-modal microwave oven was used to expedite the synthesis of small libraries of 3-substituted 1-methyl-2-thiohydantoins and 3-substituted 5-arylidene-1-methyl-2-thiohydantoins. In comparison with the traditional reflux methods, similar or higher yields were obtained.

Full text of DOI:10.3987/com-02-9452

HETEROCYCLES, Vol. 57, No. 6, 2002, pp. 1017 - 1032, Received, 1st February, 2002
SYNTHESIS OF 3-SUBSTITUTED 5-ARYLIDENE-1-METHYL-2-
THIOHYDANTOINS UNDER MICROWAVE IRRADIATION
†
Ahmed I. Khodair and John Nielsen*
Department of Chemistry, Technical University of Denmark, Kemitorvet,
Building 207, DK-2800 Kgs. Lyngby, Denmark, E-mail: jni@kemi.dtu.dk
Abstract - A mono-modal microwave oven was used to expedite the
synthesis of small libraries of 3-substituted 1-methyl-2-thiohydantoins and
3-substituted 5-arylidene-1-methyl-2-thiohydantoins. In comparison with
the traditional reflux methods, similar or higher yields were obtained.
INTRODUCTION
The pioneering reports on the use of microwave irradiation as thermal source to carry out
organic reactions were published in 1986. 1 , 2 In 1989, the first review dealing with
microwave heating in organic synthesis appeared.3 Since then a rapidly increasing number
of reports and reviews have been published demonstrating that a large variety of organic
reactions can be conducted safely in microwave ovens leading to reduction in reaction
times of up to three orders of magnitude.4 , 5 These reports also include solid-phase
reactions and the generation of combinatorial libraries.6 The timesaving ability together
with the very short response times and the minimization of thermal decomposition of
products are the main advantages of microwave heating.
In our efforts to generate combinatorial libraries of potentially biologically active
compounds using expeditious parallel synthesis, we have been interested in a series of
heterocyclic compounds. Among these are the substituted thiohydantoins whereof several
5-arylidene-2-thiohydantoins have shown potent activity against herpes simplex virus
(HSV),7 human immunodeficiency virus (HIV)8 and the leukemia sub-panel.9 In addition,
certain other series of hydantoin derivatives showed interesting activities, including
antiviral,10 anti-inflammatory,11 anticonvulsant,12 antidepressant,13 and platelet inhibitor
On leave from Department of Chemistry, Faculty of Education, Tanta University, Kafer EL-Sheikh, Egypt

activities.14 Furthermore, they are a conspicuous structural feature of several inhibitors of
aldose reductase.15,16 Our interest in 2-thiohydantoins prompted us to test the role of
microwave irradiation on the preparation of 3-substituted 1-methyl-2-thiohydantoins and 3-
substituted 5-arylidene-1-methyl-2-thiohydantoins as potential antiviral and antitumor
agents. Multi-component reactions (MCR), where three or more reactants combine to give
a single product, have lately received much attention and were also considered.17 Thus,
retrosynthetic analysis showed that 3-substituted 5-arylidene-1-methyl-2-thiohydantoins (3-
6) could be prepared using two different strategies (Figure 1). Path A relies on the
Knoevenagel-type condensation of an aldehyde with 3-substituted 1-methyl-2-
thiohydantoins (2), which can be obtained by reaction of an isothiocyante derivative (1)
with sarcosine.18 Alternatively, as outlined by path B, the reaction can be carried out as a
one-pot three-component condensation reaction of aldehydes, isothiocyante derivatives
(1) and sarcosine.
Ar
O
O
H
O
Path A
Path B
Method A
Method B
5
4
2
Ar-CHO +
+ R-NCS
N
N
N 3
R
N
OH
NH
R
1
1
S
S
2
3-6
Figure 1
3-Substituted 5-arylidene-1-methyl-2-thiohydantoins (3-6, numbering shown) are available by
two routes: (A) Two-step synthesis via 3-substituted 1-methyl-2-thiohydantoins (2) followed by a
Knoevenagel-type condensation of aldehydes. (B) One-pot reaction via three-component
condensation of aldehydes, isothiocyante derivatives (1) and sarcosine. Method A and method
B refer to microwave irradiation and thermal reflux, respectively.
RESULTS AND DISCUSSION
Herein, we report the results of several experiments in which organic reactions have been
carried out in Teflon-sealed glass vessels heated by mono-modal microwave irradiation
under moderate pressure.19 In most cases the high temperature readily obtained in the
reaction vessels led to remarkable rate enhancements and therefore an inherent dramatic
reduction in reaction times. The present work describes the synthesis and configurations
of a library of previously unreported series of 3-substituted 1-methyl-2-thiohydantoins (2a-

g) and 3-substituted 5-arylidene-1-methyl-2-thiohydantoins (3a-g to 6a-g). Four aldehydes
and seven isothiocyanates were used, giving rise to a small library of 28 different products
H
O
Method A
Method B
N
S
H
R
O
+ R-NCS
N
Me
OH
N
Me
OH
1a-g
Path B
Ar-CHO
Ar
O
O
H
Path A
N
N
R
N
N
R
Ar-CHO
S
S
3a-g - 6a-g
2a-g
1-3 R
Ar
R
Ar
O
O
Methyl
Methyl
a
b
c
5a
b
c
Phenyl
Allyl
Phenyl
Allyl
O
n-Butyl
n-Hexyl
n-Butyl
n-Hexyl
d
e
d
e
Cyclohexylmethyl
Cyclohexylmethyl
f
f
2-(4-Morpholino)ethyl
2-(4-Morpholino)ethyl
g
4a
b
c
g
6a
b
c
O
O
Methyl
Methyl
S
Phenyl
Phenyl
Allyl
Allyl
n-Butyl
n-Butyl
d
e
d
e
n-Hexyl
n-Hexyl
Cyclohexylmethyl
2-(4-Morpholino)ethyl
Cyclohexylmethyl
2-(4-Morpholino)ethyl
f
f
g
g
Scheme 1

(Scheme 1). First, path A was implemented. The condensation of aromatic aldehydes with
3-substituted 1-methyl-2-thiohydantoins (2a-g) was accomplished by reflux in a solution of
triethylamine and ethanol under either microwave irradiation (method A) or traditional
reflux methods (method B).
Likewise, intermediates (2a-g) were prepared from sarcosine and the appropriate
isothiocyanates (1a-h) by either microwave irradiation or reflux in ethanol. In addition,
reaction path B was implemented. The multi-component reaction of aromatic aldehydes,
the appropriate isothiocyanates and sarcosine was performed by heating a solution of
ethanol containing triethylamine under either microwave irradiation or traditional reflux.
Yields resulting from the different synthetic approaches are given in Table 1.
TABLE 1 Yields of 3a-6g from the different synthetic approaches.
Yields (Path A)
(%)
Yields (Path B)
(one pot, %)
Yields (Path A)
(%)
Yields (Path B)
(one pot, %)
A
B
A
B
A
B
A
B
Method
3a
Method
5a
86
88
92
86
86
84
83
83
90
86
82
87
90
86
93
92
90
84
85
80
86
88
92
93
85
91
96
92
78
84
71
73
71
74
74
74
85
82
78
80
83
78
70
80
69
65
68
67
70
72
87
88
69
74
79
72
82
94
84
80
84
84
84
84
94
94
82
86
90
86
90
98
92
82
86
92
92
88
98
98
90
92
94
94
77
88
78
70
69
78
80
70
88
86
78
80
86
76
68
86
66
64
65
72
78
68
86
88
74
72
78
74
3b
3c
3d
3e
3f
5b
5c
5d
5e
5f
3g
4a
4b
4c
4d
4e
4f
5g
6a
6b
6c
6d
6e
6f
4g
6g
1
The structures of 3a-g to 6a-g were confirmed on the basis of spectral data (IR, H-NMR,
13C-NMR and MS) and elemental analysis. The IR absorption spectrum of compound (3a)
was characterized by the presence of a signal at 1717 cm-1 due to the carbonyl group as
1
well as the thiocarbonyl group at 1230 cm-1. The H-NMR spectrum of compound (3a)
showed a singlet at δ 6.48 ppm assigned to the vinyl proton, indicating the presence of an

1
E-configuration for the exocyclic double bond. This is in agreement with the H-NMR
spectra of 5-(E)- and 5-(Z)-arylidenehydantoin derivatives whose vinyl protons appear at
δ 6.10-6.50 and 6.50-6.75 ppm, respectively.20,21 The 13C-NMR spectrum of compound (3a)
showed an absorbtion at δ 120.60 ppm assigned to the vinyl group, likewise indicating the
13
presence of an E-configuration for the exocyclic double bond, in agreement with the C-
NMR spectra of 5-(Z)- and 5-(E)-arylidenehydantoin derivatives whose vinyl groups appear
at δ 105-115 and 115-125 ppm, respectively.20 Further evidence for the E-configuration
came from nuclear Overhauser effect (NOE) experiments on compound (3a). On
irradiation of the CH3 resonance 3.63 ppm, a large NOE enhancement was found for the
ortho protons of the phenyl group (11%) and on irradiation of the ortho protons a small
NOE enhancement was found for CH3 (3%).
In conclusion, two small libraries have been synthesized consisting of 7 different 3-
substituted 1-methyl-2-thiohydantoins and 28 different 5-arylidene-1-methyl-2-
thiohydantoins, using either microwave irradiation or traditional reflux. Yields were
generally very high for both reaction paths,but microwave reactions were completed within
a few minutes as compared to hours required for reflux conditions.
EXPERIMENTAL
1
General Method: H-NMR (300.13 MHz) and 13C-NMR (75.47 MHz) spectra were
measured on a Bruker Advance DPX 300 machine using tetramethylsilane as external
reference. Analytical data were obtained using a C,H,N Elemental analyzer Carlo Erba
1106. MS was recorded on a Finnigan MAT-INCOS 500 spectrometer with ionization by
electron impact (70 eV). Melting points were uncorrected. Alumina sheets coated with
silica gel 60 F254 (Merck) were used for TLC and compounds were visualized by UV-
irradiation of the fluorescent TLC plates. IR spectra were measured on a Nicolet Magna
750. Column chromatography was performed with silica gel 60 mesh ASTM (Merck). The
microwave oven used for the experiments was a Microwell 10 from Labwell AB (now
Personal Chemistry AB, Uppsala, Sweden). The oven is mono-modal and the effect can
be adjusted within 1W intervals between 1 and 500 W.
3-substituted 1-methyl-2-thiohydantoins (2a-g)

Method A: N-Methylglycine (89 mg, 1 mmol), the appropriate isothiocyanate (1a-g; 1.1
mmol), and ethanol (3 mL) were placed in a Teflon-sealed glass vessel (10 mL capacity)
and introduced in a microwave cavity at 60 watts at 120-125°C and 2.50-3.50 Bar for 12
min. The reaction mixture was allowed to reach rt. The reaction mixture was concentrated
to dryness in vacuo. The residue was purified by silica gel column chromatography eluting
with Et2O/petroleum ether (1:1, v/v) to give products (2a-g).
Method B: The same amounts of reactants indicated in method A were heated under
reflux for 12 h. The resulting hydantoins were isolated as indicated in the method
described above.
1,3-Dimethyl-2-thiohydantoin (2a): Using methyl isothiocyanate (73 mg, 1 mmol),
method A afforded 120 mg (83%) of 2a and 100 mg (69%) were obtained following method
1
B. mp 90-92°C (lit.,22 92.0-92.5°C). IR (KBr): ν 1720 (C=O), 1225 (C=S) cm-1. H-NMR
(CDCl3): δ 3.24 (3H, s, N(3)-CH3), 3.33 (3H, s, N(1)-CH3), 4.00 (2H, s, H-5).
1-Methyl-3-phenyl-2-thiohydantoin (2b): Using phenyl isothiocyanate (135 mg, 1 mmol),
method A afforded 185 mg (90%) of 2b and 190 mg (92%) were obtained following
1
method B. mp 160-162°C (lit.,18 163°C). IR (KBr): ν 1717 (C=O), 1226 (C=S) cm-1. H-
13
NMR (CDCl3): δ 3.37 (3H, s, N(1)-CH3), 4.20 (2H, s, H-5), 7.27-7.52 (5H, m, H-Ar). C-
NMR (CDCl3): δ 34.23 (CH3), 54.21 (C-5), 128.25, 129.02, 129.07, 133.33 (C-Ar), 169.54
(C-4), 183.07 (C-2).
3-Allyl-1-methyl-2-thiohydantoin (2c): Using allyl isothiocyanate (99 mg, 1 mmol),
method A afforded 136 mg (80%) of 2c (red oil) and 123 mg (72%) were obtained
1
following method B. IR (KBr): ν 1722 (C=O), 1228 (C=S) cm-1. H-NMR (CDCl3): δ 3.32
(3H, s, N(1)-CH3), 4.01 (3H, s, H-5), 4.14 (2H, 2 x t, J = 1.35 Hz, N(3)-CH2), 5.23 (2H, m,
=CH2), 5.86 (1H, m, CH). Anal. Calcd for C7H10N2OS: C, 49.4, H, 5.9; N, 16.5. Found: C,
49.6; H, 6.2; N, 16.8.
3-n-Butyl-1-methyl-2-thiohydantoin (2d): Using n-butyl isothiocyanate (115 mg, 1
mmol), method A afforded 143 mg (77%) of 2d (red oil) and 127 mg (68%) were obtained
1
following method B. IR (KBr): ν 1720 (C=O), 1230 (C=S) cm-1. H-NMR (CDCl3): δ 0.94
(3H, m, CH3), 1.44-1.78 (4H, m, 2 x CH2), 3.29 (3H, s, N(1)-CH3), 3.97 (2H, s, H-5). 13C-
NMR (CDCl3): δ 13.77 (CH3), 20.08 (CH2), 29.79 (CH2), 34.04 (CH3), 42.08 (CH2), 53.88
(C-5), 170.42 (C-4), 183.50 (C-2). Anal. Calcd for C8H14N2OS: C, 51.6, H, 7.6; N, 15.0.
Found: C, 51.6; H, 7.2; N, 14.8.

3-n-Hexyl-1-methyl-2-thiohydantoin (2e): Using n-hexyl isothiocyanate (143 mg, 1
mmol), method A afforded 161 mg (75%) of 2e (red oil) and 150 mg (70%) were obtained
1
following method B. IR (KBr): ν 1714 (C=O), 1227 (C=S) cm-1. H-NMR (CDCl3): δ 0.84
(3H, t, J = 7.52 Hz, CH3), 1.26 (6H, m, 3CH2), 1.65 (2H, m, CH2), 3.53 (3H, s, N(1)-CH3),
3.86 (2H, t, J = 7.54 Hz, N(3)-CH2), 4.00 (2H, s, H-5). Anal. Calcd for C10H18N2OS: C, 56.0,
H, 8.5; N, 13.1. Found: C, 56.2; H, 8.2; N, 12.8.
3-Cyclohexylmethyl-1-methyl-2-thiohydantoin (2f): Using cyclohexylmethyl
isothiocyanate (155 mg, 1 mmol), method A afforded 176 mg (78%) of 2f (red oil) and 152
mg (67%) were obtained following method B. IR (KBr): ν 1712 (C=O), 1229 (C=S) cm-1. 1H-
NMR (CDCl3): δ 1.20-1.25 (6H, m, H-3, H-4, H-5cyclohexane), 1.70 (4H, m, H-2, H-6cyclohexane),
2.00 (1H, m, H-1cyclohexane), 3.63 (3H, s, N(1)-CH3), 3.76 (2H, d, J = 7.45 Hz, N(3)-CH2),
3.96 (2H, s, H-5). Anal. Calcd for C11H18N2OS: C, 58.4, H, 8.0; N, 12.4. Found: C, 58.2; H,
8.2; N, 12.7.
3-(2-(4-Morpholino)ethyl)-1-methyl-2-thiohydantoin (2g): Using 2-(4-morpholino)ethyl
isothiocyanate (172 mg, 1 mmol), method A afforded 207 mg (85%) of 2g and 199 mg
(82%) were obtained following method B. mp 74-76°C. IR (KBr): ν 1720 (C=O), 1232
(C=S) cm-1. 1H-NMR (CDCl3): δ 2.52 (4H, t, J = 4.5 Hz, H-2’, H-6’), 2.64 (2H, t, J = 13.5 Hz,
N-CH2), 3.33 (3H, s, N(1)-CH3), 3.65 (4H, t, J = 4.5 Hz, H-3’, H-5’), 3.94 (2H, t, J = 13.5
Hz, N(3)-CH2), 4.01 (2H, s, H-5). Anal. Calcd for C10H17N3O2S: C, 49.4, H, 7.0; N, 17.3.
Found: C, 49.3; H, 7.2; N, 17.7.
5-(E)-Arylidene-3-substituted 1-methyl-2-thiohydantoins (3a-g to 6a-g)
Path A: Method A: 3-Substituted 1-methyl-2-thiohydantoins (2a-g, 1 mmol), the
appropriate aromatic aldehydes (1.1 mmol), morpholine (87 µL, 1 mmol) and ethanol (3
mL) were placed in a Teflon-sealed glass vessel (10 mL capacity) and introduced in a
microwave cavity at 60 watts at 150-155°C and 3.50-5.00 Bar for 12 min. The reaction
mixture was allowed to reach rt. The reaction mixture was concentrated to dryness in
vacuo. The residue was purified by silica gel column chromatography with Et2O/petroleum
ether (1:1, v/v) to give products (3a-g/6a-g) in quantitative yields.
Path A: Method B: The same amounts of reactants indicated in method A were heated at
40-50 oC for 12 h. The resulting 2-thiohydantoins were isolated as indicated in the method
described above.

Path B: Method A: N-Methylglycine (89 mg, 1 mmol), the appropriate isothiocyanates (1a-
g; 1.1 mmol) and the appropriate aromatic aldehydes (1.1 mmol), triethylamine (202 µL, 2
mmol) and ethanol (3 mL) were placed in a Teflon-sealed glass vessel (10 mL capacity)
and introduced in a microwave cavity at 60 watts at 150-155°C and 3.50-5.00 Bar for 20
min. The reaction mixture was allowed to reach to rt. The reaction mixture was
concentrated to dryness in vacuo. The residue was purified by silica gel column
chromatography with Et2O/petroleum ether (1:1, v/v) to give products (3a-g/6a-g) in
quantitative yields.
Path B: Method A: The same amounts of reactants indicated in method A were heated
under reflux for 6 h. The resulting 2-thiohydantoins were isolated as indicated in the
method described above.
5-((E)-Benzylidene)-1,3-Dimethyl-2-thiohydantoin (3a): Using path A, method A
afforded 200 mg (86%) of 3a and 216 mg (93%) were obtained following method B. Using
path B, method A afforded 181 mg (78%) of 3a and 162 mg (70%) were obtained following
1
method B. mp 140-142°C (lit.,18 144°C). IR (KBr): ν 1717 (C=O), 1230 (C=S) cm-1. H-
NMR (CDCl3): δ 3.38 (3H, s, N(3)-CH3), 3.63 (3H, s, N(1)-CH3), 6.48 (1H, s, =CH), 7.41
(3H, m, H-Ar), 7.98 (2H, m, H-Ar). 13C-NMR (CDCl3): δ 28.28 (N(3)-CH3), 30.60 (N(1)-
CH3), 120.60 (=CH), 128.45, 129.21, 129.97, 130.80, 132.02 (C-5, C-Ar), 161.64 (C-4),
177.35 (C-2).
5-((E)-Benzylidene)-1-methyl-3-phenyl-2-thiohydantoin (3b): Using path A, method A
afforded 259 mg (88%) of 3b and 270 mg (92%) were obtained following method B. Using
path B,method A afforded 247 mg (84%) of 3b and 235 mg (80%) were obtained following
1
method B. mp 192-194°C (lit.,18 196°C). IR (KBr): ν 1720 (C=O), 1232 (C=S) cm-1. H-
NMR (CDCl3): δ 3.71 (3H, s, N(1)-CH3), 6.58 (1H, s, =CH), 7.34-8.03 (10H, m, H-Ar). 13C-
NMR (CDCl3): δ 30.88 (CH3), 121.06 (=CH), 128.45, 128.49, 128.98, 129.13, 129.18,
130.10, 130.95, 131.91, 133.30 (C-Ar), 161.24 (C-4), 176.80 (C-2).
3-Allyl-5-((E)-benzylidene)-1-methyl-2-thiohydantoin (3c): Using path A, method A
afforded 237 mg (92%) of 3c and 232 mg (90%) were obtained following method B. Using
path B, method A afforded 184 mg (71%) of 3c and 178 mg (69%) were obtained following
1
method B. mp 153-155°C (yellow crystals). IR (KBr): ν 1719 (C=O), 1234 (C=S) cm-1. H-
NMR (CDCl3): δ 3.60 (3H, s, N(1)-CH3), 4.46 (2H, 2 x t, J = 1.35 Hz, N(3)-CH2), 5.24 (2H,

m, = CH2), 5.84 (1H, m, CH), 6.48 (1H, s, =CH), 7.42 (3H, m, H-Ar), 7.97 (2H, m, H-Ar).
Anal. Calcd for C14H14N2OS: C, 65.1, H, 5.5; N, 10.8. Found: C, 65.0; H, 5.2; N, 10.8.
5-((E)-Benzylidene)-3-n-butyl-1-methyl-2-thiohydantoin (3d): Using path A, method A
afforded 236 mg (86%) of 3d and 230 mg (84%) were obtained following method B. Using
path B, method A afforded 200 mg (73%) of 3d and 178 mg (65%) were obtained following
1
method B. mp 104-106°C. IR (KBr): ν 1714 (C=O), 1232 (C=S) cm-1. H-NMR (CDCl3): δ
0.94 (3H, m, CH3), 1.40-1.70 (4H, 2m, 2 x CH2), 3.60 (3H, s, N(1)-CH3), 3.95 (2H, t, J = 7.5
13
Hz, N(3)-CH2), 6.48 (1H, s, =CH), 7.42 (3H, m, H-Ar), 7.96 (2H, m, H-Ar). C-NMR
(CDCl3): δ 13.68 (CH3), 20.05 (CH2), 29.82 (CH2), 30.71 (N(1)-CH3), 41.78 (N(3)-CH2),
120.23 (=CH), 128.30, 129.13, 129.78, 130.67, 131.97, (C-5, C-Ar), 161.49 (C-4), 176.90
(C-2). Anal. Calcd for C15H18N2OS: C, 65.7, H, 6.6; N, 10.2. Found: C, 65.5; H, 6.9; N, 10.0.
5-((E)-Benzylidene)-3-n-hexyl-1-methyl-2-thiohydantoin (3e): Using path A, method A
afforded 335 mg (86%) of 3e and 231 mg (85%) were obtained following method B. Using
path B, method A afforded 277 mg (71%) of 3e and 265 mg (68%) were obtained following
1
method B. mp 153-155°C. IR (KBr): ν 1715 (C=O), 1230 (C=S) cm-1. H-NMR (CDCl3): δ
0.80 (3H, t, J = 7.5 Hz, CH3), 1.20 (6H, m, 3CH2), 1.62 (2H, m, CH2), 3.50 (3H, s, N(1)-
CH3), 3.82 (2H, t, J = 7.5 Hz, N(3)-CH2), 6.35 (1H, s, =CH), 7.38 (3H, m, H-Ar), 7.98 (2H,
m, H-Ar). 13C-NMR (CDCl3): δ 14.26 (CH3), 22.76 (CH2), 26.73 (CH2), 27.97 (CH2), 30.72
(N(1)-CH3), 31.63 (N(1)-CH2), 42.32 (N(3)-CH2), 120.51 (=CH), 128.60, 129.45, 130.07,
130.96, 132.27, (C-5, C-Ar), 161.76 (C-4), 177.20 (C-2). MS, m/z = 302 (M+). Anal. Calcd
for C17H22N2OS: C, 67.5, H, 7.3; N, 9.3. Found: C, 67.5; H, 7.6; N, 9.2.
5-((E)-Benzylidene)-3-cyclohexylmethyl-1-methyl-2-thiohydantoin (3f): Using path A,
method A afforded 264 mg (84%) of 3f and 251 mg (80%) were obtained following method
B. Using path B, method A afforded 232 mg (74%) of 3f and 210 mg (67%) were obtained
1
following method B. mp 92-94°C. IR (KBr): ν 1710 (C=O), 1232 (C=S) cm-1. H-NMR
(CDCl3): δ 1.20-1.24 (6H, m, H-3, H-4, H-5cyclohexane), 1.68 (4H, m, H-2, H-6cyclohexane), 1.95
(1H, m, H-1cyclohexane), 3.60 (3H, s, N(1)-CH3), 3.77 (2H, d, J = 7.5 Hz, N(3)-CH2), 6.47 (1H,
s, =CH), 7.40 (3H, m, H-Ar), 7.98 (2H, m, H-Ar). MS, m/z = 314 (M+). Anal. Calcd for
C18H22N2OS: C, 68.8, H, 7.1; N, 8.9. Found: C, 68.7; H, 7.4; N, 9.1.
5-((E)-Benzylidene)-3-[2-(4-morpholino)ethyl]-1-methyl-2-thiohydantoin (3g): Using
path A, method A afforded 275 mg (83%) of 3g and 285 mg (86%) were obtained following

method B. Using path B, method A afforded 245 mg (74%) of 3g and 232 mg (70%) were
obtained following method B. mp 180-182°C. IR (KBr): ν 1714 (C=O), 1230 (C=S) cm-1.
1H-NMR (CDCl3): δ 2.47 (4H, t, J = 4.5 Hz, H-2’, H-6’), 2.60 (2H, t, J = 6.9 Hz, N-CH2),
3.50 (3H, s, N(1)-CH3), 3.59 (4H, t, J = 4.5 Hz, H-3’, H-5’), 3.98 (2H, t, J = 6.9 Hz, N(3)-
13
CH2), 6.39 (1H, s, =CH), 7.29-7.91 ( 5H, m, H-Ar). C-NMR (CDCl3): δ 30.50 (N(1)-CH3),
38.72 (N-CH2), 53.60 (C-2’, C-6’), 55.43 (C-3’, C-5’), 66.91 (N(3)-CH2), 120.39 (=CH),
128.33, 129.03, 129.82, 130.64, 131.93, (C-5, C-Ar), 161.44 (C-4), 176.72 (C-2). Anal.
Calcd for C17H21N3O2S: C, 61.6, H, 6.4; N, 12.7. Found: C, 61.3; H, 6.2; N, 12.7.
5-((E)-3,4-Methylenedioxybenzylidene)-1,3-dimethyl-2-thiohydantoin (4a): Using path
A, method A afforded 229 mg (83%) of 4a and 243 mg (88%) were obtained following
method B. Using path B, method A afforded 204 mg (74%) of 4a and 200 mg (72%) were
obtained following method B. mp 198-200°C. IR (KBr): ν 1717 (C=O), 1230 (C=S) cm-1.
1H-NMR (CDCl3): δ 3.38 (3H, s, N(3)-CH3), 3.62 (3H, s, N(1)-CH3), 5.98 (2H, s, CH2), 6.46
(1H, s, =CH), 7.35 (2H, d, J = 7.25 Hz, H-Ar), 7.95 (1H, s, H-Ar). Anal. Calcd for
C13H12N2O3S: C, 56.5; H, 4.4; N, 10.1. Found: C, 56.6; H, 4.5; N, 10.4.
5-((E)-3,4-Methylenedioxybenzylidene)-1-methyl-3-phenyl-2-thiohydantoin (4b):
Using path A, method A afforded 304 mg (90%) of 4b and 311 mg (92%) were obtained
following method B. Using path B, method A afforded 287 mg (85%) of 4b and 294 mg
(87%) were obtained following method B. mp 262-264°C. IR (KBr): ν 1718 (C=O), 1233
(C=S) cm-1. 1H-NMR (CDCl3): δ 3.70 (3H, s, N(1)-CH3), 6.00 (2H, s, OCH2O), 6.51 (1H, s,
=CH), 6.81-8.02 (8H, m, H-Ar). Anal. Calcd for C18H14N2O3S: C, 63.9, H, 4.2; N, 8.3.
Found: C, 69.1; H, 5.0; N, 9.6.
3-Allyl-5-((E)-3,4-methylenedioxybenzylidene)-1-methyl-2-thiohydantoin (4c): Using
path A, method A afforded 260 mg (86%) of 4c and 281 mg (93%) were obtained following
method B. Using path B, method A afforded 248 mg (82%) of 4c and 266 mg (88%) were
obtained following method B. mp 142-144°C. IR (KBr): ν 1720 (C=O), 1231 (C=S) cm-1.
1H-NMR (CDCl3): δ 3.62 (3H, s, N(1)-CH3), 4.56 (2H, 2 x t, J = 1.34 Hz, N(3)-CH2), 5.23
(2H, m, = CH2), 5.87 (1H, m, CH), 6.00 (2H, s, CH2), 6.48 (1H, s, =CH), 7.48 (2H, m, H-
Ar), 8.00 (1H, s, H-Ar). Anal. Calcd for C15H14N2O3S: C, 59.6; H, 4.7; N, 9.3. Found: C,
59.9; H, 4.5; N, 9.3.
5-((E)-3,4-Methylenedioxybenzylidene)-3-n-butyl-1-methyl-2-thiohydantoin (4d):
Using path A, method A afforded 261 mg (82%) of 4d and 270 mg (85%) were obtained

following method B. Using path B, method A afforded 248 mg (78%) of 4d and 219 mg
(69%) were obtained following method B. mp 143-145°C. IR (KBr): ν 1714 (C=O), 1228
(C=S) cm-1. 1H-NMR (CDCl3): δ 0.95 (3H, m, CH3), 1.40-1.70 (4H, 2m, 2 x CH2), 3.62 (3H,
s, N(1)-CH3), 3.96 (2H, t, J = 7.52 Hz, N(3)-CH2), 6.00 (2H, s, CH2), 6.48 (1H, s, =CH),
7.48 (2H, s, H-Ar), 7.98 (1H, s, H-Ar). Anal. Calcd for C16H18N2O3S: C, 60.4, H, 5.7; N, 8.8.
Found: C, 60.3; H, 5.9; N, 8.5.
5-((E)-3,4-Methylenedioxybenzylidene)-3-n-hexyl-1-methyl-2-thiohydantoin (4e):
Using path A, method A afforded 301 mg (87%) of 4e and 315 mg (91%) were obtained
following method B. Using path B, method A afforded 277 mg (80%) of 4e and 256 mg
(74%) were obtained following method B. mp 120-122°C. IR (KBr): ν 1713 (C=O), 1232
(C=S) cm-1. 1H-NMR (CDCl3): δ 0.80 (3H, t, J = 7.5 Hz, CH3), 1.25 (6H, m, 3CH2), 1.61 (2H,
m, CH2), 3.55 (3H, s, N(1)-CH3), 3.92 (2H, t, J = 7.5 Hz, N(3)-CH2), 5.98 (2H, s, CH2), 6.35
(1H, s, =CH), 7.35 (2H, 2d, J = 7.3 Hz, H-Ar), 7.94 (1H, s, H-Ar). Anal. Calcd for
C18H22N2O3S: C, 62.4, H, 6.4; N, 8.1. Found: C, 62.3; H, 6.5; N, 8.0.
5-((E)-3,4-Methylenedioxybenzylidene)-3-cyclohexylmethyl-1-methyl-2-thiohydantoin
(4f): Using path A, method A afforded 322 mg (90%) of 4f and 343 mg (96%) were
obtained following method B. Using path B, method A afforded 297 mg (83%) of 4f and
283 mg (79%) were obtained following method B. mp 160-162°C. IR (KBr): ν 1712 (C=O),
1
1228 (C=S) cm-1. H-NMR (CDCl3): δ 1.00-1.24 (6H, m, H-3, H-4, H-5cyclohexane), 1.65 (4H,
m, H-2, H-6cyclohexane), 1.96 (1H, m, H-1cyclohexane), 3.60 (3H, s, N(1)-CH3), 3.78 (2H, d, J =
7.5 Hz, N(3)-CH2), 6.02 (2H, s, CH2), 6.40 (1H, s, =CH), 6.84 (1H, d, J = 8.1 Hz, H-Ar),
7.36 (1H, d, J = 8.1 Hz, H-Ar), 7.98 (1H, s, H-Ar). Anal. Calcd for C19H22N2O3S: C, 63.7, H,
6.2; N, 7.8. Found: C, 63.5; H, 6.5; N, 7.6.
5-((E)-3,4-Methylenedioxybenzylidene)-3-[2-(4-morpholino)ethyl]-1-methyl-2-
thiohydantoin (4g): Using path A, method A afforded 348 mg (86%) of 4g and 372 mg
(92%) were obtained following method B. Using path B, method A afforded 316 mg (78%)
of 4g and 292 mg (72%) were obtained following method B. mp 163-165°C. IR (KBr): ν
1717 (C=O), 1230 (C=S) cm-1. 1H-NMR (CDCl3): δ 2.48 (4H, t, J = 4.5 Hz, H-2’, H-6’), 2.64
(2H, t, J = 6.9 Hz, N-CH2), 3.52 (3H, s, N(1)-CH3), 3.60 (4H, t, J = 4.5 Hz, H-3’, H-5’), 4.00
(2H, t, J = 6.9 Hz, N(3)-CH2), 6.02 (2H, s, CH2), 6.40 (1H, s, =CH), 6.84 (1H, d, J = 8.1 Hz,
H-Ar), 7.36 (1H, d, J = 8.1 Hz, H-Ar), 7.98 (1H, s, H-Ar). Anal. Calcd for C20H26N3O4S: C,
59.4, H, 6.5; N, 10.4. Found: C, 59.3; H, 6.2; N, 10.7.

5-((E)-3,4,5-Trimethoxybenzylidene)-1,3-dimethyl-2-thiohydantoin (5a): Using path A,
method A afforded 264 mg (82%)of 5a and 290 mg (90%) were obtained following method
B. Using path B, method A afforded 248 mg (77%) of 5a and 219 mg (68%) were obtained
1
following method B. mp 141-143°C. IR (KBr): ν 1712 (C=O), 1233 (C=S) cm-1. H-NMR
(CDCl3): δ 3.38 (3H, s, N(3)-CH3), 3.62 (3H, s, N(1)-CH3), 3.86, 3.90 (9H, 2s, 3 x OCH3),
6.50 (1H, s, =CH), 7.41 (3H, m, H-Ar), 7.50 (2H, m, H-Ar). Anal. Calcd for C15H18N2O4S: C,
55.9; H, 5.6; N, 8.7. Found: C, 55.7; H, 5.5; N, 8.5.
5-((E)-3,4,5-Trimethoxybenzylidene)-3-phenyl-1-methyl-2-thiohydantoin (5b): Using
path A, method A afforded 361 mg (94%) of 5b and 376 mg (98%) were obtained following
method B. Using path B, method A afforded 338 mg (88%) of 5b and 330 mg (86%) were
obtained following method B. mp 198-200°C. IR (KBr): ν 1718 (C=O), 1230 (C=S) cm-1.
1H-NMR (CDCl3): δ 3.74 (3H, s, N(1)-H), 3.92, 3.93 (9H, 2s, 3 x OCH3), 6.52 (1H, s, =CH),
7.36-7.54 (7H, m, H-Ar). 13C-NMR (CDCl3): δ 31.08 (CH3), 56.51, 61.11 (3 x OMe), 122.02
(=CH), 109.01, 127.60, 128.40, 128.73, 129.31, , 129.40, 133.53, 140.42, 153.03 (C-Ar),
161.42 (C-4), 176.45 (C-2). Anal. Calcd for C20H20N2O4S: C, 62.5, H, 5.2; N, 7.3. Found:
C, 62.3; H, 4.9; N, 7.2.
3-Allyl-5-((E)-3,4,5-trimethoxybenzylidene)-1-methyl-2-thiohydantoin (5c): Using path
A, method A afforded 292 mg (84%) of 5c and 320 mg (92%) were obtained following
method B. Using path B, method A afforded 271 mg (78%) of 5c and 229 mg (66%) were
obtained following method B. mp 176-178°C. IR (KBr): ν 1712 (C=O), 1232 (C=S) cm-1.
1H-NMR (CDCl3): δ 3.62 (3H, s, N(1)-CH3), 3.88, 3.91 (9H, 2s, 3 x OCH3), 4.56 (2H, 2 x t, J
= 1.35 Hz, N(3)-CH2), 5.23 (2H, m, = CH2), 5.87 (1H, m, CH), 6.48 (1H, s, =CH), 7.48 (2H,
s, H-Ar). Anal. Calcd for C17H20N2O4S: C, 58.6; H, 5.8; N, 8.0. Found: C, 58.7; H, 5.5; N,
8.3.
5-((E)-3,4,5-Trimethoxybenzylidene)-3-n-butyl-1-methyl-2-thiohydantoin (5d): Using
path A, method A afforded 291 mg (80%) of 5d and 298 mg (82%) were obtained following
method B. Using path B, method A afforded 255 mg (70%) of 5d and 233 mg (64%) were
obtained following method B. mp 164-166°C. IR (KBr): ν 1717 (C=O), 1230 (C=S) cm-1.
1H-NMR (CDCl3): δ 0.95 (3H, m, CH3), 1.40-1.70 (4H, 2m, 2 x CH2), 3.62 (3H, s, N(1)-
CH3), 3.88, 3.91 (9H, 2s, 3 x OCH3), 3.96 (2H, t, J = 7.52 Hz, N(3)-CH2), 6.46 (1H, s,
=CH), 7.47 (2H, m, H-Ar). Anal. Calcd for C18H24N2O4S: C, 59.3, H, 6.6; N, 7.7. Found: C,
59.2; H, 6.9; N, 7.5.

5-((E)-3,4,5-Trimethoxybenzylidene)-3-n-hexyl-1-methyl-2-thiohydantoin (5e): Using
path A, method A afforded 329 mg (84%) of 5e and 337 mg (86%) were obtained following
method B. Using path B, method A afforded 270 mg (69%) of 5e and 255 mg (65%) were
obtained following method B. mp 153-55°C. IR (KBr): ν 1713 (C=O), 1234 (C=S) cm-1. 1H-
NMR (CDCl3): δ 0.81 (3H, t, J = 7.6 Hz, CH3), 1.25 (6H, m, 3CH2), 1.60 (2H, m, CH2), 3.62
(3H, s, N(1)-CH3), 3.98 (11H, m, N(3)-CH2, 3 x OCH3), 6.38 (1H, s, =CH), 7.45 (2H, s, H-
Ar). MS, m/z = 392 (M+). Anal. Calcd for C20H28N2O4S: C, 61.2, H, 7.2; N, 7.1. Found: C,
61.0; H, 6.9; N, 7.3.
5-((E)-3,4,5-Trimethoxybenzylidene)-3-cyclohexylmethyl-1-methyl-2-thiohydantoin
(5f): Using path A, method A afforded 355 mg (84%) of 5f and 372 mg (92%) were
obtained following method B. Using path B, method A afforded 315 mg (78%) of 5f and
291 mg (72%) were obtained following method B. mp 138-140°C. IR (KBr): ν 1714 (C=O),
1
1232 (C=S) cm-1. H-NMR (CDCl3): δ 1.20-1.25 (6H, m, H-3, H-4, H-5cyclohexane), 1.66 (4H,
m, H-2, H-6cyclohexane), 1.97 (1H, m, H-1cyclohexane), 3.62 (3H, s, N(1)-CH3), 3.78 (2H, d, J =
7.52 Hz, N(3)-CH2), 3.98 (11H, m, N(3)-CH2, 3 x OCH3), 6.40 (1H, s, =CH), 7.46 (2H, s, H-
Ar). Anal. Calcd for C21H28N2O4S: C, 62.4, H, 7.0; N, 6.9. Found: C, 62.2; H, 6.9; N, 7.2.
5-((E)-3,4,5-Trimethoxybenzylidene)-3-[2-(4-morpholino)ethyl]-1-methyl-2-
thiohydantoin (5g): Using path A, method A afforded 353 mg (84%) of 5g and 378 mg
(92%) were obtained following method B. Using path B, method A afforded 337 mg (80%)
of 5g and 328 mg (78%) were obtained following method B. mp 103-105°C. IR (KBr): ν
1710 (C=O), 1232 (C=S) cm-1. 1H-NMR (CDCl3): δ 2.48 (4H, t, J = 4.5 Hz, H-2’, H-6’), 2.65
(2H, t, J = 6.9 Hz, N-CH2), 3.51 (3H, s, N(1)-CH3), 3.62 (4H, t, J = 4.5 Hz, H-3’, H-5’), 3.98
(9H, m, 3 x OCH3), 4.00 (2H, t, J = 6.9 Hz, N(3)-CH2), 6.40 (1H, s, =CH), 7.48 (2H, s, H-
Ar). Anal. Calcd for C20H27N3O5S: C, 57.0, H, 6.5; N, 10.0. Found: C, 57.3; H, 6.2; N, 9.7.
1,3-Dimethyl-5-((E)-2-thienylidene)-2-thiohydantoin (6a): Using path A, method A
afforded 200 mg (84%) of 6a and 209 mg (88%) were obtained following method B. Using
path B, method A afforded 166 mg (70%) of 6a and 162 mg (68%) were obtained following
1
method B. mp 188-190°C. IR (KBr): ν 1712 (C=O), 1234 (C=S) cm-1. H-NMR (CDCl3): δ
3.35 (3H, s, N(3)-CH3), 3.64 (3H, s, N(1)-CH3), 6.64 (1H, s, =CH), 7.05 (1H, t, J = 4.2 Hz,
H-4’), 7.45 (1H, d, J = 5.2 Hz, H-3’), 7.66 (1H, d, J = 3.0 Hz, H-5’). Anal. Calcd for
C10H10N2OS2: C, 50.4; H, 4.2; N, 11.8. Found: C, 50.6; H, 4.2; N, 10.5.

1-Methyl-3-phenyl-5-((E)-2-thienylidene)-2-thiohydantoin (6b): Using path A, method A
afforded 361 mg (94%) of 6b and 376 mg (98%) were obtained following method B. Using
path B, method A afforded 338 mg (88%) of 6b and 330 mg (86%) were obtained following
1
method B. mp 253-255°C. IR (KBr): ν 1716 (C=O), 1230 (C=S) cm-1. H-NMR (CDCl3): δ
3.73 (3H, s, N(1)-CH3), 6.70 (1H, s, =CH), 7.10-7.73 (8H, m, H-Ar). Anal. Calcd for
C15H12N2OS2: C, 60.0, H, 4.0; N, 9.3. Found: C, 60.3; H, 3.9; N, 9.2.
3-Allyl-1-methyl-5-((E)-2-thienylidene)-2-thiohydantoin (6c): Using path A, method A
afforded 248 mg (94%) of 6c and 259 mg (98%) were obtained following method B. Using
path B, method A afforded 227 mg (86%) of 6c and 232 mg (88%) were obtained following
1
method B. mp 167-169°C. IR (KBr): ν 1715 (C=O), 1228 (C=S) cm-1. H-NMR (CDCl3): δ
3.55 (3H, s, N(1)-CH3), 4.53 (2H, 2 x t, J = 1.5 Hz, N(3)-CH2), 5.27 (2H, m, = CH2), 5.84
(1H, m, CH), 6.65 (1H, s, =CH), 7.05 (1H, t, J = 4.2 Hz, H-4’), 7.48 (1H, d, J = 5.2 Hz, H-
3’), 7.70 (1H, d, J = 3.0 Hz, H-5’). 13C-NMR (CDCl3): δ 30.71 (N(1)-CH3), 44.18 (C-3allyl),
113.26 (=CH), 118.78 (C-1allyl), 126.26 (C-2allyl), 127.97 (C-5), 131.04, 131.99, 135.40,
135.82 (C-Ar), 161.57 (C-4), 175.85 (C-2). Anal. Calcd for C12H12N2OS2: C, 54.5; H, 4.6;
N, 10.6. Found: C, 54.2; H, 4.7; N, 10.4.
3-n-Butyl-1-methyl-5-((E)-2-thienylidene)-2-thiohydantoin (6d): Using path A, method
A afforded 230 mg (82%) of 6d and 252 mg (90%) were obtained following method B.
Using path B, method A afforded 218 mg (78%) of 6d and 207 mg (74%) were obtained
1
following method B. mp 133-135°C. IR (KBr): ν 1713 (C=O), 1229 (C=S) cm-1. H-NMR
(CDCl3): δ 0.96 (3H, m, CH3), 1.40-1.72 (4H, 2m, 2 x CH2), 3.60 (3H, s, N(1)-CH3), 3.98
(2H, t, J = 7.5 Hz, N(3)-CH2), 6.64 (1H, s, =CH), 7.04 (1H, t, J = 4.3 Hz, H-4’), 7.46 (1H, d,
J = 5.22 Hz, H-3’), 7.65 (1H, d, J = 3.1 Hz, H-5’). Anal. Calcd for C13H16N2OS2: C, 55.7; H,
5.8; N, 10.0. Found: C, 55.5; H, 5.7; N, 10.3.
3-n-Hexyl-1-methyl-5-((E)-2-thienylidene)-2-thiohydantoin (6e): Using path A, method
A afforded 265 mg (86%) of 6e and 283 mg (92%) were obtained following method B.
Using path B, method A afforded 246 mg (80%) of 6e and 222 mg (72%) were obtained
1
following method B. mp 106-108°C. IR (KBr): ν 1710 (C=O), 1226 (C=S) cm-1. H-NMR
(CDCl3): δ 0.79 (3H, t, J = 7.5 Hz, CH3), 1.23 (6H, m, 3CH2), 1.62 (2H, m, CH2), 3.51 (3H,
s, N(1)-CH3), 3.82 (2H, t, J = 7.5 Hz, N(3)-CH2), 6.73 (1H, s, =CH), 7.03 (1H, t, J = 4.2 Hz,
H-4’), 7.46 (1H, d, J = 5.1 Hz, H-3’), 7.67 (1H, d, J = 3.0 Hz, H-5’). 13C-NMR (CDCl3): δ
13.11 (CH3), 21.51 (CH2), 23.63 (CH2), 25.47 (CH2), 30.38 (N(1)-CH3), 42.80 (CH2),

112.06 (=CH), 125.10 (C-5), 126.71, 130.56, 134.27, 134.73, (C-Ar), 160.64 (C-4), 178.00
(C-2). Anal. Calcd for C15H20N2OS2: C, 58.4; H, 6.5; N, 9.1. Found: C, 58.3; H, 6.5; N, 9.2.
3-Cyclohexylmethyl-1-methyl-5-((E)-2-thienylidene)-2-thiohydantoin (6f): Using path
A, method A afforded 288 mg (90%) of 6f and 301 mg (94%) were obtained following
method B. Using path B, method A afforded 275 mg (86%) of 6f and 249 mg (78%) were
obtained following method B. mp 160-162°C. IR (KBr): ν 1714 (C=O), 1228 (C=S) cm-1.
1H-NMR (CDCl3): δ 0.98-1.23 (6H, m, H-3, H-4, H-5cyclohexane), 1.68 (4H, m, H-2, H-
6cyclohexane), 1.96 (1H, m, H-1cyclohexane), 3.59 (3H, s, N(1)-CH3), 3.80 (2H, d, J = 7.2 Hz,
N(3)-CH2), 6.69 (1H, s, =CH), 7.10 (1H, dd, J = 3.90, 5.1 Hz, H-4’), 7.51 (1H, d, J = 4.8 Hz,
H-3’), 7.73 (1H, d, J = 3.9 Hz, H-5’). Anal. Calcd for C16H20N2OS2: C, 60.0; H, 6.3; N, 8.7.
Found: C, 58.9; H, 6.1; N, 8.4.
3-(2-(4-Morpholino)ethyl)-1-methyl-5-((E)-2-thienylidene)-2-thiohydantoin (6g): Using
path A, method A afforded 290 mg (86%) of 6g and 317 mg (94%) were obtained following
method B. Using path B, method A afforded 256 mg (76%) of 6g and 249 mg (74%) were
obtained following method B. mp 204-206°C. IR (KBr): ν 1712 (C=O), 1234 (C=S) cm-1.
1H-NMR (CDCl3): δ 2.46 (4H, t, J = 4.5 Hz, H-2’, H-6’), 2.62 (2H, t, J = 6.9 Hz, N-CH2),
3.50 (3H, s, N(1)-CH3), 3.62 (4H, t, J = 4.5 Hz, H-3’, H-5’), 3.98 (2H, t, J = 6.9 Hz, N(3)-
CH2), 6.68 (1H, s, =CH), 7.10 (1H, dd, J = 3.90, 5.1 Hz, H-4’), 7.50 (1H, d, J = 4.8 Hz, H-
3’), 7.72 (1H, d, J = 3.9 Hz, H-5’). MS, m/z = 337 (M+). Anal. Calcd for C15H19N3O2S2: C,
53.4, H, 5.7; N, 12.5. Found: C, 53.3; H, 5.5; N, 12.7.
ACKNOWLEDGMENTS
Danish Ministry of Education and Egyptian Ministry of Higher Education are acknowledged
for supporting this work (AIK). Financial support for the project was provided in part by the
Technical University of Denmark, The Danish Natural Science Research Council and the
Villum Kann Rasmussen Foundation (JN).
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19 The microwave reactor used was a Microwell 10 from Labwell AB operating at 2.45 GHz
(see also the experimental section). The magnetron is placed exactly one wavelength
from the sample chamber (approximately 12-cm) and is therefore termed “mono-modal”.
Reaction vials were made of thick-wall glass and sealed by a screw-cab with 1/8 x 1/2-
inch Teflon coated silicon septa (GC-type seal) or a special device measuring both
pressure and temperature (from Personal Chemistry AB). The total volume of the liquid
was approximately 10% of the total vial size, thereby allowing headspace for pressure
build-up during microwave heating. Using this set-up, the pressure was either regulated
the PC-controlled pressure measure device or by the septum bulge, which would lift the
safety lid and stop irradiation if pressure became too high. However, it should be
emphasized, that extreme care and precaution should be taken when working with
microwave irradiation and especially sealed reactions.
20 (a) S. F. Tan, K. P. Ang, and Y. F. Fong, J. Chem. Soc., Perkin Trans. II, 1986, 1941. (b)
A. A. El-Barbary, A. I. Khodair, and E. B. Pedersen, J. Org. Chem., 1993, 58, 5994. (c) A.
I. Khodair and P. Bertrand, Tetrahedron, 1998, 54, 4859.
21 S. S. F. Brandao, V. L.Guarda; I. R. Pitta, J. Chantegrel, M. Perrissin; V. M. Souza, S. L.
Galdino, F. Thomasson, M. C. A. Lima, L. F. C. C. Leite, and C. Luu-Duc, Boll. Chim.
Farm., 2000, 139, 54.
22 J. E. Scott and G. Henderson, Biochem. J., 1968, 109, 209.