Reactions of 4-substituted 5H-1,2,3-dithiazoles with primary and secondary amines: fast and convenient synthesis of 1,2,5-thiadiazoles, 2-iminothioacetamides and 2-oxoacetamides

Article abstract of DOI:10.1016/j.tet.2010.04.033

The treatment of 5H-1,2,3-dithiazole-5-thiones 1 in chloroform under reflux and 5H-1,2,3-dithiazol-5-ones 2 in THF at room temperature with primary aliphatic amines and benzylamine afforded 1,2,5-thiadiazole-3(2H)-thiones 3 and 1,2,5-thiadiazol-3(2H)-ones 6, respectively. The structure of dithiazolone 3f was confirmed by X-ray diffraction analysis. The reaction of dithiazolone 2e bearing an electron-donating methyl group in the 4-position gave 2-oxoacetamide 7e in high yield. The reaction of thiones 1 with secondary aliphatic amines in DMSO yielded 2-iminothioacetamides 8 in moderate yields together with elemental sulfur. Interestingly, the treatment of dithiazolones 2 with secondary amines under the same conditions afforded 2-oxoacetamides 9-the products of the hydrolysis of corresponding imino derivatives 10, which was isolated as 10b. A general mechanism was proposed for the formation of the products.

Full text of DOI:10.1016/j.tet.2010.04.033

Tetrahedron 66 (2010) 4330–4338
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactions of 4-substituted 5H-1,2,3-dithiazoles with primary and secondary
amines: fast and convenient synthesis of 1,2,5-thiadiazoles,
2-iminothioacetamides and 2-oxoacetamides
Lidia S. Konstantinova a, Oleg I. Bol'shakov a, Natalia V. Obruchnikova a, Svetlana P. Golova a,
,
Yulia V. Nelyubina b, Konstantin A. Lyssenko b, Oleg A. Rakitin a
*
a N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation
b A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov Str., 28, 119991 Moscow, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:Ć
The treatment of 5H-1,2,3-dithiazole-5-thiones 1 in chloroform under reflux and 5H-1,2,3-dithiazol-5-ones 2
in THF at room temperature with primary aliphatic amines and benzylamine afforded 1,2,5-thiadiazole-3
(2H)-thiones 3 and 1,2,5-thiadiazol-3(2H)-ones 6, respectively. The structure of dithiazolone 3f was con-
firmed by X-ray diffraction analysis. The reaction of dithiazolone 2e bearing an electron-donating methyl
group in the 4-position gave 2-oxoacetamide 7e in high yield. The reaction of thiones 1 with secondary al-
iphatic amines in DMSO yielded 2-iminothioacetamides 8 in moderate yields together with elemental sulfur.
Interestingly, the treatment of dithiazolones 2 with secondary amines under the same conditions afforded 2-
oxoacetamides 9dthe products of the hydrolysis of corresponding imino derivatives 10, which was isolated
as 10b. A general mechanism was proposed for the formation of the products.
Received 25 January 2010
Received in revised form
17 March 2010
Accepted 6 April 2010
Available online 10 April 2010
Keywords:
Sulfur–nitrogen heterocycles
2H-1,2,3-Dithiazoles
Primary amines
Ó 2010 Elsevier Ltd. All rights reserved.
Secondary amines
1,2,5-Thiadiazoles
2-Iminothioacetamides
2-Oxoacetamides
1. Introduction
selectively obtained in a one pot reaction of various ethanoneox-
imes,8 undergo a new transformation to 1,2,5-thiadiazole-3(2H)-
The exploration of the synthetic utility of 1,2,3-dithiazoles1 has
been focused on the chemistry of 4-chloro-5H-1,2,3-dithiazol-5-
ones, 5-thiones, 5-arylimines, and 5-ylidenes, which can be easily
prepared from 4,5-dichloro-5H-1,2,3-dithiazolium chloride (Appel
salt).2 The best studied are reactions of 1,2,3-dithiazoles with primary
and secondary alkylamines. The nucleophilic attack occurs at the C-2
carbon of the ring yielding diatomic sulfur, S2, a chloride anion, and
various functionalized derivatives such as N0-aryl-N-alkylcyano-
formamidines,3 N-alkyl- and N,N-dialkylcyanothioformamides,4 N,
N0-disubstituted ureas,5 and (alkylamino)cyanomethylidenes.6 Re-
activity of these compounds toward nucleophiles may be in part at-
tributed to the presence of the chlorine atom at the C-4 position that
can be easily removed as a chloride anion to generate a cyano group.
Other 1,2,3-dithiazoles, except for 4-chloro-1,2,3-dithiazoles, are not
readily available.7 Meanwhile, one might expect 1,2,3-dithiazoles
with weaker leaving groups in the 4-position to have reactivity dif-
ferent from 4-chloro derivatives. Recently we have found that
4-substituted 1,2,3-dithiazoles 5-ones and 5-thiones, which can be
thiones and -ones, respectively, upon treatment with primary
amines.9 We undertook a systematic study of the reactions of 1,2,3-
dithiazoles 1 and 2 with primary and secondary amines to un-
derstand how the starting amine and the reaction conditions affect
the final product. Here, we report the conditions for the selective
synthesis of each class of compounds, the mechanisms proposed on
the basis of the reaction pathways, and the results of the X-ray dif-
fraction analysis for one compound of the class.
2. Results and discussion
2.1. Reactions with primary amines
4-Substituted 1,2,3-dithiazole-5-thiones 1 and 1,2,3-dithiazol-
5-ones 2 were found to be inert toward primary aromatic amines.
Aniline did not react in various solvents such as benzene, acetoni-
trile, or dimethylformamide, and 1,2,3 dithiazoles were isolated
from the reaction mixtures in quantitative yields.
The treatment of 4-phenyl-5H-1,2,3-dithiazole 5-thione 1a with
more basic benzylamine afforded, in various solvents (chloroform,
* Corresponding author. Tel.: þ7 499 135 53 27; fax: þ7 499 135 53 28; e-mail
address: orakitin@ioc.ac.ru (O.A. Rakitin).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.033

L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
4331
THF, and acetonitrile), novel compound 3a, a yellow solid C15H12N2S2.
According to the mass spectra, elemental analysis, and 1H and 13C
NMR data, it is formally a product of benzylamine addition and
H2S elimination, whose formation was confirmed by isolation of
benzylammonium hydrogen sulfide from the reaction mixture in
practically quantitative yield (Scheme 1).
4-Phenyl-5H-1,2,3-dithiazole 5-thione 1a reacted in the same
way with other primary amines, viz. allylamine and iso-butylamine,
to give the corresponding 2,4-disubstituted 1,2,5-thiadiazole-5-
thiones (Scheme 2).
To the best of our knowledge, 1,2,5-thiadiazole-5-thiones are
practically unknown; there is no reliable data on their synthesis.
S
CH2Ph
N
S
S
R
R
R
R
CHCl3
S
+ PhCH2NH2.H2S
CH2Ph
+ PhCH2NH2
N
S
S
N
N
N
N
Δ = 3h
N
S
S
1
S
CH2Ph
3a R = Ph, 56%
4
5
b R = 4-FC6H4, 58%
c R = 4-MeOC6H4, 54%
d R = 4-NO2C6H4, 43%
e R = Me, 62%
f R = 2-thienyl, 65%
g R = 2-benzofuryl, 49%
Scheme 1. Reaction of 5H-1,2,3-dithiazole-5-thiones 1 with benzylamine.
Three isomeric structures can be proposed for this product:
1,2,5-thiadiazolone 3a, imino-1,2,3-dithiazole 4, and 1,2,3-thiadia-
zole 5. The analysis of the spectroscopic data and the NMR spectra
calculated for these structures did not allow the best choice.
Structure 3a was finally proved by the X-ray analysis of closely
related analogue 3f (see below).
S
S
S
N
Ph
Ph
R-NH2
CHCl3
+ RNH2.H2S
R
N
N
S
1a
S
3h R = All, 41%
3i R = i-Bu, 54%
Scheme 2. Reaction of 4-phenyl-5H-1,2,3-dithiazole-5-thione 1a with aliphatic amines.
We extended the reaction with benzylamine to other 1,2,3-
dithiazole-5-thiones 1. 1,2,5-Thiadiazolothiones 3 were obtained in
all reactions in moderate yields (Scheme 1).
The structure of thieno derivative 3f was confirmed by X-ray
diffraction analysis (Fig. 1). The thiadiazole ring bond lengths and
Figure 1. General view of compound 3f (A), which is a superposition of two isomers cis-3f (B) and trans-3f (C) in a ratio 4:1, with representation of atoms via thermal ellipsoids at
ꢀ
50% probability level. Selected bond lengths (A): C(1)–S(2) 1.6799(7), S(1)–N(1) 1.6222(6), S(1)–N(2) 1.6887(6), N(1)–C(2) 1.3228(9), C(1)–C(2) 1.4614(10), C(1)–N(2) 1.3526(9), C(2)–
C(3) 1.4521(10), N(2)–C(6) 1.4675(9); selected bond angles (ꢀ): C(2)–C(1)–N(2) 106.73(6), C(1)–C(2)–N(1) 114.65(6), C(2)–N(1)–S(1) 112.07(5), N(1)–S(1)–N(2) 93.14(3), C(1)–N(2)–S
(1) 113.36(5), C(1)–C(2)–C(3) 126.23(6).

4332
L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
angles, except for S(1)–N(1) and N(1)–C(2) bonds, fall in the range
typical for such type of heterocyclic compounds. A close in-
vestigation of the molecular geometry of 3f revealed the significant
contribution of the betaine-like resonance form with formal single N
(1)–C(2) and double N(1)–S(1) bonds. Moreover, when the standard
benzylamine in THF gave 2-oxoacetamide 7e in high yield; no
traces of thiadiazolone 6e were detected (Scheme 3).
Dithiazolone 2a reacted with other primary amines in a similar
way to afford the corresponding 1,2,5-thiadiazol-5-ones 6h–j in
high yields (Scheme 4).
dataset with 2q
below 60ꢀ was used, an unexpected elongation
O
N
O
S
ꢀ
(up to 1.543(4) A) of the presumably double C(3)–C(13) bond was
Ph
Ph
R-NH2
THF
observed in the 3f crystal. The addition of high-angle data (2
q
<90ꢀ)
R
N
N
resulted in the superposition (80:20) of two isomers with cisoid and
transoid dispositions of S(2) and S(3) atoms in 3f (Fig. 1). The cis form
(cis-3f) appears to be stabilized by the extremely short in-
termolecular contact between sulfur of the C]S group and sulfur of
S
2a
S
6h R = All, 89%
6i R = n-Bu, 97%
6j R = i-Pr, 93%
ꢀ
ꢀ
the thiophene ring (S/S 3.1812(7) A, C(4)S(3)S(2) 171.33(6) ) ac-
Scheme 4. Reaction of 4-phenyl-5H-1,2,3-dithiazol-5-one 2a with aliphatic amines.
companied by a charge transfer from the lone pair (Lp) of the S(2)
s
orbital of the C–S bond. In turn, S(30) of the minor
*
Up to date, a few papers13–16 have reported syntheses of
1,2,5-thiadiazol-3-ones, but we have developed a general and
very simple method for their preparation that allows high
yields.
atom to the
component (trans-3f) presumably binds to the N(1) thiadiazole atom
ꢀ
ꢀ
(S/N 2.9342(8) A, S(1)N(1)S(4) 175.95(6) ) through the charge
transfer from one of the sulfur Lps to the S(1)–N(1) bond orbital.
Quantum chemical calculations (B3LYP/6–311þG ) and a sub-
s
*
*
sequent topological analysis of theoretical electron density func-
tions10 for two isomers showed that the cisoid-form was stabilized
by the S/S interaction that contributed 2.9 kcal/mol, as estimated
by Espinosa's correlation scheme.11,12 In the second isomer
a weaker (1.8 kcal/mole) C(130)–H/S(2) binding was observed in-
stead of the S/N–C interaction. On the other hand, trans-3f was
found to be a little more stable (0.63 kcal/mol) than cis-3f, appar-
ently, owing to a conjugation between the thiadiazole and thio-
phene cycles that was more pronounced in the transoid-form.
The N(1) atom of both isomers participates in the formation of
2.2. Reactions with secondary amines
Thione 1a did not react with morpholine in chloroform, aceto-
nitrile, or THF even under harsh conditions (refluxing for 5 h);
starting thione 1a was isolated from the reaction mixtures in
practically quantitative yields. The treatment of thione 1a with
2 equiv of morpholine in DMSO gave new product 8a along with
elemental sulfur (Scheme 5). Compound 8a (75%), a colorless solid
C12H14N2OS, according to its mass spectrum, elemental analysis,
and 1H and 13C NMR data has the structure of 2-iminothioaceta-
mide. The 1H NMR spectrum of 8a showed the NH group (9.5 ppm),
and the IR spectrum showed an intensive NH absorption at 3190–
0
ꢀ
the N/S–N interaction (S/N 2.9045(8) A, N(1 )S(1)N(2) 168.56
(7)ꢀ) with the charge being transferred from nitrogen Lp to the
s
*
3240 cmꢁ1
.
orbital of the latter bond that leads to the dimerization of the
neighboring molecules. These supramolecular associates are as-
sembled into the 3D framework by a few weak S/H,
S/S contacts.
p/p, and
S
S
S
20 oC
R
R
HN
1/4 S8
It was envisaged that, upon the reaction with primary amines,
1,2,3-dithiazol-5-ones 2 should give ketone 6. We checked this
possibility by the treatment of dithiazolone 2a with benzylamine,
yet it appeared that the formation of 1,2,5-dithiazolone 6a was
complicated by a side reaction yielding N-substituted 2-oxoaceta-
mide 7a (Scheme 3).
N
N
DMSO
HN
O
S
O
1
8a R = Ph, 75%
8b R = 4-FC6H4, 69%
8c R = 4-MeOC6H4, 77%
8d R = 4-NO2C6H4, 72%
8e R = 2-thienyl, 66%
8f R = 2-benzofuryl, 69%
O
O
O
R
R
R
CH2Ph
THF
N
H
Scheme 5. Reaction of 5H-1,2,3-dithiazole-5-thiones 1 with morpholine.
+
+ PhCH2NH2
N
CH2Ph
S
rt
N
N
O
S
S
2
7e R = Me, 87%
6a R = Ph, 94%
Dithiazole 1a reacted in the same way with other secondary
aminesddiethylamine, piperidine, and pyrrolidinedto give the
corresponding imines 8g,h,i (Scheme 6).
b R = 4-FC6H4, 100%
c R = 4-MeOC6H4, 100%
d R = 4-NO2C6H4, 90%
f R = 2-thienyl, 95%
g R = 2-benzofuryl, 96%
S
S
S
20 o
DMSO
C
Ph
Ph
Scheme 3. Reaction of 5H-1,2,3-dithiazol-5-ones 2 with benzylamine.
R2
R2
HN
R1
N
To obtain thiadiazolone 6a selectively, the reaction between 2a
N
HN
R1
S
(R¼Ph) and benzylamine was investigated in detail; the nature of
the solvent appeared crucial for reaction to occur. If the
reaction was carried out in an inert solvent such as chloroform, the
starting dithiazolone 2a was isolated in a practically quantitative
yield. Attempts to employ strong aprotic dipolar solvents such as
DMF or acetonitrile at room temperature led to formation of the
mixtures 6/7 in a ratio of 1:1 and 1:2, respectively. The treatment of
benzylamine with 2a in absolute THF gave selectively 1,2,5-thia-
diazolone 6a in 94% yield. We then applied these conditions to
other ketones 2. 1,2,5-Thiadiazolones 6 were obtained in high
yield in practically all reactions. The treatment of dithiazolone 2e
bearing the electron-donating methyl group in position-4 with
1a
8g R1 = R2 = Et, 78%
8h R1;R2 = -(CH2)5-, 84%
8i R1;R2 = -(CH2)4-, 35%
Scheme 6. Reaction of 4-phenyl-5H-1,2,3-dithiazole-5-thione 1awith secondaryamines.
If the reaction of dithiazole 1f with morpholine was carried out
in DMF, dimethylamino derivative 8j was formed instead of mor-
pholine 8e (Scheme 7). Apparently, the initially formed 8e further
reacts with dimethylamine (from DMF) to substitute the morpho-
lino group.

L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
4333
However only in one case we did manage to isolate stable 10b (49%)
that was easily transformed to oxo derivative 9b by a further re-
action with morpholine in DMSO. Low yield of 9b is explained by
the side generation of 10b.
The treatment of ketone 2e with morpholine in DMF gave de-
rivative 9e, instead of the expected morpholino, leading to dime-
thylamine 9g (Scheme 9).
S
S
S
20 o
DMF
C
S
HN
S
Me
O
N
Me
N
HN
S
1f
8j, 62%
Scheme 7. Reaction of 5H-1,2,3-dithiazole-5-thione 1f with morpholine in DMF.
O
S
O
Only one example of a 4-substituted 2-iminothioacetamide is
known.17 It was prepared by catalytic amination of the corre-
sponding oxo derivative with ammonia. They may be useful pre-
cursors in the preparation of various heterocyclic compounds, as
was shown for N0-arylthiocarbamoyl-N,N-dialkylamidines.18
The treatment of 5H-1,2,3-dithiazol 5-ones 2 with 2 equiv of
morpholine in DMSO at room temperature afforded new products,
though these were 2-morpholin-4-yl-2-oxoethanones 9 rather
than imino derivatives, as could be expected by analogy with thi-
ones 1 (Scheme 8). Elemental sulfur was also isolated in 80–85%
yield (calculated to S2).
20 o
C
S
HN
S
Me
N
Me
O
N
DMF
O
S
9g, 74%
2e
Scheme 9. Reaction of 5H-1,2,3-dithiazole-5-one 2e with morpholine in DMF.
2-Oxoacetamides 9 are well known compounds possessing
various biological activity, including inhibition of enzymes,19 anti-
viral action,20 inhibition of HIV-1 infection,21 etc.
F
O
S
O
R
20 o
DMSO
C
R
2.3. Reaction mechanisms
O
HN
+
N
N
O
O
N
S
HN
A plausible mechanism for all the described transformations
could be as follows: a nucleophilic attack of the amine onto the
C-5 position of the dithiazole ring followed by the heterocyclic
ring opening to form key intermediate 11. In the case of primary
amines, the 1,2,5-thiadiazole cycle is probably formed through
an intramolecular attack of amide (thioamide) nitrogen onto the
S-2 sulfur atom with hydrogen sulfide elimination. In the re-
action with secondary aliphatic amines, the ring closure that
gives salt 12 is unlikely or reversible. The formation of imines 8
or 10 could occur via elimination of S2 and oxamides 9 and 7e
through the further hydrolysis of 8 and 10 with NH3 elimination
(Scheme 10).
O
O
2
9a R = Ph, 55%
9b R = 4-FC6H4, 12%
10b, 49%
9c R = 4-MeOC6H4, 70%
9d R = 4-NO2C6H4, 75%
9e R = 2-thienyl, 61%
9f R = 2-benzofuryl, 55%
Scheme 8. Reaction of 5H-1,2,3-dithiazol-5-ones 2 with morpholine.
Apparently 2-iminoacetamides 10 can be considered as the
most probable intermediates in the formation of 2-oxoethanones 9.
X
R1
R
R2
N
N
S
12
R1
R1
X
X
X
X -
HN
R2
R
NH R2
R
R2 = H
- H2S
R
R
R1
N R1
N
S
S
S
R2
N
N
R
N
N
S
S
11
S
S
3, X = S
6, X = O
H
1, X = S
2, X = O
- S2
X
X
N
H2O
NH3
R
R1
R1
N
O
R2
HN
R2
9, X = O
7e, X = O, R = Me, R2 = H
8, X = S
10, X = O
Scheme 10. A plausible mechanism for the reaction of 5H-1,2,3-dithiazoles with primary and secondary amines.

4334
L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
3. Conclusion
130.0, 131.2, and 131.3 (9CH), 129.2, 133.0, 160.9, and 165.7 (four sp2
tertiary C), 177.2 (C]S). MS (EI, 70 eV), m/z (%): 302 (Mþ, 17), 269
(7), 121 (22). IR (KBr):
¼3032, 1600, 1520, 1460, 1440, 1336, 1296,
1224, 1204, 1160, 968, 820, 804, 756, 736, 700 cmꢁ1
In summary, 5H-1,2,3-dithiazole-5-thiones 1 and 5H-1,2,3-
dithiazol-5-ones 2 are found to be convenient precursors for
previously unknown 1,2,5-thiadiazole-3(2H)-thiones 3 and 1,2,5-
thiadiazol-3(2H)-ones 6 in the reactions with primary amines. The
reactions of secondary amines led to the heterocyclic ring opening
to form 2-oxoacetamides and 2-iminothioacetamides, which are
promising compounds for the preparation of various heterocyclic
systems. Finally, 4-substituted 5H-1,2,3-dithiazoles gave different
products from 4-chloro derivatives since the chlorine atom was
readily expelled as a chloride anion and the cyano group was
generated.
n
.
4.2.3. 2-Benzyl-4-(4-methoxyphenyl)-1,2,5-thiadiazole-3(2H)-thione
(3c). Yield 54%. Yellow crystalline solid, mp 86–88 ꢀC; Rf¼0.61
(hexane/CH2Cl2¼1:1). Anal. Calcd for C16H14N2OS2: C, 61.12; H,
4.49; N, 8.91. Found: C, 61.20; H, 4.63; N, 8.97. 1H NMR (250 MHz,
CDCl3)
d: 3.87 (3H, s, CH3), 5,29 (2H, s, CH2), 6.97 (2H, d, J 8.8, Ar),
7.46 (5H, m, Ar), 8.48 (2H, d, J 8.8, Ar). 13C NMR (75.5 MHz, CDCl3)
d
:
53.6 (CH2), 55.4 (CH3), 113.4, 129.4, 129.8, 129.9, and 130.7 (9CH);
125.8, 133.2, 159.9, and 161.3 (four sp2 tertiary C), 177.2 (C]S). MS
(EI, 70 eV), m/z (%): 314 (Mþ, 8), 133 (15). IR (KBr):
n
¼3028, 3008,
2956 (C–H), 2832, 1612, 1520, 1456, 1420, 1340, 1328, 1300, 1256,
1208, 1168, 1028, 832, 764, 700 cmꢁ1
4. Experimental
4.1. General
.
4.2.4. 2-Benzyl-4-(4-nitrophenyl)-1,2,5-thiadiazole-3(2H)-thione
(3d). Yield 43%. Yellow crystalline solid, mp 148 ꢀC; Rf¼0.40 (hexane/
CH2Cl2¼1:1). Anal. Calcd for C15H11N3O2S2: C, 54.69; H, 3.37; N,12.76.
Melting points were determined on a Kofler hot-stage apparatus
and are uncorrected. IR spectra were recorded on a Specord M-80
instrument in KBr pellets. 1H NMR were recorded on a Bruker WM
250 spectrometer (250 MHz) and 13C NMR spectra were recorded
on a Bruker AM 300 (75.5 MHz) in CDCl3 or D2O solutions. J values
are given in hertz. Mass spectra were recorded on a Finnigan MAT
INCOS 50 instrument using electron impact ionization. Elemental
analyses were performed on Perkin Elmer 2400 Elemental
Analyser.
Found: C, 54.82; H, 3.69; N, 12.83. 1H NMR (250 MHz, CDCl3)
d: 5.30
(2H, s, CH2), 7.51 (5H, m, Ar), 8.34(2H, d, J 8.8, Ar), 8.73 (2H, d, J 8.8, Ar).
13C NMR (75.5 MHz, CDCl3)
d: 54.0 (CH2), 123.3, 129.7, 130.0, 130.0,
and 130.2 (9CH), 132.8, 138.4, 145.3, and 168.2 (four sp2 tertiary C),
177.2 (C]S). MS (EI, 70 eV), m/z (%): 329 (Mþ,15), 297 (7),149 (12). IR
(KBr):
n
¼2960, 2924 (C–H), 2851, 1732, 1596, 1512, 1482, 1456, 1444,
1340, 1316, 1284, 1204, 1068, 860, 844, 760, 716, 704 cmꢁ1
.
5H-1,2,3-Dithiazole-5-thiones 1 and 5H-1,2,3-dithiazol-5-ones
2 were prepared as previously reported.8
DFT calculations of the isolated cis-2f and trans-2f were per-
formed with the Gaussian0322 program package using the B3LYP
functional. Full optimization of the molecules was carried out with
4.2.5. 2-Benzyl-4-methyl-1,2,5-thiadiazole-3(2H)-thione (3e). Yield
62%. Yellow crystalline solid, mp 84–85 ꢀC; Rf¼0.62 (hexane/
CH2Cl2¼4:1). Anal. Calcd for C10H10N2S2: C, 54.02; H, 4.53; N, 12.60.
Found: C, 54.08; H, 4.72; N, 12.53. 1H NMR (250 MHz, CDCl3)
d: 2.58
the 6-311þG
*
basis set starting from the X-ray structural data. As
(3H, s, CH3), 5.26 (2H, s, CH2), 7.44 (5H, m, Ar). 13C NMR (75.5 MHz,
CDCl3) : 19.2 (CH3), 53.35 (CH2), 129.2 (2CH), 129.49 (2CH), 129.52
(1CH), 133.2, and 163.2 (two sp2 tertiary C), 179.1 (C]S). MS
(EI, 70 eV), m/z (%): 222 (Mþ, 32), 189 (22). IR (KBr):
¼3032, 2924
(C–H), 2852,1496, 1456,1376,1348,1336,1208,1180, 1012, 816, 760,
700, 628 cmꢁ1
convergence criteria, the standard threshold limits of 4.5ꢂ10ꢁ4 and
1.8ꢂ10ꢁ3 au were applied for the maximum force and displace-
ment, respectively. The topological analysis of computed electron
densities was performed using the AIM2000 program packages.23
d
n
.
4.2. Reaction of 5H-1,2,3-dithiazole-5-thiones 1 and 5H-1,2,3-
dithiazol-5-ones 2 with primary amines
4.2.6. 2-Benzyl-4-(thien-2-yl)-1,2,5-thiadiazole-3(2H)-thione
(3f).
Yield 65%. Yellow crystalline solid, mp 146–147 ꢀC; Rf¼0.53 (hex-
ane/CH2Cl2¼4:1). Anal. Calcd for C13H10N2S3: C, 53.76; H, 3.47; N,
General procedure. Primary amine (1 mmol) was added to a so-
lution of the appropriate 1,2,3-dithiazole 1 or 2 (0.5 mmol) in THF
(4 mL) at room temperature. The reaction mixture was stirred for
2–3 h at room temperature, the alkylammonium hydrogen sulfide
filtered off, and the solvent evaporated under reduced pressure. The
residue was purified by column chromatography (Silica gel Merck
60, light petroleum, and then light petroleum/CH2Cl2 mixtures).
9.65. Found: C, 53.56; H, 3.67; N, 9.45. 1H NMR (250 MHz, CDCl3)
d:
5.32 (2H, s, CH2), 7.16 (1H, dd, J 3.7, 5.1, Ar), 7.46 (5H, m, Ar), 7.52
(1H, d, J 5.1, Ar), 8.57 (1H, d, J 2.9, Ar). 13C NMR (75.5 MHz, CDCl3)
d
:
53.5 (CH2), 127.2, 129.5, 129.8, 129.9, 130.1, and 130.6 (8C–H), 133.2.
135.3, and 155.4 (three sp2 tertiary C), 175.9 (C]S). MS (EI, 70 eV),
m/z (%): 290 (Mþ, 70), 257 (36), 148 (22). IR (KBr):
n
¼2920 (C-H),
1516, 1456, 1412, 1380, 1316, 1288, 1200, 816, 752, 724, 696 cmꢁ1
.
4.2.1. 2-Benzyl-4-phenyl-1,2,5-thiadiazole-3(2H)-thione (3a). Yield
56%. Yellow crystalline solid, mp 95–97 ꢀC; Rf¼0.49 (hexane/
CH2Cl2¼4:1). Anal. Calcd for C15H12N2S2: C, 63.35; H, 4.25; N, 9.85;
S, 22.55. Found: C, 63.45; H, 4.39; N, 10.05; S, 22.68. 1H NMR
4.2.7. 2-Benzyl-4-(1-benzofuran-2-yl)-1,2,5-thiadiazole-3(2H)-thi-
one (3g). Yield 49%. Yellow crystalline solid, mp 188–191 ꢀC; Rf¼0.31
(hexane/CH2Cl2¼1:1). Anal. Calcd for C17H12N2OS2: C, 62.94; H, 3.73;
N, 8.63. Found: C, 62.64; H, 3.97; N, 8.54. 1H NMR (250 MHz, CDCl3)
(250 MHz, CDCl3) d: 5.31 (2H, s, CH2), 7.49 (8H, m, Ar), 8.42 (2H, m,
Ar). 13C NMR (75.5 MHz, CDCl3)
d
: 53.8 (CH2), 128.1, 129.1, 129.5,
d
: 5.30 (2H, s, CH2), 7.29 (1H, t, Ar), 7.39 (1H, m, Ar), 7.47 (5H, m, Ar),
129.9, 129.9, and 130.5 (10CH, Ar), 133.0, 133.2, and 160.5 (three sp2
7.57 (1H, d, J 8.1, Ar), 7.73 (1H, d, J 8.1, Ar), 8.80 (1H, s, Ar). 13C NMR
tertiary C), 177.4 (C]S). MS (EI, 70 eV), m/z (%): (Mþ, 25), 251 (13).
(75.5 MHz, CDCl3) d: 53.6 (CH2), 111.4, 111.6, 123.1, 123.6, 126.9, 129.6,
IR (KBr):
n
¼3064, 2928 (C–H), 2852, 1496, 1456, 1428, 1344, 1332,
129.9, and 130.1 (10CH), 127.8, 132.9, 148.5, 151.5, and 155.2 (five sp2
1292, 1208, 1028, 848, 772, 756, 708, 696 cmꢁ1
.
tertiary C),175.8 (C]S). MS (EI, 70 eV), m/z (%): 324 (Mþ,10), 260 (5),
143 (14). IR (KBr):
n
¼2928 (C–H), 1576, 1456, 1376, 1304, 1188, 1156,
4.2.2. 2-Benzyl-4-(4-fluorophenyl)-1,2,5-thiadiazole-3(2H)-thione
(3b). Yield 58%. Yellow crystalline solid, mp 140–143 ꢀC; Rf¼0.48
(hexane/CH2Cl2¼1:1). Anal. Calcd for C15H11FN2S2: C, 59.58; H,
3.67; N, 9.26. Found: C, 59.70; H, 3.92; N, 9.32. 1H NMR (250 MHz,
1140, 1060, 972, 836, 756, 700 cmꢁ1
.
Benzylammonium hydrogen sulfide. Colorless crystalline solid.
Anal. Calcd for C7H11NS: C, 59.53; H, 7.85; N, 9.92. Found: C, 59.68;
H, 7.97; N, 9.70. 1H NMR (250 MHz, D2O)
d: 3.96 (2H, s, CH2), 6.86
CDCl3)
d
: 5.30 (2H, s, CH2), 7.17 (2H, d, J 8.8, Ar), 7.48 (5H, s, Ar), 8.49
: 53.8 (CH2), 115.2, 129.6,
(4H, m, NH2, H2S), 7.60 (5H, m, Ar). MS (EI, 70 eV), m/z (%): 107
(2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
d
(Mþꢁ34, 30), 91 (25).

L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
4335
4.2.8. 2-Allyl-4-phenyl-1,2,5-thiadiazole-3(2H)-thione (3h). Yield
41%. Yellow crystalline solid, mp 92–94 ꢀC; Rf¼0.40 (hexane/
CH2Cl2¼5:1). Anal. Calcd for C11H10N2S2: C, 56.38; H, 4.30; N,
11.95. Found: C, 56.58; H, 4.47; N, 11.70. 1H NMR (250 MHz,
123.8, 127.6, 128.8, 129.3, and 129.4 (9CH), 134.3, 137.1, 147.1, and
148.5 (four sp2 tertiary C), 161.0 (C]O). MS (EI, 70 eV), m/z (%): 313
(Mþ, 38), 180 (55), 149 (18). IR (KBr):
n
¼3084, 2924 (C-H), 2852,
1656 (C]O), 1596, 1512, 1496, 1452, 1348, 1320, 1256, 1072, 820,
756, 700 cmꢁ1
CDCl3)
d
: 4.85 (2H, d, J 6.6, CH2), 5.56 (2H, m, CH2), 6.13 (1H, m,
.
CH); 7.50 (3H, m, Ar), 8.41 (2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
d
: 51.7 (CH2), 123.9 (CH2), 129.5 (CH), 128.1 (2CH, Ar), 129.0 (2CH,
4.2.14. 2-Benzyl-4-(2-thienyl)-1,2,5-thiadiazol-3(2H)-one (6f). Yield
95%. Colorless crystalline solid, mp 101–102 ꢀC; Rf¼0.45 (hexane/
CH2Cl2¼5:1). Anal. Calcd for C13H10N2OS2: C, 56.91; H, 3.67; N,
10.21. Found: C, 57.08; H, 3.89; N, 10.40. 1H NMR (250 MHz, CDCl3)
Ar), 130.5 (1CH, Ar), 133.0, and 160.7 (two sp2 tertiary C), 177.2
(C]S). MS (EI, 70 eV), m/z (%): 234 (Mþ, 47), 193 (8), 135 (33), 104
(53). IR (KBr):
n
¼3072, 2924 (C–H), 2852, 1424, 1344, 1336, 1304,
1204, 1152, 1028, 952, 848, 780, 712, 692 cmꢁ1
.
d
: 5,05 (2H, s, CH2), 7.17 (1H, dd, J 2.9, 5.1, Ar), 7.40 (5H, m, Ar), 7.52
(1H, d, J 5.1, Ar), 8.25 (1H, d, J 2.9, Ar). 13C NMR (75.5 MHz, CDCl3)
d:
4.2.9. 2-Isobutyl-4-phenyl-1,2,5-thiadiazole-3(2H)-thione (3i). Yield
54%. Yellow crystalline solid, mp 106–109 ꢀC; Rf¼0.54 (hexane/
CH2Cl2¼5:1). Anal. Calcd for C12H14N2S2: C, 57.56; H, 5.64; N, 11.19.
48.1 (CH2), 127.9, 128.5, 128.8, 129.1, 129.3 and 129.4 (8CH), 134.6,
134.9, and 146.2 (three sp2 tertiary C), 160.2 (C]O). MS (EI, 70 eV),
m/z (%): 274 (Mþ, 43), 135 (23), 109 (40). IR (KBr):
n
¼3110, 3100,
3032, 2936, 1644, 1496, 1456, 1436, 1424, 1416, 1236, 1220, 1056,
1020, 844, 828, 756, 712, 700 cmꢁ1
Found: C, 57.68; H, 5.72; N, 11.40. 1H NMR (250 MHz, CDCl3)
d: 1.07
(6H, d, J 6.6, 2CH3), 2.45 (1H, m, CH), 4.15 (2H, m, CH2), 7.51 (3H, m,
.
Ar), 8.40 (2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
d: 20.2 (2CH3), 27.5
(CH), 56.2 (CH2), 128.1 (2CH, Ar), 129.1 (2CH, Ar), 130.5 (1CH, Ar),
4.2.15. 2-Benzyl-4-(1-benzofuran-2-yl)-1,2,5-thiadiazol-3(2H)-one
(6g). Yield 96%. Colorless crystalline solid, mp 156 ꢀC; Rf¼0.27
(hexane/CH2Cl2¼4:1). Anal. Calcd for C17H12N2O2S: C, 66.22; H,
3.92; N, 9.08. Found: C, 66.40; H, 4.12; N, 9.40. 1H NMR (250 MHz,
133.2, and 178.1 (two sp2 tertiary C), 178.9 (C]S). MS (EI, 70 eV), m/z
(%): 250 (Mþ, 28),193 (70), 135 (78), 103 (48). IR (KBr):
n
¼2960, 2928
(C–H), 2856, 1728, 1504, 1468, 1444, 1368, 1336, 1296, 1264, 1200,
1148, 1124, 1080, 940, 832, 692 cmꢁ1
.
CDCl3)
(1H, d, J 8.1, Ar), 7.72 (1H, d, J 7.3, Ar), 8.04 (1H, s, Ar). 13C NMR
(75.5 MHz, CDCl3) : 48.0 (CH2), 109.4, 111.7, 122.8, 123.7, 126.8,
d: 5.07 (2H, s, CH2), 7.29 (1H, m, Ar), 7.41 (6H, m, Ar), 7.60
4.2.10. 2-Benzyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one (6a). Yield
94%. Colorless crystalline solid, mp 87–90 ꢀC; Rf¼0.40 (hexane/
CH2Cl2¼5:1). Anal. Calcd for C15H12N2OS: C, 67.14; H, 4.51; N,
10.44. Found: C, 67.28; H, 4.39; N, 10.50. 1H NMR (250 MHz,
d
128.8, 129.2, and 129.3 (10CH), 127.8, 134.4, 142.2, 148.3, and 155.4
(five sp2 tertiary C), 160.0 (C]O). MS (EI, 70 eV), m/z (%): 308
(Mþ, 38), 175 (7), 143 (35). IR (KBr):
n
¼1640 (C]O), 1576, 1452,
CDCl3)
d
: 5.05 (2H, s, CH2), 7.40 (5H, s, Ar), 7.48 (3H, m, Ar), 8.48
: 47.9 (CH2), 126.9, 128.0,
1300, 1248, 1156, 1140, 1072, 836, 812, 772, 756, 770, 612 cmꢁ1
.
(2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
d
128.6, 128.7, 129.22, and 130.5 (10CH, Ar), 128.8, 137.2, and 149.6
4.2.16. 2-Allyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one (6h). Yield 89%.
Colorless oil; Rf¼0.52 (hexane/CH2Cl2¼5:1). Anal. Calcd for
C11H10N2OS: C, 60.53; H, 4.62; N, 12.83. Found: C, 60.68; H, 4.67; N,
(three sp2 tertiary C), 161.3 (C]O). MS (EI, 70 eV), m/z (%):
268 (Mþ, 12), 135 (10). IR (KBr):
n
¼3268, 3048, 2920 (C–H), 1648
(C]O), 1456, 1444, 1264, 1072, 824, 784, 756, 740, 700, 688,
620 cmꢁ1
12.70. 1H NMR (250 MHz, CDCl3)
d
: 4.52 (2H, d, J 6.6, CH2), 5.42 (2H,
.
m, CH2), 5.99 (1H, m, CH All), 7.49 (3H, m, Ar), 8.46 (2H, m, Ar). 13
C
NMR (75.5 MHz, CDCl3) d: 44.6 (CH2), 120.9 (CH2), 126.8, 128.5, and
4.2.11. 2-Benzyl-4-(4-fluorophenyl)-1,2,5-thiadiazol-3(2H)-one
(6b). Yield 100%. Colorless crystalline solid, mp 72–74 ꢀC; Rf¼0.42
(hexane/CH2Cl2¼1:1). Anal. Calcd for C15H11FN2OS: C, 62.92; H,
3.87; N, 9.78. Found: C, 63.08; H, 3.92; N, 9.55. 1H NMR (250 MHz,
130.5 (5CH), 149.7 (CH, All), 131.1, and 132.0 (two sp2 tertiary C),
161.0 (C]O). MS (EI, 70 eV), m/z (%): 218 (Mþ, 30), 178 (3), 135 (25),
104 (25). IR (KBr):
n
¼3068, 2924 (C–H), 2852, 1660 (C]O), 1444,
1424, 1296, 1240, 1180, 1084, 1068, 1028, 788, 744, 692 cmꢁ1
.
CDCl3)
d
: 5.03 (2H, s, CH2), 6.99 (2H, m, Ar), 7.39 (5H, m, Ar), 8.46
: 47.8 (CH2), 115.4, 115.72,
(2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
d
4.2.17. 2-Butyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one (6i). Yield 97%.
Colorless oil; Rf¼0.43 (hexane/CH2Cl2¼5:1). Anal. Calcd for
C12H14N2OS: C, 61.51; H, 6.02; N, 11.96. Found: C, 61.68; H, 6.20; N,
126.7, 128.7, 129.0, and 129.2 (9CH, Ar), 125.8, 134.7, 148.4, and 161.1
(four sp2 tertiary C), 164.1 (C]O). MS (EI, 70 eV), m/z (%): 286 (Mþ,
100), 153 (5), 121 (87). IR (KBr):
(C]O), 1596, 1512, 1444, 1268, 1236, 1156, 1076, 840, 824, 752, 700,
620 cmꢁ1
n
¼3052, 2924 (C–H), 2852, 1648
12.14. 1H NMR (250 MHz, CDCl3)
d
: 0.99 (3H, t, J 7.3, CH3), 1.45 (2H,
sext, J 7.3, CH2), 1.78 (2H, q, J 7.3, CH2), 3.93 (2H, t, J 7.3, CH2), 7.47
(3H, m, J 6.6, Ar), 8.46 (2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
: 13.6
.
d
(CH3), 20.00 (CH2), 31.5 (CH2), 43.8 (CH2), 126.9, 128.5, and 130.4
(5CH, Ar), 132.1, and 149.7 (two sp2 tertiary C), 161.3 (C]O). MS (EI,
70 eV), m/z (%): 234 (Mþ, 32), 178 (72), 149 (46), 135 (50), 104 (100).
4.2.12. 2-Benzyl-4-(4-methoxyphenyl)-1,2,5-thiadiazol-3(2H)-one
(6c). Yield 100%. Colorless crystalline solid, mp 68–72 ꢀC; Rf¼0.35
(hexane/CH2Cl2¼1:1). Anal. Calcd for C16H14N2O2S: C, 64.41, H, 4.73,
N, 9.39. Found: C, 64.65; H, 4.92; N, 9.55. 1H NMR (250 MHz, CDCl3)
IR (KBr):
n
¼2960, 2928 (C–H), 2852, 1660 (C]O), 1468, 1444, 1260,
1236, 1156, 1088, 1072, 1032, 824, 788, 744, 692, 652 cmꢁ1
.
d
: 3.87 (3H, s, CH3), 5,03 (2H, s, CH2), 7.14 (2H, d, J 9.5, Ar), 7.39 (5H,
m, Ar), 8.49 (2H, m, Ar). 13C NMR (75.5 MHz, CDCl3)
d: 47.9 (CH2),
4.2.18. 2-Isopropyl-4-phenyl-1,2,5-thiadiazol-3(2H)-one (6j). Yield
93%. Colorless oil; Rf¼0.15 (hexane/CH2Cl2¼5:1). Anal. Calcd for
C11H12N2OS: C, 59.97; H, 5.49; N, 12.72. Found: C, 60.08; H, 5.42; N,
53.4 (OCH3), 113.9, 128.6, 128.7, 128.9, and 129.2 (9CH, Ar), 125.2,
134.9, 149.2, and 161.3 (four sp2 tertiary C), 161.4 (C]O). MS
(EI, 70 eV), m/z (%): 298 (Mþ, 43), 256 (12), 160 (5), 133 (45). IR
12.90. 1H NMR (250 MHz, CDCl3)
d
: 1.50 (6H, d, J 6.6, 2CH3), 4.75 (1H,
(KBr):
n
¼3028, 2938 (C–H), 2852, 1644 (C]O), 1600, 1520, 1456,
sept, J 6.6, CH); 7.47 (3H, m, Ar), 8.46 (2H, t, J 3.7, Ar). 13C NMR
1308, 1252, 1172, 1076, 1024, 848, 756, 696, 620 cmꢁ1
.
(75.5 MHz, CDCl3) d: 22.4 (2CH3), 48.2 (CH, i-Pr), 127.0, 128.5, and
130.4 (5CH), 132.2, and 150.4 (two sp2 tertiary C), 160.9 (C]O). MS
4.2.13. 2-Benzyl-4-(4-nitrophenyl)-1,2,5-thiadiazol-3(2H)-one
(6d). Yield 94%. Colorless crystalline solid, mp 157–158 ꢀC; Rf¼0.33
(hexane/CH2Cl2¼1:1). Anal. Calcd for C15H11N3O3S: C, 57.50; H,
3.54; N, 13.41. Found: C, 57.39; H, 3.69; N, 13.54. 1H NMR (250 MHz,
(EI, 70 eV), m/z (%): 220 (Mþ, 32), 178 (73), 135 (22), 104 (100). IR
(KBr):
n
¼3068, 2968, 2924, 2852, 1732, 1664, 1464, 1444, 1392, 1300,
1240, 1180, 1152, 1132, 788, 744, 692, 768, 756, 688, 688, 632 cmꢁ1
.
CDCl3)
d
: 5.06 (2H, s, CH2); 7.42 (5H, m, Ar); 8.30 (2H, d, J 8.8, Ar),
: 48.2 (CH2),
4.2.19. N-Benzyl-2-oxopropanamide (7e). Yield 87%. Colorless
crystalline solid, mp 45–46 ꢀC, lit.24 colorless oil; Rf¼0.56
8.80 (2H, d, J 8.8, Ar). 13C NMR (75.5 MHz, CDCl3)
d

4336
L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
(CH2Cl2). Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90.
Found: C, 68.06; H, 6.48; N, 8.01. 1H NMR (250 MHz, CDCl3)
2.47 (3H, s, CH3), 4.45 (2H, s, CH2); 7.27 (6H, m, Ar, NH). 13C NMR
13C NMR (75.5 MHz, CDCl3)
d: 47.5, and 51.9 (2NCH2), 66.3 (2OCH2),
d
:
123.9, and 128.7 (4CH, Ar), 130.7, 139.7, and 172.3 (three sp2 tertiary
C), 195.1 (C]S). MS (EI, 70 eV), m/z (%): 279 (Mþ, 69), 221 (100), 194
(75.5 MHz, CDCl3)
d
: 24.4 (CH3), 43.3 (CH2), 127.7, 127.8, and
(88), 149 (72), 130 (81). IR (KBr):
n
¼3232, 2924 (C–H), 2852, 1588,
128.7 (5CH), 137.1 (one sp2 tertiary C), 160.0 and 197.0 (2C]O).
1516, 1488, 1444, 1348, 1340, 1272, 1240, 1104, 1032, 856 cmꢁ1
.
MS (EI, 70 eV), m/z (%): 177 (Mþ, 28), 106 (68), 65 (51), 43 (100).
IR (KBr):
n
¼3300 (NH), 3050 and 2930 (CH), 1724 and 1672 (C]
4.3.5. 2-Morpholin-4-yl-1-(2-thienyl)-2-thioxoethanimine (8e). Yield
66%. Colorless crystalline solid, mp 138–141 ꢀC; Rf¼0.47 (CH2Cl2/
acetone¼10:1). Anal. Calcd for C10H12N2OS2: C, 49.97; H, 5.03; N,
O), 1524, 1436, 1360, 1212, 1172, 1080, 944, 748, 704, 612 cmꢁ1
.
4.3. Reaction of 5H-1,2,3-dithiazole-5-thiones 1 and 5H-1,2,3-
11.66. Found: C, 49.99; H, 5.25; N, 11.43. 1H NMR (250 MHz, CDCl3)
d:
dithiazol-5-ones 2 with secondary amines
3.64 (4H, m, OCH2), 3.87 (2H, t, J 5.1, NCH2), 4.32 (2H, m, NCH2), 7.09
(1H, d, J 5.1, Ar), 7.39 (1H, m, Ar), 7.52 (1H, d, J 5.1, Ar),10.27 (1H, s, NH).
General procedure. Secondary amine (1 mmol) was added to
a solution of the appropriate 1,2,3-dithiazole 1 or 2 (0.5 mmol) in
DMSO (2 mL) at room temperature. The reaction mixture was stirred
for 2–3 h at room temperature, filtered from elemental sulfur. CH2Cl2
(20 mL) was added to the filtrate, which was then washed with H2O,
dried MgSO4 and the solvent was evaporated under reduced pres-
sure. The residue was separated by column chromatography (Silica
gel Merck 60, CH2Cl2, and then CH2Cl2/acetone mixtures).
13C NMR (75.5 MHz, CDCl3)
d: 48.5, and 51.8 (2NCH2), 66.3, and 66.4
(2OCH2), 127.2, 130.7, and 131.7 (3CH), 133.9, and 164.0 (two sp2
tertiary C),195.6 (C]S). MS (EI, 70 eV), m/z (%): 240 (Mþ, 36),182 (66),
155 (84), 110 (100). IR (KBr):
n
¼3260 (N–H), 3080 and 2930 (C–H),
1650, 1580, 1500, 1420, 1270, 1160, 1100, 1050, 860, 830, 730 cmꢁ1
.
4.3.6. 1-(1-Benzofuran-2-yl)-2-morpholin-4-yl-2-thioxoethanimine
(8f). Yield 69%. Colorless crystalline solid, mp 140–141 ꢀC; Rf¼0.63
(CH2Cl2/acetone¼5:1). Anal. Calcd for C14H14N2O2S: C, 61.29; H, 5.14;
N, 10.21. Found: C, 61.02; H, 5.18; N, 10.06. 1H NMR (250 MHz, CDCl3)
4.3.1. 2-Morpholin-4-yl-1-phenyl-2-thioxoethanimine (8a). Yield
75%. Colorless crystalline solid, mp 112–115 ꢀC; Rf¼0.65 (CH2Cl2/
acetone¼10:1). Anal. Calcd for C12H14N2OS: C, 61.51; H, 6.02; N,
11.96. Found: C, 61.73; H, 6.12; N, 12.10. 1H NMR (250 MHz, CDCl3)
d: 3.72 (4H, m, OCH2), 3.91 (2H, t, J 5.1, NCH2), 4.39 (2H, m, NCH2), 7.18
(1H, s, CH, Ar), 7.31 (1H, m, CH, Ar), 7.45 (1H, m, Ar), 7.56 (1H, d, J 5.1,
Ar), 7.64 (1H, d, J 5.1, Ar), 10.40 (1H, s, NH). 13C NMR (75.5 MHz,
d
: 3.57 (4H, m, 2OCH2), 3.85 (2H, t, J 5.1, NCH2), 4.33 (2H, t, J 5.1,
NCH2), 7.45 (3H, m, Ar), 7.84 (2H, d, J 6.6, Ar), 9.56 (1H, s, NH). 13
NMR (75.5 MHz, CDCl3) : 47.6 and 51.9 (2NCH2), 66.4, and 66.5
CDCl3) d: 48.0, and 52.1 (2NCH2), 66.4, and 66.7 (2OCH2), 110.7, 111.9,
C
122.9, 124.0, and 127.5 (5CH), 127.7, 140.8, 147.6, and 155.8 (four sp2
d
tertiary C), 193.5 (C]S). MS (EI, 70 eV), m/z (%): 274 (Mþ, 26), 216
(2OCH2), 127.4 (2CH, Ar), 129.1 (1CH, Ar), 131.9 (2CH, Ar), 134.0,
and 174.6 (two sp2 tertiary C), 196.6 (C]S). MS (EI, 70 eV), m/z
(%): 234 (Mþ, 9), 176 (55), 149 (67), 131 (14), 104 (100). IR (KBr):
(50), 189 (100). IR (KBr):
n
¼3240 (N–H), 2920 and 2860 (C–H), 1650,
1590, 1490, 1440, 1240, 1160, 1100, 1030, 960, 850, 760 cmꢁ1
.
n
¼3244 (N–H), 2976, 2916 (C–H), 2852, 1604, 1576, 1480, 1368,
4.3.7. N,N-Diethyl-2-imino-2-phenylethanethioamide (8g). Yield
78%. Colorless crystalline oil; Rf¼0.66 (CH2Cl2/acetone¼5:1).
Anal. Calcd for C12H16N2S: C, 65.41; H, 7.32; N, 12.71. Found: C,
1296, 1272, 1236, 1188, 1172, 1104, 1028, 932, 848, 684, 660 cmꢁ1
.
4.3.2. 2-Morpholin-4-yl-1-(4-fluorophenyl)-2-thioxoethanimine
(8b). Yield 69%. Colorless crystalline solid, mp 137–138 ꢀC; Rf¼0.52
(CH2Cl2/acetone¼5:1). Anal. Calcd for C12H13FN2OS: C, 57.12; H,
5.19; N, 11.10. Found: C, 57.13; H, 5.32; N, 11.23. 1H NMR (250 MHz,
65.53; H, 7.52; N, 12.73. 1H NMR (250 MHz, CDCl3)
d
: 1.16 (3H,
t, J 7.3, CH3), 1.35 (3H, t, J 7.3, CH3), 3.52 (2H, m, CH2), 4.07 (2H,
m, CH2), 7.45 (3H, m, Ar), 7.92 (2H, m, Ar), 9.84 (1H, s, NH). 13
NMR (75.5 MHz, CDCl3) : 10.9, and 13.5 (2CH3), 44.8, and 48.3
C
d
CDCl3)
NCH2), 7.08 (2H, d, J 8.8, Ar), 7.88 (2H, m, Ar), 9.40 (1H, s, NH). 13
NMR (75.5 MHz, CDCl3) : 47.6 and 52.0 (2NCH2), 66.4, and 66.5
d
: 3.58 (4H, m, 2OCH2), 3.86 (2H, m, NCH2), 4.33 (2H, m,
(2NCH2), 114.3 (2CH, Ar), 128.1 (1CH, Ar), 129.0 (2CH, Ar), 131.7,
and 139.6 (two sp2 tertiary C), 196.9 (C]S). MS (EI, 70 eV), m/z
(%): 220 (Mþ, 62), 205 (100), 149 (100), 116 (22), 104 (42). IR
C
d
(2OCH2), 116.1 (2CH, Ar, d, J 28.5), 129.9 (2CH, Ar), 130.4, 165.0 (d, J
(KBr):
n
¼3200 (N–H), 2980, 2932 (C–H), 2852, 1596, 1572, 1507,
251.0), and 173.3 (three sp2 tertiary C), 196.3 (C]S). MS (EI, 70 eV),
1444, 1352, 1276, 1224, 1100, 1076, 760, 700, 664 cmꢁ1
.
m/z (%): 252 (Mþ, 25),194 (63),167 (73), 122 (100). IR (KBr):
n
¼3240
(N–H), 2976, 2920 (C–H), 2852, 1604, 1508, 1488, 1272, 1236, 1184,
1152, 1104, 1060, 1032, 936, 832, 840, 728, 624 cmꢁ1
4.3.8. 1-Phenyl-2-piperidin-1-yl-2-thioxoethanimine (8h). Yield
84%. Colorless crystalline solid, mp 147–149 ꢀC; Rf¼0.81 (CH2Cl2/
acetone¼10:1). Anal. Calcd for C13H16N2S: C, 67.20; H, 6.94; N,
12.06. Found: C, 67.33; H, 6.93; N, 11.91. 1H NMR (250 MHz,
CDCl3)
NCH2), 4.26 (2H, t, J 5.9, NCH2), 7.46 (3H, m, Ar), 7.86 (2H, d, J 6.6,
Ar), 8.48 (1H, s, NH). 13C NMR (75.5 MHz, CDCl3)
: 6.4, 25.3, and
.
4.3.3. 2-Morpholin-4-yl-1-(4-methoxyphenyl)-2-thioxoethanimine
(8c). Yield 77%. Colorless crystalline solid, mp 115–117 ꢀC; Rf¼0.61
(CH2Cl2/acetone¼5:1). Anal. Calcd for C13H16N2O2S: C, 59.07; H,
6.10; N, 10.60. Found: C, 58.83; H, 6.03; N, 10.71. 1H NMR (250 MHz,
d: 1.54 (2H, m, CH2), 1.75 (4H, m, 2CH2), 3.51 (2H, t, J 5.9,
d
CDCl3)
NCH2), 6.82 (2H, d, J 8.1, Ar), 7.69 (2H, d, J 8.1, Ar), 9.06 (1H, s, NH).
13C NMR (75.5 MHz, CDCl3)
: 47.5, and 51.8 (2NCH2), 55.4 (OCH3),
d
: 3.47 (4H, m, 2OCH2), 3.74 (3H, s, OCH3), 4.23 (4H, m,
26.4 (3CH2), 48.5, and 52.9 (2-NCH2), 127.4 (2CH), 128.7 (1CH),
131.6 (2CH), 134.1, and 174.9 (two sp2 tertiary C), 195.1 (C]S). MS
(EI, 70 eV), m/z (%): 232 (Mþ, 52), 176 (36), 149 (90), 128 (20), 104
d
66.3 and 66.4 (2OCH2), 114.1 (2CH, Ar), 129.2 (2CH, Ar), 126.4, 162.5,
and 173.7 (three sp2 tertiary C), 196.8 (C]S). MS (EI, 70 eV), m/z (%):
264 (Mþ, 52), 206 (54), 179 (64), 134 (100), 130 (50). IR (KBr):
(88). IR (KBr):
1572, 1508, 1444, 1352, 1284, 1252, 1184, 1136, 1012, 892, 908,
844, 696, 660 cmꢁ1
n
¼3192 (N–H), 2988, 2944 (C–H), 2860, 1600,
.
n
¼3248 (N–H), 2920 (C–H), 2828, 1604, 1600, 1512, 1484, 1436,
1272, 1236, 1168, 1108, 1028, 932, 916, 884, 852, 732, 664 cmꢁ1
.
4.3.9. 1-Phenyl-2-pyrrolidin-1-yl-2-thioxoethanimine (8i). Yield
35%. Colorless crystalline oil. Yield 35%. Colorless oil; Rf¼0.61
(CH2Cl2/acetone¼5:1). Anal. Calcd for C12H14N2OS: C, 66.02; H,
6.46; N, 12.83. Found: C, 66.13; H, 6.52; N, 12.73. 1H NMR
4.3.4. 2-Morpholin-4-yl-1-(4-nitrophenyl)-2-thioxoethanimine
(8d). Yield 72%. Colorless crystalline solid, mp 203–204 ꢀC; Rf¼0.29
(CH2Cl2/acetone¼5:1). Anal. Calcd for C12H13N3O3S: C, 51.60; H,
4.69; N, 15.04. Found: C, 51.83; H, 4.72; N, 15.10. 1H NMR (250 MHz,
(250 MHz, CDCl3)
N–CH2), 3.90 (2H, t, J 6.6, CH2), 7.44 (3H, m, Ar), 7.84 (2H, d, J 6.6,
Ar), 9.50 (1H, s, NH). 13C NMR (75.5 MHz, CDCl3)
: 24.3, and 26.4
(2CH2), 51.9, and 52.3 (2NCH2), 114.3 (2CH), 128.1 (1CH), 129.0
d: 2.00 (4H, m, 2CH2), 3.41 (2H, t, J 5.9,
CDCl3)
d: 3.58 (4H, m, 2OCH2), 3.89 (2H, m, NCH2), 4.34 (2H, m,
d
NCH2), 8.12 (2H, d, J 9.1, Ar), 8.30 (2H, d, J 8.2, Ar), 9.81 (1H, s, NH).

L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
4337
(2CH), 131.6, and 135.2 (two sp2 tertiary C), 194.1 (C]S). MS (EI,
70 eV), m/z (%): 218 (Mþ, 32), 149 (63), 114(44), 104 (95). IR
2OCH2), 7.18 (1H, d, J 5.1, Ar), 7.81 (1H, m, Ar), 7.84 (1H, d, J 5.1,
Ar). 13C NMR (75.5 MHz, CDCl3)
d: 42.0, and 46.5 (NCH2), 66.6,
(KBr):
n
¼3200 (N–H), 2972, 2924 (C–H), 2872, 1604, 1572, 1496,
and 66.8 (2OCH2), 128.7, 136.3 and 136.8 (3CH), 140.3 (one sp2
1448, 1340, 1256, 1200, 1036, 944, 876, 692 cmꢁ1
.
tertiary C), 164.4, and 182.8 (2C]O). MS (EI, 70 eV), m/z (%): 225
(Mþ, 6), 114 (46), 111 (100). IR (KBr):
n
¼3070, 2920 and 2860
(CH), 1640 (C]O), 1520, 1410, 1360, 1300, 1270, 1230, 1120, 1040,
960, 830, 750 cmꢁ1
4.3.10. 2-Imino-N,N-dimethyl-2-(2-thienyl)ethanethioamide
(8j). Yield 62%. Colorless crystalline solid, mp 68–70 ꢀC; Rf¼0.63
(CH2Cl2/acetone¼5:1). Anal. Calcd for C8H10N2S2: C, 48.45; H,
5.08; N, 14.13. Found: C, 48.65; H, 5.38; N, 14.03. 1H NMR
.
4.3.16. 1-(1-Benzofuran-2-yl)-2-morpholin-4-yl-2-oxoethanone
(9f). Yield 55%. Colorless oil; Rf¼0.69 (CH2Cl2/acetone¼5:1). Anal.
Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.46; H,
(250 MHz, CDCl3)
d: 3.25 (3H, s, CH3), 3.54 (3H, s, CH3), 7.08 (1H,
dd, J 3.7, 5.1, Ar), 7.35 (1H, d, J 3.7, Ar), 7.51 (1H, d, J 5.1, Ar), 9.04
(1H, s, NH). 13C NMR (75.5 MHz, CDCl3)
d
: 24.3, and 26.4
5.35; N, 5.27. 1H NMR (250 MHz, CDCl3)
d: 3.62 (2H, m, 2NCH2), 3.64
(2NCH3), 127.2, 130.7, and 131.7 (3CH), 133.9, and 164.0 (two sp2
(2H, m, NCH2), 3.78 (4H, m, 2OCH2), 7.12 (1H, s, Ar), 7.26 (1H, m, Ar),
tertiary C), 195.6 (C¼S). MS (EI, 70 eV), m/z (%): 198 (Mþ, 32), 120
7.40 (1H, m, Ar), 7.51 (1H, d, J 8.1, Ar), 7.26 (1H, d, J 7.3, Ar). 13C NMR
(63), 83 (44). IR (KBr):
n
¼3200 (N–H), 2972, 2924 (C–H), 2872,
(75.5 MHz, CDCl3) d: 42.1, and 47.1 (2NCH2), 66.7, and 66.9 (2OCH2),
1604, 1572, 1496, 1448, 1340, 1256, 1200, 1036, 944, 876,
111.7, 112.1, 123.1, 124.0, and 127.6 (5CH), 128.2, 156.5, and 161.3
(three sp2 tertiary C), 164.6, and 179.8 (2C]O). MS (EI, 70 eV), m/z
(%): 259 (Mþ, 7), 173 (10), 144 (100).
692 cmꢁ1
.
4.3.11. 2-Morpholin-4-yl-2-oxo-1-phenylethanone (9a). Yield 55%.
Colorless crystalline solid, mp 51–53 ꢀC; Rf¼0.49 (CH2Cl2/
acetone¼10:1), lit.25 mp 50–51 ꢀC.
4.3.17. N,N-Dimethyl-2-oxo-2-(2-thienyl)acetamide (9g). Yield 74%.
Colorless oil; Rf¼0.43 (CH2Cl2/acetone¼5:1). IR and mass spectra
are similar to the literature data.26
4.3.12. 1-(4-Fluorophenyl)-2-morpholin-4-yl-2-oxoethanone
(9b). Yield 12%. Colorless crystalline solid, mp 76–78 ꢀC; Rf¼0.44
(CH2Cl2/acetone¼10:1). Anal. Calcd for C12H12FNO3: C, 60.76; H,
5.10; N, 5.90. Found: C, 60.83; H, 5.32; N, 6.03. 1H NMR (250 MHz,
4.4. Crystallographic data
Crystals of 3f (C13H10N2S3, M¼290.41) are monoclinic, space
ꢀ
CDCl3)
m, 2OCH2), 7.19 (2H, d, J 8.8, Ar), 7.98 (2H, m, Ar). 13C NMR
(75.5 MHz, CDCl3) : 41.8, and 46.4 (2NCH2), 66.7, and 66.8
d: 3.39 (2H, t, J 5.1, NCH2), 3.66 (2H, t, J 5.1, NCH2), 3.80 (4H,
group P21/c, at 100 K: a¼12.6684(3), b¼13.9186(7), c¼7.4243(5) A,
b
¼104.972(5) , V¼1264.66(11) A , Z¼4 (Z ¼1), dcalcd¼1.525 g cmꢁ3
,
3
ꢀ
ꢀ
0
m
(Mo Ka
)¼5.66 cmꢁ1, F(000)¼600. Intensities of 50,901 reflections
d
(2OCH2), 116.5 (2CH, d, J 23.0), 132.6 (2CH, d, J 9.8), 129.7, and
were measured with a Bruker SMART APEX2 CCD diffractometer
131.2 (two sp2 tertiary C), 166.9, and 189.4 (2C]O). MS (EI, 70 eV),
[l
(Mo K
a
)¼0.71072 A,
<90ꢀ] and 10,363 independent
ꢀ
u-scans, 2q
m/z (%): 237 (Mþ, 9), 123 (100), 114 (17). IR (KBr):
n
¼3068, 2924
(C–H), 2864, 1768 (C]O), 1672 (C]O), 1632, 1596, 1508, 1444,
1272, 1232, 1160, 1112, 984, 852, 764, 612 cmꢁ1
reflections [Rint¼0.0458] were used in further refinement. The
structure was solved by direct method and refined by the full-matrix
least-squares technique against F2 in the anisotropic–isotropic
approximation. The positions of hydrogen atoms were calculated,
and they were refined in isotropic approximation in riding model.
The molecule is disordered by two positions with the 80:20 ratio. For
3f the refinement converged to wR2¼0.0927 and GOF¼1.003 for all
independent reflections (R1¼0.0355 was calculated against F for
.
4.3.13. 1-(4-Methoxyphenyl)-2-morpholin-4-yl-2-oxoethanone
(9c). Yield 12%. Colorless crystalline solid, mp 108–110 ꢀC; Rf¼0.36
(CH2Cl2/acetone¼3:1). Anal. Calcd for C13H15NO4: C, 62.64; H, 6.07;
N, 5.62. Found: C, 62.63; H, 6.17; N, 5.76. 1H NMR (250 MHz, CDCl3)
d
: 3.35 (2H, m, NCH2), 3.61 (2H, m, NCH2), 3.74 (4H, m, 2OCH2), 3.85
(3H, s, OCH3), 6.95 (2H, d, J 7.3, Ar), 7.88 (2H, d, J 7.3, Ar). 13C NMR
(75.5 MHz, CDCl3) : 41.3, and 45.3 (2NCH2), 55.7 (OCH3), 66.7, and
7426 observed reflections with I>2s(I)). All calculations were per-
formed using SHELXTL PLUS 5.0.
CCDC 723464 contains the supplementary crystallographic data
for compound 3f. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
d
66.8 (2OCH2), 114.4 (2CH, Ar), 132.1 (2CH, Ar), 126.1, and 165.2 (two
sp2 tertiary C), 165.8, and 189.8 (2C]O). MS (EI, 70 eV), m/z (%): 249
(Mþ, 7), 135 (100), 114 (6). IR (KBr):
n
¼2980, 2940 (C–H), 2916 (C–
H), 2884, 1664 (C]O), 1628, 1600, 1576, 1424, 1256, 1192, 1176, 1112,
1024, 984, 848, 764 cmꢁ1
.
Acknowledgements
4.3.14. 2-Morpholin-4-yl-1-(4-nitrophenyl)-2-oxoethanone
(9d). Yield 75%. Colorless crystalline solid, mp 141–143 ꢀC;
Rf¼0.60 (CH2Cl2/acetone¼3:1). Anal. Calcd for C12H12N2O5: C,
54.55; H, 4.58; N, 10.60. Found: C, 54.73; H, 4.72; N, 10.72. 1H
We gratefully acknowledge financial support from the Russian
Foundation for Basic Research (grant no. 08-03-00003) and from the
Presidium of the Russian Academy of Sciences (Programme No. 7).
NMR (250 MHz, CDCl3)
2OCH2), 3.89 (2H, t, J 5.1, NCH2), 8.16 (2H, d, J 8.8, Ar), 8.35 (2H, d,
J 8.1, Ar). 13C NMR (75.5 MHz, CDCl3)
: 42.0, and 46.4 (2NCH2),
66.7, and 66.8 (2OCH2), 124.2 (2CH, Ar), 130.9 (2CH, Ar), 137.6,
and 151.2 (two sp2 tertiary C), 164.1, and 188.7 (2C]O). MS
(EI, 70 eV), m/z (%): 264 (Mþ, 4), 234 (14), 150 (32), 114 (100). IR
d: 3.41 (2H, t, J 5.1, NCH2), 3.81 (4H, m,
References and notes
d
1. Khmelnitsky, L. I.; Rakitin, O. A. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 2, Chapter 4.11, pp 433–452; Rakitin, O. A. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K.,
Eds.; Elsevier: Oxford, 2008; Vol. 6, Chapter 6.01, pp 1–36.
2. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985, 118, 1632–1643.
3. Lee, H.; Kim, K. J. Org. Chem. 1993, 58, 7001–7008.
4. Lee, H.-S.; Kim, K. Tetrahedron Lett. 1996, 37, 3709–3712.
(KBr):
n
¼3104, 3072, 2928 (C–H), 2868, 1684 (C]O), 1602, 1636,
1524, 1384, 1268, 1212, 1112, 984, 852, 728, 712 cmꢁ1
.
5. Chang, Y.-G.; Lee, H.-S.; Kim, K. Tetrahedron Lett. 2001, 42, 8197–8200.
6. Jeon, M.-K.; Kim, K. J. Chem. Soc., Perkin Trans. 1 2000, 3107–3112.
7. Gray, M. A.; Rees, C. W.; Williams, D. J. Heterocycles 1994, 37, 1827–1851;
Emayan, K.; Rees, C. W. Bull. Soc. Chim. Belg. 1997, 106, 605–611.
8. Konstantinova, L. S.; Bol'shakov, O. I.; Obruchnikova, N. V.; Laborie, H.; Tonga,
A.; Sopéna, V.; Lanneluc, I.; Picot, L.; Sablé, S.; Thiéry, V.; Rakitin, O. A. Bioorg.
Med. Chem. Lett. 2009, 19, 136–141.
4.3.15. 2-Morpholin-4-yl-2-oxo-1-(2-thienyl)ethanone (9e). Yield
61%. Colorless crystalline solid, mp 101–103 ꢀC; Rf¼0.39 (CH2Cl2/
acetone¼10:1). Anal. Calcd for C10H11NO3S: C, 53.32; H, 4.92; N,
6.22. Found: C, 52.99; H, 4.89; N, 6.17. 1H NMR (250 MHz, CDCl3)
d
: 3.49 (2H, t, J 5.1, NCH2), 3.67 (2H, t, J 5.1, NCH2), 3.76 (4H, m,

4338
L.S. Konstantinova et al. / Tetrahedron 66 (2010) 4330–4338
9. Konstantinova, L. S.; Bol'shakov, O. I.; Obruchnikova, N. V.; Golova, S. P.;
Nelyubina, Y. V.; Lyssenko, K. A.; Rakitin, O. A. Mendeleev Commun. 2009,
84–86.
10. Bader, R. F. W. Atoms in Molecules. A Quantum Theory; Clarendron: Oxford, 1990.
11. Espinosa, E.; Molins, E.; Lecomte, C. Chem. Phys. Lett. 1998, 285, 170–173.
12. Espinosa, E.; Alkorta, I.; Rozas, I.; Elguero, J.; Molins, E. Chem. Phys. Lett. 2001,
336, 457–461.
13. Masuda, K.; Adachi, J.; Nomura, K. J. Chem. Soc., Perkin Trans. 1 1981, 1033–1036.
14. Goldish, D.; Axon, B. W.; Moore, H. W. Heterocycles 1983, 2, 187–192.
15. Lunn, W. H. W.; Shadle, J. K. Tetrahedron 1992, 48, 8615–8620.
16. Ross, J. M.; Smith, W. C. J. Amer. Chem. Soc. 1964, 86, 2861–2868.
17. Maliverney, C.; Viehe, H. G. Tetrahedron Lett. 1990, 44, 6339–6342.
18. Choi, S.-H.; Kim, K. Tetrahedron 1996, 52, 8413–8438.
19. Venkatraman, S.; Bogen, S. L.; Arasappan, A.; Bennett, F.; Chen, K.; Jao, E.; Liu,
Y.-T.; Lovey, R.; Hendrata, S.; Huang, Y.; Pan, W.; Parekh, T.; Pinto, P.; Popov, V.;
Pike, R.; Ruan, S.; Santhanam, B.; Vibulbhan, B.; Wu, W.; Yang, W.; Kong, J.;
Liang, X.; Wong, J.; Liu, R.; Butkiewicz, N.; Chase, R.; Hart, A.; Agrawal, S.; In-
gravallo, P.; Pichardo, J.; Kong, R.; Baroudy, B.; Malcolm, B.; Guo, Z.; Prongay, A.;
Madison, V.; Broske, L.; Cui, X.; Cheng, K.-C.; Hsieh, Y.; Brisson, J.-M.; Prelusky,
D.; Korfmacher, W.; White, R.; Bogdanowich-Knipp, S.; Pavlovsky, A.; Bradley,
P.; Saksena, A. K.; Ganguly, A.; Piwinski, J.; Girijavallabhan, V.; Njoroge, F. G.
J. Med. Chem. 2006, 49, 6074–6086.
Barrish, J. C.; Dodd, J. H.; Schieven, G. L.; Leftheris, K. Bioorg. Med. Chem. Lett.
2007, 17, 5019–5024.
21. Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore,
F.; Gardelli, C.; Paz, O. G.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Mon-
teagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.;
Stillmock, K.; Witmer, M. V.; Rowley, M. J. Med. Chem. 2008, 51, 5843–5855.
22. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant,
J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas,
O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.;
Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T. A.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe; Gill, M. P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.9; Gaussian: Pittsburgh,
PA, 1998.
23. AIM2000 designed by Friedrich Biegler-KÎnig, University of Applied Sciences,
Bielefeld, Germany.
24. Coppola, G. M.; Damon, R. E. J. Heterocycl. Chem. 1995, 32, 1133–1139.
25. Matsumoto, K.; Hashimoto, S.; Uchida, T.; Okamoto, T.; Otani, S. Chem. Ber. 1989,
122, 1357–1364.
20. Dhar, T. G. M.; Wrobleski, S. T.; Lin, S.; Furch, J. A.; Nirschl, D. S.; Fan, Y.; Tod-
derud, G.; Pitt, S.; Doweyko, A. M.; Sack, J. S.; Mathur, A.; McKinnon, M.;
26. Campaigne, E.; Skowronski, G.; Rogers, R. B. Synth. Commun. 1973, 3, 325–332.