Synthesis, molecular structure, and applications of 2-hydroxylamino-4,5-dihydroimidazolium-o-sulfonate to the synthesis of novel heterocyclic ring systems

Article abstract of DOI:10.1021/jo034309n

2-Hydroxylamino-4,5-dihydroimidazolium-O-sulfonate (1) has been prepared by reacting 2-chloro-4,5-dihydroimidazole with hydroxylamine-O-sulfonic acid. Deprotonated compound la containing both the nucleophilic endocyclic nitrogen atoms and electrophilic exocyclic nitrogen was used for the syntheses of 3-substituted 6,7-dihydro-5H-imidazo[2,1-c] [1,2,4]oxadiazoles 2-9 and 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione (10) by tandem nucleophilic addition-electrophilic amination reaction. The method promises utility in the synthesis of a variety of other heterocycles. On the other hand, the convenient routes to 7,8-dihydroimidazo [1,2-c][1,3,5]thiadiazine-2,4(6H)-dithione (16) and 2,6,7,8-tetrahydroimidazo[1,2-][1,3,5]triazine-4(3H)-thione derivative (17) are reported starting from compound 1. The structures of the compounds prepared were established by elemental analyses, IR, NMR, and MS spectra, and in some instances X-ray analyses.

Full text of DOI:10.1021/jo034309n

Syn th esis, Molecu la r Str u ctu r e, a n d Ap p lica tion s of
-Hyd r oxyla m in o-4,5-d ih yd r oim id a zoliu m -O-su lfon a te to th e
Syn th esis of Novel Heter ocyclic Rin g System s
2
,
†
†
‡
Franciszek S a¸ czewski,* J arosław S a¸ czewski, and Maria Gdaniec
Department of Chemical Technology of Drugs, Medical University of Gda n´ sk, 80-416 Gda n´ sk, Poland,
and Faculty of Chemistry, A. Mickiewicz University, 60-780 Pozna n´ , Poland
saczew@amg.gda.pl
Received March 9, 2003
2
4
-Hydroxylamino-4,5-dihydroimidazolium-O-sulfonate (1) has been prepared by reacting 2-chloro-
,5-dihydroimidazole with hydroxylamine-O-sulfonic acid. Deprotonated compound 1a containing
both the nucleophilic endocyclic nitrogen atoms and electrophilic exocyclic nitrogen was used for
the syntheses of 3-substituted 6,7-dihydro-5H-imidazo[2,1-c][1,2,4]oxadiazoles 2-9 and 6,7-dihydro-
5
H-imidazo[2,1-c][1,2,4]thiadiazole-3-thione (10) by tandem nucleophilic addition-electrophilic
amination reaction. The method promises utility in the synthesis of a variety of other heterocycles.
On the other hand, the convenient routes to 7,8-dihydroimidazo[1,2-c][1,3,5]thiadiazine-2,4(6H)-
dithione (16) and 2,6,7,8-tetrahydroimidazo[1,2-a][1,3,5]triazine-4(3H)-thione derivative (17) are
reported starting from compound 1. The structures of the compounds prepared were established
by elemental analyses, IR, NMR, and MS spectra, and in some instances X-ray analyses.
In tr od u ction
Electronegatively substituted amine derivatives of
general formula A (Figure 1) have received considerable
attention due to the ability of the nitrogen atom bearing
a good leaving group to behave as either a nucleophile
δ-
δ+
(
2 2
NH synthon) or electrophile ( NH synthon) depend-
ing on the circumstances. Preparative methods and
synthetic uses of O-alkyl-, O-acyl-, and O-sulfonylhy-
droxylamines A have been surveyed in several compre-
1
-7
F IGURE 1.
hensive reviews.
The displacement of the leaving group on electrophilic
nitrogen atoms by carbon, nitrogen, sulfur, or phosphorus
N-hydroxyguanidine with chlorosulfonic acid to give the
corresponding hydroxyguanidine-O-sulfonic acid (HGS),
1
0
nucleophiles leads to the formation of C-N, N-N, S-N,
SdN, or PdN bonds, respectively.8 Furthermore, the
which then was successfully used in the electrophilic
guanidination of aromatic compounds under Friedel-
Crafts conditions11 and for the preparation of various
semicarbazones by means of the reaction with aldehydes
or cyclic ketones.12
Continuing our work in the field of 4,5-dihydroimida-
zole chemistry,13 we describe in this paper the facile
synthesis, molecular structure, and reactivity of 2-hy-
droxylamino-4,5-dihydroimidazolium-O-sulfonate (1) (Fig-
ure 1).
intramolecular version of this type of “Umpolung” ami-
nation has also been used for the preparation of pyrro-
lidine derivatives.9
In contrast, reports on the analogous hydroxyguani-
dine-O-sulfonic acids of type B (Figure 1) have been
scarce. Hessing and co-workers reported the reaction of
†
Medical University of Gda n´ sk.
A. Mickiewicz University.
‡
*
Corresponding author.
(
(
(
(
(
(
(
1) Wallace, R. G. Org. Prep. Proced. Int. 1982, 14, 265.
2) Tamura, Y.; Minamikawa, J .; Ikeda, M. Synthesis 1977, 1.
3) Erdik, E.; Ay, A. Chem. Rev. 1989, 89, 1947.
4) Greck, C.; Enet, J . P. Synlett 1997, 741.
5) Ragnarssan, U. Chem. Soc. Rev. 2001, 205.
6) Dembech, P.; Seconi, G.; Ricci, A. Chem.sEur. J . 2000, 1281.
7) Ricci, A. Modern Amination Methods; Wiley-VCH: New York,
Resu lts a n d Discu ssion
Our research started with the reaction between 2-chloro-
4,5-dihydroimidazole14 and hydroxylamine-O-sulfonic acid
2
000.
8) For selected examples see: (a) Vidal, J .; Damestoy, S.; Guy, L.;
Hannachi, J . C.; Aubry, A.; Collet, A. Chem.sEur. J . 1997, 3, 1691.
b) Greck, C.; Bischoff, L.; Ferreira, F.; Genet, J . P. J . Org. Chem. 1995,
(
(10) Heesing, A.; Schulze, H. Z. Naturforsch. 1965, 20b, 536.
(11) Hessing, A.; Peppmoller, R. Tetrahedron Lett. 1965, 48, 4353.
(12) Heesing, A.; Schulze, H. Angew. Chem., Int. Ed. Engl. 1967, 6,
704.
(13) S a¸ czewski, F.; S a¸ czewski, J . Applications of 2-Chloro-4,5-
dihydroimidazole in Heterocyclic and Medicinal Chemistry. Trends in
Heterocyclic Chemistry; 2003; Vol. 8, Research Trends, in press.
(14) Trani, A.; Bellasio, E. J . Heterocycl. Chem. 1974, 11, 257.
(
6
6
0, 7010. (c) Lenarsic, R.; Kocevar, M.; Polanc, S. J . Org. Chem. 1999,
4, 2558. (d) Foot, O. F.; Knight, D. W. Chem. Commun. 2000, 975. (e)
Reimer, B.; Patzel, M.; Hassoun, A.; Liebscher, J .; Friedrischsen, W.;
J ones, P. G. Tetrahedron 1993, 49, 3767.
(9) Sheradsky, T.; Yusupova, L. Tetrahedron Lett. 1995, 42, 7701.
1
0.1021/jo034309n CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003
J . Org. Chem. 2003, 68, 4791-4796
4791

S a¸ czewski et al.
SCHEME 2. P r ep a r a tion of Im id a zo[2,1][1,2,4]-
SCHEME 1. P r ep a r a tion of Zw itter ion 1 a n d th e
Dep r oton a ted Com p ou n d 1a
a
oxa d ia zoles 2-9
a
Key: calculated16 natural atomic charges (plain), charges from
Mulliken population analysis (italic), and atomic charges from
electrostatic potential (underlined) for the nitrogen atoms of 1a .
in aqueous solution at room temperature, which gave the
desired 1 in 69% yield (Scheme 1). In the 1H NMR
spectrum of the zwitterion 1 the four CH protons of the
2
imidazoline ring were seen as a singlet at 3.61 ppm, the
signal of two protons attached to endocyclic nitrogen
atoms appeared at 8.32 ppm, and the signal of the
exocyclic NH appeared at 12.01 ppm. The structure of 1
was also confirmed by X-ray crystal structure analysis
ethylamine is predicted to occur at the exocyclic nitrogen
atom, which is least able to support a positive charge,
leading to the imino tautomer 1a containing both the
nucleophilic N1 and N2 nitrogen atoms and the electro-
philic N3 nitrogen atom (Scheme 1). Further evidence
for the predominant existence of the imino tautomer in
solution was provided by a consideration of the chemical
shift of the methylene protons of the 2-imidazolidine
(Supporting Information), providing the molecular ge-
1
ometry for further molecular modeling studies.
The molecules of 1 exist in crystals as zwitterions with
a proton transferred from the sulfate group to the
guanidine moiety. The exocyclic C-N bond in the oxy-
guanidine moiety of 1 is 1.356 Å, whereas the two
endocyclic C-N bonds are 1.318 and 1.320 Å and show
more pronounced double-bond character. This is in
contrast with the geometry of the natural oxyguanidine
moiety of L-canavanine,15 which exists in crystals in the
imino tautomeric form with the C-N bond of its oxyimino
fragment 1.302 Å and the two amino C-N bonds 1.347
and 1.361 Å.
moiety in the H NMR spectrum. Thus, the observed shift
of 3.27 ppm for the imino tautomer 1a (vide infra) is in
agreement with those found for the formally related
2-iminoimidazolidine derivatives.18
Treatment of 1 with a range of aromatic aldehydes in
aqueous NaOH solution gave the 3-substituted 6,7-
dihydro-5H-imidazo[2,1-c][1,2,4]oxadiazoles 2-5 (Scheme
2). The method also allowed the synthesis of spiro
compounds 6-9 bearing the 6,7-dihydro-5H-imidazo[2,1-
c]oxadiazole unit by reacting 1 with cyclic ketones. The
yields of these processes were rather moderate (23-35%),
except for benzaldehyde, which gave 74% of the product
2. However, compound 1 under the conditions tried failed
to give any detectable reaction with less reactive aliphatic
aldehydes and open-chain ketones.
The reaction can be mechanistically explained by
nucleophilic addition of the imidazoline NH group to the
carbonyl group and subsequent abstraction of the proton
from the hydroxyl group of the heminal initially formed,
followed by intramolecular electrophilic amination of the
We have generated and optimized the molecular struc-
ture of the zwitterion 1 in vacuo using ab initio (RHF/
6
-31G** and MP2/6-31G**) as well as density functional
1
6
(B3LYP/6-31G**) computations The inspection of the
experimental and optimized calculated values of the most
relevant geometrical parameters [bond distances (Å) and
angles (deg)] (Supporting Information S8) indicates that
none of the methods studied are suitable for geometric
description of the zwitterionic structure 1, as the geo-
metric parameters calculated by these methods show
differences with respect to the experimental values.
Deprotonation of the charged guanidine moiety of 1
anionic oxygen atom with simultaneous extrusion of the
2-
SO
4
moiety. A five-membered, oxadiazole ring is thus
formed which is made up of the NsCdN substructure of
1
a and the carbonyl group of the reagent.
The mass spectrometric degradation pattern [M ], [M
NO] is in agreement with the proposed structures. The
1
7
(determined pK
a
value 4.9 ) upon treatment with tri-
+
+
-
(
(
15) Boyar, A.; Marsh, R. E. J . Am. Chem. Soc. 1982, 104, 1995.
16) The geometries of the zwitterionic structure 1 and compounds
molecular structure of these compounds was further
confirmed by X-ray crystal structure analysis of 7.
It should also be pointed out that the previously
described reaction of hydroxyguanidinium-O-sulfonate of
type B with carbonyl compounds led to the formation of
semicarbazone derivatives.6
1
0 and 15 were fully optimized using a molecular orbital ab initio
method at the Hartree-Fock level of theory with the 6-31G** basis
set, and a density functional B3LYP/6-31G** method. The ab initio
calculations were carried out using the SPARTAN program distributed
by Wavefunction Inc. and installed on a workstation. The density
functional calculations were carried out using the TITAN program
distributed by Wavefunction Inc. and installed on a PC computer.
(
17) The pK
a
value was determined at 25 °C by potentiometric
titration with TiNet 2.5 software.
(18) J ackman, L. M.; J en, T. J . Am. Chem. Soc. 1975, 97, 2811.
4
792 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of Novel Heterocyclic Ring Systems
SCHEME 3. Rea ction s of 1 w ith Ca r bon Disu lfid e in DMF Solu tion
Encouraged by our success with imidazo[2,1-c][1,2,4]-
oxadiazole synthesis, we decided to broaden the scope of
these studies by examining the reactions of 1 with
heterocumulenes such as carbon disulfide and phenyl
isothiocyanate.
Scheme 3 to afford 12 and 13, respectively. The structure
of 7-benzyl-6,7-dihydro-5H-imidazo[2,1-c][1,2,4]thiadiazole-
3-thione (13) was confirmed by an X-ray crystallographic
study (Supporting Information). On the other hand, the
reaction of 10 with benzoyl isothiocyanate carried out in
The reaction of 1 with carbon disulfide took two
different courses, dependent on a base-solvent combina-
tion. Thus, when the reaction of 1 was performed in DMF
in the presence of an equimolar amount of triethylamine,
3
THF in the presence of Et N at room temperature led to
the formation of the N7-benzoyl derivative 14 (Scheme
3).
In contrast to the above-described reactions of 1 with
carbon disulfide in DMF, an analogous reaction per-
formed in aqueous NaOH solution gave 7,8-dihydroimi-
dazo[1,2-c][1,3,5]thiadiazine-2,4(6H)-dithione in the form
of a salt with 2-aminoimidazoline (15), together with a
small amount of imidazothiadiazole 10. We assume that
the mechanism of the reaction leading to 10 is analogous
to those described in Scheme 2, whereas a plausible route
to the formation of 15 is shown in Scheme 4.
6
,7-dih ydr o-5H -im ida zo[2,1-c][1,2,4]t h ia dia zole-3-
thione (10) was produced in 50% yield as a result of
tandem nucleophilic addition-electrophilic amination
reaction (method A, Scheme 3), which mechanistically
is related to those described above for the formation of
oxadiazoles 2-9. In the presence of excess triethylamine,
compound 10 underwent subsequent reaction with a
second molecule of carbon disulfide to give di(5,6-dihydro-
7
H -im ida zo[2,1-c][1,2,4]t h ia dia zole-3-t h ion e-7-yl)-
Apparently, when the reaction is carried out in water,
which is more effective than DMF at solvating atoms with
partial negative charges, the competing nucleophilic
attack of the exocyclic nitrogen atom of 1a at carbon
disulfide may occur to give the intermediate A, which
decomposes with the formation of elemental sulfur,
sulfate anion, and 4,5-dihydroimidazol-2-yl isothiocyan-
ate B. A portion of the transiently formed B reacts
further with an excess carbon disulfide to give C, which
then cyclizes to 7,8-dihydroimidazo[1,2-c][1,3,5]thiadiazine-
2,4(6H)-dithione (16). Simultaneously, hydrolytic decom-
position of the isothiocyanate B produces 2-iminoimida-
zoline, which combines with the dithione 16, giving rise
to the formation of the stable salt 15.
methanethione (11) (method B, Scheme 3). The resulting
mixture contained 10 and 11 in a ratio of about 7:1, and
the two products could easily be separated owing to a
considerable difference in their solubility in hot methanol.
The imidazothiadiazole 10 can exist in two likely (i.e.,
low-energy) tautomeric forms, the N7-H tautomer 10
and N1-H tautomer 10a , which can interconvert via a
1
6
1
,3-prototropic shift. Calculations of the energy indi-
cated that 10 has a relative energy calculated to be 12.9
kcal/mol below that of 10a . We were able to prove by
NMR spectroscopy that the low-energy tautomer 10 is
6
also present in DMSO-d solution. The methylene groups
of the imidazoline moiety are nonequivalent, and the
NOE was observed (Supporting Information) between an
upfield-shifted C6-H proton and the N-H proton.
Compound 10 reacted in the normal manner with
acetic anhydride and benzyl bromide as indicated in
Salt 15 isolated from the reaction mixture was recrys-
tallized from DMF. The needle-shaped crystals were
unstable when removed from the mother liquor, and all
specimens checked were twinned (nonmehroedral axial
J . Org. Chem, Vol. 68, No. 12, 2003 4793

S a¸ czewski et al.
SCHEME 5. Rea ction of 1 w ith P h en yl
SCHEME 4. Rea ction s of 1 w ith Ca r bon Disu lfid e
in Aqu eou s Na OH Solu tion
Isoth iocya n a te
occur in solution with solvent effects possibly governing
their relative concentrations. On the basis of their
calculated dipole moments, 16 (9.2 D) would be predicted
to predominate over 16a (4.7 D) in polar solvents.
The reaction of 1 with phenyl isothiocyanate was
carried out in DMF at room temperature in the presence
of Et
carbamoyl)-2,6,7,8-tetrahydroimidazo[1,2-a][1,3,5]triazine-
(3H)-thione (17) as the only isolable organic product
Scheme 5). We propose that the first step of the reaction
3
N to give 3-phenyl-2-(phenylimino)-8-(phenylthio-
4
(
sequence is the formation of thioureido derivative A,
which then reacts with a third equivalent of phenyl
isothiocyanate. This leads to the dianion B, which
subsequently undergoes ring closure via a cyclodesulfu-
rization process.
It is worth noting that compounds 10, 12, and 13 have
been tested at the U.S. National Cancer Institute (Be-
thesda, MD) for their in vitro anticancer activity. Details
of this test system and the information which is encoded
twins). These crystals were triclinic, space group P 1h , a
)
6.847(1) Å, b ) 12.144(2) Å, c ) 12.939(2) Å, R ) 79.03-
by the activity pattern over all cell lines have been
published.1
9-21
Compounds 12 and 13 were inactive (log
(2)°, â ) 89.96(2)°, γ ) 82.30(1)°. For the crystal of 15
the intensity data were collected at 130 K, and the
overlap of a large group of reflections was not taken into
account when the data were processed from the CCD
camera. However, despite errors in the experimental data
set, the direct methods produced the electron-density
map, which showed the asymmetric unit cell of the
crystal consisting of a molecule of 16, 2-aminoimidazo-
line, and two DMF molecules. All these structural units
were hydrogen-bonded, forming discreet H-bonded as-
semblies. However, due to twinning refinement of the
crystal structure stopped at R1 ) 0.20 (Supporting
Information). The structure of 16 was confirmed by X-ray
analysis of the yellow blocklike crystals that precipitated
when acetic acid was added to the solution of 15 in DMF
GI50 > -4), whereas the parent imidazothiadiazole-3-
thione 10 exhibited moderate activity against the breast
cancer T-47D cell line (log GI50 ) -6.07).
Exp er im en ta l Section
Melting points determined are not corrected. FT-IR spectra
1
were recorded using a mixture of the compound and KBr. H
13
and C NMR spectra were taken at 500 and 125 MHz,
respectively, with an acquisition time of 1.8 s. Chemical shifts
were measured relative to the residual solvent signal at 2.50
or 7.26 ppm and 39.5 or 77 ppm, respectively. MS spectra were
recorded at 70 eV. All reagents were used directly as obtained
commercially. 2-Chloro-4,5-dihydroimidazole14 was prepared
according to a previous literature procedure.
2
-H y d r o x y la m in o -4,5-d ih y d r o im id a zo liu m -O -s u l-
(Supporting Information).
fon a te (1). To a solution of 2-chloro-4,5-dihydroimidazole (10
g, 0.05 mol) and hydroxylamine-O-sulfonic acid (7 g, 0.062 mol)
in water (15 mL) was added a solution of NaOH (1.9 g, 0.0475
mol) in water (10 mL). The reaction mixture was kept at room
The ab initio geometry optimization at the HF/6-31G**
level16 was performed on the imidazothiadiazine-2,4-
dithione 16 to examine its three possible tautomers 16,
1
6a , and 16b as shown in Scheme 4. These computations
(
19) Boyd, M. R. Am. Assoc. Cancer Res. 1989, 30, 652.
showed that the tautomer 16 observed in its X-ray
crystallographic analysis was the most stable among the
three tautomers. Tautomer 16 was favored over 16a by
(20) Monks, A. P.; Scudiero, D. A.; Skehan, P.; Shoemaker, R.; Poull,
K. D.; Vistica, D.; Hose, C.; Langley, J .; Cronise, P.; Vaigro-Wolff, A.
J . Natl. Cancer Inst. 1991, 83, 757.
(21) Weinstein, J . N.; Myers, T. G.; O’Connor, P. M.; Friend, S. H.;
0
.6 kcal/mol, and 16b was disfavored by 12.9 kcal/mol.
Fornance J r., A. J .; Kohn, K. W.; Buolamwini, J . K.; van Osdol, W.
W.; Monks A. P.; Scudiero, D. A.; Sansville E. A.; Zaharevitz, D. W.;
Bunow, R. E.; Paull, K. D. Science 1997, 275, 343.
However, the limited magnitude of the energy difference
between 16 and 16a suggests that both tautomers may
4
794 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of Novel Heterocyclic Ring Systems
temperature for 12 h, and then the product 1 that precipitated
9 10 4
1179. Anal. Calcd for C H N O: C, 56.83; H, 5.30; N, 29.46.
was filtered off, washed with cold water, and dried in a vacuum
Found: C, 56.66; H, 5.15; N, 29.13.
desiccator over P
2
O
5
: yield 6.2 g (69%); mp 226-228 °C dec
6,7-Dih yd r o-3-sp ir ocycloh exyl-5H-im id a zo[2,1-c][1,2,4]-
oxa d ia zole (6): yield 0.47 g (26%); mp 191-193 °C (methanol);
1
1
(
(
H
2
O); H NMR (DMSO-d ) δ 3.61 (s, 4H), 8.32 (s, 2H), 12.01
6
1
3
-1
s, 1H); C NMR (DMSO-d
6
) δ 43.2, 160.3; IR (cm ) 3329,
H NMR (DMSO-d ) δ 1.09-1.16 (m, 1H, CH), 1.40-1.54 (m,
6
3
1
128, 3038, 2900, 1654, 1269. Anal. Calcd for C S: C,
9.89; H, 3.89; N, 23.19. Found: C, 19.79; H, 3.64; N, 22.83.
3
H
7
N
3
O
4
2H, CH), 1.56-1.60 (m, 5H, CH), 1.74 (d, 2H, CH, J ) 11.7
Hz), 3.10 (t, 2H, CH , J ) 6.3 Hz), 3.63 (t, 2H, CH , J ) 6.3
2
2
Hz), 6.31 (s, 1H, NH); 13C NMR (DMSO-d
) δ 22.6, 24.5, 31.3,
Tr iet h yla m in iu m 2-H yd r oxylim in oim id a zolid in e-O-
6
-1
su lfon a te (1a ). A suspension of compound 1 (1.81 g, 10 mmol)
in DMF (15 mL) was treated with triethylamine (2.1 mL, 15
mmol) at room temperature. The reaction mixture was stirred
until 1 had dissolved (ca 10 min), and then the reaction
mixture was cooled to 15 °C. The solid that precipitated was
collected by suction, washed with DMF and acetone, and dried
41.5, 48.8, 95.2, 166.1; IR (cm ) 3159, 2925, 1651, 1486, 1440;
+
EIMS m/z (relative intensity) 181 (M , 27.1), 164 (18.5), 151
+
(M - NO, 35.5), 138 (100), 125 (28). Anal. Calcd for
9 16 3
C H N O: C, 59.64; H, 8.34; N, 23.19. Found: 59.54; H, 8.12;
N, 23.01.
6,7-Dih yd r o-3-sp ir o(4-m eth ylcycloh exyl)-5H-im id a zo-
[2,1-c][1,2,4]oxa d ia zole (7): yield 0.45 g (23%); mp 212-214
1
in a vacuum desiccator: mp 193-195 °C; H NMR (DMSO-
1
d
6
1
1
6
) δ 1.35 (t, 9H, CH
3
1
), 3.04 (q, 6H, CH
2
), 3.27 (s, 4H, CH
) δ 9.3, 43.2, 46.3,
63.4; IR (cm ) 3384, 3244, 3015, 2738, 2677, 1654, 1476,
396, 1252, 1204, 1054. Anal. Calcd for C S: C, 33.19;
2
),
°C (acetone); H NMR (CDCl
1.31-1.44 (m, 3H, CH), 1.51-1.57 (m, 2H, CH), 1.64 (d, 2H,
CH, J ) 10.7 Hz), 2.04 (d, 2H, CH, J ) 12.2), 3.21 (t, 2H, CH
3
) δ 0.92 (d, 3H, CH J ) 5.8 Hz),
3
3
.30 (br s, 3H, NH); C NMR (DMSO-d
6
-
1
2
,
C
1
3
7
H
17
N
4
O
4
J ) 6.8), 3.86 (t, 2H, CH
NMR (DMSO-d ) δ 22.2, 31.3, 31.5, 31.8, 41,7, 49.8, 96.8, 166.8;
IR (cm ) 3177, 2915, 1646, 1487, 1281. Anal. Calcd for
O: C, 61.15; H, 8.78; N, 21.52. Found: C, 61.01; H,
2
, J ) 6.8), 4.80 (br s, 1H, NH);
H, 6.77; N, 22.12. Found: C, 33.15; H, 6.69; N, 21.97.
6
-
1
P r ep a r a tion of 6,7-Dih yd r o-5H-im id a zo[2,1-c][1,2,4]-
oxa d ia zoles 2-9. Gen er a l P r oced u r e. To a suspension of
10 17 3
C H N
8
.98; N, 21.12.
1
(1.81 g, 10 mmol) and an equimolar amount of a suitable
aldehyde or ketone in water (15 mL) was added a solution of
NaOH (1.2 g, 0.03 mol) in water (15 mL) [in the case of
p-chlorobenzaldehyde methanol (5 mL) was added to enhance
solubility]. The reaction mixture was stirred vigorously at room
temperature for 12 h. Then the product was extracted with
dichloromethane (3 × 20 mL). Combined organic layers were
6,7-Dih yd r o-3-sp ir o(1-m et h ylp ip er id in -4-yl)-5H -im i-
d a zo[2,1-c][1,2,4]oxa d ia zole (8): yield 0.67 g (34%); mp 176-
1
178 °C (acetone); H NMR (CDCl
2.33-2.48 (m, 2H, CH), 2.35 (s, 3H, CH), 2.82 (d, 2H, CH, J )
11.2 Hz), 3.22 (t, 2H, CH
3
) δ 1.92-2.03 (m, 4H, CH),
2
, J ) 6.3 Hz), 3.86 (t, 2H, CH
.3 Hz), 4.71 (s, 1H, NH); 13C NMR (CDCl
) δ 31.1, 41.8, 45.9,
9.7, 52.3, 94.1, 167.0; IR (cm ) 3194, 2796, 1660, 1643, 1285.
O: C, 55.08; H, 8.22; N, 28.55. Found:
2
, J )
6
4
3
-1
2 4
dried with anhydrous Na SO , evaporated to dryness, and
9 16 4
Anal. Calcd for C H N
washed with diethyl ether, and the crude compound (2-9) thus
obtained was purified by crystallization from a suitable
solvent.
C, 55.16; H, 8.07; N, 55.22.
6,7-Dih ydr o-3-spir o(1-ben zylpiper idin -4-yl)-5H-im idazo-
[
°
2,1-c][1,2,4]oxa d ia zole (9): yield 0.65 g (24%); mp 180-181
The following compounds were obtained according to the
above procedure.
1
3
C (acetone); H NMR (CDCl ) δ 1.86-1.96 (m, 2H, CH), 1.99
(
3
d, 2H, CH, J ) 11.7 Hz), 2.40 (m, 2H, CH), 2.84 (m, 2H, CH),
.22 (t, 2H, CH , J ) 6.3 Hz), 3.55 (s, 2H, CH ), 3.85 (t, 2H,
, J ) 6.3 Hz), 4.66 (br s, 1H, NH), 7.25-7.34 (m, 5H, CH);
C NMR (CDCl ) δ 31.4, 41.9, 49.8, 50,3, 63.0, 95.2, 127.4,
28.5, 128.6, 129.5, 166.7; IR (cm ) 3207, 2938, 2815, 1640,
488, 1448. Anal. Calcd for C15 O: C, 66.15; H, 7.40; N,
3
-P h e n y l -6 ,7 -d i h y d r o -5 H -i m i d a z o [2 ,1 -c ][1 ,2 ,4 ]-
2
2
oxa d ia zole (2): yield 1.4 g (74%); mp 202-204 °C (ethanol);
CH
2
1
H NMR (DMSO-d
6
) δ 2.98-3.07 (m, 2H, CH
2
), 3.73-3.80 (m,
1
3
3
2
3
4
3
3
H, CH ), 5.53 (s, 1H, CH), 6.71 (s, 1H, NH), 7.40-7.46 (m,
2
-
1
1
1
2
1
3
H, CH), 7.52-7.57 (m, 2H, CH); C NMR (DMSO-d ) δ 45.4,
1
6
-
20 4
H N
9.3, 96.1, 127.6, 128.5, 129.6, 135.7, 168.2; IR (cm ) 3198,
0.57. Found: C, 65.42; H, 7.18; N, 20.43.
Reaction of 1 with Car bon Disu lfide. Meth od A: P r epa-
+
060, 2819, 1645, 1380; EIMS m/z (relative intensity) 189 (M ,
+
-
1.9), 159 (M
NO, 100) 131 (29.5), 117 (33), 116 (46). Anal.
O: C, 63.47; H, 5.86; N, 22.21. Found: C,
r ation of 6,7-Dih ydr o-5H-im idazo[2,1-c][1,2,4]th iadiazole-
-th ion e (10). To a solution of 1 (1.8 g, 10 mmol) and Et
Calcd for C10
H
11
N
3
3
3
N
6
3.15; H, 5.51; N, 21.87.
-(4-Ch lor oph en yl)-6,7-dih ydr o-5H-im idazo[2,1-c][1,2,4]-
oxa d ia zole (3): yield 0.48 g (23%); mp 192-193 °C (acetone);
(
(
1.4 mL, 10 mmol) in DMF (15 mL) was added carbon disulfide
3 mL, 50 mmol), and the reaction mixture was stirred at 40
3
°
C for 12 h. The volatile material was evaporated under
1
H NMR (CDCl
3
) δ 3.08-3.18 (m, 2H, CH
2
), 3.93-4.03 (m, 2H,
reduced pressure, and the oily residue was triturated with
water (20 mL). The precipitate thus obtained was filtered off
and washed with water to give 0.8 g (50%) of 10: mp 190-
1
3
d
CH ), 5.07 (s, 1H, NH), 5.66 (s, 1H, CH), 7.40 (d, 2H, CH, J )
2
1
3
8
5
3
.3 Hz), 7.55 (d, 2H, CH, J ) 8.3 Hz); C NMR (CDCl ) δ 45.8,
1
3
-
0.2, 96.7, 129.1, 129.4, 133.8, 136.2, 168.5; IR (cm ) 3205,
060, 1643, 1597, 1417, 1374, 1276, 1088. Anal. Calcd for
1
92 °C (H
2
O); H NMR (DMSO-d
6
2
) δ 3.93-3.97 (m, 2H, CH ),
13
.98-4.03 (m, 2H, CH
) δ 43.2, 47.9, 161.4, 193.4; IR (cm ) 3278, 3195, 1646, 1367.
: C, 30.17; H, 3.17; N, 26.39. Found:
2
), 7.87 (s, 1H, NH); C NMR (DMSO-
C
10
H
10
N
3
OCl: C, 51.07; H, 4.76; N, 19.85. Found: C, 50.99;
H, 4.71; N, 19.77.
-(4-Met h oxyp h en yl)-6,7-d ih yd r o-5H -im id a zo[2,1-c]-
1,2,4]oxa d ia zole (4): yield 0.77 g (35%); mp 176-178 °C
-1
6
4 5 3 2
Anal. Calcd for C H N S
C, 30.01; H, 3.28; N, 26.79.
3
[
Rea ction of 1 w ith Ca r bon Disu lfid e. Meth od B: P r e-
1
(acetone); H NMR (DMSO-d
6
) δ 2.94-3.03 (m, 2H, CH
), 3.77 (s, 3H, OCH ), 5.48 (s, 1H, CH),
.67 (s, 1H, NH), 6.97 (d, 2H, CH, J ) 8.3 Hz), 7.47 (d, 2H,
2
),
par ation of6,7-dih ydr o-5H-im idazo[2,1-c][1,2,4]th iadiazole-
3
6
.74-3.86 (m, 2H, CH
2
3
3
-th ion e (10) a n d Di(5,6-d ih yd r o-7H-im id a zo[2,1-c][1,2,4]-
th ia d ia zole-3-th ion e-7-yl)m eth a n eth ion e (11). To a solu-
tion of 1 (1.8 g, 10 mmol) and Et N (3.2 mL, 23 mmol) in DMF
15 mL) was added carbon disulfide (3 mL, 50 mmol), and the
1
3
CH, J ) 8.3 Hz); C NMR (DMSO-d
6
) δ 45.9, 49.9, 55.8, 96.6,
3
-
1
1
1
1
14.5, 128.2, 128.7, 160.9, 168.9; IR (cm ) 3207, 2955, 1646,
610, 1252. Anal. Calcd for C11 : C, 60.26; H, 5.98; N,
9.17. Found: C, 60.54; H, 5.79; N, 19.44.
-(P yr id in -3-yl)-6,7-d ih yd r o-5H -im id a zo[2,1-c][1,2,4]-
(
13 3 2
H N O
reaction mixture was stirred at 40 °C for 12 h. The volatile
material was evaporated under reduced pressure, and the oily
residue was triturated with water (20 mL). The precipitate
thus obtained was filtered off, washed with water, and then
treated with hot methanol (150 mL). The insoluble material
was separated by suction and crystallized from DMSO to give
3
1
oxa d ia zole (5): yield 0.63 g (33%); mp 184-185 °C (H
NMR (DMSO-d ) δ 3.06-3.11 (m, 2H, CH ), 3.76-3.82 (m, 2H,
CH ), 5.62 (s, 1H, CH), 6.78 (s, 1H, NH), 7.47 (dd, 1H, CH, J
4.8 Hz, J ) 7.8 Hz), 7.96 (d, 1H, CH, J ) 7.8 Hz), 8.63 (dd,
H, CH, J ) 1.5 Hz, J ) 4.8 Hz), 8.71 (d, 1H, CH, J ) 1.5 Hz);
2
O); H
6
2
2
1
)
compound 11 (0.21 g, 11%): mp 250 °C dec (DMSO); H NMR
1
(DMSO-d
CH ); IR (cm ) 1599, 1461, 1417, 1382, 1309, 1190; EIMS m/z
(relative intensity) 360 (M , 100), 284 (M - CS
6
) δ 4.06 (t, 4H, CH
2
, J ) 7.3 Hz)), 4.69 (br s, 4H,
1
3
-1
C NMR (DMSO-d
49.6, 151.6, 168.8; IR (cm ) 3201, 3056, 1644, 1595, 1370,
6
) δ 46.0, 50.00, 94.6, 124.5, 132.2, 136.0,
2
-
1
+
+
1
2
, 34), 208 (284
J . Org. Chem, Vol. 68, No. 12, 2003 4795

S a¸ czewski et al.
-
CS
2
, 9.9), 202 (25.2), 118 (35.7). Anal. Calcd for C
9
H
8
N
6
S
5
:
1406, 1338, 1277. Anal. Calcd for C
N, 20.67. Found: C, 29.11; H, 2.36; N, 20.45.
5
H
5
N
3
S
3
: C, 29.54; H, 2.48;
C, 29.98; H, 2.24; N, 23.31. Found: C, 29.90; H, 2.29; N, 23.42.
The filtrate was evaporated to dryness under reduced
pressure to give 10 (1.12 g, 70%), which was identical with
the product obtained according to method A.
3-P h en yl-2-(p h en ylim in o)-8-(p h en ylt h ioca r b a m oyl)-
2,6,7,8-t e t r a h yd r oim id a zo[1,2-a ][1,3,5]t r ia zin e -4(3H )-
th ion e (17). To a solution of 1 (1.81 g, 10 mmol) and Et
3
N
(
1.4 mL, 10 mmol) in DMF (15 mL) was added phenyl
7
-Acetyl-6,7-dih ydr o-5H-im idazo[2,1-c][1,2,4]th iadiazole-
-th ion e (12). A solution of imidazothiadiazole-3-thione 10
0.25 g, 1.57 mmol), acetic anhydride (0.6 mL, 6.36 mmol), and
Et N (0.9 mL, 6.5 mmol) in THF (10 mL) was stirred at room
isothiocyanate (3.6.mL, 30 mmol), and the reaction mixture
was kept at room temperature for 24 h. Elemental sulfur that
precipitated was separated by suction, and the filtrate was
treated with methanol (30 mL). The pale yellow solid thus
obtained was separated by suction, washed with methanol, and
3
(
3
temperature for 48 h. The solvent was evaporated under
reduced pressure, and the residue was treated with water. The
product thus obtained was filtered off and purified by crystal-
purified by crystallization from ethanol: yield 1.7 g (37%); mp
1
2
79-282 °C; H NMR (DMSO-d
6
) δ 4.08 (t, 2H, CH
2
, J ) 7.8
lization from methanol: yield 0.23 g (74%); mp 168-169 °C;
1
Hz), 4.30 (t, 2H, CH
2
, J ) 7.8 Hz), 6.73 (d, 2H, CH), 6.95 (t,
H NMR (CDCl
.49-4.57 (m, 2H, CH ); C NMR (CDCl
2 3
3
) δ 2.59 (s, 3H, CH
3
), 4.03-4.11 (m, 2H, CH
) δ 25.8, 42.6, 51.1,
54.1, 170.2, 196.4; IR (cm ) 2966, 2913, 1702, 1608, 1302,
199. Anal. Calcd for C OS : C, 35.80; H, 3.51; N, 20.88.
2
),
1
3
1H, CH), 7.00 (d, 2H, CH), 7.16 (t, 3H, CH), 7.24 (t, 2H, CH),
7.33 (d, 2H, CH), 7.40 (t, 1H, CH), 7.52 (t, 2H, CH), 12.53 (s,
4
1
1
-
1
1
1
1
1
H, NH); 13C NMR (DMSO-d
6
) δ 44.3, 46.8, 121.5, 121.6, 122.8,
6
H
7
N
3
2
26.1, 128.4, 128.7, 129.1, 129.3, 129.6, 137.8, 140.6, 145.5,
48.6, 148.8, 175.9, 176.1; IR (cm ) 2978, 1672, 1618, 1479,
418. Anal. Calcd for C24 : C, 63.13; H, 4.41; N, 18.41.
Found: C, 35.49; H, 3.69; N, 20.49.
-
1
7
-Ben zyl-6,7-d ih yd r o-5H-im id a zo[2,1-c][1,2,4]th ia d ia -
20 6 2
H N S
zole-3-th ion e (13). To a mixture of imidazothiadiazole-3-
thione 10 (0.5 g, 3.14 mmol) and finely powdered NaOH (0.5
g, 12.5 mmol) in DMSO (7 mL) was added dropwise benzyl
bromide (0.41 mL, 3.45 mmol). The resulting solution was
stirred at 35-40 °C for 1 h. Then water was added to the
reaction mixture, and the solid that precipitated was collected
by filtration. Product 13 thus obtained was purified by
Found: C, 63.02; H, 4.04; N, 18.12.
X-r a y Str u ctu r e An a lyses. The intensity data for the
crystals have been collected using a diffractometer. The crystal
2
2
structures have been solved with SHELXS-97 and refined
with SHELXL-97.23
3 7 3 4 1
Crystal data for C H N O S (1): monoclinic, space group P2 /
n, a ) 5.4594(3) Å, b ) 12.0514(7) Å, c ) 10.5212(6) Å, â )
crystallization from ethanol: yield 0.64 g (82%); mp 127-129
3
1
102.393(5)°, V ) 676.10(7) Å , Z ) 4, λ ) 0.71073 Å, T ) 130
°
CH
5
1
C; H NMR (CDCl
3
) δ 3.82-4.03 (m, 4H, CH
2
), 4.49 (s, 2H,
) δ 41.6, 49.4,
1.3, 128.3 (two overlapping signals), 128.90, 134.72, 158.90,
1
3
K, R1 ) 0.0260, wR2 ) 0.0672 for 1427 independent reflections
with I > 2σ(I).
2
), 7.30-7.44 (m, 5H, CH); C NMR (CDCl
3
-
1
Crystal data for C10
17 3 1
H N O (7): monoclinic, space group P2 /
95.17; IR (cm ) 2913, 1631, 1381, 1258. Anal. Calcd for
: C, 52.98; H, 4.45; N, 16.85. Found: C, 22.64; H,
.15; N, 16.88.
-Ben zoyl-6,7-d ih yd r o-5H-im id a zo[2,1-c][1,2,4]th ia d ia -
zole-3-th ion e (14). A mixture of imidazothiadiazole-3-thione
0 (0.3 g, 1.875 mmol), Et N (0.26 mL, 1.87 mmol), and benzoyl
c, a ) 10.6922(14) Å, b ) 9.8340(13) Å, c ) 10.9612(14) Å, â )
11 11 3 2
C H N S
3
1
15.541(13)°, V ) 1039.9(2) Å , Z ) 4, λ ) 0.71073 Å, T ) 294
4
K, R1 ) 0.0445, wR2 ) 0.1123 for 1591 independent reflections
7
with I > 2σ(I).
Crystal data for C
9 8 6 5
H N S (11): orthorhombic, space group
1
3
Pbcn, a ) 6.2662(3) Å, b ) 13.0714(7) Å, c ) 17.4538(9) Å, V
isothiocyanate (0.25 mL, 1.87 mmol) in THF (4 mL) was stirred
at room temperature for 12 h. Then the solvent was evaporated
under reduced pressure, and the solid residue was treated with
methanol (10 mL). The insoluble product 14 thus obtained was
collected by filtration and purified by crystallization from
3
)
1429.61(13)Å , Z ) 4, λ ) 0.71073 Å, T ) 140 K, R1 )
0
.0290, wR2 ) 0.0705 for 1750 independent reflections with I
>
2σ(I).
Crystal data for C11
a ) 6.6652(5) Å, b ) 8.1833(8) Å, c ) 11.2460(8) Å, R ) 83.311-
11 3 2
H N S (13): triclinic, space group P 1h ,
1
DMF: yield 0.26 g (52%); mp 219-227 °C; H NMR (DMSO-
3
(
)
7)°, â ) 77.601(6)°, γ ) 69.863(8)°, V ) 561.86(8) Å , Z ) 2, λ
0.71073 Å, T ) 130 K, R1 ) 0.0329, wR2 ) 0.0837 for 2038
independent reflections with I > 2σ(I).
Crystal data for C H N S (16): monoclinic, space group C2/
d
6
) δ 4.01 (t, 2H, CH
2
, J ) 7.8 Hz) 4.53 (t, 2H, CH , J ) 7.8
2
Hz), 7.47 (m, 2H, CH), 7.57 (m, 1H, CH, J ) 7.3 Hz), 7.69 (d,
H, CH, J ) 7.3 Hz); 1 C NMR (DMSO-d
) δ 42.0, 51.7, 128.7,
1
3
2
1
1
6
-
29.1, 132.6, 134.1, 154.0, 167.8, 193.6; IR (cm ) 1661, 1601,
469, 1415, 1326, 1316. Anal. Calcd for C11 OS : C, 50.17;
5
5
3
3
c, a ) 22.7501(13) Å, b ) 6.1929(4) Å, c ) 15.6134(9) Å, â )
H
9
N
3
2
3
1
2
32.541(5)°, V ) 1620.77(17) Å , Z ) 8, λ ) 0.71073 Å, T )
94 K, R1 ) 0.0403, wR2 ) 0.1053 for 1754 independent
H, 3.45; N, 15.96. Found: 49.87; H, 3.12; N, 3.01.
7
,8-Dih yd r oim id a zo[1,2-c][1,3,5]t h ia d ia zin e-2,4(6H )-
reflections with I > 2σ(I).
Crystal data for C24
/c, a ) 9.9784(4) Å, b ) 16.5446(6) Å, c ) 13.1448(6) Å, â
d ith ion e Im id a zolid in -2-im in e (15). To a solution of 1 (1.81
g, 10 mmol) and NaOH (1.6 g, 40 mmol) in water (12 mL) was
added carbon disulfide (5.0 mL, 82 mmol), and the reaction
mixture was stirred vigorously at room temperature for 24 h.
The excess carbon disulfide was evaporated under reduced
pressure, and the solid residue containing the salt 15 and
traces of 10 (NMR evidence) was collected by filtration.
Recrystallization of the crude product from DMF (elemental
sulfur that crystallized first was separated by suction) gave
20 6 2
H N S (17): monoclinic, space group
P2
1
3
)
91.663(4)°, V ) 2169.14(16) Å , Z ) 4, λ ) 0.71073 Å, T )
1
00 K, R1 ) 0.0392, wR2 ) 0.0947 for 3875 independent
reflections with I > 2σ(I).
Su p p or tin g In for m a tion Ava ila ble: Crystallographic
data for the structures 1, 7, 11, 13, 16, and 17, the asymmetric
part of the crystal unit cell in 15, a table showing selected
theoretical and experimental bond distances (Å) and bond
angels (deg) for zwitterionic compound 1, and NMR spectra
for compounds 6 and 10. This material is available free of
charge via Internet at http://pubs.acs.org.
pure salt 15, which melted at 172-174 °C: yield 0.45 g (31%);
1
H NMR (CDCl
2 3
m, 2H, CH ), 7.88 (s, 4H, NH); C NMR (CDCl
3
) δ 3.55 (s, 4H, CH
2
), 3.66 (m, 2H, CH
) δ 42.5, 47.4,
9.6, 151.9, 160.0, 184.7, 187.8; IR (cm-1) 3389, 2966, 1684,
614, 1497, 1260, 1042. Anal. Calcd for C ‚C : C,
5.98; H, 4.03; N, 32.02. Found: C, 36.17; H, 3.76; N, 31.88.
,8-Dih yd r oim id a zo[1,2-c][1,3,5]t h ia d ia zin e-2,4(6H )-
2
), 4.12
1
3
(
4
1
3
5
H
5
N
3
S
3
3 7 3
H N
J O034309N
7
d ith ion e (16). Salt 15 (0.2 g) was dissolved in hot DMF (4
mL), treated with 3 drops of acetic acid, and left overnight at
(
22) Sheldrick, G. M. SHELXS-97. Program for the Solution of
Crystal Structures; University of Gottingen: Gottingen, Germany,
977.
23) Sheldrick, G. M. SHELXL-97. Program for the Refinement of
room temperature for crystallization. The pure product 16
1
1
(
(
0.12 g) thus obtained melted at 249-251 °C: H NMR
(
DMSO-d
6
) δ 3.70 (t, 3H, CH
2
2
, J ) 8.8 Hz), 4.36 (t, 3H, CH ,
J ) 8.8 Hz), 10.53 (s, 1H, NH); IR (cm ) 3056, 1641, 1406,
Crystal Structures; University of Gottingen: Gottingen, Germany,
1997.
-
1
4
796 J . Org. Chem., Vol. 68, No. 12, 2003