Carbon disulfide promoted reactions of 2-chloro-4,5-dihydro-imidazole with some n-nucleophiles

Article abstract of DOI:10.1248/cpb.49.1203

The reactions of 2-chloro-4,5-dihydroimidazole 1 with o-substituted anilines and azoles promoted by carbon disulfide have been carried out. Ab initio MO calculations were used to elucidate the mechanism of the reaction of 1 with N-nucleophilic reagents. A facile synthesis of 2-(4,5-dihydroimidazol-2-yl)-1H-indazole 3e bearing structural resemblances to 2-BFI, a potent and selective agonist of imidazoline I₂ receptors, is also described. Structure of 3e was confirmed by NMR spectroscopy and X-ray analysis.

Full text of DOI:10.1248/cpb.49.1203

September 2001
Notes
Chem. Pharm. Bull. 49(9) 1203—1206 (2001)
1203
Carbon Disulfide Promoted Reactions of 2-Chloro-4,5-dihydro-imidazole
with Some N-Nucleophiles
b
Franciszek SA¸CZEWSKI, ,a Jaroslaw SA¸CZEWSKI,a and Maria GDANIEC
*
Department of Chemical Technology of Drugs, Medical University of Gdan´sk,a 80–416 Gdan´sk, Poland and Faculty of
Chemistry, A. Mickiewicz University,b 60–780 Poznan´, Poland. Received March 14, 2001; accepted May 7, 2001
The reactions of 2-chloro-4,5-dihydroimidazole 1 with o-substituted anilines and azoles promoted by carbon
disulfide have been carried out. Ab initio MO calculations were used to elucidate the mechanism of the reaction
of 1 with N-nucleophilic reagents. A facile synthesis of 2-(4,5-dihydroimidazol-2-yl)-1H-indazole 3e bearing
structural resemblances to 2-BFI, a potent and selective agonist of imidazoline I2 receptors, is also described.
Structure of 3e was confirmed by NMR spectroscopy and X-ray analysis.
Key words 2-chloro-4,5-dihydroimidazole; carbon disulfide; nucleophilic substitution; N-nucleophiles; 2-(4,5-dihydroimidazol-
2-yl)-1H-indazole; X-ray analysis
2-Chloro-4,5-dihydroimidazole 1 was first synthesized by (4,5-dihydroimidazol-2-yl-azoles 3,14) diimidazo[2,1-b:1Ј,2Ј-
Trani and Belasio in 19741) and since then has been widely e][1,3,5]thiadiazine-5-thione 4,15) 1-heteroaryl-imidazolili-
used for the synthesis of various 2-imidazoline derivatives of dine-2-ones 5,16) pyrido[1,2-a]diimidazo[1Ј,2Ј-c:1Љ,2Љ-e]-
pharmacological importance as exemplified in Chart 1. Dis- [1,3,5]triazines 6,17) imidazol-2-ylideneamino-hexa-1,3,5-
placement of the chlorine with nucleophilic reagents such as triene-1,1-dicarbonitriles 7,18) imidazo[1,2-a]pyrimidines 819)
amines, hydroxylamines, phenols and thiophenols leads to and imidazo[1,2-a][1,3,5]triazine-2,4-dithione 920) (Chart 1).
the formation of 2-substituted products 2.1—10) Compounds
2-Chloro-4,5-dihydroimidazole 1 itself proved to be ex-
of this type, and especially 2-arylimino-imidazolidines are tremely unstable, and therefore, it has to be stored in the
known to interact with a-adrenergic receptors11) and the form of a hemisulfate or hydrochloride salt.1) The reactions
recently discovered imidazoline receptors.12) Clinical uses, of 1 with nucleophilic reagents should be carried out under
which explain the interest in new and better strategies for mild conditions (room temperature) and usually require 8—
the construction of these compounds, include: hypertension, 42 h for their completion.3,5,7) On the other hand, compound 1
modulation of pituitary hormone release, depression, possesses a nucleophilic centre at the N-3 nitrogen atom and
Alzheimer’s disease, Raynauld phenomenon, noninsulin-de- tends to react with one another giving rise to the formation of
pendent diabetes, obesity, and impotence.13) Recent research self-condensation products.1) Such a side reaction prevails
by our group using compound 1 includes syntheses of N- when a reaction of 1 with a weak nucleophile is carried out
Chart 1
To whom correspondence should be addressed. e-mail: saczew@farmacja.amg.gda.pl
© 2001 Pharmaceutical Society of Japan

1204
Vol. 49, No. 9
Chart 2
under vigorous conditions (elevated temperature).
Now we wish to describe carbon disulfide promoted reac-
tions of 1 with various N-nucleophilic reagents such as o-
substituted aromatic amines and azoles, which are high
yielding and much faster than the previously reported tech-
niques for preparation of the same compounds.
Results and Discussion
Our study was initiated by examining the reactivity of 1
with sterically hindered o-substituted anilines in the presence
of carbon disulfide. It has been previously reported that the
reaction of 1 with 2-(3,4,5-trimethoxyphenoxy)aniline re-
quired 42 h at room temperature to provide the desired aryl-
liminoimidazolidine 2a.3) We found that the same reaction
could be accomplished within 3 h by using of 0.13 molar
equivlent of carbon disulfide and afforded 2a in good yield.
Analogous reaction of 1 with o-phenylenediamine proceeded
exothermically and required 0.5 h for its completion (Chart
2).
The compound 1 does not react with azoles such as imida-
zole, benzimidazole, pyrazole, benzotriazole or indazole, due
to the fact that the nucleophilicity of azoles towards 1 is low.
We previously succeeded in synthesizing N-(4,5-dihydro-imi-
dazol-2-yl)azoles by making use of the reaction of 1 with
azole adducts to aliphatic aldehydes.14) However, in this
method the reaction with benzotriazole or indazole hemiami-
nal the mixtures of benzotriazol-1-yl and benzotriazol-2-yl as
well as indazol-1-yl and indazol-2-yl isomers are formed. A
similar pattern was also observed in other N-alkylation reac-
tions of these heterocycles.21)
Chart 3
Previously we found that the compound 1 reacts with car-
bon disulfide in the presence of triethylamine to give diimi-
dazo[2,1-b:1Ј,2Ј-e][1,3,5]thiadiazine 4.15) We proposed that
in this process the imidazothiazetedine A is formed tran-
siently and subsequently reacts with a second molecule of 1
yielding the cyclic derivative 4 (Chart 3). However, when the
reaction of 1 with carbon disulfide is carried out in the pres-
ence of an azole, instead of triethylamine, no product of type
C is formed (Chart 3).
To elucidate the mechanism of the reaction of 1 with
azoles, we estimated the possible reactivity of the intermedi-
ate A with 1 and indazole using ab initio MO calculations.22)
Atomic charges, electrostatic potentials and absolute values
of HOMO and LUMO mapped on the van der Waals contact
surfaces are shown in Fig. 1.
As seen, the carbon atom C-2 in A (LUMOϭ0.305 a.u.) is
more active than the C-4 (LUMOϭ0.0118 hartree), and
therefore, the orbital-controlled reaction with N-3 nitrogen
atom of 1 (HOMOϭ0.0277 a.u.) is possible. On the other
hand, the possibility of electrostatically-controlled reaction at
C-2 of A is belived to be very low due to its negative charge.
Analogous reaction of the intermediate A with indazole
leading to compound C (Chart 3) was not observed in spite
of the large coefficient value in the HOMO at N-1 nitrogen
We now have used carbon disulfide as catalyst and found
that the reaction of 1 with azoles is very general and in all
cases the N-substituted azoles were obtained as a one posi-
tional isomer (Chart 2). Thus, with respect to benzotriazole
and indazole, the heteroalkylation process was found to be
completely regioselective in nature and no N-2 substituted
benzotriazole or N-1 substituted indazole derivative was iso-
lated.
It is worth noting that several different Lewis acids (e.g.
BF3·Et2O or TiCl4) were surveyed, but all failed to induce
the nucleophilic substitution of chlorine by azole.

September 2001
1205
Fig. 1
Fig. 2. ORTEP Drawing of 3e
Chart 4
atom (HOMOϭ0.056 a.u.). Therefore, as a possible mecha-
nism for the above discussed reaction we can advance the hy-
pothesis that 1 reacts with azoles to yield the general adduct
D which, in turn, undergoes further stabilization with con-
cominant release of carbon disulfide and formation of prod-
uct 3 as depicted in Chart 4. Carbon disulfide accelerates the
reaction mainly by stabilization of the intermediate D which
contains the electron stabilizing dithiocarbamate group. In
absence of carbon disulfide, this stabilization is lost and the
barrier for the reaction is higher.
It is pertinent to note that the newly prepared indazole de-
rivative 3e represents an interesting analog of 2-(4,5-dihy-
droimidazol-2-yl)benzofurane (2-BFI) which is known to
be a potent and selective agonist of the imidazoline I2 recep-
tors.23) The structure of 3e has been confirmed using spectro-
scopic data and by X-ray analysis (Fig. 2).
Fig. 3. Ab initio 3-D Electrostatic Potential Isocontoured at Ϫ20 kcal/mol
for the 6-31G** Optimized Structures of 2-BFI (Top) and 3e (Bottom)
1
An interesting feature of the H-NMR spectrum of 3e is
that heteroatoms in both 2-BFI and indazole analogue 3e are
surrounded by a negative envelope at Ϫ20 kcal/mol with
similar shape and the absolute minimum lying near the N-3
nitrogen atom of 2-imidazoline ring.
the presence of two distinct multiplets at 3.7 and 4.05 ppm
attributable to CH2–CH2 grouping of 2-substituted imidazo-
line ring. In 13C-NMR spectrum two signals at 45.79 and
54.57 ppm appear for the two corresponding carbon atoms.
Such a pattern is indicative of a strong intramolecular hydro-
gen bonding between imidazoline N–H group and indazole
N-1 atom in CDCl3 solution, which hinders the tautomeric
process within the amidine moiety. The E conformation of 3e
is further confirmed by a strong deshielding C3–H effect as
the signal for this proton appears at 8.74 ppm.
Experimental
Melting points (mp) were determined on a Buchi 535 apparatus without
correction. Infrared (IR) spectra (KBr pellet) were measured by a Perkin
Elmer FT-IR 1600. 1H- and 13C-Nuclear magnetic resonance (NMR) spectra
were obtained at ambient temperature with a Varian XL 200 spectropho-
tometer in DMSO-d6 or CDCl3, with tetramethylsilane as an internal stan-
dard. Compound 1 was obtained according to the procedure described in ref.
1.
The 3-D electrostatic potential maps (Fig. 3) clearly show

1206
Reaction of (1) with 2 (3,4,5-Trimethoxyphenoxy)aniline To a stirred
Vol. 49, No. 9
FϾ4s(F) [R1ϭ0.0354, wR2ϭ0.0835 for all 858 independent reflections].
solution of 1 (2.5 g, 24 mmol) in CH2Cl2 (30 ml) was added carbon disulfide
(0.2 ml, 3.3 mmol) and 2-(3,4,5-trimethoxyphenoxy)aniline (6.5 g, 24
mmol). After the slightly exothermic reaction had subsided (3 h), the reac-
tion mixture was treated with Et2O (10 ml) and the solid that precipitated
was collected by filtration. Then, the crude hydrochloride was dissolved in
water (15 ml) and the solution was made alkaline (pHϭ10) with 10% aque-
ous NaOH followed by extraction with CH2Cl2. After evaporation of solvent,
the compound 2a thus obtained was purified by crystallization from ethyl
acetete/ethanol. Yield: 5.3 g, 65%; mp 146—149 °C (ref. 3, mp 147—
150 °C).
Acknowledgements The study was supported in part by the Polish State
Committee for Scientific Research , grant No. 6P05F03821 (FS and MG).
References and Notes
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Reaction of (1) with o-Phenylenediamine A solution of 1 (2.5 g, 24
mmol) in CH2Cl2 (30 ml) was treated with carbon disulfide (0.2 ml, 3.3
mmol) and the reaction mixture was stirred for 5 min at room temperature.
Then, o-phenylenediamine (2.6 g, 24 mmol) was added and stirring was con-
tinued untill the vigorous exothermic reaction had subsided (0.5 h). Solvent
was evaporated under reduced pressure and the oily residue was triturated
with acetone. The crude hydrochloride that precipitated was collected by fil-
tration, dissolved in water (10 ml) and the resulting solution was made alka-
line (pHϭ10) with 10% aqueous NaOH. The solid product obtained was
separated by suction, washed with cold water and purified by crystallization
from EtOH to give 2b (2.1 g, 61%), mp 156—158 °C (ref. 7, mp 155—
158 °C).
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2-(4,5-Dihydro-1H-imidazol-2-yl)-1H-indazole (3e) To a solution of 1
(2.5 g, 24 mmol) in CH2Cl2 (30 ml) was added carbon disulfide (0.2 ml, 3.3
mmol) and indazole (3.5 g, 30 mmol) and the reaction mixture was stirred at
room temperature for 6 h. The solid that precipitated was separated by suc-
tion and recrystallized from EtOH to give 3e·HCl (3.6 g, 67%); mp 141—
144 °C. IR nmax (KBr) cmϪ1: 3066, 2957, 2764, 1640, 1614, 1386, 1335,
10) Clark R. D., Spedding M., U.S. Patent 5726197 [Chem. Abstr. 128,
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1
1292, 1254, 1207, 1126, 1032. H-NMR (200 MHz, DMSO-d6) d: 4.08 (s,
4H, CH2), 7.25 (t, 1H, arom.), 7.5 (t, 1H, aromat.), 7.75 (d, 1H, aromat.),
7.85 (d, 1H, arom.), 9.57 (s, 1H, arom.), 11.55 (br s, 2H, NH). Free base 3e
was obtained by treatment of an aqueous solution of the hydrochloride de-
scribed above with 10% aqueous NaOH at 5 °C and recrystallization of the
resulting precipitate from acetone; mp 131—132 °C. IR nmax (KBr)
cmϪ1: 3248, 3132, 2874, 1634, 1531, 1446, 1380, 1308, 1287, 1234, 1099.
1H-NMR (200 MHz, CDCl3) d: 3.7 (m, 2H, CH2), 4.05 (m, 2H, CH2), 6.13
(br s, 1H, NH), 7.05 (m, 1H, aromat.) 7.3 (m, 1H, aromat.), 7.65 (d, 2H, aro-
mat.), 8.74 (s, 1H, aromat.). 13C-NMR (50 MHz, CDCl3) d: 45.79, 54.57,
118.46, 121.64, 122.59, 123.79, 128.67, 150.23, 157.18. According to the
above procedure were obtained compounds 3a—d. Physicochemical and
spectroscopic data of these compounds were in agreement with those de-
scribed in ref. 14.
14) Katritzky A. R., Sa¸czewski F., Synthesis, 1990, 561—563.
15) Sa¸czewski F., Gdaniec M., J. Chem. Soc. Perkin Trans. I, 1992, 47—50.
16) Sa¸czewski F., Synthesis, 1984, 170—172.
17) Sa¸czewski F., Foks H., Synthesis, 1981, 154—155.
/
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Trans. I, 1987, 1033—1037.
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20) Sa¸czewski F., Gdaniec M., Liebigs Ann. Chem., 1987, 721—724.
21) Palmer M. H., Findlay R. H., Kennedy S. M. F., McIntyre P. S., J.
Chem. Soc. Perkin Trans. II, 1975, 1695—1700.
22) The structures of 1, A and indazole were fully optimized without any
symmetry restrictions in the gas phase. Assignment of atomic charges
and obtaining graphs that show the absolute values of the electrostatic
potential, values of the HOMO and LUMO on the electron density iso-
surface corresponding to a van der Waals contact surface were per-
formed using an ab initio module (6-31G** basis set, direct Hartree-
Fock method) as implemented into SPARTAN v. 5.0 program installed
into a Silicon Graphics O2 workstation.
X-Ray Structure Determination The data were collected on a Ku-
maCCD diffractometer using graphite monochromatized MoKa (radiation
with detector distance of 6 cm. More than hemisphere of reciprocal space
was covered by a combination of four sets of exposures; each set had a dif-
ferent j-angle (0, 90, 180, 270) and each exposure of 30 s covered 0.75 (in
w. Coverage of the unique set is over 99% complete. The collected data
were reduced using the program KM4RED.24) The structure was solved by
direct methods with the program SHELXS-9725) and refined by full-matrix
least-squares method on F2 with SHELXL-97.26) Hydrogen atoms have been
located on DF maps and refined with isotropic displacement parameters.
Crystal Data for 3e: C10H10N4, orthorhombic, Pca21, aϭ11.899 (2) Å,
23) Hudson A. L., Mallard N. J., Nutt D. J., Chapleo C. B., Brit. J. Phar-
macol., 114, 411P (1995).
/
24) KUMA Diffraction, KM4RED, Version 1.166, Wroclaw, Poland
(2000).
25) Sheldrick G. M., SHELXS-97. Program for the solution of crystal
structures, Univ. of Göttingen, Germany, 1997.
26) Sheldrick G. M., SHELXL-97. Program for the refinement of crystal
structures, Univ. of Götingen, Germany, 1997.
bϭ7.980 (2) Å, cϭ9.681 (2) Å, Vϭ919.2 (3) Å3, Zϭ4, Dxϭ1.346 g cmϪ3
,
mϭ0.087 mmϪ1. The structure was refined on 858 reflections; 168 refined
parameters; R1ϭ0.0334, wR2ϭ0.0816, GOFϭ1.048 for 818 reflections with