Mild and efficient one-pot synthesis of 2-imidazolines from nitriles using sodium hydrosulfide as catalyst

Article abstract of DOI:10.1080/00397910802109232

A simple and efficient method has been developed for the synthesis of 2-imidazolines through a one-pot reaction of various nitriles with ethylenediamine in the presence of sodium hydrosulfide as catalyst in high yield. Copyright Taylor & Francis Group, LLC.

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Mild and Efficient One-Pot
Synthesis of 2-Imidazolines
from Nitriles Using Sodium
Hydrosulfide as Catalyst
Min Sun a , Hong-Tao Wei a , Dong Li a , You-Guang
Zheng a b c , Jin Cai a b c & Min Ji a b c
a School of Chemistry and Chemical Engineering,
Southeast University, Nanjing, China
b Key Laboratory of Biomaterials and Devices of
Jiangsu Province, Suzhou, China
c Key Laboratory of Biomaterials and Technology of
Suzhou City, Suzhou, China
Version of record first published: 09 Sep 2008.
To cite this article: Min Sun, Hong-Tao Wei, Dong Li, You-Guang Zheng, Jin Cai & Min
Ji (2008): Mild and Efficient One-Pot Synthesis of 2-Imidazolines from Nitriles Using
Sodium Hydrosulfide as Catalyst, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:18, 3151-3158
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Synthetic Communications1, 38: 3151–3158, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802109232
Mild and Efficient One-Pot Synthesis of
2-Imidazolines from Nitriles Using Sodium
Hydrosulfide as Catalyst
Min Sun,1 Hong-Tao Wei,1 Dong Li,1 You-Guang Zheng,1–3
Jin Cai,1–3 and Min Ji1–3
1School of Chemistry and Chemical Engineering, Southeast University,
Nanjing, China
2Key Laboratory of Biomaterials and Devices of Jiangsu Province, Suzhou, China
3Key Laboratory of Biomaterials and Technology of Suzhou City, Suzhou, China
Abstract: A simple and efficient method has been developed for the synthesis of
2-imidazolines through a one-pot reaction of various nitriles with ethylenedia-
mine in the presence of sodium hydrosulfide as catalyst in high yield.
Keywords: 2-imidazoline, nitrile, sodium hydrosulfide
Imidazoline derivatives exhibit significant biological and pharmacologi-
cal activities[1] including antihypertension, antihistamine, antihyperglyce-
mia, anti-inflammation, antidepression, and antitumor activities and
have stimulated considerable synthetic efforts on this heterocycle. More-
over, imidazoline units are also used as synthetic intermediates,[2] chiral
auxiliaries,[3] chiral catalysts,[4] and ligands for asymmetric catalysis[5]
in organic synthesis. Imidazolines are also the precursor for the
preparation of imidazoles, which are also found in many biological
compounds.[6] It is therefore of great importance that the synthesis of
2-imidazolines be achieved by an effective method.
To date, several methods have been reported for the synthesis of 2-
imidazolines from the precursors of carboxylic acids,[7] esters,[8] alde-
hydes,[9] orthoesters,[10] hydroximoylchlorides,[11] hydroxy amides,[12] and
benzimidate.[13] However, all these methods suffer from disadvantages
Received December 18, 2007.
Address correspondence to Min Ji, School of Chemistry and Chemical
Engineering, Southeast University, Nanjing, China. E-mail: jimin@seu.edu.cn
3151

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M. Sun et al.
such as long reaction time, low yields, difficulty in preparation of starting
materials, and tedious workup. According to other reports,
2-imidazolines have also been prepared from the nitriles in the presence
of various catalysts such as ammonium polysulfide,[14] sulfur under ultra-
sonic irradiation,[15] H2S,[16] or P2S5,[17] which are somewhat hazardous
or expensive, hindering their large-scale applications in industry. In pur-
suit of a simple, mild, and high-yield protocol, we investigated the trans-
formation of various nitriles into 2-imidazolines catalyzed by sodium
hydrosulfide. Although sodium hydrosulfide has already been implicated
in the synthesis of primary thioamides from nitriles,[18] surprisingly it has
not been fully explored for its potential in 2-imidazolines synthesis from
different substituted nitriles with respect to their position on the phenyl
ring, ortho, meta, and para positions, as well as to their electronic effects.
A series of different nitriles reacted with ethylenediamine in the
presence of sodium hydrosulfide as catalyst for the formation of the cor-
responding 2-imidazolines (Scheme 1). In the first series, the reaction of
different substituted benzonitriles were investigated. Various substituents
were chosen with respect to their positions on the phenyl ring, ortho,
meta, and para positions, as well as their electronic effects. The results
demonstrated that the position and electronic effects (electron-withdraw-
ing or electron-donating) of the substituents on the phenyl ring do not
have any significant effect on the yield. The benzonitriles with a substitu-
ent such as CH3, OH, OCH3 (electron-donating), Cl and CF3 (electron-
withdrawing) underwent the cyclocondensation smoothly to form the
corresponding 2-imidazolines in high yields (Table 1). Moreover, sub-
strates with hydroxy (entry 4) or trifluoromethyl group (entry 8) could
be quantitatively converted to the corresponding imidazolines, respect-
ively. However, the protocol is not very applicable to the nitriles with
dipolar substituents such as NO2, COOH, and OCOCH3, yielding crude
products too complex for any pure compound(s) to be isolated (Table 1),
which may be attributed to side reactions with nitro and acid=ester
groups. Furthermore, the reaction of heterocyclic nitriles such as
thiophene-2-carbonitrile and 3-cyanopyridine were also investigated,
and the results obtained are in accordance with those of benzonitriles,
shown in Table 1.
A plausible explanation is that sodium hydrosulfide reacts with the
nitrile grove to produce a thioamide. The thioamide then reacts with
Scheme 1. Synthesis of 2-imidazolines using sodium hydrosulfide as a catalyst.

Synthesis of 2-Imidazolines
3153
Table 1. Reaction of nitriles with ethylenediamine in the presence of sodium
hydrosulfide
Entry
Ar
Yield (%)a
Mp (ꢀC)
Ref. mp (ꢀC)
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H5
4-CH3C6H4
4-CH3OC6H4
4-HOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-F3CC6H4
2-Thienyl
3-Pyridyl
89
91
90
96
85
89
86
95
100–101
182–184
138–139
295–296
189–190
138–139
69–70
188–189
180–181
110–111
—
101[16]
181–182[9a]
136–138[9a]
290–292[13]
188[15]
138[14]
69[14]
180[17]
86
88
178[9c]
111–113[15]
235–237[9a]
—
4-O2NC6H4
4-HO2CC6H4
4-CH3COOC6H4
Not isolatedb
Not isolatedb
Not isolatedb
—
—
—
aIsolated yield.
bCyclocondensation gave a complex mixture, and the desired 2-imidazoline
could not be isolated.
ethylenediamine, which upon eliminates ammonia and hydrogen sulfide
and produces the 2-imidazoline (Scheme 2).[16] Evolution of hydrogen
sulfide is evidence for the above statement. Reaction of benzonitrile with
a monoamine such as n-butylamine gave the corresponding thiobenza-
mide, which provided further evidence for the suggested mechanism.
On the other hand, 2-imidazoline can be synthesized by reaction of thioa-
mides and ethylenediamine.[15]
In conclusion, we have developed a mild, convenient method for the
synthesis of 2-imidazolines from nitriles without dipolar substituents such
as NO2, COOH, and OCOCH3. A catalytic amount of sodium sulfide
Scheme 2. Sodium hydrosulfide–catalysed transformation of nitriles to
2-imidazolines.

3154
M. Sun et al.
promotes the reactions to effectively give the products in high yields. The
present methodology may meet the economical and environmental
concerns in the current realm of chemistry.
EXPERIMENTAL
Melting points were determined on an RY-1 hot-stage microscope, and
1
the thermometer was uncorrected. H NMR spectra were recorded on
a Bruker Avance DPX 300=500-MHz instrument in CDCl3 or CD3OD,
and chemical shifts (d) were reported in parts per million (ppm) relative
to TMS as an internal standard. Mass spectra were recorded on Aglient
1100 LC-MS. Elementary analyses were performed on Elementar Vario
EL III instrument. All reactions were monitored by thin-layer chromato-
graphy (TLC) on silica-gel 60F-254 glass plates (E.Merk).
General Procedure for Preparation of 2-Imidazolines
A mixture of nitrile (20 mmol), 70% sodium hydrosulfide hydrate
(2 mmol), and ethylenediamine (20 mL) was refluxed with stirring for
1.5–2 h. The resulting mixture was poured into ice water, and the aqueous
layer was extracted with CH2Cl2 (3 ꢁ 50 mL). The combined CH2Cl2
extracts were washed with water (1 ꢁ 50 mL) and brine (1 ꢁ 50 mL) and
then dried with anhydrous Na2SO4. After the solvent was evaporated,
the corresponding 2-imidazoline was finally purified by recrystallization
with acetic ester and methanol.
Data
2-Phenylimidazoline (Table 1, entry 1)
1H NMR (300 MHz, CDCl3): d 3.78 (s, 4H, 2CH2), 4.78 (br s, 1H, NH),
7.39–7.45 (m, 3H, ArH), 7.76–7.80 (m, 2H, ArH); MS: m=z ¼ 147
[M þ H]þ. Anal. calcd. for C9H10N2: C, 73.94; H, 6.89; N, 19.16. Found:
C, 73.78; H, 7.06; N, 19.20.
2-(4-Methylphenyl)imidazoline (Table 1, entry 2)
1H NMR (500 MHz, CDCl3): d 2.37 (s, 3H, CH3), 3.76 (s, 4H, 2CH2),
4.76 (br s, 1H, NH), 7.20 (d, J ¼ 8.3 Hz, 2H, ArH), 7.66 (d, J ¼ 8.3 Hz,
2H, ArH); MS: m=z ¼ 161 [M þ H]þ. Anal. calcd. for C10H12N2: C,
74.97; H, 7.55; N, 17.48. Found: C, 74.72; H, 7.57; N, 17.46.

Synthesis of 2-Imidazolines
3155
2-(4-Methoxyphenyl)imidazoline (Table 1, entry 3)
1H NMR (300 MHz, CDCl3): d 3.74 (s, 4H, 2CH2), 3.83 (s, 3H, CH3O),
4.94 (br s, 1H, NH), 6.89 (d, J ¼ 8.8 Hz, 2H, ArH), 7.72 (d, J ¼ 8.8 Hz,
2H, ArH); MS: m=z ¼ 177 [M þ H]þ. Anal. calcd. for C10H12N2O: C,
68.16; H, 6.86; N, 15.90. Found: C, 67.89; H, 6.88; N, 16.04.
2-(4-Hydroxyphenyl)imidazoline (Table 1, entry 4)
1H NMR (500 MHz, CD3OD): d 3.90 (s, 4H, 2CH2), 6.60 (dd, J ¼ 7.0
and 2.0 Hz, 2H, ArH), 7.51 (dd, J ¼ 7.0 and 2.0 Hz, 2H, ArH); MS:
m=z ¼ 163 [M þ H]þ. Anal. calcd. for C9H10N2O: C, 66.65; H, 6.21; N,
17.27. Found: C, 66.46; H, 6.36; N, 17.37.
2-(4-Chlorophenyl)imidazoline (Table 1, entry 5)
1H NMR (300 MHz, CDCl3): d 3.78 (s, 4H, 2CH2), 4.73 (br s, 1H, NH),
7.37 (d, J ¼ 8.5 Hz, 2H, ArH), 7.71 (d, 2H, J ¼ 8.5 Hz, ArH); MS:
m=z ¼ 181 [M þ H]þ. Anal. calcd. for C9H9ClN2: C, 59.84; H, 5.02; N,
15.51. Found: C, 59.81; H, 5.18; N, 15.38.
2-(3-Chlorophenyl)imidazoline (Table 1, entry 6)
1H NMR (300 MHz, CDCl3): d 3.79 (s, 4H, 2CH2), 4.76 (br s, 1H, NH),
7.28–7.62 (m, 4H, ArH); MS: m=z ¼ 181 [M þ H]þ. Anal. calcd. for
C9H9ClN2: C, 59.84; H, 5.02; N, 15.51. Found: C, 59.71; H, 5.14; N,
15.44.
2-(2-Chlorophenyl)imidazoline (Table 1, entry 7)
1H NMR (300 MHz, CDCl3): d 3.76 (s, 4H, 2CH2), 5.20 (br s, 1H, NH),
7.27–7.37 (m, 3H, ArH), 7.74 (dd, 1H, J ¼ 7.2 and 2.1 Hz, ArH); MS:
m=z ¼ 181 [M þ H]þ. Anal. calcd. for C9H9ClN2: C, 59.84; H, 5.02; N,
15.51. Found: C, 59.77; H, 4.92; N, 15.62.
2-(4-Trifluoromethylphenyl)imidazoline (Table 1, entry 8)
1H NMR (300 MHz, CDCl3): d 3.81 (s, 4H, 2CH2), 4.85 (br s, 1H, NH),
7.65 (d, J ¼ 8.3 Hz, 2H, ArH), 7.88 (m, J ¼ 8.3 Hz, 2H, ArH); MS:

3156
M. Sun et al.
m=z ¼ 215 [M þ H]þ. Anal. calcd. for C10H9F3N2: C, 56.08; H, 4.24; N,
13.08. Found: C, 55.82; H, 4.22; N, 13.01.
2-(2-Thienyl)imidazoline (Table 1, entry 9)
1H NMR (300 MHz, CDCl3): d 3.77 (s, 4H, 2CH2), 4.87 (br s, 1H, NH),
7.03–7.06 (m, 1H, ArH), 7.35–7.40 (m, 2H, ArH), MS: m=z ¼ 153
[M þ H]þ. Anal. calcd. for C7H8N2S: C, 55.23; H, 5.30; N, 18.40. Found:
C, 55.03; H, 5.33; N, 18.53.
2-(3-Pyridyl)imidazoline (Table 1, entry 10)
1H NMR (300 MHz, CDCl3): d 3.41 (s, 4H, 2CH2), 4.89 (br s, 1H, NH),
7.32–7.37 (m, 1H, ArH), 8.10–8.14 (m, 1H, ArH), 8.66–8.68 (m, 1H,
ArH), 8.97–8.98 (m, 1H, ArH); MS: m=z ¼ 148 [M þ H]þ. Anal. calcd.
for C8H9N3: C, 65.29; H, 6.16; N, 28.55. Found: C, 65.17; H, 6.31; N,
28.41.
REFERENCES
1. (a) Greenhill, J. V.; Lue, L. Progress in Medicinal Chemistry; Elsevier: New
York, 1993; Vol. 3; (b) Hardman, J. G.; Limbird, L. E.; Gilman, A. G.
The Pharmacological Basis of Therapeutics, 10th ed.; Macmillan: New York,
2001; (c) Prisinzano, T.; Law, H.; Dukat, M.; Slassi, A.; MaClean, N.;
Demchyshyn, L.; Glennon, R. A. Imidazoline-modified benzylimidazolines
as h5-HT1D=1B serotonergic ligands. Bioorg. Med. Chem. 2001, 9, 613–619;
(d) Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.;
Rettori, M.-C.; Renard, P.; Merour, J.-Y. Synthesis and biological evaluation
of new 2-(4,5-dihydro-1H-imidazol-2-yl)-3,4-dihydro-2H-1,4-benzoxazine
derivatives. J. Med. Chem. 2003, 46, 1962–1979.
2. (a) Jones, R. C. F.; Nichols, J. R. Thiamine coenzyme models: Imidazolinium
ylides and the reactions of 2-(hydroxyalkyl)imidazolines. Tetrahedron Lett.
1990, 31, 1771–1774; (b) Jung, M. E.; Huang, A. Use of optically active cyclic
N,N.-dialkyl aminals in asymmetric induction. Org. Lett. 2000, 2, 2659–2661.
3. Dalko, P. I.; Langlois, Y. Stereoselective synthesis of quaternary benzylic car-
bons using C2 symmetric imidazolines and tetrahydrofuran as electrophile. J.
Org. Chem. 1998, 63, 8107–8117.
4. Corey, E. J.; Grogan, M. J. Enantioselective synthesis of a-amino nitriles
from N-benzhydryl imines and HCN with a chiral bicyclic guanidine as cata-
lyst. Org. Lett. 1999, 1, 157–160.
ꢀ
5. (a) Bastero, A.; Claver, C.; Ruiz, A.; Castillon, S.; Daura, E.; Bo, C.;
Zangrando, E. Insights into CO=styrene copolymerization by using PdII cat-
alysts containing modular pyridine-imidazoline ligands. Chem.-Eur. J. 2004,

Synthesis of 2-Imidazolines
3157
10, 3747–3760; (b) Menges, F.; Neuburger, M.; Pfaltz, A. Synthesis and
application of chiral phosphino-imidazoline ligands: Ir-catalyzed enantiose-
lective hydrogenation. Org. Lett. 2002, 4, 4713–4716.
6. (a) Haneda, S.; Okui, A.; Ueba, C.; Hayashi, M. An efficient synthesis of
2-arylimidazoles by oxidation of 2-arylimidazolines using activated carbon–
O2 system and its application to palladium-catalyzed Mizoroki–Heck
reaction. Tetrahedron 2007, 63, 2414–2417; (b) Anastassiadou, M.; Baziard-
Mouysset, G.; Payard, M. New one-step synthesis of 2-Aryl-1H-imidazoles:
Dehydrogenation of 2-aryl-D2-imidazolines with dimethylsulfoxide. Syn-
thesis 2000, 13, 1814–1816; (c) Mohammadpoor-Baltork, I.; Zolfigol, M.
A.; Abdollahi-Alibeik, M. Novel and chemoselective dehydrogenation of
2-substituted imidazolines with potassium permanganate supported on silica
gel. Tetrahedron Lett. 2004, 45, 8687–8690; (d) Amemiya, Y.; Miller, D. D.;
Hsu, F. L. Dehydrogenation of imidazolines to imidazoles with Pd-carbon.
Synth. Commun. 1990, 20, 2483–2489.
7. Vorbruggen, H.; Krolikiewicz, K. A simple synthesis of D2-oxazolines, D2-
¨
oxazines, D2-thiazolines and D2-imidazolines. Tetrahedron Lett. 1981, 22,
4471–4474.
8. Neef, G.; Eder, U.; Sauer, G. One-step conversions of esters to 2-imidazo-
lines, benzimidazoles and benzothiazoles by aluminum organic reagents. J.
Org. Chem. 1981, 46, 2824–2826.
9. (a) Ishihara, M.; Togo, H. Direct oxidative conversion of aldehydes and alco-
hols to 2-imidazolines and 2-oxazolines using molecular iodine. Tetrahedron
2007, 63, 1474–1480; (b) Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita,
Y. One-pot synthesis of imidazolines from aldehydes: Detailed study about
solvents and substrates. Tetrahedron 2007, 63, 638–643; (c) Gogoi, P.;
Konwar, D. An efficient and one-pot synthesis of midazolines and benzimi-
dazoles via anaerobic oxidation of carbonꢂnitrogen bonds in water. Tetra-
hedron Lett. 2006, 47, 79–82.
10. Hill, A. J.; Johnston, J. V. Admidines derived from ethylenediamine, II:
Imidazolines. J. Am. Chem. Soc. 1954, 76, 922–923.
´
11. Salgado-Zamora, H.; Campos, E.; Jimenez, R.; Cervantes, H. On the
reactivity of hydroximoyl chlorides: Preparation of 2-Arylimidazolines.
Heterocycles 1998, 47, 1043–1049.
12. Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Smyth, M. P. A
novel general route for the preparation of enantiopure imidazolines. J.
Org. Chem. 2002, 67, 3919–3922.
13. Spychala, J. 4-(Cyclic-amidino)phenols: Preparation and use in a diamidine
synthesis. Synth. Commun. 2000, 30, 1083–1094.
14. Crane, L. J.; Anastassiadou, M.; Stigliani, J.; Baziard-Mouysset, G.; Payard,
M. Reactions of some ortho and para halogenated aromatic nitriles with
ethylenediamine: Selective synthesis of imidazolines. Tetrahedron 2004, 60,
5325–5330.
15. Mirkhani, V.; Moghadam, M.; Tangestaninejada, S.; Kargar, H. Rapid and
efficient synthesis of 2-imidazolines and bis-imidazolines under ultrasonic
irradiation. Tetrahedron. Lett. 2006, 47, 2129–2132.

3158
M. Sun et al.
16. Levesque, G.; Gressier, J.-C.; Proust, M. 4,5-Dihydroimidazoles from dithio-
carboxylic esters, thiocarboxamides, or nitriles. Synthesis 1981, 1981,
963–965.
17. Anasatassiadou, M.; Danoun, S.; Crane, L.; Baziard-Mouysset, G.; Payard,
M.; Caignard, D. H.; Rettori, M. C.; Renard, P. Synthesis and pharmacologi-
cal evaluation of imidazoline sites I1 and I2 selective ligands. Bioorg. Med.
Chem. 2001, 9, 585–592.
18. Akira, M.; Masakazu, S. Synthesis of aromatic thioamide from nitrile
without handling of gaseous hydrogen sulfide. Synth. Commun. 2005, 35,
761–764.