Reactions of 2,3-diaryl-1-methyl-4,5-dihydroimidazolium iodides with nucleophilic reagents

Article abstract of DOI:10.1081/SCC-120003644

2,3-Diaryl imidazolium salts, represented by 1 and 2, reacted with 2-ethanolamine or ethylenediamine to produce 2-aryl oxazolines or imidazolines 5-8 respectively. Their hydrolysis resulted in ring-opened ethylenediamine derivatives 9 and 10. The reduction of 1 and 2 produced partially reduced imidazolidines 11, 12 and 11 reacted further with tryptamine to provide 2,3,4,9-tetrahydro-1-phenyl 1H-pyrido[3,4-b]indole, 13. In all these reactions one-carbon units were successfully transferred to the nucleophilic acceptors, which mimic the one-carbon unit transfer function for tetrahydrofolate coenzymes.

Full text of DOI:10.1081/SCC-120003644

This article was downloaded by: [North Dakota State University]
On: 22 October 2014, At: 19:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
REACTIONS OF 2,3-DIARYL-1-METHYL-4,5-
DIHYDROIMIDAZOLIUM IODIDES WITH NUCLEOPHILIC
REAGENTS
Chizhong Xia a , Junsheng Hao a , Yiqing Tang a , Yanping Ni a & Peiwen Zhou a
a Department of Chemistry , Shanxi University , Taiyuan, 030006, China
Published online: 17 Aug 2006.
To cite this article: Chizhong Xia , Junsheng Hao , Yiqing Tang , Yanping Ni & Peiwen Zhou (2002) REACTIONS OF 2,3-DIARYL-1-
METHYL-4,5-DIHYDROIMIDAZOLIUM IODIDES WITH NUCLEOPHILIC REAGENTS, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:9, 1457-1464, DOI: 10.1081/SCC-120003644
To link to this article: http://dx.doi.org/10.1081/SCC-120003644
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 32(9), 1457–1464 (2002)
REACTIONS OF 2,3-DIARYL-1-METHYL-
4,5-DIHYDROIMIDAZOLIUM IODIDES
WITH NUCLEOPHILIC REAGENTS
*
Chizhong Xia, Junsheng Hao, Yiqing Tang,
Yanping Ni, and Peiwen Zhouy
Department of Chemistry, Shanxi University,
Taiyuan, 030006, China
ABSTRACT
2,3-Diaryl imidazolium salts, represented by 1 and 2, reacted
with 2-ethanolamine or ethylenediamine to produce 2-aryl
oxazolines or imidazolines 5–8 respectively. Their hydrolysis
resulted in ring-opened ethylenediamine derivatives 9 and 10.
The reduction of 1 and 2 produced partially reduced imid-
azolidines 11, 12 and 11 reacted further with tryptamine to
provide 2,3,4,9-tetrahydro-1-phenyl 1H-pyrido[3,4-b]indole,
13. In all these reactions one-carbon units were success-
fully transferred to the nucleophilic acceptors, which mimic
the one-carbon unit transfer function for tetrahydrofolate
coenzymes.
*Current address: Department of Chemistry, University of Surrey, Guildford, Surrey
GU2 5XH UK.
yCorresponding author. Current address: Prolinx, Inc. 22322 20th AVE. SE, Bothell,
WA 98021, USA.
1457
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1458
XIA ET AL.
2,3-Diaryl dihydroimidazolium salts have a unique resonance C(2)
cation center between N(1) and N(3) in their imidazolium ring (Figure 1).
The imidazolium C(2) has exceptionally high susceptibility to nucleophilic
attack by sutiable nucleophiles, and can potentially be used to transfer one-
carbon units to nucleophilic acceptors as vehicles to mimic N(5), N(10)-
methyl-tetrahydrofolate coenzyme.1 Encouraged by our previous results on
this subject,2–5 we reasoned that the nucleophilic reactivity of their resonance
C(2) cation could be optimized by preparation of this dihydroimidazolium
salts with various N(1) and N(3) substituents. N(5), N(10)-methyenyl- or N(5),
N(10)-methylene-tetrahydrofolate coenzymes in biological systems promote
biochemical transfer of one-carbon unit at the oxidation level of formate
and formaldehyde. By mimicking the natural cofactor, some dihydro-
imidazolium salts, in which the transferable one-carbon unit is linked to
N(1), N(3) with different electronic properties, and related derivatives have
been studied.6 1-Methyl-3-(4-nitrophenyl)-2-phenyl-4,5-dihydroimidazolium
iodide 1 and 3-(4-methoxyphenyl)-1-methyl-2-(4-nitrophenyl)-4,5-dihydro-
imidazolium iodide 2, which have methoxy and nitro substituents on
the 2,3-diaryl groups, respectively, were designed as model compounds cap-
able of transferring benzylidyne or 4-nitrobenzylidyne units, to adjust the
reactivity of the imidazolium C(2). Their nucleophilic reactivity and ability
to transfer one-carbon units by analogy to the cofactor are presented.
The preparation of imidazolium 1 was conducted as previously
described.2
3-(4-methoxyphenyl)-1-methyl-2-(4-nitrophenyl)4,5-dihydro-
imidazolium iodide (2) was synthesized through a modification of
our previously reported method. 1-(4-Methoxyphenyl)-2-(4-nitrophenyl)-
4,5-dihydroimidazole (4) was prepared by the Bischler-Napieralski
Figure 1.

2,3-DIARYL DIHYDROIMIDAZOLIUM SALTS
1459
reaction: N-(2-chloroethyl)-4-nitrobenzamide (3) was converted into the cor-
responding imidochloride intermediate with phosphorous pentachloride,
then the imidazole 4 was obtained in the presence of 4-methoxyl aniline on
treatment with alkali.7 The imidazolium 2 precipitated immediately in the
nonpolar solvent upon gentle reflux of 4 with excess iodomethane in dry
benzene for an half hour (Scheme 1) in quantitative yield, rather than over-
night reflex in dichloromethane as reported.8,9
Scheme 1.
The reaction of the imidazolium salts 1 and 2 with bifunctional nucleo-
philic reagents such as 2-ethanolamine and ethylenediamine produced 2-aryl
oxazolines or 2-aryl imidazolines 5–8, respectively (Scheme 2). The reactions
with ethylenediamine were conducted readily at room temperature, while
the reaction with 2-ethanolamine required reflux in acetonitrile. These
simple reactions have demonstrated that the benzylidyne or 4-nitro-
benzylidyne groups as one-carbon units in 1 and 4 can be transferred to
suitable acceptors at mild conditions. The reaction of the imidazolium salts
1 and 2 with sodium hydroxide in aqueous ethanol solution resulted in
ring-opened products 9 and 10 (Scheme 2). This was similar to a previous
report on the hydrolysis of the imidazolium salts.8
Scheme 2.

1460
XIA ET AL.
Scheme 3.
The reduction of the imidazolium salts 1 and 2 with sodium boro-
hydride was performed in anhydrous ethyl alcohol with high yields
(Scheme 3), and interestingly the products were 1,2,3-trisubstituted imidazol-
idines 10 and 11; no ring-opened N0-aryl-N-benzyl-N-methyl ethylenedi-
amines were detected. Other 1,2-diaryl-1-methyl imidazolium iodides
without a nitro group on either phenyl ring afforded corresponding
N0-aryl-N-benzyl-N-methyl ethylenediamines.2,10 The strong nitro-electron
withdrawing group may have significant effect for the formation of the
imidazolidines.
The reaction of imidazoline 11 with tryptamine in acidic conditions
produced benzylidene transferred product 2,3,4,9-tetrahydro-1-phenyl-1H-
pyrido[3,4-b]indole 13, as a mimic reaction for the one-carbon unit transfer
function of N(5), N(10)-methylene-tetrahydrofolate at the oxidation level of
formaldehyde.
In summary, the reactions of both imidazolium salts 1 and 2 with
2-ethanolamine or ethylenediamine produced 2-aryl oxazolines or 2-aryl
imidazolines 5–8. Their hydrolysis resulted in ring-opened N0-aryl-N-
benzoyl-N-methyl ethylenediamines 9 and 10. Their reduction produced
partially reduced imidazolidones 11, 12 and 11 reacted with tryptamine to
provide 2,3,4,9-tetrahydro-1-phenyl 1H-pyrido[3,4-b]indole, 13. In all these
reactions benzylidyne or 4-nitrobenzylidyne, and benzyidene were success-
fully transferred to the nucleophilic acceptors as mimic reactions of the
one-carbon unit transfer function for tetrahydrofolate coenzymes at the
oxidation level of formate and formaldehyde. Further progress on this
topic will be reported in due course.
EXPERIMENTAL
Mass spectra were obtained on a JMS-D300 GC/MS spectrometer.
The 1H and 13C NMR were obtained on a JOEL FX-60Q, Varian

2,3-DIARYL DIHYDROIMIDAZOLIUM SALTS
1461
FT-80A or Bruker AC-P 300 MHz, with TMS as an internal standard.
Combustion analyses were performed on a Perkin-Elmer 240C instrument.
Infrared spectra were obtained on a Shimadzu IR-1700 spectrometer.
Melting points were uncorrected. All reactions were performed under an
inert atmosphere of nitrogen; all reagents and solvents were purified and
dried as required. The imidazolium 1 was synthesized as previously
reported.2 N-(2-Chloroethyl)-4-nitrobenzamide 3 was prepared by acylation
of 2-chloroethylamine monohydrochloride with p-nitrobenzoyl chloride.11
3-(4-Methoxyphenyl)-1-methyl-2-(4-nitrophenyl)-4,5-dihydroimidazolium
iodide (2):
A solution of 1-(4-methoxyphenyl)-2-(4-nitrophenyl)-4,5-
dihydroimidazole 4 (2.97 g, 10.0 mmol) in 10 ml dry benzene was gently
refluxed with iodomethane (14.2 g, 100.0 mmol) for 30 min. A precipitate
was observed after cooling to room temperature. The precipitate was col-
lected by vacuum filtration, and recrystallized from anhydrous ethanol to
yield 4.17 g (95%) of 2 as a yellow powder, m.p. 236–237ꢀC. 1H NMR
(CDCl3): 3.20 (s, 3H), 3.70 (s, 3H), 4.60 (s, 4H), 6.70–7.50 (q, 4H), 8.20 (s,
4H). 13C NMR (CDCl3): 162.8, 156.0, 148.8, 130.9, 127.5, 123.1, 114.0, 54.6,
52.7, 50.8, 34.7. IR (KBr): n 1640 cmꢁ1; MS: m/z 312 (molecular ion), 297,
162, 149, 142. Anal. calcd for C17H18N3O3: C, 46.24; H, 4.10; N, 9.48. Found,
C, 46.48; H, 4.13; N, 9.56.
1-(4-Methoxyphenyl)-2-(4-nitrophenyl)-4,5-dihydroimidazole (4): To a
stirred solution of phosphorus pentachloride (11.50 g, 55.2 mmol) in 50 ml
dry benzene was added N-(2-chloroethyl)-4-nitrobenzamide 3 (11.40 g,
49.4 mmol) at room temperature. The reaction mixture was allowed to
warm gently and refluxed for an additional 30 min. The solvent and phos-
phorus oxychloride were removed in vacuo, then the residue was dissolved
in 250 ml water and decolorized with charcoal, filtered and the filtrate was
rendered basic with 70 ml of concentrated ammonium hydroxide. The sus-
pension was extracted with chloroform (3 ꢂ 20 ml), and the combined
organic layers were dried over anhydrous sodium sulfate, filtered and eva-
porated. The residue was triturated with hexanes to give 8.89 g (60%) of 4 as
a yellow powder, m.p. 85–87ꢀC. H NMR (CDCl3): 3.80 (s, 3H), 4.00 (s,
1
4H), 6.70 (s, 4H), 7.60–8.10 (q, 4H) ppm; IR (KBr): n 1618 cmꢁ1; MS: m/z
297 (molecular ion), 162, 148, 135. Anal. calcd for C16H15N3O3: C, 64.57; H,
5.04; N, 14.13. Found, C, 54.54; H, 5.07; N, 13.97.
2-Phenyl-2-oxazoline (5): To a stirred solution of the imidazolium 1
(820.0 mg, 2.0 mmol) in 10 ml of acetonitrile was added 2-ethanolamine
(0.40 ml, 6.0 mmol), and the reaction mixture was heated to reflux for 5 h.
After cooling to room temperature, the solvent was removed by evaporation
and the residue was purified by column chromatography (silica gel, gradient
Hexanes/EtOAc) to afford 200 mg (69%) of 5 as an oil. Spectroscopic data
of this compound were identical to reported values.12

1462
XIA ET AL.
2-Phenyl-2-imidazoline (6): To a stirred solution of the imidazolium 1
(820.0 mg, 2.0 mmol) in 20 ml dry acetonitrile was added ethylenediamine
(130 ml, 2.0 mmol). The reaction mixture was maintained at room tempera-
ture overnight. A white precipitate was observed and collected by vacuum
filtration; it was recrystallized from acetonitrile to offer 300 mg 2-phenyl-
1
2-imidazole hydroiodide. H NMR (DMSO-d6): 3.79 (s, 4H), 5.96 (br, 2H,
exchangeable), 7.59–7.79 (m, 5H). This iodide salt was dissolved in 2 ml
acetonitrile, and 10 ml 2 M sodium hydroxide solution was added. The
mixture was stirred for 3 h at room temperature. The emulsion was extracted
with chloroform (3 ꢂ 10 ml) and the combined organic layers were washed
with water (15 ml), and dried over anhydrous sodium sulfate. 2-Phenylimi-
dazoline 6 (150 mg, 52%) was obtained as white needles after evaporation,
m.p. 101–102ꢀC (acetonitrile), (lit.12 m.p. 100–101ꢀC). Spectroscopic data of
this compound were identical to reported values.13
2-(4-Nitrophenyl)-4,5-dihydroxazole (7): To a stirred solution of
the imidazolium 2 (878.0 mg, 2.0 mmol) in 10 ml acetonitrile was added 2-
ethanolamine (132.0 ml, 2.2 mmol). The reaction mixture was refluxed over-
night; white crystals were observed after cooling to room temperature. The
crystals were collected by vacuum filtration, and recrystallized from aceto-
nitrile to yield 192 mg (50%) of 7 as white crystals, m.p. 176–178ꢀC
(lit.11 177–179ꢀC). Spectroscopic data of this compound were identical to
reported values.14
2-(4-Nitrophenyl)-4,5-dihydroimidazoline (8): To a stirred solution of
the imidazolium 2 (878.0 mg, 2.0 mmol) in 10 ml of acetonitrile was added
ethylenediamine (145 ml, 2.2 mmol). The reaction mixture was stirred for 4 h
at room temperature and a yellowish precipitate was observed. The solid
was collected by vacuum filtration and recrystallized with acetonitrile to
yield 374 mg (98%) of 8 as a yellowish powder, m.p. 105–106ꢀC, (lit.12
m.p. 104–106ꢀC). Spectroscopic data of this compound were identical to
reported values.15
General Procedure for the Hydrolysis of the Imidazolium 1 and 2,
N-Methyl-N-(4-nitrobenzoyl)-N0-(4-methoxyphenyl)
Ethylenediamine (10) as an Example
To a stirred solution of the imidazolium 2 (0.50 g, 1.14 mmol) in 20 ml
ethanol was added 20 ml 5% of NaOH solution. The reaction mixture was
stirred for 3 h at room temperature, and an orange precipitate was observed.
The solid was collected by vacuum filtration, washed with water, dried,
then recrystallized with ethanol to yield 323 mg (86%) of 10 as a yellow
powder, m.p. 106–107ꢀC. H NMR (CDCl3): 2.94 (s, 3H), 3.22 (br, 1H),
1

2,3-DIARYL DIHYDROIMIDAZOLIUM SALTS
1463
3.43 (m, 4H), 3.73 (s, 3H), 6.29–6.59 (q, 4H), 7.36–8.02 (q, 4H); IR (KBr); n
3349, 1630 cmꢁ1; MS: m/z 329 (molecular ion). Anal. calcd for C17H19N3O4:
C, 62.00; H, 5.77; N, 12.76. Found: C, 61.56; H, 5.69; N, 12.58.
N-Methyl-N-benzoyl-N0-(4-nitrophenyl) ethylenediamine (9): This
compound was obtained as yellow crystals from the hydrolysis of the
imidazolium 1 (86%), m.p. 146–148ꢀC (lit.2 146–148ꢀC). The spectroscopic
data were identical to reported values.2
General Procedure for the Reduction of the Imidazolium
1 and 2, 1-Methyl-3-(4-nitrophenyl)-2-phenyl
Imidazolidine (11) as an Example
To a solution of the imidazolium 1 (1.230 g, 3.0 mmol) in 10 ml abso-
lute ethanol, sodium borohydride (480.0 mg) was added in one portion at
room temperature, and the reaction mixture was stirred for 1 h. Water
(30 ml) was added dropwise and continuously stirred until bubbling sub-
sided, then the product was extracted with chloroform (3 ꢂ 25 ml). The
combined organic layers were washed with water and dried over anhydrous
sodium sulfate. The solvent was removed to yield 820.0 mg (97%) of 11 as a
yellow solid, m.p. 79–81ꢀC, (lit.5 m.p. 79–81ꢀC). Spectroscopic data of this
compound were identical to reported values.8
1-(4-Methoxyphenyl)-3-methyl-2-(4-nitrophenyl) imidazolidine (12):
This compound was obtained as a reddish oil from reduction of the imid-
1
azolium 2 (75%). H NMR (CDCl3): 2.40 (s, 3H), 2.60–4.10 (m, 4H), 4.70
(s, 1H), 6.30–6.80 (q, 4H), 7.50–8.22 (q, 4H). IR (KBr): n 3073, 1607. Anal.
calcd for C17H19N3O3: C, 65.17; H, 6.07; N, 13.41. Found, C, 64.95; H,
6.07; N, 13.48.
2,3,4,9-Tetrahydro-1-phenyl 1H-pyrido[3,4-b]indole (13): To a solution
of 11 (820.0 mg, 2.9 mmol) in 15 ml acetonitrile, tryptamine (557.0 mg,
3.5 mmol) and 1 ml of concentrated hydrochloride acid were added. The
reaction mixture was refluxed under nitrogen for 12 h. The solvent was
removed by evaporation. Flash column (silica gel, gradient Hexane/EtOAc)
of the residual oil and further recrystallization with acetone produced
216 mg (30%) of 13 as yellow crystals. M.p. 164–166ꢀC, (lit.15 m.p.
165–166ꢀC). The spectroscopic data were identical to reported values.16
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation
of China, and the Natural Science Foundation of Shanxi Province, China.

1464
XIA ET AL.
REFERENCES
1. Matthews, R.G.; Drummond, J.T. Chem. Rev. 1990, 90, 1275.
2. Xia, C.; Zhou, P.; Ding, J. Chin. J. Chem. (Eng. Ed.) 1990, 333.
3. Xia, C.; Tang, Y.; Zhou, P. J. Heterocyclic Chem. 2000, 37, 1329.
4. Xia, C.; Kang;C.; Zhao, B.; Chen, J.; Wang, H.; Zhou, P. Synth.
Commun. 2000, 30, 3307.
5. Zhou, P.; Zhao, B.; Chen, J.; Wang, H.; Kang, C.; Xia, C. Heterocycles
2000, 53, 433.
6. Pandit, U.K. Pure & Appl. Chem. 1994, 17, 759.
7. Perillo, I.; Lamdan, S. J. Heterocyclic Chem. 1970, 7, 791.
8. Fernandez, B.M.; Reverdito, A.M.; Paolucci, G.A.; Perillo, I.A.
J. Heterocyclic Chem. 1987, 24, 1717.
9. Xia, C.; Zhou, P.; Ding, J.; Yao, Z.; Zhao, M. Chin. J. Org. Chem.
1991, 11, 154.
10. Salerno, A.; Ceriani, V.; Perillo, I.A. J. Heterocyclic Chem. 1992, 29,
1725.
11. Raiziss, G.W. J. Am. Chem. Soc. 1941, 63, 3124.
12. Seeliger, W.; Thier, W. Justus Liebigs. Ann. Chem. 1977, 698, 158.
13. Okecha, S.A.; Stansfield, F. J. Chem. Soc., Perkin Trans 1 1977, 1811.
14. Sund, C.; Ylikoski, J.; Kwiatkowski, M. Synthesis 1987, 853.
15. Piskov, V.B.; Kasperovich, V.P.; Yakovleva, L.M. Khim. Geterotsikl.
Soedin. (in Ress. CA 86: 5372 h) 1976, 8, 1112.
16. Hiemstra, H.C.; Bieraugel, H.; Wijnbgre, M.; Pandit, U.K.
Tetrahedron 1983, 39, 3981.
Received in the USA May 4, 2001