A one-pot stereoselective synthesis of novel polyfunctionalized imidazolidines

Article abstract of DOI:10.1016/j.tetlet.2013.08.029

A facile, one-pot stereoselective synthesis of novel trans-4,5-dihydroxy-2- aryl-1,3-bis(heteroaryl)imidazolidines is achieved by a cyclocondensation reaction of 2 equiv of heteroarylamines with benzaldehyde derivatives, in the presence of guanidinium chl

Full text of DOI:10.1016/j.tetlet.2013.08.029

Accepted Manuscript
A one-pot stereoselective synthesis of novel polyfunctionalized imidazolidines
Abolfazl Olyaei, Mohsen Karbalaei Karimi, Reza Razeghi
PII:
S0040-4039(13)01382-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.029
TETL 43391
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 June 2013
20 July 2013
7 August 2013
Please cite this article as: Olyaei, A., Karimi, M.K., Razeghi, R., A one-pot stereoselective synthesis of novel
polyfunctionalized imidazolidines, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.029
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A one-pot stereoselective synthesis of novel
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Abolfazl Olyaei, Mohsen Karbalaei Karimi, Reza Razeghi
OH
N N
HO
H2N NH2
/ 120 oC
1.
NH2Cl
Ar'CHO + 2 ArNH2
Ar
Ar
Ar'
H
2. (CHO)2 (aq) / 80 oC

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A one-pot stereoselective synthesis of novel polyfunctionalized imidazolidines
Abolfazl Olyaei , Mohsen Karbalaei Karimi, Reza Razeghi
Department of Chemistry, Payame Noor University, PO BOX 19395-3697, Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A
facile, one-pot stereoselective synthesis of novel trans-4,5-dihydroxy-2-aryl-1,3-
bis(heteroaryl)imidazolidines is achieved by a cyclocondensation reaction of two equivalents of
heteroarylamines with benzaldehyde derivatives, in the presence of guanidinium chloride as a
polyfunctional organocatalyst, with aqueous glyoxal to afford the title products. This general
protocol provides a wide range of new polyfunctionalized imidazolidines in good to high yields.
Available online
Keywords:
Heteroarylamine
Aldehyde
2009 Elsevier Ltd. All rights reserved.
Imidazolidine
Glyoxal
The
synthesis
of
imidazolidines
through
the
HO OH
N N
RO OR
N N
cyclocondensation of diamines, bisamides and urea derivatives
with aqueous glyoxal and other appropriate carbonyl compounds
has been the subject of numerous investigations.1-11 In 1962, Vail
and co-workers reported the reaction of various bisamides of the
type RCONH-XNHCOR (X = alkylene or substituted alkylene)
with glyoxal to produce the desired cyclic compounds.1 In the
case of diamines, most of the reports are limited to
ethylenediamine and its derivatives.2,3 Koppes described the
reaction of hexafluorodiaminopropane with glyoxal which led to
the formation of 3,3,7,7-tetrakis(trifluoromethyl)-2,4,6,8-
tetraazabicyclo[3.3.0]octane. In this reaction, 4,5-dihydroxy-2,2-
bis(trifluoromethyl)imidazolidine could not be isolated.4
Ar
Ar
Ar
Ar
Ar = 2-pyrimidinyl, 2-pyrazinyl,
2-benzothiazolyl
Ar = 2-pyrimidinyl, R:
Me, Et, Pr, i-Pr
Ar = 2-pyrazinyl, R: Me
AcO OAc
N N
HO NHAr
N N
Ar
Ar
Ar
Ar
Ar = 2-thiazolyl
Ar = 2-pyrimidinyl
We have previously reported the synthesis of imidazolidines
by employing a one-pot reaction using 2-aminopyrimidine or 2-
aminopyrazine, aqueous formaldehyde and glyoxal in alcohols,
acetonitrile and acetic anhydride under reflux conditions (Figure
1).12-14 Based on 1H NMR analysis, it was found that trans-
Figure 1. Examples of imidazolidines
In continuation of our research aimed at developing reactions
under solvent-free conditions,20 we report herein an efficient and
simple process for the stereoselective synthesis of novel
polyfunctionalized imidazolidines via the one-pot reaction of aryl
aldehydes 1, heteroaryl amines 2 and aqueous glyoxal in the
presence of guanidine hydrochloride as the catalyst (Scheme 1).
imidazolidines
were
obtained
selectively
in
these
cyclocondensation reactions.
Imidazolidines, cyclic aminals of pharmacological interest, as
To achieve suitable conditions for the synthesis of the
imidazolidines for the first step, the reaction of benzaldehyde (1
mmol), 2-aminopyrimidine (2 mmol) and guanidine
hydrochloride (0.1 mmol) was selected as a model system. In the
second step, the reaction of the obtained gem-diamine
(intermediate 3) with aqueous glyoxal (1 mmol) was
investigated. The results indicated that in the first step a
temperature of 120 °C, and in the second reaction step a
temperature of 80 °C, were effective in terms of the reaction time
well
as
N,N'-dibenzyl-2-arylimidazolidines,
N,N'-
N,N'-
fungicidal,
antiviral
bisaminoalkylimidazolidines,
dihydroxyphenylimidazolidines
antiparasitic,
and
shown
anti-amebic, and
have
antibacterial,
activities.15,16 They are important building blocks in biologically
active compounds, and are carriers of pharmacologically active
carbonyl compounds.17-19 To the best of our knowledge, there are
no reports in the literature on the synthesis of these heterocycles.
———
 Corresponding author. Tel.: +0098-281-2224024; fax: +0098-281-2226400; e-mail: olyaei_a@pnu.ac.ir

2
and yield obtained. We also varied the amount of catalyst (5, 7,
10, 12, 15 mol%) and the results revealed that 10 mol% gave a
high yield of the product. After optimization, we investigated the
use of other aryl aldehydes (4-fluorobenzaldehyde, 4-
chlorobenzaldehyde, 2-nitrobenzaldehyde, 3-nitrobenzaldehyde,
and 2,4-dichlorobenzaldehyde) (1b-f), heteroaryl amines (2-
amino-4,6-dimethylpyrimidine and 2-amino-4-methylpyrimidine)
(2b,c) and glyoxal in this reaction, and obtained a library of
imidazolidines 4b-i in good to high yields.21 The results are
shown in Table 1. To the best of our knowledge, this new
procedure represents the first example of an efficient and one-pot
reaction for the stereoselective synthesis of novel trans-4,5-
dihydroxy-2-aryl-1,3- bis(heteroaryl)imidazolidines.
H2N NH2
NH2Cl
H
H
N
N
Ar'CHO + 2 ArNH2
Ar
Ar
Ar'
solvent-free
120 oC
1
2
3
O
O
OH
HO
(aq)
H
H
N
N
H
Ar
Ar
Ar'
80 oC
4
9 examples
Scheme 1. A one-pot, two-step approach for the synthesis of
polyfunctionalized imidazolidines 4
Table 1. Synthesis of imidazolidine derivatives 4
Time (min)
Entry
Aldehyde
Amine
Product
Yield (%)
Step 1 Step 2
OH
HO
CHO
NH2
N
N
N
N
60
60
15
10
80
1
N
N
N
N
4a
4b
4c
OH
HO
CHO
N
N
N
N
NH2
N
75
85
2
3
N
N
N
N
N
F
F
OH
HO
CHO
N
N
N
N
NH2
N
20
15
10
N
N
Cl
Cl
OH
HO
CH3
H3C
N
N
CHO
Cl
N
N
NH2
N
N
N
60
80
4
CH3
H3C
H3C
CH3
Cl
OH
4d
HO
CHO
Cl
N
N
NH2
N
N
N
70
6
83
84
5
6
N
N
N
CH3
H3C
H3C
Cl
OH
4e
4f
HO
CHO
NH2
N
N
N
N
N
45
5
NO2
N
N
N
NO2

3
Table 1. (Continued)
Time (min)
Entry
Aldehyde
Amine
Product
Yield (%)
Step 1 Step 2
OH
HO
CH3
H3C
N
NH2
N
CHO
NO2
N
N
30
15
5
8
79
7
N
N
NO2
H3C
4g
OH
HO
CHO
NO2
N
N
NH2
N
N
N
86
8
N
N
N
NO2
OH
4h
HO
CHO
Cl
N
N
N
N
NH2
N
40
40
12
77
88
N
N
9
N
N
Cl
Cl
Cl
4i
4j
OH
HO
NH2
N
O
5
10
N
N
N
N
H
H
N
N
Aldehydes containing electron-withdrawing functional groups
at various positions required different reaction times, but the
yields of products were similar. However, in the case of aryl
aldehydes bearing an electron-donating group, the reaction did
take place, but lower yields were obtained.
The stereochemistry of the products was assigned based on 1H
NMR and 13C NMR spectroscopy. It was found that compounds
4a-i had unsymmetric structures. The 1H NMR spectra of
compounds 4a-i showed two signals for the hydroxyl groups, in
agreement with a trans configuration. The IR spectra of
compounds 4 showed broad OH stretching absorptions at about
3180 cm-1 in agreement with intramolecular hydrogen bonding
between the OH and nitrogen of the heteroaryl amines.
CHO
H NH
H2N NH2
NH2Cl
ArNH2
O
NH2Cl
+
H
H NH
H2N NH2
NH2Cl
NHAr
OH
ArNH2
N Ar
-H2O
H2N NH2
NH2Cl
O
O
H
HO
N
OH
Ar
Ar
NH
H
The formation of the product in the present reaction is
expected to involve the following tandem reaction mechanism.
We propose that guanidine hydrochloride acts as a polyfunctional
organocatalyst. It is clear from the sequence of steps that
guanidine hydrochloride initially acts as a hydrogen-bond donor
to activate the aldehyde by formation of a six-membered ring
with the aldehyde oxygen. Subsequently, a Schiff base was
formed by nucleophilic addition of the amine to the aldehyde and
dehydration in the presence of the catalyst acting as an acid.
Next, the Schiff base is further attacked by a second amine to
give gem-diamine as intermediate 3. Finally, nucleophilic
addition of intermediate 3 to the carbonyls of glyoxal gave the
final product (Scheme 2).
N
Ar
NH
H2N NH2
NH2Cl
Ar
3
Scheme 2. Proposed mechanism for the formation of
imidazolidines 4
In an attempt to expand the scope of this method, we
employed formaldehyde instead of aryl aldehydes (entry 10), and
obtained compound 4j, being consistent with the expected
structure (Scheme 3).12 The H NMR spectrum of compound 4j
1
indicated that a symmetrical structure had been formed.

4
12. Ghandi, M.; Olyaei, A.; Salimi, F. Synth. Commun. 2007, 37, 247.
H2N NH2
NH2Cl
NH2
N
13. Ghandi, M.; Olyaei, A. J. Heterocycl. Chem. 2007, 44, 323.
14. Ghandi, M.; Salimi, F.; Olyaei, A. J. Heterocycl. Chem, 2006, 43,
791.
15. Caterina, M. C.; Perillo, I. A.; Boiani, L.; Pezaroglo, H.;
Cerecetto, H.; González, M.; Salerno, A. Bioorg. Med. Chem.
2008, 16, 2226.
H
H
N
N
N
N
N
2
CH2O (aq) +
N
N
solvent-free
120 oC
16. Sharma, V.; Khan, M. S. Eur. J. Med. Chem. 2001, 36, 651.
17. Sharma, V.; Crankshaw, C. L.; Piwnica-Worms, D. J. Med. Chem.
1996, 39, 3483.
18. Sage, C. R.; Michelitsch, M. D.; Stout, T. J.; Biermann, D.;
Nissen, R.; Finer-Moore, J.; Stroud, R. M. Biochemistry 1998, 37,
13893.
O
O
HO
OH
N
(aq)
N
N N
H
H
N
N
80 oC
19. Crank, G.; Harding, D. R. K.; Szinai, S. S. J. Med. Chem. 1970,
13, 1212.
4j
Scheme 3. One-pot synthesis of imidazolidine 4j
20. (a) Shockravi, A.; Sadeghpour, M. Olyaei, A. J. Chem. Res. 2009,
656; (b) Shockravi, A.; Sadeghpour, M.; Olyaei, A. Synth.
Commun. 2010, 40, 2531; (c) Olyaei, A.; Raufmoghaddam, S.;
Sadeghpour, M.; Ebadzadeh, B. Chin. J. Chem. 2010, 28, 825; (d)
Olyaei, A.; Shams, B.; Sadeghpour, M.; Gesmati, F.; Razaziane,
Z. Tetrahedron Lett. 2010, 51, 6086; (e) Olyaei, A.; Zarnegar, M.;
Sadeghpour, M.; Rezaei, M. Lett. Org. Chem. 2012, 9, 451; (f)
Olyaei, A.; Vaziri M.; Razeghi, R. Tetrahedron Lett. 2013, 54,
1963.
In summary, to the best of our knowledge, this Letter
describes the first report on the stereoselective synthesis of novel
trans-4,5-dihydroxy-2-aryl-1,3-bis(heteroaryl)imidazolidines via
the reaction of heteroaryl amines, aryl aldehydes and glyoxal.
The advantages of the present method are high efficiency and
generality, clean reaction profiles and the two-step synthetic
sequence can be carried out without isolation of the intermediate.
This leads to a reduction in the overall reaction time and energy
requirements, and constitutes an economical method for
preparing new imidazolidine compounds.
21. General procedure for the synthesis of imidazolidines (4): A
mixture of heteroarylamine (2 mmol), aldehyde (1 mmol) and
o
guanidinium chloride (0.1 mmol) was heated at 120 C for 15-70
min (Table 1), in an oil-bath under solvent-free conditions. Upon
completion, as monitored by TLC, the mixture was cooled to 80
oC, then glyoxal (40% aqueous solution, 1 mmol) was added and
the mixture stirred at the same temperature for 5-15 min as
indicated in Table 1. After completion, the mixture was cooled to
room temperature and EtOH (5 mL) was added until solid
products precipitated. The precipitate was filtered, washed with
EtOH and dried. The crude product was purified by column
chromatography on silica gel (n-hexane/EtOAc, 30/70) to afford
the corresponding pure white products 4. 4,5-Dihydroxy-2-phenyl-
Acknowledgments
The authors thank the Research Council of Payame Noor
University for financial support.
Supplementary data
o
1,3-bis(2-pyrimidinyl)imidazolidine (4a): m.p. = 201-202 C; IR
1
(KBr): 3120, 2946, 1585, 1454, 1319, 1272, 1041 cm-1; H NMR
Supplementary data (1H and 13C NMR, MS, CHN and IR)
associated with this article can be found, in the online version.
(400 MHz, DMSO-d6): δ: 5.93 (m, 2H, CH-OH), 6.23 (d, 1H, J =
6.0 Hz, OH), 6.52 (d, 1H, J = 3.6 Hz, OH), 6.71 (s, 1H, CH), 6.74
(t, 1H, J = 4.8 Hz, pyrimidinyl-H5), 6.77 (t, 1H, J = 4.8 Hz,
pyrimidinyl-H5'), 7.11-7.82 (m, 5H, phenyl-H), 8.35 (d, 2H, J =
4.8 Hz, pyrimidinyl-H4,6), 8.42 (d, 2H, J = 4.8 Hz, pyrimidinyl-
H4',6') ppm; 13C NMR (100 MHz, DMSO-d6): δ: 74.35, 85.63,
85.93, 112.36, 112.65, 127.42, 127.50, 129.62, 141.71, 158.13,
158.37, 158.83, 159.34 ppm; MS (EI): m/z 336 (M+), 319, 277,
213, 201, 184, 124, 106, 96, 79; Anal. calcd. for C17H16N6O2: C,
60.71; H, 4.76; N, 25.00. Found: C, 60.80; H, 4.70; N, 25.09. 4,5-
Dihydroxy-2-(4-chlorophenyl)-1,3-bis(4-methyl-2-pyrimidinyl)
References and notes
1. Vail, S. L.; Moran, C. M.; Moor, H. B.; Kullman, R. M. H. J. Org.
Chem. 1962, 27, 2071.
2. Alexakis, A.; Tranchier, J. P.; Lensen, N.; Mangeney, P. J. Am.
Chem. Soc. 1995, 117, 10767.
3. Willer, R. L.; Moore, D. W.; Vanderah, D. J. J. Org. Chem. 1985,
50, 2365.
4. Koppes, W. M.; Chaykovsky, M.; Adolph, H. J.; Gilardi, R. D.;
George, C. F. J. Org. Chem. 1987, 52, 1113.
o
imidazolidine (4e): m.p. = 194-196 C; IR (KBr): 3178, 2962,
1
1569, 1450, 1253, 1041 cm-1; H NMR (400 MHz, DMSO-d6): δ:
2.25 (s, 3H, CH3), 2.32 (s, 3H, CH3), 5.88 (m, 2H, CH-OH), 6.17
(br s, 1H, OH), 6.51 (br s, 1H, OH), 6.62 (s, 1H, CH), 6.64 (d,
1H, J = 5.2 Hz, pyrimidinyl-H5), 6.66 (d, 1H, J = 5.2 Hz,
pyrimidinyl-H5'), 7.27 (d, 2H, J = 8.4 Hz, phenyl-H), 7.82 (d, 2H,
J = 8.4 Hz, phenyl-H), 8.25 (m, 2H, pyrimidinyl-H6,6') ppm; 13C
NMR (100 MHz, DMSO-d6): δ: 24.05, 24.20, 73.84, 85.47, 85.62,
111.80, 112.21, 127.34, 131.73, 141.18, 157.55, 157.94, 158.56,
159.11 ppm; MS (EI): m/z 400 (M+2)+, 398 (M+), 341, 339, 234,
232, 138, 110, 93, 66; Anal. calcd. For C19H19ClN6O2: C, 57.28;
H, 4.77; N, 21.10. Found: C, 57.34; H, 4.79; N, 21.14.
5. Ferguson, I. J.; Katritzky, A. R.; Patel, R. J. Chem. Soc., Perkin
Trans. 2, 1976, 1564.
6. Dunnavant, W. R.; James, F. L. J. Am. Chem. Soc. 1956, 78, 2740.
7. Nematollah, J.; Ketcham, R. J. Org. Chem. 1963, 28, 2378.
8. Frick, J. G.; Harper, R. G. Ind. Eng. Chem. Prod. Res. Dev. 1982,
21, 599.
9. Cort, L. A.; Francis, N. R. J. Chem. Soc. 1964, 2799.
10. Willer, R. L.; Moore, D. W.; Lowe-Ma, C. K.; Vanderah, D. J. J.
Org. Chem. 1985, 50, 2368.
11. Nielsen, A. T.; Nissan, R. A.; Chafin, A. P.; Gilardi, R. D.;
George, C. F. J. Org. Chem. 1992, 57, 6756.

Scheme 2. Proposed mechanism for the formation of imidazolidines 4
CHO
H NH
H2N NH2
NH2Cl
ArNH2
O
NH2Cl
+
H
H NH
H2N NH2
NH2Cl
-H2O
NHAr
OH
ArNH2
N Ar
H2N NH2
NH2Cl
O
H
O
H
HO
Ar
OH
Ar
Ar
NH
N
N
NH
Ar
H2N NH2
NH2Cl
3

Scheme 3. One-pot synthesis of imidazolidine 4j
H2N NH2
NH2Cl
NH2
N
H
H
N
N
N
N
N
2
CH2O (aq) +
N
N
solvent-free
120 oC
O
O
HO
OH
N
(aq)
N
N N
H
H
N
N
80 oC
4j

Scheme 1. A one-pot, two-step approach for the synthesis of polyfunctionalized imidazolidines 4
H2N NH2
H
H
NH2Cl
N
N
Ar'CHO + 2 ArNH2
Ar
Ar
Ar'
solvent-free
120 oC
1
2
3
O
O
OH
HO
(aq)
H
H
N
N
Ar
Ar
Ar'
80 oC
H
4
9 examples

Table 1. Synthesis of imidazolidine derivatives 4
Time (min)
Entry
Aldehyde
Amine
Product
Yield (%)
Step 1 Step 2
OH
HO
CHO
NH2
N
N
N
N
60
60
15
10
80
1
N
N
N
N
4a
4b
4c
OH
HO
CHO
N
N
N
N
NH2
N
75
85
2
3
N
N
N
N
N
F
F
OH
HO
CHO
N
N
N
N
NH2
N
20
15
N
N
Cl
Cl
OH
HO
CH3
H3C
N
CHO
Cl
N
N
N
NH2
N
N
N
60
10
80
4
CH3
H3C
H3C
CH3
Cl
OH
4d
HO
CHO
Cl
N
N
NH2
N
N
N
70
6
83
84
5
6
N
N
N
CH3
H3C
H3C
Cl
OH
4e
4f
HO
CHO
NH2
N
N
N
N
N
45
5
NO2
N
N
N
NO2

Table 1. (Continued)
Time (min)
Entry
Aldehyde
Amine
Product
Yield (%)
Step 1 Step 2
OH
HO
CH3
H3C
N
NH2
N
CHO
NO2
N
N
30
15
5
8
79
7
N
N
NO2
H3C
4g
OH
HO
CHO
NO2
N
N
NH2
N
N
N
86
8
N
N
N
NO2
OH
4h
HO
CHO
Cl
N
N
N
N
NH2
N
40
40
12
77
88
N
N
9
N
N
Cl
Cl
Cl
4i
4j
OH
HO
NH2
N
O
5
10
N
N
N
N
H
H
N
N