Efficient synthesis of 2-(N-Substituted)-2-imidazolines and 2-(N-Substituted)-1,4,5, 6-tetrahydropyrimidines

Article abstract of DOI:10.1080/00397910500213005

A general method for the preparation of 2-(N-Substituted)-2-imidazolines and 2-(N-Substituted)-1,4,5,6-tetrahydropyrimidines is described. These heterocycles can be synthesized from their respective anilines with 2-chloro-2-imidazoline or 2-chloro-1,4,5,6-tetrahydropyrimidine, generated in situ from imidazolidin-2-one and tetrahydropyrimidin-2(1H)-one activated by dimethyl chlorophosphate, in good to excellent yields. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500213005

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Efficient Synthesis of
2‐(N‐Substituted)‐2‐imidazolines
and
2‐(N‐Substituted)‐1,4,5,6‐tetrahydr
Wai Ming Kan a , Shih‐Hsun Lin b & Ching‐Yuh Chern b
a Department of Pharmacology , National Cheng
Kung University , Tainan, Taiwan, R.O.C.
b Department of Applied Chemistry , National Chiayi
University , Chiayi, Taiwan, R.O.C.
Published online: 22 Aug 2006.
To cite this article: Wai Ming Kan , Shih‐Hsun Lin & Ching‐Yuh Chern
(2005) Efficient Synthesis of 2‐(N‐Substituted)‐2‐imidazolines and
2‐(N‐Substituted)‐1,4,5,6‐tetrahydropyrimidines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:20,
2633-2639
To link to this article: http://dx.doi.org/10.1080/00397910500213005
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Synthetic Communicationsw, 35: 2633–2639, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500213005
Efficient Synthesis of 2-(N-Substituted)-
2-imidazolines and 2-(N-Substituted)-1,4,5,
6-tetrahydropyrimidines
Wai Ming Kan
Department of Pharmacology, National Cheng Kung University, Tainan,
Taiwan, R.O.C.
Shih-Hsun Lin and Ching-Yuh Chern
Department of Applied Chemistry, National Chiayi University, Chiayi,
Taiwan, R.O.C.
Abstract: A general method for the preparation of 2-(N-Substituted)-2-imidazolines
and 2-(N-Substituted)-1,4,5,6-tetrahydropyrimidines is described. These heterocycles
can be synthesized from their respective anilines with 2-chloro-2-imidazoline or
2-chloro-1,4,5,6-tetrahydropyrimidine, generated in situ from imidazolidin-2-one and
tetrahydropyrimidin-2(1H)-one activated by dimethyl chlorophosphate, in good to
excellent yields.
Keywords: 2-(N-Substituted)-2-imidazolines, 2-(N-substituted)-1,4,5,6-tetrahydro-
pyrimidines
INTRODUCTION
2-(N-Substituted)-2-imidazolines and 2-(N-substituted)-1,4,5,6-tetrahydro-
pyrimidines are unique classes of chemicals that contain an endocyclic
C55N double bond. Many drug molecules contain these structures. One of
the examples is clonidine, 2-[N-(2,6-dichlorophenyl)]-imidazolidine, which
is a commonly used antihypertensive.[1] Literature review showed that
Received in Japan March 24, 2005
Address correspondence to Ching-Yuh Chern, Department of Applied Chemistry,
National Chiayi University, 300 University Road, Chiayi, 60083 Taiwan, R.O.C.
E-mail: cychern@mail.ncyu.edu.tw
2633

2634
W. M. Kan, S.-H. Lin, and C.-Y. Chern
these heterocycles can be synthesized by several methods. One of them
employed nucleophilic substitution of 2-chloro-4,5-dihydro-1H-imidazole[2]
or 2-nitroamino-4,5-dihydro-1H-imidazole[3] by their respective anilines to
form N-substituted imidazolines. However, the preparation of these reagents
requires the use of hazardous chemicals such as chlorine gas, which is
dangerous for large-scale preparation. Another approach uses 2-methylthio-
2-imidazoline[4,5] as reagent, which allows a milder reaction but requires
longer reaction times. Moreover, the preparation of 2-methylthio-4,5-
dihydro-1H-imidazole has an unpleasant stench reagent. Conversely, little
information is available for the preparation of N-substituted-1,4,5,6-tetrahy-
dropyrimidines although the methods previously discussed may be applicable.
In this article, we report an efficient method for the synthesis of these two
classes of chemicals.
RESULTS AND DISCUSSION
We planned to generate 2-chloro-4,5-dihydro-1H-imidazole 4 and 2-chloro-
1,4,5,6-tetrahydropyrimidine 5 in situ, which prevents the isolation of these
hazardous chemicals. Previously, Etemad-Moghadam et al.[6] described the
synthesis of phospho-biotin models. He suggested that imidazolidin-2-one 1
may form 2-chloro-4,5-dihydro-1H-imidazole 4 when it reacts with alkyl or
aryl chlorophosphates. Using their experimental method[6] for the in situ
generation of 2-chloro-4,5-dihydro-1H-imidazole 4 or 2-chloro-1,4,5,6-
tetrahydropyrimidine 5 resulted in poor yields. After extensive study, we
found that the optimal condition for the generation of these chloro-reagents
is by using one equivalent of imidazolidin-2-one or tetrahydropyrimidin-
2(1H)-one and three equivalents of dimethyl chlorophosphate and triethyl-
amine in refluxing dichloromethane for 5 h. Afterwards, one equivalent of
the respective amine was added. Most reactions were completed within
another 5 h. The results are summarized in Scheme 1 and Table 1. With the
exception of very electro-withdrawing anilines, such as nitro-aniline,
N-substituted-imidazolines were synthesized in excellent yields and tetrahy-
dropyrimidines were prepared in good yields. 4-Nitro-aniline failed to
provide any product even after 4 days of reaction. It is probably due to the
lack of basicity of the nitroaniline. For a similar reason, aminopyridine gave
inferior results for the preparation of N-(2-pyridyl)-1,4,5,6-tetrahydropyrimi-
dine. Nevertheless, this method is applicable to most anilines. Moreover,
aliphatic amine 6a also reacts accordingly. Apparently, the method is appli-
cable for the preparation of both N-alkyl and N-aryl derivatives. To verify
that the method is of practical value, we used it for the preparation of a
recently reported prostacyclin antagonist 10[7] and its derivative 11. Using
this method, both compounds 10 and 11 were prepared in excellent and
good yields respectively. The use of chlorine gas for the generation of
chloro-imidazoline is avoided. In conclusion, an efficient method for the

Efficient Synthesis of Imidazolines and Tetrahydropyrimidines
2635
Scheme 1.
synthesis of N-substituted imidazolines and tetrahydropyrimidines is
described that should be applicable for wide varieties of amines.
EXPERIMENTAL
Proton NMR spectra were recorded on a 300-MHz Varian Mercury-300 NMR
spectrometer. Carbon NMR spectra were recorded on a 75-MHz Varian
Mercury-300 NMR spectrometer. Proton and carbon chemical shifts are
reported on the delta scale as parts per million (ppm) downfield from tetra-
methylsilane (TMS) as internal reference. Mass spectra were measured with
a VG Analytical Model 70-250s mass spectrometer. All reagents were used
as obtained commercially.
General Procedure for the Synthesis of Compounds 7, 8, 10, and 11
Dimethyl chlorophosphate 3 (3 equiv) and Et3N (3 equiv) was added into a
solution of the imidazolidin-2-one 1 (or tetrahydro-pyrimidin-2-one 2) in
CH2Cl2 at room temperature under nitrogen. The reaction mixture was
stirred at 358C for 5 h. The appropriate amine 6 (1 equiv) was dissolved in
CH2Cl2 and added dropwise into the reaction mixture. The progress of the
reaction was monitored by TLC. After an aqueous workup the solvent was
evaporated under reduced pressure and the residue was purified on silica gel
(50% ethyl acetate/hexane).

2636
W. M. Kan, S.-H. Lin, and C.-Y. Chern
Table 1.
8, n ¼ 2
Entry
R
7, n ¼ 1
(yield %)
1
2
97
95
39
67
3
4
95
94
47
63
5
6
—
5
—
30
(4,5-Dihydro-1H-imidazol-2-yl)-isopropyl-amine (7a) was prepared as pre-
viously described (97%): 1H NMR (CDCl3, 300 MHz) d: 7.82 (1H, bs, –NH),
6.19 (1H, bs, –NH), 3.90 (1H, sept, J ¼ 6.6 Hz), 3.87 (2H, t, J ¼ 8.7 Hz), 3.40
(2H, t, J ¼ 8.7 Hz), 1.12 (6H, d, J ¼ 6.6 Hz); 13C NMR (CDCl3, 75 MHz) d:
159.1, 41.9, 41.6, 36.6, 22.7; HRMS calcd. for C6H13N3: 127.1109, found:
127.1104.
Benzyl-(4,5-dihydro-1H-imidazol-2-yl)-amine (7b)[3] was prepared similar
1
to the general procedure (95%): H NMR (CDCl3, 300 MHz) d: 8.41 (1H,
bs, –NH), 7.32–7.22 (5H, m), 5.67 (1H, bs, –NH), 4.47 (2H, d, J ¼ 5.7 Hz),
3.97 (2H, t, J ¼ 7.8 Hz), 3.44 (2H, td, J ¼ 7.8, 2.1 Hz); 13C NMR (CDCl3,
75 MHz) d: 158.9, 153.5, 128.5, 127.4, 127.2, 43.6, 42.1, 36.8; EI-MS m/z
(rel. int.%): 175 (Mþ, 1), 106 (100), 91 (18), 85 (9), 77 (4); HRMS calcd.
for C10H13N3: 175.1109; found: 175.1105.
(4,5-Dihydro-1H-imidazol-2-yl)-phenylamine (7c) was prepared similar to
the general procedure (95%): mp 139–1408C (water) (lit.[5] 138–1398C);
1H NMR (CDCl3, 300 MHz) d: 7.50 (2H, dd, J ¼ 7.5, 1.2 Hz), 7.30 (2H, td,
J ¼ 7.5, 1.8 Hz), 7.06 (1H, td, J ¼ 7.5, 1.2 Hz), 5.93 (1H, bs, –NH), 4.03
(2H, t, J ¼ 7.8 Hz), 3.50 (2H, t, J ¼ 7.8 Hz); 13C NMR (CDCl3, 75 MHz)
d: 158.8, 137.7, 128.9, 123.5, 119.7, 42.0, 36.6; HRMS calcd. for C9H11N3:
161.0953; found: 161.0958.
(4,5-Dihydro-1H-imidazol-2-yl)-(2,4-dimethoxy-phenyl)-ammonium
Chloride (7d) was prepared as described in the general procedure (94%):
1H NMR (CDCl3, 300 MHz) d: 8.04 (1H, dd, J ¼ 2.1, 8.4 Hz), 6.48–6.44

Efficient Synthesis of Imidazolines and Tetrahydropyrimidines
2637
(2H, m), 4.05 (2H, t, J ¼ 7.8 Hz), 3.82 (3H, s), 3.77 (3H, s), 3.51 (2H, t,
J ¼ 7.8 Hz); 13C NMR (CDCl3, 75 MHz) d: 158.6, 156.1, 150.7, 150.0,
120.5, 103.7, 98.7, 55.8, 55.5, 42.1, 36.7; HRMS calcd. for C11H16ClN3O2:
257.0931; found: 257.0928.
(4,5-Dihydro-1H-imidazol-2-yl)-pyridin-2-yl-amine (7f) was prepared by
1
following the general procedure (5%): H NMR (CDCl3, 300 MHz) d: 8.29
(1H, ddd, J ¼ 0.9, 1.8, 5.1 Hz), 8.06 (1H, dt, J ¼ 0.9, 8.4 Hz), 7.67 (1H, td,
J ¼ 1.8, 7.2 Hz), 6.99 (1H, ddd, J ¼ 0.9, 5.1, 7.2 Hz), 5.77 (1H, bs, –NH),
4.05 (2H, t, J ¼ 7.6 Hz), 3.56 (2H, t, J ¼ 7.6 Hz); 13C NMR (CDCl3,
75 MHz) d: 158.2, 157.0, 148.0, 138.1, 119.1, 113.6, 42.0, 36.6; EI-HRMS
calcd. for C8H10N4: 162.0905; found: 162.0901.
Isopropyl-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine (8a) was prepared
1
similarly (39%): H NMR (CDCl3, 300 MHz) d: 9.15(1H, bs, –NH), 5.43
(1H, bs, –NH), 3.94 (1H, sept, J ¼ 6.6 Hz), 3.81 (2H, t, J ¼ 5.7 Hz), 3.30
(2H, t, J ¼ 5.7 Hz), 1.92 (2H, quin, J ¼ 5.7 Hz), 1.16 (6H, d, J ¼ 6.6 Hz);
13C NMR (CDCl3, 75 MHz) d: 157.8, 43.5, 42.8, 41.4, 23.1, 22.5; HRMS
calcd. for C7H15N3: 141.1266; found: 141.1270.
Benzyl-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine (8b)[3] was prepared
1
similarly (67%): H NMR (CDCl3, 300 MHz) d: 7.32–7.22 (5H, m), 5.11
(1H, bs, –NH), 4.46 (2H, d, J ¼ 5.7 Hz), 3.87 (2H, t, J ¼ 6.0 Hz), 3.33
(2H, td, J ¼ 6.0, 2.1 Hz), 1.95 (2H, quin, J ¼ 6.1 Hz); 13C NMR (CDCl3,
75 MHz) d: 156.1, 155.3, 128.5, 127.5, 127.1, 44.4, 41.5, 40.9, 21.5; EI-MS
m/z (rel. int.%): 189 (Mþ, 1), 106 (100), 91 (19), 77 (4); HRMS calcd. for
C11H15N3: 189.1266; found: 189.1264.
Synthesis of Phenyl-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-amine (8c)[5] was
1
prepared similarly (47%): H NMR (CD3OD, 300 MHz) d: 7.54 (2H, dd,
J ¼ 7.8, 1.8 Hz), 7.38 (2H, t, J ¼ 7.8 Hz), 7.15 (1H, dd, J ¼ 7.8, 1.8 Hz), 3.94
(2H, t, J ¼ 6.0 Hz), 3.40 (2H, t, J ¼ 6.0 Hz), 2.06 (2H, quin, J ¼ 6.0 Hz);
13C NMR (CD3OD, 75 MHz) d: 155.9, 140.9, 129.1, 121.5, 118.1, 37.0,
36.9, 31.2; HRMS calcd. for C10H13N3: 175.1109; found: 175.1112.
(2,4-Dimethoxy-phenyl)-(1,4,5,6-tetrahydro-pyrimidin-2-yl)-ammonium
Chloride (8d) was prepared similarly (63%): 1H NMR (CDCl3, 300 MHz) d:
8.06 (1H, dd, J ¼ 1.8, 8.7 Hz), 6.47–6.43 (2H, m), 5.68 (1H, bs, –NH), 3.90
(2H, t, J ¼ 5.7 Hz), 3.85 (3H, s), 3.77 (3H, s), 3.34 (2H, t, J ¼ 5.7 Hz), 1.97
(2H, quin, J ¼ 5.7 Hz); 13C NMR (CDCl3, 75 MHz) d: 156.2, 156.0, 152.4,
150.2, 120.7, 103.6, 98.6, 55.8, 55.4, 41.2, 40.8, 21.5; HRMS calcd. for
C12H18ClN3O2: 271.1088l; found: 271.1080.
Pyridin-2-yl-(1,4,5,6-tetrahydro-pyrimidin-2-yl)amine (8f) was prepared
by following the general procedure (30%): 1H NMR (CDCl3, 300 MHz)

2638
W. M. Kan, S.-H. Lin, and C.-Y. Chern
d: 12.16 (1H, bs, –NH), 8.30 (1H, d, J ¼ 3.9 Hz), 8.10 (1H, d, J ¼ 8.4 Hz),
7.70 (1H, t, J ¼ 7.2 Hz), 7.01 (1H, ddd, J ¼ 0.9, 5.1, 6.0 Hz), 5.53 (1H,
bs, –NH), 3.92 (2H, t, J ¼ 6.0 Hz), 3.40 (2H, td, J ¼ 2.7, 6.0 Hz), 2.02
(2H, quin, J ¼ 6.0 Hz); 13C NMR (CDCl3, 75 MHz) d: 155.8, 152.3, 130.9,
128.8, 119.0, 114.9, 41.7, 41.0, 21.4; EI-HRMS calcd. for C9H12N4:
176.1062; found: 176.1066.
3-[4-(4,5-Dihydro-1H-imidazol-2-yl-amino)-phenyl]-1-(4-morpholin-4-yl-
phenyl)-propan-1-one (10)[7] was prepared as described in the general
1
procedure (88%): H NMR (CDCl3, 300 MHz) d: 10.14 (1H, s, –NH), 7.89
(2H, d, J ¼ 9.0 Hz), 7.42 (2H, d, J ¼ 8.4 Hz), 7.19 (2H, d, J ¼ 8.4 Hz), 6.86
(2H, d, J ¼ 9.0 Hz), 4.91 (1H, s, –NH), 4.06 (2H, t, J ¼ 7.2 Hz), 3.86 (4H,
t, J ¼ 4.8 Hz), 3.52 (2H, t, J ¼ 8.1 Hz), 3.30 (4H, t, J ¼ 4.8 Hz), 3.19
(2H, t, J ¼ 7.2 Hz), 3.00 (2H, t, J ¼ 8.1 Hz); 13C NMR (CDCl3, 75 MHz) d:
197.7, 158.5, 154.0, 150.7, 136.9, 135.8, 130.1, 128.9, 120.0, 113.5, 66.5,
47.7, 42.1, 40.0, 36.7, 29.9; EI-MS m/z (rel. int.%): 337 (Mþ–C2H3N,11),
336 (47), 204 (22), 190 (100), 163 (16), 132 (40); HRMS calcd. for
C22H26N4O2–C2H3N: 337.1790; found: 337.1791.
1-(4-Morpholin-4-yl-phenyl)-3-[4-(1,4,5,6-tetrahydro-pyrimidin-2-yl-
amino)-phenyl]-propan-1-one (11) was prepared similarly (62%): 1H NMR
(CDCl3, 300 MHz) d: 11.57 (1H, s, –NH), 7.90 (2H, d, J ¼ 8.7 Hz), 7.43 (2H,
d, J ¼ 8.4 Hz), 7.20 (2H, d, J ¼ 8.4 Hz), 6.87 (2H, d, J ¼ 8.7 Hz), 5.56 (1H,
bs, –NH), 3.93 (2H, t, J ¼ 5.7 Hz), 3.87 (4H, t, J ¼ 4.8 Hz), 3.39 (2H, td,
J ¼ 5.7, 2.4 Hz), 3.32 (4H, t, J ¼ 4.8 Hz), 3.22 (2H, t, J ¼ 7.2 Hz), 3.02
(2H, t, J ¼ 7.8 Hz), 2.02 (2H, quin, J ¼ 6.0 Hz); 13C NMR (CDCl3,
75 MHz) d: 197.7, 156.3, 154.1, 152.6, 136.7, 136.2, 130.0, 128.7, 127.6,
120.4, 113.3, 66.5, 47.4, 41.2, 40.9, 39.9, 29.9, 21.4; EI-MS m/z
(rel. int.%): 337 (Mþ–C3H5N,13), 336 (58), 190 (100), 163 (11), 132 (53);
HRMS calcd. for C23H28N4O2–C3H5N: 337.1790; found: 337.1792.
ACKNOWLEDGEMENT
This work was supported by the National Science Council, Taiwan, R.O.C.,
Grant No. NSC92-2113-M415-004.
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Efficient Synthesis of Imidazolines and Tetrahydropyrimidines
2639
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