Synthesis and reactivity of 3-aralkoxy-4-imino-imidazolidin-2-ones: A novel class of 4-iminohydantoins

Article abstract of DOI:10.1016/j.tet.2003.12.068

Reactions of diethylphosphonoalkyl α-aminonitriles with 1,1′-carbonyl-diimidazole or 1,1′-carbonyl-di-(1,2,4-triazole) and O-substituted hydroxylamines under acidic conditions gave 3-alkoxy-4-imino- imidazolidin-2-ones, whereas in presence of triethylamine 4-alkoxy(aralkoxy) imino-imidazolidin-2-ones were formed.

Full text of DOI:10.1016/j.tet.2003.12.068

Tetrahedron 60 (2004) 2409–2416
Synthesis and reactivity of
3-aralkoxy-4-imino-imidazolidin-2-ones:
a novel class of 4-iminohydantoins
*
Thomas Kurz, Detlef Geffken and Khalid Widyan
Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany
Received 6 August 2003; revised 25 November 2003; accepted 23 December 2003
Abstract—Reactions of diethylphosphonoalkyl a-aminonitriles with 1,10-carbonyl-diimidazole or 1,10-carbonyl-di-(1,2,4-triazole) and
O-substituted hydroxylamines under acidic conditions gave 3-alkoxy-4-imino-imidazolidin-2-ones, whereas in presence of triethylamine
4-alkoxy(aralkoxy)imino-imidazolidin-2-ones were formed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Development of preparative simple methods for the
synthesis of new analogs of bioactive heterocyclic com-
pounds represents an important task in synthetic organic and
medicinal chemistry. The hitherto unknown 3-aralkoxy-4-
imino-imidazolidin-2-ones (I) are analogs of 4-imino-
hydantoins (II), a class of compounds which has attracted
considerable attention in medicinal chemistry due to their
antiandrogenic, antineoplastic, immunomodulating and
schistosomicides properties.1–4 Phosphonic acids have
found wide applications as pesticides and pharmaceuticals
and represent important bioisosters of carboxylic acids.5–7
As a part of our ongoing studies on biologically active
phosphonic acids and on the synthesis of new analogs of
bioactive heterocyclic compounds we investigated the
applicability of diethylphosphonoalkyl a-aminonitriles as
starting materials for the synthesis of I (Fig. 1).
a-Aminonitriles (1a–d) have been prepared by Strecker
synthesis and were used for the synthesis of 4, 5 after
1
structure confirmation by H and 13C NMR.8 Successive
treatment of diethylphosphonoalkyl a-aminonitriles (1a–d)
with 1,10-carbonyldiimidazole (CDI) or 1,10-carbonyl-di-
(1,2,4-triazole) (CDT) and O-substituted hydroxylamines
led to open-chained alkoxy(aralkoxy)ureas intermediates
(3), which upon heating in the presence of a base (e.g.,
triethylamine) furnished 4-alkoxy(aralkoxy)-imino-
imidazolidin-2-ones 5, which arose from 4 by base
catalyzed Dimroth rearrangement in 50–75% overall
yield.9,10
The structure of Dimroth rearrangement product 5f was
elucidated by X-ray crystal structure analysis. The crystal
structure clearly showed that the 4-methylbenzyloxy-imino
group is located at the C-3 of the imidazolidine nucleus and
that only a hydrogen atom is attached to the N-1 ring
nitrogen (Fig. 2).
Ring closure of intermediates 3a,b in anhydrous EtOH–HCl
and treatment of the resulting hydrochlorides of 4 with
K2CO3 solution provided the desired isomeric 3-aralkoxy-4-
imino-imidazolidin-2-ones (4a–f) as oily compounds in
60–75% yield (Scheme 1, Table 1).
Figure 1. 3-Aralkoxy-4-imino-imidazolidin-2-ones (I) and 4-iminohydan-
toins (II).
By refluxing 4e in THF for half an hour in presence of
triethylamine we succeeded to prove the rearrangement of
4f to 5f. Discrimination between the structures of com-
pounds 4 and 5 was accomplished by spectroscopic
methods, by treatment of 4, 5 with phenylisocyanate and
by the acidic hydrolysis of 4b into the corresponding
Keywords:
Alkoxy(aralkoxy)imino-imidazolidin-2-ones; Diethylphosphonoalkyl a-
3-Aralkoxy-4-imino-imidazolidin-2-ones;
4-
aminonitriles; Dimroth rearrangement.
*
Corresponding author. Tel.: þ49-40-42838-3467; fax: þ49-40-42838-
6573; e-mail address: kurz@chemie.uni-hamburg.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.068

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T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
Furthermore, reactions of 4a–f with phenylisocyanate
afforded the corresponding urea derivatives 7a–f as stable
and solid compounds in 82–85% yield, whereas no reaction
was observed when 5f was treated with phenylisocyanate
under similar reaction conditions.
Catalytic hydrogenation of 5a and 7a led to semicyclic
hydroxamidines 8a and 10a, which can serve as bioisosters
of hydroxamic acids due to their ability to act as chelators
for various metal cations. Dealkylation of phosphonic esters
5a–d,k and 7b,c with bromotrimethylsilane gave phos-
phonic acids 9a–d,k and 11b,c (Scheme 2).
The structures of all novel compounds were confirmed by
1
IR, H, 13C NMR spectra and mass spectra or elemental
analysis.
Figure 2. Perspective view of the X-ray crystal structure of 5f.
3. Conclusion
imidazolidin-2,4-dione 6. While the IR spectra of 4 where
characterized by strong (CvO) absorption bands at 1758–
1763 cm21, the spectra of 5 showed hypsochromic shifted
In conclusion, we have developed the first synthesis of
3-aralkoxy-4-imino-imidazolidine-2-ones 4 and a new
convenient one pot method for the preparation of
(CvO) absorptions at 1730–1740 cm21
.
4-alkoxy(aralkoxy)imino-imidazolidine-2-ones
5
by
Scheme 1. Synthesis and reactivity of 3-aralkoxy-4-imino-imidazolidin-2-ones (4a–f) and 4-alkoxy(aralkoxy)imino-imidazolidin-2-ones (5a–i). Reagents: i:
CDI or CDT; ii: H2NOR4; iii: Et3N/heating; iv: EtOH-HCl, K2CO3; v: 20% HCl; vi: PhNCO; n¼0, 1; Y¼CH, N; R1, R2, R3¼H, CH3; R4¼C6H5CH2-
C6H5(CH2)2, 4-CH3-C6H4CH2, CH3, 4-Br-C6H4CH2.

T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
2411
Table 1. 3-Aralkoxy-4-imino-imidazolidin-2-ones (4, 7) and 4-alkoxy(ar-
alkoxy)imino-imidazolidin-2-ones (5)
reacting diethylphosphonoalkyl a-aminonitriles with 1,10-
carbonyldiimidazole or 1,10-carbonyl-di-(1,2,4-triazole) and
O-substituted hydroxylamines. Furthermore we got access
to the corresponding hydroxyamidine derivatives 8a, 10a
and phosphonic acids 9, 11.
Compound
n
R1
R2
R3
R4
Yield (%)
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
1
1
1
1
1
1
1
1
1
1
1
1
1
1
0
0
1
1
1
1
1
1
1
1
H
H
CH3 C6H5CH2
CH3 C6H5(CH2)2
CH3 4-CH3-C6H4-CH2
65
75
60
62
68
70
75
70
72
55
52
60
55
60
60
60
52
50
85
85
80
82
83
85
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5CH2
C6H5(CH2)2
4-CH3-C6H4-CH2
4. Experimental
4.1. General
CH3 C6H5CH2
CH3 C6H5(CH2)2
CH3 4-CH3-C6H4-CH2
Melting points (uncorrected) were determined on a Mettler
FP 62 apparatus. Elemental analyses were carried out with a
Heraeus CHN-O-Rapid instrument. IR spectra were
recorded on a Shimadzu FT-IR 8300. 1H NMR
(400.1 MHz) und 13C NMR spectra were recorded on a
Bruker AMX 400 spectrometer using tetramethylsilane as
an internal standard and DMSO-d6, D2O and CDCl3 as
solvents. Mass spectra were recorded on a Finnigan MAT
311A and on a VG 70-250S (VG Analytical) instrument.
Column chromatography was conducted on silica gel (ICN
H
H
H
H
H
H
H
H
H
C6H5CH2
C6H5(CH2)2
4-CH3-C6H4-CH2
CH3
4-Br-C6H4-CH2
C6H5CH2
C6H5(CH2)2
C6H5CH2
CH3
CH3 CH3
CH3 CH3
7a
7b
7c
97d
7e
7f
H
H
H
H
H
H
H
H
H
H
H
H
CH3 C6H5CH2
CH3 C6H5(CH2)2
CH3 4-CH3-C6H4-CH2
˚
Silica 100–200, active 60 A).
H
H
H
C6H5CH2
C6H5(CH2)2
4-CH3-C6H4-CH2
Previously unreported aminonitriles (1c,d) have been
prepared according to an established literature procedure.8
4.1.1. 3-Amino-3-cyano-1,1-dimethyl-propylphosphonic
acid diethyl ester (1c). Colorless oil (94%), 1H NMR
(CDCl3) d (ppm): 1.28 (q, J¼10.43 Hz, 6H), 1.34 (t,
Scheme 2. Synthesis of hydroxyamidines (8a, 10a) and phosphonic acids (9, 11). Reagents: i: H2/Pd-C; ii: TMSBr; R1, R2, R3¼H, CH3; R4¼C6H5CH2,
C6H5(CH2)2, 4-CH3-C6H4CH2, CH3; n¼0, 1.

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T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
J¼7.12 Hz, 6H), 1.78 (s, 2H), 1.91–2.10 (m, 2H), 4.03–
4.18 (m, 5H); 13C NMR (CDCl3) d (ppm): 16.82 (d,
4.2.3. Diethyl 2-[4-imino-5-methyl-3-(4-methylbenzyl-
oxy)-2-oxo-imidazolidin-5-yl]ethylphosphonate (4c).
2
3Jcp¼5.60 Hz), 22.57 (d, Jcp¼3.05 Hz), 23.59 (d,
Colorless oil (60%), IR (film): n¼1758 (CvO), 1682
1
1
2Jcp¼3.56 Hz), 34.34 (d, Jcp¼143.42 Hz), 40.27 (d,
(CvN), 1245, 1220 (PvO), 1057, 1030 (POC), cm21; H
2
3Jcp¼7.63 Hz), 44.07, 62.58 (d, Jcp¼7.63 Hz), 123.37;
NMR (CDCl3) d (ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.38 (s,
3H), 1.47–2.00 (m, 4H), 2.35 (s, 3H), 4.01–4.12 (m, 4H),
5.05 (s, 2H), 6.67 (s, 1H), 7.19 (d, J¼7.63 Hz, 2H), 7.34 (d,
J¼7.89 Hz, 2H); 13C NMR (CDCl3) d (ppm): 16.81 (d,
MS(EI) 248.
4.1.2. 3-Amino-3-cyano-3-methyl-propylphosphonic
acid diethyl ester (1d). Colorless oil (95%), 1H NMR
(CDCl3) d (ppm): 1.34 (t, J¼7.12 Hz, 6H), 1.49 (s, 3H), 1.81
(s, 2H), 1.89–2.03 (m, 4H), 4.07–4.17 (m, 4H); 13C NMR
1
3Jcp¼5.59 Hz), 20.41 (d, Jcp¼143.43 Hz), 21.26, 26.32,
2
3
32.32 (d, Jcp¼3.56 Hz), 59.18 (d, Jcp¼17.81 Hz), 62.30
2
(d, Jcp¼5.59 Hz), 79.15, 129.92, 130.51, 131.50, 139.98,
3
(CDCl3) d (ppm): 16.84 (d, Jcp¼5.59 Hz), 21.55 (d,
153.82, 162.62; MS(EI) 397.
2
1Jcp¼143.44 Hz), 27.55, 35.21 (d, Jcp¼3.96 Hz), 50.23
3
2
(d, Jcp¼19.84 Hz), 62.29 (d, Jcp¼6.61 Hz), 123.98.
4.2.4. Diethyl 2-(3-benzyloxy-4-imino-2-oxo-imidazo-
lidin-5-yl)ethylphosphonate (4d). Colorless oil (62%), IR
(film): n¼1763 (CvO), 1682 (CvN), 1245, 1220 (PvO),
MS(EI) 234.
1
4.2. General procedure for the preparation of 4a–f
1245, 1025 (POC) cm21; H NMR (CDCl3) d (ppm): 1.32
(t, J¼7.12 Hz, 6H),1.68–2.19 (m, 4H), 4.01–4.15 (m, 5H),
4.97–5.14 (m, 2H), 6.66 (s, 1H), 7.33–7.47 (m, 5H); 13C
NMR (CDCl3) d (ppm): 16.82 (d, 3Jcp¼5.59 Hz), 21.43 (d,
A solution of aminonitriles (1a–d) (10 mmol) in anhydrous
THF (10 mL) was added dropwise over a period of 10 min
to a suspension of 1,10-carbonyl-di-(1,2,4-triazole)
(10.5 mmol) in anhydrous THF (10 mL) under ice cooling.
After stirring at room temperature for 10 min a solution of
the appropriate hydroxylamine (10 mmol) was added and
the reaction mixture was stirred at room temperature for 3 h.
The solvent was removed under reduced pressure, the
remaining residue dissolved in EtOAc and washed with
brine and water. The organic layer was dried over MgSO4,
concentrated in vacuo and the resulting oil was dissolved in
anhydrous EtOH–HCl (15 mL). The reaction mixture was
stirred at room temperature for 4 days, the solvent was
evaporated under reduced pressure and the remaining
hydrochlorides of 4a–f were dissolved in water. Afterwards
the pH was adjusted to 8 with K2CO3 solution under ice
cooling in order to liberate the free bases (4a–f). The
aqueous layer was extracted with diethyl ether, dried over
MgSO4 and the solvent was evaporated to give 4a–f as oily
products.
2
1Jcp¼142.42 Hz), 27.05 (d, Jcp¼4.07 Hz), 54.26 (d,
2
3Jcp¼13.73 Hz), 62.43 (d, Jcp¼6.62 Hz), 79.35, 128.09,
129.22, 130.38, 134.48, 152.67, 160.09; MS (EI) 369.
4.2.5. Diethyl 2-(4-imino-2-oxo-3-phenylethyloxy-imida-
zolidin-5-yl)-ethylphosphonate (4e). Colorless oil (68%);
IR (film): n¼1758 (CvO), 1681 (CvN), 1248, 1215
(PvO), 1030 (POC) cm21; 1H NMR (CDCl3) d (ppm): 1.32
(t, J¼7.12 Hz, 6H), 1.73–2.26 (m, 4H), 2.88–3.14 (m, 2H),
3.98–4.19 (m, 5H), 4.27–4.37 (m, 2H), 7.21–7.40 (m, 6H);
13C NMR (CDCl3) d (ppm): 16.82 (d, 3Jcp¼5.60 Hz), 21.61
(d, 1Jcp¼143.44 Hz), 27.10 (d, 2Jcp¼4.58 Hz), 35.00, 54.31
(d, 3Jcp¼12.72 Hz), 62.50 (d, 2Jcp¼3.56 Hz), 75.59, 126.72,
127.27, 128.96, 129.41, 148.25, 154.37; MS(EI) 384.
4.2.6. Diethyl 2-[4-imino-3-(4-methylbenzyloxy)-2-oxo-
imidazolidin-5-yl]ethylphosphonate (4f). Colorless oil
(70%); IR (film): n¼1760 (CvO), 1681 (CvN), 1250,
1225 (PvO), 1020 (POC) cm21 1H NMR (CDCl3) d
;
4.2.1. Diethyl 2-(3-benzyloxy-4-imino-5-methyl-2-oxo-
imidazolidin-5-yl)ethylphosphonate (4a). Colorless oil
(65%), IR (film): n¼1763 (CvO), 1682 (CvN), 1245,
1218 (PvO), 1050, 1025 (POC), cm21; 1H NMR (CDCl3) d
(ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.38 (s, 3H), 1.49–2.01 (m,
4H), 4.02–4.13 (m, 4H), 5.12 (s, 2H), 6.65 (s, 1H), 7.26–
7.40 (m, 5H); 13C NMR (CDCl3) d (ppm): 16.82 (d,
3Jcp¼6.10 Hz), 20.37 (d, 1Jcp¼142.93 Hz), 26.27, 32.26 (d,
(ppm): 1.32 (t, J¼7.12 Hz, 6H), 1.66–2.17 (m, 4H), 2.36 (s,
3H), 4.03–4.16 (m, 5H), 4.93–5.10 (m, 2H), 6.71 (s, 1H),
7.19 (d, J¼7.88 Hz, 2H), 7.33 (d, J¼7.88 Hz, 2H); 13C
NMR (CDCl3) d (ppm): 16.81 (d, 3Jcp¼6.10 Hz), 21.39 (d,
1Jcp¼142.93 Hz), 21.72, 26.99 (d, 2Jcp¼4.07 Hz), 54.24 (d,
2
3Jcp¼13.22 Hz), 62.40 (d, Jcp¼4.58 Hz), 79.23, 128.70,
129.52, 131.50, 139.75, 154.54, 160.45; MS(EI) 384.
3
2Jcp¼3.56 Hz), 59.24 (d, Jcp¼17.29 Hz), 62.37 (d,
4.3. General procedure for the preparation of 5a–l
2Jcp¼6.61 Hz), 79.17, 128.91, 129.63, 130.56, 136.53,
152.04, 160.17; MS(EI) 384.
A solution of aminonitriles (1a–d) (10 mmol) in anhydrous
THF (10 mL) was added dropwise over a period of 10 min
to a suspension of 1,10-carbonyldiimidazole or 1,10-car-
bonyl-di-(1,2,4-triazole) (10.5 mmol) in anhydrous THF
(10 mL) under ice cooling. After stirring at room tempera-
ture for 10 min a solution of the appropriate hydroxylamine
(10 mmol) was added dropwise and the reaction mixture
was stirred at room temperature for 3 h. The solvent was
removed under reduced pressure, triethylamine (2.5 mL)
was added and the reaction mixture was heated to 60–70 8C
for 45–75 min. After cooling to room temperature, the
reaction mixture was dissolved in EtOAc and washed with
brine and water in order to remove 1,2,4-1H-triazole. The
organic layer was dried over MgSO4, concentrated and the
4.2.2. Diethyl 2-(4-imino-5-methyl-2-oxo-3-phenylethyl-
oxy-imidazolidin-5-yl)ethylphosphonate (4b). Colorless
oil (75%); IR (film): n¼1760 (CvO), 1680 (CvN),
1
1248, 1225 (PvO), 1050, 1025 (POC) cm21; H NMR
(CDCl3) d (ppm): 1.31 (t, J¼7.12 Hz, 6H), 1.46 (s, 3H),
1.64–2.09 (m, 4H), 3.05 (t, J¼6.78 Hz, 2H), 4.03–4.13
(m, 4H), 4.29–4.36 (m, 2H), 6.61 (s, 1H), 7.26–7.35 (m,
5H); 13C NMR (CDCl3)
d
(ppm): 16.81 (d,
1
3Jcp¼6.10 Hz), 20.48 (d, Jcp¼142.93 Hz), 26.03, 32.45
2
3
(d, Jcp¼3.56 Hz), 34.98, 59.14 (d, Jcp¼17.29 Hz), 62.40
2
(d, Jcp¼6.10 Hz), 78.12, 127.31, 129.12, 129.27, 137.50,
153.50; MS(EI) 397.

T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
2413
2
remaining oil was crystallized from EtOAc/hexane or
purified by column chromatography on silica gel with
EtOAc or EtOAc/MeOH (9.5:0.5) as eluents to give 5a–l as
colorless solids. Due to its higher reactivity, CDT was used
in case of aminonitriles derived from ketones. In case of
aminonitriles derived from aldehydes CDT led to 6–10%
higher yields than CDI. Yields of compounds 5 are however
reported for reactions run with CDI.
1Jcp¼142.42 Hz), 27.61 (d, Jcp¼4.07 Hz), 54.25 (d,
3Jcp¼15.77 Hz), 61.89 (d, Jcp¼2.55 Hz), 76.13, 127.97,
2
128.12, 128.40, 137.52, 149.92, 156.97. Anal. Calcd for
C16H24N3O5P: C, 52.03; H, 6.55; N, 11.38. Found: C, 51.88;
H, 6.52; N, 11.19.
4.3.5. Diethyl 2-(2-oxo-4-phenylethyloxyimino-imidazo-
lidin-5-yl)ethylphosphonate (5e). Colorless crystals
(52%). Mp 129 8C (EtOAc/hexane); IR (KBr): n¼1740
(CvO), 1676 (CvN), 1245, 1213 (PvO), 1052, 1033
4.3.1. Diethyl 2-(4-benzyloxyimino-5-methyl-2-oxo-imi-
dazolidin-5-yl)ethylphosphonate (5a). Colorless crystals
(75%). Mp 102 8C (EtOAc/hexane); IR (KBr): n¼1736
(CvO), 1678 (CvN), 1247, 1215 (PvO), 1053, 1028
(POC) cm21
;
1H NMR (CDCl3) d (ppm): 1.33 (t,
J¼7.12 Hz, 6H), 1.78–2.18 (m, 4H), 2.95 (t, J¼6.86 Hz,
2H), 4.02–4.12 (m, 4H), 4.19 (t, J¼7.12 Hz, 2H), 4.39 (t,
J¼5.09 Hz, 1H), 6.39 (s, 1H), 7.14–7.28 (m, 5H), 7.50 (s,
(POC) cm21
;
1H NMR (CDCl3) d (ppm): 1.30 (t,
3
J¼7.12 Hz, 6H), 1.45 (s, 3H), 1.54–2.04 (m, 4H), 3.98–
4.13 (m, 4H), 5.00 (s, 2H), 6.18 (s, 1H), 7.28–7.36 (m,
5H), 7.73 (s, 1H); 13C NMR (CDCl3) d (ppm): 16.43
(d, 3Jcp¼6.10 Hz), 20.04 (d, 1Jcp¼142.93 Hz), 26.51, 32.86
1H); 13C NMR (CDCl3) d (ppm): 16.46 (d, Jcp¼6.11 Hz),
21.16 (d, 1Jcp¼142.42 Hz), 27.84 (d, 2Jcp¼4.57 Hz), 35.55,
3
2
54.31 (d, Jcp¼14.24 Hz), 61.99 (d, Jcp¼4.07 Hz), 74.69,
126.34, 128.46, 128.92, 138.49, 149.48, 156.79. Anal. Calcd
for C17H26N3O5P: C, 53.26; H, 6.82; N, 10.96. Found: C,
53.26; H, 7.00; N, 10.96.
2
3
(d, Jcp¼3.56 Hz), 59.98 (d, Jcp¼18.31 Hz), 61.81 (d,
2Jcp¼2.04 Hz), 76.11, 127.94, 128.11, 128.39, 137.54,
152.73, 155.88. Anal. Calcd for C17H26N3O5P: C,
53.25; H, 6.83; N, 10.96. Found: C, 53.13; H, 6.89; N,
10.55.
4.3.6. Diethyl 2-[4-(4-methylbenzyloxyimino)-2-oxo-imi-
dazolidin-5-yl]ethylphosphonate (5f). Colorless crystals
(60%). Mp 98 8C (EtOAc/hexane); IR (KBr): n¼1732
(CvO), 1678 (CvN), 1240, 1210 (PvO), 1048, 1030
4.3.2. Diethyl 2-(5-methyl-2-oxo-4-phenylethyloxyimino-
Colorless
imidazolidin-5-yl)ethylphosphonate
(5b).
(POC) cm21 1H NMR (CDCl3) d (ppm): 1.32 (t,
;
crystals (70%). Mp 115 8C (EtOAc/hexane); IR (KBr):
n¼1740 (CvO), 1678 (CvN), 1248, 1220 (PvO), 1050,
1025 (POC) cm21 1H NMR (CDCl3) d (ppm): 1.32 (t,
;
J¼7.12 Hz, 6H), 1.75–2.11 (m, 4H), 2.34 (s, 3H), 4.03–
4.13 (m, 4H), 4.37 (t, J¼5.34 Hz, 1H), 4.95 (s, 2H), 6.35 (s,
1H), 7.15 (d, J¼7.89 Hz, 2H), 7.89 (d, J¼7.89 Hz, 2H), 7.59
J¼7.12 Hz, 6H), 1.48 (s, 3H), 1.69–2.08 (m, 4H), 2.95 (t,
J¼6.87 Hz, 2H), 4.04–4.14 (m, 4H), 4.19 (t, J¼7.12 Hz,
2H), 6.18 (s, 1H), 7.19–7.31 (m, 5H), 7.53 (s, 1H); 13C
(s, 1H); 13C NMR (CDCl3)
d (ppm): 16.43 (d,
1
3Jcp¼6.10 Hz), 20.89 (d, Jcp¼142.93 Hz), 21.21, 27.67
2
3
(d, Jcp¼4.07 Hz), 54.25 (d, Jcp¼14.75 Hz), 61.94 (d,
2Jcp¼4.07 Hz), 76.09, 128.33, 129.11, 134.37, 137.80,
149.73, 156.74. Anal. Calcd for C17H26N3O5P: C, 53.26;
H, 6.82; N, 10.96. Found: C, 53.21; H, 6.98; N, 10.99,
deposition number for the X-ray crystal structure of 5f:
CCDC 215669.
3
NMR (CDCl3) d (ppm): 16.45 (d, Jcp¼5.59 Hz), 20.26 (d,
2
1Jcp¼142.92 Hz), 26.41, 33.03 (d, Jcp¼3.56 Hz), 35.53,
3
2
59.96 (d, Jcp¼18.31 Hz), 61.87 (d, Jcp¼4.07 Hz), 74.63,
126.32, 128.45, 128.93, 138.52, 152.17, 155.90. Anal. Calcd
for C18H28N3O5P: C, 54.40; H, 7.10; N, 10.57. Found: C,
54.36; H, 7.10; N, 10.49.
4.3.7. Diethyl 2-(4-methoxyimino-2-oxo-imidazolidin-5-
yl)ethylphosphonate (5g). Colorless crystals (55%). Mp
112 8C (EtOAc/hexane); IR (KBr): n¼1736 (CvO), 1678
4.3.3. Diethyl 2-[5-methyl-4-(4-methylbenzyloxyimino)-
2-oxo-imidazolidin-5-yl]ethylphospho-nate (5c). Color-
less crystals (72%). Mp 140 8C (EtOAc/hexane); IR
(KBr): n¼1736 (CvO), 1678 (CvN), 1250, 1217
1
(CvN), 1240, 1211 (PvO), 1050, 1016 (POC) cm21; H
NMR (CDCl3) d (ppm): 1.33 (t, J¼7.12 Hz, 6H), 1.77–2.16
(m, 4H), 3.80 (s, 3H), 4.08–4.15 (m, 4H), 4.39 (t,
J¼5.08 Hz, 1H), 6.34 (s, 1H), 7.63 (s, 1H); 13C NMR
(PvO), 1055, 1022 (POC) cm21 1H NMR (CDCl3) d
;
(ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.46 (s, 3H), 1.53–2.04 (m,
4H), 2.34 (s, 3H), 3.98–4.09 (m, 4H), 4.96 (J¼11.82 Hz,
2H), 6.12 (s, 1H), 7.15 (d, J¼7.63 Hz, 2H), 7.23 (d,
J¼8.14 Hz, 2H), 7.62 (s, 1H); 13C NMR (CDCl3) d (ppm):
16.44 (d, 3Jcp¼5.59 Hz), 20.06 (d, 1Jcp¼142.93 Hz), 21.20,
3
(CDCl3) d (ppm): 16.83 (d, Jcp¼6.11 Hz), 21.43 (d,
2
1Jcp¼142.93 Hz), 28.17 (d, Jcp¼4.07 Hz), 54.67 (d,
2
3Jcp¼15.77 Hz), 62.39 (d, Jcp¼4.58 Hz), 62.44, 149.75,
157.66. MS(FAB); calcd for C10H20N3O5P: 294.1219;
found: 294.1228.
2
3
26.54, 32.91 (d, Jcp¼3.57 Hz), 59.96 (d, Jcp¼17.80 Hz),
2
61.82 (t, Jcp¼5.08 Hz), 76.08, 128.32, 129.09, 134.36,
137.76, 152.50, 155.66. Anal. Calcd for C18H28N3O5P:
C, 54.40; H, 7.10; N, 10.57. Found: C, 54.49; H, 7.13; N,
10.49.
4.3.8. Diethyl 2-[4-(4-bromobenzyloxyimino)-2-oxo-imi-
dazolidin-5-yl]ethylphosphonate (5h). Colorless crystals
(60%). Mp 120 8C (EtOAc/hexane); IR (KBr): n¼1736
(CvO), 1680 (CvN), 1240, 1213 (PvO), 1040, 1016
4.3.4. Diethyl 2-(4-benzyloxyimino-2-oxo-imidazolidin-
5-yl)ethylphosphonate (5d). Colorless crystals (55%). Mp
113 8C (EtOAc/hexane); IR (KBr): n¼1736 (CvO), 1676
(POC) cm21 1H NMR (CDCl3) d (ppm): 1.31 (t,
;
J¼7.12 Hz, 6H), 1.70–2.10 (m, 4H), 4.02–4.12 (m, 4H),
4.37 (t, J¼5.34 Hz, 1H), 4.94 (s, 2H), 6.70 (s, 1H), 7.21 (d,
J¼8.40 Hz, 2H), 7.46 (d, J¼8.40 Hz, 2H), 7.68 (s, 1H); 13C
1
(CvN), 1245, 1210 (PvO), 1016 (POC) cm21; H NMR
3
(CDCl3) d (ppm): 1.31 (t, J¼7.12 Hz, 6H), 1.70–2.10 (m,
4H), 4.02–4.15 (m, 4H), 4.37 (t, J¼5.09 Hz, 1H), 5.00 (s,
2H), 6.47 (s, 1H), 7.28–7.35 (m, 5H), 7.76 (s, 1H); 13C
NMR (CDCl3) d (ppm): 16.44 (d, Jcp¼6.10 Hz), 20.80 (d,
2
1Jcp¼142.93 Hz), 27.60 (d, Jcp¼4.07 Hz), 54.25 (d,
2
3Jcp¼15.77 Hz), 61.97 (d, Jcp¼2.54 Hz), 75.27, 129.77,
3
NMR (CDCl3) d (ppm): 16.43 (d, Jcp¼5.59 Hz), 20.79 (d,
131.52, 135.14, 136.67, 150.19, 157.13. Anal. Calcd for

2414
T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
C16H23BrN3O5P: C, 42.87; H, 5.17; N, 9.37. Found: C,
42.93; H, 5.17; N, 9.38.
(15 mL, 20%) was added to a solution of 4b (3 mmol) in
THF (3 mL) and the mixture was stirred at room
temperature for 2 h. The mixture was extracted with
CH2Cl2, the combined extracts were dried over MgSO4
and the solvent was evaporated. The resulting residue was
chromatographed using EtOAc/MeOH (95:5) to give 6.
Colorless oil (60%); IR (film): n¼1784, 1732 (CvO), 1220
4.3.9. Diethyl (4-benzyloxyimino-2-oxo-imidazolidin-5-
yl)methylphosphonate (5i). Colorless crystals (60%). Mp
110 8C (EtOAc/hexane); IR (KBr): n¼1730 (CvO), 1686
1
(CvN), 1240, 1207 (PvO); 1050, 1030 (POC) cm21; H
NMR (CDCl3) d (ppm): 1.34 (t, J¼7.12 Hz, 6H), 1.71–2.16
(m, 2H), 4.10–4.18 (m, 4H), 4.54 (t, J¼8.39 Hz, 1H), 5.00
(s, 2H), 7.26 (s, 1H), 7.29–7.38 (m, 5H), 7.66 (s, 1H); 13C
(PvO), 1050, 1025 (POC) cm21 1H NMR (CDCl3) d
;
(ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.43 (s, 3H), 1.63–2.06 (m,
4H), 3.09 (t, J¼7.38 Hz, 2H), 4.03–4.14 (m, 4H), 4.34 (t,
J¼7.38 Hz, 2H), 7.07 (s, 1H), 7.20–7.30 (m, 5H); 13C NMR
3
NMR (CDCl3) d (ppm): 16.43 (t, Jcp¼5.60 Hz), 31.63 (d,
2
3
1Jcp¼140.89 Hz), 49.70 (d, Jcp¼5.09 Hz), 62.33 (d,
(CDCl3) d (ppm): 16.39 (d, Jcp¼5.59 Hz), 19.56 (d,
2Jcp¼6.61 Hz), 76.30, 128.09, 128.18, 128.44, 137.26,
1Jcp¼143.43 Hz), 23.51, 30.38 (d, Jcp¼3.56 Hz), 34.44,
2
3
3
2
149.63 (d, Jcp¼19.83 Hz), 155.77. Anal. Calcd for
59.66 (d, Jcp¼16.79 Hz), 62.25 (d, Jcp¼4.07 Hz), 78.14,
126.71, 128.60, 128.96, 138.68, 152.57, 170.78. Anal. Calcd
for C18H27N2O6P: C, 54.26; H, 6.83; N, 7.03. Found: C,
54.22; H, 6.95; N, 7.06.
C15H22N3O5P: C, 50.70; H, 5.95; N, 11.82. Found: C,
50.34; H, 6.26; N, 11.69.
4.3.10. Diethyl (2-oxo-4-phenylethyloxyimino-imidazol-
idin-5-yl)methylphosphonate (5j). Colorless crystals
(60%). Mp 138 8C (EtOAc/hexane); IR (KBr): n¼1736
(CvO), 1684 (CvN), 1250, 1210 (PvO), 1050, 1025
4.4. General procedure for the preparation of 7a–f
Phenylisocyanate (3 mmol) was added to a solution of 4a–f
(3 mmol) in anhydrous THF (10 mL) under ice cooling, and
the reaction mixture was stirred at room temperature for
30 min. The solvent was evaporated under reduced pressure
and the remaining oil was purified by column chromato-
graphy on silica gel with EtOAc/MeOH (9.5:0.5) as an
eluent. Crystallization from EtOAc/hexane afforded 7a–f as
colorless solids.
(POC) cm21
;
1H NMR (CDCl3) d (ppm): 1.35 (t,
J¼7.12 Hz, 6H), 1.97–2.39 (m, 2H), 2.95 (t, J¼7.12 Hz,
2H), 4.07–4.16 (m, 4H), 4.20 (t, J¼6.87 Hz, 2H), 4.56 (m,
1H), 5.91 (s, 1H), 7.19–7.32 (m, 5H), 7.53 (s, 1H); 13C
3
NMR (CDCl3) d (ppm): 16.44 (t, Jcp¼6.10 Hz), 31.68 (d,
1Jcp¼140.89 Hz), 35.56, 49.70 (d, 2Jcp¼5.09 Hz), 62.36 (d,
2Jcp¼6.61 Hz), 74.78, 126.35, 128.47, 128.92, 138.43,
3
149.22 (d, Jcp¼19.83 Hz), 155.82. Anal. Calcd for
C16H24N3O5P: C, 52.03; H, 6.54; N, 11.37.Found: C,
52.17; H, 6.70; N, 11.41.
4.4.1. Diethyl 2-(3-benzyloxy-5-methyl-2-oxo-4-phenyl-
carbamoylimino-imidazolidin-5-yl)-ethylphosphonate
(7a). Colorless crystals (85%). Mp 103 8C (EtOAc/hexane);
IR (KBr): n¼1773, 1713 (CvO), 1647 (CvN), 1245, 1220
(PvO), 1050, 1030 (POC) cm21 1H NMR (CDCl3) d
;
4.3.11. Diethyl 2-(4-benzyloxyimino-2-oxo-imidazolidin-
5-yl)-1,1-dimethylethylphosphonate
(5k).
Colorless
crystals (52%). Mp 133 8C (EtOAc/hexane); IR (KBr):
n¼1730 (CvO), 1674 (CvN), 1240, 1209 (PvO), 1055,
1025 (POC) cm21; 1H NMR (CDCl3) d (ppm): 1.23 (q, 6H),
1.33 (t, J¼7.12 Hz, 6H), 1.71–2.08 (m, 2H), 4.08–4.19 (m,
4H), 4.42 (d, J¼10.68 Hz, 1H), 5.00 (s, 2H), 7.26 (s, 1H),
7.30–7.36 (m, 5H), 7.38 (s, 1H); 13C NMR (CDCl3) d
(ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.63 (s, 3H), 1.82–2.25 (m,
4H), 4.02–4.13 (m, 4H), 5.19 (q, J¼8.51 Hz, 2H), 6.85 (s,
1H), 7.05–7.49 (m, 10H), 7.66 (s, 1H); 13C NMR (CDCl3) d
(ppm): 16.39 (d, Jcp¼5.60 Hz), 19.87 (d, Jcp¼142.96),
25.44, 31.79 (d, 2Jcp¼2.54 Hz), 62.19, 62.22, 78.89, 119.35,
123.44, 128.27, 128.84, 129.08, 129.08, 130.30, 133.30,
152.90, 160.82, 167.46. Anal. Calcd for C24H31N4O6P: C,
57.36; H, 6.21; N, 11.14. Found: C, 57.16; H, 6.38; N, 10.94.
3
1
3
(ppm): 16.49 (d, Jcp¼5.6 Hz), 21.05, 26.05 (d,
1
1Jcp¼4.58 Hz), 33.62 (d, Jcp¼142.42 Hz), 45.45, 51.37
3
2
(d, Jcp¼2.04 Hz), 62.49 (d, Jcp¼7.12 Hz), 76.13, 128.00,
128.17, 128.40, 137.38, 151.46, 155.82. Anal. Calcd for
C18H28N3O5P: C, 54.40; H, 7.10; N, 10.57. Found: C, 54.45;
H, 7.06; N, 10.58.
4.4.2. Diethyl 2-(5-methyl-2-oxo-3-phenylethyloxy-4-
phenylcarbamoylimino-imidazolidin-5-yl)ethylphospho-
nate(7b). Colorless crystals (85%). Mp 123 8C (EtOAc/
hexane); IR (KBr): n¼1768, 1718 (CvO),1648 (CvN),
1245, 1220 (PvO), 1050, 1025 (POC) cm21 1H NMR
;
4.3.12. Diethyl 2-(4-methoxyimino-2-oxo-imidazolidin-5-
yl)-1,1-dimethylethylphosphonate (5l). Colorless crystals
(50%). Mp 139 8C (EtOAc/hexane); IR (KBr): n¼1740
(CvO), 1676 (CvN), 1250, 1210 (PvO), 1057, 1025
(POC) cm21; 1H NMR (CDCl3) d (ppm): 1.24 (q, 6H), 1.33
(t, J¼7.12 Hz, 6H), 1.78–2.10 (m, 2H), 3.80 (s, 3H), 4.10–
4.17 (m, 4H), 4.44 (d, J¼10.93 Hz, 1H), 7.28 (s, 1H), 7.69
(CDCl3) d (ppm): 1.29 (t, J¼7.12 Hz, 6H), 1.61 (s, 3H),
1.82–2.24 (m, 4H), 2.75–2.95 (s, br 2H), 4.03–4.13 (m,
4H), 4.32–4.39 (m, 2H), 6.89 (s, 1H), 7.04–7.69 (m, 10H),
7.69 (s, 1H); 13C NMR (CDCl3) d (ppm): 16.39 (t,
1
3Jcp¼5.60 Hz), 19.80 (d, Jcp¼142.42 Hz), 25.42, 31.78
2
(d, Jcp¼3.56 Hz), 34.15, 60.41, 62.24, 77.72, 118.88,
(s, 1H); 13C NMR (CDCl3)
d
(ppm): 16.46 (d,
120.08, 123.34, 128.46, 128.60, 128.86, 138.69, 138.70,
152.82, 160.00, 168.10. Anal. Calcd for C25H33N4O6P: C,
58.13; H, 6.43; N, 10.84. Found: C, 58.23; H, 6.57; N, 10.80.
2
3Jcp¼5.60 Hz), 21.05, 26.02 (d, Jcp¼4.07 Hz), 33.62 (d,
1Jcp¼142.42 Hz), 45.48, 51.33 (d, Jcp¼2.03 Hz), 61.94,
3
2
62.42 (d, Jcp¼7.12 Hz), 150.97, 156.24. Anal. Calcd for
C12H24N3O5P: C, 44.85; H, 7.52; N, 13.07. Found: C, 44.97;
H, 7.49; N, 13.04.
4.4.3. Diethyl 2-[4-methyl-3-(4-methylbenzyloxy)-2-oxo-
4-phenylcarbamoyliminoimidazolidin-5-yl]ethylphos-
phonate (7c). Colorless crystals (80%). Mp 113 8C (EtOAc/
hexane); IR (KBr): n¼1778, 1707 (CvO), 1646 (CvN),
1250, 1230 (PvO), 1048, 1025 (POC) cm21 1H NMR
;
4.3.13. Diethyl 2-(5-methyl-2,4-dioxo-3-phenylethoxy-
imidzoldin-5-yl)ethylphosphonate (6). Aqueous HCl

T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
2415
(CDCl3) d (ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.62 (s, 3H),
1.74–2.04 (m, 4H), 2.28 (s, 3H), 4.01–4.12 (m, 4H), 5.14
(q, J¼8.39 Hz, 2H), 6.83 (s, 1H), 6.90–7.40 (m, 9H), 7.66
(92%). Mp 189 8C (EtOAc/hexane); IR (KBr): n¼1718
(CvO), 1691 (CvN), 1245, 1225 (POC), 1050, 1028
(PvO) cm21 1H NMR (DMSO-d6) d (ppm): 1.22 (t,
;
(s, 1H); 13C NMR (CDCl3)
d
(ppm): 16.79 (d,
J¼7.12 Hz, 6H), 1.27 (s, 3H), 1.45–1.77 (m, 4H), 3.91–
4.08 (m, 4H), 7.44 (s, 1H), 9.70 (s, 1H), 9.77 (s, 1H); 13C
NMR (DMSO-d6) d (ppm): 16.17 (d, 3Jcp¼5.59 Hz), 19.56
(d, 1Jcp¼140.90 Hz), 26.03, 32.87 (d, 2Jcp¼3.05 Hz), 58.23
1
3Jcp¼5.60 Hz), 19.75 (d, Jcp¼142.42 Hz), 21.69, 25.81
32.17, 62.56, 62.62, 79.21, 119.68, 123.83, 128.80, 129.22,
129.35, 130.72, 130.70, 138.90, 152.93, 160.71, 167.72.
Anal. Calcd for C25H33N4O6P: C, 58.13; H, 6.43; N, 10.84.
Found: C, 58.04; H, 6.47; N, 10.83.
3
2
(d, Jcp¼19.84 Hz), 60.96 (d, Jcp¼6.62 Hz), 152.39,
156.37. Anal. Calcd for C10H20N3O5P: C, 40.95; H, 6.87;
N, 14.32. Found: C, 40.70; H, 7.01; N, 14.20.
4.4.4. Diethyl 2-(3-benzyloxy-2-oxo-4-phenylcarbamoyl-
imino-imidazolidin-5-yl)ethylphosphonate (7d). Color-
less crystals (82%). Mp 101 8C (EtOAc/hexane); IR
(KBr): n¼1778, 1710 (CvO), 1666 (CvN), 1245, 1220
4.5.2. Diethyl 2-(3-hydroxy-5-methyl-2-oxo-4-phenyl-
carbamoylimino-imidazolidin-5-yl)ethyl-phosphonate
(10a). Colorless crystals (90%). Mp 189 8C (EtOAc/
hexane); IR (KBr): n¼1792, 1724 (CvO), 1655 (CvN),
(PvO), 1050, 1025 (POC) cm21 1H NMR (CDCl3) d
;
(ppm): 1.25 (d, J¼7.13 Hz, 6H), 1.75–2.30 (m, 4H), 4.01–
4.20 (m, 4H), 4.79 (s, 1H), 5.19 (s, 2H), 6.90 (s, 1H), 7.10–
7.40 (m, 10H), 7.50 (s, 1H); 13C NMR (CDCl3) d (ppm):
1250, 1225 (PvO), 1050, 1020 (POC) cm21 1H NMR
;
(DMSO-d6) d (ppm): 1.21 (t, J¼7.12 Hz, 6H), 1.41 (s, 3H),
1.63–1.99 (m, 4H), 3.94–4.02 (m, 4H), 6.96–7.44 (m, 5H),
3
1
16.44 (d, Jcp¼5.60 Hz), 21.45 (d, Jcp¼143.44 Hz), 25.02
7.55 (s, 1H), 8.22 (s, 1H), 9.49 (s, 1H); 13C NMR (DMSO-
2
3
3
(d, Jcp¼4.58 Hz), 54.90 (d, Jcp¼11.70 Hz), 62.20 (d,
2Jcp¼6.61 Hz), 78.80, 120.21, 123.45, 128.51, 128.89,
129.13, 129.24, 130.07, 130.25, 153.01, 160.11, 167.73.
Anal. Calcd for C23H29N4O6P: C, 56.55; H, 5.98; N, 11.46.
Found: C, 56.65; H, 6.12; N, 11.40.
d6)
d
(ppm): 16.14 (d, Jcp¼6.11 Hz), 20.50 (d,
1Jcp¼143.94 Hz), 24.88, 31.59, 61.03, 61.07, 118.05,
121.67, 128.66, 139.62, 152.44, 159.69, 167.83. Anal.
Calcd for C17H25N4O6P: C, 49.51; H, 6.11; N, 13.68.
Found: C, 49.32; H, 5.93; N, 13.69.
4.4.5. Diethyl 2-(2-oxo-3-phenylethyloxy-4-phenylcarba-
moylimino-imidazolidin-5-yl)ethyl-phosphonate
4.6. General procedure for the preparation of
phosphonic acids 9,11
(7e).
Colorless crystals (83%). Mp 118 8C (EtOAc/hexane); IR
(KBr): n¼1775, 1710 (CvO), 1660 (CvN), 1248, 1228
(PvO), 1048, 1030 (POC) cm21 1H NMR (CDCl3) d
;
Bromotrimethylsilane (6 mmol) was added to a solution of 5
or 7 (1 mmol) in dry CH2Cl2 (10 mL) under ice cooling and
the reaction mixture was stirred at room temperature for
24 h. The solvent was evaporated and the residue was
dissolved in THF (3 mL). Water (0.1 mL) was added and the
mixture was stirred for 10 min. Afterwards EtOAc (10 mL)
was added and a solid product was filtrated and recrystal-
lized from CH2Cl2/MeOH/EtOAc to yield colorless solids.
(ppm): 1.30 (t, J¼7.12 Hz, 6H), 1.80–2.30 (m, 4H), 2.75–
2.90 (br, 2H), 4.08–4.20 (m, 4H), 4.30–4.39 (m, 2H), 4.80
(s, 1H), 6.90 (s, 1H), 7.10–7.60 (m, 11H); 13C NMR
3
(CDCl3) d (ppm): 16.40 (t, Jcp¼6.10 Hz), 21.40 (d,
2
1Jcp¼143.43 Hz), 25.02 (d, Jcp¼4.55 Hz), 34.20, 54.91
(d, 3Jcp¼14.24 Hz), 62.19 (d, 2Jcp¼6.61 Hz), 78.80, 118.22,
120.96, 123.53, 128.77, 129.00, 129.24, 130.07, 138.50,
153.01, 160.21, 167.70. Anal. Calcd for C24H31N4O6P: C,
57.36; H, 6.21; N, 11.14. Found: C, 57.27; H, 6.42; N, 10.88.
4.6.1. 2-(4-Benzyloxyimino-5-methyl-2-oxo-imidazoli-
din-5-yl)ethylphosphonic acid (9a). Colorless crystals
(82%). Mp 192 8C; IR (KBr): n¼2890 (POH), 1740
4.4.6. Diethyl 2-[3-(4-methylbenzyloxy)-2-oxo-4-phenyl-
carbamoylimino-imidazolidin-5-yl]-ethylphosphonate
(7f). Colorless crystals (85%). Mp 113 8C (EtOAc/hexane);
IR (KBr): n¼1772, 1705 (CvO), 1660 (CvN), 1245, 1218
(CvO), 1680 (CvN), 1215 (PvO) cm21 1H NMR
;
(DMSO-d6) d (ppm): 1.25 (s, 3H), 1.30–1.74 (m, 4H),
4.94 (s, 2H), 7.24–7.39 (m, 5H), 7.61 (s, 1H), 10.08 (s, 1H);
13C NMR (DMSO-d6) d (ppm): 22.42 (d, 1Jcp¼138.35 Hz),
(PvO), 1052, 1020 (POC) cm21
;
1H NMR (CDCl3) d
26.39, 34.09 (d, Jcp¼3.05 Hz), 59.10 (d, Jcp¼19.33 Hz),
75.13, 127.72, 127.86, 128.43, 138.58, 154.47, 156.57.
Anal. Calcd for C13H18N3O5P: C, 47.71; H, 5.54; N, 12.84.
Found: C, 47.53; H, 5.69; N, 12.51.
2
3
(ppm): 1.28 (t, J¼6.87 Hz, 6H), 1.77–1.91 (m, 4H), 2.34 (s,
3H), 4.01–4.12 (m, 4H), 4.97 (s, 1H), 5.16 (s, 2H), 7.07–
7.62 (m, 11H); 13C NMR (CDCl3) d (ppm): 16.32 (d,
3Jcp¼6.10 Hz), 21.33 (d, 1Jcp¼143.40), 26.17 (d,
3
2Jcp¼4.58 Hz), 54.46 (d, Jcp¼14.24 Hz), 62.17 (d,
4.6.2. 2-(5-Methyl-2-oxo-4-phenethyloxyimino-imidazo-
lidin-5-yl)ethylphosphonic acid (9b). Colorless crystals
(80%). Mp 199 8C; IR (KBr): n¼2885 (POH), 1735 (CvO),
2Jcp¼6.61 Hz), 78.79, 119.00, 120.25, 123.47, 123.79,
129.01, 129.15, 130.31, 138.30, 152.70, 160.73, 167.26.
Anal. Calcd for C24H31N4O6P: C, 57.36; H, 6.21; N, 11.14.
Found: C, 57.35; H, 6.45; N, 10.92.
1
1675 (CvN), 1220 (PvO) cm21; H NMR (DMSO-d6) d
(ppm): 1.29 (s, 3H), 1.40–1.84 (m, 4H), 2.88 (t, J¼6.87 Hz,
2H), 4.04 (t, J¼6.61 Hz, 2H), 7.19–7.30 (m, 5H), 7.60 (s,
1H), 9.94 (s, 1H); 13C NMR (DMSO-d6) d (ppm): 22.55 (d,
1Jcp¼137.84 Hz), 26.41, 34.21, 35.25, 59.10 (d,
3Jcp¼19.33 Hz), 74.12, 126.36, 126.58, 129.40, 139.16,
154.01, 156.61. Anal. Calcd for C14H20N3O5P: C, 49.26; H,
5.90; N, 12.31. Found: C, 48.98; H, 6.11; N, 12.02.
4.5. General procedure for the preparation 8a, 10a
Compounds 5a,7a were hydrogenated in MeOH using
catalytic amounts of 10% Pd/C for 3 h. The suspension was
filtrated and the solvent was evaporated.
4.5.1. Diethyl 2-(4-hydroxyimino-5-methyl-2-oxo-imida-
zolidin-5-yl)ethylphosphonate (8a). Colorless crystals
4.6.3. 2-[5-Methyl-4-(4-methylbenzyloxyimino)-2-oxo-
imidazolidin-5-yl]ethylphosphonic acid (9c). Colorless

2416
T. Kurz et al. / Tetrahedron 60 (2004) 2409–2416
crystals (80%). Mp 205 8C; IR (KBr): n¼2900 (POH), 1735
(CvO), 1670 (CvN), 1225 (PvO) cm21 1H NMR
4.6.7. 2-(5-Methyl-4-methylbenzyloxy-2-oxo-4-phenyl-
carbamoylimino-imidazolidin-5-yl)ethylphosphonic
acid (11c). Colorless crystals (70%). Mp 204 8C; IR (KBr):
n¼2885 (POH), 1775, 1705 (CvO), 1650 (CvN), 1230
;
(DMSO-d6) d (ppm): 1.25 (s, 3H), 1.39–1.73 (m, 4H),
2.28 (s, 3H), 4.88 (s, 2H), 7.14 (d, J¼7.88, 2H), 7.26 (d,
J¼7.88, 2H), 7.61 (s, 1H), 10.04 (s, 1H); 13C NMR (DMSO-
d6) d (ppm): 21.13, 22.42 (d, 1Jcp¼138.35 Hz), 26.40, 34.12,
1
(PvO) cm21; H NMR (DMSO-d6) d (ppm): 1.29 (s, 3H),
1.43–1.99 (m, 4H), 2.60 (s, 3H), 5.01 (s, 1H), 6.86–7.43
(m, 9H), 8.80 (s, 1H); 13C NMR (DMSO-d6) d (ppm): 21.23,
22.36 (d, 1Jcp¼137.84 Hz), 23.36, 31.62 (d, 2Jcp¼2.54 Hz),
3
59.07 (d, Jcp¼19.32 Hz), 75.06, 128.01, 129.00, 135.50,
136.87, 154.35, 156.57. Anal. Calcd for C14H20N3O5P: C,
49.26; H, 5.90; N, 12.31. Found: C, 49.00; H, 6.10; N, 12.12.
3
59.13 (d, Jcp¼19.33 Hz), 78.55, 118.06, 118.35, 121.38,
128.92, 129.29, 130.17, 140.90, 153.78, 171.76. Anal. Calcd
for C21H25N4O6P: C, 54.78; H, 5.47; N, 12.16. Found: C,
54.54; H, 5.27; N, 11.93.
4.6.4. 2-(4-Benzyloxyimino-2-oxo-imidazolidin-5-
yl)ethylphosphonic acid (9d). Colorless crystals (82%).
Mp 204 8C; IR (KBr): n¼2880 (POH), 1740 (CvO), 1670
(CvN), 1215 (PvO) cm21; 1H NMR (DMSO-d6) d (ppm):
1.63–1.85 (m, 4H), 4.22 (t, J¼6.61 Hz, 1H), 4.94 (q,
J¼12.84 Hz, 2H), 7.32–7.39 (m, 5H), 7.68 (s, 1H), 10.11 (s,
Acknowledgements
1H); 13C NMR (DMSO-d6)
d
(ppm): 23.16 (d,
1Jcp¼138.35 Hz), 28.98, 53.79 (d, Jcp¼18.82 Hz), 75.09,
127.73, 127.88, 128.47, 138.71, 151.62, 157.72. Anal. Calcd
for C12H16N3O5P: C, 46.01; H, 5.14; N, 13.41. Found: C,
45.80; H, 5.28; N, 13.21.
The authors thank Professor Dr. J. Kopf for his valuable help
in the preparation of the X-ray crystal structure.
2
4.6.5. 2-(4-Benzyloxyimino-2-oxo-imidazolidin-5-yl)-1,1-
dimethylethylphosphonic acid (9k). Colorless crystals
(83%). Mp 200 8C; IR (KBr): n¼2895 (POH), 1735
References and notes
1. Perronnet, J. M.; Girault, P.; Bonne, C. (Roussel-UCLAF).
Ger. Offen. 2,649,925 (Cl C07D23/64), May 12, 1977; Chem.
Abstr. 1977, 87, 85005z.
(CvO), 1670 (CvN), 1210 (PvO) cm21
;
1H NMR
(DMSO-d6) d (ppm): 1.09 (q, 6H), 1.74–1.79 (m, 2H),
4.33 (t, J¼6.11 Hz, 1H), 4.94 (q, J¼12.71 Hz, 2H), 7.26–
7.89 (m, 5H), 7.71 (s, 1H), 10.12 (s, 1H); 13C NMR (DMSO-
2. Bernauer, K.; Link, H.; Stohler, H. (Hoffmann-La Roche, F.,
und Co. AG.). Ger. Offen. 3.846,946 (Cl. C07D133/66), May
3, 1979; Chem. Abstr. 1979, 97, 57020q.
1
d6) d (ppm): 22.08, 24.45 (d, Jcp¼2.54 Hz), 33.14 (d,
3
1Jcp¼138.86 Hz), 44.14, 50.84 (d, Jcp¼7.12 Hz), 75.08,
3. Short, K. M.; Ching, B. W.; Mjalli, A. M. M. Tetrahedron Lett.
1996, 37, 7489–7492.
127.72, 127.85, 128.45, 138.67, 152.80, 157.54. Anal. Calcd
for C14H20N3O5P: C, 49.26; H, 5.90; N, 12.31. Found: C,
48.98; H, 6.15; N, 12.01.
4. Link, H.; Stohler, H. L. Eur. J. Med. Chem. 1984, 3, 261–265.
5. Dutra, G. A. (Monsanto Co.). Ger. Offen. 2,700,017 (Cl.
C07F9/38), July 14, 1977; Chem. Abstr. 1978, 88, 74538v.
6. Kuroda, Y.; Okuhara, M.; Goto, T.; Okamoto, M.; Terano, H.;
Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1980, 33,
29–35.
4.6.6. 2-(5-Methyl-2-oxo-3-phenylethyloxy-4-phenyl-
carbamoyl-iminoimidazolidin-5-yl)ethyl-phosphonic
acid (11b). Colorless crystals (75%). Mp 216 8C; IR (KBr):
n¼2880 (POH), 1765, 1720 (CvO), 1650 (CvN), 1215
7. Morphy, J. R.; Beeley, N. R. A.; Boyce, B. A.; Leonard, J.;
Mason, B.; Millican, A.; Millar, K.; O’Connell, J. P.; Porter, J.
Bioorg. Med. Chem. Lett. 1994, 4, 2747–2752.
8. Varlet, J. M.; Fabre, G.; Sauveur, F.; Collignon, N.; Savignac,
P. Tetrahedron 1981, 37, 1377–1384.
1
(PvO) cm21; H NMR (DMSO-d6) d (ppm): 1.30 (s, 3H),
1.46–1.99 (m, 4H), 2.96 (t, J¼7.12 Hz, 2H), 4.24 (t,
J¼6.87 Hz, 2H), 6.88 (s, 1H), 7.18–7.46 (m, 10H), 8.60 (s,
1H); 13C NMR (DMSO-d6)
d
(ppm): 21.36 (d,
1Jcp¼137.84 Hz), 23.38, 31.62 (d, Jcp¼2.54 Hz), 59.04,
59.23, 78.55, 118.06, 120.92, 121.38, 128.92, 129.29,
130.17, 139.61, 152.78, 164.78, 171.76. Anal. Calcd for
C21H25N4O6P: C, 54.78; H, 5.47; N, 12.16. Found: C, 54.94;
H, 5.62; N, 11.89.
2
9. Fujii, T.; Tanaka, F.; Mohri, K.; Itaya, T. Chem. Pharm. Bull.
1974, 22, 2211–2216.
10. Fujii, T.; Itaya, T.; Wu, C. C. K.; Tanaka, F. Tetrahedron
1971, 27, 2415–2423.