Novel structural analogs of glyphosate based on azoles. 1. Synthesis of 1H-imidazoles containing carboxyl and phosphoryl groups in the ring

Article abstract of DOI:10.1007/s10593-011-0717-0

A general method has been developed for the synthesis of 1H-imidazoles containing a phosphoryl group in positions 2 or 4(5) based on lithium intermediates. The possibility of further functionalization of the ring using electrophiles has also been demonstrated.

Full text of DOI:10.1007/s10593-011-0717-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 1, April, 2011 (Russian Original Vol. 47, No. 1, January, 2011)
NOVEL STRUCTURAL ANALOGS OF GLYPHOSATE
BASED ON AZOLES. 1. SYNTHESIS OF 1H-IMIDAZOLES
CONTAINING CARBOXYL AND PHOSPHORYL GROUPS
IN THE RING
N. V. Pavlenko1, T. I. Oos1, Yu. L. Yagupolskii1*,
A. van Almsick2, and L. Willms2
A general method has been developed for the synthesis of 1H-imidazoles containing a phosphoryl group
in positions 2 or 4(5) based on lithium intermediates. The possibility of further functionalization of the
ring using electrophiles has also been demonstrated.
Keywords: imidazole, lithium intermediates, electrophiles, hydrolysis, protecting groups, phosphorylation.
Glyphosate (N-phosphonomethylglycine 1 [1]) is the active component of the very efficient,
ecologically clear herbicide Roundup® with a broad spectrum of activity. The commercial success of glyphosate
has stimulated a vigorous search for similar phosphonates with improved biological properties [2]. Cyclic
structural analogs of N-phosphonomethylglycine, e.g. 5-phosphonoproline 2 [3] and 3-hydroxy-1,2,4-triazol-
5-ylphosphonic acid 3 [4] have also been prepared.
N
N
HOOC
P(O)(OH)2
N
H
HOOC
P(O)(OH)2
P(O)(OH)2
N
N
H
HO
H
1
2
3
Until now, compounds in this series with biological activity comparable to that of glyphosate have not
been discovered. Continuing our search in this direction we have turned to developing novel spatial structures
for this herbicide based on imidazole. The synthesis of the structural mimetics of glyphosate 4 and 5, as chosen
on the basis of molecular modelling, is the goal of our study.
_______
* To whom correspondence should be addressed, e-mail: Yagupolskii@ioch.kiev.ua.
1Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kyiv 02094, Murmanska Str., 5,
Ukraine.
2Bayer CropScience GmbH, Chemistry Frankfurt, G 836, Industriepark Höchst, Frankfurt am Main 65926,
Germany.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 52-62, January 2011. Original
article submitted March 29, 2010.
36
0009-3122/11/4701-0036©2011 Springer Science+Business Media, Inc.

There are several examples of the electrophilic introduction of phosphorus-containing substituents into
an imidazole ring in the literature. Thus imidazol-2-ylphosphinic acids were prepared by the phosphorylation of
N-substituted imidazoles by P(III) [5] and P(V) [6, 7] acid chlorides. Reaction of 1,2-disubstituted imidazoles
with P(III) halo derivatives in pyridine gave a series of 5-phosphorylated imidazoles with substituent at
positions 1 and 2 in the heterocycle [8]. Phosphorylation of imidazole in position 4(5) has also been reported in
a publication [9] for the Pd-catalyzed reaction of 4(5)-bromoimidazoles with diethylphosphite and in a patent
[10] which describes the reaction of the corresponding lithio imidazole derivatives with diethylchlorophosphate.
H
HOOC
N
HOOC
N
N
N
H
P(O)(OH)2
P(O)(OH)2
5
4
There are several methods reported in the literature for the construction of imidazol-4(5)-
ylphosphonates, viz. heterocyclization of functionalized enamines [11], the base-catalyzed cycloaddition of
diethyl isocyanomethylphosphonate to imidoylchlorides [12], and the condensation of secondary amines with
diethyl (2,2-dichloro-1-isocyanoethenyl)phosphonate [13]. Finally, a method has been reported for the synthesis
of diethyl 2-(ethoxycarbonyl)imidazol-4(5)-ylphosphonate through the thermal rearrangement of a functionalized
O-vinyl-oxime [14].
For preparing 2- and 4(5)-phosphorylated 1H-imidazoles we have turned to the widespread used for
functionalization of this heterocycle method of the metallation of N-substituted imidazoles and subsequent
reaction of the carbanions obtained with the appropriate electrophiles [15]. The generation of the carbanions was
brought about using BuLi. As electrophiles for the introduction of a phosphoryl group we used the P(V) and
P(III) compounds (Et2O)2P(O)Cl and (Et2N)2PCl. For protection of the nitrogen atom of the imidazole ring, two
alkyl type groups were used, viz. benzyl and [2-(trimethylsilyl)ethoxy]methyl (SEM) and the electron- acceptor
dimethylsulfamoyl group SO2NMe2.
This investigation began with a study of the C-2 phosphorylation of imidazoles having the three types of
protecting groups noted above with the (Et2O)2P(O)Cl as electrophile and this allowed the introduction of a
fragment with a tetracoordinated phosphorus atom into the imidazole ring.
1. BuLi,
2. (EtO)2P(O)Cl
N
N
N
N
P(O)(OEt)2
SO2NMe2
SO2NMe2
6
All three examples gave a complex reaction mixture from which only the imidazole 6 could be isolated
in a yield of ~ 8%. The use of bis(diethylamino)chlorophosphite in place of the chlorophosphate and subsequent
oxidation of the P(III) derivatives 7a-c gave the 2-phosphorylated imidazoles 8a-c.
1. BuLi,
2. (Et2N)2PCl
N
N
N
15% H2O2
P(O)(NEt2)2
P(NEt2)2
N
R
N
R
N
R
8а–c
c R = SEM (38%)
7а–c
a R = SO2NMe2 (85%),
b R = CH2Ph (33%),
37

The imidazole 8a formed in high yield can be hydrolyzed by hydrochloric acid to give the N-substituted
imidazolylphosphonic acid 9. Saponification of compound 8a removed the N-protection to give the known
phosphonamide 10 [7] which was converted to the imidazol-2-ylphosophonic acid 11 with acid.
_
+
+
N
N
N
H
OH
H
8a
P(O)(NEt2)2
N
H
N
H
N
P(O)(OH)2
P(O)(OH)2
SO2NMe2
10
11
9
Treatment of compound 8a with BuLi generates a carbanion at position 5 of the heterocycle [15] which
gives the imidazole 12 in 92% yield upon carboxylation.
The N-sulfamoyl protection in compound 12 can be readily removed by the action of dilute HCl at 20ºC
to give the hydrochloride 13 which yields the target imidazole 4 upon refluxing with HCl. It should be noted
that compound 4 is formed in 62% yield since partial decarboxylation to the phosphonic acid 11 occurs in the
course of the hydrolysis.
1. BuLi,
2. CO2
N
.
HCl, 100°C
N
HCl
HCl, 20°C
4
8a
HOOC
P(O)(NEt2)2
N
H
LiOOC
P(O)(NEt2)2
SO2NMe2
12
N
13
Phosphorylation at position 5 of the N-substituted imidazole ring using lithium reagents is only possible
in those cases where the 2 position is protected. We have used the readily available and readily removed
Me2(t-Bu)Si group (TBDMS) [16] which is stable to lithiation and migration and used the electron-acceptor
sulfamoyl group (based on the positive results we obtained for the synthesis of imidazole 4) as protection for the
heterocyclic N atom.
Stepwise lithiation of 1-(N,N-dimethylsulfamoyl)imidazole with successive addition of the Si- and then
the P-electrophile gave compound 14, oxidation of which in aqueous-acetone medium is accompanied by
desilylation to give the phosphonamide 15 in high yield.
1. BuLi,
2. (Et2N)2PCl
1. BuLi,
2. Me2(t-Bu)SiCl
N
N
N
N
Si
SO2NMe2
SO2NMe2
_
OH
N
N
N
15% H2O2
N
Si
P(NEt2)2
P(O)(NEt2)2
SO2NMe2
14
SO2NMe2
15
N
+
N
H
N
H
N
P(O)(NEt2)2
P(O)(OH)2
H
16
17
38

Saponification of compound 15 occurred with removal of the ring N-protection to give the 1H-imidazole
16, from which refluxing in hydrochloric acid gave imidazol-4(5)-ylphosphonic acid 17. Lithiation and
subsequent carboxylation of phosphonamide 15 allowed us to prepare compound 18 as the key precursor of
imidazole 5.
1. BuLi,
2. CO2
–
+
N
OH or H
16
15
LiOOC
N
P(O)(NEt2)2
SO2NMe2
18
Hydrolysis of the 1,2,5-functionalized imidazole 18 in both acid and basic conditions is accompanied by
decarboxylation to yield the phosphonamide 16. This did not prove unexpected to us as the low stability of
imidazol-2-ylcarboxylic acids is well known. In addition, the carboxyl group can be used as a C(2)-protecting
group in the lithiation of N-substituted imidazoles at the 5 position of the ring [17]. None the less we decided to
repeat the synthesis of the precursor of imidazole 5 by the scheme reported above using N–SEM protection
which can be removed using F- in anhydrous media [18]. Carrying out this synthesis gave unexpected results in
that the imidazole phosphorylation occurred only at the ring position 2 despite the fact that TBDMS protection
(which was stable to migration) had been used for blocking this position.
1. BuLi,
2. Me2(t-Bu)SiCl
1. BuLi,
2. (Et2N)2PCl
N
O
P
N
N
N
8c
+
N
N
Si
Si
3. 15% H2O2
N
N
NEt2
O
O
O
O
Si
Si
Si
19
The appearance of the bis(imidazolyl)phosphonamide 19 can be explained by assuming the formation of
Et2NPCl2 in the reaction course as the product of disproportionation of the electrophilic (Et2N)2PCl reagent used.
In order to prepare the precursor of the target imidazole 5 with N–SEM protection we first alkylated the
phosphonamide 16 with SEMCl to give a mixture of isomers 20 and 21 in the ratio ~ 6:1.
P(O)(NEt2)2
N
N
1. MeONa,
2. SEMCl
+
N
N
16
P(O)(NEt2)2
O
O
20
21
Si
Si
Compounds 20 and 21 were separated by column chromatography. The major 1,4-isomer 20 was
lithiated and then reacted with CO2 and chloroformate.
39

Salt 22 and ester 23 were separated and characterized. However we were unable to remove the
N-protection using F- in this case (Me4NF, glyme or acetonitrile) while also retaining the carboxyl function at
ring position 2.
P(O)(NEt2)2
N
2. CO2
LiOOC
22
N
Si
O
1. BuLi
20
P(O)(NEt2)2
N
2. ClCOOMe
N
MeOOC
23
Si
O
Based on the experiments reported we can conclude that preparation of imidazole 5 or its NH-precursor
does not appear possible using lithium reagents.
Unfortunately, initial experiments with imidazole 4 did not reveal biological activity comparable with
that of glyphosate. However, we have been able to develop a general method for the synthesis of 1H-imidazoles
which contain a phosphoryl group both at position 2 and at position 5 of the ring via use of lithium reagents and
this allows further functionalization of the heterocycle using various electrophile.
EXPERIMENTAL
1H and 31P NMR spectra were recorded on a Varian VXR-300 instrument (300 and 121 MHz
respectively) using DMSO-d6 (compound 4), CDCl3 (compounds 6, 8a-c, 12, 15, 16, 19-23) and D2O
(compounds 9, 11, 13, 17, 18) with the undeuterated solvent as internal standard. Chromatography was carried
out on Fluka 40-60 m silica gel and Aldrich Dowex WX-50 ion exchange resin. The purity of the compounds
prepared was monitored by TLC on Silufol UV-254 plates. All of the operations connected with the lithiation
and alkylation of the heterocycles were carried out under an argon atmosphere with solvents purified by a
standard method. The hydrolysis reaction course was monitored by the 31P NMR method.
Phosphorylation of N-substituted Imidazoles at Position 2 of the Heterocycle (General Method). A
solution of the N-substituted imidazole (5 mmol) in anhydrous THF (30 ml) was cooled to -80ºC and a solution
of BuLi (2.5 M solution, 2.2 ml, 5.5 mmol) in hexane was added dropwise, the solution was maintained at this
temperature for 30 min. A solution of (Et2N)2PCl or (EtO)2P(O)Cl (5.5 mmol) in THF (10 ml) was added
dropwise maintaining the reaction mixture temperature at -80 ± 2ºC. The product was stirred at this temperature
for 30 min, the temperature raised to 20ºC, and stirring was continued for 12 h. Solvent was evaporated in vacuo
and the residue was dissolved in acetone (10 ml), cooled to 0ºC, and hydrogen peroxide (15%, 5ml) was added
dropwise. The product was stirred for 5 h at 20ºC, acetone evaporated in vacuo, the residue diluted with water to
a volume of 30 ml, and extracted with ether. The extract was dried over MgSO4, ether was evaporated in vacuo,
and the residue was purified either by crystallization of by chromatography on SiO2.
Diethyl (1-Dimethylsulfamoyl-1H-imidazol-2-yl)phosphonate (6) was prepared chromatographically
1
(eluent ethyl acetate) as a pale-yellow, waxy material (8%) with Rf 0.86 (ethyl acetate). H NMR spectrum, ,
3
3
3
ppm (J, Hz): 1.37 (6H, t, J = 7.0, CH2CH3); 2.99 (6H, s, NCH3); 4.28 (4H, quin, J = 7.0, JHP = 7.0,
POCH2CH3); 7.18 (1H, br. s, H-4); 7.44 (1H, d, 3J = 1.5, H-5). 31P NMR spectrum, , ppm: 1.5 (m). Found, %:
C 35.23; H 6.11. C9H18N3O5PS. Calculated, %: C 34.72; H 5.83.
40

(1-Dimethylsulfamoyl-1H-imidazol-2-yl)phosphonic Acid Bis(diethylamide) (8a) was prepared by
freezing out from hexane as a pale-yellow, crystalline material (85%) with mp 75ºC and Rf 0.75 (ethyl acetate–
1
3
methanol, 2:1). H NMR spectrum, , ppm (J, Hz): 1.09 (12H, t, J = 7.0, CH2CH3); 3.02 (6H, s, NCH3);
3.00-3.20 (8H, m, PNCH2CH3); 7.13 (1H, m, H-4); 7.48 (1H, m, H-5). 31P NMR spectrum, , ppm: 16.5 (m).
Found, %: N 19.36. C13H28N5O3PS. Calculated, %: N 19.17.
(1-Benzyl-1H-imidazol-2-yl)phosphonic Acid Bis(diethylamide) (8b) was prepared chromato-
graphically (eluent ethyl acetate–hexane, 1:1) as a colorless, viscous oil (33%) with Rf 0.19 (ethyl acetate–
1
3
hexane, 1:1). H NMR spectrum, , ppm (J, Hz): 0.94 (12H, t, J = 7.0, CH2CH3); 3.00 (8H, m, PNCH2CH3);
5.64 (2H, s, NCH2Ph); 6.95 (1H, m, H-4); 7.15 (1H, m, H-5); 7.20 (5H, m, H arom). 31P NMR spectrum, , ppm:
15.6 (m). Found, %: C 62.41; H 8.03. C18H29N4OP. Calculated, %: C 62.05; H 8.39.
{1-[2-(Trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl}phosphonic Acid Bis(diethylamide) (8c) was
separated chromatographically (eluent hexane–ethyl acetate, 8:5) as a colorless oil (38%). 1H NMR spectrum, ,
ppm (J, Hz): -0.07 (9H, s, Si(CH3)3); 0.87 (2H, t, 3J = 8.5, CH2Si); 0.99 (12H, t, 3J = 7.0, CH2CH3); 3.06 (8H, m,
3
3
PNCH2CH3); 3.53 (2H, t, J = 8.5, OCH2CH2); 5.81 (2H, s, NCH2O); 7.15 (1H, d, J = 1.4, H-4); 7.25 (1H, d,
3J = 1.4, H-5). 31P NMR spectrum, , ppm (J, Hz): 16.4 (m, JPH = 14.5). Found, %: C 52.40; H 9.28.
3
C17H37N4O2PSi. Calculated, %: C 52.55; H 9.60.
(1-Dimethylsulfamoyl-1H-imidazol-2-yl)phosphonic Acid (9). Compound 8a (0.4 g, 1.1 mmol) was
hydrolyzed in HCl (5 N, 15 ml) for ~ 16 h at 80ºC. The obtained solution was extracted with chloroform, the
aqueous solution evaporated to dryness, and the residue was triturated with ether to give compound 9 (0.24 g,
89%) as a colorless powder with mp 284ºC. 1H NMR spectrum, , ppm: 2.65 (6H, s, NCH3); 7.16 (1H, m, H-4);
7.17 (1H, m, H-5). 31P NMR spectrum, , ppm: -10.0 (m). Found, %: N 16.09. C5H10N3O5PS. Calculated, %: N
16.47.
(1H-Imidazol-2-yl)phosphonic Acid (11). A solution of KOH (2%, 25 ml) was added to a solution of
imidazole 8a in alcohol (15 ml) and refluxed for ~ 24 h. Alcohol was evaporated off and the residue was
extracted with ether, the extract dried over MgSO4, and the ether evaporated to give amide 10 (0.48 g) [7] which
was 90% pure according to 1H and 31P NMR data. HCl (5 N, 20 ml) was added and the product was refluxed for
~ 12 h. The solution obtained was extracted with chloroform, the water evaporated, and the residue
1
recrystallized to give acid 11 (0.17 g, 53%) as a colorless, hygroscopic powder with mp 169ºC (ethanol). H
NMR spectrum, , ppm: 7.27 (1H, s, H-4); 7.29 (1H, s, H-5). 31P NMR spectrum, , ppm: -8.8 (s). Found, %:
C 24.12; H 3.48; N 18.51. C3H5N2O3P. Calculated, %: C 24.34; H 3.40; N 18.93.
Lithium Salt of 2-[Bis(diethylamino)phosphoryl]-1-(N,N-dimethylsulfamoyl)-1H-imidazole-
5-carboxylic Acid (12). A solution of BuLi (2.5 M, 2.3 ml, 5.75 mmol) in hexane was added dropwise to a
solution of imidazole 8a (1.89 g, 5.18 mmol) in THF (50 ml) cooled to -80ºC. It was held at this temperature for
30 min and an excess of gaseous CO2 was passed through the reaction mixture regulating the flow such that the
temperature was maintained at -80±2ºC. The product was held at this temperature for 30 min, heated to 20ºC
over 3 h, and held at this temperature for 12 h. Solvent was evaporated in vacuo and the residue was dissolved in
moist acetone, filtered, and the salt 12 (2.0 g, 92%) was precipitated using ether as a light-gray powder with mp
182ºC (decomp.). 1H NMR spectrum, , ppm (J, Hz): 0.99 (12H, t, 3J = 7.0, CH2CH3); 2.86 (6H, s, NCH3); 3.00
(8H, m, PNCH2CH3); 7.21 (1H, m, H-4). 31P NMR spectrum, , ppm: 17.7 (m). Found, %: C 39.94; H 6.37;
N 16.38. C14H27LiN5O5PS. Calculated, %: C 40.48; H 6.55; N 16.86.
2-[Bis(diethylamino)phosphoryl]-3H-imidazole-4-carboxylic Acid Hydrochloride (13). Salt 12
(1.3 g, 3.13 mmol) was stirred in HCl (5 N, 15 ml) for 12 h at 20ºC, the solution obtained was evaporated to
dryness, and the residue was triturated with acetone to give hydrochloride 13 (0.82 g, 78%) as a white powder
1
3
with mp 178ºC (decomp.). H NMR spectrum, , ppm (J, Hz): 0.80 (12H, t, J = 7.0, CH2CH3); 2.88 (8H, dq,
3JPH = 11.0, J = 7.0, PNCH2CH3); 7.91 (1H, d, JPH = 2.0, H-4). P NMR spectrum, , ppm: 13.2 (m). Found,
3
4
31
%: C 42.47; H 6.54; N 16.44. C12H24ClN4O3P. Calculated, %: C 42.54; H 7.14; N 16.54.
41

2-Phosphono-1H(3H)-imidazole-4(5)-carboxylic acid (4). The hydrochloride 13 (0.52 g, 1.54 mmol)
was heated at 70ºC in HCl (5 N, 10 ml) for ~ 48 h, periodically cooling the reaction mixture and filtering off the
1
precipitated imidazole 4. According to H and 31P NMR data the filtrate accumulated the phosphonic acid
decarboxylation product 11. Compound 4 (0.18 g, 62%) was obtained as colorless crystals with mp 291ºC
1
(decomp.) (water). H NMR spectrum, , ppm: 5.91 (1H, br. s, NH); 8.05 (1H, s, H-4). 31P NMR spectrum, ,
ppm: -7.6. Found, %: C 24.84; H 3.04. C4H5N2O5P. Calculated, %: C 25.01; H 2.62.
Phosphorylation of the N-Substituted Imidazoles at Position 5 of the Heterocycle (General
Method). BuLi (2.5 M, 4.4 ml, 11 mmol) in hexane was added dropwise to a solution of the N-substituted
imidazole (10 mmol) in anhydrous THF (50 ml) held at -80ºC. This temperature was maintained for 30 min, the
temperature raised to 20ºC, and stirred for 1 h. The reaction mixture was then cooled to -80ºC, a further aliquot
of BuLi (11 mmol) was added dropwise, held for 30 min, and (Et2N)2PCl (2.31 g, 11 mmol) in THF (10 ml) was
added. Stirring was continued at this temperature for 1 h, the temperature was raised to 20ºC over 3 h, and the
product was held for a further 12 h. Solvent was removed in vacuo and the residue was dissolved in acetone
(20 ml), cooled to 0ºC, and hydrogen peroxide (15%, 10 ml) was added dropwise. Stirring was continued at
20ºC for 5 h, acetone was evaporated in vacuo, the residue was diluted with water to a volume of 50 ml, and
extracted with ether. The extract was dried over MgSO4, ether was evaporated in vacuo, and the residue was
purified either by crystallization or chromatographically on SiO2.
(1-Dimethylsulfamoyl-1H-imidazo-5-yl)phosphonic Acid Bis(diethylamide) (15) was prepared
chromatographically on SiO2 (eluent ethyl acetate) as a pale-yellow, waxy material (72%). 1H NMR spectrum, ,
ppm (J, Hz): 1.03 (12H, t, 3J = 7.0, CH2CH3); 2.98 (6H, s, NCH3); 3.04 (8H, m, PNCH2CH3); 7.22 (1H, m, H-4);
8.06 (1H, m, H-2). 31P NMR spectrum, , ppm: 14.80 (m). Found, %: C 42.92; H 8.12. C13H28N5O3PS.
Calculated, %: C 42.73; H 7.72.
[3H(1H)-Imidazol-4(5)-yl]phosphonic Acid Bis(diethylamide) (16). Imidazole 15 (1.6 g, 4.38 mmol)
was dissolved in alcohol (15 ml), KOH solution (2%, 25 ml) was added, and refluxed for ~ 28 h. The reaction
mixture was extracted with ether, the aqueous layer was evaporated to dryness, and the residue was purified by
1
freezing out from hexane to give compound 16 (0.94 g, 83%) as pale-yellow crystals with mp 67ºC. H NMR
3
spectrum, , ppm (J, Hz): 1.01 (12H, t, J = 7.0, CH2CH3); 3.06 (8H, m, PNCH2CH3); 7.33 (1H, m, H-4(5));
4
7.48 (1H, br. s, NH); 7.67 (1H, d, JPH = 1.5, H-2). 31P NMR spectrum, , ppm: 15.80 (m). Found, %: C 50.91;
H 8.89. C11H23N4OP. Calculated, %: C 51.14; H 8.97.
[3H(1H)-Imidazol-4(5)-yl]phosphonic Acid (17). Amide 16 (0.35 g, 1.36 mmol) was hydrolyzed at
60ºC in HCl (5 N, 10 ml) for ~ 12 h. The reaction mixture was extracted with chloroform, the aqueous layer was
evaporated to dryness, and the residue was dissolved in NH4OH solution (10%, 10 ml). The product was stirred
for 15 min, evaporated to dryness, and the residue was triturated with acetone to give a crystalline product which
was dissolved in water (5 ml). Chromatography of the obtained solution on H+ form ion exchange resin gave the
1
acid hydrate 17 (0.16, 80%) as a white powder with mp 127ºC. H NMR spectrum, , ppm: 7.18 (1H, br. s, H-
4(5)); 8.37 (1H, br. s, H-2). 31P NMR spectrum, , ppm: -4,5 (br. s). Found, %: C 21.27; H 4.38; N 16.72.
C3H7N2O4P. Calculated, %: C 21.69; H 4.25; N 16.87.
Lithium Salt of 5-[Bis(diethylamino)phosphoryl]-1-(dimethylsulfamoyl)-1H-imidazole-2-carboxylic
Acid (18). The synthesis was carried out as for compound 12. Amide 15 (2.25 g, 6.16 mmol) gave compound 18
1
(1.9 g, 74%) as a pale-yellow, hygroscopic powder with mp ˃ 300ºC. H NMR spectrum, , ppm (J, Hz): 0.89
3
4
(12H, t, J = 7.0, CH2CH3); 2.79 (6H, s, NCH3); 2.91 (8H, m, PNCH2CH3); 7.13 (1H, d, JPH = 2.4, H-4). 31P
NMR spectrum, , ppm: 19.9 (m). Found, %: C 40.06; H 6.83; N 16.48. C14H27LiN5O5PS. Calculated, %:
C 40.48; H 6.55; N 16.86.
Bis(1-[2-(trimethylsilyl)ethoxymethyl]-1H-imidazol-2-yl)phosphinic Acid Diethylamide (19). N–SEM-
imidazole (2 g, 10.1 mmol) gave a reaction mixture which was chromatographed on SiO2 using gradient elution
with mixtures of hexane and ethyl acetate (5:1 going to 1:1) to yield the imidazole 8c (0.52 g) (eluent hexane–
ethyl acetate, 3: 1) and compound 19 (0.18 g, 3.5%) (eluent hexane–ethyl acetate, 1:1) as a pale-yellow, waxy
42

1
3
material. H NMR spectrum, , ppm (J, Hz): -0.06 (18H, s, SiCH3); 0.83 (4H, m, CH2Si); 1.12 (6H, t, J = 7.0,
CH2CH3); 3.30 (4H, dq, 3JPH = 14.0, 3J = 7.0, PNCH2CH3); 3.48 (4H, m, OCH2CH2); 5.72 (4H, s, NCH2O); 7.27
(2H, d, J = 1.4, H-4(5)); 7.32 (2H, d, J = 1.4, H-5(4)). 31P NMR spectrum, , ppm (J, Hz): 9.59 (quin,
3
3
3JPH = 14.0). Found, %: C 51.61; H 8.75. C22H44N5O3PSi2. Calculated, %: C 51.43; H 8.63.
Alkylation of Phosphonamide 16 Using SEMCl. A solution of compound 16 (2.88 g, 11 mmol) in
anhydrous THF (30 ml) was cooled to -78ºC and a solution of BuLi (2.5 M, 4.6 ml, 11.5 mmol) in hexane was
added dropwise. The solution was held at the same temperature for 15 min, then a solution of SEMCl (1.92g,
15 mmol) in THF (10 ml) was added dropwise. the product was held for 15 min, the temperature raised to 20ºC,
and stirred for 2 h. THF was evaporated off, HCl (1 N, 30 ml) was added to the residue at 0ºC, and the product
was extracted with ethyl acetate, and dried over MgSO4. Solvent was evaporated off and the residue was
chromatographed with gradient elution successively with ethyl acetate and a mixture of ethyl acetate–methanol
(10:1) to give the isomeric imidazoles 20 and 21.
(1-[2-(Trimethylsilyl)ethoxymethyl]-1H-imidazol-4-yl)phosphonic Acid Bis(diethylamide) (20).
Compound 20 (1.69 g, (40%) (eluent ethyl acetate–methanol 10:1) was separated as a pale-yellow oil with
1
Rf 0.54 (ethyl–acetate, methanol, 10:1). H NMR spectrum, , ppm (J, Hz): -0.07 (9H, s, SiCH3); 0.87 (2H, t,
3
3J = 8.5, CH2Si); 1.02 (12H, t, J = 7.0, CH2CH3); 3.10 (8H, m, PNCH2CH3); 3.44 (2H, t, 3J = 8.5, OCH2CH2);
5.28 (2H, s, NCH2O); 7.69 (1H, d, 3JPH = 2.1, H-5); 7.77 (1H, br. s, H-2). 31P NMR spectrum, , ppm: 20.9 (m).
Found, %: C 52.81; H 9.98. C17H37N4O2PSi. Calculated, %: C 52.54; H 9.60.
(1-[2-(Trimethylsilyl)ethoxymethyl]-1H-imidazol-5-yl)phosphonic Acid Bis(diethylamide) (21).
Compound 21 (0.29 g, 7%) (eluent ethyl acetate) was separated as a light-yellow oil with Rf 0.73 (ethyl acetate–
1
3
methanol, 10:1). H NMR spectrum, , ppm (J, Hz): -0.04 (9H, s, SiCH3); 0.88 (2H, t, J = 8.5, CH2Si); 1.02
3
3
(12H, t, J = 7.0, CH2CH3); 3.04 (8H, m, PNCH2CH3); 3.55 (2H, t, J = 8.5, OCH2CH2); 5.62 (2H, s, NCH2O);
7.26 (1H, br. s, H-4); 7.83 (1H, br. s, H-2). 31P NMR spectrum, , ppm: 17.73 (m). Found, %: C 52.93; H 9.78.
C17H37N4O2PSi. Calculated, %: C 52.54; H 9.60.
Lithium Salt of 1-[2-(Trimethylsilyl)ethoxymethyl]-4-[bis(diethylamino)phosphoryl]-1H-imidazole-
2-carboxylic Acid (22). Prepared by the method for synthesis of compound 12. Compound 20 (0.27 g,
0.69 mmol) was carboxylated and the residue after evaporation of THF was extracted with refluxing hexane and
1
frozen out of hexane solution to give the imidazole 22 (0.12 g, 40%) as colorless crystals with mp 198ºC. H
3
3
NMR spectrum, , ppm (J, Hz): -0.06 (9H, s, SiCH3); 0.87 (2H, t, J = 8.5, CH2Si); 0.97 (12H, t, J = 7.0,
3
CH2CH3); 3.07 (8H, m, PNCH2CH3); 3.57 (2H, t, J = 8.5, OCH2CH2); 5.72 (2H, s, NCH2O); 7.67 (1H, d,
3JPH = 2.0, H-5). 31P NMR spectrum, , ppm: 25.1 (m). Found, %: C 48.82; H 8.34; N 13.08. C18H36LiN4O4PSi.
Calculated, %: C 49.30; H 8.28; N 12.78.
Methyl (1-[2-(Trimethylsilyl)ethoxymethyl]-4-[bis(diethylamino)phosphoryl]-1H-imidazole-2-carb-
oxylate (23). Compound 20 (1.29 g, 3.3 mmol) was lithiated using the method for compound 12. ClCOOMe
(0.35 g, 3.65 mmol) was added dropwise to the solution at -78ºC, the reaction mixture was stirred at this
temperature for 30 min, and then for 12 h at 20ºC. THF was evaporated off and the residue at 0ºC was treated
with HCl (1 N, 30 ml), extracted with ethyl acetate, the solution dried over MgSO4, the solvent was evaporated,
and residue was chromatographed using ethyl acetate as eluent to give compound 23 (0.42 g, 29%) as a viscous,
colorless oil. 1H NMR spectrum, , ppm (J, Hz): -0.08 (9H, s, SiCH3); 0.89 (2H, t, 3J = 8.5, CH2Si); 1.03 (12H,
t, 3J = 7.0, CH2CH3); 3.10 (8H, m, PNCH2CH3); 3.52 (2H, t, 3J = 8.5, OCH2CH2); 3.92 (3H, s, OCH3); 5.72 (2H,
s, NCH2O); 7.85 (1H, br. s, H-5). 31P NMR spectrum, , ppm: 21.5 (m). Found, %: C 50.86; H 8.12; N 13.10.
C19H39N4O4PSi. Calculated, %: C 51.10; H 8.80; N 12.55.
REFERENCES
1.
2.
J. E. Franz, Ger. Pat. 2327680 (1973); Chem. Abstr., 80, 70958 (1974).
L. Maier, Heteroatom Chem., 11, 454 (2000).
43

3.
4.
5.
P. J. Diehl and L. Maier, Phosphorus, Sulfur, Relat. Elem., 18, 482 (1983).
D. K. Anderson, D. L. Deuwer, and J. A. Sikorski, J. Heterocycl. Chem., 32, 893 (1995).
A. A. Tolmachev, A. A. Yurchenko, A. V. Rozhenko, and M. G. Semenova, Zh. Obshch. Khim., 63,
1911 (1993).
6.
7.
8.
I. V. Komarov, M. Yu. Kornilov, A. V. Turov, M. V. Gorichko, V. O. Popov, A. A. Tolmachev, and
A. J. Kirby, Tetrahedron, 51, 12417 (1995).
I. V. Komarov, A. V. Strizhak, M. Yu. Kornilov, A. N. Kostyuk, and A. A. Tolmachev, Synth.
Commun., 28, 2355 (1998).
A. A. Yurchenko, A. N. Huryeva, E. V. Zarudnitskii, A. P. Marchenko, G. N. Koidan, and
A. M. Pinchuk, Heteroatom Chem., 20, 289 (2009).
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
J. Lin and Ch. M. Thompson, J. Heterocycl. Chem., 31, 1701 (1994).
M. A. Poss, US Pat. 5208234 (1993); Chem. Abstr., 119, 139549 (1993).
F. Palacios, A. M. O. de Retana, J. Oyarzabal, and J. M. Ezpeleta, Tetrahedron, 54, 2281 (1998).
W. Huang and C. Yan, Synthesis, 511 (1996).
M. Schnell, M. Ramm, and A. Kockritz, J. Prakt. Chem., 336, 29 (1994).
M. Vuilhorgne, J. Malpart, S. Mutti, and S. Mignani, J. Heterocycl. Chem., 40, 159 (2003).
B. Iddon and R. I. Ngochindo, Heterocycles, 38, 2487 (1994).
R. I. Ngochindo, J. Chem. Soc., Perkin Trans. 1, 1645 (1990).
G. Shapiro and B. Gomez-Lor, J. Org. Chem., 59, 5524 (1994).
B. H. Lipshutz, B. Huff, and W. Hagen, Tetrahedron Lett., 29, 3411 (1988).
44