Preparation of new imidazol-2-yl-(amino)methylphosphonates, phosphinates and phosphine oxides and their unexpected cleavage under acidic conditions

Article abstract of DOI:10.1016/j.tet.2011.11.054

The efficient synthesis of new imidazol-2-yl-(amino)methylphosphonic acids, phosphonates phosphinate esters and phosphine oxides is described. The synthetic methodology is based on nucleophilic addition of phosphorus species to imidazole-2 derived imines.

Full text of DOI:10.1016/j.tet.2011.11.054

Tetrahedron 68 (2012) 1223e1229
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of new imidazol-2-yl-(amino)methylphosphonates, phosphinates
and phosphine oxides and their unexpected cleavage under acidic conditions
*
Bogdan Boduszek, Tomasz K. Olszewski , Waldemar Goldeman, Kamila Grzegolec, Patrycja Blazejewska
Faculty of Chemistry, Department of Organic Chemistry, Wroclaw University of Technology, Wybrzeze St. Wyspianskiego 27, 50-370 Wroclaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2011
Received in revised form 31 October 2011
Accepted 21 November 2011
Available online 27 November 2011
The efficient synthesis of new imidazol-2-yl-(amino)methylphosphonic acids, phosphonates phosphi-
nate esters and phosphine oxides is described. The synthetic methodology is based on nucleophilic
addition of phosphorus species to imidazole-2 derived imines. Additionally, it was discovered that
heating the imidazol-2-yl-(amino)methylphosphonates with aqueous HCl or H2SO4 leads to their de-
composition resulting in a rupture of the CeP bond, elimination of the phosphorous-containing fragment
and formation of the corresponding secondary imidazole-2 alkylamines. A mechanistic pathway for the
cleavage is postulated.
Keywords:
Imidazole
Aminophosphonates
Heterocycles
Imines
Ó 2011 Elsevier Ltd. All rights reserved.
Cleavage
1. Introduction
diazoles are known to possess antibiotic and antifungal activities.2 In
addition, these heterocycles include inhibitors of p38 MAP kinases,
Imidazole is a common heterocyclic fragment of many highly
significant naturally occurring small molecules, such as histidine,
histamine, adenine, biotin etc.1 Additionally, imidazole derivatives
are well-known structural scaffolds in medicinal chemistry endowed
with numerous important activities (Fig. 1). Members of this class of
a subgroup of mitogen-activated protein kinases, thought to be in-
volved in a variety of inflammatory and immunological disorders.3
On the other hand, as phosphorus analogues of natural amino-
carboxylic acids, a-aminomethylphosphonic acids, their phospho-
nate and phosphinate esters and short peptides incorporating this
fragment exhibit a variety of intriguing biological properties, and
thus they have found diverse applications in many areas of modern
medicine and agriculture.4
Based on the aforementioned facts, the union of a heteroaromatic
fragment with a phosphorous-containing moiety could result in
valuable chemical and biological properties of such heteroaromatic
phosphonates and their derivatives, and thus the development of new
protocols leading to these compounds would be especially desirable.5
As a part of our continuous interest in the preparation of new
heteroaromatic phosphonates,6 we describe the results of a study on
the synthesis of new imidazol-2-yl-(amino)methylphosphonic acids,
their phosphonateand phosphinate esters, and phosphine oxides and
the unusual cleavage of these compounds under acidic conditions.
2. Results and discussion
2.1. Preparation of imdazol-2-yl-(amino)
Fig. 1. Imidazole derivatives in nature and medicine.
methylphosphonates phosphinates and phosphonic acids
Initially, we have examined the preparation of imdazol-2-yl-
(amino)methylphosphonic and phenylphosphinic ethyl esters 3
* Corresponding author. Tel./fax: þ48 71 328 4064; e-mail address: tom-
asz.olszewski@pwr.wroc.pl (T.K. Olszewski).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.054

1224
B. Boduszek et al. / Tetrahedron 68 (2012) 1223e1229
and diphenylphosphine oxides 4 by addition of, respectively,
diethyl phosphite, ethyl phenylphosphinate, or diphenylphosphine
oxide to imidazole derived imines 2. Imines were prepared in situ
from imidazole-2-carboxaldehyde (1) and secondary amines
(benzyl and n-butyl amine) (Scheme 1, Table 1). Addition of phos-
phorus nucleophiles to imines 2 proceeded well at reflux in tolu-
ene. After 2 h the reaction was complete and the desired products
3aed and 4a,b were formed. Diethyl phosphonate esters 3a,b were
isolated and characterized as oxalate salts obtained by treatment of
the crude esters 3a,b with oxalic acid [(COOH)2$2H2O] in acetone.
In turn, phosphinate esters 3c,d and phosphine oxides 4a,b were
purified, without recourse to chromatography, by simple crystalli-
zation from a mixture of toluene/hexane.
reacted with silylated phosphorous esters to give the silylated es-
ters 5, as intermediates, which were subsequently desilylated
producing the desired imidazol-2-yl-aminophosphonic acids 6aee
as crystalline, non-hygroscopic white solids (Scheme 2, Table 2).
Table 2
Obtained imidazol-2-yl-(amino)methylphosphonic acids 6
Imine
R1
Product (%)a
2a
2b
2c
2d
2e
n-Bu
Bn
2-PyCH2
3-PyCH2
6a (54)
6b (85)
6c (37)
6d (73)
6e (58)
Imidazol-1-yl-(CH2)3
a
Yield of the desired product after simple crystallization.
The use of bromotrimethylsilane (BrTMS) resulted in an easier
silylation process of the alkyl phosphoesters6g,11a due to a higher
reactivity of the BrTMS in comparison with chlorotrimethylsilane,
frequently used in silylation reactions. Application of BrTMS gave
excellent results and formed the desired imidazole-2 amino-
phosphonic acids by a direct way and in high yield and purity after
simple crystallization.
Scheme 1. Synthesis of phosphonates and phosphinates 3aed and phosphine oxides
4a,b.
It has to be noted, that the direct hydrolysis of the imidazol-2-yl-
Table 1
(amino)methylphosphonates 3a,b,
a classical method for the
Prepared phosphonates and phosphinates 3aed and phosphine oxides 4a,b
preparation of aminophosphonic acids, failed in our case. After
heating of phosphonic esters 3a,b (R2¼R3¼OEt) for 2 h at reflux in
the presence of aqueous 6 M HCl, evaporation of the solvent, neu-
tralization of the remaining residue with aqueous Na2CO3 and ex-
traction with CH2Cl2, surprisingly, the secondary amines 7 were
isolated. In turn, when the remaining aqueous layer was evapo-
rated and 31P NMR was recorded from the remaining residue,
a sharp singlet at dP w1.12 ppm corresponding to the formed
phosphoric acid was observed. Later on, we observed that heating
of phosphine oxides 4a,b in 6 M HCl for 1 h also leads to their de-
composition and formation of the corresponding amines 7 and
phosphorus-containing fragment (diphenylphosphinic acid
HOP(O)Ph2).9f The general mechanism of the cleavage of the im-
idazole-2-aminophosphorus derivatives is depicted in Scheme 3.
Imine
R1
Product (%)a
R2
R3
2a
2b
2a
2b
2a
2b
n-Bu
Bn
n-Bu
Bn
n-Bu
Bn
3a (48)b
3b (41)b
3c (82)
3d (74)
4a (48)
4b (89)
OEt
OEt
OEt
OEt
Ph
OEt
OEt
Ph
Ph
Ph
Ph
Ph
a
Yield of the desired product after simple crystallization.
Products isolated as an oxalate salts.
b
Imidazol-2-yl-(amino)methylphenylphosphinates 3c,d were
obtained as mixtures of two diastereoisomers (due to the presence
of a chiral centre at P and a-C atoms) in approximately 1:1 ratio, as
shown by their 31P NMR spectra.
Subsequently, we became interested in the preparation of imi-
dazol-2-yl-aminophosphonic acids 6. Our interest in these com-
pounds grew from the fact that biological activities presented by
aminomethylphosphonic acids is often related to their strong af-
finity for binding metal ions.4 In this context, heterocyclic amino-
phosphonic acids incorporating an imidazole moiety are especially
interesting as they exhibit strong chelating activity towards tran-
sition metal ions [e.g., Cu(II) and Ni(II)].7 The imidazol-2-yl-ami-
nophosphonate derivatives presented here are unknown and could
have valuable chemical and biological properties, and thus the
synthesis of those compounds was desirable.
Scheme 3. Decomposition of imidazole-2-yl-(amino)methylphosphorous derivatives
3, 4 and 6 in the presence of a strong mineral acid.
Based on the obtained results, we postulate that the observed
decomposition of imidazol-2-yl-(amino)methylphosphonates and
phosphinates 3 and phosphine oxides 4 to secondary amines 7 and
phosphorus-containing fragment is a result of the CeP bond
cleavage. In fact, such a process (cleavage of CeP bond) is recog-
nized to play an important role in biological tasks exhibited by
organophosphorus compounds and is present in living organisms.8
Imidazol-2-yl-aminophosphonic acids 6 were obtained using
the protocol depicted in Scheme 2, based on the nucleophilic ad-
dition of silylated phosphorus esters6g to the corresponding
imidazole-2 aldimines 2. The aldimines, formed in situ, were
Scheme 2. Preparation of imidazol-2-yl-(amino)methylphosphonic acids 6.

B. Boduszek et al. / Tetrahedron 68 (2012) 1223e1229
1225
Table 3
2.2. Cleavage of the imidazol-2-yl-(amino)
methylphosphonates phosphinates and phosphonic acids
under acidic conditions
Determination of kinetic parameters of the cleavage of selected imidazol-2-yl-
(amino)methylphosphonates, phosphine oxides and phosphonic acidsa
Entry
1
Compound
Concn of acid mol Lꢀ1
Kinetic parameters
Taking into account literature reports6,8,9 two alternative
mechanistic pathways for the cleavage of the corresponding
imidazole-2-yl-(amino)methylphosphorus derivatives under
acidic conditions can be postulated (Scheme 4, R2¼R3¼OEt, OH,
or Ph). The first proposed mechanistic pathway is a dissocia-
tive-type SN1(P) mechanism that relies upon the rupture of
the CeP bond in protonated aminophosphonate A and sub-
sequent formation of two intermediate products: an enamine-
10ꢀ4 kobs sꢀ1
kH/kD
3d
1.0 (H2SO4)
2.0 (H2SO4)
1.0 (D2SO4)
2.0 (D2SO4)
1.0 (H2SO4)
2.0 (H2SO4)
1.0 (D2SO4)
2.0 (D2SO4)
1.0 (H2SO4)
2.0 (H2SO4)
1.0 (D2SO4)
2.0 (D2SO4)
1.0 (H2SO4)
2.0 (H2SO4)
1.0 (D2SO4)
1.0 (H2SO4)
2.0 (H2SO4)
1.0 (D2SO4)
2.43
4.92
1.09
1.21
2.23
4.05
2
3
4a
0.317
0.497
0.298
0.354
0.191
0.566
0.143
0.530
0.0310
0.0355
0.0312
0.0671
0.0553
0.0682
1.06
1.41
4bb
1.33
1.07
like moiety
B and a metaphosphate-like moiety C. In-
termediate B transforms into the secondary amine 7 by in-
corporation of a proton. In turn, C is actually closely associated
with the well-known monomeric metaphosphate (HOPO2).10 As
reactive intermediate, C can react with water to form, in the
case of decomposition of imidazol-2-yl-(amino)methyl-
phosphonic acids 6, the phosphoric acid (H3PO4) D as a final
product (Scheme 4). Similar mechanism of CeP bond cleavage
4
5
6a
6b
w1.0
w1.0
can
be
postulated
for
imidazol-2-yl-(amino)methyl-
a
Kinetic measurements were conducted in 50% (v/v) aqueous methanol solutions
or 50% (v/v) D2O in CD3OD. Experiments were run at 22 ꢁC (except for acids 6a and
6b in which case the experiments were run at 90 ꢁC). In all cases concentration of the
diphenylphosphine oxides 4a,b (Scheme 4, R2¼R3¼Ph). In the
latter case, the product D is the diphenylphosphinic acid,
HOP(O)Ph2.9f Phosphonic acids 6aee however, were found to
be more stable and a longer reaction time was required to
complete the cleavage process (Table 3).
starting material was 0.1 mol Lꢀ1
.
b
For 4b additional kinetic measurements were performed that allowed calcula-
tion of the activation parameters: Ea¼79.15 [kJ molꢀ1];
D
H¼76.60 [kJ molꢀ1]; and
D
S¼ꢀ76.15 [J molꢀ1 Kꢀ1].
Scheme 4. Possible mechanistic pathways of the cleavage.
The second postulated mechanism is an associative-type SN2(P)
mechanism9a,b that involves a direct nucleophilic attack of water
molecule at phosphorus in the protonated aminophosphonate A
prior to the cleavage of the CeP bond. Further reorganizations lead
to the formation of the same products as in the case of SN1(P)
mechanism (Scheme 4).
cleavage together with the decay of the signal corresponding to the
starting material was observed (Fig. 2). A pseudo-first-order re-
action was deduced and the rate constants for all experiments were
determined (Table 3). It was found that the rate constants were
considerably dependent on the concentration of the acid used.
These results demonstrate that the protonation of imidazole-2-yl-
(amino)methylphosphonates has a profound effect on the cleavage
of the CeP bond. Kinetic measurements performed in deuterated
solvents allowed calculation of isotope effects (kH/kD>1) showing
that protons are involved in the rate-determining step. For com-
pound 4b additional kinetic measurements were carried out that
2.2.1. Kinetic measurements of the cleavage of the imidazol-2-yl-
(amino)methylphosphonates, phosphinates and phosphonic acids
under acidic conditions. In order to gather more details about the
observed decomposition mechanism, kinetic measurements were
performed. For kinetic purposes, the cleavage of the selected imi-
dazol-2-yl-(amino)methylphosphonate ester 3d, phosphine oxides
4a,b and phosphonic acids 6a,b were run in 50% (v/v) aqueous
methanol solutions, containing a well define quantity of H2SO4. All
reactions were run directly in NMR tubes and the kinetics were
measured with the use of 31P NMR spectroscopy (Fig. 2).
allowed calculation of the activation parameters (Ea,
DH and DS,
Table 3). Low value of the activation energy (Ea) calculated for the
cleavage of 4b confirms the observed facility of cleavage of this
aminophosphine oxide under acidic conditions.
It has to be noted, that the corresponding imidazole-4(5)-yl-
(amino)methylphosphonates11a and phosphine oxides11b are stable
under acidic conditions and the cleavage of the CeP bond in the
case of those compounds does not take place (this was proved
experimentally). In this case, the reason for stability of these de-
rivatives is that there is no possibility of formation of an
The relative quantities of the phosphorus-containing products
and starting materials were estimated from the corresponding in-
tegrated 31P NMR signals. The appearance of a signal assigned to the
phosphorus-containing fragment resulting from the CeP bond

1226
B. Boduszek et al. / Tetrahedron 68 (2012) 1223e1229
Fig. 2. Kinetic experiment of the cleavage of 6b in 1.0 M H2SO4 monitored by 31P NMR.
appropriate resonance structure B (Scheme 4), responsible for
In summary, we have presented an efficient synthesis of new
imidazol-2-yl-(amino)methylphosphonic acids, corresponding
phosphonate and phosphinate esters, and phosphine oxides via
nucleophilic addition of appropriate phosphorus species to
imidazole-2 derived imines. The desired new compounds were
obtained in good yields as crystalline, non-hygroscopic solids after
simple crystallization. In addition, we have discovered that all the
synthesized compounds were unstable and decompose under
acidic conditions with formation of the corresponding secondary
amines and corresponding phosphorous-containing fragment.
The cleavage phenomenon was investigated and two possible
mechanistic pathways were postulated, an associative-type SN2(P)
mechanism and a dissociative-type SN1(P) mechanism. In light of
the obtained results the dissociative-type SN1(P) mechanism
seems to be the correct mechanistic pathway for the cleavage of
the imidazol-2-yl(amino)methylphosphonate and phosphinate
derivatives.
cleavage in the postulated mechanisms.9def
2.3. Cleavage of the imidazol-2-yl-(amino)methylphosphine
oxides in the presence of an electrophilic reagent and in
aprotic solvent
In addition, we discovered that the cleavage of the imidazol-2-
yl-(amino)methylphosphonates, phosphinates and phosphine ox-
ides can occur in aprotic solvents (such as chloroform, dichloro-
methane etc.), by the use of electrophilic reagents (e.g., elemental
bromine Br2). Heating of aminophosphine oxide 4a in CHCl3 for 2 h
in the presence of Br2 leads (after evaporation of the solvent) to the
mixture composed of imine 8 and diphenylphosphinic acid bro-
mide 9 (Scheme 5). Subsequent treatment of the crude reaction
mixture with methanol, acidification and extraction with CH2Cl2
allows isolation of the diphenylphosphinic acid methyl ester 109f in
80% yield (Scheme 5). From the aqueous phase (after neutraliza-
tion) imidazole-2-carboxaldehyde (1) was isolated, as a product of
the decomposition of imine 8 (Scheme 5). More insights into this
particular cleavage reaction will be presented in a separate com-
munication.9h On the basis these results however, the occurrence of
the SN2(P) mechanism9a,b seems to be questionable.9h
3. Experimental section
3.1. General
1H (300 MHz), 13C (75 MHz) and 31P (120 MHz) NMR spectra
were recorded on a Bruker Avance TM DRX (300 MHz) spectrom-
eter. Chemical shifts (
internal tetramethylsilane (Me4Si,
for 13C NMR and external 85% phosphoric acid (
d
) are reported in parts per million relative to
0.0) for 1H NMR, CDCl3 (
77.0)
0.0) for 31P NMR.
d
d
d
Coupling constants (J) are reported in hertz. HRMS analyses were
performed on LCT Premier XE Waters apparatus, on mode ESIþ
(TOF MS ESþ). IR spectra were recorded on a PerkineElmer 1600
FTIR spectrometer. All reagents were used as received from the
commercial supplier. All solvents for extractions and reactions were
technical grade and were dried before use using standard
techniques.
3.2. Preparation of diethyl imidazol-2-yl-(amino)
methylphosphonates and phosphinates 3aed
Neat secondary aromatic or aliphatic amine (5.0 mmol) was
introduced at rt to a solution of imidazole-2-carboxaldehyde (1)
(0.48 g, 5.0 mmol) in MeOH (100 mL) and the reaction was stirred
Scheme 5. Cleavage of imidazol-2-yl-(amino)methylphosphonates in the presence of
Br2 in CHCl3.

B. Boduszek et al. / Tetrahedron 68 (2012) 1223e1229
1227
at reflux for 1 h. After that time, solvent was evaporated under
reduced pressure affording crude imines 2 that were used directly
in the next step. The crude imine (5.0 mmol) was dissolved in dry
toluene (50 mL) and diethyl phosphite (0.65 mL, 5.0 mmol) or
ethyl phenylphosphinate (0.75 mL, 5.0 mmol) was added. The
mixture was heated to reflux for 2 h and then concentrated under
reduced pressure affording crude esters 3 as thick oils or semi-
solids. The phosphinate esters 3c,d were recrystallized from
a mixture of toluene/hexane. The phosphonate esters 3a,b were
characterized as oxalate salts. The oxalates were obtained in the
following way; the crude ester (1.0 equiv) was dissolved in ace-
tone (10 mL) and oxalic acid (COOH)2$2H2O (2.0 equiv) in acetone
(10 mL) was added and the mixture was refrigerated. The sepa-
rated precipitate was filtered, washed with cold acetone (10 mL)
and dried on air.
1035 (PeO), 959, 776, 749, 697, 569, 551, 525, 510 cmꢀ1. HRMS:
calcd for C19H23N3O2P (MþH)þ 356.1528. Found 356.1508.
3.3. Preparation of imidazol-2-yl-(amino)methylphosphine
oxides 4a,b
Protocol described above for the preparation of esters 3aed was
followed. Here, H-diphenylphosphine oxide was used as a nucleo-
philic reagent for addition to the double bond of imine. Reagents
were refluxed in toluene for 1 h. After work-up, crude imidazol-2-
yl-aminodiphenylphosphine oxides 4, were purified by crystalli-
zation from mixture toluene/hexane.
3.3.1. Imidazol-2-yl-methyl(N-butylamino)diphenylphosphine oxide
(4a). White solid; 0.84 g (yield 48%); mp 138e144 ꢁC. 1H NMR
(DMSO-d6): dH¼7.83e7.25 (m, 12H, imidazole and Ph), 6.84 (br s,
1H, NH), 4.89 (d, 1H, CHeP, JHeP¼11.9 Hz), 2.38e2.31 (m, 2H, CH2N),
1.21e1.16 (m, 2H, CH2), 1.08e0.95 (m, 2H, CH2), 0.74e0.61 (m, 3H,
CH3). 31P NMR (DMSO-d6): dP¼28.88. 13C NMR (DMSO): dC¼143.9,
133.4, 132.1, 131.8, 131.7, 131.4, 129.2, 128.6, 128.6, 128.4, 127.9, 57.5
(d, JCeP¼83.3 Hz), 48.3, 31.6, 20.1, 14.1. IR, nmax (KBr): 3432 (NH),
3303 (NH), 3138, 3061, 2959, 2926, 2894, 2827, 1591, 1553, 1485,
1438, 1172 (P]O), 1122, 1098 (PeO), 1070, 1037, 855, 743, 726, 693,
561, 542, 525, 439 cmꢀ1. HRMS: calcd for C20H25N3OP (MþH)þ
354.1735. Found 354.1719.
3.2.1. Imidazol-2-yl-methyl(N-butylamino)phosphonate diethyl ester
(3a). Oxalate; white solid; 0.90 g (yield 48%); mp 118e119 ꢁC. 1H
NMR (D2O): dH¼7.20 (d, 1H, J¼6.9 Hz, imidazole), 7.07 (d, 1H,
J¼6.7 Hz, imidazole), 4.21 (d, 1H, CHeP, JHeP¼13.1 Hz), 4.14 (m, 4H,
CH2O), 2.82 (m, 2H, CH2N), 1.45 (m, 2H, CH2), 1.22e1.10 (m, 8H, CH2,
CH3 from OEt), 0.82 (t, 3H, CH3, J¼7.24 Hz). 31P NMR (D2O):
dP¼14.71. 13C NMR (D2O): dC¼164.9 (COOH)2, 136.8, 121.5, 121.0,
66.4, 62.8, 51.1 (d, JCeP¼129.4 Hz), 48.0, 28.7, 19.2, 15.5. IR, nmax
(KBr): 3405 (NH), 3110, 2981, 1925, 1720, 1632, 1562, 1198 (P]O),
1174, 1020 (PeO), 781, 743, 721, 695, 542, 531, 507 cmꢀ1. HRMS:
calcd for C12H25N3O3P (MþH)þ 290.1634. Found 290.1628.
3.3.2. Imidazol-2-yl-methyl(N-benzylamino)diphenylphosphine ox-
ide (4b). White solid; 1.71 g (yield 89%); mp 162e168 ꢁC. 1H NMR
(CDCl3): dH¼7.71e7.12 (m,17H, Ph and imidazole), 6.86 (br s, 2H, NH
amine, NH imidazole) 4.87 (d, 1H, CHeP, JHeP¼11.4 Hz), 3.87 (d, 1H,
PhCH2, J¼13.1 Hz), 3.60 (d, 1H, PhCH2, J¼13.2 Hz). 31P NMR (CDCl3):
dP¼33.22. 13C NMR (CDCl3): dC¼143.2, 139.1, 132.0, 131.9, 131.7,
131.3, 131.2, 130.9, 128.7, 128.5, 128.4, 128.3, 128.2, 127.7, 127.0, 56.8
(d, JCeP¼83.7 Hz), 52.4 (d, 3JCeP¼13.8 Hz). IR, nmax (KBr): 3436 (NH),
3292 (NH), 3137, 3057, 2971, 2895, 1962, 1590, 1552, 1490, 1438,
1167 (P]O), 1123, 1100 (PeO), 1070, 1025, 850, 789, 738, 693, 566,
554, 525, 435 cmꢀ1. HRMS: calcd for C23H23N3OP (MþH)þ 388.1579.
Found 388.1584.
3.2.2. Imidazol-2-yl-methyl(N-benzylamino)phosphonate diethyl es-
ter (3b). Oxalate; white solid; 0.84 g (yield 41%); mp 187e188 ꢁC.
1H NMR (D2O): dH¼7.33e7.09 (m, 7H, Ph and imidazole), 4.28 (1H,
CHP, d, JHeP¼12.7 Hz), 4.01 (m, 4H, CH2Oꢂ2), 3.78 (m, 2H, CH2N),
1.11 (m, 6H, CH3ꢂ2). 31P NMR (D2O): dP¼17.62. 13C NMR (D2O):
dC¼164.3 (COOH)2, 140.9, 136.4, 132.6, 130.0, 129.9, 129.4, 120.1,
65.7, 51.9, 50.8 (d, JCeP¼128.7 Hz), 15.6. IR, nmax (KBr): 3400e3350
(NH), 3131, 2985, 2652, 1923, 1727, 1634 [(COOH)2], 1457, 1271, 1217
(P]O), 1044 (PeO), 961, 914, 752, 708, 565, 494 cmꢀ1. HRMS: calcd
for C15H23N3O3P 324.1477. Found 324.1468.
3.2.3. Imidazol-2-yl-methyl(N-butylamino)phenylphosphinate ethyl
ester (3c). Yellowish solid; 1.31 g (yield 82%); mp 85e90 ꢁC. 1H
NMR (CDCl3): dH¼7.81e7.26 (m, 5H, Ph), 7.00 (d, J¼7.0 Hz, 1H, im-
idazole), 6.88 (d, J¼7.2 Hz, 1H, imidazole), 4.44e4.41 (d, 1H
JHeP¼8.2 Hz, CHeP diastereoisomer 1). 4.39e4.36 (d, 1H,
JHeP¼8.1 Hz, CHeP diastereoisomer 2), 4.18e4.01 (m, 2H, CH2O),
2.50e2.39 (m, 2H, CH2N), 1.37e1.14 (m, 7H, CH2, CH3), 0.80e0.74
(m, 3H, CH3). 31P NMR (CDCl3): dP¼37.51 and 37.12 (two di-
astereoisomers). 13C NMR (CDCl3): dC¼133.9, 133.0, 131.9, 128.9,
128.7, 128.6, 127.4, 65.1, 47.6 (d, JCeP¼79.9 Hz diastereoisomer 1),
46.8 (d, JCeP¼80.1 Hz diastereoisomer 2), 38.2, 37.1, 24.5, 15.8, 9.6.
IR, nmax (KBr): 3410 (NH), 3114, 2956, 2874, 2782, 1509, 1440, 1205
(P]O), 1174, 1026 (PeO), 784, 752, 727, 708, 698, 574, 552, 532,
509 cmꢀ1. HRMS: calcd for C16H25N3O2P (MþH)þ 322.1684. Found
322.1691.
3.4. Preparation of imidazol-2-yl-methyl(amino)phosphonic
acids 6aee
To a solution of crude imine 2 (prepared as described above,
2.5 mmol) in dry CH2Cl2 (25 mL) was added trimethyl phosphite
(0.32 g, 2.5 mmol), followed by bromotrimethylsilane (1.6 g,
10 mmol). The mixture was stirred for 24 h at room temperature
and evaporated under reduced pressure. The resulted oil was
treated with methanol (5 mL) and refrigerated for several hours.
The products, imidazole-2-yl-(amino)methylphosphonic acids
(6aec) separated as white solids and were collected by filtration,
washed with methanol/diethyl ether 1:1 (20 mL) and dried in air. In
the case of imidazole-2-yl-(amino)methylphosphonic acids 6d,e,
methanol from reaction mixture was evaporated under reduced
pressure and the products were crystallized from acetone/water
solution (1:1) (10 mL).
3.2.4. Imidazol-2-yl-methyl(N-benzylamino)phenylphosphinate ethyl
ester (3d). Yellowish solid; 1.30 g (yield 74%); mp 131e133 ꢁC. 1H
NMR (DMSO-d6): dH¼7.67e6.92 (m, 10H Ph and imidazole), 4.16 (d,
1H, CHP, JHeP¼8.3 Hz diastereoisomer 1), 4.12 (d, 1H, CHP,
JHeP¼8.3 Hz diastereoisomer 2), 4.10e3.67 (m, 4H, CH2O, CH2N),
1.21e1.02 (m, 3H, CH3). 31P NMR (DMSO-d6): dP¼36.06 and 36.14
(two diastereoisomers). 13C NMR (DMSO): dC¼142.8, 139.5, 139.3,
132.2, 131.9, 131.8, 131.7, 128.3, 128.1, 128.0, 127.9, 61.3, 56.2 (d,
JCeP¼77.0 Hz diastereoisomer 1), 54.7 (d, JCeP¼76.9 Hz di-
astereoisomer 2), 50.9, 16.2. IR, nmax (KBr): 3412 (NH), 3184, 3058,
2979, 2902, 2848, 2782, 1592, 1539, 1455, 1440, 1205 (P]O), 1123,
3.4.1. Imidazol-2-yl-methyl(N-butylamino)phosphonic acid (6a).
White solid; 0.31 g (yield 54%); mp 224e226 ꢁC. 1H NMR (D2O):
dH¼7.34 (s, 2H, imidazole), 4.67 (d, 1H, CHP, JHeP¼17.1 Hz), 2.98e2.80
(m, 2H, CH2N), 1.50e1.44 (m, 2H, CH2), 1.18e1.03 (m, 2H, CH2), 0.80 (t,
3H, CH3, J¼7.2 Hz). 31P NMR (D2O): dP¼4.07. IR, nmax (KBr): 3410 (NH),
3143 (NH), 2965, 2937, 2875, 2687, 2563, 1922, 1616, 1516, 1471, 1308,
1110 (P]O), 1074 (PeO), 975, 901, 785, 744, 677, 577, 551, 511,

1228
B. Boduszek et al. / Tetrahedron 68 (2012) 1223e1229
484 cmꢀ1. HRMS: calcd for C8H17N3O3P (MþH)þ 234.1008. Found
alkalized with solid Na2CO3. Then the formed layers were separated
and the aqueous layer was washed with CH2Cl2 (3ꢂ15 mL). The
combined organic extracts were dried over anhydrous Na2SO4, fil-
trated and concentrated under reduced pressure affording the
amines 7, as semi-solids. The amines were purified as oxalate salts.
For this, the obtained amines (1 equiv) were dissolved in acetone
(10 mL) and acetone solution of oxalic acid (2 equiv) (5 mL) was
added. The separated oxalates of amines were filtered off and dried
on air. In the case of cleavage of imidazole-phosphonic acids 6cee,
the reaction mixture was evaporated to dryness, remaining residue
was dissolved in water (25 mL), resulting solution was made alka-
line with solid Na2CO3 and again evaporated to dryness. Obtained
solid residue was mixed with acetone (30 mL), stirred, filtered and
again washed twice with acetone (2ꢂ10 mL). Then, oxalic acid
(2 equiv) dissolved in acetone (10 mL) was added to the combined
acetone filtrate and cooled. The formed solid oxalates were filtered
off, and dried.
234.1007.
3.4.2. Imidazol-2-yl-methyl(N-benzylamino)phosphonic
acid
(6b). White solid; 0.56 g (yield 85%); mp 216e219 ꢁC. 1H NMR
(0.1 M D2SO4): dH¼7.25 (s, 2H, imidazole), 7.22e7.09 (m, 5H, Ph),
4.98 (d, 1H, CHP JHeP¼17.9 Hz), 4.39 (d, 1H, J¼13.2 Hz, NCH2Ph),
4.22 (d, 1H, J¼13.2 Hz, NCH2Ph); 31P NMR (0.1 M D2SO4): dP¼2.24.
13C NMR (0.1 M D2SO4): dC¼133.2, 130.0, 128.3, 128.0, 127.6, 126.5,
119.4, 50.8, 49.3 (d, JCeP¼134.4 Hz). IR, nmax (KBr): 3472, 3443 (NH),
3148, 3033, 2941, 2733, 2533, 2433, 1874, 1617, 1495, 1457, 1332,
1200, 1167, 1092 (P]O), 1060 (PeO), 978, 876, 753, 693, 605, 573,
504, 484 cmꢀ1. HRMS: calcd for C11H15N3O3P (MþH)þ 268.0851.
Found 268.0874.
3.4.3. Imidazol-2-yl-methyl(N-2-pyridylmethylamino)phosphonic
acid (6c). White solid; 0.24 g (yield 37%); mp 146e148 ꢁC. 1H NMR
(D2O): dH¼8.39 (d, 1H, 6-Py, J¼5.6 Hz), 8.02 (m, 1H, 4-Py), 7.92 (d,
1H, 3-Py, J¼7.9 Hz), 7.81 (t, 1H, 5-Py, J¼6.6 Hz), 7.22 (s, 2H, 4(5)-
imidazole), 4.34 (d, 1H, CHP, JHeP¼21.4 Hz), 4.12 (dd, 1H, CHaHb,
J¼16.3 Hz), 4.08 (dd, 1H, CHaHb, J¼16.3 Hz). 31P NMR (D2O):
dP¼11.20. 13C NMR (D2OþNaOD): dC¼153.6 (d, 2-imidazole,
2JCeP¼4.2 Hz),148.9,146.5,145.2,140.8,126.7 (d, J¼3.5 Hz),125.7 (d,
3.5.1. N-(Imidazol-2-yl-methyl)-butylamine (7a). Oxalate, white
solid; 0.17 g (yield 72%); mp 205e206 ꢁC. 1H NMR (D2O): dH¼7.37 (s,
2H, imidazole-4, imidazole-5), 4.48 (s, 2H, CH2N), 2.97 (t, 2H,
J¼7.29 Hz, CH2), 1.49e1.43 (m, 2H, CH2), 1.19e1.09 (m, 2H, CH2),
0.70 (t, 3H, J¼7.2 Hz, CH3). IR, nmax (KBr): 3393 (NH), 3141, 2961,
2932, 2873, 1922, 1622 [(COOH)2], 1439, 1299, 1221, 1102, 906, 757,
721, 710, 623, 556, 495 cmꢀ1. HRMS: calcd for C8H16N3 (MþH)þ
154.1344. Found 154.1332.
1
J¼1.8 Hz), 118.8, 60.2 (d, CHP, JCeP¼128.0 Hz), 42.9 (d, CH2,
3JCeP¼12.3 Hz). IR, nmax (KBr): 3321 (NH), 3295 (NH), 2852, 2674,
2567, 1630, 1603, 1524, 1470, 1287, 1171 (P]O), 1080 (PeO), 908,
772, 552 cmꢀ1. HRMS: calcd for C10H14N4O3P (MþH)þ 269.0804.
Found 269.0802.
3.5.2. N-(Imidazol-2-yl-methyl)-benzylamine (7b). Oxalate, white
solid; 0.21 g (yield 78%); mp 206e208 ꢁC. 1H NMR (D2O): dH¼7.14 (s,
1H, imidazole-4), 7.09 (s, 5H, Ph), 7.06 (s, 1H, imidazole-5), 4.34 (s,
3.4.4. Imidazol-2-yl-methyl(N-3-pyridylmethylamino)phosphonic
acid (6d). White solid; 0.48 g (yield 73%); mp 216e218 ꢁC. 1H NMR
(D2OþNaOD): dH¼8.02 (br s, 1H, 6-Py), 7.98 (s, 1H, 2-Py), 7.38 (d,1H,
4-Py, J¼6.6 Hz), 7.03 (t, 1H, 5-Py, J¼6.6 Hz), 6.63 (s, 2H, 4(5)-imid-
azole), 3.53 (d, 1H, CHP, JHeP¼17.3 Hz), 3.37 (dd, 1H, CHaHb,
J¼13.1 Hz), 3.29 (dd, 1H, CHaHb, J¼13.1 Hz). 31P NMR (D2OþNaOD):
dP¼13.80. 13C NMR (D2OþNaOD): dC¼148.4, 147.3 (d, 2-imidazole,
2JCeP¼4.4 Hz), 147.1, 137.4, 134.9, 123.9, 123.8, 121.4, 57.0 (d, CHP,
2H, CH2), 4.02 (s, 2H, CH2N). 13C NMR (D2O):
d
¼160.6 (COOH)2,
135.5 (2-imidazole), 129.7, 129.6, 129.1, 128.9, 128.5, 120.7 (4,5-
imidazole), 51.4 (CH2), 39.2 (CH2). IR, nmax (KBr): 3421 (NH), 3070,
3020, 2984, 2887, 2790, 2724, 1738 [(COOH)2], 1621, 1497, 1467,
1439, 1303, 1214, 1105, 919, 750, 738, 710, 699, 582, 494 cmꢀ1
.
HRMS: Calcd for C11H14N3 (MþH)þ 188.1188. Found 188.1174.
3
1JCeP¼132.0 Hz), 49.7 (d, CH2, JCeP¼13.1 Hz). IR, nmax (KBr): 3434
3.5.3. N-(Imidazol-2-yl-methyl)-N-(2-pyridylmethyl)-amine
(7c). Oxalate, white solid; 38 mg (yield 37%); mp 176e177 ꢁC. 1H
NMR (D2O): dH¼8.54 (d, 1H, J¼7.2 Hz, 6-PyH), 8.26 (t, 1H, J¼7.9 Hz,
4-PyH), 7.73 (d, 1H, J¼7.9 Hz, 3-PyH), 7.71 (t, 1H, J¼7.2 Hz, 5-PyH),
7.27 (s, 2H, imidazole-4, imidazole-5), 4.24 (s, 4H, 2ꢂCH2). 13C NMR
(NH), 2742, 2551, 1962, 1620, 1461, 1429, 1125 (P]O), 1035 (PeO),
980, 882, 505 cmꢀ1
269.0804. Found 269.0802.
.
HRMS: calcd for C10H14N4O3P (MþH)þ
3.4.5. Imidazol-2-yl-methyl[(N-imidazol-1-yl-n-propyl)amino]phos-
phonic acid (6e). White solid; 0.41 g (yield 58%); mp 116e118 ꢁC. 1H
NMR (D2O): dH¼8.58 (s, 1H, 2-imidazole), 7.34 (s, 1H, 5-imidazole),
7.28 (s, 1H, 4-imidazole), 7.24 (s, 2H, 4(5)-imidazole), 4.27 (d, 1H,
CHP, JHeP¼18.1 Hz), 4.15 (m, 2H, CH2 imidazole), 2.56 (dt, 1H,
NHCHaHb, J¼7.2, 12.3 Hz), 2.72 (dt, 1H, NHCHaHb, J¼7.2, 12.3 Hz),
2.01 (quintet, 2H, CH2, J¼7.2 Hz). 31P NMR (D2O): dP¼6.29. 13C NMR
(D2O):
d
¼161.1 (COOH)2, 147.8, 144.4 (1-Py), 142.8, 135.8 (1-
imidazole), 128.4, 127.9, 120.8 (4,5-imidazole), 47.2 (CH2), 40.4
(CH2). IR, nmax (KBr): 3421 (NH), 3071, 3031, 2779, 1743 [(COOH)2],
1621, 1523, 1476, 1208 [(COOH)2], 712, 487 cmꢀ1. HRMS: calcd for
C10H13N4 (MþH)þ 189.1140. Found 189.1132.
3.5.4. N-(Imidazol-2-yl-methyl)-N-(3-pyridylmethyl)-amine
(7d). Oxalate, white solid; 0.20 g (yield 73%); mp 201e202 ꢁC. 1H
NMR (D2OþD2SO4): dH¼8.77 (s, 1H, 2-PyH), 8.62 (d, 1H, J¼7.8 Hz, 6-
PyH), 8.54 (d,1H, J¼7.8 Hz, 4-PyH), 7.91 (t,1H, J¼7.8 Hz, 5-PyH), 7.30
(s, 2H, imidazole-4, imidazole-5), 4.60 (s, 2H, CH2), 4.45 (s, 2H, CH2).
2
(D2O): dC¼141.4 (d, 2-imidazole, JCeP¼4.2 Hz), 134.4, 129.0, 121.5,
119.8, 119.7, 54.0 (d, CHP, J¼122.6 Hz), 46.3 (s, CH2 imidazole), 44.6
(d, NHCH2, J¼7.5 Hz), 27.1 (s, CH2). IR, nmax (KBr): 3339 (NH), 2942,
2795, 2694, 2531, 1961, 1659, 1627, 1465, 1122 (P]O), 1081 (PeO),
995, 900, 775, 573 cmꢀ1. HRMS: calcd for C10H17N5O3P (MþH)þ
286.1069. Found 286.1052.
13C NMR (D2OþD2SO4):
¼160.3 (COOH)2, 148.3, 142.1, 142.1, 134.7,
d
130.1, 127.7, 120.7 (4,5-imidazole), 47.2 (CH2), 39.7 (CH2). IR, nmax
(KBr): 3444 (NH), 3408 (NH), 3024, 2787, 1733 [(COOH)2], 1622,
1500, 1219 [(COOH)2], 709, 592, 493 cmꢀ1. HRMS: calcd for
C10H13N4 (MþH)þ 189.1140. Found 189.1152.
3.5. Cleavage of imidazol-2-yl-(amino)methylphosphonates
under acidic conditions and isolation of the products
A
sample of corresponding imidazole-2-yl-(amino)methyl-
3.5.5. N-(Imidazol-2-yl-methyl)-N-(imidazol-1-yl-n-propyl)-amine
(7e). Oxalate, white solid; 0.25 g (yield 86%); mp >260 ꢁC (dec). 1H
NMR (D2O): dH¼8.66 (s, 1H, imidazole-2), 7.43 (s, 2H, imidazole-4,
imidazole-5), 7.41 (s, 1H, imidazole-5), 7.35(s, 1H, imidazole-4),
4.58 (s, 2H, CH2eimidazole-2), 4.24 (t, 2H, J¼7.5 Hz,
CH2eimidazole-1), 3.14 (t, 2H, J¼7.5 Hz, CH2N), 2.23 (q, 2H,
phosphonate 3, or phosphine oxide 4 (1.0 mmol) was dissolved in
HCl (25 mL of 6 M aqueous solution) and heated at reflux for 2 h. In
the case of imidazole-phosphonic acids 6 (1.0 mmol) the reaction
solution (50 mL of 6 M HCl) was refluxed for 6e8 h. After that time,
the reaction mixture was cooled down to room temperature,
CH2Cl2 was added (25 mL) and the resulting liquid mixture was
J¼7.5 Hz, CH2). 13C NMR (D2O):
¼165.3 (COOH)2, 135.5, 134.7, 121.6,
d

B. Boduszek et al. / Tetrahedron 68 (2012) 1223e1229
1229
121.1, 120.0, 119.9, 46.0 (CH2), 44.8 (CH2), 40.0 (CH2), 26.8
(NCH2CH2). IR, nmax (KBr): 3443 (NH), 3433 (NH), 2711, 1869, 1744
[(COOH)2], 1645, 1619, 1452, 1416, 1235 [(COOH)2], 1030, 719, 595,
557, 494, 473 cmꢀ1. HRMS: calcd for C10H16N5 (MþH)þ 206.1406.
Found 206.1403.
grant No. 344151/Z0305). We thank Mr. Pawe1 Da˛browski for re-
cording the NMR spectra and Dr. Gabriela Maciejewska for mea-
_
ꢀ_
suring HRMS spectra and Ms. Elzbieta Mroz for recording IR spectra
in the Central Laboratory of Faculty of Chemistry WUT.
3.6. Cleavage of imidazol-2-yl-(amino)-methyldiphenyl-
phosphine oxides 4 in the presence of elemental bromine and
isolation of the products
References and notes
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A
sample of imidazole-2-yl-(N-butylamino)-methyldiphenyl-
phosphine oxide 4a (353 mg, 1.0 mmol) was dissolved in CHCl3
(25 mL), containing 320 mg of Br2 (2.0 mmol). Then concentrated
sulfuric acid (196 mg, 2.0 mmol) was added and the mixture was
stirred at room temperature for 2 h, until bromine disappeared.
Methanol (10 mL) was added and the mixture was stirred for addi-
tional 5 h, then evaporated under reduced pressure. The obtained oily
residue was treated with 0.5 M H2SO4 (20 mL) and extracted with
methylene chloride (2ꢂ25 mL). The combined extracts were dried
(anhyd Na2SO4), filtered and evaporated to afford methyl diphenyl-
phosphinate 109f as an oil that solidifies with time (186 mg, w80%).
The remaining aqueous, acidic solution was neutralized with solid
Na2CO3 and evaporated to dryness. The obtained solid residue was
treated with 25 mL methanol, stirred, filtered and the filtrate evapo-
rated to dryness, to give imidazole-2-carboxaldehyde 1 (79 mg,
w80%).
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3.7. Kinetic measurements
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in aqueous 50% methanol, containing an appropriate quantity of
H2SO4 (1.0 or 2.0 M solutions) in NMR tubes were prepared. The 31
P
NMR spectra were consecutively recorded after desired period of
time. The use of different concentrations of H2SO4 allowed calcu-
lating the pseudo-first-order rate constants (kobs). The rate constants
were determined by plotting the dependence of log(aꢀx) on time
(where the ‘a’ is a relative quantity of the starting material and the
‘aꢀx’ represents a relative quantity of unreacted starting material).
Acknowledgements
Authors are thankful to the Faculty of Chemistry, Wroclaw
11. (a) Boduszek, B.; Olszewski, T. Pol. J. Chem. 2002, 76, 1619e1623; (b) Boduszek,
University of Technology (WUT) for financial support. (Internal
B.; Olszewski, T. Pol. J. Chem. 2005, 79, 553e559.