1,3-Dipolar cycloaddition of diazoalkanes onto dimethyl 1-(formylamino)ethylenephosphonate: A new route to 1-aminocyclopropanephosphonic acids and 3-phosphorylated pyrazoles

Article abstract of DOI:10.1016/j.tet.2011.10.010

Diazoalkanes regiospecifically react with dimethyl 1-(formylamino) ethylenephosphonate (1a) to afford 5-substituted dimethyl 3-(formylamino)-4,5- dihydro-3H-pyrazol-3-phosphonates 2 in high yields. Their thermal decomposition followed by hydrolysis provid

Full text of DOI:10.1016/j.tet.2011.10.010

Tetrahedron 67 (2011) 9535e9540
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
1,3-Dipolar cycloaddition of diazoalkanes onto dimethyl 1-(formylamino)
ethylenephosphonate: a new route to 1-aminocyclopropanephosphonic acids
and 3-phosphorylated pyrazoles
*
*
Nataliya S. Goulioukina , Nikolay N. Makukhin, Irina P. Beletskaya
Department of Chemistry, Moscow State University, Leninskie Gory, GSP-1, Moscow 119991, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2011
Received in revised form 15 September 2011
Accepted 3 October 2011
Available online 8 October 2011
Diazoalkanes regiospecifically react with dimethyl 1-(formylamino)ethylenephosphonate (1a) to afford
5-substituted dimethyl 3-(formylamino)-4,5-dihydro-3H-pyrazol-3-phosphonates in high yields.
Their thermal decomposition followed by hydrolysis provides a straightforward access to 2-substituted
1-aminocyclopropanephosphonic acids 4. Aromatization of 2 under acidic conditions leads to 3-
phosphorylated pyrazoles 5.
2
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Dipolar cycloaddition
1-Aminocyclopropanephosphonates
Phosphorylated pyrazoles
1. Introduction
ring-cleaving enzyme active site and to clarify the catalytic mech-
anism of the biosynthesis of
a-ketobutyrate and ammonia from
Interest in 1-aminocyclopropanephosphonic acids began only in
the middle of 1980s, and this class of compounds still remains poorly
studied in comparison with both 1-aminocyclopropanecarboxylic
acids1 and acyclic 1-aminophosphonates.2 Meanwhile, structural
peculiarities of the 1-aminocyclopropanephosphonate unit are quite
interesting. Indeed, the tetrahedral phosphonic acid functionality
gives rise to important implications in the design of the transition
state-analogue enzyme-inhibitors.2aed,3 1-Aminocyclopropane-
phosphonic acids can be incorporated via an amide linkage into
peptide sequences. Furthermore, the placement of the rigid cyclo-
propane ring into peptide chains is the most prominent pathway to
conformationally constrained peptidomimetics, a modern drug-
design tool.1b,4
The 1-aminocyclopropanephosphonic acid was found to be
a potent inhibitor of 1-aminocyclopropanecarboxylate (ACC) de-
aminase from Pseudomonas sp. and alanine racemase from Bacillus
stearothermophilus, its activity toward other pyridoxal 50-phos-
phate linked enzymes being assumed.5 Tight binding of the 1-
aminocyclopropanephosphonic acid with ACC deaminase made it
possible to determine the three-dimensional structure of the
crystalline binary complex and hence elucidate the nature of the
ACC.6 Several types of oligopeptides (including macrocyclic ones)
comprising the 1-aminocyclopropanephosphonic moiety have
been recently disclosed to be potent Hepatitis C virus (HCV) NS3
protease inhibitors and potential candidates for treating HCV
infection.7
The reported syntheses of the 1-aminocyclopropanephosphonic
acid can be divided into four principal strategies (Scheme 1). The
first group of methods is based on the standard cyclodialkylation
of convenient 1,1-biscarbanionic 1-aminomethanephosphonate
equivalents with various 1,2-bidentate electrophiles.7,8 The alter-
native approach involves the phosphonylation of cyclo-
propylideneiminium intermediates derived from cyclopropanone
ethyl trimethylsilyl acetale.9 The third, the most extensive and
frequently utilized group of methods comprises Curtius or Hoff-
mann rearrangements of appropriate 1-(dialkoxyphosphoryl)
cyclopropanecarboxylic acid derivatives as the crucial step.10 A re-
cently reported11 reduction of 1-nitrocyclopropanephosphonates
should be attributed to the last fourth group. These diverse meth-
odologies have been lately surveyed by us in a short review.12 All of
them bear close analogies among synthetic routes to ACC.1b,13
The 1,3-dipolar cycloaddition of diazo compounds onto dehy-
droamino esters is one of the common practices in the ACC chemis-
try.1b,13,14 Asfaras weareaware, asimilardiazoadditionmethod for1-
aminocyclopropanephosphonates preparation is still lacking. Mean-
while, it seems veryattractive because 1-aminoethylenephosphonate
derivatives are easily accessible15 and there is no requirement for
* Corresponding authors. Tel.: þ7 495 939 4828; fax: þ7 495 939 1854; e-mail
addresses: goulioukina@org.chem.msu.ru (N.S. Goulioukina), beletska@org.chem.
msu.ru (I.P. Beletskaya).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.010

9536
N.S. Goulioukina et al. / Tetrahedron 67 (2011) 9535e9540
H
R
N=X
P(O)(OR)2
OEt
OSiMe3
X=N
P(O)(OR)2
N
(2)
(1)
NH2
P(O)(OR)2
(3)
COOH
P(O)(OR)2
(4)
NO2
NO2
P(O)(OR)2
ROOC
P(O)(OR)2
N2
P(O)(OR)2
Scheme 1. Synthetic routes to 1-aminocyclopropanephosphonic acids.
further functional groups modification. The main limitation is caused
by hazardsassociatedwith preparing and handling diazo compounds.
Herein we would like to report our results on the investigation of 1,3-
dipolar cycloaddition of diazo compounds onto dimethyl 1-(for-
mylamino)alk-1-enephosphonates and further transformations of
forming pyrazolines.
The structure of the product 2a, isolated in 94% yield, was de-
termined by the elemental analysis and spectral data. The IR spec-
trum shows P]O absorption at 1260 cmꢀ1. A prominent band at
1050 cmꢀ1 and a medium-strong one at 795 cmꢀ1 are assigned to
the PeOeC stretch. The amide group absorbs strongly at 1695
(amide I) and 1535 cmꢀ1 (amide II); a broad band of
n
(NH) occurs at
3270 cmꢀ1. The weak endocyclic N]N vibration band appears at
1565 cmꢀ117a,b
Tautomerization of 4,5-dihydro-3H-pyrazol-3-
phosphonates to 4,5-dihydro-1H-pyrazol-5-phosphonates is
.
2. Results
17b,18
known to be possible,
(usuallyat 1595e1635 cm
the product 2a.
but the absence of C]N stretching mode
)
Starting dimethyl 1-(formylamino)alk-1-enephosphonates
1aec (Fig. 1) were synthesized by the HornereWadsworthe
Emmons reaction of tetramethyl (formylamino)methanediphos-
phonate and aldehydes.15aec Single (E)- and (Z)-isomers of 1b,c
were isolated by chromatography as described by R. Noyori et al.15b
All the individual isomers exist as a mixture of two rotamers15b
arising from the lack of free rotation around the C(O)eN bond16
and reveal two sets of signals in NMR spectra.
ꢀ1 17 indicates that this is not the casewith
Each of the 1H, 13C{1H}, and 31P{1H} NMR spectra shows two sets
of signals corresponding to two rotamers of 2a (see Experimental
part). 13C{1H} resonance of the distinctive quaternary carbon
atom appears as a doublet at dC¼100.1 ppm (1JCP¼169.7 Hz) for the
major rotamer and at dC¼99.8 ppm (1JCP¼171.7 Hz) for the minor
one. Methoxy groups being equal in 1a become diastereotopic in 2a
and give rise to a pair of signals in both 1H and 13C{1H} NMR spectra.
The 1H NMR spectrum reveals four multiplets due to the hetero-
cycle ring protons for each rotamer of 2a. The lower field signals (at
dH¼4.67, 5.07 ppm for the major rotamer and at dH¼4.59, 4.95 ppm
for the minor rotamer) can be most probably assigned to the
strongly coupled CH2N protons, whereas the high field multiplets
(at dH¼2.07e2.26 ppm for the major rotamer and at dH¼1.67,
2.53 ppm for the minor rotamer) are attributable to CH2CP protons.
4,5-Dihydro-3H-pyrazol-3-phosphonates can be fragmented
with nitrogen extrusion through either photolysis17b,18b,19 or ther-
molysis.18b,20 We have found that in toluene at reflux the pyrazoline
2a decomposes completely within 3 h affording dimethyl 1-(for-
mylamino)cyclopropanephosphonate (3a) in 85% yield along
with unsaturated isomeric by-products (E)-1b (14%) and (Z)-1b
(1%), which were recognized by 31P{1H} NMR spectroscopy15b
(Scheme 2).
NHCHO
P(O)(OMe)2
(Z)-1
R
NHCHO
R
P(O)(OMe)2
(E)-1
a: R=H; b: R=Me; c: R=Ph
Fig. 1. Dimethyl 1-(formylamino)alk-1-enephosphonates 1.
We have found that the cycloaddition of diazomethane onto
dimethyl 1-(formylamino)ethylenephosphonate (1a) smoothly
proceeds in ether at room temperature to furnish dimethyl 3-
(formylamino)-4,5-dihydro-3H-pyrazol-3-phosphonate (2a) after
24 h in a quantitative yield, as monitored by 31P{1H} NMR spec-
troscopy (Table 1, entry 1).
Table 1
N
The 1,3-dipolar cycloaddition reaction of diazo compounds with 1a
NHCHO
toluene
N
NHCHO
P(O)(OMe)2
reflux, 3 h
N
RCHN2, Et2O, r.t.
100%
NHCHO
P(O)(OMe)2
N
2a
P(O)(OMe)2
1a, δP=15.00,13.60
R
δP
19.81, 18.61
2a-c
NHCHO
Me
+
NHCHO
NHCHO
P(O)(OMe)2
Entry
R
Time (h) Product Isolated yield (%) 31P{1H} NMR, dP
+
Me
P(O)(OMe)2
1
2
3
H
24
2a
94
88
90
19.81, 18.61
P(O)(OMe)2
(E)-1b, 14%
16.35, 15.25
Me 1.5
Ph
2ba
2cb
19.85, 18.58 and 18.72, 17.97
20.33, 19.71
3a, 85%
27.15, 26.49
(Z)-1b, 1%
δP 16.77, 14.06
5
δP
δP
a
The diastereomers in the ratio (67:33).
Single diastereomer.
b
Scheme 2. Thermal deazetization of 2a.

N.S. Goulioukina et al. / Tetrahedron 67 (2011) 9535e9540
9537
The 1H NMR spectrum of the reaction mixture shows two
Table 2
1-Aminocyclopropanephosphonic acids 4 prepared
complicated multiplets due to the cyclopropane ring protons at
dH¼1.08e1.16 and 1.39e1.47 ppm. A doublet due to the equal
methoxy groups at dH¼3.74 ppm (3JPH¼11.3 Hz), a broad singlet due
to NH proton at dH¼7.09 ppm, and a singlet due to formyl proton at
dH¼8.09 ppm are corresponding to the major rotamer of 3a. For the
minor rotamer of 3a, a doublet due to OCH3 protons is observed at
dH¼3.81 ppm (3JPH¼11.2 Hz); doublets due to NH and CHO protons
appear at dH¼7.20 and 8.21 ppm, respectively, revealing a coupling
constant of 11.5 Hz (3JHH). The 1H NMR analysis also unambiguously
confirms the admixture of geometric isomers of 1b.15b
The similar ratio of the products of the pyrazoline 2a thermol-
ysis was observed when the reaction was carried out in o-xylene at
reflux. Attempts to diminish the undesirable alkenephosphonates
formation by photodecomposition of the pyrazoline 2a were also
unsuccessful.
NH2
P(O)(OH)2
N
1. toluene, reflux, 3 h
P(O)(OMe)2 2. 6N HClaq, reflux, 6 h
3. propylene oxide, MeOH
NHCHO
N
R
R
2a-c
4a-c
Entry
R
Product Isolated yielda (%) Z/E-ratiob,c 31P{1H} NMR, dP
(Z)
(E)
1
H
4a
Me 4b
Ph 4c
85
75
63
d
13.33
12.15
17.27
2d
3
55:45
Only (Z)
14.01
d
a
The yields were calculated from 2aec.
b
The (Z)- and (E)-notation is based on the relationship of R to the dihydrox-
yphosphoryl group.
The ratios were determined by integral values of 31P{1H} NMR.
c
d
The treatment with propylene oxide in EtOH.
We have failed to purify the cyclopropanephosphonate 3a by
distillation or chromatography. Treating of the crude product with
potassium permanganate in aqueous acetone20 for oxidizing the
alkenes led also to the appreciable degradation of 3a. Fortunately,
the impurities turned out to be easily removable by simple acidic
hydrolysis. Thus, the treatment of the unseparated mixture with
6 N hydrochloric acid under reflux5,9a results in the formation of
two products as indicated by the 31P{1H} NMR spectrum of the
crude reaction mixture (two signals at dP¼13.33 and 4.11 ppm in
the ratio ca. 86:14 that precisely enough corresponds to a parity of
the main and by-products after thermolysis). Simultaneously, the
1H NMR spectrum discloses a set of signals due to the protons of 1-
aminocyclopropanephosphonic acid (4a) as well as a doublet at dH
6.77 ppm with typical coupling constant of 665.2 Hz (1JPH) denoting
formation of phosphorous acid as a result of hydrolysis of by-
products 1b (Scheme 3).
Phosphonate 1a was found to react rapidly with diazoethane
in ether to afford two diastereomers (or, more precisely, two di-
astereomeric racemates) of dimethyl 3-(formylamino)-5-methyl-
4,5-dihydro-3H-pyrazol-3-phosphonate (2b) in the ratio 67:33
without formation of any by-products (31P{1H} NMR monitoring)
(Table 1, entry 2). The composition of inseparable mixture iso-
lated in 88% yield and the structure of the diastereomers were
confirmed by the elemental analysis and spectroscopic methods
(see Experimental part). At the same time, when phosphonate 1a
reacted with phenyldiazomethane (Table 1, entry 3) in ether,
a single diastereomer of dimethyl 3-(formylamino)-5-phenyl-4,5-
dihydro-3H-pyrazol-3-phosphonate (2c) was formed quantita-
tively as indicated by the 31P{1H}, 1H, and 13C{1H} NMR spectra
of the crude product, although its stereochemistry is not
determined.
Me
NH2
Me
NHCHO
Thermolysis of the pyrazolines 2b,c followed by hydrolysis leads
to corresponding 2-substituted 1-aminocyclopropanephosphonic
acids 4b,c (Table 2, entries 2 and 3). 1-Amino-2-methylcyclo-
propanephosphonic acid (4b) was isolated in 75% overall yield as
a 55:45 Z/E mixture. The relative stereochemistry of the di-
astereomers 4b was deduced from 31P NMR data based on the
known correlation 3JP/cis-H>3JP/trans-H for the coupling constants
between cyclopropane protons and phosphorus atom. In both 1H
and 13C{1H} NMR spectra the sets of signals from minor (E)-di-
astereomer (phosphorus analogue of racemic allo-norcoronamic
acid) as well as from major (Z)-diastereomer are in agreement with
the reported data.8b,9bed,10a Luckily, (Z)- and (E)-diastereomers are
easily separable by simple precipitation from water solution by
addition of ethanol, (Z)-isomer being more insoluble. Pure (Z)-4b
was thus obtained after two crystallizations from H2O/EtOH.
The variation in diastereomers ratio in the starting pyrazolines
mixture 3b (67:33) and in the obtained mixture 4b (55:45) is
noteworthy. The thermolysis leads to a perceptible equalizing of the
reaction mixture composition with a slight predominance of the
thermodynamically less stable (Z)-isomer with methyl and dihy-
droxyphosphoryl groups located on the one side of the ring plane.
The same methodology was also adopted to prepare 1-amino-2-
phenylcyclopropanephosphonic acid (4c), which was isolated in 63%
yield for two steps as a single diastereomer. The relative configura-
tion at C-1 and C-2 atoms in 4c was assigned by 31P and 1H NMR
spectroscopy to be Z. The 1He31P coupling constants were measured
6N HClaq
P(O)(OH)2
P(O)(OMe)2
(E)-1b and (Z)-1b
Me
O
H3PO3 + CH3CH2CO2H
δP 4.11
P(O)(OH)2
Scheme 3. Possible transformations of 1b under hydrolysis.
Final treatment of the crude product with propylene oxide in
methanol leads to pure acid 4a in 85% overall yield (Table 2, entry
1). The spectral data are consistent with those reported in the
literature.5,8a,9a
Attempted widening of the scope of the aforesaid cycloaddition
reaction on dimethyl 1-(formylamino)alk-1-enephosphonates 1b,c
met with failure. When we have tested the action of diazomethane
on (Z)- or (E)-1b,c the 31P{1H} NMR spectra of the reaction mixtures
did not indicate the formation of the corresponding pyrazolines.
This is most likely due to electronic or steric factors.21
In principle, there are two possible synthetic pathways to 2-
substituted 1-aminocyclopropanephosphonates based on ‘diazo
addition’ method (Scheme 4). The first one is the [2þ3]-
cycloaddition reaction of diazomethane with 1-(formylamino)
alk-1-enephosphonates followed by deazetization of the in-
termediate 4-substituted 3-(formylamino)-4,5-dihydro-3H-pyr-
azol-3-phosphonate. The second one is the 1,3-dipolar cyclo-
addition of the diazoalkanes onto unsubstituted 1-(formylamino)
ethylenephosphonate with subsequent decomposition of isomeric
5-substituted 3-(formylamino)-4,5-dihydro-3H-pyrazol-3-phos-
phonate. Having failed on the first path, we turned to alterna-
tive possibility.
3
3
3
as JP/cis-3-H¼11.7 Hz, JP/trans-3-H¼4.2 Hz, JP/trans-2-H¼6.2 Hz. These
values are in agreement with those reported for similar
structures.9bed
Pyrazoline 2a is quite stable when stored in a refrigerator for
several months, but at room temperature it turned out to be slowly
converting into dimethyl 3-(1H or 2H)pyrazolphosphonate (5a),

9538
N.S. Goulioukina et al. / Tetrahedron 67 (2011) 9535e9540
1
N
N
(1)
(2)
N
NHCHO
NHCHO
NHCHO
N
P(O)(OMe)2
P(O)(OMe)2
P(O)(OMe)2
R
2
R
R
R
NHCHO
NHCHO
+ CH2N2
+ RCHN2
P(O)(OMe)2
P(O)(OMe)2
1b,c
1a
Scheme 4. Possible synthetic approaches to 2-substituted 1-aminocyclopropanephosphonates based on [2þ3]-cycloaddition reaction.
which was isolated by column chromatography and identified. The
IR spectrum reveals a set of characteristic bands confirming the
retention of dimethoxyposphoryl moiety along with a strong broad
band of NH stretch at 3127 cmꢀ1. In the 1H NMR spectrum the NH
proton resonates at dP 13.64 ppm. The structure of the pyrazole
skeleton was also readily confirmed by characteristic chemical
shifts of the signals from aromatic protons and carbon atoms in 1H
and 13C{1H} NMR spectra, respectively. It should be also mentioned
that tautomerism22aec for 5a was not observed by 1H and 13C{1H}
and 31P{1H} NMR.
This reaction thus represents a cleavage of formamide, rather
than nitrogen, from pyrazoline 2a. Formamide formation was un-
doubtedly confirmed by the observation of the corresponding sig-
nals23 in the 1H and 13C{1H} NMR spectra of the crude product.
The similar conversion of pyrazolines into pyrazoles with formal
elimination of acetamide or benzamide,14a hydrogen bromide,22d
hydrogen cyanide,22eeg diethyl phosphite,22f methanesulfinic,22f
p-toluenesulfinic,17c,22h p-toluenesulfenic22i or nitrous22aec acids,
or SO2 and diethylcyanamide22j are known processes, being also
adopted for preparation of phosphonylated pyrazoles.22aec,e,f,i,j
These latter are of special interest in different fields, such as agro-
chemical and medicinal chemistry and also as efficient co-
ordinating ligands.22a,e,24 Nevertheless, methods for 3(5)-
pyrazolphosphonates preparation are few in number and often
involve multistep reaction sequences.25 In this context, the
revealed aromatization reaction may be of benefit.
Δ1-pyrazolin 2 into isomeric Δ2-pyrazolin.14a This latter eliminates
formamide to give pyrazole 5. A high yield in the case of pyrazole 5c
(Table 3, entry 3) can be explained by the conjugation of the aro-
matic
p-system with the double bond in the molecule of corre-
sponding Δ2-pyrazoline, which may contribute to the motive force
of the reaction.
3. Conclusion
In conclusion, we have shown that phosphonate 1a and
diazoalkanes undergo [2þ3]-cycloaddition reactions regiospe-
cifically. The 1,3-dipolar cycloadducts
2 thus obtained in
high yields can serve as versatile synthones not only for the
1-aminocyclopropanephosphonic acids 4, but also for 3-
phosphonylated pyrazoles 5.
4. Experimental
4.1. General information
All chemicals, except commercial products of a satisfactory
quality, were purified by literature procedures prior to use. Solvents
were dried according to standard methods. Phosphonates 1 were
obtained as described earlier.15a The ethereal solutions of diazo-
methane, diazoethane, and phenyldiazomethane were prepared
from corresponding mono-substituted ureas according to the
known procedures26 (CAUTION! diazo compounds are poisonous
and potentially explosive); the concentration being determined by
titration with the benzoic acid.
In Table 3, the results on the transformation of pyrazolines 2aec
into corresponding pyrazoles 5aec are shown. The reaction takes
place at room temperature in methanol in the presence of catalytic
additive of Me3SiCl. The products 5aec were isolated in moderate
to excellent yields and totally characterized.
1H, 13C{1H}, and 31P{1H} NMR spectra were recorded on a Bruker
Avance-400 instrument at 400, 101 and 162 MHz, respectively.
Chemical shifts (d) are reported in parts per million relative to TMS
(0 ppm for 1H NMR), solvent CDCl3 (77.0 for 13C NMR), residual
CHCl3 (7.25 for 1H NMR) or HDO (4.75 for 1H NMR), and external
85% H3PO4 (0 ppm for 31P NMR). Infrared spectra were obtained
using SPECORD 75 IR and Carl Zeiss UR-20 spectrophotometers.
HRMS (ESI) were measured on a Bruker micrOTOF II instrument in
both positive and negative ion modes. Elemental analyses were
done on an Elementar Vario MICRO Cube analyzer. Column chro-
matography was performed using Chemapol Silicagel LL254 5/40.
TLC was carried out using 0.20 mm thick Macherey-Nagel plates
(ALUGRAMÒ SIL G/UV254).
Table 3
Dimethyl pyrazol-3(5)-phosphonates 5 prepared
H
N
N
NHCHO
P(O)(OMe)2
N
MeOH, cat Me3SiCl
- HC(O)NH2
N
P(O)(OMe)2
R
R
5
2
Entry
R
Time (h)
Product
Yielda (%)
31P{1H} NMR, dP
1
2
3
H
Me
Ph
5
48
12
5a
5b
5c
78 (61)
73 (37)
98 (93)
14.00
13.12
11.85
a
Determined by 31P{1H} NMR spectroscopy of the crude reaction mixture; iso-
4.2. Synthesis of dimethyl 3-(formylamino)-4,5-dihydro-3H-
pyrazol-3-phosphonates 2
lated yields are given in the parentheses.
For base-assisted transformation of Δ1-pyrazolines into pyr-
azoles a mechanism implying initial elimination of a leaving group
followed by intramolecular proton transfer has been postu-
lated.22a,eeg,i For acidic reaction conditions, such as in our case, it
is reasonable to assume a preliminary tautomerization of the
4.2.1. Dimethyl 3-(formylamino)-4,5-dihydro-3H-pyrazol-3-
phosphonate (2a). To a foil-covered flask containing phosphonate
1a (0.450 g, 2.51 mmol) at room temperature the 0.07 M ethereal
solution of diazomethane (75 mL, 5 mmol) was added dropwise
with stirring over 2 h. The mixture was stirred for 22 h. Volatile

N.S. Goulioukina et al. / Tetrahedron 67 (2011) 9535e9540
9539
components were removed on a rotary evaporator and then under
high vacuum. The crude product was crystallized from ether to give
pyrazoline 2a (0.523 g, 94%) as white solid that turned yellow in air;
87:13 mixture of two rotamers in CDCl3. Found: C, 32.33; H, 5.34; N,
18.61. C6H12N3O4P requires C, 32.59; H, 5.47; N, 19.00%; IR nmax
(Nujol) 3270, 3220 sh, 1695, 1565, 1535, 1260, 1195, 1050, 855,
oxide was added dropwise while heating to 30 ꢁC. The precipitate
formed was filtered off and washed with MeOH. The acid 4a
(180 mg, 85%) was obtained as white solid. Found: C, 26.18; H, 5.90;
N, 10.15. C3H8NO3P requires C, 26.29; H, 5.88; N, 10.22%; IR nmax
(Nujol): 2700 vbr, 2300 vbr, 1630 br, 1557, 1210, 1170, 1060, 1035,
970, 870 cmꢀ1 31P{1H} NMR (D2O) 13.33; 1H NMR (D2O) 1.01e1.14
;
795 cmꢀ1
;
31P{1H} NMR (CDCl3) 19.81 (major), 18.61 (minor); 1H
(4H, m, cycle). 13C{1H} NMR (D2O) 8.9, 28.9 (J¼198.1 Hz).
NMR (CDCl3) 1.67 (0.13H, m, CH2CP, minor), 2.07e2.26 (1.74H, m,
CH2CP, major), 2.53 (0.13H, m, CH2CP, minor), 3.86 (3H, d,
J¼10.7 Hz, OCH3), 3.90 (3H, d, J¼10.7 Hz, OCH3), 4.59 (0.13H, m,
CH2N, minor), 4.67 (0.87H, m, CH2N, major), 4.95 (0.13H, m, CH2N,
minor), 5.07 (0.87H, m, CH2N, major), 7.42 (1H, br, NH), 8.19 (0.87H,
s, CHO, major); 8.52 (0.13H, d, J¼11.6 Hz, CHO, minor); 13C{1H} NMR
(CDCl3) 23.7 (major), 29.5 (minor), 54.3 (J¼6.7 Hz, major), 54.5
(J¼6.7 Hz, major), 54.4 (J¼6.7 Hz, minor), 54.6 (J¼6.1 Hz, minor),
78.2 (minor), 79.3 (major), 99.8 (J¼171.7 Hz, minor), 100.1
(J¼169.7 Hz, major), 160.5 (J¼12.1 Hz, major), 163.9 (J¼11.8 Hz,
minor).
4.3.2. 1-Amino-2-methylcyclopropanephosphonic
acid
(4b).
Compound 4b was synthesized in 75% yield similar to 4a from
pyrazoline 2b (250 mg, 1.06 mmol) as white solid; a 55:45 mix-
ture of Z/E isomers. Found: C, 31.39; H, 6.64; N, 8.99. C4H10NO3P
requires C, 31.80; H, 6.67; N, 9.27%; IR nmax (Nujol): IR nmax
(Nujol): 2680 vbr, 2350 vbr, 1735 br, 1640 sh, 1610, 1545, 1250,
1185, 1097, 1030, 955, 855 cmꢀ1. Pure (Z)-4b was isolated by
crystallization from the mixture H2O/EtOH (7:2). 31P{1H} NMR
(D2O) 12.15; 1H NMR (D2O) 1.00 (1H, ddd, Jgem¼6.5 Hz,
Jcis¼11.7 Hz, 3JP/trans-3-H¼7.2 Hz, 3-Hcycle), 1.19 (1H, ddd,
Jgem¼6.5 Hz, Jtrans¼4.5 Hz, 3JP/cis-3-H¼10.5 Hz, 3-Hcycle), 1.25 (3H, d,
3
4.2.2. Dimethyl 3-(formylamino)-5-methyl-4,5-dihydro-3H-pyrazol-
3-phosphonate (2b). Compound 2b was obtained in 88% yield
analogous to 2a from phosphonate 1a (0.400 g, 2.23 mmol) in 4 mL
of ether and diazoethane (6.0 mL of 0.75 M solution in ether,
4.50 mmol) as white solid; a 67:33 mixture of two diastereomers.
Found: C, 35.92; H, 6.11; N, 17.89. C7H14N3O4P requires C, 35.75; H,
6.00; N, 17.87%; IR nmax (Nujol) 3285, 3280 sh, 1695, 1565, 1525,
1260, 1210, 1055, 850, 800 cmꢀ1. The major diastereomer is a 89:11
mixture of two rotamers in CDCl3. 31P{1H} NMR (CDCl3) 19.85
(major), 18.58 (minor); 1H NMR (CDCl3) (only for the major
rotamer) 1.54 (3H, d, J¼7.3 Hz, CH3), 1.63 (1H, m, CH2), 2.36 (1H, m,
CH2), 3.86 (3H, d, J¼10.7 Hz, OCH3), 3.92 (3H, d J¼10.7 Hz, OCH3),
5.20 (1H, m, CHN), 7.70 (1H, d, J¼9.1 Hz, NH), 8.16 (1H, s, CHO); 13C
{1H} NMR (CDCl3) (only for the major rotamer) 18.0, 30.5, 54.4
(J¼5.9 Hz), 54.5 (J¼6.7 Hz), 87.6 (J¼5.0 Hz), 100.6 (J¼172.0 Hz),
160.2 (J¼12.0 Hz). The minor diastereomer is a 81:19 mixture of
two rotamers in CDCl3. 31P{1H} NMR (CDCl3) 18.72 (major), 17.97
(minor); 1H NMR (CDCl3) (only for the major rotamer) 1.68 (3H, d,
J¼7.1 Hz, CH3), 1.80 (1H, m, CH2), 2.59 (1H, m, CH2), 3.85 (3H, d,
J¼10.7 Hz, OCH3), 3.86 (3H, d, J¼10.7 Hz, OCH3), 4.65 (1H, m, CHN),
7.83 (1H, d, J¼6.8 Hz, NH), 8.24 (1H, s, CHO); 13C{1H} NMR (CDCl3)
(only for the major rotamer) 18.0, 33.0, 54.3 (J¼6.7 Hz), 54.4
(J¼6.7 Hz), 87.2, 95.4 (J¼175.1 Hz), 163.4 (J¼25.8 Hz).
J¼6.4 Hz, CH3), 1.42 (1H, dddq, Jcis¼11.7 Hz, Jtrans¼4.5 Hz, JP/trans-
¼7.2 Hz, J¼6.4 Hz, 2-Hcycle); 13C{1H} NMR (D2O) 12.5
2-H
(J¼3.0 Hz), 16.5, 17.7, 33.9 (J¼192.2 Hz). For (E)-4b: 31P{1H} NMR
(D2O) 14.01; 1H NMR (D2O) 0.77 (1H, ddd, Jgem¼6.4 Hz,
3
Jtrans¼6.8 Hz, JP/trans-3-H¼6.9 Hz, 3-Hcycle), 1.20 (3H, d, J¼6.5 Hz,
CH3), 1.27 (1H, ddd, Jgem¼6.4 Hz, Jcis¼9.4 Hz, 3JP/cis-3-H¼12.7 Hz, 3-
Hcycle), 1.49 (1H, dddq, Jcis¼9.4 Hz, Jtrans¼6.8 Hz, J¼6.5 Hz, 3JP/cis-2-
¼12.7 Hz, 2-Hcycle); 13C{1H} NMR (D2O) 10.7, 14.6, 15.9, 33.5
H
(J¼192.2 Hz).
4.3.3. (1S*,2S*)-1-Amino-2-phenylcyclopropanephosphonic acid
(4c). Compound 4c was synthesized in 63% yield similar to 4a from
2c (250 mg, 0.84 mmol) as white solid. Found: C, 50.43; H, 5.72; N,
6.35. C9H12NO3P requires C, 50.71; H, 5.67; N, 6.57%; IR nmax (Nujol):
2700 vbr, 2350 vbr,1730 br,1640,1610,1535,1230,1140 br,1030, 960,
870, 780, 757, 710 cmꢀ1
.
31P{1H} NMR (D2O/K2CO3) 17.27; 1H NMR
3
(D2O/K2CO3) 0.94 (1H, ddd, Jgem¼4.7 Hz, Jcis¼9.4 Hz, JP/trans-3-
3
¼4.2 Hz, 3-Hcycle), 1.37 (1H, ddd, Jgem¼4.7 Hz, Jtrans¼6.8 Hz, JP/cis-
H
3
¼11.7 Hz, 3-Hcycle), 2.20 (1H, ddd, Jcis¼9.4 Hz, Jtrans¼6.8 Hz, JP/
3-H
¼6.2 Hz, 2-Hcycle), 7.17 (1H, t, J¼7.4 Hz, ArH), 7.26 (2H, t,
trans-2-H
J¼7.4 Hz, ArH), 7.36 (2H, d, J¼7.4 Hz, ArH).
4.4. Synthesis of 3-phosphonylated pyrazoles 5
4.2.3. Dimethyl 3-(formylamino)-5-phenyl-4,5-dihydro-3H-pyrazol-
3-phosphonate (2c). Compound 2c was obtained analogous to 2a
from phosphonate 1a (107 mg, 0.60 mmol) in 1 mL of ether and
phenyldiazomethane (2.4 mL of 0.5 M solution in ether,
1.20 mmol). The crude product was purified by column chroma-
tography (EtOAc, Rf 0.12) to give 2c (0.160 g, 90%) as white solid;
a 78:22 mixture of two rotamers in CDCl3. 31P{1H} NMR (CDCl3)
20.33 (major); 19.71 (minor); 1H NMR (CDCl3) (only for the major
rotamer) 3.26e3.83 (3H, m, CH2 and CH), 3.87 (3H, d, J¼10.1 Hz,
OCH3), 3.89 (3H, d, J¼10.7 Hz, OCH3), 7.35 (3H, m, ArH), 7.48 (1H, br,
NH), 7.64 (2H, m, ArH), 8.14 (1H, s, CHO); 13C{1H} NMR (CDCl3) (only
for the major rotamer) 42.3, 54.4 (J¼7.1 Hz), 54.9 (J¼6.6 Hz), 75.2,
100.8 (J¼172.0 Hz), 126.2, 128.6, 129.4, 140.2, 161.9.
4.4.1. Dimethyl 3-(1H or 2H)pyrazolphosphonate (5a). To a solution
of pyrazoline 2a (116 mg, 0.52 mmol) in anhydrous methanol
(2 mL) three drops of Me3SiCl was added, and the reaction mixture
was stirred at room temperature for 5 h. After completion of the
reaction (TLC monitoring, EtOAc) the volatile components were
removed on a rotary evaporator and the residue was treated with
saturated aqueous NaHCO3 (1 mL). The product was extracted with
CHCl3 (3ꢂ3 mL). The organic extracts were dried over anhydrous
Mg2SO4 and concentrated at reduced pressure. The residue was
washed several times with hexane to give 5a (56 mg, 61%) as col-
orless solid. Found: C, 33.94; H, 4.77; N, 15.29. C5H9N2O3P requires
C, 34.10; H, 5.15; N, 15.91%; IR nmax (film): 3127, 3006, 2915, 1222,
1037, 846, 788 cmꢀ1 31P{1H} NMR (CDCl3) 14.00; 1H NMR (CDCl3);
;
3.81 (6H, d, J¼11.4 Hz, OCH3), 6.77 (1H, dd, JPH¼1.3 Hz, J¼2.0 Hz,
4.3. Synthesis of 1-aminocyclopopanephosphonic acids 4
CH), 7.90 (1H, dd, JPH¼2.2 Hz, J¼2.0 Hz, CH),13.64 (1H, br s, NH); 13
C
{1H} NMR (CDCl3) 53.0 (J¼6.1 Hz), 110.9 (J¼23.3 Hz), 131.6
(J¼11.8 Hz), 137.6 (J¼231.0 Hz).
4.3.1. 1-Aminocyclopropanephosphonic acid (4a). The solution of
pyrazoline 2a (340 mg, 1.54 mmol) in anhydrous toluene (17 mL)
was heated to reflux for 3 h. The solvent was thoroughly evaporated
at reduced pressure. The residue was dissolved in aqueous 6 M HCl
(16 mL) and heated at reflux for 6 h. The volatile materials were
removed at reduced pressure to dryness. The residue was dissolved
in the minimum amount of MeOH, and an excess of propylene
4.4.2. Dimethyl 5-methyl-3-(1H or 2H)pyrazolphosphonate (5b).
Compound 5b was obtained in 37% yield analogous to 5a from 2b
(100 mg, 0.43 mmol) as colorless transparent oil. 31P{1H} NMR
(CDCl3) 13.12; 1H NMR (CDCl3) 2.34 (3H, s, CH3), 3.76 (6H, d,
J¼11.4 Hz, OCH3), 6.45 (1H, s, CH), 8.16 (1H, br s, NH); 13C{1H} NMR

9540
N.S. Goulioukina et al. / Tetrahedron 67 (2011) 9535e9540
12. Gulyukina, N. S.; Makukhin, N. N.; Beletskaya, I. P. Russ. J. Org. Chem. 2011, 47,
633e649.
(CDCl3) 11.2, 53.0 (J¼5.9 Hz), 110.4 (J¼21.9 Hz), 137.3 (J¼232.7 Hz),
143.0 (J¼14.3 Hz). HRMS MHþ, found 191.0582. C6H12N2O3P re-
quires 191.0586.
13. Adams, L. A.; Aggarwal, V. K.; Bonnert, R. V.; Bressel, B.; Cox, R. J.; Shepherd, J.;
de Vicente, J.; Walter, M.; Whittingham, W. G.; Winn, C. L. J. Org. Chem. 2003, 68,
9433e9440.
ꢀ
14. (a) Cativiela, C.; Diaz de Villegas, M. D.; Mayoral, J. A.; Melendez, E. J. Org. Chem.
4.4.3. Dimethyl 5-phenyl-3-(1H or 2H)pyrazolphosphonate (5c).
Compound 5c was obtained analogous to 5a from 2c (160 mg,
0.54 mmol). The crude product was purified by silica gel column
chromatography (EtOAc, Rf 0.26) to give 5c (126 mg, 93%) as a pale
yellow oil. Found: C, 52.37; H, 5.54; N,10.81. C11H13N2O3P requires C,
52.38; H, 5.2; N, 11.11%; IR nmax (film): 3150, 2940, 2875, 1255, 1045,
1985, 50, 3167e3169; (b) Srivastava, V. P.; Roberts, M.; Holmes, T.; Stammer, C.
~
H. J. Org. Chem. 1989, 54, 5866e5870; (c) Bunuel, E.; Cativiela, C.; Diaz-de-
Villegas, M. D.; Jimenez, A. I. Synlett 1992, 579e581; (d) Suzuki, M.; Gooch, E. E.;
Stammer, C. H. Tetrahedron Lett. 1983, 24, 3839e3840.
€
15. Application of the HornereWadswortheEmmons reaction: (a) Schollkopf, U.;
Hoppe, I.; Thiele, A. Liebigs Ann. Chem. 1985, 555e559; (b) Kitamura, M.;
Yoshimura, M.; Tsukamoto, M.; Noyori, R. Enantiomer 1996, 1, 281e303; (c)
Talley, J. J. U.S. Patent 5,321,153, 1994; Chem. Abstr. 1994, 121, 301315; Con-
densation of isocyanomethane-phosphonates with aldehydes or ketones: (d)
850, 797, 770, 700 cmꢀ1 31P{1H} NMR (CDCl3) 11.85; 1H NMR
;
(CDCl3) 3.86 (6H, d, J¼11.5 Hz, OCH3), 7.03 (1H, d, J¼1.9 Hz, CH), 7.37
(1H, t, J¼7.4 Hz, ArH), 7.45 (2H, t, J¼7.4 Hz, ArH), 7.77 (2H, d, J¼7.4 Hz,
ArH), 12.27 (1H, br s, NH); 13C{1H} NMR (CDCl3) 52.4 (J¼6.0 Hz),
108.3 (J¼22.8 Hz),125.2,126.9,127.1,127.8,128.2,130.2 (J¼201.5 Hz).
€
€
€
Schollkopf, U.; Schroder, R. Tetrahedron Lett. 1973, 14, 633e636; (e) Schollkopf,
€
U.; Schroder, R.; Stafforst, D. Liebigs Ann. Chem. 1974, 44e53; Synthesis from 2-
acylamino-2,3-dichlorocarboxylic acids: (f) Brovarets, V. S.; Zyuz, K. V.; Budnik,
L. V.; Solodenko, V. A.; Drach, B. S. Zhur. Obshch. Khim. (Russian) 1993, 63,
1259e1265; (g) Brovarets, V. S.; Budnik, L. V.; Drach, B. S. Zhur. Obshch. Khim.
(Russian) 1992, 62, 707e708; Phosphonylation of polychlorocarboxamides: (h)
Drach, B. S.; Mis’kevich, G. N.; Lavrenyuk, T. Y. Zhur. Obshch. Khim. (Russian)
1976, 12, 421e426; Reduction of 1-hydroxyiminoalkanephosphonates: (j)
Quiclet-Sire, B.; Zard, S. Z.; Zhang, H. J. Organomet. Chem. 2002, 643e644,
404e408.
Acknowledgements
This work was performed in the framework of CNRS Frenche
Russian Associated Laboratory ‘LAMREM’ supported by the Russian
Foundation for Basic Researches (grant N 09-03-01128-a) and CNRS.
16. Barton, D.; Ollis, W. D. In Comprehensive Organic Chemistry: The Synthesis and
Reactions of Organic Compounds; Sutherland, I. O., Ed.; Pergamon: Oxford, New
York, NY, 1979.
17. (a) Lin-Vien, D.; Colthup, N. B.; Fateley, W. G.; Grasselli, J. G. The Hand Book of
Infrared and Raman Characteristic Frequencies of Organic Molecules; Academic:
San Diego, CA, 1991; (b) Gareev, R. D.; Pudovik, A. N. Zhur. Obshch. Khim.
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Gareev, R. D.; Chernova, A. V.; Ishmaeva, E. A.; Berdnikov, E. A.; Shagidullin, R.
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Supplementary data
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.010.
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