An efficient method for the phosphonation of C=X compounds

Article abstract of DOI:10.1134/S1070363210040055

Reaction of trialkyl phosphites with C=X electrophiles (aldehydes, ketones, ketophosphonates, aldimines, ketimines, isocyanates, isothiocyanates, and activated olefins) in the presence of amines and anilines hydrohalides was studied. We found that pyridine hydrohalides effectively activate the reaction of tralkyl phosphites with various C=X electrophiles: aldehydes, ketones, ketophosphonates, aldimines, ketimines, isocyanates, isothiocyanates, and activated olefins. Particularly high activity showed pyridine hydroiodide. This reaction is a convenient method of synthesis of hydroxyphosphonates, aminophosphonates, carbamoylphosphonates, carbamoylthiophosphonates, and methylenebisphosphonates. Pleiades Publishing, Ltd., 2010.

Full text of DOI:10.1134/S1070363210040055

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 4, pp. 709–722. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.O. Kolodyazhnaya, O.O. Kolodyazhnaya, O.I. Kolodyazhnyi, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 4,
pp. 549–562.
An Efficient Method for the Phosphonation of C=X Compounds1
A. O. Kolodyazhnaya, O. O. Kolodyazhnaya, and O. I. Kolodyazhnyi
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02094 Ukraine
e-mail: olegkol321@rambler.ru
Received October 8, 2009
Abstract―Reaction of trialkyl phosphites with C=X electrophiles (aldehydes, ketones, ketophosphonates,
aldimines, ketimines, isocyanates, isothiocyanates, and activated olefins) in the presence of amines and anilines
hydrohalides was studied. We found that pyridine hydrohalides effectively activate the reaction of tralkyl
phosphites with various C=X electrophiles: aldehydes, ketones, ketophosphonates, aldimines, ketimines,
isocyanates, isothiocyanates, and activated olefins. Particularly high activity showed pyridine hydroiodide. This
reaction is a convenient method of synthesis of hydroxyphosphonates, aminophosphonates, carbamoylphos-
phonates, carbamoylthiophosphonates, and methylenebisphosphonates.
DOI: 10.1134/S1070363210040055
Intensive development of the chemistry and biology
of functionalized phosphonic acids led in the last
decade to the development of highly effective routes
for the preparation of such compounds [1–4]. There
are several methods for the synthesis of α-func-
tionalized phosphonates, which in most cases are based
on the reaction of dialkyl phosphites with aldehydes
(Abramov reaction) in the presence of acids or bases
[5, 6], the reaction of dialkyl phosphites with
aldehydes and amines or imines (Kabachnik–Fields
reaction ) [7, 8], the reaction of dialkyl phosphites with
activated alkenes in the presence of Brønsted bases or
Lewis acids (Pudovik reaction) [9, 10]. Less com-
monly the reactions of triakyl phosphites with
aldehydes or alkyl imines in the presence of Lewis
acids are used [7, 11]. The disadvantage of these
methods consists in insufficient activity of reacting
compounds, and phosphonation of not activated
ketones or ketenimines either proceeds difficultly or
cannot be reached at all. In addition, in the presence of
a base the reaction is accompanied by phosphonate–
phosphate rearrangement [12], and by reverse
processes such as Abramov retro-reaction [13].
philes. We found that reaction couple trialkyl phos-
phite–pyridinium iodide is very active and easily
phosphonates various C=X electrophiles, where X = O,
S, NR, and CR2 (Scheme 1).
The reaction was carried out without a solvent or in
methylene chloride at room temperature. The activity
of the reaction couple is due to high acidity of
pyridinium iodide: it easily protonated betaine
intermediate A with the formation of alkoxy-
phosphonium iodide B, which then through the
Arbuzov type raction is converted into phosphonate C
(Scheme 2).
As shown by our studies, the reaction course is
affected by the acidity of the proton donor and the
nature of the halogen ion. The acidity of the organic
base hydrohalide should not be too high or too low; it
should be optimal, that is, such as that of pyridinium
halides. We investigated hydrohalides of various
amines and anilines and found that aniline and
dimethylaniline hydrohalides, owing to a high mobility
of the proton, dealkylate trialkyl phosphites turning
them into dialkyl phosphites, while triethylamine and
diisopropylethylamine hydrohalides due to low
mobility of the proton are not active in this reaction.
We developed a convenient and general method of
phosphonation of various unsaturated C=X electro-
(AlkO)3P + [C6N5NR2H]+X–
1
This work is a part of the master’s thesis of the student
O.O. Kolodyazhnaya at the National Technical University of
Ukraine (KPI).
→ (AlkO)2P(O)H + AlkX + C6H5NR2,
X = Cl, Br, I; Alk = Me, Et; R = H, Me.
709

710
KOLODYAZHNAYA et al.
Scheme 1.
H
R'
OH
H
R'
OH
R
R'
O
C
O
P(O)
C
P(O)
(RO)2
(RO)2
R'
R'
R'
(RO)3P
+
R
O
NR'
R'
NHR
R
P(O)(OR)2
OH
R
(RO)
2 P(O)
R'
P(O)
(RO)2
P(O)
(RO)2
+
N
X−
RN=C=O
RN=C=S
H
R'NH
(RO)
R'NH
O
S
CH2=CHY
2P(O)
(RO)
2P(O)
(RO)2P(O)CH2CH2Y
X = Cl, Br, I; R, R' = Alk, Ar; Y = NO2, CN.
Scheme 2.
R
R
R
R'
OH
AlkO
AlkO
R
R'
OH
PyH+X−
+
3 P
+
P
O−
R'
X−
(AlkO)
(AlkO)3P + O
P
(AlkO)3
−Py
−AlkX
R'
O
A
B
C
X = Cl, Br, I; Alk = Me, Et; R, R' = Alk, Ar.
Replacing the pyridinium iodide by pyridinium
chloride significantly slows down this reaction, which
is especially notable in the case of the reaction with
ketones (Table 1). This is explainable by easier
dealkylation of the intermediate alkoxyphosphonium
salt B by iodide ion than bromide or chloride ion, just
as it happens in the decay of an intermediate in the
Arbuzov reaction. Probably dealkylation of alkoxy-
phosphonium salt defines the rate of this reaction.
also are active and able to initiate the reaction of
trialkyl phosphite with C=X electrophiles.
Reaction of trialkyl phosphites with aldehydes in
the presence of pyridine halides proceeds very actively,
with high rate and with heat release, and leads to the
corresponding hydroxyphosphonates I–IX in high
yield (Table 2). For the preparation of hydroxy-
phosphonates I–IX the best is to use pyridinium
bromide, which results in less vigorous reaction than
with pyridinium iodide, although actually in both cases
were achieved high yields of compounds. The reaction
Thus, pyridinium iodide most actively initiated the
reaction. Note that the pyridinium bromide or chloride
Table 1. The effect of the nature of proton donor on the reaction of triethylphosphite with cyclohexanone
PhNH3+Cl–
PhNHMe2+Cl–
PyH+Cl–
PyH+Br–
PyH+I–
5.3
6
Et3NH+Cl–
i-Pr2EtNH+Cl–
Proton donor
pKa [14, 15]
4.6
24
5.1
24
5.3
5.3
10.64
24
11.0±0.2
Time, h
12
12
24
25
10
Temperature, ºC
25
25
35
35
25
25
Yield, %
~0а
~0а
50
70
90
5
a To the end of the given time the reaction mixture contained a mixture of diethylphosphite and triethylphosphite.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

AN EFFICIENT METHOD FOR THE PHOSPHONATION OF C=X COMPOUNDS
711
was carried out in methylene chloride or without a
solvent, at cooling.
giving a mixture of the hydroxyphosphonate III (S,R)-
and (S,S)-diastereomers in 4:1 ratio, as revealed by the
31
analysis of the reaction mixture using P–{1H} NMR
H
(O)
(EtO)2P
R
+
Py
HX
+ RCH
O
(EtO)3P
spectroscopy (the signals δP 26.9 and 26.3 ppm). By
the crystallization of the diastereomeric mixture from
hexane we succeeded to isolate (S,R)-hydroxyl-
phosphonate III, whose configuration was established
using chiral Mosher’s acid along the known procedure
[17]. Previously only racemic compound III has been
described [16].
OH
I−IX
Reaction of trimethyl phosphite with chiral
aldehyde (S)-N-Boc-prolinal in the presence of
pyridinium bromide proceeds diastereoselectively,
O
P(O)(OMe)2
OH
P(O)(OMe)2
[PyH]+Br−
N
(MeO)3P
N
N
+
crystallization
OH
O
O
O
O
O
O
(S,S) + (S,R)-III
(S,R)-III
The structures of products I–IX were proved by the
NMR analysis of purified samples. In the H NMR
aminopropanol I and II, which are potential biolo-
gically active substances [18]. To perform the syn-
thesis, 3-aminopropanol was protected at the NH group
by conversion to chlorocarbonate or by acylation with
Boc2O (Boc is t-butoxycarbonyl) that gave amides Xa
and Xb. These compounds were oxidized by the Swern
method [19] to aldehydes XIa, XIb, which were
purified by a vacuum distillation; the aldehydes were
obtained in good yield. Finally, these aldehydes were
phosphonated by the action of (RO)3P–[PyH]+Br–. The
final compounds, hydroxyphosphonates I and II were
obtained in almost quantitative yields.
1
spectra of the compounds a broad signal of OH proton
was detected in a weak field and a doublet of the
proton of PCH groups. In the 13C NMR spectra there is
a signal of the P–C carbon as a doublet with large 1JPC
coupling constant in the region of 50–60 ppm.
Using the method we developed a series of hyd-
roxyphosphonates has been synthesized, which are
interesting as C–P analogs of natural compounds. For
example, we synthesized phosphonate derivatives of γ-
(EtO)3P−PyH+Br−
(COCl)2−DMSO
H
N
H
H
O
HO
HO
O
N
O
N
O
R
R
R
Et3N
P(O)(OEt)2
O
O
O
I, II
Xа, Xb
XIа, XIb
R = MeOCO (а), R = Boc = t-BuOC(O) (b).
1
The synthesized α-hydroxy-γ-aminopropanols I and
II were used as starting compounds for the synthesis of
new analogs of lysophosphatidic acid [20]. This acid is
an intercellular signal phospholipid that induces a
number of important biological effects [21]. Replacing
carbon for the oxygen atom in the phosphate group
gives hydrolytically stable phosphonate that can be an
inhibitor of the processes in which lysophosphatidic
acid participates. By a reaction of the hydroxy-
phosphonate I with oleoyl chloride and triethylamine
at 80°C in THF we prepared oleinate XII, which was
purified by the column chromatography. The structure
of this compound was proved by 31P and H NMR
spectroscopy.
The reaction couple trialkyl phosphite–pyridinium
iodide relatively easily phosphonates ketones, which
under the condition of Abramov reaction are phospho-
nated difficultly or not at all. Commonly dialkyl phos-
phite sodium salts are used, and therefore reaction is ac-
companied by side processes like phosphonate–phos-
phate rearrangement. All our methods can be used for the
phosphonation in high yields of not only simple ke-
tones Ia, but also of complex ketones of natural origin.
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712
KOLODYAZHNAYA et al.
Table 2. Conditions of the reaction (R1O)3P + R2R3C=X + [PyH]+I– → (R1O)2P(O)C(XH)R2R3
Comp.
no.
Temperature,
R1
Et
R2
R3
X
O
Time, h Yield, %а
°C
H
H
H
20
2
2
2
95
90
90
I
HN
O
O
Et
O
O
20
20
II
III
HN
O
O
*
Me
N
O
O
Et
Et
H
H
O
O
20
20
4
4
90
90
IV
V
Et
H
H
H
H
O
O
O
O
20
20
20
20
2
2
2
2
90
90
90
90
VI
Me
Et
VII
VIII
IX
Et
*
Et
Ph
Me
Me
Me
O
O
O
O
40
25
25
30
5
6
80
80
70
70
XIII
XIV
XV
Et
3-F3CC6H4
4-t-BuC6H4
Ph
Et
24
12
Me
CH2Cl
Et
XVI
Et
O
O
O
25
24
80
XVII
Et
Et
O
O
25
25
24
24
65
XVIII
XIX
Me
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

AN EFFICIENT METHOD FOR THE PHOSPHONATION OF C=X COMPOUNDS
Temperature,
713
Table 2. (Contd.)
Comp.
R1
R2
R3
X
Time, h Yield, %а
no.
°C
Et
Et
O
25
12
12
XX
O
25
XXI
O
Et
Et
Me
(EtO)2P(O)
(EtO)2P(O)
O
O
20
20
10
10
70
70
XXVII
XXVIII
Et
Et
(EtO)2P(O)
(EtO)2P(O)
O
O
20
20
10
10
70
70
XXIX
XXX
Et
(EtO)2P(O)
O
20
12
90
XXXI
Et
Et
Ph
Ph
H
H
NBn
30
30
12
10
70
70
XXXII
Me
XXXIII
H
Et
Et
Н
Ph
40
30
12
12
50
60
XXXIV
XXXV
Ph
Et
Et
Ph
Ph
H
H
CHNO2
CHNO2
25
25
6
6
70
65
XXXVI
XXXVII
a Yields of purified products are reported.
1
The reaction was carried out in methylene chloride
as a solvent, at room temperature or at gentle heating.
The structure of final products XIII–XXI was proved
by NMR spectroscopy. In the spectra of proton
magnetic resonance a broad signal of OH proton
appeared in a weak field. In the 13C NMR spectra a
signal of PC carbon nucleus is observed in the region
of 50–60 ppm as a doublet with a large JPC coupling
constant (Table 2).
The reaction couple (RO)3P–[PyH]+I– phosphonated
ketophosphonates with the formation of 1-hydroxy-
1,1-bisphosphonates. High biological activity of 1-
hydroxy-1,1-bisphosphonoalkanes is well known [22].
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714
KOLODYAZHNAYA et al.
O
O
P(O)(OEt)2
P(O)(OEt)2
HO
C17H33C(O)Cl
NH
O
NH
O
O
O
H
H
I
XII
R2
R3
R2
R3
(R1O)3P +
+
(R1O)2
P(O)
O
PyH+I−
OH
XIII−XXI
On the basis of 1-hydroxy-1,1-bisphosphonates some
highly effective drugs have been produced: etidronate,
alendronate, risedronate, zoledronate and others;
various methods for their synthesis were developed
[23–25]. We developed another convenient pathway
for the synthesis of hydroxybisphosphonates.
completed within few hours affording in a good yield
hydroxybisphosphonates XXVII–XXXI (Table 2).
We applied this method to the synthesis of
bisphosphonates XXVIII–XXX, the derivatives of
terpenes such as farnesol, geraniol, citronellol, and
others [26]. The initial ketophosphonates were
obtained by oxidation of unsaturated hydroxyphos-
phonates VI, VIII by the Swern method with a
complex of oxalyl chloride with dimethylsulfoxide.
The method in this case is very useful, since the
reaction proceeds regioselectively and only at the OH
group, without affecting the multiple C=C bond, as
used to occur with other oxidants. By this method the
ketophosphonates XXIII–XXV were obtained in high
yields and were introduced in the next stage in the
reaction with (EtO)3P–[PyH]+Br– and converted into
isoprenylbisphosphonates XXVIII–XXX. The bis-
phosphonates were purified by chromatography on
silica gel. The structure of bisphosphonates XXVIII–
XXX was confirmed by the data of NMR spec-
troscopy.
The reaction was carried out in methylene chloride
as a solvent, at room temperature. The reaction was
O
(R1O)2P(O)
R
XXII−XXVI
(R1O)3P
C6H5N⋅ΝΙ
OH
P(O)
P(O)(OR1)2
(R1O)2
R
XXVII−XXXI
R
(COCl)2
(EtO)2P=O
(EtO)2P=O
(RO)3P
P(O)(EtO)2
(EtO)2 P(O)
Me2SO⋅Et3N
[C6H5NH]+I−
R
R
HO
O
OH
XXVIII−XXX
V, VI, VIII
XXIII−XXV
(VI, XXIV, XXIX);
(V, XXIII, XXVIII);
R =
(VIII, XXV, XXX).
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AN EFFICIENT METHOD FOR THE PHOSPHONATION OF C=X COMPOUNDS
715
A similar scheme was applied to obtain chiral
bisphosphonates XXXI based on (+)-(R)-citronellal.
By reaction of citronellal with the reagent (EtO)3P–
[PyH]+Br– hydroxyphosphonate IX was quantitatively
obtained and purified by distillation in a vacuum. Then
the hydroxyphosphonate was oxidized by the Swern
method, and with the yield 70% the chiral keto-
phosphonate XXV was obtained, which was purified
by distillation in a vacuum. In the last stage of the
synthesis the ketophosphonate by the reaction with
(EtO)3P–[PyH]+I– was in a high yield transformed into
bisphosphonate XXXI.
(RO)2P=O
(RO)2P=O
HO
(RO)2P=O
O
(RO)3P
(COCl)2
Me2SO
HO
[C5H5NH]+I−
(RO)2P=O
XXV
(S)-XXXI
IX
Compound XXXI was purified by column
chromatography and obtained in analytically and spec-
troscopically pure form. As in the previous case, an
interesting feature of the chiral compounds is the
presence of diastereotopic phosphonic groups affecting
which requires heating at 140°C for several hours.
Reaction of (EtO)3P–[PyH]+I– with a chiral (S)-1-
methylbenzylbenzaldimine also occurs at room
temperature and leads to the formation of (S,S)-dia-
stereomer of N-benzyl-substituted aminophosphonic
acid diester with 80% de. It was noted that initially a
mixture formed of (S,S)- and (S,R)-diastereomers of N-
benzyl-substituted aminophosphonic acid diester in the
3:1 ratio. Upon heating to 130–140°C the ratio of
diastereomers changed in favor of the (S,S)-diastereo-
isomer and became equal to 9:1. In contrast to this
reaction, addition of diethyl phosphite to (S)-1-methyl-
benzylbenzaldimine proceeds with predominant forma-
tion of (S,R)-diastereoisomer [27]. We succeeded also
to involve into the reaction with (EtO)3P–[PyH]+I– some
ketimines which do not enter into the Kabachnik–
Fields reaction under normal condition [28], as
exemplified by the phosphonation of cyclohexenyl-
idenaniline with the formation of compound XXXIII.
31
their NMR spectra. A special feature of the P NMR
spectrum is the presence of two signals of
diastereotopic phosphonic groups. The presence of a
chiral center in the molecule makes the ethoxy groups
also diastereotopic as seen in 1H NMR spectrum.
The reaction of (EtO)3P–[PyH]+I– with imines leads
to the formation of the respective aminophosphonates
XXXII–XXXV under relatively mild conditions
(Table 2). Thus, the reaction of (EtO)3P–[PyH]+I– with
benzylbenzaldimine proceeds at room temperature
with the formation of N-benzyl-substituted amino-
phosphonic acid, namely, much easier than the
reaction of the same imine with diethylphosphite,
Scheme 3.
H
(EtO)2P(O)
Ph
(RO)2P(O)
PhNH
NHCH2Ph
N
XXXII
Ph
XXXIII
PhCH=NCH2Ph
(RO)3P−[PyH]+Br−
(S)-PhCH=NCH(Me)Ph
PhN
H
Ph
(RO)2P(O)
H
NH
Me
(RO)2P(O)
Ph
H
NHPh
XXXV
XXXIV
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716
KOLODYAZHNAYA et al.
Triethyl phosphite and trimenthyl phosphite in the
Thus, we developed a convenient general method
for the synthesis of phosphonic acids with the use of
the reaction couple (RO)3P–[PyH]+X–. The use of
pyridinium halides allows to activate the reaction of
trialkyl phosphites with C=X electrophiles, thus
providing ready phosphonation of aldehydes, ketones,
aldimines and ketimines, ketophosphonates, and
compounds containing activated multiple C=C bond,
with the formation of functionalized phosphonates.
The advantage of this method in comparison with
existing ones is a high activity of the reagents, absence
of rearrangements and isomerizations (of the type of
phosphonate-phosphate rearrangement), and of reverse
processes (such as Abramov retro-reaction).
presence of pyridinium bromide phosphonylated nitro-
styrene with the formation of β-nitro-α-phenylethyl-
phosphonates XXXVI, XXXVII [29, 30]. The reaction
proceeded readily with heat evolution. Moreover, the
reaction of nitrostyrene with trimenthyl phosphite
proceeded stereoselectively with the formation of
optically active phosphonate XXXVII, which was
isolated and purified by crystallization from aceto-
nitrile. Previously compound XXXVII we obtained by
the reaction of nitrostyrene with dimenthylphosphite
[30]. Physicochemical characteristics of the com-
pounds obtained by the two methods coincided.
(RO)3P + PhCH=CHNO2
PyH+Br−
EXPERIMENTAL
The NMR spectra were recorded on a Varian VXR-
300 spectrometer at 300 (1H) and 126.16 (31P) MHz
with internal reference TMS (1H) and external
reference 85% H3PO4 in D2O (31P). All chemical shifts
are expressed in the δ scale (ppm).
Ph
H
P(O)
(RO)2
NO2
XXXVI, XXXVII
R = Et, (1R,2S,5R)-Mentyl.
The melting points were not corrected. For column
chromatography was used silica gel Merck 60, eluent a
mixture of hexane with ethyl acetate. Experiments
were carried out in an inert atmosphere (Ar). For
reactions were used anhydrous solvents: THF freshly
distilled over sodium in the presence of benzophenone,
methylene chloride distilled over P4O10. Other reagents
were purchased from Merck and Acros, and were used
without purification.
The the couple (EtO)3P–[PyH]+Br– reacts readily
with isocyanates and isothiocyanates transforming
them in very high yields into respective carbamoyl-
phosphonates XXXVI or carbamoylthiophosphonates
XXXVII, XXXVIII. The reaction was carried out in a
methylene chloride solution at cooling. The reaction
products were purified by a vacuum distillation. Their
1
structure and purity were proved by H, 13C, and 31P
The general method of the synthesis of hyd-
roxyphosphonates I–IX. To 0.01 mol of triethyl
phosphite and 0.01 mol of aldehyde in 3 ml of
methylene chloride at 0°C was added 0.011 mol of
pyridinium bromide, and the mixture was left at room
temperature during the time specified in Table 1. Then
the reaction mixture was filtered, the filtrate was
evaporated in a vacuum of water-jet pump and then
kept in a vacuum of 0.01 mm Hg at 80°C for 1 h. The
product was either purified by distillation in a vacuum,
or recrystallized, or used without special treatment
when was spectroscopically pure. Yields are listed in
Table 2.
NMR spectra, as well as by elemental analysis.
Carbamoylphosphonates attract attention due to their
high biological activity and, therefore, they were
intensively studied [31–36]. Earlier carbamoyl-
phosphonates were synthesized by the reaction of
alkylthiocarbonylphosphonates with ammonia [31, 32].
They also were prepared by the Arbuzov reaction of
dialkylcarbamoyl chlorides with trialkyl phosphites
[34, 35]. Thiocarbamoylphosphonates were prepared
by a reaction of trialkyl phosphonothioformates with
ammonia or amines [37]. Our method is simpler and
gives higher yields of products compared with the
previously described methods.
Diethyl
3-(metoxycarbonylamino)-1-hydroxy-
X
PyH+Br−
R
+
propylphosphonate (I). Yield 90%. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.36 t (6H, CH3,
J 7), 1.87 m (2H, CH2), 3.35 m (2H, CH2), 3.62 s (3H ,
CH3O), 4.05 m (1H, PCH), 4.15 m (4H, OCH2), 5.88
br (1H, OH). 31P NMR spectrum (CDCl3), δP, ppm:
(O)
(EtO)2P
(EtO)3P
X
N
C
NHR
XXXVIII−XL
R = Pr, X =O (XXXIV); R = CH2=CHCH2, X = S
(XXXV); R = Ph, X = S (XXXVI).
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AN EFFICIENT METHOD FOR THE PHOSPHONATION OF C=X COMPOUNDS
717
25.24. Found, %: N 5.22; P 11.56. C9H20NO6P. Cal-
culated, %: N 5.20; P 11.50.
25.63. Found, %: C 62.53; H 9.64; P 9.10. C18H33O4P.
Calculated, %: C 62.77; H 9.66; P 8.99.
Diethyl (2E)-1-hydroxy-3,7-dimethyl-2,6-octadi-
enylphosphonate (VI). Yield 80%, bp 135°C
(0.08 mm Hg). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.28 t (CH3, JHH 7), 1.29 t (CH3, JHH 7), 1.61 s
(3H, CH3), 1.69 s (3H, CH3), 2.1 br (4H, CH2), 4.12 m
(4H, OCH2), 4.52 d.d (1H, JHH 9, JHP 9), 5.12 br (1H,
CH=C), 5.36 br (1H, CH=C). 31P NMR spectrum
(CDCl3), δP, ppm: 24.19. Found, %: P 10.69.
C14H27O4P. Calculated, %: P 10.67.
Diethyl 1-hydroxy-3-tert-butoxycarbonylamino)-
propylphosphonate (II). Yield 95%. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.34 t (6H, CH3,
J 7), s 1.44 [9H, (CH3)3C], 1.89 m (2H, CH2), 3.23 m
(1H, NCH2), 3.46 m (1H, NCH2), 3.96 m (1H, PCH),
4.18 m (OCH2), 5.1 br (1H, OH). P NMR spectrum
(CDCl3), δP, ppm: 25.7. Found, %: N 4.55; P 9.91.
C12H26NO6P. Calculated, %: N 4.50; P 9.95.
1
31
Dimethyl
(S,R)-2-N-Boc-pyrrolidine(hydroxy-
Dimethyl [(2E,6E)-1-hydroxy-3,7,11-trimethyl-
2,6,10-dodecatrienylphosphonate (VII). Yield 90%,
oil. Purified by column chromatography on silica gel.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.59 s
(3H, CH3C=), 1.66 s (3H, CH3C=), 1.69 d (3H,
CH3CH, JHH 1.5), 1.71 d (3H, CH3CH, JHH 1.5), 2.09
m (6H, CH2), 2.25 m (2H, CH2), 3,78 d (3H, CH3O,
methyl)phosphonate (III). To 0.01 mol of trimethyl-
phosphite at –10°C was added 0.01 mol of N-Boc-
prolinal and 0.01 mol of pyridine bromide. The
mixture was stirred at –10°C for 5 h, then at 0°C for
2 h and at room temperature for 1 h. The reaction
mixture was diluted with diethyl ether, filtered, the
filtrate was evaporated. Hydroxyphosphonate III was
obtained with the yield 95% as a mixture of (S,R)- and
(S,S)-diastereomers in 4:1 ratio. 31P NMR spectrum
(CDCl3), δP, ppm: 26.9 and 26.3 [16]. The product was
recrystallized from cooled to –20°C chloroform–
hexane mixture and then several times from hexane,
resulting in pure (S,R)-diastereomer, mp 79°C, [α]D
J
HP 10), 3.8 d (3H, CH3O, JHP 10), 4.5 br (1H, OH), 4.7
m (1H, PCH, JHP 10), 5.09 br (1H, CH=C), 5.35 br
(2H, CH=C). 31P NMR spectrum (CDCl3), δP, ppm:
26.05 [36].
Diethyl (2E,6E)-1-hydroxy-3,7,11-trimethyl-2,6,10-
dodecatrienylphosphonate (VIII). Yield 88%, oil.
1
1
–60 (c 2, CHCl3). H NMR spectrum (CDCl3), δ, ppm
Purified by column chromatography on silica gel. H
(J, Hz): 1.42 s [9H, (CH3)3C], 1.8–2.3 m (4H, CH2),
3.2 m (1H, PCH), 3.7–3.8 m (2H, CH2N), 3.7 d (6H,
CH3O, J 10), 4.1 m (1H, NCH). 31P NMR spectrum
(CDCl3), δP, ppm: 6.9.
NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.28 t (CH3,
J
HH 7), 1.29 t (CH3, JHH 7), 1.58 s (3H, CH3C=), 1.65 s
(3H, CH3C=), 1.68 d (3H, CH3CH, JHH 1.5), 1.70 (3H,
CH3CH, JHH 1.5), 2.1 m (6H, CH2), 2.2 m (2H, CH2),
4.1 m (4H, OCH2), 4.5 br (1H, OH), 4.7 m (1H PCH,
JHP 10), 5.1 br (1H, CH=C), 5.3 br (2H, CH=C). 31P
NMR spectrum (CDCl3), δP, ppm: 25.00. Found, % C
63.78; H 9.86; P 8.34. C19H35O4P. Calculated, %: C
63.66; H 9.84; P 8.64.
Diethyl hydroxy[6-methyl-4-(4-methylpentene-3-
enyl)cyclohexyl-3-ene-1-yl]methylphosphonate (IV).
Yield 80%. Purified by column chromatography on
silica gel. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.99 d (3H, CH3, J 6), 1.33 t (6H, CH3CH2, J 7), 1.6 s
(3H, CH3), 1.87 s (3H, CH3), 1.91–2.22 m (10H, CH2 +
CH), 3.51 br (OH), 4.17 m (5H, OCH2 + PCH, J 7,
J 8), 6.28 s (1H, CH=C), 5.32 m (2H, CH=C). 31P
NMR spectrum (CDCl3), δP, ppm: 26.6. Found, %: C
62.68; H 9.65; P 8.88. C18H33O4P. Calculated, %: C
62.77; H 9.66; P 8.99.
Diethyl (6E)-1-hydroxy-3,7-dimethyl-6-octenyl-
phosphonate (IX). Yield 80%, bp 145–150°C
1
(0.08 mm Hg). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 0.96 d (3H, CH3, J 7), 1.29 t (3H, CH3CH2,
J 7), 1.30 t (3H, CH3CH2, J 7), 1.58 s (3H, CH3C=),
1.65 s (3H, CH3C=), 1.83 m (2H, CH2), 1.96 m (2H,
CH2), 3.82 m (1H, PCH), 4.09 m (4H, OCH2 ), 5.07 m
(1H, CH=C, J 7), 5.7 br (1H, OH). 31P NMR spectrum
(CDCl3), δP, ppm: 26.5. Found, %: P 10.69.
C14H29O4P. Calculated, %: P 10.59.
Diethyl hydroxy(3,8,8-trimethyl-1,2,3,4,5,6,7,8-
octahydronaphthalen-2-yl)methylphosphonate (V).
Yield 80%, bp 190°C (0.1 mm Hg), mp 107–110°C
1
(hexane). H NMR spectrum (CDCl3), δ, ppm (J, Hz):
0.957 d (3H, CH3C, J 6), 0.975 s (6H, CH3), 1.34 t
(6H, CH3CH2O, J 7), 1.43 m (2H, CH2), 1.6 m (4H,
CH2), 1.8 m (2H, CH2), 1.9 m (1H, CH), 2.0 m (1H,
CH), 2.19 m (2H, CH2), 2.91 m ( 1H, OH), 4.2 m (5H,
CH2O+PCH). 31P NMR spectrum (CDCl3), δP, ppm:
N-Methoxycarbonyl-3-aminopropanol (Xa). To
0.1 mol of 3-aminopropanol and 0.1 mol of triethyl-
amine in 100 ml of diethyl ether was added dropwise
0.1 mol of methyl chlorocarbonate, the mixture was
cooled to 0°C at stirring. Then stirring was continued
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718
KOLODYAZHNAYA et al.
for 1 h at room temperature. The precipitate formed
was filtered off, the solution was evaporated, and the
residue was distilled in a vacuum. Yield 75%, bp 80°C
(1H, OH). Found, %: C 54.55; H 9.67; N 8.11.
C8H17NO3. Calculated, %: C 54.84; H 9.78; N 7.99.
N-Boc-aminopropanal (XIb). Prepared analogously
to compound XIa. Yield 60%, bp 75–80°C (0.1 mm
1
(10 mm Hg). H NMR spectrum (CDCl3), δ, ppm
(J, Hz): 1.7 t (2H, CH2, J 7) 3.33 m (5H, NH + CH2),
3.67 s (3H, CH3), 6.34 br (1H, OH). Found, %: C
45.18; H 8.12; N 11.32. C5H11NO3. Calculated, %: C
45.10; H 8.33; N 10.52.
1
Hg). H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.41
s [9H, (CH3)3C], 2.7 t (2H, CH2, J 7), 3.45 m (2H,
CH2N), 5.05 br (1H, NH), 9.8 s (1H, CH=O). Found,
%: C 55.1; H 8.65. C8H15NO3. Calculated, %: C 55.47;
H 8.73.
N-Methoxycarbonyl-3-aminopropanal (XIa). In
a flask 40 ml of anhydrous dichloromethane and 1.7 ml
of oxalyl chloride was placed. The solution was cooled
with stirring, and at –50 to –60°C was added dropwise
2.9 ml of dimethyl sulfoxide in 10 ml of dichloro-
methane. Then 5 min later, 2.9 g of alcohol Xa was
added dropwise over 10 min maintaining the tempera-
ture at –50 to –60°C. After 15 minutes, 11.5 ml of
triethylamine was added dropwise, maintaining the
temperature below –50°C. The stirring was continued
for 5 min, then the mixture was heated to room
temperature and poured into 70–80 ml of water with
ice. The water layer was separated and extracted with
2 × 30 ml of dichloromethane. The organic layers were
combined, washed with 2 × 10 ml of saturated solution
of sodium chloride, and dried over magnesium sulfate.
The solution was filtered and evaporated, the residue
after evaporation was extracted with hexane. Then, this
extract was evaporated and the residue was distilled in
1-(Dietoxyphosphinyl)-3-[(N-metoxycarbonyl-
amino)-propoxy-(9Z)-octadecenoate (XII). To
0.005 mol of hydroxyphosphonate II and 0.0075 mol
of triethylamine in 5 ml of THF at cooling to 0°C was
added 0.005 mol of oleoyl chloride. The mixture was
left for 2 h at room temperature. Then triethylamine
hydrochloride was filtered off, the solvent was
evaporated, and the residue was subjected to
chromatography on a column with silica gel. Eluent
hexane–ethyl acetate, 6:1. The purified product is a
1
colorless viscous oil. H NMR spectrum (CDCl3), δ,
ppm (J, Hz): 0.87 t (3H, CH3, J 7), 1.3 m (20H, CH2),
2.0–2.3 m (4H, CH2), 2.45 m (4H, CH2C=), 3.3 m (2H,
CH2N), 3.6 s (3H, CH3O), 4.05 m (4H, OCH2), 5.2 m
(CH=C); 5.4 m (1H, PCH), 5.5 m ( NH). 31P NMR
spectrum (CDCl3), δP, ppm: 29.3. Found, %: N 2.62; P
5.80. C27H52NO7P. Calculated, %: N 2.62; P 5.80.
General method of the synthesis of hydroxy-
phosphonates XIII–XXI. A mixture of 0.01 mol of
ketone, 0.01 mol of trialkyl phosphate, and 0.01 mol of
pyridinium iodide in 3 ml of methylene chloride was
stirred for the period specified in Table 2. Then the
solvent was evaporated and the residue was dissolved
in 5 ml of ether, filtered, the solvent was evaporated,
the product was purified by crystallization from a
solvent or distilled in a vacuum. Yields are listed in
Table. 2.
1
a vacuum. Yield 60%, bp 100°C (10 mm Hg). H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.71 t (2H,
CH2, J 7), 3.46 m (2H, NCH2), 3.63 s (3H, OCH3),
5.49 br (1H, NH), 9.79 s (1H, CH=O). Found, %: C
45.80; H 6.92; N 10.68. C5H9NO3. Calculated, %: C
45.80; H 6.92; N 10.68.
N-Boc-3-aminopropanol (Xb). In a flask was
placed 2.0 g of 3-aminopropanol and a solution of 7 g
of 97% aqueous di-tert-butyl dicarbonate in 20 ml of
THF was added dropwise at stirring and cooling to 0°C.
The reaction mixture was stirred for 10 min at 0°C and
then 14 h at room temperature, and boiled for 3 h with
a reflux condenser. The solvent was then removed
under reduced pressure; the residue was washed with
saturated aqueous solution of sodium hydrogen car-
bonate. The aqueous phase was extracted with diethyl
ether, the extract was dried over anhydrous sodium
sulfate, filtered, evaporated and the residue after
evaporation was distilled in a vacuum. Yield 80%, bp
Diethyl
1-hydroxy-1-phenylethylphosphonate
(XIII). Recrystallized from a mixture of hexane–ether
1
or acetonitrile. Yield 70%, mp 75°C. H NMR spec-
trum (CDCl3), δ, ppm (J, Hz): 1.2 m (3H, CH3, J 7),
1.82 d (3H, J 16.5), 4.07 m (4H, OCH2), 7.6 m (5H,
C6H5). 31P NMR spectrum (CDCl3), δP, ppm: 27.
Found, %: P 11.99. C12H19O4P. Calculated, %: P 11.99
[1, 28].
Diethyl 1-hydroxy-1-(3-trifluoromethylphenyl)-
ethylphosphonate (XIV). Prepared according to the
general scheme. Yield 80%, purified by crystallization
1
90°C (0.1 mm Hg). Colorless viscous liquid. H NMR
1
spectrum (CDCl3), δ, ppm (J, Hz): 1.4 s [9H, (CH3)3C],
1.7 t (2H, CH2, J 7), 3.33 m (5H, NH+CH2), 6.4 br
from hexane, mp 125–128°C. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.24 t (6H, CH3, J 7), 1.83 d
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AN EFFICIENT METHOD FOR THE PHOSPHONATION OF C=X COMPOUNDS
719
(3H, CH3SP, J 15.6), 4.04 m (2H, OCH2), 4.12 m (2H,
OCH2), 4.66 br (1H, NH), 7.44–7.9 m (4H, C6H4). 13C
NMR spectrum (CDCl3), δC, ppm (J, Hz): 16.17 s
(CH3), 26.33 s (CH3), 63.5 q (OCH2, J 94), 73.5 d (PC,
J 161), 127 q (CF3, J 271), 123.1, 123.88, 128.16,
130.01, 130.27, 143.00 (C6H4). 19F NMR spectrum
(CDCl3), δF, ppm: –57.67. 31P NMR spectrum
(CDCl3), δP, ppm: 25.3 d, J 8. Found, %: P 9.49.
C13H18F3O4P. Calculated, %: P 9.55.
phonate (XIX). The product was purified by column
chromatography on silica gel (eluent ethyl acetate–
1
hexane, 1:1), Rf 0.3 (hexane–ethyl acetate, 2:1). H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.8 m (3H,
CH3), 0.9 m (3H, CH3), 1.32 t (6H, CH3CH2), 1.5 s
(3H, CH3), 1.6 s (3H, CH3), 1.4–1.9 m (13H, CH2),
2.25 d (3H, CH3), 4.17 d.q (4H, CH2O, J 7, J 8), 5.7
d.d (1H, J 4.5, J 16), 5.9 d.d (1H, CH=C, J 10.5,
J 13.5), 6.65 d.d.d (1H, CH=C, J 4.5, J 10.5, J 15). 31P
NMR spectrum (CDCl3), δP, ppm: 24.5. Found, %: C
66.00; H 9.55; P 7.41. C22H39O4P. Calculated, %: C
66.30; H 9.86; P 7.77.
Diethyl 1-hydroxy-1-(4-tert-butylphenyl)ethyl-
phosphonate (XV). Yield 80%, mp 84–86°C (hexane).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.15 t
(3H, CH3) 1.17 t (3H, CH3) 1.24 s [9H, (CH3)3C], 1.8 d
(CH3, J 14.5), 3.93 m (2H, OCH2), 4.07 m (2H,
OCH2), 7.3–7.5 m (4H, C6H4). 31P NMR spectrum
(CDCl3), δP, ppm: 26.0. Found, %: P 9.65. C16H27O4P.
Calculated, %: P 9.85.
Diethyl 1-hydroxycyclohexylphosphonate (XX).
A mixture of 1 g of cyclohexanol, 2.25 g of triethyl
phosphite and 1.6 g of pyridinium bromide was
dissolved in 3 ml of methylene chloride and was
stirred for 6 h at 40°C. Then the solvent was
evaporated and the residue was dissolved in 5 ml of
ether, the solution was filtered, evaporated, and the
residue was distilled in a vacuum. Yield 80%, bp 120°C
(0.1 mm Hg). The product was recrystallized from
Dimethyl
1-hydroxy-2-chloro-1-phenylethyl-
1
phosphonate (XVI). Yield 70%, mp 152–155°C. H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 3.60, d (3H,
OCH3, J 12), 3.81 d (3H, OCH3, J 12), 4.11 d (1H,
CHCl, J 3), 4.26 d (1H, CHCl, J 3), 7.36–7.4 m (5H,
1
hexane cooled to 0°C. Prisms, mp 61–63°C. H NMR
31
spectrum (CDCl3), δ, ppm (J, Hz): 1.3 t (6H, CH3CH2,
J 7.2), 1.52 m (2H, CH2), 1.66 m (4H, CH2), 1.87 m
(4H, CH2), 3.6 br (1H, OH), 4.16 d.q (4H, OCH2, J 7,
J 8). 31P NMR spectrum (CDCl3), δP, ppm: 26.93.
Found, %: C 50.62; H 8.91; P 13.09. C10H21O4P.
Calculated, %: C 50.84; H 8.96; P 13.11.
C6H5), 4.32 s (1H, OH). P NMR spectrum (CDCl3),
δP, ppm: 25. Found, %: Cl 13.42; P 11.65. C10H14ClO4P.
Calculated, %: Cl 13.40; P 11.70.
Diethyl [1-(3,4-dimethoxyphenyl)-1-hydroxypropyl]-
phosphonate (XVII). Prepared similarly. The product
was purified by chromatography on a column with
silica gel (ethyl acetate–hexane, 1:1). Rf 0.33, yield
60%. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.77
t (3H, CH3, J 7.2), 1.15 t (3H, CH3CH2O, J 7), 1.27 t
(3H, CH3CH2O, J 7), 2.13 d.q (1H, J 7, J 8), 2.24 d.q
(1H, J 7, J 8), 3.87 s, 3.89 s (3H, CH3O), 4.1 m (4H,
CH2O), 6.9–7.5 m (3H, C6H3). 31P NMR spectrum
(CDCl3), δP, ppm: 24.3. Found, %: P 9.32. C15H25O6P.
Calculated, %: P 9.32.
Diethyl 4-hydroxy-2,2-dimethyltetrahydro(2H)-
pyran-4-ylphosphonate (XXI). The product was
purified by vacuum distillation or by crystallization
from hexane cooled to 0°C. Yield 80%, bp 130–135°C
1
(0.08 mm Hg), mp 72–75°C. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.19 [3H, (CH3)2C], 1.43 s
[3H, (CH3)2C], 1.64–1.9 m (4H, CH2) , 3.65 m (2H,
CH2O), 3.95 br (1H, OH), 3.65 m (1H, CH2), 4.05 m
(1H, CH2), 4.15 d.q (4H, CH3CH2O, J 7, J 8). 13C
NMR spectrum (CDCl3), δC, ppm (J, Hz): 16.45 s
(CH3CH2), 24.29 s (CH2), 31.09 s (CH3), 32.61 s
(CH3), 39.87 s (CH2), 56.1 d (PCCH2, J 12.5), 62.8 d
(OCH2, J 8.5), 63.0 d (CH2, J 7.5), 70 d (PC, J 183.5),
70.57 s (CMe2). 31P NMR spectrum (CDCl3), δP, ppm:
23.6. Found, %: P 11.63. C11H23O5P. Calculated, %: P
11.63.
Diethyl (9-Hydroxy-9H-fluorene-9-yl)phosphonate
1
(XVIII). Yield 60%, mp 150–152°C (acetonitrile). H
NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.08 t (6H,
CH3, J 7) 3.94 d.q (4H, OCH2, J 7, J 8), 7.34 t (2H,
CH, J 7.5), 7.42 t (2H, CH, J 7.5), 7.67 d (2H, CH,
J 7.2), 7.87 d (2H, CH, J 7.2). 13C NMR spectrum
(CDCl3), δC, ppm (J, Hz): 16.17 (CH3), 63.47 (CH2),
80.6 d (PC, JPC 160), 119.9 s, 126.3 s, 127.6 s, 129.5 s,
140.8 s, 143 s (C6H5). 31P NMR spectrum (CDCl3), δP,
ppm: 20.34. Found, %: C 64.15; H 6.02; P 9.73.
C17H19O4P. Calculated, %: C 64.15; H 6.02; P 9.73.
Diethyl (6E)-3,7-dimethyl-1-oxo-6-octenylphos-
phonate (XXIII). To a solution of 0.5 ml of oxalyl
chloride in 10 ml of anhydrous dichloromethane at
–60°C was added 0.9 ml of DMSO in 2 ml of
dichloromethane and then a solution of 1.4 ml of
Diethyl (2E,4E)-1-hydroxy-1,5-dimethyl-7-(2,6,6-
trimethyl-1-cyclohexene-1-yl)-2,4-heptadienylphos-
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720
KOLODYAZHNAYA et al.
hydroxyphosphonate IX in 4 ml of dichloromethane
was added at the same temperature. After 15 min,
3.5 ml of triethylamine was added at –50°C. The
mixture was stirred for 5 min, heated to room
temperature, and poured into 35 ml of ice water. The
water layer was separated and extracted with 2 × 10 ml
of dichloromethane. The solution was dried over
magnesium sulfate, then the solvent was evaporated,
and the residue was distilled in a vacuum. Yield 70%,
The general method for the synthesis of bis-
phosphonohydroxyalkanes (XXVII–XXXI). A mix-
ture of 0.01 mol of a ketophosphonate, 0.01 mol of
trialkyl phosphate, and 0.01 mol of pyridinium iodide
in 3 ml of methylene chloride was stirred for the time
specified in Table 2. Then the solvent was evaporated
and the residue was dissolved in 5 ml of ether (or
THF), the solution was filtered, evaporated, and the
residue was purified by column chromatography or
distilled in a vacuum. Yields are listed in Table 2.
1
bp 115°C (0.08 mm Hg). H NMR spectrum (CDCl3),
δ, ppm (J, Hz): 0.87 m (3H, CH3), 0.91 d (CH3CH,
J 7), 1.37 t (CH3CH2, J 7), 1.58 s (3H, CH3C =), 1.66 s
(3H, CH3C =), 1.97 m (2H, CH2), 2.14 m (2H, CH2),
2.6–2.8 m (2H, CH2C=O), 4.21 m (4H, OCH2), 6.06 t
(2H, CH=C, J 6.5). 31P NMR spectrum (CDCl3), δP,
ppm: –1.96. Found, %: P 10.76. C14H27O4P. Cal-
culated, %: P 10.67.
1,1-Bis(dietoxyphosphoryl)-1-hydroxyetane (ethyl
etidronate) (XXVII). Compound was purified by
distillation in a vacuum. Yield 65%, bp 160°C
(0.08 mm Hg), which corresponds to the data of the
1
previously described compound [37]. H NMR spec-
trum (CDCl3), δ, ppm (J, Hz): 1,32 t (12H, CH3CH2,
J 7), 1.56 t (3H, CH3CP, J 16), 4.16 m (8H, OCH2)
31
4 br (1H, OH). P NMR spectrum (CDCl3), δP, ppm:
Diethyl (2E)-3,7-dimethyl-1-oxo-2,6-octadienyl-
phosphonate (XXIV). Prepared similarly to com-
pound XXVIII. Yield 70%, bp 115°C (0.08 mm Hg).
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.87 m
(3H, CH3), 1.24 s (3H, CH3C=), 1.29 s (3H, CH3C=),
1.31 m (6H, CH3CH2O, JHH 7), 1.6 m (2H, CH2), 2.0 m
(2H, CH2), 2.29 m (2H, CH2), 4.1 m (4H, CH2O), 5.33
20.3. Found, %: C 37.62; H 7.55. C10H24O7P2. Cal-
culated, %: C 37.74; H 7.60.
1,1-Bis(dietoxyphosphoryl)-(2E)-1-hydroxy-3,7-
dimethyl-2,6-octadiene (XXVIII). The product was
purified by column chromatography on silica gel, yield
1
65%, oil. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
31
1.27 t (6H, CH3, J 7), 1.28 t (6H, CH3, J 7), 1.6 s (3H,
CH3), 1.63 s (3H, CH3), 1.8 d (3H, CH3 , JHH 8), 2.0 m
(4H, CH2), 4.21 m (8H, OCH2), 4.8 m (1H, CH=), 5.1
m (=CH–C=O). P NMR spectrum (CDCl3), δP, ppm:
–1.2. Found, %: P 10.76. C14H25O4P. Calculated, %: P
10.74.
31
m (1H, CH=, JHH 7). P NMR spectrum (CDCl3), δP,
ppm: 23.3. Found, %: C 50.45; H 8.41; P 14.50.
C18H36O7P2. Calculated, %: C 50.70; H 8.51; P 14.53.
Dimethyl (2E,6E)-3,7,11-trimethyl-1-oxo-2,6,10-
dodecatrienylphosphonate (XXV). Yield 60%, bp
145°C (0.1 mm Hg). H NMR spectrum (CDCl3), δ,
1
1,1-Bis(dietoxyphosphoryl)-1-hydroxy-(2E,6E)-
3,7,11-trimethyl-2,6,10-dodecatriene (XXIX). Purified
by column chromatography (eluent hexane–ethyl
ppm (J, Hz): 1.6 s (3H, CH3C=), 1.66 s (3H, CH3C=),
1.69 d (3H, CH3C=, J 1.5), 1.71 d (3H, CH3C=, J 1.5),
2.1 m (6H, CH2), 2.25 m (2H, CH2), 3,75 d (3H,
CH3O, JHP 10), 3.8 d (3H, CH3O, JHP 10), , 5.1 br (1H,
CH=C), 5.5 br (2H, CH=C). 31P NMR spectrum
(CDCl3), δP, ppm: –0.98. Found, %: C 62.38; H 8.89; P
9.45. C17H29O4P. Calculated, %: C 62.18; H 8.90; P
9.43.
1
acetate, 3:1). Yield 60%. H NMR spectrum (CDCl3),
ppm (J, Hz): 1.6 s (3H, CH3), 1.69 s (3H, CH3), 1.8 d.d
(3H, JHP 8, JHH 7), 2.0 m ( 4H, CH2), 3,75 d (3H,
CH3O, JHP 10), 3.8 d (3H, CH3O, JHP 10), 4.8 m (2H,
31
CH=), 5.1 m (1H, CH=). P NMR spectrum (CDCl3),
δP, ppm: 23. Found, %: P 14.60. C18H34O7P2. Cal-
culated, %: P 14.60.
Diethyl [(1,2,3,4,5,6,7,8-octahydro-3,8,8-trimethyl-
Bis(diethylphosphoryl)hydroxy(3,5,5-trimethyl-
1,2,3,4,5,6,7,8-octahydro-2-naphthyl)methane (XXX).
31P NMR spectrum (CDCl3), δP, ppm: 23. Found, %: P
14.60. C22H42O7P2. Calculated, %: P 12.89.
2-naphthyl)carbonyl] phosphonate (XXVI). Yield
60%, bp 150°C (0.1 mm Hg). H NMR spectrum
1
(CDCl3), δ, ppm (J, Hz): 0.94 d (CH3, J 6.5), 1.36 t
(CH3, J 7.2), 1.58 s [3H, (CH3)2C], 1.67 s [ 3H, (CH3)2C],
1.93 m (2H, CH2), 2.04 m (2H, CH2), 2.31 m (1H,
1,1-Bis(dietoxyphosphoryl)-(6E)-1-hydroxy-3,7-
dimethyl-6-octene (XXXI). The product was purified
by chromatography on silica gel column. Yield 65%,
oil. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.02 d
(3H, J 4), 1.34 m (12H, CH3CH2), 1.59 s (3H, CH3C=),
31
CH), 3.01 m (1H, CHC=O), 4.2 m (OCH2). P NMR
spectrum (CDCl3), δP, ppm: –2.54. Found, %: C 63.35;
H 9.09; P 9.15. C18H31O4P. Calculated, %: C 63.14; H
9.13; P 9.05.
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AN EFFICIENT METHOD FOR THE PHOSPHONATION OF C=X COMPOUNDS
721
1.66 s (3H, CH3C=), 2.0 m (4H, CH2), 4.23 m (8H,
OCH2), 5.1 m (CHC=, J 7). 31P NMR spectrum
(CDCl3), δP, ppm: 20.6. Found, %: C 50.45; H 8.41; P
14.50. C18H38O7P2. Calculated, %: C 50.46; H 8.94; P
14.46.
OCH2Me, JHH 7.0), 1.33–1.46 m (C6H4), 1.59–2.10 m
(6H), 3.86–3.93 m (4H, OCH2CH3), 5.38 br (1H, NH),
6.63 t (1H, ArH, J 7.1), 6.86 d (2H, ArH, J 8.1), 6.99
m (2H, ArH, J 8.1). 31P NMR spectrum (CDCl3), δP,
ppm: 31. Found, %: N 4.56; P 9.85. C16H26NO3P.
Calculated, %: N 4.50; P 9.95.
Diethyl phenyl(benzylamino)methylphosphonate
(XXXII). To the cooled to 0°C solution of 0.01 mol of
trialkyl phosphite and 0.01 mol of Schiff base in 3 ml
of methylene chloride was added at stirring 0.01 mol
of pyridinium bromide. The mixture was stirred at 0°C
for 30 min, then heated to room temperature and left at
stirring for 12 h, then filtered, the solvent was
evaporated, and the residue was dissolved in hexane,
filtered, again evaporated, and distilled in a vacuum.
Diethyl 2-nitro-1-phenylethylphosphonate
(XXXVI). To a solution of 0.01 mol of triethyl
phosphite and 0.01 mol of nitrostyrene in 3 ml of
methylene chloride cooled to 0°C was added at stirring
0.01 mol of pyridinium bromide. Stirring at 0°C was
continued for 30 min, then the mixture was heated to
room temperature and stirred for 6 h. Certain amount
of precipitate formed and was filtered off, from the
filtrate the solvent was evaporated, and the residue was
recrystallized from acetonitrile. Yield 70%, mp 65°C
(hexane). Found, %: P 10.78. C12H18NO5P. Calculated,
%: P 10.78 [29].
31
Yield 70%, bp 150°C (0.08 mm Hg). P NMR spec-
trum (CDCl3), δP, ppm: 24 [38].
Dimethyl phenyl[(1-methylbenzyl)amino]methyl-
phosphonate (XXXIII). Prepared similarly to com-
pound XXX. Yield 70%, mp 60°C. 1H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 1.4 d (3H, CH3, J 7), 3.51 m
(1H, NH), 3.79 d (3H, CH3, J 11.8), 3.83 d (3H, CH3,
J 10.1), 5.2 d (1H, PCH, J 24), 6.8–7.28 m (5H, C6H5),
Dimenthyl (2-nitro-1-phenyl)ethylphosphonate
(XXXVII). Prepared similarly. Yield 65%, mp. 140°C,
31
[α]D –68 (c 1, C6H6). P NMR spectrum (CDCl3), δP,
ppm: 19.6, which corresponds to the previously
described compound [30].
13
7.3 d (2H, J 8.5), 7.5 d (2H, C6H5, J 8.5) . C NMR
spectrum (CDCl3), δC, ppm (J, Hz): 16 d (CH3), 56.1 q
(OCH3, 2JPC 7.0), 56.2 d (OCH3, 2JPC 6.8), 57.2 d (CH,
1JPC 150 ), 114.3 s (CH), 120.0 s (CH), 128.2 d (CH,
3JPC 5.8), 128.4 d (CH, 3JPC 3.1), 130.1 s (CH), 131.2 s,
140.0 s, 146.6 d (2JPC 14.5) . 31P NMR spectrum (CDCl3),
δP, ppm: 24, which corresponds to the previously
described compound [27].
Diethyl (propylamino)carbonylphosphonate
(XXXVIII). A mixture of 0.01 mol of triethyl
phosphite, 0.01 mol propyl isocyanate, and 0.01 mol of
pyridinium bromide was left standing for 2 h. After 2 h
the reaction mixture was diluted with ether and
filtered. The solvent was evaporated, the residue was
distilled in a vacuum. Yield 90%, bp 100–110°C
1
(0.08 mm Hg). H NMR spectrum (CDCl3), δ, ppm
Diethyl (2E)-1-phenylamino-3,7-dimethylocta-2,6-
dienylphosphonate (XXXIV). Purified by column
chromatography on silica gel. Oil, yield 50%. 1H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.27–1.17 m (6H,
CH3), 1.49 s (3H, CH3), 1.54 s (3H, CH3), 1.61 s (3H,
CH3), 1.72–1.71 m (2H), 2.06–1.97 m (2H), 4.15–3.97
(J, Hz): 0.87 t (3H, CH3, J 7.5), 1.3 t (6H, CH3CH2O,
J 7), 1.51 m (2H, CH3CH2CH2), 3.2 q (4H, NCH2, J 7),
4.15 m (4H, CH2O), 7.34 m (1H, NH). 13C NMR
spectrum (CDCl3), δC, ppm (J, Hz): 11.2 d (CCC, J 8),
16.15 d (CH3CO, J 15), 22.6 s (CCCN), 40.98 s (CN),
64.15 d (OC, J 8), 165 d (PC, JPC 221). 31P NMR
spectrum (CDCl3), δP, ppm: –0.71. Found, %: N 6.28;
P 13.88. C8H18NO4P. Calculated, %: N 6.28; P 13.88.
2
3
m (4H, CH2), 4.38 d.d (1H, PCH, JPH 20.7, JHH 9.4),
4.95–5.12 m (2H, C=CH), 7.13–6.54 m (5H, C6H5).
13C NMR spectrum (CDCl3), δC, ppm (J, Hz): 16.4,
1
16.5, 17.1, 17.7, 25.6, 26.2, 39.6, 50.6 d (CP, JPC
Diethyl (allylamino)thiocarbonylphosphonate
2
158.5), 62.8 d (OCH2CH3, JPC 7.3), 63.1 d
(XXXIX). Prepared like compound XXXV. Yield
2
(OCH2CH3, JPC 6.6), 113.9, 118.4, 119.9, 123.6,
1
80%, bp 120°C (0.08 mm Hg). Yellowish liquid. H
31
129.1, 131.8, 141.6, 146.8 (C6H5). P NMR spectrum
NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.36 t (6H,
CH3CH2), 4.08–4.3 m (6H, OCH2+NCH2), 5.27 d.d
(1H, C=CH2, J 6, J 1), 5.31 d.d (1H, C=CH2, J 12.5,
J 1), 5.91 d.d.t (1H, CH2CH=C, J 17, J 10.2, J 6), 9.27
br (1H, NH). 13C NMR spectrum (CDCl3), δC, ppm
(J, Hz): 16.24 d (CCO, J 10), 42.4 d (CN, J 9), 63 d
(POC, J 6), 119 s (C=CH), 130.7 s (CH2=C), 193 d
(CDCl3), δP, ppm: 28.4. Found, %: N 3.72; P 8.48.
C20H32NO3P. Calculated, %: N 3.83; P 8.48.
Diethyl 1-phenylaminocyclohexylphosphonate
(XXXV). Synthesized like compound XXXII. Yield
1
60%, mp 100°C (published: 93–95°C) [39]. H NMR
spectrum (CDCl3), δ, ppm (J, Hz): 1.07 t (6H,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 4 2010

722
KOLODYAZHNAYA et al.
(PC, J 155). 31P NMR spectrum (CDCl3), δP, ppm:
–1.7. Found, %: N 5.88; P 13.37. C8H16NO3PS.
Calculated, %: N 5.90; P 13.05.
17 Dale, J.A. and Mosher, H.S., J. Am. Chem. Soc., 1973,
vol. 95, no. 2, p. 512.
18. Santos, W.L., Heasley, B.H., Jarosz, R., Carter, K.M.,
Lynch, K.R., and Macdonald, T.L., Bioorg. Med. Chem.
Lett., 2004, vol. 14, no. 13, p. 3473.
Diethyl phenylaminothiocarbonylphosphonate
(XL). Yield 90%, bp 160°C (0.1 mm Hg), yellow
19. Manscuso, A.J. and Swern, D., Synthesis, 1981, no. 3,
1
liquid. H NMR spectrum (CDCl3), δ, ppm (J, Hz):
p. 165.
1.36 t (6H, CH3, J 7), 4.27 d.q (CH2, J 7, J 8), 7.28–
7.96 m (5H, C6H5), 10.86 br (1H, NH). 13C NMR
spectrum (CDCl3), δC, ppm (J, Hz): 15.7 d (CH3C,
J 7), 61.3 d (CH2O, J 5), 123.9 s, 127.1 s, 131 s, 140.1
s (C6H5 ), 154.5 d (PC, J 90). 31P NMR spectrum
(CDCl3), δP, ppm: –2.07. Found, %: N 5.11; P 11.30.
C11H16NO3PS. Calculated, %: N 5.13; P 11.33.
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25. Shull, L.W., Wiemer, A.J., Hohlb, R.J., and Wiemer, D.F.,
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