Synthesis and reactivity of substituted alkoxymethylphosphonites and their derivatives

Article abstract of DOI:10.1002/hc.21015

Alkoxy-substituted methylphosphonites and their derivatives are prepared using an organomagnesium method of synthesizing the organophosphorus compounds and alkoxymethylation of various PH acids and their derivatives. Also, certain properties of these promising compounds as important precursors of new functionalized organophosphorue compounds with alkoxymethyl fragments are presented.

Full text of DOI:10.1002/hc.21015

Heteroatom Chemistry
Volume 23, Number 3, 2012
Synthesis and Reactivity of Substituted
Alkoxymethylphosphonites and Their
Derivatives
Andrey A. Prishchenko, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, and Valery S. Petrosyan
Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia
Received 21 September 2011; revised 12 January 2012
nomycin (fosfomycin), is a low molecular weight
ABSTRACT: Alkoxy-substituted methylphospho-
cell wall active antibiotic [2,4], and the substituted
nites and their derivatives are prepared using
derivatives of hydroxymethylphosphonic acid, in-
an organomagnesium method of synthesizing the
cluding the fragments of adenine (tenofovir, tru-
organophosphorus compounds and alkoxymethyla-
vada, and viread) and cytosine (cidofovir), are ef-
tion of various PH acids and their derivatives.
fective antiviral drugs [3,5]. Also, various deriva-
Also, certain properties of these promising com-
tives of substituted alkoxy- or hydroxymethyl phos-
pounds as important precursors of new functionalized
phonites and their analogs present great interest as
organophosphorue compounds with alkoxymethyl
effective polydentate ligands and organophospho-
ꢀ
C
fragments are presented. 2012 Wiley Periodicals, Inc.
rus biomimetics of hydroxyl-substituted carboxylic
acids [1–3]. Recently, we have proposed convenient
methods for synthesis of the series of function-
Heteroatom Chem 23:281–289, 2012; View this article on-
line at wileyonlinelibrary.com. DOI 10.1002/hc.21015
alized trimethylsiloxymethylphosphonites [6] and
tris(alkoxymethyl)phosphines [7]. The present paper
is devoted to the synthesis and study of the reac-
tivity of substituted alkoxymethylphosphonites and
their analogs, which are not available and almost
unknown (cf. [1]).
INTRODUCTION
The functionalized organophosphorus compounds
with the various hydroxyl- or alkoxymethyl frag-
ments and their derivatives containing tetracoor-
dinated phosphorus have been intensively investi-
gated in recent years; rather convenient methods
of synthesis of these compounds have been pro-
posed and their properties have been studied in
detail [1–3]. Interesting biological activity of these
compounds was found, so the well-known 1,2-
epoxypropylphosphonic acid, also called phospho-
RESULTS AND DISCUSSION
Following our previous investigations of di-
alkoxymethylation of some PH acids and their
derivatives [8], we have studied the alkoxymethyla-
tion of PH acids by acetals of various structures,
which have not previously been brought into this in-
teraction [1]. We found that dialkoxymethanes, even
on heating to 160–200◦C, do not react with dibutyl
and dibutoxyphosphines, or with dialkylphosphites.
For dialkoxymethane activation, we used catalytic
quantities of boron trifluoride etherate—a tradi-
tional reagent for generation of highly reactive
alkoxycarbonium ions [8–12]. It was shown that
Dedicated to Professor Ivan F. Lutsenko (1912–1993).
Correspondence to: Andrey A. Prishchenko; e-mail: apr-
ishchenko@yandex.ru.
Contract grant sponsor: Russian Foundation for Basic Re-
search.
Contract grant numbers: 11-03-00402 and 12-03-00003.
2012 Wiley Periodicals, Inc.
c
ꢀ
281

282 Prishchenko et al.
only dibutylphosphite enters into reaction with
dibutoxymethane up to 180–200◦C to yield bu-
toxymethylphosphonate 1. Apparently, the scheme
of this interaction is similar to the Arbuzov reac-
tion (Eq. (1)). The reaction begins with attack of an
electrophilic complex A on the tricoordinated phos-
phorus atom of dibutylphosphite with formation of
a phosphonium complex, the decomposion of which
leads to butoxymethylphosphonate 1.
phosphines, which is due to the lower nucleophilic-
ity and the low concentration of the reactive tau-
tomer C with a tricoordinated phosphorus atom (Eq.
(4)), (cf. Eq. (1)). The corresponding compounds 5–
10 are obtained in high yields.
+
–
+
ArCHOR ROBF3
–
X2PH
O
X2PCH(OR) ROBF3
X2POH
X2PCH(OR)Ar
– ROH, – BF3
OH
O
C
D
5–10
X = MeO (5), EtO (6-9), i-PrO (10); R = Me (5,10), Et (6–9);
Ar = Ph (5,6,10), 4-MeC6H4 (7), 4-MeOC6H4 (8), 4-ClC6H4 (9).
Et2O BF3
– Et2O
+
–
+CH2OBu BuOBF3
(BuO)2P(O)H
–
CH2(OBu)2
(BuO)2PCH2OBu BuOBF3
– BuOH, – BF3
OH
(4)
A
B
(BuO)2PCH2OBu
Note the compounds of this type may be syn-
thesized in the absence of catalyst; however, in this
case prolonged heating of the mixture (180–210◦C)
in a sealed ampul is required [1], due to the low
electrophilicity of starting acetals as compared with
intermediate complexes of the type D. Thus, the
reaction of acetals of aromatic aldehydes with PH
acids in the presence of boron trifluoride ether-
ate as a catalyst is a convenient method of synthe-
sizing alkoxymethylphosphonites and their deriva-
tives. Also, for the first time, we have suggested
the organometallic method of synthesis of several
organophosphorus compounds with alkoxymethyl
fragments using available alkoxymethylmagnesium
chlorides, which are easily formed in high yields
on the reaction of chloromethyl alkyl esters with
magnesium in tetrahydrofuran (THF) at a temper-
ature of the mixture of about −25◦C [13–15]. Note
that dialkoxymethyl compounds of magnesium have
not been reported [16]; therefore, the possibilities
of the organometallic method for the synthesis of
(dialkoxymethyl)phosphonites and their derivatives
are extremely limited (cf. [8]). So, the reaction
of alkoxymethylmagnesium chlorides with various
chlorophosphines proceeds under cooling to −70◦C
in THF in the presence of pyridine and leads to
alkoxymethylphosphines and their derivatives 11–
24 of various structures (Eq. (5)).
O
1
(1)
Under similar conditions, dibutylphosphine
practically does not react with dibutoxymethane,
whereas dibutoxyphosphine decomposes to tri-
butylphosphite and polymer. Acetals of aliphatic
aldehydes react with dialkylphosphites under these
conditions to form a complex mixture of products,
which is due to the instability of the intermediate
alkyl-substituted alkoxycarbenium ions, which un-
der the conditions of the reaction may be trans-
formed to vinyl esters [12]. Much more active in
the reactions with various PH acids are acetals of
benzaldehyde and its derivatives. Thus, the highly
nucleophilic dibutylphosphine reacts smoothly with
dimethylacetal of benzaldehyde even at 100◦C in
the presence of boron trifluoride etherate to form
methoxy(benzyl)phosphine 2 (Eq. (2)).
+
Et2
O
BF3
+
-
Bu2PH
–
PhCH(OMe)2
PhCHOMe MeOBF3
Bu2PCH(OMe)Ph MeOBF3
– Et2
O
– MeOH, – BF3
H
A
B
Bu2PCH(OMe)Ph
2
(2)
The reaction of dibutoxyphosphine with ben-
zaldehyde dibutylacetal takes place under the same
conditions; however, as a result of the reaction, in
addition with phosphonite 3 we also obtained the
product of its isomerization in the presence of boron
trifluoride–phosphinate 4 (Eq. (3)).
X2PCl
+
ROCH2MgCl
X2PCH2OR
– MgCl2
11–15
XPCl2
+
2 ROCH2MgCl
XP(CH2OR)2
– 2 MgCl2
16–20
Bu
PhCH(OBu) ,
Et2O BF3
BF3
2
(BuO)2PH
(BuO)2PCH(OBu)Ph
PCH(OBu)Ph
PCl3
+ 3 ROCH2MgCl
P(CH2OR)3
– BuOH, – Et2O
– 3 MgCl2
BuO
O
21–24
3
4
(3)
X = i-Pr (11), t- Bu (16,17), Ph (12,18), EtO (19), BuO (13), Me2N (14), Et2N (15,20);
R = Me (12-14,16,18,21), Et (11,15,17,19,20,22), Pr (23), Bu (24).
The reaction of PH acids of trivalent phosphorus
with acetals of benzaldehyde and its derivatives in
the presence of boron trifluoride etherate takes place
under more severe conditions (150–170◦C) than for
(5)
Note that tris(alkoxymethyl)phosphines 21–
24 were yet obtained by using more expensive
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactivity of Substituted Alkoxymethylphosphonites and Their Derivatives 283
ClCH2OEt, FeCl3
tris(trimethylsilyl)phosphine
(cf.
[7]).
Since
Cl2PCH2OEt
EtOPCl2
– EtCl
alkoxymethylmagnesium chlorides are stable at
temperature below −20◦C, they cannot be intro-
duced into a reaction with low activity phosphorus
acids chlorides for which substitution of the chlo-
rine atom takes place slowly and requires heating.
So, on the reaction of di-tert-butylchlorophosphine
with alkoxymethylmagnesium chlorides, formation
of the corresponding alkoxymethylphosphine was
not observed by 31P NMR even in the reaction
mixture, and the original chlorophosphine was
returned in a yield of 90%. On the reaction with
alkoxymethylmagnesium chlorides, acid chlo-
rides of tetracoordinated phosphorus form in low
yields (5%–10%); the corresponding oxides of
alkoxymethylphosphines are strongly contaminated
by oligomeric products of decomposition of the
starting organomagnesium compounds. At the same
time, it is interesting to note the different yields of
oxide of tris(ethoxymethyl)phosphine 25, which is
formed on the reaction of ethoxymethylmagnesium
chloride with phosphorus oxychloride (yield 13%)
and dichloro ethoxymethyl phosphonate 26 (yield
44%) (Eq. (6)).
O
26
(8)
The unique reactivity of chloromethyl alkyl
esters was used by us for preparing several
functionalized organophosphorus compounds with
alkoxymethyl fragments (see [8]). So it was re-
ported previously that trichloromethylphosphonite
F does not enter into the Arbuzov reaction [17]. We
succeeded in rearrangement of phosphonite with
chloromethyl methyl ether in the presence of zinc
chloride, that is, under conditions of generation of
a highly reactive methoxycarbenium ion, and the
corresponding phosphinate 27 was obtained in high
yield (Eq. (9)).
CCl3
ClCH2OMe, ZnCl2
(EtO)2PCCl3
EtOP
O
– EtCl
CH2OMe
27
F
2 EtOCH2MgCl
3 EtOCH2MgCl
(9)
Cl2PCH2OEt
(EtOCH2)3P
Cl3P
O
– 3 MgCl2
– 2 MgCl2
O
O
25
26
The more nucleophilic dichloromethylphospho-
nite G slowly reacts with chloromethyl methyl ether
even when the mixture is boiled in the absence of
catalyst to give phosphinate 28 (Eq. (10)).
(6)
The significant increase in the yield of phos-
phine oxide in the latter case is apparently related
to the formation of an intermediate complex E
with participitation of the alkoxy and phosphoryl
groups of the starting phosphonate 26, in which
there may be an increase in the reaction capacity
of the alkoxymethylmagnesium chloride (Eq. (7)).
CHCl2
ClCH2OMe
(EtO)2PCHCl2
EtOP
O
– EtCl
CH2OMe
28
G
(10)
Cl2P
O
CH2
OR
Also,
ether as
for
using
chloromethyl
the reaction
ethyl
of
intermediate,
bis(dichlorophosphino)methane with an excess
of diethoxymethane was carried out by us. The first
step of this reaction is an exchange of chloro and
ethoxy groups with formation of the bisphosphonite
H and chloromethyl ethyl ether as intermediates,
which were completely transformed under boiling
of mixture into bisphosphinate 29 (cf. [8,18]),
(Eq. (11)).
Mg
Cl
ROCH2
E
(7)
Thus, the organomagnesium method may suc-
cessfully be used basically for the synthesis of
alkoxymethylphosphines and their derivatives 11–
25. Note that dichlorophosphonate 26 was specially
obtained by us via the interaction of highly reactive
chloromethyl ethyl ether with dichloro ethyl phos-
phite in the presence of iron(III) chloride as a cata-
lyst under heating to 90◦C (cf. [1]) (Eq. (8)).
(EtO)2CH2
2 ClCH2OEt
EtO
(Cl2P)2CH2
[(EtO)2P]2CH2
P
CH2
– 4 ClCH2OEt
– 2 EtCl
EtOCH2
O
2
H
29
(11)
Heteroatom Chemistry DOI 10.1002/hc

284 Prishchenko et al.
In contrast to dialkoxymethylphosphonites (cf.
[8]), the high stability of the P C bond in
alkoxymethylphosphonites permits one to prepare
chlorine-substituted alkoxymethylphosphines 30,
31 via the treatment of the corresponding amino
derivatives 15, 20 with an excess of hydrogen chlo-
ride under mild conditions (Eq. (12)).
bonds giving methoxycarbonylphosphine oxide 34.
So, the increase in the strength of the P C bond and
the decrease in the electrophilicity of the central car-
bon atom in the ethoxy group in the quasiphospho-
nium compound J lead to the usual direction of the
Arbuzov reaction—dealkylation with the formation
of phosphine oxide 34 (Eq. (15)).
4 HCl
(Et2N)2PCH2OEt
Cl2PCH2OEt
+
– 2 Et2NH HCl
ClCOOMe
-
EtOP(CH2OEt)2
EtOP(CH2OEt)2 Cl
MeOOCP(CH2OEt)2
O
– EtCl
15
30
COOMe
2 HCl
J
34
Et2NP(CH2OEt)2
ClP(CH2OEt)2
– Et2NH HCl
(15)
20
31
(12)
The reaction of diisopropyl(ethoxymethyl)-
phosphine 11 with alkoxy chloroformates takes
place in an unusual manner. Even at 20◦C, one ob-
serves rapid liberation of a gas and the original phos-
phine remains in the reaction mixture, that is, the
reaction amounts to decomposition of the alkoxy
chloroformates to alkyl chloride and carbon dioxide.
Consequently, the decomposition of quasiphospho-
nium compound K takes place with attack of a chlo-
rine anion on the electrophilic carbon atom in the
radical of the alkoxycarbonyl group with breakage
of the labile P C bond. A similar decomposition of
alkoxy chloroformates is also observed in the pres-
ence of catalytic quantities of tertiary phosphines
under 20◦C, whereas in the presence of triethylamine
the decomposition takes place on heating of the mix-
ture to 40–60◦C, which is in agreement with the data
in the literature on the stability of alkoxy chlorofor-
mates [23] (Eq. (16)).
It is interesting to note that in distinction from
dihalogen(halogenmethyl)phosphines, which reacts
with 2 equiv of sodium bis(trimethylsilyl)amide to
form halogen-substituted phosphaethylenes [19,20],
dichloro(ethoxymethyl)phosphine 30 reacts under
analogous conditions by the path of double nu-
cleophilic substitution of the chlorine atom to
form diamino(ethoxymethyl)phosphonite 32 but not
the expected ethoxy-substituted phosphaethylene I
(Eq. (13)).
[(Me3Si)2N]2PCH2OEt
2 (Me3Si)2NNa
– 2 NaCl
32
Cl2PCH2OEt
(Me3Si)2NP=CHOEt
– (Me Si)2NH
3
I
(13)
The impossibility of the dehydrochlorination
reaction in this case and the formation of phos-
phaethylene I are due to the low CH acidity of the
methylene component of the ethoxymethyl group
(cf. [21]). Chlorophosphine 31 reacts with an excess
of triethyl orthoformate via usual direction (cf. Eq.
(11)) forming substituted phosphine oxide 33 in high
yield (Eq. (14)), (cf. [8,22]).
+
ClCOOR
– RCl, –CO
-
i-Pr2PCH2OEt
i-Pr2PCH2OEt Cl
2
COOMe
11
K
R = Me, Bu.
(16)
(EtOCH2)2PCl + HC(OEt)3
(EtOCH2)2PCH(OEt)2
O
– EtCl
On the basis of alkoxymethyl derivatives of triva-
lent phosphorus using standard methods of oxida-
tion and addition of sulfur, we suggested new un-
known or alkoxymethyl compounds of phosphorus
that are available with difficulty, including phos-
phoryl or thiophosphoryl groups. So, yellow mer-
cury oxide and iodosobenzene smoothly oxidize
alkoxymethylphosphines 11, 18 to the correspond-
ing oxides 35, 36 on boiling in benzene (Eq. (17)).
31
33
(14)
In contrast to dialkoxymethylphosphonites
(cf. [8]), the interaction of bis(ethoxymethyl)-
phosphinite 19 with methoxy chloroformate pro-
ceeds under mild conditions with retention of P C
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactivity of Substituted Alkoxymethylphosphonites and Their Derivatives 285
HgO
– Hg
Also, we observed the lability of the P C bond on
i-Pr2PCH2OEt
i-Pr2PCH2OEt
the similar reduction or diethoxymethylphosphine
oxide 44, which was specially prepared via the in-
teraction of diisopropylphosphine oxide and triethyl
orthoformate in the presence of boron trifluoride di-
ethyl etherate as a catalyst under heating to 150◦C
(cf. [8]) (Eq. (21)).
O
11
35
PhIO
– PhI
PhP(CH2OMe)2
PhP(CH2OMe)2
O
18
36
(17)
HC(OEt)3,
Et2O BF3
i-Pr2PCH(OEt)2
i-Pr2PH
O
Note that oxidation of tris(ethoxymethyl)-
phosphine 20 by dry atmospheric oxygen, even un-
der moderate conditions, leads to a mixture of
phosphine oxide 25 and phosphinate 37 formed due
to insertion of oxygen in the P C bond in a ratio 4:1
(Eq. (18)).
– EtOH
O
44
(21)
So, the direction of this reaction with an excess
of lithium aluminum hydride is greatly dependent
on the temperature conditions under which it is car-
ried out. Under cooling to −50◦C, the only prod-
uct of the reaction is diisopropylphosphine—a prod-
uct of breakage of the P C bond in the interme-
diate compound M by the hydride anion (cf. [8]).
When the reaction is carried out at −20◦C, diiso-
propyl(diethoxymethyl)phosphine 45—a product of
usual reduction—was obtained with a yield of 30%.
When the reaction mixture is boiled in ether (36◦C),
diisopropyl(ethoxymethyl)phosphine 11—a product
of the reduction of both the phosphoryl group and
the diethoxymethyl fragment of the starting oxide
44—was obtained with a yield of 31%; in both cases,
diisopropylphosphine was also found (Eq. (22)).
O2
(EtOCH2)3P
(EtOCH2)2POCH2OEt
O
(EtOCH2)3P
+
O
20
25
37
Phosphinate 37, fragment POCH2: δP 41.72 s; δH 5.12 d, 3JPH 12.
(18)
Sulfur is smoothly added to alkoxymethylphos-
phines during boiling in diethyl ether or benzene
with formation of thiooxides 38–43 in high yields
(Eq. (19)).
S
X2PCH2OR
X2PCH2OR
11,14
–50°C
S
i-Pr2PH
38,39
S
+
–
LiAlH4
XP(CH2OR)2
16,18
LiAlH4
–20°C
36°C
XP(CH2OR)2
i-Pr2PCH(OEt)2
i-Pr2PCH(OEt)2 AlH4
(22)
i-Pr2PCH(OEt)2 + i-Pr2PH
O
44
OLi
45
S
40,41
M
i-Pr2PCH2OEt + i-Pr2PH
S
X2PCH(OR)Ph
X2PCH(OR)Ph
11
S
2,3
42,43
X = i-Pr (11,38), Bu (2,42), t-Bu (16,40), Ph (18,41), BuO (3,43), Me2N (14,39);
R = Me (2,14,16,18,39-42), Et (11,38), Bu (3,43).
It should be noted that lithium aluminum
hydride does not react with diisopropyl-
(diethoxymethyl)phosphine 45 on boiling in di-
ethyl ether, which shows the possibility of reduction
of the diethoxymethyl fragment only at the stage of
the complex M with the more electrophilic central
carbon atom of the dialkoxymethyl group (cf. [8]).
Thus, in the present investigation, we found
preparative methods for obtaining of alkoxy-
substituted methylphosphonites and their deriva-
tives; in addition, the detailed investigations of the
reactivity of these promising compounds were car-
ried out.
(19)
The reduction of the phosphine oxide 10 with
an excess of lithium aluminum hydride results in
the breakage of the P C bond and formation of di-
isopropylphosphine and methylbenzyl ether, but not
the expected phosphine L (Eq. (20)).
i-Pr2PH + PhCH2OMe
LiAlH4
i-Pr2PCH(OMe)Ph
O
The structures of compounds 1–45 were con-
10
i-Pr2PCH(OMe)Ph
1
firmed by the H, 13C, and 31P NMR spectra, which
L
show characteristic signals of the central PCH2O
and other fragments by the tri- or tetracoordinated,
(20)
Heteroatom Chemistry DOI 10.1002/hc

286 Prishchenko et al.
phosphorus (see Table 1). According to the NMR
spectra, the compounds 4 and 29 are the mixtures of
the stereoisomers. Their ratio was determined from
The compounds 26–29 were prepared in a simi-
lar way.
1
the H NMR and 31P spectra. The elemental analy-
Dichloro(ethoxymethyl)phosphine (30)
sis data of synthesized compounds is summarized in
Table 2.
Dry hydrogen chloride, 16 g, which was obtained
from 27 g of ammonium chloride, and excess of con-
centrated sulfuric acid was bubbled into a solution of
23.4 g of bis(diethylamino)ethoxymethylphosphine
15 in 250 mL of pentane with stirring and cooling
to −40◦C. The mixture was slowly heated to room
temperature and was diluted with 200 mL of pen-
tane. The precipitate was separated, the solvent was
removed, and the residue was distilled to give 10.4 g
of phosphine 30.
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were registered
on a Bruker Avance-400 spectrometer (400, 100,
and 162 MHz, respectively), in CDCl3 or C6D6 (1–
45) against tetramethylsilane (TMS) (1H and 13C)
and 85% H3PO4 in D2O (31P). All reactions were
performed under dry argon in anhydrous solvents.
Starting organic derivatives of trivalent phospho-
rus were prepared according to the procedures de-
scribed in [24].
Phosphine 31 was prepared similarly.
Bis[bis(trimethylsilyl)amino]-
ethoxymethylphosphine (32)
O,O-Dibutyl Butoxymethylphosphonate (1)
A solution of 1 M sodium bis(trimethylsilyl)amide
in diethyl ether, 100 mL, was added to a solution of
7.5 g of dichloro(ethoxymethyl)phosphine 30 under
stirring and cooling to −70◦C, The mixture was left
for 2 h and then was diluted with 100 mL of pentane.
The precipitate was separated, the solvents were re-
moved, and the residue was distilled to obtain 9.8 g
of phosphine 32.
A mixture of dibutyl phosphite, 9.7 g, dibu-
toxymethane, 8 g, and boron trifluoride diethyl
etherate, 0.3 g, was heated at 180–200◦C for 1.5 h
with the distillation of butanol. The residue was dis-
tilled to give 4.5 g of phosphonate 1.
The compounds 2–10, 44 were obtained simi-
larly.
Diisopropyl(ethoxymethyl)phosphine (11)
Diethoxymethylbis(ethoxymethyl)phosphine
Oxide (33)
A solution of 9.5 g pyridine in 10 mL of diethyl
ether was added dropwise to a solution of 15.3 g of
diisopropyl(chloro)phosphine in 100 mL of diethyl
ether under stirring and cooling to −70◦C; then a so-
lution of ethoxymethylmagnesium chloride, which
was cooled to −40◦C and prepared from 3.1 g of
magnesium and 12.3 g of chloromethyl ethyl ether
in 80 mL of THF under cooling to −30◦C, was added
dropwise. The mixture was stirred with slow heat-
ing to room temperature, then diethyl ether, 100 mL,
and a saturated solution of sodium bicarbonate, 50
mL, were added to the mixture. The organic part was
separated and dried with magnesium sulfate, the sol-
vents were removed, and the residue was distilled to
give 11.2 g of phosphine 11.
Chlorobis(ethoxymethyl)phosphine 31, 5.2 g, was
added by stirring to triethyl orthoformate, 5.3 g; and
the obtained mixture was heated under 100◦C for 1
h and was distilled to give 6.5 g of oxide 33.
Methoxycarbonylbis(ethoxymetyl)phosphine
Oxide (34)
Methoxy chloroformate, 3.4 g, was added to a solu-
tion of 6.8 g of phosphinite 19 in 15 mL of benzene.
The mixture was heated to boil, the solvent was re-
moved, and the residue was distilled to give 6.7 g of
oxide 34.
The compounds 12–25 were obtained similarly.
The Interaction of
Diisopropyl(ethoxymethyl)phosphine 11 with
Butoxycarbonyl Chloroformate
O-Ethyl(trichloromethyl)-
methoxymethylphosphinate (27)
Butoxy chloroformate, 4.1 g, was added to 5.3 g of
phosphine 11. The formation of a gas was observed,
which was bubbled through a solution of calcium
chloride in water with precipitation of calcium car-
bonate. The mixture was stirred for 1 h and then was
The mixture of diethyl trichloromethylphosphonite,
8.1 g, chloromethyl methylether, 5.4 g, and zinc chlo-
ride, 0.1 g, was refluxed for 1.5 h, and then it was
distilled to give 8 g of phosphinate 27.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactivity of Substituted Alkoxymethylphosphonites and Their Derivatives 287
TABLE 1 Yields, Product Constants, and NMR Spectral Data (δ, ppm, J, Hz) for the PC1HnO Fragments of Compounds 1–45a
No.
Yield (%)
B.p. (◦C), (p, mm Hg)
nD20
δ C1Hd
2JPH
δ (C1) d
1JPC
δ , sb
H
P
1
2
3
4
32
87
18
28
122 (1)
104 (1)
120 (1)
180 (1)
1.4345
3.60
4.42
4.28
4.33
4.38
4.80
4.88
4.42d
4.45
4.38
4.33
4.35
4.58
3.75
4.05
3.51
3.73
3.73
3.67
8.0
1.5
1.5
64.69
78.49
80.03
79.02
77.85
77.16
78.43
80.12
81.30
79.18
78.97
79.96
73.26
72.65
71.04
70.65
74.85
73.57
68.24
67.92
68.96
69.23
71.42
68.15
68.20
74.65
72.74
69.30
77.77
67.73
67.28
66.83
67.64
79.87
74.09
75.47
64.35
65.62
68.95
69.03
69.94
71.76
75.61
72.08
81.26
104.10
102.28
106.55
110.1
4.3
21.12
−13.49
163.94
38.81
38.03
36.21
38.78
20.61
19.26
18.75
19.59
17.66
51.52
0.11
−21.64
165.30
82.57
77.74
−16.33
−15.85
−33.10
110.72
37.03
−42.28
−42.08
−40.69
−41.11
36.35
19.96
32.42
34.69
41.17
40.60
166.68
75.13
97.65
34.28
27.60
49.74
28.92
64.30
79.14
54.91
34.93
54.81
88.83
48.92
−6.87
c
c
12.8
110.5
108.1
116.5
109.2
112.1
115.2
114.3
114.9
115.5
108.1
5.2
1.51.42
10.3
10.1
12.3
12.0
16.2
16.0
16.1
16.0
16.3
14.0
5.4
5
85
83
60
54
71
78
63
80
72
38
55
35
62
64
54
58
59
54
61
68
44
74
86
86
43
118 (1)
121 (1)
130 (1)
155 (1)
132 (1)
128 (1)
66 (8)
133 (1)
60 (1)
53 (1)
71 (1)
55 (1)
68 (1)
94 (1)
51 (1)
60 (1)
74 (8)
78 (1)
104 (1)
130 (1)
104 (1)
81 (10)
92 (1)
94 (1)
142 (1)
1.5085
1.4886
1.4892
1.4965
1.4995
1.5273
1.4565
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27g
28g
29g
1.6085
5.0
8.5
9.0
9.0
4.9
c
10.9
22.3
21.1
7.2
6.8
6.4
8.1
9.1
7.5
6.8
1.4695
1.4685
c
5.0
c
c
c
3.72
5.0
e
e
f
f
f
f
1.4600
c
3.75
3.68
3.70
3.71
3.87
4.11
4.17
4.8
4.8
5.0
4.9
5.0
22.1
3.3
c
c
c
5.0
5.8
1.4515
64.30
116.6
92.6
94.1
116.6
117.2
56.8
39.9
25.5
67.9
64.8
65.3
63.5
64.7
105.5
66.7
65.9
62.9
108.7
101.7
3.3
c
1.4845
1.4712
1.4620
3.93
6.2
f
f
f
f
c
c
30
31
32
33g
34g
35
36
38
39
40
41
42g
43
44
45
65
67
51
84
85
87
86
86
84
79
85
87
83
76
30
51 (15)
39 (1)
122 (1)
105 (1)
115 (1)
70 (1)
130 (1)
75 (1)
68 (1)
3.90
3.98
3.98
3.81
3.89
3.65
3.88
3.78
3.92
3.92
3.95
4.48
4.50
4.62
5.02
18.2
10.4
12.6
5.2
5.0
7.1
5.2
6.2
5.9
4.2
1.4925
1.4475
1.4558
1.4560
1.5375
1.5035
1.5090
1.5107
1.5817
1.5477
1.4980
1.4543
1.4572
87 (1)
140 (1)
143 (1)
141 (1)
86 (1)
4.0
10.2
13.0
6.2
70 (2)
2.3
aAll signals of alkyl, aryl, and trimethylsilyl fragments are in the standard area. The ratio of stereoisomers of compounds, %: 4, 35:30:20:15;
29, 55:45. Compound 37 was observed only in the mixture.
bData of 31P–{ H} spectra.
1
cBecause of the ease of oxidation and hydrolysis, the refractive index of this compound was not measured.
dIn 1H NMR spectrum for fragment (MeO)2P(O): δH 3.52 d, 3JPH 10.4, and 3.57 d, 3JPH 10.4.
em ABX, δ (HA) 4.05, δ (HB) 3.95, 2J (HAHB) 11.8, 2J (HAP) 4.3, and 2J (HBP) 6.5.
f Overlapping multiplets.
gFragment for compounds: CCl3, 27, δC 98.12 d, 1JPC 107.5; CHCl2, 28, δH 6.02 d, 2JPH 2.1, δC 62.03 d, 1JPC 101.2; PCH2P, 29, δH 2.61 t, 2JPH
1
1
2
1
16.9 and 2.4–2.8 m ABXY, δC 25.83 t, JPC 79.9 and 25.15 t, JPC 81.0; PCHO, 33, δH 4.80 d, JPH 8.1, δC 99.83 d, JPC 104.5; PC O, 34, δC
167.81 d, 1JPC 158.7; (PrCH2)2P(S), 42, δC 26.80 d, 1JPC 49.4 and 25.49 d, 1JPC 48.2.
Heteroatom Chemistry DOI 10.1002/hc

288 Prishchenko et al.
TABLE 2 Elemental Analyses Data of Compoundsa
Calcd. (%)
Found (%)
No
Empirical Formula
Formula Weight
C
H
C
H
2
C16H27OP
C19H33O3P
C19H33O3P
266.36
340.44
340.44
254.31
176.24
230.24
222.26
164.19
234.32
178.21
206.27
198.20
194.21
221.28
166.16
208.24
250.32
292.40
224.24
176.97
255.47
221.02
316.27
160.97
184.60
410.83
268.29
224.19
192.24
214.20
208.30
196.25
210.27
230.26
298.42
372.50
236.29
220.29
72.15
67.03
67.03
66.12
61.34
73.03
54.15
43.89
56.38
53.92
58.21
60.60
49.48
54.28
43.37
51.91
57.58
61.62
48.21
20.36
23.50
27.16
41.77
22.39
39.04
43.85
49.24
42.86
56.23
56.07
51.90
36.72
45.70
52.16
64.40
61.26
55.91
59.97
10.22
9.77
9.77
9.12
12.01
6.57
10.37
10.45
11.61
10.75
11.25
7.63
9.86
10.93
9.10
10.17
10.87
11.38
9.44
3.99
3.94
5.01
8.29
4.38
7.64
10.55
9.39
7.64
11.01
7.06
10.16
8.73
9.11
6.57
9.12
8.93
71.86
66.85
66.91
65.83
60.85
72.78
54.04
43.68
56.21
54.20
58.07
60.42
49.31
54.43
43.11
52.07
57.35
61.42
48.03
20.20
23.69
27.48
41.49
22.15
39.31
43.59
49.58
42.49
56.18
56.38
52.23
36.69
45.59
52.27
64.23
61.03
55.90
60.22
10.03
9.59
9.62
8.91
11.52
6.52
10.43
10.37
11.55
10.62
11.13
7.55
9.80
10.85
8.98
10.09
10.65
11.10
9.28
3.91
3.90
5.07
8.07
4.29
7.54
10.47
9.27
7.56
11.07
7.13
10.07
8.63
9.07
6.48
9.01
8.87
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
38
39
40
41
42
43
44
45
C14H23O2P
C9H21OP
C14H15OP
C10H23O3P
C6H17N2OP
C11H27N2OP
C8H19O2P
C10H23O2P
C10H15O2P
C8H19O3P
C10H24NO2P
C6H15O3P
C9H21O3P
C12H27O3P
C15H33O3P
C9H21O4P
C3H7Cl2O2P
C5H10Cl3O3P
C5H11Cl2O3P
C11H26O6P2
C3H7Cl2OP
C6H14ClO2P
C15H43N2OPSi4
C11H25O5P
C8H17O5P
C9H21O2P
C10H15O3P
C9H21OPS
C6H17N2OPS
C8H19O2PS
C
C
10H15O2PS
16H27OPS
C19H33O3PS
C11H25O3P
C11H25O2P
10.66
11.44
10.75
11.70
aThe constants of compounds 1, 5–9 are in agreement with the reported values [1,25,26]. Compound 37 was observed only in the mixture with
compound 25.
distilled to give 4.9 g starting phosphine 11, yield
93%.
Diisopropyl(ethoxymetyl)phosphine Thiooxide
(38)
The mixture of 4.2 g of phosphine 11, 0.8 g of sulfur,
and 10 mL of benzene was refluxed for 0.5 h, then the
solvent was removed, and the residue was distilled
to give 4.3 g of thiooxide 38.
The thiooxides 39–43 were synthesized simi-
larly.
Diisopropyl(ethoxymetyl)phosphine Oxide (35)
The mixture of 3.4 g of phosphine 11, 4.2 g of yel-
low mercury(II) oxide, and 10 mL of benzene was
refluxed for 4 h. Then the organic solution was de-
canted, the solvent was removed, and the residue
was distilled to give 3.2 g of oxide 35.
The Interaction of Phosphine Oxide 10 with
Lithium Aluminum Hydride
Phosphine oxide 36 was obtained similarly using
iodosobenzene.
A solution of 7.1 g of phosphine oxide 10 in 40 mL of
diethyl ether was added under stirring to a mixture
Heteroatom Chemistry DOI 10.1002/hc

Synthesis and Reactivity of Substituted Alkoxymethylphosphonites and Their Derivatives 289
[7] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.;
Livantsova, L. I.; Milaeva, E. R. Heteroatom Chem
2010, 21, 441–445.
[8] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.;
Livantsova, L. I.; Petrosyan, V. S. Heteroatom Chem
2012, 22.
[9] Meervein, H.; Borner, P.; Fuchs, O.; Sasse, H. J.,
Schrodt, H.; Spille, J. Chem Ber 1956, 89, 2060–2079.
[10] Borch, R. F. J Org Chem 1969, 34, 627–629.
[11] Mezheritsky, V. V.; Olekhnovich, E. P.; Dorofeenko,
G. N. Usp Khim 1973, 42, 896–940 (in Russian).
[12] Rakhmankulov, D. L.; Akhmatdinov, F. T.; Kantor, E.
A. Usp Khim 1984, 53, 1523–1547 (in Russian).
[13] Normant, H.; Castro, B. C R Acad Sci Fr 1963, 257,
2115–2117.
of 1.1 g of lithium aluminum hydride and 50 mL of
ether. The mixture was refluxed for 1 h and left for
1 day, and then an excess of lithium aluminum hy-
dride was neutralized by moisture ether and water.
The organic solution was separated and dried with
magnesium sulfate; the solvent was removed and en-
trapped in low-temperature traps. The residue was
distilled to give 2.7 g of methyl benzyl ether, yield
1
79%, bp 60◦C (10 mmHg), n2D0 1.5020. In H NMR
spectra, δH: 3.18 s (OMe), 4.28 s (OCH2), 7.1–7.2 m
(C6H5). The distillation of the trap contents gives 2
g of diisopropylphosphine, yield 61%, bp 60◦C (120
mmHg), δP: 17.3 d, 1 JPH 193.
[14] Taeger, E.; Fiedler, C.; Chiari, A.; Berndt, H. J Pract
Chem 1965, 28, 1–12.
The interaction of diisopropyl(diethoxymethyl)-
phosphine oxide 44 with lithium aluminum hy-
dride was carried out similarly, and the fol-
lowing results were obtained depending on
the temperature of the reaction mixture: this
interaction was carried out under −50◦C to
give only diisopropylphosphine, yield 64%; under
−20◦C: diisopropylphosphine, yield 59%, and di-
isopropyl(diethoxymethyl)phosphine 45, yield 30%;
under 36◦C :diisopropyl(ethoxymethyl)phosphine
11, yield 31%.
[15] Castro, B. Bull Soc Chim Fr 1967, 1533–1540.
[16] Quintard, J. P.; Elissondo, B.; Pereyre, M.
Organometal Chem 1981, 212, C31–C34.
J
[17] Atkinson, R. E.; Cadogan, J. I. G.; Dyson, J. J Chem
Soc (C) 1967, 2542–2543.
[18] Prishchenko, A. A.; Novikova, Z. S.; Lutsenko, I. F.
Zh Obsh Khim 1977, 47, 2689–2698 (in Russian).
[19] Prishchenko, A. A.; Gromov, A. V.; Luzikov, Yu. N.;
Borisenko, A. A.; Lazhko, E. I.; Klaus, C.; Lutsenko, I.
F. Zh Obsh Khim 1984, 54, 1520–1527 (in Russian).
[20] Regitz, M.; Scherer, O. J. Multiple Bonds and Low Co-
ordination in Phosphorus Chemistry; Georg Thieme
Verlag: Stuttgart, Germany, 1990.
[21] Lutsenko, I. F.; Prishchenko, A. A.; Borisenko, A. A.;
Novikova, Z. S.; Dokl Akad Nauk SSSR 1981, 256,
1401–1405 (in Russian).
REFERENCES
[22] Moskva, V. V.; Maykova, A. I.; Razumov, A. I. Zh Obsh
Khim 1969, 39, 595–599 (in Russian).
[1] Petrov, K. A.; Chauzov, V. A.; Agafonov, S. V. Usp
Khim 1982, 51, 412–437(in Russian).
[23] Hagemann, H. Methoden der Organischen Chemie
(Houben–Weil); Georg Thieme Verlag: Stuttgart,
Germany, 1983, E4, 14 (in German).
[2] Fields, S. C. Tetrahedron 1999, 55, 12237–12273.
[3] Kolodiazhnyi, O. I. Usp Khim 2006, 75, 254–282 (in
Russian).
[24] Regitz, M. Methoden der Organischen Chemie
(Houben–Weil); Georg Thieme Verlag: Stuttgart,
Germany, 1983, E4, 14 (in German).
[25] Schaumann, E.; Grabley, F. F. Lieb Ann 1977, 88–100
(in German).
[4] Iorga, B.; Eymery, F.; Savignac, P. Synthesis 1999, 2,
207–224.
[5] Holy, A. Antiviral Res 2006, 71, 248–253.
[6] Prishchenko, A. A.; Livantsov, M. V.; Novikova, O. P.;
Livantsova, L. I.; Milaeva, E. R. Heteroatom Chem
2008, 19, 562–568.
[26] Burkhouse, D.; Zimmer, H. Synthesis 1984, 330–332.
Heteroatom Chemistry DOI 10.1002/hc