Organophosphorus chemistry without PCl3: A bridge from hypophosphorous acid to H-phosphonate diesters

Article abstract of DOI:10.1002/ejoc.201301412

A process for the conversion of hypophosphorous acid (H₃PO ₂, HPA) and alcohols into various H-phosphonate diesters [(RO) ₂P(O)H] is described. The new reaction provides a missing bridge between HPA and important H-phosphonates, completely avoiding the use of PCl₃. Nickel chloride or nickel on silica catalyze the oxidative phosphorylation of alkyl phosphinates with various alcohols or water. The reaction is atom economic and avoids the formation of waste products. The previous need for both chlorine and base is completely avoided. Esterification of hypophosphorous acid followed by reaction with another molecule of alcohol under the action of a nickel catalyst provides a green method for the preparation of H-phosphonates. This method entirely avoids the need for any stoichiometric chloride unlike those based on phosphorus trichloride. Copyright

Full text of DOI:10.1002/ejoc.201301412

FULL PAPER
DOI: 10.1002/ejoc.201301412
Organophosphorus Chemistry without PCl3: A Bridge from Hypophosphorous
Acid to H-Phosphonate Diesters
Henry C. Fisher,[a] Lucie Prost,[a] and Jean-Luc Montchamp*[a]
Keywords: Industrial chemistry / Green chemistry / Heterogeneous catalysis / Nickel / Phosphorus / Esterification
A process for the conversion of hypophosphorous acid
(H3PO2, HPA) and alcohols into various H-phosphonate di-
esters [(RO)2P(O)H] is described. The new reaction provides
a missing bridge between HPA and important H-phosphon-
ates, completely avoiding the use of PCl3. Nickel chloride or
nickel on silica catalyze the oxidative phosphorylation of
alkyl phosphinates with various alcohols or water. The reac-
tion is atom economic and avoids the formation of waste
products. The previous need for both chlorine and base is
completely avoided.
of accessible functionalities, and the fact that each phos-
phorus atom can be incorporated into products.[3]
Introduction
Organophosphorus compounds are currently made from
PCl3 even though chlorine is not incorporated into the
major industrial products.[1] As a result, much interest has
been devoted to finding alternatives to PCl3. Possibilities
include the direct functionalization of elemental phos-
phorus (white P4 and red Pred) and phosphine PH3.[2] Based
on their superior solubility and considerably lower toxicity,
we have proposed the use of phosphinates [hypophosphor-
ous acid (HPA) and its derivatives] as the best practical al-
ternative to PCl3.[3] Additional support for phosphinates re-
sides in their synthetic flexibility in terms of the wide range
H-Phosphonate diesters [(RO)2P(O)H] and phosphorus
acid (R = H) are a major class of intermediates used in
fine and industrial organophosphorus chemistry.[4] They are
currently prepared from the alcoholysis of PCl3 (Scheme 1).
Both the base (such as Et3N) and chlorine can be recycled,
but the process requires extensive manipulations and electri-
cal power. The exception is with phenol, which does not
require any base because PhCl cannot form. Herein, we de-
scribe the catalytic oxidative phosphorylation of various
alcohols with HPA to form H-phosphonate diesters in a
simple, yet chlorine- and base-free process (Scheme 2).
Scheme 2. Synthesis of H-phosphonate diesters from HPA.
Results and Discussion
We have previously reported two catalytic phosphorus–
oxygen bond-forming reactions.[5,6] For example, with
H3PO2 (1.5 equiv.) and an alcohol (1 equiv.) using either
Pd/C or Ni/Al2O3/SiO2 as catalysts, we were able to prepare
H-phosphonate monoesters.[6] These compounds are nor-
mally prepared from PCl3 or a reagent derived from it.[7]
The work exploited the well-known transfer hydrogenation
pathway[8] for the preparation of organophosphorus com-
pounds through catalytic P–O bond formation. Until this
work, the fate of the hypophosphite in transfer hydro-
genation was largely overlooked because it was the organic
product that was desired.[8] However, Dorfman and Alesh-
kova reported in 1998 the results of a seminal study on the
oxidation of sodium hypophosphite by alcohols using palla-
dium or nickel catalysts.[9] The reaction produces
Scheme 1. Preparation of H-phosphonate diesters.
[a] Department of Chemistry, Texas Christian University,
Box 298860, Fort Worth, Texas 76129, USA
E-mail: j.montchamp@tcu.edu
http://personal.tcu.edu/jmontchamp/montchamp.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301412.
Eur. J. Org. Chem. 2013, 7973–7978
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7973

H. C. Fisher, L. Prost, J.-L. Montchamp
FULL PAPER
ROP(O)(ONa)H and an equivalent amount of hydrogen.[9] group. The decomposition of ROP(O)H2 is well known,[13]
The authors proposed a radical pathway. but entry 3 shows that this uncatalyzed process is inefficient
However, dialkyl H-phosphonates are much more impor- as a synthetic procedure. The addition of NiCl2 results in a
tant industrially than the monoesters because dialkyl phos- clean reaction with the quantitative formation of (BuO)2-
phonates are ubiquitous. Perhaps the best illustration is the P(O)H. Entries 4 and 5 show that the reaction is fast and
synthesis of N-phosphonomethylglycine, the active compo- that even inexpensive nickel chloride hexahydrate is an ex-
nent of the herbicide glyphosate. Industrial preparations of cellent catalyst.
glyphosate rely either on PCl3 or its derivatives: Phosphorus
acid or dialkyl H-phosphonates.[1a,10]
Table 1. Optimization of the reaction conditions for the synthesis
of H-phosphonate diesters.
Alkyl phosphinates [ROP(O)H2] can be prepared in sev-
eral ways from HPA.[11] The most general and inexpensive
methods use alkoxysilanes[11a,11b] or the Dean–Stark
method for higher boiling alcohols.[11c–11e] It occurred to us
that alkyl phosphinates might be converted into symmetri-
cal H-phosphonate diesters as long as excess alcohol ROH
is available. Therefore conditions that maximize the transfer
hydrogenation when both ROP(O)H2 and excess ROH are
combined were optimized. The proposed mechanism is
shown in Scheme 3.
Entry
R
ROH
[equiv.]
Catalyst
Catalyst Time
31P NMR
yield [%]
[mol-%]
[h]
(isolated
yield [%])[a]
1[b]
2[b]
3
4
5
6
7
8
9
Et
Et
0
0
2.5
3
2.5
2.5
2.5
2.5
2.5
2.5
0
NiCl2
NiCl2
none
NiCl2
NiCl2·6H2O
NiBr2
NiI2
Ni(OAc)2
Ni(acac)2
Ni powder
Ni/SiO2
Ni/SiO2
Ni/SiO2
1.5
3
0
3
3
3
3
3
3
3
3
3
5
5
5
5
2
5
3
3
3
3
3
3
18
3
3
3
3
3
3
3
36
95
17
95
95
99
95
51
67
27
53
55
77
100 (84)
100 (90)
100 (75)
65
72 (71)
78
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
10
11[b,c] Et
16
3
12
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
Bu
2.5
2.5
13[d]
14
30
18
18
18
3
16
3
3
(solvent) Ni/SiO2
3
3
2.5
3
2.5
2.5
2.5
2.5
15
Ni/SiO2
Ni/SiO2
Pd/C
Pd/C
PdCl2
CuCl
CuCl2
Cu powder
16[e]
17
18
19
20
21
16
26
17
3
3
22
[a] NMR yields were determined by the integration of all reso-
nances in the 31P NMR spectra. For isolation, see the Exp. Sect.
[b] Prepared by the alkoxysilane method. [c] An extra equivalent of
(EtO)2SiMe2 was added in the second step. [d] Catalyst was added
at the start (before esterification). [e] The catalyst from entry 14
was recycled and used for this experiment on a 25 mmol scale.
Scheme 3. Proposed mechanism for the metal-catalyzed formation
of H-phosphonate diesters.
Ligandless metals are expected to catalyze the transfer
hydrogenation process through facile β-hydrogen elimi-
nation. Also, because of their strong reducing properties,
alkyl phosphinates are able to reduce metal salts easily.[12]
Scheme 4 summarizes the conditions that were investigated.
Not surprisingly, other nickel(II) halides also reacted sat-
isfactorily (entries 6 and 7). On the other hand, nickel(II)
acetate, nickel acetylacetonate, and nickel powder gave po-
orer results. Nickel on silica was investigated next because
it had given good results in the synthesis of H-phosphonate
monoesters.[6] This catalyst is clearly less efficient than
NiCl2 (entries 4 and 5), but increasing the reaction time
gave clean reactions and high conversions (entry 15). Note
that addition of catalyst from the start of the reaction was
unsatisfactory (entry 13). The use of n-butanol as solvent
instead of toluene also gave excellent results (entry 14 vs.
15). This might be useful for the easy recycling of BuOH in
industrial processes. In spite of lower activity, one advan-
Scheme 4. Reaction conditions employed for the synthesis of H-
phosphonate diesters.
Table 1 shows the results of various experiments. First, tage of Ni/SiO2 over NiCl2 is that it can be recycled (en-
a solution of EtOP(O)H2 was treated with nickel chloride. try 16). Finally, palladium (entries 17–19) and copper cata-
Entries 1 and 2 show the influence of the amount of catalyst lysts (entries 20–22) were investigated but did not offer bet-
on the transformation. To avoid any additional silicate rea- ter results.
gent, we next focused on BuOP(O)H2 prepared by the
After the above investigation, it was concluded that
Dean–Stark reaction,[11,12] because in this case excess NiCl2 is the best catalyst for converting ROP(O)H2 into
alcohol could be used as the source of the second ester (RO)2P(O)H, but, because Ni/SiO2 can be recycled, it pro-
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Organophosphorus Chemistry without PCl3
vides a greener process. Next we turned our attention to the lyst, HPA remained unchanged. This type of metal-cata-
scope of the reaction under conditions similar to those in lyzed process was described more than 100 years ago with
Scheme 4. The results are shown in Table 2. For low boiling both Cu and Pd.[14] The industrial potential of the transfor-
alcohols like ethanol, which cannot be conveniently esteri- mation of HPA to H3PO3 has not yet been realized. The
fied by the azeotropic removal of water, the alkoxysilane case of sodium hypophosphite is interesting because, unlike
method was used. Diethyl H-phosphonate was prepared by with HPA, over-oxidation to sodium dihydrogen phosphate
this method in good yield (entry 1). For diisopropyl H- is the dominant pathway in our hands (entry 13). Shorten-
phosphonate, the intermediate phosphinate was prepared ing the reaction time improved the yield significantly (en-
by using a Soxhlet extractor with molecular sieves (3 Å) to try 14), but a large amount of phosphate was still formed.
remove water and by substituting cyclohexane for toluene
to give the product in excellent yield (entry 2).
Surprisingly, 3-butyn-1-ol, 2-chloroethanol, and phenol
(entries 15–17, respectively) were mostly or completely con-
verted into the H-phosphonate diester during the Dean–
Stark esterification step. Although a rationale for the reac-
tion can only be speculative at this time, it must rely on
minute variations in the tautomeric equilibria of ROP(O)-
H2 that depend on the nature of the R group and the reac-
tivity of the PIII tautomer. Our laboratory is actively trying
to understand these effects both experimentally and compu-
tationally.[15] A plausible mechanism for the uncatalyzed
process is proposed in Scheme 5.
Table 2. Scope of the synthesis of H-phosphonate diesters.[a]
Entry
R
Catalyst
31P NMR yield [%]
(isolated yield [%])[b]
1[c–e]
2[f]
3
Et
iPr
iBu
nPent
Cy
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
Ni/SiO2
NiCl2
Ni/SiO2
Ni/SiO2
Ni/SiO2
none
none
none
92 (75)
100 (87)
100 (84)
100 (55)
100 (75)
68 (64)
100 (81)
100 (49)
100 (82)
81 (26)
68 (60)
100 (84)
14[i]
4[g]
5
6
7
8
9
10
11
Bn
PhCH2CH2
(–)-menthyl
fenchyl
Cl3CCH2
1-adamantyl
H
Na
Na
3-butynyl
ClCH2CH2
Ph
12[h]
13[h]
14[h,j]
15[k]
16[k]
17[k]
53[i]
83 (51)
100 (68)
74[l] (63)
[a] Unless otherwise noted, the reactions were conducted with ROH
(3 equiv.) and 5 mol-% of catalyst for 18 h. [b] NMR yields are
determined by integration of all the resonances in the 31P NMR
spectra. For isolation, see the Exp. Sect. [c] Prepared by the alk-
oxysilane method. [d] Reaction time of 40 h. [e] Anhydrous ethanol
(3 equiv.) was added in the second step. [f] Cyclohexane was used
as the solvent. [g] Reaction time of 87 h. [h] Water was used as the
solvent. [i] Reaction time of 2 h. [j] The balance is NaH2PO4. [k]
The H-phosphonate diester was obtained in the absence of catalyst
during the esterification step. [l] The remainder was
PhOP(O)(OH)H.
Scheme 5. Plausible mechanism for the uncatalyzed formation of
H-phosphonate diesters.
As before (Scheme 3), tautomerization of alkyl phos-
phinate 1 into PIII-2 occurs but now oxidative addition can
take place with the alcohol to form pentacoordinate 3. In-
termediate 3 can isomerize by Berry pseudorotation to ulti-
mately form dialkoxyphosphine 4, which can be oxidized
Overall, a wide range of primary and secondary alcohols by air to the H-phosphonate diester 5. There is significant
were transformed into the corresponding H-phosphonate support for this mechanism. Gallagher and Honegger pro-
diester (entries 3–10), and in the vast majority of examples posed a virtually identical mechanism for the transesterifi-
chromatographic purification was completely avoided. In cation of alkylphosphinates[16] and Stec et al. characterized
1
some cases isolation was difficult, for example, the H-phos- a species with a structure related to 3 by using H NMR
phonate prepared from (–)-menthol, which azeotropes off spectroscopy.[17] Several dialkoxyphosphines 4 have been
with the starting alcohol during distillation (entry 8). The synthesized and some are so easily oxidized in the pure state
product prepared from trichloroethanol was difficult to that the reaction is pyrophoric.[18] Finally, in some Dean–
separate from the dechlorinated products formed during the Stark esterifications, the presence of NMR signals corre-
reaction (entry 10). 1-Adamantanol reacted in moderate sponding to small amounts of 4 can sometimes be detected.
yield (entry 11), which supports the intermediacy of a An equally possible alternative mechanism is the oxidation
highly reactive phosphinidene oxide (Scheme 3).[13] Other of 2 followed by esterification of the H-phosphonate mono-
tertiary alcohols were problematic because of competing eli- ester (see below).
mination in the esterification step. In the preparation of
Because HPA can be oxidized easily to H3PO3, an alter-
phosphorus acid (H3PO3), because HPA is a 50 wt.-% solu- native approach to bypassing PCl3 is to use H3PO3. As
tion in water, which is the desired nucleophile, heating the mentioned earlier, glyphosate can be manufactured by using
solution in the presence of catalyst gave an excellent yield of H3PO3. In terms of H-phosphonate diesters, we briefly in-
product. Similar results were obtained with Ni/Al2O3 (71% vestigated the Dean–Stark esterification of H3PO3. This
isolated yield). In a control experiment without any cata- kind of reaction has been described previously.[19] In our
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H. C. Fisher, L. Prost, J.-L. Montchamp
FULL PAPER
process, the intermediate H3PO3 does not need to be iso- with PCl3. The elucidation and prediction of subtle effects
lated because it is formed in quantitative yield (see Table 2, in phosphinylidene P(O)H chemistry are currently being in-
entry 12).
vestigated.
Although the conversion of HPA into H3PO3 is
known,[14] our method is mild even if the subsequent con-
version of H3PO3 into (RO)2P(O)H is limited, often only
giving the monoester or a mixture of mono- and diester
(Scheme 6).[19]
Experimental Section
General Procedure for the Nickel-Catalyzed Transformation of HPA
into (RO)2P(O)H: As an example, see Table 1, entry 14. Aqueous
H3PO2 (50 wt.-%, 25 mmol) was concentrated in vacuo for 15 min
at room temp. [Note: this step can be omitted as long as the esterifi-
cation time is monitored]. Butanol (3 equiv., 75 mmol) followed by
toluene (reagent grade, 50 mL) was added to the flask to which a
Dean–Stark trap filled with excess toluene was fitted. The reaction
mixture was heated at reflux for 2 h under nitrogen. The solution
was cooled and the yield of BuOP(O)H2 was quantitative, as deter-
mined by 31P NMR spectroscopy. The Dean–Stark trap was re-
moved and Ni/SiO2 (64 wt.-%, 5 mol-%) was added to the Bu-
OP(O)H2 solution. The solution was heated at reflux under nitro-
gen for 18 h. After cooling, the reaction was filtered through Ce-
lite® and rinsed with ethyl acetate (20 mL). The organic layer was
washed with brine (50 mL) and the aqueous layer was further ex-
tracted with ethyl acetate (3ϫ 15 mL). The combined organic lay-
ers were dried with MgSO4 and concentrated in vacuo to afford
dibutyl H-phosphonate as a pale-yellow liquid in 4.37 g (90% iso-
Scheme 6. One-pot conversion of HPA into (RO)2P(O)H via
H3PO3.
1
lated yield). 1H NMR (300 MHz, CDCl3): δ = 6.83 (d, JHP
=
691.9 Hz, 1 H, P-H), 4.09 (q, 3J = 7.46 Hz, 4 H, CH2), 1.70 (quint,
3J = 6.68 Hz, 2 H, CH2), 1.43 (quint, 3J = 7.25 Hz, 2 H, CH2),
0.96 (t, 3J = 5.33 Hz, 6 H, CH3) ppm. 31P NMR (121.46 MHz,
2-Chloroethanol is an excellent substrate, which suggests
that the transformation of 2 into 6 in Scheme 5 might be an
explanation for the uncatalyzed process observed in Table 2
(entry 16). The ease of oxidation of ClCH2CH2OP(O)H2
would be due to the higher availability of its PIII tautomer.
The Dean–Stark esterification of H3PO3 with phenol is
slow (3 days) and gives a mixture of products (Table 2, en-
try 17), which also suggests that ROP(O)(OH)H might be
an intermediate.
1
3
CDCl3): δ = 7.82 (dquint, JPH = 693.23, JPOC = 9.72 Hz) ppm.
[21,22]
Diethyl H-Phosphonate:[21] Aqueous H3PO2 (50 wt.-%, 25 mmol)
was concentrated in vacuo for 30 min at room temp. Octyltriethox-
ysilane (1 equiv., 25 mmol) and toluene (reagent grade, 50 mL) were
added, and the reaction was heated at reflux for 3 h. After comple-
tion, the solution was cooled to room temp. and Ni/SiO2 (64 wt.-
%, 5 mol-%) and anhydrous ethanol (3 equiv., 75 mmol) were
added. The reaction was heated at reflux and allowed to react un-
der nitrogen for 40 h. After cooling, the reaction mixture was fil-
tered through Celite® and the residue rinsed with ethyl acetate
(20 mL). The organic layer was concentrated and subsequently dis-
solved in CH3CN (HPLC grade, 50 mL). The CH3CN layer was
partitioned with hexanes (4ϫ 15 mL) and concentrated in vacuo to
Conclusions
There are numerous literature methods for preparing H-
phosphonate diesters, including transesterification.[20] How-
ever, to the best of our knowledge, the methodology pre-
sented herein is the only one that does not rely on PCl3 at
any point and is atom economic. Our reaction is greener
than the alternatives because it only uses HPA, an alcohol,
and nickel on silica gel as a catalyst, which might perhaps
be reused, and no byproducts were formed. Although nickel
1
obtain a discolored liquid in 2.59 g (75% isolated yield). H NMR
1
(400 MHz, CDCl3): δ = 6.82 (d, JHP = 692.8 Hz, 1 H, P-H), 4.16
(quint, 3J = 7.20 Hz, 4 H, CH2), 1.37 (t, J = 6.80 Hz, 6 H,
1
CH3) ppm. 31P NMR (161.97 MHz, CDCl3): δ = 7.77 (dm, JPH
=
691.61 Hz) ppm.
Diisopropyl H-Phosphonate:[21–23] Aqueous H3PO2 (50 wt.-%,
62.5 mmol) was concentrated in vacuo for 30 min at room temp.
chloride is a superior catalyst for this transformation, it Isopropanol (7 equiv., 438 mmol) and cyclohexane (92 mL) were
added and a Soxhlet extractor was placed on the reaction flask
with molecular sieves (3 Å) placed inside the extraction thimble.
The solution was heated at reflux for a total of 18 h with the molec-
ular sieves replaced after 4 and 8 h. Ni/SiO2 (64 wt.-%, 5 mol-%)
was added to the iPrOP(O)H2 solution (25 mmol, 50 mL) and
heated at reflux for 18 h under nitrogen. The cooled solution was
filtered through Celite® and concentrated in vacuo to obtain a clear
liquid in 4.15 g (87% isolated yield). 1H NMR (400 MHz, CDCl3):
cannot be reused. The present reaction thus provides an
important link between hypophosphorous chemistry and
key intermediates that are normally prepared by using PCl3.
Thus, it is another tool in the growing methodological tool-
box for a phosphorus economy based on hypophosphites.
Also, the reaction via ROP(O)H2 appears to be much more
general than the direct esterification of phosphorus acid.
Our process not only provides access to an important class
of industrial intermediates, it could also provide valuable
1
δ = 6.85 (d, JHP = 687.60 Hz, 1 H, P-H), 4.74 (m, 2 H, CH), 1.36
(d, 3J = 8.40 Hz, 12 H, CH3) ppm. 31P NMR (161.97 MHz,
1
3
hydrogen instead of hydrogen chloride, which is produced CDCl3): δ = 4.45 (dt, JPH = 686.75, JPOC = 8.10 Hz) ppm.
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Organophosphorus Chemistry without PCl3
Diisobutyl H-Phosphonate:[22,23] After concentration, 4.08 g (84%)
Phosphorous Acid:[28] After concentration of water, 1.72 g (84%) of
of a light-yellow liquid was obtained. 1H NMR (300 MHz, CDCl3):
a clear liquid was obtained. 1H NMR (400 MHz, CDCl3): δ = 6.72
1
1
δ = 6.83 (d, JHP = 692.7 Hz, 1 H), 3.88–3.82 (m, 4 H), 1.97 (m, 1 (d, JHP = 663.2 Hz, 1 H) ppm. 31P NMR (161.97 MHz, CDCl3):
H), 0.97 (d, 3J = 6.9 Hz, 6 H) ppm. 31P NMR (121.46 MHz,
δ = 4.37 (d, JPH = 664 Hz) ppm.
1
3
CDCl3): δ = 7.99 (d, JPH = 693, JPOC = 7.76 Hz) ppm.
Dibutynyl H-Phosphonate: After kugelrohr distillation of excess
Dineopentyl H-Phosphonate:[23] After kugelrohr distillation of ex-
cess alcohol, 3.06 g (55%) of a light-yellow liquid was obtained. 1H
NMR (400 MHz, CDCl3): δ = 6.85 (d, 1JHP = 693.6 Hz, 1 H), 3.77–
3.73 (quint, 3J = 6.8 Hz, 4 H), 0.98 (s, 18 H) ppm. 31P NMR
alcohol, 2.37 g (51%) of a clear liquid was obtained. 1H NMR
1
(400 MHz, CDCl3): δ = 6.95 (d, JHP = 711 Hz, 1 H), 4.28–4.17
(m, 4 H), 2.65–2.61 (td, 3J = 6.68, 4J = 2.64 Hz), 2.07 (t, 4J =
2.64 Hz) ppm. 13C NMR (100.62 MHz, CDCl3): δ = 79.3, 70.7,
1
3
2
3
63.5 (d, JCOP = 6.01 Hz), 20.9 (d, JCCOP = 6.26 Hz) ppm. 31P
(CDCl3, 161.97 Hz):
8.10 Hz) ppm.
δ = 8.38 (d, JPH = 695, JPOC =
1
3
NMR (161.97 MHz, CDCl3): δ = 7.74 (dquint, JPH = 712, JPOC
= 9.72 Hz) ppm. HRMS (ESI): calcd. for C8H11O3P [M + H]+,
187.0524; found 187.0570.
Dicyclohexyl H-Phosphonate:[23] After kugelrohr distillation of ex-
cess alcohol, 6.16 g (75%) of a clear liquid was obtained. 1H NMR
1
Bis(2-chloroethyl) H-Phosphonate:[23] After kugelrohr distillation of
(400 MHz, CDCl3): δ = 6.89 (d, JHP = 688.4 Hz, 1 H), 4.46–4.44
excess alcohol, 5.17 g (68%) of a clear liquid was obtained. 1H
(m, 2 H), 1.96–1.93 (m, 4 H), 1.78–1.74 (m, 4 H), 1.58–1.53 (m, 6
H), 1.37–1.1.30 (m, 6 H) ppm. 31P NMR (161.97 MHz, CDCl3): δ
1
NMR (400 MHz, CDCl3): δ = 7.02 (d, JHP = 720.8 Hz, 1 H),
1
4.40–4.33 (m, 4 H), 3.76–3.71 (t, 3J = 8.4 Hz, 4 H) ppm. 31P NMR
= 4.46 (d, JPH = 688 Hz) ppm.
1
3
(161.97 MHz, CDCl3): δ = 8.18 (dquint, JPH = 720, JPOC
=
Dibenzyl H-Phosphonate:[24] After kugelrohr distillation of excess
alcohol, 4.20 g (64%) of a light-yellow liquid was obtained. 1H
NMR (400 MHz, CDCl3): δ = 7.39–7.37 (m, 10 H, ArCH), 6.97
(d, 1JHP = 706.8 Hz, 1 H, P-H), 5.08 (m, 4 H, CH2) ppm. 31P NMR
8.9 Hz) ppm.
Diphenyl H-Phosphonate:[29] After kugelrohr distillation of excess
alcohol, 3.69 g (63%) of a light-yellow liquid was obtained. 1H
1
3
1
(161.97 MHz, CDCl3): δ = 7.74 (dquint, JPH = 706, JPOC
=
NMR (400 MHz, CDCl3): δ = 7.41–7.22 (m, 10 H), 7.34 (d, JHP
= 728.4 Hz, 1 H) ppm. 31P NMR (161.97 MHz, CDCl3): δ = 0.34
9.3 Hz) ppm.
1
(d, JPH = 733 Hz) ppm.
Bis(2-phenethyl) H-Phosphonate:[25] After kugelrohr distillation of
excess alcohol, 7.26 g (81%) of a light-yellow liquid was obtained.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.23 (m, 10 H), 6.66 (d,
1JHP = 700.8 Hz, 1 H), 4.24–4.20 (m, 4 H) ppm. 31P NMR
Preparation of Dibutyl H-Phosphonate from Phosphorus Acid: Ni/
SiO2 (64 wt.-%, 5 mol-%) was added to a round-bottomed flask
containing aqueous H3PO2 (50 wt.-%, 25 mmol), and the mixture
was heated at reflux for 18 h under nitrogen. [Note: if the reaction
was conducted open to air, the reaction time was lowered to 6 h.]
Once cooled, 31P NMR analysis showed that the formation of
phosphorus acid was complete. The solution was filtered through
Celite® and rinsed with several aliquots of deionized water (ca.
20 mL total). The acid was concentrated and butanol (4 equiv.,
100 mmol) and toluene (reagent grade, 50 mL) were added. A
Dean–Stark trap prefilled with toluene was attached to the reaction
vessel and the solution was heated at reflux for 18 h under nitrogen.
After cooling, the solution was extracted with brine (50 mL), dried
with MgSO4, and concentrated in vacuo to afford a light-yellow
liquid in 4.18 g (86%) isolated yield.
1
3
(161.97 MHz, CDCl3): δ = 7.65 (dquint, JPH = 700, JPOC
=
8.10 Hz) ppm.
Dimenthyl H-Phosphonate:[26] After kugelrohr distillation, 4.39 g
(49%) of a clear liquid was obtained. 1H NMR (400 MHz, CDCl3):
1
δ = 6.91 (d, JHP = 686.8 Hz, 1 H), 4.28–4.18 (m, 2 H), 2.20–2.16
(m, 2 H), 2.15–2.04 (2 m, 2 H), 1.69, 1.65 (2 br. s), 1.47–1.44 (m,
3
2 H), 1.26–1.16 (m, 2 H), 1.07–0.96 (m, 4 H), 0.92 (2 d, J = 1.32,
3J = 1.68 Hz, 12 H), 0.89–0.84 (m, 2 H), 0.82 (d, 3J = 1.68 Hz, 3 H),
0.79 (d, 3J = 1.68 Hz, 3 H) ppm. 31P NMR (161.97 MHz, CDCl3): δ
1
3
= 5.45 (dt, JPH = 686.8, JPOC = 8.73 Hz) ppm.
Difenchyl H-Phosphonate: After kugelrohr distillation of excess
alcohol, 7.27 g (82%) of a light-brown liquid was obtained. 1H
NMR (400 MHz, CDCl3): δ = 6.89 (d, 1JHP = 686.4 Hz, 1 H), 4.06–
3.98 (m, 2 H), 1.74–1.70 (m, 6 H), 1.56–1.53 (m, 2 H), 1.49–1.44
Supporting Information (see footnote on the first page of this arti-
cle): General chemistry, method for determining yields by 31P
NMR, purification of H-phosphonate diesters, 1H, 13C, and 31P
NMR spectra.
3
(m, 2 H), 1.23–1.20 (m, 2 H), 1.14 (d, J = 8.6 Hz, 6 H), 1.09 (m,
8 H), 0.96 (s, 3 H), 0.94 (s, 3 H) ppm. 13C NMR (100.62 MHz,
2
CDCl3): δ = 89.3 (d, JCOP = 7.3 Hz), 49.1, 40.9, 39.5, 29.8, 25.8,
21.4, 19.3 ppm. 31P NMR (161.97 MHz, CDCl3): δ = 8.12 (dt, 1JPH
Acknowledgments
3
=
688.4, JPOC
=
10.6 Hz) ppm. HRMS (ESI): calcd. for
C20H35O3P [M + H]+ 355.2402; found 355.2489.
This article is based on work supported by the National Science
Foundation (NSF), USA (grant number 0953368). Partial support
from the Texas Christian University (TCU) (Invest in Scholarship
Program, TCU-IS) is also acknowledged (grant to H. C. F.).
Bis(2,2,2-trichloroethyl) H-Phosphonate:[27] After kugelrohr distill-
ation of excess alcohol and column chromatography, 2.24 g (26%)
of a light-yellow liquid was obtained. 1H NMR (400 MHz, CDCl3):
1
δ = 7.22 (d, JHP = 746 Hz, 1 H), 4.75–4.66 (m, 4 H) ppm. 31P
1
3
NMR (161.97 MHz, CDCl3): δ = 7.23 (dquint, JPH = 753, JPOC
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Diadamantyl H-Phosphonate: After kugelrohr distillation of excess
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(400 MHz, CDCl3): δ = 7.04 (d, JHP = 680 Hz, 1 H), 2.18 (m, 6
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351.2089; found 351.2104.
Eur. J. Org. Chem. 2013, 7973–7978
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7977

H. C. Fisher, L. Prost, J.-L. Montchamp
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Received: September 13, 2013
Published Online: October 9, 2013
7978
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Eur. J. Org. Chem. 2013, 7973–7978