Synthesis of dialkyl and diaryl benzylphosphonates through a ZnI 2-mediated reaction

Article abstract of DOI:10.1016/j.tetlet.2012.09.114

Several trialkyl and two triaryl phosphites have been tested for their reactivity in the zinc iodide mediated conversion of benzyl alcohol to the corresponding phosphonates. Most react smoothly to afford the desired phosphonate diesters, including hindered and nonracemic phosphites. The implications of this reactivity on the reactions involved in the transformation are discussed.

Full text of DOI:10.1016/j.tetlet.2012.09.114

Tetrahedron Letters 53 (2012) 6682–6684
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Tetrahedron Letters
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Synthesis of dialkyl and diaryl benzylphosphonates through a
ZnI2-mediated reaction
⇑
Rebekah M. Richardson, Rocky J. Barney, David F. Wiemer
Department of Chemistry, The University of Iowa, Iowa City, Iowa 52242-1294, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Several trialkyl and two triaryl phosphites have been tested for their reactivity in the zinc iodide medi-
ated conversion of benzyl alcohol to the corresponding phosphonates. Most react smoothly to afford the
desired phosphonate diesters, including hindered and nonracemic phosphites. The implications of this
reactivity on the reactions involved in the transformation are discussed.
Received 22 August 2012
Revised 21 September 2012
Accepted 24 September 2012
Available online 29 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
This paper is dedicated in honor of Professor
Henri-Jean Cristau on the occasion of his
70th birthday.
Keywords:
Phosphonate
Synthesis
Zinc iodide
Arbuzov reaction
For many years the Horner–Wadsworth–Emmons (HWE) con-
densation has remained a popular reaction for the synthesis of
a
allylic alcohols, and offered some mechanistic insight. However,
limitations with respect to the nature of the phosphite component
remained unclear. Given the increasing application of more hin-
dered phosphonate esters in HWE reactions and our longstanding
interest in phosphonate chemistry,13 the potential use of this pro-
cess toward the preparation of other phosphonate esters was of
interest.
Benzyl alcohol was selected as the test compound because it
gave good yields under relatively mild conditions in reactions with
ZnI2/P(OEt)3.11 Several other trialkyl and triaryl phosphites now
have been examined under standard reaction conditions (Table 1,
entries 2–8). Attempted preparation of bis(1,1,1-trifluoroethyl)
benzylphosphonate (entry 2) from the corresponding phosphite
(4) through this methodology was not successful under the stan-
dard conditions, which may be due to the strong electron with-
drawing nature of the 1,1,1-trifluoroethyl substituents combined
with the steric hindrance these substituents engender. In some-
what surprising contrast, the reaction of triisopropyl phosphite
,b-unsaturated esters.1,2 In its original incarnation,3 the conden-
sation of an a-phosphonoester with an aldehyde was shown to fa-
vor the formation of the trans olefin isomer. More recent
modifications, including those reported by Breuer,4 Savignac,5
Stille,6 and perhaps especially Ando,7 have allowed preferential
formation of the cis olefin isomer in a variety of cases when specific
phosphonate esters are employed. This stereocontrol has only in-
creased the value of the phosphonate reagents and the popularity
of this strategy for the synthesis of a,b-unsaturated esters. Further-
more, other applications of phosphonates in carbon-carbon bond
formation have been reported as well.1,2 For example, the applica-
tions of benzylic phosphonates in stilbene synthesis have been rec-
ognized for many years,8 and this strategy has been particularly
useful to us in the synthesis of natural stilbenes such as the
schweinfurthins9 and pawhuskins.10
In contrast to the many studies on the scope and stereochemis-
try of the HWE condensation, strategies for phosphonate synthesis
have not changed a great deal over the years.1,2 The Arbuzov
reaction is easily the most commonly employed strategy, but
recent reports have described a Lewis acid mediated approach to
the preparation of diethyl phosphonates (Scheme 1).11,12 Our stud-
ies11 have suggested that this is a general reaction for benzylic and
P(OEt)3 (2)
ZnI2, toluene, Δ
O
OH
P(OEt)2
84%
1
3
⇑
Corresponding author. Tel.: +1 319 335 1365; fax: +1 319 335 1270.
E-mail address: david-wiemer@uiowa.edu (D.F. Wiemer).
Scheme 1. Conversion of benzyl alcohol to diethyl benzylphosphonate.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.114

R. M. Richardson et al. / Tetrahedron Letters 53 (2012) 6682–6684
6683
Table 1
Synthesis of varied esters of benzylphosphonate through a ZnI2 mediated reaction
OMe
OMe
(CH2O)n, DMF
K2CO3, 0 °C
O
O
O
ZnI2 (1.5 eq.),
67%
OH
P(OR)2
18
solvent
17
40%
OH
LiAlD4, AlCl3,
ether, 0 °C
P(OR)3
Entry R (phosphite/
phosphonate)
Solvent Rx temp (°C) Isolated yield (%)
111
2
3
4
5
6
7
8
CH2CH3 (2/3)
CH2CF3 (4/-)
(CH)(CH3)2 (5/6)
(CH)(CH3)2 (5/6)
C6H5 (7/8)
o-Tolyl (9/10)
S-2-Methylbutyl (11/12)
S-Citronellyl (13/14)
Toluene 80
84
—
DMF
THF
120
66
D
D
59
97
81
34
81
76
DMF
DMF
80
120
19
Toluene 111
P(OEt)3, ZnI2,
THF, reflux
11%
THF
THF
66
66
D
D
O
O
P(OEt)2
P(OEt)2
(5) with benzyl alcohol in THF gave a moderate yield of diisopropyl
benzylphosphonate (6, entry 3), and in DMF at a higher tempera-
ture the transformation became virtually quantitative (entry 4).
Even triphenyl phosphite (7) in DMF gave an attractive yield of di-
phenyl benzylphosphonate (8, entry 5). While the ZnI2-mediated
reaction of benzyl alcohol with o-tolylphosphite (9) proceeded in
poor yield in DMF, and the product proved very difficult to isolate
even when toluene was utilized, a 34% yield of the very sterically
hindered o-tolyl phosphonate 10 was achieved (Table 1, entry 6).
Because phosphonate esters prepared from nonracemic alco-
hols have been employed in a number of studies,14 the applicabil-
ity of this methodology in the preparation of such compounds was
also examined. Synthesis of one nonracemic phosphite was accom-
plished through the reaction of (S)-2-methyl-1-butanol (15) with
PCl3 in the presence of pyridine to give the new trialkylphosphite
11 in modest yield (Scheme 2). Through a parallel process the reac-
tion of (S)-citronellol (16) with PCl3, gave the new trialkylphos-
phite 13 in moderate yield. Both these nonracemic phosphites
reacted smoothly with benzyl alcohol under the standard reaction
conditions. When heated at reflux in THF with benzyl alcohol and
ZnI2, phosphite 11 gave the desired phosphonate 12 in 81% yield.
Phosphite 13, derived from citronellol, also reacted smoothly to af-
ford phosphonate 14 in comparable yield (76%). These results cer-
tainly suggest that nonracemic phosphites derived from other
primary alcohols would undergo parallel reactions.
D
D
20
21
(56:44 ratio)
Scheme 3. A deuterium labeling experiment.
temperature, and reaction duration, only traces of the diphenyl
benzylphosphonate product were observed based on the analysis
of the 31P NMR spectra. While the preparation of diisopropyl ben-
zylphosphonate has been reported in 70% yield under standard
Arbuzov conditions,15 the phenyl analogue required a nickel cata-
lyst to be obtained in good yield (92%),16 and the o-tolyl has not
been reported prior to this study.
It has been suggested11 that this transformation might involve
the formation of a tetracoordinate zinc species17 which undergoes
C–P bond formation and the loss of ZnO through an SN1-like pro-
cess. The observed loss of stereochemistry in the reaction with
(S)-1-phenylethanol supports an SN1-like process,11 and a final
Arbuzov-like reaction would afford the observed product 2. To
study this reaction sequence in more detail, a number of additional
experiments have been conducted.
To examine further the first component of this transformation,
an isotopic labeling experiment was envisioned with a deuterated
alcohol (Scheme 3). After preparation of the acrylate 1818 through
a Knoevenagel condensation of methyl phenylacetate (17) and
formaldehyde, the allylic alcohol could be obtained easily through
the reduction of ester 18 with LiAlH4 or DIBAL, albeit in low yield.
When the resulting allylic alcohol was treated under the standard
reaction conditions, the expected phosphonate was obtained. Even
though the product phosphonate was obtained in low yield, this
system offered a reasonable test of the reaction sequence. There-
fore, reduction of ester 18 was conducted with LiAlD4/AlCl3 to ob-
tain the desired isotopically labeled alcohol 19 (Scheme 3).
Subsequent treatment with zinc iodide and triethyl phosphite in
THF provided a mixture of both the methylene deuterated (20)
and the vinyl deuterated (21) phosphonates, and analysis of the
NMR spectra suggested a 56:44 ratio of 20, 21 (Scheme 3). Forma-
tion of these products might be explained by a mixture of SN2 and
SN20 reactions, but an SN1-like mechanism may be a more fitting
explanation.
Of the examples listed in Table 1, perhaps most surprising are
the attractive results obtained in the isopropyl and phenyl series,
as well as observation of even modest yields of product with the
o-tolyl phosphite. The bulky nature of these nucleophiles implies
that a standard Arbuzov mechanism is unlikely, both because these
phosphites are relatively poor nucleophiles and because after for-
mation of a tetrasubstituted phosphorus intermediate, the ester
substituents are not readily susceptible to an SN2 attack by a halide
ion. For example, when benzyl bromide was treated under Arbuzov
conditions with triphenyl phosphite and variations in solvent,
PCl3, pyr
THF
HO
R
P(OR)3
15 R =
16 R =
= 11 (40%)
The observed reactivity of the aryl phosphites in this transfor-
mation sheds some light on the second half of the reaction se-
quence. For the diethyl phosphonates and perhaps for the
diisopropyl phosphonates, formation of a tetracoordinate zinc spe-
cies (22), loss of zinc oxide, and a direct Arbuzov reaction on an
intermediate such as 23 would explain formation of phosphonate
= 13 (57%)
Scheme 2. Synthesis of nonracemic trialkyl phosphites.

6684
R. M. Richardson et al. / Tetrahedron Letters 53 (2012) 6682–6684
Path A
-
I
I
(CH3CH2O)3P Zn
I
HO
CH3CH2
O
3
(CH3CH2O)3P
ZnI2
O
H
+
(CH3CH2O)2P
1
23
22
-
I
Path B
I
I
H
O
C6H5CH2
O
8
(C6H5O)3P Zn
(C6H5O)3P
ZnI2
C6H5 O
1
+
O
(C6H5O)2P
H
+
(C6H5O)2P
24
25
26
Figure 1. A possible reaction sequence for the zinc-mediated transformations.
4. Breuer, E.; Bannet, D. M. Tetrahedron Lett. 1977, 18, 1141–1144.
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3 (Fig. 1, Path A). However, loss of an aryl iodide through a simple
SN2 mechanism is unlikely, and the low yields for the formation of
compound 8 under traditional Arbuzov conditions support that
view. Instead (Path B), after the formation of a parallel zinc com-
plex (24) from the aryl phosphite and loss of zinc oxide to generate
the C–P bond (25), it is possible that exchange with unreacted ben-
zyl alcohol affords an intermediate (26) that is capable of a final
Arbuzov reaction to afford phosphonate 8. However, if this type
of exchange were involved the exchange process would have to
be catalytic in terms of the benzyl alcohol, because an excess of
this reagent was not employed and yields are well above the 50%
that might be expected if an equivalent were needed for the second
step. Thus there are mechanistic aspects of this transformation that
still would benefit from further studies.
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dide mediated transformation of benzylic alcohols to phospho-
nates is viable with both trialkyl and triaryl phosphites. Because
it allows access to the hindered phosphonate esters that have been
employed in newer variations of the Horner-Wadsworth-Emmons
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Acknowledgments
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Financial support in the form of a Presidential Fellowship (to
RMR) from the University of Iowa Graduate College, and as a Re-
search Program of Excellence from the Roy J. Carver Charitable
Trust is gratefully acknowledged.
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Supplementary data
Supplementary data (experimental procedures and/or spectral
data for compounds 6, 8, 10–14, and 18–21) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.09.114.
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