The phosphorus-Claisen condensation

Article abstract of DOI:10.1016/j.tetlet.2012.11.119

1,1-Bisphosphorus compounds are easily synthesized through the phosphorus-Claisen (phospha-Claisen) condensation between a phosphorus- stabilized anion and a phosphorus electrophile. The preliminary scope of this reaction is investigated in terms of employable phosphorus reagents. Valuable intermediates are conveniently prepared in a single step. Overall, the method is competitive with multistep procedures which require the preparation of PCl intermediates derived from the P(OR) reagents we instead employ directly, and it delivers complex organophosphorus compounds in moderate to good isolated yields. An example of the intramolecular version of the reaction, the phospha-Dieckmann condensation, is also reported.

Full text of DOI:10.1016/j.tetlet.2012.11.119

Tetrahedron Letters 54 (2013) 817–820
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Tetrahedron Letters
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The phosphorus-Claisen condensation
⇑
Laurent Gavara, Fabien Gelat, Jean-Luc Montchamp
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, TX 76129, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
1,1-Bisphosphorus compounds are easily synthesized through the phosphorus-Claisen (phospha-Claisen)
condensation between a phosphorus-stabilized anion and a phosphorus electrophile. The preliminary
scope of this reaction is investigated in terms of employable phosphorus reagents. Valuable intermedi-
ates are conveniently prepared in a single step. Overall, the method is competitive with multistep proce-
dures which require the preparation of PCl intermediates derived from the P(OR) reagents we instead
employ directly, and it delivers complex organophosphorus compounds in moderate to good isolated
yields. An example of the intramolecular version of the reaction, the phospha-Dieckmann condensation,
is also reported.
Received 14 November 2012
Accepted 16 November 2012
Available online 2 December 2012
Keywords:
1,1-Bisphosphorus compound
Phosphonate
Phosphinate
Claisen condensation
Ó 2012 Elsevier Ltd. All rights reserved.
Because of our laboratory’s continued efforts in the preparation
of 1,1-bisphosphorus compounds,1 we became interested in inves-
tigating the condensation between a phosphonate-stabilized anion
and a phosphonate electrophile, a process analogous to the Claisen
ester condensation. Because phosphorus compounds provide much
more structural variety than their carboxylic ester counterparts,
we decided to explore this reaction, and its generalized version:
the phosphorus-Claisen condensation (heretofore referred to as
‘phospha-Claisen’).
Examination of the literature revealed surprisingly few exam-
ples of this reaction, always limited to the self-condensation of a
phosphonate diester anion. In pioneering research nearly thirty
years ago, Savignac and co-workers studied the thermal stability
dianion (RO)2P(O)CHMP(O)(OR)CH2M.4 On the other hand, the
condensation between a phosphonate anion and a P–Cl electro-
phile has been used more commonly to prepare various 1,1-
bisphosphorus compounds.1b–d,5 Of course, this approach necessi-
tates a reactive electrophile, which is either commercially/readily
available R2P(Y)Cl (Y = lone pair, O, BH3, etc.), or requires prior
synthesis of a chlorophosphonate R1P(O)(OR)Cl from the corre-
sponding phosphonate diester. Alternatively, another approach
has been the Arbuzov or Michaelis–Becker reactions between
P(O)CH2X and P(OR)3, or MOP(O)(OR)2, respectively.1a,6
Thus, it occurred to us that the general phospha-Claisen
condensation between a nucleophile 1 and an electrophile 2 would
be a convenient and powerful tool for the synthesis of methylene-
1,1-bisphosphorus compounds 3 (Eq. 2), with enormous versatility
in terms of substitution pattern and functional groups. Preliminary
studies of the feasibility of the reaction are presented below.
of various phosphonate diester
a
-anions (RO)2P(O)CHLiR1 and re-
ported on their generally undesirable self-condensation (Eq. 1).2
As in the classic Claisen condensation, the driving force is the for-
mation of a stabilized anion with lower basicity. Further, realizing
the potential of this type of intermediate, Savignac and co-workers
also described some synthetic application through the Wads-
worth–Horner–Emmons (WHE) olefination.2
ð2Þ
ð1Þ
Because the condensation product is a stabilized anion and
alcohol, nucleophile 1 either needs to be used in excess, or the base
to generate it must be present in at least two molar equivalents
(Eq. 1). Based on this requirement and on Savignac’s autoconden-
sation studies, the first nucleophile we selected was (i-PrO)2P(O)-
CH2Li 1a. This compound is generated easily from the
deprotonation of the corresponding phosphonate with n-BuLi at
low temperature.
However, very little work has appeared concerning the use of
the autocondensation products, except in the simplest case
(RO)2P(O)CH2P(O)(OR)CH3. For example, McClard3 reported the
alkylation of (RO)2P(O)CHMP(O)(OR)CH3, and the corresponding
Table 1 shows the results obtained for the condensation
between 1a and a range of phosphorus electrophiles 2. Various
⇑
Corresponding author. Tel.: +1 817 257 6201; fax: +1 817 257 5851.
E-mail address: j.montchamp@tcu.edu (J.-L. Montchamp).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.119

818
L. Gavara et al. / Tetrahedron Letters 54 (2013) 817–820
Table 1
Phospha-Claisen condensation between (i-PrO)2P(O)CH2Li and some phosphorus electrophiles 2a
Entry
1
Electrophile 2
Product 3
Isolated (31P NMR) yield %
71 (89)
2a
3a
2
56 (75)
2b
3b
3
4
5
6
7
8
9
80 (99)b
2c
2d
2e
2f
3c
b,c
76 (85)
3d
3e
3f
39 (56)d
52 (64)
70 (82)e
66 (89)
10 (64)
2g
2h
2i
3g
3h
3i
a
General conditions: (i-PrO)2P(O)CH3 (2 equiv), nBuLi (2.2 equiv), THF, ꢀ78 °C, 1 h, then electrophile 2, 1 h at ꢀ78 °C, then 2 h at rt. See Supplementary data for details.
Product purity varies between 92% and 98+%.
b
Isolated without any chromatography.
c
(i-PrO)2P(O)CH3 (1 equiv), LDA (3.2 equiv), THF, ꢀ78 °C, 30 min, then electrophile 2d (1.2 equiv), 30 min at ꢀ78 °C, then 4 h at rt. The isolated yield was adjusted to take
into account the presence of a small amount of starting materials.
d
The crude mixture was quenched with AcOH and treated with TsCl (2 equiv), i-Pr2NEt (3 equiv), CH2Cl2, rt 16 h.
nBuLi (3.3 equiv).
e
phosphonate diesters 2 reacted in good to high yields (entries
1–3), and as expected the more activated electrophiles (electron-
withdrawing group on the phosphorus atom in 2) gave higher
yields (entries 1 and 3, vs entry 2). Compound 3c was isolated in
good purity without the need for chromatographic purification.
Diethyl (hydroxymethyl)phosphonate also reacted successfully,
provided an additional equivalent of base is employed in order to
deprotonate the alcohol functionality in 2d (entry 4). Although
3d is contaminated with a small amount of reagents, it was ob-
tained without chromatography. Compounds related to 3d have
been prepared before but through lengthy and cumbersome syn-
thetic sequences via chlorophosphonate BnOCH2P(O)(OEt)Cl, or
phosphonite (RO)2P(Y)CH2P(OR)2 (Y = lone pair, O).7 Various com-
pounds with the general structure (RO)2P(O)CH2P(O)(OR)CH2OR1
have been used in the synthesis of biologically active compounds.7
Our method circumvents the need for protection of the alcohol and
for the preparation of chlorophosphonate (or a structurally com-
plex phosphonite) and should be useful for a variety of applications
using 3d.
A similar reaction with acetic acid as the quenching reagent and
in the presence of tosyl chloride gave acetate 3e directly, albeit in
moderate yield (entry 5). Interestingly, diethyl (2,2-diethoxy)eth-
ylphosphonate 2f underwent condensation with concomitant
elimination of ethoxide producing 2-ethoxyvinyl phosphinate 3f
(entry 6). This type of functionality is known to be versatile toward
nucleophilic addition and other functionalization.8
Other phosphorus electrophiles can also be employed:
(hydroxymethyl)phosphinate 2g gave the corresponding product
3g in good yield (entry 7), whereas phosphinate 2h gave phosphine
oxide 3h (entry 8). Reaction with dimethyl H-phosphonate

L. Gavara et al. / Tetrahedron Letters 54 (2013) 817–820
819
produced the bis-substituted phosphine oxide 3i (entry 9),
although the isolated yield is very much lower than the crude
yield, due to the high polarity of product 3i, and its propensity to-
ward oxidation. Improvements and trapping of the presumed P(III)
intermediate (i-PrO)2P(O)CH2)2POLi with an electrophile for the
preparation of interesting complexing agents remain to be
investigated.
Having demonstrated the general validity of the phospha-
Claisen condensation approach using 1a, the reaction between
other nucleophiles and diethyl phenylphosphonate 2a was investi-
gated (Table 2).
The reaction between phosphine oxide-derived Ph2P(O)CH2Li 1j
and 2a takes place uneventfully (entry 1). As expected, conditions
can have a significant impact on the yield: when equimolar
amounts of 1j and 2a were employed product 3j formed in 50%
31P NMR yield, but increasing the quantity of 1j/LDA to 1.5 equiv
gave a significant improvement to 76% (entry 1a vs 1b). A further
increase to 2 equivalents gave an even higher 85% NMR yield,
but then product 3j could not be purified from excess 1j. A cumber-
some synthesis of the n-butyl ester analog to 3j has been reported
from Ph2P(O)CH2Cl and phosphonite PhP(OEt)2 in 58% yield.6c
Phosphonite- borane anion 1k9 condensed with 2a to produce 3k
in good yield using LDA as the base (entry 2). Finally, the phosph-
inate anion 1l (prepared with LDA) also reacted to afford 3l in mod-
erate yield (entry 3).
thesis (alkylation, olefination),1b and as pyrophosphate mimics of
potential medicinal interest, the present methodology might be
applied to a broad range of applications.
Although some specific reagent 1 and/or 2 combinations might
not be employed, the phospha-Claisen condensation (Eq. 2) is still
a rather general and expeditious method. For example, compounds
3k and 3l (Table 2, entries 2 and 3) can be converted into the same
phosphinyl-H-phosphinate
4
through standard conditions10
(Scheme 1). Of course, intermediate 4 can then undergo typical
reactions of H-phosphinates such as Michael addition to produce
5. The yield optimization and use of various compounds 3 (for
example, 3d and 3f) will be investigated in future work.
ð3Þ
Luke and Shakespeare11 reported an interesting preparation of
(arylphosphinyl)methylphosphonates like 7 via the palladium-
catalyzed cross-coupling of aryl halides with reagent 612,1b which
itself was prepared (in their work) from the condensation
between 1l and ClP(O)(OEt)2 followed by acetal deprotection
(Eq. 3). Clearly, our phospha-Claisen approach is much shorter
and more convenient, since 3a (Table 1, entry 1) is obtained in
71% yield (the only difference between 7 and 3a being Et vs i-Pr
esters on the phosphonate, respectively).
Finally, the intramolecular version of the phospha-Claisen
condensation, that is, the phospha-Dieckmann reactions, was
evaluated as a ‘proof of concept’ experiment, using tetraethyl
o-xylylenebisphosphonate 8 as the model compound (Eq. 4).13
Treatment of 8 with 2 equiv of n-BuLi at ꢀ78 °C and warming to
room temperature gave the corresponding heterocycle 9 in good
yield (84%, mixture of diastereoisomers) after protonation and
purification over silica gel.
The 1H NMR spectra of compounds 3 can be quite complicated
(diastereotopic hydrogens, P–H and P–P couplings, diastereoiso-
mers as in 3l, etc.). Additionally, in some cases, it appears that hin-
dered rotation (or slow on the NMR timescale) around the P–C–P
motif is responsible for even more complex spectra, which look like
diastereoisomers: a good example being compound 3f (this is not
due to the double-bond stereochemistry which is trans). This effect
was already observed on (i-PrO)2P(O)CH2P(O)(OBu)Ph in which the
two sets of 31P NMR signals collapsed into one set upon conversion
to (MeO)2P(O)CH2P(O)(OMe)Ph with smaller ester groups.1a
The results shown in Tables 1 and 2 demonstrate the versatility
of the phospha-Claisen condensation as a general tool for the syn-
thesis of complex 1,1-bisphosphorus functionalities in a single
step, using various nucleophile/electrophile combinations. Because
of the importance of the products as both reagents for further syn-
ð4Þ
Table 2
Phospha-Claisen condensation between some phosphorus nucleophiles 1 and diethyl
phenylphosphonate 2aa
Because many 1,n-bisphosphonates are easily prepared, the
phospha-Dieckmann condensation could become a very simple en-
try into phosphorus heterocycles, and the presence of a pendant
phosphonate moiety would allow further functionalization, or
the heterocycle itself would constitute a new class of pyrophos-
phate analogs after hydrolysis. The generality of this reaction
needs to be explored fully, but the preparation of 9 bodes well
for future success, including phospha-Dieckmann using temporary
tethers.14
Entry Nucleophile 1
Product 3
Isolated (31P NMR) yield
%
1a
43 (50)
65 (76)
1b
1j
3j
2
71 (78)
52 (68)
1k
3k
3
3l
1l
a
See Supplementary data for details. R1R2P (O)CH3 (x equiv), LDA (x equiv), THF,
Scheme 1. Phosphinyl-H-phosphinate 4 from 3k and 3l. (a) EtOH, reflux, 24 h, 91%.
(b) TMSCl (2.5 equiv), EtOH, CH2Cl2, rt, 6 h, 87%. (c) DBU (1.1 equiv), benzyl acrylate
(1.1 equiv), CH3CN, 0 °C to rt, 2 h, 73%.
ꢀ78 °C, 1 h, then electrophile 2a (1 equiv), 1 h at ꢀ78 °C, and 2 h at rt. Entry 1a:
x = 1; entry 1b: x = 1.5; entry 2: x = 1; entry 3, x = 1.5.

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L. Gavara et al. / Tetrahedron Letters 54 (2013) 817–820
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Acknowledgments
We thank the Robert A. Welch Foundation (Grant P-1666) for
the financial support of the bulk of this research (LG). Some mate-
rial is based, in part, upon work supported by the National Science
Foundation under Grant No. 0953368 (FG).
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Supplementary data
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Supplementary data (detailed experimental procedures, spectra
data, and NMR spectra) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.11.
119.
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6 the ‘Bisseret reagent’ based on the original
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