Alkenylphosphonates: Unexpected products from reactions of methyl 2-[(diethoxyphosphoryl)methyl]benzoate under Horner-Wadsworth-Emmons conditions

Article abstract of DOI:10.1039/c1ob05506b

Methyl 2-[(diethoxyphosphoryl)methyl]benzoate reacts with several aldehydes to produce an alkenylphosphonate as the major product, together with varying amounts of the expected Horner-Wadsworth-Emmons product, a 1,2-disubstituted E-alkene. Use of a bulky aldehyde or the tert-butyl ester favours the normal HWE product.

Full text of DOI:10.1039/c1ob05506b

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Alkenylphosphonates: unexpected products from reactions of methyl
2-[(diethoxyphosphoryl)methyl]benzoate under Horner–Wadsworth–Emmons
conditions†
Lynton J. Baird,a Ce´dric Colomban,a Claire Turner,a Paul H. Teesdale-Spittleb and Joanne E. Harvey*a
Received 31st March 2011, Accepted 27th April 2011
DOI: 10.1039/c1ob05506b
Methyl 2-[(diethoxyphosphoryl)methyl]benzoate reacts with
several aldehydes to produce an alkenylphosphonate as the
major product, together with varying amounts of the expected
Horner–Wadsworth–Emmons product, a 1,2-disubstituted
E-alkene. Use of a bulky aldehyde or the tert-butyl ester
favours the normal HWE product.
The Horner–Wadsworth–Emmons (HWE) variation of the Wittig
reaction is one of the most utilised transformations in organic
chemistry; it involves the coupling of a b-stabilised phosphonate
anion with an aldehyde to form an E-alkene.1 The mechanism
Scheme 1 Proposed HWE route to aigialomycin D (1).
is well understood2 and modifications that select for the kinetic
product, the Z-alkene, have been developed.3 The precise ratio
ies using
a simple 2-(methoxycarbonyl)benzylphosphonate
of E- to Z-isomers depends on the identity of the base, the
structures of aldehyde and phosphonate, the reaction temperature
and the solvent.4 Asymmetric versions that operate by kinetic
resolution processes, and HWE reactions in sequence with other
reactions, are also known.5 If there is no carbanion-stabilising
group (usually a carbonyl) at the b-position of the phosphonate
partner, the HWE reaction often does not proceed to completion,
giving stable b-hydroxyphosphonates instead. However, a method
to eliminate b-hydroxyphosphonates provides a reliable multi-step
variant of the HWE.6 2-(Methoxycarbonyl)benzylphosphonates
represent a form of vinylogous b-carboxyphosphonates and might
be expected to behave in a similar manner to the normal
HWE substrates. Indeed, a number of examples demonstrat-
ing the HWE reaction of benzylic phosphonates exist in the
literature.7,8,9,10 During an early stage of our research on the
total synthesis of aigialomycin D (1),11 HWE reaction between
a 2-(methoxycarbonyl)benzylphosphonate 2 and a sugar-derived
aldehyde 3 appeared to be a viable method for formation of the
C1¢–C2¢ E-olefin (Scheme 1).
lacking aromatic oxygen substituents. Thus, methyl 2-
[(diethoxyphosphoryl)methyl]benzoate (4)7,8,12 was prepared by
bromination13 of commercially available methyl 2-methylbenzoate
(5) followed by an Arbuzov reaction of benzylic bromide 6 with
triethylphosphite (Scheme 2). It was found that purification of
the bromide intermediate 6 was unnecessary, due to the lack
of reactivity of the by-products (mostly the benzylic dibromide)
with triethylphosphite. Treatment of 4 with various bases and
sugar-derived aldehydes 3 led to decomposition of the aldehydes
and some recovery of starting material 4. To deconvolute the
impact of the carbohydrate functional groups, we investigated
the reaction of 4 with simple model aldehydes. Thus, treatment
of a cold (-78 ◦C) ethereal solution of benzylphosphonate 4
with lithium bis(trimethylsilylamide) (LiHMDS) and subsequent
addition of octanal (7a) provided the expected HWE product, E-
alkene 8a (Scheme 2). The spectroscopic data from this material
were consistent with its structure, namely the presence of mutually
coupled (J = 15.7 Hz) olefinic peaks at 7.12 and 6.14 ppm indicative
of a E-disubstituted alkene, together with the expected aromatic,
aliphatic and methyl ester signals. However, the yield was low
(7%) and the 1H NMR spectrum of the crude reaction mixture had
indicated the presence (and dominance) of another olefinic species.
Further acidification and extraction of the aqueous washings
generated during work up of the reaction led to the isolation of a
highly polar material, assigned the structure E-9a (Scheme 2).
The 1H NMR spectrum of this compound displayed a one-
proton signal at 6.72 ppm (dt, J = 23.1, 7.3 Hz) that exhibited
COSY correlations only with signals in the aliphatic region. The
Our initial appraisal of the HWE reaction in the syn-
thesis of aigialomycin
D focussed around model stud-
aSchool of Chemical and Physical Sciences, Victoria University of Welling-
ton, PO Box 600, Wellington 6140, New Zealand. E-mail: joanne.harvey@
vuw.ac.nz; Fax: +64-4-4635237; Tel: +64-4-4635956
bSchool of Biological Sciences, Victoria University of Wellington, PO Box
600, Wellington 6140, New Zealand
† Electronic supplementary information (ESI) available: Procedures for all
reactions and spectroscopic data for all new compounds, 1H and 13C NMR
spectra for new compounds. See DOI: 10.1039/c1ob05506b
1
23 Hz coupling constant is consistent with three-bond H–31P
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Scheme 2 Synthesis of methyl 2-[(diethoxyphosphoryl)methyl]benzoate (4) and its reactions with aldehydes 7a–7d.
interactions in a cis-relationship within an alkenylphosphonate.14
In addition, appropriate aliphatic and aromatic peaks accounting
for the remainder of the structure were observed in the spectrum.
Notably, the methyl ester singlet was absent from the spectrum and
a broad hump was observed in the low-field region, indicating the
presence of a carboxylic acid instead. HRMS analysis confirmed
the molecular formula of the assigned structure 9a.
Mechanistically, formation of the alkenylphosphonates 9 may
arise from the normal HWE intermediate 11 (Scheme 3). Pathway
A gives the expected HWE product, alkene 8, by elimination of
oxaphosphetane 12. The alternative mechanism, pathway B, in
which the oxyanion of 11 attacks the ester, is available for this
vinylogous ester but not for b-carboxyphosphonates (the normal
The reaction was then repeated with a range of conditions and
several different aldehydes, as described in Table 1. In all cases
except that involving pivaldehyde (entry 12), the major product
was the alkenylphosphonateE-9 (entries 1–11). The corresponding
Z-isomer was also present in minor amounts in some of the
crude reaction mixtures but it has not yet been isolated; its main
3
distinguishing feature by NMR was the much larger JH,P of
48 Hz.14 In the octanal reactions (entries 1–6), an additional by-
product was noted in variable amounts whose spectral data match
those of a,b-enal 10a, the self-condensation product of octanal.15
There was a trend in the effect of the solvent on the outcome,
such that increasing the polarity generally increased the preference
for formation of the alkenylphosphonate (entries 1–3 and 7–8).
Performing the reaction at a higher temperature seemed to de-
crease slightly the preference for the alkenylphosphonate product
(entries 3 vs. 5). The ratio of alkene to alkenylphosphonate was
also dependent on the counterion to the base (entries 3 vs. 4). Use
of methoxide as the base also favoured the alkenylphosphonate
(entries 6 and 11). The reactions with benzaldehyde produced
significant quantities of the alkenylphosphonate E-9c (entries 9–
11), but not its Z-isomer. It is noteworthy that the sterically bulky
pivaldehyde gave exclusively the disubstituted alkene product 8d
in excellent yield (entry 12).
Scheme 3 Proposed mechanisms of product formation.
Table 1 Reactions of methyl 2-[(diethoxyphosphoryl)methyl]benzoate (4) with aldehydes
Entry
Aldehyde
Conditions
Ratio of 8 : E-9 : Z-9a
Yield of 8b
Yield of E-9b
1
2
3
4
5
6
7
8
7a
7a
7a
7a
7a
7a
7b
7b
7c
7c
7c
7d
LiHMDS, Et2O, -78 ◦
C
13 : 81 : 6
22 : 78 : 0
0 : 79 : 21
45 : 55 : 0
13 : 66 : 21
0 : 100 : 0
ca. 30 : 70 : 0
ca. 35 : 65 : 0
15 : 85 : 0
7 : 93 : 0
7%
12%
0%
57%
49%
71%
LiHMDS, toluene, -78 ◦C
LiHMDS, THF, -78 ◦
KHMDS, THF, -78 ◦
LiHMDS, THF, 0 ◦
NaOMe, THF, 0 - 67 ◦
LiHMDS, Et2O, -78 ◦
LiHMDS, toluene, -78 ◦C
LiHMDS, THF, -78 ◦
LiHMDS, toluene, -78 ◦C
NaOMe, THF, 0 - 67 ◦
LiHMDS, THF, -78 ◦
C
C
(33%)c
(8%)c
(0%)c
21%
24%
11%
(5%)c
(8%)c
88%
(41%)c
28% (34%)c
(42%)c
31%
C
C
C
21%
9
C
37%
10
11
12
(64%)c
(21%)c,d
0%
C
C
29 : 71 : 0
100 : 0 : 0
a Ratios were calculated from the 1H NMR spectrum of the crude reaction mixture. b Isolated yields except where otherwise stated. c Numbers in brackets
1
are NMR yields, calculated from H NMR spectra of the crude reaction mixtures and included for cases where the isolated yields were not obtained.
d Poor conversion was noted in this reaction, possibly due to the quality of NaOMe used.
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Table 2 Reactions of tert-butyl ester 15 with octanal (7a)
Entry
Conditions
Ratio 16 : 9aa
Yield 16b
Yield E-9a
1
2
3
LiHMDS, THF, -78 ◦
C
C
67 : 33
80 : 20
100 : 0
41% (45%)c
(55%)c
31%
(23%)c
(14%)c
0%
KHMDS, THF, -78 ◦
NaOtBu, THF, 0 - 67 ◦C
a Ratios were calculated from the 1H NMR spectrum of the crude reaction mixture. b Isolated yields except where otherwise stated. c Numbers in brackets
are NMR yields, calculated from 1H NMR spectra of the crude reaction mixtures and included for cases where the isolated yields were not obtained.
HWE substrates). Pathway B produces the lactone 13 and leads,
upon eliminative opening of the lactone ring, to the observed
alkenylphosphonates 9. Steric minimisation during this process
would favour the E-alkenylphosphonates over the Z-isomers. The
precise roles of solvent and temperature in controlling the product
distribution are presently unclear. An alternative mechanism
involving the cyclic phosphonate 1416 was ruled out by performing
a control reaction in which the phosphonate 4 was treated with
LiHMDS in THF at -78 C in the absence of an aldehyde; after
quenching with aqueous hydrochloric acid and extracting, only
unmodified starting material was obtained.
The result obtained with pivaldehyde (R = tert-butyl) indicates
that a bulky R group inhibits formation of the lactone 13d, instead
leading exclusively to the expected disubstituted alkene 8d, in good
yield (88%), via the normal HWE mechanism. This implies that
the transition state leading to 13 is more crowded than for the
oxaphosphetane 12, as borne out by a simple visual inspection of
the structures.
formation (viz. 13a, Scheme 3) and directs the mechanism through
the HWE pathway.
Optimisation of the conditions that select for the alkenylphos-
phonates would allow efficient preparation of these interesting
products that have potential utility as synthetic intermediates18
and biologically active compounds.19
Conclusions
Observation of alkenylphosphonates 9 as dominant products in
the reactions of phosphonate 4 with several aldehydes has led to a
proposed mechanism that involves intermediacy of the phospho-
nolactone 13. This process competes with the normal HWE mech-
anism in reactions of 2-(methoxycarbonyl)benzylphosphonates
with straight-chain and aromatic aldehydes, which explains the
variability of yields in their reported HWE reactions.7,8,9 Addition
of steric bulk to the aldehyde or ester shuts down this competing
pathway and allows efficient preparation of the normal HWE
products.
Based on the mechanism outlined above, it seems reasonable to
propose that the lactonisation step of pathway B (viz. 11 to 13)
would be disfavoured in systems with higher electron density in
the aromatic ring (and correspondingly at the carbonyl centre)
and, therefore, that the HWE pathway would dominate. This
correlates well with literature precedent, in which more electron-
rich, phenolic benzylphosphonates are reported to produce HWE
products reliably and in good yields.9 Use of a bulky ester
might also be expected to disfavour pathway B. This hypothesis
was probed by treating the tert-butyl ester equivalent of 4, viz.
compound 15‡ (Scheme 4), with LiHMDS and octanal under
the same conditions as entry 3, Table 1. A mixture of alkene 16
and alkenylphosphonate E-9a, was obtained in a 2 : 1 ratio (Table
2, entry 1). This proportion of alkene to alkenylphosphonate
contrasts markedly with the exclusive formation of the latter
(9a) by reaction of the methyl ester 4 under the same reaction
conditions. As with the methyl ester, use of KHMDS increased
the preference for the alkene (entry 2). Furthermore, treatment
of 15 with sodium tert-butoxide and octanal produced only
the normal HWE product, alkene 16 (entry 3). None of the
Z-alkenylphosphonate Z-9a was observed in the reactions of 15.
These results indicate that the bulky ester group prevents lactone
Acknowledgements
Funding was gratefully received from the Foundation for Re-
search, Science and Technology (NZ) for a Bright Futures PhD
Scholarship (LJB). The Faculty of Science at Victoria University
is thanked for financial support.
Notes and references
‡ tert-Butyl 2-[(diethoxyphosphoryl)methyl]benzoate (15) was prepared by
trans-esterification of methyl ester 5,17 followed by bromination and an
Arbuzov reaction.20
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