New solid-supported phosphonate reagents for the synthesis of Z-α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2004.02.138

Novel solid-supported phosphonate reagents have been prepared and evaluated for the synthesis of α,β-unsaturated esters with a preference for the Z-alkene. The optimal reagent was a hybrid of both Still-Gennari and Ando reagents, and showed good to high yields and fair to good Z-selectivity for the conversion of both aliphatic and aromatic aldehydes.

Full text of DOI:10.1016/j.tetlet.2004.02.138

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3279–3282
New solid-supported phosphonate reagents for the synthesis of
Z-a,b-unsaturated esters
*
ꢀ
Sebastien L. X. Martina and Richard J. K. Taylor
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 9 January 2004; accepted 20 February 2004
Abstract—Novel solid-supported phosphonate reagents have been prepared and evaluated for the synthesis of a,b-unsaturated
esters with a preference for the Z-alkene. The optimal reagent was a hybrid of both Still–Gennari and Ando reagents, and showed
good to high yields and fair to good Z-selectivity for the conversion of both aliphatic and aromatic aldehydes.
Ó 2004 Elsevier Ltd. All rights reserved.
The use of polymer-supported reagents in organic syn-
thesis is now well established.1 In this context, the use of
polymer-supported Wittig reagents2 and Horner–
Wadsworth–Emmons (HWE) reagents3 have been
reported, the latter methods leading predominantly to
the formation of E-a,b-unsaturated esters and related
compounds. This methodology is extremely useful in
terms of facilitating the work-up process, particularly
the removal of the phosphorus-containing by-products,
and in the generation of libraries.
We now report the preparation and evaluation of new
solid-supported HWE reagents related to 1 and 2 for the
synthesis of Z-a,b-unsaturated esters.
The mixed solid-supported phosphonates used in the
present study were readily prepared via ethyl(di-
chlorophosphonoacetate) (4), obtained from commer-
cially available triethyl phosphonoacetate (3) and
PCl5.5;6 The reaction of ethyl(dichlorophosphonoacet-
ate) (4) with 1 equiv of a free alcohol in the presence of
triethylamine, followed by 1 equiv of supported phenol 5
(polymer-bound phenol, product number: 56479-6 pur-
chased from Aldrich) in the presence of triethylamine,
enabled the preparation of a range of mixed solid-sup-
ported phosphonates 6–9 (Scheme 2).
In 1983, Still and Gennari described the synthesis of a,b-
unsaturated esters with high Z-stereoselectivity from a
variety of aromatic, saturated and unsaturated aliphatic
aldehydes using electrophilic bis(trifluoroethyl)phos-
phonoesters 1.4 A few years later, Ando reported the
formation and the utilisation of new HWE reagents,
ethyl (diarylphosphono)acetates 2, which are also
selective for the formation of a range of Z-a,b-unsatu-
rated esters (Scheme 1).5
Following this approach, we synthesised four different
solid-supported phosphonates 6–9. After filtration and
thorough washing, the resulting resins were obtained
and evidence of the coupling was determined by FT-IR
1, 95%, Z:E > 50:1
O
P
O
O
P
O
PhCHO
2 (Ar = Ph),
CO2Et
Ph
CF3CH2O
CF3CH2O
ArO
ArO
OEt
OEt
93%, Z:E = 92:8
98%, Z:E = 99:1
(with 18-crown-6)
1
2
Scheme 1.
Keywords: Solid supported; Ando; Still–Gennari; Horner–Wadsworth–Emmons.
* Corresponding author. Tel.: +44-(0)1904-432606; fax: +44-(0)1904-434523; e-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.138

3280
S. L. X. Martina, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 3279–3282
O
P
O
O
P
O
PCl5
O
P
O
1. ROH, Et3N, THF, 2 h
2.
80°C
Cl
EtO
EtO
OEt
OEt
O
RO
76%
Cl
OEt
5
OH
3
4
6 R = Ph
7 R = CF3CH2
8 R = CF3CF2CH2
Et3N, THF, 15 h
pentafluorophenyl
9 R =
Scheme 2. General synthesis of solid-supported phosphonates.
(NaCl), showing typical carbonyl absorptions (1739–
1741 cmꢀ1). The yields for the formation of resins
6–9 were estimated by weight to be ca. 70–80%, based on
the initial loading of the polymer-bound phenol
(1.7 mmol/g).
improvement in Z-stereoselectivity, presumably due to
acceleration of the elimination rate of the phosphonyl
group. However, resin 9 substituted with a pentafluoro-
phenol moiety again favoured the E-isomer (entry iv).
This preliminary study indicated an enhancement of the
Z-stereoselectivity using fluorinated alcohols. A similar
result using methyl bis(2,4-difluorophenyl)phosphono-
acetate has been observed in solution.7
The reaction of THF swollen resins 6–9 with benzalde-
hyde and heptanal or octanal were carried out in the
presence of sodium hydride at )78 °C. The results are
summarised in Table 1.
In order to achieve higher cis-selectivity under conve-
nient conditions, we therefore decided to complete the
synthesis of the Merrifield-supported mixed phospho-
nate 14, combining elements of both Still–Gennari and
Ando reagents, which would be expected to be even
more electrophilic at the phosphonate centre. The new
resin 14 was prepared as described in Scheme 3. Reac-
Resin 6 (R ¼ Ph), modelled on the well-known Ando
phosphonate, gave poor Z-stereoselectivity (entry i,
E-adduct predominated). Incorporation of trifluoroeth-
anol and pentafluoropropanol (7 and 8, entries ii and
iii), to mimic the Still–Gennari reagent, showed a clear
Table 1. Reaction of resins 6–9 with aldehydesa
Entry
Resinb
IR resin C@O stretch (cmꢀ1
)
PhCHO yieldc (E/Z)d
C6H13CHO yieldc (E/Z)d
C7H15CHO yieldc (E/Z)d
i
6
7
8
9
1740
1739
1739
1741
89% (71:29)
69% (52:48)
71%e (48:52)
90% (70:30)
67% (69:31)
––
ii
––
––
––
67% (50:50)
68%e (44:56)
95% (64:36)
iii
iv
a Swelling of the resin (2 equiv) in THF at room temperature followed by addition of NaH (3 equiv) at 0 °C. After adding aldehyde (1 equiv) at
)78 °C, the mixture was kept at )78 °C for 5 h and was warmed over 10 h to room temperature.
b Theoretical loading of resins 6–9, based on the initial loading of the polymer-bound phenol (1.7 mmol/g) is, respectively, 1.23, 1.22, 1.15 and
1.11 mmol/g.
c Yields were determined after filtration of the crude reaction mixture through a pad of silica and concentration. Purity was determined to be >95% by
1H NMR spectroscopy.
d Ratio was determined by integration of the 1H NMR spectrum of the crude reaction mixture.
e Containing 10% of recovered aldehyde and determined by integration of the 1H NMR spectrum of the crude reaction mixture.
F
F
F
F
F
F
F
NaH, DMF
60 °C, 10 h
purple resin
O
+
OAc
Cl
HO
OAc
96%
F
10
12
11
NaOMe (5 equiv.),
THF, 4 h
93%
(i) 4 (1.2 equiv.),
CF3CF2CH2OH
(1.2 equiv.),
O
F
F
F
F
Et3N, THF, 2 h
F
F
O
brown resin
O
OH
O
(ii) 13, Et3N, THF, 14 h
F
O
P
OEt
84%
F
CF3CF2CH2O
13
14
pale green resin
Scheme 3. Synthesis of the mixed resin 14.

S. L. X. Martina, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 3279–3282
3281
tion of DMF swollen Merrifield resin 10 (Merrifield
resin 1%–divinylbenzene, catalogue number SC5004,
purchased from Advanced ChemTech) with excess
(2 equiv) of the sodium alkoxide of the mono-protected
tetrafluorohydroquinone8 11 resulted in the formation
of the resin 12. Saponification of the latter with sodium
methoxide in THF gave resin 13. This was then sub-
mitted to the methodology described earlier, leading to
the novel solid-supported phosphonate 14. The progress
of the reaction was easily monitored by the change of
colour as well as by FT-IR spectroscopy. As a result of
the coupling with the protected hydroquinone, the col-
our of resin 11 changed from white to purple, and a
carbonyl band at 1789 cmꢀ1 appeared. After, the
saponification step, the resin 13 was characterised by its
brown colour and the disappearance of the carbonyl
band. A pale green colour and a carbonyl band at
1741 cmꢀ1 characterised the supported phosphonate 14.
Yields were estimated by weight assuming an initial
loading of 1.4 mmol/g for 10.
Using sodium hydride at room temperature offered a
technically straightforward procedure for the utilisation
of the resin 14: after 14 h, the crude mixture is simply
filtered through a short plug of silica, concentrated and
dried. Using these conditions, a range of aldehydes was
screened to determine the versatility of resin 14. The
results are summarised in Table 3.
As can be seen, phosphonate resin 14 provides a mod-
erate to high degree of Z-selectivity under convenient
reaction conditions with a range of aromatic and ali-
phatic aldehydes. Thus, in the aromatic examples
(entries i–iii), benzaldehyde, p-nitrobenzaldehyde and
Table 3. Z-Selective HWE olefination with resin 14a using NaH at
room temperatureb
Entry
Aldehyde
Product
Yieldc
(E/Z)d
CHO
i
96%
(23:77)e
With the new resin 14 in hand, we screened a range of
conditions (bases, counterions and temperature) using
benzaldehyde. The results are shown in Table 2.
CO2Et
15
CHO
Of the anionic bases used, potassium tert-butoxide
offered a moderate stereoselectivity, but the presence
of salts even after filtration was a problem (entry i).
Potassium hexamethyldisilazide (KHMDS) gave
decomposition of benzaldehyde (entry ii). However, we
were delighted to find that NaH gave an excellent yield
with 3:1 Z/E stereoselectivity. The addition of sodium
iodide did not lead to an improvement in the Z-selec-
tivity, as has been reported9 in related solution state
studies (compare entries iii and iv). Surprisingly at 25 °C
using NaH, the selectivity was the same or slightly
improved (compare entries iii and v).
ii
85%10
(27:73)
CO2Et
O2N
O2N
16
CO2Et
iii
91%
(31:69)
CHO
O
O
iv
v
CH3(CH2)6CHO
84%
(31:69)
CH3(CH2)6
CO2Et
46%f
(37:63)
CO2Et
CHO
Table 2. Bases and temperature screened for the conversion of benz-
aldehyde with resin 14
CHO
vi
98%
(40:60)
CO2Et
CO2Et
Resin 14 (3.2 equiv.)
Base
CHO
Temperature
CHO
vii
84%
(33:67)
CO2Et
15
Yield of 15a (E/Z)b
a Loading of resin 14 determined to be 0.459 mmol/g by phosphorus
elementary analysis based on the initial loading of the Merrifield resin
of 1.4 mmol/g.
b To pre-swollen in THF resin 14 (3.2 equiv) at 0 °C was added NaH
(10 equiv). After stirring at 25 °C for 1 h, the aldehyde (1 equiv) was
added. After 14 h (2–4 h with p-nitrobenzaldehyde depending on the
reaction temperature), the resin was filtered and the organic phase
concentrated.
c Yields were determined after filtration of the crude reaction mixture
through a pad of silica and concentration. Purity determined to be
>95% by 1H NMR spectroscopy.
d Ratio was determined by integration of the 1H NMR spectrum of the
crude reaction mixture.
Entry
i
Conditions
t-BuOK (5 equiv), )78 °C, 6 h, Yield not determined
then 10 h at 25 °C
(55:45)
No product
ii
KHMDS (10 equiv), )78 °C,
5 h, then 10 h at 25 °C
NaH (10 equiv), )78 °C, 6 h,
then 25 °C for 11 h
NaH (5 equiv), )78 °C, NaI
(1 equiv), 6 h, then 25 °C for
4 h
iii
iv
83% (25:75)
86% conversion (41:59)
v
NaH (10 equiv), 14 h, 25 °C
96% (23:77)
a Yields were determined after filtration of the crude reaction mixture
through a short plug of silica and concentration. Purity determined to
be >95% by 1H NMR spectroscopy.
e A control reaction has been carried out using resin 14 left for two
weeks in air. Product 15 was obtained in 90% yield and 50:50 E/Z
ratio.
f Reaction filtered after 22 h at 25 °C and yield obtained after column
chromatography to remove a by-product.
b Ratio was determined by integration of the 1H NMR spectrum of the
crude reaction mixture.

3282
S. L. X. Martina, R. J. K. Taylor / Tetrahedron Letters 45 (2004) 3279–3282
dron Lett. 1996, 37, 7595–7598; (d) Bolli, M. H.; Ley, S. V.
J. Chem. Soc., Perkin Trans. 1 1998, 2243–2246.
3. (a) Nicolaou, K. C.; Pastor, J.; Winssinger, N.; Murphy,
F. J. Am. Chem. Soc. 1998, 120, 5132–5133; (b) Barrett, A.
G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org.
Lett. 1999, 1, 579–582; (c) Salvino, J. M.; Kiesow, T. J.;
Darnbrough, S.; Labaudiniere, R. J. Comb. Chem. 1999, 1,
134–139; (d) Wipf, P.; Henninger, T. C. J. Org. Chem.
1997, 62, 1586–1587; (e) Cainelli, G.; Contento, M.;
Manescalchi, F.; Regnoli, R. J. Chem. Soc., Perkin Trans.
1 1980, 2516–2519; (f) Salvino, J. M.; Patel, S.; Drew, M.;
Krowlikowski, P.; Orton, E.; Kumar, N. V.; Caulfield, T.;
Labaudiniere, R. J. Comb. Chem. 2001, 3, 177–180 (see
also Salvino, J. M.; Kumar, N. V.; Orton, E.; Airey, J.;
Kiesow, T.; Crawford, K.; Mathew, R.; Krowlikowski, P.;
Drew, M.; Engers, D.; Krowlikowski, D.; Herpin, T.;
Gardyan, M.; McGeehan, G.; Labaudiniere, R. J. Comb.
Chem. 2000, 2, 691–697).
2-furfural all gave good yields and Z-stereoselectivity.
Octanal behaved similarly (entry iv) but the yield with
citronellal was disappointing (entry v); an unidentified
by-product was formed and column chromatography
was required for the separation. trans-2-Hexenal and
trans-cinnamaldehyde both underwent efficient conver-
sion with reasonable stereoselectivity (entries vi and vii).
As the reaction with p-nitrobenzaldehyde proceeded so
quickly, we undertook a brief optimisation study. We
found that the scale of the reaction could be easily
increased to 0.3 mmol in terms of the aldehyde. The
amount of resin could be reduced to 2.5 equiv and the
amount of NaH to 3 equiv.10 We also established that
resin 14 was still active after two weeks in the open air,
although the stereoselectivity diminished (23:77% to
50:50).
4. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4408.
In summary, we have demonstrated the synthesis and
the use of a novel solid-supported fluorinated phos-
phonate, which in combination with NaH as base,
allows the formation of Z-a,b-unsaturated esters with
good to high stereoselectivity without the need for
chromatographic purification. The development of a
range of improved high loading resins and a method to
recycle the resins are under investigation.
5. (a) Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108; (b)
Ando, K. J. Org. Chem. 1997, 62, 1934–1939; (c) Ando, K.
J. Org. Chem. 1998, 63, 8411–8416; (d) Ando, K. J. Org.
Chem. 1999, 64, 8406–8408.
6. Motoyoshiya, J.; Kusaura, T.; Kokin, K.; Yokoya, S.-I.;
Tagaguchi, Y.; Narita, S.; Aoyama, H. Tetrahedron 2001,
57, 1715–1721.
7. Kokin, K.; Motoyoshiya, J.; Hayashi, S.; Aoyama, H.
Synth. Commun. 1997, 27, 2387–2392.
8. All novel compounds were fully characterised (including
by high field 1H and 13C NMR spectroscopy and high
resolution mass spectrometry).
Acknowledgements
9. Pihko, P. M.; Salo, T. M. Tetrahedron Lett. 2003, 44,
4361–4364.
We are grateful to Yorkshire Cancer Research
(S.L.X.M. Y244) for studentship support. We also
thank Dr. Anne Routledge (University of York) for
helpful discussions and advice.
10. Optimal conditions for the olefination of 4-nitrobenzalde-
hyde using resin 14: To pre-swollen in THF (20 mL) resin
14 (1.669 g, 0.766 mmol) at 0 °C was added pre-washed
NaH (22 mg, 0.917 mmol). The mixture was stirred gently
(<200 rpm) for 45 min at 0 °C, then solid p-nitrobenzalde-
hyde (46 mg, 0.304 mmol) was added. The reaction mix-
ture was stirred gently at 0 °C for 3 h, then 1 h at room
temperature. The resin was filtered, washed with Et2O and
the organic phase was concentrated in vacuo to afford 16
(57 mg, 85%, E/Z ¼ 27:73) as a yellow oil. The data were
consistent with those published.11
References and notes
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S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
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