Horner-Emmons synthesis with minimal purification using ROMPGEL: A novel high-loading matrix for supported reagents

Article abstract of DOI:10.1021/ol990694k

(Matrix presented) The synthesis and use of two novel high-loading Horner-Emmons ring-opening metathesis polymers are described. α,β-Unsaturated ethyl esters (E:Z> 99:1) and α,β-unsaturated nitriles (E:Z> 70:30) are obtained in excellent yields and purities from aldehydes with minimal purification.

Full text of DOI:10.1021/ol990694k

ORGANIC
LETTERS
1999
Vol. 1, No. 4
579-582
Horner−Emmons Synthesis with Minimal
Purification Using ROMPGEL: A Novel
High-Loading Matrix for Supported
Reagents
,†
Anthony G. M. Barrett,* Susan M. Cramp,‡ Richard S. Roberts,† and
Frederic J. Zecri†
Department of Chemistry, Imperial College of Science, Technology and Medicine,
London, SW7 2AY, U.K., and Rhoˆne-Poulenc Agriculture Limited, Fyfield Road,
Ongar, Essex, CM5 0HW, U.K.
am.cooper@ic.ac.uk
Received May 27, 1999
ABSTRACT
The synthesis and use of two novel high-loading Horner−Emmons ring-opening metathesis polymers are described. r,â-Unsaturated ethyl
esters (E:Z > 99:1) and r,â-unsaturated nitriles (E:Z > 70:30) are obtained in excellent yields and purities from aldehydes with minimal purification.
Combinatorial chemistry has received much attention of late
as an engine for the discovery of new pharmaceuticals,
catalysts, and materials.1 Library generation may be ac-
complished using solid phase organic synthesis or by using
conventional solution phase chemistry. There is, however,
an unending controversy as to which of the major synthetic
strategies for library synthesis is superior. The primary
advantage of solution phase chemistry is its familiarity to
the synthetic chemist. Additionally, reactions are generally
amenable to easy tracking and analysis. Nonetheless the
complicated workup procedures usually associated with such
reactions in solution have been a major hurdle to automation
and the use of multistep sequences. Advances in automated
chromatography (MPLC and HPLC) have gone some way
toward addressing this problem, although each purification
must still be monitored, since the polarities of compounds
and impurities cannot be generalized across a library.2 Acidic
or basic aqueous extraction again relies on the requisite
functionality on the impurities only.3 Other strategies include
the use of fluorous phase chemistry, although the lack of
fluorinated reagents which often need to be prepared by
highly specialized syntheses makes this method less attrac-
tive.4
† Imperial College of Science, Technology and Medicine
‡ Rhoˆne-Poulenc Agriculture Limited.
(1) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor; S. P. A.; Gordon,
E. M. J. Med. Chem. 1994, 37, 1233. Terrett, N. K.; Gardner, M.; Gordon,
D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135. Hermkens,
P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1996, 52, 4527.
Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. Tetrahedron 1997,
53, 5643. Boots, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1998, 54, 15385. Armstrong, R. W.; Combs, A. P.; Tempest,
P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123. Ellman,
J. A. Acc. Chem. Res. 1996, 29, 132. Gordon, E. M.; Gallop, M. A.; Patel,
D. V. Acc. Chem. Res. 1996, 29, 144. Balkenhohl, F.; von dem Bussche-
Hu¨nnefeld, C.; Lansky, A.; Zechel, C. Angew. Chem., Int. Ed. 1996, 35,
2289.
A wide range of polymer-supported reagents have been
developed, both for chemical transformations5 and for
(2) Griffey, R. H.; An, H.; Cummins, L. L.; Gaus, H. J.; Haly, B.;
Herrmann, R.; Cook, D. P. Tetrahedron 1998, 54, 4067.
(3) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D. L.
J. Am. Chem. Soc. 1996, 118, 2567. Kiankarimi, M.; Lowe, R.; McCarthy,
J. R.; Whitten, J. P. Tetrahedron Lett. 1999, 40, 4497.
(4) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996, 118, 2531. Curran,
D. P.; Hadida, S. J. Org. Chem. 1996, 61, 6480. Curran, D. P. Angew.
Chem., Int. Ed. 1998, 37, 2292.
10.1021/ol990694k CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/21/1999

sequestering excesses of solution reactants6 or chemically
tagged reagents.7 Simple filtration eliminates the need for
any time-consuming chromatographic workup. Sequestering
reagents can however suffer from slow rates of removal of
contaminants and the complementarity of product and
impurity functionality.
The polymer thus formed was a solid when dry but
demonstrated remarkable swelling properties in a range of
organic solvents (MeCN, CH2Cl2, THF) and possessed a
consistency similar to that of gelatin when solvated.17 We
term ROM polymers of this consistency as ROMPGELs.
ROMPGEL 3 could be stored at room temperature and in
the air over several weeks without any noticeable decom-
position.
We have already reported a method of impurity annihila-
tion of a solution-phase reaction by incorporation of excess
reagents into an insoluble polymer, formed in situ.8 We now
report a chromatography-free Horner-Emmons reaction of
aldehydes to R,â-unsaturated ethyl esters and nitriles.9
There is a clear need for maximizing the substrate loading
of a polymer-supported reagent. In our approach, the reagent
is also the monomer building block for the polymer.10 As
such, the polymer loading should ideally approach quantita-
tive. Commercially available 2-norbornenemethanol (a mix-
ture of endo- and exo-isomers) was converted to the
phosphite11 1 followed by Arbusov12 reaction to give the
Horner-Emmons monomer 2. Ring-opening metathesis
polymerization13 (ROMP) of the monomer was achieved in
quantitative yield with Grubbs’ catalyst14 and terminated with
ethyl vinyl ether (Scheme 1).15 Since this new polymer is
Horner-Emmons Reaction. A range of bases was
screened for the ROMPGEL Horner-Emmons reaction using
p-nitrobenzaldehyde. The results are shown in Table 1. Of
Table 1. Bases Screened for the Horner-Emmons Reaction
run
base
T/h
convn to 5a
1
2
3
4
5
6
7
8
K2CO3, toluene
KHMDS, toluene
NaOEt, EtOH
NaOH, THF
LDA, THF
24
24
4
4
1
24
16
24
24
48
4
no reaction
complex mixture
complex mixture
20%a
Scheme 1
20%a
LDA, THFb
100%
100%
no reaction
no reaction
50%
LHMDS, THFb
pyridine
NEt3
DBU, LiCl, MeCN
TMG,c MeCN
Barton base,d MeCN
9
10
11
12
100%
100%
4
a 4-NO2-C6H4CH2OH isolated in 80% yield. b 3 pretreated with base (4
equiv, 2 h). Excess base removed by washing with dry THF prior to addition
of aldehyde. c N,N,N′,N′-Tetramethylguanidine. d N-tert-Butyl-N′,N′,N′′,N′′-
tetramethylguanidine.
the anionic bases used, solid potassium carbonate in toluene
showed no detectable reaction after 24h (run 1). Both
potassium hexamethyldisilazide (KHMDS, run 2) and sodium
ethoxide (run 3) gave a complex mixture of products. Sodium
hydroxide (run 4) and, unexpectedly though unsurprisingly,
lithium diisopropylamide (LDA, run 5) both resulted in high
undiluted by cross-linking units or co-polymerization agents,
the loading of the polymer should be identical to the molarity
of the monomer, namely 3.3 mmol g-1.16
(5) Akelah, A.; Sherrington, D. C. Chem. ReV. 1981, 81, 557. Habermann,
J.; Ley, S. V.; Schucht, O.; Thomas, A. W.; Murray, P. J. J. Chem. Soc.,
Perkin Trans. 1 1999, 1251 and references therein. Habermann, J.; Ley, S.
V.; Scott, J. S. J. Chem. Soc., Perkin Trans. 1 1999, 1253 and references
therein.
(6) Flynn, D. L.; Crich, J. Z.; Devraj, R. V.; Hockerman, S. L.; Parlow,
J. J.; South, M. S.; Woodard, S. S. J. Am. Chem. Soc. 1997, 119, 4874.
Parlow, J. J.; Mischke, D. A.; Woodard, S. S. J. Org. Chem. 1997, 62,
5908. Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119, 4882.
Armstrong, R. W.; Keating, T. A. J. Am. Chem. Soc. 1996, 118, 2574.
Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.; Hanh, P. J.
Tetrahedron Lett. 1996, 37, 7193. Janda, K. D. J. Org. Chem. 1998, 63,
889.
(7) Starkey, G. W.; Parlow, J. J.; Flynn, D. L. Bioorg. Med. Chem. Lett.
1998, 2385.
(8) Barrett, A. G. M.; Smith, M. L.; Zecri, F. J. Chem. Commun. 1998,
2317.
(9) Boutagy, J.; Thomas, R. Chem. ReV., 1974, 74, 87. Wadsworth, W.
S. Org. React. 1977, 25, 73. Maryanoff, B. E., Reitz, A. B. Chem. ReV.
1989, 89, 863.
(11) Huyser, E. S.; Dieter, J. A. J. Am. Chem. Soc. 1968, 90, 4205.
(12) Lombardo, L.; Taylor, R. J. K. Synthesis 1978, 131. Wadsworth,
W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733.
(13) Gibson, V. C. AdV. Mater. 1994, 6, 37. Novak, B. M.; Grubbs, R.
H. J. Am. Chem. Soc. 1988, 110, 960. Novak, B. M.; Grubbs, R. H. J. Am.
Chem. Soc. 1988, 110, 7542. Schrock, R. H. Acc. Chem. Res. 1990, 23,
158. Breslow, D. S. Prog. Polym. Sci. 1993, 18, 1141.
(14) Bis(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride,
commercially available from Fluka.
(15) ROM polymerization can easily be monitored by taking the 1H NMR
of aliquots in CDCl3. The norbornene monomers have characteristic vinyl
protons at 6-6.2 ppm. Releasing the ring strain shifts these signals to 5.2-
5.5 ppm in the polymer.
(16) For a high-loading (2.6 mmol g-1) ion-exchange Wadsworth-
Emmons resin, see: Cainelli, G.; Contento, M.; Manescalchi, F.; Regnoli,
R. J. Chem. Soc., Perkin Trans. 1 1980, 2516. For a moderate loading (0.6
mmol g-1) polystyrene-derived Wadsworth-Emmons resin, see: Salvino,
J. M.; Kresow, T. J.; Darnbrough, S.; Labaudiniere, R. J. Comb. Chem.
1999, 1, 134.
(10) Ball, C. P.; Barrett, A. G. M.; Poitout, L. F.; Smith, M. L.; Thorn,
Z. E. Chem. Commun. 1998, 2453.
(17) Typically, 50 mg of dry ROMPGEL would swell to 5 mL when
solvated in acetonitrile.
580
Org. Lett., Vol. 1, No. 4, 1999

yields of p-nitrobenzyl alcohol, through Canizzarro and
Meerwein-Pondorf-Verley reactions, respectively.18 How-
ever, pretreating ROMPGEL 3 with excess LDA (4 equiv)
for 2 h to generate the specific enolate, followed by removal
the excess base and diisopropylamine by filtration and
washing, before addition of the aldehyde gave the desired
R,â-unsaturated ester in quantitative yield (run 6). Lithium
hexamethyldisilazide (LHMDS, run 7) by the same procedure
also gave a quantitative conversion.
Of the tertiary amine bases screened, the efficacy followed
the increasing basicity. Neither pyridine nor triethylamine
showed any reaction after 24 h (runs 8 and 9). Diazabicyclo-
[4.3.0]undecane (DBU) with LiCl19 (run 10) showed a slow
rate of conversion whereas the guanidine bases tetrameth-
ylguanidine (TMG, run 11) and tert-butyltetramethylguani-
dine (Barton base,20 run 12) both showed quantitative
conversion after only 4 h.
Table 2. ROMPGEL 3 Horner-Emmons Reaction. All
Purities Were >95% As Measured by GCMS22 (All Esters Were
Exclusively Trans. Isolated Yields Are Given.)
run
aldehyde 4
base
T/h
5
% yield
1
2
3
4
5
6
7
8
9
4a 4-O2N-C6H4CHO
Bartona
TMGb
LHMDSc
Barton
TMG
LHMDS
Barton
TMG
LHMDS
Barton
TMG
LHMDS
Barton
LHMDS
Barton
LHMDS
Barton
LHMDS
4
4
4
4
4
4
5a
94
95
92
84
88
88
88
92
60
96
53
97
85
98
85
92
88
4b 2-F-C6H4CHO
4c 3-Br-C6H4CHO
5b
16 5c
16
24
4
4
4
24 5e
24
48 5f
48
16 5g
16
16 5h
16 5i
10 4d 4-pyr-CHO
11
12
13 4e 4-Ph-C6H4CHO
14
15 4f 4-Me-C6H4CHO
16
17 4g PhCH2CH2CHO
18
19 4h 5-norbornene-2-CHOd Barton
20 4i citronellal
5d
Our purification-free strategy relies on the fact that after
Horner-Emmons reaction the base will be trapped on the
ROMPGEL (Scheme 2). Pretreatment of ROMPGEL 3 with
82
92
Scheme 2
Barton
a 2.0 equiv. b 1.5 equiv. c ROMPGEL 3 pretreated with 4.0 equiv of base
followed by filtration and washing. d Exo:endo mixture.
unsaturated esters, with little difference between the three
bases (runs 1-9); however the Barton base proved to be the
most general and versatile. In all cases, the R,â-unsaturated
esters obtained were of exclusively trans geometry.9
Reaction rates for LHMDS were generally slower (run 9).
Also, we obtained a complex mixture of products when an
aliphatic aldehyde was used (run 18), presumably due to
aldehyde enolization.
TMG performed well except when polar aldehydes were
used. Filtration of the reaction mixture through a pad of silica
removed the excess TMG but also trapped some of the
product (run 10). Elution of the remaining product off the
silica pad also carried through TMG which could not easily
be removed by evaporation (bp 162 °C). Contaminant TMG
could be removed in a second purification step, either with
Dowex 50WX 8-400 strong acid resin (53% isolated yield
of product, 95% purity), or Amberlite IRP 64 weak acid resin
(95% yield, 95% purity). As well as being inconvenient, this
was a nongeneral synthetic route, since purification condi-
tions would depend on the structure of the aldehyde 4.
The Barton base suffered none of the above problems. In
the case of polar aldehydes (run 11), simple evaporation
resulted in the removal of any contaminant base (bp 82 °C).
Filtration through a plug of silica was necessary only to
remove nonvolatile (presumably carbonate) salts of the
Barton base. We recommend the use of the Barton base in
combinatorial chemistry as a strong, Volatile, organic base,
in the same way that trifluoroacetic acid is becoming
uniVersal.
LHMDS forms specific enolate 6 (X+ ) Li+) (LHMDS and
HMDS in solution are then removed by filtration). Both
guanidine bases generate submolar concentrations of enolate
+
6 (X+ ) RNHdC(NMe2)2 , R ) H for TMG, tBu for Barton
base). The byproduct after Horner-Emmons reaction is the
polymeric phosphate salt 7, with X+ as counterion. The
ROMPGEL 3 is therefore limited to a single use per
equivalent of aldehyde 4.
All three bases, LHMDS, TMG, and the Barton base, were
assayed in Horner-Emmons reaction on a range of aldehydes
(Table 2).21,22 Initial results showed that the reactions
proceeded with excellent yields and purities of the R,â-
(18) Majewski, M. Tetrahedron Lett. 1988, 29, 4057.
(19) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(20) Commercially available from Fluka.
(21) In a typical procedure, the aldehyde 4 (0.045 mmol) and Barton
base (0.09 mmol) were added to the ROMPGEL (0.09 mmol) in acetonitrile
(1.5 mL). After stirring for the required time, the mixture was filtered
through a 200 mg silica cartridge (Alltech Associates, cat. no. 209150),
the silica was washed with EtOAc (10 mL), and the combined washings
were evaporated in a stream of nitrogen.
1
(22) All compounds were characterized by H and 13C NMR, GC, and
HRMS.
Org. Lett., Vol. 1, No. 4, 1999
581

We have extended the methodology to another function-
alized ROMPGEL. Thus phosphite 1 was condensed with
bromoacetonitrile and the monomer 8 polymerized as before
to give ROMPGEL 9 (Scheme 3). Again, in the loading of
Table 3. ROMPGEL 9 Horner-Emmons Reaction. All
Purities Were >95% As Measured by GCMS.22 All Yields Are
Isolated Yields
Scheme 3
run
aldehyde 4
T/h
E:Z ratioa
10
% yield
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
4
4
16
4
16
16
16
16
16
80:20
70:30
90:10
100:0
85:15
80:20
70:30
80:20
70:30
10a
10b
10c
10d
10e
10f
10g
10h
10i
95
94
90
86
91
98
93
86
85
1
a Ratio determined by H NMR.
the polymer, the molarity of the polymer should be the same
as the molarity of the monomer, namely 3.9 mmol g-1.
Treatment of the same range of aldehydes 4 with ROMP-
GEL 9 (2 equiv) and Barton base (2 equiv) gave the R,â-
unsaturated nitriles 10 in good to excellent yields and >95%
purity after only filtration and evaporation. Generally, the
rates of reaction of nitrile ROMPGEL 9 were faster than
that of the ester ROMPGEL 3, although now we obtained
E:Z mixtures in most cases, as described in classical Horner-
Emmons reactions (Table 3).
Acknowledgment. We thank Rhoˆne-Poulenc Agriculture
for their generous support this project (F.J.Z.). We also thank
GlaxoWellcome Ltd. for their endowment (to A.G.M.B.),
Rhoˆne-Poulenc Rorer, under the auspices of the TeknoMed
project (to R.S.R.), and the Wolfson Foundation for estab-
lishing the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College.
In summary, we have demonstrated the use of two novel
high-loading polymer phosphonate resins which in combina-
tion with the Barton base allow a general purification-free
Horner-Emmons synthesis of R,â-unsaturated esters and
nitriles from both aromatic and aliphatic aldehydes. Further
applications of ROMPGELs will be reported in due course.
1
Supporting Information Available: H NMR spectra for
compounds 1, 2, 3, 8, and 9. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL990694K
582
Org. Lett., Vol. 1, No. 4, 1999