Parallel synthesis of terminal alkynes using a ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate

Article abstract of DOI:10.1021/ol049915z

ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate has been prepared, and the supported reagent has been effectively employed in the conversion of a variety of aldehydes into terminal alkynes under mild reaction conditions. The influence of cross-link structure, comonomers, and polymer structure on reaction efficiency has been examined.

Full text of DOI:10.1021/ol049915z

ORGANIC
LETTERS
2004
Vol. 6, No. 5
835-837
Parallel Synthesis of Terminal Alkynes
Using a ROMPgel-Supported Ethyl
1-Diazo-2-oxopropylphosphonate
Anthony G. M. Barrett,* Brian T. Hopkins, Andrew C. Love, and Livio Tedeschi
Department of Chemistry, Imperial College London, Exhibition Road,
London SW7 2AZ, England
agmb@imperial.ac.uk
Received January 14, 2004
ABSTRACT
ROMPgel-supported ethyl 1-diazo-2-oxopropylphosphonate has been prepared, and the supported reagent has been effectively employed in
the conversion of a variety of aldehydes into terminal alkynes under mild reaction conditions. The influence of cross-link structure, comonomers,
and polymer structure on reaction efficiency has been examined.
In recent years, the subject of supported reagents has attracted
considerable research interest. The synthesis of compound
libraries is readily performed using supported reagents in a
sequential and multistep fashion. The use of supported
reagents in parallel synthesis simplifies purification, as only
filtration and washing procedures are required to remove
excess reagent and side products. They also allow straight-
forward reaction monitoring, applying classical solution-
phase methods. Efforts to improve the loading and physical
properties of supported reagents continue with many new
and improved reagents reported.1
ROMPgel are a general class of high-loading polymer-
supported reagents derived from the ring-opening metathesis
polymerization (ROMPolymerization) of norbornene or
7-oxanorbornene monomers.2 Readily available monomers
can be easily functionalized in solution, in a small number
of steps, purified and fully characterized prior to ROMPo-
lymerization by ruthenium carbenes.3 Living polymeriza-
tion occurs since each chain generated by the alkylidene
transition-metal catalyst does not facilitate chain transfer or
chain termination, thus generating well-defined polymers
with respect to molecular weight and polydispersity. In the
presence of a cross-linker, a plethora of ROMPgel-supported
reagents have been prepared in good yield and high purity
and used in “purification free” parallel synthesis.2
Our recent interest has focused on the requirements for
more functionalized building blocks and the rapid introduc-
tion of chemical diversity using readily available reagents.
In particular, the synthesis of terminal alkynes has attracted
our attention since further rapid increases in molecular
complexity can be performed from these key intermediates.
Only one supported reagent has been previously prepared
for the synthesis of alkynes, and only two examples were
reported.4 Using a solid base, consisting of alumina coated
with potassium fluoride (KF), ethynylbenzene (70% yield)
(1) (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.; Leach,
A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.; Storer, R. I.; Taylor, S.
J. J. Chem. Soc., Perkin Trans. 1 2000, 23, 3815-4195. (b) Kirschning,
A.; Monenschein, H.; Wittenberg, R. Angew. Chem., Int. Ed. 2001, 40, 650-
679.
(2) (a) Barrett, A. G. M.; Hopkins, B. T.; Ko¨bberling, J. Chem. ReV.
2002, 102, 3301-3324. (b) Flynn, D. L.; Hanson, P. R.; Berk, S. C.; Makara,
G. M. Curr. Opin. Drug Discuss. DeV. 2002, 5, 571-579.
(3) Buchmeiser, M. R. Chem. ReV. 2000, 100, 1565-1604.
(4) Yamawaki, J.; Kawate, T.; Ando, T.; Hanafusa, T. Bull. Chem. Soc.
Jpn. 1983, 56, 1885-1886.
10.1021/ol049915z CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/07/2004

and (phenylethynyl)benzene (89% yield) were synthesized
through â-elimination from the corresponding vicinal dibro-
mides. The need for both elevated temperatures and indi-
vidually optimized reaction conditions reduces the general
applicability of this reagent. The increased basicity of KF-
alumina, compared to KF alone, may also prove incompatible
with certain substrates.
Table 1. Effect of Polymer Architecture on ROMPgel
Swelling Properties in Methanol
The increasing use of phosphonate reagents in the synthesis
of alkynes suggested milder reaction conditions could be
developed for more readily available reaction precursors.
Specifically, our attention was drawn to reagents containing
a diazomethyl group. Both the dimethyl5 and diethyl diazo-
methylphosphonates6 and, more recently, dimethyl 1-diazo-
2-oxopropylphosphonate7 have attracted considerable interest.
They have been used in the preparation of simple alkynes,
in high yields and on large scale, or alternatively in the
installation of a triple bond into more highly functionalized
substrates, particularly in the latter stages of natural product
syntheses.8 The use of dimethyl 1-diazo-2-oxopropylphos-
phonate in basic methanol represents a significant improve-
ment over the standard synthetic procedure for alkyne
synthesis using dialkyl diazomethylphosphonates.9 The re-
agent, under basic conditions, reacts with aldehydes and
ketones by a Horner-Wadsworth-Emmons olefination reac-
tion to generate an unstable diazoalkene, which may then
thermally eliminate nitrogen. The resulting alkylidene car-
bene then rearranges smoothly to provide the alkyne.8 By
applying ROMPgel methodology, we investigated the prepa-
ration of a supported 1-diazo-2-oxopropylphosphonate re-
agent 8 (Scheme 1). The need to use methanol as solvent
for the reaction9 additionally provided the opportunity to
explore the effect of polymer architecture on the swelling
characteristics of the overall support (Table 1).
Bicyclo[2.2.1]hept-5-en-2-ylmethyl diethyl phosphite (2)
was prepared from commercially available alcohol 1, as
previously reported.10 Reaction of phosphite 2 with iodoac-
etone gave the desired Michaelis-Arbuzov product 4, but
in variable yield (23-46%). A higher overall yield of
phosphonate 4 was obtained by reaction of phosphite 2 with
iodomethane to give phosphonate 3 in 82% yield, followed
by deprotonation with sec-butyllithium and subsequent
addition of ethyl acetate (87% yield). Monomer 4 was readily
polymerized in the presence of cross-linker 5 (10 mol %),
using the second-generation Grubbs catalyst 6 to give
ROMPgel 7 in 96% yield. Mild reaction conditions were
developed for diazo-transfer to the ROMPgel 7 to give
ROMPgel 8 in a loading of 2.86 mmol g-1, and the route
was found to be readily amenable to large-scale synthesis
(38 mmol).
Scheme 1. Preparation of an Ethyl
1-Diazo-2-oxopropylphosphonate ROMPgel.
Applying the optimized reaction conditions previously
reported for solution-phase chemistry9 to ROMPgel 8 resulted
in poor swelling of the polymer, inefficient conversion, and
low yields for the transformation of aldehydes into alkynes.
Consequently, two approaches were investigated to improve
the ROMPgel swelling properties (Table 1). Replacement
(5) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,
1379-1386.
(6) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1 1977,
869-874.
(7) (a) Ohira, S. Synth. Commun. 1989, 19, 561-564. (b) Roth, G. J.;
Liepold, B.; Mu¨ller, S. G.; Bestmann, H. J. Synthesis 2004, 59-62.
(8) Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000, 2, 185-213.
(9) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 6,
521-522.
(10) Barrett, A. G. M.; Cramp, S. M.; Roberts, R. S.; Zecri, F. J. Org.
Lett. 1999, 1, 579-582.
836
Org. Lett., Vol. 6, No. 5, 2004

of cross-linker 5 with the more polar cross-linker 9 (5 mol
%) gave ROMPgel 10 in 98% yield. Diazo-transfer to keto-
phosphonate 10 proceeded to give ROMPgel 11, which
unfortunately failed to swell significantly in methanol and
was much less effective than the previously prepared
ROMPgel 8. The second approach involved the preparation
of a three-component ROMPgel 13 in 75% yield, containing
monomer 4, cross-linker 5, and comonomer 12 (Table 1).
Diazo-transfer to ROMPgel 13 gave reagent 14, which
demonstrated superior swelling properties to the previously
prepared diazo-functionalized ROMPgels 8 and 11. Unfor-
tunately, copolymerization of 5 and 12 was incomplete and
the comonomer 12 was consequently replaced by the pure
exo-isomer 15. With this modification, copolymerization
proceeded in quantitative yield. The resultant polymer
phosphonate was converted into the ROMPgel 17, which was
obtained with a loading of 2.70 mmol g-1 (Table 1). Similar
observations of slower rates of ROMPolymerization of endo
isomers, compared to the corresponding exo isomer, have
been previously reported.11 Reaction of ROMPgel 17 with
a variety of aldehydes proceeded to give the corresponding
terminal alkynes in good yield and high purity12 (Scheme 2,
Table 2. Yields and Purities of Terminal Alkynes 19
Scheme 2. Parallel Synthesis of Terminal Alkynes Using a
ROMPgel-Supported Ethyl 1-Diazo-2-oxopropylphosphonate.
a Yields refer to isolated products. Purities as judged by 1H and 13C NMR
spectra, GC-MS, and microanalysis.
Table 2). No racemization of compounds 19g and 19h was
observed, by comparison of measured optical rotations
against existing literature values,13 which are in agreement
with the earlier studies using diazophosphonate reagents.14
The supported reagent 17 is stable at 0 °C with no significant
loss in activity observed over a 3-week period of storage.
In conclusion, ROMPgel-supported ethyl 1-diazo-2-oxo-
propylphosphonate 17 has been prepared and the immo-
bilized reagent used to convert a variety of aldehydes 18
into their corresponding terminal alkynes 19. The ability to
readily fine-tune the composition of the polymer support
allowed high product yields to be obtained and thus provided
further demonstration of the flexibility and compatibility of
ROMPgels with conventional organic solvents.
(11) (a) Ivin, K. J. In Olefin Metathesis; Academic Press: London, 1983.
(b) Dragutan, V.; Balaban, A. T.; Dimonie, M. In Olefin Metathesis and
Ring Opening Polymerization of Cyclo-Olefins, 2nd ed.; Wiley-Inter-
science: New York, 1985. (c) Castner, K. F.; Calderon, N. J. Mol. Catal.
1982, 15, 47.
Acknowledgment. We thank GlaxoSmithKline for the
generous endowment (to A.G.M.B), Merck KGaA and the
EPSRC for grant support, The Royal Society and the
Wolfson Foundation for a Royal Society-Wolfson Research
Merit Award (to A.G.M.B), and the Wolfson Foundation for
establishing the Wolfson Centre for Organic Chemistry in
Medicinal Science at Imperial College London.
(12) In a typical experiment, degassed (N2) MeOH (5 mL) was added to
the aldehyde 18 (0.1 mL, 0.56 mmol), K2CO3 (0.38 g, 2.79 mmol), and
polymer 17 (0.81 g, 2.19 mmol) under nitrogen, and the reaction mixture
was shaken vigorously at 4 °C. When the transformation was complete (as
monitored by TLC), MeOH was evaporated in vacuo, and the resulting
residue was extracted with hexanes and filtered. The combined filtrates were
concentrated in vacuo to leave the corresponding acetylene 19.
(13) (a) Garvey, D. S.; Wasicak, J. T.; Elliott, R. L.; Lebold, S. A.;
Hettinger, A.-M.; Carrera, G. M.; Lin, N.-H.; He, Y.; Holladay, M. W.;
Anderson, D. J.; Cadman, E. D.; Raszkiewicz, J. L.; Sullivan, J. P.; Arneric,
S. P. J. Med. Chem. 1994, 37, 4455-4463. (b) Hauske, J. R.; Dorff, P.;
Julin, S.; Martinelli, G.; Bussolari, J. Tetrehedron Lett. 1992, 33, 3715-
3716.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(14) (a) Reginato G.; Mordini A.; Messina F.; Degl’Innocenti A.; Poli
G. Tetrahedron 1996, 52, 10985-10996 (b) see ref (9)
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