Resin-bound (succinimid-1-yloxycarbonylmethyl)triphenylphosphonium ylide - A synthon for rapid access to diverse heterocycles under microwave heating

Article abstract of DOI:10.1055/s-2008-1032046

The synthesis of a novel and versatile resin-bound (succinimid-1- yloxycarbonylmethyl)triphenylphosphonium ylide is described. The use of this resin to the synthesis of several diverse heterocycles, whilst allowing for ease of workup, is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032046

LETTER
355
Resin-Bound (Succinimid-1-yloxycarbonylmethyl)triphenylphosphonium
Ylide – A Synthon for Rapid Access to Diverse Heterocycles under Microwave
Heating
Resin-Bound
Ylie
Morphochem AG, Gmunder Straße 37-37a, 81379 München, Germany
Fax +49(89)78005555; E-mail: bernd.henkel@morphochem.de
Received 22 October 2007
combination with microwave heating.5 However, despite
the utility of this building block, one drawback observed
is that the liberated triphenylphosphinoxide cannot be eas-
ily separated off from the desired product by common
separation techniques.
Abstract: The synthesis of a novel and versatile resin-bound (suc-
cinimid-1-yloxycarbonylmethyl)triphenylphosphonium ylide is de-
scribed. The use of this resin to the synthesis of several diverse
heterocycles, whilst allowing for ease of workup, is reported.
Key words: Wittig reactions, solid-phase synthesis, heterocycles,
olefination, microwave heating
Herein we report on the investigations performed into the
synthesis and the use of a novel versatile solid-phase-
bound reagent that can lead to the same heterocyclic scaf-
folds as (triphenylphosphoranylidene)ethanone, but
which allows ease of purification as the liberated triphen-
ylphosphinoxide remains on the resin. The idea was to
make a resin containing a N-hydroxysuccinimidylester
that can undergo the same reaction as the ketene in 2. The
synthon was obtained by coupling bromoacetic acid N-hy-
droxysuccinimidyl ester (NHS ester) to polymer-bound
triphenylphosphine6 to yield 3 (Scheme 2), and the ylide 4
can be formed by simple treatment with triethylamine.7
In the synthesis of organic compound libraries there is a
strong demand for building blocks that can serve as com-
mon starting materials to access diverse heterocycles. One
of these building blocks is (triphenylphosphora-
nylidene)ethanone (2) which was first described by Mat-
thews et al.2 They synthesised this by reacting
triphenylphosphine with bromoacetic acid methylester to
give the phosphonium salt 1 (Scheme 1). Addition of base
to this salt led to ylide formation and subsequent elimina-
tion of methanol3 to provide 2.
It was hypothesised that the novel and versatile solid-
phase-bound (succinimid-1-yloxycarbonylmethyl)tri-
phenylphosphonium ylide (4) can be used to introduce a
carbon–carbonyl building block into the synthesis, similar
Several applications using 2 have been reported so far,4
and one in particular we found very interesting which
dealt with the synthesis of diverse heterocycles using 2 in
O
O
–
C
base
P+
P+
C
O
P
Br
+
O
O
Br–
1
2
Scheme 1 Formation of (triphenylphosphoranylidene)ethanone
O
O
O
O
O
O
–
C
H
Et3N
O
P+
N
P
Br
N
+
P+
N
O
O
O
O
O
Br–
4
3
Scheme 2 Preparation of (succinimid-1-yloxycarbonylmethyl)triphenylphosphonium ylide
to that of 2. This would be achieved by a cascade reaction
SYNLETT 2008, No. 3, pp 0355–0358
Advanced online publication: 16.01.2008
x
x.
x
x.
2
0
0
8
consisting of a substitution and a Wittig reaction8
DOI: 10.1055/s-2008-1032046; Art ID: G31607ST
© Georg Thieme Verlag Stuttgart · New York

356
B. Henkel
LETTER
thesising the cytostatic mirabimide,15 can be obtained
from an amino acid ester in one step as well as phenopyr-
rozin-like compounds16 (Figure 1).
O
O
O
–
H2N
MeO
P+
C
H
heat
With the solid-phase-bound ylide 4 in hand, it was decid-
ed to optimise the reaction using the SmithSynthesizerTM
microwave apparatus.17 A test reaction using anthranilic
acid methyl ester with resin-bound 4 to give 4-methoxy-
1H-quinolin-2-one was studied. The reaction conditions
were optimised using various solvents like DCE, DMF,
toluene, xylene, and dioxane (Figure 2), reaction times
from 5–30 minutes (Figure 3), and a range of tempera-
tures from 80–200 °C (Figure 4) being applied. The pro-
gression of the reaction was followed by LC-MS. The
areas of the product peaks (AUC = area under curve, y-
axis) in HPLC were compared, the product was not isolat-
ed. The optimised reaction conditions were eventually
found to be dioxane as solvent at 180 °C for 15 minutes.
The resin remained stable under these conditions. N,N-
Dimethylformamide was not considered as solvent at
higher temperatures due to its tendency to decompose un-
der microwave heating.18
+
N
O
O
O
O
–
P+
C
heat
HO
N
+
H
HN
O
O
OMe
H
N
O
P
O
+
OMe
Using these optimised conditions several other heterocy-
cles were synthesised in good yield (Table 1). After the
reaction was finished, an extremely simple workup was
pursued, filtration of the resin, washing the solid resin
with dioxane, and then evaporation, followed by purifica-
tion by preparative HPLC to give the required products.
This is in contrast to the problematic workup involved
when using 2 in solution.
Scheme 3 Reaction of resin-bound (succinimid-1-yloxycarbonyl-
methyl)triphenylphosphonium ylide with anthranilic acid methylester
to give 4-methoxy-1H-quinolin-2-one
(Scheme 3). This solid-phase-assisted cascade synthesis
is also a new example of a catch-and-release reaction.9
Using the new resin it was envisaged that several medical-
ly relevant heterocycles like the coumarins, which can be
used as antiaggregants10 or anticoagulants,11 or the quino-
lin-2(1H)-ones, which can be used as anticonvulsants,12 as
antimalarial agents,13 or nitric oxide antagonists,14 are
quickly accessible. Special pyrrolidones, useful for syn-
In conclusion it has been shown that a new and versatile
resin-bound (succinimid-1-yloxycarbonylmethyl)tri-
phenylphosphonium ylide (4), under microwave heating,
offers an excellent tool for rapid access to diverse hetero-
O
OH
OH
O
HO
O
O
Cl
N
O
O
O
H
scopoletin10
warfarin11
MDL 104,65312b
O
O
O
HO
O
N
O
N
O
N
O
O
O
N-methylpreskimmianine13
orixalone A14
phenopyrrozin15
O
H2N
O
O
Cl
Cl
O
N
O
Cl
Cl
mirabimide E16
Figure 1 Heterocycles bearing a motif that could be synthesised by using resin-bound ylide 4
Synlett 2008, No. 3, 355–358 © Thieme Stuttgart · New York

LETTER
Resin-Bound Ylide
357
Table 1 Reaction of Different Starting Materials with Resin-Bound
Ylide 4
Starting material
Product
Isolated yield (%)
H
N
NH2
OMe
O
O
69
OMe
H
N
O
65
59
OEt
H2N
OEt
·
HCl
O
Figure 2 Test reactions in different solvents at 120 °C, 10 min; sol-
vent dioxane gave best result
O
O
O
OH
O
Br
HO
70
73
64
O
O
Br
OH
O
O
O
Ot-Bu
Ot-Bu
N
O
N
H
Figure 3 Test reactions in dioxane at 120 °C; the best result was ob-
tained after 15 min, no further increase of product yield was observed
at longer reaction times
O
Me
NH
Me
N
O
49
67
OMe
O
OMe
H
N
O
OMe
O
NH2
Cl
OMe
Cl
References and Notes
(1) New address: Sanofi-Aventis Deutschland GmbH,
Industriepark Höchst, D729, 65926 Frankfurt am Main,
Germany; fax: +49 (69)30549497; email:
Figure 4 Test reactions in dioxane, 15 min at different tempera-
tures; the best result was obtained at 180 °C
Bernd.Henkel@sanofi-aventis.com.
(2) Matthews, C. N.; Birum, G. H. Tetrahedron 1966, 46, 5707.
(3) (a) Bestmann, H. J.; Schmidt, M.; Schobert, R. Synthesis
1988, 49. (b) Isler, O.; Gutmann, H.; Montavon, M.; Rüegg,
R.; Ryser, G.; Zeller, P. Helv. Chim. Acta 1957, 40, 1242.
(c) Bestmann, H. J.; Sandmeier, D. Chem. Ber. 1980, 113,
274. (d) Bestmann, H. J.; Sandmeier, D. DE 2530329, 1975;
Chem. Abstr. 1977, 87, 6188. (e) Matthews, C. N.; Birum,
G. H. US 3459804, 1969; Chem. Abstr. 1969, 71, 815269.
(f) Matthews, C. N.; Birum, G. H. US 3655766, 1972; Chem.
Abstr. 1972, 77, 19803.
cycles. The resulting products could be purified easily,
with the undesirable triphenylphosphinoxide remaining
attached to the resin. The use of this resin to access other
medicinally important heterocycles can be foreseen.
Synlett 2008, No. 3, 355–358 © Thieme Stuttgart · New York

358
B. Henkel
LETTER
(4) (a) Schobert, R.; Müller, S.; Bestmann, H. J. Synlett 1995,
425. (b) Schobert, R.; Löffler, J. J. Chem. Soc., Perkin
Trans. 1 1996, 2799. (c) Schobert, R.; Siegfried, S.;
Nieuwenhuyzen, M.; Millius, W.; Hampel, F. J. Chem. Soc.,
Perkin Trans. 1 2000, 1723. (d) Löffler, J.; Schobert, R.
Synlett 1997, 283. (e) Schobert, R.; Siegfried, S.; Gordon,
G. J. Chem. Soc., Perkin Trans. 1 2001, 2393.
(f) Bestmann, H. J. Angew. Chem., Int. Ed. Engl. 1977, 16,
349; Angew. Chem. 1977, 89, 361.
(5) Westmann, J.; Orrling, K. Comb. Chem. High Throughput
Screening 2002, 7, 571.
H), 5.88 (s, 1 H), 7.13–7.17 (t, 1 H, J = 7.4 Hz), 7.28–7.30
(d, 1 H, J = 8.1 Hz), 7.48–7.52 (t, 1 H, J = 7.5 Hz), 7.75–7.77
(d, 1 H, J = 8.0 Hz), 11.36 (s, 1 H). 13C NMR (100 MHz,
DMSO-d6): d = 56.0, 96.6, 114.4, 115.2, 121.3, 122.1,
130.9, 138.2, 163.1, 163.2.
(9) (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, 3815. (b) Kirschning, A.; Monenschein, H.;
Wittenberg, R. Angew. Chem. Int. Ed. 2001, 40, 650.
(c) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324.
(10) Okada, Y.; Miyauchi, N.; Suzuki, K.; Kobayashi, T.;
Tsutsui, C.; Mayuzum, K.; Nishibe, S.; Okuyama, T. Chem.
Pharm. Bull. 1995, 43, 1385.
(6) Henkel, B. DE 102004014120A1, 2004; Chem. Abstr. 2005,
143, 387168.
(7) Procedure for the Synthesis of Resin-Bound 4
Triphenylphosphino resin (10 g, 15.5 mmol; Polymer
Laboratories) was swollen in 70 mL of abs. toluene and
bromoacetic acid N-hydroxysuccinimidyl ester (7.317 g, 31
mmol) was added. This mixture was agitated for 16 h. The
resin was filtered off and washed three times with toluene,
CH2Cl2, and Et2O each. Finally, the resin was dried under
high vacuum yielding 13.52 g resin-bound (succinimid-1-
yloxycarbonylmethyl)triphenylphosphonium bromide
(95.5%), loading approx. 1.2 mmol/g after weight gain.
The ylide was formed by treatement of the resin with a
mixture of CH2Cl2–Et3N (80 mL, 1:1) for 16 h. The resin
was filtered off and washed twice with CH2Cl2–Et3N (1:1)
and three times with CH2Cl2 and Et2O. The resin was dried
under high vacuum yielding 12.2 g (100%) of 4, loading
approx. 1.1 mmol/g after weight loss.
(11) Bell, R. G.; Sadowski, J. A.; Matschiner, J. T. Biochemistry
1972, 11, 1959.
(12) (a) Kulagowski, J. J.; Baker, R.; Curtis, N. R.; Leeson, P. D.;
Mawer, I. M.; Moseley, A. M.; Ridgill, M. P.; Rowley, M.;
Stansfield, I.; Foster, A. C.; Grimwood, S.; Hill, R. G.;
Kemp, J. A.; Marshall, G. R.; Saywell, K. L.; Tricklebank,
M. D. J. Med. Chem. 1994, 37, 1402. (b) Chapmann, A. G.;
Dürmüller, N.; Harrison, B. L.; Baron, B. M.; Parvez, N.;
Meldrum, B. S. Eur. J. Pharmacol. 1995, 274, 83.
(c) Carling, R. W.; Leeson, P. D.; Moore, K. W.; Moyes, C.
R.; Duncton, M.; Hudson, M. L.; Baker, R.; Foster, A. C.;
Grimwood, S.; Kemp, J. A.; Marshall, G. R.; Tricklebank,
M. D.; Saywell, K. L. J. Med. Chem. 1997, 40, 754.
(13) Christopher, E.; Bedir, E.; Dunbar, C.; Khan, I. A.; Okunji,
C. O.; Schuster, B. M.; Iwu, C. O. Helv. Chim. Acta 2003,
86, 2914.
(8) Synthesis of 4-Methoxy-1H-quinolin-2-one; General
Procedure
(14) Ito, C.; Itoigawa, M.; Furukawa, A.; Hirano, T.; Murata, T.;
Kaneda, N.; Hisada, Y.; Okuda, K.; Furukawa, H. J. Nat.
Prod. 2004, 67, 1800.
Resin-bound 4 (182 mg, 0.2 mmol) was loaded into a Smith
Process glass reaction vial and swollen in abs. dioxane (1
mL). Anthranilic acid methyl ester (0.039 mL, 0.3 mmol)
and a little stirring bar were added. The vial was sealed and
heated for 15 min to 180 °C in the microwave system Smith
Creator. After cooling down the vial was opened and the
resin filtered off. The resin was washed twice with dioxane
and discarded. The solvent was evaporated and the
remainder subjected to preparative HPLC [C18-RP-Phase;
MeOH and AcOH (0.5%), H2O and AcOH (0.5%)]; yield 24
mg (69%). 1H NMR (400 MHz, DMSO-d6): d = 3.92 (s, 3
(15) (a) Huang, P.-Q.; Deng, J. Synlett 2004, 247. (b) Paik, S.;
Carmeli, S.; Cullingham, J.; Moore, R. E.; Patterson, G. M.
L.; Tius, M. A. J. Am. Chem. Soc. 1994, 116, 8116.
(16) Shiomi, K.; Yang, H.; Xu, Q.; Arai, N.; Namiki, M.;
Hayashi, M.; Inokoshi, J.; Takeshima, H.; Masuma, R.;
Komiyama, K.; Omura, S. J. Antibiotics 1995, 48, 1413.
(17) Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250.
(18) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org.
Chem. 2002, 67, 6232.
Synlett 2008, No. 3, 355–358 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.