Ketenes in soluble polymer bound synthesis: Preparation of succinamides and 4-pyridones

Full text of DOI:10.1021/jo981714j

8636
J . Org. Chem. 1998, 63, 8636-8637
Ta ble 1. Yield a n d P u r ity of 4a -h
Keten es in Solu ble P olym er Bou n d
Syn th esis: P r ep a r a tion of Su ccin a m id es a n d
4-P yr id on es
compd
R1
R2
yield (%)
purity (%)
4a
4b
4c
4d
4e
4f
PhCH2
n-Bu
PhCHCH3
(CH2)5
(CH2CH2)2O
Ph
4-BrC6H4
3-AcC6H4
H
H
H
30
66
44
38
53
71
59
62
97
84
99
88
90
99
99
98
Adel Rafai Far and Thomas T. Tidwell*
Department of Chemistry, University of Toronto, Toronto,
Ontario M5S 3H6, Canada
H
H
H
4g
4h
Received August 24, 1998
Ketenes are versatile reactive intermediates,1 but despite
the great current interest in synthesis using polymer bound
reagents2 and reports of cumulenes attached to polymer
supports for use as reactive reagents, including carbodi-
imides,3a-c isocyanates,3d diazoalkanes,3e and isothio-
cyanates,3f,g ketenes have received little attention in such
reactions. In several instances ketenes4a-d or metal-com-
plexed ketenes4e have reacted with polymer-bound reagents,
and a cyclobutenedione-derived reagent attached to Wang
resin has been shown to have many synthetic applications
via ketene formation, including the preparation of quinone
precursors (eq 1).4f The highly variegated reactivity of
ketenes makes them attractive candidates for polymer bound
reactions, and we now report two different applications of
this approach, both utilizing poly(ethylene glycol) supports.2a
reported ketene bound to a PEG support.6 The 1H NMR
spectrum showed the formation of 2 (R ) CH3OPEG) was
complete, although there was evidently some desilylation
adjacent to the ester function.
Reaction of 2 (R ) CH3OPEG) with aliphatic primary and
secondary amines to give amide 3 was quite rapid, while
reaction with anilines took 3 days for completion. The 1H
NMR spectra showed amide formation was complete, but
partial desilylation had occurred, and this was carried to
completion by treatment with tetrabutylammonium fluoride
(TBAF). Cleavage of the succinamide from the polymer with
n-BuNH2 gave the N-substituted N′-n-butyl 1,4-butanamides
4,7a which were obtained by simple filtration through silica
gel, with purities assessed by HPLC and 1H NMR (Table
1).
We have previously shown that the long-lived bisketene
1 is efficiently converted to ketenyl esters 25a,b and more
recently have shown these may be converted to ester amides
3 (eq 2).5c To prepare a polymer bound ketene, monomethyl
poly(ethylene glycol) ether (MPEGOH) with an average MW
of 5000 g mol-1 was reacted with 1 and Et3N, and the
polymer was precipitated with Et2O and shown to contain
the ketene by the IR band at 2086 cm-1. This is the first
Desilylation and cleavage of 3 with CH3OH catalyzed by
KCN8a gave ester amides 5 with the N,N-disubstituted
(1) (a) Ketenes; Tidwell, T. T., Ed.; Wiley: New York, 1995. (b) Allen, A.
D.; Ma, J .; McAllister, M. A.; Tidwell, T. T.; Zhao, D.-c. Acc. Chem. Res.
1995, 28, 265-271. (c) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273-279.
(2) (a) Gravert, D. J .; J anda, K. D. Chem. Rev. 1997, 97, 489-510. (b)
Fru¨chtel, J . S.; J ung, G. Angew Chem., Int. Ed. Engl. 1996, 35, 17-42. (c)
Hermkens, P. H. H.; Ottenheijm, H. C. J .; Rees, D. C. Tetrahedron 1997,
53, 5643-5678.
(3) (a) Adamczyk, M.; Fishpaugh, J . R.; Mattingly, P. G. Tetrahedron
Lett. 1995, 36, 8345-8346. (b) Chezal, J . M.; Delmas, G.; Mavel, S.;
Elakmaoui, H.; Me´tin, J .; Diez, A.; Blache, Y.; Gueiffier, A.; Rubiralta, M.;
Teulade, J . C.; Chavignon, O. J . Org. Chem. 1997, 62, 4085-4087. (c)
Weinshenker, N. M.; Shen, C. M.; Wong, J . Y. Organic Syntheses; Wiley:
New York, 1988; Coll. Vol. VI, pp 951-954. (d) Scialdone, M. A. Tetrahedron
Lett. 1996, 37, 8141-8144. (e) Chapman, P. H.; Walker, D. J . Chem. Soc.,
Chem. Commun. 1975, 690-691. (f) Dowling, L. M.; Stark, G. R. Biochem-
istry 1969, 8, 4728-4734. (g) Stephensen, H.; Zaragoza, F. J . Org. Chem.
1997, 62, 6096-6097.
(4) (a) Pei, Y.; Houghten, R. A.; Kiely, J . S. Tetrahedron Lett. 1997, 38,
3349-3352. (b) Ruhland, B.; Bhandari, A.; Gordon, E. M.; Gallop, M. A. J .
Am. Chem. Soc. 1996, 118, 253-254. (c) Ruhland, B.; Bombrun, A.; Gallop,
M. A. J . Org. Chem. 1997, 62, 7820-7826. (d) Molteni, V.; Annunziata, R.;
Cinquini, M.; Cozzi, F.; Benaglia, M. Tetrahedron Lett. 1998, 39, 1257-
1260. (e) Pulley, S. R.; Hegedus, L. S. J . Am. Chem. Soc. 1993, 115, 9037-
9047. (f) Tempest, P. A.; Armstrong, R. W. J . Am. Chem. Soc. 1997, 119,
7607-7608.
amides, while the monosubstituted amides gave succinim-
(6) For a polystyrene bound persistent ketene see: Liu, R., Ph.D. Thesis,
University of Toronto, 1996.
(7) (a) These products were isolated and their own purity assessed by
their 1H NMR spectra, and new compounds were further characterized by
13C NMR, IR, EIMS, and HRMS. (b) These products were isolated; their
purity was assessed by their 1H NMR spectra, and they were further
characterized by IR and EIMS.
(8) (a) Zhu, J .; Hegedus, L. S. J . Org. Chem. 1995, 60, 5831-5837. (b)
Sato, M.; Ogasawara, H.; Kato, K.; Sakai, M.; Kato, T. Chem. Pharm. Bull.
1983, 31, 4300-4305. (c) Look, G. C.; Murphy, M. M.; Campbell, D. A.;
Gallop, M. A. Tetrahedron Lett. 1995, 36, 2937-2940. (d) Zaragoza, F.;
Petersen, S. V. Tetrahedron 1996, 52, 10823-10826.
(5) (a) Zhao, D.-c.; Allen, A. D.; Tidwell, T. T. J . Am. Chem. Soc. 1993,
115, 10097-10103. (b) Egle, I.; Lai, W. Y.; Moore, P. A.; Renton, P.; Tidwell,
T. T.; Zhao, D.-c. J . Org. Chem. 1997, 62, 18-25. (c) Allen, A. D.; Ma, J .;
Moore, P. A.; Missiha, S.; Tidwell, T. T. Manuscript in preparation.
10.1021/jo981714j CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/03/1998

Communications
J . Org. Chem., Vol. 63, No. 24, 1998 8637
Sch em e 1
ides 6, with purities of 89-99% for 5d ,e, 6a ,f-h and 66%
for 6c as assessed by HPLC (eq 3).7a
A second approach utilized the thermolysis of dioxinone
7a to form acetylketene (8a ) (eq 4)8b for use in cycloaddition
reactions with polymer bound enamines. As shown in
Scheme 1 7a was also used for functionalization of MPE-
GOH, which was transformed to acetoacetate 9 by reaction
with 7a in refluxing toluene, and reaction8c,d with amines
using trimethyl orthoformate gave enamines 10. Reaction
with 7a in refluxing toluene gave the bound pyridones 11.
These were cleaved to the free pyridones 12 using KCN-
catalyzed transesterification with CH3OH, and the MPEG
was removed by filtration through silica gel giving the
products in 91-98% purity as assessed by HPLC after
evaporation of the solvent.7b
reaction of acetylketene 8a with polymer bound enamines
have been demonstrated.
These procedures proved to be sensitive to the substitution
pattern. Thus an amine with a secondary alkyl group
(PhCHNH2CH3) gave the enamine 10, but this did not react
with 7a , and acylketene precursors 7b-d gave mixtures of
products from which pyridones were not isolated.
Ack n ow led gm en t. Financial support by the Natural
Sciences and Engineering Research Council of Canada is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and NMR spectra (32 pages).
In summary, the preparation and utilization of a polymer
bound ketene 3 and the preparation of 4-pyridones through
J O981714J