synthesis. Ideally, the reaction would produce an amide bond
between two coupling partners without an intervening
triarylphosphine oxide group. Here we report the first
example of such a “traceless” Staudinger ligation.
Scheme 4. Synthesis of Phosphines
The phosphines we designed for this purpose incorporate
two key elements (Scheme 2). First, the acyl component
Scheme 2. Design of a Phosphine Reagent for the Selective
Formation of Amides from Azides
destined for the amide bond is attached to an aryl ring by a
cleavable linkage. The nucleophilic nitrogen atom of the aza-
ylide attacks the carbonyl group, displacing the cleavable
linkage and attached phosphonium group. Hydrolysis of the
rearranged adduct produces an amide bond and liberates a
phosphine oxide. Second, at least two aromatic phosphine
substituents were included to impart stability toward oxida-
tion under ambient conditions.
compound 4. In each case, intramolecular transfer of the
acetyl group from the phosphine to an azide-bearing com-
pound would indicate a successful ligation reaction.
Compound 1 (50 mM) was reacted with an azidonucleo-
side9 (9, 50 mM) in wet THF, and the reaction was monitored
by reversed-phase HPLC over a 24-h period (Scheme 5).10
The azidonucleoside was selected to demonstrate a modicum
of functional group compatibility, since the intramolecular
cyclization obviates the need for protection of coexisting
functional groups.11 We speculated that the aza-ylide inter-
mediate [10] would share key similarities with that generated
during the original Staudinger ligation (Scheme 1), i.e.,
intramolecular reaction via a five-membered ring transition
state and an alkoxy anion leaving group. However, the only
products observed were those of aza-ylide hydrolysis,
compounds 11 and 12. The traceless Staudinger ligation
products 13 and 14 were not observed.12 We concluded that
the flexibility of the methylene bridge in 10 sufficiently
reduced the rate of cyclization such that the hydrolysis
reaction pathway predominated.
Four suitable phosphines (1-4, Scheme 3) are synthesized
to test the traceless Staudinger ligation. Compound 1 was
Scheme 3. Phosphines Designed To Test the Traceless
Staudinger Ligation
Phosphine 2 introduces conformational rigidity into the
aza-ylide intermediate, similar to the phosphine depicted in
Scheme 1, although the intramolecular reaction now must
proceed via a six-membered ring transition state. When 2
was reacted with azide 9 (both reagents at 50 mM) in wet
THF, only the desired Staudinger ligation products were
observed (Scheme 6a). There was no evidence by HPLC
prepared by reaction of diphenylphosphine with paraform-
aldehyde to give the known compound 5,5 followed by
acetylation (Scheme 4a). Compound 2 was synthesized by
Pd-mediated coupling of diphenylphosphine with 2-iodophe-
nol to afford the known compound 6,6 which was then
acetylated (Scheme 4b). Imidazole was transformed to
imidazole phosphine 77 (Scheme 4c), which was acetylated
to yield compound 3. Finally, ortholithiation of thiophenol
followed by reaction with chlorodiphenylphosphine yielded
intermediate 88 (Scheme 4d), which was acetylated to provide
(7) Curtis, N. J.; Brown, R. S. J. Org. Chem. 1980, 45, 4038.
(8) Figuly, G. D.; Loop, C. K.; Martin, J. C. J. Am. Chem. Soc. 1989,
111, 654.
(9) Mag, M.; Engels, J. W. Nucleosides Nucleotides 1988, 7, 725.
(10) CH3CN/H2O gradient (20-70% CH3CN over 40 min).
(11) (a) Mizuno, M.; Haneda, K.; Iguchi, R.; Muramoto, I.; Kawakami,
T.; Aimoto, S.; Yamamoto, K.; Inazu, T. J. Am. Chem. Soc. 1999, 121,
284. (b) Urpi, F.; Vilarrasa, J. Tetrahedron Lett. 1986, 27, 4623.
(12) All products were purified by HPLC and analyzed by NMR and
mass spectrometry.
(5) Slany, M.; Caminade, A. M.; Majoral, J. P. Tetrahedron Lett. 1996,
37, 9053.
(6) Herd, O.; Hessler, A.; Hingst, M.; Machnitzki, P.; Tepper, M.; Stelzer,
O. Catal. Today 1998, 42, 413.
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Org. Lett., Vol. 2, No. 14, 2000