following N2 evolution.22 The primary imination products,
retaining the azide-derived nitrogen triad, are sometimes
sufficiently stable to permit isolation. As a rule though, these
phosphazides proceed rapidly to the iminophosphorane via
loss of N2. Significantly, phosphazides derived from aryl
azides and triarylphosphines have been effectively trapped
through formation of transition metal complexes (Pd, V, W,
Zr) and are well-known to undergo intramolecular electro-
cyclic reactions affording access to extended heterocyclic
systems.22-25 Isolable phosphazides have been formed from
sterically hindered azides and phosphines or in cases where
phosphorus electron density has been increased.23 Sub-
stituent-dependent decreases in azide NR electron density
also correlate to phosphazide stability.23 Steric bulk, in
particular, is believed to play an important role in abrogating
formation of the betaine necessary for N2 liberation.
is the significantly enhanced stability, attenuated nucleo-
philicity, and greater steric bulk of aryl phosphazides relative
to their alkyl analogues.
Scheme 2
Given this, we propose initial generation of the extended
azaphosphonium ylide 19, the viability of which is supported
by seminal mechanistic work by Temple and Leffler.26 Model
building reveals that the arylamine of 19 is in close proximity
to the carbonyl of 19 via a seven-membered transition state
with the azide-derived triad in the thermodynamically more
stable cis conformation.27 The o-carboalkoxy moiety serves
then to quench the negatively charged NR center, and the
resulting tetrahedral intermediate immediately satisfies charge
on the positively charged phosphorus, thus rendering bicyclic
20. Alternatively, this process can be viewed as an electro-
cyclic closure to 20. The phosphazido oxide 20 is proposed
to decompose in short order via loss of nitrogen and
concomitant installation of the phosphine oxide moiety in a
fashion closely paralleling Molina’s synthesis of carbodi-
imides from R-azidodiphenylacetonitrile and triphenylphos-
phine.28 The resultant 21 is very often, in our hands, a stable
material highly resistant to hydrolysis to 22. That N2
evolution is the final step in this path contrasts sharply with
the mechanism shown in Scheme 1 (and most S-AW
processes), wherein loss of N2 precedes formation of bicyclic
4 (Scheme 1). Such an intermediate, or a closely related one,
is supported by 31P NMR data,8 which was unattainable in
our experiments due to mechanistic independence from a
hydrolytic step.29 Thus, mechanistic and functional differ-
ences of Staudinger ligations with alkyl versus aryl azides
appear to be quite profound. At the heart of this difference
In summary, we demonstrate here the application of a
Staudinger reaction in obtaining ligated materials from aryl
azides. More importantly, the principal product that results
from these ligations bears a relatively stable imidate linkage.
The preference of aryl azides to give rise to imidate over
amide Staudinger ligation products is likely a reflection of
steric and electronic differences between the two types of
azides. Modulation of these differences is expected to impact
product profiles and must clearly be considered in the design
of new abiotic coupling reagents. Studies detailed herein
suggest the importance of simple esterification of com-
mercially available triarylphosphines en route to a simplified
and more broadly accessible Staudinger ligation scenario for
use in chemical biology.
Acknowledgment. We thank Professors Ron Raines
(UW, Departments of Chemistry & Biochemistry,), Laura
Kiessling (UW, Departments of Chemistry & Biochemistry),
and Jon Thorson (UW, School of Pharmacy) for very helpful
discussions and insightful comments, Mr. Gary Giradaukus
for technical assistance, the American Foundation for
Pharmaceutical Education (AFPE) and Burroughs-Wellcome
Trust Fund for a New Investigator in Pharmacy Award
(administered by American Association of Colleges of
Pharmacy), and University of Wisconsin Graduate School
and School of Pharmacy for generous startup funding.
(20) Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281.
(21) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003,
125, 8112.
(22) Cadierno, V.; Zablocka, M.; Donnadieu, B.; Igau, A.; Majoral, J.-
P. Skowronska, A. Chem. Eur. J. 2000, 6, 345.
(23) Velasco, M. D.; Molina, P.; Fresneda, P. M.; Sanz, M. A.,
Tetrahedron 2000, 56, 4079.
(24) Molina, P.; Arques, A.; Vinader, M. V. Tetrahedron Lett. 1989,
30, 6237.
(25) Molina, P.; Arques, A.; Cartagena, I.; Obon, R. Tetrahedron Lett.
1991, 32, 2521.
Supporting Information Available: Experimental pro-
cedures and accompanying characterization for all new
materials and representative HPLC traces for reactions
involving phosphine 6a, 7, and related substances highlighted
in the text. This material is available free of charge via the
(26) Leffler, J. E.; Temple, R. D. J. Am. Chem. Soc. 1967, 89, 5235
(27) Widauer, C.; Grutzmacher, H.; Shevchenko, I.; Gramlich, V. Eur.
J. Inorg. Chem. 1999, 1659.
(28) Molina, P.; Lopez-Leonardo, C.; Llamas-Botia, J.; Foces-Foces, C.;
Fernandez-Castano, C. Tetrahedron 1996, 52, 9629.
(29) As initially ascertained by HPLC-MS experiments, which showed
that use of 18OH2 during ligation/coupling of 6a to 7 did not lead to
detectable 18O incorporation into 9a. This result was independently supported
by 31P NMR experiments in which trace amounts of H2O (as a component
of THF-d8) did not get consumed during the coupling of 6b and 7.
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