the hydride source required to initiate the reaction, and
the introduction of alternative reaction solvents beyond
the water and aqueous buffer4 we originally disclosed. The
extension of the results of these studies for the preparation
of a key series of otherwise inaccessible vinblastine ana-
logues bearing alternative C200 functionalization is detailed.
The substrate scope and optimization of the reaction
parameters were first examined with the hydroazidation of
alkenes.4,7 In part, we focused initially on the azide intro-
duction not only because of their ability to serve as
precursors to amines, but also because of their ability to
serve as groups for photoaffinity or bioconjugation stud-
ies. Sodium azide (NaN3) was found to be the most
effective azide source for this reaction,8 although LiN3
and CsN3 serve as attractive alternatives. Complementary
to its use in water alone,4 solvent mixtures of water (H2O)
with ethanol (EtOH), tetrahydrofuran (THF), or acetoni-
trile (MeCN) also provided good yields of the desired
products. EtOH was an effective cosolvent for polar sub-
strates with hydrogen bond donors, while THF was the
optimal cosolvent when using nonpolar substrates. A
survey of Fe(III) reagents revealed that ferric oxalate9
[Fe2(ox)3 > Fe2(SO4)3 > FeCl3 > Fe(NO3)3 > Fe(acac)3]
performed best in the mixed solvent systems as it did in
aqueous buffer.4 NaBH4 was the most convenient of the
initiating hydride sources (vs NaCNBH3, LiBH4, NaBH-
(OAc)3, BH3) although PhSiH3 also supports the reaction
(>24 h vs 30 min), whereas Bu3SnH was ineffective.
Unactivated terminal alkenes including styrenes, as well
as di- and trisubstituted alkenes participate in the hydro-
azidation reaction effectively (Figure 1). The only sub-
strate class examined that failed to participate is electron-
deficient alkenes (e.g., 1l) that undergo preferential
conjugate reduction. A wide range of substrate functional
groups are tolerated under the reaction conditions includ-
ing unprotected alcohols, basic amines, phenols, free ani-
lines, epoxides, carboxylic acids, and alkyl bromides, and
proximal polar (1d) or halide (1h) groups did not result in
cyclization or intramolecular atom transfer reactions.
Finally, the hydroazidation reaction displayed the char-
acteristic 5:1 axial selective delivery of the azide (1e)
observed in radical reduction reactions.10
Figure 1. Alkene substrate scope. aMethod A conditions: EtOH
as cosolvent, Fe2(ox)3 6H2O (2 equiv). Method B conditions:
3
b
THF as cosolvent, Fe2(ox)3 6H2O (3 equiv). 5 equiv of Fe2-
(ox)3 and 8 equiv of NaN3 were employed.
3
hydroxide, provided the urea in 50% yield (Figure 2).13
Tosyl cyanide14 and TEMPO4 provided their addition
products in 35% and 44% yield, respectively. KSCN and
KOCN have not been widely used as radical traps and may
prove more generally useful. They display an interesting
difference in radical trap regioselectivity with the thiocya-
nate trapping on sulfur, whereas addition to nitrogen is
observed with cyanate. Although not exhaustively exam-
ined, this brief survey represents useful O, S, N, C, and
halide functionalization of an alkene.
Although each of these alkene functionalizations is
stoichiometric in its use of Fe(III), we found that the
oxidation reaction using O2 can be conducted in a catalytic
fashion using phathalocyanineꢀFe(II) (FePc) where O2
serves as both the radical trap and metal oxidant. Thus,
extending the oxidation of styrenes disclosed by Kasuga,15
the FePc-catalyzed(5 mol %) reaction proved general inits
substrate scope, oxidizing a range of alkenes to the corre-
sponding alcohols (Figure 3).
Alternative radical traps were found to be compatible
with the reaction conditions. Potassium thiocyanate,11
air (O2),4 and N-acetylsulfanilyl chloride12 provided
their respective addition product in good yields. Use of
potassium cyanate, followed by workup with ammonium
Complementary to the mechanistic studies conducted
on the oxidation of anhydrovinblastine to vinblastine,4 the
reaction of diethyl diallylmalonate was used to further
probe the mechanism (Scheme 1). In the presence of NaN3,
the cyclized product 4 was observed in a 25% yield, along
with byproduct 5 (32%).16 No product arising from simple
addition to the alkene was observed. Additionally, both
(7) For a Co-catalyzed hydroazidation of alkenes using sulfonyl
azides and silanes, see: (a) Waser, J.; Nambu, H.; Carreira, E. M.
J. Am. Chem. Soc. 2005, 127, 8294. (b) Waser, J.; Gaspar, B.; Nambu,
H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693.
(8) Arylsulfonyl azides were also found to be a competent azide
source.
(9) In our survey, commercial Fe2(ox)3 from Aldrich versus Alfa
Aesar provided higher yields of 1a (88% vs 74%).
(10) Baumberger, F.; Vasella, A. Helv. Chim. Acta 1983, 66, 2210.
(11) Northrup, F. J.; Sears, T. J. J. Chem. Phys. 1990, 93, 2337.
(12) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47,
5758.
(13) (a) Druliner, J. D. Macromolecules 1991, 24, 6079. (b) Kianmehr,
E.; Baghersad, M. H. Adv. Synth. Catal. 2011, 353, 2599.
(14) (a) Barton, D. H. R.; Jaszbere, R.; Jaszberenyi, J. C.; Theodorakis,
E. A. Tetrahedron 1992, 48, 2613. (b) Gaspar, B.; Carreira, E. Angew.
Chem., Int. Ed. 2007, 46, 4519.
(15) (a) Okamoto, T.; Oka, S. J. Org. Chem. 1984, 49, 1589.
(b) Sugimori, T.; Horike, S.-I.; Tsumura, S.; Handa, M.; Kasuga, K.
Inorg. Chem. Acta 1998, 283, 275.
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