Organic Letters
Letter
Information for full details of screen). Reaction of alkene 7
(1.0 equiv), peroxide 6 (1.8 equiv), and saccharin 10 (2.0
equiv) in chloroform at 40 °C for 24 h gave the anti-
oxyaminated product 11 (30%) (Scheme 2). Saccharin 10 is an
Table 1. Optimization of Nitrogen Nucleophile
Scheme 2. Alkene Oxyamination in the Presence of
Saccharin
ambident nucleophile which can react through either its
nitrogen or oxygen atom.17 Along with the oxyaminated
product 11 the anti-dioxygenated coproduct 12 was also
isolated from the reaction mixture in 20% yield. The structures
of both 11 and 12 were confirmed by single-crystal X-ray
details). In contrast to the related intramolecular oxyamination
procedure,2b the product isolated has undergone decarbox-
ylation. It is proposed that the low nucleophilicity of the amine
nucleophile allows for decaboxylation of the initial adduct16 to
give 8 prior to trapping with saccharin. We believed synthesis
of 11 represented a simple and effective anti-oxyamination
which proceeded under mild conditions and warranted further
investigation.
We sought to understand the ambident reactivity of
saccharin 10 to improve the selectivity for N-alkylation over
O-alkylation. Literature reports suggest the reactivity of
ambident nucleophiles can be altered through changes in
solvent and temperature;18 however, despite extensive
investigation we were unable to significantly alter the ratio of
11 and 12 obtained. We therefore turned our attention to
modifying the structure of saccharin 10. Seven acyl
sulfonamide derivatives 13−19 were prepared by altering
both the steric and electronic environments of the nitrogen
atom, which were then reacted with stilbene 7 in the presence
of malonoyl peroxide 6 (CHCl3, 40 °C, 24 h) (Table 1). N-
(Methylsulfonyl)acetamide 13 represents the simplest nucle-
ophile to contain the acyl sulfonamide moiety and was found
to produce the oxyaminated product 20A and dioxygenated
coproduct 20B in a combined yield of 38% as a 1:1 mixture
(entry 1). Nucleophiles 14, 15, and 16 were prepared to study
the influence of the steric environment around the
heteroatoms on the transformation. Under the reaction
conditions examined, all three examples were selective toward
O-alkylation, resulting in the anti-dioxygenated products 21B−
23B (entries 2−4; 22−60%). The added steric bulk clearly
shielded the nitrogen atom, leading to the observed O-
selectivity. We therefore altered the electronic environment of
the nitrogen nucleophile by preparing the N-sulfonyl
carbamates 17−19. Under standard reaction conditions, all
three nucleophiles were N-selective, providing the anti-
oxyaminated products 24A−26A (entries 5−7; 39−49%).
This remarkable switch in selectivity by changing the steric or
electronic environment of the nitrogen nucleophile represents
a powerful observation that presents an intriguing opportunity
for further investigation.
O-tert-Butyl-N-tosylcarbamate 18 was selected as the
preferred nucleophile. Further optimization of the reaction
conditions failed to improve the yield of oxyamination product
25A beyond 49%. However, the conversion of nucleophile 18
to oxyaminated product 25A was an efficient process.
Therefore, in examining the substrate scope of the reaction
we employed the conditions outlined in Scheme 3 (entry 1,
97%), using the nitrogen nucleophile 18 as the limiting
reagent.
Examination of a series of stilbene derivatives showed the
reaction to proceed efficiently at room temperature with
complete anti-diastereoselectivity (Scheme 3). The reaction
was tolerant of substitution in the 2-, 3-, and 4-positions of the
stilbene substrate (entries 2−4, 62−92%). In addition, fluorine
(entry 6, 71%), chlorine (entry 7, 90%), and bromine (entry 8,
85%) substituents on the aromatic ring also led to the expected
products, providing useful handles for further synthetic
manipulation. Alternative N- and O-substituted carbamates
B
Org. Lett. XXXX, XXX, XXX−XXX
Curle, Jonathan M.
