Angewandte
Communications
Chemie
Table 1: Electrophile scope with linchpin 15.[a]
migrations,[6] the potential for premature collapse of the
tetrahedral intermediate in the polar medium typically
required to trigger the Brook rearrangement (i.e., C-to-O
silyl group migration) would have to be overcome to realize
our goal.
To explore the envisioned new ARC tactic, we first
constructed the prospective linchpins 12–15 (Scheme 3).
Carboxylic acid 12 and ethyl ester 13 were prepared in
analogous fashion, namely by nucleophilic addition of TMS-
Scheme 3. Linchpin synthesis and preliminary studies.
[a] Reaction conditions: i) 15, THF, À788C, then slow addition of nBuLi;
ii) electrophile, HMPA, THF, À788C to À308C; iii) sat. aq. NH4Cl.
dithiane to lithium bromoacetate and ethyl bromoacetate,
respectively.[7] In turn, amide coupling of 12 with the HCl salts
of N,N-dimethylamine and N,O-dimethylhydroxylamine pro-
vided amide linchpins 14 and 15; the latter compound is
a Weinreb amide (Scheme 3).[8] With the first linchpins 12 and
13 in hand, the feasibility of the proposed ARC tactic was
explored in THF at À788C, using n-butyl lithium (nBuLi) as
the nucleophile and benzyl bromide (BnBr) as the electro-
phile; hexamethylphosphoramide (HMPA) was employed to
trigger the Brook rearrangement. Unfortunately, the reaction
sequence resulted in the formation of complex mixtures, with
only minor amounts of the desired product 16 (< 16%).
Pleasingly, however, when 14 and 15 were subjected to the
aforementioned reaction conditions, the desired product 16
could be isolated in good to excellent yield after protic
workup and flash chromatography. The superiority of the
Weinreb amide linchpin 15, relative to congener 14, suggests
that the stabilization of the tetrahedral intermediate imparted
by the N-methoxy moiety, presumably by chelation of lithium,
prevents premature Brook rearrangement and is pivotal to
the success of this ARC tactic.[8]
provide adduct 22 in 71% yield. Finally, when epichlorohy-
drin was employed as the terminating electrophile, epoxide 23
was obtained in good yield, resulting as expected from
nucleophilic attack at the terminal epoxide carbon atom
rather than direct displacement of the chloride.[9]
Next, we explored the nature of the nucleophilic compo-
nent of the ARC reaction, employing benzyl bromide as the
electrophilic species (Table 2). Again, the ARC reactions
proceeded in good yield with alkyl, alkenyl, alkynyl, allyl, and
aryl lithium nucleophiles (entries 1–7). The addition of softer
nucleophiles was also explored (entries 8–10). To achieve
these transformations, greater control over the timing of the
Brook rearrangement was required: Key to success was the
addition of a solution of benzyl bromide in THF to the
tetrahedral intermediate, followed by the slow addition of
a precooled HMPA/THF solution. With this procedure, the
reactions furnished the desired tricomponent adducts in
generally good yields.
Excited by the initial results, we proceeded to analyze the
scope and utility of this new ARC tactic with linchpin 15 and
diverse electrophiles and nucleophiles (Tables 1 and 2).
Pleasingly, the ARC reactions proceeded smoothly in good
yield with methyl iodide and allyl bromide (entries 1 and 2,
Table 1), whereas the yields achieved with homoallylic,
alkynyl, and alkyl bromides were somewhat lower than with
the corresponding iodide congeners (entries 3–5). The reac-
tion with chlorotriethylsilane also proceeded effectively to
To demonstrate the utility of the monoprotected 1,3-
diketone motif that is now readily accessible by this ARC
tactic, we studied the one-pot construction of substituted
pyran and spiroketal scaffolds from structurally simple
components (Scheme 4).[10] Initial attempts at the single-
flask ARC cyclization method entailed use of nBuLi as the
initiating nucleophile with ethylene oxide as the terminating
electrophile; 41 was isolated in good yield after protic workup
and chromatography (entry 1, Table 3). Use of (R)-benzyl
Angew. Chem. Int. Ed. 2016, 55, 232 –235
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