Organic Letters
Letter
positions of the ligand, 60% ee was obtained (entry 5). When
WingPhos (L6) was employed with anthracenyl groups at R2
positions, a much improved ee (74% ee) was achieved (entry
6). Both the reactivity and enantioselectivity decreased when
DI-BIDIME (L7) was employed, indicating the importance of
the anthracenyl structures for the high enantioselectivity (entry
7). BABIBOP-type ligands21 (L8, L9) were also tested, leading
to moderate enantioselectivities (entries 8−9). Among various
palladium precursors screened, [Pd(C3H5)Cl]2 proved to be
the best in terms of both yield and enantioselectivity (entries
9−12). Solvent screening showed that the enantioselectivity
diminished substantially in dioxane and toluene, albeit with
acceptable yields (entries 12−15). Furthermore, substrates
1a−h with various N-protecting groups were tested. Bulky aryl
sulfonamides such as 2,4,6-(CH3)3C6H2SO2 or 1-NpSO2 led to
diminished ee’s (entries 16−17). To our delight, excellent
results were achieved (99% yield, 90% ee) when 2-NpSO2 was
employed as the N-protecting group (entry 18). The ee was
promoted to 95% by reducing the reaction temperature to 15
°C (entry 19). A further decrease of the reaction temperature
led to an inferior yield and ee (entry 20). Interestingly, a good
isolated yield and enantioselectivity (99% yield, 88% ee) were
achieved when N-Ms protecting groups were employed (entry
21). A more electron-deficient substrate with N-Tf or N-Ns
protecting groups showed no reactivity under similar reaction
conditions (entry 22). A substrate with N-Bn protecting
groups led to a moderate ee (45%) albeit with an excellent
yield (99%). A Boc-protected substrate 1i also provided a good
yield (87%) and a decent ee (87%) (entry 24). It should be
noted that tetrahydroquinoxaline derivatives were formed for
the first time in excellent yields and ee’s by palladium-catalyzed
tandem allylic substitution.
Scheme 2. Mechanistic Investigation
In order to gain mechanistic insight of the reaction, a series
of experiments were performed using Pd-WingPhos (Pd-L6) as
the catalyst. First, both (Z)- and (E)-but-2-ene- dimethyl
bis(carbonate) (2a and 2b) were subjected to the trans-
formation under similar reaction conditions, respectively
(Scheme 2, entries a−b). The fact that both reactions provided
similarly high ee’s indicated that the two reactions were likely
to proceed through the same reaction intermediate. Their
presumed intermediates 4a and 4b after the first allylic
substitution were also prepared and further subjected under
similar reaction conditions (entries c−d). We were surprised
that both reactions were incomplete under similar reaction
conditions, and the formed product 3d was isolated in low ee’s
(20−30%). The vastly different results between entries a−b
and entries c−d raised a question about the true mechanism of
the palladium-catalyzed nucleophilic substitution. Trost and
co-workers reported that the enediol dicarbonates underwent
elimination under reduced conditions to form conjugated
dienes.22 Besides a previously proposed tandem allylic
substitution pathway I which goes through palladium
intermediates H and I, we pondered the possibility of an
alternate mechanism II involving a dicationic diene-bound
palladium species J, which could also undergo two consecutive
nucleophilic attacks to form the product 3d (CCDC
1964498). To determine whether the palladium species J is
formed, stoichiometric amounts of [Pd(C3H5)Cl]2, L6, and 2a
were mixed in THF at rt for 12 h; no change was observed
[Pd(C3H5)Cl]2 (0.5 mol %) and L6 (1 mol %), (E)-buta-
1,3-dien-1-yl methyl carbonate (4c) was formed in an almost
quantitative yield, which was presumably generated through
oxidative addition followed by β-hydride elimination from 2a
(entry e). The formation of 4c excluded the presence of a
palladium species J in the allylic substitution process, further
supporting the credibility of a tandem allylic substitution
pathway. Interestingly, a stoichiometric mixture of Pd2(dba)3,
L6, and (E)-1,4-dichloro-2-butene (2c) led to the formation of
1,3-butadiene in 80% yield along with Pd(L6)Cl2, whose
structure was characterized by X-ray diffraction (CCDC
Further experiments between 1d and 2a or 2b with a
stoichiometric amount of [Pd(C3H5)Cl]2 and L6 revealed no
1
formation of an intermediate 4a or 4b by HNMR. We also
performed the allylic substitution between N-phenylnaphtha-
lene-2-sulfonamide (4d) and 2a at equal mole ratio, and the
substitution product 4a was formed in almost quantitative yield
(entry f). No formation of a monosubstitution product was
observed either at reaction end point or in the middle of the
transformation, which suggested that a continuous coordina-
tion of the palladium catalyst after the first allylic substitution
leads to a facile second allylic substitution. These experiments
well explained the vastly different results between entries a−b
and entries c−d. The relative fast reaction rates in the former
cases could be attributed to the relative facile oxidative
addition of 2a and 2b followed by a tandem substitution
process, while slow reaction rates in the latter cases could be
due to the slow oxidative addition rates of 4a and 4b. The
1
according to H and 31P NMR. No consumption of 2a was
observed when Pd2(dba)3 instead of [Pd(C3H5)Cl]2 was
employed as the precursor. However, when 2a was stirred at 60
°C in THF in the presence of a catalytic amount of
C
Org. Lett. XXXX, XXX, XXX−XXX