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(3m–3o), while smooth transformations were obtained for the
para-halo-substituted substrates in 78–85% yields (3i–3l) under
optimized condition. 2,6-Dimethylbenzyl alcohol showed steric
impact on the reactivity (3p, 42%), whereas 2-methyl alcohol
and 1-naphthalenemethanol furnished the products 3e (84%)
and 3q (77%) effectively. 2-Naphthalenemethanol and 4-
biphenylmethanol with extended aromatic systems can also
convert to the corresponding products in attractive yields of
85% for 3r and 83% for 3s. Heteroatom-containing substrates
also operated with slightly lower yields (3t, 74%; 3u, 67%) or
under more severe reaction conditions to generate products
3v–3x in 49–65% yields.
1-(2-naphthyl)ethanol to afford 4s (73%), showing the impact
of the steric effect. Comparing to electron-withdrawing halo
and trifluoromethyl groups, electron-donating groups, such as
methyl and methoxy, facilitate the processes of β-alkylation
(4a–4q). It is noteworthy that substrate containing 2-chloro
substitution led to a lower yield of 4q (40%) than 3-chloro (4n,
73%) or 4-chloro (4j, 79%) substitution. 1-Indanol, 1-ferroceny-
lethanol, and 1-cyclohexylethanol were alkylated by 2a to give
4t, 4u, and 4v in 44%, 65%, and 41% yields, respectively.
Encouraged by these promising results,
a gram-scale
reaction and synthetic application of Vitamin E derivation were
carried out to further demonstrated the synthetic potentials of
this protocol. Firstly, 1.25 g of 3a with 78% yield was delivered
by coupling of 1a with 2a (Scheme 2a). Furthermore, the
Vitamin E derivatives 6 could be synthesized in 70% yield by
this β-alkylation process catalyzed by bis-NHC Mo complex C1.
To better understand the reaction mechanism, control
experiments have been conducted (Scheme 3; for more details
see SI). The smooth transformation upon adding 3 drops Hg to
the reaction mixture [Eq. (1)] implies a homogenous nature of
this Mo catalysis. A radical process could be ruled out by the
observed high yield in the presence of 1.0 eq. of a radical
scavenger, TEMPO [Eq.(2)]. Under the standard condition, the β-
alkylation reaction was performed with 1.0 mmol 1a and
0.5 mmol 2a to generate 3a and 3a* in 71% and 10% yields
[Eq. (3)], respectively. Similar results can also be obtained by the
reaction between acetophenone 1a* and benzyl alcohol 2a in
a molar ratio of 1:2 (Scheme S2). Additionally, the results of
control experiments revealed the vital role of NaOH for the
condensation of acetophenone with benzaldehyde to afford
chalcone 3a**, while the absence of C1 has no obvious effect
on it [Eq. (4)]. With 1a or 2a as the hydrogen source, transfer
hydrogenation of chalcone 3a** to 3a could be achieved in
71% and 41% yields, respectively [Eq. (5)]. Although our
attempts for direct observation of the MoÀ H species by 1H NMR
failed, a considerable concentration of H2 (ca. 18700 ppm) was
detected from the headspace of the vessel during the reaction
by GC analysis [Eq. (6)] (Figure S1–S5, Table S3). These results
imply a BH process involving dehydrogenation, condensation,
and hydrogenation for this reaction.[29]
The applicability of aliphatic primary alcohols has also been
investigated. Under the conditions of higher catalyst (2–
°
5 mol%) and base (1.0 eq.) loadings, temperature (150 C), and
reaction time (12–24 h), the reactions of 2y–2ad with 1a were
conducted to form the target products 3y–3ad in 33–83%
yields, exhibiting decreased activity than benzyl alcohols.
Remarkably, in the case of vinyl-containing substrates, selective
transformations of 4-vinyl benzyl alcohol (2ae) and citronellol
(2af) to the desired products with preservation of the C=C
bond were achieved, highlighting the chemoselectivity of this
protocol.
After successfully varying primary alcohols, structurally
diverse secondary alcohols were also studied (Table 3). The
position of methyl on the phenyl ring has no obvious impact on
the formation of 4a–4c (79%-90%), whereas significant sup-
pression existed in the formation of 4d (29%) with 2,6-dimethyl
groups. For the naphthyl group, a harsher reaction condition
was needed for 1-(1-naphthyl)ethanol to afford 4r (72%) than
Table 3. Scope of Secondary Alcohol.[a]
To gain further mechanistic insight, we performed deute-
rium-labeling and kinetic isotope effect (KIE) experiments
[Eqs. (7–8)]. Similar to previous work,[26c] no incorporation of
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), C1 (0.5 mol%), NaOH
°
(0.5 eq.), toluene (1 mL), at 140 C for 6 h, isolated yield. [b] C1 (2 mol%),
°
NaOH (1.0 eq.), at 140 C for 24 h. [c] C1 (5 mol%), NaOH (1.0 eq.), at
°
150 C for 24 h.
Scheme 2. Gram-scale reaction and synthetic application.
Chem Asian J. 2021, 16, 1–6
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