Organic Letters
Letter
c
primary alcohols to access β-alkylated secondary alcohol
products under dehydrogenative conditions.14 Recently,
notable progress has been made in the development of
homogeneous catalysts used for the Guerbet-type reactions.15
Notably, the first enantioselective Guerbet reaction at room
temperature has been achieved using a commercially available
chiral ruthenium complex developed by Zhao and co-
workers.15f
Table 1. Optimization Studies
Lang and co-workers have studied the homogeneous Ni(II)
N-heterocycle thiolate cluster mediated coupling of secondary
and primary alcohols to yield α,β-unsaturated ketones, α-
alkylated ketones, and β-alkylated secondary alcohols by tuning
the reaction conditions.16 However, this hexanuclear nickel
thiolate cluster catalyzed cross-coupling reaction of alcohols
requires high catalyst loading, multistep synthesis of [Ni-
(dmpymt)2]6 cluster, and limited substrate scope. Thus, the
development of a simple, elegant catalytic system for C−C
bond formation via the Guerbet type strategy is highly
desirable and demanding in contemporary science. Herein,
we have reported the selective β-alkylation of secondary
alcohols with primary alcohols, using a commercially available,
inexpensive NiBr2/TMEDA as an efficient catalytic system.
Interestingly, more challenging substrate conversions were
achieved under benign conditions using primary alcohols as
potential alkylating agents with various secondary alcohols. A
broad range of substrates including aromatic, cyclic, acyclic,
and aliphatic alcohols was well tolerated. Gratifyingly, the
double C-alkylation of cyclopentanol with various alcohols was
also demonstrated.
For the nickel-catalyzed dehydrogenative C-alkylation of
secondary alcohols with primary alcohols, we have chosen 1-
phenyl ethanol (1a) and benzyl alcohol (2a) as the benchmark
substrates. Initially, a model reaction was performed using
NiBr2 (5 mol %) as nickel source, N,N,N′,N′-tetramethylethy-
lenediamine (TMEDA, 5 mol %) as a ligand, and KOtBu (1
equiv) as a base in toluene solvent at 130 °C for 18 h (Table 1,
entry1). To our delight, the β-alkylated product 3a was
obtained in 72% of isolated yield. It was found that n-octane
could be the optimal solvent achieving the desired product 3a
in excellent yield with selectivity (Table 1, entry 2). Under
identical conditions, the effect of various bases such as KOH,
LiOtBu, NaOtBu, NaOH, LiOH·H2O, and K2CO3 was
examined (Table 1, entries 3−8). Notably, KOH was found
to be efficient and gave the desired product 3a in excellent
yield (Table 1, entry 3). The variation of solvent indicated that
the reaction proceeded efficiently in n-octane (Table 1, entries
1,3 and 9−11).
Other nickel catalysts were not effective for the present
catalytic transformation and yielded the product 3a in
moderate yields (Table1, entries 3 and 12−15). Also, attempts
to decrease the mole percentage of base ended with low yields
of the desired product 3a. Next, we have examined the effect of
various commercially available nitrogen-based bidentate
ligands (L1−L6) (Table 1, entries 19−23). Gratifyingly, the
ligand L1 was found to be more effective for this reaction
(Table1, entry 3).
a
1
Yield calculated by H NMR using dibromomethane as an internal
b
c
standard. Isolated yield. Reaction conditions: 1a (0.5 mmol), 2a
(0.5 mmol), [Ni] source (5 mol %), Ligand (L1−L6) (5 mol %), base
(0.5 mmol), and 1 mL of solvent heated in an oil-bath for 18 h.
With the optimized reaction conditions in hand, we next
explored the applicability of the present nickel catalysis for the
β-alkylation of secondary alcohols using diverse primary
alcohols as an alkylating agent. At first, the scope of primary
alcohols with secondary alcohols under standard reaction
conditions was investigated (Table 2). As shown in Table 2,
the electron-donating substituents such as methyl, ethyl,
isopropyl, t-butyl, methoxy, and thioether groups containing
benzyl alcohols afforded good to excellent yields of the β-
alkylated product (products 3b−3l in 74−87% isolated yields).
Notably, halide substituted benzyl alcohols resulted in the
products 3m−3o in 66−79% of isolated yields. In particular, a
fused aromatic compound, 1-naphthyl methanol, produced the
corresponding product 3p in 71% yield under the optimized
reaction conditions. Moreover, aliphatic alcohols such as 1-
hexanol and 1-pentanol resulted in the corresponding products
3q in 75%, and 3r in 72% of isolated yields, respectively.
Subsequently, we have explored the scope of secondary
alcohol for the selective β-alkylation reaction using 4-methoxy
benzyl alcohol (2e) as the benchmark substrate (Table 3).
Pleasingly, the dehydrogenative C−C coupling reactions
proceeded smoothly for a variety of secondary alcohols with
electron-neutral, electron-deficient, and electron-rich substitu-
ents led to the corresponding β-alkylated product in good to
excellent yields. Under the optimized reaction conditions, the
A control experiment in the absence of a base, ligand, as well
as nickel catalyst led to no product formation (Table 1, entries
16−18). These results confirmed that the combination of the
base, ligand, and nickel catalyst is necessary to access the
desired β-alkylated alcohols. By lowering the reaction temper-
ature from 130 to 100 °C, the yield of the product 3a was
reduced to 70% (Table 1, entries 3 and 24−25).
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Org. Lett. 2021, 23, 3320−3325
Babu, Reshma
