2
M.B. Dambatta et al. / Tetrahedron xxx (xxxx) xxx
Scheme 1.
a-C-Alkylation of ketones with secondary alcohols.
Scheme 2. Mechanistic considerations.
Table 1
Optimization of the base-mediated a
-C-alkylation of ketonesa.1
alcohol 2 [12]. In line with these observations, and previous related
investigations [10,11], a plausible reaction mechanism would
initiate with an Oppenauer-type alcohol oxidation followed by a
selective cross-aldol condensation to form an enone intermediate
(Scheme 2B). A subsequent Meerwein-Ponndorf-Verley (MPV)-
type enone reduction would form the observed alkylation product.
With optimized reaction conditions in hand (Table 1, entry 10),
the full scope of the base-mediated a-C-alkylation of ketones with
secondary alcohols was explored (Scheme 3). Fixing pentan-3-ol 2
as the alkylating agent, a selection of aryl methyl ketones could be
employed as the nucleophilic component to access the corre-
sponding alkylated products in high isolated yields (Scheme 3A,
products 3e9, 69% average yield). Within the aryl methyl ketone,
sterically encumbered aryl units containing 2,6-substitution were
required to prevent undesired ketone self-condensation processes.
This requirement was illustrated by the complex mixture of un-
identified products formed when the Ph* group was substituted
with a 1-Np moiety (Scheme 3B). Within the aryl unit, other alkyl
substitution addition to the incorporation of pyridyl, aryl bromide,
and aniline moieties. Furthermore, a symmetrical diketone under-
entry
variation from “standard” conditions
1
2
3
4
5
6
7
8
none
>98
>98
>98
<2
<2
77
17
47
42
91 (84)
13
NaOt-Bu (3 equiv.) instead of KOt-Bu
NaOt-Am (3 equiv.) instead of KOt-Bu
KOH (3 equiv.) instead of KOt-Bu
K2CO3 (3 equiv.) instead of KOt-Bu
2 (4 equiv.)
2 (2 equiv.)
130 ꢀC
9
10
11
reaction time ¼ 8 h
KOt-Bu (1 equiv.)
KOt-Bu (0.1 equiv.)
a
Reactions performed using 0.5 mmol of ketone 1 and bench-grade xylenes.
went bisalkylation to give product
9 in 74% isolated yield.
[1] ¼ 1 M.
b
Yield after 24 h as determined by 1H NMR analysis of the crude reaction mixture
Employing an aryl ethyl ketone as the nucleophile resulted in
complete recovery of starting materials. Fixing ketone 1 as the
nucleophile, a variety of secondary alcohols could be employed as
the alkylating agent (Scheme 3C), accessing the corresponding
alkylated products in high isolated yields (products 10e25, 63%
average yield). A selection of both acyclic and cyclic aliphatic sec-
ondary alcohols were employed, including 4-(t-butyl)cyclohexan-
1-ol, which gave product 13 with 86:14 d.r. and in 92% combined
isolated yield. A selection of 1-arylethanols could also be employed
as the alkylating agent, with a variety of heteroaryls incorporated
into products 22e25 including pyridyl, furanyl and thiophenyl
moieties. Starting materials were recovered when 1-indanol, 1,3-
diphenylpropan-2-ol and diphenylmethanol were employed,
which may be attributed towards increased steric hinderance. An
attempted alkylation using pentane-2,4-diol also resulted in com-
plete recovery of starting materials.
with 1,3,5-trimethylbenzene as the internal standard. Isolated yield given in
parentheses.
equivalent without significant detriment to conversion (entries 10
and 11). Using one equivalent of KOt-Bu, the alkylated product 3
was formed in 91% NMR yield and isolated in 84% yield.
To obtain insight into the reaction mechanism, the a-C-alkyl-
ation of ketone 1 was performed using isopropanol-d8 as the
alkylating agent (Scheme 2A). Analysis of the alkylation product
revealed 46% D, >95% D and 42% D incorporation at the
-positions, respectively. The H/D scrambling at both the
positions result from carbonyl acid-base equilibria. Adventitious
a b-, and
-,
g
a
- and g-
H2O and/or t-BuOH may account for the high % H incorporation at
the
a- and g-positions. The >95% D recovery at the b-position
provided supporting evidence for the MPV-type reduction of an
enone intermediate. Furthermore, during reaction optimization
studies, trace quantities of the secondary alcohol that would be
generated via a MPV-type reduction of ketone 1 was observed,
which supported the initial Oppenauer-type oxidation of secondary
In conclusion, we have developed the first base-mediated
transition metal free
alcohols as the alkylating agent. Ketones undergo selective mono-
-C-alkylation with a variety of aliphatic secondary alcohols and 1-
a-C-alkylation of ketones using secondary
a
Please cite this article as: M.B. Dambatta et al., Transition metal free
doi.org/10.1016/j.tet.2020.131571
a-C-alkylation of ketones using secondary alcohols, Tetrahedron, https://
Dambatta, Mubarak B.
