Organic Letters
Letter
could undergo oxidation and subsequent β-elimination to build
conjugated dienes. To our best knowledge, a method targeting
privileged 1,3-dienes through selective addition of carbon-
centered radicals to allenes has never been disclosed, despite
their versatile applications in organic synthesis.12
Table 1. Evaluation of Reaction Conditions for Cu-
Catalyzed Tertiary Alkylation of β-Allenyl Silane
a
1,3-Dicarbonyl compounds have been recognized by many
research groups including us as the sources of functionalized
sp3 carbon-centered radicals via single electron oxidation,13
and recently, our laboratory has documented their use in the
tertiary alkylation of alkenes and alkynes.14 Features of note in
our protocols include the following: (a) efficient generation of
tertiary carbon-centered radicals from aliphatic C−H bonds,15
instead of prefunctionalized substrates, such as halides,
alcohols, carboxylic acids, etc.;16 (b) incorporation of
functionalized alkyl moieties holding the options for
derivatizations; (c) sustainable catalytic systems (using Cu or
Fe) without the need for expensive ligand. Because of the
ubiquitous nature and high importance of conjugated dienes,
we wonder whether this principle could be engaged in radical-
mediated functionalization of reactive allenes to produce 1,3-
dienes. Described herein are the discovery, exploration, and
application of an unprecedented copper-catalyzed oxidative
coupling of allenes with tertiary C−H bonds (Scheme 1c). The
protocol gives rise to the regio- and chemoselective formation
of highly functionalized 1,3-dienes, thus leaving ample room
for further synthetic manipulations.
b
entry
copper salt
x
t (°C)
yield (%)
1
2
3
4
5
6
CuBr2
CuCl2
Cu(OAc)2
CuBr
20
20
20
20
20
20
20
20
20
20
20
10
40
50
40
40
40
70
70
70
70
70
70
70
70
80
60
50
60
60
60
60
60
60
44
18
trace
28
42
trace
38
37
19
47
13
39
54
52
31
68
70
CuI
CuCN
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
c
7
d
8
9
10
11
12
13
14
e
15
16
f
f g
17 ,
a
Unless otherwise noted, all reactions were conducted with 1a (0.15
mmol), 2a (0.225 mmol), copper salt (20 mol %), and oxidant (0.3
mmol) in DMSO (1.5 mL) under N2 for 12 h. Isolated yield. PCy3
(20 mol %) was added. 2,2-Bipyridyl (20 mol %) was added.
Cy2NH (0.3 mmol) was added. The reaction was performed using
To assess the feasibility of our expected transformation, we
synthesized a set of allene substrates affiliated with different α-
alkyl substituents, and tested their reactivity (Scheme 2). By
b
c
d
e
f
g
1a (0.21 mmol) and 2a (0.15 mmol). DTBP (3 equiv) was used.
Scheme 2. Reaction Discovery
conducted. A dramatically reduced yield of 3aa was observed
at the elevated temperature (80 °C), which was ascribed to the
substantial decomposition of 1a (entry 9). The minimum
appropriate temperature was ascertained to be 60 °C, at which
point 3aa was obtained in an undiminished yield (entries 10
and 11). Increasing the amount of CuBr2 resulted in an
enhancement to the reactivity (entries 12−14). The addition
of Cy2NH as base, which usually played a beneficial role in the
β-elimination process, proved to be deleterious to the reaction
at this time (entry 15). Employing 1a in an excess of
stoichiometry (1.4 equiv) with 2a as a limiting reagent afforded
3aa in 68% yield (entry 16), which was further improved to
70% upon an increase of DTBP loading (entry 17). An
additional survey of oxidant and solvent choices indicated that
The established optimal conditions stimulated us to explore
the scope and limitation of various β-allenyl silanes with 2a as
the coupling partner. A satisfactory yield of 3aa (71%) was
maintained while enlarging the reaction to a 1 mmol scale. As
shown in Scheme 3, a wide range of allenes bearing diverse
substituents on the phenyl ring could be converted to
functionalized 1,3-dienes in moderate to good yields under
simple copper catalysis (3ba−3la). Synthetically useful func-
tional groups, such as halides (3ea, 3ja, and 3ka), nitrile (3fa),
trifluoromethyl (3ga), nitro (3ha), and ester (3ia), were well
tolerated. Substitution patterns with electronic differentiation
had an inapparent effect on the efficiency in most cases.
However, decorating sterically encumbered substituents (F
and Me) on the ortho position of the phenyl ring caused a drop
in reaction rate and by means of raising the temperature, the
corresponding products 3ka and 3la could be furnished in 61%
employing commercial diethyl methylmalonate (2a) as an alkyl
radical precursor, the coupling product 3aa was produced in
20% yield from α-methyl allene (1a′) isomerization17 by using
CuBr2 as the catalyst and di-tert-butyl peroxide (DTBP) as the
oxidant. Replacement of the methyl group at the α position of
allene with carbinol carbonate (1a″) led to no conversion. The
negative outcome implied that nucleophilic allenylation of
malonate might not be involved in this reaction.18 To our
delight, exposure of allenylmethylsilane (1a) to the identical
conditions gave a 44% yield of 3aa. It is known that β-allenyl
silanes often act as versatile nucleophiles which tend to attack
carbonyls, iminiums, or other reactive electrophilic agents via
an SE2′ pathway.19 This newly developed methodology
unlocks the potential utility of such silicon-based carbon π-
systems for the installation of 1,3-diene motifs in cross-
nucleophile coupling reactions.20
Once determining the β-allenyl silane 1a as the model
substrate, we centered on evaluating the reaction parameters
with low-cost copper salts. Through extensive screening of
copper salts with different counterions and oxidant states
(Table 1, entries 1−6), it was found that CuBr2 showed the
best performance. Extra addition of phosphine (entry 7) or
nitrogen (entry 8) ligands did not improve the conversion. The
reaction appeared to be sensitive to the temperature
6042
Org. Lett. 2021, 23, 6041−6045