Angewandte
Research Articles
Chemie
Table 1: Optimization of the reaction conditions.[a]
aminoquinoline directing group. This approach enabled the
3
À
cross-coupling of terminal alkynes with primary C(sp ) H
bonds.[16] Despite significant effort, the cross-coupling of
3
À
tertiary C(sp ) H bonds with terminal alkynes remains
largely underdeveloped.
Entry
Variation from the standard conditions
Yield [%][b]
Recently, our laboratory described a copper-catalyzed
cross-coupling of alkenes with 1,3-dicarbonyl compounds,[17]
1
2
3
4
5
6
7
8
none
no FeCl3
no Ag2CO3
no K3PO4
Lewis acids instead of FeCl3
Ag2O as an oxidant
AgOAc as an oxidant
AgNO3 as an oxidant
DTBP as an oxidant
other bases instead of K3PO4
other solvents instead of DMSO
76
trace
0
17
0–60
12
18
trace
0
14–55
7–40
wherein the intermediacy of a dicarbonyl radical was
2
proposed.[18] Motivated by this oxidative C(sp ) H function-
À
3
À
alization, we became interested in developing C(sp) C(sp )
cross-couplings from terminal alkynes and 1,3-dicarbonyl
compounds.[19] A somewhat related reaction is Leiꢀs elegant
silver-mediated oxidative coupling of aryl acetylenes and 1,3-
dicarbonyl compounds to generate furans. This reaction
employed similar reagents (Figure 1d) and it was proposed
that alkylated alkynes were intermediates en route to furans.
This hypothesis has not yet been verified to our knowledge.[20]
Herein we present an iron-catalyzed tertiary alkylation of aryl
alkynes and 1,3-enynes with 1,3-diesters that enables the
streamlined synthesis of functionalized alkynes (Figure 1e).
This transformation avoids nucleophilic addition of 1,3-di-
esters to terminal alkynes with the formation of alkene-
containing products.[21] Mechanistically, we propose that the
reaction proceeds via a radical oxidative coupling pathway.[22]
9
10
11
[a] Reaction conditions unless otherwise noted: 1a (0.2 mmol), 2a
(0.4 mmol), FeCl3 (10 mol%), Ag2CO3 (0.4 mmol), K3PO4 (0.4 mmol),
DMSO (2.5 mL), 1008C, 24 h. [b] Yield of isolated product.
4). Other common Lewis acids like FeCl2, CuCl2, ZnCl2,
AlCl3, and BF3·OEt2, gave inferior results (Table 1, entry 5).
A series of silver salts were examined as oxidants, but none
were competitive with Ag2CO3 (Table 1, entries 6–8). Per-
À
oxides, which have been extensively utilized in oxidative C
À
Results and Discussion
H/C H cross-coupling reactions, gave no conversion (Table 1,
entry 9). Replacing K3PO4 with other bases such as K2CO3,
KOAc, and Cy2NH, was found to be detrimental to the
product yield. Solvent effects were also evaluated. Among
polar aprotic solvents examined, dimethyl sulfoxide proved to
be optimal (Table 1, entry 11).
3
À
À
At the outset, the cross-coupling of C(sp) H/C(sp ) H
bonds was evaluated by selecting p-tolylacetylene (1a) and
diethyl methylmalonate (2a) as the model substrates. Copper
salts exhibited superior catalytic performance in promoting
alkylation of alkenes in our previous studies.[17] Exploratory
studies using CuBr2 as catalyst and Ag2CO3 as oxidant,
however, gave a low chemical yield of the dehydrogenative
product 3a, together with cis-hydroalkylation byproduct 4
and undesired dimerization by-product 5 (Scheme 1, percen-
tages refer to yields of isolated products). This competitive
reductive pathway for the formation of disubstituted al-
kenes[23] was viewed as potentially problematic and inspired
us to consider use of other metals.
After an extensive survey of reaction parameters (see the
Supporting Information for details), we arrived at the
optimized conditions that involved 10 mol% FeCl3 with
Ag2CO3 as the oxidant and K3PO4 base in DMSO (0.08 m)
at 1008C, affording the desired product 3a in 76% isolated
yield (Table 1, entry 1). Control experiments showed that
both FeCl3 and Ag2CO3 were essential for the coupling and
With the optimized reaction conditions in hand, we began
to explore the generality and selectivity of the Fe-catalyzed
3
À
À
C(sp) H/C(sp ) H bond coupling by using tolyl acetylene
(1a) as coupling partner (Table 2). Dimethyl methylmalonate
proved to be amenable to this oxidative cross-coupling,
delivering the corresponding product 3b in 64% yield.
Extending the chain attached to the a-position of the
malonate to ethyl resulted in an increase in the yield to
75% (3c). In contrast, the more sterically demanding
isopropyl derivative exhibited diminished reactivity, but still
permitted isolation of the product 3d (30% yield). Tertiary
alkylation of tolyl acetylene (1a) with various malonate
derivatives bearing desirable functionality, such as fluoride,
benzyl, cyclopropyl, cyclohexyl, ester, acetal, nitrile, silyl
ether, and tetrahydrofuranyl motifs, proceeded efficiently,
providing access to functionalized alkynes (3e–3m) with
the base greatly improved the efficiency (Table 1, entries 2– yields ranging from 41 to 88%. It is noteworthy that
À
substrates bearing C H bonds that are susceptible to hydro-
gen atom transfer processes, such as those positioned at
À
benzylic centers or C H bonds alpha to oxygen, were
compatible with the reaction conditions. In the case involving
ethyl 2-methylacetoacetate, no evidence of the coupling
product was detected. This result showed that the diester
moiety appeared to be uniquely suitable under these reaction
conditions.[24]
3
Next, we turned our attention to the scope of the aryl
À
Scheme 1. Preliminary results for direct coupling of C(sp ) H/
À
C(sp) H bonds.
alkynes (Table 3). The functional group compatibility of the
Angew. Chem. Int. Ed. 2021, 60, 9706 –9711
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