Earlier couplings of 1,1-dibromo-1-alkenes reported with
organometallic reagents provided di- or trisubstituted alkenes
and internal alkynes under different conditions.11-13 For
example, reactions under the Stille coupling conditions
needed longer reaction time,12a whereas Suzuki-type cou-
plings needed a two-step protocol for alkyne formation.11c
This variance in reactivity prompted us to explore and expand
the potential of these synthons with triarylbismuths to
develop a domino multicoupling protocol for the synthesis
of internal alkynes (Figure 1). This novel protocol was
c
Table 1. Screening Conditionsa
-
entry
catalysts
base
solvent
C (%) 2a (%)
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
K3PO4 1,4-dioxane
K3PO4 MeCN
K3PO4 THF
K3PO4 DME
K3PO4 NMP
K2CO3 DMF
KOAc DMF
K3PO4 DMF
K3PO4 DMA
K3PO4 DMF
36
36
4
9
47
<1
22
38
20
5
14
62
67
75
5
4
95 (88)
91 (82)
70 (65)
63d
9
Figure 1. Domino coupling with triarylbismuths.
10
11
12
13
14
15
16
17
19
25
12
23
6
3
35
3
PdCl2(MeCN)2 K3PO4 DMF
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
none
K3PO4 DMF
K3PO4 DMF
K3PO4 DMF
K3PO4 DMF
88 (80)e
67f
expected to deliver 3 equiv of internal alkynes in a multi-
coupling one-pot domino operation.
34g
62 (53)h
19
The envisioned domino coupling process is quite chal-
lenging because of: (i) the high propensity of triarylbismuths
to give biaryls under palladium catalysis,7a (ii) homocoupling
or elimination reactions of 1,1-dibromo-1-alkenes,14 and (iii)
the combined reactivity of both triarylbismuths and 1,1-
dibromo-1-alkenes in a domino one-pot operation under
palladium-catalyzed conditions.
none
DMF
K3PO4 DMF
3i
a Reaction conditions: 1,1-dibromo-1-alkene, 1b (0.75 mmol, 3 equiv),
BiPh3 (0.25 mmol, 1 equiv), Pd catalyst (0.0225 mmol, 0.09 equiv), base
(1.5 mmol, 6 equiv), solvent (3 mL), 90 °C, 2 h. b Products based on GC
analysis of crude reaction mixtures. c Isolated yields are given in parentheses.
d With PPh3 (0.18 equiv). e 4 equiv of base. f 2 equiv of base. g At 60 °C.
h At 80 °C. i 75% of 1-bromo-2-(4-methoxyphenyl)acetylene was formed.
Therefore, the initial focus was to drive the reaction toward
the desired domino cross-coupling using 1,1-dibromo-1-
alkene, 1b, with BiPh3 to obtain disubstituted alkyne, 2a
(Table 1). The reaction with a Pd(PPh3)4 catalyst using
different solvents and bases furnished mixed results (entries
1-9).
The GC analysis of the crude product mixtures revealed
the formation of cross-coupled alkyne (2a) and homocoupling
biphenyl (C) from BiPh3 along with unreacted 1,1-dibromo-
1-alkene and triphenylbismuth in minor amounts in some
cases. This study revealed that the domino process is more
effective with K3PO4 base in N,N-dimethylformamide (DMF)
and N,N-dimethylacetamide (DMA) solvents with 88% and
82% yield of alkyne, 2a (entries 8 and 9). With the additional
study using different catalyst precursors (entries 10 and 11),
it was clear that Pd(PPh3)4 provided better product yield.
Further, different amounts of base and temperature conditions
showed that lowering base equivalents or temperature is
detrimental to alkyne formation (entries 12-16). A control
reaction without palladium catalyst delivered a large amount
of elimination product, 1-bromo-2-(4-methoxyphenyl)acet-
ylene, in 75% yield from 1,1-dibromo-1-alkene (entry 17).
Similarly, formation of 1-bromoalkyne has also been ob-
served at lower temperature conditions in 39% and 23%
amounts (entries 14 and 15). Overall, this investigation
revealed that the protocol using Pd(PPh3)4 catalyst in
combination with K3PO4 base and DMF solvent at 90 °C
was optimal (entry 8). Gratifyingly, these conditions deliv-
ered the disubstituted alkyne with high yield and in short
reaction time in a facile manner. It is to be noted that the
reaction involves three C-C domino cross-couplings involv-
ing the bismuth reagent. In this domino process, triphenyl-
bismuth was also involved as a multicoupling nucleophile
for coupling with 3 equiv of 1,1-dibromo-1-alkene ef-
fectively. It is also to be mentioned that the homocoupling
product biphenyl from BiPh3 invariably formed in minor
amounts depending on the degree of cross-coupling conver-
sion.
With the optimized condition in hand, we further examined
the scope of this reaction. The generalization of the reaction
performed with divergently functionalized 1,1-dibromo-1-
alkenes and BiAr3 is summarized in Tables 2 and 3. In
general, the domino coupling process afforded a variety of
unsymmetrical internal alkynes in high yields. Thus, a series
of divergent 2-aryl-1,1-dibromo-1-alkenes reacted with tri-
arylbismuths very efficiently. Further couplings carried out
with 2-heteroaryl-1,1-dibromo-1-alkenes also furnished high
yields of heteroaryl-substituted alkynes in a facile manner
(11) (a) Bauer, A.; Miller, M. W.; Vice, S. F.; McCombie, S. W. Synlett
2001, 254–256. (b) Chelucci, G.; Capitta, F.; Baldino, S.; Pinna, G. A.
Tetrahedron Lett. 2007, 48, 6514–6517. (c) Chelucci, G.; Capitta, F.;
Baldino, S. Tetrahedron 2008, 64, 10250–10257. (d) Shen, W. Synlett 2000,
737–739
(12) (a) Shen, W.; Wang, L. J. Org. Chem. 1999, 64, 8873–8879. (b)
Zapata, A. J.; Ruiz, J. J. Organomet. Chem. 1994, 479, C6–C8
(13) Riveiros, R.; Saya, L.; Sestelo, J. P.; Sarandeses, L. A. Eur. J. Org.
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(14) (a) Okutani, M.; Mori, Y. J. Org. Chem. 2009, 74, 442–444. (b)
Lera, M.; Hayes, C. J. Org. Lett. 2000, 2, 3873–3875. (c) Shen, W.; Thomas,
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