Angewandte
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participate in undesired oligomerization through subsequent
iterative alkyne insertion.[17a,23]
We initially explored the possibility of transforming
a simple internal alkyne into the corresponding alkenyl
iodide using Xantphos (L01) as a ligand (Table 1). The
We next explored the scope with respect to aryl iodides in
this transformation, using dArFpe as a ligand and Pd2(dba)3
and [(allyl)PdCl]2 as Pd sources (Table 2). A large range of
substituted aryl iodides worked well under these conditions
when either electron-rich or electron-deficient functional
groups were present. A wide range of sterically encumbered
ortho-substituted aryl iodides (4–7, 23–29) were also tolerated
in this process. Using this catalytic reaction, several electron-
rich functional groups, such as mono (24, 30, 35), di (8), and tri
(9) alkoxy, thiomethoxy (36), tertiary amine (12, 37), and
alkyl (4, 26, 38) substituents gave the corresponding products
in high yields. Electron-poor aryl iodides also afforded
excellent stereoselectivity and yields in this transformation,
as illustrated by the tolerance of nitro (42), cyano (43),
bis(trifluoromethyl) (11), fluoro (5, 6, 10, 27), ester (33, 44),
ketone (45), and even aldehyde (46) and azo (15) groups. The
reaction could also be used to react the more electrophilic
iodide site exclusively, with other less-reactive (pseudo)hal-
ogens, such as chlorides (20, 28, 39), bromides (19, 31, 32, 40)
and triflate (41) remaining intact. Even an aryl boronate ester
(52) that can engage in Suzuki-type couplings survived the
conditions. A range of electron-rich and electron-poor
heterocycles (13, 14, 17–23) can serve as good substrates in
the transformation. However, the use of heterocycles without
any proximal substituent to hinder the plausible coordination
of heteroatom to a metal center resulted in low conversions.
Protic functionalities such as an alcohol (47), a carboxylic acid
(48), indole (13), and amide (49, 50) groups were tolerated to
give moderate yields. This result is noteworthy in light of the
limitation of traditional methods, which require protection of
such functionalities. This high functional-group tolerance can
be rationalized by the high chemoselectivity of Pd-catalyzed
reactions under mild and neutral reaction conditions, partic-
ularly in the absence of a strong base or anionic organome-
tallic species.[15] Alkyl, alkenyl, alkynyl, and allylic iodides
were mostly unreactive under the present reaction conditions,
a result that further highlights the high chemoselectivity of
this catalytic system (see Figure S3 in the Supporting Infor-
mation). Various symmetrical internal alkynes were reacted
smoothly with aryl iodides (Table 3). We successfully per-
formed a late-stage functionalization of three structurally
different compounds, derived from a chiral catalyst precursor
(58),[28] a natural product (estrone, 59), and a pharmaceutical
intermediate (60; Table 3).
Table 1: Ligand screening and optimization.[a]
Entry
Ligand
x (mol%)
Yield (%)[b]
Z/E selectivity
1
2
3
4
5
6
7
8
L01
L01
L01
L02
L02
L02
L03–L05
L06–L09
5
7
64
84 (79)
10
73
82 (78)
<1
<1
65:35[c]
59:41[c]
46:54[d]
>99:1[d]
>99:1[d]
>99:1[d]
–
10
15
5
10
15
15
30
–
[a] 1 (0.25 mmol), 2 (1 equiv), Pd2(dba)3 (2.5 mol%), toluene, 1258C,
12 h. [b] GC yields; yields of isolated product given in parentheses.
[c] Determined by GC analysis. [d] Determined by 1H NMR.
catalytic Pd system resulted in low but unambiguous con-
version to the desired products as a mixture of stereoisomers.
This result is likely due to the high stability of the PdII
intermediates generated from oxidative addition, which
prevents the regeneration of the active Pd0 species. Inspired
by Hartwigꢀs seminal work, which has shown that the rate of
reductive elimination has a linear dependence on the
concentration of a phosphine ligand,[24] we were able to
increase the yield to 84% when additional ligand was
employed. Various other ligands, including Xantphos ana-
logues, resulted in low conversion. In contrast, dArFpe (L02),
which is rarely employed in Pd catalysis,[25] led to a very active
and selective catalyst for the desired transformation (82%
yield, Z/E > 99:1). We surmise that the use of an excess of
a ligand that is both electron-deficient and bidentate is key to
favor the reductive elimination step. The configuration of the
alkenyl iodides was determined by NOESY NMR analysis
and X-ray crystallography. No excess of either of the reaction
partners is required for this transformation. While the
potential of electron-withdrawing ligands to facilitate reduc-
tive elimination has been noted,[24b,26] the vast majority of
Next, we focused on the scope with respect to unsym-
metrical internal alkynes (Table 4). A steric variation of the
alkynes gave a mixture of regioisomers with small but non-
negligible differences in regioselectivity. The observed selec-
tivity apparently arises from preferential aryl insertion at the
distal position relative to the bulky group. This is consistent
with reported examples of unsymmetrical alkyne hydro-
functionalization, where the regiochemistry is often con-
trolled by steric effects in the absence of strong differences in
electronics.[4d,5,23a,29] However, in our case, the small differ-
ence in size between the aryl moiety and the Pd center does
not seem to be significant enough to obtain high regioselec-
tivity. In line with this hypothesis, two sterically hindered aryl
iodides (68, 69) resulted in improved regioselectivity. An aryl
iodide bearing a tethered alkyne group in its ortho position
À
successful examples of C I bond reductive elimination have
described the use of electron-rich, sterically hindered
ligands.[20] A rare exception to this is the result reported by
Arndtsen and co-workers, in which they proposed that the
presence of CO as a ligand on the PdII center is crucial to the
reductive elimination of extremely reactive aroyl triflate
products.[27]
2
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Angew. Chem. Int. Ed. 2019, 58, 1 – 6
These are not the final page numbers!
Lee, Yong Ho
