Angewandte
Chemie
Herein, we report that by systematically tuning the steric
properties of the substrate, in addition to using a bulky Pd
catalyst, an intramolecular alkyne carbohalogenation can be
realized (Scheme 1c). The bulky alkynyl substituent serves to
enhance steric congestion close to the PdII center, beyond the
inherent effects imparted by the ligand, during the key
reductive elimination step. In addition to promoting the
desired reactivity, the increased steric bulk of the substrate
also suppresses product decomposition pathways that are
a result of oxidative addition of the Pd catalyst into the
PMP to the reaction was not necessary for full conversion at
higher catalyst loadings (7.5 mol%), and the reaction temper-
ature and time could be decreased to 508C and 15 min,
respectively (entry 4).
Significant decomposition and trace amounts of the
desired product were observed when 1d was subjected to
the unoptimized reaction conditions (entry 6). We speculated
that the introduction of ortho-substituents on the phenyl ring
may favorably increase steric crowding close to the Pd center
during the key reductive elimination. Indeed upon screening
several ortho-substituted derivatives, a dramatic increase in
reactivity was observed upon replacing the phenyl ring with
a mesityl group (Table S4).[9] Substrate 1e required more time
than 1c to reach full conversion at 508C (entry 7), which is
consistent with our rationale that larger substituents promote
À
product Csp2 X bond.
This newly developed reaction can be conducted at lower
temperatures compared to our previous systems and can be
applied to aryl chlorides, bromides, and iodides. Experimental
studies suggest that reversible oxidative addition is operative
in the catalytic system, which serves to thwart unproductive
catalyst consumption pathways and, more interestingly,
enables a thermodynamically driven isomerization of vinyl
halide product at elevated temperatures. By simply modulat-
ing the reaction temperature, both stereoisomers of the
reaction can be readily accessed using the same catalyst. To
the best of our knowledge, this atom-economical reaction
represents the first Pd0-catalyzed stereodivergent addition of
an aryl halide across an alkyne.[6]
À
the Csp2 X reductive elimination process more effectively
(i.e., TIPS > mesityl).[10] At higher reaction temperatures
(1008C), the efficiency of the reaction was not significantly
affected, but the stereoselectivity had reversed completely,
with high selectivity observed for trans-2e (entry 8). In situ
NMR studies show that the formation of trans-2e, which is
presumably the thermodynamic product, arises primarily
from isomerization of the kinetic product, cis-2e, rather than
directly from 1e.[9]
Our study commenced with a substrate screening employ-
ing previously developed conditions for the carboiodination
of diiodinated aromatics [Eq. (1)].[4e] We noticed that the use
of bulkier substituents at the terminal position of the alkyne
led to increased yields of the desired carbohalogenation
product 2 (Table 1, entries 1–3), with substrate 1c displaying
the best reactivity. Notably, an isomeric mixture of 2 was
observed under a range of conditions, with the expected cis-2
isomer, resulting from a cis-carbopalladation, being the major
product.[7] Mechanistic studies suggest that the formation of
trans-2, the product of an apparent trans-carbopalladation, is
formed through a Pd-mediated olefin isomerization process
(see below).[8] Upon further optimization with 1c
(Table S2),[9] we found that the addition of Q-Phos and
Having identified optimized conditions for substrates 1c
and 1e, the substrate scope was investigated (Scheme 2). In
addition to aryl bromides, our method could be applied to aryl
chlorides (1 f) and iodides (1g, 1i). Although the use of 1 f
required more forcing conditions, this example represents the
first disclosure of a Pd0-catalyzed carbochlorination reaction.
Table 1: Substrate optimization.
Entry R (1)
x [mol%] Temp [8C]/ Yield[a] [%] cis/trans[a]
(Time [h])
1[b]
2[b]
3[b]
4[c]
5[c]
6[b]
7[c]
8[c]
Me (1a)
5.0
5.0
5.0
7.5
0
110 (1.0)
110 (1.0)
110 (1.0)
50 (0.25)
50 (0.25)
110 (1.0)
50 (18)
40
83
94
96
0
<5
85
90
N/D
tBu (1b)
TIPS (1c)
TIPS (1c)
TIPS (1c)
Ph (1d)
82:18
87:13
90:10
N/D
N/D
>95:5
10:90
5.0
mesityl (1e) 5.0
mesityl (1e) 5.0
Scheme 2. Substrate scope for cis-selective examples. Values in paren-
theses represent the major/minor isomer ratios. [a] With PMP
(0.25 equiv) at 1108C for 18 h. [b] At 1008C. [c] With Pd(Q-Phos)2
(10 mol%), PMP (0.25 equiv) at 1108C for 1 h. [d] With Pd(Q-Phos)2
(5 mol%), PMP (1.0 equiv) at 1108C for 72 h. Ts=tosyl; TBS=tert-
butyldimethylsilyl ether; TIPS=triisopropylsilyl ether.
100 (18)
[a] Combined yields and cis/trans-ratios were determined by 1H NMR
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene as
internal standard. [b] Q-Phos (10 mol%), PMP=1.0 equiv. [c] No Q-
Phos or PMP. PMP=1,2,2,6,6-pentamethylpiperidine; N/D=not deter-
mined.
Angew. Chem. Int. Ed. 2015, 54, 254 –257
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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