Angewandte
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tion have recently been published and could serve as a direct
comparison with regard to regioselectivity.[17–20] In early
optimization stages, several traditional stoichiometric chlor-
ine radical sources were evaluated. In combination with Mes-
Acr-Me+ as a photocatalyst, tosyl chloride (TsCl)[21] provided
an early hit for aliphatic alkenes, but proved ineffective for
styrenyl substrates (Table 1, entry 1). Other potential chlorine
radical sources, such as N-chlorosuccinimide (NCS) and N-
chlorophthalimide (NCP), tended to produce solely the
undesired regioisomer (Table 1, entries 2 and 3). Copper(II)
chloride is known to be a competent chlorine-atom transfer
agent in atom-transfer radical-polymerization (ATRP) reac-
tions, and although highly reversible, most copper catalysts
favor the CuI oxidation state.[22] Additionally, CuCl2 under-
goes irreversible chlorine-atom transfer with carbon-centered
radicals; these features together made it a suitable candidate
for this reaction.[23–25] We were pleased to find that the use of
CuCl2 in MeCN as a chlorine-atom source afforded small
amounts of the desired regioisomer, the yield of which could
be improved to 62% through the use of 2,2’-bipyridine (bpy)
as a supporting ligand (Table 1, entry 4).
To avoid the use of a stoichiometric amount of the metal
and the ligand, we screened conditions for rendering the
reaction catalytic in copper. When the reaction was carried
out with CuCl2 (20 mol%) and the ligand under air or O2
pressure in the presence of lutidinium chloride (Lut+ClÀ),
unwanted oxygen-trapped products were formed, and no
catalyst turnover was observed (Table 1, entry 5). The use of
stoichiometric NCP alone failed to afford the desired adduct
(X = Cl). However, in combination with CuCl2/bpy
(10 mol%), the chlorolactone product was obtained in
excellent yield (90%) with modest diastereoselectivity
(2.3:1 d.r.; Table 1, entry 6).
The use of CuCl/bpy as a catalyst gave comparable results
(Table 1, entry 7), thus suggesting that oxidation by NCP was
generating CuCl2. With 1,10-phenanthroline (phen) as the
ligand, the reaction proceeded in similar yield (85%), but
with slightly improved diastereoselectivity (3.2:1 d.r.) and
a shorter reaction time (Table 1, entry 8). In most cases,
reactions reached full conversion after only 2 h. In the
absence of a photocatalyst, some product formation was
detected (both regioisomers), but the reaction only reached
40% conversion after 18 h (Table 1, entry 9). When the same
reaction was quenched after 2 h, reflective of the final
conditions, adduct A was not formed, and unreacted starting
material was returned. Importantly, when both Mes-Acr-Me+
and the copper catalyst were omitted, no reaction was
observed. These results, in combination with the observed
formation of B in the reactions described in entries 2 and 3 of
Table 1, led us to hypothesize that, in the presence of the
photocatalyst, a strong acid may be generated in situ,[26] thus
leading to activation of the chlorinating reagent and the
subsequent formation of B. To test this hypothesis, we carried
out a reaction between NCS and the substrate in the presence
of a strong acid (CF3SO3H) and observed the production of
significant amounts of product B (see the Supporting
Information for details).
Concurrently, we developed conditions for the synthesis
of the complementary bromolactone adducts. Under the
catalytic conditions with CuBr2 and N-bromophthalimide
(NBP) as the bromine source, the desired product was
obtained in a 39% yield with a significant amount (61%) of
the undesired regioisomer (Table 1, entry 10). After some
experimentation, it was determined that diethyl bromomal-
onate (DEBM) afforded A (X = Br) selectively in 97% yield
(Table 1, entry 11). Notably, no reaction occurred when the
photocatalyst was omitted from the reaction mixture (Table 1,
entry 12). The omission of CuBr2 and the ligand from the
reaction led solely to the formation of the anti-Markovnikov
hydrolactonization product (Table 1, entry 13), consistent
with previous results from our laboratory.[15]
Table 1: Optimization of reaction conditions.[a]
Entry
X source
CuX2/ligand
A [%][b]
B [%][b]
d.r. (A)
Once the optimized halolactonization conditions were
established, we examined the scope of the transformation
(Scheme 2). Both sets of conditions were successfully applied
to the halolactonization of 1,2-disubstituted styrenes to give
1a–d in good to excellent yields (73–94%) with modest
diastereoselectivity (2.1–2.5:1 d.r.). A trisubstituted styrene
was successfully difunctionalized under the chlorination
(product 1e) and bromination conditions; however, the
latter product was also obtained under the classical halofunc-
tionalization conditions. Substituted electron-poor (product
1 f) and electron-rich styrenes (products 1h,i) were viable
chlorolactonization substrates, whereas only electron-poor
(product 1g) and mildly electron rich styrenes (product 1j)
were successful substrates under the bromolactonization
conditions, presumably owing to the instability of the
electron-rich benzyl bromide adducts. The versatility of the
chlorolactonization conditions was further demonstrated in
the chlorofunctionalization of trisubstituted aliphatic alkenes
1
2
3
TsCl
–
–
–
–
–
–
–
50
30
–
–
–
–
–
12
61
3
–
–
–
NCS
NCP
–
4[c]
5[d]
6
CuCl2/bpy
CuCl2/bpy
CuCl2/bpy
CuCl/bpy
CuCl2/phen
CuCl2/phen
CuBr2/bpy
CuBr2/bpy
CuBr2/bpy
–
62
19
90
92
85
25
39
97
–
1.5:1
2.6:1
2.3:1
2.4:1
3.2:1
2.2:1
3.0:1
2.4:1
–
Lut+Cl-
NCP
NCP
NCP
NCP
NBP
DEBM
DEBM
DEBM
7
8
9[e]
10
11
12[e]
13
–
–
–
–
[a] Reactions were carried out in N2-sparged MeCN [0.1m] under two
LED lamps (lmax =450 nm) for 18 h. [b] Yield as determined by 1H NMR
spectroscopic analysis of the crude reaction mixture relative to the
internal standard (Me3Si)2O. [c] The reaction was carried out with
1 equivalent of CuCl2/bpy under air. [d] The reaction was carried out with
CuCl2/bpy (20 mol%) in the presence of O2. [e] The reaction was carried
out without Mes-Acr-Me+.
2
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Angew. Chem. Int. Ed. 2017, 56, 1 – 5
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