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Table 1: Screening of optimal reaction conditions.[a]
Entry
Variation from the standard reaction conditions
Yield [%][b]
1[c]
2
3
4
5
none
83
81
70
68
0
[Fe(acac)3] (10 mol%)
without [Fe(acac)3]
FeCl3, FeCl2, or [Cu(acac)2] instead of [Fe(acac)3]
without Ag2CO3
6
K2CO3 or Cs2CO3 instead of Ag2CO3
Ag2CO3 (1 equiv)
AgOAc instead of Ag2CO3
Ag2O instead of Ag2CO3
AgF instead of Ag2CO3
at 1008C
0
7[d]
8
42
45
42
55
20
84
82
61
81
9
10
11
12
13
14[e]
15[f]
Scheme 2. Variation of the alkenes 1. [a] Reaction conditions:
at 1308C
1 (0.4 mmol), 2b (0.4 mmol), 3a (0.2 mmol), [Fe(acac)3] (5 mol%),
Ag2CO3 (2 equiv; 0.4 mmol), and 1,4-dioxane (2 mL) at 1208C under
argon atmosphere for 12 h. Yield of isolated product based on the
amount of 3a. The d.r. value is given within the parenthesis and was
PhCl instead of 1,4-dioxane
MeCN instead of 1,4-dioxane
none
1
[a] Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), 3a (0.2 mmol),
[Fe(acac)3] (5 mol%; 0.01 mmol), Ag2CO3 (2 equiv; 0.4 mmol), and
MeCN (2 mL) at 1208C under argon atmosphere for 12 h. The d.r. value
is 1.6:1, as determined by 1H NMR analysis of the crude reaction
mixture. [b] Some side-products, including 3-methyl-5-(p-tolyl)dihydro-
furan-2(3H)-one (4a; 16% yield), methyl 4-bromo-2-methyl-4-(p-tolyl)-
butanoate (4b; <5% yield), and ethyl 2-methyl-4-(p-tolyl)but-3-enoate
(4c; <5% yield) from the reaction of 1a with 2a, and ethyl 2-(1-methyl-
1H-indol-3-yl)propanoate (4d; 12% yield) from the reaction of 2a with
3a, were detected by GC-MS analysis. [c] Yield of isolated product based
on the amount of 3a. [d] In the presence or absence of Cs2CO3, identical
results were observed. [e] For 36 h. [f] Used 3a (1 g; 7.634 mmol) and
1,4-dioxane (10 mL) for 48 h.
determined by H NMR analysis of the crude reaction mixture.
tively, furnished the corresponding 5 and 7 with consistent
yields. However, the alkene 1d, with a CN group, had no
reactivity (8). While the reaction of 1c enabled the synthesis
of 6 in 90% yield, the reaction of m- and o-methyl-substituted
aryl alkenes 1 f,g afforded 10 and 11, respectively, in lower
yields. 2-Vinylnaphthalene (1h) was transformed into 12
smoothly, albeit with a diminished yield. Gratifyingly, the
optimal reaction conditions were compatible with the 1,1-
disubstutited alkenes 1j,k, and the reaction delivered 14 and
15, respectively, with concomitant generation of a quaternary
carbon center. Noted that anethole (1l), an internal alkene,
was viable for constructing 16 in good yield.
Next, the scope with respect to the a-carbonyl alkyl
bromides 2 and indoles 3 were investigated (Scheme 3). We
found that this protocol was subjected to various primary,
secondary, and tertiary a-carbonyl alkyl bromides (2), includ-
ing a-bromoalkyl esters, ketones, and nitrile (products 17–25).
Using the secondary a-bromoalkyl esters 2a and 2c, and
ketones 2d,e, the reaction with 1b, 3a, [Fe(acac)3], and
Ag2CO3 selectively furnished 17–20 with high yields. Gratify-
ingly, the current reaction was not limited to the primary
bromoalkyl ester 2 f and ketone 2g (21 and 22), but 2-
bromoacetonitrile 2h could be converted into 23 in 62%
yield. Tertiary a-bromoalkyl esters, namely ethyl 2-bromo-2-
methylpropanoate (2i) and diethyl 2-bromo-2-methylmalo-
nate (2j), also showed high reactivity, thus leading to 24 and
25,[9] respectively, in high yields. Subsequently, we set out to
study the generality of the indoles 3 in the presence of 1b, 2j,
[Fe(acac)3], and Ag2CO3 (26–35). The results showed that
electron-rich indoles had higher reactivity than electron-
deficient indoles: The reaction tolerated 5-methyl- and 5-
bromo-substitued indoles (3b,c), thus affording 26 and 27,
respectively, in excellent yields, whereas 5-cyano- and 4-nitro-
substitued indoles (3d,e) were transformed into the corre-
perature (at 1308C) did not improve the yield compared with
the results at 1208C (entry 12), but lower temperature (at
1008C) dramatically reduced the yield (entry 11). The reac-
tion proved sensitive to the effect of solvent: While 1,4-
dioxane and chlorobenzene were highly effective mediums
for the reaction (entries 1 and 13), acetonitrile showed lower
reactivity (entry 14). Notably, the reaction is applicable to
a 1 gram scale of 3a, thus giving 4 in good yield (entry 15).
With the optimal reaction conditions in hand, the scope of
this [Fe(acac)3]-facilitated, Ag2CO3-mediated 1,2-alkylaryla-
tion protocol was investigated with regard to the scope of the
alkenes 1, a-carbonyl alkyl bromides 2, and indoles 3. As
shown in Scheme 2, the optimal reaction conditions were
applicable to a wide range of alkenes. In the presence of
phenyl 2-bromopropanoate (2b), the indole 3a, [Fe(acac)3],
and Ag2CO3, a variety of terminal aryl alkenes (1a–c and 1e–
h) were successfully converted into the corresponding 1,2-
alkylarylation products (5–7 and 9–12) with moderate to good
yields, but the strongly electron-deficient aryl alkene 1d and
aliphatic alkene 1i were not suitable substrates (products 8
and 13). We found that both the electronic nature of the aryl
group and the substituent position on the aryl group had
a fundamental influence on the reactivity. The alkenes 1a and
1c, bearing a p-MeC6H4 group and p-ClC6H4 group, respec-
3188
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 3187 –3191