Angewandte
Communications
Chemie
Table 1: Test of different substituents on nitrogen of anilines.[a]
and Zhang[8d] independently reported the oxidative carbon-
ylation of ortho-aryl anilines with CO using stoichiometric
copper or silver salts as the oxidants (Scheme 1B). Although
these methods are step-efficient, atom-economic, and display
a good substrate scope, the use of highly toxic CO and high-
valence transition metals as the oxidants causes safety issues,
high cost, and risk for heavy metal residues, all of which
hamper industrial applications, especially in the pharmaceut-
ical sector. Therefore, developing a method that avoids toxic
CO or heavy metal salts is highly desirable.[9] In principle,
CO2, with its higher oxidation state than CO, might act
[a] Reaction conditions: 1 (0.2 mmol), NaOtBu (4.5 equiv.), 1 atm of
CO2, 2 mL of diglyme, 24 h, 1408C. The yields are isolated yields. [b] 2a
was obtained as the product. n.d.=not detected.
similarly to the combination of CO and oxidants. Herein, we
2
À
report the first lactamization of sp C H bonds with CO2 to
generate diverse 2-quinolinones and polyheterocycles under
transition-metal-free and redox-neutral conditions (Sche-
me 1C). Our process is scalable and green, with broad
substrate scope and good functional group tolerance. More-
over, the products readily can be transformed into diverse
derivatives and important drugs.
Table 2: Lactamization of 2-alkenylanilines with CO2.[a]
It is well known that anilines can react with CO2 under
À
basic conditions by nucleophilic attack/C N bond formation
to generate carbamates/carbamic acids.[4g,10] We envisioned
that the electron-rich alkene at the ortho position of an aniline
might undergo an intramolecular nucleophilic attack on the
in situ generated carbamates/carbamic acids to provide the
corresponding lactams. Based on this hypothesis, we first
tested the direct lactamization of 2-(prop-1-en-2-yl)aniline 1a
to generate 2-quinolinone 2a in the presence of 1 atm of CO2
(Supporting Information, Table S1). We explored a variety of
bases using 1,4-dioxane as the solvent. Although many kinds
of bases elicited no reactivity (Table S1, entries 1–3), several
alkali metal tert-butoxides promoted the reaction to generate
2a in moderate to good yields (Table S1, entries 4–6). Many
other solvents, including tetrahydrofuran (THF), N,N-dime-
thylformamide (DMF), and diglyme, were tested to generate
2a with KOtBu as the base (Table S1, entries 7–11). Mean-
while, NaOtBu also promoted the reaction to give 2a in 82%
yield when diglyme was applied as the solvent (Table S1,
entry 12). Excess of base and high temperature are important
for high efficiency. For example, no conversion was observed
when no or 1 equivalent of NaOtBu was used, demonstrating
the critical role of the base (Table S1, entries 12–15). The
yield improved to 95% when 4.5 equivalent of NaOtBu was
used at 1408C (Table S1, entry 17). Under these conditions,
good conversion was observed in just 2.5 hours (Table S1,
entry 18). Importantly, the inductively coupled plasma atomic
emission spectrometer (ICP-AES) detection of transition
metal sources demonstrated that this reaction is free of
transition metals (see the Supporting Information for details).
With the best reaction conditions in hand, we investigated
the effect of substituents on the aniline nitrogen (Table 1).
Neither alkyl (1b) nor aryl (1c) substituted anilines afforded
the desired products. When amide 1d and carbamate 1e were
applied as substrates, 2a was obtained in 22% and 95% yield,
respectively. This might arise from in situ generation of free
aniline 1a or the intermediates under the reaction conditions
(see the Supporting Information).
[a] Reaction conditions: the same as Table 1. [b] 1 (0.3 mmol), NaOtBu
(3.0 equiv).
(Table 2). First, varying the substitution on the alkene moiety
was tested. We found that both terminal alkenes (1a) and
internal alkenes (1 f and 1g) could be applied in the reaction
to give the products in good yields. Moreover, the substrate
with a methyl group on the alkene (1a) showed better
reactivity than those with a hydrogen (1h) or an ethyl group
(1i). Secondly, we tested various kinds of substituents on the
arene. It was found that the steric hindrance did not hamper
the reaction, forming 2j in 81% yield. The anilines with
electron-donating groups (EDGs; 1k and 1p) showed similar
reactivity to those with electron-withdrawing groups (EWGs;
1l and 1q). Many kinds of functional groups, including OMe
(2k and 2p), CF3 (2l and 2q), Cl (2m and 2r), and Br (2s),
were well tolerated, providing great opportunities for drug
synthesis[6c,11] and further functionalization.[12]
Considering the high importance of 4-aryl-2-quinolinones,
we further tested the reactivities of ortho a-styrenyl-substi-
tuted anilines (Table 3), which can be easily synthesized from
simple anilines with alkynes.[14] We found that most of the 2-
Based on these results, we further investigated the
reactivities of free anilines with ortho-alkenyl substitution
2
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Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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