Metal/Benzoyl Peroxide (BPO)-Controlled Chemoselective Cycloisomerization of (o-Alkynyl)phenyl Enaminones: Synthesis of α-Naphthylamines and Indeno[1,2-c]pyrrolones

Article abstract of DOI:10.1021/acs.orglett.6b02615

Synthetic methods involving chemoselective tandem reactions for the synthesis of α-naphthylamines and indeno[1,2-c]pyrrolones starting from (o-aklynyl)phenyl enaminones are described. When reactions were carried out in N,N-dimethylformamide (DMF) using a AgNO₃ catalyst, α-naphthylamines were obtained in up to 89% isolated yields within 2 h. Whereas indeno[1,2-c]pyrrolones were produced in high isolated yields in the presence of benzoyl peroxide (BPO) and CuCl catalysis.

Full text of DOI:10.1021/acs.orglett.6b02615

Letter
pubs.acs.org/OrgLett
Metal/Benzoyl Peroxide (BPO)-Controlled Chemoselective
Cycloisomerization of (o‑Alkynyl)phenyl Enaminones: Synthesis of
α‑Naphthylamines and Indeno[1,2‑c]pyrrolones
Fangfang Zhang, Zhengchen Qin, Lingkai Kong, Yulei Zhao, Yuanyuan Liu, and Yanzhong Li*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China
Normal University, 500 Dongchuan Road, Shanghai, 200241, China
S
* Supporting Information
ABSTRACT: Synthetic methods involving chemoselective tandem reactions for the synthesis of α-naphthylamines and
indeno[1,2-c]pyrrolones starting from (o-aklynyl)phenyl enaminones are described. When reactions were carried out in N,N-
dimethylformamide (DMF) using a AgNO3 catalyst, α-naphthylamines were obtained in up to 89% isolated yields within 2 h.
Whereas indeno[1,2-c]pyrrolones were produced in high isolated yields in the presence of benzoyl peroxide (BPO) and CuCl
catalysis.
romatic compounds containing nitrogen are of great
importance and abundance in nature.1 Among them,
compounds.10 We have disclosed novel protocols for the
selective synthesis of nitrogen- or oxygen-containing cyclic
and/or acyclic compounds starting from enaminones by
variation of catalysis systems, ensuring an α-carbon, oxygen,
or amino group as nucleophilic centers (Scheme 1).11 As part
of our continuing efforts to explore enaminone chemistry, we
envision that it might be possible to prepare different
heterocycles starting from exactly the same substrates by
A
arylamines are valuable building blocks and play important
roles as intermediates in synthesis of pigments, agrochemicals,
and pharmaceuticals.2 Substituted pyrroles as key structural
units are present in many bioactive compounds, natural
products, and functional materials.3 The development of
convenient and efficient methods for the synthesis of
arylamines and pyrrole derivatives has attracted considerable
attention. In the preparation of arylamines, the transition-metal-
mediated amination of aryl halides with amines and amides via
C(aryl)−N bond-forming processes has recently been regarded
as a powerful tool.2c,4 Other strategies for the synthesis of
naphthylamines includes the simultaneous construction of
aromatic rings. Recently, Wen’s group reported Cu-catalyzed
aminobenzannulation for the synthesis of α-naphthylamines.5
In 2009, Liang’s group developed a one-pot synthesis of β-
naphthylamines via Pd-catalyzed aminobenzannulation.6 Lu’s
group disclosed an intramolecular addition to a cyano group
initiated by nucleopalladation of alkynes to construct β-
naphthylamines.7 The synthetic methods to pyrrole derivatives
mainly include the classical approaches, modern transition-
metal-mediated cyclizations, multicomponent reactions, et al.8
Chemoselectivity in organic synthesis is of great value, and
controlling the selective reaction of one specific functional
group among several others is challenging.9 Enaminones as
versatile building blocks have several nucleophilic centers, such
as the α-carbon, oxygen, and amino group. They are widely
employed in synthetic organic chemistry, such as the
preparation of heterocycles, including alkaloids, α- and β-
amino acids, peptides, and other synthetically relevant
Scheme 1. Previous Work
Received: August 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02615
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Letter
tuning the reaction parameters. It is of great value from the
point of view of drug discovery, where rapid access to a broad
diversity of skeletal classes is required. Herein we report metal-
controlled selective reactions of o-alkynylphenyl enaminones
for the synthesis of α-naphthylamine and indeno[1,2-c]-
pyrrolone derivatives by modifying reaction conditions.
We started our study by investigating the reaction of the
enaminone 1a in the presence of different silver salts in
dimethylformamide (DMF) at 80 °C under air (Table 1, entries
desired naphthylamine was reduced to 73% (Table 1, entries 13
vs 16). When the reaction was performed under N2, 2a was
obtained in 86% yield (Table 1, entry 17). So, the optimal
reaction conditions for the preparation of 2a included 10 mol %
of AgNO3 as the catalyst and 2.0 equiv of the corresponding
arylamine as the additive at 80 °C in DMF under air.
With the optimized reaction conditions in hand, the scope of
this reaction was investigated on a series of enaminones with
different substituents of electronic properties (Figure 1). First,
a
Table 1. Screening of Reaction Conditions
catalyst
(mol %)
additive
(equiv)
time
(h)
yield
b
entry
solvent
(%)
1
Ag2SO4 (20)
AgOTf (20)
AgNO3 (20)
AgNO3 (10)
AgNO3 (10)
AgClO4 (10)
AgSbF6 (10)
AgPF6 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (5)
AgNO3 (10)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
toluene
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
−
−
−
−
−
−
−
−
−
−
−
6
38
34
69
68
2
5
3
6
4
6
c
5
17
3.5
3.5
3.5
5
52
6
58
7
53
8
43
9
trace
trace
trace
68
10
11
12
13
14
15
16
17
5
5
HOAc (2.0)
PhNH2 (2.0)
PhNH2 (3.0)
PhNH2(1.0)
PhNH2 (2.0)
PhNH2 (2.0)
6
2
86
2
79
2
80
Figure 1. Synthesis of α-naphthylamines. Unless otherwise noted, the
reactions were carried out in DMF with 2.0 equiv of corresponding
NH2R1 using 10 mol % of AgNO3 at 80 °C under air. Isolated yield.
2
73
d
2
86
a
Unless otherwise noted, the reactions were carried out at 80 °C
b
c
d
under air. Isolated yield. At room temperature. Under N2.
enaminones (1b−d) with different substituents on nitrogen
were examined and good to high yields of the corresponding
products were obtained, in which enaminone (1b) with a p-
methoxyphenyl group on nitrogen gave a lower yield than that
with electron-withdrawing groups (2b: 48% vs 2c: 77%, 2d:
76%). Second, the effects of substituents on the triple bond
terminus were investigated. Enaminones (1e−h) both with aryl
or alkyl groups were compatible in the reaction and produced
the desired naphthylamines in moderate to good yields,
respectively (Figure 1, 2e−2h). It is noteworthy that n-butyl
offered a good result (2h, 78% yield). A bulky group such as 1-
naphthyl resulted in a lower yield of the desired product (2g,
37% yield). Lastly, the electronic effect of R3 was examined
(2i−2l). An electron-donating group (−OMe) gave a good
yield of desired 2i. Enaminones with a highly electron-
withdrawing group (−CF3) provided much better yields of
the corresponding α-naphthylamine (2k, 89%; 2l, 83%).
In order to clarify the reaction mechanism, several controlled
reactions were performed. First, the reaction of 1a was carried
out with 10 equiv of H218O under optimized conditions to
check the oxygen source of α-naphthylamine 2a (Scheme 2a).
None of the product containing 18O was detected, indicating
that the carbonyl oxygen of the final product did not come
from H2O. The cross-reaction with different arylamines was
also investigated (Scheme 2b). When the reaction of 1a was
1−8). The results were not so promising when Ag2SO4 (20 mol
%, 6 h, 38% yield) and AgOTf (20 mol %, 5 h, 34% yield) were
employed in this system (Table 1, entries 1 and 2). When
AgNO3 was applied, the yield of 2a was increased to 69%, and
the same yield could be achieved with a reduced amount of
AgNO3 (10 mol %) (Table 1, entries 3 and 4). The yield of 2a
was decreased to 52% even after 17 h when the reaction was
carried out at room temperature (Table 1, entry 5). Moderated
yields were obtained using AgClO4 (58%), AgSbF6 (53%), and
AgPF6 (43%) in 3.5 h (Table 1, entries 6−8). In addition, 2a
was obtained as a yellow solid and characterized by X-ray
crystallography.
Next, the solvents and additives were screened with 10 mol
% of AgNO3 at 80 °C under air. Solvents, such as DMAc,
toluene, and 1,4-dioxane gave only a trace amount of the
desired 2a (Table 1, entries 9−11). HOAc (2.0 equiv) as an
additive had no influence on the reaction outcome, whereas
PhNH2 (2.0 equiv) shortened the reaction time and increased
the yield of 2a dramatically (Table 1, entries 4 vs 13). Then,
when the amount of PhNH2 was examined, it was found that
either an increase or a decrease in the amount of PhNH2
resulted in lower yields of 2a (Table 1, entries 14 and 15). By
lowering the amount of AgNO3 to 5 mol %, the yield of the
B
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Letter
(BPO) as the oxidants and DMAc as the solvent. Structural
identification of 3a was carried out by X-ray crystallography.
Thus, the scope of the reaction was explored using various
(o-alkynyl)phenyl enaminones with different electronic proper-
ties (Figure 2). This method is so efficient that reactions could
Scheme 2. Reaction Mechanism Investigation
carried out under the standard reactions with 4-chloroaniline (2
equiv) as the additive, a mixture of two products with different
substituted amino groups (2a, 27%; 2c, 54%) was obtained.
The ratio of 2a:2c was 1:2 which was the same as the ratio of
free arylamines in the system. It indicated that the amino group
of α-naphthylamine came from the free arylamine in this
reaction system, and the amino moiety of enaminone was
transformed to free amines during the reaction process.
Based on our results and reported work,12 a mechanistic
proposal is outlined in Scheme 3. The alkynyl moiety of 1a first
Scheme 3. Plausible Mechanisms
Figure 2. Synthesis of indeno[1,2-c]pyrrolones. Unless otherwise
noted, the reactions were carried out using 1.2 equiv of BPO with 10
mol % of CuCl in predried DMAc at 80 °C under N2. Isolated yield.
complete in 1 h with all of the substrates screened. For the
substituents R1 on the nitrogen, substrates with both electron-
withdrawing and -donating groups on the aryl ring were
suitable for the reaction, offering the desired products (3a−3h)
in yields of 45−83%. Among which electron-rich aryl groups
gave slightly higher yields (3b, 62% yield; 3c, 78% yield) than
those with electron-poor aryl groups (3f, 52% yield; 3g, 54%
yield). The bulky groups resulted in relatively lower yields (3d,
47% yield; 3e, 45% yield; 3h, 70% yield). For the substituents
on the triple bond, excellent yields were obtained with either
electron-rich or -poor aryl groups (3j, 90%; 3l, 90%; 3m, 90%
yield) with the exception of a bulky substituent (3k, 45% yield),
while the p-tolyl group afforded 3i in 54% yield. Substrates
bearing different R3 groups were also compatible in the reaction
to give the corresponding products 3n and 3o in good yields,
respectively.
To understand the reaction mechanism, several controlled
experiments were carried out with 1a (Scheme 4). When the
reaction was performed in the absence of BPO, 2a was obtained
in 46% yield with no detection of 3a. On the other hand,
reaction of 1a in the absence of CuCl resulted in a complex
mixture. These results indicate that both CuCl and BPO are
essential for the formation of 3a. When the reaction was
performed in the presence of TEMPO (1.0 equiv), 1a was
is activated by silver and attacked by the oxygen of the carbonyl
group yielding an oxonium ion as intermediate A. Nucleophilic
attack of H2O to the carbonyl group followed by ring opening
via protonation gives intermediate C. Protonolysis of C
provides D. Z/E isomerization gives F. Intramolecular
annulation of intermediate F forms six-membered ring G.
Free aniline relieved from intermediate G attacks the newly
formed carbonyl group to give imine I, followed by
aromatization to give desired product 2a.
Considering the interesting structure of substrate 1a, we
envisioned that different modes of reactivity may be accessed by
modification of reaction conditions, such as the addition of
oxidants. Thus, K2S2O8 (1.5 equiv) was added to the reaction
system under the aforementioned optimal reaction conditions.
Unfortunately, a complex reaction mixture was detected.
Interestingly, when CuCl was used instead of AgNO3, a new
product of indeno[1,2-c]pyrrolone 3a was generated selectively
over 2a. To improve the yield of 3a, different reaction
parameters, such as temperature, solvents, and oxidants, were
screened (see Supporting Information, Table S1). It was found
that the best result for the synthesis of 3a was to use 10 mol %
CuCl in combination with 1.2 equiv of benzoyl peroxide
C
DOI: 10.1021/acs.orglett.6b02615
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Letter
and Innovative Research Team in University (PCSIRT) for
financial support.
Scheme 4. Control Experiments
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02615.
■
S
X-ray crystallographic data for 2a (CIF)
X-ray crystallographic data for 3a (CIF)
Experimental details and spectroscopic characterization
of all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yzli@chem.ecnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(grant no. 21272074) and the Program for Changjiang Scholars
■
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DOI: 10.1021/acs.orglett.6b02615
Org. Lett. XXXX, XXX, XXX−XXX