Copper powder-catalyzed chelation-assisted cascade reaction of: O -chloroarylacetic acids with amines under solvent- and ligand-free conditions: Synthesis of oxindoles

Article abstract of DOI:10.1039/c7ra08123e

An efficient method to construct oxindole scaffolds from o-chloroarylacetic acids/esters with amines has been explored. This cascade protocol involves the in situ generation of o-aminoarylacetic acid derivatives by the copper powder catalyzed and weak O-chelation assisted Ullmann amination of unactivated C-Cl bonds under air, and solvent-/ligand-free conditions followed by annulative N-acylation.

Full text of DOI:10.1039/c7ra08123e

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Copper powder-catalyzed chelation-assisted
cascade reaction of o-chloroarylacetic acids with
amines under solvent- and ligand-free conditions:
synthesis of oxindoles†
Cite this: RSC Adv., 2017, 7, 45227
*
Jiang-Sheng Li,
Guo-Qin Chen, Qian Yang, Zhi-Wei Li, Ci-Zhi Liu
and Peng-Mian Huang
Received 23rd July 2017
Accepted 15th September 2017
An efficient method to construct oxindole scaffolds from o-chloroarylacetic acids/esters with amines has
been explored. This cascade protocol involves the in situ generation of o-aminoarylacetic acid derivatives
by the copper powder catalyzed and weak O-chelation assisted Ullmann amination of unactivated C–Cl
bonds under air, and solvent-/ligand-free conditions followed by annulative N-acylation.
DOI: 10.1039/c7ra08123e
rsc.li/rsc-advances
Oxindoles are privileged heterocycles prevalent in naturally derivatives are far less used. The methods documented include
occurring products and pharmacologically active compounds the nitro reduction/intramolecular cyclization of o-nitro-
(Fig. 1),1 and they also serve as important precursors in drug phenylacetic acid,2g the intramolecular oxidative amidation of
design and organic synthesis.1b Over the past few decades, an N-acetoxy-2-phenylacetamides,2g and the intramolecular
array of efficient methods have been developed to access oxin- Ullmann-type N-arylation of o-halophenylacetamides.2g,5 The
doles. Basically, these methods involve the derivatization of former two limit to the preparation of free NH oxindoles. The
three types of starting materials: anilide derivatives,2 isatins2g,3 latter provides a powerful strategy for the construction of
or indoles,2g,4 and arylacetic acid derivatives.2g,5 One of the most oxindoles functionalized at N-, C3-positions. For instance,
remarkable features is the pre-installation of a nitrogen- Turner's group has reported the access to oxindoles via
containing functional group on the precursors. Among them, sequential
amide
formation/palladium-catalyzed
intra-
the use of anilide derivatives is predominate in contemporary molecular amidation in two steps (Scheme 1a),5 wherein the
organic synthetic methodologies, whereas arylacetic acid expensive noble metal catalyst, toxic phosphine ligand, and
strong base are required besides the high temperature of
ꢀ
150 C. To our knowledge, the direct construction of oxindole
scaffold by the introduction of amino group to the benzene ring
of o-haloarylacetic acids, especially o-chloroarylacetic acids, is
yet unexplored.
Copper catalyzed Ullmann-type reaction of arylic C-halo
bonds has emerged as a fundamental tool for C–N bond
Fig. 1 Naturally occurring and pharmaceutical oxindoles.
Hunan Provincial Key Laboratory of Materials Protection for Electric Power and
Transportation, School of Chemistry and Biological Engineering, Changsha
University of Science & Technology, Changsha 410114, P. R. China. E-mail: jsli@
csust.edu.cn; Fax: +86-731-85258733
† Electronic supplementary information (ESI) available: Detailed experimental
Scheme 1 The representative C–N bond formation and access to
oxindoles from o-haloarylacetic acids.
procedures and copies of NMR spectra are included. See DOI: 10.1039/c7ra08123e
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formation in academic and industrial elds.6 These protocols as the catalyst in the absence of any additive, and the cyclized
usually require ligands, and in particular hardly avoid using product oxindole 3aa was obtained in 77% yield (entry 1). This
organic solvents such as DMSO, DMF, and NMP. Later on, Wei positive result suggested that the carboxyl group tethered at
reported a copper powder catalyzed amination of aromatic ortho position did facilitate the C–Cl Ullmann reaction via ortho
C-halo bonds without ligands in water,7 which allows efficient chelating effect,10 just like acting as a directing group in C–H
access to C–N bonds from C–I, C–Br bonds, and some C–Cl activation. Reducing the water volume, the 2a equivalent or the
bonds (Scheme 1b). However, the substrates without electron- catalyst loading resulted in lower efficiency (entries 2, 3, 6).
withdrawing groups (e.g. chlorobenzene and p-chloroanisole) Prolonging the reaction time or elevating the reaction temper-
are inert in such a transformation. Consequently, the trans- ature enhanced the yield while shortening the time or lowering
formation of simple arylic C–Cl bonds remains a challenge.6a
the temperature diminished the efficiency (entries 4 vs. 5, 7 vs.
In the realm of C–H activation, a carboxyl group acts as an 8). It is worthwhile to note that the activated copper powder
effective directing group to promote coupling reactions by weak delivered a comparable yield of 78% (entry 9). Interestingly, the
O-coordination with the metal centers of catalysts.8 Yu reported higher yield of 85% resulted under solvent-free condition (entry
some elegant transformations of arylacetic acids C–H bonds 10). As expected, no reaction occurred under N2 atmosphere
directed by carboxyl groups.8b–i We speculated that the COOH (entry 11), which further conrmed that the small amount of O2
group will also facilitate copper powder catalyzed Ullmann is essential in the copper powder catalyzed transformation as
amination through the activation of C–Cl bond, and then pointed out by Wei.7 Other copper sources such as cuprous salts
subsequent intramolecular cyclization will give oxindole scaf- (CuCl, CuBr) or oxide (Cu2O) could also catalyze this cascade
folds. Following our continuous interest in the synthesis of reaction under N2 atmosphere, providing the similar yields
heterocycles,9 herein, we present a facile and efficient cascade (entries 12–14). The cupric species (CuCl2$2H2O, CuO) were
protocol for the construction of oxindole derivatives from ineffective in water and N2 systems (entries 14 & 15). Intrigu-
readily available o-chlorophenylacetic acids with amines cata- ingly, they could trigger the current transformation with less
lyzed by copper powder under air and neat conditions efficacy (58% & 65%) under the solvent-free and N2 conditions.11
(Scheme 1c).
These results revealed that the catalytically active species is
o-Chlorophenylacetic acid 1a and ethylamine 2a were chosen Cu(I).7 Thus, the optimum conditions for this cascade reaction
as prototype substrates for this cascade reaction (Table 1). The were summarized as follows: 1a (2 mmol), 2a (10 mmol), Cu
reaction proceeded smoothly in water with a small amount of powder (10 mol%) all sealed in a 15 mL reaction tube under air
air sealed in the tube when copper powder (10 mol%) was used atmosphere, stirring at 100 ꢀC for 16 h, affording N-ethyl
indolin-2-one 3aa in 85% yield.
With the optimized reaction conditions in hand, we set out
to investigate the scope of amines 2 for this copper powder
Table 1 Screening optimal conditions for cascade cyclizationa
catalyzed C–Cl amination and the results are compiled in
Table 2. In general, all the tested aliphatic primary amines are
effective substrates with o-chlorophenylacetic acid 1a, providing
the corresponding 3-unsubstituted oxindoles in moderate to
Table 2 Substrate scope for 3-unsubstituted oxindolesa
Entry
Cat. (mol%)
Temp. (oC)
Time (h)
Yieldb (%)
1
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (5)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
Cu (10)
CuCl (10)
CuBr (10)
Cu2O (5)
CuO (10)
CuCl2 (10)
100
100
100
100
100
100
80
120
100
100
100
100
100
100
100
100
16
16
16
12
24
16
16
16
16
16
16
16
16
16
16
16
77
70
66
73
82
66
67
80
78
85
N. R.
67
67
80
N. R.
Trace
2c
3d
4
5
6
7
8
9e
10f
11f,g
12g
13g
14g
15g
16g
a
Reaction conditions: 1a (2 mmol), 2a (10 mmol), Cu powder or other
a
copper catalyst, H2O (2 mL, not degassed) added to a 15 mL sealed
Reaction conditions: 1 (2 mmol), 2 (10 mmol), Cu powder (10 mol%) in
b
tube under air atmosphere, 100 ꢀC unless otherwise stated. Isolated
a 15 mL sealed tube, 100 ꢀC for 16 h unless otherwise stated. Isolated
yields based on the acids. The use of o-bromophenylacetic acid as
the precursor.
c
d
e
b
yields. H2O (1 mL, not degassed). 3 equiv. of 2a. Cu powder
f
g
activated by I2 in acetone. Without water. Under N2. N. R. means
no reaction.
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Table 3 Substrate scope for 3-substituted oxindolesa
good yields (entries 3aa–3af). The amines with longer chains
gave relatively lower yields (3aa, 3ab, 3ac). The straight-chain
amine 2c was preferred over the branched-chain one 2d.
Benzyl amine 2e delivered the desired product only in 57% yield
when the reaction time was xed at 24 h (3ae). Noteworthy,
aqueous methyl amine 2f afforded oxindole 3af in 82% yield,
and aqueous ammonium gave free NH oxindole 3ag in 80%
yield. Besides, the o-bromophenylacetic acid instead of 1a
generated a comparable yield of 87%.
When aromatic amines were used instead, for example,
aniline, o/p-toluidines, o/p-anisidines, and p-chloroaniline, no
obvious N-arylated oxindoles were observed (3ah), even in the
case of strong nucleophilic p-anisidine, but their corresponding
amides 4ah were veried based on NMR and MS analysis (please
see ESI†). The additional bases (e.g. NaOH 2.0 equiv., t-BuONa
2.0 equiv.) could not trigger Ullmann-type C–N bond formation,
even in higher temperature (120 ꢀC or 130 ꢀC). This failure
might be ascribed to the weaker nucleophilicity of aromatic
amines than that of aliphatic amines.
When 2,4-dichlorophenylacetic acid 1b and 2,6-dichlor-
ophenylacetic acid 1c were used in this transformation, their
corresponding oxindoles were obtained. It is worth noting that
in the former case the Ullmann-type amination reaction
occurred selectively at the ortho C–Cl bond of carboxylates (3ba
& 3bf). In both cases, no sequential Ullmann-type amination
process re-occurred at the other C–Cl bond. These results sug-
gested that the tethered carboxyl group presumably plays an
essential role in this cascade reaction. Besides, it should be
noted that further oxidation products such as 3-hydroxylox-
indoles or isatins were not observed although oxindole C3–H
bonds are very reactive to O2 in all the cases of the aforemen-
tioned 3-unsubstituted oxindoles.
a
Reaction conditions: 1 (2 mmol), 2 (10 mmol), Cu powder (10 mol%) in
a 15 mL sealed tube, 100 ꢀC for 24 h. Isolated yields based on the
substrates 1. Z/E ratios were calculated from the isolated isomer yields.
Scheme 2 Tandem cyclization from hydrazines or hydroxylamine.
The synthesis of 3-monosubstituted oxindoles remains
a challenge. Because 3-unsubstituted oxindoles are reactive
enough to alkylation, sequential double alkylation usually
occurs. Normally, they are produced via post-functionalization, aqueous hydrazine 2i is an effective coupling partner, and its
for example, by the condensation of 3-unsubstituted indolin-2- desired product N-amino oxindole 3ai was obtained in 70%
ones with carbonyl compounds followed by reduction. As such, yield aer 24 h of reaction. However, N-phenyl hydrazine 2j gave
we attended to extend this cascade reaction to the synthesis of 3- a negative result. Hydroxylamine hydrochloride 2k was used,
monosubstituted oxindoles. Delightedly, 2-alkylated o-chlor- even in combination with equivalent base (e.g. NaOH, Et3N),
ophenylacetic acid esters can be smoothly converted into and no product was detected except with the starting acid 1a
3-alkylated oxindoles in moderate yields (3da, 3df, 3ea, 3ef, recovered.
Table 3). In these cases, it is not necessary to use the acetic acids
To explore the application possibility of this chemistry in
as precursor. Additionally, the use of 2-(2-chlorophenyl)acrylic industry or organic synthesis, the scale-up experiment was
acids 1f–k were attempted, and the desired 3-methyleneindolin- carried out. When 10 mmol of 1a was used to react with ethyl-
2-ones were furnished in acceptable yields (3fa–3ka). In the amine 2a in a 48 mL sealed tube under the standard conditions,
cases of 1g–I, the products were mixtures of Z/E isomers, which the reaction proceeded smoothly, providing 80% yield of 3aa
can readily be isolated by preparative thin-layer chromatog- with a small amount of 1a detected aer 16 h.
raphy. Interestingly, as for the acids 1j & 1k, only the E-isomers
To gain an insight into the mechanism of this cascade
were isolated in yields of 52% & 50%, respectively. The cong- reaction, simple experiments were carried out to unveil the
urations of all the isomers were assigned based on the docu- cascade process. When methyl 2-chlorophenylacetamide was
mented reports including the results of Studer.12 Noteworthy, used as cyclization precursor under the standard conditions,
no aza-Michael adducts resulted under standard conditions, intramolecular cyclization to indolin-2-one did not occur with
although 3fa–ka, especially 3ha and 3ia, are good Michael the amide almost fully recovered (Scheme 3). This result
acceptors.
excluded the possibility of a sequential amide formation/
Aer the investigation of amines, their analogues hydrazines intramolecular Ullmann-type N-arylation process. When the
or hydroxylamine were attempted (Scheme 2). Interestingly, ester of 1f reacted with ethylamine 2a, no reaction also
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (21202010), Scientic Research Fund of Hunan Provin-
cial Education Department (16B003), Hunan Provincial Natural
Science Foundation of China (2017JJ2275 & 2015JJ3012), the
Hunan Provincial Key Laboratory of Materials Protection for
Electric Power and Transportation (2015CL05), Changsha
University of Science & Technology, P. R. China.
Scheme 3 Control experiments.
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We have disclosed a ligand- and solvent-free catalytic approach
to access oxindoles from o-chloroarylacetic acids with amines
using copper powder via one pot sequential Ullmann type
amination, and annulative N-acylation. The ortho chelating
effect of a carboxyl/ester group and the presence of a small
amount of O2 both play essential roles in the C–Cl activation
and catalytic activity of copper powder. In view of its efficiency
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