Cu(i)-catalyzed intramolecular oxidative C-H amination of 2-aminoacetophenones: A convenient route toward isatins

Article abstract of DOI:10.1039/c3cc44435j

2-Aminoaryl methyl ketones undergo intramolecular oxidative C-H amination to give the corresponding substituted isatins under an oxygen atmosphere in the presence of [CuI(bpy)]₂. The Royal Society of Chemistry 2013.

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Cu(I)-Catalyzed Intramolecular Oxidative CH Amination of
2-Aminoacetophenones: a Convenient Route toward Isatins
Pang-Chi Huang, Parthasarathy Gandeepan and Chien-Hong Cheng*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Isatins are an important class of heterocyclic compounds due
2-Aminoaryl methyl ketones undergo intramolecular
oxidative CH amination to give the corresponding
substituted isatins under an oxygen atmosphere in the
presence of [CuI(bpy)]2.
to their biological activity and wide applications in the synthesis
of heterocyclic compounds.7 They were also known as
anticonvulsant, antidepressant, antiinflammatory, antimicrobial,
40 antipox virus, and cytotoxic agents.8
10 Transition-metal-catalyzed
construction
of
CC
and
Table 1. Optimization studies for the formation of N-methylisatina
Cheteroatom bonds has become a proven method for the
synthesis of bioactive compounds and advanced materials.1 In
recent years, great effort has been made toward the direct
functionalization of CH bond rather than the pre-functionalized
15 carbon-halogen or carbon-pseudohalogen bond of which
additional steps are required for preparation.2 However, most of
these reactions require the use of expensive Pd-, Rh-, Ru- and Ir-
complexes as catalysts. Lately, copper-catalyzed CH
functionalization reactions have gained great attention due to
20 their cost effectiveness, availability, low toxicity and wide
entry
CuI/bpy, mol%
solvent
DMF
T °C
140
140
140
140
120
140
140
140
140
140
yield %b
68
1
2
10
5
DMF
22
functional
group
tolerances.3
Copper-catalyzed
cross
3
20
20
10
10
10
10
10
---
DMF
67
dehydrogenative coupling (CDC) transformations via a single
electron transfer (SET) mechanism allow the access of complex
structures in a single step and can be applied to the CC, CN,
25 CO, Chalogen, and CP bond formations.4 Recently, Jiao and
Ji groups had independently developed an attractive method for
the formation of α-ketoamides from phenyl acetaldehydes or aryl
methyl ketones with amines.5 In this reaction, both the oxygen
atoms of α-ketoamides are deduced from the molecular oxygen.
30 Our recent success in the transition metal-catalyzed CH
activation and heterocyclic compound synthesis6 prompt us to
explore the possibility of direct oxidative synthesis of isatins
from ortho-aminoaryl methyl ketones (Scheme 1).
4
DMF
59c
5
DMF
31
6
DMAc
o-DCB
o-xylene
DMSO
DMSO
65
7
47
8
26
9
91 (89)d
---
10
a Unless otherwise mentioned, all reactions were carried out using 1a
(0.3 mmol), CuI (0.03 mmol) and bpy (0.03 mmol) in 0.6 mL solvent
b
for 12 h under O2 atmosphere. Yields were determined by the 1H
NMR integration method using CH2Br2 as the internal standard. c 1.2
d
mL DMF was used. Isolated yield. bpy = 2,2'-bipyridine. DMAc =
N,N-dimethylacetamide. o-DCB = 1,2-dichlorobenzene.
The most commonly used method for the preparation of isatin is
45 the Sandmeyer procedure by treating a substituted aniline with
chloral hydrate and hydroxylamine hydrochloride (or other
hydroxylamine salt) in an aqueous sodium sulfate medium.9
Another frequently used method developed by Stollé involves the
treatment of an aniline with oxalyl chloride followed by a
50 Friedel-Crafts intramolecular acylation in the presence of a strong
Lewis acid.10 Since both methods involves intramolecular
electrophilic aromatic cyclization, the reactions are highly limited
35
Scheme 1
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Table 3. Scope and results of CuI-catalyzed N-arylisatins synthesisa,b
to substrates with electron-donating substituents on the aromatic
rings. Other traditional methods11 also have some drawbacks such
as the requirement of strong acid or base condition and the
availability of starting materials. Recent report by Li et al.
involving the CuCl2-catalyzed intramolecular cyclization of
formyl-N-arylformamides to give isatins appears to be the only
method available using transition metal complex as the catalyst.12
A drawback of this reaction is the formation of inseparable
regioisomers for meta substituted substrates. Due to wide
5
10 applications of isatins in organic synthesis and medicinal
chemistry, the development of new and effective routes for their
synthesis is still highly desirable. Herein, we report a convenient
method for the synthesis of isatins from 2-aminoacetophenones
via copper-catalyzed intramolecular oxidative CH amination.
15
Treatment of 1-(2-(methylamino)phenyl)ethanone (1a) in the
presence of 10 mol% CuI/bpy in DMSO at 140 C for 12 h under
an oxygen atmosphere gave N-methylisatin (2a) in 89% isolated
yield (Table 1, entry 9). Product 2a was thoroughly characterized
1
by its H and 13C NMR and mass data. The solvent employed is
20 vital to the catalytic reaction. Other solvents such as DMF,
DMAc, o-DCB also gave 2a in 68, 65 and 47% yields,
respectively (see Supporting Information for detailed studies). It
is important to mention that controlled experiment showed that in
the absence of CuI, no desired product 2a was obtained (Table 1,
25 entry 10).
Table 2. Scope of CuI-Catalyzed N-alkylisatins synthesis a,b
35 a Unless otherwise mentioned, all reactions were carried out using N-aryl
2-aminoacetophenones 1 (0.3 mmol), CuI (0.03 mmol) and bpy (0.03
mmol) in 0.6 mL o-DCB at 140 C for 3 h under O2 atmosphere. b Isolated
yields. c 120 C, 12 h.
By using the standard reaction conditions, various substituted
40 1-(2-(alkylamino)aryl)ethanone were converted to N-alkylisatins
in good to excellent yields (Table 2). Thus, N-methyl, propyl, 2-
methoxyethyl substituted isatins (2a-2c) were synthesized in 89,
86 and 71% yields respectively. 5-Methyl and 4,6-dimethyl
substituted isatin derivatives 2d and 2e are obtained in 62 and
45 71% yields respectively. The catalytic reaction is compatible
nicely with the halo substituents on the aromatic ring to form
corresponding isatins. Thus, bromo-substituted isatin 2f was
produced in 77% yield. Similarly, 5,6-methylenedioxy isatin 2g is
formed in 67% yield at 120 C. N-Benzyl substituted isatin 2h is
50 formed from the corresponding 2-aminoacetophenone in 58%
yield. 2-Acetylaniline underwent the transformation to give isatin
2i in moderate yield. Electron withdrawing groups on the amino
group failed to give desired products (2j and 2k).
The copper-catalyzed intramolecular oxidative CH amination
55 reaction
was
successfully extended
to
N-aryl
2-
aminoacetophenones (Table 3), but the reaction conditions were
modified. The solvent used was changed from DMSO to 1,2-
dichlorobenzene (o-DCB) leading to completion of the reaction in
3 h. Thus, N-phenylisatin 2l is obtained in 70% yield using the
60 standard reaction conditions. Similarly, substrates 1 with N-aryl
group containing Me, F, Br, CF3, and OMe substituents gave the
corresponding isatins (2m-2t) in good yields. This reaction also
provided 5,6-methylenedioxy- and bromo substituted isatins 2s
and 2t from the corresponding substrates 1 in 45 and 61% yields
a Unless otherwise mentioned, all reactions were carried out using N-alkyl
30 2-aminoacetophenones 1 (0.30 mmol), CuI (0.03 mmol) and bpy (0.03
b
mmol) in 0.6 mL DMSO at 140 C for 12 h under O2 atmosphere.
Isolated yields. c 120 C. d 130 C.
2
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The mechanism for the present catalytic reaction is not yet
clear. Based on the present results and the known copper
chemistry in literature,5,13 we propose a possible pathway for this
CuI-catalyzed isatin formation as shown in Scheme 2. Under the
reaction conditions, 2-aminoglyoxal A is expected to be formed
from 2-aminoaryl methyl ketone 1.5b The intramolecular addition
of amino group to the aldehyde group of glyoxal A results in the
formation of 2-hydroxyindolin-3-one derivative B which is
5
55
60
65
70
75
80
10 further oxidized by Cu(I)/O2 to form the final product 2.5b,13,15
4
5
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6
Scheme 2
7
In conclusion, we have successfully developed a convenient
Cu(I)-catalyzed intramolecualr oxidative CH amination reaction
15 of 2-aminoacetophenones for the synthesis of isatins. This
reaction allows the synthesis of various N-alkyl or aryl
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*Department of Chemistry, National Tsing Hua University, Hsinchu
25 30013, Taiwan Fax: 886-3-5724698; Tel: 886-3-5721454; E-mail:
chcheng@mx.nthu.edu.tw
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