Copper-catalyzed intramolecular oxidative C(sp3)-H amidation of 2-aminoacetophenones: Efficient synthesis of indoline-2,3-diones

Article abstract of DOI:10.1002/ejoc.201400012

An efficient synthesis of diverse indoline-2,3-diones from 2-aminoacetophenones through copper-catalyzed intramolecular C(sp³)-H amidation is developed. The reaction proceeds in DMSO by using O₂ as the sole oxidant to provide the desired products in moderate to good yields.

Full text of DOI:10.1002/ejoc.201400012

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201400012
Copper-Catalyzed Intramolecular Oxidative C(sp3)–H Amidation of
2-Aminoacetophenones: Efficient Synthesis of Indoline-2,3-diones
Jinbo Huang,*[a] Tingting Mao,[a] and Qiang Zhu*[a]
Keywords: Nitrogen heterocycles / Fused-ring systems / Amidation / Copper / C–H activation
An efficient synthesis of diverse indoline-2,3-diones from 2-
aminoacetophenones through copper-catalyzed intramolec-
ular C(sp3)–H amidation is developed. The reaction proceeds
in DMSO by using O2 as the sole oxidant to provide the de-
sired products in moderate to good yields.
paid to the preparation of this valuable structural unit since
1840.[10–12] The traditional synthesis of isatins mainly in-
volves strong acid (often H2SO4) or base-mediated conden-
sation of aniline with oxalyl chloride (Stollé procedure),[13]
diethyl ketomalonate (Martinet procedure),[14] or chloral
hydrate (Sandmeyer procedure).[15] However, these reac-
tions suffer from relatively harsh reaction conditions, poor
yields, limited diversity, and the need for an excess amount
of the acid or base. Recently, the strategy of transition-
metal-catalyzed C–H activation[16] was also applied to the
synthesis of isatins. In this context, Li and co-workers re-
ported an efficient synthetic route involving the copper-cat-
alyzed intramolecular C–H oxidation/acylation of formyl-
N-arylformamides (Scheme 1, path a).[17] Later on, Fu and
co-workers disclosed the copper-catalyzed selective acyl-
ation of secondary anilines with ethyl glyoxalate for the syn-
thesis of isatin derivatives (Scheme 1, path b).[18] Other
methods to build this useful scaffold include the copper-
catalyzed tandem oxidative cyclization of arylacetamides
Introduction
In the past decade, the direct transformation of C–H to
C–N bonds catalyzed by transition metals has been recog-
nized as a step-efficient and environmentally benign alter-
native to traditional C–N bond-forming methods for the
synthesis of azaheterocycles.[1] Notable progress has been
made by using ruthenium-,[2] rhodium-,[3] and palladium-
based[4] systems, in which stoichiometric or excess amounts
of oxidants, such as Cu(OAc)2, AgOAc, 1,4-benzoquinone,
CeSO4, and/or F+, are generally used to achieve catalyst
turnover.[2–4] More recently, much cheaper copper salts
along with dioxygen as the terminal oxidant have been used
in direct C–H/C–N oxidative coupling processes.[5,6] Despite
significant advances in Cu/O2 catalytic systems in C–H
cycloamination reactions, examples of azaheterocycle con-
struction through C(sp3)–H amination or amidation are
still limited. In 2012, Du and Ji reported an efficient cop-
per-catalyzed intermolecular C(sp3)–H amidation reaction
to form α-ketoamides from aryl methyl ketones, amines,
and molecular oxygen.[7] Very recently, MacMillan devel-
oped a general approach to the synthesis of complex α-
amino carbonyls through a copper-catalyzed aerobic oxi-
dative C(sp3)–H amination reaction.[8]
through
a tandem C–O/C–N bond-forming process
(Scheme 1, path c).[19] Although these strategies provide ac-
cesses to isatin derivatives, the development of alternative
practical approaches starting from readily available sub-
strates is still desirable.
Indoline-2,3-dione derivatives (or isatins), such as arund-
aphine, tenidap, and maremycin B,[9] show a wide range of
biological and pharmacological activities (Figure 1). More-
over, isatins are synthetically versatile building blocks for
the synthesis of various heterocyclic compounds,[10] such as
isatoic anhydrides, indoles, quinolines, and spiro-fused
frameworks.[11] As a result, continuous efforts have been
[a] State Key Laboratory of Respiratory Disease, Guangzhou
Institutes of Biomedicine and Health, Chinese Academy of
Sciences,
Figure 1. Representative biologically active indoline-2,3-dione ana-
logues.
190 Kaiyuan Avenue, Guangzhou 510530, China
E-mail: huang_jinbo@gibh.ac.cn
During the preparation of this manuscript, Ilangovan re-
ported the conversion of 2Ј-N-aryl/alkylaminoacetophen-
ones into isatins by using the divalent copper catalyst
Cu(OAc)2 (50 mol-%) in the presence of NaOAc
zhu_qiang@gibh.ac.cn
http://www.gibh.cas.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400012.
Eur. J. Org. Chem. 0000, 0–0
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J. Huang, T. Mao, Q. Zhu
Table 1. Optimization of the reaction conditions.[a]
SHORT COMMUNICATION
Entry
Cat.
[20 mol-%]
Additive
[1.0 equiv.]
Solvent
Yield[b]
[%]
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr
Cu(OAc)2
Cu(OTf)2
Cu(tfa)2
CuCl
–
–
–
–
–
–
–
–
–
–
–
–
DMF
DMA
NMP
n.d.
n.d.
36
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
68[c]
15
n.d.
n.d.
Scheme 1. Major approaches to isatin derivatives.
53
9
CuI
76[c]
10
11
12
13
14
15
16
17
CuOAc
CuBr/Me2S
CuTc
–
CuI
CuI
66
60
(1.5 equiv.).[20] Herein, we would like to report a similar re-
action catalyzed by monovalent copper CuI (20 mol-%) un-
der acidic conditions (1 equiv. of PivOH) with O2 as the
terminal oxidant.
78[c] (60)[d]
–
n.d.
PivOH
CF3CO2H
Cs2CO3
K2CO3
84[c] (Ͻ5)[e]
63
30
45
CuI
CuI
[a] Unless otherwise stated, the reactions were performed at 130 °C
under an atmosphere of O2 (101.3 kPa) by using 1a (0.2 mmol),
catalyst (0.04 mmol), and additive (0.2 mmol) in solvent (2 mL) for
23 h. Cu(OTf)2 = copper(II) trifluoromethanesulfonate, Cu(tfa)2 =
copper(II) trifluoroacetate, CuTc = copper(I) thiophene-2-carb-
oxylate, PivOH = trimethylacetic acid, NMP = N-methyl-2-pyrrol-
idone, DMA = dimethylacetamide, NMP = N-methylpyrrolidone,
n.d. = not determined. [b] Yields were determined by NMR spec-
troscopy. [c] Yield of isolated product. [d] 120 °C. [e] The reaction
Results and Discussion
We commenced our investigation with 2-(methylamino)-
acetophenone (1a) as the substrate in the presence of vari-
ous copper catalysts under an atmosphere of O2, as summa-
rized in Table 1. Our initial trials with 20 mol-% of CuBr in
DMF and DMA at 130 °C under an oxygen balloon failed
to generate desired product 2a (Table 1, entries 1 and 2). To was performed under an Ar atmosphere.
our delight, this reaction afforded product 2a in 36% yield
in NMP (Table 1, entry 3). The yield of 2a was increased to
68% upon switching the solvent to DMSO (Table 1, en- products were obtained in moderate to good yields. In gene-
try 4). Of all the cuprous salts screened, CuTc and CuI were ral, substrates with electron-donating groups were more re-
the two best catalysts (Table 1, entries 5–12). A control re- active (see 2b–f). Halogen atoms in substrates remained in-
action in the absence of any copper salt confirmed that the tact during the reaction (see 2c–e, 2g), and this provides the
transformation did not occur even at a high temperature opportunity for further elaboration of the scaffold. More-
(Table 1, entry 13). In addition, lowering the reaction tem- over, N-ethyl- and N-allyl-protected substrates were also
perature to 120 °C decreased the yield considerably compatible with the reaction conditions, and the cyclized
(Table 1, entry 12). The effects of acidic and basic additives products were delivered in good yields (see 2h and 2i). Sub-
were also investigated (Table 1, entries 14–17). Pleasingly, stituents on the N-aryl ring were also investigated. Func-
the yield of 2a was improved to 84% (Table 1, entry 14) if tional groups such as methoxy (see 2k), methyl (see 2l, 2m),
pivalic acid (1.0 equiv.) was added. However, alteration of chloro (see 2n), bromo (see 2o), and nitro (see 2p) groups
the amount of pivalic acid did not improve the yield of 2a on the N-aryl moiety were well tolerated, and the corre-
further (see Table S1, Supporting Information). Moreover, sponding products were delivered in moderate to good
the reaction was shut down if it was performed under an yields. However, the substrate bearing a cyano group at the
atmosphere of Ar, which suggests that O2 played a vital para position was less compatible with the oxidative and
role in this process (Table 1, entry 14). In contrast, basic acidic conditions (see 2q, 26%). In addition, an N-free sub-
additives including Cs2CO3 and K2CO3 gave poor results strate also survived the conditions (see 2r), albeit in low
(Table 1, entries 16 and 17). Finally, the reaction conditions yield. Notably, a benzylic C–H bond adjacent to the amine
involving 1a (2 mmol), CuI (20 mol-%), PivOH (1.0 equiv.), remained intact under the oxidative conditions, and desired
under an atmosphere of O2 (101.3 kPa) at 120 °C in DMSO N-benzylisatin (2s) was obtained in moderate yield. How-
were identified.
ever, electron-withdrawing N-protecting groups such as
With the optimized conditions in hand, we then explored acetyl and tosyl did not tolerate the reaction (see 2t, 2u),
the scope of the reaction (Scheme 2). Various substituents and the starting materials remained intact under the stan-
on the benzene ring worked well, and the corresponding dard conditions.
2
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Efficient Synthesis of Indoline-2,3-diones
Scheme 2. Copper-catalyzed intramolecular oxidative amidation. Reaction conditions: 1 (0.2 mmol), CuI (10 mol-%), PivOH (1.0 equiv.)
in DMSO (2 mL) at 130 °C under an atmosphere of O2 for 23 h, yields of the isolated products are reported; Ts = p-tolylsulfonyl.
Notably, 1-[2-(methylamino)phenyl]propan-1-one (3a), 1-
[2-(methylamino)phenyl]pentan-1-one (3b), 1-[2-(meth-
ylamino)phenyl]hexan-1-one (3c), and cyclopentyl[2-(meth-
ylamino)phenyl]methanone (3d) all underwent oxidative
cleavage of the C–C bond to produce 2a in 45–72% yield,
as determined by NMR spectroscopy, under the same con-
ditions (Scheme 3). The expected product, 2-hydroxy-
indolin-3-one, was not detected. Interestingly, 3-methyl-1-
[2-(methylamino)phenyl]butan-1-one (4) was successfully
cyclized to give 2-hydroxy-2-isopropyl-1-methylindolin-3-
one (5), which demonstrates that this approach is applicable
to the synthesis of 2-hydroxyindolin-3-one derivatives.
To gain insight into this reaction mechanism, radical-
trapping experiments were performed. If (2,2,6,6-tetrameth-
ylpiperidin-1-yl)oxidanyl (TEMPO) or 1,1-diphenylethylene
Scheme 3. Synthesis of 2-hydroxyindolin-3-one derivatives.
(1 equiv.), both known to be effective radical scavengers, Table S2, Supporting Information), which suggests that
was present in the reaction of 1a under otherwise identical radical intermediates may be involved in the catalytic cycle.
conditions, the reaction was partially suppressed (see In addition, an experiment was performed under a 18O2 at-
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J. Huang, T. Mao, Q. Zhu
SHORT COMMUNICATION
Scheme 4. Proposed reaction mechanism.
mosphere in DMSO. Approximately 80% of the product a diverse array of isatins were obtained in moderate to good
(16O/18O-2a, 42% and 18O/18O-2a, 32%) was 18O incorpo- yields. A reaction mechanism involving radical intermedi-
rated.
ates was also proposed. The new methodology not only
serves as an alternative approach for the synthesis of isatins
but also broadens the application of Cu-catalyzed C–H ac-
tivation reactions in the preparation of nitrogen-containing
heterocycles.
Experimental Section
On the basis of our observations and previous reports,[21]
General Procedure for the Synthesis of 2 and 3: To a solution of 2-
substituted aminoacetophenone (0.20 mmol, 1 equiv.) and CuI
(0.04 mmol, 0.2 equiv.) in DMSO (2 mL) was added PivOH
(0.22 mmol, 25 μL, 1.0 equiv.) under an oxygen atmosphere. The
resulting mixture was stirred at 130 °C for 23 h. The reaction was
monitored by TLC until the starting material was completely con-
sumed. The reaction mixture was diluted with EtOAc (5 mL) and
washed with brine (5 mL). The organic layer was dried with
Na2SO4 and concentrated under vacuum. The residue was purified
by column chromatography to give the corresponding product.
a plausible reaction mechanism was proposed, as shown in
Scheme 4. Initially, CuI is oxidized by molecular oxygen to
form a superoxide radical–CuII intermediate,[22] which is at-
tacked by 1a in its enol form to form CuII complex A. Isom-
erization of resulting peroxy–copper(II) intermediate A
yields copper(I) species B with concurrent formation of a
C–O bond. Further transformation results in dioxetane in-
termediate C, which undergoes O–O bond cleavage to pro-
duce aryl glyoxal D and CuOH.[21a] Formation of D
through direct O–O bond cleavage in B is also possible,
which is consistent with the results of the 18O2 study. Then,
intermediate D is oxidized to final product 2a via possible
2-hydroxy-1-methylindolin-3-one intermediate E (R = H).
In contrast, 2a may be generated through intermediate F
and G by overoxidation, along with the release of alde-
hyde(R ϶ H).[21a,21f]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H NMR and 13C
NMR spectra of all new compounds.
Acknowledgments
The authors are grateful for financial support of this work by the
National Natural Science Foundation of China (NSFC) (grant
numbers 21202167, 21072190, and 21272233) and the Guangdong
Natural Science Foundation (S2011020000806).
Conclusions
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In summary, we developed an efficient approach for the
preparation of isatins through intramolecular C(sp3)–H
amidation by using molecular oxygen as the oxidant. Many
functional groups were compatible with this procedure, and
4
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Efficient Synthesis of Indoline-2,3-diones
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shkhodzhaev, M. G. Levkovich, S. F. Arpova, A. S. Shashkov,
Received: January 3, 2014
Published Online: ᭿
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Job/Unit: O40012
/KAP1
Date: 02-04-14 16:44:49
Pages: 6
J. Huang, T. Mao, Q. Zhu
SHORT COMMUNICATION
C–H Amidation
J. Huang,* T. Mao, Q. Zhu* ............ 1–6
Copper-Catalyzed Intramolecular Oxidat-
ive C(sp3)–H Amidation of 2-Aminoaceto-
phenones: Efficient Synthesis of Indoline-
2,3-diones
An efficient synthesis of diverse indoline-
2,3-diones from 2-aminoacetophenones
through copper-catalyzed intramolecular
C(sp3)–H amidation is reported. The reac-
tion proceeds in DMSO by using O2 as the
sole oxidant to provide the desired prod-
ucts in moderate to good yields; Piv = piv-
aloyl.
Keywords: Nitrogen heterocycles / Fused-
ring systems / Amidation / Copper / C–H
activation
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