Synthesis of isatins by the palladium-catalyzed intramolecular acylation of unactivated aryl C(sp2)-H bonds

Article abstract of DOI:10.1039/c5ra23837d

Synthesis of isatins from formyl-N-arylformamides is achieved via PdCl₂-catalyzed intramolecular acylation. This method shows the possibility of Pd-catalyzed aryl C(sp²)-H bond activation on the synthesis of isatins, affording an array of isatins in good yields. Yet this protocol is operationally simple and atom economical.

Full text of DOI:10.1039/c5ra23837d

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Synthesis of isatins by the palladium-catalyzed intramolecular
acylation of unactivated aryl C(sp2)-H bond†
Received 00th January 20xx,
Accepted 00th January 20xx
Jue Li, Yang Zheng, Xinling Yu, Songyang Lv, Qiantao Wang, Li Hai*, Yong Wu*
DOI: 10.1039/x0xx00000x
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Synthesis of isatins from formyl-N-arylformamides is achieved via and the I2-mediated9 or Cu-catalyzed10 intramolecular cyclic
PdCl2-catalyzed intramolecular acylation. This method shows the amidation from ortho-substituted anilines. Although these
possibility of Pd-catalyzed aryl C(sp2)-H bond activation on the reactions showed some improvements, the requirement of the
synthesis of isatins, affording an array of isatins in good yields. Yet ortho-functionalized aromatic substrates, which were not
this protocol is operationally simple and atom economical.
readily available, were the obvious drawbacks. In contrast to
preparation of ortho-functionalized substrates, the direct
transformation from sp2 C-H bonds of aryl moiety to C-C bonds
for the synthesis of isatin is a more appealing alternative
approach.
Over the last decade, transition-metal-catalyzed C-H bond
functionalization has emerged as a useful and powerful
synthetic strategy, and has allowed chemist to assemble
complex molecular structures efficiently. Metals such as Pd, Cu,
Ni, Fe, Ru, etc. play vital roles on the transformation of
unactivated C(sp2)-H bond to C(sp2)-C bond with the assistance
of directing group.1 In particular, the Pd-catalyzed direct C-H
bond acylation protocols using aryl compounds and some
simple precursors have been widely investigated,2 such as the
Pd catalyzed ortho-aroylation using benzyl bromides as aroyl
surrogates,2a the decarboxylative acylation of arenes with
mandelic acid derivatives via palladium catalyst,2b and the Pd-
catalyzed oxidative C-H bond acylation of acetanilides
employing toluene derivatives as the coupling precursors.2c
These methods provide efficient pathway to afford arylketone
motifs.
In a recent J. Am. Chem. Soc. communication, Li and co-
workers have reported intramolecular acylation of formyl-N-
arylformamides
catalyzed activation of C-H bond of aldehyde[Scheme 1a, Eq.
(1)
11. Their work was interesting as it simplified the substrate
1 to indoline-2,3-diones 2 based on Cu-
]
preparation and revealed the possibility of intramolecular
acylation. They suggested that the C-H bond on aldehyde can
be activated by CuCl2 with O2 in Schlenk tube at 100oC. Notably,
they also mentioned that some palladium complexes, including
Xiao’s catalytic system [Pd(dba)2 and dppp in DMF at 115oC],12
Martin’s catalytic system [Pd(OAc)2 and rac-BINAP in dioxane
at 110oC]13 and Cheng’s catalytic system [Pd(OAc)2 in xylene at
120oC],14 are not compatible to this reaction[Scheme 1a, Eq.
(2)]. This, however, is in contrary with the well accepted Pd-
catalyzed ortho-acylation of acetanilides.2c,2h-2i Considering
On the other hand, the isatin derivatives, which have similar
structures with arylketone motifs, have received much
attention, due to their biological activity and potential medical
formyl-N-arylformamide 1 is a acetanilide derivative, it is
3
value and the activities of C-3 carbonyl group as a synthetic
intermediate.4 Traditionally, Sandmeyer procedure,5 Stoll
é
procedure6 and Martinet procedure7 are used to synthesize
isatin. However, these methods suffer from the harsh
conditions, poor yields and limited substrate choices. This
motivates the development of new synthetic methods to
overcome these limitations. Inspiringly, a number of modern
and efficient methods have been exploited, for example, the
ylide-mediated carbonyl homologation of anthranilic acids,8
Key Laboratory of Drug-Targeting of Education Ministry and Department of
Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu,
610041, P. R. of China. Email: wyong@scu.edu.cn (Y. Wu), smile@scu.edu.cn (L.
Hai); Fax: +86 02885506666
†Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra See
DOI: 10.1039/x0xx00000x
Scheme 1. Synthesis of isatins using Pd catalyst
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Table 1. Optimization of the reaction conditions.
Entry
1
Catalyst(mol%)
Pd(OAc)2(10)
Pd(dba)2(10)
Pd(OAc)2(10)
PdCl2(10)
Additive
Solvent
dioxane
DMF
Temperature(oC)
Time(h)
Yieldb(%)
6
Cs2CO3/BINAP/air
110
115
120
120
100
100
100
100
100
100
100
100
100
100
100
100
100
14
6
2
pyrrolidine/dppp/air
11
13
61
70
76
65
73
92
90
<5
33
<5
-
3
air
air
xylene
xylene
xylene
dioxane
DMF
24
24
3
4
5
PdCl2(10)
air
6
PdCl2(10)
air
3
7
PdCl2(10)
air
3
8
PdCl2(10)
air
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
9
PdCl2(10)
air
3
10
11
12
13
14
15
16
17
Pd(TFA)2 (10)
Pd(PPh3)4 (10)
PdCl2(dppf)•CH2Cl2 (10)
PdCl2(PPh3)2
-
air
3
air
3
air
3
air
3
air
3
PdCl2(5)
air
3
78
92
18
PdCl2(20)
air
3
PdCl2(100)
argon
3
aReaction conditions: 1a (0.4mmol), catalyst(as indicated), solvent(2ml) and additive(as indicated) were heated for indicated reaction
time. bIsolated yield. BINAP = 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl; TFA = Trifluoroacetate; dba = Dibenzylideneacetone; PPh3 =
Triphenylphosphine; dppf = 1,1’-Bis(diphenylphosphino)ferrocene; dppp = 1,3-bis(diphenylphosphino)propane.
possible that unactivated aryl C(sp2)-H bond of compound
would be activated via suitable Pd catalyst and intramolecular when the reaction ran at 120oC for more than 24 hours (Table
acylation could happen, upon which isatins could be entry 4). After testing the reaction with different
obtained(Scheme 1b). So we carefully reviewed Li and co- temperatures and different reaction time, it was found that
workers’ work, and repeated the experiments with conditions the reaction gave a better yield at 100oC after 3h (Table 1
mentioned above. N-Methyl-2-oxo-N-phenylacetamide 1a
entry 5). Thus, later reactions were carried out at 100oC for 3h.
1
In beginning of our study, side products were detected
2
1,
,
,
which we had previously synthesized, was employed as the Then we tested different solvents and found that DMSO was
substrate (Table 1, entry 1-3). 15 Not surprisingly, all reactions more effective than other solvents such as DMF, toluene and
suffered from poor yield (6-13%) although the reaction 1,4-dioxane(Table 1, entry 6-9). Furthermore, evaluation on
facilitated by Pd(OAc)2 in xylene had a relatively higher yield other Pd compounds was carried out, and suggested that PdCl2
(13%). However, replacing Pd(OAc)2 by PdCl2 in the later was still the most suitable catalyst (Table 1, entry 10-13). It is
reaction, the yield of 2a was increased to 61% (Table 1, entry also found that 10mol% PdCl2 was necessary as neither
4). This encouraged us as it implies that there might be a increasing nor decreasing the catalyst loading did not give a
possibility to further improve the reaction. By our best higher yield of 2a. No desired product was obtained without
knowledge, no previous reports have described such the presence of PdCl2 (Table 1, entry 14-16). Notably air served
intramolecular acylation of acetanilide derivatives via Pd- as the essential factor because the yield of 2a was unsatisfied
activated aryl C(sp2)-H bond(Scheme 1b)
,
therefore, we when this reaction was run in argon atmosphere, even though
explored more about it.
the catalyst loading was up to 1 equiv (Table 1, entry 17).
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Table 2. Synthesis of indoline-2,3-diones a,b
N
CHO
R2
O
R2
N
O
PdIICl2
H
PdCl2, under air
N
H
CHO
1a
R1
R1
DMSO, 100oC
O
ortho-
Palladation
O
[O]
2
1
CHO
N
Pd(0)
O
PdII
Cl
O
3a
ꢀHydride
elimination
β
Carboꢀ
palladation
O
N
2a
ClPd(II)O
H
O
N
4a
Scheme 2. Proposed mechanism
Conclusions
In conclusion, we have described an efficient synthesis of isatin
derivatives via PdCl2-catalyzed intramolecular acylation of
formyl-N-arylformamides using air as oxidant. This atom
economical method implies that such a transformation could
also be facilitated by a suitable Pd catalyst, albeit some
reported palladium complexes did not work.12-14 This method
offers not only good yields of the corresponding product, but
also has a good tolerance with different functional groups. In
addition, this protocol can be easily scaled up. Also, using air
and DMSO as catalytic system makes this method
operationally simple. This powerful tool that shows versatility
and flexibility can be a good addition to thefield of organic
synthesis and medicinal chemistry.
aReaction conditions:
were heated at 100oC for 3h under air. bIsolated yield.
1 (0.4mmol), PdCl2 (10mol%), DMSO(2ml)
Accordingly, the reaction conditions are optimized as follows:
10mol% PdCl2 under air in DMSO at 100oC for 3h.
After the reaction condition was optimized, the substrate
scope of this synthetic methodology was also established and
the results were shown in Table 2. Functional groups attached
to the nitrogen atom, such as ethyl, n-butyl, allyl, gave the
corresponding products in good yields (Table 2, Compound 2a
2d). Electron-donating and electron- withdrawing groups at 4th
-
position of aromatic ring were well tolerated during the
reaction (Table 2, Compound 2f-2l). Notably the substrates
with meta-methyl or meta-halogens provided a mixture of 4-
Acknowledgements
substituted and 6-substituted indoline-2,3-diones in different
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC) (grant number 81373259).
proportion (Table 2, Compound 2m
groups, such as cyano, substituted phenyls, and heterocycle,
were compatible with the optimal condition Table 2,
-2o). Other functional
(
Compound 2p-2v). It was noteworthy that under the optimal
condition the reaction can be easily scaled up, for example,
when 6.1 mmol of 1a (1.0 g) was used, this reaction was
showed to have similar efficiency when it was under the
optimal condition (88%).
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