CF 3 COOH/O 2 -Mediated Metal-Free Domino Construction of the Isatin Skeleton

Article abstract of DOI:10.1055/s-0039-1690018

Directed by the strategy of C-H activation, an efficient construction of the isatin skeleton was developed through aerobic oxidation of glycine esters. The reactions were performed under CF ₃ COOH/O ₂ conditions in the absence of met

Full text of DOI:10.1055/s-0039-1690018

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©
Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
Synlett
J. Zhou et al.
Letter
CF COOH/O -Mediated Metal-Free Domino Construction of the
3
2
Isatin Skeleton
Jiadi Zhoua
Yongjian Chena
C–H, C–O, C–N bond cleavage
C–C, C=O, C–N bond formation
Fang Wangb
Qiwei Zhangb
Jianjun Li*a,b
O
Ar
+
Ar
Ar
O
R1
O
N
R1
Ar
Ar
O
N
H
0
0
0
0-
0
0
0
2-8
1
8
4-7
0
0
5
H
N
O
O
CF3COOH (1 equiv)
O2 (1 atm)
O
R1 = alkyl
R1 = alkyl
a
Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, P. R. of China
College of Pharmaceutical Sciences, Zhejiang University of Tech-
nology, Hangzhou 310014, P. R. of China
O
O
R1
O
b
O
R1
N
R2
N
R2
O
lijianjun@zjut.edu.cn
1
2
R , R = alkyl
C–H, C–O bond cleavage
C–C, C=O bond formation
Metal-free
Mild and simple reaction conditions
Divergent glycine esters
3
2
1 examples
3–81% yield
Received: 18.06.2019
Accepted after revision: 28.07.2019
Published online: 14.08.2019
Here, we reported an efficient construction of the isatin
skeleton through aerobic oxidation of glycine esters under
mild reaction conditions that requires only CF COOH and O
DOI: 10.1055/s-0039-1690018; Art ID: st-2019-u0315-l
3
.
2
Our efforts toward this C–H activation strategy for the
synthesis of isatins initially focused on intramolecular cy-
clization of N-alkyl-N-arylglycinates. When a mixture of 1a
Abstract Directed by the strategy of C–H activation, an efficient con-
struction of the isatin skeleton was developed through aerobic oxida-
tion of glycine esters. The reactions were performed under
CF COOH/O conditions in the absence of metal catalysts. The reaction
(
1.0 mmol), CuCl (10 mol%), and O (1 atm) was stirred in
2
3
2
mechanisms were investigated with control experiments.
acetonitrile at 70 °C for 12 hours, a trace amount of 2a was
indeed formed (Table 1, entry 1). This encouraging result
prompted us to optimize the reaction conditions further. A
series of Brønsted acids, such as CCl COOH, CF COOH, H SO ,
Key words metal-free, isatin skeleton, C–H activation, CF COOH,
oxygen
3
3
3
2
4
and TfOH were screened, and the results indicated that
Isatin and its derivatives exist widely in natural prod-
CF COOH (1 equiv) could promote the aerobic oxidation to a
3
ucts and many of them are bioactive compounds or phar-
maceutics. Although, a number of methods have been es-
significant extent (entries 2–5). To our surprise, a similar
yield of 2a was obtained without copper catalyst, albeit
with an extended reaction time of 48 hours (entry 7).
1
tablished for the construction of such structures, the re-
ported syntheses of isatins often require substrate pre-
functionalization, multiple steps, and starting materials
Screening of the loading amounts of CF COOH indicated
3
that 1 equiv was optimal (entries 7–10). In the absence of CuCl,
other Brønsted acids were also less active (entries 11–13).
Acid could promote the formation of intermediates A, E,
and H by the generation of H O , which is crucial to the re-
2
that are not readily available. Therefore, the development
of novel and practical methods for the synthesis of isatins
by double carbonylation of aromatic C–H bonds ortho to an
amino group has drawn much attention. In recent years,
2
2
action (Scheme 3 and Scheme 4). On the other hand, in the
3
4
5
6
Cu-based, Sb-based, Pd-based, and Oxone/NaNO -based
absence of O , almost none of the desired product was de-
2
2
coupling reactions have been developed (Scheme 1). Never-
theless, the development of more practical methods for the
synthesis of isatin and its derivatives remains highly desirable.
The direct -C–H bond functionalization of glycine de-
rivatives has become a straightforward strategy for the syn-
tected (Table 1, entry 14). Various solvents, such as, DCE,
THF, MeOPh, and EtOH were further examined, and MeCN
was still the best solvent (entries 15–18). The optimal reac-
tion conditions were thus established as 1a (1.0 mmol),
CF COOH (1.0 mmol), and O (1 atm) stirring in acetonitrile
3
2
7
thesis of -substituted amino acid derivatives and other
at 70 °C for 48 hours.
8
useful structures. Nevertheless, the oxidative coupling of
glycine derivatives without metal catalysts and chemical
oxidants is rare.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
J. Zhou et al.
Letter
Previous work:
R2
N
Ar
Ar
O
N
R
or
N
R1
O
O
TBPA
O2
HCO-COOEt
O
O
Ar
Ar
Cu/TBHP
O
H
N
R
or
Ar
O2
Cu
O
CO
Ar
O
NH
R
N
R
Cu/Pd
N2
N
R
HCO-COH
Cu
O
O
Oxone (0.5 equiv)
NaNO2 (1.3 equiv)
O
O
+
O
N
N
N
2
O N
MeCN, 110 °C, 12 h
This work:
C–H, C–O, C–N bond cleavage
C–C, C=O, C–N bond formation
O
Ar
+
R1
Ar
O
N
O
N
R1
Ar
Ar
O
H
H
N
O
O
CF3COOH (1 equiv)
O2 (1 atm)
O
R1 = alkyl
R1 = alkyl
O
O
R1
O
Ar
O
N
R1
R2
N
O
R2
1
2
R , R = alkyl
C–H, C–O bond cleavage
C–C, C=O bond formation
Metal-free
Mild and simple reaction conditions
Divergent glycine esters
31 examples
23–81% yield
Scheme 1 Synthesis of isatins via carbonylation of C–H bonds
Table 1 Optimization of Reaction Conditionsa
Entry Cat. (10 mol%) Acid (equiv)
Solvent
Time Yield (%)b
(
h)
O
10
11
–
–
–
–
–
–
–
–
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeOPh
DCE
48
n.d.
50
N
O2, Brønsted acid
N
O
CCl COOH (1)
48
48
48
48
48
48
48
48
O
3
solvent
12
H
2
SO
4
(1)
trace
trace
trace
61
O
1a
2a
13
CF SO H (1)
3
3
3
3
3
3
3
1
1
1
1
4c
CF
CF
CF
CF
CF
COOH (1)
Entry Cat. (10 mol%) Acid (equiv)
Solvent
Time Yield (%)b
h)
5
6
7
8
COOH (1)
COOH (1)
COOH (1)
COOH (1)
(
53
1
2
3
4
5
6
7
8
9
CuCl
CuCl
CuCl
CuCl
CuCl
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
12
trace
57
EtOH
THF
12
CCl
3
COOH (1)
COOH (1)
SO (1)
H (1)
12
12
12
12
12
48
48
48
1
50
CF
3
67
a
2
Reaction conditions: 1a (1.0 mmol), catalyst, acid, O (1 atm) in the sol-
H
2
4
trace
trace
31
vent at 70 °C.
b
Isolated yield.
The reaction was performed under N atmosphere.
2
CF
CF
CF
CF
CF
3
3
3
3
3
SO
3
c
COOH (1)
COOH (1)
–
65
With the best conditions established, the scope of the
reaction with substituted N-alkyl-N-arylglycinates was in-
vestigated (Table 2). Electron-donating groups on the para-
–
COOH (0.5) MeCN
40
–
COOH (2)
MeCN
63
9
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

C
Synlett
J. Zhou et al.
Letter
position of the phenyl ring of 1 enhanced the efficiency of
the reaction, giving the desired products 2a–i in moderate
to good yields (52–81%). However, when electron-with-
drawing groups were introduced, the desired products 2k
and 2l were obtained in low yields. A meta-substituted gly-
cine ester also delivered the corresponding product 2j. No-
tably, when substrates with ortho-methyl substituted or
unsubstituted aromatic moiety were used, the reaction be-
came complex (2m and 2n). We then investigated the sub-
strate scope with respect to the N-groups, such as methyl,
ethyl, n-propyl, and n-butyl, which also gave the corre-
sponding isatins 2a–d in moderate yields.
gave a complex reaction mixture (4t and 4u). If strong
EWGs (NO , and CF ) were introduced, no desired products
2
3
were detected due to poor conversion of the starting mate-
rials (4v and 4w).
Table 3 Reaction of N-Alkyl-N-arylglycinatesa
R2
O
O
H
N
O
R2
N
O
R1
R1
CF3COOH, O2
MeCN, 70 °C
O
O
3
4
Table 2 Reaction of N-Alkyl-N-arylglycinatesa
Entry
R1
R2
Product
Yield (%)b
R2
N
O
R2
1
4-methyl
4-isopropyl
4-tert-butyl
4-methoxy
4-fluoro
methyl
methyl
methyl
methyl
methyl
methyl
ethyl
4a
4b
4c
4d
4e
4f
65
N
O
CF3COOH, O2
MeCN, 70 °C
2
75
R1
R1
O
3
78
O
4
56
1
2
5
62
Entry
R1
R2
methyl
Product
Yield (%)b
6
4-chloro
53
1
2
3
4
5
6
7
8
9
1
1
1
1
4-methyl
2a
2b
2c
2d
2e
2f
65
7
4-methyl
4-isopropyl
4-tert-butyl
4-fluoro
4g
4h
4i
64
4-methyl
ethyl
66
8
ethyl
79
4-methyl
n-propyl
n-butyl
methyl
ethyl
62
9
ethyl
51
4-methyl
52
10
11
12
13
14
15
16
17
18
19
20
21
22
ethyl
4j
72
4-isopropyl
4-isopropyl
4-tert-butyl
4-tert-butyl
4-methoxy
81
4-chloro
ethyl
4k
4l
55
70
4-bromo
4-methyl
4-tert-butyl
4-methoxy
4-fluoro
ethyl
52
methyl
ethyl
2g
2h
2i
74
isopropyl
isopropyl
isopropyl
isopropyl
methyl
isopropyl
benzyl
ethyl
4m
4n
4o
4p
4q
4r
46
64
72
methyl
ethyl
63
50
0
1
2
3
4
3,5-dimethyl
4-fluoro
4-chloro
2-methyl
H
2j
72
46
methyl
methyl
methyl
methyl
2k
2l
25c
23c
mixture
mixture
3,5-dimethyl
3,5-dimethyl
4-methyl
2-methyl
H
70
66
2m
2n
4s
4t
70
1
mixture
mixture
none
none
a
Reaction conditions: 1 (1 mmol), CF
(1 atm).
Isolated yield.
NMR yield.
3
COOH (1 equiv), MeCN (5 mL), 70 °C
ethyl
4u
4v
4w
under O
2
b
4-nitro
ethyl
c
2
3
4-trifluoromethyl
ethyl
a
Reaction conditions: 3 (1 mmol), CF
(1 atm).
Isolated yield (based on 0.5 equiv of 3).
3
COOH (1 equiv), MeCN (5 mL), 70 °C
under O
2
The scope of the reaction with substituted N-H-N-aryl-
b
10
glycine esters 3 were investigated (Table 3). None of intra-
molecular cyclization products were detected, which indi-
cated that the reaction proceeded through different mecha-
nism. To our delight, several functional groups, such as
methyl, isopropyl, tert-butyl, methoxy, fluoro, chloro, and
bromo groups, on the aromatic moiety were well-tolerated,
gave the corresponding products 4a–p and 4s in moderate
to good yields. When meta-methyl substituted substrates
were reacted, the target products 4q and 4r were obtained
in 70% and 66% yields, respectively. However, ortho-methyl
substituted and unsubstituted aniline glycine derivatives
To explore the mechanism, a series of control reactions
were conducted, as shown in Scheme 2. It was found that
the addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEM-
PO) (1 equiv) inhibits the reaction, suggesting a single-elec-
tron-transfer pathway might be involved. We are delighted
to detect compound I by high-resolution mass spectrome-
try (HRMS), implying that the C–O bond in the ester was ac-
tivated (Scheme 2, eq. 1).11 Under the standard intermolec-
ular cyclization, intermediates D, E, F, and H were detected
by a similar method (Scheme 4).11 Compound 5 was found
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

D
Synlett
J. Zhou et al.
Letter
to react with N-methyl-p-toluidine under the standard con-
ditions, and 2a was obtained in 70% yield (Scheme 2, eq. 2).
Then the standard conditions were applied to 6 and 7
O
N
R
N
O
CF3COOH
O2
TEMPO
no
reaction
O
I
O
(Scheme 2, eq. 3 and 4), and no reaction occurred, which
(1)
(2)
TEMPO
(1 equiv)
R = Me or H
[M+H]+ calcd., 333.2173
found, 333.2180
ruled out the possibility of a direct intramolecular Friedel–
Crafts type reaction of glycine ester. 2-(Methyl(p-tolyl)amino)-
acetamide and p-tolylglycine showed no reactivity (Scheme
O
H
N
N
2, eq. 5 and 6). Furthermore, substrates with different ester
N
standard
conditions
O
O
groups were investigated: the methyl ester, ethyl ester, iso-
propyl ester, tert-butyl ester, and benzyl ester gave 2a in 61,
+
5
O
2a
O
70%
67, 57, 0, and 68% yield, respectively (Scheme 2, eq. 7). The
H
H
N
standard
conditions
N
results show that the -proton adjacent to the ester group is
O
(3)
+
no reaction
crucial for the formation of isatin. Finally, the source of the
O
O
6
18
oxygen atom in the amide was studied by adding H O to
2
O
the reaction mixture, whereupon product 2h was formed in
N
18
18
6
0% yield without the O-incorporation product [ O] 2h
O
standard conditions
standard conditions
(4)
no reaction
(Scheme 2, eq. 8). The possibility that the oxygen atom comes
7
from H O was thus excluded.
2
O
O
N
Based on the above results, a possible mechanism of in-
tramolecular cyclization was proposed (Scheme 3). In the
presence of dioxygen, the relatively active C–H bond of the
N
O
NH2
(5)
O
n.d.
n.d.
OH
glycine ester is oxidized by O to give a radical intermediate
2
H
N
O
O
A. Second, A is trapped by dioxygen to produce a peroxide
radical B. After a possible intramolecular 1,6-H shift, the C–
H bond adjacent to the oxycarbonyl group is activated, fol-
lowed by -cleavage and elimination of water, to give acyl
radical C. This species is further oxidized to a carbonyl cat-
ion, which is followed by an intramolecular Friedel–Crafts
cyclization. After a proton loss and rearomatizaion, the isat-
in product is afforded.
standard conditions
standard conditions
N
OH
(6)
O
O
N
N
R
(7)
O
O
O
R
Me Et i-Pr t-Bu Bn
Relative rate 1.0 1.2 0.7
0
0
1.3
68
Yield (%)
61 67 57
A plausible mechanism for intermolecular cyclization is
depicted in Scheme 4. The glycine ester 3g was first oxi-
N
O
dized by O to give the hydroperoxide intermediate D. The
2
O
iminium ion intermediate E could then be formed through
O
N
2h 60%
an acid-catalyzed S 1-type procedure from D. Subsequent-
O
N
H2O18 (4.0 equiv)
ly, coupling of E with another 3g results in the intermediate
F; intramolecular nucleophilic attack of the NH group to the
ester in F affords the intermediate G, which is further oxi-
dized to give the intermediate H. Finally, hydrolytic cleav-
age of H produces the isatin product.
In conclusion, a metal-free domino construction of the
isatin skeleton was developed through aerobic oxidation of
glycine esters. The reaction thus provides a new way to
achieve C–H activation. Based on the published reports and
on our experiments, two plausible mechanisms were pro-
posed. A detailed investigation of the mechanism and fur-
ther application of this protocol is under way in our labora-
tory.
(8)
CF3COOH, O2
N
dry MeCN, 70 °C
O18
1h
O
[18
O]2h 0%
Scheme 2 Control experiments
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690018
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
References
Funding Information
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ati
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©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

E
Synlett
J. Zhou et al.
Letter
O
H
O
R1
H , O2
+
R1
O
O2
R1
O
O
N
N
N
O
O
–
H2O2
O
A
B
1,6-H shift
OH
O
O
O
[
O]
R1
O
R1
2
R1
O
N
N
H+
N
O
O
CH3CHO + H2O
C
Scheme 3 A possible mechanism for intramolecular cyclization
O
O
O
H
H
H
N
N
N
+ H+
O2
O
O
O
OOH
3g
D
E
H2O2
[M]+ calcd., 192.1019
found, 192.1016
[
M+Na]+ calcd., 248.0893
found, 248.0902
3g
O
O
O
O
O
NH
O
O
O2, H+
H2O2
N
H2O
O
N
4g
O
O
C2H5OH
NH
NH
HN
F
G
H
[M+Na]+ calcd., 407.1941
found, 407.1935
M]+ calcd., 337.1547
found, 337.1540
[
Scheme 4 A possible mechanism for intermolecular cyclization
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(
e) Salman, M.; Zhu, Z. Q.; Huang, Z. Z. Org. Lett. 2016, 18, 1526.
f) Wei, X. H.; Wang, G. W.; Yang, S. D. Chem. Commun. 2015, 51,
round-bottom
flask
containing
N-alkyl-N-arylglycinate
(1 mmol), CF COOH (0.5 mmol), and MeCN (5 mL) was stirred at
3
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F

F
Synlett
J. Zhou et al.
Letter
7
0 °C under O (1 atm) for 12 h. CF COOH (0.5 mmol) was added
propylphenyl) glycinate (207 mg, 1.0 mmol). Purification by
2
3
and, after stirring for 36 h, the reaction mixture was concen-
trated under reduced pressure and the crude product was puri-
fied by column chromatography on silica gel.
column chromatography (n-hexane/EtOAc, 8:1) gave 4b (98 mg,
1
75%) as a red solid. H NMR (400 MHz, CDCl ):  = 7.53 (s, 1 H),
3
7.46 (d, J = 8.1 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 4.49 (s, 2 H),
3.79 (s, 3 H), 2.90 (hept, J = 6.8 Hz, 1 H), 1.24 (d, J = 6.9 Hz, 6 H).
5-Methoxy-1-methylindoline-2,3-dione (2i)
1
3
Prepared by following General Procedure A using ethyl N-(4-
methoxyphenyl)-N-methylglycinate (223 mg, 1.0 mmol). Purifi-
cation by column chromatography (n-hexane/EtOAc, 5:2) gave
C NMR (101 MHz, CDCl ):  = 182.8, 167.4, 158.3, 148.3, 145.3,
3
+
136.8, 123.4, 117.7, 110.0, 52.8, 41.1, 33.5, 23.8 (2C). MS (ESI ):
m/z = 262.05 [M + H] . HRMS (ESI ): m/z [M + Na] calcd for
+
+
+
1
2
7
3
1
i (120 mg, 63%) as a red solid. H NMR (400 MHz, CDCl ):  =
C14H15NNaO : 284.0893; found: 284.0889.
3
4
.17–7.13 (m, 2 H), 6.82 (d, J = 8.4 Hz, 1 H), 3.81 (s, 3 H), 3.22 (s,
H). C NMR (101 MHz, CDCl ):  = 183.7, 158.3, 156.6, 145.3,
24.6, 117.8, 110.9, 109.6, 56.0, 26.2. HRMS (ESI ): m/z
M + Na] calcd for C H NNaO : 214.0475; found: 214.0476.
(11) Detailed analysis conditions for intermediates I: A 25 mL round-
13
bottom flask containing 1a (1 mmol), CF COOH (0.5 mmol),
3
3
+
TEMPO (1 equiv), and MeCN (5 mL) was stirred at 70 °C under
O2 (1 atm) for 12 h. The reaction mixture was concentrated
under reduced pressure and the crude material was analyzed by
+
[
10
9
3
(
10) Intermolecular Cyclization; General Procedure B: A 25 mL
+
round-bottom flask with N-H-N-arylglycinate (1 mmol),
HRMS-APCI using ESI ionization.Detailed analysis conditions
CF COOH (0.5 mmol) and MeCN (5 mL) was stirred at 70 °C
for intermediates D, E, F, and H: To a 25 mL round-bottom flask
3
under O (1 atm) for 6 h. CF COOH (0.5 mmol) was added and,
containing 3g (1 mmol), CF COOH (0.5 mmol), and MeCN (5 mL)
2
3
3
after stirring for 6 h, the reaction mixture was concentrated
under reduced pressure and the crude product was purified by
column chromatography on silica gel.
was stirred at 70 °C under O (1 atm) for 2 h, then the reaction
2
mixture was concentrated under reduced pressure and the
+
crude material was analyzed by HRMS-APCI using ESI ioniza-
Methyl 2-(5-Isopropyl-2,3-dioxoindolin-1-yl)acetate (4b)
Prepared by following General Procedure B using methyl (4-iso-
tion.
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–F