Active sp3 C-H Bond Oxidation Initiated sp3-sp2 Consecutive C-H Functionalization of N-Arylglycine Amides: Construction of Isatins

Article abstract of DOI:10.1021/acs.joc.7b01480

In the presence of catalytic triarylamine radical cation, an sp³-sp² consecutive C-H functionalization of N-arylglycine amides was achieved, providing a series of isatin derivatives in high yields. In this transformation, the initial aerobic oxidation of the relatively active sp³ C-H bonds triggered the following intramolecular cyclization, in which the aniline group was employed as a removable auxiliary group to enable the consecutive process.

Full text of DOI:10.1021/acs.joc.7b01480

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Note
Active sp3 C-H Bonds Oxidation Initiated sp3-sp2 Consecutive C-
H Functionalization of N-Arylglycine Amides: Construction of Isatins
Honghe Ji, Yingzu Zhu, Yu Shao, Jing Liu, Yu Yuan, and Xiaodong Jia
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01480 • Publication Date (Web): 17 Aug 2017
Downloaded from http://pubs.acs.org on August 18, 2017
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Active sp C-H Bonds Oxidation Initiated sp -sp Consecutive C-H
Functionalization of N-Arylglycine Amides: Construction of Isatins
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†
, §
†, §
ǁ
†
*, ‡
*, †, ‡
Honghe Ji, Yingzu Zhu, Yu Shao, Jing Liu Yu Yuan, and Xiaodong Jia
†
College of Chemistry & Chemical Engineering, Northwest Normal University, Lanzhou, Gansu
730070, China
‡
School of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou, Jiangsu
2
25002, China
ǁ
School of Information Engineering, Yangzhou University, Yangzhou, Jiangsu 225127, China
These authors contributed equally.
§
Eꢀmail: jiaxd1975@163.com
Table of Contents Graphic
3
2
Abstract: In the presence of catalytic triarylamine radical cation, a sp -sp consecutive CꢀH
functionalization of Nꢀarylglycine amides was achieved, providing a series of isatin derivatives in
3
high yields. In this transformation, the initial aerobic oxidation of the relatively active sp CꢀH
bonds triggered the followed intramolecular cyclization, in which the aniline group was employed
as a removable auxiliary group to enable the consecutive process.
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Due to the ubiquitous and diverse nature of C−H bonds in organic compounds, direct
functionalization of CꢀH bonds has been focused for years, and numerous methodologies have
1
been developed to construct complex structures from synthetically available substrates.
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Compared with sp CꢀH activation, which was generally achieved by the use of transitionꢀmetal
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promoted reactions, functionalization of sp CꢀH bond is still a big challenge for organic
3
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chemists. Recently, Yu and coꢀworkers reported a series of elegant examples of sp CꢀH
activation by transitionꢀmetal catalyzed transformations, in which a directing group is generally
4
crucial to achieve selectivity control and high reaction efficiency. Another approach to realize the
3
sp CꢀH functionalization is by free radical mediated process, in which an oxidant is added to
5, 6
oxidize the CꢀH bonds, providing a radical intermediate followed by further functionalization.
In this area, several model substrates were investigated extensively, such as THIQ, Nꢀarylglycines,
Nꢀarylbenzylamines, and so on.
It is wellꢀknown that the CꢀH bonds adjacent to heteroatoms are relatively active, and the
corresponding radical intermediate could be stabilized by pꢀπ conjugation with the lone pair
electrons of the heteroatoms. In the cases of Nꢀarylglycines, the generated free radicals could also
7
be stabilized by the captodative effect. So we questioned whether we could make use of these
active CꢀH bonds to initiate further functionalization of inert CꢀH bonds through any
intramolecular process.
Recently, we reported an efficient construction of isatin skeleton by a novel transformation named
8
CꢀH activation relay (CHAR). In this reaction, we designed and realized an intramolecular
1,6ꢀhydrogen atom shift, which triggered further activation of inert CꢀH and CꢀO bonds in ester
group, providing a series of isatin derivatives from synthetically available Nꢀarylglycine esters
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(
Figure 1, eq 1). In this research, the αꢀCꢀH bonds in Nꢀarylglycines were found extremely active,
and could be easily oxidized to the corresponding radical intermediate. Inspired by this work, we
2
hypothesized that in the presence of a radical trapper, for example a phenyl group, a sp CꢀH
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functionalization might be possible by an intramolecular radical cyclization (Figure 1, eq 2). If this
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idea is feasible, the initial sp CꢀH oxidation will act as a trigger to promote the consecutive
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sp -sp CꢀH functionalization, and the aniline group will be employed as a removable auxiliary
group to enable the consecutive process. Herein, we reported a different version of isatin synthesis
3
through a radical cation salt induced aerobic oxidation of sp CꢀH bonds in Nꢀarylglycine amides.
Figure 1. Different Ways to Isatin Derivatives
Isatin is an important pharmacophore and present in many natural products, synthetic
9
intermediates, and pharmaceuticals. It is reported that structures with isatin skeleton exhibit a
1
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variety of biological activities such as anticancer, anticonvulsant, antifungal, antiꢀHIV,
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antiꢀinflammatory and others . Although as early as 1840, the first synthesis of isatin was
1
6
reported, considerable efforts were devoted to the construction of isatin motif, and some new
17ꢀ20
methods were developed.
For example, using various oxidant, the oxidative cyclization of
17
2
’ꢀamino acetophenone is an efficient way to construct isatin skeleton. Li and coꢀworks reported
a copperꢀcatalyzed intramolecular CꢀH oxidation/acylation of formylꢀNꢀarylformamides, using O
2
1
8
as the terminal oxidant.
Lei and coꢀworkers have disclosed an elegant method that utilizes
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readily available anilines for Pdꢀcatalyzed double carbonylation with CO.
Other methods
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involving oxidation of an indole ring or carbonꢀcarbon unsaturated bonds were also reported.
Furthermore, construction of spiroꢀ and tetraꢀsubstituted oxoindole skeletons also plays an
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important role in organic synthesis. Although these methods provided different routes to isatin
derivatives, some shortcomings such as harsh reaction conditions, tedious starting material
synthesis and narrow substrate scope still restricted their broader applications in synthesis of
isatins. Therefore, the diverse synthesis of biologically relevant isatins through facile and
applicable methods is still highly desirable.
Figure 2. Our Initial Attempts to Isatin Synthesis
+
.
Initially, in the presence of 10 mol % TBPA (tris(4ꢀbromophenyl)aminium hexachloroantimonate)
in MeCN, a series of Nꢀarylglycine amides were employed to confirm the possibility of our
hypothesis (Figure 2, eq 1). Unfortunately, a complicated mixtures were obtained, and through
crude products analysis, only trace amount of the desired isatins was detected. Furthermore, other
2
2
23
oxidative products, such as carbonylation product
and 3,4ꢀdihydroquinazoline,
were also
detected by HPLCꢀMS. Then, a methyl group was installed on the nitrogen atom to block the
undesired side reactions. To our delight, the reaction became cleaner, and the isatin products were
isolated in moderate yields. Since the aniline group (highlighted by blue) acts as not only an
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auxiliary group, activating the sp αꢀCꢀH bonds, but also a leaving group, different substituents on
anilines were then tested. Although the chloro group might increase the tendency of CꢀN bond
2
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cleavage,
the electronꢀwithdrawing nature exert negative effect on the oxidation of sp CꢀH
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bonds, resulting in lower yield of the desired product and elongated reaction time. The results
show that the 4,Nꢀdimethylaniline is a proper removable auxiliary group, giving the desired
product in 54% yield.
After the removable auxiliary group was established, we started our study on substrate 1aa to find
the best conditions to achieve the efficient synthesis of isatin derivatives (Table 1). The solvent
screen was then performed (entries 1ꢀ5), and the results show that anisole is superior in higher
yield and shorter reaction time, giving the expected isatin in 93% yield (entry 5). Lower catalyst
loading and reaction temperature led to decreased yields and elongated reaction time (entries 6 and
+.
8
). Initiated by 15 mol % TBPA , the reaction time was shortened to 24 hours with a slightly
lower yield of the desired product (entry 7).
a
Table 1. Optimization of Reaction Conditions
o
b
Entry Solvent
Temp ( C) Time (h) Yield (%)
o
1
2
3
4
CH
3
CN
60 C
72
72
72
72
54
33
46
64
o
CH Cl
60 C
2
2
o
CHCl
3
60 C
o
DCE
60 C
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MeOPh
MeOPh
MeOPh
MeOPh
60 C
36
72
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72
93
68
88
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o
c
60 C
o
d
60 C
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40 C
a
Unless otherwise specified, the reaction was carried out with 1aa (0.1 mmol) in the presence of
+.
b
1
TBPA , and anhydrous solvent (1.0 mL).
Yield of crude product HNMR using
c
+. d
1
,3,5ꢀtrimethoxylbenzene as internal standard. Induced by 5 mol % TBPA . Induced by 15 mol %
+.
TBPA .
With the best reaction conditions established, the scope and limitations of the title procedure were
further investigated. Firstly, the substituents on aryl groups were varied to evaluate their effect on
the reaction efficiency, and the results were compiled in Scheme 1. The substrates with
electronꢀdonating groups, such as MeO and Me, at the paraꢀposition of the aromatic ring
underwent this transformation smoothly, producing the desired products in excellent yields
(
2aa-2ba). Slightly lower yields were obtained for the halogenated substrates with elongated
reaction time (2ca-2da), probably due to the lower electron density decreasing the intramolecular
cyclization. Similar results were provided by 2,4ꢀdisubstituted and unsubstituted analogues (2ea
and 2fa). When metaꢀMeO substituted substrate was employed, only one isomer was isolated in
9
2% yield (2ga), and the cyclization occurred selectively on paraꢀposition, probably due to the
steric hindrance. The reaction efficiency was not decreased, when orthoꢀsubstituents existed, and
the desired products were obtained in 87% (2ha) and 89% (2ia) yields, respectively. The
cyclization on naphthalene ring also proceeded smoothly, giving the expected benzoisatin in 83%
yield (2ja). We also employed the 1,2,3,4ꢀtetrahydroquinline derived amide subjected to the
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standard reaction conditions, and a tricyclic skeleton was afforded smoothly (2ka), which is an
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important pharmacophore exhibiting antiꢀleukaemic activity, and present in natural alkaloid.
a
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Scheme 1. Scope of Aryl Groups on Amides
a
+.
Reaction conditions: 1 (1 mmol), TBPA (10 mol %), anisole (5 mL), 60 °C under O
2
, 36 h,
isolated yield.
Next, various groups on nitrogen were examined to test the reaction scope and functional group
tolerance (Scheme 2). All of the alkyl groups performed well with high yields, affording the
desired products in good to excellent yields (2ab to 2be), in which even the bulky groups (2ac,
2
be and 2bg) did not exert negative effect on the reaction efficiency. Other sensitive groups such
as cyclopropyl ring (2bf), and CꢀC double bond (2bh) were completely tolerated in these mild
oxidative conditions. In the cases of substrates with another active benzyl CꢀH bonds, the desired
reaction process was partly disturbed, and the yields were lower (2bi and 2bj). Then, the amides
derived from diarylamine were tested (2ad to 2cd). The symmetric substrates gave the desired
products in high yields (2ad and 2cb). When different aryl groups existed, the intramolecular
cyclization mainly occurred on the electronꢀrich ring (2db), and in the case of
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NꢀphenylꢀNꢀtolylamide, a 1.4 : 1 mixture was provided (2cc and 2cd), in which the electronꢀrich
ring exhibited slightly higher activity, implying the electrophilic nature of the intramolecular
cyclization step.
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a
Scheme 2. Scope of Alkyl Groups on Amides
Me
O
R2
N
TBPA
(
10 mol %)
R1
O
N
R1
O
o
MeOPh, O2, 60 C
aqueous work-up
N
R2
Me
O
1
2
O
O
O
O
O
O
O
N
N
N
N
R2
R2 = Et, 86%, 2ab; R2 = Et, 86%, 2bb;
R2
Me
Bu-n
Me
Me
8
9%, 2bd
89%, 2be
=
i-Pr, 90%, 2ac.
= n-Pr, 88%, 2bc.
O
O
O
O
Me
O
O
N
O
O
N
N
N
Me
Me
Me
Ph
O
86%, 2bf
87%, 2bg
84%, 2bh
75%, 2bi
O
O
O
Me
O
O
O
N
N
O
N
Me
Ph
N
Ph
Ph
83%, 2db
4
2%, 2bj
81%, 2ad
93%, 2cb
O
N
O
Me
Me
O
+
O
N
Ph
2
cc
2cd
9
2% (2cc : 2cd = 1.4 : 1)
Me
a
+.
Reaction conditions: 1 (1 mmol), TBPA (10 mol %), anisole (5 mL), 60 °C under O , 36 h,
2
isolated yield.
To probe the reaction mechanism, several control experiments were performed, and the results
were compiled in Scheme 3. In the absence of dioxygen, no reaction occurred and the starting
material was fully recovered (eq 1). Then, a radical inhibition experiment was conducted. In the
presence of 1 equivalent TEMPO, the reaction was totally inhibited, implying the participation of
a free radical intermediate (eq 2). To track the reaction intermediate, we performed HRMS
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experiments 12 hours after the reaction was conducted. We are delighted to observe the signal at
+
m/z 329.0285 (calcd for C16
H
13BrNO
2
+ H , 329.0284), which is the demethylated intermediate A
(
eq 3, path a). The eliminated Nꢀmethylaniline was also detected by HRMS (eq 3, path b; calcd for
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+
C
8
H11N + H , 122.0964; found, 122.0964). These results suggested that the designed
intramolecular cyclization was involved in this reaction, and after hydrolysis of the generated
iminium ion B, the desired isatins were afforded (see Scheme 4 for details).
Scheme 3. Control Experiments
Me
Me
TBPA
(10 mol %)
N
(1)
N
no reaction
anisole, 60 o
C
Me
O
Br
N2
1da
TBPA
(
10 mol %)
anisole, 60 o
O2
(2) 1da
no reaction
C
TEMPO (1 eq)
Me
Me
N
NH
Me
TBPA
(
10 mol %)
Br
(3) 1da
anisole, O2, 60 o
O
+
C
N
1
2 h
A
Me
Calc'd, 329.0284;
Found, 329.0285.
HRMS
Calc'd, 122.0964;
Found, 122.0964.
H2O
Me
a
a
Me
b
b
N
Br
product
O
N
B
Me
Scheme 4. Proposed Mechanism
26
Based on the control experiments and previous research, a possible mechanism was proposed
(
Scheme 4). In the presence of dioxygen, the more active CꢀH of glycine amide is oxidized
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initially, generating a radical intermediate C. Then the electrophilic radical intermediate adds to
the electronꢀrich aryl ring, followed by further oxidation and rearomatization. The benzyl CꢀH
bond in intermediate D is more active, and oxidized smoothly, providing another radical under the
oxidative reaction conditions. Further oxidation leads to the formation of an isatin derived
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iminium B, and after aqueous workꢀup, the Nꢀmethylaniline is released (detected by HRMS; for
27
details, see Scheme 3, eq 3), giving the desired isatin product.
The trace amount of
demethylated intermediate observed by HRMS is also derived from the iminium E through a
demethylation process (see Scheme 3, eq 3).
In conclusion, we designed and developed an efficient method to construct biologically relevant
3
isatin derivatives. In this reaction, the aerobic oxidation of the relatively active sp CꢀH bonds acts
2
as a handle to promote further intramolecular sp CꢀH functionalization, affording a series of isatin
derivatives from synthetically available substrates. The mild reaction conditions, broad reaction
scope and functional group tolerance makes it a facile approach to isatin synthesis. This reaction
3
2
also provides a conceptually novel way, which is oxidation of active CꢀH bonds initiated sp -sp
2
CꢀH functionalization, to design and achieve sp CꢀH bond functionalization. Further applications
and more designed consecutive reactions are still underway in our laboratory.
Experimental Section
General
+
.
Solvents are anhydrous. TBPA was purchased from commercial sources and used without
treatment. Flash chromatography was carried out with silica gel (200ꢀ300 mesh). Analytical TLC
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was performed with silica gel GF254 plates, and the products were visualized by UV detection. H
1
3
NMR (400 MHz or 600 MHz) and C NMR (100 MHz or 150 MHz) spectra were recorded in
CDCl . Chemical shifts (δ) are reported in ppm using TMS as internal standard and spinꢀspin
3
10
11
12
13
14
15
16
17
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60
coupling constants (J) are given in Hz. EIꢀMS spectra were measured by direct inlet at 70eV. The
high resolution mass spectra (HRMS) were measured on an electrospray ionization (ESI)
apparatus using time of flight (TOF) mass spectrometry.
+
.
Typical Procedure for TBPA Induced Construction of Isatins
+.
A solution of 1 (1 mmol), in anisole (5 ml) was mixed fully, then TBPA (10 mol %) was added
o
dropwise. The reaction solution was stirred at 60 C under O
2
atmosphere. After completion
2 3
monitored by TLC (by UV visualization), the reaction was quenched by addition of Na CO in
2
H O (10 ml) solution. The mixture was poured into a separator funnel with the addition of excess
DCM (10 ml), and then the crude organic solution was extracted three times with water to remove
inorganic salts. The organic phase was then dried over anhydrous magnesium sulfate, filtered, and
the solvent was removed under reduced pressure. The products were separated by silica gel
column chromatography eluted with petroleum ether/acetone (v/v 15:1) to afford the products.
18
5-Methoxy-1-methylindoline-2,3-dione (2aa)
1
Compound 2aa was isolated in 90% yield (172 mg, red crystal); mp 170ꢀ171 °C; H NMR (400
MHz, CDCl ) δ 7.11 (dd, J = 8.5, 2.7 Hz, 1H), 7.07 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 8.5 Hz, 1H),
3
13
3
.76 (s, 3H), 3.17 (s, 3H). C NMR (101 MHz, CDCl
3
) δ 183.7, 158.3, 156.5, 145.3, 124.5, 117.7,
110.9, 109.55, 55.9, 26.2. EIꢀMS m/z (relative intensity, %): 191 (100%), 163 (58.7%), 148
(34.1%), 135 (43.7%), 134 (49.3%), 120 (62.9%), 92 (19.1%).
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1,5-Dimethylindoline-2,3-dione (2ba)
1
Compound 2ba was isolated in 93% yield (163 mg, red crystal); mp 149ꢀ151 °C; H NMR (400
13
MHz, CDCl
3
) δ 7.33 (m, 2H), 6.72 (d, J = 7.6 Hz, 1H), 3.15 (s, 3H), 2.26 (s, 3H). C NMR (101
0
1
2
3
4
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6
7
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9
0
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2
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8
9
0
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2
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7
8
9
0
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2
3
4
5
6
7
8
9
0
MHz, CDCl ) δ 183.5, 158.3, 149.2, 138.7, 133.68, 125.5, 117.4, 109.7, 26.1, 20.6. EIꢀMS m/z
3
(
relative intensity, %): 175 (76.1%), 147 (42.4%), 119 (59.7%), 118 (100%), 91 (34.3%), 77
(17.5%).
2
8
5
-Chloro-1-methylindoline-2,3-dione (2ca)
1
Compound 2ca was isolated in 76% yield (148 mg, red crystal); mp 169ꢀ171 °C; H NMR (400
13
MHz, CDCl ) δ 7.58 – 7.50 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 3.23 (s, 3H). C NMR (101 MHz,
3
3
CDCl ) δ 182.3, 157.6, 149.7, 137.8, 129.6, 125.2, 118.2, 111.2, 26.4. EIꢀMS m/z (relative
intensity, %): 197 (28.3%), 195 (91.3%), 169 (15.6%), 167 (48.2%), 141 (25.2%), 140 (35.9%),
139 (75.5%), 138 (100%), 112 (25.3%).
2
9
5
-Bromo-1-methylindoline-2,3-dione (2da)
1
Compound 2da was isolated in 84% yield (202 mg, red crystal); mp 169ꢀ170 °C; H NMR (600
1
3
3
MHz, CDCl ) δ 7.71 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 6.81 (d, J = 8.3 Hz, 1H), 3.24 (s, 3H). C
NMR (101 MHz, CDCl
m/z (relative intensity, %): 241 (98.0%), 239 (100%), 213 (67.5%), 211 (74.5%), 185 (71.3%), 184
87.2%), 183 (77.7%), 182 (90.9%), 170 (19.0%), 156 (17.6%), 104 (15.4%), 77 (36.9%).
3
) δ 182.1, 157.4, 150.1, 140.6, 128.0, 118.5, 116.6, 111.6, 26.3. EIꢀMS
(
1
,5,7-Trimethylindoline-2,3-dione (2ea)
1
Compound 2ea was isolated in 91% yield (172 mg, red crystal); mp 155ꢀ156 °C; H NMR (600
13
3
MHz, CDCl ) δ 7.23 (s, 1H), 7.12 (s, 1H), 3.47 (s, 3H), 2.50 (s, 3H), 2.26 (s, 3H). C NMR (151
3
MHz, CDCl ) δ 184.0, 159.3, 146.7, 142.7, 133.6, 123.6, 121.6, 118.6, 29.6, 20.3, 18.6. EIꢀMS
m/z (relative intensity, %): 189 (100%), 161 (40.9%), 133 (65.9%), 132 (81.1%), 91 (30.8%).
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HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO , 190.0863; found, 190.0870.
11
12
2
28
1
-Methylindoline-2,3-dione (2fa)
1
Compound 2fa was isolated in 90% yield (145 mg, orange crystal); mp 129ꢀ131 °C; H NMR (600
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
28
29
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl ) δ 7.63 – 7.56 (m, 2H), 7.12 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 3.24 (s,
3
13
3
3
H). C NMR (151 MHz, CDCl ) δ 183.3, 158.2, 151.4, 138.4, 125.3, 123.8, 117.4, 109.9, 26.2.
EIꢀMS m/z (relative intensity, %): 161 (99.7%), 133 (51.9%), 104 (100%), 78 (33.4%).
30
6-Methoxy-1-methylindoline-2,3-dione (2ga)
1
Compound 2ga was isolated in 92% yield (176 mg, red crystal); mp 197ꢀ198 °C; H NMR (400
MHz, CDCl ) δ 7.53 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 8.4 Hz, 1H), 6.33 (s, 1H), 3.90 (s, 3H), 3.18
3
13
(
s, 3H). C NMR (101 MHz, CDCl
6.2. EIꢀMS m/z (relative intensity, %): 191 (100%), 163 (48.6%), 148 (33.4%), 135 (21.9%), 134
28.6%), 120 (60.3%), 92 (22.2%)
3
) δ 180.7, 168.3, 159.6, 154.0, 127.9, 111.1, 107.9, 97.2, 56.2,
2
(
1-Methyl-7-phenylindoline-2,3-dione (2ha)
1
Compound 2ha was isolated in 87% yield (206 mg, red crystal); mp 212ꢀ213 °C; H NMR (600
MHz, CDCl ) δ 7.62 (d, J = 7.3 Hz, 1H), 7.48 – 7.39 (m, 4H), 7.38 – 7.33 (m, 2H), 7.13 (t, J = 7.5
3
13
Hz, 1H), 2.75 (s, 3H). C NMR (151 MHz, CDCl
3
) δ 183.5, 159.4, 148.0, 141.2, 137.1, 129.6,
128.5, 128.3, 127.4, 124.5, 123.3, 118.6, 30.2. EIꢀMS m/z (relative intensity, %): 237 (68.0%), 208
(10.6%), 181 (52.8%), 180 (100%), 152 (15.7%), 139 (9.9%), 90 (8.4%). HRMS (ESIꢀTOF) m/z:
+
[
M + H] Calcd for C15
H
12NO
2
, 238.0863; found, 238.0860.
18
1
,7-Dimethylindoline-2,3-dione (2ia)
1
Compound 2ia was isolated in 89% yield (156 mg, red crystal); mp 166ꢀ168 °C; H NMR (600
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6
MHz, CDCl ) δ 7.43 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 3.50 (s,
3
1
3
3
H), 2.55 (s, 3H). C NMR (151 MHz, CDCl
18.5, 29.7, 18.8. EIꢀMS m/z (relative intensity, %): 175 (100%), 147 (34.6%), 119 (60.0%), 118
84.7%), 91 (34.1%).
3
) δ 183.7, 159.2, 149.0, 142.2, 123.8, 123.3, 121.9,
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0
(
3-Methyl-1H-benzo[e]indole-1,2(3H)-dione (2ja)
1
Compound 2ja was isolated in 83% yield (175 mg, red crystal); mp 208ꢀ209 °C; H NMR (400
MHz, CDCl
3
) δ 8.59 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.64 (t,
13
J = 7.7 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 3.29 (s, 3H). C NMR (151
3
MHz, CDCl ) δ 182.4, 158.9, 154.7, 140.6, 131.3, 130.2, 129.1, 129.0, 125.5, 123.3, 110.0, 108.9,
26.2. EIꢀMS m/z (relative intensity, %): 211 (94.0%), 183 (51.3%), 155 (48.0%), 154 (100%), 140
+
(
14.6%), 127 (25.0%), 113 (10.7%). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C H NO ,
13 10 2
212.0706; found, 212.0708.
31
5
,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1,2-dione (2ka)
1
Compound 2ka was isolated in 80% yield (150 mg, red crystal); mp 222ꢀ223 °C; H NMR (600
3
MHz, CDCl ) δ 7.36 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.98 (t, J = 7.6 Hz, 1H), 3.77 –
13
3
.72 (m, 2H), 2.77 (t, J = 6.0 Hz, 2H), 2.06 – 2.01 (m, 2H). C NMR (151 MHz, CDCl ) δ 183.9,
3
156.9, 147.6, 137.1, 123.2, 123.0, 121.9, 115.7, 38.4, 23.9, 20.2. EIꢀMS m/z (relative intensity, %):
187 (81.2%), 159 (80.8%), 158 (46.3%), 131 (64.3%), 130 (100%), 103 (15.7%), 92 (19.1%).
3
2
1-Ethylindoline-2,3-dione (2ab)
1
Compound 2ab was isolated in 86% yield (151 mg, red crystal); mp 160ꢀ162 °C; H NMR (600
MHz, CDCl ) δ 7.58 (m, 2H), 7.10 (t, J = 7.2 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 3.77 (q, J = 7.0
3
13
Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl
3
) δ 183.7, 157.8, 150.6, 138.4, 125.4,
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23.6, 117.5, 110.0, 34.9, 12.5. EIꢀMS m/z (relative intensity, %): 175 (100%), 147 (19.8%), 132
(32.5%), 119 (58.2%), 118 (62.1%), 104 (59.4%).
31
1-Isopropylindoline-2,3-dione (2ac)
10
11
12
13
14
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16
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18
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1
Compound 2ac was isolated in 90% yield (170 mg, red crystal); mp 158ꢀ159 °C; H NMR (600
MHz, CDCl
3
) δ 7.59 (d, J = 7.3 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 7.02 (d,
13
J = 8.0 Hz, 1H), 4.59 – 4.47 (m, 1H), 1.52 (s, 6H). C NMR (151 MHz, CDCl ) δ 183.8, 157.8,
3
1
50.5, 138.1, 125.6, 123.2, 117.9, 111.3, 44.8, 19.4. EIꢀMS m/z (relative intensity, %): 189
(85.3%), 147 (13.2%), 146 (100%), 132 (68.5%), 118 (14.1%), 90 (24.9%).
1-Ethyl-7-methylindoline-2,3-dione (2bb)
1
Compound 2bb was isolated in 86% yield (163 mg, red crystal); mp 154ꢀ155 °C; H NMR (600
MHz, CDCl ) δ 7.45 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 3.99 (q,
3
13
J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). C NMR (151 MHz, CDCl
3
) δ 184.1,
159.2, 148.4, 142.4, 123.7, 123.5, 121.4, 118.9, 36.9, 18.7, 14.6. EIꢀMS m/z (relative intensity, %):
1
89 (92.6%), 160 (14.2%), 146 (14.9%), 132 (22.7%), 118 (100%), 91 (24.4%). HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C11
H12NO
2
, 190.0863; found, 190.0871.
7-Methyl-1-propylindoline-2,3-dione (2bc)
Compound 2bc was isolated in 88% yield (179 mg, red crystal); mp 160ꢀ161 °C; H NMR (600
MHz, CDCl ) δ 7.46 (d, J = 6.9 Hz, 1H), 7.32 (d, J = 7.0 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 3.93 –
3.82 (m, 2H), 2.49 (s, 3H), 1.78 – 1.67 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H). C NMR (151 MHz,
CDCl ) δ 184.1, 159.3, 148.6, 142.4, 123.7, 123.5, 121.4, 118.9, 43.5, 22.7, 18.7, 11.0. EIꢀMS m/z
1
3
1
3
3
(relative intensity, %): 203 (100%), 161 (17.9%), 146 (68.1%), 132 (16.1%), 118 (78.5%), 91
+
(
27.6%). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C12
H
14NO
2
, 204.1019; found, 204.1016.
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1-Butyl-7-methylindoline-2,3-dione (2bd)
Compound 2bd was isolated in 89% yield (193 mg, red crystal); mp 163ꢀ164 °C; H NMR (600
MHz, CDCl ) δ 7.45 (d, J = 7.2 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 3.94 –
3.88 (m, 2H), 2.50 (s, 3H), 1.74 – 1.61 (m, 2H), 1.49 – 1.36 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
NMR (151 MHz, CDCl ) δ 184.1, 159.3, 148.6, 142.4, 123.7, 123.5, 121.4, 118.9, 41.8, 31.5, 19.9,
1
3
1
3
0
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8
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0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C
3
18.8, 13.7. EIꢀMS m/z (relative intensity, %): 217 (80.0%), 189 (22.7%), 175 (20.1%), 160
+
(
32.2%), 146 (100%), 118 (75.2%), 91 (31.9%). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for
13 2
C H16NO , 218.1176; found, 218.1184.
1
-Isobutyl-7-methylindoline-2,3-dione (2be)
Compound 2be was isolated in 89% yield (193 mg, red oil); H NMR (600 MHz, CDCl
J = 7.3 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 3.74 (d, J = 7.4 Hz, 2H), 2.48 (s,
1
3
) δ 7.46 (d,
13
3H), 2.11 – 1.92 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H). C NMR (151 MHz, CDCl
3
) δ 184.0, 159.5,
1
2
48.8, 142.5, 123.8, 123.5, 121.6, 118.9, 49.0, 29.0, 19.8, 18.9. EIꢀMS m/z (relative intensity, %):
17 (62.5%), 161 (41.8%), 146 (100%), 118 (25.1%), 91 (24.5%). HRMS (ESIꢀTOF) m/z: [M +
+
H] Calcd for C13
H
16NO
2
, 218.1176; found, 218.1177.
1-(Cyclopropylmethyl)-7-methylindoline-2,3-dione (2bf)
1
Compound 2bf was isolated in 86% yield (185 mg, red oil); H NMR (600 MHz, CDCl
3
) δ 7.47 (d,
J = 6.3 Hz, 1H), 7.34 (d, J = 7.0 Hz, 1H), 7.00 (t, J = 7.4 Hz, 1H), 3.85 (d, J = 6.5 Hz, 2H), 2.59 (s,
13
3
H), 1.16 – 1.06 (m, 1H), 0.61 – 0.52 (m, 2H), 0.47 (m, 2H). C NMR (151 MHz, CDCl ) δ 184.1,
3
159.7, 148.9, 142.4, 123.7, 123.6, 121.5, 118.8, 45.9, 19.0, 11.3, 3.8. EIꢀMS m/z (relative
intensity, %): 215 (40.87%), 185 (13.3%), 173 (8.8%), 160 (100%), 131 (11.4%), 104 (18.8%), 55
+
(
25.4%). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C13
H
14NO
2
, 216.1019; found, 216.1020.
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1-(Cyclohexylmethyl)-7-methylindoline-2,3-dione (2bg)
Compound 2bg was isolated in 87% yield (224 mg, red oil); H NMR (600 MHz, CDCl
d, J = 7.3 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 3.75 (d, J = 6.8 Hz, 2H),
1
3
) δ 7.45
(
13
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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47
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49
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59
60
2.47 (s, 3H), 1.85 – 1.52 (m, 6H), 1.17 (t, J = 7.9 Hz, 3H), 1.08 (t, J = 10.8 Hz, 2H). C NMR
151 MHz, CDCl ) δ 184.1, 159.5, 148.8, 142.5, 123.7, 123.5, 121.6, 118.9, 47.8, 38.2, 30.4, 26.1,
25.7, 19.0. EIꢀMS m/z (relative intensity, %): 257 (72.0%), 229 (22.4%), 186 (10.8%), 175
(
3
(31.4%), 161 (85.7%), 146 (100%), 133 (40.8%), 118 (31.1%), 91 (32.9%). HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C16
H20NO
2
, 258.1489; found, 258.1499.
1
-Allyl-5-methylindoline-2,3-dione (2bh)
Compound 2bh was isolated in 84% yield (169 mg, red oil); H NMR (600 MHz, CDCl
s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), 5.83 (dtd, J = 15.7, 10.5, 5.3 Hz, 1H),
1
3
) δ 7.41
(
1
3
5.33 – 5.26 (m, 2H), 4.34 (d, J = 5.3 Hz, 2H), 2.32 (s, 3H). C NMR (151 MHz, CDCl
3
) δ 183.5,
158.0, 148.6, 138.7, 133.6, 130.5, 125.7, 118.5, 117.6, 110.7, 42.5, 20.6. EIꢀMS m/z (relative
intensity, %): 201 (85.8%), 173 (48.6%), 160 (19.6%), 144 (100%), 130 (30.4%). HRMS
+
(
ESIꢀTOF) m/z: [M + H] Calcd for C12
H
12NO
2
, 202.0863; found, 202.0858.
7-Methyl-1-phenethylindoline-2,3-dione (2bi)
1
Compound 2bi was isolated in 75% yield (199 mg, red oil); H NMR (400 MHz, CDCl
3
) δ 7.49 (d,
J = 7.2 Hz, 1H), 7.32 (m, 3H), 7.25 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H), 4.23 – 4.09 (m, 2H), 3.07 –
1
3
2
1
2
.94 (m, 2H), 2.55 (s, 3H). C NMR (101 MHz, CDCl ) δ 183.8, 159.3, 148.4, 142.4, 137.2,
3
28.8, 128.7, 127.0, 123.8, 123.7, 121.4, 118.9, 43.5, 35.4, 19.0. EIꢀMS m/z (relative intensity, %):
65 (52.8%), 231 (9.4%), 161 (16.4%), 158 (27.5%), 146 (100%), 104 (30.0%), 91 (27.1%).
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C17
H
16NO
2
, 266.1176; found, 266.1177.
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1-Benzyl-7-methylindoline-2,3-dione (2bj)
Compound 2bj was isolated in 42% yield (105 mg, red oil); H NMR (600 MHz, CDCl
J = 7.3 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.31 – 7.23 (m, 2H), 7.20 (d, J = 7.5 Hz, 2H), 7.01 (t, J =
1
3
) δ 7.53 (d,
1
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0
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0
7.5 Hz, 1H), 5.20 (s, 2H), 2.26 (s, 3H). C NMR (151 MHz, CDCl ) δ 183.6, 159.6, 148.6, 142.5,
3
136.2, 129.1, 127.7, 125.6, 124.0, 123.6, 122.0, 118.8, 45.3, 18.6. EIꢀMS m/z (relative
intensity, %): 251 (67.3%), 194 (19.5%), 160 (100%), 118 (11.3%), 104 (16.+9%), 91 (31.0%).
+
HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C16
H
14NO
2
, 252.1019; found, 252.1018.
2
0a
1-Phenylindoline-2,3-dione (2ad)
1
Compound 2ad was isolated in 81% yield (181 mg, red crystal); mp 133ꢀ135 °C; H NMR (600
MHz, CDCl ) δ 7.73 – 7.66 (m, 1H), 7.60 – 7.50 (m, 3H), 7.49 – 7.38 (m, 3H), 7.17 (t, J = 7.5 Hz,
3
13
1
H), 6.89 (d, J = 8.1 Hz, 1H). C NMR (151 MHz, CDCl
3
) δ 182.9, 157.3, 151.7, 138.3, 132.9,
129.9, 128.8, 126.0, 125.6, 124.3, 117.5, 111.3. EIꢀMS m/z (relative intensity, %): 223 (17.9%),
195 (100%), 167 (32.9%), 139 (6.7%), 92 (6.0%), 77 (10.2%).
5-Methyl-1-(p-tolyl)indoline-2,3-dione (2cd)
1
Compound 2cb was isolated in 93% yield (233 mg, red crystal); mp 138ꢀ140 °C; H NMR (600
MHz, CDCl ) δ 7.48 (s, 1H), 7.33 (t, J = 7.3 Hz, 3H), 7.30 – 7.24 (m, 2H), 6.77 (d, J = 8.1 Hz,
3
13
1
H), 2.42 (s, 3H), 2.34 (s, 3H). C NMR (151 MHz, CDCl
3
) δ 183.3, 157.5, 149.7, 138.7, 138.7,
134.0, 130.5, 130.4, 125.7, 125.7, 117.5, 111.1, 21.2, 20.7. EIꢀMS m/z (relative intensity, %): 251
(24.3%), 223 (100%), 208 (20.9%), 194 (23.6%), 180 (12.7%), 134 (13.1%). HRMS (ESIꢀTOF)
+
m/z: [M + H] Calcd for C16
H14NO
2
, 252.1019; found, 252.1018.
3-Phenyl-1H-benzo[e]indole-1,2(3H)-dione (2db)
1
Compound 2db was isolated in 83% yield (227 mg, red crystal); mp 216ꢀ217 °C; H NMR (400
MHz, CDCl
3
) δ 8.71 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.69 (t,
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J = 7.6 Hz, 1H), 7.58 (t, J = 7.7 Hz, 2H), 7.53 – 7.39 (m, 4H), 7.09 (d, J = 8.7 Hz, 1H). C NMR
151 MHz, CDCl ) δ 181.9, 158.0, 154.9, 140.4, 132.9, 131.5, 130.4, 130.0, 129.3, 129.0, 128.8,
26.3, 125.8, 123.6, 111.3, 109.3. EIꢀMS m/z (relative intensity, %): 273 (29.5%), 245 (100%),
(
3
1
2
2
10
11
12
13
14
15
16
17
18
19
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17 (21.6%), 189 (7.8%), 108 (12.2%). HRMS (ESIꢀTOF) m/z: [M + H] Calcd for C18
2
H12NO ,
74.0863; found, 274.0868.
2
0a
5-Methyl-1-phenylindoline-2,3-dione (2cc) and 1-(p-Tolyl)indoline-2,3-dione (2cd)
1
Mixture of 2cc and 2cd was isolated in 92% yield (218 mg, red oil); H NMR (600 MHz, CDCl
3
)
δ 7.66 (d, J = 7.4 Hz, 1H), 7.58 – 7.46 (m, 5H), 7.41 – 7.34 (m, 4H), 7.34 (t, J = 6.4 Hz, 3H), 7.31
–
3
1
1
7.24 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 2.42 (s,
13
13
3
H), 2.35 (s, 3H). C NMR (151 MHz, CDCl ) δ 183.1, 183.0, 157.4 (two C), 151.9, 149.5,
1
3
38.9, 138.8, 138.3, 134.2, 133.1, 130.5, 130.2, 129.9, 129.6, 128.6, 125.8 (two C), 125.5, 124.2,
13
17.5 (two C), 111.3, 111.1, 21.2, 20.7. EIꢀMS m/z (relative intensity, %): 237 (23.5%), 209
(100%), 180 (44.3%), 152 (5.6%), 134 (5.8%), 77 (11.1%).
Acknowledgments
This work was financially supported by National Natural Science Foundation of China (NNSFC,
No. 21362030 and 21562038) for supporting our research. The authors also thank Jiangsu
Provincial Natural Science Foundation (BK20161328) for financial support.
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Supporting Information. Copies of all H NMR and C NMR spectra of all compounds and
HRMS of the reaction intermediates. This material is available free of charge via the Internet at
http://pubs.acs.org.
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