Direct N-Alkylation and Kemp Elimination Reactions of 1-Sulfonyl-1H-Indazoles

Article abstract of DOI:10.1002/asia.201800741

The reactions of 1-sulfonyl-1H-indazoles under basic conditions are discussed, and the direct N-alkylation and Kemp elimination reactions of these compounds are reported. A series of 2-(p-tosylamino)benzonitriles and N-alkyl indazoles were prepared in good yields. Moreover, the 2-(p-tosylamino)benzonitriles could be transformed into a diverse range of important derivatives in a one-pot reaction. This method was successfully applied to the total syntheses of quindolinone and cryptolepinone; quindolinone was prepared in a one-pot reaction from 1-sulfonyl-1H-indazole.

Full text of DOI:10.1002/asia.201800741

DOI: 10.1002/asia.201800741
Full Paper
Synthetic Methods
Direct N-Alkylation and Kemp Elimination Reactions of 1-Sulfonyl-
1H-Indazoles
Meng Tang,* Bingjie Chu, and Xiaowei Chang[a]
Abstract: The reactions of 1-sulfonyl-1H-indazoles under
basic conditions are discussed, and the direct N-alkylation
and Kemp elimination reactions of these compounds are re-
ported. A series of 2-(p-tosylamino)benzonitriles and N-alkyl
indazoles were prepared in good yields. Moreover, the 2-(p-
tosylamino)benzonitriles could be transformed into a diverse
range of important derivatives in a one-pot reaction. This
method was successfully applied to the total syntheses of
quindolinone and cryptolepinone; quindolinone was pre-
pared in a one-pot reaction from 1-sulfonyl-1H-indazole.
1. Introduction
2. Results and Discussion
Indazoles and their derivatives constitute an important class of
compounds that are extensively used in the pharmaceutical in-
dustry.[1] However, reactions of 1-tosyl-1H-indazoles have rarely
been reported, presumably owing to the difficulties associated
with their preparation, although detosylation of these com-
pounds under basic conditions or by using phase-transfer cat-
alysis have been reported.[2] Since its introduction, the Kemp
elimination has been exclusively applied to benzisoxazoles,
with most reports focusing on discussions of the reaction
mechanism.[3]
We began our investigation by screening a variety of bases. As
shown in Table 1, treating compound 1a with MeONa, NaOH,
or K2CO3 in MeOH afforded compound 2a in good yield
(Table 1, entries 1–3). However, when THF was used as the sol-
vent, the treatment of compound 1a with MeONa gave a sur-
prising result: following the complete consumption of com-
pound 1a within 2 h, compound 2a was isolated in 29% yield,
whilst compounds 3a and 4a were also obtained in 30% and
38% yield, respectively (Table 1, entry 5). When the reaction
time was prolonged to 24 h, compound 2a disappeared, and
compound 3a and 4a were isolated in 43% and 53% yield, re-
spectively (Table 1, entry 6). We found that performing the re-
action in 1,4-dioxane gave a similar result (Table 1, entry 13),
whereas Et2O, DCE, toluene, and MeCN afforded mixtures of
compounds 2a, 3a, and 4a (Table 1, entries 14–17). When
DMF and DMSO were used, no products were isolated (Table 1,
entries 18 and 19).
Recently, we developed an efficient synthesis of 1-tosyl-1H-
indazoles from readily accessible o-haloaryl N-tosylhydrazones.
A series of valuable derivatives were prepared in good yields,
and this method was successfully applied to the synthesis of
bioactive compounds.[4] With the 1-tosyl-1H-indazole deriva-
tives in hand, we attempted their detosylation, with the goal
of further functionalizing the indazoles. Although this reaction
occurred smoothly in the presence of both magnesium in
MeOH and TBAF in THF, as described by Inamoto et al.,[2e,f]
more than 10 equivalents of magnesium were required, whilst
TBAF was unsuitable in some cases. Therefore, we wanted to
develop a more satisfactory method for this detosylation reac-
tion.
Next, we tested other bases in THF as the solvent. We were
pleasantly surprised to find that the use of tBuOK and LDA
each afforded 2-(p-tosylamino)benzonitrile (5a) in almost-
quantitative yield (Table 1, entries 20 and 21), through a Kemp
elimination reaction. The structure of compound 5a was estab-
lished by NMR spectroscopy and by single-crystal X-ray analysis
(see the Supporting Information). DMF, DMSO, and 1,4-dioxane
each gave similar results (Table 1, entries 22–24), whilst the re-
action also occurred with K2CO3 as the base in DMF at higher
temperature (Table 1, entry 26). We also screened several Lewis
bases, including Et3N and DABCO, in different solvents, but no
reaction was observed, even at higher temperatures (Table 1,
entries 4, 11, 12, and 28).
[a] Prof. M. Tang, B. Chu, X. Chang
School of Pharmacy
Lanzhou University
Lanzhou 730000 (P. R. China)
E-mail: tangmeng@lzu.edu.cn
N-Alkyl indazoles are typically prepared from the corre-
sponding 1H-indazoles by using an alkylating agent,[5] such as
methyl iodide and methyl p-toluenesulfonate.[6] The regioselec-
tive synthesis of 2-methyl-2H-indazoles has been reported pre-
viously by the groups of Bandichhor and Cheung,[7] and so we
Supporting information and the ORCID identification number(s) for the au-
thor(s) of this article can be found under:
https://doi.org/10.1002/asia.201800741.
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Table 1. Optimization of the reaction of 1-tosyl-1H-indazole (1a) under
basic conditions.[a]
Entry
Base
Solvent
T [8C] t [h]
Yield [%][b]
2a 3a 4a 5a
1
2
3
4
5
6
7[c]
8
MeONa
NaOH
K2CO3
Et3N
MeONa
MeONa
MeONa
MeONa
NaOH
K2CO3
Et3N
MeOH
RT
RT
RT
10
10
10
87
98
85
–
29
–
–
–
76
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
MeOH
MeOH
MeOH
THF
THF
THF
THF
THF
THF
THF
reflux 24
–
–
RT
RT
RT
2
24
24
30
53
53
49
–
–
–
–
58
19
15
15
19
–
–
–
–
–
38
43
46
40
–
–
–
–
41
50
65
51
54
–
–
–
–
–
Scheme 1. Proposed pathway for the direct N-alkylation and Kemp elimina-
tion reactions. Ts=p-toluenesulfonyl.
reflux 12
RT 24
reflux 10
reflux 10
reflux 10
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
tured a hydrogen ion to form 1H-indazole 2. However, in
aprotic solvent, such as THF and 1,4-dioxane, anion 7 reacted
DABCO
MeONa 1,4-dioxane
THF
–
–
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
24
24
24
24
24
24
24
with TsOMe to afford compounds
3 and 4 (path a;
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
tBuOK
LDA
tBuOK
tBuOK
tBuOK
K2CO3
K2CO3
K2CO3
Et3N
Et2O
DCE
toluene
MeCN
DMF
DMSO
THF
THF
26
8
26
17
–
–
–
–
–
–
–
–
–
–
–
Scheme 1).[6] Meanwhile, a parallel pathway could occur, in
which intramolecular isomerization and direct N-alkylation of
intermediate 6 would give compound 3 (path b, Scheme 1). In
the presence of a non-nucleophilic base, such as tBuOK and
LDA, a Kemp elimination reaction would occur. According to
the classical mechanism, we proposed a plausible pathway for
this transformation, in which the 1-tosyl-1H-indazole (1) under-
went a concerted E2 elimination reaction, with cleavage of the
NÀN bond, thereby resulting in the desired 2-(p-tosylamino)-
benzonitrile (5; Scheme 1).
–
–
0.5
96
99
96
88
59
–
93
trace
–
0.5
0.5
0.5
0.5
DMF
DMSO
1,4-dioxane
DMF
DMF
DMSO
DMF
–
–
–
–
–
–
–
–
–
–
–
–
24
120 10
120 10
120 10
Next, we prepared a series of 2-(p-tosylamino)benzonitriles
(5) in good yields under our optimized conditions (Table 3).
The presence of substitutes with various electronic effects on
the aromatic ring had little influence on the reaction: both
electron-donating (5d–5 f) and electron-withdrawing (5b, 5c,
5g) substituents worked well to furnish the corresponding
products, whilst the yield was unaffected when a phenolic hy-
droxy group was present (5 f). Furthermore, 1-methylsulfonyl-
1H-indazole and 1-benzenesulfonyl-1H-indazole were also tol-
erated in this reaction (Table 3, entries 7–9), although the reac-
tion of 1-methylsulfonyl-1H-indazole resulted in a lower yield
(Table 3, entry 7).
[a] Reaction conditions: compound 1 (0.2 mmol), base (0.4 mmol), solvent
(2 mL), argon atmosphere; [b] yield of the isolated product; [c] MeONa
(2.0 mmol) was added. DABCO=1,4-diazabicyclo[2.2.2]octane, DCE=1,2-di-
chloroethane, LDA=lithium diisopropylamide.
tried to improve the regioselectivity of the reaction by chang-
ing the amount of alkali and the reaction temperature (Table 1,
entries 7 and 8), but we did not achieve the desired result.
Next, with our optimized conditions in hand, we attempted
to synthesize a variety of N-alkyl indazoles to test the scope of
this reaction. Thus, a range of N-alkyl indazoles were prepared
in good yields (Table 2), and the structure of compound 3d
was confirmed by NMR spectroscopy and by single-crystal X-
ray analysis (see the Supporting Information). Hydrogen,
methyl, phenyl, furyl, and benzyl groups were all well-tolerated
at the R1 position, and the corresponding N-methyl indazoles
were all formed in good yields (Table 2, entries 1–8). NaOEt
was also a suitable substrate for this reaction and gave the cor-
responding N-ethyl indazoles in good yields (Table 2, entries 9
and 10).
The products of the Kemp elimination reaction (5) are useful
building blocks in organic chemistry.[8] To demonstrate their
utility, we investigated the further elaboration of these prod-
ucts, with the aim of transforming them into a diverse range
of derivatives in a one-pot reaction. First, we considered a
Thorpe–Ziegler cyclization reaction of the cyano group. Thus,
2-chloroacetonitrile and 18-crown-6 were added to compound
1a as a model substrate after the Kemp elimination reaction,
which led to the formation of compound 8a in 77% yield. Fur-
thermore, the addition of a second equivalent of tBuOK
caused the Thorpe–Ziegler cyclization reaction to occur
smoothly, thereby affording compound 9a in 39% yield
(Scheme 2).
We proposed a simple mechanism for the direct N-alkylation
reaction (Scheme 1). The reaction was initiated by the nucleo-
philic addition of NaOMe to the 1-tosyl-1H-indazole, which re-
sulted in the formation of intermediate 6, followed by detosy-
lation to give the 1H-indazole anion (7). In MeOH, anion 7 cap-
Under the same reaction conditions, compounds 9b–9j
were readily obtained by using 5-bromopentanenitrile, 4-chlor-
obutyronitrile, bromoacetone, and ethyl bromoacetate
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Table 2. Scope of the synthesis of N-alkyl indazoles.[a]
Table 3. Preparation of 2-(p-tosylamino)benzonitriles.
Entry
1
5
Conditions[a]
Yield [%][b]
Entry
3
4
Yield [%][b]
3
4
A
92
1
2
3
4
39
40
34
37
35
2
A
A
A
A
A
B
B
B
95
72
83
83
65
54
95
90
33
47
44
3
4
5[c]
6
5
6
31
27
45
71
7
8
9
7
26
70
[a] Conditions A: compound 1 (0.2 mmol), tBuOK (0.3 mmol), THF (2 mL),
RT, argon atmosphere, 30–60 min; Conditions B: compound 1 (0.2 mmol),
K2CO3 (0.4 mmol), DMF (2 mL), 1208C, argon atmosphere, 10 h; [b] yield
of the isolated product; [c] tBuOK (1.0 mmol) was added. Ms=methane-
sulfonyl.
8
45
41
27
49
30
57
9
10
[a] Reaction conditions: compound 1 (0.2 mmol), NaOR (0.4 mmol), THF
(2 mL), RT, argon atmosphere; [b] yield of the isolated product.
Scheme 2. Preparation of compound 9a from compound 1a in a one-pot
reaction. 18-C-6=1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6).
(Scheme 3). This is the first report of the construction of benza-
zocine derivatives 9b–9d. Indole derivatives 9a and 9h–9j,
and benzazepine derivatives 9e–9g have been used widely in
the design and synthesis of bioactive compounds through sub-
sequent transformations. For example, compound 9e has been
reported in connection with the preparation of antiplatelet
drugs.[9]
none[10] were performed (Scheme 4). Compound 10 was pre-
pared from compound 1a and 2-bromo-2’-fluoroacetophenone
in a one-pot reaction. Then, intramolecular cyclization of com-
pound 10 resulted in compound 11 and quindolinone; detosy-
lation of compound 11 afforded quindolinone. N-Methylation
of quindolinone gave cryptolepinone. Quindolinone was also
prepared in a one-pot reaction from compound 1a in 12%
yield (Scheme 5).
To further explore the usefulness of compounds 5, the syn-
theses of the antimalarial alkaloid quindolinone and cryptolepi-
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3. Conclusion
In summary, we have investigated the reactivity of 1-sulfonyl-
1H-indazoles under basic conditions, including their direct N-al-
kylation and Kemp elimination reactions, which have been re-
ported in detail. These procedures were applied to a wide
range of substrates, and a series of 2-(p-tosylamino)benzoni-
triles and N-alkyl indazoles were prepared in good yields.
Moreover, the 2-(p-tosylamino)benzonitriles were subsequently
transformed into a diverse range of important derivatives in a
one-pot reaction, and this method was also applied to the syn-
thesis of quindolinone and cryptolepinone.
Experimental Section
General Information
Purification was performed by flash column chromatography on
silica gel (200–300 mesh) with light petroleum ether (b.p. 60–908C)
as the eluent. All of the organic extracts were dried over anhydrous
1
MgSO4. H NMR spectra were recorded on a 400 MHz spectrome-
ter; chemical shifts (d) and coupling constants (J) are reported rela-
tive to tetramethylsilane (TMS) as an internal standard. 13C NMR
spectra were recorded on a 100 MHz spectrometer.
General Procedure for the Synthesis of N-Alkyl Indazoles 3
and 4
A mixture of the 1-sulfonyl-1H-indazole (1; 0.2 mmol) and NaOR
(0.4 mmol) in THF (2 mL) was stirred at RT for 24 h under an argon
atmosphere. After quenching with water, the product was extract-
ed with EtOAc and the organic layer was washed with a saturated
aqueous solution of NH4Cl and brine, dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Purification by column chroma-
tography on silica gel (petroleum ether/EtOAc) afforded the prod-
ucts (3 and 4).[5]
Scheme 3. Preparation of compounds 9b–9j in a one-pot reaction.
Compound 3a: 11.5 mg (43% yield); white solid; m.p. 65.0–65.18C;
1H NMR (400 MHz, CDCl3): d=4.17 (s, 3H), 7.05–7.09 (m, 1H), 7.25–
7.29 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.68–7.71 (dd, J=8.8, 0.8 Hz,
1H), 7.84 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=40.2, 117.0,
119.8, 121.5, 122.0, 123.4, 125.8, 148.9 ppm.
1
Compound 4a: 14.0 mg (53% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=4.06 (s, 3H), 7.11–7.15 (m, 1H), 7.37 (d, J=3.6 Hz, 2H),
7.71–7.73 (m, 1H), 7.97 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=
35.4, 108.8, 120.3, 121.0, 123.9, 126.1, 132.6, 139.8 ppm.
1
Compound 3b: 11.8 mg (39% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=4.22 (s, 3H), 7.08 (td, J=9.2, 2.4 Hz, 1H), 7.21–7.24 (dd,
J=9.2, 2.4 Hz, 1H), 7.65–7.68 (m, 1H), 7.86 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=40.4, 102.5 (J=24 Hz), 117.2 (J=29 Hz), 119.2
(J=10 Hz), 121.3 (J=12 Hz), 123.6 (J=8 Hz), 146.3, 15.4 ppm (J=
237 Hz).
Scheme 4. Syntheses of quindolinone and cryptolepinone.
Compound 4b: 10.5 mg (35% yield); colorless oil; 1H NMR
(400 MHz, CDCl3): d=4.08 (s, 3H), 7.17 (td, J=8.8, 2.4 Hz, 1H),
7.32–7.36 (m, 2H), 7.94 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=
35.8, 104.9 (J=23 Hz), 109.9 (J=9 Hz), 115.9 (J=27 Hz), 123.9 (J=
10 Hz), 132.4 (J=6 Hz), 136.9, 157.8 ppm (J=237 Hz).
Compound 3c: 12.0 mg (40% yield); white solid; m.p. 57.1–58.58C;
1H NMR (400 MHz, CDCl3): d=4.18 (s, 3H), 6.88 (td, J=9.2, 2.4 Hz,
1H), 7.26–7.29 (m, 1H), 7.57–5.61 (m, 1H), 7.87 ppm (s, 1H);
13C NMR (100 MHz, CDCl3): d=40.3, 100.4 (J=23 Hz), 113.1 (J=
Scheme 5. Synthesis of quindolinone in a one-pot reaction.
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28 Hz), 119.2, 121.7 (J=11 Hz), 124.0, 148.8 (J=13 Hz), 161.6 ppm
(J=242 Hz).
106.5, 109.0, 111.3, 121.1, 121.5, 126.6, 135.9, 140.8, 142.0,
148.9 ppm; HRMS (ESI): m/z calcd for C12H11N2O: 199.0866 [M+H]+;
found: 199.0865.
Compound 4c: 10.0 mg (33% yield); colorless oil; 1H NMR
(400 MHz, CDCl3): d=4.02 (s, 3H), 6.88 (td, J=9.2, 2.4 Hz, 1H),
7.01–7.04 (m, 1H), 7.64–7.67 (m, 1H), 7.94 ppm (d, J=0.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=35.6, 94.6 (J=26 Hz), 110.4 (J=
26 Hz), 120.8, 122.4 (J=11 Hz), 128.9 (J=178 Hz), 133.0, 162.1 ppm
(J=244 Hz).
Compound 3d: 11.2 mg (34% yield); colorless oil; 1H NMR
(400 MHz, CDCl3): d=3.83 (s, 3H), 4.18 (s, 3H), 6.87 (d, J=2.4 Hz,
1H), 6.98–7.01 (dd, J=9.2, 2.4 Hz, 1H), 7.60 (d, J=9.2 Hz, 1H),
7.76 ppm (s, 1H); 13C NMR (100 MHz, CDCl3): d=40.2, 55.3, 96.4,
118.4, 120.6, 121.9, 122.7, 145.4, 155.0 ppm.
1
Compound 3i: 20.0 mg (45% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=4.01 (s, 3H), 4.38 (s.2H), 7.03 (t, J=7.2 Hz, 1H), 7.11 (d,
J=7.2 Hz, 2H), 7.21–7.30 (m, 4H), 7.48 (d, J=8.8 Hz, 1H), 7.66 ppm
(d, J=8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=30.6, 37.7, 117.0,
119.5, 121.0, 121.5, 126.1, 126.9, 128.2, 128.8, 133.6, 136.9,
147.7 ppm.
1
Compound 4i: 21.8 mg (49% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=3.97 (s, 3H), 4.26 (s.2H), 6.95–6.99 (m, 1H), 7.10–7.13
(m, 1H), 7.18–7.30 (m, 6H), 7.41 ppm (d, J=8.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=33.6, 35.2, 108.9, 119.8, 120.7, 122.7, 126.19,
126.23, 128.4, 128.7, 139.3, 141.0, 143.8 ppm.
Compound 4d: 15.3 mg (47% yield); white solid; m.p. 111.3–
112.88C; 1H NMR (400 MHz, CDCl3): d=3.84 (s, 3H), 4.04 (s, 3H),
7.06–7.08 (m, 2H), 7.26–7.29 (m, 1H), 7.87 ppm (s, 1H); 13C NMR
(100 MHz, CDCl3): d=35.6, 55.6, 100.0, 109.9, 118.6, 124.2, 131.8,
135.9, 154.5 ppm.
1
Compound 3j: 12.0 mg (41% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=1.63 (t, J=7.2 Hz, 3H), 4.47 (q, J=7.2 Hz, 2H), 7.05–7.09
(m, 1H), 7.25–7.29 (m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.70–7.72 (dd,
J=8.8, 0.8 Hz, 1H), 7.90 ppm (s,1H); 13C NMR (100 MHz, CDCl3): d=
15.8, 48.4, 117.3, 120.0, 121.5, 121.8, 125.7, 148.7 ppm.
Compound 4j: 9.0 mg (30% yield); yellow oil; 1H NMR (400 MHz,
CDCl3): d=1.51 (t, J=7.2 Hz, 3H), 4.43 (q, J=7.2 Hz, 2H), 7.13 (t,
J=7.2 Hz, 1H), 7.34–7.42 (m, 2H), 7.72 (d, J=8.0 Hz, 1H), 7.99 ppm
(s, 1H); 13C NMR (100 MHz, CDCl3): d=14.9, 43.6, 108.8, 120.3,
121.1, 124.1, 126.0, 132.7, 138.9 ppm.
Compound 3e: 13.1 mg (37% yield); yellow solid; m.p. 95.7–
1
97.38C; H NMR (400 MHz, CDCl3): d=4.15 (s, 3H), 5.97 (s, 2H), 6.86
(s, 1H), 6.99 (s, 1H), 7.70 ppm (s, 1H); 13C NMR (100 MHz, CDCl3):
d=39.9, 93.8, 94.9, 100.8, 117.2, 123.2, 145.4, 145.8, 149.0 ppm;
HRMS (ESI): m/z calcd for C9H9N2O2: 177.0669 [M+H]+; found:
177.0660.
1
Compound 3k: 8.8 mg (27% yield); yellow oil; H NMR (400 MHz,
Compound 4e: 15.6 mg (44% yield); white solid; m.p. 133.9–
135.88C; 1H NMR (400 MHz, CDCl3): d=3.96 (s, 3H), 5.99 (s, 2H),
6.73 (s, 1H), 6.96 (s, 1H), 7.76 ppm (s, 1H); 13C NMR (100 MHz,
CDCl3): d=35.6, 88.5, 97.6, 101.4, 118.3, 132.3, 136.7, 144.1,
148.8 ppm; HRMS (ESI): m/z calcd for C9H9N2O2: 177.06691 [M+H]+;
found: 177.066.
CDCl3): d=1.53 (t, J=7.2 Hz, 3H), 2.60 (s. 3H), 4.39 (q, J=7.2 Hz,
2H), 7.01 (t, J=7.2 Hz, 1H), 7.23–7.27 (m, 1H), 7.54 (d, J=8.4 Hz,
1H), 7.64 ppm (d, J=8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
9.7, 15.5, 45.1, 117.0, 119.5, 120.2, 121.1, 125.9, 130.2, 147.7 ppm.
1
Compound 4k: 18.4 mg (57% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=1.47 (t, J=7.2 Hz, 3H), 2.58 (s, 3H), 4.36 (q, J=7.2 Hz,
2H), 7.08–7.12 (m, 1H), 7.34–7.35 (m, 2H), 7.64 ppm (d, J=8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=11.8, 15.0, 43.3, 108.7, 119.5,
120.4, 123.3, 126.0, 139.8, 141.1 ppm.
1
Compound 3 f: 9.2 mg (31% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=2.65 (s, 3H), 4.19 (s, 3H), 7.09–7.13 (m, 1H), 7.34–7.38
(m, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.67 ppm (d, J=8.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=9.8, 37.1, 116.4, 119.6, 120.6, 120.9,
126.5, 132.1, 146.9 ppm.
1
General Procedures for the Synthesis of 2-(p-Tosylamino)ben-
Compound 4 f: 13.2 mg (45% yield); yellow oil; H NMR (400 MHz,
zonitriles (5)
CDCl3): d=2.57 (s, 3H), 4.00 (s, 3H), 7.09–7.13 (m, 1H), 7.31–7.39
(m, 2H), 7.65 ppm (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=11.8, 35.0, 108.7, 119.5, 120.3, 123.2, 126.2, 140.8, 141.2 ppm.
Conditions A: A mixture of the 1-sulfonyl-1H-indazole (1; 0.2 mmol)
and tBuOK (34.0 mg, 0.3 mmol) in THF (2 mL) was stirred at RT for
30–60 min under an argon atmosphere. After quenching with
water, the product was extracted with EtOAc and the organic layer
was washed with a saturated aqueous solution of NH4Cl and brine,
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography on silica gel (petroleum
ether/EtOAc) afforded the product (5).
1
Compound 3g: 11.4 mg (27% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=4.19 (s, 3H), 7.06–7.10 (m, 1H), 7.29–7.33 (m, 1H),7.46–
7.60 (m, 6H), 7.71 ppm (d, J=8.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=38.5, 117.0, 120.1, 121.2, 121.8, 126.2, 128.7, 129.0,
129.6, 129.7, 136.0, 148.0 ppm.
Compound 4g: 29.8 mg (71% yield); white solid; m.p. 72.2–
74.08C; 1H NMR (400 MHz, CDCl3): d=4.10 (s, 3H), 7.17–7.21 (m,
1H), 7.36–7.42 (m, 3H), 7.49 (t, J=8.0 Hz, 2H), 7.96 (d, J=7.2 Hz,
2H), 8.00 ppm (d, J=8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
35.5, 109.1, 120.9, 121.3, 121.6, 126.2, 127.3, 127.8, 128.8, 133.7,
141.4, 143.7 ppm.
Conditions B: A mixture of the 1-sulfonyl-1H-indazole (1; 0.2 mmol)
and K2CO3 (52.8 mg, 0.4 mmol) in DMF (2 mL) was stirred at 1208C
for 10 h under an argon atmosphere. After quenching with water,
the product was extracted with EtOAc and the organic layer was
washed with brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. Purification by column chromatography on
silica gel (petroleum ether/EtOAc) afforded the product (5).[7]
1
Compound 3h: 10.5 mg (26% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=4.34 (s, 3H), 6.61–6.63 (m, 1H), 6.77 (d, J=3.6 Hz, 1H),
7.12–7.16 (m, 1H), 7.29–7.33 (m, 1H), 7.64 (d, J=1.6 Hz, 1H), 7.69
(d, J=8.8 Hz, 1H), 7.86 ppm (d, J=8.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=40.0, 109.3, 111.6, 117.2, 120.3, 120.5, 122.3, 126.3, 143.0,
144.7, 147.9 ppm; HRMS (ESI): m/z calcd for C12H11N2O: 199.0866
[M+H]+; found: 199.0867.
Compound 5a: conditions A; 52.4 mg (96% yield); white solid;
1
m.p. 114.1–115.88C; H NMR (400 MHz, CDCl3): d=2.39 (s, 3H), 7.17
(td, J=7.6, 0.8 Hz, 1H), 7.27 (d, J=2.0 Hz, 2H), 7.46–7.49 (dd, J=
7.6, 1.2 Hz, 1H), 7.54 (td, J=7.6, 1.2 Hz, 1H), 7.70–7.72 ppm (m,
3H); 13C NMR (100 MHz, CDCl3): d=21.6, 104.3, 115.8, 121.7, 125.0,
127.3, 129.9, 132.7, 134.1, 135.5, 139.5, 144.6 ppm.
1
Compound 4h: 28.0 mg (70% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=4.10 (s, 3H), 6.55–6.56 (m, 1H), 6.89 (d, J=3.6 Hz, 1H),
7.20–7.25 (m, 1H), 7.36–7.44 (m, 2H), 7.57 (d, J=1.2 Hz, 1H),
8.06 ppm (d, J=8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=35.6,
Compound 5b: conditions A; 53.5 mg (92% yield); white solid;
m.p. 153.5–155.08C; 1H NMR (400 MHz, CDCl3): d=2.40 (s, 3H),
6.81–6.86 (m, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.44–7.50 (m, 2H),
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7.76 ppm (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.6,
99.3 (J=3 Hz), 108.4 (J=27 Hz), 112.2 (J=24 Hz), 115.5, 127.3,
130.0, 134.7 (J=11 Hz), 135.5, 142.6 (J=12 Hz), 144.9, 165.6 (J=
255 Hz) ppm.
(19 mL, 0.3 mmol) and 18-crown-6 (8.0 mg, 0.03 mmol) were added
and the mixture was stirred at reflux for 10 h. The mixture was
cooled to RT, tBuOK (22.5 mg, 0.2 mmol) was added, and the mix-
ture was stirred at RT for a further 5 min. After quenching with
water, the product was extracted with EtOAc and the organic layer
was washed with a saturated aqueous solution of NH4Cl and brine,
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
Purification by column chromatography on silica gel (petroleum
ether/EtOAc) afforded the product (9a; 12.4 mg, 39% yield).
Yellow solid; m.p. 159.2–160.18C; 1H NMR (400 MHz, CDCl3): d=
2.33 (s, 3H), 4.49 (br s, 2H), 7.18 (d, J=8.0 Hz, 2H), 7.31 (t, J=
7.6 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.54 (td, J=8.4, 1.2 Hz, 1H),
7.72 (d, J=8.4 Hz, 2H), 8.18 ppm (d, J=8.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=21.6, 88.7, 113.5, 116.0, 118.9, 122.5, 124.3,
127.1, 129.6, 129.8, 133.2, 137.2, 145.1, 145.3 ppm.
Compound 5c: conditions A; 55.3 mg (95% yield); white solid;
m.p. 121.0–122.58C; 1H NMR (400 MHz, CDCl3): d=2.40 (s, 3H),
7.17–7.19 (dd, J=7.6, 2.8 Hz, 2H), 7.26–7.32 (m, 2H), 7.66 (d, J=
8.0 Hz, 2H), 7.70–7.73 ppm (m, 1H); 13C NMR (100 MHz, CDCl3): d=
21.6, 106.9 (J=9 Hz), 114.6 (J=2 Hz), 119.1 (J=25 Hz), 121.8 (J=
22 Hz), 125.7 (J=9 Hz), 127.3, 130.0, 135.2, 135.6 (J=3 Hz), 144.8,
159.2 ppm (J=248 Hz); HRMS (ESI): m/z calcd for C14H11FN2O2SNa:
313.0417 [M+Na]+; found: 313.0419.
Compound 5d: conditions A; 43.6 mg (72% yield); white solid;
m.p. 171.5–172.68C; 1H NMR (400 MHz, CDCl3): d=2.40 (s, 3H), 3.78
(s, 3H), 6.83 (br s, 1H), 6.92(d, J=2.8 Hz, 1H), 7.09–7.12 (dd, J=9.2,
3.2 Hz, 1H), 7.24–7.26 (m, 2H), 7.62 ppm (d, J=8.4 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=21.6, 55.8, 107.5, 115.5, 116.6, 120.5,
126.4, 127.4, 129.8, 131.8, 135.3, 144.5, 157.3 ppm; HRMS (ESI): m/z
calcd for C15H14N2O3SNa: 325.0617 [M+Na]+; found: 325.0619.
One-Pot Synthesis of Compounds 9b–9d
A
mixture of the 1-sulfonyl-1H-indazole (1; 0.1 mmol), K2CO3
(27.0 mg, 0.2 mmol) in DMF (2 mL) was stirred at 1208C for 10 h
under an argon atmosphere. Then, 5-bromopentanenitrile (24 mL,
0.2 mmol) was added and the mixture was stirred at 808C for a fur-
ther 3 h. After quenching with water, the product was extracted
with EtOAc and the organic layer was washed with brine, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by column chromatography on silica gel (petroleum ether/
EtOAc) afforded the products (9b–9d).
Compound 5e: conditions A; 52.5 mg (83% yield); white solid;
m.p. 153.1–153.78C; 1H NMR (400 MHz, CDCl3): d=2.40 (s, 3H), 6.07
(s, 2H), 6.78 (s, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.26–7.28 (m, 1H),
7.67 ppm (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.6,
97.4, 102.9, 105.0, 110.1, 115.9, 127.4, 129.9, 135.2, 136.0, 144.6,
145.4, 152.6 ppm; HRMS (ESI): m/z calcd for C15H14N2O3SNa:
339.0410 [M+Na]+; found: 339.0407.
Compound 5 f: conditions A; 53.0 mg (83% yield); white solid;
m.p. 174.8–175.28C; 1H NMR (400 MHz, CDCl3): d=2.40 (s, 3H), 3.99
(s, 2H), 5.72 (s, 1H), 6.84 (br s, 1H), 6.92 (s, 1H), 7.26 (d, J=6.4 Hz,
2H), 7.62 ppm (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
21.6, 56.5, 98.1, 107.5, 115.8, 116.6, 127.4, 129.9, 133.1, 135.1, 143.8,
144.6, 150.8 ppm; HRMS (ESI): m/z calcd for C15H14N2O4SNa:
341.0566 [M+Na]+; found: 341.0568.
Compound 9b: 29.0 mg (82% yield); white solid; m.p. 237.8–
239.28C; 1H NMR (300 MHz, CDCl3): d=1.58–1.62 (m, 2H), 1.82–
1.86 (m, 2H), 2.38–2.43 (m, 2H), 2.46 (s, 3H), 3.64 (br s, 2H), 7.11
(dd, J=7.9, 2.6 Hz, 1H), 7.29–7.33 (m, 2H), 7.45–7.49 (m, 1H), 7.57–
7.62 (m, 3H), 7.71–7.73 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=
16.5, 21.6, 21.9, 26.9, 50.0, 115.5, 116.4, 119.3, 127.9, 129.0, 129.7,
129.8, 133.5, 134.1, 134.3, 141.3, 144.4 ppm; HRMS (ESI): m/z calcd
for C19H20N3O2S: 354.1271 [M+H]+; found: 354.1263.
Compound 5g: conditions A; 41.5 mg (65% yield); yellow oil;
1H NMR (400 MHz, [D6]DMSO): d=2.34 (s, 3H), 7.31 (t, J=4.0 Hz,
3H), 7.70 (d, J=8.0 Hz, 2H), 8.09–8.12 (dd, J=9.6, 2.8 Hz, 1H),
8.38 ppm (d, J=2.8 Hz, 1H); 13C NMR (100 MHz, [D6]DMSO): d=
21.4, 104.3, 117.3, 120.0, 126.8, 128.9, 129.8, 130.6, 142.3 ppm.
Compound 9c: 32.6 mg (82% yield); white solid; m.p. 220.7–
221.28C; 1H NMR (300 MHz, CDCl3): d=1.58–1.62 (m, 2H), 1.78–
1.80 (m, 2H), 2.37–2.41 (m, 2H), 2.46 (s, 3H), 3.57 (br s, 2H), 6.14 (s,
2H), 6.61 (s, 1H), 7.01 (s, 1H), 7.33 (d, J=7.2 Hz, 2H), 7.65 ppm (d,
J=7.2 Hz, 2H); 13C NMR (75 MHz, CDCl3): d=16.6, 21.6, 22.0, 27.0,
50.1, 103.3, 108.1, 110.5, 111.7, 116.4, 119.3, 128.0, 129.8, 134.4,
137.3, 144.5, 147.9, 151.9 ppm; HRMS (ESI): m/z calcd for
C20H20N3O4S: 398.1169 [M+H]+; found: 398.1162.
Compound 5h: conditions B; 21.4 mg (54% yield); white solid;
m.p. 94.8–95.88C; 1H NMR (400 MHz, CDCl3): d=3.14 (s, 3H), 7.18
(br s, 1H), 7.29–7.31 (dd, J=7.6, 0.8 Hz, 1H), 7.61–7.66 (m, 2H),
7.73 ppm (d, J=8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=40.6,
104.5, 116.0, 121.8, 125.4, 133.1, 134.5, 139.4 ppm.
Compound 9d: 33.7 mg (88% yield); white solid; m.p. 199.8–
200.18C; 1H NMR (400 MHz, CDCl3): d=1.56–1.63 (m, 2H), 1.80–
1.87 (m, 2H), 2.41 (t, J=6.8 Hz, 2H), 2.45 (s, 3H), 3.60 (br s, 2H),
3.85 (s, 3H), 6.98 (d, J=8.8 Hz, 1H), 7.07 (dd, J=8.8, 2.8 Hz, 1H),
7.16 (d, J=2.8 Hz, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.58 ppm (d, J=
8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=16.5, 21.6, 21.9, 26.9,
50.1, 55.9, 116.18, 116.23, 118.2 119.3, 119.7, 127.9, 129.8, 130.9,
133.5, 134.5, 144.3, 159.1 ppm; HRMS (ESI): m/z calcd for
C20H22N3O3S: 384.1376 [M+H]+; found: 384.1371.
Compound 5i: conditions B; 49.2 mg (95% yield); white solid; m.p.
147.8–149.28C; 1H NMR (400 MHz, CDCl3): d=7.20 (td, J=7.6,
0.8 Hz, 1H), 7.25 (br s, 1H), 7.46–7.50 (m, 3H), 7.54–7.61 (m, 2H),
7.73 (d, J=8.4 Hz, 1H), 7.82–7.84 ppm (m, 2H); 13C NMR (100 MHz,
CDCl3): d=104.6, 115.6, 122.1, 125.4, 127.3, 129.3, 132.8, 133.6,
134.2, 138.4, 139.1 ppm.
Compound 5j: conditions B; 52.0 mg (90% yield); white solid; m.p.
148.2–149.48C; 1H NMR (400 MHz, CDCl3): d=3.79 (s, 3H), 6.77
(br s,1H), 6.92 (d, J=2.8 Hz, 1H), 7.11–7.14 (dd, J=9.2, 2.8 Hz, 1H),
7.47 (t, J=8.0 Hz, 2H), 7.57–7.65 (m, 2H), 7.73–7.75 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=55.8, 107.7, 115.4, 116.6, 120.6, 126.8,
127.4, 129.2, 131.5, 133.5, 138.2, 157.4 ppm; HRMS (ESI): m/z calcd
for C14H12N2O3SNa: 311.0461 [M+Na]+; found: 311.0463.
One-Pot Synthesis of Compounds 9e–9g
A mixture of the 1-sulfonyl-1H-indazole (1; 0.1 mmol) and tBuOK
(17.0 mg, 0.15 mmol) in THF (2 mL) was stirred at RT for 30 min
under an argon atmosphere. Then, 4-chlorobutyronitrile (18 mL,
0.2 mmol), KI (8.3 mg, 0.05 mmol), and 18-crown-6 (8.0 mg,
0.03 mmol) were added and the mixture was stirred at reflux for
20 h. The mixture was cooled to RT, tBuOK (112.2 mg, 1 mmol) was
added, and the mixture was stirred at RT for a further 5 min. After
quenching with water, the product was extracted with EtOAc and
One-Pot Synthesis of Compound 9a
A mixture of 1-sulfonyl-1H-indazole (1a; 27.2 mg, 0.1 mmol) and
tBuOK (17.0 mg, 0.15 mmol) in THF (2 mL) was stirred at RT for
30 min under an argon atmosphere. Then, 2-chloroacetonitrile
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the organic layer was washed with a saturated aqueous solution of
NH4Cl and brine, dried over anhydrous MgSO4, filtered, and con-
centrated in vacuo. Purification by column chromatography on
silica gel (petroleum ether/EtOAc) afforded the products (9e–9g).
layer was washed with brine, dried over anhydrous MgSO4, filtered,
and concentrated in vacuo. Purification by column chromatogra-
phy on silica gel (petroleum ether/EtOAc) afforded the product (9j;
11.0 mg, 30% yield).
Compound 9e: 22.2 mg (65% yield); yellow solid; m.p. 226.1–
227.68C; H NMR (400 MHz, [D6]DMSO): d=2.02 (br s, 2H), 2.41 (s,
3H), 3.67 (br s, 1H), 4.04 (br s, 1H), 6.22 (s, 2H), 7.31–7.37 (m, 3H),
7.44–7.54 ppm (m, 5H); 13C NMR (100 MHz, [D6]DMSO): d=21.6,
26.6, 56.6, 69.3, 121.0, 127.3, 128.8, 129.3, 130.2, 131.2, 132.2, 136.3,
136.4, 137.4, 143.5, 158.6 ppm.
Yellow solid; m.p. 181.6–182.58C; 1H NMR (400 MHz, CDCl3): d=
1.28 (t, J=7.2 Hz, 3H), 2.33 (s, 3H), 4.19 (q, J=7.2 Hz, 2H), 7.11 (d,
J=8.0 Hz, 2H), 7.21 (t, J=8.0 Hz, 1H), 7.29–7.38 (m, 2H), 7.48 (d,
J=8.4 Hz, 2H), 7.74 (br s, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.48 ppm
(br s, 1H); 13C NMR (100 MHz, CDCl3): d=14.3, 21.5, 61.1, 111.6,
117.0, 121.3, 121.4, 122.9, 123.0, 126.8, 127.5, 129.1, 134.95, 135.01,
143.6, 161.0 ppm; HRMS (ESI): m/z calcd for C18H18N2O4SNa:
381.0879 [M+Na]+; found: 381.0883.
1
Compound 9 f: 28.5 mg (74% yield); white solid; m.p. 226.5–
1
227.68C; H NMR (400 MHz, CDCl3): d=2.13 (br s, 2H), 2.42 (s, 3H),
3.73 (s, 2H), 3.86 (br s, 1H), 4.51 (br s, 1H), 6.08 (s, 2H), 6.76 (s, 1H),
7.05 (s, 1H), 7.26 (t, J=4.0 Hz, 2H), 7.49 ppm (d, J=8.4 Hz, 2H);
13C NMR (100 MHz, CDCl3): d=21.5, 26.4, 58.0, 102.5, 106.2, 113.8,
127.6, 129.1, 129.5, 130.6, 137.0, 143.2, 148.6, 149.8, 156.9 ppm.
HRMS (ESI): m/z calcd for C19H17N3O4SNa: 406.0832 [M+Na]+;
found: 406.0827.
Syntheses of Quindolinone and Cryptolepinone
A mixture of 1-sulfonyl-1H-indazole (1a; 1.65 g, 6.0 mmol) and
K2CO3 (1.67 g, 12 mmol) in DMF (3.5 mL) was stirred at 1208C for
10 h under an argon atmosphere. Then, 2-bromo-2’-fluoroaceto-
phenone (0.92 mL, 6.6 mmol) was added and the mixture was
stirred at RT for 30 min. After quenching with water, the product
was extracted with EtOAc and the organic layer was washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. Purification by column chromatography on silica gel (petro-
leum ether/EtOAc) afforded the product (10; 0.97 g, 39% yield).
White solid; m.p. 174.4–175.38C; 1H NMR (400 MHz, CDCl3): d=2.23
(s, 3H), 6.18 (br s, 2H), 6.97 (d, J=8.0 Hz, 2H), 7.10–7.46 (m, 7H),
7.52–7.56 (m, 1H), 7.62–7.66 (m, 1H), 8.12 ppm (d, J=8.4 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=21.5, 115.9, 116.2, 117.0, 119.2, 119.7,
123.5, 123.6, 125.2, 125.3, 127.6, 128.7, 129.8, 129.9, 130.4, 130.8,
132.1, 132.2, 140.7, 144.4, 148.3, 158.8, 161.3, 185.0 ppm; HRMS
(ESI): m/z calcd for C22H18FN2O3S: 409.1017 [M+H]+; found:
409.1007.
Compound 9g: 24.5 mg (66% yield); white solid; m.p. 269.9–
1
271.58C; H NMR (400 MHz, CDCl3): d=2.13 (br s, 2H), 2.41 (s, 3H),
3.83 (s, 3H), 3.85 (s, 2H), 4.48 (br s, 1H), 6.84 (d, J=2.8 Hz, 1H),
7.01–7.04 (dd, J=8.8, 2.8 Hz, 1H), 7.24–7.27 (m, 2H), 7.46 (d, J=
8.4 Hz, 2H), 7.50 ppm (d, J=8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=21.5, 26.3, 55.6, 57.2, 112.6, 116.2, 119.5, 127.5, 128.3, 129.4,
134.7, 136.6, 137.1, 143.1, 156.8, 160.0 ppm. HRMS (ESI): m/z calcd
for C19H19N3O3SNa: 392.1039 [M+Na]+; found: 392.1031.
One-Pot Synthesis of Compounds 9h and 9i
A mixture of the 1-sulfonyl-1H-indazole (1; 0.1 mmol) and tBuOK
(17.0 mg, 0.15 mmol) in THF (2 mL) was stirred at RT for 30 min
under an argon atmosphere. Then, bromoacetone (17 mL,
0.2 mmol) and 18-crown-6 (8.0 mg, 0.03 mmol) were added and
the mixture was stirred at RT for 2 h. tBuOK (22.5 mg, 0.2 mmol)
was added and the mixture was stirred at RT for a further 5 min.
After quenching with water, the product was extracted with EtOAc
and the organic layer was washed with a saturated aqueous solu-
tion of NH4Cl and brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. Purification by column chromatography on
silica gel (petroleum ether/EtOAc) afforded the products (9h and
9i).
A mixture of compound 10 (99.0 mg, 0.24 mmol) and K2CO3
(51 mg, 0.37 mmol) in DMF (2 mL) was stirred at 658C for 6 h
under an argon atmosphere. After quenching with water, the prod-
uct was extracted with CH2Cl2 and the organic layer was washed
with brine, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo. Purification by column chromatography on silica gel
(CH2Cl2/MeOH) afforded compound 11 (49.9 mg, 53% yield) and
quindolinone (19.3 mg, 34% yield).
Compound 11: yellow solid; m.p.>3008C; 1H NMR (400 MHz,
[D6]DMSO): d=2.33 (s, 3H), 7.32–7.37 (m, 3H), 7.53–7.56 (m,1H),
7.68–7.75 (m, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.23–8.29 (m, 2H), 8.37
(d, J=8.8 Hz, 1H), 12.62 ppm (br s, 1H); 13C NMR (100 MHz,
[D6]DMSO): d=21.5, 117.1, 118.3, 120.6, 121.7, 122.9, 124.6, 125.9,
126.2, 127.8, 129.9, 130.6, 132.2, 136.1, 137.0, 139.2, 140.0, 144.8,
166.8 ppm.
1
Compound 9h: 20.2 mg (61% yield); yellow oil; H NMR (400 MHz,
CDCl3): d=2.24 (s, 3H), 2.66 (s, 3H), 6.06 (br s, 2H), 6.96 (d, J=
8.0 Hz, 2H), 7.22–7.28 (m, 4H), 7.49–7.53 (m, 1H), 8.10 ppm (d, J=
8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=21.5, 29.6, 118.0, 119.47,
119.54, 125.3, 125.8, 127.7, 128.6, 130.1, 130.3, 141.0, 144.4, 146.7,
193.8 ppm.
Compound 9i: 12.7 mg (35% yield); yellow solid; m.p. 162.2–
164.08C; 1H NMR (400 MHz, CDCl3): d=2.25 (s, 3H), 2.65 (s, 3H),
3.79 (s, 3H), 6.01 (br s, 2H), 6.68 (d, J=2.4 Hz, 1H), 6.98 (d, J=
8.4 Hz, 2H), 7.07–7.10 (dd, J=8.8, 2.4 Hz, 1H), 7.23–7.27 (m, 2H),
7.98 ppm (d, J=9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=21.5,
29.6, 55.7, 102.1, 118.4, 118.8, 120.6, 126.8, 127.8, 128.6, 130.2,
135.0, 144.3, 146.7, 157.7, 193.8 ppm; HRMS (ESI): m/z calcd for
C18H18N2O4SNa: 381.0879 [M+Na]+; found: 381.0883.
A mixture of compound 11 (40.0 mg, 0.1 mmol) and NaOEt (25 mg,
0.36 mmol) in EtOH (2 mL) was stirred at reflux for 8 h under an
argon atmosphere. After quenching with water, the product was
extracted with CH2Cl2 and the organic layer was washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated in
vacuo. Purification by column chromatography on silica gel
(CH2Cl2/MeOH) afforded quindolinone (16.9 mg, 70% yield).
1
Yellow solid; m.p.>3008C; H NMR (400 MHz, [D6]DMSO): d=7.19–
7.23 (m, 1H), 7.28–7.32 (m, 1H), 7.46–7.50 (m, 1H), 7.54 (d, J=
8.0 Hz, 1H), 7.66–7.75 (m, 2H), 8.20 (d, J=8.0 Hz, 1H), 8.37 (dd, J=
8.4, 1.2 Hz, 1H), 11.69 (br s, 1H), 12.44 ppm (br s, 1H); 13C NMR
(100 MHz, [D6]DMSO): d=113.1, 116.4, 118.2, 119.3, 120.9, 121.3,
123.3, 123.6, 125.7, 127.9, 129.4, 131.10, 139.09, 139.5, 167.9 ppm.
One-Pot Synthesis of Compound 9j
A mixture of 1-sulfonyl-1H-indazole (1a; 27.2 mg, 0.1 mmol) and
K2CO3 (27.0 mg, 0.2 mmol) in DMF (2 mL) was stirred at 1208C for
10 h. Then, ethyl bromoacetate (22 mL, 0.2 mmol) was added and
the mixture was stirred at 1008C for a further 3 h. After quenching
with water, the product was extracted with EtOAc and the organic
Under an argon atmosphere, a mixture of quindolinone (40.0 mg,
0.17 mmol), K2CO3 (33 mg, 0.24 mmol), and MeI (30 mL, 0.48 mmol)
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in DMF (1 mL) was stirred at RT for 26 h. After quenching with
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1
Yellow solid; m.p.>3008C; H NMR (300 MHz, [D6]DMSO): d=4.37
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(s, 3H), 7.20 (ddd, J=8.2, 6.8, 1.2 Hz, 1H), 7.37 (ddd, J=7.9, 6.9,
0.8 Hz, 1H), 7.46–7.51 (m, 1H), 7.57 (d, J=8.2, 1H), 7.78 (ddd, J=
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11.97 ppm (br s, 1H).
Acknowledgements
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This research was supported by the NSFC (21772073) and by
the Fundamental Research Funds for the Central Universities
(lzujbky-2017-201).
Conflict of interest
The authors declare no conflict of interest.
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ÝÝ These are not the final page numbers!

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FULL PAPER
Synthetic Methods
Meng Tang,* Bingjie Chu, Xiaowei Chang
&& – &&
Direct N-Alkylation and Kemp
Elimination Reactions of 1-Sulfonyl-
1H-Indazoles
Elimination chamber: The direct N-alky-
lation reaction and the Kemp elimina-
tion reaction of 1-sulfonyl-1H-indazoles
to afford 2-(p-tosylamino)benzonitriles
and N-alkyl indazoles in good yields are
reported for the first time.
Chem. Asian J. 2018, 00, 0 – 0
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ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ