Cu(II)-Mediated Cross-Dehydrogenative Coupling of Indolines with Sulfonamides, Carboxamides, and Amines

Article abstract of DOI:10.1021/acs.joc.9b01893

A facile and efficient Cu-mediated protocol for the cross-dehydrogenative coupling of indoline with sulfonamides, carboxamides, and anilines is reported. The reaction takes place through Cu-mediated C7-H activation via a 6-membered metallacycle to afford the amide and amine derivatives in good yields with a wide range of functional group tolerance. The importance of the protocol has been demonstrated by synthesizing the antiproliferative agent, ER-67836.

Full text of DOI:10.1021/acs.joc.9b01893

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Article
Cu(II)-mediated Cross-Dehydrogenative Coupling of
Indolines with Sulfonamides, Carboxamides and Amines
Mohit Kumar, . Raziullah, Afsar Ali Khan, Ashfaq Ahmad,
Himangsu Sekhar Dutta, Ruchir Kant, and Dipankar Koley
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01893 • Publication Date (Web): 12 Sep 2019
Downloaded from pubs.acs.org on September 12, 2019
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Cu(II)-mediated Cross-Dehydrogenative Coupling of Indolines with
Sulfonamides, Carboxamides and Amines
Mohit Kumar,§ Raziullah,† Afsar Ali Khan,§ Ashfaq Ahmad,† Himangsu Sekhar Dutta,§ Ruchir
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Kant,‡ Dipankar Koley*,†,§
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†Medicinal and Process Chemistry Division and ‡Molecular and Structural Biology Division,
§
CSIR-Central Drug Research Institute, Lucknow, 226031, India. Academy of Scientific and
Innovative Research, New Delhi, 110001, India
GRAPHICAL ABSTRACT
R1SO2NH2
Cu, air
or
46 examples
upto 69% yield
R2CONH2
+
N
N
or
R3NH2
RNH
H
DG
sulfonamidation
carboxamidation
amination
DG
R = R1SO2/R2CO/R3
ABSTRACT. A facile and efficient Cu-mediated protocol for the cross-dehydrogenative
coupling of indoline with sulfonamides, carboxamides, and anilines is reported. The reaction
takes place through Cu-mediated C7−H activation via six membered metallacycle to afford
the amide and amine derivatives in good yields with a wide range of functional group
tolerance. The importance of the protocol has been demonstrated by synthesizing the
antiproliferative agent ER-67836.
INTRODUCTION
Indoles and related heterocycles are considered to be the most privileged scaffolds as more
than 200 indole based moieties are either marketed pharmaceuticals or under clinical trials.1
In sharp contrast to the remarkable advancement in functionalizing the indoles at the C2 and
C3 positions exploiting the inherent reactivity of the pyrrole ring,2 attention for the
functionalization on the benzenoid ring has gained very recently.3 Particularly, owing to their
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diverse biological activity profile that includes hMGMAT2 inhibition, antiproliferative and
antiperoxidative properties, C7 substituted indoles are in high demand (Scheme 1).4 In this
regard, C‒C bond formation reactions like arylation,5 allylation,6 alkenylation,7 alkylation,8
acylation9 at the C7 position are well explored. Strikingly, despite the ubiquity of aromatics10
having nitrogen-containing functional groups like sulfonamide,10a-b carboxamide,10c-d
phosphoramidite10e-f in drugs, agrochemicals and organic materials, C7‒N11 bond formation
reaction in indole scaffold has been less reported, presumably due to the less favored
electrophilic nature of the nitrogen atom, However, indole based sulfonamide derivative
indisulam4g (Scheme 1a), a clinical candidate for cancer therapy, potentiated the efforts
towards the development of C7‒N bond formation. For instance, Zhu et al.11a reported a
ruthenium-catalyzed protocol for sulfonamidation using organic sulfonyl azides (Scheme 2b).
Inspired by this, Chang et al.11b-d and others11f,m have developed methods for amidation to
indoles and indolines using sulfonyl-, phosphoryl-, aryl-, alkyl-, and acyl azides.
Interestingly, few of these Ir-catalysed protocols can be performed at room temperature.11d,f
Very recently, azidoformates have been used for the synthesis of C7 amidated indoline
derivatives, albeit again via Ir-catalysis.11e Anthranil11h,j,k and dioxazolone11g,i,l derivatives
have also been successfully employed as aminating precursors for the indoline C7
functionalization (scheme 2c). Despite their efficiency in promoting the C7 amination, these
protocols require expensive and toxic ruthenium and iridium based catalysts. Additionally,
the aminating sources like anthranils, dioxazolones, azidoformates, tosyl-, aryl-, and
phsophoryl azides used are either explosive or require multi-steps for their preparation. Very
recently, Ackermann et al. reported C7‒H chalcogenation12 via copper catalysis. Inspired by
the environmental and economical benefits of using 1st row transition metal catalysts, we
have also developed copper catalyzed protocols for the indoline C7 acyloxylation13 and
imidation11n via cross-dehydrogenative coupling (CDC).
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Scheme 1. C7 functionalized bioactive indole derivatives.
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a) bioactive scaffolds: indole/Indoline C7-sulfonamides
6
Cl
Cl
7
8
9
NH2
S
N
N
N
H
N
Cl
H
H
H
HN
O
O
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HN
O
HN
O
HN
O
O
O
O
S
S
S
S
S
OCH3
SO2NH2
Indisulam (I)
cell cycle inhibitor
OCH3
(IV)
glucokinase
activatior
ER-67836 (II)
anti-proliferative anti-proliferative
ER-67880 (III)
b) bioactive scaffolds: indole/Indoline C7-carboxamides
O
R2
S
HOOC
R1
N
H
O
N
O
N
R3
N
S
O
NH
N
O
NH
N
O
O
O
R3 = C8H17
R1 = 4-CF3Ph
R2 = 2,4-difluoroPh
OMe
tubulin polymerization inhibitor
(V)
(VI)
(VII)
hMGMAT2 inhibitor
MDAT2 ingibitor
c) bioactive scaffolds: indole/Indoline C7/C6-amines
N
O
N
N
CF3
N
HN
HN
O
Cl
O
N
N
N
HN
HO
O
N
F
NH
H
HN
O
TAK-285 (IX)
HER1 and HER2 inhibitor
GSK1838705A (VIII)
IGF-1R inhibitor
We, therefore, questioned whether similar copper catalyzed CDC protocol could be
established using sulfonamide as the amidating source under aerobic condition. In this regard,
Yu et al.14 and others15 have developed copper-catalyzed or –mediated protocols for
amidation to arene carboxamides using TsNH2 as aminating sources (Scheme 2a). However,
the reaction proceeded through both kinetically and thermodynamically favoured five-
membered cupracycle intermediate and use of tethered oxazoline as bidentate chelating
ligand was obligatory for the mentioned outcome. On the other hand, kinetically less
favorable six-membered cupracycle intermediate was not explored for amidation reaction.
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Herein, we wish to disclose an aerobic copper mediated indoline C7–H amidation and
amination protocol using sulfonamides, carboxamides, and anilines.
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Scheme 2. Arene sulfonamidation using TsNH2 and C7‒H bond amidations of indolines.
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Previous work
a) sulfonamidation to carboxamides using TsNH2 via 5-membered metallacycle
[Cu]
TsNH2
DG
NHTs
DG
R

R

via 5-membered cupracycle
DG = Directing Group
b) sulfonamidation to indoles/indolines using TsN3
[Ru], [Ir]
TsN3
R

R

C7-H sulfonamidation
N
N
DG
DG
H
TsNH
c) amidation to indolines using diaoxazolones/anthranils
[Ru], [Ir]
dioxazolones/anthranils
R

R

C7-H amidation
N
N
DG
DG
H
RCONH
This work
[Cu]
R

R

R1SO2NH2 / R2CONH2 / R3NH2
via 6-membered cupracycle
N
N
cross-dehydrogenative coupling
sulfonamidation
RNH
H
DG
DG
carboxamidation
R = R1SO2/R2CO/R3
amination
RESULTS AND DISCUSSION
To optimize the reaction conditions, we employed N–pyrimidyl indoline (1a) as the model
substrate and TsNH2 (2a) as the amide source (Table 1). The optimization studies revealed
that none of the copper salts was catalytically effective to provide the desired product in
isolable yield (entries 1‒13). However, although stoichiometric Cu(OAc)2 furnished traces of
product, use of basic additive afforded 3aa in 20% isolated yield (entries 14‒15). Thus, other
inorganic and organic bases as additive were tested and 2,6-di-tertbutyl-4-methylpyridine
proved to be the most effective (entries 16‒21). Toluene was found to be the best solvent and
62% of 3aa was formed at 140 °C (entries 22‒23).
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Table 1. Sulfonamidation reaction optimizationa
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6
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[Cu]
2-pym =
TsNH2
2a
+
N
N
N
N
conditions: see below
2-pym
2-pym
TsNH
H
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3aa
1a
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entry
1
Cu (equiv)
solvent
additive (equiv)
Temp
(°C)
130
130
130
130
130
130
130
130
130
130
130
Yield[b]
(%)
Trace
Trace
Trace
5
Trace
Trace
Trace
Trace
10
Cu2O (0.3)
Cu2O (0.3)
Cu(TC) (0.3) DCE
Cu(TC) (0.3) DCE
DCE
DCE
--
Pivalic acid (1.0)
3
4
5
6
7
8
9
10
11
--
Pivalic acid (1.0)
CuBr (0.3)
DCE
--
--
--
--
Cu(OBz)2 (0.3) DCE
Cu(OAc)2 (0.3) DCE
Cu(OAc)2 (0.3) CHCl3
Cu(OAc)2 (0.3) DCE
Cu(OAc)2 (0.3) DCB
Cu(OAc)2 (0.3) DCB:Toluene
(1:1)
Cu(OAc)2 (0.3) DMSO
Cu(OAc)2 (0.3) DMF
Cu(OAc)2 (1.0) DCE
Cu(OAc)2 (1.0) DCE
Cu(OAc)2 (1.0) DCB
Cu(OAc)2 (1.0) DCB
Cu(OAc)2 (1.0) DCB
Cu(OAc)2 (1.0) DCB
Cu(OAc)2 (1.0) DCB
Cu(OAc)2 (1.0) DCB
Cu(OAc)2 (1.0) Toluene
Cu(OAc)2 (1.0) Toluene
Cu(OAc)2 (1.5) Toluene
Cu(OAc)2 (2.0) Toluene
Na2CO3 (1.0)
Na2CO3 (1.0)
Na2CO3 (1.0)
15
13
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Na2CO3 (1.0)
Na2CO3 (1.0)
--
Na2CO3 (1.0)
Na2CO3 (1.0)
Ag2SO4 (1.0)
DMAP (1.0)
B1 (1.0)
130
130
130
130
130
130
130
130
130
130
130
140
140
140
140
140
140
140
140
140
140
Trace
Trace
Traces
20%
30%
20%
20%
26%
23%
36%
42%
62%
55%
50%
57%
50%
47%
63%
38%
27%
42%
B2 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.5)
B3 (2.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
B3 (1.0)
26c Cu(OAc)2 (1.0) Toluene
27
28
Cu(OAc)2 (1.0) Toluene
Cu(OAc)2 (1.0) Toluene
29d Cu(OAc)2 (1.0) Toluene
30e Cu(OAc)2 (1.0) Toluene
31
32
33
Cu(OAc)2 (0.2) Toluene
Cu(OAc)2 (0.3) Toluene
Cu(OAc)2 (0.4) Toluene
140
50%
aReaction Conditions: 1a (0.25 mmol), 2a (0.3 mmol), solvent (2.5 mL), air, 30 h. Isolated yield. 2a (0.37
b
c
d
e
mmol), under O2, under Ar; B1=2,6-dimethylpyridine, B2=2,4,6-trimethylpyridine, B3=2,6-di-tertbutyl-4-
methylpyridine
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The yield of the product could not be significantly improved by varying either the equivalent
of salt, or 2a, or additives (entries 24‒28). Instead of air, oxygen atmosphere was not helpful
to improve the yield (entry 29). However, low yield of 3aa was obtained under an inert
atmosphere (entry 30). Unfortunately, efforts to implement catalytic use of copper salts did
not provide satisfactory yields (entries 31‒33).
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Having optimized reaction conditions in hand, we first tested the scope and limitation of this
sulfonamidation protocol with respect to the various sulfonamide derivatives (Scheme 3). In
general, the reaction was found to be tolerant of diverse substitutions on the sulfonamide
scaffold. As shown in Scheme 3, a series of sulfonamides bearing electron donating and
electron withdrawing substituents were coupled with indoline derivative 1a to furnish the
desired products (3ab–3am) in good to moderate yields. Substitution pattern had very little
impact on the yield of the products as ortho-, meta- and para-substituted sulfonamide
components furnished the products with similar yields (3ah, 3am; 3ad, 3ak). Halogenated
sulfonamides (3af, 3ag, 3aj) were also compatible with this protocol. Gratifyingly, the scope
of this reaction could be extended for the naphthyl (3an), heteroaryl (3ao) and alkyl (3ap,
3aq) sulfonamide derivatives. The formation of C7 sulfonamide derivative was
unambiguously confirmed by X-ray analysis of 3ah (CCDC 1917173). Subsequently, we
wondered whether this amidation protocol could be applied for the carboxamide derivative as
well. To our delight, carboxamides were found to be suitable coupling partner and the
products (3ar–3az) were obtained in good to moderate yields (69–22%). Notably, thiophene-
2-carboxamide, acetamide and trifluoroacetamide were also coupled with the indoline
scaffold.
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Scheme 3. Scope of sulfonamides and carboxamidesa
5
6
7
8
RSO2NH2
or
RCONH2
Cu(OAc)2
+
N
2,6-di-tert-butyl-4-methylpyridine
N
2-pym
H
toluene, 140 C, 36 h

2-pym
R(CO)SO2NH
1a
2b-2z
3ab-3az
9
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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3ab
3ac
3ad
3ae
, 50%, R = H
1
, 38%, R = nBu
N
1
, 65%, R = OCH3
O
S
2-pym
NH
1
N
R1
, 36%, R = OCF3
O
S
2-pym
NH
1
3af
, 64%, R = Cl
O
1
3ag
3ah
, 55%, R = CF3
O
1
1
3aj
, 50%, R = Cl
, 55%, R = NO2
R1
1
1
3ak
, 55%, R = OCH3
3ai
, 30%, R = COCH3
N
R1
O
2-pym
N
NH
S
O
N
O
S
2-pym
O
NH
2-pym
NH
S
1
3al
, 59%, R = CH3
O
O
1
3ao
, 50%
3am
, 57%, R = NO2
3an
S
, 55%
N
N
N
2-pym
NH
2-pym
O
O
S
HN
O
2-pym
NH
R1
1
1
3ar
, 55%, R = H
3ap
, 55%, R = CH3
O
1
1
3as
, 48%, R = Me
3aq
,
, 30% R = CF3
1
3at
, 39%, R = NO2
3av
, 63%,
R1
3au
1
, 43%, R = CF3
O
S
HN
1
3ax
3ay
3az,
, 31%, R = CH3
N
1
, 40%, R = CF3
2-pym
N
NH
O
2-pym
1
t
22%, R = Bu
R1
3aw
, 69%,
aReaction conditions: 1a (0.25 mmol), 2b–2z (0.3 mmol), Cu(OAc)2 (0.25 mmol), 2,6-ditertbutyl-4-
methylpyridine (0.25 mmol), Toluene (2.5 mL), 140 ºC, 36 h, isolated yields
The scope of the indoline substrates was next explored using 2a as the coupling counterpart.
As shown in Scheme 4, various substituents at the C2, C3, C4, C5, and C6 positions on the
indoline moiety were very well tolerated. Under the optimized conditions, indoline moieties
containing methyl (3ba, 3da, 3fa), phenyl (3ca), methoxy (3ga), fluoro (3ha), chloro (3ia,
3ka), and bromo (3ea, 3ja) were successfully coupled with 2a in moderate to good yields.
Unfortunately, indolines containing strong electron-withdrawing substituent, such as nitro,
furnished poorly yielded products (3la). The title reaction was also applicable for carbazole
and hexahydrocarbazole derivatives and the products (3ma, 3na) were obtained in good
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yields. The reaction was also conducted in preparatory scale using 1a and 2a, and the product
3aa was obtained in 54% yield.
7
8
9
Scheme 4. Scope of indolinesa
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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35
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37
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39
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60
R1
R1
Cu(OAc)2
N
+
TsNH2
2a
N
2,6-di-tert-butyl-4-methylpyridine
toluene, 140 C, 36 h
2-pym
TsNH
2-pym
H

3aa-na
1a-n
Br
Me
b
3aa
3ba
3ca
, 54%, R = H
R
N
, 68%, R = Me
N
N
c
2-pym
, 58%, R = Ph
TsNH
2-pym
2-pym
TsNH
3da
TsNH
3ea
, 61%
, 49%
3fa
, 61%, R = Me
R
3ga
3ha
, 65%, R = OMe
, 61%, R = F
3ka
, 32%, R = Cl
3la
, 21%, R = NO2
N
N
R
3ia
3ja
, 55%, R = Cl
, 40% R = Br
2-pym
2-pym
TsNH
TsNH
3na
, 66%
3ma
, 42%
N
N
2-pym
TsNH
2-pym
TsNH
aReaction Conditions:. 1a–1n (0.25 mmol), 2a (0.3 mmol), Cu(OAc)2 (0.25 mmol), 2,6-ditertbutyl-4-
methylpyridine (0.25 mmol), Toluene (2.5 mL), 140 ºC, 36 h, isolated yields. bpreparative scale reaction, c48h
In view of the medicinal significance of N-arylanilines,16 we tested the feasibility of aniline
derivatives as the coupling partner (Scheme 5). To our delight, a wide range of electron-
deficient anilines were coupled with 1a. For instances, nitroanilines, aminobenzonitriles,
fluorinated anilines provided the corresponding products (5aa–5ag) in 61–20%. However,
although aniline furnished the desired product in 25% yield, electronically rich precursor (4-
methoxyaniline) did not furnish any desired product.
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Scheme 5. Scope of anilinesa
5
6
7
8
9
Cu(OAc)2
+
ArNH2
N
N
2,6-di-tert-butyl-4-methylpyridine
2-pym
2-pym
ArNH
H
1a
toluene, 140 C, 36 h

4a 4g

5aa-5ag
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N
N
N
2-pym
2-pym
NH
2-pym
NH
NH
O2N
5aa, 52%
5ab, 54%
5ac, 61%
O2N
NC
N
2-pym
N
N
NO2
F3C
NH
2-pym
NH
2-pym
NH
O2N
F
O2N
CF3
5af, 24%
5ad, 56%
5ae, 20%
N
N
2-pym
2-pym
NH
NH
MeO
5ag, 25%
5ah, 0%
aReaction Conditions:. 1a (0.25 mmol), 4a–4f (0.3 mmol), Cu(OAc)2 (0.25 mmol), 2,6-ditertbutyl-4-
methylpyridine (0.25 mmol), Toluene (2.5 mL), 140 ºC, 36 h, isolated yields
Finally, to demonstrate the utility of this amidation, the antiproliferative agent ER-67836 (II)
was synthesized from 3ad in two steps (Scheme 6). ER-67836 can be further converted to
either ER-6788017 (III) or cell growth inhibitor (7)18 via reported methods.
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Scheme 6. Synthetic application
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7
3ad
DDQ (2 equiv)
1,4 dioxane, 90°C, 12h, 86%
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O
H
N
S
O
MeO
N
N
N
6
NaOEt (20 % in EtOH)
DMSO, Ar, 100°C, 4h, 63%
HN
N
H
O
S
O
Ref 18
Ref 17
III
(
)
II
( )
ER-67880
ER-67836
7
(cell growth inhibitor)
OCH3
CONCLUSION
In conclusion, we have developed copper (II)-mediated indoline C7‒H sulfonamidation,
carboxamidation and amination using sulfonamides, carboxamides and anilines directly. This
is the first general method for the amidation to indolines at the C7 position via CDC protocol
using non-explosive, non-toxic and readily available precursors.
EXPERIMENTAL SECTION
A. General Information.
Reactions were performed using borosil sealed tube vial with dry solvents under anhydrous
conditions, unless otherwise noted. Anhydrous 1,2-dichloroethane (DCE) and toluene were
used. Ethyl acetate (EtOAc), dichloromethane (DCM) and petroleum ether were purchased
commercially and were used without further purification, unless otherwise stated. Column
chromatography was done in 60Å-120Å silica gel of Merck Company. All spectra 1H NMR,
13C NMR, recorded on Bruker AV 400 MHz spectrometer in CDCl3 using as internal
standards the residual CHCl3 for 1H NMR (δ = 7.26 ppm) and the deuterated solvent signal
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for 13C NMR (δ = 77.16 ppm). The following abbreviations were used to describe peak
splitting patterns when appropriate: s = singlet, d = doublet, t = triplet, q = quartet, dd =
doublet of doublet, m = multiplet. Coupling constants, J, were reported in Hertz (Hz). HRMS
analysis was performed using Q-TOF mass spectrometer of the SAIF Division in CSIR-CDRI
Lucknow. IR analysis was also performed in SAIF Division. Reagents and starting materials
were purchased from Aldrich, Alfa Aesar and other commercial sources and used without
further purification unless otherwise noted. The indoline pyrimidine derivatives (1a-1n)19-20
as the precursors were prepared via reported methods.
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B. General procedure for the synthesis of Sulfonamidation, Amidation and Amination:
To a solution of indoline pyrimidine (0.25 mmol) in toluene (2.5 mL), Cu(OAc)2 (0.25
mmol),
2,6-di-tert-butyl-4-methylpyridine
(0.25
mmol)
and
sulfonamide/carboxamides/anilines (0.30 mmol) was added in sealed tube vial and the
reaction mixture was kept at 140 ˚C in preheated oil bath for 36 hours. After completion of
the reaction, reaction mixture was allowed to cool at room temperature. Diluted with DCM (5
mL) and filtered through a silica pad. The silica pad was washed with DCM (2 X 10 mL).
The combined organic layer was evaporated under reduced pressure. Crude mixture was
purified by silica gel column chromatography to yield the corresponding C7 amidated
product.
C. Gram scale synthesis of 3aa: To a solution of indoline pyrimidine 1a (1g, 5.0 mmol) in
toluene (20 mL), Cu(OAc)2 ( 5.0 mmol), 2,6-di-tert-butyl-4-methylpyridine (5.0 mmol) and
p-toluenesulfonamide (6.0 mmol) was added in sealed tube vial and the reaction mixture was
kept at 140 ˚C for 48 hours. After completion of the reaction, reaction mixture was allowed to
cool at room temperature. Diluted with DCM (50 mL) and filtered through a silica pad. The
combined organic layer was evaporated under reduced pressure. Crude mixture was purified
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by silica gel column chromatography to yield the corresponding C7 amidated product 3aa
5
6
992 mg, 54%).
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Cu(OAc)2
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+
TsNH2
2a
N
N
2,6-di-tert-butyl-4-methylpyridine
toluene, 140 C, 48 h
2-pym
2-pym
TsNH
3aa
H
1a

4-methyl-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3aa): 3aa was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3aa (57 mg, 62%) as a white solid. Rf: 0.41
(silica gel, 30% DCM); M. P.: 152−157 ˚C; IR (in CHCl3, cm-1): vmax; 2955, 2873, 1549,
1
1455, 1330, 1250, 1209, 1161, 1087, 1017; H NMR (400 MHz, CDCl3): δ 10.86 (s, 1H),
8.46 (d, J = 4.6 Hz, 2H), 7.42−7.35 (m, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.09−7.04 (m, 2H),
7.00 (d, J = 8.1 Hz, 2H), 6.74 (t, J = 4.7 Hz, 1H), 3.88 (t, J = 8.0 Hz, 2H), 2.92 (t, J = 8.0 Hz,
2H), 2.32 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 157.8, 142.9, 137.3, 137.1, 135.6,
13
129.0, 127.2, 126.7, 125.0, 124.7, 123.0, 111.5, 51.1, 28.2, 21.5; HRMS (ESI): calcd for
C19H19N4O2S+ [M+H]+ 367.1223, found 367.1222.
N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide(3ab): 3ab was prepared according
to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), sulfonamide 2b
(47 mg, 0.30 mmol). The crude reaction mixture was purified by column chromatography
using 2% EtOAc/DCM to afforded 3ab (44 mg, 50%) as a white solid. Rf: 0.41 (silica gel,
DCM); M. P.: 153−158 ˚C; IR (in CHCl3, cm-1): vmax; 2954, 2852, 2361, 1576, 1558, 1507,
1472, 1419, 1386, 1260, 1087, 907; 1H NMR (400 MHz, CDCl3): δ 10.88 (s, 1H), 8.46 (d, J
= 4.8 Hz, 2H), 7.44−7.37 (m, 2H), 7.26−7.18 (m, 4H), 7.10−7.05 (m, 2H), 6.74 (t, J = 4.8
Hz, 1H), 3.85 (t, J = 8.1 Hz, 2H), 2.91 (t, J = 8.2 Hz, 2H); 13C {1H} NMR (100 MHz,
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CDCl3): δ 157.7, 140.2, 137.2, 135.6, 132.3, 128.4, 127.5, 126.6, 124.8, 124.7, 123.2, 111.5,
51.2, 28.1; HRMS (ESI): calcd for C18H17N4O2S+ [M+H]+ 353.1067 found 353.1063.
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4-butyl-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ac): 3ac was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2c (63 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3ac (39 mg, 38%) as a white solid. Rf: 0.50
(silica gel, DCM); M. P.: 110−115 ˚C; IR (in CHCl3, cm-1): vmax; 2951, 2935, 2358, 1580,
1465, 1378, 1330, 1255, 1159, 1118, 1087, 1016, 992; 1H NMR (400 MHz, CDCl3): δ 10.86
(s, 1H), 8.45 (d, J = 4.8 Hz, 2H), 7.42−7.35 (m, 1H), 7.15 (d, J = 8.2 Hz, 2H), 7.10−7.03 (m,
2H), 6.99 (d, J = 8.2 Hz, 2H), 6.73 (t, J = 4.8 Hz, 1H), 3.87 (t, J = 8.2 Hz, 2H), 2.90 (t, J =
8.0 Hz, 2H), 2.57 (t, J = 7.7 Hz, 2H), 1.60−1.49 (m, 2H), 1.40−1.23 (m, 2H), 0.92 (t, J = 7.3
Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 157.8, 147.8, 137.4, 137.2, 135.5, 128.4,
127.4, 126.7, 125.0, 124.7, 123.0, 111.5, 51.1, 35.5, 33.3, 28.2, 22.3, 13.9; HRMS (ESI):
calcd for C22H25N4O2S+ [M+H]+ 409.1693 found 409.1692.
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4-methoxy-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ad): 3ad was
prepared according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25
mmol), sulfonamide 2d (56 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ad (63 mg, 65%) as a orange
solid. Rf: 0.40 (silica gel, DCM); M. P.: 175−180 ˚C; IR (in CHCl3, cm-1): vmax; 2981, 2357,
1
2323, 1558, 1507, 1488, 1435, 1396, 1155, 950; H NMR (400 MHz, CDCl3): δ 10.83 (s,
1H), 8.46 (d, J = 4.8 Hz, 2H), 7.41−7.35 (m, 1H), 7.19 (d, J = 9.0 Hz, 2H), 7.08−7.03 (m,
2H), 6.74 (t, J = 4.8 Hz, 1H), 6.67 (d, J = 9.0 Hz, 2H), 3.94 (t, J = 8.3 Hz, 2H), 3.79 (s, 3H),
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2.93 (t, J = 8.0 Hz, 2H); C {1H} NMR (100 MHz, CDCl3): δ 162.6, 157.9, 157.8, 137.1,
135.6, 132.0, 128.8, 127.2, 125.1, 124.7, 123.0, 113.6, 111.5, 55.7, 51.2, 28.2; HRMS (ESI):
calcd for C19H19N4O3S+ [M+H]+ 383.1172 found 383.1174.
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N-(1-(pyrimidin-2-yl)indolin-7-yl)-4-(trifluoromethoxy)benzenesulfonamide (3ae): 3ae
was prepared according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25
mmol), sulfonamide 2e (73 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 10% EtOAc/Hexane to afford 3ae (40 mg, 36%) as a yellow
solid. Rf: 0.66 (silica gel, 30% EtOAc/Hexane); M. P.: 105−110 ˚C; IR (in CHCl3, cm-1):
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vmax; 3648, 2364, 1684, 1558, 1540, 1507, 826, 790, 778; H NMR (400 MHz, CDCl3): δ
11.07 (s, 1H), 8.47 (d, J = 4.8 Hz, 2H), 7.41−7.36 (m, 1H), 7.31−7.26 (m, 2H), 7.09 (d, J =
5.4 Hz, 2H), 7.05−7.00 (m, 2H), 6.76 (t, J = 4.8 Hz, 1H), 3.90 (t, J = 8.4 Hz, 2H), 2.93 (t, J =
8.0 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ 157.8, 151.8, 138.6, 137.2, 135.7, 128.8,
127.5, 124.9, 124.3, 12.5, 120.3 (q, J = 260.0 Hz), 120.4, 111.7, 51.1, 28.1; HRMS (ESI):
calcd for C19H16F3N4O3S+ [M+H]+ 437.0890 found 437.0886.
4-chloro-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3af): 3af was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2f (57 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3af (62 mg, 64%) as a orange solid. Rf:
0.41 (silica gel, DCM); M. P.: 148−153 ˚C; IR (in CHCl3, cm-1): vmax; 2980, 2970, 2360,
1
1583, 1508,1458, 1337, 1273,1166, 1091; H NMR (400 MHz, CDCl3): δ 11.04 (s, 1H),
8.48 (d, J = 4.6 Hz, 2H), 7.37 (t, J = 4.2 Hz, 1H), 7.24−7.12 (m, 4H), 7.07 (d J = 5.7 Hz, 2H),
13
6.76 (t, J = 4.6 Hz, 1H), 3.93 (t, J = 7.9 Hz, 2H), 2.94 (t, J = 8.0 Hz, 2H); C {1H} NMR
(100 MHz, CDCl3): δ 157.8, 138.7, 138.6, 137.2, 135.7, 128.6, 128.2, 127.2, 124.8, 124.5,
123.4, 111.7, 51.2, 28.2; HRMS (ESI): calcd for C18H16ClN4O2S+ [M+H]+ 387.0677 found
387.0673.
N-(1-(pyrimidin-2-yl)indolin-7-yl)-4-(trifluoromethyl)benzenesulfonamide (3ag): 3ag
was prepared according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25
mmol), sulfonamide 2g (67 mg, 0.30 mmol). The crude reaction mixture was purified by
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column chromatography using 10% EtOAc/Hexane afforded 3ag (58 mg, 55%) as a yellow
solid. Rf: 0.62 (silica gel, 30% EtOAc/Hexane); M. P.: 169−174 ˚C; IR (in CHCl3, cm-1):
vmax; 2979, 2358, 2342, 1579, 1551, 1454, 1319, 1280, 1164, 1065, 1014, 999; 1H NMR (400
MHz, CDCl3): δ 11.19 (s, 1H), 8.47 (d, J = 4.8 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 7.42−7.34
(m, 3H), 7.09 (d, J = 5.3 Hz, 2H), 6.77 (t, J = 4.8 Hz, 1H), 3.85 (t, J = 8.0 Hz, 2H), 2.92 (t, J
= 8.0 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ 157.8, 143.7, 137.2, 135.8, 134.0 (q, JC-
F = 33.6 Hz), 127.3, 127.2, 125.5 (q, JC-F = 3.7 Hz), 124.9, 124.2, 123.5, 123.2 (q, JC-F = 272
Hz), 111.7, 51.2, 28.1; HRMS (ESI): calcd for C19H16F3N4O2S+ [M+H]+ 421.0941 found
421.0940.
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4-nitro-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ah): 3ah was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2h (60 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3ah (55 mg, 55%) as a yellow solid. Rf:
0.50 (silica gel, DCM); M. P.: 185−190 ˚C; IR (in CHCl3, cm-1): vmax; 2979, 2358, 2323,
1
1582, 1553,1507,1469, 1375, 1253, 1167, 1066, 992; H NMR (400 MHz, CDCl3): δ 11.38
(s, 1H), 8.47 (d, J = 4.7 Hz, 2H), 8.05 (d, J = 8.6 Hz, 2H), 7.53−7.33 (m, 3H), 7.18−7.04 (m,
13
2H), 6.79 (t, J = 4.7 Hz, 1H), 3.87 (t, J = 8.0 Hz, 2H), 2.95 (t, J = 8.0 Hz, 2H); C {1H}
NMR (100 MHz, CDCl3): δ 157.7, 149.8, 146.0, 137.0, 135.8, 127.9, 127.1, 125.1, 123.9,
123.7, 123.6, 111.9, 51.4, 28.1; HRMS (ESI): calcd for C18H16N5O4S+ [M+H]+ 398.0918
found 398.0918.
4-acetyl-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ai): 3ai was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2i (59 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3ai (30 mg, 30%) as a white solid. Rf: 0.55
(silica gel, DCM); M. P.: 120−125 ˚C; IR (in CHCl3, cm-1): vmax; 2966, 2360, 2320, 1557,
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1541, 1507, 1488, 1417, 1338, 1161, 831; H NMR (400 MHz, CDCl3): δ 11.20 (s, 1H),
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6
7
8
8.47 (d, J = 4.8 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.44−7.32 (m, 3H), 7.08 (d, J = 5.3 Hz,
2H), 6.76 (t, J = 4.8 Hz, 1H), 3.85 (t, J = 8.2 Hz, 2H), 2.92 (t, J = 8.1 Hz, 2H), 2.58 (s, 3H);
13C {1H} NMR (100 MHz, CDCl3): δ 196.9, 157.8, 144.2, 139.7, 137.0, 135.7, 128.2, 127.1,
127.0, 124.9, 124.3, 123.4, 111.7, 51.2, 28.1, 27.0; HRMS (ESI): calcd for C20H19N4O3S+
[M+H]+ 395.1172 found 395.1170.
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3-chloro-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3aj): 3aj was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2j (57 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3aj (49 mg, 50%) as a orange solid. Rf:
0.50 (silica gel, DCM); M. P.: 132−137 ˚C; IR (in CHCl3, cm-1): vmax; 3295, 2359, 2329,
1582, 1550, 1507, 1466, 1335, 1318, 1161, 811, 787; 1H NMR (400 MHz, CDCl3): δ 11.01
(s, 1H), 8.47 (d, J = 4.8 Hz, 2H), 7.41−7.35 (m, 2H), 7.19−7.07 (m, 5H), 6.76 (t, J = 4.8 Hz,
1H), 3.92 (t, J = 8.4 Hz, 2H), 2.96 (t, J = 8.2 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ
157.7, 141.9, 137.3, 135.7, 134.8, 132.3, 129.6, 127.8, 126.6, 124.9, 124.8, 124.2, 111.7,
51.4, 28.1; HRMS (ESI): calcd for C18H16ClN4O2S+ [M+H]+ 387.0677 found 387.0678.
3-methoxy-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ak): 3ak was
prepared according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25
mmol), sulfonamide 2k (56 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ak (53 mg, 55%) as a orange
solid. Rf: 0.50 (silica gel, DCM); M. P.: 110−115 ˚C; IR (in CHCl3, cm-1): vmax; 2953, 2852,
1
1592, 1557, 1507, 1457, 1418, 1396, 1319, 1285, 1259, 1184, 1078; H NMR (400 MHz,
CDCl3): δ 10.85 (s, 1H), 8.46 (d, J = 4.8 Hz, 2H), 7.44−7.38 (m, 1H), 7.14−7.06 (m, 3H),
6.97−6.91 (m, 1H), 6.84−6.79 (m, 1H), 6.74 (t, J = 4.8 Hz, 1H), 6.70 (dd, J = 1.7 Hz, 0.7 Hz,
13
1H), 3.89 (t, J = 8.1 Hz, 2H), 3.57 (s, 3H), 2.93 (t, J = 8.0 Hz, 2H); C {1H} NMR (100
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MHz, CDCl3): δ 159.4, 157.7, 141.1, 137.4, 135.5, 129.4, 127.6, 124.8, 124.7, 123.2, 119.4,
118.8, 111.5, 110.6, 55.4, 51.2, 28.1; HRMS (ESI): calcd for C19H19N4O3S+ [M+H]+
383.1172 found 383.1169.
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2-methyl-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3al): 3al was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2l (51 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3al (54 mg, 59%) as a yellow solid. Rf:
0.41 (silica gel, DCM); M. P.: 110−115 ˚C; IR (in CHCl3, cm-1): vmax; 3217, 2364, 2321,
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1556, 1507, 1457, 1316, 1212, 1105, 1089, 1006; H NMR (400 MHz, CDCl3): δ 10.90 (s,
1H), 8.46 (d, J = 4.8 Hz, 2H), 7.55 (d, J = 8.1 Hz, 1H), 7.36−726 (m, 2H), 7.13 (d, J = 7.5
Hz, 1H), 7.10−6.98 (m, 3H), 6.74 (t, J = 4.8 Hz, 1H), 4.02 (t, J = 8.2 Hz, 2H), 2.94 (t, J = 8.1
Hz, 2H), 2.19(s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 158.3, 157.9, 138.7, 137.4,
136.6, 135.8, 132.4, 132.2, 129.3, 125.9, 125.4, 124.9, 122.5, 111.6, 51.2, 28.3, 20.2; HRMS
(ESI): calcd for C19H19N4O2S+ [M+H]+ 367.1223 found 367.1221.
2-nitro-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3am): 3am was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2m (60 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3am (57 mg, 57%) as a yellow solid. Rf:
0.51 (silica gel, DCM); M. P.: 219−224 ˚C; IR (in CHCl3, cm-1): vmax; 2916, 1580, 1555,
1462, 1384, 1330, 1293, 1252, 1174, 1127, 1085, 997; 1H NMR (400 MHz, CDCl3): δ 10.87
(s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.71−7.57 (m, 3H), 7.55−7.46 (m, 1H), 7.37−7.32 (m, 1H),
7.09 (d, J = 5.2 Hz, 2H), 6.79 (t, J = 4.8 Hz, 1H), 4.05 (t, J = 8.2 Hz, 2H), 2.97 (t, J = 8.0 Hz,
13
2H); C {1H} NMR (100 MHz, CDCl3): δ 158.9, 158.2, 147.5, 137.2, 135.9, 133.9, 131.7,
125.5, 125.1, 125.0, 124.6, 122.9, 112.3, 51.3, 28.7; HRMS (ESI): calcd for C18H16N5O4S+
[M+H]+ 398.0918 found 398.0917.
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N-(1-(pyrimidin-2-yl)indolin-7-yl)naphthalene-2-sulfonamide (3an): 3an was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2n (62 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3an (56 mg, 55%) as a white solid. Rf: 0.50
(silica gel, DCM); M. P.: 219−224 ˚C; IR (in CHCl3, cm-1): vmax; 2365, 1580, 1516, 1507,
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1455, 1397, 1313, 1254, 1204, 1144, 1107, 990; H NMR (400 MHz, CDCl3): δ 11.00 (s,
1H), 8.41 (d, J = 4.6 Hz, 2H), 7.86−7.74 (m, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.58 (t, J = 7.6
Hz, 1H), 7.54−7.47 (m, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 9.2 Hz, 1H), 7.12−6.98 (m,
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2H), 6.73 (t, J = 4.7 Hz, 1H), 3.48 (t, J = 8.1 Hz, 2H), 2.76 (t, J = 8.1 Hz, 2H); C {1H}
NMR (100 MHz, CDCl3): δ 157.6, 137.2, 136.9, 135.5, 134.6, 132.0, 129.0, 128.6, 128.5,
127.9, 127.8, 127.4, 127.2, 124.8, 124.7, 123.2, 122.1, 111.5, 50.8, 28.0; HRMS (ESI):
calcd for C22H19N4O2S+ [M+H]+ 403.1223 found 403.1219.
N-(1-(pyrimidin-2-yl)indolin-7-yl)thiophene-2-sulfonamide (3ao): 3ao was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2o (48 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 2% EtOAc/DCM to afford 3ao (45 mg, 50%) as a yellow solid. Rf:
0.50 (silica gel, DCM); M. P.: 150−155 ˚C; IR (in CHCl3, cm-1): vmax; 2980, 2357, 2343,
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2311, 1583, 1507, 1457, 1449, 1372, 1312, 1252, 1111; H NMR (400 MHz, CDCl3): δ
11.20 (s, 1H), 8.47 (d, J = 4.8 Hz, 2H), 7.45−7.39 (m, 1H), 7.37 (dd, J = 5.0 Hz, 1.3 Hz, 1H),
7.13−7.08 (m, 2H), 6.95 (dd, J = 3.7 Hz, 1.3 Hz, 1H), 6.85 (dd, J = 5.0 Hz, 3.7 Hz, 1H), 6.75
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(t, J = 4.8 Hz, 1H), 4.04 (t, J = 8.3 Hz, 2H), 2.98 (t, J = 8.2 Hz, 2H); C {1H} NMR (100
MHz, CDCl3): δ 157.8, 141.0, 137.2, 135.7, 131.5, 131.4, 127.4, 127.0, 124.7, 124.5, 123.4,
+
111.6, 51.3, 22.2; HRMS (ESI): calcd for C16H15N4O2S2 [M+H]+ 359.0631 found
359.0629.
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N-(1-(pyrimidin-2-yl)indolin-7-yl)methanesulfonamide (3ap): 3ap was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
sulfonamide 2p (28 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 25% EtOAc/Hexane to afford 3ap (40 mg, 55%) as a white solid. Rf:
0.60 (silica gel, 30% EtOAc/Hexane); M. P.: 167−172 ˚C; IR (in CHCl3, cm-1): vmax; 2359,
2345, 1582, 1456, 1445, 1385, 1321, 1271, 1166, 989; 1H NMR (400 MHz, CDCl3): δ 11.00
(s, 1H), 8.49 (d, J = 4.8 Hz, 2H), 7.44−7.39 (m, 1H), 7.14−7.07 (m, 2H), 6.77 (t, J = 4.8 Hz,
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1H), 4.46 (t, J = 8.4 Hz, 2H), 3.14 (t, J = 8.0 Hz, 2H), 2.74 (s, 3H); C {1H} NMR (100
MHz, CDCl3): δ 158.8, 158.0, 136.3, 136.2, 125.8, 125.2, 124.7, 122.6, 112.0, 51.6, 39.4,
28.4; HRMS (ESI): calcd for C13H15N4O2S+ [M+H]+ 291.0910 found 291.0907.
1,1,1-trifluoro-N-(1-(pyrimidin-2-yl)indolin-7-yl)methanesulfonamide (3aq): 3aq was
prepared according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25
mmol), sulfonamide 2q (44 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 10% EtOAc/Hexane to afford 3aq (26 mg, 30%) as a white
solid. Rf: 0.60 (silica gel, 30% EtOAc/Hexane); M. P.: 97−103 ˚C; IR (in CHCl3, cm-1):
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vmax; 3010, 2926, 1593, 1555, 1484, 1419, 1376, 1288, 1226, 1186, 1115; H NMR (400
MHz, CDCl3): δ 13.38 (s, 1H), 8.48 (d, J = 4.8 Hz, 2H), 7.36 (dd, J = 7.9 Hz, 1.2 Hz, 1H),
7.16−7.06 (m, 2H), 6.78 (t, J = 4.8 Hz, 1H), 4.47 (t, J = 8.3 Hz, 2H), 3.14 (t, J = 8.1 Hz, 2H);
13C {1H} NMR (100 MHz, CDCl3): δ 158.1, 136.2, 125.2, 124.2, 123.4, 123.3, 120.2 (q, JC-F
= 324 Hz), 111.7, 51.4, 28.2; HRMS (ESI): calcd for C13H12F3N4O2S+ [M+H]+ 345.0628
found 345.0625.
N-(1-(pyrimidin-2-yl)indolin-7-yl)benzamide (3ar): 3ar was prepared according to general
procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), carboxamide 2r (37 mg,
0.30 mmol). The crude reaction mixture was purified by column chromatography using 25%
EtOAc/Hexane to afford 3ar (44 mg, 55%) as a yellow solid. Rf: 0.50 (silica gel, 30%
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EtOAc/Hexane); M. P.: 151−156 ˚C; IR (in CHCl3, cm-1): vmax; 3018, 1615, 1583, 1553,
1422, 1379, 1214, 1107, 1068, 995; 1H NMR (400 MHz, CDCl3): δ 11.41 (s, 1H), 8.43 (d, J
= 4.8 Hz, 2H), 7.93 (d J = 8.0 Hz, 1H), 7.88−7.80 (m, 2H), 7.51−7.45 (m, 1H), 7.44−7.38 (m,
2H), 7.15 (t, J = 7.8 Hz, 1H), 7.06 (dd, J = 7.2 Hz, 1.0 Hz, 1H), 6.70 (t, J = 4.8 Hz, 1H), 4.46
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(t, J = 8.3 Hz, 2H), 3.10 (t, J = 8.0 Hz, 2H); C {1H} NMR (100 MHz, CDCl3): δ 165.9,
159.5, 157.9, 136.2, 136.0, 134.7, 131.4, 128.5, 127.4, 127.3, 124.7, 123.9, 121.3, 111.5,
52.0, 28.8; HRMS (ESI): calcd for C19H17N4O+ [M+H]+ 317.1397 found 317.1393.
4-methyl-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzamide (3as): 3as was prepared according
to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), carboxamide 2s
(41 mg, 0.30 mmol). The crude reaction mixture was purified by column chromatography
using 25% EtOAc/Hexane to afford 3as (40 mg, 48%) as a orange solid. Rf: 0.51 (silica gel,
30% EtOAc/Hexane); M. P.: 192−196 ˚C; IR (in CHCl3, cm-1): vmax; 3008, 2361, 1749,
1656, 1584, 1460, 1423, 1316, 1224, 1061, 832, 796; 1H NMR (400 MHz, CDCl3): δ 11.29
(s, 1H), 8.44 (d, J = 4.8 Hz, 2H), 7.91 (d J = 8.0 Hz, 1H), 7.73 (d J = 8.0 Hz, 2H), 7.22 (d J =
7.7 Hz, 2H), 7.15 (t, J = 7.9 Hz, 1H), 6.06 (dd, J = 7.3 Hz, 1.1 Hz, 1H), 6.71 (t, J = 4.8 Hz,
1H), 4.46 (t, J = 8.0 Hz, 2H), 3.10 (t, J = 8.0 Hz, 2H), 2.39 (s, 3H); C {1H} NMR (100
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MHz, CDCl3): δ 165.8, 159.5, 157.9, 141.8, 136.0, 134.7, 133.4, 129.2, 127.4, 124.7, 123.9,
121.2, 111.5, 52.0, 28.9, 21.6; HRMS (ESI): calcd for C20H19N4O+ [M+H]+ 331.1553 found
331.1546.
4-nitro-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzamide (3at): 3at was prepared according to
general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), carboxamide 2t (50
mg, 0.30 mmol). The crude reaction mixture was purified by column chromatography using
25% EtOAc/Hexane to afford 3at (36 mg, 39%) as a yellow solid. Rf: 0.41 (silica gel, 30%
EtOAc/Hexane); M. P.: 206−211 ˚C; IR (in CHCl3, cm-1): vmax; 3007, 2925, 1668, 1585,
1527, 1461, 1347, 1282, 1107, 1015, 995. 1H NMR (400 MHz, CDCl3): δ 11.86 (s, 1H), 8.43
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(d, J = 4.8 Hz, 2H), 8.82 (d J = 8.7 Hz, 2H), 7.99 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.1 Hz,
1H), 7.18 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 6.6 Hz, 1H), 6.74 (t, J = 4.8 Hz, 1H), 4.49 (t, J =
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8.2 Hz, 2H), 3.13 (t, J = 8.1 Hz, 2H); C {1H} NMR (100 MHz, CDCl3): δ 163.7, 159.3,
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157.9, 149.6, 142.0, 136.3, 134.7, 128.5, 126.5, 124.8, 123.8, 123.7, 121.9, 111.7, 51.9, 28.7;
+
HRMS (ESI): calcd for C19H16N5O3 [M+H]+ 362.1248 found 362.1243.
N-(1-(pyrimidin-2-yl)indolin-7-yl)-4-(trifluoromethyl)benzamide (3au): 3au was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
carboxamide 2u (57 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 10% EtOAc/Hexane to afford 3au (41 mg, 43%) as a white solid. Rf:
0.62 (silica gel, 30% EtOAc/Hexane); M. P.: 149−154 ˚C; IR (in CHCl3, cm-1): vmax; 3009,
2926, 1733, 1669, 1554, 1459, 1379, 1282, 1133, 1067, 995; 1H NMR (400 MHz, CDCl3): δ
11.66 (s, 1H), 8.43 (d, J = 4.8 Hz, 2H), 7.99−7.88 (m, 3H), 7.69 (d, J = 8.4 Hz, 2H), 7.17 (t, J
= 7.7 Hz, 1H), 7.09 (dd, J = 7.2 Hz, 1.0 Hz, 1H), 6.74 (t, J = 4.8 Hz, 1H), 4.48 (t, J = 7.9 Hz,
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2H), 3.12 (t, J = 8.0 Hz, 2H); C {1H} NMR (100 MHz, CDCl3): δ 164.5, 159.4, 157.9,
139.6, 136.2, 134.7, 133.2 (q, JCF = 32.3 Hz), 127.9, 126.8, 125.6 (q, JCF = 3.3 Hz), 123.9, (q,
JCF = 271.0 Hz), 123.8, 121.7, 111.7, 52.0, 28.8; HRMS (ESI): calcd for C20H16F3N4O+
[M+H]+ 385.1271 found 385.1271.
2-methyl-N-(1-(pyrimidin-2-yl)indolin-7-yl)benzamide (3av): 3av was prepared according
to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), carboxamide 2v
(41 mg, 0.30 mmol). The crude reaction mixture was purified by column chromatography
using 25% EtOAc/Hexane to afford 3av (53 mg, 63%) as a white solid. Rf: 0.41 (silica gel,
30% EtOAc/Hexane); M. P.: 144−149 ˚C; IR (in CHCl3, cm-1): vmax; 3007, 2925, 1663,
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1584, 1553, 1458, 1326, 1282, 1225, 1188, 995; H NMR (400 MHz, CDCl3): δ 11.42 (s,
1H), 8.23 (d, J = 4.8 Hz, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.30 (td, J =
7.4 Hz, 1.0 Hz, 1H), 7.24−7.11 (m, 3H), 7.05 (dd, J = 7.3 Hz, 0.8 Hz, 1H), 6.59 (t, J = 4.8
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Hz, 1H), 4.45 (t, J = 8.1 Hz, 2H), 3.11 (t, J = 8.1 Hz, 2H), 2.28 (s, 3H); 13C {1H} NMR (100
MHz, CDCl3): δ 167.8, 159.1, 157.7, 137.3, 137.0, 136.0, 134.2, 131.3, 129.0, 127.3, 127.0,
125.5, 124.6, 123.1, 121.1, 111.4, 51.9, 28.7, 20.1; HRMS (ESI): calcd for C20H19N4O+
[M+H]+ 331.1553 found 331.1548.
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N-(1-(pyrimidin-2-yl)indolin-7-yl)thiophene-2-carboxamide (3aw): 3aw was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
carboxamide 2w (38 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 25% EtOAc/Hexane to afford 3aw (56 mg, 69%) as a white solid. Rf:
0.41 (silica gel, 30% EtOAc/Hexane); M. P.: 144−149 ˚C; IR (in CHCl3, cm-1): vmax; 3061,
2921, 1652, 1584, 1553, 1455, 1424, 1368, 1303, 1210, 1067, 994, 855, 734; 1H NMR (400
MHz, CDCl3): δ 11.15 (s, 1H), 8.53 (d, J = 4.8 Hz, 2H), 7.84 (d, J = 8.0 Hz, 1H), 7.56 (dd, J
= 3.6 Hz, 1.0 Hz, 1H), 7.45 (dd, J = 4.9 Hz, 1.0 Hz, 1H), 7.14 (t, J = 7.7 Hz, 1H), 7.10−7.04
(m, 2H), 6.76 (t, J = 4.8 Hz, 1H), 4.48 (t, J = 7.9 Hz, 2H), 3.10 (t, J = 7.7 Hz, 2H); 13C {1H}
NMR (100 MHz, CDCl3): δ 160.0, 159.6, 158.1, 140.3, 136.1, 134.9, 129.8, 128.8, 127.6,
126.9, 124.7, 124.2, 121.4, 111.6, 51.9, 28.9; HRMS (ESI): calcd for C17H15N4OS+
[M+H]+ 323.0961found 323.0957.
N-(1-(pyrimidin-2-yl)indolin-7-yl)acetamide (3ax): 3ax was prepared according to general
procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), carboxamide 2x (18 mg,
0.30 mmol). The crude reaction mixture was purified by column chromatography using 15%
EtOAc/Hexane to afford 3ax (20 mg, 31%) as a white solid. Rf: 0.60 (silica gel, 30%
EtOAc/Hexane); M. P.: 125−129 ˚C; IR (in CHCl3, cm-1): vmax; 3006, 2360, 1733, 1672,
1600, 1584, 1507, 1457, 1379, 1282, 1188, 1064, 995; 1H NMR (400 MHz, CDCl3): δ 10.65
(s, 1H), 8.47 (d, J = 4.8 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 7.02 (d, J
= 7.3 Hz, 1H), 6.74 (t, J = 4.8 Hz, 1H), 4.44 (t, J = 7.8 Hz, 2H), 3.08 (t, J = 8.0 Hz, 2H), 2.06
9s, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 168.1, 159.4, 157.8, 135.9, 134.2, 127.1,
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2,2,2-trifluoro-N-(1-(pyrimidin-2-yl)indolin-7-yl)acetamide (3ay): 3ay was prepared
according to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol),
carboxamide 2y (34 mg, 0.30 mmol). The crude reaction mixture was purified by column
chromatography using 10% EtOAc/Hexane to afford 3ay (31 mg, 40%) as a white solid. Rf:
0.66 (silica gel, 30% EtOAc/Hexane); M. P.: 72−77 ˚C; IR (in CHCl3, cm-1): vmax; 2920,
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2852, 1580, 1551, 1420, 1376, 1282, 1144, 1116, 1081, 1015, 997; H NMR (400 MHz,
CDCl3): δ 13.15 (s, 1H), 8.46 (d, J = 4.8 Hz, 2H), 7.92−7.86 (m, 1H), 7.17−7.08 (m, 2H),
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6.77 (t, J = 4.8 Hz, 1H), 4.47 (t, J = 8.4 Hz, 2H), 3.13 (t, J = 8.1 Hz, 2H); C {1H} NMR
(100 MHz, CDCl3): δ 158.6, 157.8, 154.9 (q, JC-F = 36 Hz), 136.2, 134.4, 124.6, 124.2,
122.9, 122.6, 116.5 (q, JC-F = 288 Hz), 111.8, 51.5, 28.4; HRMS (ESI): calcd for
C14H12F3N4O+ [M+H]+ 309.0958 found 309.0958.
N-(1-(pyrimidin-2-yl)indolin-7-yl)pivalamide (3az): 3az was prepared according to general
procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), carboxamide 2z (31 mg,
0.30 mmol). The crude reaction mixture was purified by column chromatography using 25%
EtOAc/Hexane to afford 3az (16 mg, 22%) as a white solid. Rf: 0.41 (silica gel, 30%
EtOAc/Hexane); M. P.: 72−77 ˚C; IR (in CHCl3, cm-1): vmax; 3006, 2360, 1668, 1584, 1507,
1457, 1378, 1286, 1172, 1068, 995. 1H NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 8.46 (d, J =
4.8 Hz, 2H), 7.68 (dd, J = 8.0 Hz, 0.5 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 7.02 (dd J = 7.2 Hz,
1.0 Hz, 1H), 6.73 (t, J = 4.8 Hz, 1H), 4.46 (t, J = 8.0 Hz, 2H), 3.06 (t, J = 7.7 Hz, 2H), 1.18
(s, 9H); 13C {1H} NMR (100 MHz, CDCl3): δ 176.9, 160.0, 158.1, 135.9, 135.1, 127.6,
124.7, 124.6, 121.1, 111.6, 52.1, 39.6, 29.1, 27.8; HRMS (ESI): calcd for C17H21N4O+
[M+H]+ 297.1710 found 297.1710.
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4-methyl-N-(2-methyl-1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ba): 3ba
was prepared according to general procedure (A) using indoline pyrimidine 1b (53 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ba (65 mg, 68%) as a white solid.
Rf: 0.50 (silica gel, DCM); M. P.: 142−147 ˚C; IR (in CHCl3, cm-1): vmax; 2980, 2933, 2358,
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1542, 1473, 1339, 1251, 1157, 1089, 1006; H NMR (400 MHz, CDCl3): δ 10.97 (s, 1H),
8.48 (d, J = 4.8 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.3 Hz, 2H), 7.10−7.01 (m,
2H), 6.99 (d, J = 8.1 Hz, 2H), 6.75 (t, J = 4.8 Hz, 1H), 4.93−4.82 (m, 1H), 3.27 (dd, J = 15.4
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Hz, 8.9 Hz, 1H), 2.38 (d, J = 15.4 Hz, 1H), 2.27 (s, 3H), 0.68 (d, J = 6.4 Hz, 3H); C {1H}
NMR (100 MHz, CDCl3): δ 157.8, 143.0, 137.7, 135.3, 134.5, 129.3, 126.9, 126.6, 125.4,
124.8, 123.4, 111.7, 58.6, 35.7, 21.4, 19.4; HRMS (ESI): calcd for C20H21N4O2S+ [M+H]+
381.1380, found 381.1382.
4-methyl-N-(2-phenyl-1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3ca): 3ca was
prepared according to general procedure (A) using indoline pyrimidine 1c (68 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ca (65 mg, 58%) as a white solid.
Rf: 0.50 (silica gel, DCM); M. P.: 178−183 ˚C; IR (in CHCl3, cm-1): vmax; 2362, 2331, 2319,
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1575, 1557, 1541, 1507, 1488, 1456, 1396, 1338, 1315, 1123, 1091; H NMR (400 MHz,
CDCl3): δ 11.64 (s, 1H), 8.47 (d, J = 4.9 Hz, 2H), 7.58−7.44 (m, 3H), 7.21−7.15 (m, 1H),
7.14−7.07 (m, 2H), 7.06−6.98 (m, 3H), 6.97−6.87 (m, 3H), 6.70 (t, J = 4.9 Hz, 1H), 6.09 (d, J
= 9.7 Hz, 1H), 3.70 (dd, J = 15.7 Hz, 10.1 Hz, 1H), 2.86 (d, J = 15.5 Hz, 1H), 2.3 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3): δ 158.8, 157.9, 142.9, 142.8, 138.2, 135.3, 134.2, 129.5,
128.6, 127.2, 126.9, 125.8, 125.5, 125.3, 123.7, 122.0, 112.2, 65.0, 37.7, 21.7; HRMS (ESI):
calcd for C25H23N4O2S+ [M+H]+ 443.1536, found 443.1531.
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4-methyl-N-(3-methyl-1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3da): 3da
was prepared according to general procedure (A) using indoline pyrimidine 1d (53 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3da (58 mg, 61%) as a yellow
solid. Rf: 0.50 (silica gel, DCM); M. P.: 133−138 ˚C; IR (in CHCl3, cm-1): vmax; 2355, 2328,
1549, 1454, 1395, 1286, 1156, 1119, 1108, 1024, 993; 1H NMR (400 MHz, CDCl3): δ 10.81
(s, 1H), 8.46 (d, J = 4.8 Hz, 2H), 7.39 (dd, J = 7.9 Hz, 0.8 Hz, 1H), 7.14−7.07 (m, 3H),
7.04−6.97 (m, 3H), 6.73 (t, J = 4.8 Hz, 1H), 4.22−4.09 (m, 1H), 3.30−3.16 (m, 2H), 2.32 (s,
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3H), 1.18 (d, J = 6.6 Hz, 3H); C {1H} NMR (100 MHz, CDCl3): δ 157.8, 142.9, 140.6,
137.2, 136.8, 128.9, 127.3, 126.8, 124.8, 121.8, 111.5, 58.7, 34.3, 21.5, 19.2; HRMS (ESI):
calcd for C20H21N4O2S+ [M+H]+ 381.1380, found 381.1377.
N-(4-bromo-1-(pyrimidin-2-yl)indolin-7-yl)-4-methylbenzenesulfonamide (3ea): 3ea was
prepared according to general procedure (A) using indoline pyrimidine 1e (69 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ea (55 mg, 49%) as a yellow
solid. Rf: 0.50 (silica gel, DCM); M. P.: 147−152 ˚C; IR (in CHCl3, cm-1): vmax; 2954, 2852,
1578, 1455, 1412, 1376, 1316, 1282, 1184, 1084, 988; 1H NMR (400 MHz, CDCl3): δ 10.84
(s, 1H), 8.48 (d, J = 4.8 Hz, 2H), 7.27 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.15 (d, J
= 8.2 Hz, 2H), 7.02(d, J = 8.0 Hz, 2H), 6.78 (t, J = 4.8 Hz, 1H), 3.91 (t, J = 8.4 Hz, 2H),
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2.92 (t, J = 8.3 Hz, 2H), 2.34 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 157.8, 143.2,
138.0, 137.1, 135.7, 129.1, 128.8, 127.5, 126.7, 124.0, 117.3, 112.1, 50.5, 29.7, 21.5; HRMS
(ESI): calcd for C19H18BrN4O2S+ [M+H]+ 445.0328, found 445.0327.
4-methyl-N-(5-methyl-1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3fa): 3fa was
prepared according to general procedure (A) using indoline pyrimidine 1f (53 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3fa (58 mg, 61%) as a white solid.
Rf: 0.50 (silica gel, DCM); M. P.: 130−135 ˚C; IR (in CHCl3, cm-1): vmax; 2964, 2371, 2357,
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1586, 1541, 1474, 1404, 1312, 1285, 1164, 1082; H NMR (400 MHz, CDCl3): 10.88 (s,
1H), 8.43 (d, J = 4.8 Hz, 2H), 7.19 (s, 1H), 7.14 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 8.2 Hz, 2H),
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6.87 (s, 1H), 6.70 (t, J = 4.8 Hz, 1H), 3.84 (t, J = 8.2 Hz, 2H), 2.86 (t, J = 8.2 Hz, 2H), 2.32
(s, 6H); 13C {1H} NMR (100 MHz, CDCl3): δ 157.7, 142.8, 137.2, 135.5, 134.8, 134.7,
127.4, 128.9, 126.7, 124.5, 123.9, 111.2, 51.1, 28.2, 21.5, 20.8; HRMS (ESI): calcd for
C20H21N4O2S+ [M+H]+ 381.1380, found 381.1384.
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N-(5-methoxy-1-(pyrimidin-2-yl)indolin-7-yl)-4-methylbenzenesulfonamide (3ga): 3ga
was prepared according to general procedure (A) using indoline pyrimidine 1g (57 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ga (65 mg, 65%) as a yellow
solid. Rf: 0.41 (silica gel, DCM); M. P.: 140−145 ˚C; IR (in CHCl3, cm-1): vmax; 2953, 2852,
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1587, 1549, 1527, 1514, 1375, 1282, 1144, 1105, 1015; H NMR (400 MHz, CDCl3): δ
11.13 (s, 1H), 8.43 (d, J = 4.5 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H),
6.91 (s, 1H), 6.78 (t, J = 4.5 Hz, 1H), 6.63 (s, 1H), 3.89 (t, J = 7.9 Hz, 2H), 3.81 (s, 3H), 2.88
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(t, J = 7.9 Hz, 2H), 2.33 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 157.7, 157.2, 143.0,
137.3, 136.9, 130.4, 129.0, 126.8, 125.7, 111.0, 110.3, 110.1, 55.9, 51.0, 28.6, 21.5; HRMS
(ESI): calcd for C20H21N4O3S+ [M+H]+ 397.1329, found 397.1330.
N-(5-fluoro-1-(pyrimidin-2-yl)indolin-7-yl)-4-methylbenzenesulfonamide (3ha): 3ha was
prepared according to general procedure (A) using indoline pyrimidine 1h (52 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ha (59 mg, 61%) as a yellow
solid. Rf: 0.50 (silica gel, DCM); M. P.: 210−215 ˚C; IR (in CHCl3, cm-1): vmax; 2920, 2851,
1585, 1454, 1339, 1312, 1224, 1131, 1088, 1035, 1007, 978; 1H NMR (400 MHz, CDCl3): δ
11.25 (s, 1H), 8.46 (d, J = 4.8 Hz, 2H), 7.29−7.23 (m, 2H), 7.11 (dd, J = 9.9 Hz, 2.5 Hz, 1H),
7.05 (d, J = 8.2 Hz, 2H), 6.79−6.71 (m, 2H), 3.96 (t, J = 8.2 Hz, 2H), 2.91 (t, J = 8.2 Hz,
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2H), 2.34 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 159.7 (d, JC-F = 243 Hz), 157.8,
143.2, 137.2 (d, JC-F = 9.2 Hz), 137.1, 132.8, 129.2, 126.8, 126.0 (d, JC-F = 11.3 Hz), 112.3 (d,
JC-F = 25.6 Hz), 111.5, 110.1 (d, JC-F = 11.3 Hz), 51.3, 28.5, 21.5; HRMS (ESI): calcd for
C19H18FN4O2S+ [M+H]+ 385.1129, found 385.1131.
N-(5-chloro-1-(pyrimidin-2-yl)indolin-7-yl)-4-methylbenzenesulfonamide (3ia): 3ia was
prepared according to general procedure (A) using indoline pyrimidine 1i (58 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ia (55 mg, 55%) as a orange solid.
Rf: 0.50 (silica gel, DCM); M. P.: 175−180 ˚C; IR (in CHCl3, cm-1): vmax; 2360, 2326, 1595,
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1461, 1409, 1151, 1091, 1066, 956, 886; 1H NMR (400 MHz, CDCl3): δ 11.12 (s, 1H), 8.47
(d, J = 4.9 Hz, 2H), 7.38 (d, J = 1.8 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.06−6.97 (m, 3H),
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{1H} NMR (100 MHz, CDCl3): δ 157.7, 143.2, 137.1, 135.6, 129.4, 129.1, 126.8, 126.2,
125.8, 123.0, 111.8, 51.3, 28.1, 21.6; HRMS (ESI): calcd for C19H18ClN4O2S+ [M+H]+
401.0834, found 401.0835.
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N-(5-bromo-1-(pyrimidin-2-yl)indolin-7-yl)-4-methylbenzenesulfonamide (3ja): 3ja was
prepared according to general procedure (A) using indoline pyrimidine 1j (70 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ja (44 mg, 40%) as a yellow
solid. Rf: 0.50 (silica gel, DCM); M. P.: 163−168 ˚C; IR (in CHCl3, cm-1): vmax; 2979, 2957,
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1457, 1394, 1261, 1149, 1082, 1041, 1026, 969; H NMR (400 MHz, CDCl3): δ 11.09 (s,
1H), 8.47 (d, J = 4.5 Hz, 2H), 7.25 (s, 1H), 7.23−7.12 (m, 3H), 7.03 (d, J = 7.9 Hz, 2H), 6.77
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(t, J = 4.5 Hz, 1H), 3.91 (t, J = 8.0 Hz, 2H), 2.91 (t, J = 8.2 Hz, 2H), 2.33 (s, 3H); C {1H}
NMR (100 MHz, CDCl3): δ 157.8, 157.6, 143.2, 137.4, 137.0, 136.2, 129.1, 126.8, 126.0,
125.9, 116.6, 111.9, 51.2, 28.0, 21.5; HRMS (ESI): calcd for C19H18BrN4O2S+ [M+H]+
445.0328, found 445.0328.
N-(6-chloro-1-(pyrimidin-2-yl)indolin-7-yl)-4-methylbenzenesulfonamide (3ka): 3ka was
prepared according to general procedure (A) using indoline pyrimidine 1k (57 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ka (32 mg, 32%) as a white solid.
Rf: 0.50 (silica gel, DCM); M. P.: 207−212 ˚C; IR (in CHCl3, cm-1): vmax; 2920, 2852, 1575,
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1558, 1507, 1489, 1457, 1418, 1396, 1339, 771; H NMR (400 MHz, CDCl3): δ 10.08 (s,
1H), 8.43 (d, J = 4.8 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.3 Hz, 2H), 7.03 (d, J =
8.0 Hz, 1H) 7.00 (d, J = 8.0 Hz, 2H), 6.75 (t, J = 4.8 Hz, 1H), 3.88 (t, J = 7.5 Hz, 2H), 2.90
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(t, J = 8.0 Hz, 2H), 2.32 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 157.6, 143.2, 140.9,
137.8, 134.5, 134.4, 129.0, 126.7, 126.6, 126.3, 124.0, 122.3, 111.9, 51.6, 27.8, 21.6; HRMS
(ESI): calcd for C19H18ClN4O2S+ [M+H]+ 401.0834 found 401.0835.
4-methyl-N-(6-nitro-1-(pyrimidin-2-yl)indolin-7-yl)benzenesulfonamide (3la): 3la was
prepared according to general procedure (A) using indoline pyrimidine 1l (60 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3la (23 mg, 21%) as a yellow solid.
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Rf: 0.50 (silica gel, DCM); M. P.: 232−237 ˚C; IR (in CHCl3, cm-1): vmax; 2955, 2853, 1712,
1463, 1377, 1252, 1085, 908, 721; 1H NMR (400 MHz, CDCl3): δ 10.43 (s, 1H), 8.52 (d, J =
4.9 Hz, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 2H), 6.99
(d, J = 8.1 Hz, 2H), 6.85 (t, J = 4.9 Hz, 1H), 3.88 (t, J = 8.0 Hz, 2H), 2.98 (t, J = 8.0 Hz,
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2H), 2.34 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 157.9, 157.3, 149.5, 143.5, 140.8,
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140.3, 136.9, 129.1, 126.6, 123.1, 121.2, 117.1, 112.7, 51.8, 28.0, 21.6; HRMS (ESI): calcd
for C19H17N5O4S+ [M+Na]+ 434.0893, found 434.0893.
4-methyl-N-(9-(pyrimidin-2-yl)-9H-carbazol-1-yl)benzenesulfonamide (3ma): 3ma was
prepared according to general procedure (A) using indoline pyrimidine 1m (61 mg, 0.25
mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude reaction mixture was purified by
column chromatography using 2% EtOAc/DCM to afford 3ma (43 mg, 42%) as a white
solid. Rf: 0.50 (silica gel, DCM); M. P.: 137−142 ˚C; IR (in CHCl3, cm-1): vmax; 2953, 2851,
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2361, 2322, 1557, 1541, 1507, 1488, 1416, 1337, 1317, 1256, 1155, 1084, 998; H NMR
(400 MHz, CDCl3): δ 10.14 (s, 1H), 8.85 (d, J = 4.7 Hz, 2H), 8.44 (d, J = 8.5 Hz, 1H), 7.97
(d, J = 7.3 Hz, 1H), 7.92 (dd, J = 7.7 Hz, 1.0 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.40 (t, J =
7.6 Hz, 2H), 7.33 (t, J = 6.7 Hz, 1H), 7.22 (t, J = 4.8 Hz, 1H), 7.0 (d, J = 8.2 Hz, 2H), 6.81 (d,
J = 8.2 Hz, 2H), 2.15 (s, 3H); C {1H} NMR (100 MHz, CDCl3): δ 158.2, 157.6, 143.3,
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140.2, 136.7, 132.4, 129.3, 128.4, 127.0, 126.3, 125.6, 124.3, 123.7, 123.1, 119.5, 118.1,
116.7, 115.9, 21.4; HRMS (ESI): calcd for C23H19N4O2S+ [M+H]+ 415.1223 found 415.1222
4-methyl-N-(9-(pyrimidin-2-yl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-8-
yl)benzenesulfonamide (3na): 3na was prepared according to general procedure (A) using
indoline pyrimidine 1n (62 mg, 0.25 mmol), sulfonamide 2a (51 mg, 0.30 mmol). The crude
reaction mixture was purified by column chromatography using 2% EtOAc/DCM to afford
3na (70 mg, 66%) as a white solid. Rf: 0.50 (silica gel, DCM); M. P.: 197−202 ˚C; IR (in
CHCl3, cm-1): vmax; 2359, 2332, 1575, 1558, 1541, 1507, 1472, 1436, 1418, 1386, 1316,
1160, 1005; 1H NMR (400 MHz, CDCl3): δ 10.87 (s, 1H), 8.46 (d, J = 4.8 Hz, 2H), 7.45 (d,
J = 8.0 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 7.04−6.94 (m, 3H), 6.72 (t,
J = 4.8 Hz, 1H), 4.84−4.71 (m, 1H), 3.36 (t, J = 5.9 Hz, 1H), 2.27 (s, 3H); ), 2.21 (d, J = 14.3
Hz, 1H), 1.77−1.64 (m, 1H), 1.52−1.33 (m, 3H), 1.21−0.90 (m, 2H), 0.18−0.03 (m, 1H); 13C
{1H} NMR (100 MHz, CDCl3): δ 157.9, 143.0, 138.1, 137.7, 136.0, 129.3, 126.8, 126.2,
126.0, 124.9, 120.6, 111.4, 63.8, 39.6, 26.2, 24.3, 22.9, 21.4, 20.8; HRMS (ESI): calcd for
C23H25N4O2S+ [M+H]+ 421.1693, found 421.1694.
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1-(pyrimidin-2-yl)-N-(p-tolyl)indolin-7-amine (5aa): 5aa was prepared according to
general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), aniline 4a (42 mg,
0.30 mmol). The crude reaction mixture was purified by column chromatography using 25%
EtOAc/Hexane to afford 5aa (44 mg, 52%) as a yellow solid. Rf: 0.41 (silica gel, 30%
EtOAc/Hexane); M. P.: 155−160 ˚C; IR (in CHCl3, cm-1): vmax; 2980, 2360, 2331, 1541,
1520, 1507, 1395, 1387, 1374, 773; 1H NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 8.51 (d, J =
4.8 Hz, 2H), 8.03 (d, J = 9.2 Hz, 2H), 7.28 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H),
7.06−7.02 (m, 1H), 6.83−6.73 (m, 3H), 4.47 (t, J = 8.3 Hz, 2H), 3.15 (t, J = 8.2 Hz, 2H); 13C
{1H} NMR (100 MHz, CDCl3): δ 159.6, 157.8, 150.6, 139.1, 137.1, 135.8, 129.4, 126.4,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
124.9, 121.8, 120.8, 113.1, 111.8, 52.2, 29.0; HRMS (ESI): calcd for C18H16N5O2 [M+H]+
334.1299 found 334.1295.
N-(3-nitrophenyl)-1-(pyrimidin-2-yl)indolin-7-amine (5ab): 5ab was prepared according
to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), aniline 4b (44
mg, 0.30 mmol). The crude reaction mixture was purified by column chromatography using
25% EtOAc/Hexane to afford 5ab (45 mg, 54%) as a yellow solid. Rf: 0.41 (silica gel, 30%
EtOAc/Hexane); M. P.: 157−162 ˚C; IR (in CHCl3, cm-1): vmax; 2955, 2923, 2361, 1717,
1595, 1541, 1507, 1487, 1418, 1320, 1286, 1153, 1120, 1071; 1H NMR (400 MHz, CDCl3):
δ 8.46 (s, 1H), 8.51 (d, J = 4.8 Hz, 2H), 7.66 (t J = 2.24 Hz, 1H), 7.56 (ddd, J = 8.0 Hz, 2.3
Hz, 0.9 Hz, 1H), 7.30−7.22 (m, 2H), 7.13 (ddd, J = 8.1 Hz, 2.3 Hz, 0.8 Hz, 1H), 7.09 (t, J =
7.8 Hz, 1H), 6.99 (dd, J = 7.9 Hz, 1.0 Hz, 1H), 6.74 (t, J = 4.8 Hz, 1H), 4.47 (t, J = 8.0 Hz,
13
2H), 3.12 (t, J = 8.0 Hz, 2H); C {1H} NMR (100 MHz, CDCl3): δ 159.9, 157.9, 149.5,
146.0, 137.0, 135.2, 131.1, 129.8, 125.1, 121.1, 120.3, 119.6, 113.5, 116.6, 109.5, 52.3, 29.2;
+
HRMS (ESI): calcd for C18H16N5O2 [M+H]+ 334.1299 found 334.1297.
4-((1-(pyrimidin-2-yl)indolin-7-yl)amino)benzonitrile (5ac): 5ac was prepared according
to general procedure (A) using indoline pyrimidine 1a (50 mg, 0.25 mmol), aniline 4c (36
mg, 0.30 mmol). The crude reaction mixture was purified by column chromatography using
25% EtOAc/Hexane to afford 5ac (48 mg, 61%) as a yellow solid. Rf: 0.50 (silica gel, 30%
EtOAc/Hexane); M. P.: 146−151 ˚C; IR (in CHCl3, cm-1): vmax; 2972, 2359, 2216, 1595,
1583, 1519, 1380, 1242, 1126, 1070; 1H NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.49 (d, J
= 4.8 Hz, 2H), 7.38 (d J = 8.9 Hz, 2H), 7.26 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.00
(dd, J = 7.3 Hz, 1.1 Hz, 1H), 6.82 (d, J = 8.9 Hz, 2H), 6.74 (t, J = 4.8 Hz, 1H), 4.46 (t, J = 7.9
Hz, 2H), 3.11 (t, J = 7.9 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ 159.7, 157.8, 148.5,
29
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