Ru(ii)-Catalyzed C7-acyloxylation of indolines with carboxylic acids

Article abstract of DOI:10.1039/c8ob01603h

Ruthenium(ii)-catalyzed site-selective C7-acyloxylation of indolines with carboxylic acids is presented. The substrate scope and functional group tolerance are important practical features. The kinetic isotope studies suggest that C-H bond activation may be the rate-determining step.

Full text of DOI:10.1039/c8ob01603h

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Ru(II)-catalyzed C7-acyloxylation of indolines with carboxylic acids
Pinaki Bhusan De, Sonbidya Banerjee, Sourav Pradhan and Tharmalingam Punniyamurthy*
Received 00th January 20xx,
Accepted 00th January 20xx
Ruthenium(II)-catalyzed site-selective C7-acyloxylation of indolines with carboxylic acids is presented. The substrate scope
and functional group tolerance are the important practical features. The kinetic isotope studies suggests that C-H bond
activation may be the rate-determining step.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Results and discussion
Transition-metal-catalyzed chelation-guided site-selective C-H
functionalization1 has appeared as a prospective synthetic tool
for the regioselective formation of carbon-heteroatom bonds.2
In this context, direct C-H oxygenations are focused on site-
selective C-O bond construction, because of the prevalence of
C-O bonds in pharmaceuticals, agrochemicals and material
science. Due to the biological prominence of the indole
moiety, functionalization of its core has attracted considerable
attention (Figure 1).3 Several efforts have thus been made for
the functionalization of indoles.4 The C7 functionalization on
indole scaffolds has thus far proven elusive, while it can be
assembled by incorporating directing group on the N-atom of
indoline, followed by C-H functionalization and late-stage
oxidation.5-7 In 2004, Sanford and co-workers reported a Pd-
catalyzed directd acetoxylation of C-H bonds using PhI(OAc)2
as an acylating agent,8a while Yu group showed a directed Pd-
catalyzed acetoxylation of methyl C-H bond utilizing acetic
anhydride.8b Subsequently, much attention has been devoted
for the acyloxylation of C-H bonds using transition metal
catlaysis.8c-n Among them, the direct C-H acyloxylation using
RCOOH is attractive as they are atom economical. In
continuation of our study on C-H acyloxylation,9 we here
report a Ru(II)-catalyzed C7- acyloxylation of indolines with
carboxylic acids, which can be subsequently oxidized using
DDQ to furnish C7-oxygenated indoles. The reaction of aryl,
alkyl and α,β-unsaturated carboxylic acids can be
accomplished with diverse functional groups in good yields.
Initially, our optimization studies commenced by employing N-
pyrimidyl indoline 1a with benzoic acid 2a as the model
substrates using Ru(II) with different additives, oxidants and
solvents at varied temperature (Table 1). To our delight, the C7
oxygenated indoline 3a was produced in 7% yield utilizing 5
mol % [Ru(p-cymene)Cl2]2 and 20 mol % KPF6 as an additive in
(CH2Cl)2 at 100 οC. The yield increased to 64% upon addition of
2 equiv Ag2CO3 as an oxidant, whereas Cu(OAc)2•H2O, K2S2O8
and Na2S2O8 gave inferior results (entries 2-5). Subsequent
screening of the additives led to an enhancement in the yield
to 77% using AgSbF6, while the reaction with NaOAc gave 34%
yield (entries 6-7). (CH2Cl)2 was found to be the solvent of
choice, whereas toluene, DMSO and 1,4-dioxane produced
<48% yield (entries 8-10). Altering the reaction temperature
ο
ο
(80 C and 120 C) led to the drop the yield to 51% (entry 11-
12). A control experiment confirmed that no desired C-H
oxygenation was observed in the absence of the Ru-catalyst
(entry 13). In addition, the effect of directing groups such as
acetyl (1A’), pivalyl (1B’), N,N-dimethyl carbamoyl (1C’) and
Boc (1D’) was investigated (Scheme 1). The substrates 1A-C’
underwent reaction to produce the acyloxylation products 3A’-
C’ in 46-62% yields, whereas 1D’ was an unsuccessful substrate
and 3D’ was not formed.
SMe
NMe2
OH
O
OMe
NH
H
N
HN
Br
N
OMe
NH
MeO
N
O
N
N
N
N
H
CH3
O
HO
OH
O
N
H
O
Eudistomidin-A
(+)-Yatakemycin
Phalarine
Figure 1 Some examples of bio-active C7-oxygenated indole derivatives.
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Having optimized the reaction condition, we explored the
substrate scope utilizing diversely substituted carboxylic acids
with indoline 1a as a representative example (Scheme 2). The
reaction of ortho-substituted benzoic acids such as 2-chloro 2b
and 2-iodo 2c delivered 3b and 3c in 73 and 55% yields,
respectively. Pleasingly, medicinally essential drug aspirin 2d
was effectively engaged to produce 3d in 40% yield. Similarly,
meta-substituted benzoic acids such as 3-chloro 2e, 3-methyl
2f and 3-methoxy 2g underwent coupling to give 3e-g in 68-
73% yields. Similar results observed with substituted benzoic
acids at the para-position, such as chloro 2h, fluoro 2i, methyl
2j and nitro 2k groups, affording 3h-k in 74-81% yields. A
strong electron withdrawing group, 4-CF3 substituted benzoic
acid 2l was also operative and provided 3l in 80% yield.
Gratifyingly, the di-substituted benzoic acid bearing 3,4-
dimethyl group 2m and 1-naphthoic acid 2n successfully
reacted to afford 3m and 3n in 69 and 54% yields, respectively.
In addition, heterocyclic carboxylic acid like 2-thienyl
carboxylic acid 2o was amenable, giving 3o in 64% yield, while
picolinic acid 2p and isonicotinic acid 2q showed no reaction,
which may be due to chelation of nitrogen lone pair to the Ru-
complex.
S
cheme 1 Screening of directing groups.a,b aReaction conditions: 1A’-D’ (0.2
mmol), 2a (0.4 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %), Ag2CO3
(0.4 mmol), (CH2Cl)2 (2 mL), 100 °C, 16 h. bIsolated yield.
[Ru(p-cymene) Cl2]2 (5 mol %)
AgSbF6
mol
.
)
N
N
+
RCOOH
Ag2CO3 equiv)
(CH2Cl)2, 100 C, air
N
N
R
O
N
N
O
2b-q
1a
3b-q
N
N
N
N
O
N
O
N
N
O
N
N
Cl
O
Me
O
I
O
O
3b, 73%, 18 h
3c, 55%, 20 h
3d, 40%, 20 h
However, the coupling of α,β-unsaturated and aliphatic
carboxylic acids can be readily accomplished (Scheme 3). For
examples, crotonic 2r and cinnamic 2s acids reacted to deliver
3r and 3s in 65 and 67% yields, respectively, whereas ethanoic
2t, pivalic 2u and 1-adamentylcarboxylic 2v acids underwent
reaction to convey the C7-oxygenated indolines 3t-v in 69-70%
yields.
O
N
N
N
N
O
N
O
N
O
Me
N
Cl
N
MeO
N
O
O
O
3g, 68%16 h
3e, 73%, 16 h
3f, 70%, 16 h
R
N
Cl
O2N
N
N
Table 1 Optimization of the reaction conditionsa
N
O
N
N
O
N
O
N
N
O
O
O
3i, R=F, 80%, 15 h
3j, R= Me, 74%.16 h
3h, 80%, 15 h
3k, 81%, 15 h
Me
F3C
N
N
N
N
N
O
N
O
N
N
O
Me
N
O
O
O
3m, 69%,16 h
3l, 80%, 15 h
3n
, 54%18 h
Entry
1
Additive
KPF6
Oxidant
-
Solvent
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
toluene
DMSO
Yield(%)b
7
N
N
S
N
N
2
KPF6
Ag2CO3
Cu(OAc)2•H2O
K2S2O8
64
N
N
O
N
O
N
O
N
3
KPF6
trace
13
N
N
4
KPF6
O
O
O
3o, 64%, 18 h
3q, 00%, 20 h
3p, 00%, 20 h
5
KPF6
Na2S2O8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
n.d.
77
6
AgSbF6
NaOAc
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
7
34
S
cheme 2 Substrate scope of carboxylic acids 2b-q with indoline 1a.a,b aReaction
8
48
conditions: 1a (0.2 mmol), 2b-q (0.4 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6
(20 mol %), Ag2CO3 (0.4 mmol), (CH2Cl)2 (2 mL), 100 °C, 15-20 h. bIsolated yield.
9
9
10
11
12
13e
1,4-dioxane
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
6
51c
74d
n.d.
The utility of the methodology was extended to the reaction
of electronically varied indolines with benzoic acid 2a as a
standard substrate (Scheme 4). Diverse functionalities ranging
from 2 to 6 positions on the indoline moiety reacted smoothly
to deliver the target products. Indolines having 2-methyl 1b, 3-
methyl 1c and 4-bromo 1d substituents underwent reaction to
furnish the target products 3w-y in 69-75% yields. Moreover,
5-substituted indolines with bromo 1e, fluoro 1f and methoxy
1g groups found to be well tolerated under identical
aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Ru(p-cymene)Cl2]2 (5 mol %),
additive (20 mol %), oxidant (0.4 mmol), solvent (2 mL), 100 °C, 16 h. bIsolated
yield. cReaction at 80 °C. dReaction at 120 °C. eWithout [Ru] catalyst. n.d. = not
detected.
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conditions, giving 3z-ab in 69-77% yields. Similar results bond cleavage might be the rate-determining step (see SI).9,10c
observed for the sterically demanding indoline substrate Thus, the reaction of [Ru(p-cymene)Cl2]2 with silver salt may
bearing 6-bromo 1h and 6-chloro 1i functionalities, affording lead to the formation of the reactive Ru(II) carboxylate
3ac and 3ad in 67 and 71% yields, respectively. Furthermore, (Scheme 8).10 Co-ordination of the pyrimidyl-nitrogen with
carboxylation of a carbazole derivative 1j was effective, complex may generate intermediate along with
furnishing a mixture of 3ae (mono) and 3af (di) in 22 and 51% elimination of RCOOH. The proximal C-H metalation may
yields, respectively. produce a six-membered ruthenacycle . Reductive elimination
To reveal the scale-up, the reaction of indoline 1a with of may provide the desired and regenerate the catalytically
a
a
,
b
c
c
3
carboxylic acid 2a was investigated as the representative active Ru species upon oxidation with Ag(I) to fulfil the
substrate (Scheme 5). The oxygenation readily occurred to give catalytic cycle.
3a in 53% yield, which suggests that the reaction can be
utilized for the gram scale synthesis.
To get insight in the reaction pathway, intermolecular
competitive experiments have been performed employing
electronically dissimilar benzoic acids 2j and 2k with indoline
1a as a representative example. The results revealed that
electron-deficient aromatic carboxylic acid reacts at a faster
rate than the other one. This may be reflected in terms of
lower pKa value of p-NO2-benzoic acid 2k (Scheme 6a). In
addition, the competition experiment between aryl and alkyl
carboxylic acids 2j and 2u indicated that, aryl substrate
facilitates the reaction to a greater extent, owing to the
resonance stabilization of the corresponding conjugate base of
the acid (Scheme 6b). Further,
Scheme 4 Substrate scope of indolines 1b-j with benzoic acid 2a.a,b aReaction
conditions: 1b-j (0.2 mmol), 2a (0.4 mmol), [Ru(p-cymene)Cl2]2 (5 mol %), AgSbF6
(20 mol %), Ag2CO3 (0.4 mmol), (CH2Cl)2 (2 mL), 100 °C, 16-18 h. bIsolated yield.
S
cheme 3 Substrate scope of α,β-unsaturated and aliphatic carboxylic acids 2r-v
Scheme 5 Scale-up synthesis.
with indoline 1a.a,b aReaction conditions: 1a (0.2 mmol), 2r-v (0.4 mmol), [Ru(p-
cymene)Cl2]2 (5 mol %), AgSbF6 (20 mol %), Ag2CO3 (0.4 mmol), (CH2Cl)2 (2 mL),
100 °C, 16-18 h. bIsolated yield.
a significant H/D exchange (40%) was witnessed at the C7
position of the parent indoline upon addition of D2O as the co-
solvent (Scheme 7a), which confides that a reversible C-H
activation at C7 position of the indoline is involved by Ru-
catalysis.7b Moreover, isotope experiment using 1a and 1a-d
with 2a gave kH/kD = 6.7 (Scheme 7b). In addition, parallel
experiment of 1a and deuterio-1a with 2a under optimal
conditions exhibited kH/kD = 2.65, which implies that the C−H
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DDQ, 1,4-dioxane
90 C ,14 h
N
2-pym
Ph
O
oxidation
4, 90%
O
N
2-pym
Ph
O
de-esterification
N
3a
O
NaOH, EtOH
70 C, 8 h
2-pym
OH
5, 83%
Scheme 9 Post-synthetic application of 3a.
Scheme 6 Competitive experiments.
Finally, the oxidation of C7-oxygenated indoline was studied
using 3a as a representative example (Scheme 9).9 The
oxidation occurred to produce indole
90% yield.9 In addition, the ester can be readily hydrolysed
using base to afford 7-hydroxy indole scaffold in high yield.
4 in presence of DDQ in
5
In summary, we have demonstrated a Ru(II)-catalyzed site-
selective C7-oxygenation of indolines with carboxylic acids and
subsequent oxidation to produce C7-oxygenated indoles. The
reaction of aryl, alkyl and α,β-unsaturated carboxylic acids can
be accomplished with functional group tolerance.
Experimental section
General information
2-Chloropyrimidine (95%), [Ru(p-cymene)Cl2]2, AgSbF6 (98%),
KPF6 (≥99%), Ag2CO3 (99%), Cu(OAc)2·2H2O and DDQ (98%)
were purchased from Aldrich. NaCNBH3 was procured from
Spectrochem. K2S2O8 and Na2S2O8 were obtained from
Molychem. N-Acetyl 1A’, N-pivaloyl 1B’ and N-carbamoyl
Indolines 1C’ were synthesized according to the literature.5j
Merck silica gel G/GF 254 plates were utilized for analytical
TLC. Rankem silica gel (100-200 mesh) was employed for
column chromatography. DRX-400 Varian, and Bruker Avance
III 600 and 400 spectrometers were used for recording NMR
(1H and 13C) spectra utilizing CDCl3 as solvent and TMS as an
internal standard. Chemical shifts (δ) and spin-spin coupling
constant (J) are reported in ppm and in Hz, respectively, and
other data are reported as follows: s = singlet, d = doublet, t =
triplet, m = multiplet, q = quartet, and br s = broad singlet.
Melting points were determined using a Büchi B-540 apparatus
and are uncorrected. FT-IR spectra were collected on
PerkinElmer IR spectrometer. Q-Tof ESI-MS instrument (model
HAB 273) was used mass spectra.
Scheme 7 Preliminary mechanistic investigations.
General procedure for the preparation of N-pyrimidyl
indolines 1.7 Indole (5.0 mmol) and NaCNBH3 (25.0 mmol)
were stirred in AcOH (25 mL) at room temperature. The
progress of the reaction was monitored using TLC with ethyl
acetate and hexane as an eluent. The resultant mixture was
treated with water (15 mL) and neutralized using aq. NaOH.
The solution was extracted with ethyl acetate (3 x 30 mL).
Drying (Na2SO4) and evaporation of the solvent gave a residue
that was purified on silica gel column chromatography using n-
hexane and ethyl acetate to give indoline. Indoline (1.0 mmol)
was then stirred with 2-chloropyrimidine (1.2 mmol) at 100 °C
Scheme 8 Plausible catalytic cycle
.
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in DMSO (3 mL). The reaction was monitored using TLC with a
1-(Pyrimidin-2-yl)indolin-7-yl benzoate 3a. Analytical TLC on
mixture of ethyl acetate and hexane. After completion, the silica gel, 1:3 ethyl acetate/hexane Rf = 0.49; colorless solid;
reaction mixture was diluted with ethyl acetate (30 mL) and mp 124-125 °C; yield 77% (48.8 mg); 1H NMR (600 MHz, CDCl3)
washed with brine (2 x 5 mL) and water (1 x 5 mL). Drying δ 8.05 (d, J = 4.8 Hz, 2H), 8.01-8.00 (m, 2H), 7.54 (t, J = 7.8 Hz,
(Na2SO4) and evaporation of the solvent gave a residue that 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.14 (t, J = 8.4 Hz, 2H), 7.08-7.06
was purified on silica gel column chromatography using n- (m, 1H), 6.39 (t, J = 4.8 Hz, 1H), 4.41 (t, J = 7.8 Hz, 2H), 3.18 (t, J
hexane and ethyl acetate as an eluent to afford 1-(pyrimidin-2- = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 164.9, 159.9, 157.5,
yl)indoline.
139.2, 136.9, 135.2, 133.2, 130.5, 130.0, 128.5, 123.8, 123.3,
General procedure for Ru(II)-catalyzed C7-oxygenation of 122.2, 112.1, 52.4, 29.4; FT-IR (KBr) 2958, 2923, 2852, 1740,
indolines. To a stirred solution of 1-(pyrimidin-2-yl)indoline 1636, 1577, 1552, 1473, 1431, 1382, 1265,1240, 1191, 1174,
(0.2 mmol), [Ru(p-cymene)Cl2]2 (5 mol %, 0.01 mmol, 6.1 mg), 1085, 1067, 1024 cm-1; HRMS (ESI) m/z [M+H]+ calcd for
AgSbF6 (20 mol%, 0.04 mmol, 13.7 mg) and Ag2CO3 (2 equiv, C19H16N3O2: 318.1237, found: 318.1257.
0.4 mmol, 110.2 mg) in (CH2Cl)2 (2 mL) under air, carboxylic
1-(Pyrimidin-2-yl)indolin-7-yl
2-chlorobenzoate
3b.
acid (0.4 mmol) was added. The resultant mixture was stirred Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.47;
o
1
at 100 C and the progress of the reaction was monitored by colorless solid; yield 73% (51.2 mg); mp 115-116 oC; H NMR
TLC using a mixture of ethyl acetate and hexane. The reaction (600 MHz, CDCl3) δ 8.20 (d, J = 4.8 Hz, 2H), 7.85 (dd, J = 7.8, 1.8
mixture was then diluted with dichloromethane (30 mL) and Hz, 1H), 7.46 (d, J = 7.2 Hz, 1H), 7.42–7.39 (m, 1H), 7.24–7.23
passed through a short pad of celite. Drying (Na2SO4) and (m, 1H), 7.16 – 7.14 (m, 2H), 7.09–7.06 (m, 1H), 6.50 (t, J = 4.8
evaporation of the solvent gave a residue that was purified on Hz, 1H), 4.43 (t, J = 7.8 Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H); 13C NMR
silica gel column chromatography using n-hexane and ethyl (150 MHz, CDCl3) δ 162.9, 160.1, 157.6, 139.1, 137.0, 135.2,
acetate as an eluent to afford analytically pure substituted C7 135.0, 133.2, 132.5, 131.6, 129.0, 126.6, 123.9, 123.1, 122.4,
oxygenated indolines.
112.3, 52.4, 29.4; FT-IR (KBr) 2958, 2923, 2852, 1750,
1578,1553, 1471, 1433, 1383, 1281, 1237, 1215, 1190, 1110,
1037 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C19H15ClN3O2:
352.0847, found: 352.0852.
Characterization Data
1-Acetylindolin-7-yl benzoate 3A’. Analytical TLC on silica gel,
1:3 ethyl acetate/hexane Rf = 0.18; colorless solid; yield 52%
(29.2 mg); mp 120-121oC; 1H NMR (600 MHz, CDCl3) δ 8.19 (d, J
= 7.2 Hz, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 2H),
7.13-7.11 (m, 2H), 7.07– 7.06 (m, 1H), 4.15 (t, J = 7.8 Hz, 2H),
3.13 (t, J = 7.8 Hz, 2H), 2.15 (s, 3H).; 13C NMR (150 MHz, CDCl3)
δ 163.9, 139.6, 136.7, 134.3, 133.5, 130.4, 129.8, 128.7, 125.6,
122.7, 122.4, 50.8, 29.5, 23.5; FT-IR (KBr) 2963, 2924, 2892,
1736, 1674, 1607, 1474, 1454, 1395, 1265, 1231, 1065 cm-1;
HRMS (ESI) m/z [M+H]+ calcd for C17H16NO3:282.1125, found:
282.1138.
1-(Pyrimidin-2-yl)indolin-7-yl 2-iodobenzoate 3c. Analytical
TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.39; colorless
1
ο
solid; mp 148-149 C; yield 55% (48.7 mg); H NMR (600 MHz,
CDCl3) δ 8.20 (d, J = 4.8 Hz, 2H), 8.05 (d, J = 7.8 Hz, 1H), 7.88
(dd, J = 7.8 , 1.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.16-7.12 (m,
3H), 7.09-7.06 (m, 1H), 6.50 (t, J = 4.8 Hz, 1H), 4.43 (t, J = 7.8
Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ
163.5, 160.0, 157.7, 142.2, 139.1, 137.0, 135.1, 133.3, 133.2,
132.2, 128.0, 123.9, 123.1, 122.4, 112.3, 95.4, 52.4, 29.4; FT-IR
(KBr) 2926, 2654, 1658, 1440, 1390, 1256, 1101 cm-1; HRMS
(ESI) m/z [M+H]+ calcd for C19H15IN3O2: 444.0203, found:
444.0203.
1-Pivaloylindolin-7-yl benzoate 3B’. Analytical TLC on silica
gel, 1:3 ethyl acetate/hexane Rf = 0.45; colorless solid; yield
46% (29.7 mg); mp 142-143oC; 1H NMR (600 MHz, CDCl3) δ
8.19 – 8.18 (m, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.8 Hz,
2H), 7.13 – 7.08 (m, 3H), 4.18 (t, J = 7.8 Hz, 2H), 3.13 (t, J = 7.8
Hz, 2H), 1.18 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 177.0, 163.6,
140.5, 136.0, 135.9, 133.2, 130.4, 130.0, 128.4, 125.2, 122.3,
121.8, 51.1, 39.9, 31.1, 28.3; FT-IR (KBr) 2958, 2924, 2853,
1742, 1647, 1474, 1263, 1095 cm-1; HRMS (ESI) m/z [M+H]+
calcd for C20H22NO3:324.1594, found: 324.1603.
1-(Pyrimidin-2-yl)indolin-7-yl
2-acetoxybenzoate
3d.
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.37;
colorless liquid; yield 40% (30 mg); 1H NMR (600 MHz, CDCl3) δ
8.16 (d, J = 4.8 Hz, 2H), 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 7.56-7.53
(m, 1H), 7.21 (t, J = 7.8 Hz, 1H), 7.14 (d, J = 6.6 Hz, 1H), 7.11 (d,
J = 8.4 Hz, 2H), 7.07-7.05 (m, 1H), 6.45 (t, J = 4.8 Hz, 1H), 4.40
(t, J = 7.8 Hz, 2H), 3.16 (t, J = 7.8 Hz, 2H), 2.33 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 170.1, 162.5, 160.0, 157.7, 151.6, 138.9,
137.0, 135.2, 134.4, 132.4, 126.1, 124.3, 123.8, 123.5, 122.9,
122.3, 112.4, 52.4, 29.4, 21.2; FT-IR (neat) 2924, 2853, 1745,
1639, 1578, 1554, 1471, 1433, 1240, 1191cm-1; HRMS (ESI) m/z
[M+H]+ calcd for C21H18N3O4: 376.1292, found: 376.1307.
1-(Dimethylcarbamoyl)indolin-7-yl benzoate 3C’. Analytical
TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.14; yellow
liquid; yield 62% (38.4 mg); 1H NMR (600 MHz, CDCl3) δ 8.17 –
8.15 (m, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H),
7.08-7.05 (m, 2H), 7.05 – 6.97 (m, 1H), 3.91 (t, J = 7.8 Hz, 2H),
3.15 (t, J = 7.8 Hz, 2H), 2.74 (s, 6H); 13C NMR (150 MHz, CDCl3)
δ 164.1, 160.3, 138.8, 137.1, 135.2, 133.4, 130.3, 129.9, 128.5,
123.3 , 122.2, 121.9, 52.4, 37.6, 30.2; FT-IR (neat) 2959, 2924,
2853, 1738, 1643, 1478, 1385, 1262, 1090, 1065 cm-1; HRMS
(ESI) m/z [M+H]+ calcd for C18H19N2O3:311.1390, found:
311.1396.
1-(Pyrimidin-2-yl)indolin-7-yl
3-chlorobenzoate
3e.
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.40;
colorless solid; yield 73% (51.2 mg); mp 117-118oC; 1H NMR
(600 MHz, CDCl3) δ 8.08 (d, J = 4.8 Hz, 2H), 7.99 (t, J = 1.8 Hz,
1H), 7.89 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.34 (t, J =
7.8 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.09
– 7.06 (m, 1H), 6.44 (t, J = 4.8 Hz, 1H), 4.42 (t, J = 7.8 Hz, 2H),
3.18 (t, J = 7.8 Hz, 2H).; 13C NMR (150 MHz, CDCl3) δ 163.7,
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159.9, 157.6, 138.9, 137.0, 135.1, 134.6, 133.3, 132.2, 130.1, (600 MHz, CDCl3) δ 8.09 (d, J = 4.8 Hz, 2H), 7.92 (d, J = 7.4 Hz,
129.8, 128.1, 123.9, 123.1, 122.5, 112.2, 52.4, 29.4 ; FT-IR (KBr) 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 7.2 Hz, 2H), 7.10-7.07
2961, 2924, 2853, 1732, 1636, 1577, 1554, 1466, 1417, 1254, (m, 1H), 6.43 (t, J = 4.8 Hz, 1H), 4.43 (t, J = 8.4 Hz, 2H), 3.20 (t, J
1109 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C19H15ClN3O2: = 8.4 Hz, 2H), 2.42 (s, 3H); 13C NMR (150 MHz,) δ 165.0, 159.9,
352.0847, found: 352.0856.
157.5, 143.9, 139.2, 136.8, 135.2, 130.1, 129.2, 127.7, 123.8,
123.4, 122.2, 112.1, 52.4, 29.4, 21.9; FT-IR (KBr) 2923, 2853,
1-(Pyrimidin-2-yl)indolin-7-yl
3-methylbenzoate
3f.
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.43; 1730, 1610, 1576, 1549, 1485, 1471, 1445, 1433, 1270, 1140,
colorless solid; mp 91-92oC; yield 70% (46.3 mg); 1H NMR (600 1173, 1085, 1018 cm-1; HRMS (ESI) m/z [M+H]+ calcd for
MHz, CDCl3) δ 8.10 (d, J = 4.8 Hz, 2H), 7.84 (s, 1H), 7.82 (d, J = C20H18N3O2: 332.1394, found: 332.1398.
7.2 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16
1-(Pyrimidin-2-yl)indolin-7-yl 4-nitrobenzoate 3k. Analytical
(t, J = 8.4 Hz, 2H), 7.10–7.08 (m, 1H), 6.43 (t, J = 4.8 Hz, 1H), TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.41; yellow
o
1
4.44 (t, J = 7.8 Hz, 2H), 3.20 (t, J = 7.8 Hz, 2H), 2.38 (s, 3H); 13C solid; mp 159-160 C; yield 81% (58.6 mg); H NMR (400 MHz,
NMR (150 MHz, CDCl3) δ 165.0, 159.9, 157.6, 139.2, 138.2, CDCl3) δ 8.26 (d, J = 8.4 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H), 8.04 (d,
136.8, 135.2, 134.0, 130.5, 130.3, 128.3, 127.2, 123.8, 123.3, J = 4.0 Hz, 2H), 7.20 – 7.10 (m, 3H), 6.42 (t, J = 4.0 Hz, 1H), 4.43
122.2, 112.1, 52.4, 29.4, 21.4; FT-IR (KBr) 2956, 2924, 2853, (t, J = 8.0 Hz, 2H), 3.19 (t, J = 7.6 Hz, 2H); 13C NMR (150 MHz,
1739, 1578, 1553, 1472, 1443, 1383, 1275, 1186, 1092, 1073 CDCl3) δ 163.0, 159.9, 157.6, 150.7, 138.8, 137.2, 135.9, 135.0,
cm-1; HRMS (ESI) m/z [M+H]+ calcd for C20H18N3O2: 332.1394, 131.1, 124.0, 123.7, 122.9, 122.8, 112.3, 52.4, 29.3; FT-IR (KBr)
found: 332.1400.
2958, 2923, 2852, 1744, 1638, 1578, 1527, 1472, 1432, 1347,
1265, 1240, 1191, 1088, 1014 cm-1; HRMS (ESI) m/z [M+H]+
1-(Pyrimidin-2-yl)indolin-7-yl
3-methoxybenzoate
3g
.
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.34; calcd for C19H15N4O4: 363.1088, found: 363.1091.
o
colorless solid; yield 68% (47.1 mg); mp 119-120 C; H NMR
1
1-(Pyrimidin-2-yl)indolin-7-yl 4-(trifluoromethyl)benzoate
(600 MHz, CDCl3) δ 8.07 (d, J=4.8 Hz, 2H), 7.60(d, J =7.2 Hz, 3l. Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf =
1H), 7.51 (s,1H), 7.29 (t, J =7.8 Hz, 1H), 7.16 – 7.12(m, 2H), 0.40; colorless solid, mp 126-127 °C; yield 80% (61.6 mg); 1H
7.09 -7.06(m, 2H), 6.41 (t, J =4.8 Hz, 1H), 4.41 (t, J = 8.4 Hz, 2H), NMR (600 MHz, CDCl3) δ 8.13 (d, J = 7.8 Hz, 2H), 8.05 (d, J = 4.8
3.79(s, 3H), 3.18 ( t, J = 7.8Hz, 2H) ; 13C NMR (150 MHz, CDCl3) Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 7.2 Hz, 1H), 7.14 (d,
δ 164.7, 159.6, 157.6, 139.1, 136.9, 135.2, 131.7, 129.5, 123.8, J = 7.8 Hz, 1H), 7.10-7.07 (m, 1H), 6.42 (t, J = 4.8 Hz, 1H), 4.42
123.3, 122.6, 122.3, 120.0, 114.1, 112.1, 55.6, 52.4, 29.4 ; FT-IR (t, J = 8.4 Hz, 2H), 3.18 (t, J = 7.8 Hz, 2H); 13C NMR (150 MHz,
(KBr) 2924, 2853, 1737, 1639, 1576, 1551, 1466, 1424, 1277, CDCl3) δ 163.7, 159.9, 157.6, 138.9, 137.1, 135.0, 134.7 (q, J =
1107 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C20H18N3O3: 32.7 Hz), 133.7, 130.4, 125.6 (q, J = 3.9 Hz), 124.0, 123.8 (q, J =
348.1343, found: 348.1357.
271.05 Hz), 123.0, 122.6, 112.2, 52.4, 29.4; FT-IR (KBr) 2956,
1-(Pyrimidin-2-yl)indolin-7-yl
4-chlorobenzoate
3h. 2921, 2850, 1743, 1638, 1579, 1471, 1434, 1263, 1130, 1109,
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.41; 966 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C20H15F3N3O2:
1
colorless solid; mp 137-138 οC; yield 80% (56.1 mg); H NMR 386.1111, found: 386.1118.
(600 MHz, CDCl3) δ 8.06 (d, J = 4.8 Hz, 2H), 7.95 (d, J = 8.4 Hz,
1-(Pyrimidin-2-yl)indolin-7-yl 3,4-dimethylbenzoate 3m.
2H), 7.37 (d, J = 8.4 Hz, 2H), 7.16-7.15 (m, 1H), 7.13 (d, J = Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.43;
1
7.2Hz, 1H), 7.08-7.06 (m, 1H), 6.43 (t, J = 4.8 Hz, 1H), 4.41 (t, J = colorless solid, mp 135-136 °C; yield 69% (47.6 mg); H NMR
8.4 Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ (600 MHz, CDCl3) δ 8.08 (d, J = 4.8 Hz, 2H), 7.76 (s, 1H), 7.71 (d,
164.1, 159.9, 157.6, 139.6, 139.0, 137.0, 135.1, 131.4, 128.93, J = 7.8 Hz, 1H), 7.13 (t, J = 7.2 Hz, 3H), 7.07-7.05 (m, 1H), 6.41
128.91, 123.9, 123.1, 122.4, 112.2, 52.4, 29.4; FT-IR (KBr) 2958, (t, J = 4.8 Hz, 1H), 4.41 (t, J = 7.8 Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H),
2924, 2853, 1741, 1591, 1578, 1553, 1471, 1433, 1400, 1263, 2.29 (s, 3H), 2.25 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 165.1,
1171, 1089, 1014 cm-1; HRMS (ESI) m/z [M+H]+ calcd for 160.0, 157.6, 142.5, 139.3, 136.8, 135.3, 131.1, 129.7, 128.0,
C19H15ClN3O2: 352.0847, found: 352.0856.
1-(Pyrimidin-2-yl)indolin-7-yl 4-fluorobenzoate
127.7, 123.8, 123.4, 122.1, 112.1, 52.4, 29.4, 20.2, 19.8; FT-IR
3i. (KBr) 2957, 2923, 2853, 1734, 1611, 1578, 1553, 1479, 1469,
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.44; 1432, 1405, 1286, 1260, 1169, 1088 cm-1; HRMS (ESI) m/z
colorless solid, mp 151-152 °C; yield 80% (53.6 mg); 1H NMR [M+H]+ calcd for C21H20N3O2: 346.1550, found: 346.1553.
(600 MHz, CDCl3) δ 8.06 (d, J = 4.8 Hz, 2H), 8.04-8.01 (m, 2H),
1-(Pyrimidin-2-yl)indolin-7-yl 1-naphthoate 3n. Analytical
7.16-7.12 (m, 2H), 7.08-7.05 (m, 3H), 6.42 (t, J = 4.8 Hz, 1H), TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.41; colorless
1
4.41 (t, J = 7.8 Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H); 13C NMR (150 liquid; yield 54% (39.6 mg); H NMR (600 MHz, CDCl3) δ 9.09
MHz, CDCl3) δ 166.7 (JC-F = 252.76 Hz), 163.9, 159.9, 157.5, (d, J = 9.0 Hz, 1H), 8.20 (dd, J = 7.2, 1.2 Hz, 1H), 8.03 – 8.01 (m,
139.0, 136.9, 135.1, 132.6 (JC-F = 9.3 Hz), 126.7 (JC-F = 3.15 Hz), 3H), 7.89 (d, J = 8.4 Hz, 1H), 7.61 – 7.59 (m, 1H), 7.54 (t, J = 7.2
123.9, 123.2, 122.4, 115.7 (JC-F = 21.75 Hz), 112.2, 52.4, 29.4; Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.21- 7.17 (m, 2H), 7.11 (t, J = 7.8
FT-IR (KBr) 2956, 2924, 2854, 1735, 1637, 1603, 1552, 1488, Hz, 1H), 6.29 (t, J = 4.8 Hz, 1H), 4.45 (t, J = 8.4 Hz, 2H), 3.20 (t, J
1446, 1271, 1234, 1160, 1108, 991 cm-1; HRMS (ESI) m/z = 7.8 Hz, 2H).; 13C NMR (150 MHz, CDCl3) δ 165.0, 160.0, 157.6,
[M+H]+ calcd for C19H15FN3O2: 336.1143, found: 336.1152.
1-(Pyrimidin-2-yl)indolin-7-yl 4-methylbenzoate
139.2, 137.0, 135.3, 134.1, 133.9, 131.8, 131.4, 128.7, 128.2,
3j. 126.4, 126.2, 126.0, 124.5, 123.9, 123.4, 122.3, 112.2, 52.4,
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.46; 29.4; FT-IR (neat) 2963, 2924, 2853, 1732, 1639, 1577, 1552,
1
colorless solid, mp 172-173 °C; yield 74% (48.9 mg); H NMR
6 | J. Name., 2012, 00, 1-3
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1471, 1432, 1236, 1186, 1120 cm-1; HRMS (ESI) m/z [M+H]+ 1750, 1592, 1577, 1552, 1472, 1400, 1382, 1243, 1120, 1030
calcd for C23H18N3O2: 368.1394, found: 368.1408.
cm-1; HRMS (ESI) m/z [M+H]+ calcd for C17H20N3O2: 298.1550,
1-(Pyrimidin-2-yl)indolin-7-yl thiophene-2-carboxylate 3o. found: 298.1559.
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.40; 1-(Pyrimidin-2-yl)indolin-7-yl
(3r,5r,7r)-adamantane-1-
1
colorless solid, mp 102-103 °C; yield 64% (41.3 mg); H NMR carboxylate 3v. Analytical TLC on silica gel, 1:3 ethyl
(600 MHz, CDCl3) δ 8.13 (d, J = 4.8 Hz, 2H), 7.80 (dd, J = 3.6, 1.2 acetate/hexane Rf = 0.34; yellow liquid; yield 70% (52.5 mg);
Hz, 1H), 7.53 (dd, J = 5.4, 1.8 Hz, 1H), 7.14 (t, J = 6.0 Hz, 2H), 1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 4.8 Hz, 2H), 7.09-7.08
7.07-7.04 (m, 2H), 6.45 (t, J = 4.8 Hz, 1H), 4.40 (t, J = 7.8 Hz, (m, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.93 – 6.91 (m, 1H), 6.71 (t, J =
2H), 3.17 (t, J = 8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 160.3, 4.8 Hz, 1H), 4.38 (t, J = 8.4 Hz, 2H), 3.11 (t, J = 8.4 Hz, 2H), 1.94
159.9, 157.5, 138.8, 136.9, 135.2, 134.1, 134.0, 132.9, 127.8, – 1.91 (m, 4H), 1.795-1.791 (m, 5H), 1.72-1.62 (m, 6H); 13C
123.8, 123.3, 122.4, 112.2, 52.3, 29.4; FT-IR (KBr) 2922, 2851, NMR (150 MHz, CDCl3) δ 175.2, 160.8, 157.9, 140.2, 136.7,
1730, 1639, 1577, 1553, 1472, 1442, 1432, 1416, 1383, 1239, 135.6, 124.2, 122.2, 121.8, 112.4, 52.9, 41.1, 38.8, 36.6, 29.8,
1190, 1070, 1030 cm-1; HRMS (ESI) m/z [M+H]+ calcd for 28.0; FT-IR (neat) 2920, 2852, 1747, 1578, 1552, 1479, 1433,
C17H14N3O2S: 324.0801, found: 324.0801.
1-(Pyrimidin-2-yl)indolin-7-yl (E)-but-2-enoate 3r. Analytical calcd for C23H26N3O2: 376.2020, found: 376.2029.
TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.28; colorless 2-Methyl-1-(pyrimidin-2-yl)indolin-7-yl benzoate
1382, 1211, 1179, 1103, 1065 cm-1; HRMS (ESI) m/z [M+H]+
3w
.
solid; yield 65% (37 mg); mp 112-113oC; 1H NMR (600 MHz, Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.51;
CDCl3) δ 8.32 (d, J = 4.2 Hz, 2H), 7.11 – 7.09 (m, 1H), 7.04 – brown liquid; yield 73% (48.3 mg); 1H NMR (600 MHz, CDCl3) δ
6.97 (m, 3H), 6.64 (t, J = 4.8 Hz, 1H), 5.88 (dd, J = 15.6, 1.8 Hz, 8.05 (d, J = 4.8 Hz, 2H), 8.02-8.01 (m, 2H), 7.54-7.52 (m, 1H),
1H), 4.38 (t, J = 7.8 Hz, 2H), 3.14 (t, J = 8.4 Hz, 2H), 1.86 (dd, J 7.40-7.38 (m, 2H), 7.15 (d, J = 7.8 Hz, 2H), 7.09-7.07 (m, 1H),
=7.2, 1.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 164.5, 160.0, 6.37 (t, J = 4.8 Hz, 1H), 4.96-4.93 (m, 1H), 3.51 (dd, J = 15.0, 8.4
157.7, 145.8, 139.1, 136.8, 135.1, 123.8, 123.1, 122.8, 122.0, Hz, 1H), 2.64 (d, J = 15.6 Hz, 1H), 1.47 (d, J = 6.6 Hz, 3H); 13C
112.2, 52.3, 29.4, 18.2; FT-IR (KBr) 2961, 2924, 2854, 1733, NMR (150 MHz, CDCl3) δ 164.7, 159.7, 157.6, 139.8, 135.8,
1653, 1577, 1554, 1467, 1102 cm-1; HRMS (ESI) m/z [M+H]+ 133.9, 133.1, 130.5, 130.1, 128.4, 123.9, 123.2, 122.7, 112.1,
calcd for C16H16N3O2:282.1237, found: 282.1249.
60.0, 36.9, 21.2; FT-IR (neat) 2957, 2923, 2851, 1740, 1578,
1-(Pyrimidin-2-yl)indolin-7-yl cinnamate 3s. Analytical TLC 1552, 1479, 1433, 1385, 1265, 1242, 1199, 1086, 1068, 1025
on silica gel, 1:3 ethyl acetate/hexane Rf = 0.38; colorless solid; cm-1; HRMS (ESI) m/z [M+H]+ calcd for C20H18N3O2: 332.1394,
mp 101-102 oC; yield 67% (46 mg); 1H NMR (600 MHz, CDCl3) δ found: 332.1399.
8.31 (d, J = 4.8 Hz, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.50-7.48 (m,
3-Methyl-1-(pyrimidin-2-yl)indolin-7-yl
benzoate
3x.
2H), 7.39-7.38 (m, 3H), 7.14 (d, J = 7.8 Hz, 1H), 7.09-7.04 (m, Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.51;
2H), 6.57 (t, J = 4.8 Hz, 1H), 6.48 (d, J = 16.2 Hz, 1H), 4.41 (t, J = yellow liquid; yield 75% (49.6 mg); 1H NMR (400 MHz, CDCl3) δ
8.4 Hz, 2H), 3.16 (t, J = 7.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 8.05-8.00 (m, 4H), 7.54 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.6 Hz,
165.1, 160.0, 157.7, 145.6, 139.1, 136.9, 135.1, 134.4, 130.6, 2H), 7.14-7.08 (m, 3H), 6.38 (t, J = 4.8 Hz, 1H), 4.60 (t, J= 9.6 Hz,
129.1, 128.3, 123.8, 123.2, 122.2, 118.2, 112.3, 52.3, 29.4; FT- 1H), 3.94-3.90 (m, 1H), 3.53-3.48 (m, 1H), 1.37 (d, J = 6.4 Hz,
IR (KBr) 2956, 2923, 2852, 1731, 1637, 1577, 1552, 1472, 1442, 3H).; 13C NMR (150 MHz, CDCl3) δ 164.8, 159.9, 157.6, 142.0,
1383, 1328, 1309, 1237, 1191, 1138, 1065, 990 cm-1; HRMS 139.1, 134.8, 133.2, 130.5, 130.0, 128.4, 124.0, 123.4, 121.0,
(ESI) m/z [M+H]+ calcd for C21H18N3O2: 344.1394, found: 112.0, 60.1, 36.0, 19.0.; FT-IR (neat) 2959, 2925, 2854, 1742,
344.1400.
1578, 1553, 1470, 1434, 1383, 1265, 1242, 1190, 1087, 1023
1-(Pyrimidin-2-yl)indolin-7-yl propionate 3t. Analytical TLC cm-1; HRMS (ESI) m/z [M+H]+ calcd for C20H18N3O2: 332.1394,
on silica gel, 1:3 ethyl acetate/hexane Rf = 0.35; yellow liquid; found: 332.1397.
yield 70% (37.6 mg); 1H NMR (600 MHz, CDCl3) δ 8.39 (d, J =
4-Bromo-1-(pyrimidin-2-yl)indolin-7-yl
benzoate
3y.
4.8 Hz, 2H), 7.11 (d, J = 7.2 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.99 Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.49;
(d, J = 8.4 Hz, 1H), 6.70 (t, J = 4.8 Hz, 1H), 4.39 (t, J = 7.8 Hz, colorless solid; mp 86-87 °C; yield 69% (54.5 mg); 1H NMR (600
2H), 3.13 (t, J = 7.8 Hz, 2H), 2.37 (q, J = 7.2 Hz, 2H), 1.10 (t, J = MHz, CDCl3) δ 8.06 (d, J = 4.8 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H),
7.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 172.3, 160.2, 157.6, 7.54 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 2H), 7.21 (d, J = 8.4
139.3, 136.9, 135.1, 124.0, 122.9, 122.1, 112.4, 52.5, 29.5, Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.43 (t, J = 4.8 Hz, 1H), 4.42 (t, J
28.0, 9.0; FT-IR (neat) 2956, 2924, 2853, 1761, 1638, 1578, = 8.4 Hz, 2H), 3.17 (t, J = 7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3)
1551, 1470, 1432, 1382, 1243, 1139, 1080 cm-1; HRMS (ESI) δ 164.6, 159.8, 157.6, 138.1, 136.9, 136.4, 133.4, 130.16,
m/z [M+H]+ calcd for: C15H16N3O2: 270.1237, found: 270.1239.
130.10, 128.5, 126.4, 125.1, 116.0, 112.6, 51.7, 31.0; FT-IR
1-(Pyrimidin-2-yl)indolin-7-yl pivalate 3u. Analytical TLC on (KBr) 2961, 2924, 2853, 1741, 1640, 1563, 1551, 1460, 1407,
silica gel, 1:3 ethyl acetate/hexane Rf = 0.35; colorless liquid; 1261, 1238, 1100, 1023 cm-1; HRMS (ESI) m/z [M+H]+ calcd for
1
yield 69% (41 mg); H NMR (600 MHz, CDCl3) δ 8.41 (d, J = 4.8 C19H15BrN3O2: 396.0342, found: 396.0343.
Hz, 2H), 7.10 (d, J = 7.2 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.93 (d,
5-Bromo-1-(pyrimidin-2-yl)indolin-7-yl
benzoate
3z.
J = 8.4 Hz, 1H), 6.70 (t, J = 4.8 Hz, 1H), 4.38 (t, J = 7.8 Hz, 2H), Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.44;
3.12 (t, J = 7.8 Hz, 2H), 1.12 (s, 9H); 13C NMR (150 MHz, CDCl3) yellow solid, mp 98-99 °C; yield 73% (57.6 mg); 1H NMR (600
δ 176.2, 160.8, 157.9, 140.2, 136.8, 135.6, 124.3, 122.2, 122.0, MHz, CDCl3) δ 8.05 (d, J = 4.8 Hz, 2H), 7.99-7.97 (m, 2H), 7.55
112.5, 52.9, 39.2, 29.8, 27.2; FT-IR (neat) 2959, 2924, 2853, (t, J = 7.8 Hz, 1H), 7.39 (t, J = 8.4 Hz, 2H), 7.30 (s, 1H), 7.27 (s,
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1H), 6.41 (t, J = 4.8 Hz, 1H), 4.41 (t, J = 7.8 Hz, 2H), 3.17 (t, J = solid; yield 22% (16 mg); mp 150-151oC; 1H NMR (600 MHz,
8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 164.5, 159.7, 157.6, CDCl3) δ 8.44 (d, J = 4.8 Hz, 2H), 8.18 (d, J = 8.4 Hz, 1H), 8.10 (d,
139.2, 138.5, 134.8, 133.4, 130.1, 129.9, 128.5, 126.3, 125.4, J = 7.2 Hz, 1H), 8.03 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 7.2 Hz, 2H),
115.1, 112.5, 52.4, 29.2; FT-IR (KBr) 2951, 2923, 2852, 1746, 7.58 (t, J = 7.8 Hz, 1H), 7.46 -7.35 (m, 6H), 6.77 (t, J = 4.8 Hz,
1578, 1552, 1477, 1451, 1411, 1380, 1262, 1250, 1239, 1191, 1H).; 13C NMR (150 MHz, CDCl3) δ 164.3, 158.2, 140.9, 137.7,
1078, 996 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C19H15BrN3O2: 133.6, 131.0, 130.0, 129.8, 128.9, 128.6, 127.2, 125.1, 122.5,
396.0342, found: 396.0344.
122.4, 121.6, 120.2, 117.8, 117.2, 112.9 ; FT-IR (KBr) 2963,
3aa. 2924, 2852, 1729, 1637, 1566, 1452, 1413, 1211, 1090 cm-1;
5-Fluoro-1-(pyrimidin-2-yl)indolin-7-yl
benzoate
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.58; HRMS (ESI) m/z [M+H]+ calcd for C23H16N3O2:366.1237, found:
yellowish solid; mp 175-176 °C; yield 69% (46.2 mg); 1H NMR 366.1251.
(600 MHz, CDCl3) δ 8.05 (d, J = 4.8 Hz, 2H), 7.99-7.98 (m, 2H),
9-(Pyrimidin-2-yl)-9H-carbazole-1,8-diyl dibenzoate 3af.
7.56-7.53 (m, 1H), 7.40-7.37 (m, 2H), 6.92-6.90 (m, 2H), 6.39 (t, Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.24;
J = 4.8 Hz, 1H), 4.43 (t, J = 8.4 Hz, 2H), 3.15 (t, J = 7.8 Hz, 2H); colorless solid; yield 51% (49.4 mg); mp 240-241oC; 1H NMR
13C NMR (150 MHz, CDCl3) δ 164.5, 159.9, 159.8 (JC-F = 241.5 (600 MHz, CDCl3) δ 8.08 (dd, J = 8.4, 1.2 Hz, 2H), 7.99 (d, J = 4.8
Hz), 157.6, 139.1(JC-F =11.55 Hz), 138.0 (JC-F =9.45 Hz), 133.4, Hz, 2H), 7.77 – 7.76 (m, 4H), 7.53 (t, J = 7.21 Hz, 2H), 7.39 (t, J =
131.7 (JC-F =2.7 Hz), 130.1, 130.0, 128.5, 112.2, 110.5 (JC-F =25.8 7.8 Hz, 2H), 7.34 (t, J = 7.8 Hz, 4H), 7.28 (d, J = 7.8, 2H), 6.32 (t,
Hz), 110.0 (JC-F =23.7 Hz), 52.5, 29.7 (JC-F =2.1 Hz); FT-IR (KBr) J = 4.8 Hz, 1H) ; 13C NMR (150 MHz, CDCl3) δ 164.4, 159.2,
2956, 2924, 2853, 1736, 1596, 1580, 1552, 1490, 1467, 1424, 158.1, 136.5, 133.6, 132.9, 130.1, 129.2, 128.4, 127.3, 121.7,
1386, 1255, 1124, 1083, 1026 cm-1; HRMS (ESI) m/z [M+H]+ 121.3, 118.9, 118.3 ; FT-IR (KBr) 2924, 2853, 1748, 1632, 1583,
calcd for C19H15FN3O2: 336.1143, found: 336.1151.
1566, 1450, 1432, 1408, 1260, 1213, 1174, 1062, 1051 cm-1;
5-Methoxy-1-(pyrimidin-2-yl)indolin-7-yl benzoate 3ab. HRMS (ESI) m/z [M+H]+ calcd for C30H20N3O4:486.1448, found:
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.44; 486.1458.
yellow liquid; yield 77% (53.4 mg); 1H NMR (400 MHz, CDCl3) δ
1-(Pyrimidin-2-yl)-1H-indol-7-yl benzoate 4. To a stirred
8.03 – 8.01 (m, 4H), 7.54 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, solution of 1-(pyrimidin-2-yl)indolin-7-yl benzoate 3a (0.1
2H), 6.77 (s, 1H), 6.70-6.69 (m, 1H), 6.35 (t, J = 4.8 Hz, 1H), 4.40 mmol, 31.7 mg) in 1,4-dioxane, DDQ (0.2 mmol, 45.4 mg) was
(t, J = 8.0 Hz, 2H), 3.81 (s, 3H), 3.13 (t, J = 8.0 Hz, 2H); 13C NMR added at room temperature. The resultant solution was
(100 MHz, CDCl3) δ 164.8, 160.1, 157.6, 156.8, 139.4, 137.8, further stirred at 90 °C for 14 h. After completion, as indicated
133.2, 130.4, 130.1, 128.8, 128.5, 111.7, 109.7, 107.8, 56.1, by TLC, the reaction mixture was cooled to room temperature
52.3, 29.8; FT-IR (neat) 2958, 2924, 2852, 1739, 1622, 1579, and diluted with ethyl acetate (15 mL). The mixture was
1550, 1488, 1424, 1381, 1261, 1190, 1140, 1088, 1069, 1026 successively washed with brine (2 x 5 mL) and water (5 mL).
cm-1; HRMS (ESI) m/z [M+H]+ calcd for C20H18N3O3: 348.1343, Drying (Na2SO4) and evaporation of the solvent gave a residue
found: 348.1347.
that was purified on silica gel column chromatography using n-
6-Bromo-1-(pyrimidin-2-yl)indolin-7-yl
benzoate
3ac. hexane and ethyl acetate as an eluent to afford 1-(pyrimidin-2-
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.40; yl)-1H-indol-7-yl benzoate
4 as a colorless liquid. Analytical TLC
1
yellow liquid; yield 67% (53 mg); H NMR (600 MHz, CDCl3) δ on silica gel, 1:3 ethyl acetate/hexane Rf = 0.50; colorless
8.10 – 8.06 (m, 4H), 7.57 – 7.54 (m, 1H), 7.42 (t, J = 7.8 Hz, 2H), liquid; yield 84% (56.7 mg); 1H NMR (600 MHz, CDCl3) δ 8.15
7.30 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.44 (t, J = 4.2 (d, J = 4.8 Hz, 2H), 8.10 – 8.08 (m, 2H), 8.03 (d, J = 3.6 Hz, 1H),
Hz, 1H), 4.40 (s, 2H), 3.12 (t, J = 7.8 Hz, 2H); 13C NMR (150 MHz, 7.62 – 7.59 (m, 1H), 7.57-7.55 (m, 1H), 7.47 – 7.45 (m, 2H),
CDCl3) δ 163.3, 159.5, 157.5, 137.3, 136.7, 136.4, 133.4, 130.2, 7.28 (t, J = 7.8 Hz, 1H), 7.16-7.15 (m, 1H), 6.76 – 6.73 (m, 2H);
129.9, 128.5, 127.6, 123.2, 117.1, 112.5, 52.9, 29.1; FT-IR 13C NMR (150 MHz, CDCl3) δ 165.2, 158.2, 157.4, 137.8, 134.9,
(neat) 2923, 2852, 1744, 1576, 1553, 1438, 1381, 1260, 1221, 133.3, 130.5, 130.2, 129.5, 128.6, 127.0, 122.7, 119.2, 118.9,
1108 cm-1; HRMS (ESI) m/z [M+H]+ calcd for C19H15BrN3O2: 116.7, 107.2; FT-IR (neat) 2923, 2852, 1738, 1637, 1572, 1482,
396.0342, found: 396.0361.
1421, 1357, 1264, 1217, 1093 cm-1; HRMS (ESI) m/z [M+H]+
3ad. calcd for C19H14N3O2: 316.1081, found: 316.1097.
6-Chloro-1-(pyrimidin-2-yl)indolin-7-yl
benzoate
Analytical TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.43;
1
1-(Pyrimidin-2-yl)indolin-7-ol 5. 1-(Pyrimidin-2-yl)indolin-7-
colorless solid; mp 129-130 oC; yield 71% (49.8 mg); H NMR yl benzoate 3a (0.1 mmol, 31.7 mg) and NaOH (40% solution, 2
ο
(400 MHz, CDCl3) δ 8.09-8.05 (m, 4H), 7.55 (t, J = 7.2 Hz, 1H), mL) (2 mL) were stirred at 70 C for 2 h in ethanol (4 mL). The
7.41 (t, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 7.6 resultant mixture was treated with water (2 mL) and the
Hz, 1H), 6.44 (t, J = 4.8 Hz, 1H), 4.41 (s, 2H), 3.13 (t, J = 7.2 Hz, stirring was continued at 70 οC for 6 h. After completion, as
2H); 13C NMR (150 MHz, CDCl3) δ 163.6, 159.6, 157.5, 137.3, indicated by TLC, the reaction mixture was neutralized using
135.8, 135.6, 133.4, 130.2, 129.9, 128.5, 127.9, 124.4, 122.6, 1N HCL. Ethanol was removed on a rotary evaporator and
112.5, 53.0, 29.0; FT-IR (KBr) 2958, 2922, 2852, 1748, 1635, aqueous solution was extracted with ethyl acetate (3 x 15 mL).
1577, 1554, 1468, 1383, 1261, 1223, 1175, 1080, 1024 cm-1; Drying (Na2SO4) and evaporation of the solvent gave a residue
HRMS (ESI) m/z [M+H]+ calcd for C19H15ClN3O2: 352.0847, that was purified on silica gel column chromatography using n-
found: 352.0852.
9-(Pyrimidin-2-yl)-9H-carbazol-1-yl benzoate 3ae. Analytical yl)indolin-7-ol
TLC on silica gel, 1:3 ethyl acetate/hexane Rf = 0.44; colorless 1:3 ethyl acetate/hexane Rf = 0.55; yield 83% (42.6 mg); mp 98-
hexane and ethyl acetate as an eluent to afford 1-(pyrimidin-2-
5
as a yellow solid. Analytical TLC on silica gel,
8 | J. Name., 2012, 00, 1-3
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99 oC; 1H NMR (600 MHz, CDCl3) δ 13.0 (br s, 1H), 8.49-8.26 (m, acid 2a under the standard reaction conditions. The two
ο
2H), 6.94 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.73 (d, J = reactions were allowed to stir at 100 C for 4 h. For the both
7.8 Hz, 1H), 6.63 (t, J = 4.8 Hz, 1H), 4.26 (t, J = 8.4 Hz, 2H), 3.14 cases, was cooled to room temperature, diluted with
(t, J = 8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 160.3, 157.4, dichloromethane (10 mL), and passed through a short pad of
145.5, 135.2, 129.6, 125.4, 117.9, 116.1, 110.3, 49.7, 28.2; FT- celite using dichloromethane (25 mL). Drying (Na2SO4) and
IR (KBr) 3436, 2925, 2854, 1633, 1596, 1554, 1482, 1465, 1424 evaporation of the solvent gave a residue that was purified on
cm-1; HRMS (ESI) m/z [M+H]+ calcd for C12H12N3O: 214.0975, silica gel column chromatography using n-hexane and ethyl
found: 214.0982 .
acetate as an eluent to afford 3a. The yield of 3a was obtained
Competition experiment using acids 2j and 2k (Scheme 6a). as 18% and 43% yields respectively. The KIE value of 2.65 was
1-(Pyrimidin-2-yl)indoline 1a (19.7 mg, 0.1 mmol), 2j (13.6 mg, determined by the ratio of obtained yield of 3a (KIE =
0.1 mmol), 2k (16.7 mg, 0.1 mmol), [RuCl2(p-cymene)]2 (3.0 43%/18%/90% = 2.65).
mg, 5.0 mol %), AgSbF6 (7.0 mg, 20 mol %) and Ag2CO3 (55.2
mg, 0.2 mmol) in (CH2Cl)2 (1.0 mL) were subjected to the
Acknowledgements
reaction conditions described in the general procedure (100
oC) for 5 h and 3j and 3k were formed in 10 and 19% yields,
We thank Science and Engineering Research Board (EMR-2015-43)
respectively.
and Council of Scientific and Industrial Research (02(0255)-2016-
EMR-II) for the financial support. We also thank Central
Instrumentation Facility, Indian Institute of Technology Guwahati
for NMR and Mass analyses (FIST).
Competition experiment using acids 2j and 2u (Scheme 6b).
The reaction of 1-(pyrimidin-2-yl)indoline 1a (19.7 mg, 0.1
mmol) was performed with 2j (13.6 mg, 0.1 mmol) and 2u
(10.2 mg, 0.1 mmol) in the presence of [RuCl2(p-cymene)]2 (3.0
mg, 5.0 mol %), AgSbF6 (7.0 mg, 20 mol %) and Ag2CO3 (55.2
mg, 0.2 mmol) for 5 h in (CH2Cl)2 (1.0 mL) as described above
to produce 3j and 3u in 26 and 6% yields, respectively.
Notes and references
1
For some recent reviews on C-H functionalization, see: (a) T.
W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (b)
A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem.,
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52, 11726; (g) M.-L. Louillat and F. W. Patureau, Chem. Soc.
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H/D Exchange with D2O. 1-(Pyrimidin-2-yl)indoline 1a (19.7
mg, 0.2 mmol), [RuCl2(p-cymene)]2] (6.0 mg, 5.0 mol %),
AgSbF6 (13.7 mg, 20 mol %) and Ag2CO3 (110 mg, 0.4 mmol)
were stirred at 100 °C for 16 h in (CH2Cl)2:D2O (1.8:0.2) under
air. The reaction mixture was cooled to room temperature,
diluted with dichloromethane (10 mL), and passed through a
short pad of celite using dichloromethane (25 mL). Drying
(Na2SO4) and evaporation of the solvent gave a residue that
was purified using column chromatography on silica gel to give
1a-d in 87% (34.4 mg) yield with 40% deuterium incorporation
as estimated by 400 MHz 1H NMR.
2
For examples, see: (a) J. Y. Kim, S. H. Park, J. Ryu, S. H. Cho, S.
H. Kim and S. Chang, J. Am. Chem. Soc., 2012, 134, 9110; (b)
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L. Ackermann, Chem. Commun., 2014, 50, 29; (e) L. Wang, D.
Preparation of 1-(pyrimidin-2-yl)indoline-7-d (1a-d).7a The
titled compound was prepared according to the reported
procedure as a pale yellow liquid. The deuterium incorporation
was determined using 600 MHz 1H NMR as 90%.
L. Priebbenow, W. Dong and C. Bolm, Org. Lett., 2014, 16
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Intermolecular kinetic isotope study.5j Benzoic acid 2a (0.2
mmol, 24.4 mg) was reacted with 1-(pyrimidin-2-yl)indoline 1a
(0.1 mmol, 19.7 mg) and 1-(pyrimidin-2-yl)indoline-7-d 1a-d
(0.1 mmol, 19.8 mg) for 4 h under standard reaction condition.
The reaction mixture was cooled to room temperature, diluted
with dichloromethane (10 mL), and passed through a short pad
of celite using dichloromethane (25 mL). Drying (Na2SO4) and
evaporation of the solvent gave a residue that was purified on
silica gel column chromatography using n-hexane and ethyl
acetate as an eluent to afford 3a and a mixture of unreacted
1a and 1a-d as a yellowish liquid. The intermolecular kH/kD was
found to be 6.67 after 4 h at 23% conversion, based on 400
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3
4
MHz 1H NMR of the recovered substrates 1a and 1a-d
.
Independent kinetic isotope effect study.5j In a set of two
experiments: in first set, benzoic acid 2a (0.2 mmol, 24.4 mg)
was reacted with 1-(pyrimidin-2-yl)indoline 1a (0.1 mmol, 19.7
mg) under standard reaction conditions. Whereas in another
set, 1-(pyrimidin-2-yl)indoline-7-d 1a-d (0.1 mmol, 19.8 mg,
90% D) was used instead of 1a in the reaction with benzoic
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Journal Name
3434; (h) Q. Lu, S. Cembellín, S. Greßies, S. Singha, C. G.
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9
5
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,
6
For C-N bond formation: (a) K. Shin and S. Chang, J. Org.
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7
8
For C-S/Se bond formation: (a) W. Xie, B. Li and B. Wang, J.
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9
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10 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C8OB01603H
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