Copper-Catalyzed Amination of C(sp3)-H bonds: From Anilides to Indolines

Article abstract of DOI:10.1021/acs.joc.9b02404

Copper-catalyzed oxidative intramolecular cyclization of o-alkylated anilines via cleavage of C(sp³)-H and N-H bonds for the production of indolines is described. This approach provides a straightforward strategy for the synthesis of nitrogen-c

Full text of DOI:10.1021/acs.joc.9b02404

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Article
Copper-catalyzed amination of C(sp3)-H bonds: from anilides to indolines
Jinguo Long, Liyuan Le, Takanori Iwasaki, Renhua Qiu, and Nobuaki Kambe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02404 • Publication Date (Web): 26 Nov 2019
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The Journal of Organic Chemistry
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Copper-catalyzed amination of C(sp3)−H bonds: from anilides to
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indolines
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Jinguo Long,† Liyuan Le,† Takanori Iwasaki,‡,¶ Renhua Qiu,*,†,‡ Nobuaki Kambe*,†,‡
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, P.R. China, 410082
‡Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka, 565-0871, Japan
¶Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113-8656, Japan
Supporting Information
ABSTRACT: Copper-catalyzed oxidative intramolecular cyclization of o-alkylated anilines via cleavage of C(sp3 )−H and N−H bonds
for the production of indolines is described. This approach provides a straightforward strategy for the synthesis of nitrogen-containing
heterocyclic compounds through the functionalization of unactivated C(sp3)−H bonds with high site-selectivity. The present catalytic
system shows high preference for functionalization of unactivated C(sp3)−H bonds over C(sp2)−H bonds leading to C−N bond formation.
INTRODUCTION
The introduction of a directing group on aromatic rings is a powerful ap-
proach for site-selective functionalization of C−H bonds using transition-
metal catalysts. In recent years, much attention has been paid to the func-
tionalization of unactivated C−H bonds on sp3-carbons (Figure 1).1 In the
organic synthesis, the formation of C−N bonds as well as C−C bonds is of
Figure 2. C(sp2)−H vs C(sp3)−H functionalization.
Indolines are important structural motifs in natural products and exhibit
interesting biological activities.8 The preparation of indolines through the
cleavage of unactivated C(sp3)−H bond was first developed by Glorius and
coworkers using Pd catalyst and AgOAc as an oxidizing reagent (Figure
2).6a In addition to the Pd catalyst,6a it was reported that iodine6d and Cu7e
can work as the catalyst or mediator for producing indolines by oxidative
Figure 1. C−H functionalization with directing groups (DG).
intramolecular cross-coupling. The Pd system is an important work which
has a wide substrate scope except the substrates having substituents on the
nitrogen. The formation of C(sp2)−N bond predominates over that of
C(sp3)−N bond when both C(sp2)−H and C(sp3)−H bonds are present at the
appropriate positions in Pd-Ag system.7e Herein, we disclose a method for
the synthesis of indolines via copper-catalyzed oxidative cross-coupling of
C(sp3)−H and N−H bonds, which preferentially functionalize C(sp3)−H
bonds over C(sp2)−H bonds, giving rise to indolines selectively over car-
bazoles (Figure 2).
great importance and amination via C−H bond cleavage will make an
extremely promising and useful method for constructing nitrogen contain-
ing compounds.2 Since the pioneering work on the formation of C(sp2)−N
bonds via oxidative cross-coupling using a Pd catalyst for the synthesis of
carbazoles,3 numerous methods have been established for C(sp2)−N bond
formation using transition-metal catalysts.4,5 Despite such progresses of
C(sp2)−N bond forming reactions via C−H bond activation, the synthesis
of N-heterocycles by means of C(sp3)−H bond functionalization is still a
challenge in organic synthesis. 6,7
RESULTS AND DISCUSSION
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We examined the intramolecular cyclization of 1a by the combined use of
for 24 h, indicating that the present catalytic system exhibits high
chemoselectivity for C(sp3)−H bond over the C(sp2)−Br bond. Further-
more, the reaction of naphthylamide 5j and p-phenylbenzamide 5k afford-
ed the corresponding products in good yields (6j, 68% and 6k, 62%), and
the thienyl group of 5l survived to give 6l in 68% yield. However, the
pyridine substituent suppressed the reaction, resulting in the recovery of
the starting material 5m.
CuBr (0.25 equiv.) and DTBP (di-tert-butylperoxide, 3.0 equiv.) as an
oxidizing reagent using different additives and solvents under various
conditions, and the selected results are shown in Table 1. The best yield
(97%) of the desired product 2a was attained when the reaction was con-
ducted in refluxing p-Cl-C6H4CH3 at 130 °C for 24 h using NMI (N-
methylimidazole) as an additive (entry 8). When the reaction was
quenched in 1 h, 2a was formed in 90% and obtained in pure form in 85%
after column chromatography (entry 9). High temperature 140 °C for 1 h
gave 2a in the yield of 91% (entry11), indicating 130 °C was suitable for
this cyclization. The detail results were listed in Table S1−S5 in SI.
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Table 2. Oxidative cyclization of N-arylactamides.
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Table 1. Optimization of reaction condition
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Reaction conditions: 1a (0.25 mmol), DTBP (3.0 equiv.), additive (2.0 equiv.), sol-
vent (1.0 mL), GC Yield. aIsolated yield in parenthesis.
Firstly, we examined the reaction using various substrates under the same
conditions as entry 9 of Table 1, and the results were listed in Table2. The
reaction can be applied to acetanilides possessing a variety of substituents
on the phenyl ring to give the corresponding indolines in good yields (Ta-
ble 2a): 7-Me (2b, 78%), 5-Br (2c, 80%), 6-tBu (2d, 85%), and 5-Ph (2e,
78%). It should be noted that the ortho-methyl group (a benzylic position)
in the benzene ring in 1b did not participated in the reaction giving rise to
2b in good yield. In addition, the 2,5-di-t-butylaniline derivative 1d un-
derwent the catalytic cyclization reaction with the ortho-tBu group.
We then investigated the effect of the acyl moietis of the amides (Table
t
2b). All substrates having an alkyl group such as Bu, nC3H7, nC5H11 or
nC6H13 at the carbonyl carbon afforded the corresponding products (4a−4e)
in high yields (72%−86%). It took 24 h to promote the yield of 4a to 83%,
suggesting that the steric hindrance effect of tert-butyl may have an inhibi-
tion work for this cyclization. Indolines carrying an unsaturated amide
group, 4g and 4h, were obtained in 70% and 68%. Unfortunately, the
desired products 4f and 4i were not obtained from phenylacetamide 3f and
2-tert- butylaniline 3i. The free nitrogen radicals generated from 4i cannot
proceed subsequent 1.5 -Hydrogen-shift to generate the target carbon
radicals and then the intramolecular cyclization of o-alkylated anilines
cannot take place. When sulfonamides were used as substrate, there were
no reaction with the starting materials recovered.
Reaction conditions: 1/3/5 (0.25 mmol, 1.0 equiv.), CuBr (0.25 equiv.), N-
methylimidazole (2.0 equiv.), DTBP (3.0 equiv.), p-Cl-C6H4CH3 (1.0 mL), 1 h,
130 °C, isolated yield of 2/4/6. a24 h.
The unsubstituted benzamide 5a and ortho-methyl benzamide 5b gave 6a
and 6b in moderate yields (52% and 35%, respectively) along with several
unidentified byproducts. Electron withdrawing substituents such as F, CF3,
and NO2 at the ortho- or para-position improved the yields up to 85%
(6c−6f). Substrates possessing an electron-donating group, methyl or t-
butyl group, at the aromatic ring efficiently underwent intramolecular C−H
amination, giving the desired products 6g and 6h in 92% and 88% yields,
respectively. As in the case of 2c in Table 2, 6i was obtained in 88% yield
with the Ar-Br bond of substrate 5i retained intact even after the reaction
Table 3 summarizes the results from various aromatic amides that cannot
afford the desired indolines in the Pd-Ag system due to the predominated
carbazole formation (vide infra, see Figure 2).6a It is noteworthy that cy-
clization took place exclusively at the sp3-carbons to form indolines 8a in
72% yields (Table 3). The present result is different to that of the Pd-Ag6a
systems in which the C(sp2)−H bond is preferred rather than the C(sp3)−H
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bond, giving carbazole from acetanilides. The target products with elec-
was not formed, suggesting that a radical intermediate(s) is involved.
tron-donating groups were also obtained in moderate yield (8b−d,
43%−56%). Acetanilides 7 bearing electron withdrawing substituents such
as Cl or Ph at the para-position also afforded the corresponding products
8e, 8f in good yields (55% and 72%, respectively). Di-tert-butylperoxide
(DTBP) as HAT (Hydrogen Atom Transfer) oxidant to furnish the ex-
pected substituted indolines as the sole product via intramolecular oxida-
tive cyclisation. In that catalytic system, the free nitrogen radicals generat-
ed from anilides are easier to proceed subsequent 1.5 -Hydrogen-shift to
generate the target sp3 carbon radicals than sp2 carbon radicals. So ignor-
ing the C(sp2)−H bonds. These results demonstrated the usefulness of the
present catalytic system as a complementally method to the hitherto
known Pd6a catalytic systems.
When CuBr and NMI (N-methylimidazole) were added to a mixture of
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Scheme 3. Gram scale application experiment.
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Table 3. Competition reaction of C(sp2)−H and C(sp3)−H bond.
t
DTBP and p-Cl-C6H4CH3 in C6D6 (Figure 3), a shift of the BuO signal
from 1.23 ppm to 1.08 ppm was observed in 2 h by 1H NMR analysis,
implying a possible formation of a Cu (II/III)-OtBu complex or tBuOH.10,11
Figure 3. 1H MNR time-course of DTBP in Cu system.
To show the real valence of the copper species during the reaction process,
we analyzed the Cu 2p binding energies of samples A to D as illustrated in
Reaction conditions:
7 (0.25 mmol, 1.0 equiv.), CuBr (0.25 equiv.), N-
methylimidazole (2.0 equiv), DTBP (3.0 equiv), p-Cl-C6H4CH3 (1.0 mL), 1 h, 130 °C,
isolated yield of 8.
Scheme 4. Preparation of XPS samples.
Scheme 1. Competition experiment of different (sp3)C−H.
Notably, substrate 9, possessing one ethyl group at the benzylic carbon,
was preferentially amidated at the secondary carbon to give indolines 10a
in 83% along with 10b in only 5% formed by amidation at the terminal
methyl group (eq. 1). A possible six-membered product 10c was not de-
tected(Scheme 1). When tert-butyl was replaced by isopropyl, ethyl or
propyl, there were no reaction with the starting materials recovered.
Scheme 4 by using the XPS technique (Figure 4). The Cu 2p binding ener-
gies of sample A prepared without filtration but just direct evaporation (as
Scheme 2. Radical control experiment.
A gram scale application has been conducted based on the substrate 5a, 5
mmol 5a (1.267 g) can convert into the substrate 6a (0.625 g) in the yield
of 50% in the standard reaction condition (eq. 3)(Scheme 3).
To gain insights into the mechanism of the reaction, we ran the reaction of
1a in the presence of a radical inhibitor such as TEMPO, BHT or hydro-
quinone (eq. 2)(Scheme 2). In any cases, the corresponding product 2a
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In summary, we developed a copper-catalyzed system that can functional-
ize inactivated C(sp3)−H bond to give indolines from anilines by means of
intramolecular C−N bond formation. This reaction is straight
forward for the synthesis of nitrogen-containing heterocycles. The system
is highly site selective in favor of C(sp3)−H bond cleavage over C(sp2)−H
bond cleavage. In addition, the Cu-DTBP system shows a wider scope of
substrates giving higher yields of products in many cases. Copper is a
cheap base metal and DTBP is less expensive, therefore the present reac-
tion will be advantageous for large-scale production of indolines.
Figure 4. The XPS Cu 2p spectra
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shown in Scheme 4) showed peaks 1 (953.4 eV) and 4 (933.5 eV) ascriba-
ble to Cu (II) species,12 suggesting the oxidation of Cu(I) to Cu (II) by
DTBP in the presence of NMI. After sample A reacted with amide 1a at
130 °C for 2 h, the sample B obtained through direct evaporation showed
peaks 1 (954.3 eV) and 4(934.5 eV) with Cu 2p binding energies about 1.0
eV higher than those of sample A, suggesting some of the copper species
may be oxidized to Cu(III) during the reaction with 1a. We obtained the
solid and filtrate through filtration of sample A. The solid reacted with 1a
at 130 °C for 2 h to obtain sample C after evaporation. The filtrate reacted
with 1a at 130 °C for 2 h to obtain sample D after evaporation. The peaks
1 and 4 of samples C and D showed Cu 2p binding energies lower than
those of sample B by about 0.4−0.5 eV but higher than those of sample A
by about 1.3 eV suggesting Cu (II) species binding with 1a One can see
that samples B−D showed shake-up satellite features higher than those of
sample A. It is noted that after the reaction with amide 1a at 130 °C for 2 h,
all the samples increased in Cu 2p binding energy, suggesting the for-
mation of Cu (III) during the catalytic process and/or coordinating pro-
cesses that involved Cu (II)/Cu (III) species.
EXPERIMENTAL SECTION
General Information. All commercially available regents were used
without further purification. The dehydrated solvents were purchased and
redistilled before use. Nuclear magnetic resonance (NMR) spectra was
acquired at 298 K on a 400 MHz Bruker NMR spectrometer with the
sample dissolved in DMSO-d6 or CDCl3 (unless stated otherwise). All
values of chemical shift were reported in parts per million (ppm) relative
to the solvent signal with the coupling constant (J) reported in hertz. All
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1
compounds were characterized by H NMR, 13C NMR and EI (or HRMS
(double focusing mass analyzer). For substrates and products that con-
tained F, selected ones were also characterized by 19F NMR. Column
chromatography was performed on silica gel (300−400 mesh) using petro-
leum ether (PE)/ethyl acetate (EA) as developing solvent.
On the basis of these results and precedent studies,7,
we proposed
10-14
plausible reaction pathways in Scheme 5, although various alternative
pathways are possible (see SI for details). In the presence of DTBP, CuX
is known to be oxidized to Cu(II) by the reaction with tBuO radical or with
DTBP with the generation of tBuO radical.10a An acetamide 1a reacts with
CuX2L to give a Cu(II) intermediate V directory or via a Cu(I) intermedi-
ate IV, which reacts with DTBP to give V with the concomitant generation
General Procedure for Synthesis of Substrates. The procedure was
reported by S. H. Bergens,15a and was modified by us. Briefly, acyl chlo-
ride (6.0 mmol, 1.5 equiv.) was added dropwise with stirring to a solution
of 2-tert-Butylaniline (4.0 mmol, 1.0 equiv.) and dried triethylamine (6.0
mmol, 1.5 equiv.) in dried dichloromethane (10 mL) at 0 °C. The mixture
was stirred at room temperature for 4 h, then concentrated using a rotary
evaporator. The residue was dissolved in dichloromethane, washed with
saturated NaHCO3 and extracted with dichloromethane. The solution was
concentrated using a rotary evaporator. The crude product was purified by
flash column chromatography (silica, PE/EA). Compounds 1a,6a 1b, 6a 1c,
t
t
of BuO radical. In Path A, BuO radical abstracts a hydrogen from the
t
tert-butyl group to form a radical VI with the elimination of BuOH.Thus
formed carbon radical VI undergoes a radical addition to form Cu(III)
intermediate X, which undergoes reductive elimination to give the product
2a with regeneration of Cu(I). The rate constant of hydrogen abstraction
from tBuPh by tBuO radical is sufficiently rapid with a rate constant of 3.9
x 104 M-1s-1,15a therefore this process seems possible. However, if Cu (II)
6a
t
1d, 6a 1e, 6a 1f, 6d 1i, 6a 3a,6a 3b, 6d 3c,6d 3d,6d 3e,15b 3f,5 3g, 15b 3h, 15b 5a,6a
intermediate VII is formed by the trapping of IV with BuO radical or if
5b,6d 5c,6d 5d,6d 5e, 5f, 5g,6d 5h,6d 5i, 5j,6d 5k,6d 5l,6d and 5m,6d were ob-
tained by this preparation method. Compounds 7a, 7b, 7c, and 7d−f,6d
were prepared by literature procedures. 6a Compound 97e was prepared by
literature procedures.
elimination of CuXL form VII is rapid, an amidoyl radical VIII is formed
(Path B). The subsequent 1,5-hydrogen shift followed by the reaction with
CuX2L affords Cu (III) intermediate X giving rise to the product 2a. The
Scheme 5. Proposed Catalytic Pathways
N-(3-(tert-Butyl)-3',5'-difluoro-[1,1'-biphenyl]-4-yl)pivalamide
(1g).
Following the procedure for the synthesis of 1e,6a the amide was obtained
1.187 g, in 86% yield in the form of white solid. Melt point:159-161 °C.
1H NMR (400 MHz, DMSO-d6): 8.85 (s, 1H), 7.63 (s, 1H), 7.57 (d, J = 8.0
Hz, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.23 (t, J = 9.3 Hz, 1H), 7.06 (d, J = 8.1
Hz, 1H), 1.37 (s, 9H), 1.27 (s, 9H); 13C{1H} NMR (101 MHz, DMSO-d6):
177.7, 164.6 (d, J = 10.1 Hz), 162.1 (d, J = 20.2 Hz), 148.0, 144.5, 138.2,
136.5, 133.0, 125.6 (d, J = 40.4 Hz), 110.4 (d, J = 30.3 Hz), 103.0, 39.0,
35.5, 31.1, 27.7; 19F NMR (376 MHz, DMSO-d6): -109.4; HRMS (EI) m/z
calculated for C21H25F2NO (M)+: 345.1904; Found: 345.1901.
N-(2-(tert-Butyl)-4-(naphthalen-1 ylthio)phenyl)acetamide (1h). Fol-
lowing the procedure for the synthesis of 1e,6a the amide was obtained
1.229 g, in 88% yield in the form of brown oil. 1H NMR (400 MHz,
DMSO-d6): 9.23 (s, 1H), 7.98 (s, 1H), 7.95 − 7.87 (m, 3H), 7.55 − 7.53 (m,
2H), 7.44 − 7.38 (m, 2H), 7.14 − 7.11 (m, 1H), 7.06 − 7.04 (m, 1H), 2.04
(s, 3H), 1.27 (s, 9H); 13C{1H}NMR (100 MHz, DMSO-d6): 169.7, 148.0,
135.8, 133.9, 133.6, 133.4, 132.4, 132.3, 130.3, 129.6, 129.0, 128.7, 128.4,
128.2, 127.9, 127.4, 127.1, 35.3, 30.9, 23.6; HRMS (EI) m/z calculated for
C22H23NOS (M)+: 349.1500; Found: 349.1499.
DFT calculations at b3pw91 level of theory showed that the 1,5-hydrogen
shift from VIII to IX is exothermic by 5.3 kcal/mol with an activation
energy of 23.2 kcal/mol, suggesting that this Path B is also possible. The
result that only a trace amount of bibenzyl was detected in the reaction
N-(2-(tert-Butyl)phenyl)-2,6-difluorobenzamide(5e). Following the
procedure for the synthesis of 1a,6a the amide was obtained 0.937 g, in
81% yield in the form of white solid. Melt point: 162-163 °C. 1H NMR
(400 MHz, DMSO-d6): 10.20 (s, 1H), 7.61 – 7.51 (m, 1H), 7.48 – 7.42 (m,
1H), 7.33 – 7.27 (m, 2H), 7.26 – 7.21 (m, 2H), 7.13 – 7.08 (m, 1H), 1.37 (s,
9H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.2 (d, J = 7.1 Hz), 159.2,
158.7 (d, J = 7.1 Hz), 143.7, 134.3, 131.9 (t, J = 10.2 Hz), 128.6, 127.0 (d,
J = 7.1 Hz), 126.7, 114.8 (t, J = 20.2 Hz), 112.1(d, J = 25.3 Hz), 34.6,
30.6.; 19F NMR (376 MHz, DMSO-d6): -114.1; HRMS (EI) m/z calculated
for C17H17F2NO (M)+: 289.1278; Found: 289.1275.
t
mixture, although H abstraction from toluene by BuO radical is 4.8 times
t
t
faster at 25 °C than that from BuPh,15b indicates that free BuO radical is
not generated in the reaction mixture or, if generated, it is quickly trapped
by Cu-species. Therefore, Path B via a 1,5-hydrogen shift seems to be
more plausible,7e C(sp3)−H is more easily to generate free radical than
C(sp2)−H, all of this indicate the the origin of selectivity C(sp2)−H vs
C(sp3)−H.
N-(2-(tert-Butyl)phenyl)-4-fluoro-2-(trifluoromethyl)benzamide(5f).
1.207 g, in 89% yield White solid. Melt point: 171-173 °C.H NMR (400
MHz, DMSO-d6): 10.03 (s, 1H), 7.83 − 7.80 (m, 1H), 7.75 − 7.73 (m, 2H),
CONCLUSIONS
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7.47 − 7.45 (m, 1H), 7.30 − 7.28 (m, 2H), 7.14 − 7.12 (m, 1H), 1.40(s, 9H);
3H), 2.15 (s, 3H), 1.22 (s, 6H); 13C{1H}NMR (100 MHz, DMSO-d6):
144.1, 141.1, 129.6, 125.6, 119.4, 64.6, 41.6, 26.3, 20.6, C (carbonyl) is
missing; MS (EI): m/z = 203.1 [M+H]+.
13C{1H} NMR (101 MHz, CDCl3) δ 165.0, 162.8 (d, J = 253.5 Hz) 143.1,
134.5, 132.5, 130.6(d, J = 8.1 Hz), 127.9, 127.0 (d, J = 13.1 Hz), 126.7,
121.4(q, J = 3.0 Hz), 119.3 (d, J = 19.2 Hz), 114.7(d, J = 6.1 Hz), 114.4(d,
J = 5.1 Hz), 34.6, 30.7; 19F NMR (376 MHz, DMSO-d6): -57.9, -109.57;
HRMS (EI) m/z calculated for C18H17F4NO (M)+: 339.1246; Found:
339.1245.
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3
4
5
6
7
8
1-(5-Bromo-3,3-dimethylindolin-1-yl)ethanone (2c) 6a. Brown oil was
obtained in 80% yield for 1 h, 53.4 mg. Rf = 0.38 (PE/EA= 3:1). 1H NMR
(400 MHz, DMSO-d6): 7.96 (d, J = 7.6 Hz, 1H), 7.43 (s, 1H), 7.31 (dd, J
= 8.4 Hz, 2.0 Hz, 1H), 3.85 (s, 2H), 2.15 (s, 3H), 1.30 (s, 6H);
13C{1H}NMR (100 MHz, DMSO-d6): 169.3, 144.1, 141.3, 130.4, 125.8,
117.9, 115.3, 63.0, 40.4, 28.6, 24.3; MS (EI): m/z =267.0 [M+H]+.
2-bromo-N-(2-(tert-Butyl)phenyl)-5-methoxybenzamide(5i). 1.329 g in
92% yield, White solid. Melt point: 121-123 °C. 1H NMR (400 MHz,
DMSO-d6): 9.85 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 4.8 Hz, 1H),
7.27 (dd, J = 6.0, 3.5 Hz, 3H), 7.02 (d, J = 7.4 Hz, 2H), 3.82 (s, 3H), 1.38
(s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6): 167.2, 158.9, 147.4, 140.4,
136.1, 134.3, 132.1, 127.8, 127.2, 127.0, 116.8, 114.7, 109.8, 56.1, 35.4,
31.4; MS (EI): m/z = 361.1 [M+H]+. This compound has been previously
reported, CAS: 903791-84-4.
6a
1-(6-(tert-Butyl)-3,3-dimethylindolin-1-yl)ethanone (2d)
. Yellow
solid was obtained in 85% yield for 1 h, 52.1 mg.Rf = 0.40 (PE/EA= 3:1).
Melt point: 98-99 °C. 1H NMR (400 MHz, DMSO-d6): 8.15 (s, 1H), 7.14
(d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 3.84 (s, 2H), 2.14 (s, 3H),
1.26 (s, 6H), 1.25 (s, 9H); 13C{1H}NMR (100 MHz, DMSO-d6): 169.0,
150.3, 142.1, 138.5, 122.0, 120.7, 113.4, 63.4, 34.9, 31.8, 28.9, 24.6; MS
(EI): m/z = 245.2 [M+H]+.
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N-(3-(tert-Butyl)-biphenyl-2-yl)pivalamide (7a). Following the proce-
dure described by F. Glorius 6a: To a screw capped vial equipped with a
magnetic stir bar was added 3a (233.0 mg, 1.0 mmol, 1.0 equiv), AgOAc
(367 mg, 2.2 mmol, 1.1 equiv) and Pd(OAc)2 (4.5 mg, 0.02 mmol, 2
mol%), previously dried in vacuo and filled with nitrogen. After adding
trifluoroacetic acid (1.0 mL) and iodobenzene (0.3 mL, 2.7 mmol, 2.7
equiv) under a stream of nitrogen, the reaction was conducted with stirring
at 100 °C for 24 h. The mixture was concentrated using a rotary evaporator.
The crude product was purified by flash column chromatography (silica,
PE/EA). We obtained the amide 0.235 g, in 76% yield, in the form of a
white solid. Melt point: 121-123 °C. 1H NMR (400 MHz, DMSO-d6): 8.61
(s, 1H), 7.41 − 7.35(m, 1H), 7.30 − 7.26 (m, 6H), 7.09 − 7.07 (m, 1H),
1.34 (s, 9H), 0.82 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6): 176.3,
148.5, 144.3, 141.1, 135.1, 131.2, 129.8, 128.7, 128.1, 127.7, 127.3, 126.9,
126.4, 38.6, 35.7, 31.6, 27.3; HRMS (EI) m/z calculated for C21H27NO
(M)+: 309.2093; Found: 309.2091.
1-(3,3-Dimethyl-5-phenylindolin-1-yl)ethanone (2e) 6a. Yellow solid
was obtained in 78% yield for 1 h, Rf = 0.23 (PE/EA=3:1). Melt point:
126-128 °C. 1H NMR (400 MHz, DMSO-d6): 8.08 (d, J = 8.4 Hz, 1H),
7.65 (d, J = 7.6 Hz, 2H), 7.55 (s, 1H), 7.48 – 7.42 (m, 3H), 7.32 (d, J = 6.4
Hz, 1H), 3.89 (s, 2H), 2.18 (s, 3H), 1.36 (s, 6H); 13C{1H}NMR (100 MHz,
DMSO-d6): 169.1, 142.2, 141.5, 140.6, 135.9, 129.3, 127.4, 126.8, 126.2,
121.0, 116.5, 63.3, 28.9, 24.4(one of the carbon was lost due to overlap
with DMSO); MS (EI): m/z = 265.1 [M+H]+.
1-(3,3-Dimethyl-5-(pyridin-4-yl)indolin-1-yl)ethanone (2f) 6d. Yellow
solid was obtained in 68% yield for 24 h, 45.2 mg. Rf = 0.42 (PE/EA= 0:1).
1
Melt point: 148-150 °C. H NMR (400 MHz, DMSO-d6): 8.60 – 8.59 (m,
2H), 8.12 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J = 5.2 Hz, 2H), 7.66
(d, J = 8.3 Hz, 1H), 3.92 (s, 2H), 2.19 (s, 3H), 1.37 (m, 6H). 13C{1H}
NMR (100 MHz, DMSO-d6): 169.5, 150.6, 147.2, 143.1, 142.5, 132.5,
126.6, 121.2, 116.5, 63.3, 40.3, 28.9, 24.5(one of the carbon was lost due
to overlap with DMSO); MS (EI): m/z = 266.1 [M+H]+.
N-(3-(tert-Butyl)-4'-methoxy-biphenyl-2-yl)pivalamide (7b). Following
the procedure for the synthesis of 7a,6a the amide was obtained in the form
of white solid 0.285 g, in 84%. Melt point: 193-195 °C. 1H NMR (400
MHz, DMSO-d6): 8.59 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz,
3H), 7.06 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H), 1.34
(s, 9H), 0.87 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-d6): 176.3, 158.5,
148.5, 143.9, 135.3, 133.4, 130.7, 128.9, 127.2, 126.1, 113.2, 55.6. 38.6,
35.7, 31.6, 27.4; HRMS (EI) m/z calculated for C22H29NO2 (M)+: 339.2198;
Found: 339.2197.
1-(5-(3,5-Difluorophenyl)-3,3-dimethylindolin-1-yl)-2,2-
dimethylpropan-1-one (2g). Yellow solid was obtained in 57% yield for
1
1 h, 48.9 mg. Rf = 0.45 (PE/EA= 10:1). Melt point: 159-161 °C. H NMR
(400 MHz, DMSO-d6): 8.12 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H), 7.57 (d, J =
8.5 Hz, 1H), 7.46 – 7.44 (m, 2H), 7.15 (t, J = 9.2 Hz, 1H), 4.04 (s, 2H),
1.35 (s, 6H), 1.31 (s, 9H); 13C{1H}NMR (101 MHz, DMSO-d6): 176.3,
164.6 (d, J = 14.1 Hz), 162.1 (d, J = 14.1 Hz), 144.2, 142.0, 133.3, 128.9
(d, J = 68.7 Hz), 126.3, 118.3, 109.7 (d, J = 26.3 Hz), 102.3 (d, J = 25.3
Hz), 63.8, 41.1, 28.2, 27.7, 27.2.; 19F NMR (376 MHz, DMSO-d6): -109.7;
HRMS (EI) m/z calculated for C21H23 F2NO (M)+: 343.1748; Found:
343.1746.
N-(3-(tert-Butyl)-4'-methyl-biphenyl-2-yl)pivalamide (7c). Following
the procedure for the synthesis of 7a,6a the amide was obtained 0.246 g, in
1
76% yield, in the form of white solid. Melt point: 181-183 °C. H NMR
(400 MHz, DMSO-d6): 8.57 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.26 (t, J =
7.8 Hz, 1H), 7.20 (d, J = 7.7 Hz, 2H), 7.12 (d, J = 7.7 Hz, 2H), 7.05 (d, J =
7.4 Hz, 1H), 2.30 (s, 3H), 1.33 (s, 9H), 0.83 (s, 9H); 13C{1H} NMR (100
MHz, DMSO-d6): 176.3, 148.5, 144.2, 138.2, 135.9, 135.2, 129.7, 128.8,
128.2, 127.3, 126.2, 38.6, 35.7, 31.6, 27.4, 21.2; HRMS (EI) m/z calculat-
ed for C22H29NO (M)+: 323.2247; Found: 323.2244.
1-(3,3-Dimethyl-5-(naphthalen-1-ylthio)indolin-1-yl)ethanone (2h).
Brown oil was obtained in 61% yield for 1 h, 52.9 mg. Rf = 0.40 (PE/EA=
1:1). 1H NMR (400 MHz, DMSO-d6): 8.06 (d, J = 8.4 Hz, 1H), 7.89 –
7.85 (m, 2H), 7.80 – 7.78 (m, 1H), 7.71 (s, 1H), 7.52 – 7.47 (m, 2H), 7.40
(s, 1H), 7.32 – 7.27 (m, 2H), 3.90 (s, 2H), 2.18 (s, 3H), 1.30 (s, 6H);
13C{1H}NMR (100 MHz, DMSO-d6): 169.5, 143.2, 142.4, 135.2, 133.8,
133.0, 131.9, 129.3, 128.1, 127.6, 127.5, 127.3, 126.9, 126.8, 126.5, 117.2,
63.1, 28.7, 24.4 (one of the carbon was lost due to overlap with DMSO);
HRMS (EI) m/z calculated for C22H21NOS (M)+: 347.1344; Found:
347.1342.
General Procedure for the Synthesis of Indolines. To a screw capped
vial equipped with a magnetic stir bar was added substrate (1a – 1i, 3a – 3i,
5a – 5m, 7a – 7f) (0.25 mmol, 1.0 equiv), CuBr (25 mol%), N-
methylimidazole (2.0 equiv.), and DTBP (3.0 equiv.) in p-Cl-toluene (1
mL). The reaction was allowed to proceed at 130 °C by oil bath for 1-24 h.
Upon completion, the mixture was cooled down to room temperature, and
the solvent was removed under reduced pressure. The residue was purified
by means of silica gel chromatography using PE/EA to afford the target
compound.
6a
3,3-Dimethyl-5-(p-tolylthio)indolin-1-yl)(phenyl)methanone (2i)
.
Brown oil was obtained 70.0 mg in 90% yield for 24 h, Rf = 0.42 (PE/EA=
1
1:1 ). H NMR (400 MHz, DMSO-d6): 8.01 (d, J = 8.0 Hz, 1H), 7.30 (s,
1H), 7.19 – 7.12 (m, 5H), 3.88 (s, 2H), 2.27 (s, 3H), 2.16 (s, 3H), 1.29 (s,
6H); 13C{1H} NMR (100 MHz, DMSO-d6): 169.3, 143.0, 142.0, 136.6,
133.6, 132.2, 130.5, 129.0, 128.7, 128.1, 126.8, 117.0, 63.1, 28.7, 24.4,
21.0 (one of the carbon was lost due to overlap with DMSO); MS (EI): m/z
= 311.1 [M+H]+.
1-(3,3-dimethylindolin-1-yl)ethan-1-one (2a)6a. Yellow solid was ob-
tained in 97% yield for 24 h, 45.8 mg. Rf = 0.40 (PE/EA= 2:1). Melt point:
96-98 °C. 1H NMR (400 MHz, DMSO-d6): 8.03 (d, J = 8.0 Hz, 1H), 7.23
(d, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.2 Hz, 1H), 3.84
(s, 2H), 2.16 (s, 3H), 1.30 (s, 6H); 13C{1H}NMR (100 MHz, DMSO-d6):
169.1, 142.0, 141.2, 127.6, 123.8, 122.7, 116.2, 62.9, 40.1, 28.9, 24.5; MS
(EI): m/z = 189.1 [M+H]+.
1-(3,3-Dimethylindolin-1-yl)-2,2-dimethylpropan-1-one (4a) 7e. Yel-
low solid was obtained 47.6 mg, in 83% yield for 24 h, Rf = 0.50 (PE/EA=
1
5:1). Melt point: 87-89 °C. H NMR (400 MHz, CDCl3): 8.20 (d, J = 8.1
1-(3,3,7-Trimethylindolin-1-yl)ethanone (2b)6d. Brown oil was ob-
Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.3
Hz, 1H), 3.95 (s, 2H), 1.37 (s, 9H), 1.33 (s, 6H); 13C{1H} NMR (100 MHz,
CDCl3): 176.5, 143.4, 140.0, 127.6, 124.0, 121.4, 118.5, 63.9, 40.9, 40.1,
27.7, 27.3; MS (EI): m/z = 231.1 [M+H]+.
1
tained 39.6 mg, in 78% yield for 1 h, 39.6 mg. Rf =0.23 (PE/EA=5:1). H
NMR (400 MHz, DMSO-d6): 7.06 – 7.01 (m, 3H), 3.78 (s, 2H), 2.20 (s,
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Page 6 of 9
1-(3,3-Dimethylindolin-1-yl)hexan-1-one (4b) 6d. Yellow brown oil
was obtained 46.0 mg ,in 75% yield for 1 h, Rf = 0.51 (PE/EA= 5:1). H
(PE/EA=3:1). Melt point: 79-80 °C. Rotational isomers may exist (ratio is
1
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about 1: 4.5). H NMR (400 MHz, DMSO-d6): 8.11 (d, J = 8.0 Hz, 1H),
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5
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NMR (400 MHz, DMSO-d6): 8.06 (d, J = 7.6 Hz, 1H), 7.23 – 7.16 (m,
1H), 7.15 – 7.13 (m, 1H), 7.02 – 6.99 (m, 1H), 3.83 (s, 2H), 2.44 – 2.41 (m,
2H), 1.60 – 1.54 (m, 2H) 1.33 – 1.31 (m, 4H), 1.29 (s, 6H), 0.88 (t, J = 6.6
Hz, 3H); 13C{1H}NMR (100 MHz, DMSO-d6): 171.3, 142.1, 141.2, 127.6,
123.7, 122.6, 116.3, 62.2, 40.1, 35.4, 31.4, 31.1, 28.8, 24.2, 22.5, 14.3; MS
(EI): m/z = 245.1 [M+H]+.
7.87 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 7.4 Hz, 1H), 7.71 (t, J = 7.4 Hz, 2H),
7.31 – 7.25 (m, 2H), 7.16 – 7.12 (m, 1H), 3.58 (s, 2H), 1.22 (s, 6H);
13C{1H} NMR (100 MHz, DMSO-d6): 165.8, 142.1, 142.0, 135.8, 133.7,
130.4, 127.9, 127.8, 127.2, 127.1, 125.2, 122.9, 116.9, 64.3, 40.5, 38.9
28.4, 28.0; 19F NMR (376 MHz, DMSO-d6): -58.8; MS (EI): m/z = 319.1
[M+H]+.
1-(3,3-Dimethylindolin-1-yl)heptan-1-one (4c) 6d. Yellow oil was ob-
(3,3-Dimethylindolin-1-yl)(2-nitrophenyl)methanone (6d) 6d. Yellow
solid was obtained 60.0 mg in 81% yield for 24 h, Rf = 0.41 (PE/EA=5:1).
Rotational isomers may exist (ratio is about 1: 5.7). Melt point: 126-128
°C. 1H NMR (400 MHz, DMSO-d6): 8.26 (d, J = 8.0 Hz, 1H), 8.07 (d, J =
8.0 Hz, 1H), 7.93 (t, J = 7.6 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.33 – 7.26
(m, 2H), 7.15 (t, J = 7.4 Hz, 1H), 3.56 (s, 2H), 1.26 (s, 6H); 13C{1H} NMR
(100 MHz, DMSO-d6): 164.8, 145.2, 142.1, 141.2, 135.7, 133.1, 131.2,
128.6, 127.9, 125.3, 125.2, 123.0, 116.8, 63.9, 40.6, 28.1; MS (EI): m/z =
296.1 [M+H]+. This compound has been previously reported.
1
tained 59.7 mg, in 86% yield for 1 h, Rf = 0.60 (PE/EA= 5:1). H NMR
(400 MHz, DMSO-d6): 8.06 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H),
7.15 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.4 Hz, 1H), 3.83 (s, 2H), 2.43 (t, J =
7.3 Hz, 2H), 1.56 (m, 2H), 1.31 (m, 12H), 0.88 (t, J = 6.7 Hz, 3H).
13C{1H} NMR (100 MHz, DMSO-d6): 171.5, 142.1, 141.2, 127.6, 123.7,
122.6, 116.3, 62.2, 35.4, 31.6, 28.8, 28.8, 24.5, 22.5, 14.4; MS (EI): m/z =
259.2 [M+H]+.
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1-(3,3-dimethylindolin-1-yl)butan-1-one (4d) 6d. Yellow oil was ob-
tained 45.6 mg, in 84% yield for 1 h, Rf = 0.45 (PE/EA=5:1). 1H NMR
(400 MHz, DMSO-d6): 7.99 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 7.2 Hz, 1H),
7.08 (t, J = 7.2 Hz, 1H), 6.94 (t, J = 7.2 Hz, 1H), 3.76 (s, 2H), 2.35 (t, J =
7.2 Hz, 2H), 1.56 – 1.51 (m, 2H), 1.22 (s, 6H), 0.87 (t, J = 7.2 Hz, 3H);
13C{1H}NMR (100 MHz, DMSO-d6): 171.3, 142.1, 141.2, 127.6, 123.7,
122.6, 116.3, 62.2, 37.3, 28.8, 18.0, 14.2 (one of the carbon was lost due to
overlap with DMSO); HRMS (EI) m/z calculated for C14H19NO (M)+:
217.1467; Found: 217.1465. This compound has been previously reported.
(2,6-Difluorophenyl)(3,3-dimethylindolin-1-yl)methanone (6e). Yel-
low solid was obtained 60.3 mg, in 84% yield for 1 h, Rf = 0.50
(PE/EA=3:1). Melt point: 144-146 °C. Rotational isomers may exist (ratio
is about 1: 5.0). 1H NMR (400 MHz, DMSO-d6): 8.11 (d, J = 8.0 Hz, 1H),
7.65 – 7.61 (m, 1H), 7.34 – 7.27 (m, 4H), 7.18 (t, J = 7.4 Hz, 1H), 3.61 (s,
2H), 1.26 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6): 158.8, 142.3, 140,
132.89, 128.0, 125.7, 123.1, 116.9, 113.0, 112.8, 63.1, 40.4, 27.8, 27.6; 19
F
NMR (376 MHz, DMSO-d6): -114.7; HRMS (EI) m/z calculated for
C17H15F2NO (M)+: 287.1122; Found: 287.1121.
Cyclohexyl(3,3-dimethylindolin-1-yl)methanone (4e). Brown oil was
1
obtained 46.3 mg, in 72% yield for 1 h, Rf = 0.60(PE/EA=3:1). H NMR
(3,3-Dimethylindolin-1-yl)(4-fluoro-2 (trifluoromethyl) phenyl)
methanone (6f). Yellow oil was obtained 71.6 mg, in 85% yield for 1 h,
Rf = 0.50 (PE/EA=3:1). Rotational isomers may exist ( ratio is about 1:
5.6). 1H NMR (400 MHz, DMSO-d6): 8.10 (d, J=8.0, 1H), 7.82 (dd, J =9.1,
3.5, 2H), 7.72 – 7.67 (m, 1H), 7.32 – 7.26 (m, 2H), 7.15 (t, J =7.4, 1H),
3.59 (s, 2H), 1.23 (s, 6H); 13C NMR (100 MHz, DMSO-d6): 13C{1H} NMR
(101 MHz, DMSO) 164.9, 142.1, 141.1, 130.8, 130.8, 127.9, 125.3, 122.9,
120.9, 120.6, 117.0, 64.4, 40.6, 28.4, 27.9; 19F NMR (376 MHz, DMSO-
d6): -59.1, -109.4; HRMS (EI) m/z calculated for C18H15F4NO (M)+:
337.1090; Found: 337.1091.
(400 MHz, DMSO-d6): 8.08 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H),
7.15 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 3.90 (s, 2H), 1.77 (t, J =
13.2 Hz, 4H), 1.67 (d, J = 12.6 Hz, 1H), 1.41 (dd, J = 23.2, 11.1 Hz, 3H),
1.33 (d, J = 1.8 Hz, 1H), 1.29 (s, 6H), 1.21 (dd, J = 15.0, 9.7 Hz, 2H);
13C{1H} NMR (100 MHz, DMSO-d6): 174.4, 142.2, 141.4, 127.6, 122.5,
116.7, 62.1, 40.6, 29.2, 28.5, 26.0, 25.6; HRMS (EI) m/z calculated for
C17H23NO (M)+: 257.1780; Found: 257.1781.
6d
(E)-1-(3,3-Dimethylindolin-1-yl)-3-phenylprop-2-en-1-one (4g)
.
Yellow oil was obtained 48.5 mg, in 70% yield for 1 h, Rf = 0.41 (PE/EA=
5:1). 1H NMR (400 MHz, DMSO-d6): 8.20 (d, J = 7.1 Hz, 1H), 7.79 –
7.77(m, 2H), 7.66 (d, J = 14.4 Hz, 1H), 7.45 – 7.43 (m, 3H), 7.27 (d, J =
7.6 Hz, 1H), 7.23 – 7.19 (m, 2H), 7.09 – 7.05 (m, 1H), 4.13 (s, 2H), 1.33 (s,
6H); 13C{1H} NMR (100 MHz, DMSO-d6): 164.1, 142.6, 135.4, 130.4,
129.3, 128.7, 127.8, 124.3, 122.7, 120.6, 116.9, 62.4, 28.8 (one of the
carbon was lost due to overlap with DMSO); MS (EI): m/z = 277.1
[M+H]+. This compound has been previously reported.
Phenyl(3,3,7-trimethylindolin-1-yl)methanone (6g) 6d. Yellow solid
was obtained 61.0mg, in 92% yield for 1 h, Rf = 0.50 (PE/EA=3:1). Melt
point: 116-118 °C. 1H NMR (400 MHz, DMSO-d6): 7.74 – 7.72 (m, 2H),
7.60 – 7.57 (m, 1H), 7.54 – 7.50 (m, 2H), 7.11 – 7.05 (m, 3H), 3.77 (s, 2H),
2.17 (s, 3H), 1.17 (s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6): 169.5,
144.1, 141.3, 136.2, 129.1, 128.9, 128.6, 125.9, 119.6, 67.4, 42.2, 26.2,
20.1; MS (EI): m/z = 265.1 [M+H]+.
(E)-1-(3,3-Dimethylindolin-1-yl)but-2-en-1-one (4h) 6d. Yellow solid
was obtained 35.5 mg, in 66% yield for 1 h, Rf = 0.50 (PE/EA=3:1). Melt
point: 107-109 °C. 1H NMR (400 MHz, DMSO-d6): 8.09 (s, 1H), 7.23(m,
1H), 7.15 (m, 1H), 7.05 – 7.01 (m, 1H), 6.90 – 6.82 (m, 1H), 6.45 – 6.41
(m, 1H), 3.92 (s, 2H), 1.91 – 1.89 (m, 3H); 1.28 (s, 6H) 13C{1H} NMR
(100 MHz, DMSO-d6): 164.0, 142.6, 127.7, 124.4, 124.1, 122.7, 116.8,
62.4, 28.7, 18.3 (one of the carbon was lost due to overlap with DMSO);
MS (EI): m/z = 215.1 [M+H]+.
6d
(6-(tert-Butyl)-3,3-dimethylindolin-1-yl)(phenyl)methanone (6h)
.
brown oil was obtained 67.6 mg, in 88% yield for 1 h, Rf = 0.51
(PE/EA=3:1). 1H NMR (400 MHz, DMSO-d6): 7.57 – 7.52 (m, 5H), 7.18 –
7.11 (m, 2H), 3.76 (s, 2H), 1.25 (m, 15H); 13C{1H}NMR (100 MHz,
DMSO-d6): 168.3, 150.1, 141.8, 139.4, 137.5, 130.5, 129.1, 127.3, 122.2,
121.5, 114.4, 65.4, 40.2, 34.9, 31.7, 28.0; MS (EI): m/z = 307.1 [M+H]+.
(2-Bromo-5-methoxyphenyl)(3,3-dimethylindolin-1-yl)methanone
(6i). yellow oil was obtained 79.0 mg, in 88% yield for 24 h, Rf =0.40
(PE/EA=3:1). Rotational isomers may exist (ratio is about 1: 4.7). 1H
NMR (400 MHz, DMSO-d6): 8.18 – 8.16 (m, 1H), 7.65 – 7.63 (m, 1H),
7.35 – 7.28 (m, 2H), 7.19 – 7.17 (m, 2H), 7.05 – 6.99 (m, 1H), 3.83 – 3.57
(m, 5H), 1.30 (s, 6H); 13C{1H}NMR (100 MHz, DMSO-d6): 165.8, 159.5,
142.1, 141.1, 140.1, 134.0, 127.8, 125.1, 123.0, 117.4, 116.8, 113.6, 108.3,
63.7, 56.2, 40.3, 29.1; HRMS (EI) m/z calculated for C18H18BrNO2 (M)+:
359.0521; Found: 359.0524.
(3,3-Dimethylindolin-1-yl)(phenyl)methanone (6a) 7e. Yellow solid
was obtained 32.6 mg in 52% yield for 1 h, Rf = 0.50 (PE/EA= 3:1). Melt
point: 108-110 °C. 1H NMR (300 MHz, DMSO-d6): 7.60 – 7.49 (m, 6H),
7.28 (d, J = 7.6 Hz, 1H), 7.19 (s, 1H), 7.09 – 7.07 (m, 1H), 3.77 (s, 2H),
1.26 (s, 6H); 13C{1H}NMR (75 MHz, DMSO-d6): 168.4, 142.2, 141.7,
137.3, 130.7, 129.0, 127.5, 127.4, 124.6, 122.8, 117.1, 64.9, 27.9 (one of
the carbon was lost due to overlap with DMSO); MS (EI): m/z = 251.1
[M+H]+.
6d
[1,1'-Biphenyl]-4-yl(3,3-dimethylindolin-1-yl)methanone(6j)
.
(3,3-Dimethylindolin-1-yl)(o-tolyl)methanone (6b) 6d. Yellow oil was
Brown yellow oil was obtained 55.6 mg, in 68% yield for 1 h, Rf = 0.33
(PE/EA=10:1). 1H NMR (400 MHz, DMSO-d6): 7.78 (d, J = 8.4 Hz, 2H),
7.74 – 7.69 (m, 4H), 7.52 – 7.43 (m, 2H), 7.43 – 7.39 (m, 1H), 7.29 – 7.27
(m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 7.10 – 7.07 (m, 1H), 3.83 (s, 2H), 1.25
(s, 6H); 13C{1H} NMR (100 MHz, DMSO-d6): 168.2, 142.4, 142.2, 141.7,
139.7, 136.9, 136.1, 131.2, 130.4, 129.5, 128.5, 128.4, 128.3, 127.6, 127.3,
127.2, 124.7, 122.8, 64.8, 40.4, 27.9; MS (EI): m/z = 327.1 [M+H]+.
obtained 23.2 mg, in 35% yield for 1 h, Rf = 0.45 (PE/EA=3:1). Rotation-
1
al isomers may exist (ratio is about 1: 2.6). H NMR (400 MHz, DMSO-
d6): 8.15 (d, J = 7.6 Hz, 1H), 7.34 – 7.28 (m, 6H), 7.14 – 7.10 (m, 1H),
3.44 (s, 2H), 2.27 (s, 3H), 1.23 (s, 6H); 13C{1H}NMR (100 MHz, DMSO-
d6): 168.6, 142.1, 141.4, 137.9, 133.5, 130.8, 128.5, 127.7, 125.9, 124.9,
122.8, 116.9, 64.0, 28.0, 18.8; MS (EI): m/z = 265.1 [M+H]+.
(3,3-Dimethylindolin-1-yl)(naphthalen-1-yl)methanone (6k) 6d. yellow
solid was obtained 46.7 mg, in 62% yield for 1 h, Rf = 0.50 (PE/EA= 5:1).
(3,3-Dimethylindolin-1-yl)(2-trifluoromethylphenyl)methanone (6c)
6d. Yellow solid was obtained 63.8 mg, in 80% yield for 1 h, Rf = 0. 45
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Rotational isomers may exist (ratio is about 1: 5.3). Melt point: 146-148
°C. H NMR (400 MHz, DMSO-d6): 8.31 – 8.29 (m, 1H), 8.07 – 8.06 (m,
2H), 7.90 – 7.80 (m, 1H), 7.67 – 7.59 (m, 4H), 7.35 – 7.30 (m, 2H), 7.19 –
7.15 (m, 1H), 3.44 (s, 2H), 1.42 (s, 1H), 1.21 (s, 5H). 13C{1H} NMR (100
MHz, DMSO-d6): 167.9, 142.2, 141.4, 135.5, 133.6, 129.7, 129.0, 127.9,
127.1, 126.0, 125.1, 124.7, 124.3, 122.9, 117.2, 64.1, 40.3, 27.9; MS (EI):
m/z = 301.1 [M+H]+.
72% yield for 1 h, Rf = 0.40 (PE/EA= 10:1). Melt point: 121-123°C. H
NMR (400 MHz, CDCl3): 7.64 – 7.57 (m, 4H), 7.50 (d, J = 7.8 Hz, 2H),
7.42 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.3 Hz, 1H), 7.26 (t, J = 7.5 Hz, 1H),
7.20 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 3.92 (s, 2H), 1.33 (s, 6H),
1.18 (d, J = 9.7 Hz, 9H). 13C{1H} NMR (101 MHz, CDCl3): 177.4, 143.7,
141.2, 141.0, 140.5, 139.4, 132.8, 128.7, 128.6, 127.1, 127.1, 125.4, 120.5,
64.5, 42.8, 39.7, 28.1, 26.3 (two carbons was lost due to overlap). MS (EI):
m/z = 383.2 [M+H]+.
1
1
2
3
4
5
6
7
8
(3,3-Dimethylindolin-1-yl) (thiophen-2-yl)methanone (6l) 6d. yellow
oil was obtained 51.2 mg, in 68% yield for 24 h, Rf = 0. 40 (PE/EA=5:1).
1H NMR (400 MHz, DMSO-d6): 7.99 (d, J = 7.9 Hz, 1H), 7.87 (dd, J = 5.0,
0.9 Hz, 1H), 7.76 (dd, J = 3.8, 0.9 Hz, 1H), 7.30 (dd, J = 7.4, 0.8 Hz, 1H),
7.22 (m, 2H), 7.10 (td, J = 7.4, 1.0 Hz, 1H), 4.17 (s, 2H), 1.31 (s, 6H);
13C{1H} NMR (100 MHz, DMSO-d6): 161.0, 142.1, 141.9, 139.9, 131.0,
130.7, 128.3, 127.7, 124.8, 122.8, 117.4, 64.7, 40.9, 28.4; MS (EI): m/z =
257.0 [M+H]+.
7e
1-(2,3,3-Trimethylindolin-1-yl)ethan-1-one (10a)
methylindolin-1-yl)ethan-1-one (10b)
and 1-(3-ethyl-3-
.
1H NMR (400 MHz, DMSO-
7e
d6): 7.94 (s, 1H), 7.23 – 7.09 (m, 2H), 7.02 (t, J = 7.4 Hz, 1H), 4.14 (s,
1H), 3.92 (d, J = 10.5 Hz, 0.06H), 3.77 – 3.70 (m, 0.06H), 2.23 (s, 3H),
1.28 (s, 3H), 1.12 (s, 3H), 1.06 (d, J = 5.5 Hz, 3H), 0.74 (d, J = 7.4 Hz,
0.22H).
9
10
11
12
13
14
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16
17
18
19
20
21
22
23
24
25
26
27
28
29
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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
General procedure for radical experiment To a screw capped vial
equipped with a magnetic stir bar was added substrate 1a (0.25 mmol, 1.0
equiv), CuBr (25 mol%), N-methylimidazole (2.0 equiv), DTBP (3.0
equiv) , and radical inhibitor (4 equiv) in p-Cl-toluene (1.0 mL) at 130 °C
for 24 h.
1-(3,3-Dimethyl-7-phenylindolin-1-yl)-2,2-dimethylpropan-1-one
(8a). yellow oil was obtained 56.8 mg, in 74% yield for 1 h, Rf = 0.40
(PE/EA= 10:1). The structure of compound 8a was definitively confirmed
by single crystal X-ray diffraction of crystals obtained from petroleum
ether and dichloromethane (CCDC 1949686). Crystal data: Bond preci-
sion: C–C = 0.0019 A, Wavelength= 0.71073; a = 18.3228(9), b =
9.5884(5), c = 19.9324(10); α = 90, β = 92.554(5), γ = 90; Temperature,
100 K; Volume, 3498.4(3); Space group, C2/c; Hall group, -C 2yc; Sum
formula, C21 H25 N O; Mr,307.42; Dx, 1.167 g·cm–3,; Z: 8; Mu, 0.071
General procedure for control experiment of NMR detection Mix
DTBP (12 μL, 1 equiv), NMI (6 μL, 1.0 equiv.) and p-Cl-toluene (8.0 μL,
1.0 equiv.) with C6D6 (0.5 mL) in a 5 mm high pressure valved NMR
sample tube under nitrogen atmosphere and proceed at 130 °C and NMR
detection was proceeded for every one hour interval
mm–1; F000, 1328.0; h, k, lmax, 21,11,23; Nref, 3089; Tmin = 0.992, Tmax
0.993, Data completeness= 1.000, θmax 24.998, R(reflections)=
=
=
General procedure for preparation of XPS samples.(Scheme 4)
0.0394( 2751), wR2(reflections)= 0.0986( 3089), S = 1.045, Npar = 213.
CCDC 1949686 contains the supplementary crystallographic data for this
paper. These data are provided free of charge by The Cambridge Crystal-
lographic Data Centre. 1H NMR (400 MHz, DMSO-d6): 7.39 – 7.31 (m,
4H), 7.24 – 7.17 (m, 4H), 3.93 (s, 2H), 1.25 (s, 6H), 1.10 (s, 9H);
13C{1H}NMR (100 MHz, DMSO-d6): 177.5, 145.7, 141.3, 141.1, 132.7,
128.6, 128.3, 126.8, 125.7, 121.0, 64.1, 42.8, 31.9, 28.1, 26.1 (One carbon
was lost due to overlap with DMSO); HRMS (EI) m/z calculated for
C21H25NO (M)+: 307.1936; Found: 307.1931.
Sample A: CuBr (0.2 mmol, 1.0 equiv.), N-methylimidazole (2.0 equiv.),
DTBP (3.0 equiv.), p-Cl-C6H4CH3 (1.0 mL) were added into a screw
capped tube with a magnetic stir bar at 140 °C for 2 hours. Sample A was
obtained without filtration but just direct evaportion.
Sample B: CuBr (0.2 mmol, 1.0 equiv.), N-methylimidazole (2.0 equiv.),
DTBP (3.0 equiv.), p-Cl-C6H4CH3 (1.0 mL) were added into a screw
capped tube with a magnetic stir bar at 140 °C for 2 hours, subsequently,
amide 1a (1.0 equiv.) was added at 130 °C for 2 hours and the sample B
obtained through direct evaporation.
1-(7-(4-Methoxyphenyl)-3,3-dimethylindolin-1-yl)-2,2-
dimethylpropan-1-one (8b). Yellow oil was obtained 43.0 mg, in 51%
Sample
C
and Sample D:
CuBr (0.2 mmol, 1.0 equiv.), N-
1
yield for 1 h, Rf = 0.43 (PE/EA= 10:1). H NMR (400 MHz, DMSO-d6):
methylimidazole (2.0 equiv.), DTBP (3.0 equiv.), p-Cl-C6H4CH3 (1.0 mL)
were added into a screw capped tube with a magnetic stir bar at 140 °C for
2 hours, solid and filtrate were obtained by filtration. The solid reacted
with amide 1a (1.0 equiv.) at 130 °C for 2 hours to obtain sample C after
direct evaporation and the filtrate reacted with amide 1a (1.0 equiv.) at
130 °C for 2 h to obtain sample D after direct evaporation.
7.31 (d, J = 8.8 Hz, 2H), 7.07 – 7.14 (m, 3H), 6.90 (d, J = 8.0 Hz, 2H),
3.91 (s, 2H), 3.74 (s, 3H), 1.24 (s, 6H), 1.12 (s, 9H); 13C{1H} NMR (100
MHz, DMSO-d6): 177.5, 158.4, 144.7, 141.2, 133.5, 132.4, 128.1, 127.9,
125.6, 120.4, 114.0, 64.1, 55.5, 40.2, 28.2, 26.1.(one of the carbon was lost
due to overlap with DMSO); HRMS (EI) m/z calculated for C22H27NO2
(M)+: 337.2042; Found: 337.2039.
1-(3,3-Dimethyl-7-(p-tolyl)indolin-1-yl)-2,2-dimethylpropan-1-one
(8c). Yellow oil was obtained 45.0 mg, in 56% yield for 1 h, Rf = 0.41
(PE/EA= 10:1). 1H NMR (400 MHz, DMSO-d6): 7.29 (d, J = 7.8 Hz, 2H),
7.19 (s, 1H), 7.18 (s, 1H), 7.16 – 7.15 (m, 2H), 7.13 (s, 1H), 3.92 (s, 2H),
2.30 (s, 3H), 1.25 (s, 6H), 1.12 (s, 9H); 13C{1H} NMR (100 MHz, DMSO-
d6): 177.5, 144.7, 141.3, 138.2, 136.0, 132.6, 129.1, 128.2, 126.6, 125.6,
120.7, 64.1, 42.8, 31.9, 28.2, 26.1, 21.2; HRMS (EI) m/z calculated for
C22H27NO (M)+: 321.2084; Found: 321.2087.
ASSOCIATED CONTENT
Supporting Information
Information related to NMR spectra of new compounds and the
isolated products, reaction optimization, mechanistic studies,
computational data, X-ray crystallography data and CIF file. This
material is available free of charge via the Internet at
http://pubs.acs.org
1-(3,3-Dimethyl-7-(m-tolyl)indolin-1-yl)-2,2-dimethylpropan-1-one
(8d) 6d. Yellow oil was obtained 34.5 mg, in 43% yield for 1 h, Rf = 0.39
(PE/EA= 10:1). 1H NMR (400 MHz, CDCl3): 7.26 – 7.22 (m, 4H), 7.17 (t,
J = 7.4 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 7.06 – 7.05 (m, 1H), 3.90 (s, 2H),
2.35 (s, 3H), 1.32 (s, 6H), 1.17 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3):
177.3, 143.6, 141.2, 140.9, 137.5, 133.1, 128.7, 128.3, 127.3, 127.2, 125.3,
123.8, 120.2, 64.5, 42.7, 39.7, 28.0, 26.3, 21.6. MS (EI): m/z = 321.2
[M+H]+.
AUTHOR INFORMATION
Corresponding Author
renhuaqiu@hnu.edu.cn (R. Q.),
kambe@chem.eng.osaka-u.ac.jp (N. K.)
Author Contributions
1-(7-(4-Chlorophenyl)-3,3-dimethylindolin-1-yl)-2,2-
dimethylpropan-1-one (8e) 6d. Yellow oil was obtained 46.9 mg in 55%
yield for 1 h, Rf = 0.40 (PE/EA= 10:1). 1H NMR (400 MHz, CDCl3): 7.35
– 7.30 (m, 4H), 7.20 – 7.15 (m, 2H), 7.14 – 7.11 (m, 1H), 3.90 (s, 2H),
1.32 (s, 6H), 1.17 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3): 177.3, 143.7,
140.9, 139.9, 132.4, 132.0, 128.5, 128.4, 128.0, 125.5, 120.7, 64.4, 42.7,
39.7, 28.0, 26.3. MS (EI): m/z = 341.1 [M+H]+.
Jinguo Long and Liyuan Le contributed equally to this work and
should be considered as co-first authors. The authors declare no
competing financial interest.
ACKNOWLEDGMENT
1-(7-([1,1'-Biphenyl]-4-yl)-3,3-dimethylindolin-1-yl)-2,2-
dimethylpropan-1-one (8f) 6d. Yellow solid was obtained 69.0 mg, in
7
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Page 8 of 9
amination reactions of acetylenes. J. Am. Chem. Soc. 2012, 134, 15505–
The authors thank the Natural Science Foundation of China
(21676076, 21725602, 21878071), Hu-Xiang High Talent of Hu-
nan Province (2016RS3023, 2018RS3042), and Recruitment Pro-
gram for Foreign Experts of China (WQ20164300353) for finan-
cial support.
15511. C(sp2)–H amination: (b) Antonchick, A. P.; Samanta, R.; Kulikov,
K.; Lategahn, J. Organocatalytic, Oxidative, intramolecular C–H bond
amination and metal-free cross-amination of unactivated arenes at ambient
temperature. Angew. Chem. Int. Ed. 2011, 50, 8605–8608. (c) Cho, S. H.;
Yoon, J.; Chang, S. Intramolecular oxidative C–N bond formation for the
synthesis of carbazoles: Comparison of reactivity between the copper-
catalyzed and metal-free conditions. J. Am. Chem. Soc. 2011, 133, 5996–
1
2
3
4
5
6
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6005. (d) Martínez, C.; Bosnidou, A. E.; Allmendinger, S.; Muñiz, K.
Towards uniform iodine catalysis: Intramolecular C–H amination of
arenes under visible light. Chem. - Eur. J. 2016, 22, 9929–9932. C(sp3)–H
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