Synthesis of indolines by copper-mediated intramolecular aromatic C-H amination

Article abstract of DOI:10.1021/acs.joc.5b00307

A Cu(OAc)₂-mediated intramolecular aromatic C-H amination proceeds with the aid of a picolinamide-type bidentate coordination group to deliver the corresponding indolines in good yields. The reaction occurs smoothly even under noble-metal-free conditions, and in some cases the use of an MnO₂ terminal oxidant renders the process catalytic in Cu. The mild oxidation aptitude of Cu(OAc)₂ and/or MnO₂ accommodates the formation of electron-rich thiophene-and indole-fused indoline analogues. The Cu-based system can provide an effective approach to various indolines of potent interest in pharmaceutical and medicinal chemistry.

Full text of DOI:10.1021/acs.joc.5b00307

Article
pubs.acs.org/joc
Synthesis of Indolines by Copper-Mediated Intramolecular Aromatic
C−H Amination
Kazutaka Takamatsu, Koji Hirano,* Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: A Cu(OAc)2-mediated intramolecular aromatic C−H amination proceeds with the aid of a picolinamide-type
bidentate coordination group to deliver the corresponding indolines in good yields. The reaction occurs smoothly even under
noble-metal-free conditions, and in some cases the use of an MnO2 terminal oxidant renders the process catalytic in Cu. The mild
oxidation aptitude of Cu(OAc)2 and/or MnO2 accommodates the formation of electron-rich thiophene- and indole-fused
indoline analogues. The Cu-based system can provide an effective approach to various indolines of potent interest in
pharmaceutical and medicinal chemistry.
adopted in the oxidative C−H amination. The observed unique
feature of the Cu/Mn catalysis encouraged us to develop a Cu-
based system for the construction of other related N-
heterocycles. Herein, we report Cu(OAc)2-mediated and
Cu(OAc)2/MnO2-catalyzed intramolecular C−H aminations
for the synthesis of indolines. Similar to the previous carbazole
construction, the reaction proceeds smoothly under noble-
metal-free conditions and tolerates a wide range of substrates,
including electron-rich thiophene and indole (Scheme 1). To
the best of our knowledge, this is the first successful synthesis of
indolines by Cu-promoted intramolecular C−H amination.10
INTRODUCTION
■
Indolines are representative alicyclic N-heterocycles and are
ubiquitous in biologically active compounds and pharmaceut-
ical targets.1 Many research groups thus have studied and
developed versatile methodologies for the efficient synthesis of
indolines. Among them, metal-catalyzed C−N cross-coupling
ranks as a powerful and reliable access to the above targets.
This process generally includes a two-step sequence: i.e.,
halogenation of an aromatic C−H bond followed by intra-
molecular aromatic C−N formation by Pd,2 Cu,3 or Ni4
catalyst. On the other hand, recent advances in metal-mediated
C−H activation5 can skip the prefuctionalization, that is
halogenation, of the starting aromatic compounds and provide
a potentially more efficient and atom-economical C−H
amination approach to the indoline structure.6 However,
most precedents still rely on palladium catalysts and relatively
strong F+- or I(III)-based oxidants. Moreover, the synthesis of
electron-rich heteroarene-fused indoline analogues under such
oxidative conditions is still challenging, probably due to the
harsh conditions associated with the above strong oxidants.
Therefore, there still remains a large demand for further
development of the intramolecular aromatic C−H amination
directed toward the indoline synthesis.
RESULTS AND DISCUSSION
■
We initially prepared some 2-methyl-2-phenylpropan-1-amines
1 and attempted the C−H amination with 2.0 equiv of
Cu(OAc)2 in DMF under microwave irradiation (200 °C, 40
min), which are the standard stoichiometric conditions in our
previous work,7g to identify an appropriate substituent on the
nitrogen atom (Scheme 2). To our delight, substrates bearing
the picolinoyl11 (1a) and quinolinoyl12 (1a-COQ) groups
showed promising activity, while the benzamide 1a-Bz and
parent 1a-H did not form the indoline ring at all. The above
results apparently suggest the critical effect of the N,N-
bidentate coordination ability in 1a and 1a-COQ. In view of
the more ready availability and better reactivity with the
picolinamide 1a, we began to optimize catalytic conditions
(Table 1). Among the terminal oxidants we tested, only MnO2
worked well, and the corresponding indoline 2a was detected in
Meanwhile, our group7 and others8 focused on Cu salts as
inexpensive, less toxic, and abundant alternatives to noble
transition metals and succeeded in the development of some
unique transformations via directed C−H cleavage. In the
course of this study, we recently found the Cu(OAc)2/MnO2-
catalyzed intramolecular C−H/N−H coupling for the synthesis
of carbazoles.7g,9 The mild reaction conditions allow relatively
oxidation labile electron-rich heteroaromatic substrates to be
Received: February 10, 2015
© XXXX American Chemical Society
A
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Scheme 1. Copper-Mediated and Copper-Catalyzed Intramolecular Aromatic C−H Amination for the Synthesis of Indolines
indoline product through simple acid/base extraction (see the
Experimental Section for details). Representative products are
shown in Scheme 3. In addition to 2a-H, the reaction
accommodated electronically diverse functions such as Me,
Ph, MeO, CF3, and Cl (2b-H, 2c-H, 2d-H, 2e, and 2f-H). The
stoichiometric conditions A generally gave higher yields, but
the catalytic conditions B were specifically suitable for the Cl-
substituted substrate owing to the suppression of the undesired,
competitive protodechlorination (2f-H). When the substituent
was introduced at the meta position on the benzene ring,
sterically more accessible C−H bonds were selectively aminated
(2g-H and 2h-H). In contrast, the reaction of an ortho-
substituted substrate was sluggish, probably due to steric factors
(2i).13 It should be noted that the mild oxidation aptitude of
the present Cu(OAc)2 and MnO2 enabled the formation of
thiophene- and indole-fused indoline analogues 2j,k even under
oxidative conditions. The Cu-based systems could also be
applicable to the vinylic C−H amination, and the dihydro-
pyrrole 2l was obtained, albeit in a moderate yield.
Scheme 2. Effects of Substituents on Nitrogen in Copper-
Mediated C−H Amination for Synthesis of Indoline 2
Table 1. Optimization Studies for Copper-Catalyzed
a
Intramolecular C−H Amination of 1a
Some substitution patterns at the benzylic position were
tolerated: 3-methyl-3-phenylindoline (2m-H) and spiroindoline
2n-H as well as monosubstituted 3-phenylindoline (2o-H) and
3-methylindoline 2p were readily available. The gem-dimethyl
and phenyl groups α to the nitrogen were also compatible
under the reaction conditions (2q,r). It should be noted that
the C−H amination proceeded with only slight to negligible
erosion of enantiomeric purities of optically active starting
materials (2p,r), which was confirmed by chiral HPLC analysis
with authentic racemic samples (see the Supporting Informa-
tion for details). Such chiral indolines are especially useful and
are frequently found in biologically active and natural
products.1 On the other hand, the simplest phenylethylamine
was the relatively reluctant substrate (2s),14 thus indicating a
positive Thorpe−Ingold effect15 in the cyclization event.
Although the above substituent-dependent reactivity remains
to be addressed, conformationally regulated 3,3-disubstituted
indolines obtained herein are known to show biological activity
higher than that of the parent unsubstituted indolines and have
received some attention in the field of medicinal chemistry.16
Additionally notable is that all experiments conducted in
Scheme 3 could be set up on the benchtop and performed
without any special precautions related to air and moisture.
Some deuterium-labeling studies were next performed with
1a-d5 (Scheme 4). The following experiments were carried out
under the conventional heating conditions with an oil bath
(170 °C, N2), because under microwave-assisted conditions the
reaction proceeded in the course of the preheating time up to
200 °C, and the conversion at an early stage was difficult to
monitor. When the reaction was stopped in 1 h and the
recovered starting material was analyzed by NMR, no H/D
scrambling was observed. Additionally, major kinetic isotope
effect (KIE) values of 2.5 and 2.6 were obtained from the
parallel and competitive reactions of 1a and 1a-d5 (see the
Supporting Information for detailed kinetic profiles in the
parallel reaction). The above results suggest the irreversible,
oxidant (amt
(equiv))
additive (amt
(equiv))
temp
time
GC yield
(%)
entry
(°C)
(min)
1
2
3
4
5
6
7
8
MnO2 (2.0)
MnO2 (4.0)
Na2S2O8 (4.0)
K2S2O8 (4.0)
MnO2 (4.0)
MnO2 (4.0)
MnO2 (4.0)
MnO2 (6.0)
MnO2 (6.0)
none
200
200
200
200
200
250
180
200
200
90
60
60
60
60
60
60
90
90
41
54
0
none
none
none
0
AcOH (1.0)
none
32
51
40
61
0
none
none
b
9
none
a
Reaction conditions: 1a (0.25 mmol), Cu(OAc)2 (0.050 mmol),
oxidant, additive, DMF (1.5 mL). Without Cu(OAc)2.
b
54% GC yield (entries 1−4). Inconsistent with the precedented
carbazole formation,7g the addition of AcOH was detrimental
(entry 5). Neither increasing nor decreasing the reaction
temperature improved the GC yield of 2a (entries 6 and 7).
Finally, with 6.0 equiv of MnO2 and a prolonged reaction
period (90 min), we obtained 2a in 61% GC yield (entry 8).
Excess MnO2 was essential for a satisfactory conversion,
probably because of its lower solubility in DMF. The control
experiment without Cu(OAc)2 confirmed the Cu catalysis in
this process (entry 9).
We subsequently implemented the Cu-promoted C−H
amination of various phenylethylamines 1. For all substrates,
both stoichiometric (A) and catalytic (B) conditions were
applied. In several cases, including the model material 1a, an
additional hydrolysis was performed for easy purification of the
B
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Scheme 3. Synthesis of Various Indolines 2 and 2-H by Copper-Mediated and Copper-Catalyzed Intramolecular C−H
a
Amination of 1
a
Reaction conditions A: 1 (0.25 mmol), Cu(OAc)2 (0.50 mmol), DMF (1.5 mL), 200 °C, 40 min, microwave irradiation. Reaction conditions B: 1
(0.25 mmol), Cu(OAc)2 (0.050 mmol), MnO2 (1.5 mmol), DMF (1.5 mL), 200 °C, 90 min, microwave irradiation. Hydrolysis: crude 2, aqueous
b
NaOH (6.0 M, 1.0 mL), EtOH (3.0 mL), 100 °C, 4 h. The yields are given. The conditions employed are given in parentheses (A or B). NMR
yield. The protodechlorination product, namely 2a-H, was also formed in 13% NMR yield. 2g-H:2g-H′ ratio. GC yield. 20 min. Starting from 1p
with 93:7 er. With 0.25 mmol of AcOH. Starting from 1r with 99:1 er.
c
d
e
f
g
h
rate-limiting, and product-determining C−H cleavage of the
substrate. On the other hand, addition of the radical scavengers
TEMPO and galvinoxyl had a minor impact on the reaction
efficiency, thus indicating that a single electron transfer (SET)
pathway is less likely (Scheme 5).
On the basis of literature information and our findings, we
are tempted to assume the reaction mechanism of 1a to give 2a
is as follows (Scheme 6). Initial neutral and anionic N,N-
bidentate coordination of the picolinamide moiety in 1a to the
Cu(OAc)2 species 3 occurs to form the chelated cyclometalated
Cu complex 4 with the liberation of AcOH. The crucial effect of
the picolinamide-type directing groups in Scheme 1 is
consistent with the proposed coordination mode. Subsequent
irreversible, rate-limiting C−H cupration (4 → 5) is followed
by one-electron oxidation (disproportionation) of Cu(II) into
Cu(III)17 with an additional Cu(OAc)2 to generate the Cu(III)
intermediate 6. Productive reductive elimination provides the
desired indoline 2a along with the CuOAc species 7. The
catalytic cycle is completed by the MnO2/AcOH-promoted
reoxidation of 7 into the starting Cu(OAc)2 species 3.18
Additionally, MnO2 also reoxidizes the CuOAc species
generated through the disproportionation. Although the
detailed mechanism in the C−H cleavage step is still unclear,
it is considered to involve an acetate-ligand-assisted concerted
metalation−deprotonation pathway.19
CONCLUSION
■
We have developed a Cu(OAc)2-mediated intramolecular
aromatic C−H amination protocol for the synthesis of
indolines. Moreover, the use of cheap and abundant MnO2
renders the reaction catalytic in Cu(OAc)2. The reaction
proceeds smoothly even without Pd catalysts and F+- and
C
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Scheme 4. Deuterium-Labeling Experiments
Scheme 5. Effects of Radical Scavengers
further development of related C−H activation catalysis based
on Cu are ongoing in our laboratory.
Scheme 6. Plausible Mechanism
EXPERIMENTAL SECTION
■
Instrumentation and Chemicals. 1H, 13C, and 19F NMR spectra
were recorded at 400, 100, and 376 MHz, respectively, for CDCl3 or
DMSO-d6 solutions. HRMS data were obtained by EI or APCI using a
double-focusing mass spectrometer or TOF, respectively. GC analysis
was carried out using a silicon OV-17 column (2.6 mm i.d. × 1.5 m) or
a CBP-1 capillary column (0.5 mm i.d. × 25 m). TLC analyses were
performed on commercial glass plates bearing a 0.25 mm layer of
Merck silica gel 60F254. Silica gel was used for column chromatog-
raphy. Gel permeation chromatography (GPC) was performed with a
CHCl3 eluent (3.5 mL/min, UV detector). Microwave irradiation was
conducted with Initiator+ (Biotage), and the reaction temperature was
measured by an internal probe. Unless otherwise noted, materials
obtained from commercial suppliers were used as received. DMF was
dried on a Glass Contour Solvent dispending system (Nikko Hansen
& Co., Ltd.) prior to use. The starting amides 1a−m were prepared
from the corresponding benzyl nitriles in three steps: i.e., methylation,
reduction, and condensation with picolinoyl chloride (see the
following experimental procedure). Compounds 1n−s were synthe-
sized by the condensation of the commercially available parent
secondary amines with picolinoyl chloride under the same conditions
as in the synthesis of 1a−m. The enantiomeric ratios of 1p,r were 93:7
and 99:1 er, respectively, because the commercial sources, (R)-(+)-2-
phenyl-1-propylamine (93:7 er, from TCI) and (S)-(+)-1-phenyl-2-(p-
tolyl)ethylamine (99:1 er, from TCI), were employed without further
optical resolution.
I(III)-based oxidants, which are common promoters in the
precedented C−H amination.6 The mild oxidation aptitudes of
both Cu(OAc)2 and MnO2 also allow the otherwise challenging
formation of electron-rich thiophene- and indole-fused indoline
analogues under oxidative conditions. Some deuterium-labeling
experiments suggest irreversible, rate-limiting, and product-
determining C−H cupration directed by the picolinamide-type
bidentate coordination group. Detailed mechanistic studies and
Preparation of Starting Materials 1. The synthesis of 2-methyl-
2-phenylpropanenitrile (1a) is representative: sodium hydride (60 wt
%, 1.5 g, 38 mmol) was placed in a 100 mL two-necked reaction flask,
D
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and the flask was flushed with nitrogen. Tetrahydrofuran (THF, 30
mL) and 2-phenylacetonitrile (1.8 g, 15 mmol) were then added at 0
°C, and the resulting solution was stirred at room temperature for 1 h.
Iodomethane (6.4 g, 45 mmol) was then added at 0 °C, and the
resulting solution was stirred at room temperature for an additional 13
h. The resulting mixture was quenched with water at 0 °C. The
mixture was extracted with dichloromethane, and the combined
organic layers were dried over sodium sulfate. Concentration in vacuo
followed by silica gel column purification with hexane/ethyl acetate
(5/1, v/v) gave 2-methyl-2-phenylpropanenitrile (2.1 g, 15 mmol) in
96% yield.
Lithium aluminum hydride (0.83 g, 22 mmol) was placed in a 100
mL two-necked reaction flask, and the flask was flushed with nitrogen.
Tetrahydrofuran (THF, 30 mL) and 2-methyl-2-phenylpropanenitrile
(2.1 g, 15 mmol) were added at 0 °C, and the resulting solution was
stirred at room temperature for 4 h. The resulting mixture was then
quenched with a minimum amount of water at 0 °C and filtered
through a short pad of Celite. The filtrate was extracted with
dichloromethane, and the combined organic layers were dried over
sodium sulfate. Concentration in vacuo gave 2-methyl-2-phenyl-
propan-1-amine (2.0 g, 13 mmol) in 87% yield.
Pyridine-2-carbonyl chloride hydrochloride (2.6 g, 14 mmol) and
N,N-dimethyl-4-aminopyridine (0.48 g, 3.9 mmol) were placed in a
100 mL two-necked reaction flask, and the flask was flushed with
nitrogen. Dichloromethane (26 mL), triethylamine (2.9 g, 29 mmol),
and the crude 2-methyl-2-phenylpropan-1-amine (1.9 g, 13 mmol)
obtained above were added, and the mixture was stirred at room
temperature for 24 h. The resulting mixture was then quenched with
water. The mixture was extracted with dichloromethane, and the
combined organic layers were dried over sodium sulfate. Concen-
tration in vacuo followed by silica gel column purification with hexane/
ethyl acetate (2/1, v/v) gave N-(2-methyl-2-phenylpropyl)-
picolinamide (1a; 3.0 g, 12 mmol) in 91% yield.
Preparation of 1a-d5. A 100 mL two-necked reaction flask was
flushed with nitrogen. Tetrahydrofuran (THF, 20 mL) and 1-bromo-
2,3,4,5,6-pentadeuteriobenzene (1.6 g, 10 mmol) were added.
Butyllithium (1.6 M hexane solution, 6.9 mL, 11 mmol) was then
added at −78 °C, and the resulting solution was stirred for 30 min at
the same temperature. Trimethoxyborane (1.4 g, 13 mmol) was added,
and the mixture was stirred for an additional 30 min at −78 °C. The
resulting mixture was then warmed to room temperature and
quenched with 1 M aqueous HCl. The mixture was extracted with
dichloromethane, and the combined organic layers were dried over
magnesium sulfate. Concentration in vacuo gave 2,3,4,5,6-pentadeu-
teriophenylboronic acid (1.3 g, 10 mmol). The crude material was
used for the next step without further purification.
extracted with ethyl acetate, and the combined organic layers were
dried over sodium sulfate. The volatile materials were evaporated
under high vacuum. The residual oil, ethanol (3 mL), and 6 M
aqueous NaOH (1 mL) were placed in a 100 mL recovery flask
equipped with a reflux condenser, and the flask was flushed with
nitrogen. The resulting solution was stirred at 100 °C for 4 h. The
resulting mixture was quenched with water and extracted five times
with 0.5 M aqueous HCl. The combined aqueous layer was neutralized
with 6 M aqueous NaOH (4 mL) and then extracted three times with
Et2O. The combined organic layer was dried over magnesium sulfate.
Concentration in vacuo gave 3,3-dimethylindoline (2a-H; 24 mg, 0.16
mmol) in 64% yield in an analytically pure form.
Conditions B. Cu(OAc)2 (9.1 mg, 0.050 mmol), N-(2-methyl-2-
phenylpropyl)picolinamide (1a; 64 mg, 0.25 mmol), manganese
dioxide (130 mg, 1.5 mmol), and N,N-dimethylformamide (DMF, 1.5
mL) were placed in a 2 mL microwave vessel. The vessel was sealed
with a cap, and the mixture was irradiated under microwave reactor
conditions at 200 °C for 90 min. The resulting mixture was then
quenched with water. The mixture was extracted with ethyl acetate,
and the combined organic layers were dried over sodium sulfate. After
concentration under reduced pressure, the residual oil, ethanol (3
mL), and 6 M aqueous NaOH (1 mL) were placed in a 100 mL
recovery flask equipped with a reflux condenser, and the flask was
flushed with nitrogen. The resulting solution was stirred at 100 °C for
4 h. The resulting mixture was quenched with water and extracted 5
times with 0.1 M aqueous HCl. The combined aqueous layer was
neutralized with 6 M aqueous NaOH (2 mL) and then extracted three
times with Et2O. The combined organic layers were dried over
magnesium sulfate. Concentration in vacuo gave 3,3-dimethylindoline
(2a-H; 19 mg, 0.13 mmol) in 50% yield in an analytically pure form.
3,3-Dimethylindoline (2a-H). Conditions A: purified by acid/base
extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6 M
aqueous NaOH (4 mL); 24 mg (64%). Conditions B: purified by acid/
base extraction with 0.1 M aqueous HCl (5 mL × 5 times) and 6 M
1
aqueous NaOH (2 mL); 19 mg (50%), oil. H NMR (400 MHz,
CDCl3): δ 1.31 (s, 6H), 3.30 (s, 2H), 6.63 (ddd, J = 0.8, 1.2, 7.4 Hz,
1H), 6.74 (ddd, J = 0.8, 7.2, 7.6 Hz, 1H), 7.02 (ddd, J = 0.8, 1.2, 7.6
Hz, 1H), 7.04 (ddd, J = 1.2, 7.2, 7.6 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 27.7, 41.8, 61.7, 109.7, 118.9, 122.1, 127.4, 138.5,
150.4. HRMS (EI): m/z (M+) calcd for C10H13N 147.1048, found
147.1049.
3,3,6-Trimethylindoline (2b-H). Conditions A: purified by acid/
base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6 M
aqueous NaOH (4 mL); 26 mg (64%). Conditions B: purified by acid/
base extraction with 0.1 M aqueous HCl (5 mL × 5 times) and 6 M
1
aqueous NaOH (2 mL); 21 mg (53%), oil. H NMR (400 MHz,
CDCl3): δ 1.29 (s, 6H), 2.26 (s, 3H), 3.29 (s, 2H), 6.48 (t, J = 0.8 Hz,
1H), 6.56 (ddd, J = 0.8, 1.6, 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 21.6, 27.7, 41.5, 62.0, 110.6,
119.5, 121.8, 135.8, 137.3, 150.6. HRMS (EI): m/z (M+) calcd for
C11H15N 161.1204, found 161.1206.
2,3,4,5,6-Pentadeuteriophenylboronic acid (1.3 g, 10 mmol),
Ni(acac)2 (64 mg, 0.25 mmol), triphenylphosphine (130 mg, 0.50
mmol), and potassium phosphate (6.4 g, 30 mmol) were placed in a
50 mL two-necked reaction flask equipped with a reflux condenser,
and the flask was flushed with nitrogen. Toluene (30 mL) and
bromoacetonitrile (580 mg, 5.0 mmol) were added, and the resulting
solution was stirred at 80 °C for 3 h.20 After being cooled to room
temperature, the resulting mixture was then quenched with water. The
mixture was extracted with ethyl acetate, and the combined organic
layers were dried over sodium sulfate. Concentration in vacuo followed
by silica gel column purification with hexane/ethyl acetate (5/1, v/v)
gave 2-(2,3,4,5,6-pentadeuteriophenyl)acetonitrile (460 mg, 3.8
mmol) in 76% yield.
This compound was converted to 1a-d5 by the same three-step
sequence as for 1a: i.e., methylation, reduction, and condensation. The
three-step yield is 32% (98% D).
Typical Procedure for Synthesis of N−H Indolines 2-H. The
synthesis of 2a-H is representative.
Conditions A. Cu(OAc)2 (91 mg, 0.50 mmol), N-(2-methyl-2-
phenylpropyl)picolinamide (1a; 64 mg, 0.25 mmol), and N,N-
dimethylformamide (DMF, 1.5 mL) were placed in a 2 mL microwave
vessel. The vessel was sealed with a cap, and the mixture was irradiated
under microwave reactor conditions at 200 °C for 40 min. The
resulting mixture was then quenched with water. The mixture was
3,3-Dimethyl-6-phenylindoline (2c-H). Conditions A: purified by
acid/base extraction with 0.5 M aqueous HCl (5 mL × 8 times) and 6
M aqueous NaOH (6 mL); 39 mg (69%). Conditions B: purified by
acid/base extraction with 0.5 M aqueous HCl (5 mL × 8 times) and 6
M aqueous NaOH (6 mL); 30 mg (54%). Mp: 59.5−60.5 °C (from
1
Et2O). H NMR (400 MHz, CDCl3): δ 1.34 (s, 6H), 3.36 (s, 2H),
3.78 (bs, 1H), 6.85 (d, J = 1.6 Hz, 1H), 6.96 (dd, J = 1.6, 7.6 Hz, 1H),
7.10 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 7.2 Hz,
2H), 7.54 (d, J = 7.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
27.7, 41.7, 62.0, 108.5, 118.2, 122.3, 127.0, 127.3, 128.7, 137.8, 141.0,
142.0, 151.0. HRMS (EI): m/z (M+) calcd for C16H17N 223.1361,
found 223.1362.
6-Methoxy-3,3-dimethylindoline (2d-H). Conditions A: purified by
acid/base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6
M aqueous NaOH (4 mL); 30 mg (69%). Conditions B: purified by
acid/base extraction with 0.1 M aqueous HCl (5 mL × 5 times) and 6
1
M aqueous NaOH (2 mL); 24 mg (54%), oil. H NMR (400 MHz,
CDCl3): δ 1.28 (s, 6H), 3.31 (s, 2H), 3.75 (s, 3H), 6.22 (d, J = 2.4 Hz,
1H), 6.28 (dd, J = 2.4, 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H). 13C{1H}
E
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NMR (100 MHz, CDCl3): δ 27.9, 41.2, 55.5, 62.2, 96.4, 103.5, 122.3,
131.1, 151.7, 160.0. HRMS (EI): m/z (M+) calcd for C11H15NO
177.1154, found 177.1154.
Typical Procedure for Synthesis of N-Picolinoyl Indolines 2.
The synthesis of 2j is representative.
Conditions A. Cu(OAc)2 (91 mg, 0.50 mmol), N-(2-methyl-2-
(thiophen-2-yl)propyl)picolinamide (1j, ;65 mg, 0.25 mmol), and
N,N-dimethylformamide (DMF, 1.5 mL) were placed in a 2 mL
microwave vessel. The vessel was sealed with a cap, and the mixture
was irradiated under microwave reactor conditions at 200 °C for 40
min. The resulting mixture was then quenched with water. The
mixture was extracted with ethyl acetate, and the combined organic
layers were dried over sodium sulfate. Concentration in vacuo followed
by silica gel column purification with hexane/ethyl acetate (2/1, v/v)
gave (6,6-dimethyl-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)(pyridin-
2-yl)methanone (2j; 54 mg, 0.21 mmol) in 83% yield.
6-Chloro-3,3-dimethylindoline (2f-H). Conditions A: purified by
acid/base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6
M aqueous NaOH (4 mL); 23 mg (2f-H 40% + 2a-H 13%).
Conditions B: purified by acid/base extraction with 0.5 M aqueous
HCl (5 mL × 5 times) and 6 M aqueous NaOH (4 mL); 23 mg
(50%), oil. 1H NMR (400 MHz, CDCl3): δ 1.28 (s, 6H), 3.32 (s, 2H),
6.58 (d, J = 2.0 Hz, 1H), 6.67 (dd, J = 2.0, 8.0 Hz, 1H), 6.91 (d, J = 8.0
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 27.7, 41.4, 61.9, 109.6,
118.4, 122.8, 132.9, 137.0, 151.6. HRMS (EI): m/z (M+) calcd for
C10H12ClN: 181.0658, found 181.0662.
Conditions B. Cu(OAc)2 (9.1 mg, 0.050 mmol), N-(2-methyl-2-
(thiophen-2-yl)propyl)picolinamide (1j; 65 mg, 0.25 mmol), man-
ganese dioxide (130 mg, 1.5 mmol), and N,N-dimethylformamide
(DMF, 1.5 mL) were placed in a 2 mL microwave vessel. The vessel
was sealed with a cap, and the mixture was irradiated under microwave
reactor conditions at 200 °C for 90 min. The resulting mixture was
then quenched with water. The mixture was extracted with ethyl
acetate, and the combined organic layers were dried over sodium
sulfate. Concentration in vacuo followed by silica gel column
purification with hexane/ethyl acetate (2/1, v/v) gave (6,6-dimethyl-
5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)(pyridin-2-yl)methanone (2j;
53 mg, 0.21 mmol) in 83% yield.
(3,3-Dimethyl-6-(trifluoromethyl)indolin-1-yl)(pyridin-2-yl)-
methanone (2e). Conditions A: purified by column chromatography
on silica gel with hexane/ethyl acetate (2/1, v/v) as an eluent; 59 mg
(74%). Conditions B: purified by column chromatography on silica gel
with hexane/ethyl acetate (2/1, v/v) as an eluent; 36 mg (45%). Mp:
94.0−95.0 °C (from CHCl3). 1H NMR (400 MHz, CDCl3): δ 1.35 (s,
6H), 4.21 (s, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H),
7.38−7.44 (m, 1H), 7.88 (dt, J = 1.6, 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz,
1H), 8.60 (s, 1H), 8.65 (dt, J = 1.6, 5.2 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 28.2, 40.8, 65.3, 115.1, 121.8, 122.3, 124.4 (q, J =
271.4 Hz), 124.7, 125.5, 130.2 (q, J = 31.9 Hz), 137.3, 142.7, 145.3,
148.1, 153.9, 166.3. 19F NMR (376 MHz, CDCl3): δ −62.00. HRMS
(EI): m/z (M+) calcd for C17H15F3N2O 320.1136, found 320.1137.
(6,6-Dimethyl-5,6-dihydro-4H-thieno[3,2-b]pyrrol-4-yl)(pyridin-2-
yl)methanone (83:17 Mixture of Rotamers) (2j). Conditions A:
purified by column chromatography on silica gel with hexane/ethyl
acetate (2/1, v/v) as an eluent; 54 mg (83%). Conditions B: purified
by column chromatography on silica gel with hexane/ethyl acetate (2/
1, v/v) as an eluent; 53 mg (83%). Mp: 90.0−91.0 °C (from CH2Cl2);
1H NMR (400 MHz, DMSO-d6, at 25 °C): δ 1.34 (s, 0.83 × 6H for
3,3,5-Trimethylindoline (2g-H). Conditions A: purified by acid/
base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6 M
aqueous NaOH (4 mL); 24 mg (59%, 2g-H:2g-H′ 11:1). Conditions
B: purified by acid/base extraction with 0.1 M aqueous HCl (5 mL × 5
times) and 6 M aqueous NaOH (2 mL); 16 mg (39%, 2g-H:2g-H′
15:1), oil. 1H NMR (400 MHz, CDCl3): δ 1.29 (s, 6H), 2.27 (s, 3H),
3.28 (s, 2H), 6.56 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.86
(s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 21.0, 27.6, 41.9, 62.0,
109.8, 122.9, 127.7, 128.3, 138.9, 148.0. HRMS (EI): m/z (M+) calcd
for C11H15N 161.1204, found 161.1205.
3,3-Dimethyl-2,3-dihydro-1H-benzo[f ]indole (2h-H). Conditions
A: purified by acid/base extraction with 0.5 M aqueous HCl (5 mL × 8
times) and 6 M aqueous NaOH (6 mL); 29 mg (59%). Conditions B:
purified by acid/base extraction with 0.5 M aqueous HCl (5 mL × 8
times) and 6 M aqueous NaOH (6 mL); 16 mg (32%). Mp: 71.5−73.0
°C (from Et2O). 1H NMR (400 MHz, CDCl3): δ 1.40 (s, 6H), 3.38 (s,
2H), 3.97 (bs, 1H), 6.85 (s, 1H), 7.18 (ddd, J = 0.8, 7.2, 8.0 Hz, 1H),
7.29 (ddd, J = 0.8, 7.2, 8.0 Hz, 1H), 7.42 (s, 1H), 7.57 (d, J = 8.0 Hz,
1H), 7.66 (d, J = 8.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
27.9, 41.4, 61.6, 102.5, 120.6, 122.1, 125.5, 125.9, 127.8, 129.0, 134.7,
141.7, 149.3. HRMS (EI): m/z (M+) calcd for C14H15N 197.1204,
found 197.1205.
3-Methyl-3-phenylindoline (2m-H). Conditions A: purified by
acid/base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6
M aqueous NaOH (4 mL); 38 mg (72%). Conditions B: purified by
acid/base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6
1
M aqueous NaOH (4 mL); 34 mg (65%), oil. H NMR (400 MHz,
CDCl3): δ 1.72 (s, 3H), 3.57 (d, J = 8.8 Hz, 1H), 3.72 (d, J = 8.8 Hz,
1H), 3.77 (bs, 1H), 6.72 (d, J = 7.6 Hz, 1H), 6.76 (t, J = 7.6 Hz, 1H),
6.97 (td, J = 1.2, 7.6 Hz, 1H), 7.09 (dt, J = 1.2, 7.6 Hz, 1H), 7.19 (tt, J
= 1.6, 6.8 Hz, 1H), 7.26−7.35 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3): δ 26.3, 49.8, 63.9, 110.1, 119.2, 124.3, 126.3, 126.7, 127.8,
128.3, 137.2, 147.8, 150.9. HRMS (EI): m/z (M+) calcd for C15H15N
209.1204, found 209.1206.
major isomer), 1.40 (s, 0.17 × 6H for minor isomer), 4.22 (s, 0.17 ×
2H for minor isomer), 4.43 (s, 0.83 × 2H for major isomer), 5.07 (d, J
= 5.2 Hz, 0.17 × 1H for minor isomer), 7.13 (d, J = 5.2 Hz, 0.17 × 1H
for minor isomer), 7.42 (d, J = 5.2 Hz, 0.83 × 1H for major isomer),
7.45 (d, J = 5.2 Hz, 0.83 × 1H for major isomer), 7.56 (ddd, J = 1.2,
4.8, 7.6 Hz, 0.83 × 1H for major isomer), 7.55−7.62 (m, 0.17 × 1H for
minor isomer), 7.63 (d, J = 7.6 Hz, 0.17 × 1H for minor isomer), 7.89
(td, J = 1.2, 7.6 Hz, 0.83 × 1H for major isomer), 8.00 (dt, J = 1.6, 7.6
Hz, 0.83 × 1H for major isomer), 7.97−8.04 (m, 0.17 × 1H for minor
isomer), 8.65 (td, J = 0.8, 4.8 Hz, 0.17 × 1H for minor isomer), 8.67
Spiro[cyclopropane-1,3′-indoline] (2n-H). Conditions A: purified
by acid/base extraction with 0.5 M aqueous HCl (5 mL × 5 times)
and 6 M aqueous NaOH (4 mL); 21 mg (58%). Conditions B:
purified by acid/base extraction with 0.1 M aqueous HCl (5 mL × 5
1
times) and 6 M aqueous NaOH (2 mL); 17 mg (47%), oil. H NMR
(400 MHz, CDCl3): δ 0.93 (dt, J = 1.6, 5.2 Hz, 2H), 0.99 (dt, J = 1.6,
5.2 Hz, 2H), 3.58 (s, 2H), 3.80 (bs, 1H), 6.60 (ddd, J = 0.4, 1.2, 7.6
Hz, 1H), 6.63 (td, J = 0.8, 7.6 Hz, 1H), 6.69 (dt, J = 0.8, 7.6 Hz, 1H),
6.99 (dt, J = 1.2, 7.6 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
16.6, 24.6, 55.6, 109.3, 118.5, 118.9, 126.8, 134.5, 151.9. HRMS (EI):
m/z (M+) calcd for C10H11N 145.0891, found 145.0892.
1
(qd, J = 0.8, 4.8 Hz, 0.83 × 1H for major isomer). H NMR (400
MHz, DMSO-d6, at 105 °C): δ 1.38 (s, 6H), 4.40 (bs, 2H), 7.34 (bs,
2H), 7.53 (dd, J = 5.2, 8.0 Hz, 1H), 7.83 (brs, 1H), 7.97 (dt, J = 2.0,
7.6 Hz, 1H), 8.65 (d, J = 4.4 Hz, 1H). 13C{1H} NMR (100 MHz,
DMSO-d6, at 25 °C) for mixture δ 28.8, 28.9, 41.1, 66.6, 69.0, 114.7,
117.4, 122.5, 12.1, 125.5, 127.6, 127.7, 137.1, 137.4, 137.5, 137.7,
143.7, 148.2, 149.0, 153.0, 162.5 (all observed signals are shown
because of complication associated with rotamers.). HRMS (EI): m/z
(M+) calcd for C14H14N2OS 258.0827, found 258.0827.
3-Phenylindoline (2o-H). Conditions A: purified by acid/base
extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6 M
aqueous NaOH (4 mL); 30 mg (61%). Conditions B: purified by acid/
base extraction with 0.5 M aqueous HCl (5 mL × 5 times) and 6 M
1
aqueous NaOH (4 mL); 21 mg (44%), oil. H NMR (400 MHz,
CDCl3): δ 3.50 (t, J = 9.2 Hz, 1H), 3.80 (bs, 1H), 3.94 (t, J = 9.2 Hz,
1H), 4.49 (t, J = 9.2 Hz, 1H), 6.71 (dt, J = 0.8, 7.2 Hz, 1H), 6.73 (d, J
= 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.07 (tt, J = 0.8, 7.6 Hz, 1H),
7.21−7.34 (m, 5H). 13C{1H} NMR (100 MHz, CDCl3): δ 48.8, 56.8,
109.9, 119.2, 125.2, 126.8, 127.9, 128.3, 128.7, 132.5, 143.7, 151.7.
HRMS (EI): m/z (M+) calcd for C14H13N 195.1048, found 195.1049.
Pyridin-2-yl(3,3,8-trimethyl-3,8-dihydropyrrolo[2,3-b]indol-1(2H)-
yl)methanone (2k). Conditions A: purified by column chromatog-
raphy on silica gel with hexane/ethyl acetate (2/1, v/v) as an eluent
followed by GPC; 41 mg (54%). Conditions B: purified by column
chromatography on silica gel with hexane/ethyl acetate (2/1, v/v) as
1
an eluent followed by GPC; 26 mg (34%), oil. H NMR (400 MHz,
F
DOI: 10.1021/acs.joc.5b00307
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3): δ 1.43 (s, 6H), 3.93 (s, 3H), 4.34 (s, 2H), 7.11 (dt, J = 1.2,
7.2 Hz, 1H), 7.16 (dt, J = 1.2, 7.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H),
7.42−7.47 (m, 2H), 7.88 (dt, J = 1.6, 7.6 Hz, 1H), 8.01 (d, J = 7.6 Hz,
1H), 8.68 (d, J = 4.0 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ
27.6, 33.2, 39.1, 73.2, 110.3, 114.3, 117.5, 120.0, 120.3, 122.2, 124.8,
125.9, 137.3, 139.8, 142.6, 148.6, 153.2, 165.9. HRMS (EI): m/z (M+)
calcd for C19H19N3O 305.1528, found 305.1530.
Indolin-1-yl(pyridin-2-yl)methanone (2s). Conditions A: purified
by column chromatography on silica gel with hexane/ethyl acetate (2/
1, v/v) as an eluent; 25 mg (45%). Conditions B: purified by column
chromatography on silica gel with hexane/ethyl acetate (2/1, v/v) as
1
an eluent; 17 mg (31%). Mp: 99.5−101.0 °C (from CH2Cl2). H
NMR (400 MHz, CDCl3): δ 3.15 (t, J = 8.4 Hz, 2H), 4.35 (t, J = 8.4
Hz, 2H), 7.08 (t, J = 7.2 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 7.26 (t, J =
8.0 Hz, 1H), 7.39 (t, J = 5.6 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.88 (d,
J = 7.2 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.63 (d, J = 4.4 Hz, 1H).
13C{1H} NMR (100 MHz, CDCl3): δ 28.8, 50.7, 118.1, 124.3, 124.5,
124.7, 125.1, 127.5, 132.3, 137.2, 143.4, 148.1, 154.7, 166.2. HRMS
(APCI): m/z ([M + H]+) calcd for C14H13N2O: 225.1022, found
225.1028.
(3,3-Dimethyl-2,3-dihydro-1H-pyrrol-1-yl)(pyridin-2-yl)-
methanone (72:28 Mixture of Rotamers) (2l). Conditions B: purified
by column chromatography on silica gel with hexane/ethyl acetate (2/
1
1, v/v) as an eluent; 18 mg (36%), oil. H NMR (400 MHz, DMSO-
d6, at 25 °C): δ 1.12 (s, 0.28 × 6H for minor isomer), 1.16 (s, 0.72 ×
6H for major isomer), 3.66 (s, 0.72 × 2H for major isomer), 3.87 (s,
0.28 × 2H for minor isomer), 5.20 (d, J = 4.4 Hz, 0.72 × 1H for major
isomer), 5.38 (d, J = 4.4 Hz, 0.28 × 1H for minor isomer), 6.95 (d, J =
4.4 Hz, 0.28 × 1H for minor isomer), 7.20 (d, J = 4.4 Hz, 0.72 × 1H
for major isomer) 7.52−7.57 (m, 0.28 × 1H for minor isomer), 7.56
(ddd, J = 1.2, 4.8, 7.6 Hz, 0.72 × 1H for major isomer), 7.83 (td, J =
1.2, 7.6 Hz, 0.72 × 1H for major isomer), 7.83−7.87 (m, 0.28 × 1H for
minor isomer), 7.97 (dt, J = 1.6, 7.6 Hz, 0.28 × 1H for minor isomer),
7.98 (dt, J = 1.6, 7.6 Hz, 0.72 × 1H for major isomer), 8.63 (ddd, J =
0.8, 1.6, 4.8 Hz, 0.72 × 1H for major isomer), 8.62−8.66 (m, 0.28 ×
1H for minor isomer). 1H NMR (400 MHz, DMSO-d6, at 115 °C): δ
1.17 (s, 6H), 3.71 (bs, 2H), 5.20 (bs, 1H), 7.17 (bs, 1H), 7.51 (ddd, J
= 0.8, 5.2, 7.6 Hz, 1H), 7.82 (d, J = 7.6 Hz, 1H), 7.94 (dt, J = 1.2, 7.6
Hz, 1H), 8.62 (d, J = 4.8 Hz, 1H). 13C{1H} NMR (100 MHz, DMSO-
d6, at 25 °C) for mixture δ 27.9, 28.2, 40.5, 43.7, 59.6, 61.6, 122.6,
123.4, 124.1, 124.2, 125.5, 125.6, 127.2, 128.6, 137.4, 137.6, 148.1,
148.2, 152.5, 152.9, 162.5, 162.6. HRMS (APCI): m/z ([M + H]+)
calcd for C12H15N2O 203.1179, found 203.1179.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Detailed kinetic profiles for the reaction of 1a and 1a-d5, H,
13C{1H}, and 19F NMR spectra for products, and chiral HPLC
charts of 2p,r. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for K.H.: k_hirano@chem.eng.osaka-u.ac.jp.
*E-mail for M.M.: miura@chem.eng.osaka-u.ac.jp.
■
Notes
The authors declare no competing financial interest.
(R)-(3-Methylindolin-1-yl)(pyridin-2-yl)methanone (2p). Condi-
tions A: purified by column chromatography on silica gel with
hexane/ethyl acetate (2/1, v/v) as an eluent followed by GPC; 30 mg
(51%). Conditions B: purified by column chromatography on silica gel
with hexane/ethyl acetate (2/1, v/v) as an eluent followed by GPC; 20
ACKNOWLEDGMENTS
This work was supported by Grants-in-Aid for Scientific
Research from the MEXT and JSPS of Japan.
■
20
1
mg (37%), oil. [α]D = −0.18° (c 0.50, CHCl3, 93:7 er). H NMR
(400 MHz, CDCl3): δ 1.33 (d, J = 6.8 Hz, 3H), 3.43−3.50 (m, 1H),
3.90 (dd, J = 7.2, 11.2 Hz, 1H), 4.50 (dd, J = 9.2, 11.2 Hz, 1H), 7.11 (t,
J = 7.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.39
(t, J = 5.2 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H),
8.30 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 4.8 Hz, 1H). 13C{1H} NMR (100
MHz, CDCl3): δ 19.6, 35.3, 58.5, 117.9, 123.4, 124.2, 124.5, 125.0,
127.6, 137.1, 137.3, 142.8, 148.0, 154.6, 166.0. HRMS (APCI): m/z
([M + H]+) calcd for C15H15N2O 239.1179, found 239.1178.
(2,2-Dimethylindolin-1-yl)(pyridin-2-yl)methanone (2q). Condi-
tions A: purified by column chromatography on silica gel with hexane/
ethyl acetate (2/1, v/v) as an eluent; 54 mg (86%). Conditions B:
purified by column chromatography on silica gel with hexane/ethyl
acetate (2/1, v/v) as an eluent; 46 mg (73%). Mp: 126.0−127.0 °C
(from CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 1.70 (s, 6H), 3.06 (s,
2H), 5.30−6.30 (bs, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.89 (t, J = 7.2 Hz,
1H), 7.14 (d, J = 7.2 Hz, 1H), 7.41 (qd, J = 1.2, 4.8, 7.6 Hz, 1H), 7.66
(d, J = 7.6 Hz, 1H), 7.85 (dt, J = 1.6, 7.6 Hz, 1H), 8.61 (qd, J = 0.8, 4.8
Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 45.6, 67.7, 115.9,
123.3, 123.6, 125.37, 125.42, 126.6, 130.6, 137.4, 142.3, 149.3, 155.1,
167.3. HRMS (APCI) m/z ([M + H]+) calcd for C16H17N2O
253.1335, found 253.1333.
REFERENCES
■
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(S)-(6-methyl-2-phenylindolin-1-yl)(pyridin-2-yl)methanone (2r).
Conditions A: purified by column chromatography on silica gel with
hexane/ethyl acetate (2/1, v/v) as an eluent followed by GPC; 50 mg
(64%). Conditions B: purified by column chromatography on silica gel
with hexane/ethyl acetate (2/1, v/v) as an eluent followed by GPC; 23
(5) Selected reviews and accounts: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174. (b) Satoh, T.; Miura, M.
Chem. Lett. 2007, 36, 200. (c) Campeau, L. C.; Stuart, D. R.; Fagnou,
K. Aldrichchim. Acta 2007, 40, 35. (d) Seregin, I. V.; Gevorgyan, V.
Chem. Soc. Rev. 2007, 36, 1173. (e) Park, Y. J.; Park, J.-W.; Jun, C.-H.
Acc. Chem. Res. 2008, 41, 222. (f) Lewis, L. C.; Bergman, R. G.;
Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (g) Kakiuchi, F.; Kochi,
T. Synthesis 2008, 3013. (h) Daugulis, O.; Do, H.-Q.; Shabashov, D.
Acc. Chem. Res. 2009, 42, 1074. (i) Kulkarni, A. A.; Daugulis, O.
Synthesis 2009, 4087. (j) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-
Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (k) Ackermann, L.; Vicente,
20
mg (30%). Mp: 132.0−133.0 °C (from CHCl3). [α]D = −3.14° (c
1
0.50, CHCl3, 99:1 er). H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H),
2.97 (dd, J = 2.8, 16.0 Hz, 1H), 3.76 (dd, J = 10.0, 16.0 Hz, 1H), 6.20
(d, J = 8.8 Hz, 1H), 6.80−7.23 (m, 9H), 7.51 (t, J = 5.6 Hz, 1H), 8.34
(s, 1H), 8.54 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3): δ 21.9, 38.4,
63.7, 118.1, 124.0, 124.6, 125.3, 125.5, 127.1, 127.3, 128.6 (2C), 136.8,
137.8, 144.0, 144.3, 147.7, 154.8, 167.6. HRMS (APCI): m/z ([M +
H]+) calcd for C21H19N2O: 315.1492, found 315.1494.
G
DOI: 10.1021/acs.joc.5b00307
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (l) Sun, C.-L.;
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H
DOI: 10.1021/acs.joc.5b00307
J. Org. Chem. XXXX, XXX, XXX−XXX