Copper-Salt-Promoted Carbocyclization Reactions of α-Bromo- N -arylacylamides

Article abstract of DOI:10.1055/s-0036-1588642

A mild and convenient synthetic method for oxindoles and α-arylacylamides bearing an all carbon quaternary stereocenter from the readily available α-bromo-N-arylacylamides has been developed. This Cu(acac)₂/Phen-promoted radical cyclization rea

Full text of DOI:10.1055/s-0036-1588642

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
C.-P. Chuang et al.
Paper
Synthesis
Copper-Salt-Promoted Carbocyclization Reactions of α-Bromo-
N-arylacylamides
Che-Ping Chuang*
O
Br
R1
Ying-Yu Chen
Cu(acac)2
Cu(acac)2
R1
R1
O
N
Phen
R2 = Alkyl, Ar
Phen
R2 = ArSO2
Tsung-Han Chuang
Cheng-Hao Yang
N
R2
H
O
N
R2
Ar
26 examples
yields: 29–92%
10 examples
yields: 76–87%
Department of Chemistry, National Cheng Kung University,
Tainan 70101, Taiwan
cpchuang@mail.ncku.edu.tw
Received: 05.09.2016
Accepted after revision: 11.10.2016
Published online: 07.11.2016
HO
N
DOI: 10.1055/s-0036-1588642; Art ID: ss-2016-f0606-op
N
O
S
N
H
O
Abstract A mild and convenient synthetic method for oxindoles and
α-arylacylamides bearing an all carbon quaternary stereocenter from
the readily available α-bromo-N-arylacylamides has been developed.
This Cu(acac)2/Phen-promoted radical cyclization reaction, via the in-
tramolecular radical cyclization onto the aryl moiety, can proceed in
two different routes depending on the substituents on the nitrogen at-
om. In this transformation, oxindoles and α-arylacylamides were
formed in high chemoselectivity. A variety of useful functional groups
such as methoxy, fluoro, chloro, bromo, methoxycarbonyl, and cyano
are compatible with the reaction conditions. The use of inexpensive,
readily available Cu(acac)2 and Phen makes this protocol very efficient
and practical.
N
OMe
H
Cl
selective 5-HT7
receptor antagonist
antitumor reagent
N
R
CN
N
O
O
N
H
N
H
progesteron
receptor agonist
horsfiline (R = OMe)
coeresculine (R = H)
Figure 1 Several biologically active oxindole derivatives2
Key words copper salts, carbocyclization, α-bromo-N-arylacylamides,
oxindoles, α-arylacylamides
radical precursors have been developed as a powerful tool
for the tertiary alkenylation of α-carbonyl alkyl bromides
without either β-hydrogen elimination or oxidative addi-
tion, which are problematic in Mizoroki–Heck cou-
plings.10,11 The copper-promoted cyclization reactions have
received considerable attention because of their efficien-
cies, low-costs, and good functional group tolerances in the
substrates. Many useful N-heterocyclic compounds such as
pyrroles,12 indoles,13 oxazoles,14 pyrazoles,15 and quino-
lines16 have been efficiently synthesized by these methods.
Although a number of effective methods for the synthe-
ses of 3,3′-disubstituted oxindoles are available, the explo-
ration of mild and efficient methods is continuously being
pursued. As part of our research interest in developing new
methods for the preparation of heterocyclic systems,17–21
we now report a mild method for the synthesis of 3,3′-
disubstituted oxindoles through the copper salts-promoted
radical cyclizations of α-bromo-N-arylacylamides (Scheme
1).
3,3′-Disubstituted oxindoles are an important class of
nitrogen heterocycles found in a wide range of natural
products and bioactive molecules (Figure 1).1,2 Owing to
their significance of biological activities and a wide range of
applications in organic synthesis, they become attractive
targets in organic synthesis. Therefore, numerous methods
for the synthesis of these motifs have been established, in-
cluding Pd-catalyzed cyclization reactions of N-(o-halo-
aryl)amides (Mizoroki–Heck couplings3 and arylations4),
base-promoted cyclization reactions of α-activated-N-aryl-
amides,5 radical cyclization reactions of N-arylamides,6,7
and tandem radical addition-cyclization reactions of N-aryl-
acrylamides.8
Copper-promoted atom-transfer radical cyclization re-
action (ATRC) has been extensively studied and is widely
used in the preparation of carbocycles and heterocyles.9 Re-
cently, their analogous reactions using alkyl bromides as
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

B
C.-P. Chuang et al.
Paper
Synthesis
amide 4a, derived from the β-hydrogen elimination, was
not observed. Several other inexpensive, readily available
copper salts were next tested, the results showed that
Cu(acac)2 and Cu2O were more efficient than the others.
The effect of solvent was also investigated, and the re-
sults revealed that DMF and EtCN were the most suitable
solvents for this reaction (Table 1, entries 3, 8–12). Notably,
the addition of ligand is crucial for the success of this reac-
tion. Compared to Phen, other pyridine ligands such as 2,2′-
bipyridine and pyridine are less efficient (entries 14 and
15). In the absence of Phen, product 2a could not be found
and the starting 1a was recovered (85%) after heating for 6
hours at 90 °C (entry 16). In addition, the temperature has
an obvious influence on this reaction, thus reaction at 90 °C
provided 2a in high yield (entries 12, 17, and 18). We also
performed this reaction under air atmosphere. After heat-
ing for 6 hours, the target product 2a was obtained in 83%
Br
O
Cu salt
O
R1
R1
N
R2
N
R2
1
2
Scheme 1 Cyclization of α-bromo-N-arylacylamides
In our initial experiment, α-bromo-N-arylacylamide 1a
[R1 = H, R2 = 2,4,6-trimethylbenzyl (TMBn)] was treated
with Cu(acac)2 (0.5 equiv), and 1,10-phenanthroline (Phen)
(0.5 equiv) in DMF at 90 °C under a nitrogen atmosphere for
8 hours (Table 1, entry 1). The 3,3′-disubstituted oxindole
2a, formed via the five-membered-ring cyclization of car-
bamoylmethyl radical I (Scheme 2), was produced in 77%
yield and another unexpected N-benzylaniline 3a was also
obtained in 12% yield. The reaction yield of 2a can be im-
proved to 90% by increasing the amount of Cu(acac)2 and
Phen up to 2 equivalents and the reaction time was shorten
to 6 hours (entry 3). In this transformation, N-arylacryl-
Table 1 Optimization of Reaction Conditions for the Copper-Promoted Carbocyclization Reactions with α-Bromo-N-arylacylamides 1a
Br
Cu salt
+
+
O
O
N
O
N
N
HN
TMBn
TMBn 1a
3a
TMBn 4a
TMBn 2a
Entry
Cu salt (equiv)
Ligand (equiv)
Solvent
Temp (°C)
Time (h)
Yield (%)a
1
2
Cu(acac)2 (0.5)
Cu(acac)2 (0.5)
Cu(acac)2 (1)
Cu(acac)2 (2)
Cu2O (1)
Phen (0.5)
Phen (2)
Phen (1)
Phen (2)
Phen (2)
Phen (2)
Phen (2)
Phen (2)
Phen (2)
Phen (2)
Phen (2)
Phen (2)
Phen (0.5)
2,2′-bipyridine (2)
pyridine (2)
–
DMF
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
80
70
90
8
8
6
6
6
6
6
6
6
6
6
6
8
6
6
6
6
6
6
2a (77)
2a (73)
2a (82)
2a (90)
2a (90)
2a (61)
2a (0)
3a (12)
3a (11)
3a (7)
DMF
3
DMF
4
DMF
5
DMF
6
CuCl (2)
DMF
7
CuBr (2)
DMF
8
Cu(OAc)2
DMF
2a (0)
4a (87)
9
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (0.5)
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (2)
Cu(acac)2 (2)
DMAcb
1,4-dioxane
toluene
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
EtCN
2a (82)
2a (83)
2a (86)
2a (90)
2a (68)c
2a (76)
2a (0)
10
11
12
13
14
15
16
17
18
19e
3a (16)c
1a (97)d
1a (85)d
2a (0)
Phen (2)
Phen (2)
Phen (2)
2a (86)
2a (71)
2a (83)
a Isolated yield.
b DMAc: N,N-Dimethylacetamide.
c Based on 76% conversion.
d The starting 1a was recovered.
e Under air.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

C
C.-P. Chuang et al.
Paper
Synthesis
stituent and N-TMBn group. Indeed, as the size of R2 group
decreased, the reaction yields of 2t–v (R2 = Me) were in-
creased. In spite of the size of the phenyl group, substrates
1y and 1z bearing a phenyl group at ortho-position dis-
played high reactivity in this transformation and provided
the corresponding oxindoles in moderate yields (2y and 2z).
The other expected spirodihydroquinolinones 5y and 5z,
generated via the 6-exo-trig (6-ipso) cyclization, were not
found.18b,23 This Cu(acac)2-promoted carbocyclization of α-
bromo-N-arylacylamides 1 provides an efficient method for
the synthesis of 3,3′-disubstituted oxindoles 2 using easily
available Phen as the ligand.24
Cu(II)
Cu(III)
O
Br
N
•
syn-I
O
N
TMBn
TMBn
1a
Cu(III)
Cu(II)
•
O
•
N
TMBn
O
N
anti-I
II
TMBn
O
O
Br
N
N
TMBn
R1
Cu(acac)2
III
2a
R1
TMBn
O
Phen
O
N
R2
N
R2
1
Scheme 2 Proposed reaction mechanism for the formation of 3,3′-
disubstituted oxindoles
2
2a, R2 = TMBn, 90%
2b, R2 = Bn, 87%
2c, R2 = Me, 83%
2d, R2 = Ph, 62%
2e, R2 = H, 0%
2f, R1 = Me, 92%
2g, R1 = OMe, 88%
2h, R1 = F, 58%
R1
O
O
N
R2
N
yield (entry 19). With these screening studies, the optimal
conditions were established using Cu(acac)2 (2 equiv) and
Phen (2 equiv) in EtCN under N2 atmosphere (entry 12).
Under the optimal Cu(acac)2/Phen conditions (Table 1,
entry 12), the scope and limitations of this copper-promot-
ed cyclization reaction were then investigated and the re-
sults are summarized in Scheme 3. N-Alkyl protecting acyl-
amides 1a–c underwent efficient intramolecular ring clo-
sure. With 1a bearing a bulkier TMBn group, the reaction
provided the expected oxindole 2a in best yield (90%), pre-
sumably because the introduction of a larger N-protecting
group would shift the equilibrium in favor of the anti-I con-
former, which could cyclize to produce 2a (Scheme 2). N-
Phenylacylamide 1d is also suitable for this transformation
and the corresponding oxindole 2d was formed in moder-
ate yield (62%). Acylamide 1e bearing a free NH group failed
to give the desired product 2e due to the dominance of the
syn-conformer with unfavorable geometry for cyclization.
Next, we turned our attention to the substituent effect on
the N-aryl ring of acylamides 1. A variety of electron-donat-
ing groups such as methyl and methoxy as well as electron-
withdrawing groups such as fluoro, chloro, bromo, meth-
oxycarbonyl, and cyano at the para-position of the aniline
moiety were well tolerated. The electron-donating substit-
uents clearly gave higher yields than their electron-with-
drawing counterparts (2f–l). Halo-substituted oxindoles
2h–j, which could allow for further modifications, were
synthesized in lower yields. As for the meta-substituted
substrates 1m–p, the reaction provided a mixture of two
regioisomers in good yields; however, the regioselectivity is
rather poor. In most cases, products 2m–p derived from cy-
clization at the more hindered site are preferred.22 Further-
more, the ortho-substituents exhibit a particularly distinct
steric hindrance effect, and the corresponding oxindoles
2q–s and 2x were obtained in relatively low yields. This is
presumably due to the steric effect between the ortho-sub-
2i, R1 = Cl, 71%
TMBn
2j, R1 = Br, 71%
2k, R1 = CO2Me, 82%
2l, R1 = CN, 86%
R1
2m + 2m', R1 = Me, 94% (2.76:1)
2n + 2n', R1 = OMe, 96% (1.74:1)
2o + 2o', R1 = Br, 71% (2.74:1)
2p + 2p', R1 = CO2Me, 82% (1.05:1)
O
+
O
O
R1
N
N
TMBn
TMBn
2q, R1 = Me, 57%
2r, R1 = Cl, 39%
2s, R1 = Br, 29%
2t, R1 = Me, 81%
2u, R1 = Cl, 54%
2v, R1 = Br, 49%
O
N
N
Me
1
TMBn
R
R1
O
O
O
N
O
+
N
N
R2
2w, 94%
2x, 62%
TMBn
TMBn
O
N
R2
R3
2y, R2 = Bn, R3 = H, 65%
2z, R2 = TMBn, R3 = OMe, 70%
5y, R2 = Bn, 0%
5z, R2 = TMBn, 0%
Scheme 3 Cu(acac)2-promoted carbocyclization reactions of α-bro-
mo-N-arylacylamides 1. Reaction conditions: The reaction was carried
out using 1 (0.40 mmol) with Cu(acac)2 (2 equiv) and Phen (2 equiv) in
EtCN (3 mL) at 90 °C for 6 h under N2 atmosphere. Isolated yields are
shown. The product ratios were determined by 1H NMR spectroscopy.
To gain a further understanding about the reaction
mechanism, several inhibition experiments were conduct-
ed. As shown in Scheme 4, the reaction of 1a with Cu(acac)2
and Phen proceeded under the optimized conditions in the
presence of a radical scavenger TEMPO (2,2,6,6-tetrameth-
ylpiperidinyloxy, 1 equiv) and a 67% yield of 2a was ob-
tained. By increasing the loading of TEMPO to 3 equivalents,
the yield of the target product 2a was further reduced to
12%. Another radical inhibitor BHT (2,6-di-tert-butyl-4-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

D
C.-P. Chuang et al.
Paper
Synthesis
methylphenol, 3 equiv) was also applied. The reaction was
suppressed and 2a was isolated in low yield (9%). In addi-
tion, the radical-trapping adduct 6a was also formed in 50%
yield. These results could indicate that a radical intermedi-
ate is involved in the reaction.
On the basis of these observations and the previous lit-
erature reports,8,10 we propose a plausible reaction mecha-
nism for the generation of oxindoles 2 (see Scheme 2). The
reaction of α-bromoacylamide 1a with copper(II) species
leads to the formation of carbamoylmethyl radical I and
copper(III)25 species via a single-electron transfer process. A
five-membered-ring cyclization of radical I onto the aryl
ring would generate the radical intermediate II. Subse-
quently, the copper(III) oxidation of II affords the corre-
sponding carbocation III, followed by the loss of H+, thus
producing oxindole 2a and regenerating the copper(II) spe-
cies.
To further expand the substrate scope of this chemistry,
we also extended the substrates to N-arylsulfonyl-substi-
tuted acylamides 7 (Scheme 5). Initially, we examined the
reaction of 7a (R1 = H) with Cu(acac)2 and Phen in EtCN at
90 °C. The α-phenylacylamide 8a bearing a quaternary ste-
reocenter, derived from the radical 1,4-aryl migration (via
5-ipso cyclization/desulfonylation) was produced exclusive-
ly in 77% yield (Scheme 6) and another expected oxindole
9a, generated via the five-membered-ring radical cycliza-
tion, was not observed. Notably, the reaction proceeded
with high site-selectivity through the carbon that was
bonded to the SO2 group in the starting acylamide 7a. The
scope and limitations of this transformation were next ex-
plored and the results are presented in Scheme 6. As ex-
pected, α-phenylacylamides 8 were formed successfully
from the corresponding acylamides 7. Both electron-donat-
ing (methyl and methoxy) and electron-withdrawing
groups (fluoro, chloro, bromo, and cyano) at the para-posi-
tion of the arylsulfonyl ring do not influence the reactivity
remarkably and the target products 8a–g could be obtained
in good to excellent yields. In contrast to the results shown
in Scheme 3, the ortho-substituents showed no significant
steric effect on this reaction and the target products 8h–j
were generated in good yields. This Cu(acac)2/Phen-pro-
moted carbocyclization of N-arylsulfonyl-substituted acyl-
Br
Cu(acac)2
+
O
Phen
HN
TMBn
O
N
N
TMBn
TMBn
1a
TEMPO
1 equiv
2 equiv
3 equiv
2a
3a
67%
31%
12%
11%
12%
12%
tBu
O
Br
Cu(acac)2
Phen
O
+
tBu
O
N
N
1a
TMBn
TMBn
O
N
TMBn
2a
6a
BHT
53%
18%
9%
24%
44%
50%
1 equiv
2 equiv
3 equiv
Scheme 4 Cyclization reactions of 1a in the presence of radical scav-
engers
O
Br
Tol
O
R1
N
H
Cu salt
base
O
S
+
O
N
N
O
R1
Tol
7
8
9
SO2Ar
Scheme 5 Cyclization of N-arylsulfonyl-substituted acylamides
O
Br
Tol
R1
Cu salt
base
O
N
H
S
O
N
O
R1
Tol
8
7
O
O
O
O
O
Tol
Tol
Tol
Tol
Tol
N
N
N
N
N
H
H
H
H
H
8c, 83%
8e, 79%
8a, 77%
8b, 83%
8d, 77%
Cl
F
OMe
O
O
O
O
O
Tol
Tol
Tol
Tol
Tol
N
H
N
H
N
H
N
H
N
H
Cl
Br
8h, 76%
8f, 87%
8g, 81%
8i, 87%
8j, 84%
Br
CN
Scheme 6 Cu(acac)2-promoted reactions of α-bromo-N-arylsulfonylacylamides 7. Reagents and conditions: The reaction was carried out using 7 (0.45
mmol) with Cu(acac)2 (2 equiv) and Phen (2 equiv) in EtCN (3 mL) at 90 °C for 6 h under N2 atmosphere. Isolated yields are shown.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
C.-P. Chuang et al.
Paper
Synthesis
amides 7 provides a mild and facile route for the synthesis
of α-arylacylamides 8 containing an all-carbon quaternary
center.
relative to TMS as internal reference. The multiplicity of the 13C NMR
signals was determined by means of DEPT 135 experiments. Elemen-
tal analyses were performed with Heraeus CHN-Rapid Analyzer. Mass
spectra were recorded on a Jeol JMS-SX 102A mass spectrometer. An-
alytical TLC was performed with precoated silica gel 60 F254 plates
(0.25 mm thick) from EM Laboratories and visualized by UV. The re-
action mixture was purified by column chromatography over EM Lab-
oratories silica gel (70–230 mesh).
α-Arylacylamides 8 are presumably formed by the reac-
tion mechanism shown in Scheme 7.26 Carbamoylmethyl
radical IV, generated via a SET process of 7a, undergoes a 5-
exo-trig (5-ipso) radical cyclization onto the arylsulfonyl
ring to generate radical V. Subsequently, the desulfonyla-
tion of radical V, followed by the extrusion of SO2, takes
place to produce amidyl radical VI. Finally, amidyl radical VI
gets transformed into α-arylacylamide 8a after hydrogen
abstraction.
The preparation of α-bromo-N-arylacylamides 1 and α-bromo-N-ar-
ylsulfonylacylamides 7 are provided in the Supporting Information.
Cu(acac)2-Promoted Carbocyclization Reactions of α-Bromo-N-
arylacylamides 1; 3,3-Dimethyl-1-(2,4,6-trimethylbenzyl)indolin-
2-one (2a); Typical Procedure
Cu(II)
Cu(III)
A mixture of α-bromo-N-arylacylamide 1a (150 mg, 0.40 mmol),
Cu(acac)2 (212 mg, 0.81 mmol) and Phen (147 mg, 0.81 mmol) in
EtCN (3 mL) was stirred at 90 °C for 6 h under N2 atmosphere. The
reaction mixture was then diluted with EtOAc (50 mL), washed with
H2O (3 × 50 mL), dried (Na2SO4), and concentrated in vacuo. The crude
product was purified by column chromatography over silica gel (20 g)
(eluent: 1:20 EtOAc–hexane) followed by crystallization (EtOAc–hex-
ane) to give 2a as colorless needles; yield: 106 mg (90%); mp 93–94 °C
(EtOAc–hexane).
Br
•
O
O
S
S
O
N
O
N
7a
O
O
IV
Tol
Tol
O
O
Tol
N
Tol
N
•
SO2
•
– SO2
IR (KBr): 2975, 1710, 1610, 1485, 1350 cm–1
.
V
VI
1H NMR (400 MHz, CDCl3): δ = 1.39 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.31 (s, 6 H, 2 × CH3), 4.98 (s, 2 H, NCH2), 6.38 (dd, J = 7.5, 1.2 Hz, 1 H,
ArH), 6.85 (s, 2 H, ArH), 6.95 (td, J = 7.5, 1.2 Hz, 1 H, ArH), 7.00 (td, J =
7.5, 1.5 Hz, 1 H, ArH), 7.16 (dd, J = 7.5, 1.5 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.8 (q), 24.6 (2 q), 39.5
(t), 43.8 (s), 109.4 (d), 122.1 (2 d), 127.5 (d), 128.4 (s), 129.7 (2 d),
135.9 (s), 137.14 (2 s), 137.19 (s), 141.9 (s), 180.9 (s).
O
hydrogen
abstraction
Tol
N
H
8a
Scheme 7 Proposed reaction mechanism for the formation of α-aryl-
acylamides
Anal. Calcd for C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found: C, 81.89;
H, 7.92; N, 4.75.
1-Benzyl-3,3-dimethylindolin-2-one (2b)
In conclusion, an efficient method has been developed
for the synthesis of oxindoles and α-arylacylamides bearing
an all carbon quaternary stereocenter from the readily pre-
pared α-bromo-N-arylacylamides. Carbamoylmethyl radi-
cal, produced from the Cu(acac)2-promoted SET reaction of
α-bromo-N-arylacylamides, undergoes either a five-mem-
bered-ring cyclization onto the N-aryl ring to produce oxin-
doles or a 5-exo-trig (5-ipso) cyclization with the arylsulfo-
nyl ring followed by desulfonylation to generate α-arylacyl-
Yield: 101mg (87%); colorless crystals; mp 90–91 °C (EtOAc–hexane).
IR (KBr): 1715, 1615, 1490, 1380, 1360 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.44 (s, 6 H, 2 × CH3), 4.92 (s, 2 H,
NCH2), 6.72 (d, J = 7.6 Hz, 1 H, ArH), 7.02 (t, J = 7.6 Hz, 1 H, ArH), 7.13
(td, J = 7.6, 1.2 Hz, 1 H, ArH), 7.21 (d, J = 7.6 Hz, 1 H, ArH), 7.25–7.34
(m, 5 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 24.5 (2 q), 43.5 (t), 44.2 (s), 109.0 (d),
122.3 (d), 122.5 (d), 127.1 (2 d), 127.49 (d), 127.53 (d), 128.7 (2 d),
135.8 (s), 136.1 (s), 141.6 (s), 181.4 (s).
amides.
In
this
Cu(acac)2/Phen-promoted
radical
Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.32;
H, 6.83; N, 5.53.
cyclization reaction, oxindoles and α-arylacylamides were
formed in high chemoselectivity depending on the substit-
uents on the nitrogen atom. This process has the advantag-
es such as mild reaction conditions, high reaction yields
and tolerance of a broad range of functional groups includ-
ing methoxy, fluoro, chloro, bromo, methoxycarbonyl, and
cyano groups.
1,3,3-Trimethylindolin-2-one (2c)
Yield: 85 mg (83%); yellow liquid.
IR (neat): 1715, 1615, 1470, 1350, 1125 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.37 (s, 6 H, 2 × CH3), 3.21 (s, 3 H, CH3),
6.84 (d, J = 7.6 Hz, 1 H, ArH), 7.06 (t, J = 7.6 Hz, 1 H, ArH), 7.20 (d, J =
7.6 Hz, 1 H, ArH), 7.25 (t, J = 7.6 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 24.2 (2 q), 26.0 (q), 44.0 (s), 107.9
(d), 122.1 (d), 122.3 (d), 127.5 (d), 135.7 (s), 142.5 (s), 181.2 (s)
HRMS (EI): m/z [M]+ calcd for C11H13NO: 175.0997; found: 175.0991.
Melting points are uncorrected. IR spectra were recorded on a Hitachi
260-30 spectrometer. 1H and 13C NMR spectra were recorded on a
Bruker AMX-400 spectrometer. Chemical shifts are reported in ppm
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

F
C.-P. Chuang et al.
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Synthesis
3,3-Dimethyl-1-phenylindolin-2-one (2d)
Anal. Calcd for C20H22FNO: C, 77.14; H, 7.12; N, 4.50. Found: C, 77.26;
H, 7.20; N, 4.46.
Yield: 70 mg (62%); colorless crystals; mp 84–85 °C (EtOAc–hexane).
IR (KBr): 1725, 1610, 1590, 1480, 1205 cm–1
.
5-Chloro-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2i)
1H NMR (400 MHz, CDCl3): δ = 1.49 (s, 6 H, 2 × CH3), 6.85 (d, J = 7.4 Hz,
1 H, ArH), 7.10 (t, J = 7.4 Hz, 1 H, ArH), 7.19 (t, J = 7.4 Hz, 1 H, ArH),
7.27 (t, J = 7.4 Hz, 1 H, ArH), 7.39 (d, J = 7.4 Hz, 1 H, ArH), 7.42 (d, J =
7.7 Hz, 2 H, ArH), 7.52 (d, J = 7.7 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 24.7 (2 q), 44.3 (s), 109.3 (d), 122.6
(d), 122.9 (d), 126.5 (2 d), 127.5 (d), 127.8 (d), 129.5 (2 d), 134.6 (s),
135.6 (s), 142.5 (s), 180.7 (s).
Yield: 84 mg (71%); colorless crystals; mp 145–146 °C (EtOAc–hex-
ane).
IR (KBr): 1715, 1610, 1485, 1325 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.39 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.28 (s, 6 H, 2 × CH3), 4.96 (s, 2 H, NCH2), 6.25 (d, J = 8.4 Hz, 1 H, ArH),
6.85 (s, 2 H, ArH), 6.96 (dd, J = 8.4, 2.1 Hz, 1 H, ArH), 7.13 (d, J = 2.1 Hz,
1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.5 (2 q), 39.6
(t), 44.0 (s), 110.4 (d), 122.7 (d), 127.5 (d), 127.6 (s), 128.0 (s), 129.8 (2
d), 137.1 (2 s), 137.5 (s), 137.6 (s), 140.4 (s), 180.4 (s).
Anal. Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.71;
H, 6.38; N, 5.83.
3,3,5-Trimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2f)
Yield: 110 mg (92%); colorless crystals; mp 137–138 °C (EtOAc–hex-
ane).
Anal. Calcd for C20H22ClNO: C, 73.27; H, 6.76; N, 4.27. Found: C, 73.21;
H, 6.75; N, 4.25.
IR (KBr): 1715, 1495, 1330 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.38 (s, 6 H, 2 × CH3), 2.25 (s, 3 H, CH3),
2.26 (s, 3 H, CH3), 2.30 (s, 6 H, 2 × CH3), 4.96 (s, 2 H, NCH2), 6.26 (d, J =
8.0 Hz, 2 H, ArH), 6.79 (d, J = 8.0 Hz, 2 H, ArH), 6.84 (s, 2 H, ArH), 6.98
(s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.8 (q), 20.9 (q), 24.7 (2
q), 39.5 (t), 43.8 (s), 109.1 (d), 122.9 (d), 127.8 (d), 128.5 (s), 129.6 (2
d), 131.5 (s), 136.0 (s), 137.1 (3 s), 139.4 (s), 180.8 (s).
5-Bromo-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2j)
Yield: 88 mg (71%); colorless crystals; mp 166–167 °C (EtOAc–hex-
ane).
IR (KBr): 1715, 1605, 1485, 1465 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 6 H, 2 × CH3), 2.25 (s, 3 H, CH3),
2.27 (s, 6 H, 2 × CH3), 4.92 (s, 2 H, NCH2), 6.25 (d, J = 8.4 Hz, 1 H, ArH),
6.86 (s, 2 H, ArH), 7.12 (dd, J = 8.4, 2.1 Hz, 1 H, ArH), 7.29 (d, J = 2.1 Hz,
1 H, ArH).
Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 81.96;
H, 8.22; N, 4.52.
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.6 (2 q), 39.6
(t), 44.0 (s), 110.9 (d), 115.0 (s), 125.5 (d), 127.9 (s), 129.8 (2 d), 130.4
(d), 137.1 (2 s), 137.5 (s), 138.0 (s), 140.9 (s), 180.3 (s).
5-Methoxy-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2g)
Yield: 105 mg (88%); colorless crystals; mp 131–132 °C (EtOAc–hex-
ane).
Anal. Calcd for C20H22BrNO: C, 64.52; H, 5.96; N, 3.76. Found: C, 64.54;
H, 5.95; N, 3.71.
IR (KBr): 1700, 1600, 1490, 1430 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.38 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.30 (s, 6 H, 2 × CH3), 3.72 (s, 3 H, OCH3), 4.95 (s, 2 H, NCH2), 6.25 (d,
J = 8.6 Hz, 1 H, ArH), 6.52 (dd, J = 8.6, 2.6 Hz, 1 H, ArH), 6.77 (d, J = 2.6
Hz, 1 H, ArH), 6.84 (s, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.7 (2 q), 39.5
(t), 44.2 (s), 55.6 (q), 109.7 (d), 109.8 (d), 111.4 (d), 128.5 (s), 129.7 (2
d), 135.3 (s), 137.2 (3 s), 137.4 (s), 155.6 (s), 180.6 (s).
5-(Methoxycarbonyl)-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)in-
dolin-2-one (2k)
Yield: 99 mg (82%); colorless needles; mp 169–170 °C (EtOAc–hex-
ane).
IR (KBr): 1715, 1620, 1295, 1250 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.42 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.29 (s, 6 H, 2 × CH3), 3.86 (s, 3 H, OCH3), 5.00 (s, 2 H, NCH2), 6.39 (d,
J = 8.3 Hz, 1 H, ArH), 6.86 (s, 2 H, ArH), 7.75 (dd, J = 8.3, 1.7 Hz, 1 H,
ArH), 7.83 (d, J = 1.7 Hz, 1 H, ArH).
Anal. Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 78.00;
H, 7.85; N, 4.32.
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.5 (2 q), 39.7
(t), 43.6 (s), 51.9 (q), 108.9 (d), 123.4 (d), 124.0 (s), 127.9 (s), 129.8 (2
d), 130.3 (d), 135.8 (s), 137.1 (2 s), 137.5 (s), 146.1 (s), 166.9 (s), 181.2
(s).
5-Fluoro-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2h)
Yield: 69 mg (58%); colorless crystals; mp 128–129 °C (EtOAc–hex-
ane).
Anal. Calcd for C22H25NO3: C, 75.19; H, 7.19; N, 3.99. Found: C, 75.04;
H, 7.17; N, 3.95.
IR (KBr): 1710, 1610, 1490, 1445 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.39 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.29 (s, 6 H, 2 × CH3), 4.96 (s, 2 H, NCH2), 6.26 (dd, J = 8.6, 4.3 Hz, 1 H,
ArH), 6.69 (td, J = 8.6, 2.6 Hz, 1 H, ArH), 6.85 (s, 2 H, ArH), 6.90 (dd, J =
8.6, 2.6 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.5 (2 q), 39.6
(t), 44.2 (s), 109.9 (dd, J = 8.0 Hz), 110.2 (d, J = 24.1 Hz), 113.7 (dd, J =
23.1 Hz), 128.1 (s), 129.7 (2 d), 137.1 (2 d), 137.4 (s), 137.6 (sd, J = 6.0
Hz), 137.7 (s), 159.0 (sd, J = 241.4 Hz), 180.5 (s).
5-Cyano-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2l)
Yield: 115 mg (86%); colorless crystals; 208–209 °C (EtOAc–hexane).
IR (KBr): 2220, 1720, 1615, 1490, 1330 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.41 (s, 6 H, 2 × CH3), 2.27 (s, 3 H, CH3),
2.28 (s, 6 H, 2 × CH3), 4.99 (s, 2 H, NCH2), 6.39 (d, J = 8.3 Hz, 1 H, ArH),
6.87 (s, 2 H, ArH), 7.31 (dd, J = 8.3, 1.7 Hz, 1 H, ArH), 7.40 (d, J = 1.7 Hz,
1 H, ArH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

G
C.-P. Chuang et al.
Paper
Synthesis
13C NMR (100.6 MHz, CDCl3): δ = 20.2 (2 q), 20.8 (q), 24.4 (2 q), 39.7
(t), 43.6 (s), 105.2 (s), 109.7 (d), 119.2 (s), 125.5 (d), 127.4 (s), 129.9 (2
d), 132.9 (d), 136.7 (s), 137.0 (2 d), 137.8 (s), 145.8 (s), 180.5 (s).
4-Bromo-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2o) and 6-Bromo-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-
2-one (2o′)
Yield: 147 mg (71%, 2.74:1).
Anal. Calcd for C21H22N2O: C, 79.21; H, 6.96; N, 8.80. Found: C, 79.31;
H, 6.98; N, 8.83.
2o
3,3,4-Trimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2m) and
Colorless crystals; mp 137–138 °C (EtOAc–hexane).
3,3,6-Trimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2m′)
IR (KBr): 1715, 1600, 1450, 1325, 1170 cm–1
.
Yield: 112 mg (94%, 2.76:1).
1H NMR (400 MHz, CDCl3): δ = 1.55 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.29 (s, 6 H, 2 × CH3), 4.97 (s, 2 H, NCH2), 6.34 (d, J = 8.0 Hz, 1 H, ArH),
6.85 (s, 2 H, ArH), 6.86 (t, J = 8.0 Hz, 1 H, ArH), 7.06 (d, J = 8.0 Hz,1 H,
ArH).
2m
Colorless crystals; mp 157–158 °C (EtOAc–hexane).
IR (KBr): 2970, 2925, 1705, 1595, 1470 cm–1
.
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 21.6 (2 q), 39.6
(t), 46.1 (s), 108.4 (d), 118.5 (s), 126.4 (d), 128.1 (s), 129.0 (d), 129.8 (2
d), 133.2 (s), 137.1 (2 s), 137.4 (s), 144.0 (s), 180.3 (s).
1H NMR (400 MHz, CDCl3): δ = 1.48 (s, 6 H, 2 × CH3), 2.25 (s, 3 H, CH3),
2.30 (s, 6 H, 2 × CH3), 2.37 (s, 3 H, CH3), 4.97 (s, 2 H, NCH2), 6.27 (d, J =
7.8 Hz, 1 H, ArH), 6.72 (d, J = 7.8 Hz, 1 H, ArH), 6.83 (s, 2 H, ArH), 6.91
(t, J = 7.8 Hz, 1 H, ArH).
Anal. Calcd for C20H22BrNO: C, 64.52; H, 5.96; N, 3.76. Found: C, 64.45;
H, 5.99; N, 3.70.
13C NMR (100.6 MHz, CDCl3): δ = 18.2 (q), 20.3 (2 q), 20.8 (q), 22.6 (2
q), 39.6 (t), 44.6 (s), 107.2 (d), 124.7 (d), 127.3 (d), 128.6 (s), 129.7 (2
d), 132.6 (s), 133.8 (s), 137.1 (3 s), 142.2 (s), 180.9 (s).
2o′
Colorless crystals; mp 125–126 °C (EtOAc–hexane).
IR (KBr): 1715, 1600, 1485, 1330, 1170 cm–1
.
Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 82.12;
H, 8.21; N, 4.52.
1H NMR (400 MHz, CDCl3): δ = 1.37 (s, 6 H, 2 × CH3), 2.27 (s, 3 H, CH3),
2.30 (s, 6 H, 2 × CH3), 4.94 (s, 2 H, NCH2), 6.53 (d, J = 1.7 Hz, 1 H, ArH),
6.87 (s, 2 H, ArH), 7.01 (d, J = 7.9 Hz, 1 H, ArH), 7.09 (dd, J = 7.9, 1.7 Hz,
1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.5 (2 q), 39.6
(t), 43.6 (s), 112.9 (d), 120.9 (s), 123.4 (d), 124.9 (d), 127.7 (s), 129.8 (2
d), 134.8 (s), 137.1 (2 s), 137.6 (s), 143.3 (s), 180.7 (s).
4-Methoxy-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2n) and 6-Methoxy-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indo-
lin-2-one (2n′)
Yield: 195 mg (96%, 1.74:1).
2n
Anal. Calcd for C20H22BrNO: C, 64.52; H, 5.96; N, 3.76. Found: C, 64.49;
H, 6.08; N, 3.67.
Colorless crystals; mp 162–163 °C (EtOAc–hexane).
IR (KBr): 1715, 1600, 1470, 1260 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 (s, 6 H, 2 × CH3), 2.25 (s, 3 H, CH3),
2.30 (s, 6 H, 2 × CH3), 3.81 (s, 3 H, OCH3), 4.95 (s, 2 H, NCH2), 6.05 (d,
J = 8.2 Hz, 1 H, ArH), 6.51 (d, J = 8.2 Hz, 1 H, ArH), 6.83 (s, 2 H, ArH),
6.96 (t, J = 8.2 Hz, 1 H, ArH).
4-(Methoxycarbonyl)-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)in-
dolin-2-one (2p) and 6-(Methoxycarbonyl)-3,3-dimethyl-1-(2,4,6-
trimethylbenzyl)indolin-2-one (2p′)
Yield: 167 mg (82%, 1.05:1).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.8 (q), 22.3 (2 q), 39.6
(t), 44.2 (s), 55.2 (q), 102.8 (d), 105.4 (d), 121.2 (s), 128.6 (d), 128.7 (s),
129.6 (2 d), 137.07 (s), 137.11 (2 s), 143.1 (s), 155.9 (s), 181.3 (s).
2p
Colorless crystals; mp 148–149 °C (EtOAc–hexane).
IR (KBr): 1730, 1715, 1600, 1455 cm–1
.
Anal. Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 77.95;
H, 7.83; N, 4.27.
1H NMR (400 MHz, CDCl3): δ = 1.58 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.30 (s, 6 H, 2 × CH3), 3.91 (s, 3 H, OCH3), 5.01 (s, 2 H, NCH2), 6.59 (dd,
J = 8.0, 0.8 Hz, 1 H, ArH), 6.85 (s, 2 H, ArH), 7.08 (t, J = 8.0 Hz, 1 H, ArH),
7.55 (dd, J = 8.0, 0.8 Hz, 1 H, ArH).
2n′
Colorless crystals; mp 138–139 °C (EtOAc–hexane).
IR (KBr): 1715, 1625, 1500, 1165 cm–1
.
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.8 (q), 22.4 (2 q), 39.7
(t), 45.9 (s), 52.0 (q), 113.1 (d), 124.2 (d), 127.1 (s), 127.5 (d), 128.1 (s),
129.8 (2 d), 136.5 (s), 137.0 (2 s), 137.3 (s), 143.3 (s), 166.4 (s), 181.2
(s).
1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 6 H, 2 × CH3), 2.25 (s, 3 H, CH3),
2.31 (s, 6 H, 2 × CH3), 3.59 (s, 3 H, OCH3), 4.96 (s, 2 H, NCH2), 6.00 (d,
J = 2.2 Hz, 1 H, ArH), 6.46 (dd, J = 8.1, 2.2 Hz, 1 H, ArH), 6.85 (s, 2 H,
ArH), 7.04 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.8 (q), 24.9 (2 q), 39.5
(t), 43.3 (s), 55.1 (q), 97.0 (d), 106.5 (d), 122.5 (d), 127.8 (s), 128.4 (s),
129.7 (2 d), 137.2 (2 s), 137.3 (s), 143.0 (s), 159.4 (s), 181.5 (s).
Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C, 75.21;
H, 7.19; N, 3.94.
2p′
Colorless crystals; mp 131–132 °C (EtOAc–hexane).
Anal. Calcd for C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 77.97;
H, 7.77; N, 4.27.
IR (KBr): 1720, 1465, 1450, 1280 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

H
C.-P. Chuang et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.40 (s, 6 H, 2 × CH3), 2.26 (s, 3 H, CH3),
2.35 (s, 6 H, 2 × CH3), 3.83 (s, 3 H, OCH3), 4.99 (s, 2 H, NCH2), 6.88 (s, 2
H, ArH), 7.15 (s, 1 H, ArH), 7.21 (d, J = 7.8 Hz, 1 H, ArH), 7.68 (dd, J =
7.8, 1.4 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.9 (q), 24.4 (2 q), 39.6
(t), 44.1 (s), 52.1 (q), 110.3 (d), 121.9 (d), 124.0 (d), 127.9 (s), 129.7 (2
d), 137.3 (3 s), 137.5 (s), 141.0 (s), 142.2 (s), 166.7 (s), 180.5 (s).
1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 6 H, 2 × CH3), 2.59 (s, 3 H, CH3),
3.50 (s, 3 H, NCH3), 6.91–7.00 (m, 2 H, ArH), 7.04 (d, J = 7.0 Hz, 1 H,
ArH).
13C NMR (100.6 MHz, CDCl3): δ = 19.0 (q), 24.7 (2 q), 29.5 (q), 43.5 (s),
119.6 (s), 120.2 (d), 122.4 (d), 131.3 (d), 136.5 (s), 140.3 (s), 182.1 (s)
HRMS(EI): m/z [M]+ calcd for C12H15NO: 189.1154; found: 189.1157.
Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C, 75.23;
H, 7.19; N, 3.95.
7-Chloro-1,3,3-trimethylindolin-2-one (2u)
Yield: 79 mg (54%); colorless oil.
IR (neat): 1715, 1455, 1365, 1085, 1065 cm–1
.
3,3,7-Trimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2q)
1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 6 H, 2 × CH3), 3.59 (s, 3 H,
NCH3), 6.96 (t, J = 7.7 Hz, 1 H, ArH), 7.08 (d, J = 7.7 Hz, 1 H, ArH), 7.18
(dd, J = 7.7, 0.7 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 24.6 (2 q), 29.5 (q), 43.9 (s), 115.4 (s),
120.8 (d) 123.3(d), 129.9 (d), 138.5 (s), 138.6 (s), 181.5 (s).
Yield: 68 mg (57%); colorless crystals; mp 122–123 °C (EtOAc–hex-
ane).
IR (KBr): 1705, 1605, 1460, 1355, 1175 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.35 (s, 6 H, 2 × CH3), 2.21 (s, 9 H, 3 ×
CH3), 2.24 (s, 3 H, CH3), 5.16 (s, 2 H, NCH2), 6.79 (s, 2 H, NCH2), 6.90–
6.97 (m, 2 H, ArH), 7.03–7.08 (m, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 18.6 (q), 20.5 (2 q), 20.7 (q), 24.7 (2
q), 42.7 (t), 43.2 (s), 120.0 (s), 120.3 (d), 122.4 (d), 130.1 (2 d), 131.4
(s), 131.6 (d), 135.7 (2 s), 136.2 (s), 136.7 (s), 140.8 (s), 182.3 (s).
HRMS (EI): m/z [M]+ calcd for C11H12ClNO: 209.0607; found:
209.0605.
7-Bromo-1,3,3-trimethylindolin-2-one (2v)
Yield: 75 mg (49%); colorless oil.
Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56. Found: C, 82.08;
H, 8.21; N, 4.52.
IR (neat): 1700, 1455, 1360, 1335, 1060 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 6 H, 2 × CH3), 3.60 (s, 3 H,
NCH3), 6.90 (t, J = 7.7 Hz, 1 H, ArH), 7.12 (d, J = 7.7 Hz, 1 H, ArH), 7.36
(d, J = 7.7 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 24.6 (2 q), 29.7 (q), 43.9 (s), 102.3 (s),
121.3 (d), 123.6 (d), 133.2 (d), 138.9 (s), 139.9 (s), 181.6 (s).
7-Chloro-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2r)
Yield: 47 mg (39%); colorless crystals; mp 139–140 °C (EtOAc–hex-
ane).
HRMS (EI): m/z [M]+ calcd for C11H12BrNO: 253.0102; found:
IR (KBr): 1710, 1460, 1380, 1345, 1165 cm–1
.
253.0095.
1H NMR (400 MHz, CDCl3): δ = 1.32 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
2.27 (s, 6 H, 2 × CH3), 5.36 (s, 2 H, NCH2), 6.79 (s, 2 H, ArH), 6.96 (t, J =
7.7 Hz, 1 H, ArH), 7.10 (dd, J = 7.7, 1.1 Hz, 1 H, ArH), 7.16 (dd, J = 7.7,
1.1 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.5 (2 q), 20.8 (q), 24.6 (2 q), 42.3
(t), 43.5 (s), 115.3 (s), 121.0 (d), 123.2 (d), 129.6 (2 d), 130.4 (d), 130.8
(s), 136.23 (s), 136.30 (2 s), 138.77 (s), 138.82 (s), 181.6 (s).
3,3,4,6-Tetramethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2w)
Yield: 115 mg (94%); colorless crystals; mp 142–143 °C (EtOAc–hex-
ane).
IR (KBr): 1700, 1615, 1455, 1340, 1165 cm–1
1H NMR (400 MHz, CDCl3): δ = 1.45 (s, 6 H, 2 × CH3), 2.13 (s, 3 H, CH3),
2.25 (s, 3 H, CH3), 2.31 (s, 6 H, 2 × CH3), 2.33 (s, 3 H, CH3), 4.94 (s, 2 H,
NCH2), 6.13 (s, 1 H, ArH), 6.55 (s, 1 H, ArH), 6.84 (s, 1 H, ArH).
.
Anal. Calcd for C20H22ClNO: C, 73.27; H, 6.76; N, 4.27. Found: C, 73.17;
H, 6.75; N, 4.22.
13C NMR (100.6 MHz, CDCl3): δ = 18.1 (q), 20.3 (2 q), 20.8 (q), 21.5 (q),
22.7 (2 q), 39.6 (t), 44.4 (s), 108.1 (d), 125.3 (d), 128.7 (s), 129.6 (2 d),
129.7 (s), 133.5 (s), 137.03 (s), 137.07 (2 s), 137.10 (s), 142.4 (s), 181.3
(s).
7-Bromo-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one
(2s)
Yield: 36 mg (29%); colorless crystals; mp 165–166 °C (EtOAc–hex-
ane).
Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 82.15;
H, 8.53; N, 4.31.
IR (KBr): 1710, 1460, 1445, 1345, 1165 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3),
2.27 (s, 6 H, 2 × CH3), 5.39 (s, 2 H, NCH2), 6.79 (s, 2 H, ArH), 6.90 (t, J =
7.6 Hz, 1 H, ArH), 7.14 (d, J = 7.6 Hz, 1 H, ArH), 7.37 (d, J = 7.6 Hz, 1 H,
ArH).
3,3,5,7-Tetramethyl-1-(2,4,6-trimethylbenzyl)indolin-2-one (2x)
Yield: 100 mg (62%); colorless crystals; mp 157–158 °C (EtOAc–hex-
ane).
13C NMR (100.6 MHz, CDCl3): δ = 20.5 (2 q), 20.8 (q), 24.5 (2 q), 42.4
(t), 43.4 (s), 102.3 (s), 121.6 (d), 123.5 (d), 129.6 (2 d), 130.6 (s), 133.8
(d), 136.21 (s), 136.25 (2 s), 139.1 (s), 140.2 (s), 181.8 (s).
IR (KBr): 1710, 1480, 1455, 1335, 1165 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.33 (s, 6 H, 2 × CH3), 2.15 (s, 3 H, CH3),
2.20 (s, 6 H, 2 × CH3), 2.23 (s, 3 H, CH3), 2.27 (s, 3 H, CH3), 5.13 (s, 2 H,
NCH2), 6.72 (s, 1 H, ArH), 6.78 (s, 2 H, ArH), 6.87 (s, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 18.5 (q), 20.5 (2 q), 20.7 (2 q), 24.7 (2
q), 42.6 (t), 43.2 (s), 119.7 (s), 121.1 (d), 130.0 (2 d), 131.4 (s), 131.8
(s), 132.1 (d), 135.8 (2 s), 136.1 (s), 136.8 (s), 138.3 (s), 182.2 (s).
Anal. Calcd for C20H22BrNO: C, 64.52; H, 5.96; N, 3.79. Found: C, 64.63;
H, 6.02; N, 3.72.
1,3,3,7-Tetramethylindolin-2-one (2t)
Yield: 85 mg (81%); colorless oil.
IR (neat): 1705, 1600, 1465, 1345, 1080 cm–1
Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 82.00;
H, 8.51; N, 4.35.
.
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Synthesis
1-Benzyl-3,3-dimethyl-7-phenylindolin-2-one (2y)
1H NMR (400 MHz, CDCl3): δ = 0.85 (s, 6 H, 2 × CH3), 1.23 (s, 18 H, 6 ×
CH3), 1.39 (s, 3 H, CH3), 1.92 (s, 6 H, 2 × CH3), 2.22 (s, 3 H, CH3), 4.95 (s,
2 H, NCH2), 6.70 (s, 2 H, ArH), 6.74 (s, 2 H, ArH), 6.75 (d, J = 7.5 Hz, 2 H,
ArH), 7.13 (t, J = 7.5 Hz, 2 H, ArH), 7.22 (t, J = 7.5 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 19.5 (2 q), 20.9 (q), 23.0 (q), 25.6 (2
q), 29.5 (2 q), 34.9 (2 s), 45.1 (s), 49.1 (t), 53.0 (s), 127.9 (d), 128.2 (2
d), 128.8 (2 d), 130.0 (s), 130.4 (2 d), 137.1 (s), 138.5 (2 s), 141.9 (s),
145.1 (2 d), 146.3 (2 s), 175.7 (s), 186.9 (s).
Yield: 109 mg (65%); yellow oil.
IR (neat): 1710, 1600, 1440, 1345, 1160 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.51 (s, 6 H, 2 × CH3), 4.68 (s, 2 H,
NCH2), 6.46 (d, J = 7.5 Hz, 2 H, ArH), 6.94 (dd, J = 7.5, 1.2 Hz, 1 H, ArH),
6.96–7.11 (m, 6 H, ArH), 7.18 (t, J = 7.5 Hz, 2 H, ArH), 7.24 (dd, J = 7.5,
1.2 Hz, 1 H, ArH), 7.28 (t, J = 7.5 Hz, 1 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 25.1 (2 q), 43.4 (s), 44.6 (t), 121.4 (d),
121.9 (d), 125.8 (2 d), 125.9 (s), 126.6 (d), 127.2 (d), 127.5 (2 d), 128.0
(2 d), 129.8 (2 d), 131.1 (d), 136.4 (s), 136.9 (s), 138.1 (s), 138.8 (s),
182.6 (s).
Anal. Calcd for C35H47NO2: C, 81.82; H, 9.22; N, 2.73. Found: C, 81.95;
H, 9.26; N, 2.69.
Cu(acac)2-Promoted Reactions of α-Bromo-N-arylsulfonylacyl-
amides 7; 2-Methyl-2-phenyl-N-(p-tolyl)propanamide (8a); Typi-
cal Procedure
HRMS (EI): m/z [M]+ calcd for C23H21NO: 327.1623; found: 327.1629.
7-(4-Methoxyphenyl)-3,3-dimethyl-1-(2,4,6-trimethylbenzyl)in-
dolin-2-one (2z)
A mixture of α-bromo-N-arylsulfonylacylamide 7a (180 mg, 0.45
mmol), Cu(acac)2 (237 mg, 0.91 mmol), and Phen (164 mg, 0.91
mmol) in EtCN (3 mL) was stirred at 90 °C for 6 h under N2 atmo-
sphere. After workup as described as above, the crude product was
purified by column chromatography over silica gel (20 g) (eluent:
1:20 EtOAc–hexane) followed by crystallization (EtOAc–hexane) to
give 8a as colorless needles; yield: 88 mg (77%); mp 105–106 °C
(EtOAc–hexane).
Yield: 88 mg (70%); colorless crystals; mp 145–146 °C (EtOAc–hex-
ane).
IR (KBr): 1715, 1515, 1445, 1245 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.30 (s, 6 H, 2 × CH3), 2.07 (s, 6 H, 2 ×
CH3), 2.17 (s, 3 H, CH3), 3.81 (s, 3 H, OCH3), 4.39 (s, 2 H, NCH2), 6.67 (s,
2 H, ArH), 6.85 (d, J = 8.6 Hz, 2 H, ArH), 7.04–7.08 (m, 2 H, ArH), 7.16–
7.27 (m, 3 H, ArH).
IR (KBr): 3285, 1655, 1600, 1515, 1400, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.66 (s, 6 H, 2 × CH3), 2.27 (s, 3 H, CH3),
6.73 (br s, 1 H, NH), 7.06 (d, J = 8.4 Hz, 2 H, ArH), 7.23 (d, J = 8.4 Hz, 2
H, ArH), 7.31 (t, J = 7.3 Hz, 1 H, ArH), 7.40 (t, J = 7.3 Hz, 2 H, ArH), 7.44
(d, J = 7.3 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (2 q), 20.7 (q), 24.6 (2 q), 43.2
(t), 43.6 (s), 55.2 (q), 113.6 (2 d), 121.4 (d), 121.7 (d), 125.2 (s), 129.0
(2 d), 130.3 (s), 130.5 (2 d), 131.4 (d), 131.5 (s), 136.1 (s), 136.7 (2 s),
136.9 (s), 140.1 (s), 159.0 (s), 182.1 (s).
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 27.0 (2 q), 48.0 (s), 119.7 (2
q), 126.5 (2 d), 127.3 (d), 129.0 (2 d), 129.3 (2 d), 133.7 (s), 135.4 (s),
144.7 (s), 175.5 (s).
Anal. Calcd for C27H29NO2: C, 81.17; H, 7.32; N, 3.51. Found: C, 81.16;
H, 7.34; N, 3.46.
Radical Inhibition Experiments; Typical Procedure
Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N, 5.53. Found: C, 80.49;
H, 7.60; N, 5.51.
A mixture of α-bromo-N-arylacylamide 1a (150 mg, 0.40 mmol),
Cu(acac)2 (213 mg, 0.81 mmol), Phen (147 mg, 0.81 mmol), and TEMPO
(190 mg, 1.21 mmol) in EtCN (3 mL) was stirred at 90 °C for 6 h under
N2 atmosphere. After workup as described as above, the crude prod-
uct was purified by column chromatography over silica gel (20 g) (elu-
ent: 1:20 EtOAc–hexane) followed by crystallization (EtOAc–hexane)
to give 2a (19 mg, 12%) and 3a (11 mg, 12%).
2-Methyl-N,2-di(p-tolyl)propanamide (8b)
Yield: 81 mg (83%); colorless needles; mp 117–118 °C (EtOAc–hex-
ane).
IR (KBr): 3355, 1665, 1600, 1515, 1400, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.63 (s, 6 H, 2 × CH3), 2.27 (s, 3 H, CH3),
2.36 (s, 3 H, CH3), 6.77 (br s, 1 H, NH), 7.05 (d, J = 8.2 Hz, 2 H, ArH),
7.20 (d, J = 8.2 Hz, 2 H, ArH), 7.23 (d, J = 8.2 Hz, 2 H, ArH), 7.32 (d, J =
8.2 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 20.9 (q), 27.1 (2 q), 47.6 (s),
119.6 (2 d), 126.4 (2 d), 129.3 (2 d), 129.6 (2 d), 133.6 (s), 135.4 (s),
137.0 (s), 141.6 (s), 175.7 (s).
N-(2,4,6-Trimethylbenzyl)aniline (3a)
Yield: 11 mg (12 %); colorless crystals; mp 63–64 °C (EtOAc-hexane).
IR (KBr): 1605, 1505, 1480, 1430, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 2.28 (s, 3 H, CH3), 2.33 (s, 6 H, 2 × CH3),
3.38 (br s, 1 H, NH), 4.16 (s, 2 H, NCH2), 6.64 (d, J = 7.5 Hz, 2 H, ArH),
6.71 (t, J = 7.5 Hz, 1 H, ArH), 6.88 (s, 2 H, ArH), 7.20 (t, J = 7.5 Hz, 2 H,
ArH).
13C NMR (100.6 MHz, CDCl3): δ = 19.4 (2 q), 20.9 (q), 42.3 (t), 112.4 (2
d), 117.2 (d), 129.0 (2 d), 129.2 (2 d), 132.1 (s), 137.2 (s), 137.4 (2 s),
148.6 (s).
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.85;
H, 7.93; N, 5.23.
2-(4-Methoxyphenyl)-2-methyl-N-(p-tolyl)propanamide (8c)
Yield: 112 mg (83%); colorless crystals; mp 104–105 °C (EtOAc–hex-
ane).
Anal. Calcd for C16H19N: C, 85.28; H, 8.50; N, 6.22. Found: C, 85.28; H,
8.57; N, 6.20.
IR (KBr): 3380, 1650, 1600, 1515, 1405, 1255 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.63 (s, 6 H, 2 × CH3), 2.27 (s, 3 H, CH3),
3.82 (s, 3 H, OCH3), 6.79 (br s, 1 H, NH), 6.92 (d, J = 8.9 Hz, 2 H, ArH),
7.05 (d, J = 8.3 Hz, 2 H, ArH), 7.23 (d, J = 8.3 Hz, 2 H, ArH), 7.35 (d, J =
8.9 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 27.1 (2 q), 47.3 (s), 55.3 (q),
114.2 (2 d), 119.6 (2 d), 127.7 (2 d), 129.3 (2 d), 133.6 (s), 135.4 (s),
136.6 (s), 158.6 (s), 175.8 (s).
Radical-Trapping Adduct 6a
Yield: 103 mg (50%); colorless crystals; mp 152–153 °C (EtOAc–hex-
ane).
IR (KBr): 1620, 1470, 1355, 1240, 1165 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

J
C.-P. Chuang et al.
Paper
Synthesis
Anal. Calcd for C18H21NO2: C, 76.26; H, 7.47; N, 4.94. Found: C, 76.43;
H, 7.50; N, 4.95.
IR (KBr): 3340, 1665, 1595, 1515, 1400, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.65 (s, 6 H, 2 × CH3), 2.28 (s, 3 H, CH3),
2.31 (s, 3 H, CH3), 6.80 (br s, 1 H, NH), 7.07 (d, J = 8.2 Hz, 2 H, ArH),
7.18–7.31 (m, 5 H, ArH), 7.47–7.51 (m, 1 H, ArH).
2-(4-Fluorophenyl)-2-methyl-N-(p-tolyl)propanamide (8d)
13C NMR (100.6 MHz, CDCl3): δ = 20.3 (q), 20.8 (q), 26.9 (2 q), 47.8 (s),
119.8 (2 d), 126.1 (d), 126.4 (d), 127.6 (d), 129.4 (2 d), 132.4 (d), 133.8
(s), 135.5 (s), 137.3 (s), 142.2 (s), 176.4 (s).
Yield: 101 (77%); colorless crystals; mp 108–109 °C (EtOAc–hexane).
IR (KBr): 3340, 1650, 1600, 1510, 1315, 1235 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.64 (s, 6 H, 2 × CH3), 2.28 (s, 3 H, CH3),
6.72 (br s, 1 H, NH), 7.07 (d, J = 8.5 Hz, 2 H, ArH), 7.07 (t, J = 8.7 Hz, 2 H,
ArH), 7.24 (d, J = 8.5 Hz, 2 H, ArH), 7.38–7.44 (m, 2 H, ArH).
Anal. Calcd for C18H21NO: C, 80.86; H, 7.92; N, 5.24. Found: C, 80.71;
H, 7.95; N, 5.21.
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 27.2 (2 q), 47.5 (s), 115.75
(2 dd, JC,F = 21.1 Hz), 119.7 (2 d), 128.1 (2 dd, JC,F = 8.0 Hz), 129.4 (2 d),
133.9 (s), 135.2 (s), 140.5 (sd, JC,F = 3.0 Hz), 161.9 (sd, JC,F = 246.5 Hz),
175.1 (s).
2-(2-Chlorophenyl)-2-methyl-N-(p-tolyl)propanamide (8i)
Yield: 131 mg (87%); colorless needles; mp 101–102 °C (EtOAc–hex-
ane).
Anal. Calcd for C17H18FNO: C, 75.25; H, 6.69; N, 5.16. Found: C, 75.24;
H, 6.73; N, 5.14.
IR (KBr): 3300, 1605, 1595, 1515, 1380, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.73 (s, 6 H, 2 × CH3), 2.28 (s, 3 H, CH3),
6.77 (br s, 1 H, NH), 7.08 (d, J = 8.3 Hz, 2 H, ArH), 7.19 (td, J = 7.7, 1.5 H,
1 H, ArH), 7.26 (d, J = 8.3 Hz, 2 H, ArH), 7.40 (td, J = 7.7, 1.2 Hz, 1 H,
ArH), 7.57 (dd, J = 7.7, 1.5 Hz, 1 H, ArH), 7.63 (dd, J = 7.7, 1.2 Hz, 1 H,
ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 26.6 (2 q), 49.3 (s), 120.3 (2
d), 124.5 (s), 128.0 (d), 128.3 (d), 129.1 (d), 129.3 (2 d), 133.8 (s), 135.2
(d), 135.5 (s), 143.0 (s), 174.6 (s).
2-(4-Chlorophenyl)-2-methyl-N-(p-tolyl)propanamide (8e)
Yield: 105 (79%); colorless needles; mp 114–115 °C (EtOAc–hexane).
IR (KBr): 3320, 1650, 1595, 1515, 1400, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.63 (s, 6 H, 2 × CH3), 2.28 (s, 3 H, CH3),
6.75 (br s, 1 H, NH), 7.07 (d, J = 8.3 Hz, 2 H, ArH), 7.24 (d, J = 8.3 Hz, 2
H, ArH), 7.33–7.39 (m, 4 H, ArH).
Anal. Calcd for C17H18ClNO: C, 70.95; H, 6.30; N, 4.87. Found: C, 70.95;
H, 6.36; N, 4.87.
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 27.0 (2 q), 47.6 (s), 119.8 (2
d), 127.8 (2 d), 129.0 (2 d), 129.3 (2 d), 133.2 (s), 133.9 (s), 135.2 (s),
143.3 (s), 174.7 (s).
2-(2-Bromophenyl)-2-methyl-N-(p-tolyl)propanamide (8j)
Anal. Calcd for C17H18ClNO: C, 70.95; H, 6.30; N, 4.87. Found: C, 70.97;
H, 6.29; N, 4.87.
Yield: 132 mg (84%); colorless crystals; mp 108–109 °C (EtOAc–hex-
ane).
IR (KBr): 3300, 1665, 1595, 1515, 1470, 1315 cm–1
.
2-(4-Bromophenyl)-2-methyl-N-(p-tolyl)propanamide (8f)
1H NMR (400 MHz, CDCl3): δ = 1.73 (s, 6 H, 2 × CH3), 2.28 (s, 3 H, CH3),
6.75 (br s, 1 H, NH), 7.08 (d, J = 8.3 Hz, 2 H, ArH), 7.20 (td, J = 7.7, 1.5
Hz, 1 H, ArH), 7.26 (d, J = 8.3 Hz, 2 H, ArH), 7.40 (td, J = 7.7, 1.2 Hz, 1 H,
ArH), 7.57 (dd, J = 7.7, 1.5 Hz, 1 H, ArH), 7.64 (dd, J = 7.7, 1.2 Hz, 1 H,
ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 26.6 (2 q), 49.3 (s), 120.4 (2
d), 124.5 (s), 128.0 (d), 128.3 (d), 129.1 (d), 129.3 (2 d), 133.9 (s), 135.2
(d), 135.5 (s), 143.0 (s), 174.6 (s).
Yield: 122 mg (87%); colorless crystals; mp 118–119 °C (EtOAc–hex-
ane).
IR (KBr): 3325, 1650, 1515, 1475, 1395, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.63 (s, 6 H, 2 × CH3), 2.28 (s, 3 H, CH3),
6.74 (br s, 1 H, NH), 7.07 (d, J = 8.4 Hz, 2 H, ArH), 7.24 (d, J = 8.4 Hz, 2
H, ArH), 7.30 (d, J = 8.6 Hz, 2 H, ArH), 7.51 (d, J = 8.6 Hz, 2 H, ArH).
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 27.0 (2 q), 47.7 (s), 119.8 (2
d), 121.3 (s), 128.2 (2 d), 129.4 (2 d), 132.0 (2 d), 134.0 (s), 135.2 (s),
143.8 (s), 174.7 (s).
Anal. Calcd for C17H18BrNO: C, 61.46; H, 5.46; N, 4.22. Found: C, 61.43;
H, 5.47; N, 4.21.
Anal. Calcd for C17H18BrNO: C, 61.46; H, 5.46; N, 4.22. Found: C, 61.47;
H, 5.51; N, 4.22.
Acknowledgment
2-(4-Cyanophenyl)-2-methyl-N-(p-tolyl)propanamide (8g)
We are grateful to the National Science Council of ROC for financial
support (Grant No. MOST-104-2113-M-006-003).
Yield: 122 mg (81%); colorless crystals; mp 110–111 °C (EtOAc–hex-
ane).
IR (KBr): 3325, 2230,1655, 1605, 1515, 1400, 1315 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.66 (s, 6 H, 2 × CH3), 2.29 (s, 3 H, CH3),
6.83 (br s, 1 H, NH), 7.08 (d, J = 8.4 Hz, 2 H, ArH), 7.27 (d, J = 8.4 Hz, 2
H, ArH), 7.54 (d, J = 8.4 Hz, 2 H, ArH), 7.65 (d, J = 8.4 Hz, 2 H, ArH).
Supporting Information
Supporting information for this article is available online at
13C NMR (100.6 MHz, CDCl3): δ = 20.8 (q), 26.8 (2 q), 48.2 (s), 111.1 (s),
118.5 (s), 120.0 (2 d), 127.1 (2 d), 129.4 (2 d), 132.6 (2 d), 134.2 (s),
134.9 (s), 150.3 (s), 173.7 (s).
http://dx.doi.org/10.1055/s-0036-1588642.
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References
Anal. Calcd for C18H18N2O: C, 77.67; H, 6.52; N, 10.06. Found: C, 77.27;
H, 6.49; N, 10.04.
(1) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b) Lin,
H.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2003, 42, 36.
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8748. (d) Millemaggi, A.; Taylor, R. J. K. Eur. J. Org. Chem. 2010,
2-Methyl-2-(o-tolyl)-N-(p-tolyl)propanamide (8h)
Yield: 100 mg (76%); colorless needles; mp 74–75 °C (EtOAc–hexane).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
C.-P. Chuang et al.
Paper
Synthesis
4527. (e) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011,
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L