Palladium-catalyzed alkylarylation of acrylamides with unactivated alkyl halides

Article abstract of DOI:10.1021/acs.joc.5b02433

An efficient palladium-catalyzed alkylarylation of acrylamides with unactivated alkyl halides has been developed. This method is highlighted by its broad substrate scope and excellent functional group tolerance. In addition to alkyl halides, fluoroalkyl halides and benzyl bromides also participated well in this transformation. A detailed mechanistic investigation suggests that a radical pathway is probably involved in the cyclization process.

Full text of DOI:10.1021/acs.joc.5b02433

Article
pubs.acs.org/joc
Palladium-Catalyzed Alkylarylation of Acrylamides with Unactivated
Alkyl Halides
Hua Wang, Li−Na Guo, and Xin-Hua Duan*
Department of Chemistry, School of Science and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed
Matter, Xi’an Jiaotong University, Xi’an 710049, China
*
S Supporting Information
ABSTRACT: An efficient palladium-catalyzed alkylarylation
of acrylamides with unactivated alkyl halides has been
developed. This method is highlighted by its broad substrate
scope and excellent functional group tolerance. In addition to
alkyl halides, fluoroalkyl halides and benzyl bromides also
participated well in this transformation. A detailed mechanistic
investigation suggests that a radical pathway is probably
involved in the cyclization process.
INTRODUCTION
Scheme 1. Palladium-Catalyzed Cyclization of Acrylamides
with Alkyl Halides
■
Palladium-catalyzed Heck reactions are one of the most
powerful tools for C−C bond formation and have been used
widely in organic synthesis. In this field, aryl and vinyl
1
electrophiles are the most commonly used substrates for this
transformation. In contrast, alkyl halides, especially unactivated
substrates bearing β-hydrogen, are rarely used owing to their
facile β-hydride elimination. Recently, some great progress has
2
−4
been made in the more challenging alkyl-Heck reaction. For
instance, Fu and co-workers developed the first palladium-
catalyzed intramolecular alkyl-Heck reaction of primary alkyl
2
electrophiles and monosubstituted alkenes. The palladium-
catalyzed radical reactions using alkyl halides as reactants have
5
been previously reported. In 2014, the groups of Alexanian and
Zhou independently described the palladium-catalyzed inter-
molecular Heck-type coupling of unactivated alkyl halides with
alkenes, in which a radical rather than a metal-mediated process
the drawbacks of this protocol are the use of a stoichiometric
oxidant and limited substrate scopes (only activated alkyl
halides were investigated). As part of our ongoing work on
8
f,g,10
3
tandem cyclization reaction,
we surmised that the
was involved. Moreover, several radical Heck-type reactions of
unactivated alkyl halides containing a β-hydrogen might be
suitable alkylation reagents in the palladium-catalyzed difunc-
tionalization of activated alkenes. Herein, we wish to report an
efficient palladium-catalyzed alkylarylation of acrylamides with
various unactivated alkyl halides, giving a series of oxindoles in
good to high yields.
alkyl halides with alkenes catalyzed by other transition metals
have also been reported. Although significant achievements
4
have been made in the alkyl-Heck-type reaction, the palladium-
catalyzed tandem coupling/cyclization of unactivated alkyl halides
with alkenes is less explored and remains a challenging topic.
Recently, catalytic difunctionalization of alkenes has emerged
as an attractive strategy for accessing structurally diverse
6
RESULTS AND DISCUSSION
heterocyclic compounds. Among them, the tandem radical
■
To optimize the reaction conditions, N-phenyl acrylamide 1a
and iodocyclohexane 2a were chosen as the initial model
substrates. We were pleased to find that the desired product 3a
cyclization of acrylamides has attracted much attention and a
variety of functionalized oxindoles have been easily synthesized
through the difunctionalization of acrylamides with diverse
7
was isolated in 10% yield when a combination of PdCl /dppf
radicals. Furthermore, this tandem radical cyclization strategy
2
was used as a catalyst and K PO ·3H O as a base in toluene at
has also been applied successfully for the construction of other
3
4
2
1
00 °C (Table 1, entry 1). Further screening of solvents
heterocycles such as dihydroquinolin-2(1H)-ones, dihydro-
8
revealed that diglyme is the best choice, affording the desired
furans, benzoxazines, and so on. More recently, Li and
co-workers reported an efficient palladium-catalyzed oxidative
difunctionalization of acrylamides with α-carbonyl alkyl
bromides for the synthesis of oxindoles (Scheme 1). However,
Received: October 21, 2015
9
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02433
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of the Reaction Conditions
afford the cyclized products 3b−t in moderate to good yields.
Both electron-donating and -withdrawing substituents at the
para position of the aniline moiety were compatible with this
transformation (3b−g). Remarkably, substrates with highly
electron-deficient substituents such as CF , CN, and CO Et
3
2
groups on the aniline moiety worked well to furnish the de-
sired products in 80−91% yields (3d−f), which cannot be
7d
b
obtained by Liu’s protocol. As expected, the iodo-substituted
acrylamides 1h could not survive the reaction conditions and
the corresponding deiodinated oxindole 3a was obtained in
entry
catalyst (mol %)
ligand (mol %)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
PdCl (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
−
Tol
10
12
16
51
41
88
76
63
40
55
2
PdCl (10)
PhCF3
EtOAc
2
6
0% yield. It turned out that the substrate 1h easily underwent
PdCl (10)
2
the deiodination process to give 1a under the present con-
ditions. Fortunately, the chloro-substituted acrylamide gave the
desired product 3g in 76% yield. On the other hand, the steric
effect of ortho-substituents had no significant effect on this
reaction, resulting in good yields (3i−l). Polysubstituted acryl-
amides 1m−o also reacted smoothly to give the corresponding
oxindoles in satisfactory yields, respectively. In addition to the
methyl group, substrates bearing other N-protecting groups
such as benzyl and phenyl also provided the corresponding
products in 83% and 80% yields, respectively (3p and 3q).
Furthermore, substrates with a benzyl, phenyl, or hydrox-
ymethyl group at the α-position of the acrylamide moiety also
led to the corresponding products 3r−3t in good yields.
However, unsubstituted acrylamide 1u furnished a mixture of
unidentified products. It should be mentioned that cinnamamide
was also a suitable substrate in this cyclization reaction; the
PdCl (10)
Et O
2
2
PdCl (10)
DME
2
PdCl (10)
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
2
c
d
e
f
PdCl (10)
2
PdCl (10)
2
PdCl (10)
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
PdCl (10)
2
PdCl (10)
n.r.
41
21
15
45
55
66
62
40
2
PdCl (10)
dppe (10)
2
PdCl (10)
PCy (10)
2
3
PdCl (10)
Ph P (10)
3
2
Pd(OAc) (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
dppf (5)
2
Pd (dba) (10)
2
3
Pd(PPh ) (10)
3
4
PdCl (5)
2
PdCl (10)
2
11
g
desired dihydroquinolinone was isolated in 39% yield (eq 1).
PdCl (10)
dppf (10)
dppf (10)
dppf (10)
dppf (10)
93
48
40
2
g
g
CoCl (10)
2
FeCl (10)
2
g
NiCl ·6H O (10)
trace
2
2
a
Reaction conditions: catalyst (10 mol %), 1a (0.2 mmol, 1.0 equiv),
2
a (0.4 mmol, 2.0 equiv), ligand (10 mol %), K PO ·3H O (0.4 mmol,
3 4 2
b
2
.0 equiv), solvent (2.0 mL), 100 °C, 24 h, under nitrogen. Yield of
c d
isolated product. K CO (0.4 mmol, 2.0 equiv) was used. Cs CO
2
3
2
3
e
(0.4 mmol, 2.0 equiv) was used. NaHCO (0.4 mmol, 2.0 equiv) was
Subsequently, we examined the scope of alkyl halides with 1a
under the palladium-catalyzed system (Table 3). Both cyclic
and acyclic iodides reacted smoothly to provide the desired pro-
ducts in moderate to good yields (4a−f). As shown in Table 3,
the secondary alkyl iodides were more efficient than the
primary ones. These results may be attributed to the stability
of alkyl radicals (secondary > primary) generated from the
corresponding alkyl iodides. With the aim of obtaining more
interesting molecules, we applied this cyclization protocol to
3
f
g
used. Et N (0.4 mmol, 2.0 equiv) was used. 2a (0.5 mmol,
3
2
.5 equiv).
product in 88% yield (entries 2−6). Other inorganic and
organic bases were also tested and no better results were
obtained (entries 7−10). Notably, the addition of ligand is
crucial for the success of this transformation (entry 11).
Compared to dppf, other biphosphine ligands such as dppe
and monophosphine ligands such as PCy and Ph P were less
12
the perfluoroalkyl iodides. To our delight, the primary
perfluoroalkyl iodides were good reaction partners and gave the
fluorinated products 4d−f in good yields, which cannot be
easily prepared by previous approaches. Furthermore, the
reactions of 1a with relatively available and unexpensive alkyl
bromides were also investigated. It should be mentioned that
the addition of NaI was essential for the success of cyclization
3
3
efficient (entries 12−14). Among the palladium(0) and
palladium(II) catalysts examined, the simplest PdCl showed
2
the best catalytic activity (entries 15−17). Furthermore, the
amounts of catalyst and ligand were also adjusted. However,
reducing the amount of the palladium catalyst or ligand both
resulted in lower yields (entries 18 and 19). Satisfactorily, a
slight increase in the ratio of 1a and 2a from 1.0/2.0 to 1.0/2.5
resulted in a better yield (entry 20), while a further increase
gave a similar result. We confirmed that more than 1.0 equiv of
3h
when secondary alkyl bromides were used. In the presence of
a stoichiometric amount of NaI, the secondary alkyl bromides
were also suitable substrates and furnished the desired products
in good yields (4a, 4g, and 4h). We speculated that a more
reactive alkyl iodide generated through a Br/I exchange process
2
a was required for a good yield due to the formation of
the major byproduct bicyclohexyl and other unidentified
3h,13
byproducts. Finally, other inexpensive catalysts such as CoCl2
might be involved in this transformation.
and FeCl were also investigated. However, lower yields of 3a
Satisfactorily, the hindered tertiary bromides such as tert-
butyl bromide and 1-bromoadamantane also worked without
NaI to give the desired products but in relatively low yields
(4i and 4j). Unfortunately, when alkyl chlorides were used as
substrates, no reaction occurred. Remarkably, benzyl bromides
also exhibited good reactivities under the present conditions
2
were obtained (entries 21 and 22). When NiCl ·6H O was
2
2
used, only a trace amount of the desired product was detected.
With the optimal conditions in hand, we then evaluated the
scope of acrylamides with 2a (Table 2). To our delight, a
variety of substituted N-arylacrylamides proceeded efficiently to
B
DOI: 10.1021/acs.joc.5b02433
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The Journal of Organic Chemistry
Article
a
Table 2. Scope of N-Arylacrylamides
a
Reaction conditions: 10 mol % of PdCl , 1 (0.2 mmol, 1.0 equiv), 2a (0.5 mmol, 2.5 equiv), dppf (10 mol %), K PO ·3H O (0.4 mmol, 2.0 equiv),
2
3
4
2
b
diglyme (2.0 mL), 100 °C, 24 h, under nitrogen, yield of isolated product. In this case, the corresponding deiodinated oxindole 3a was obtained as
the major product and the corresponding yield was given in parentheses.
affording the desired products in good yields (4k−o). Both
electron-donating and -withdrawing groups such as Me, Cl,
CN, and CO Me on the aromatic moiety of benzyl bromides
2
were tolerated well in this procedure. However, incorporation
of a substitute such as ethyl at the benzyl position prevented
the formation of oxindole.
To shed some light on the mechanism of this reaction, some
the intra- and intermolecular competition experiments were
control experiments were carried out (for details see the
observed, respectively (eqs 4 and 5). These results indicate that
Supporting Information). When a stoichiometric amount of
C−H bond cleavage is not the rate-determining step in this
TEMPO or BHT, well-known radical scavengers, was added
reaction. Finally, cyclopropylmethyl bromide and 6-bromo-1-
into the reaction of 1a and 2a under the standard conditions, the
hexene were also treated with 1a under the standard conditions,
reaction was suppressed markedly (eqs 2 and 3). Furthermore,
respectively. However, only small amounts (<5 isolated yields)
the intra- and intermolecular kinetic isotope effect (KIE) experi-
of the corresponding pentenyl and cyclopentylethyl substituted
oxindoles were obtained due to the low conversion of 1a. All
ments were also performed. A negligible KIE (k /k = 1.0) for
11
H
D
of these results imply that free-radical substitution was probably
3
−5
involved in this reaction.
However, an alternative mecha-
nism involving a traditional Pd(0)/Pd(II) catalytic cycle cannot
9a
be excluded completely at present. It should be noted that the
recyclability of the palladium catalyst for this reaction was also
investigated. After filtering the reaction mixture followed by
C
DOI: 10.1021/acs.joc.5b02433
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 3. Scope of Alkyl, Fluoroalkyl, and Benzyl Halides
perfluoroalkyl iodides and benzyl bromides were compatible
with the palladium-catalyzed system. Furthermore, this pro-
cedure can be utilized to synthesize some oxindoles, which
cannot be accessed by reported methods. Mechanistic investi-
gation revealed that this cyclization reaction proceeds via a
cascade radical pathway.
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out in sealed tubes
filled with nitrogen. Column chromatography was carried out on
silica gel. 1H and C NMR spectra were recorded on a 400 M
spectrometer in solvents as indicated. The chemical shifts are reported
in ppm from TMS with the solvent resonance as the internal standard
13
1
13
(
CDCl : H NMR: δ = 7.26; C NMR: δ = 77.0). IR spectra were
3
recorded on a spectrometer, and only major peaks are reported in
−
1
cm . HRMS data were obtained on a Q-TOF micro spectrometer.
All acrylamides 1 were prepared according to a previously reported
procedure, and the NMR spectroscopies were in full accordance with
1
5
the data in the literature. Alkyl iodides were purchased from
commercial sources, which were stabilized with copper. 2-Iodo-octane
3
a
was prepared according to literature. Alkyl bromides and benzyl
bromides were purchased from commercial sources. All of the com-
mercially available compounds were used without further purification.
General Procedure for the Cyclization of Acrylamides with
Alkyl Iodides or Fluoroalkyl Iodides. Acrylamides 1 (0.2 mmol,
1
.0 equiv), PdCl (3.4 mg, 10 mol %), dppf (11.8 mg, 10 mol %), and
2
K PO ·3H O (106 mg, 0.4 mmol, 2.0 equiv) were added into an oven-
3
4
2
a
Reaction conditions: 10 mol % of PdCl , 1a (0.2 mmol, 1.0 equiv),
dried sealed tube. The tube was evacuated and backfilled with nitrogen
(three times). Then, a solution of alkyl iodides or fluoroalkyl iodides 2
(0.5 mmol, 2.5 equiv) in diglyme (2.0 mL) was injected into the tube
by syringe. The tube was then sealed with a Teflon lined cap, and the
mixture was stirred at 100 °C for 24 h. The resulting mixture was
diluted with EtOAc, and the organic phase was washed successively
with H O (three times) and brine (one time), then dried (Na SO ),
2
alkyl or fluoroalkyl iodides 2 (0.5 mmol, 2.5 equiv), dppf (10 mol %),
K PO ·3H O (0.4 mmol, 2.0 equiv), diglyme (2.0 mL), 100 °C, 24 h,
under nitrogen, yield of isolated product. The alkyl bromides were
used as substrates (for 4a, the corresponding yield was given in
parentheses). 3.0 equiv of NaI was used as an additive.
3
4
2
b
c
2
2
4
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (gradient eluent of EtOAc/petroleum
ether: 1/20 to 1/10) to give the corresponding product 3 or 4 in yields
listed in Tables 2 and 3.
7
d
3
-Cyclohexylmethyl-1,3-dimethylindolin-2-one (3a). Colorless
liquid (93%, 48 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
f
1
H NMR (400 MHz, CDCl ): δ = 7.28−7.23 (m, 1H), 7.15 (dd,
J = 7.6, 0.8 Hz, 1H), 7.05 (td, J = 7.6, 0.8 Hz, 1H), 6.84 (d, J = 7.6 Hz,
3
1
H), 3.21 (s, 3H), 1.93 (dd, J = 14.0, 6.8 Hz, 1H), 1.72 (dd, J = 14.0,
.8 Hz, 1H), 1.48−1.44 (m, 3H), 1.31−1.21 (m, 5H), 0.98−0.83
4
(
m, 6H); 13C NMR (100 MHz, CDCl ): δ = 181.1, 143.1, 134.4, 127.5,
3
1
22.7, 122.3, 107.9, 47.8, 45.4, 34.7, 34.4, 33.5, 26.2, 26.1, 26.0 ppm.
7d
3
-Cyclohexylmethyl-1,3,5-trimethylindolin-2-one (3b). Color-
less liquid (79%, 43 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
f
1
H NMR (400 MHz, CDCl ): δ = 7.04 (d, J = 7.6 Hz, 1H), 6.96
3
(
s, 1H), 6.71 (d, J = 7.6 Hz, 1H), 3.18 (s, 3H), 2.34 (s, 3H), 1.90 (dd,
J = 14.0, 6.8 Hz, 1H), 1.69 (dd, J = 14.0, 5.2 Hz, 1H), 1.52−1.45 (m,
13
3
H), 1.35−1.20 (m, 5H), 1.00−0.76 (m, 6H); C NMR (100 MHz,
CDCl ): δ = 181.1, 140.7, 134.4, 131.7, 127.7, 123.5, 107.6, 47.8, 45.4,
3
3
4.6, 34.4, 33.4, 26.2, 26.1, 26.0, 21.2 ppm.
-Cyclohexylmethyl-5-methoxy-1,3-dimethylindolin-2-one
3
7d
(
3c). Colorless liquid (87%, 50 mg); R 0.2 (EtOAc/petroleum
f
1
washing to remove organic compounds, the catalyst was reused
in the next reaction. In this case, the desired product 3a was still
isolated in 52% yield which suggested that Pd nanoparticles
ether = 1:10); H NMR (400 MHz, CDCl ): δ = 6.79−6.72 (m, 3H),
3
3
.80 (s, 3H), 3.18 (s, 3H), 1.91 (dd, J = 14.0, 6.8 Hz, 1H), 1.68 (dd,
J = 14.0, 5.2 Hz, 1H), 1.52−1.45 (m, 3H), 1.34−1.19 (m, 5H), 1.01−
14
0.73 (m, 6H); 13C NMR (100 MHz, CDCl ): δ = 180.7, 155.8, 136.6,
from catalyst death might be the actual active catalyst.
3
1
35.8, 111.3, 110.4, 108.1, 55.7, 48.2, 45.3, 34.7, 34.4, 33.4, 26.3, 26.2,
CONCLUSION
26.0 ppm.
■
3
-Cyclohexylmethyl-5-trifluoromethyl-1,3-dimethylindolin-2-one
In summary, we have demonstrated an efficient Pd-catalyzed
alkylarylation of acrylamides with alkyl halides, thus providing
an alternative approach to a variety of functionalized oxindoles
in moderate to good yields. This protocol shows broad sub-
strate scope and excellent functional group compatibility.
Remarkably, not only alkyl iodides and bromides but also
(
3d). Colorless liquid (91%, 54 mg); R 0.3 (EtOAc/petroleum ether =
f
1
1
1
1
:10); H NMR (400 MHz, CDCl ): δ = 7.54 (dd, J = 8.0, 0.8 Hz,
3
H), 7.37 (t, J = 0.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.24 (s, 3H),
.95 (dd, J = 14.0, 6.8 Hz, 1H), 1.75 (dd, J = 14.0, 5.2 Hz, 1H),
1.51−1.45 (m, 3H), 1.33 (s, 3H), 1.29−1.16 (m, 2H), 1.01−0.69
(m, 6H); 13C NMR (100 MHz, CDCl ): δ = 181.0, 146.0, 135.0, 125.4
3
D
DOI: 10.1021/acs.joc.5b02433
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
(
q, J = 4.0 Hz), 124.5 (q, J = 32.2 Hz), 124.4 (q, J = 269.9 Hz), 119.6
q, J = 3.6 Hz), 107.7, 47.8, 45.2, 34.7, 34.3, 33.4, 26.4, 26.0, 25.9 ppm;
3-Cyclohexylmethyl-1,3,6,7-tetramethylindolin-2-one (3m). Col-
orless liquid (40%, 23 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
f
−1
1
IR (KBr): υmax 2926, 2852, 1724, 1621, 1455, 1330, 1287, 1122 cm ;
HRMS (ESI) calcd for C H F NNaO [M + Na] 348.1546, found
3
H NMR (400 MHz, CDCl ): δ = 6.88−6.84 (m, 2H), 3.51 (s, 3H),
3
+
18
22 3
2.48 (s, 3H), 2.30 (s, 3H), 1.89 (dd, J = 14.0, 6.8 Hz, 1H), 1.66 (dd,
J = 14.0, 5.2 Hz, 1H), 1.52−1.45 (m, 3H), 1.36−1.20 (m, 5H), 1.00−
48.1537.
-Cyclohexylmethyl-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-
-carbonitrile (3e). White solid, mp = 113−115 °C (80%, 45 mg);
0.69 (m, 6H); 13C NMR (100 MHz, CDCl ): δ = 182.4, 141.1, 137.1,
3
3
5
1
32.9, 123.9, 119.9, 118.7, 46.8, 45.6, 34.5, 34.4, 33.4, 30.4, 26.8, 26.1,
1
R 0.1 (EtOAc/petroleum ether = 1:10); H NMR (400 MHz,
f
26.0, 25.9, 20.9, 14.2 ppm; IR (KBr): υ 2922, 2851, 1712, 1608,
max
−
1
CDCl ): δ = 7.60 (dd, J = 8.0, 1.6 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H),
3
1451, 1363, 1057 cm ; HRMS (ESI) calcd for C H NNaO
19 27
+
6
1
1
.91 (d, J = 8.0 Hz, 1H), 3.24 (s, 3H), 1.95 (dd, J = 14.4, 6.8 Hz, 1H),
.73 (dd, J = 14.0, 4.8 Hz, 1H), 1.51−1.46 (m, 3H), 1.31 (s, 3H),
[
M + Na] 308.1985, found 308.1976.
3
-Cyclohexylmethyl-5,7-dimethoxy-1,3-dimethylindolin-2-one
13
7d
.27−1.16 (m, 2H), 1.01−0.73 (m, 6H); C NMR (100 MHz, CDCl ):
(3n). Colorless liquid (65%, 52 mg); R 0.2 (EtOAc/petroleum
3
f
1
δ = 180.7, 146.9, 135.4, 133.0, 126.0, 119.4, 108.4, 105.4, 47.6, 45.1,
ether = 1:10); H NMR (400 MHz, CDCl ): δ = 6.38 (s, 1H), 6.33 (s,
3
3
1
4.7, 34.4, 33.3, 26.4, 26.0, 25.9 ppm; IR (KBr): υ 2924, 2851, 2222,
1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.40 (s, 3H), 1.86 (dd, J = 14.0,
6.8 Hz, 1H), 1.61 (dd, J = 14.0, 5.2 Hz, 1H), 1.52−1.43 (m, 3H),
max
−1
724, 1614, 1496, 1338 cm ; HRMS (ESI) calcd for C H N NaO
18
22
2
+
13
[
M + Na] 305.1624, found 305.1621.
-Cyclohexylmethyl-1,3-dimethyl-2-oxo-2,3-dihydro-1H-indole-
-carboxylic Acid Ethyl Ester (3f). Colorless liquid (88%, 55 mg);
1.36−1.20 (m, 5H), 0.96−0.67 (m, 6H); C NMR (100 MHz,
3
CDCl ): δ = 180.9, 156.4, 145.7, 136.7, 124.3, 100.6, 98.5, 55.7, 48.3,
3
5
45.4, 34.5, 34.3, 33.3, 29.2, 26.5, 26.0, 25.9 ppm.
3-Cyclohexylmethyl-1,3,4,6-tetramethylindolin-2-one (3o).
1
7d
Rf 0.2 (EtOAc/petroleum ether = 1:10); H NMR (400 MHz,
CDCl ): δ = 8.01 (dd, J = 8.0, 1.6 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H),
3
Colorless liquid (76%, 43.3 mg); R 0.3 (EtOAc/petroleum ether =
f
1
6
.86 (d, J = 8.0 Hz, 1H), 4.39−4.34 (m, 2H), 3.23 (s, 3H), 1.93 (dd,
1:10); H NMR (400 MHz, CDCl ): δ = 6.63 (s, 1H), 6.51 (s, 1H),
3
J = 14.4, 7.2 Hz, 1H), 1.77 (dd, J = 14.0, 4.8 Hz, 1H), 1.50−1.38 (m,
3.17 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.92 (s, 2H), 1.49−1.21 (m,
13
13
6
H), 1.32−1.17 (m, 5H), 1.01−0.73 (m, 6H); C NMR (100 MHz,
8H), 0.98−0.76 (m, 6H); C NMR (100 MHz, CDCl ): δ = 181.5,
3
CDCl ): δ = 181.4, 166.6, 147.1, 134.3, 130.3, 124.6, 123.9, 107.4,
143.3, 137.2, 133.8, 127.9, 125.4, 106.7, 48.4, 43.8, 35.1, 34.1, 32.9,
26.2, 26.0, 25.9, 24.1, 21.5, 18.1 ppm.
1-Benzyl-3-cyclohexylmethyl-3-methylindolin-2-one (3p).
3
6
0.9, 47.6, 45.2, 34.7, 34.3, 33.3, 26.4, 26.1, 26.0, 25.9, 14.4 ppm; IR
−1
7d
(
(
KBr): υ max 2923, 1716, 1614, 1455, 1274, 1105, 769 cm ; HRMS
ESI) calcd for C H NNaO [M + Na] 352.1883, found 352.1875.
+
20
27
3
White solid (83%, 55 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
f
7
d
1
5
-Chloro-3-cyclohexylmethyl-1,3-dimethylindolin-2-one (3g).
H NMR (400 MHz, CDCl ): δ = 7.31−7.24 (m, 5H), 7.17−7.12 (m,
3
Colorless liquid (76%, 44 mg); R 0.3 (EtOAc/petroleum ether =
f
2H), 7.02 (t, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 5.05 (d, J =
15.6 Hz, 1H), 4.80 (d, J = 15.6 Hz, 1H), 1.99 (dd, J = 14.0, 6.4 Hz,
1
1
1
1
1
:10); H NMR (400 MHz, CDCl ): δ = 7.23 (dd, J = 8.4, 2.0 Hz,
3
H), 7.12 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.20 (s, 3H),
.93 (dd, J = 14.0, 6.8 Hz, 1H), 1.69 (dd, J = 14.0, 5.2 Hz, 1H), 1.52−
1
H), 1.76 (dd, J = 14.0, 5.6 Hz, 1H), 1.51−1.42 (m, 4H), 1.37 (s, 3H),
1
.16−1.13 (m, 1H), 1.04−0.80 (m, 5H), 0.75−0.66 (m, 1H);
13
13
.47 (m, 3H), 1.32−1.20 (m, 5H), 1.03−0.77 (m, 6H); C NMR
C NMR (100 MHz, CDCl ): δ = 181.0, 142.2, 136.1, 134.5,
3
(
100 MHz, CDCl ): δ = 180.6, 141.7, 136.2, 127.8, 127.5, 123.2,
3
128.7, 127.5, 127.4, 122.7, 122.3, 109.0, 47.9, 45.4, 43.7, 34.8, 34.3,
3.9, 26.6, 26.1, 26.0 ppm.
-Cyclohexylmethyl-3-methyl-1-phenylindolin-2-one (3q).
White solid (80%, 51 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
1
08.9, 48.1, 45.3, 34.7, 34.4, 33.4, 26.3, 26.2, 26.0 ppm.
3
7d
7
d
3
-Cyclohexylmethyl-1,3,7-trimethylindolin-2-one (3i). Colorless
3
liquid (71%, 38 mg); R 0.4 (EtOAc/petroleum ether = 1:10);
f
f
1
H NMR (400 MHz, CDCl ): δ = 6.97−6.89 (m, 3H), 3.48 (s, 3H),
1
3
H NMR (400 MHz, CDCl ): δ = 7.53 (t, J = 8.4 Hz, 2H), 7.42−7.38
3
2
.57 (s, 3H), 1.90 (dd, J = 14.0, 6.8 Hz, 1H), 1.67 (dd, J = 14.0, 5.2
(
8
m, 3H), 7.25−7.18 (m, 2H), 7.10 (t, J = 7.2 Hz, 1H), 6.85 (d, J =
.0 Hz, 1H), 2.06 (dd, J = 14.0, 7.2 Hz, 1H), 1.83 (dd, J = 14.0, 5.2 Hz,
1H), 1.58−1.52 (m, 4H), 1.46 (s, 3H), 1.32−1.28 (m, 1H), 1.16−0.68
Hz, 1H), 1.52−1.44 (m, 3H), 1.36−1.18 (m, 5H), 0.99−0.69 (m, 6H);
1
3
C NMR (100 MHz, CDCl ): δ = 181.7, 140.7, 134.9, 131.1, 122.1,
3
120.5, 119.4, 47.0, 45.5, 34.5, 34.4, 33.4, 29.4, 26.5, 26.0, 25.9, 19.0 ppm.
13
(
m, 6H); C NMR (100 MHz, CDCl ): δ = 180.3, 142.9, 134.7,
3
7d
3
-Cyclohexylmethyl-7-methoxy-1,3-dimethylindolin-2-one (3j).
1
34.1, 129.5, 127.7, 127.3, 126.4, 122.9, 122.7, 109.2, 47.8, 45.8, 34.9,
Colorless liquid (79%, 45 mg); R 0.2 (EtOAc/petroleum ether =
1
6
f
34.3, 33.5, 26.4, 26.1, 26.0 ppm.
1
:10); H NMR (400 MHz, CDCl ): δ = 6.97 (t, J = 8.0 Hz, 1H),
3
3-Benzyl-3-cyclohexylmethyl-1-methylindolin-2-one (3r). White
.80 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.47
solid, mp = 68−70 °C (81%, 54 mg); R 0.3 (EtOAc/petroleum ether
f
1
(
s, 3H), 1.89 (dd, J = 14.0, 6.8 Hz, 1H), 1.67 (dd, J = 14.0, 4.8 Hz,
=
6
1:10); H NMR (400 MHz, CDCl ): δ = 7.18−7.13 (m, 2H), 7.05−
.98 (m, 4H), 6.74 (dd, J = 7.6, 1.2 Hz, 2H), 6.54 (d, J = 7.6 Hz, 1H),
3
1
H), 1.51−1.44 (m, 3H), 1.37−1.19 (m, 5H), 0.98−0.68 (m, 6H);
1
3
C NMR (100 MHz, CDCl ): δ = 181.3, 145.2, 136.0, 130.7, 122.7,
3
3.07 (d, J = 12.4 Hz, 1H), 2.92 (d, J = 12.8 Hz, 1H), 2.90 (s, 3H), 2.08
115.4, 111.2, 55.7, 47.8, 45.4, 34.6, 34.4, 33.4, 29.4, 26.4, 26.0, 25.9 ppm.
(
(
dd, J = 14.0, 7.2 Hz, 1H), 1.88 (dd, J = 14.0, 5.2 Hz, 1H), 1.52−1.45
13
7
d
3
-Cyclohexylmethyl-7-fluoro-1,3-dimethylindolin-2-one (3k).
m, 3H), 1.36−1.23 (m, 2H), 1.06−0.73 (m, 6H); C NMR
Colorless liquid (80%, 43.8 mg); R 0.3 (EtOAc/petroleum ether =
1
f
(100 MHz, CDCl ): δ = 179.5, 143.6, 135.6, 131.3, 129.8, 127.6,
3
1
:10); H NMR (400 MHz, CDCl ): δ = 6.99−6.92 (m, 3H), 3.42
3
127.2, 126.3, 123.7, 121.8, 107.6, 54.1, 46.2, 43.8, 34.7, 34.5, 33.4, 26.1,
(
5
(
d, J = 2.4 Hz, 3H), 1.92 (dd, J = 14.0, 6.8 Hz, 1H), 1.70 (dd, J = 14.0,
.2 Hz, 1H), 1.53−1.47 (m, 3H), 1.36−1.19 (m, 5H), 1.01−0.76
m, 6H); 13C NMR (100 MHz, CDCl ): δ = 180.7, 147.7 (d, J =
2
1
6.0, 25.8 ppm; IR (KBr): υmax 2921, 2850, 1712, 1612, 1493, 1469,
−
1
377, 1343, 1088, 751, 700 cm ; HRMS (ESI) calcd for
+
3
C H NNaO [M + Na] 356.1985, found 356.1979.
23
27
2
41.8 Hz), 137.4 (d, J = 2.9 Hz), 129.6 (d, J = 7.7 Hz), 122.8 (d,
J = 6.3 Hz), 118.5 (d, J = 3.1 Hz), 115.5 (d, J = 19.1 Hz), 48.2 (d, J =
.6 Hz), 45.5, 34.7, 34.4, 33.4, 26.4, 28.6, 26.1, 26.0 ppm.
-Cyclohexylmethyl-1,3-dimethyl-7-phenylindolin-2-one (3l).
3
-Cyclohexylmethyl-1-methyl-3-phenylindolin-2-one (3s). White
solid, mp = 62−64 °C (82%, 52 mg); R 0.3 (EtOAc/petroleum
f
1
1
ether = 1:10); H NMR (400 MHz, CDCl ): δ = 7.38−7.31 (m, 3H),
7.28−7.20 (m, 4H), 7.12 (td, J = 7.6, 0.8 Hz, 1H), 6.90 (d, J = 7.6 Hz,
1H), 3.20 (s, 3H), 2.41 (dd, J = 14.0, 7.2 Hz, 1H), 2.15 (dd, J = 14.0,
5.2 Hz, 1H), 1.54−1.25 (m, 5H), 1.06−0.85 (m, 6H); C NMR
(100 MHz, CDCl ): δ = 178.9, 143.8, 141.5, 131.9, 128.3, 128.0,
3
3
White solid, mp = 90−92 °C (82%, 55 mg); R 0.3 (EtOAc/petroleum
ether = 1:10); H NMR (400 MHz, CDCl ): δ = 7.43−7.31 (m, 5H),
f
1
13
3
7
.15 (dd, J = 6.8, 2.0 Hz, 1H), 7.10−7.04 (m, 2H), 2.73 (s, 3H), 1.96
3
(
(
(
dd, J = 14.0, 7.2 Hz, 1H), 1.75 (dd, J = 14.0, 5.2 Hz, 1H), 1.56−1.50
127.0, 126.6, 125.2, 122.3, 108.2, 55.9, 45.2, 34.8, 34.5, 33.5, 26.4, 26.1,
13
m, 3H), 1.42−1.23 (m, 5H), 1.02−0.76 (m, 6H); C NMR
26.0 ppm; IR (KBr): υ
1061 cm ; HRMS (ESI) calcd for C H NNaO [M + Na]
2922, 1764, 1715, 1609, 1461, 1376, 1244,
max
−
1
+
100 MHz, CDCl ): δ = 182.2, 140.1, 139.2, 135.4, 130.5, 129.9,
3
22 25
1
2
1
27.8, 127.5, 125.3, 121.7, 121.6, 47.1, 45.9, 34.8, 34.5, 33.6, 30.1, 26.2,
342.1828, found 342.1825.
6.1 ppm; IR (KBr): υ 2922, 1769, 1716, 1455, 1372, 1245,
3-Cyclohexylmethyl-3-hydroxymethyl-1,5-dimethylindolin-2-one
max
−1
+
061 cm ; HRMS (ESI) calcd for C H NO [M + H] 334.2165,
(3t). White solid, mp = 121−123 °C (35%, 20 mg); R 0.2 (EtOAc/
23
28
f
1
found 334.2160.
petroleum ether = 1:2); H NMR (400 MHz, CDCl ): δ = 7.10
3
E
DOI: 10.1021/acs.joc.5b02433
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 6.76 (d, J = 7.6 Hz, 1H), 3.75 (d, J =
26.0, 24.0, 23.7, 22.2, 13.9 ppm; IR (KBr): υmax 2928, 1714, 1612,
−1
1
3
1
2
0.0 Hz, 1H), 3.60 (dd, J = 10.4, 2.4 Hz, 1H), 3.21 (s, 3H), 2.36 (s,
H), 2.29 (dd, J = 8.8, 3.2 Hz, 1H), 2.05 (dd, J = 14.0, 7.6 Hz, 1H),
.73 (dd, J = 14.0, 5.2 Hz, 1H), 1.52−1.46 (m, 3H), 1.33−1.23 (m,
1464, 1376, 1346, 1252, 1126, 1087, 1024, 750 cm ; HRMS (ESI)
+
calcd for C H NNaO [M + Na] 254.1515, found 254.1516.
15
21
1,3-Dimethyl-3-(2,2,3,3,4,4,5,5,5-nonafluoro-pentyl)indolin-2-
13
7f
H), 1.03−0.93 (m, 4H), 0.84−0.76 (m, 2H); C NMR (100 MHz,
one (4d). Colorless liquid (76%, 60 mg); R
f
0.3 (EtOAc/petroleum
): δ = 7.33−7.27 (m, 2H),
7.08 (td, J = 7.6, 0.8 Hz, 1H), 6.89 (d, J = 7.6 Hz, 1H), 3.24 (s, 3H),
1
CDCl ): δ = 179.6, 141.6, 132.1, 130.2, 128.5, 123.9, 108.0, 68.8, 53.9,
3
2
ether = 1:10); H NMR (400 MHz, CDCl
3
3
9.9, 34.4, 34.2, 33.3, 26.2, 26.0, 25.9, 21.2 ppm; IR (KBr): υ 2923,
max
−1
13
855, 1703, 1612, 1498, 1454, 1359, 1247, 1069 cm ; HRMS (ESI)
2.94−2.53 (m, 2H), 1.43 (s, 3H); C NMR (100 MHz, CDCl ):
δ = 178.5, 142.8, 131.2, 128.5, 123.5, 122.6, 120.2−112.2 (m), 108.4,
44.2, 36.9 (t, J = 20.2 Hz), 29.7, 26.4, 25.8 ppm; 19F NMR (376 MHz,
3
+
calcd for C H NNaO [M + Na] 310.1777, found 310.1763.
18
25
2
General Procedure for the Cyclization of Acrylamides with
Secondary Alkyl Bromides. Acrylamides 1 (0.2 mmol, 1.0 equiv),
PdCl (3.4 mg, 10 mol %), dppf (11.8 mg, 10 mol %), K PO ·3H O
CDCl ) −81.2 (t, J = 7.5 Hz, 3F), −109.0 (m, 1F), −114.6 (m, 1F),
3
−124.7 (m, 2F), −126.0 (m, 2F).
2
3
4
2
(
3
106 mg, 0.4 mmol, 2.0 equiv), and NaI (89.4 mg, 0.6 mmol,
.0 equiv) were added into an oven-dried sealed tube. The tube was
1,3-Dimethyl-3-(2,2,3,3,4,4,5,5,6,6,7,7,7-tridecafluoro-heptyl)-
indolin-2-one (4e). Colorless liquid (65%, 64 mg); R
0.3 (EtOAc/
): δ = 7.34−7.27
(m, 2H), 7.09 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 3.25 (s,
f
1
evacuated and backfilled with nitrogen (three times). Then, a solution
of alkyl bromides 2 (0.5 mmol, 2.5 equiv) in diglyme (2.0 mL) was
injected into the tube by syringe. The tube was then sealed with a
Teflon lined cap, and the mixture was stirred at 100 °C for 24 h. The
resulting mixture was diluted with EtOAc, and the organic phase was
petroleum ether = 1:10); H NMR (400 MHz, CDCl
3
13
3H), 2.95−2.54 (m, 2H), 1.43 (s, 3H); C NMR (100 MHz, CDCl ):
3
δ = 178.6, 142.8, 131.2, 128.5, 123.6, 122.6, 120.0−110.1 (m), 108.5,
44.2, 37.0 (t, J = 19.4 Hz), 26.4, 25.9 ppm; 19F NMR (376 MHz,
washed successively with H O (three times) and brine (one time),
CDCl ) −80.9 (t, J = 11.3 Hz, 3F), −108.7 (m, 1F), −114.5 (m, 1F),
3
2
then dried (Na SO ), and concentrated in vacuo. The residue was
−121.8 (m, 2F), −123.0 (m, 2F), −123.7 (m, 2F), −126.2 (m, 2F);
IR (KBr): υmax 2931, 1722, 1615, 1495, 1474, 1351, 1240, 1144,
2
4
purified by column chromatography on silica gel (gradient eluent of
EtOAc/petroleum ether: 1/20 to 1/10) to give the corresponding
products 4 in yields listed in Table 3.
−
1
H F
13NNaO [M + Na] +
12
1050 cm ; HRMS (ESI) calcd for C17
516.0603, found 516.0605.
General Procedure for the Cyclization of Acrylamides with
3-(2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-Heptadecafluoro-nonyl)-1,3-
dimethylindolin-2-one (4f). Colorless liquid (68%, 81 mg); R 0.3
(EtOAc/petroleum ether = 1:10); H NMR (400 MHz, CDCl ): δ =
3
Tertiary Alkyl Bromides and Benzyl Bromides. Acrylamides 1
(
f
1
0.2 mmol, 1.0 equiv), PdCl (3.4 mg, 10 mol %), dppf (11.8 mg,
2
1
0 mol %), and K PO ·3H O (106 mg, 0.4 mmol, 2.0 equiv) were
7.33−7.28 (m, 2H), 7.11−7.07 (m, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.25
3
4
2
13
added into an oven-dried sealed tube. The tube was evacuated and
backfilled with nitrogen (three times). Then, a solution of tertiary alkyl
bromides or benzyl bromides 2 (0.5 mmol, 2.5 equiv) in diglyme
(s, 3H), 2.97−2.55 (m, 2H), 1.44 (s, 3H); C NMR (100 MHz,
CDCl ): δ = 178.6, 142.8, 131.3, 128.4, 123.5, 122.6, 120.2−107.5
3
19
(m), 44.2, 37.0 (t, J = 20.3 Hz), 26.3, 25.8 ppm; F NMR (376 MHz,
(
2.0 mL) was injected into the tube by syringe. The tube was then
CDCl ) −81.1 (t, J = 11.3 Hz, 3F), −108.8 (m, 1F), −114.5 (m, 1F),
3
sealed with a Teflon lined cap, and the mixture was stirred at 100 °C
for 24 h. The resulting mixture was diluted with EtOAc, and the
organic phase was washed successively with H O (three times) and
brine (one time), then dried (Na SO ), and concentrated in vacuo.
−121.7 (m, 2F), −122.2 (m, 4F), −123.0 (m, 2F), −123.8 (m, 2F),
−126.4 (m, 2F); IR (KBr): υ 3061, 2975, 1720, 1616, 1495, 1474,
max
−1
1427, 1351, 1207, 1080, 1051, 1026 cm ; HRMS (ESI) calcd for
C H F NO [M + H] 594.0720, found 594.0734.
3-Cycloheptylmethyl-1,3-dimethylindolin-2-one (4g). Colorless
2
+
2
4
19 13 17
7
d
The residue was purified by column chromatography on silica gel
gradient eluent of EtOAc/petroleum ether: 1/20 to 1/10) to give the
corresponding products 4 in yields listed in Table 3.
-Cyclopentylmethyl-1,3-dimethylindolin-2-one (4a). Colorless
(
liquid (70%, 38 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
f
1
H NMR (400 MHz, CDCl ): δ = 7.27−7.24 (m, 1H), 7.16 (dd, J =
3
7d
3
7.2, 0.8 Hz, 1H), 7.07−7.03 (m, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.21 (s,
liquid (86%, 42 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
3H), 1.99 (dd, J = 13.6, 6.8 Hz, 1H), 1.75 (dd, J = 14.0, 4.4 Hz, 1H),
f
1
13
H NMR (400 MHz, CDCl ): δ = 7.27−7.23 (m, 1H), 7.15 (dd, J =
1.43−1.32 (m, 10H), 1.18−0.97 (m, 6H); C NMR (100 MHz,
CDCl ): δ = 181.0, 143.1, 134.2, 127.4, 122.7, 122.2, 107.8, 48.1, 45.9,
3
7
1
6
1
.2, 0.8 Hz, 1H), 7.04 (td, J = 7.6, 0.8 Hz, 1H), 6.83 (d, J = 7.6 Hz,
H), 3.20 (s, 3H), 2.05 (dd, J = 13.6, 7.2 Hz, 1H), 1.88 (dd, J = 14.0,
.0 Hz, 1H), 1.51−1.36 (m, 3H), 1.33 (s, 3H), 1.31−1.20 (m, 4H),
3
36.1, 35.8, 34.4, 28.4, 26.1, 25.8, 25.7 ppm.
1,3-Dimethyl-3-(2-methyl-butyl)indolin-2-one (4h). Colorless
13
.04−0.95 (m, 1H), 0.87−0.76 (m, 1H); C NMR (100 MHz,
liquid (76%, 34 mg); R 0.3 (EtOAc/petroleum ether = 1:10). The
f
CDCl ): δ = 181.0, 143.2, 134.3, 127.5, 122.8, 122.2, 107.8, 48.4, 44.4,
3
mixture of isomers cannot be separated by column chromatography on
3
1
7.1, 33.7, 32.7, 26.1, 25.2, 24.9, 24.8 ppm.
silica gel. The NMR spectroscopy of mixture (d.r. = 1:1), H NMR
1
,3-Dimethyl-3-(2-methyl-octyl)indolin-2-one (4b). Colorless
(400 MHz, CDCl ): δ = 7.26−7.22 (m, 1H), 7.17−7.12 (m, 1H),
3
liquid (55%, 31.6 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
The mixture of isomers cannot be separated by column chromatog-
raphy on silica gel. The NMR spectroscopy of mixture (d.r. = 1:1), H
NMR (400 MHz, CDCl ): δ = 7.28−7.23 (m, 1H), 7.18−7.13 (m,
H), 7.07−7.03 (m, 1H), 6.84 (dd, J = 8.0, 4.0 Hz, 1H), 3.21 (s, 3H),
.01 (dd, J = 14.0, 5.6 Hz, 0.5H), 1.85 (d, J = 6.0 Hz, 1H), 1.66 (dd,
7.06−7.02 (m, 1H), 6.84−6.81 (m, 1H), 3.20 (s, 3H), 2.01 (dd, J =
14.0, 5.2 Hz, 0.5H), 1.85 (d, J = 5.6 Hz, 1H), 1.64 (dd, J = 14.0,
6.4 Hz, 0.5H), 1.31 (s, 3H), 1.17−0.90 (m, 3H), 0.70 (q, J = 6.8 Hz,
f
1
1
3
3
3H), 0.58 (d, J = 6.4 Hz, 1.5H), 0.47 (d, J = 6.8 Hz, 1.5H); C NMR
1
2
(100 MHz, CDCl ): δ = 181.2, 180.8, 143.1, 134.5, 133.9, 127.5,
3
122.8, 122.7, 122.2, 107.8, 48.1, 47.8, 44.9, 44.3, 31.5, 30.6, 30.0, 26.1,
J = 14.0, 6.4 Hz, 0.5H), 1.32 (s, 3H), 1.23−0.87 (m, 11H), 0.84 (t, J =
26.0, 25.7, 20.2, 19.2, 11.0, 10.9 ppm; IR (KBr): υmax 2962, 2926,
−1
7
.2, 2.4 Hz, 3H), 0.60 (d, J = 6.4 Hz, 1.5H), 0.50 (d, J = 6.8 Hz, 1.5H);
1717, 1613, 1492, 1469, 1376, 1346, 1247, 1123, 1087, 1022 cm ;
1
3
+
C NMR (100 MHz, CDCl ): δ = 181.3, 180.9, 143.2, 134.5, 134.1,
HRMS (ESI) calcd for C H NNaO [M + Na] 254.1515, found
3
15 21
1
27.5, 122.9, 122.8, 122.3, 122.2, 107.9, 48.1, 47.9, 45.5, 44.8, 38.1,
254.1513.
7
g
37.2, 31.7, 30.1, 29.9, 29.3, 26.5, 26.4, 26.2, 26.1, 25.8, 22.6, 20.8, 19.9,
3-(2,2-Dimethyl-propyl)-1,3-dimethylindolin-2-one (4i). White
1
7
4.1 ppm; IR (KBr): υ
49 cm ; HRMS (ESI) calcd for C H NO [M + H] 288.2322,
2930, 1717, 1611, 1463, 1376, 1344, 1125,
solid, (40%, 14 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
H NMR (400 MHz, CDCl ): δ = 7.26−7.23 (m, 1H), 7.19 (dd, J =
3
7.6, 0.8 Hz, 1H), 7.02 (td, J = 7.2, 0.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H),
f
max
−1
+
1
19
30
found 288.2319.
1
,3-Dimethyl-3-pentylindolin-2-one (4c). Colorless liquid (39%,
3.21 (s, 3H), 2.15 (d, J = 14.4 Hz, 1H), 1.85 (d, J = 14.4 Hz, 1H),
1
13
1
8 mg); R 0.3 (EtOAc/petroleum ether = 1:10); H NMR (400 MHz,
1.29 (s, 3H), 0.60 (s, 9H); C NMR (100 MHz, CDCl ): δ = 181.0,
f
3
CDCl ): δ = 7.28−7.24 (m, 1H), 7.17 (dd, J = 7.2, 0.8 Hz, 1H), 7.06
142.8, 134.2, 127.5, 123.8, 121.9, 108.0, 50.8, 47.4, 31.7, 30.8, 28.2,
3
(
(
1
td, J = 7.6, 0.8 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.21 (s, 3H), 1.88
td, J = 13.2, 4.8 Hz, 1H), 1.72 (td, J = 13.2, 4.0 Hz, 1H), 1.35 (s, 3H),
.18−1.08 (m, 4H), 1.03−0.76 (m, 5H); C NMR (100 MHz,
26.2 ppm.
7
g
3-Adamantan-1-ylmethyl-1,3-dimethylindolin-2-one (4j).
13
White solid, (31%, 19 mg); R 0.3 (EtOAc/petroleum ether = 1:10);
f
1
CDCl ): δ = 180.8, 143.2, 134.2, 127.5, 122.3, 107.8, 48.3, 38.4, 31.8,
H NMR (400 MHz, CDCl ): δ = 7.28−7.24 (m, 1H), 7.19 (d,
3
3
F
DOI: 10.1021/acs.joc.5b02433
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 7.2 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 3.23
1.94−1.92 (m, 1H), 1.71−1.68 (m, 2H), 1.60−1.58 (m, 2H), 1.40−
1
3
(
3
(
s, 3H), 2.00 (d, J = 14.4 Hz, 1H), 1.75−1.69 (m, 4H), 1.52−1.49 (m,
1.37 (m, 1H), 1.30−1.21 (m, 1H), 1.13−1.05 (m, 4H); C NMR
13
H), 1.39−1.36 (m, 3H), 1.27 (s, 3H), 1.21−1.13 (m, 6H); C NMR
(100 MHz, CDCl ): δ = 170.4, 142.3, 140.0, 129.6, 128.6, 128.0, 127.0,
3
100 MHz, CDCl ): δ = 181.2, 142.6, 134.7, 127.5, 123.6, 122.0,
126.6, 123.2, 114.8, 55.6, 44.4, 37.7, 31.3, 31.1, 29.4, 26.1, 26.0 ppm.
3
1
08.0, 52.0, 46.6, 43.3, 36.7, 33.9, 28.6, 28.5, 26.3 ppm.
10c
1
,3-Dimethyl-3-phenethylindolin-2-one (4k). White solid (62%,
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02433.
■
1
33 mg); R 0.3 (EtOAc/petroleum ether = 1:10); H NMR (400 MHz,
f
*
S
CDCl ): δ = 7.31 (t, J = 7.6 Hz, 1H), 7.25−7.20 (m, 3H), 7.16−7.10
3
(
3
(
m, 2H), 7.04 (d, J = 7.2 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 3.22 (s,
13
H), 2.36−2.25 (m, 2H), 2.18−1.99 (m, 2H), 1.41 (s, 3H); C NMR
1H and 13C spectra of all new compounds; the primary
mechanistic and KIE studies of the reactions (PDF)
100 MHz, CDCl ): δ = 180.2, 143.3, 141.3, 133.7, 128.2, 128.1,
3
1
27.8, 125.8, 122.5, 122.4, 107.9, 48.3, 40.2, 30.9, 26.0, 23.9 ppm.
10c
1
,3-Dimethyl-3-(2-p-tolyl-ethyl)indolin-2-one(4l).
White solid
1
(
60%, 33 mg); R 0.3 (EtOAc/petroleum ether = 1:10); H NMR
f
AUTHOR INFORMATION
Corresponding Author
*E-mail: duanxh@mail.xjtu.edu.cn.
(
400 MHz, CDCl ): δ = 7.31 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2 Hz,
■
3
1
8
5
H), 7.12 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 2H), 6.93 (d, J =
.0 Hz, 2H), 6.88 (d, J = 7.6 Hz, 1H), 3.22 (s, 3H), 2.29−2.22 (m,
H), 2.13−1.97 (m, 2H), 1.40 (s, 3H); C NMR (100 MHz, CDCl ):
13
3
Notes
δ = 180.3, 143.4, 138.3, 135.2, 133.7, 128.9, 128.1, 127.7, 122.5, 122.4,
07.9, 48.3, 40.4, 30.4, 26.1, 23.9, 20.9 ppm.
-[2-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-ethyl]-
The authors declare no competing financial interest.
1
4
1
0c
ACKNOWLEDGMENTS
benzonitrile (4m).
White solid (77%, 47 mg); R 0.3 (EtOAc/
■
f
1
petroleum ether = 1:5); H NMR (400 MHz, CDCl ): δ = 7.47 (d,
J = 8.0 Hz, 2H), 7.31 (td, J = 7.2, 0.8 Hz, 1H), 7.22 (d, J = 6.8 Hz,
Financial support from Natural Science Basic Research Plan in
Shaanxi Province of China (No. 2014JQ2071) and the
Fundamental Research Funds of the Central Universities
3
1
H), 7.12−7.09 (m, 3H), 6.89 (d, J = 7.6 Hz, 1H), 3.20 (s, 3H), 2.38−
13
2.19 (m, 3H), 2.06−2.00 (m, 1H), 1.40 (s, 3H); C NMR (100 MHz,
(
No. 2015qngz17) are greatly appreciated.
CDCl ): δ = 179.7, 146.8, 143.1, 133.0, 131.8, 128.9, 127.9, 122.5,
3
1
22.2, 118.7, 109.5, 108.0, 48.0, 39.1, 31.0, 25.9, 23.8 ppm.
REFERENCES
■
4
-[2-(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-3-yl)-ethyl]-ben-
(
1) (a) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314.
zoic Acid Methyl Ester (4n). White solid, mp = 67−69 °C (79%, 51
mg); R 0.4 (EtOAc/petroleum ether = 1:5); H NMR (400 MHz,
CDCl ): δ = 7.87 (d, J = 8.4 Hz, 2H), 7.30 (td, J = 7.6, 0.8 Hz, 1H),
1
(
(
(
b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009.
c) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103, 2945.
d) Oestreich, M. The Mizoroki−Heck Reaction; Wiley-VCH:
Weinheim, 2009. (e) Le Bras, J. L.; Muzart, J. Chem. Rev. 2011, 111,
170. (f) McCartney, D. M.; Guiry, P. J. Chem. Soc. Rev. 2011, 40,
f
3
7
2
.22 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 8.0 Hz,
H), 6.86 (d, J = 7.6 Hz, 1H), 3.87 (s, 3H), 3.19 (s, 3H), 2.37−2.16
13
1
5
(
(
(
m, 3H), 2.05−1.98 (m, 1H), 1.39 (s, 3H); C NMR (100 MHz,
122.
CDCl ): δ = 180.1, 167.0, 146.8, 143.3, 133.4, 129.5, 128.3, 127.9,
3
2) Firmansjah, L.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 11340.
3) (a) McMahon, C. M.; Alexanian, E. J. Angew. Chem., Int. Ed.
014, 53, 5974. (b) Zou, Y.; Zhou, J. Chem. Commun. 2014, 50, 3725.
127.8, 122.6, 122.4, 108.1, 51.9, 48.3, 39.6, 31.0, 26.1, 23.9 ppm; IR
(
KBr): υmax 2939, 1716, 1611, 1464, 1443, 1376, 1346, 1280, 1184,
−
1
+
2
1107, 757 cm ; HRMS (ESI) calcd for C H NNaO [M + Na]
20 21 3
For other examples of palladium-catalyzed radical reactions using
unactivated alkyl halides, see: (c) Ryu, I.; Kreimerman, S.; Araki, F.;
Nishitani, S.; Oderaotoshi, Y.; Minakata, S.; Komatsu, M. J. Am. Chem.
Soc. 2002, 124, 3812. (d) Bloome, K. S.; Alexanian, E. J. J. Am. Chem.
Soc. 2010, 132, 12823. (e) Bloome, K. S.; McMahen, R. L.; Alexanian,
E. J. J. Am. Chem. Soc. 2011, 133, 20146. (f) Xiao, B.; Liu, Z.-J.; Liu, L.;
Fu, Y. J. Am. Chem. Soc. 2013, 135, 616. (g) Monks, B. M.; Cook, S. P.
Angew. Chem., Int. Ed. 2013, 52, 14214. (h) Wu, X.; See, J. W. T.; Xu,
K.; Hirao, H.; Roger, J.; Hierso, J.-C.; Zhou, J. Angew. Chem., Int. Ed.
3
46.1414, found 346.1413.
-[2-(2,6-Dichloro-phenyl)-ethyl]-1,3-dimethylindolin-2-one (4o).
3
White solid, mp = 70−72 °C (78%, 52 mg); R 0.3 (EtOAc/petroleum
ether = 1:10); H NMR (400 MHz, CDCl ): δ = 7.31−7.28 (m, 2H),
f
1
3
7
1
1
1
.19 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz,
H), 6.87 (d, J = 8.4 Hz, 1H), 3.26 (s, 3H), 2.65 (td, J = 12.8, 4.8 Hz,
H), 2.45 (td, J = 12.8, 4.4 Hz, 1H), 2.16 (td, J = 12.8, 4.8 Hz, 1H),
13
.94 (td, J = 13.2, 4.4 Hz, 1H), 1.41 (s, 3H); C NMR (100 MHz,
CDCl ): δ = 179.9, 143.3, 137.2, 135.1, 133.3, 128.0, 127.9, 127.6,
1
2
3
2
014, 53, 13573. (i) Venning, A. R. O.; Bohan, P. T.; Alexanian, E. J. J.
Am. Chem. Soc. 2015, 137, 3731.
4) For recent reviews, see: (a) Rudolph, A.; Lautens, M. Angew.
22.7, 122.4, 107.9, 48.1, 35.7, 26.6, 26.2, 23.6 ppm; IR (KBr): υ
max
−1
927, 1714, 1611, 1442, 1346, 1250, 1128, 764 cm ; HRMS (ESI)
+
(
calcd for C H Cl NO [M + H] 334.0760, found 334.0747.
18
18
2
Chem., Int. Ed. 2009, 48, 2656. (b) Sumino, S.; Fusano, A.; Fukuyama,
T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563. (c) Tang, S.; Liu, K.; Liu,
C.; Lei, A. Chem. Soc. Rev. 2015, 44, 1070 and references cited therein.
(5) For pioneering studies of palladium-catalyzed radical reactions,
see: (a) Chen, Q. Y.; Yang, Z. Y.; Zhao, C. X.; Qiu, Z. M. J. Chem. Soc.,
Perkin Trans. 1 1988, 563. (b) Curran, D. P.; Chang, C.-T. Tetrahedron
Lett. 1990, 31, 933. (c) Nagashima, H.; Isono, Y.; Iwamatsu, S. J. Org.
Chem. 2001, 66, 315. (d) Jahn, U. Top. Curr. Chem. 2012, 320, 363.
(6) For reviews, see: (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571.
(b) Wolfe, J. P. Synlett 2008, 2913. (c) Schultz, D. M.; Wolfe, J. P.
Synthesis 2012, 44, 351. For recent examples, see: (d) An, G.; Zhou,
W.; Zhang, G.; Sun, H.; Han, J.; Pan, Y. Org. Lett. 2010, 12, 4482.
(e) Yip, K.-T.; Yang, D. Org. Lett. 2011, 13, 2134. (f) Wu, T.; Mu, X.;
Liu, G. Angew. Chem., Int. Ed. 2011, 50, 12578. (g) Mu, X.; Wu, T.;
Wang, H.-Y.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878 and
references cited therein.
General Procedure for the Cyclization of Cinnamamide with
Iodocyclohexane 2a. Cinnamamide 5a (0.2 mmol, 1.0 equiv), PdCl
(
(
2
3.4 mg, 10 mol %), dppf (11.8 mg, 10 mol %), and K PO ·3H O
3 4 2
106 mg, 0.4 mmol, 2.0 equiv) were added into an oven-dried sealed
tube. The tube was evacuated and backfilled with nitrogen (three
times). Then, a solution of iodocyclohexane 2a (0.5 mmol, 2.5 equiv)
in diglyme (2.0 mL) was injected into the tube by syringe. The tube
was then sealed with a Teflon lined cap, and the mixture was stirred at
1
00 °C for 24 h. The resulting mixture was diluted with EtOAc, and
the organic phase was washed successively with H O (three times) and
2
brine (one time), then dried (Na SO ), and concentrated in vacuo.
2
4
The residue was purified by column chromatography on silica gel
gradient eluent of EtOAc/petroleum ether: 1/20 to 1/10) to give the
corresponding product 6a in 39% yield (25 mg).
(
3
-Cyclohexylmethyl-1-methyl-4-phenyl-3,4-dihydro-1H-quinolin-
10f
2
1
1
2
-one (6a). Colorless liquid; R 0.3 (EtOAc/petroleum ether =
f
1
:10); H NMR (400 MHz, CDCl ): δ = 7.34 (td, J = 8.0, 1.2 Hz,
(7) For reviews, see: (a) Chen, J.-R.; Yu, X.-Y.; Xiao, W.-J. Synthesis
2015, 47, 604. (b) Song, R.-J.; Liu, Y.; Xie, Y.-X.; Li, J.-H. Synthesis
2015, 47, 1195. For recent examples, see: (c) Shen, T.; Yuan, Y.; Jiao,
3
H), 7.24−7.13 (m, 4H), 7.07 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 7.2 Hz,
H), 4.22 (s, 1H), 3.37 (s, 3H), 2.68 (dd, J = 8.8, 1.6 Hz, 1H),
G
DOI: 10.1021/acs.joc.5b02433
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The Journal of Organic Chemistry
Article
N. Chem. Commun. 2014, 50, 554. (d) Li, Z.; Zhang, Y.; Zhang, L.; Liu,
Z.-Q. Org. Lett. 2014, 16, 382. (e) Yin, F.; Wang, X.-S. Org. Lett. 2014,
16, 1128. (f) Tang, X.-J.; Thomoson, C. S.; Dolbier, W. R., Jr. Org.
Lett. 2014, 16, 4594. (g) Xie, J.; Xu, P.; Li, H.; Xue, Q.; Jin, H.; Cheng,
Y.; Zhu, C. Chem. Commun. 2013, 49, 5672 and references cited
therein.
(
8) (a) Guo, W.; Cheng, H.-G.; Chen, L.-Y.; Xuan, J.; Feng, Z.-J.;
Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Adv. Synth. Catal. 2014, 356, 2787.
b) Yu, J.; Yang, H.; Fu, H. Adv. Synth. Catal. 2014, 356, 3669. (c) Liu,
D.; Tang, S.; Yi, H.; Liu, C.; Qi, X.; Lan, Y.; Lei, A. Chem. - Eur. J.
014, 20, 15605. (d) Deng, Q.-H.; Chen, J.-R.; Wei, Q.; Zhao, Q.-Q.;
(
2
Lu, L.-Q.; Xiao, W.-J. Chem. Commun. 2015, 51, 3537. (e) Lv, L.; Lu,
S.; Guo, Q.; Shen, B.; Li, Z. J. Org. Chem. 2015, 80, 698. (f) Guo, L.-
N.; Wang, S.; Duan, X.-H.; Zhou, S.-L. Chem. Commun. 2015, 51,
4803. (g) Yang, H.; Duan, X.-H.; Zhao, J.-F.; Guo, L.-N. Org. Lett.
2
015, 17, 1998.
(
9) (a) Fan, J.-H.; Wei, W.-T.; Zhou, M.-B.; Song, R.-J.; Li, J.-H.
Angew. Chem., Int. Ed. 2014, 53, 6650. The Rh-catalyzed alkylarylation
of acrylamides has also been reported, but the alkylation reagents were
limited to benzyl bromides, see: (b) Li, C.-C.; Yang, S.-D. Org. Lett.
2
(
3
015, 17, 2142.
10) (a) Wang, H.; Guo, L.-N.; Duan, X.-H. Adv. Synth. Catal. 2013,
55, 2222. (b) Meng, Y.; Guo, L.-N.; Wang, H.; Duan, X.-H. Chem.
Commun. 2013, 49, 7540. (c) Zhou, S.-L.; Guo, L.-N.; Wang, H.;
Duan, X.-H. Chem. - Eur. J. 2013, 19, 12970. (d) Wang, H.; Guo, L.-
N.; Duan, X.-H. Chem. Commun. 2013, 49, 10370. (e) Wang, H.; Guo,
L.-N.; Duan, X.-H. Org. Lett. 2013, 15, 5254. (f) Zhou, S.-L.; Guo, L.-
N.; Wang, S.; Duan, X.-H. Chem. Commun. 2014, 50, 3589. (g) Yang,
H.; Guo, L.-N.; Duan, X.-H. RSC Adv. 2014, 4, 52986.
(
(
11) For details, see the Supporting Information.
12) Fluoroalkylated organic molecules are widely used in functional
materials, agrochemicals and pharmaceuticals. For selected examples
see: (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH:
Weinheim, 2004. (b) Mu
17, 1881. (c) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305.
d) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology;
̈
ller, K.; Faeh, C.; Diederich, F. Science 2007,
3
(
Wiley-Blackwell: Chichester, U.K., 2009. (e) Reddy, V. Organofluorine
Compounds in Biology and Medicine; Elsevier: Amsterdam, 2015.
(
13) (a) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R.
Tetrahedron 2007, 63, 1970. (b) Vechorkin, O.; Proust, V.; Hu, X.
Angew. Chem., Int. Ed. 2010, 49, 3061. (c) Zhao, Y.; Chen, G. Org. Lett.
2
011, 13, 4850.
(
14) For recent examples of cross-coupling reactions using Pd
nanoparticles as catalyst, see: (a) Feng, X.; Sun, A.; Zhang, S.; Yu, X.;
Bao, M. Org. Lett. 2013, 15, 108. (b) Zhou, Q.; Wei, S.; Han, W. J. Org.
Chem. 2014, 79, 1454. (c) Hemelaere, R.; Desroches, J.; Paquin, J.-F.
Org. Lett. 2015, 17, 1770. (d) Korwar, S.; Brinkley, K.; Siamaki, A. R.;
Gupton, B. F.; Ellis, K. C. Org. Lett. 2015, 17, 1782 We also gratefully
acknowledge valuable suggestions by a reviewer for the reaction
mechanism.
(
15) Fabry, D. C.; Stodulski, M.; Hoerner, S.; Gulder, T. Chem. - Eur.
J. 2012, 18, 10834.
H
DOI: 10.1021/acs.joc.5b02433
J. Org. Chem. XXXX, XXX, XXX−XXX